PL144514B1 - Method of obtaining novel derivatives of n-/4-piperidinolo/-2-imidazoloamine - Google Patents

Description

The subject of the invention is a process for the preparation of the new N- (4-piperidinyl) -2-imidazoleamine derivatives of the general formula I, in which the group of the formula -A * A -A ** -A ^ - represents a bivalent radical of the formula - CH * CH-CH »CH-, -N» CH-CH = CH-, -CH »N-CH = CH-, -CH» CH-N = N- or -CH = CH-CH-N-, R is a hydrogen atom or a (C1 *) alkyl radical, R1 is a (C - 4) -alkyl radical, substituted phenyl, chloro-phenyl, thiazolyl, furanyl, (C-,) alkyl-furanyl, piperazinyl, thienyl or pyridinyl, L represents a group of the formula 2af 2bf 2cf 2df 2e or 2ff where in the formula 2a the symbol Alk stands for a (Cjg) alkadienyl group, W is a hydrogen atom, 1-piperidinyl, 1-pyrrolidinyl, 4-norpholinyl, / Cj, / alkoxy, / C -. (C1-4alkylthiophene) - / - alkylamino, a group of formula 3a or 3b, or a group of formula 3cf where W 2 is a (C 1-6) cycloalkyl radical, hydrogen atom, amino or nitro group, a (C 1-6) alkyl radical, optionally substituted hydroxy, (C 1-4) alkoxy, 1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl or phenyl, or an oxygen atom, a sulfur atom or a group of the formula: NR in which R4 is a hydrogen atom, a C1-4alkyl, cyano or nitro group, and Y1 is an oxygen atom, a sulfur atom or a group of the formula = NR, in which R - * represents a hydrogen atom, a (C 1-6) alkyl radical, a group of the formula (Ar) - (C) | , n -alkyl, in which Ar is a phenyl radical having optionally up to three identical or different substituents, such as halogen atoms, hydroxyl, nitro, cyano, trifluoromethyl, (C-) alkyl, / C-, alkoxy, / C "J *" alkylthio, mercapto, amino, mono- or two (C-.) Alkylamino, carboxylic, (c1-z) alkoxycarbonyl and (C1-Zf) alkylcarbonyl, or R5 is a group of formula -C) "X1 / -R where X represents an oxygen or sulfur atom and R6 represents a (C.sub.1) alkyl radical, a (C1.44) alkoxy group or a group represented by the above-described symbol Ar, in the formula 2b and the symbol W1 represents the group (C1.2) alkylamino, di (C 1-6) alkylamino or group 11 with the symbol Ar as described above, and * X1 has the meaning given above, in formula 2c the symbols X and Alk have the above meaning and R represents a hydrogen atom or a radical (C 1-6) alkyl, in formula 2d the symbol Alk has the meaning given above and T represents a group of formula 4a or 4b, where in formula 2 144 514 4a X 1 in the above meaning 1 R is the group amine, phenyl, (C 1-4) alkyl or (C 1-4) alkylamino in formulas 2e and 2f Alk has the meaning given above and Het in formula 2e is a group of formula 3a, 3b or 5A or is also a furyl group substituted with an / C-J alkyl radical, which may be a hydroxyl group, a / "amino- (C-1) alkylJP-thio group, a 2-pyrimidinyloxy group, or a group of the formula 6, in which Y is as defined above and s is completely free. 1-4, or also Het is a group of the formula 7, wherein R 'is a hydrogen atom, a (C 1-6) alkyl radical or an amino group, where when the group of the formula - ^ A = * A ^ A. = A 1 - represents the group -CH = N-CH = CH-, -CH = CH-N = CH- or -CH = CH-CH = N-. or when the group -A1 = A2-A ^ = A4- is the group -CH = CH-CH »CH- or -N = CH-CH = CH- and at the same time R is a pyrazinylmethyl or thiazolylmethyl group, then L may also be the group of formula 2g, in which Ar and Alk have the meaning given above, and if the group -A = A -A ^ = A - means the group -CH = CK-CH = CH- or -N = CH-CH = CH and simultaneously L represents the group of formula IIa, in which W is as defined above, but with the exception of hydrogen, groups of formula 3a and group of formula 3b, then X in formula 2a is sulfur or the group of formula 2a described above = NR, and also , if L is a group of formula IIa, where W is a group of formula 3o, then W in formula 3c has the meaning given above, but with the exception of hydrogen and the (Cj / alkyl) radical. The preparation of pharmacologically acceptable additive salts is also within the scope of the invention. The compounds of formula I with acids and / or the individual stereoisomers of these compounds. The compounds according to the invention have antihistamines. new and useful in combating allergic diseases. No. 4,219,559 are known 4-piperidinamine derivatives of the formula 8 which also have an antihistamine effect. The compounds of the invention differ from these known compounds in structure and have a very favorable antihistamine action. In the compounds of formula I the term "halogen" means fluorine, chlorine, bromine or iodine, the term "halogen" means fluorine, chlorine, bromine or iodine, the term "C 1-4 alkyl" denotes saturated hydrocarbon radicals of 1-4 carbon atoms, having a straight or branched chain, for example methyl, ethyl, 1-methylethyl, 1,1- dimethylethyl, propyl, 2-methylpropyl or butyl. The term "C2 * alkenyl" denotes hydrocarbon radicals with 2 to 4 carbon atoms having a straight or branched chain, for example, ethenyl, 2-propenyl and 2-butenyl. The term "(C 1-6) alkadienyl" denotes divalent hydrocarbon radicals of 1-6 carbon atoms, having a straight or branched chain and free bonds at both chain ends. Some of the compounds of formula I may contain a tautomeric keto-enol or vinyl system, and may also have ketone or enol forms. Compounds of formula I have preferred properties, where L is the group of formula 2a, where Y is the group = NH, I is oxygen and W is hydrogen, or I is sulfur, group = NH or * NCN, Y is aNH and W is 1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl or 3o, where W is amino, nitro or (C 1-6 alkyl), optionally substituted with (C) groups. , l-alkoxy, 1-piperidinyl, 1-pyrrolidinyl, 4-morpholinylphenyl or two (C-) alkoxy groups, or L is a group of formula IIa, where X is sulfur, e = NH or = NCN, Y is = NH and W is / C * j) alkoxy or / C-, / alkylthio, or L is a group of formula 2a, where W is a group of formula 3a or 3b. of formula I in which L is a group of formula IIb, where X is oxygen or sulfur and W is a group of formula IIIc in which W is a (C-) alkyl radical. Equally preferred properties have compounds of formula I in which L is a group of formula IIc in which I is oxygen. L is also preferably a group of formula 2d, in which T is a group of formula 4a, in which X is oxygen or sulfur and R "4 is a (C 1-6) alkylamino group or T is