PL147092B1 - Process for preparing novel n-/bicycloheterocyclo/-4-piperidinamines - Google Patents

Description

The subject of the invention is a process for the preparation of new N- (bicycloheterocyclo) -4-piperidinamines of the general formula I, in which A is a bivalent radical of the formula —CH = € H — CH = CH—, —N = CH — CH = CH— , —CH = N — CH = CH—, —CH = CH — N = CH— or —CH = CH — CH — N =, in which formulas one or two hydrogen atoms can be replaced by the same or different halogen atoms, lower alkyl radicals, lower alkoxy groups, trifluoromethyl groups or hydroxyl groups, R is a hydrogen atom or a lower alkyl radical, R1 is a hydrogen atom, an alkyl radical, a group represented by the symbol Ar1 or a lower alkyl radical substituted with a group represented by the symbol Ar1, where the symbol Ar1 represents a phenyl radical, optionally having 1, 2 or 3 identical or different substituents, such as halogen atoms, hydroxyl, nitro, cyano or trifluoromethyl groups, lower alkyl, alkoxy or alkylthio groups, mercapto groups, amino groups or carboxyl, lower mono- or di (alkyl) amino groups, lower e alkoxycanbonyl groups or (lower alkyl) -CO- or Ar1 groups is a thienyl, halothienyl or furyl group, a furyl group substituted with a lower alkyl radical, a pyridinyl group, a pyrazinyl group, or a thiazolyl or imidazolyl group, optionally substituted with a lower alkyl radical , R2 is a hydrogen atom, a lower alkyl radical or a 'benzyl radical, s is zero or an integer 1-6, Alk is a lower alkanediyl group, Y is an oxygen or sulfur atom or a group of the formula —NR3 in which R3 represents a hydrogen atom, a lower alkyl radical, a benzyl radical or an acetyl or benzoyl group, and Het represents a pyridinyl group, optionally having 1 or 2 identical or different substituents, such as halogen atoms, amino groups , nitro, cyano, amino carboxyl, carboxy or hydroxy groups, lower alkyl, alkoxy, alkylthio, alkoxycorbonyl or alkylcarbonyloxy groups or groups of the formula Ar2-lower alkyl, where Ar2 is a phenyl radical, optionally substituted with halogen, lower alkyl or methoxy, or Het is pyridinyl oxide, optionally substituted nitro, quinolinyl, optionally substituted with lower radical an alkyl group, a pyrimidyl group, optionally having 1 or 2 identical or different substituents, such as halogen atoms, amino and hydroxyl groups, lower alkyl, alkoxyl and alkylthio groups, or groups having the formula Ar 2 below alkyl or also Het is a quinazolinyl group, an optionally substituted hydroxyl or lower alkyl group, a pyridazinyl group, optionally substituted with a lower alkyl radical or a halogen atom, a quinoxalinyl group, optionally substituted with a lower alkyl radical, a pyrazine group, / Iowa, optionally substituted with halogen, amino or lower alkyl, phthalazinyl ova, optionally substituted ato-; halogen, or 5,6-dihydro-4H-1,3-thiazinyl-2-o. It is also within the scope of the invention to prepare pharmacologically acceptable addition salts of the compounds of Formula 1 above and the stereoisomers of these compounds. The term "halogen" as used herein means fluorine, chlorine, bromine or iodine, the lower group "alkyl" means a straight or branched chain hydrogen group having 1-6 carbon atoms, e.g. methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl and hexyl groups . The term "alkyl" denotes the above-mentioned lower alkyl groups and their higher homologues having 7-10 carbon atoms. The compounds of the invention are antihistamine and serotonin antagonistic, and are also useful in combating allergic diseases. with the invention, compounds of formula I are prepared in such a way that a compound of formula II, in which Y, Alk, R, R1, R2 and A have the meaning given above, is alkylated in an inert solvent with a compound of formula III wherein Het is as defined above and W is a cleavable group such as, for example, chlorine, bromine or iodine, or a sulfonyloxy group, e.g., methylsulfonyloxy or 4-methylphenylsulfonyloxy, while in formula 3 is the number zero, then W can also stand for a lower alkoxy or alkylthio group. The reactions are carried out in an inert organic solvent, such as, for example, N N-dimethylformamide, N, N-dimethylacetamide, 1-methylpyrrolidinone-2 tetrahydrofuran or a lower alkanol, e.g. ethanol or methanol, at room or elevated temperature. a base such as carbonate, hydrogen carbonate or sodium hydride, or an organic base such as N, N-diethylamine or N- (1-methylethyl) -2-propylamine. Sometimes it is also advantageous to use an addition of an iodide salt, especially an alkali metal iodide. The compounds of formula I produced are separated and purified by known methods, for example by chromatography or by recrystallization. The compounds of formula 1 have basic properties and can therefore be converted into in pharmacologically acceptable acid addition salts with inorganic or organic acids, e.g. , methylsulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexylsulfamic, 2-hydroxybenzoic, or 4-amino-2-hydroxybenzoic. The salts of the compounds of formula I can be converted into volatile compounds by treatment with alkali. US No. 4,219,559, the N-heterocyclo-4-piperidinamines of formula IV are known, wherein 1 is an optionally lower alkyl radical, an alkenyl lower radical, an arylalkenyl lower radical, a cycloalkyl radical, a substituted cyclo radical. - alkyl, 1- (aryl-lower alkyl) -1H-benzimidazolyl or a group of the formula Z-CmH2m where m is an integer 1-6 and Z is an optionally substituted 4,5-dihydro group -5-keto-1H-tetrazolyl-1, 2,3-dihydro-1,4-benzodioxynyl-2 group, 2,3-dihydro-1,4-benzodioxinyl-6 group, group 2, 3-dihydro-2-keto-1H-benzimidazolyl-1, 2,3-dihydro-3-keto-4H-i-benzoxazinyl-4 group, group (10,1l-dihydro-5H-dibenzo [a, d ] cyclo-hepten-5-ylidene) -methyl, 4-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl or TN- (R4) - where R4 is hydrogen, lower alkyl or aryl - lower alkyl and T is a lower alkyl group, aryl group, aryl lower alkyl group or p 1H-benzimidazolyl, or also Z is a group of formula WC / = 0 / - / X / s-, wherein s is zero or 1, X is an oxygen atom or a group of formula -N (R5) -, wherein R 5 is hydrogen, lower alkyl, aryl lower alkyl, lower