DK171841B1 - N-hetero-cyclyl-4-piperidineamines - Google Patents

Description

in DK 171841 B1

The present invention relates to novel N-heterocyclyl-4-piperidinamines which can be used as intermediates in the preparation of other similarly novel N-heterocyclyl-4-piperidinamines.

IN USA. U.S. Patent No. 2,971,005 discloses 2- (phenylmethyl-5-amino) benzimidazoles having local anesthetic and antifibrillatory properties, and in U.S.A. U.S. Patent No. 2,857,391 discloses a number of 2- (aminomethylbenzimidazoles). The compounds prepared by the process of the parent application, DK Patent Application No. 1298/79, differ substantially therefrom, structurally by the nature of the 4-piperidinyl group to which 10 is attached. the compound 1-methyl-N-phenyl-N-phenylmethyl-4-piperidinamine, which is an antihistaminic compound of the trivial name Bamipin (see Merck index, 8). edition (1968) p. 118) The compounds prepared according to the parent application differ substantially from this in that they contain a 1H-benzimidazol-2-yl or 3H-imidazo [4,5-b] pyridin-2-yl- group attached to the amino nitrogen atom.

The novel N-heterocyclyl-4-piperidinamines disclosed herein can be reproduced by the general formula (XX) of claim 1, while the novel N-heterocyclyl-4-piperidinamines which can be prepared from these compounds are similar. can be reproduced by the general formula:

R

And pharmaceutically acceptable acid addition salts thereof, wherein 30 R is hydrogen or methyl, R 1 is hydrogen or lower alkyl of 1 to 6 carbon atoms, R2 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms , aryl, mono- or diphenyl-C 1-8 lower alkyl, wherein the phenyl group is optionally substituted by 1 to 2 identical or different substituents which are halogen atoms or methyl or nitro groups, R 1 is hydrogen, halogen, methyl or trifluoromethyl, 2 DK 171841 B1 L is a lower alkyl group containing 1 to 6 carbon atoms and optionally substituted with a cyano or hydroxy group or a C 1 lower alkoxy group, C 1-4 lower alkyl carbonyl oxy group or an aryl, aryloxy, arylthio - or amino group, diphenyl-Cj_-lower alkyl, di- (halogenophenyl) Cj-lower alkyl, 3-cyano-3,3-diphenyl propyl, 2-propenyl, 3-aryl-2-propenyl, 3-aryloxy-2 -hydroxypropyl or a group of the formula: Z-CH. wherein m Zm m is an integer from 1 to 4 and Z is 4-aryl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl, 4- (C1-6 lower alkyl) -4,5-dihydro-5-oxo-1H-tetrazol-1-yl-2,3-dihydro-1,4-benzodioxy-2-yl, 2,3-dihydro-1,4-benzodioxin-6-yl , 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl, 2,3-dihydro-3-oxo-4H-benzoxazin-4-yl, (10,11-dihydro-5H-dibenzo- [a , d] cyclohepten-5-ylidene) methyl, 4-morpholinyl, arylcarbonyl, arylaminocarbonyl, C arylamino, wherein when L is a lower alkyl group substituted with 1 to 6 carbon atoms, the aryl group represents phenyl, substituted phenyl, naphthalenyl, thienyl or pyrridinyl, wherein said substituted phenyl contains 1 to 3 substituents which are independently halogen atoms or methyl, C 1-4 lower alkyloxy, trifluoro-methyl, hydroxy, nitro or amino groups, and wherein one of the substituents additionally may be methylthio, Cj ^ lower alkyloxy, carbonylmethoxy, phenyl acetyloxy, benzoyloxy, methoxybenzoyloxy, phenylmethoxy, C - or disubstituted where each substituent is independently a halogen atom or a methyl or methoxy group and Q is CH or N.

The compounds of formula (XX) according to the invention are intermediates for the preparation of the compounds disclosed in the parent application, DK Patent Application No. 1298/79, which compounds have common useful antihistaminic effect.

In the foregoing definitions, the term "lower alkyl" means a straight-chain or branched hydrocarbon group having from 1 to 6 carbons, e.g. methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like, the term "alkyl" as used in the definition of R 2 comprises straight and branched hydrocarbon groups having from 1 to 10 carbon atoms, e.g. the above lower alkyl groups and higher homologues such as heptyl, octyl, nonyl and decyl, the term "lower alkenyl" refers to straight chain alkenyl groups 5 having from 3 to 6 carbon atoms, the unsaturation being preferably in β-st for 11 , but may also be in the y, 6, or e position, e.g.

2-propenyl, 2-butenyl, 3-pentenyl, 2-hexenyl and the like, the term "cycloalkyl" refers to cyclic hydrocarbon groups having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the term "halogen" is generic for fluorine, chlorine, bromine and iodine.

The compounds of general formula (I) can generally be derived from a starting material of formula:

R

wherein R, R1, R2, R3, n and Q have the above meanings by introducing the desired L substituent on the piperidine nitrogen atom by methods known per se.