a group of formula 4b. Compounds of formula 1f also have features in which L is a group of formula 2e, in which Het is a group of formula 5t or Het is a group of formula 7 »or Het is a furyl group substituted with a lower alkyl radical which is substituted with a hydroxyl group or a group of formula VI, in which Y is oxygen or sulfur atom, or L is a group of formula IIf, or L is a group of formula IIg9 in which Ar is a phenyl radical substituted with a hydroxyl group or a lower alkoxy group. the compounds of formula I, in which all symbols are as defined above, are prepared with a piperidine derivative of formula 11 in which D is a group of formula 9 in which R, R and the group -A = A -A = A ^ - they have the meaning given above, but the following is alkylated in an inert solvent environment with the compound of formula 10, in which L is as defined above and G is a suitable leaving group such as a halogen atom or a sulfonyloxy group, especially methylsulfonyloxy or 4-methylphenylsulfonyloxy. These reactions are carried out by methods analogous to those used in known alkylation processes. ! and the reaction products are isolated and purified by known methods. Compounds of formula I are basic in nature and can therefore be converted into pharmacologically acceptable acid addition salts by treatment with appropriate inorganic or organic acids, e.g. hydrobromic, sulfuric, nitric, phosphoric, acetic, propionic, 2-hydroxyacetic, pyruvic, oxalic, malonic, cis-ethylenedicarboxylic-1,2-fumaric, tartaric, citric, methane sulfonic, ethanesulfonic, benzenesulfonic, 4-oethylbenzenesulfonic, cyclohexylsulfamic, 2-hydroxybenzoic, 4-mino-2-hydroxybenzoic and the like. These salts can be converted into the free bases by treatment with an alkali. Formula 1 shows that the compounds of the invention may have several asymmetric carbon atoms. Each of these refrigeration centers may have R and S configurations according to the rules given in J.Org.Chem. 35/9 / 2849-2867 /1970 /. Stereochemically pure isomeric forms of the compounds of formula I can be obtained by conventional methods. Diastereoisomers can be separated by physical methods such as selective crystallization and chromatographic methods, e.g. by selective crystallization of their diastereoisomeric salts with optically active acids * Stereochemically pure isomeric forms can also be prepared by using stereochemically pure isomers of the corresponding starting products if the reaction is stereospecific. The invention, of course, also includes the preparation of stereochemically isomeric forms of the compounds of formula 1. The compounds of formula I are histamine antagonists, some of which are also active against serotonin. Useful antihistamine properties of compounds of formula 1 have been demonstrated in the following tests * Protection of rats against the lethal effect of compound 48/80. Compound 48/80 is a mixture of oligomers obtained by condensation of 4-methoxy-N-methylbenzenomethylamine with formaldehyde and has been described as a substance causing a strong release of histamine f Int.Arch.Allergy, 13f 336/1958 / _7 «Protection against compound 48 / 80 Fatal cardiovascular reserve can be considered a simple method of quantifying the anti-histamine effect of the compounds tested. Male rats of the Wistar strain with a body weight of 240-260 g were used in the trials. subcutaneously or orally tested compound or 0.9% sodium chloride solution. After 1 hour, rats were injected intravenously with a freshly prepared aqueous solution of the compound 48/80 at doses of 0.5 mg / kg, ie 0.2 ml per 100 g of body weight. In the control trials, 250 rats were used that had received only the solvent, i.e. sodium chloride solution4 144 514, and these rats were also injected with the compound 48/80 at the dose indicated above * After 4 hours, only 2.8% of the rats from the control test remained alive. that is, keeping alive for more than 4 hours was considered an appropriate protective criterion. Table 1 gives the EDc0 values for compounds of formula 1, i.e. cause the maintenance of 50 fc of test animals administered compound 48/80. The compounds listed in the table do not, of course, limit the scope of the invention, but merely demonstrate the pharmacological utility of the compounds of formula 1. The compound numbers given in the table are the numbers with which these compounds are designated in the examples below. In the entry of the table entitled "form" the word "base" means that it is a free base compound, the acid symbol means an acid addition salt with the specified acid and the symbol "HpO" means that the compound contains water of crystallization. In the formulas of the L group of compounds Nos. 51 and 52, the symbol Ac denotes the cetyl group. Table 1 INnumber 1 of the compound 1 47 50 5 1 2 1 3 59 13 17 23 25 24 I 21 26 35 I 34 40 I 28 31 32 30 36 LI and LZ Pattern 12 Pattern 13 Pattern 14 * l-CH30C6H4 / CH2 / 2 4-CH30C6H4 / CH2 / 2 4-H0C6H4 / CH2 / 2 4-CH30C6H4 / CH2 / 2 4-CH30C6H4 / CH2 / 2 Pattern 15 Pattern 16 Formula 17 Formula 18 Formula 19 / C2H50 / -C / = s / -NH / CH2 / 2 H ^ -NH-C / aSZ-HH / CH ^ Formula 20 Formula 21 / CH3 / 2NH-C / = S / -NH / CH2 / 2 / C ^^ / ^ EC / ^ S / ^ HR / OE ^ \ H0 / CH2 / 3NH-C / = S / -NH / CH2 / 2 Formula 22 Formula 23 R1 3 4-P-C6H4CH2 4 -F-C6H4CH3 4-F-C6H4CH2 4-P-C6H4CH2 4-F-C6H4CH2 / 4-thiazolyl / CH2 / 2-pyrazinyl / CH2 / 4-thiazolyl / CH2 4-P-C6H4CH2 4-P-C6H4CH2 4-F -C6H4CH2 4-P-C6H4CH2 and 4-P-C6H4CH2 4-P-C6H4CH2 4-P-C6H4CH2 4-P-C6H4CH2 4-P-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4-F-C6H4CH2 4- P-C6H4CH2 4-F-C6H4CH2 I -aU2-a3 = a4- 4 -CH = CH-CH * CH- -CH = CH-CH = CH- -CH = CH-CH = xCH- -CH = CH-CH = N- -CH = CH-N = CH- -CH = CH-CHaCH- -CH = CH-CH = CH- -CH = CH-CH = CH- -CH »CH-CH = CH- -CH = CH -CH = CH- -VH = CH-CH = CH- -N = 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 = CH- -CH = CH-CH = CH- - CH = CH-CH = CH- Character! base base base base 2HBr base 2HBr base base fumarate (1/1: 2) base H 2 ° base H 2 ° base base base H 2 ° H 2 ° base base Melting point α b 148.8 128.9 245. 