alkanoyl or aroyl and W is lower alkyl, aryl lower alkyl, optionally substituted amino, 1-piperidinyl, 1-pyrrolidinyl or 4-morpholinyl, r in formula 4 is hydrogen or lower alkyl, r 1 is hydrogen, lower alkyl, aryl lower alkyl or lower alkanoyl , R2 is hydrogen, alkyl, aryl, cycloalkyl or mono- or diaryl lower alkyl, Q is CH or nitrogen, R8 is halogen, lower alkyl, lower alkoxy or the trifluoromethyl group and n is zero, 1 or 2. of known compounds, first of all the structure of the substituent in the 1-position of the piperidyl group, and also because they are not only strong antihistamines, but also strong antiserotonic agents. they have several asymmetric carbon atoms in the molecule. Each of these chiral centers may have the R or S configuration, with the designations R and S corresponding to the designations adopted by R. S. Cahn, C. Gold and V. Prelog in Angew. Chem., Int. Ed. Engl., 5, 385, 511 (1966). Using known methods, pure stereochemical isomers of the compounds of formula 1 may be obtained. Diastereoisomers may be separated using physical separation methods such as selective crystallization and chromatographic techniques, for example the method of anti-current separation, and enantions may be separated by the selective crystallization of their diastereoisomeric salts with 65 optically active acids. The cis and trans units can be further separated into their optical isomers, cis (+), cis (-), trans (+) and trans (-) using known methods. The preparation of the stereochemical isomers of formula I is within the scope of the invention. The useful antihistaminic and anti-serotonin properties of the compounds of formula I were determined in the following tests, the results of which are given in Tables 1, 2 and 3. Table 1 relates to compounds b in formula Ia. Table 2 relates to the compounds of formula Ib and Table 3 contains the results of tests carried out with compounds of formula Ic. All symbols in formulas Ia, Ib and Ib are given in the corresponding formula. In these tables, and in Tables 1 and 3, the "N" column indicates the absence or presence of a nitrogen atom in the aromatic ring, while in the second case the positions of this atom are also given. ED60, i.e. the amount of tested compounds in milligrams per 1 kg of the animal's body weight, at which the given compound protects 50 Vd of the tested animals against death caused by administration of the compound 48/80. of compounds in mg per kg of body weight, at which enlargement of the stomach of the animals and damage to the gastric glands after administration of the compound 48/80 to the animals did not occur in 50% of the animals; rats against the lethal action of Compound 48/80. Compound 48/80, which is a mixture of oligomers obtained by the condensation of 4-methoxy-N-methylphenylethylamine and formaldehyde, is known to be a potent release agent. what histamine (Int. Arch. Allergy 13, 336, (1958)). The prevention of fatal cardiovascular storage induced by compound 48/80 is a simple method of quantifying the antihistamine activity of test compounds. In this experiment, male rats of the inbred Wistar breed weighing 240-260 g were studied. The rats were fasted for one night and then transferred to laboratory conditions (temperature: 21 ± 1 ° C, relative humidity 65 ± 5). %). Rats were administered subcutaneously or orally with the test compound, optionally with a solvent (0.9% solution of Nad). One hour later, compound 48/80 was injected intravenously as a freshly prepared aqueous solution at a dose of 0.5 mg / kg (0.2 ml / 100 g of body weight). In control experiments, 250 animals treated with solvent alone were injected Then the standard dose of the compound 48/80 was determined, after which, after 4 hours, no more than 2.8% of the animals from this group survived. Number of survivors after the lapse of 4; hours was a good measure of the protective effect of the administered drug. 2. Test for antagonistic activity against serotonin-induced effects in which gastrointestinal damage was examined. Method A. Compound 48/80 induced damage. Compound 48/80 is a potent agent that releases vascularly active amines from internal sources such as histamine and serotonin. Rats injected with 48/80 exhibited state changes in blood flow in various vessels: of the ears and limbs five minutes after injection of the compound, death of the animal was due to shock after 30 minutes. Shock and death could have been avoided if rats were previously administered an antagonist to HI. However, the stimulatory effect on gastric secretion has not been abolished, so that rats treated with 46/80 and shock-protected with an H 1 antagonist may show all signs of intense glandular activity. splitting of gastric juices: complete selection revealed an enlarged stomach with abnormal contents and rough, bright red spots on all mucous membranes corresponding to 25 areas of damaged glands. The numerous known serotonin antagonists such as methysergide, cyproheptadine, cinanserin, mianserin, pipamperon, spiperone, pizotifen and metergoline completely prevent cyanosis of the ears and corns, as well as damage to the gastric glands and the lamectomy. -. digestive water. * ¦ Method B. Male Inbred Wistar rats weighing 220-250 g were paced for 1 night, subjecting the necessary amounts to water. Test compounds were administered orally as a solution or suspension in water. A control rat and a "pure" rat received the test compound. After one hour, all rats were subcutaneously administered at a dose of 2.5 mg / kg of 5- [4-dif-l-piperazinylmethyl] -1-methyl-lH- benzimidazole. -2-methanol. After 2 hours after oral or subcutaneous administration of the test compound, all rats were administered intravenously (in a dose of 1 mg / kg), 45 except for "pure" rats, the compound 48/80 freshly dissolved in water at 0, 25 mg / 7ml. 4 hours after administration of Compound 48/80, rats were decapitated and their stomachs were removed. The stomachs were then examined for size and contents (blood, fluid and food) and rinsed thoroughly. Macroscopic lesions were rated on a scale from 0 to ++ +, with 0 representing the total absence of visible lesions, and the highest score corresponding to all-red, rough spots covering more than half of the gland area. The results are given in the tables. 