8 186.8 184.5 291.0 127.4 239.2 146.7 110.5 173.1 172f2 125.6 148.6 183.8 162.7 191.6 159.7 175.5 124.6 152.4 218.8 | ro50 mg / kg V 0.08 0.16 0.08 0.08 0.16 0.08 0.04 0.08 1 0.08 0.08 0.16 0.16 0 , 16 0.16 0.02 0.16 0.16 0.08 0.16 0.08 | 0.16 0.06 and the table continues on page 5H4514 5 the table continues yr 45 I 46 56 52 51 1 57 53 12 114 15 16 20 6 7 8 9 10 I 2 HC0-HH- / CH2 / 2 HC0- MH- / CH2 / 2 Pattern 24 Pattern 25 Pattern 26 CH2 * CH-0- / CH2 / 2 Pattern 27 Pattern 28 Pattern 29 Pattern 29 Pattern 29 Pattern 29 Pattern 30 Pattern 29, Pattern 29 Pattern 29 Pattern 29 Pattern 29 IJ 4- Α-C6H4CH2 / 2-iuranyl / CH2 4-F-C6H4CH2 4-FC H CH 4-P-C6H4CH2 4-F-C6H4CH2 4-P-C6H4CH2 4-F-C6H4CH2 4-P-CgH4CH2 / 2-furanyl / CHg / 2-furanyl / CH2 4-P-C6H4CH2 4-P-C6H4CH2 / 4-thiazolyl / CH2 / 2-pyridinyl / CH2 / 2-thienyl / CH2 / 2-pyridinyl / CH2 / 3-pyridinyl / CH2 1 - -CHaCH -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- -GH» CH-CH = CH- -N »CH-CH« CH- -N-CH- CH-CH- -CH «CH-CH = CH- -CH = CH-CH» CH- -N = CH-CH = CH- -CH ^ CH-CH-CH- -CH = CH-CH * CH- - CH »CH-CH = CH- | * base ^ H2O base fumarate / 1: 2 / base base H2O base H2O base H2O base H2O base 2HCl, 1fH2 ° 3HCl 2H20 base 2HCl 2H20 H2O | b 153.2 125.2 186.9 175.2 170.9 138.5 300 191.0 168.4 133.2 171.5 167.1 170.5 187.2 190.6 167.6 185.1 H7.3 I (| 0.08 0.16 0.04 0.31 0.16 0.08 0.08 0.16 0.16 0.08 0.01 0.04 0.31 0.16 0, 04 0.16 0.08 0.31 Due to their antihistamine action of the compound of formula I and their acid addition salts are highly useful in the treatment of allergic diseases such as, for example, allergic rhinitis, allergic conjunctivitis, chronic urticaria and Allergic asthma * Pharmaceuticals containing these compounds as active substances are prepared by mixing a specific compound of formula I or its acid addition salt with a pharmacologically acceptable carrier which is selected depending on the intended method of administration * These agents are preferably prepared in the form of unit doses for oral administration, rectal administration or parenteral injection * The substances usually used in pharmacology are used as carriers, e.g. in the case of liquids such as solutions, suspensions and syrups, or solid carriers such as starch, sugars and kaolin in the case of powders, pills, tablets and capsules, it is also possible to use the addition of lubricants and / or disintegrants take pills. For parenteral administration, sterilized water is usually used as the carrier, but other substances, for example, to facilitate dissolution of the active substance, may also be added. Injectable solutions may also be prepared using solutions of sodium chloride or glucose or both as a carrier. Due to their increased water solubility, acid addition salts of the compounds of formula I are particularly suitable for the preparation of water-containing agents. It is preferable to prepare the above-mentioned agents in unit doses (6H45Hl per unit, containing a predetermined amount of the active substance needed to produce the desired effect. The daily doses of these compounds vary from 0.1 to 100 mg, and preferably from 1-50 mg). The invention is illustrated in the Examples below, whereby Examples I-II relate to the production of starting or intermediate products, and the following relate to the production of the compounds of formula 1. In the examples, unless otherwise stated, the parts are by weight. Preparation of intermediate products. Example 1 A mixture of 90 parts of 4-chloro-3-nitropyridine, 71 parts of fluorobenzene-methylamine, 63 parts of sodium carbonate and 90 parts of N, N-dimethylacetamide is stirred at 50 ° C for 1 hour, then added water and the mixture was extracted with 4-methylpentanone-2 The extract was dried, filtered, evaporated and the residue recrystallized from acetonitrile to give 106 parts / 75% of theory / N - / * / 4 -fluorophenyl) -methyl <-7-3-nitro-4-pyridinamine melting point 136.8 ° C. A similar process was prepared for the following intermediates: Ir-f (4-fluorophenyl) -methyl-7 -2,3-pyridine diamine, N - / "(4-fluorophenyl) -methyl-7-4-nitro-3-pyridine amine as 1-oxide, 2-nitro-N- (thienylmethyl) -phenylamine, N- (3-nitro-2-pyridinyl-2-pyridinomethylamine) Mp 113.6 ° C. and 3-nitro-N- (2-thienylmethyl) -2-pyridineamine having a melting point of 100 ° C. Example II. A solution of 10.2 parts of phosphorus trichloride is added dropwise to a mixed and maintained at 0 ° C solution of 8.7 parts of N - ("/ 4-fluorophenyl) -methyl-4-nitro-3-pyridinamine in 150 parts of trichloromethane. in 75 parts of trichloromethane, then the mixture is allowed to warm to room temperature and then stirred for 1 hour, keeping the mixture refluxed under reflux, then the mixture is cooled, the solvent is evaporated, the residue is mixed with trichloromethane, filtered off the precipitate and dried it, obtaining 9 parts of N - / 'M-FluorophenylZ-methyl ^ - Nitro ^ -pyridinamine monohydrochloride. Example III A mixture of 11 parts of intermediate No. 7, 2 parts of A% ethanol solution of thiophene and 240 parts of saturated methanol ammonia is hydrogenated under atmospheric pressure at room temperature in the presence of 3 parts of 5% platinum on charcoal. After absorption of the calculated amount of hydrogen, the mixture is heated, the catalyst is drained off, washed it is washed with 2-methoxyethanol, the filtrate is evaporated and the residue is heated in acetonitrile. After stirring and cooling, the precipitate was filtered off to obtain 6.5 parts (58% of theory) of N - (4-fluorophenyl) methyl 7-3,4-pyridinediamine monohydride, m.p. 208.9 ° C. * p The following intermediates are prepared in an analogous manner: 70C, N- (2-thienylmethyl) -1,2-phenyldiamine, N- (2-pyridinylmethyl) -2,3-pyridinium diamine with a melting point of 134-9 ° C and N- (2-thienylmethyl) -2.3- pyridine diamine with a melting point of 92.1 ° C. Example 4 To a stirred and cooled mixture of 4 parts of sodium hydroxide in 60 parts of water, 7.9 parts of carbon disulphide and 17.2 parts of 4-amino acid ethyl ester are successively added. -piperidine-1-carboxylate and stirred at a temperature below 10 ° C for 30 minutes, then 10.9 parts of ethyl chloroformate are added dropwise, causing an exothermic reaction and increasing the temperature to about 35 ° C. Stirring is then continued at 60 ° C. C for 2 hours, cooling the mixture and extracting with methylbenzene. The extract is dried, filtered and evaporated to leave 22 parts / 100% theoretical / 4-isothiocyanatopiperidine carboxylic acid ethyl ester-1. 