1 and 2 show that the compounds of the invention are effective antagonists of histamine and serotonin. The abbreviations used in these tables have the following meanings: Bz is benzyl, Ph is phenyl and is Ac acedyl group. Ul 092 7 8 Table 1 Compounds of formula 1 a Y * NH NH NH NH NH NH. NH NH NH NH O NH NH O NH NH NH NH NH NH NBz NMe NAc NH NH NH NH NH NCPh O NH NH. NH NH NH NH NH NH NH NH SOO o NH NH NH 1 NH NH NH NH O NH ¦ NH S NH NH NH -o - ;. NH m 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 3 2 2 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2. 2 2 2 2 2 2 2 2 2 2 2 Ar 3 3-NH2-2-pyridyl 3-NH2CO-2-pyridyl 5-Br-2-pyridyl 3- Cl-2-pyridyl 5-NO2-2-pyridyl 5-NH2CO-2-pyridyl 3-Cl-2-pyridyl 3-NH2CO-2-pyridyl 5-NO2,6-NH2-2-pyridyl 3-NH2CO-2- pyridyl 5-Br-2-pyridyl 4-NO2-3-pyridyl, N -0 2-quinolyl 2-quinolyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 4-C1, 6-3H8-2-pyrimidyl 2- pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 4-n-C3H7, 6-OH-2-pyrimidyl 4-OH-2-pyrimidyl 6-Bz-4-OH-2-pyrimidyl 6-Me, 4-OH-2 -pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 5-brimidyl -2-pyridyl 2-pyrimidyl 2-pyrimidyl 2-Cl-4-pyrimidyl 2-C1,6-CH3-4-pyrimids 1 6-Cl-4-pyrimidyl 4-pyrimidyl 2,6- (NH2) 2-4-pyrimidyl 2-NH, 6-CH3-4-pyrimidyl 6-CH30-4-pyrimidyl 2-CH3S-4-pyrimidyl 4- OH, 5- (4-Cl-C6H4) CH2-4-pyrimidyl 4-OH-2-quinazolyl 4-OH-2-quinazolyl 4-quinazolyl 2-pyrazinyl 3-CH3-2-quinoxalyl 3-CH3-2 -quinoxalyl 6-Cl-3-pyridazinyl R 1. 4 4-F-QH4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 1 4-F-QtH4CH2 4-F-C6H4CH2 4-F-C6H4GH2 2-furyl -CH2 2-furyl-CH, 4-F-QH4CH2 4-F-C6H4CH2 4-F-QH4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-QH4CH2 2-furyl-CH2 4-F-C6H4CH2 4- F-C6H4CH2 4-F-QH4CH2 4-F-CflH4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-QH4CH2 F-CeH4CH2 2-pyridyl CH2 4-F-QH4CH2 3-pyridyl CH2 2-pyrazinyl CH2 4-F-C6H4CH2 2-furyl CH2 4-F-C6H4CH2 2-thienyl CH2 3-furyl CH2 5-CH3-2-furyl CH2 4-F-C6H4CH2 4-F-QH4CH2 4-F-C6H4CH2 2-furyl CH2 2-pyridyl CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-QH4CH2 4- F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-CeH4CH2 4-F-C6H4CH2 4-F-QH4CHa 4-F-C6H4CH2 4- F-QH4CH2 R ^ 5 HHHHHHHHHHHHHHHHHHHHH HHHHHHHHHH 2i3 FHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHN 6 _ - - - - - 1 1 - - - - - - - - 2 - - - - - 1 - - - - - - - - 2 - - - - - - - -, - - 1 - - - - - - • - - - - - - - -. Rule rule rule rule rule rule rule rule rule rule rule rule rule rule rule rule rule rule rule 2 (E) -fumarari rule rule rule rule rule rule rule rule 2 (E) -fumarari rule rule rule rule rule rule rule rule rule 2 (E) -fumarate rule rule rule rule rule rule 2 (E) -fumarate 3/2 / E / -fumarate 2HC1 • HaO rule 2HC1 1/2 HaO hydrate hydrate rule rule hydrate rule rule rule rule rule L column compound 48/90 mortality test in rats ED50 value in mg / kg body weight 8 0.08 0.08 0.31 0.16 0.31 0.04 0.08 0.04 0.31 0.04 0.31 0.04 0.31 1.25 0.16 0.16 0.16 0.16 0.63 0.63 0.63 0.08 0.04 0.31 0.08 0.63 0, 16 0.02 0.08 0.08 0.04 0.04 1.25 0.01 0.04 0.04 0.16 0.02 0.04 0.04 0.16 0.16 0.16 0 , 08 0.04 0.31 0.08 0.31 0.08 0.08 1 0.31 0.16 0.16 1.25 0.63 0.31 0.08 0.16 1.25 2, 5 0.08 | Column 2 digestive damage test ED10 in mg / kg body weight 9 0.31 0.16 2.5 0.31 2.5 0.08 0.31 0.04 2.5 0 , 63 - 1.25 - 2.5 0.63 2.5. - 0.04 - 0.63 0.63 0.63 0.63 2.5 0.63 - 0.63 0.16 0.63 0.63 0.08 0.63 0.08 0.63 - 2 , 5 0.63 0.63 0.16 0.63 - 1.25 2.5 2.5 2.5 1.25 0.16 - - 2.5 2.5 2.5 2.5 2.5 2.5 - - 1.25 1147 092 Table 2 Formula 1b 10 Het ~ r ~ 2-pyridyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 5-Br-2-pyridyl 2- pyrimidyl 5-Br-2-pyridyl. 2-pyrimidyl 2-pyrimidyl 5-NH2,6-Cl-4-pyrimidyl 5-NH2-4-pyrimidyl 2-pyrimidyl 2-pyrimidyl 5-Cl-2-pyridyl 5-Cl-2-pyridyl Y 2 O NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NCH3 NH Alk 3 (CH2) 2 ¦¦ (CH2) 2 (CH2) 5 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 (CH2) 2 R1 4 4-F-C6H4CH2 4-thiazolyl -CH2 4-F-C6H4CH2 C6H5CH2 4-CH3-C6H4CH2 4C1-C6H4CH2 4-CH3O- -CgH4CH2 CeH5CH2 4-F-C6H4CH2 4-CH3-C6H4CH2 4-F-C6H4CH2 4-OH4CH2-C6H4-C6H4 F-CBH4CH2 4-F-C6H4CH2 4-F-QH4CH2 4-F-C6H4CH2 4-F-C6H4CH2 R2 T "HHHHHHHHHHHHHHH CH HH 1. A 5 CH = CH— —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH CH = CH - ^ C = CH— 1 "CH3O CH = CH— —CH = CH CH = CH— —C = CH 1 HO CH = CH— —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH CH = C— = CH = CH 1 OCH3 CH = CH— —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH base or salt 7 2 (E) -fumarate 2 (E) - fumarate rule rule rule rule rule rule rule rule rule rule rule rule rule rule rule gives the base 3HCl.H2O Column 1 Compound 48/80 Rat mortality test ED50 value in mg / kg body weight 8 0.08 0.02 0.31 0.08 0.16 0 16 0.31 0.31 1.25 0.02 0.16 2.5 0.16 0.08 1.25 0.08 0.31 1 0.63 Column 2 Food Line Damage Test ¬ ED60 in mg / kg body weight 9 "2.5 0.08 0.08 0.31 0.63 2.5 2.5 2.5 2.5 0.08 2.5 2.5 1.25 0.02 2.5 0.63 1.25 2.5 1 - Due to their antihistamine and serotonin antagonist activity, the compounds of formula I and their acid addition salts are very useful in the treatment of allergic diseases such as allergic diseases. rhinitis, allergic conjunctivitis, chronic urticaria or allergic asthma These compounds can be used in various formulations. To obtain a pharmaceutical composition containing a compound according to the invention, an effective amount of the compound of choice, in the form of a base or acid addition salt of the active ingredient, is mixed with a pharmacologically acceptable carrier which is selected as appropriate. depending on the method of administration. The pharmaceutical compositions are preferably formulated in unit dosage form, especially for oral, rectal and parenteral administration. For example, additives such as water, glycols, alcohols, or oils may be used to obtain compositions for oral administration, when preparing oral liquid preparations such as syrups, elixirs, and solutions, or solid carriers such as starches, sugars, kaolin, substances. slip, binders, disintegrating agents and the like when preparing powders, pills, capsules and tablets. In view of the