4-pyridine dibasic and 450 parts of tetrahydrofuran are stirred and refluxed for 3 hours, then evaporated and the residue recrystallized from acetonitrile. There are obtained 90 parts (52% of theoretical yield) of 4 ^^ "^" ^ 4-^ "^ (4-fluorophenyl) -methyl-amino-7-3-pyr-144 514 7 dynyl-7-amino-thioketomethyl-7 -amino / -piperidinecarboxylic-1 with a melting point of 166 ° C »The following intermediates are prepared in an analogous manner: ethyl ester of l-CCCC thioketOBietyl-1-piperidinecarboxylic acid-1, 4-N -piperidinecarboxylic acid ethyl ester, 3 - ^^ (4-fluorophenyl) Haetyl ^ - ^ minoy-2-pyridinyl ^ -amino ^ N -thioketomethylamino ^ -piperidinecarboxylic acid-1, ethyl acid ester 4 - ^^^ 2 - ^ (2-furanyl acetyl) -sminoy-3 * pyridinyl-aainothioketomethyl-amino-piperidinecarboxylic-1, m.p. 132.7 ° C, 4 - ("^)" 3- ^ acid ethyl ester N (4-fluoro-phenyl), H-methyl, N-amino-thioketo, ethyl-7-amino-7-piperidinecarboxylic-1, 4 - / "N-2 - /" (2-thienyl) -azidioyl, ethyl ester -phenyl, 7- aainothioketomethyl, 7-amino, 7-piperidinecarboxylic-1, ethyl ester of A- α- £ m £ ~ 2-f / 2-plry & yiiylmethyl / -aaino / - 3-pyridinyl-7-aminothioketomethyl-7-ejaine / - piperidinoxroxy-1-acid ethyl ester and 4 - ^ / ~ ^ 2 - ^ / 2- thienylmethyl) -3-pyridinyl-piperidinecarboxylic acid-1 • Example VI • A mixture of 74 parts of 4 - "^" Y ~ 2 - ^ "72-furanyl (- methyl ./-amino-3-pyridinyl) 1, 96 parts of mercuric oxide, 0.1 parts of sulfur and 800 parts of ethanol are boiled under reflux and stirred for 3 hours, then filtered using Hyflo auxiliary and the filtrate evaporates. The residue was recrystallized from acetonitrile, yielding 52.5 parts (79% of theory) of ethyl ester 4 - 4 "/" "3- (2-furanylmethyl) -3H-imidazo, 4" 5-b-7 pyridinyl-2_ / -amino-piperidinecarboxylic-1 with a melting point of 149 * 2 ° C. The following intermediates are prepared in an analogous manner: ethyl ester of 4- ^ ^ 1- (2-fur8-xylmethyl) -1H-benzimidazolyl-2 - / - Aniino-1-piperidinecarboxylic-1, m.p. 135.8 ° C, 4- ("^" 1-4 "(4-fluoro-phenyl) -methyl-1H-imidazo," 4,5-b-7-pyridinyl, ethyl ester -2-amino-piperidinecarboxylic-1, m.p. 212.5 ° C, 4- (")" 1-4 "(4-fluoro-phenyl) -methyl-7-1H-imidazo-4f5-d6, ethyl ester (pyridinyl-2'-amino-1 -piperidinecarboxylic-1 in the form of the dihydrochloride monohydrate, ethyl ester of 4-4 "Y" 3-4 "V4-fluoro-phenyl) -methyl J7-3H-imidazo) -4,5-o-7-pyridinyl-2-7 - araino - / - piperidinecarboxylic-1 in the form of the dihydrochloride monohydrate with a melting point of 168.6 ° C, ester e 4- (~) 1- (2-thienylmethyl) -1H-benzimidazolyl-2'-einine-1-piperidinecarboxylic acid-1, mp 142t7 ° C, 4- (b &apos; 3- (2-) ethyl ester) pyridinylmethyl (-3H-imidazo) "4,5-b% (pyridinyl-2 -) -amino-1-piperidinecarboxylic-1, m.p. 141.3 ° C and 4 - 4" "(-3-) acid ethyl ester thienylmethyl) -3 H -imidazo-4-b-5 -pyridinyl-2-amino-piperidinecarboxylic-1 • Example VII. A mixture of 14.5 parts of 4- (1H-benzimidazolyl-2-amino / -piperidine-1-carboxylic acid ethyl ester), 13 parts of 2-chloromethylpyrazine, 10.5 parts of sodium carbonate and 135 parts of N, N-dimethylformamide is mixed at 50 ° C C for 3 hours and then at 70 ° C overnight, then cooled, poured into water and 4-methylpentanone-2 was extracted. The extract is dried, the filter screen is evaporated and the residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethane and methanol (95: 5 by volume). Pure fractions are evaporated and the residue converted in 2-propanone to the hydrobromic acid salt. The salt is filtered off and dried, yielding 8.7 parts (32% of theory) of 4 - "^" 1- (2-pyrazinylmethyl) -1H-benzimidazolyl-2-7-araino-piperidinecarboxylic acid dihydrobromide monohydrate. 1, melting at 178.5-179.3 ° C, the following products were prepared in an analogous manner: 8 144 514 carboxylic-1 with a melting point of 156.2 ° C, 4 - ^^ lV3-pyridinylmethyl / -1H-benzinddazolyl-2-aminooy-plperidine-carboxylic acid-1 with a melting point of 191.4 ° C and an ester 4 - ^^ 1 - ^ (2-pyridinyl) -methyl-1H-benzimidazol-2'-amino - / - piperidinecarboxylic-1-acid with a melting point of 161.5 ° C »Example VIII» 50 parts of acid ethyl ester 4 - ("(3- (2-furanylmethyl) -3H-imidazo)" 4f5-b-7pyridinyl-2 - / - amino-7-piperidinecarboxylic-1 and 50 parts of potassium hydroxide are mixed with 400 parts of propanol -2 with the addition of 20 drops of water y and boiled under reflux for 5 hours, then evaporated. * Add water to the residue and extract twice with 4-methylpentanone-2. The combined extracts are dried, filtered, evaporated and the solid residue mixed with diethyl ether, filtered off the precipitate and dried to give 34 parts / 85 * theoretical / 3- / 2-furanylmethyl / -N- / 4-piperidinyl / - 3H-imidazo ^ " 4 »5-b1 / pyridin-2-amine with a melting point of 159f00C» The following compounds are prepared in an analogous manner: 1- (2-furanylornethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine mp 211.0 ° C t H- (4-piperidinyl) -1- (2-thienylmethyl) -1H-benzimidazole-2-amine and N- (4-piperidinyl) -3- (2-thienylmethyl) * 3H- i "Idazo-4f5-b -7pyridine-2-aaine, m.p. 189f6-193t5 ° C. • Example DC. -imidazo-4-t5-c-7-pyridinyl-2-7-amino-1-piperidinecarboxylic-1 and 275 parts of 48% aqueous hydrobromic acid solution are stirred at 80 ° C overnight, then evaporated to dryness and the residue recrystallized from ethanol You get 14.7 parts / 48 # theorist performance 3 -4 "" (4-fluorophenyl) -methyl-7-H- (4-piperidinyl) -3H-imidazo-4-pyridin-2-amine dihydrate / monohydrate, mp 291.6 ° C analogue The method is prepared as follows: 1-4-(4-fluorophenyl) -methyl-N- (4-piperidinyl) -1H-imidazo) -4,5-b-pyridine-2-aaine dibromide, m.p. 300.6 ° C, 1- (- (4-fluorophenyl) -methyl) - N- (4-piperidinyl) -1H-imidazo-4 -4,5-c-7-pyridin-2-amine dibromide, m.p. 279.4 ° C, N- (4-piperidinyl) -1- (4-thiazolylmethyl) -1H-benzimidazol-2-amine dibromide monohydrate, m.p. 232.5 ° C. N- (4-piperidinyl) -1- (2-pyrazinylmethyl) -1E-benzimidazole-2-amine trihydrobromide, N- (4-piperidinyl) -1- (3-pyridinyl acetyl) -1H-benzimidazole-2-amine trihydromide mp 260 ° C., N- (4-piperidinyl) -3- (2-pyridinylmethyl) -3H-imidazo-4f5-b-7-pyridin-2-amine trihydrohydride, mp 265.5 ° C. and N- (4-piperidinyl) -1- ^ "(2-pyridinyl) -methyl-7-1H-benzimidazole-2-amine tribromide, m.p. 295.9 ° CB" Preparation of compounds of formula 1 * Example I. Mixture 1 , 6 parts of 1-chloro-2- (ethenyloxy) -ethane, 7.3 parts of 1- (4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide, 3.1 parts sodium carbonate, 0.1 parts potassium iodide and 135 parts N, N-dimethylformamide are kept under stirring at 70 ° C overnight, then poured into water and extracted with 4-methylpentanone-2. The extract is dried, filtered, evaporated and the residue chromatographed on a silica gel column, eluting with a 96: 4 mixture by volume of methane trichloromethane / methanol saturated with ammonia * The pure fractions are combined, evaporated and the residue recrystallized from acetonitrile to give 1.9 parts / 32 # theoretical yield (N- ^ "" 1- (2-) (ethenyloxy) ethyl- 7-4-piperidinyl. 