convenience of administration, tablets and capsules are the most preferred forms for oral administration, in which case solid carriers are used. with other additives, for example, to aid dissolution. In injectable solutions, the carrier may be a saline solution, a glucose solution, or a mixture of salt and glucose. You can also prepare suspensions by using appropriate liquid carriers. The acid addition salts of the compounds of formula I exhibit greater solubility in water than the free bases and are therefore more suitable for the preparation of aqueous solutions. A particularly valuable advantage of the said pharmaceutical compositions in unit dose form is their convenience. administration and uniform dosage amounts. Unit dose means small uniform doses, each containing a predetermined amount of active ingredient chosen so as to produce the desired therapeutic effect and combined with the desired pharmaceutical carrier. Examples of such dosage unit doses include tablets (including scored tablets and coated tablets), capsules, pills, powder packets, wafers, injection solutions and suspensions, which are administered in a dose in the amount of teaspoonful or tablespoonful, and divisible therefrom. In the following, Examples 1-5 illustrate the preparation of some of the starting compounds and Examples VI-XII illustrate the preparation of the compounds of formula 1. Unless otherwise stated, all parts in the examples are parts by weight. The numerous starting compounds used in the present invention are known compounds. For example, in U.S. Patent No. In US 4,219,559, the preparation of the following compounds is shown: Nh [1- (3-aminopropyl) -4-piperidyl] -1- [t (4-fluorophenyl) methyl] -1H- benzimidazolylamine-2,1 - [(4-fluorophenyl) methyl] -N- [trihydrochloride 1- [2- [methyl) amino] ethyl] -4-piperidyl] -1H- benzimidazolylamine-2, Nl [1- (2-chloroethyl) 4-piperidyl] -1 - [(4-fluorophenyl) methyl dihydrochloride ] -1H-benimidazolylammonium-2. 25 parts of 1- (4-fluorophenylmethyl) -N- (4-piperidyl) -1H-ben- 'Zimidazolylamine-2 and 200 parts of methane. The whole was hydrogenated under atmospheric pressure at room temperature with 5 parts of 5% carbon-supported platinum as a catalyst. After the calculated amount of hydrogen was consumed, the catalyst was filtered off and the solvent was distilled off from the filtration. The residue was purified by chromatography column packed with silica gel, eluting with a 90:10 mixture by volume of chloroform and methanol. The pure product fractions were collected and their solvent was distilled off. The residue is taken up in the hydrochloride salt in a mixture of isopropanol and acetone. The salt was filtered off and dried to obtain 13.6 parts of 4- [1- (4-flu- "orophenylmethyl) -1H-benzimidazolylamino-2] [1,4'-12 4) -piperidyl] -ethyl-carboxylate hydrate melting point 260 ° C. A mixture of 25 parts of l * yl) -3-piperidinone hydrochloride, 55 parts of 5 l - [(4-fluorophenyl) methyl] -N4 (4-piperidyl) -1H-benimidazolylamine-2 dihydrobromide 1 part of a 4% solution of thiophene in ethanol, 50 parts of potassium acetate and 500 parts of 2-methoxyethanol were hydrogenated under atmospheric pressure at 50 ° C, 10 parts with 10% palladium on carbon as a catalyst. After uptake of the calculated amount of hydrogen, the catalyst was filtered off and the solvent was distilled off the filtrate. The residue was taken up in water and the whole was made alkaline with sodium hydroxide. The product was extracted with methylene chloride, the extract was dried, filtered, and the filtrate's solvent was distilled off. The residue was crystallized twice with aeetone. receiving 9.75 parts 1 - [(4-fluorophenyl) methyl] -N- 20 - [1-CphenylmethylJ-1- ^^ bipiperidyl-1-yl-1H-benzimidazolylamine-2 with a melting point of 174.6 ° C. Example II . A mixture of 21 parts of 4- [1- (4-fluorophenylmethyl) -1H-benzimidazolylamino-2] -1,4'-bipiperidyl] carboxylic acid ethyl ester 25-1 and 450 parts of 48% hydrobromic acid solution After stirring and refluxing for 16 hours, the solvent was distilled off from the reaction mixture, and the residue was freed free basically in a known manner by treatment with aqueous sodium hydroxide solution and extracted with methyl chloride. The extract was dried, filtered and the solvent was distilled off the filtrate, leaving as residue 8 parts (50% yield) 35 N- [1- (4-fluorophenylmethyl) -1H-benzimidazolyl-2] [1,4'bipyridifl] amine-4. Example III. A mixture of 11.3 parts of 1 - [(4-fluorophenyl) methyl-Nl [1 '- (phenylmethyl) - [1,3'-bipiperidyl] -4-yl-1HH-2-benzimidazoylamine and 200 c and methanol was hydrogenated under atmospheric pressure at room temperature with 2 parts of 10% palladium on carbon as a catalyst. After uptake of the calculated amount of hydrogen, the catalyst was filtered off and the solvent was distilled from the filtrate. The residue was mixed with diisopropyl ether, the product was filtered off and dried to obtain 8.5 parts (91.5% yield) of Ni [1,3'-bipiperidine] -4-yl) -1 - [(4-fluorophenyl) methyl] -1H-benzimidazolylamine-2. 50 Example IV. A mixture of 9.25 parts of 2-chloropropanone, 48.6 parts of 1- (4-fluorophenylmethylJ-N - ^ - piperidylJ-1H-benzimidazolylamine-2-hydrobromide, 32 parts of sodium carbonate and 135 parts of N, N) -Dimethylformamide was stirred and kept overnight at 50 ° C. The reaction mixture was poured into water and the product was extracted] -1H- benzimidazolyl-2] amino] -1-piperidylate was treated with methyl isobutyl ketone. The extract was dried, filtered and the solvent was distilled off the filtrate. The residue was crystallized from methyl isobutyl ketone to obtain 15 parts (yield 39.5% 1- [44 [1 - [(4-fluorophenyl) methyl] -1H-ibenzimidazoyl- 2] amino] -1-piperidyl-propanone-2 * 65 A mixture of 5.7 parts of 1- [4- [and [1 - [<4-fluorophenyl) mc-147 092 2-propanone-13, 2.1 parts of hydrochloride hydroxylamine, 20 parts of pyridine, 10 parts of ethanol and 12.5 parts of water were stirred for 3 hours at 65 ° C, then poured into water and all made alkaline with sodium hydroxide. dried to obtain 5.5 parts (yield 93%) of oxime lt [4 - [[1 - [(4-fluoro-phenyl) methyl] -1H- benzimidazolyl-2] amino] -1-piperidyl] -propa ¬non-2, melting point 202 ° C. A mixture of 4 parts of 1- [4 - [[1 - [(4-fluorophenyl) methyl] -1H-ibenzimidazolyl-2] amino] -1-riiper- oxime. 2-dyl] -propanone and 120 parts of methanol were saturated with ammonia and hydrogenated under atmospheric pressure at room temperature with 2 parts of Raney nickel as catalyst. After uptake of the calculated amount of hydrogen, the catalyst was filtered off and the solvent was distilled off with a filter. The residue was crystallized? acetonitrile, obtaining 1.3 parts (34% yield) No. [1- (2-aminopropyl) -4-piperidyl] -1 - [(4-fluorophenyl) methyl] -1H-benzimidazolylamine-2, melting point 178.3 ° C. Example 5 A mixture of 5.04 parts of carbon disulfide, 2.06 parts of N, N'-methyl-tetraylbis [cyclohexylamine] and 45 parts of tetrahydrofuran, cooled to a temperature below 10 ° C, was added dropwise while stirring solution 3 , 7 parts of N- [1- (2-aminoethyl) -4-piperidyl] -1- (4-fluorophenylmethyl) -1H- benzimidazolylamine-2 in tetrahydrofuran. After completion of the dropwise addition, stirring was continued overnight, bringing the temperature of the mixture gradually to room temperature. The solvent was distilled off from the reaction mixture, the residue was purified by chromatography on a silica gel column, eluting with a 98: 2 mixture of chloroform and methanol by volume. containing the pure product were combined and after distilling the solvent from them, 4 parts (yield 100%) of 1- (4-fluorophenylmethyl) -N- [1- <2-isothiocyanatoethyl) -4-piperidyl] -1H-benzimidazolylamine were obtained. -2 as the remainder. The following compounds were prepared by an analogous method; 1- (2-furylmethyl) -N- [1- (2-isothiocyanatoethyl) -4-piperidyl] -1H-n-benzimidazolylamine-2,1 - [<4-fluorophenyl) methyl] -N- [1- (2-isothiocyanate - ethyl) -4-piperidyl] -1H-imrdazo [4,5Hb] pyridylamine-2, N- [1- (2-isothiocyanatoethyl) -4-piperidyl] -3- (2-pyridylmethyl) -3H- imidazo [4,5 ^ b] pyridylamine-2 and 3 - <[(4-fluorophenyl) methyl] -N- [1- (2-isothiocyanat | anoethyl) -4-piperyclyl] -3H-imidadium [ 4,5-b] pyridylamine-2. Example VI. Method 1. A mixture of 1.14 parts of 2-chloropyrimidine, 3.7 parts of N - [1- (2-amino-ethyl) -4-piperidyl] -1- <4-fluorophenylmethyl) -1H-benzimidazolylamine -2, 1.06 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N, N-dimethylformamide were mixed and kept at 70 ° C overnight. The reaction mixture was then poured into water and the product was extracted with methyl isobutyl ketone, the extract was dried, filtered and its solvent was distilled off. The residue was purified by column chromatography on silica gel, eluting with a mixture of chloroform. and methanol 96: 4 by volume saturated with ammonia. The pure product fractions were combined and their solvent was distilled off. The remainder was recrystallized from acetonitrile, yielding 1.5 parts (yield 34 ° / e l - {(4-fluorophenyl) methyl] -N - [[1- [2- and [(2-pyrimidylamino] ethyl] -4-piperidyl] -1H-benzimidazolylamine-2 with a melting point of 168.4 ° C (compound 1). Method 2. A mixture of 34.5 parts of 2-chloropyrimidine , 110 parts N- [1- (2-aminoethyl) -4-piperidyl] -1 - [(4-fluorophenyl) methyl] -1H-benzimidazolylamine-2, 25 parts sodium bicarbonate and 1200 parts ethanol were mixed and maintained under reflux overnight, then cooled and filtered, the filtrate was distilled of solvent, and the residue was purified using high-pressure liquid chromatography on silica gel, eluting with a 95: 5 mixture of chloroform and methanol by volume. saturated with ammonia The fractions containing pure product were combined and their solvent was distilled off. The remainder was recrystallized from ac etonitrile to obtain 82 parts (yield 61%) 1- "4-fluorophenyl) methyl] -N- [li [2 - [(2-pyrimidyl) amino] ethyl] - 25] -4-piperidyl] - 1H-benzimidazolylamine-2, m.p. 168.4 ° C (Compound 1). By the method described in Method One, using equivalent amounts of the appropriate starting materials, compounds of formula Rn has the meanings given in Table 3. The form of the product obtained and its melting point are also given in this table. If Rn is a non-hydrogen atom, the type of that substituent or substituents and the positions they are in are given in Section 4 of Table 3 and the positions they are in. The following compounds were also prepared using the method described in the first method: 3- [0 -fluorophenyl) methyl] -N- [1-i [2 - [(2Hridinyl) amincJ-ethyl] * 40 -4-piperidyl] -3H-imidazo [4,5-b] pyridin-2-amine at mp 181.8 ° C (compound 20), acid amide 2- [and [2- [4 ~ [[3 - [(4-fluoro-phenylac) -methyl] -3H-imidazo [4,5-b] pyridinyl- 2] amino] -1-piperidinyl] ethyl] amino] -pyridinecarboxylic-3 with a melting point of 205.4 ° C (compound 21), H (4-fluorophenyl) methyl] -N- [1- [ 2 - [1 - PyrimMynylJaminol-ethyl] -4-piperidinyl] -1H-imidazo [4,5-fo) pyridin--2-amine, m.p. 165.6 ° C (compound 22), 1 - [( 4-fluorophenyl) methyl] -N- [1- [2- (2-pyrimidinylamino) ethyl] -4-piperidinyl] -1H-imidazo- [4, Sc] pyridin-2-amine, mp 203, 1 ° C (comp. 23), 3- (2-pyridinylmethyl) -N fumarate (2: 3) - [1- [2- (2-pyrimidinylamino / ethyl] -4-piperidinyl] -3H-imidazo [4,5-to] pyridin-2-amine 55, mp 181.2 ° C {comp. 24) , 3- (2-furanylmethyl) -N- [1- [Z- (2-pyrimidinylamino) ethyl] -4-piperidinyl] -3H-imidazo [4,54)] pyridin-2-amine, m.p. 139 , 9 ° C (Compound 25), (1: 2) 3 * (4-fluoroiphenyl) methyl] -N- [li [2 - [(2-pyrimidinyl) amino] ethyl] -4-piper- dynyl] -3H-imidazo [4,5-c] pyridin-2-amine, m.p. 19.0 ° C (compound 26), N- [1- [3- [(5- chlorq-2-pyridinyl) amino] propyl] -4-piperidinyl] -1- [(4-fluoro-phenyl) methyl] -1H-benzimidazol-2-amine p tern-147 092 15 16 Table 3 Compounds and Formula lc Compound number 1 2 3 4 5 6 7 8 ¦9 10 11 12 13 14! 