7-1- (4-fluorophenylmethyl) -1H-benziraidazole-2-amine, m.p. 133.5 ° C / compound No.! / •• The following compounds are prepared in an analogous manner: 1 - ^ "7 4-fluoro-phenyl) -methyl-7-N - /" 1- / "2- (4-methoxyphenyl) -ethyl-7 -4-piperidinyl-7-1H-imi-144 514 9 dazo 4f5-b-7pyridin-2-amine, m.p. 186.8 ° C (compound No. 2), 1-4-fluorophenyl) -methyl-7 -N - ^ "1- /" 2- (4-methoxyphenyl) -ethyl-7-4-piperidinylOfP7-1H-iindazo (~ 4,5-c_7pyridin-2-amine, m.p. 184 * 5 ° C / compound no. 3 /, fumarate / 1: 2 / 3- / ~ / 4-fluorophenyl / -methyl-N- / ~ 1- / ~ 2- / 4-methoxyphenyl / -ethyl-74-piper dy- nyl-7-3H-iraidazo ^ "4,5-c-7pyridin-2 amine, m.p. 202.8 ° C / Compound No. 4 / '• 3- ^ 2 - /" 4 - / "/" l - ("(4-fluorophenyl) -methyl) -1H-benzimidazolyl-2-7-amino-7-1-piperidinyl-7-ethyl) -1H, 3H-pyrimidinedione-2,4, m.p. 245.8 ° C / compound No. 5 / »3 - (2 - ^" 4 - ^ "/ 1- (4-thiazolylmethyl) -1H-benzimidazolyl-2-7-amino-1-piperidinyl-ethyl / -2H-1-benzopyranone dihydrochloride hydrochloride -2, m.p. 187.2 ° C (Compound No. 6), 3- ("2-4" "" 4- "" 3- (2-pyridinylmethyl) -3H-imidazo4.5-trihydrochloride dihydrate " -b JP-pyridinyl-2- / - aminofc7-1-piperidinyl-7-ethyl-2H-1-benzopyranone-2, m.p. 190.6 ° C (compound No. 7), 3 - 4 "2- E" 4- (~ £ "1- (2-tenylmethyl) -1H-benzimidazolyl-2-amino-1-piperidinyl - N-ethyl-7-2H-1-benzopyranone-2, m.p. 1667t6 ° C (compound No. 8 / f dihydrate 3 - ^ "2-2f" 4 - ^ "" (-1- (2-pyridinylmethyl) 1H-benzimidazolyl-2-7-amino-7-1-piperidinylethyl-2H-2H-1-benzopyranone dihydrochloride melting point 181.5 ° C (compound No. 9 / f 3-2-, 4- (N-N-W3-pyridinylethyl) -1H-benzimidazolyl-2-amino, -1-piperidinyl-7-ethyl-7-2H- monohydrate 1-benzopyranone-2, m.p. 147.3 ° C (compound No. 10) and 3- ("2-" 4- "4" 1- (2-thienylmethyl) -1H-benzimidazolyl-2-7-amino -7-1-piperidinyl-7-ethyl-7-2H-1-benzopyranone-2 with a melting point of 164.6 ° C (compound No. 11). Example XI * 3f8 parts of 3- (2-bromoethyl) -2H-1-benzopyranone-2 . 7.3 parts of 1-4 "dihydrobromide (4-fluorophenyl) -methyl -7-N- (4-piperidinyl) -1H-benzimidazole -2-amine and 4.8 parts of sodium carbonate in 135 parts of NN-dimethylformamide are mixed The extract is dried, filtered, evaporated and the residue is chromatographed on a silica gel column, eluting with a 96: 4 mixture by volume of trichloromethane and methanol. The eluent was evaporated from the pure fractions and the residue was recrystallized from acetonitrile, yielding 1.6 parts (21.5% of theory) (3 - ^ "2 -" 4- ^ 1 - ^ 74-fluorophenyl) - methyl-7-1H-benzimidazolyl-2J-amino-7-1-piperidinyl J-ethyl-2H-1-benzopyranone-2, m.p. 168.4 ° C (compound No. 12). compounds N - ('"1-" 2- (4-methoxyphenyl) -ethyl-7 -4-piperidinyl- (-1- ^ "(2-pyrazinyl), ethyl-7-1H-benzimidazole-2-amine with mp 127.4 ° C / compound No. 13), 3- (2 -4 "4 -" Y * "W2-furanylmethyl) -1H-benzimidazolyl-2-7-amino-7-1-piperidinyl-7-ethyl-7- monohydrate 2H-1-benzopyranone-2, m.p. 133 t2 ° C (Compound No. 14) * 3- ("2-" "4-") "3- (2-furanylmethyl) -3H-imidazo4f" 4f 5- b. / pyridinyl-2. / amino. 7-1-piperidinyl J-ethyl-7-2H-1-benzopyranone -2 with a melting point of 171.5 ° C (compound 15) and 3- (2- (2f) monohydrate) - (- 3- (A-fluorophenyl) -methyl) -3H-imidazole fi95- * J pyridinyl-27-aminq7 -1-piperidinylq7-ethyl) -2H- 1-benzopyranone-2, m.p. 167.1 ° C / compound No. 16 /. Example III. 4 * 7 parts 1- / 2-chloroethyl / -4-aethoxybenzenttf 14 parts N- (4-piperidinyl / -1- / 4-thiazolyl-methyl / -1H-benzimidazole-2-amine dihydrobromide monohydrate) 15 parts carbonate of sodium and 0.3 parts of sodium iodide in 90 parts of N, N-dimethylacetamide is stirred at 80 ° C overnight, then added to water and the mixture is extracted with 4-methylpentanone-2. The extract is dried, filtered, evaporated and the oily residue is converted into the hydrobromide in an ethanol environment. The precipitate is filtered off and dried to give 9 parts of N - 4-thiazolyl / -ethyl dihydrate dihydrate. -1H-benzimidazole-2-amine, m.p. 239f2 ° C (compound 17). Example XIII. For a mixture of 4 parts of H - "1- (4-fluorophenylmethyl) -and H-benzimidazolyl-2y-) -114 # -dupiperidine7-4-aminef 1 parts of N, H-diethylethanamine and 91 parts of di-10 144 514 chloromethane are added dropwise while stirring a solution of 196 parts of 4-fluorobenzoyl chloride in 39 parts of dichloromethane9 where an exothermic reaction takes place and the temperature of the mixture rises from 25 ° C up to 30 ° C. Stirring is then continued at room temperature for 1 hour and the mixture is purified by liquid pressure chromatography using a mixture of trichloromethane with hexane and methanol (45: 45: 10 by volume) as eluent. The eluent was evaporated from the pure fractions to give 198 parts (34% theoretical) (1 '- (4-fluorobenzoyl) -N- (1- (4-fluorophenylmethyl) .7-1H-benzimidazolyl-2] -C *) , 4'-bis-piperidine-4-amine, m.p. 19493 ° C (Compound No. 18). N9N-Diethyl-4- (-1-) (4-fluorophenylmethyl) -1H-benzimidazolyl-2-amide is prepared in an analogous manner. -amino ^ - ^ 194 # -dupiperidine-carboxylic-1 # mp 176 ° C (Compound No. 19) The following compounds of formula 1: 1 are also prepared by following the procedure described in Example 1 and using the appropriate starting products. - "(4-fluoro-phenyl) -methyl-7-N - /" 1- / "2- (2-methyl-1H-imidazolyl-1) ethyl J-4-piperidinyl J -1H-benzimidazole-2-amine, m.p. 16995 ° C / compound No. 20/9 N # -cyano-N - / * 2 - / "4 - /" Z * 3 - / * / 4-fluorophenyl / -methyl y-3H-imidazo / "" 4.5- S-methyl b-7-pyridinyl-2-7-amino / -1-piperidinyl-7-ethyl-7-carbamimidothioate, m.p. 17292 ° C (compound no. "Y" "1- (" Y "" (4-fluoro-phenyl) -methyl-1-H-benzimidazolyl-2-7-amino-7-1 "P1" peridinyl-7-ethyl-7-carbamimidothionate 3-methyl / compound 22/9 N- 4 2-4-4- "/" 1-4- (4-fluorophenyl) -methyl- • 1H-benzimidazolyl-2-7-amino-7-1-piperidinyl-ethyl, N-N-nitroguanidine, m.p. 