5 16 17 18 1 19 L 2 4 - [(2-pyrimidyl) NH] butyl 2- | (3-NO2-2-pyridyl ) NH] ethyl 3 - [(2-pyrimidyl) NH] propyl 2 - [(6-Cl-4-pyrimidyl) NH] ethyl 2 - [(2-pyrimidyl) NH] propyl 2 - [(phenylmethyl) (2- pyrimidyl) NH] -ethyl 2- (3-NO2-2-pyridyl) NH] propyl 2- [CH3 (2-pyrimidyl) N] ethyl 2- [(5-NO2-2-pyridyl) NH] ethyl 2 - [(4-NOa, N * oxide-3-pyridyl) NH] - —ethyl 2 - [(2-pyrimidyl) NH] ethyl 2 - [(2 -pyrimidyl / NHletyl 2 - [(2-pyrimidyl) NH] ethyl 2 - [(2-pyrimidyl) NH] ethyl 2 - [(2-pyrimidyl) NH] ethyl 2 - [(2-pyrimidyl) NH] ethyl 2- [(2-pyrimidyl) NH] ethyl 5 - [(2-pyrimidyl) NH] pentyl R1 3 4-F-C6H4CH2 4-FC -H4CH2 4-F-QH4CH2 4-F-QH4CH2 4-F-C6H4CH2 4-F -QH4CH2 4-F-QH4CH2 4-F-QH4CH2 4-F-C6H4CH1 4-F-C6H4CH2 (2-pyridyl) CBJ2 4-F-C6H4CH2 (3-pyridyl) CH2 (2-pyrazinyl) CH2 (2-thienyl) CH2 (3-furyl) CH2 (5-CH3-2-furyl) CH2 4-F-C6H4CH2 | R * 4 HHHHHHHHHH 2 / i 3 / FHHHHHH base or salt 5 base base base 2HC1 base base 2HC1 • 1V2H20 base base base base base base base base base base base base base base Melting point 6 150.0 1.48.1 143.8 1 277.9 160.8 148.7 167.2 167.2 175.7 199.0 150.8 180.9 218.9 185.8 181.5 213.3 143.7 136.5 - melting point 196.5 ° C (compound 27), 6-chloro-N4H [2- [4- [t1 - [(4-fluorophenyl) methyl] -1H-benzimidazolyl-2] amino] -1-piperidyl] ethyl] 4.5 -pyridyl-diamine, m.p. 216.7 ° C (compound 28) and 8-cMoro-N- [2- [4- [[1 -, [(4-fluorophenyl) methyl] -1T-benzimidazole isopropanol adduct - l,6-2] amino] -1-piperidyl] ethyl] -3-phthalazinamine In a ratio of 1: 1, m.p. 139.7 ° C (compound 29). Example XXVII. Compounds of formula Ia 'in which Ar and R1 have the meaning given in Table 4, as well as compounds of formula Id, in which L, R, R1, R2 and A are as defined in Table 5. Example VIII. A mixture of 3.7 parts of N- [1- (2-aminoethyl) -4-piperidyl] -1- (4-fluorophenyl) methyl-1H-benzimidazolylamine-2, 1 parts of N, N-diethylamine and 45 parts of tetrahydrofuran was stirred at -20 ° C and a solution of 1.5 parts 2.4 was added dropwise to it at the same temperature. Table 4 Compounds of formula 1 a Compound number 30 31 32 33 34 35 36 37 38 39 40 41 1 42 Ar 2 -pyrazinyl 2,6- (NH2) 2-4-pyrimidyl 2'NHt, 6-CH3-4-pyrimidyl 3-NH2CO2-pyridyl 6-Cl-3-pyridazinyl 4-quinolyl 5-Br-2-pyridyl 3-Cl -2-pyridyl 3-CH3-2-quinoxali-5-NHaCO-2-pyridyl 2-pyrimidyl 2-quinolite 3: NH9CQ-2-pyridyl. R1 4-F-C6H4CH2 4-F-C6H4CHt 4-F-CeH4CH2 4-F-C6H4CH2 4-F-CA: H4CH2 4-F-QH4CHa 4-F-QH4CH, 4-F-QH4CH. and 4-F- C6H7CH2 4-F-C6H4CH2 (2-furyl) CH, 4-F-QH4CHa (2-furylCHJ Base or salt base HaO HaO base base base base base base base base base Melting point at. ° C 209.5 133.3 124.7, 221.2 196.8 227.8 183.3 124-145 198.2 268.2 186.8, 145.2 246.2-dichloropyrimidine in tetrahydrofuran. the mixture was slowly raised to room temperature and stirring was continued at this temperature overnight. The precipitate was filtered off and the solvent was distilled off the filtrate. The residue was purified by column chromatography on silica gel, eluting with a mixture of chloroform and methanol (relative to 35 90:10) saturated with ammonia. The fractions containing the pure product were combined and the solvent was distilled off. The residue was converted to hydrochloride in isopropanol. Wound and dried to give 1.7 parts of N- [1- [2- [and (2-chloro-4-pyrimidyl) amino] ethyl] -4-piperidyl] -1- [(4-fluorophenyl) dihydrochloride hydrate methyl] -1H- benzimidazolylamine-2, m.p. 287.4 ° C (compound 48). The following compounds were obtained analogously: N- [1 - [- [(2-chloro-6-methyl- 4-pyrimidyl) amino] ethyl] -4-piperidyl] -1- [(4-fluoro-phenyl) methyl] -1H- benzimidazolyl-amintj-2 with temperature 147 092 17 18 Table 5 Compounds of formula Id Number compound 43 44 .45 46 47 L 2 - [(3-Cl-2-pyridyl) amino] ethyl 2 - [(2-pyrimidyl) amino] ethyl 2 - [(5-Br-2-pyridyl) amino] ethyl 2 - [5-Cl-2-pyridyl) methyl] amino] ethyl 2 - [(2-pyrimidyl) amino] ethyl RHHHH CH3 'R1 4-F-QH4CH2 5-CH3-4-imidazolyl— —CH2 C6H5CH2 4-F- C6H4CH2 4-F-QH4CH2 R * HHHHHAN = CH ^ CH = = CH CH = CH — CH —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH CH = CH— —CH = CH Principle or . salt 1 base base base base (cis + trans) 3HCl Melting point ° C 146.5 184.2 1 164.0 143.2 217.2 melting point 124.4 ° C (compound 49) and N - [1- [2- [(4-chloro-6-methyl-2-pyrimidyl) amino] -ethyl] -ethyl] -4-piperidyl] -14 &lt; 4-fluorophenyl) methyl] -1H-ben- Zimidazolylamine-2 with a melting point of 151.9 ° C (Compound 50). Example IX. A mixture of 3.4 parts of 6-chloro-3-nitropyridylamine-2, 7.4 parts of N4 [1- (2-aminoethyl) -4-piperidyl] -1 - [(4-fluorophenyl) methyl] -1H - 2-benzimidazolylamine-2 and 10 parts of 1-methyl-pyrrolidinone-2 were mixed and kept at 150 ° C for 2 hours, then cooled and poured into ammonia-saturated methanol. The solvent was distilled off completely to the left. water was added to the solid, and the mixture was extracted three times with methyl isobutyl ketone. The combined extracts were dried, filtered and the filtrate distilled off the solvent under reduced pressure. The remainder of the purification was by column chromatography on silica gel, eluting with a 95: 5 mixture of chloroform and methanol. The pure product fractions were combined, the solvent was distilled off and the residue was recrystallized from methyl isobutyl ketone. 5 parts (yield 50%) of N6- [2- [4H [t1] (4-fluorophenyl) methyl] -1H-benzimidazolyl-21amino] -1-piperidyl] ethyl] -3-nitropyridyl diamine-2 were obtained. 6, m.p. 205.7 ° C (compound 51). Example X. Mixture of 1.7 parts of 2-chloropyrimidine, 99.66 parts of 2-t [[1- (2-aminoethyl) -4 -piperidyl] amino] -1 - [(4-fluorophenyl) methyl] -1H-benzimidazoyl-5, 5 parts sodium bicarbonate and 80 parts ethanol were stirred and refluxed overnight, then the solvent was distilled from the mixture and the residue was mixed with chloroform. The organic layer was washed with water, dried, filtered and its solvent was distilled off. The residue was recrystallized from a mixture of acetonitrile and methanol, obtaining 5.2 parts (yield 83%) of 1- [< 4-fluorophenyl) -methyl] -2-i [[1- [2- (2-pyrimidinylamino) ethyl] -4-piperidinyl) amino] -1H-i-benzimidazole-5-ol, mp 194.4 ° C (Compound 52). Also prepared in a similar manner: 1- (phenylmethyl) -Ni [ 1- [2 - [(2-pyrimidinyl) amino] ethyl J-4-piperidinyl] -1H-benzimidazole-2-amine, mp 188.3 ° C (compound 53 ), 1-methyl-N- [1-] 2 - [(2-pyrimidinyl) amino] ethyl-4-plperidinyl] -1H-benzimidazole-2-amine hemihydrate, mp 120.9 ° C (compound 54), 1 - [(4-methylphenyl) methyl] -N- [1-] 2 - [(2-pyrimidinyl) amino] ethyl] -4-piperidinyl] -1H-benzimidazole-2-amine mp 123.6 ° C (compound 55), H [< 