14697 ° C / compound 23 / fumarate N "-cyano-N- (292-dimethoxyethyl) -N * - / '" 2 - / "4 - /" "^ ~ 1- /" y4-fluorophenyl) -methyl-IH - benzimidazolyl-2-amino-1-piperidinyl-1-ethyl-guanidine, m.p. 173 ° C (compound No. 24/9 N, - cyano-N - "2 - f" 4 - F "^ 1- ^ "(4-fluorophenyl) -methyl-7-1H-benzimidazolyl-2-7-amino-1-piperidinyl-7-ethyl-N, H * -dimethylguanidine, melting point 11095 ° C / compound 25 /» Nn monohydrate -cyano-N- (~ 2- / "4 - /" "/" 1-4 "/ 4-fluorophenyl) -methyl-7-1H-benziniidazolyl-2-7-amino-7-1-piperidinyl-7-ethyloyHI - (2- 2- (4-morpholinyl) -ethyl-7-guanidine, melting point 12,595 ° C (compound No. 26 (f cis-N-) (-2- "4 -4" Y "1-4" (4-fluorophenyl) -methyl-7-1H-benzimidazolyl-2-7-amino-N-3-methyl-1 - piperidinyl, 7-ethyl-7-N 9 N # - dimethylthiourea, m.p. 126 ° 7 ° C (compound No. 27), N - 2 - 3 - 4 - "Y - 1 - 4" (4-fluorophenyl) - methyl 7-1H-benzimidazolyl-2J-amino-7-1-piperidinylJ-ethyl ^^ - morpholinecarbothioamide, m.p. 191 * 5 ° C / compound No. 28/9 N - ^ * 2 - / "4 - /" / ~ 1 -if (4-fluoro-phenyl) -methyl-7-1 H-benzimidazolyl-2,7-amino-1 -piperidinyl-ethyl-1 -piperidinecarbothioamide, m.p. 175 ° 5 ° C / compound 29/9 N - / * 2- monohydrate &Quot; 4 - / " -thiourea, m.p. 12496 ° C (compound No. 30) (f N - (2 -) "4- (Y" 1- (4-fluoro-phenyl) -methi-7-1 H-benzimidazolyl-2-7-amino. 7-1 -piperidinylJ-ethyl ^ -Nj * N # -dimethylthiourea, m.p. 159-7 ° C / Compound No. 3V # N, N-diethyl-N * - / "2- ^ ~ 4 - /" / ~ 1 - ^ "/ 4 -fluorophenyl / -methyl ^ -IH-benzimidazolyl ^^ - amino ^ -1-piperidinyl-7-ethyl-7thiourea, m.p. 175.5 ° C / compound n r 32 (f N- (-2-) "4 - /" Y -1- "(4-fluorophenyl) -methyl-7-1H-benzimidazolyl-2.7-amino, 7-1-piperidinyl-7-ethyl fumarate JN * - (2-phenylethyl) thiourea, m.p. 19698 ° C (Compound No. 33/9, N - (2 -) α - 4 "2" 1-4 "(4-fluorophenyl) -methyl -7-1H monohydrate -benzimidazolyl-2-n-7-amino. 7-1-piperidinyl-1-ethyl-4-hydrazinocarbothioamide, m.p. 183.8 ° C / compound no. - 4 "(4-fluoro-phenyl) -methyl-1 H -benzimidazolyl-2-amino-7-1-piperidinyl, 7-ethyl-7-carbamothioate, m.p. 148.6 ° C (compound No. 35 / f monohydrate 4 - N-"1- (4-fluorophenyl) -methyl-1 H-benziridazolyl-2-amino-N-methyl - N-methyl - N -methyl-N-methyl-1 f4 # - dipiperidine-7-carbonamide-1 *, m.p. 152t5 ° C / compound No. 36 /, 4 - / "Y" 1-7 4-fluorophenyl) -methyl, 7-1H-benzimidazolyl-2J-aminoJ-R-methyl- "1 f3 # -dupiperidine-7-carbothioamide-1 ', m.p. 218, 8 ° C (compound No. 37) * 4- 4 -4 "1-" (4-fluorophenyl) -methyl-1 H -benzimidazolyl-2.7-amino-7-N-methyl-1 , 4 &apos; -dupiperidine-7-carbonamide-1 *, m.p. 222.7 ° C (compound No. 38), N-cyclohexyl-N, - (- 2 - 4 - ("Y" 1-4 ") 4-fluorophenyl) -methyl-7-1H-benzimidazolyl-2'-amino-1-piperidinyl-7-ethyl'-thiourea, m.p. 177 ° C (Compound No. 39), N - 4 * 2 - 4 "4-" ("1- (*) 4-fluorophenyl) methyl-7-1H-benzimidazolyl-2-7-amino-7-1-piperidinyl-7- ethyl-7-N # -phenylthiurea, m.p. 162.7 ° C / compound No. 40 /, N- 2 - ("4 -)" 1- (fluorophenylmethyl) -1H-benzimidazolyl-2-amino-7-1-piperidinyl-7-ethyl-7-N- (4-methoxyphenyl) - thiourea, m.p. 165.9 ° C (compound No. 41), acid addition salt N - ("2-4" 4 - ")" 1-4 "(4-fluorophenyl) -methyl-7-1H-bexizimidazolyl- 2-7-amtno-7 -1-piperidinyl. 7-ethyl-7-2-keto-2 H -benzopyranecarboxylic-3 with fumaric acid, melting at 205.0 ° C (compound No. 42), N- 4 addition salt "2 - ^" 4 - ^ "^" 1 - 4 "(4-fluorophenyl) -methyl. 7-1H-benzimidazolyl-2.7-amino. 7-1-piperidinyl-7-ethyl-7-4-keto-AH -1-benzopyranecarbonamide-2 with acid fumarate, melting at 248.8 ° C (compound No. 43), N- 2 - 4 - 4 "Y" addition salt - 1- (4-fluorophenyl) -methyl-7-1 H-benzimidazolyl-2-amino N-1-piperidinyl-7-ethyl-7-2-keto-2H-1-benzopyranecarbonamld-3 with fumaric acid, melting at 216.8 ° C (compound No. 44), N- 2 - N "4-" N 1 -N (4-fluorophenyl) -methyl. 7-1 H -benzimidazolyl-2-7-amino-1-piperidinyl-7-ethyl-7-formamide, m.p. 153.2 ° C (compound 45), N dihydrate - 1H-benzimidazolyl-2-amino-1-1-piperidinylJ-ethyl. 7-formamide, m.p. 125.0 ° C / compound No. 46 /, 5-4- / -4- "" Y "" 1-4-(4-fluorophenyl) -methyl, 7-1 H-benzimidazolyl-2-7-amino J - *, - piperidinyl J-methyl-7-2 -furanomethanol, m.p. 148.8 ° C (Compound No. 47), 1 -f "(4-fluoro-phenyl) -methyl-N-N-1 -" "-" 5 -beta. (2-pyrimidinyloxy) -methyl 7-2-furanyl J-methyl J -4-piperidinyl-7-1 H-benzimidazolyl-2-amine, m.p. 167.8 ° C (compound No. 48), N- ("1-4" &lt; " &gt; 5 - &lt; 2 &gt; -aminoethyl / thi omethyl-7-2-furanyl-7-methyl-4-piperidinyl-1 -4 "(4-fluorophenyl) -methyl-7-1H-benzimidazolyl-2-amine (compound No. 49, oily), 1 - / "Y" 4-fluorophenyl) -methyl ^ -N - / "1 - /" / "5 - ^" ^ "2- (2-pyrimidinylamino) -ethyl-thymethyl-J- -2-furanyl-7-methyl-7- 4-piperidinyl-7 -1H-benzimidazolyl-2-amine, m.p. 128.9 ° C (compound No. 50), 2- (acetylamino) -N- (-2- "4 -4") "1-4" 74-fluorophenyl) -methyl-7-1H-benzimidazolyl-2-7-amino-1-piperidinyl-7-ethyl. 7-benzamide, m.p. 170.9 ° C (compound 51), 2- addition salt (acetylamino) -N- (~ 2 - ^ "4 - ^" Y ~ 1 - ^ "74-fluorophenyl) -methyl ^ -1H-benzimidazolyl--2./- amino ^ -1-piperidinyl J-ethyl-7-benzamide with fumaric acid, melting at 175.2 ° C (compound 52), N - "" 4- (2- (4-) "Y-1- (4-fluorophenyl) -methyl) -1H-benzimidazolyl-2-monohydrate. 7-amino. 7-1-piperidinyl. 7-ethyl. 7-methanesulfonamide, m.p. 191.0 ° C (Compound No. 53), N - (4-) - 2 - 4 - 4 "Y - monohydrochloride. 1- ^ ~ (4-fluorophenyl) - methyl-7-1H-benzimidazolyl-2J-amino-7-1-piperidinyl-7-ethyl-7-phenyl, 7-benzaraid, m.p. 217.3 ° C (compound No. 54), 12 144 514 N- 4 - / "2- /"4-^^1-Z"/4-fluorophenyl/-metyloy-1H-benzimidazolyl-2^-amino.7-1- piperidinyl^7-ethyl7-phenyl.7-acetamide with a melting point of 227t2 ° C / compound No. 55), N - (4-) "2 - 4" 4 - 4 "^" 1- (4-fluorophenyl) -methyl-1H-benzimidazolyl-2-7-aminoy-1-piperidinyl-ethyl-7 -phenyl. 