4-chlorophenyl) methyl] -N- [1- [2- (2-pyrimidinyl) / amino) ethyl] -4-piperidinyl] -1H-benzirnidazole- 2- amine, m.p. 137.8 ° C (compound 56), 1- [(4-methoxyphenyl) methyl] -N4 [1- [2- (2-pyrim - dynylamino) ethyl] -4-piperidinyl] -1H-benzimidazole-2-amine, m.p. 160.4 ° C (compound 57), N- [1- [2- (2-pyrimidylamino) ethyl] -4 - -piperidyl] -1HJ-benzimidazolylamine-2, m.p. 208.6 ° C (compound 58), 1H [(4-fluorophenyl) methyl] -5-methoxy-NH [1- [2- (2-pyrimidylamines) - no) ethyl] -4-piperidyl] -1H-benzimidazolylamine-2 melting point 160.7 ° C (compound 59), 2: 1 fumaran Ni [1- [2- <2-pyrimidylamino) ethyl] - 4-piperidyl] -1 (4-thiazolrlmethyl) -1H-benzimidazolylamine-2, m.p. 173.9 ° C (compound 60), 4- [and [2 - [[1- [2- <2 -pyrimidylamino) ethyl] -4-piperidyl] -amino] -1H-ibenzimidazolyl] methyl] penol, m.p. 230.8 ° C (compound 61), 1-! [(4-fluorophenyl) methyl] - 6-methoxy-N- [1- [2- {2-pyrimidylamino) ethyl] -4-piperidyl] -1H-benzimidazolylamine-2, m.p. 200.1 ° C (compound 62), 1- [ (4-fluorophenyl) methyl [-N-methyl-N- [1- [2- (2-pyrimidylamino) ethyl] -4-piperidyl] -1H-i-benzimidazolylamine-2 at a temperature of at 101.3 ° C (compound 63) and N- (phenylmethyl) -N- [1- [2-i (2-pyrimidylamino) ethyl] -4-piperidyl] -1HH-benzimidazolylamine-2 at a temperature of mp 207.1 ° C (comp. 64). Example XI. 5.5 parts of 4- {1- (4-fluoro-phenylmethyl-1H-benzimidazolyl-amino-11-piperidyl-ethanol and 135 parts of N, N-dimethylformamide) were stirred at room temperature and 0.75 parts of 50% were added. The sodium hydride suspension was stirred for 1 hour at room temperature, then 2.5 parts of 2-chloroquinoline was added and stirred at room temperature overnight, then poured into water and extracted. Methyl isobutyl ketone. The extract was dried, filtered and the solvent was distilled off. The remainder was recrystallized from acetonitrile C147 092 19 to give 4.3 parts (yield 58% (1 - [(4-fluoro-phenyl) methyl] -NH [ 1- [2- (2-quinoyloxy (ethyl] -4-piperidio] -1H-benzimidazolylamine-2, melting point 149.9 ° C (compound 65). * The following compounds were obtained analogously: N- [1- [2-i [(5-bromo-2-pyridyl) oxy] ethyl] -4-piperidyl] -1- (2-furylmethyl) -1H-benzimidazolylamine-2, m.p. 160.5 ° C (comp. 66), l - [(4-f luorophenyl) methyl] -N- [1- [2 - [[2- (methylthio) -4-pyrimidyl] -oxy] ethyl] -4-piperidyl] -1H-benzimidazolylamine-2, m.p. 120.6 ° € (compound 67), 1 - [(4-fluorophenyl) methyl] -N- [1- [2 - [(3-methyl-2-quinoxalyl) oxy] ethyl] -4-piperidyl] -1- Hjbe, n-dimazolyl-amine-2 m.p. 168.4 ° C (compound 68), 1- [(4-fluorophenyl) methyl] -N- [1- [2- (2-pyrimidyloxyethyl] -4 -piperidyl] -1H- benzimidazOilylamine-2 m.p. 133.8 ° C (compound 69), N- [1- {2 - [(5-bromo-2-pyridyl) oxy] ethyl] -4-piperidyl } -1-] and (4-fluorophenyl) methyl] -1H-benzimidazolylamine-2, m.p. 161.5 ° C (compound 70), fumarate 2: 1 1- (2-furylmethyl) -N41- [2 - (2-pyrrinidfHloxy) ethyl] -4-piperidyl] -1H-benzimidazolylamine-2, m.p. 190.4 ° C (compound 71) and 1- [(4-fluorophenyl) methyl] -N- - [1 - [2- (2-pyridylmethoxy) ethyl] -4-piperidyl] -1H-benzimidazolylamine-2, m.p. 162 ° C (compound 72). Example XII. A mixture of 2.7 parts 5h [(4-chloroenylmethyl] -2- (methylthio) - (1H) -piperidinone-4 and 3.67 parts N- [1- <2-aminoethyl) -4-piper - Dyl] -1 (4-fluorophenylethyl) -1H- benzimidazolylamine-2 was stirred at 140 ° C. for 4 hours, then cooled and poured onto chloroform. The solution was purified by column chromatography on silica gel, eluting with the mixture. chloroform and methanol in a 96: 4 volumetric ratio saturated with ammonia. The fractions containing the pure product were collected, the solvent was distilled from them, the residue was mixed with diethyl ether and 4.5 parts (76.8% yield) of the monohydrate were obtained from the suspension. -K4-chlorophenyl) methyl] -2- [[2- [4 - <[[1 - {(4-fluorophenyl) methyl] -1H-benzimidazolyl-2-amino] -1-piperidylJetyl] amino] - ( 1H) -pyrimidinone-4 with a melting point of 150.6-158.7 ° C (Compound 73). By an analogous method, using equivalent amounts of the appropriate starting materials, the following compounds were also prepared: 2 - [[2. 4- - [[M (4-fluorophenyl) methyl-1H benzimidazolyl-2] amino] -1-piperidyl] ethylamino] -6-propylpyrimidinone-4, m.p. 164.8 ° C (compound 74) , 2H [{2 - [[4 - [[1 - [(4-fluorophenyl) methyl] -1H- -baziniviazol-2] amino} -1-pipTidyl] ethyl] amino] - (iH) -pyrimidinone 4 m.p. 150.4 ° C (comp. 75), 2 - [[2- {4 - [[1 - [(4-fluorophenyl) -m-methyl] -1H- henzimidazol-2]. nono] -1-piperidyl] ethyl] aminoH1H) -quinazolsnon-4 m.p. 264.2 ° C (compound 76), 2- [and [2- [4- {fl-H (4-fluorophenyl ) methyl] -1H-benzimidazolyl-2] amino] -1-piperidyl] ethyl] amino] -6- (phenylmethylMlH) -pyrimidinone-4, mp 134.5 ° C (compound 77) and 2-P - [4- [11 - {(4-phytiorophenyl) methyl] -1H-benzimidazolyl-2] amino] -1-piperidyl] ethyl] amino] -6-methyl-4 (1H) -pyridinone mp 143.6 ° C (compound 78), 1 - [(4-fluorophenyl) methyl] -N- [1- [2- (2-pyrimidinylthio) ethyl] -4-piperidinyl] -1H- benzimidazoleamine-2 m.p. 147 ° C (Compound 79) and 2- [2- [4- [and [1 - [(4-fluorophenyl) methyl] -1H-benzimidazolyl-2] amino] - monohydrate 1-pipridinyl] -ethylthio] -1H-chinazolinone-4 with a melting point of 133.4 ° C (compound 80). Wherein A is a bivalent radical of the formula —CH = CH — CH = CH—, —N = CH — CH = CH—, —CH = N — CH = CH—, —CH = C H — N = CH— or. CH = CH — CH — N =, in which formulas one or two hydrogen atoms can be replaced by identical or different halogen atoms, lower alkyl radicals, lower alkoxy groups, trifluoromethyl groups or hydroxyl groups, R is a hydrogen atom or a lower alkyl radical, R1 is a hydrogen atom, an alkyl radical, a group Ar1 or a lower alkyl radical substituted with a group represented by the symbol Ar1, the symbol Ar1 representing a phenyl radical, optionally Various or different substituents such as halogen atoms, hydroxyl, nitro, cyano or trifluoromethyl groups, lower alkyl, alkoxy or alkylthio groups, mercapto, amino or carboxyl groups, lower mono- or di-( alkyl) amino, lower alkoxycarbonyl groups or (lower alkyl) groups —CO—, or Ar1 is thienyl, halothienyl or furyl group, furyl group substituted with lower alkyl radical, pyridinyl group, pyrazine group A yl or a thiazolyl or imidazolyl group, optionally substituted with a lower alkyl radical, R2 is a hydrogen atom, a loweralkyl radical or a benzyl radical, s is an integer 1-6, Alk is a lower alkanediyl group, m Y is an oxygen atom or sulfur or a group of the formula —NR8, where Rs represents a hydrogen atom, a lower alkyl radical, a benzyl radical or an acetyl or benzoyl group, and Het represents a pyridinyl group, optionally having 1 or 2 organic or miscellaneous substituents such as halogen atoms, amino, nitro, cyano, aminocarbonyl, carboxyl or hydroxyl groups, lower alkyl, alkoxy, alkylthio, alkoxycarbonyl or alkylcarbonyloxy groups 55 or groups of the formula Ar * is a phenyl radical, optionally substituted with a halogen atom, lower alkyl radical or methoxy group, or Het is a pyridinyl oxide group, optionally substituted nitro group a, a quinolinyl group, optionally substituted with a lower alkyl radical, a pyrimidinium group, optionally having 1 or 2 identical or different substituents, such as halogen atoms, amino and hydroxy groups, lower alkyl, alkoxy and alkylthio groups or groups of the above-described formula Ar 2 -lower alkyl, or also Het is a quinazolinyl group, optionally substituted hydroxy or lower alkyl group, pyridazine-Iowa group, optionally substituted with lower alkyl or Halogen, quinoxalyl, optionally substituted with lower radical an alkyl group, a pyrazinyl group, optionally substituted with a halogen atom, an amino or lower alkyl group, a phthalazinyl group, optionally substituted with a halogen atom, or a 5,6-dihydro-4H-1,3-thiazinyl-2-group, as well as the pharmacologically acceptable addition salts of the compounds of formula 1 above or the stereoisomers of these compounds, Otherwise, the compound of formula II, in which Y, Alk, R, R1, R2 and A are as defined above, is alkylated in an inert solvent with a compound of formula III in which Het is as defined above, and W is a cleavable group and the resulting compound of formula I is then optionally converted to its pharmacologically acceptable addition salt by treatment with an appropriate acid, or the resulting addition salt is optionally converted to the above-described base. according to formula I, is treated with an alkali. i.2t-Cc% Y-Alk-N Formula 1 Ar Yy ^ N Formula 1a Ar-NH-CH2-CH2- ^ PX H R1 Formula 1a 'R' l * tY-Alk-lQ-p- £ N £ A Formula 1b147 092 LN H R1 t & ~ Formula 1c R1 rk? N- R2 A Formula 1d / R H-Y-Alk-K) -IN R1 R2 N Formula 2 Rn A Het --- CsH2s-w Formula 3 Formula ^ WZ Graph. Z-d 2 - order 72/89 - 85 Price PLN 400 PL PL

Claims (1)

Claim 1. A process for the preparation of the new N- (bicycloheterocyclo) -4-piperidinamines of the general Formula 1, wherein A is a divalent radical of the formula —CH = CH — CH = CH—, —N = CH — CH = CH—, —CH = N — CH = CH—, —CH = CH — N = CH— or. CH = CH — CH — N =, in which formulas one or two hydrogen atoms can be replaced by identical or different halogen atoms, lower alkyl radicals, lower alkoxy groups, trifluoromethyl groups or hydroxyl groups, R is a hydrogen atom or a lower alkyl radical, R1 is a hydrogen atom, an alkyl radical, a group Ar1 or a lower alkyl radical substituted with a group represented by the symbol Ar1, the symbol Ar1 representing a phenyl radical, optionally Various or different substituents such as halogen atoms, hydroxyl, nitro, cyano or trifluoromethyl groups, lower alkyl, alkoxy or alkylthio groups, mercapto, amino or carboxyl groups, lower mono- or di-( alkyl) amino, lower alkoxycarbonyl groups or (lower alkyl) groups —CO—, or Ar1 is thienyl, halothienyl or furyl group, furyl group substituted with lower alkyl radical, pyridinyl group, pyrazine group A yl or a thiazolyl or imidazolyl group, optionally substituted with a lower alkyl radical, R2 is a hydrogen atom, a loweralkyl radical or a benzyl radical, s is an integer 1-6, Alk is a lower alkanediyl group, m Y is an oxygen atom or sulfur or a group of the formula —NR8, where Rs represents a hydrogen atom, a lower alkyl radical, a benzyl radical or an acetyl or benzoyl group, and Het represents a pyridinyl group, optionally having 1 or 2 organic or miscellaneous substituents such as halogen atoms, amino, nitro, cyano, aminocarbonyl, carboxyl or hydroxyl groups, lower alkyl, alkoxy, alkylthio, alkoxycarbonyl or alkylcarbonyloxy groups 55 or groups of the formula Ar * is a phenyl radical, optionally substituted with a halogen atom, lower alkyl radical or methoxy group, or Het is a pyridinyl oxide group, optionally substituted nitro group a, a quinolinyl group, optionally substituted with a lower alkyl radical, a pyrimidinium group, optionally having 1 or 2 identical or different substituents, such as halogen atoms, amino and hydroxy groups, lower alkyl, alkoxy and alkylthio groups or groups of the above-described formula Ar 2 -lower alkyl, or also Het is a quinazolinyl group, optionally substituted hydroxy or lower alkyl group, pyridazine-Iowa group, optionally substituted with lower alkyl or Halogen, quinoxalyl, optionally substituted with lower radical an alkyl group, a pyrazinyl group, optionally substituted with a halogen atom, an amino or lower alkyl group, a phthalazinyl group, optionally substituted with a halogen atom, or a 5,6-dihydro-4H-1,3-thiazinyl-2-group, as well as the pharmacologically acceptable addition salts of the compounds of formula 1 above or the stereoisomers of these compounds, Otherwise, the compound of formula II, in which Y, Alk, R, R1, R2 and A are as defined above, is alkylated in an inert solvent with a compound of formula III in which Het is as defined above, and W is a cleavable group and the resulting compound of formula I is then optionally converted to its pharmacologically acceptable addition salt by treatment with an appropriate acid, or the resulting addition salt is optionally converted to the above-described base. according to formula I, is treated with an alkali. i.2t-Cc% Y-Alk-N Formula 1 Ar Yy ^ N Formula 1a Ar-NH-CH2-CH2- ^ PX H R1 Formula 1a 'R' l * tY-Alk-lQ-p- £ N £ A Formula 1b147 092 LN H R1 t & ~ Formula 1c R1 rk? N- R2 A Formula 1d / R H-Y-Alk-K) -IN R1 R2 N Formula 2 Rn A Het --- CsH2s-w Formula 3 Formula ^ WZ Graph. Z-d 2 - order 72/89 - 85 Price PLN 400 PL PL