7-urea, m.p. 186.9 ° C (Compound No. 56/1 N - 4 - 4 - 2 - 4 - 4 ")" 1 - 4 "(4-fluorophenyl) -methyl - 1H-benzimidazolyl-2-7-amino-1-piperidin-1-7-ethyl-7-phenyl-7-N * -methyl-urea melting point + 300 ° C / compound No. 57 / f monohydrate N - ^ "4 - ^" 2 - &lt; 1 &gt; "4 - ^" and &lt; 1 &gt; (4-fluorophenyl) -methyl-7-1H-benzimidazolyl-2'-amino-7- -1-piperidinyl'-ethyl'-phenyl] -N * - methylthiourea melting point 120.2 ° C (compound No. 58), 4 - (2 - 4 "4 - 4" 4 "1- (4-thiazolylmethyl) -1 H -benzimidazolyl-2-araine-1-piperidinyl .7-ethylJ-phenol, m.p. 29 1.0 ° C (compound No. 59) and N-1H-imidazolyl-1) -ethyl-7-4-pip, -1H-benzimidazolyl-2-amine monohydrate, m.p. 171F5 ° C (compound No. 60) • Claims 1 • A method for the preparation of new N- (4-piperidinyl) -2-imidazole araine derivatives of the general formula 1, in which the group -A = * A -A ^ = A - is a divalent radical of the formula -CHaCH-CH-CH-, -NaGH-CHsCH-, -CH »N-CH = CH-, -CH = CH-N» CH-, or -CH = CH-CH = N-, R is an atom hydrogen or a (C 1-) alkyl radical, R is a (C 1-) alkyl substituted phenyl, halo-phenyl, thiazolyl, furanyl, / C 1- / alkyl-furanyl, piperazine, thienyl or pyramid radical dyinyl, L is a group of formula 2a, 2b, 2c, 2d, 2e or 2f, where in formula 2a the symbol Alk is a (C-g) alkadienyl group, I is a hydrogen atom, 1-piperidinyl, 1-pyrrolidinyl group , 4-morpholinyl, (C 1-4) alkoxy, (C 1-6) alkylthio, di (C 1-6) alkylamino, a group of formula 3a or 3b, or a group of formula 3c where W is the radical (C 1-6) N-cycloalkyl, hydrogen, amino or nitro, (C-) alkyl, optionally substituted hydroxy, (C-) alkoxy, 1-piperidinyl, 1-pyrrolidinyl, 4-norpholinyl or phenyl, or W is a (C 1-6) alkyl radical substituted with two (C 1-6) alkoxy groups, X in formula 2a is oxygen, sulfur or -NR, in which R * represents a hydrogen atom, a (C 1-6) alkyl group, cyano or nitro, and Y1 is oxygen, sulfur or a group of the formula = HR in which R5 is a hydrogen atom, a (Cj-) alkyl radical, a group of the formula (Ar) -) -) alkyl, in which Ar denotes a phenyl radical, optionally having up to three identical or different substituents, such as halogen atoms, hydroxyl, nitro, cyano, trifluoromethyl, (G4) alkyl, (C1) alkoxy, (C1) alkylthio, mercapto, amine, mono- or di (C 1-6 -alkyl aaine, carboxyl, (C 1-6) alkoxycarbonyl and (C 1-6)) - (alkyl-carbonyl) or R 5 represents a group of the formula -C (= I) -r 6, in which I represents an oxygen or sulfur atom and R represents a (C 1-6) alkyl radical, a (C 1-8) alkoxy group or a group of in the above-described symbol Ar, in formula IIb W1 represents a (C1-Z) alkylamino group, a di (C1-4) alkylamino group or a group with the above symbol Ar, and X has the meaning given above, in formula IIc the symbols X and Alk is as defined above and R is a hydrogen atom or a cyclic alkyl radical, in formula 2d Alk is as defined above and T is a group of formula 4a or 4b, where X is as defined above in formula 4a and R3 is an amino group , phenyl, (C, alkyl or (C 1-4) alkylamino in formulas 2e and 2f) Alk has the meaning given above, and Het in formula 2e is a group of formula 3a, 3b or 5, or is also a furyl group substituted with a (C1-4) alkyl radical, which may be a hydroxyl group, a ("amino- (C1-4A) alkyl,) -thio group, a 2-pyrimidinyloxy group or a group of formula 6, in which where Y1 has the meaning given above and s is an integer 1-4, where when the group of formula -A1 »A2-A ^ = A * -144 514 13 it skips the group -CH" N-CH "CH-, -CH" CH-N "CH- or -CH" CH-CH-N-, or when the group -A1 »A2-A 4 = A 4 - is a group -CH" CH-CH "CH- or -N = CH-CH = CH- and at the same time R represents a pyrazinylmethyl or thiazolylmethyl group, then L can also represent a group of formula 2g, in which Ar and Alk have the meaning given above, and if the group -A = A -A * aA * - means the group -CHaCH- CHi = CH- or -N = CH-CH * CH- and L is the group of formula 2a9 where W is as defined above, but with the exception of hydrogen, 3a and 3bt then X in formula 2a c represents a sulfur atom or a group of the above-described formula = NR, and also, if L is a P group of formula 2a, where W is a group of formula 3c, then W in formula 3c has the meaning given above, but with the exception of hydrogen and the radical (C * -) alkyl or pharmacologically acceptable addition salts of compounds of formula I with acids and / or stereoisomers of these compounds, characterized in that the piperidine derivative of formula 11 in which D represents a group of formula 9 # in which Rf R, R and the group -A = A -A ^ = A4 - have the meaning given above , is alkylated in an inert solvent with a compound of formula 10, in which L is as defined above and G is a cleavable group, and the resulting compound of formula 1 is then optionally converted to its pharmacologically acceptable acid addition salts or from addition salts with with acids - the compound of formula 1 is released in the form of a base by treatment with alkali and / or stereoisomers of compounds of formula 1 are prepared. , R and the group -A * k -A »A * - have the meaning given in claim 1, and L is a group of formula 2e, in which Alk is a * / C * r / alkadienyl group and Het is a group of formula 7, wherein R 'is a hydrogen atom, a (c *) / alkyl radical or a group of groups the amine, or pharmacologically acceptable acid addition salts of compounds of formula I and / or stereoisomers of these compounds, characterized by a piperidine derivative of formula 11, 12 12 3 4 in which D is a group of formula 9 in which R, R f R and the group -A = A -A = A - are as defined above, are alkylated in an inert solvent with a compound of formula 10, in which L is a group of formula 2e, in which Alk and Het are as defined above, and G- oz A cleavable group is then obtained, and the resulting compound of formula I is optionally converted into its pharmacologically acceptable acid addition salts, or the acid addition salts are liberated from the acid addition salts by treatment with an alkali of the compound of formula I as a base and / or prepared 'stereoisomers of compounds of formula 1 * Wz $ r1 WC-Y1-Alk- Wcl {3' WW2a Formula 2b X "0 (d-flkyl) - C-NR2- ^ y6-NH-Alk- Formula Ze144 514 T- £ ^ Alk- Wuor Zd Het-Alk- Formula 2e C2-C4-atken O-0-Alk- Ar-Alk Formula 2q Formula 2f 0 ^ 0 Formula 3a W2-NH- Formula 3c Wz or 36 X1 R3-d-NH- Formula 4a C1_4alkyl) -SOz-NH- Formula 4b Formula 5 -N Formula 6144 514 R7 Chip? Formula 8 RR Formula 9 LG Formula 10 HD Formula 11 HOCH ^ O ^ Hg Formula 12 jCHj ^ N ^ NH (CHASCH2Y0 ^ n2 -NyO l ^ l-CHjrCH2 O Extfr 14 Formula 73 HN = C-NH (CH2) Z NH- NO- '2 Formula 15144 514 (CH ^ N-ONI-KCHzk II N-CN Formula i6 CH30-CHCH2NHCNH (CH2) 2 CH30 N-CN Formula 17 CH3S-C-NH (CH2) 2 N-CN mar 18 cCAllCH ^ NHCNHfCH ^ N-CN Formula 19 S w. Formula 20 O Formula 21 CHj-NH-CO-N ^ CHj-NH-CS-tO Formula 22 Formula 23 H2N-C0-NHhO ^ (CH2) j Formula 24144 514 (C ^ N -Ac \ _v of \ tm- (CUM NH-Ac (JC-NH- (CH ^ Formula 26 CH3-NH-C0-NH ^ (3 ^ (CH2) 2 Formula 27 CH ^ NH-O-ItHa) mor 28 (CH2) 2 N = / CH3 VZ <5r * 9 N- (CH2); l = / '2; Z PL PL

Claims (2)

1. Claims 1. • A method for the preparation of new N- (4-piperidinyl) -2-imidazole araine derivatives of the general formula 1, in which the group -A = * A -A ^ = A - represents a bivalent radical of the formula -CHaCH-CH -CH-, -NaGH-CHsCH-, -CH »N-CH = CH-, -CH = CH-N" CH-, or -CH = CH-CH = N-, R is hydrogen or the radical / C " - / alkyl, R is a radical /C-, / alkyl substituted phenyl, halo-phenyl, thiazolyl, furanyl, / C- | alkyl-furanyl, piperazine, thienyl or pyridinyl group, L is a group o formula 2a, 2b, 2c, 2d, 2e or 2f, where in formula 2a the symbol Alk represents the alkadienyl group, I represents hydrogen, 1-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, / C1-6 alkoxy, (C1-6) alkylthio, di (C1-6) alkylamino, a group of formula 3a or 3b, or a group of formula IIIc where W is a (C1-6) cycloalkyl radical, hydrogen atom , amino or nitro group, / C- / alkyl radical, optionally substituted hydroxy, / C- / alkoxy, 1-piperidinyl, 1 -pyrrolidinyl, 4-norpholinyl or phenyl, or W is a (C 1-4) alkyl radical substituted with two (C 1 -) alkoxy groups, X in formula 2a is oxygen, sulfur or a -NR group in which R * is hydrogen, (C 1-6) alkyl, cyano or nitro, and Y 1 is oxygen, sulfur or = HR, in which R 5 is hydrogen, (C 1-6) alkyl, and Ar N - (N -) alkyl, in which Ar is a phenyl radical optionally having up to three identical or different substituents, such as halogen atoms, hydroxyl, nitro, cyano, trifluoromethyl, j) alkoxy, (C1-6) alkylthio, mercapto, amine, mono- or di (C1-6) - alkyl aaine, carboxyl, (C1-6) alkoxycarbonyl and (C1-6). - (alkyl-carbonyl) or R 5 represents a group of the formula -C (= I) -r 6, in which I represents an oxygen or sulfur atom and R represents a (C 1-6) alkyl radical, a (C 1-8) alkoxy group or a group of in the above-described symbol Ar, in formula IIb W1 represents a (C1-Z) alkylamino group, a di (C1-4) alkylamino group or a group with the above symbol Ar, and X has the meaning given above, in formula IIc the symbols X and Alk is as defined above and R is a hydrogen atom or a cyclic alkyl radical, in formula 2d Alk is as defined above and T is a group of formula 4a or 4b, where X is as defined above in formula 4a and R3 is an amino group , phenyl, (C, alkyl or (C 1-4) alkylamino in formulas 2e and 2f) Alk has the meaning given above, and Het in formula 2e is a group of formula 3a, 3b or 5, or is also a furyl group substituted with a (C1-4) alkyl radical, which may be a hydroxyl group, a ("amino- (C1-4A) alkyl,) -thio group, a 2-pyrimidinyloxy group or a group of formula 6, in which where Y1 has the meaning given above and s is an integer 1-4, where when the group of formula -A1 »A2-A ^ = A * -144 514 13 it skips the group -CH" N-CH "CH-, -CH" CH-N "CH- or -CH" CH-CH-N-, or when the group -A1 »A2-A 4 = A 4 - is a group -CH" CH-CH "CH- or -N = CH-CH = CH- and at the same time R represents a pyrazinylmethyl or thiazolylmethyl group, then L can also represent a group of formula 2g, in which Ar and Alk have the meaning given above, and if the group -A = A -A * aA * - means the group -CHaCH- CHi = CH- or -N = CH-CH * CH- and L is the group of formula 2a9 where W is as defined above, but with the exception of hydrogen, 3a and 3bt then X in formula 2a c represents a sulfur atom or a group of the above-described formula = NR, and also, if L is a P group of formula 2a, where W is a group of formula 3c, then W in formula 3c has the meaning given above, but with the exception of hydrogen and the radical (C * -) alkyl or pharmacologically acceptable addition salts of compounds of formula I with acids and / or stereoisomers of these compounds, characterized in that the piperidine derivative of formula 11 in which D represents a group of formula 9 # in which Rf R, R and the group -A = A -A ^ = A4 - have the meaning given above , is alkylated in an inert solvent with a compound of formula 10, in which L is as defined above and G is a cleavable group, and the resulting compound of formula 1 is then optionally converted to its pharmacologically acceptable acid addition salts or from addition salts with acid-liberated by treatment with alkali of a compound of formula 1 in the form of a base and / or stereoisomers of compounds of formula 1 are prepared * 2. * A method for the preparation of new N- (4-piperidinyl) -2-imidazoleamine derivatives of the general formula 1, in which R, R and the group -A * k -A »A * - have the meaning given in claim 1, and L is a group of formula 2e in which Alk is a * (C * r) alkadienyl group and Het is a group of formula 7 in which R 'is a hydrogen atom, a (c *) alkyl radical or an amino group, or pharmacologically acceptable addition salts of the compounds of formula I with acids and / or stereoisomers of these compounds, characterized by tyra, with the piperidine derivative of formula 11, 12 12 3 4 in which D represents a group of formula 9, in which R, R f R and the group -A = A -A = A - as defined above, alkylated in an inert solvent with a compound of formula 10, in which L is a group of formula IIe, in which Alk and Het are as defined above, and G- is a cleavable group, and the resultant the compound of formula (I) is optionally converted into its pharmacologically acceptable acid addition salts, or acid addition compounds are released by treatment with an alkali of a compound of formula 1 in the form of a base and / or stereoisomers of compounds of formula 1 are prepared ) - C-NR2- ^ y6-NH-Alk- Formula Ze144 514 T- £ ^ Alk- Wuor Zd Het-Alk- Formula 2e C2-C4-athenes O-0-Alk- Ar-Alk Formula 2q Formula 2f 0 ^ 0 Formula 3a W2-NH- Formula 3c Formula 36 X1 R3-d-NH- Formula 4a C1_4alkyl) -SOz-NH- Formula 4b Formula 5 -N Formula 6144 514 R7 Chip? Formula 8 RR Formula 9 LG Formula 10 HD Formula 11 HOCH ^ O ^ Hg Formula 12 jCHj ^ N ^ NH (CHASCH2Y0 ^ n2 -NyO l ^ l-CHjrCH2 O Extfr 14 Formula 73 HN = C-NH (CH2) Z NH- NO- '2 Formula 15144 514 (CH ^ N-ONI-KCHzk II N-CN Formula i6 CH30-CHCH2NHCNH (CH2) 2 CH30 N-CN Formula 17 CH3S-C-NH (CH2) 2 N-CN mar 18 cCAllCH ^ NHCNHfCH ^ N-CN Formula 19 S w. Formula 20 O Formula 21 CHj-NH-CO-N ^ CHj-NH-CS-tO Formula 22 Formula 23 H2N-C0-NHhO ^ (CH2) j Formula 24144 514 (C ^ N -Ac \ _v of \ tm- (CUM NH-Ac (JC-NH- (CH ^ Formula 26 CH3-NH-C0-NH ^ (3 ^ (CH2) 2 Formula 27 CH ^ NH-O-ItHa) mor 28 (CH2) 2 N = / CH3 VZ <5r * 9 N- (CH2); l = / '2; Z PL PL