In general, the introduction of L into the intermediate (II) may conveniently be effected by reacting (II) with a suitable reactive ester of formula LY (III), wherein L has the meaning given above and Y means a reactive ester residue such as .g. halogen, preferably chlorine or bromine, or a sulfonyloxy residue, e.g. methylsulfonyloxy or 4-methylphenyl sulfonyloxy and the like.

The condensation reaction between (II) and (III) is conveniently carried out in an inert organic solvent such as e.g. an aromatic hydrocarbon, e.g. benzene, methyl benzene, dimethyl benzene and the like, a lower alkanol, e.g. methanol, ethanol, 1-butanol and the like, a ketone, e.g. 4-methyl-2-pentanone and the like, an ether, e.g. 1,4-dioxane, Ι, Γ-oxybisethane and the like, Ν, Ν-dimethylformamide (DMF), nitrobenzene and the like.

Addition of a suitable base, e.g. an al potassium metal carbonate or hydrogen carbonate or an organic base such as e.g. N, N-diethyl-ethanamine or N- (1-methylethyl) -2-propanamine can be used to collect the acid which is released during the course of the reaction. Under certain circumstances, the addition of an iodide salt, preferably an alkali metal iodide, is appropriate.

Slightly elevated temperatures can be used to increase the reaction rate.

When L in formula (I) represents a (2,3-dihydro-2-oxo-1H-benzimidanol-1-yl) lower alkyl group, it is convenient to use a reactive ester (III) wherein the nitrogen atom at the 3-position of The 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl group is substituted by an appropriate protecting group, preferably a 1-methylethenyl group, and removing this protecting group upon completion of the condensation reaction. The removal of the protecting group may occur in a manner known per se such as by acid hydrolysis when a 1-methylethenyl group is involved.

When L represents a 2-aryl-2-hydroxyethyl or a 3-aryloxy-2-hydroxypropyl group, the introduction of the substituent into the intermediate (II) is conveniently carried out by reacting (II) at an elevated temperature with an appropriate temperature. oxirane of the formula: 20 «yMOCH ^ -Δ UV> wherein m is 0 or 1.

The reaction of formula (II) with (IV) may be carried out in a suitable organic solvent or, optionally, in the absence of any solvent. Suitable solvents which may be used include, e.g. aromatic hydrocarbons such as benzene, methylbenzene, dimethyl benzene and the like, halogenated hydrocarbons such as e.g. trichloromethane, dichloromethane and the like, lower all channels such as methanol, ethanol, 2-propanol and similar alcohols, and mixtures of such solvents. When the piperidine derivative (II) is in the form of an acid addition salt, it is convenient for the reaction mixture to add a suitable base such as e.g. sodium carbonate to release the free acid from the salt.

The compounds of formula (I) wherein L represents a 2-hydroxyethyl group can be prepared by reacting an appropriate piperidine of formula (II) with oxirane using the same procedure as described for the reaction of (IV) with ( II).

When at the time of attachment to the piperidine nitrogen atom, L is a primary or secondary alkyl group, compounds (I) can also be prepared by reductive amination of an aldehyde or ketone corresponding to the alcohol L-OH with a piperidine derivative of formula (II) of 5 known in itself. A convenient process consists of hydrogenating a mixture of the aldehyde or ketone and (II) in a suitable organic solvent in the presence of a suitable catalyst such as e.g. palladium-on-charcoal.

Suitable organic solvents include lower alkanols such as methanol, ethanol, propanol and the like. The rate of the hydrogenation reaction can be increased by being carried out in the presence of a suitably weak acid such as e.g. acetic acid. When the piperidine derivative (II) is in the form of an addition salt with a strong acid, e.g. hydrochloric acid or hydrobromic acid, it is convenient to add a strong base salt with weak acid, e.g. sodium acetate, to bind the strong acid. When (II) contains groups which are themselves susceptible to catalytic hydrogenation, e.g. when R 2 represents an aryl methyl group, it may be appropriate for the reaction mixture to add an appropriate catalyst poison such as e.g. thiophene.

When L represents a group of formula wherein m is an integer from 2 to 4 and Z has the meaning given above, the compounds of formula (I) can also be prepared by reacting (II) with a suitable alkenyl derivative, ZC1-1, in a manner known per se for carrying out similar addition reactions, e.g. by stirring 25 and heating the reactants with each other in a suitable, inert organic solvent reaction, e.g. a lower alkanol such as 2-propanol, butanol and the like.

When L represents a 2- (aroylamino) ethyl group or a 2-arylethyl group, compounds (I) can also be obtained by reacting (II) with an appropriate 1-aroyalaziridine or an appropriate ethenylarene, respectively. These reactions are preferably carried out in a suitable reaction-inert solvent, e.g. a lower alkanol, e.g. methanol, ethanol, propanol, butanol and similar alcohols, an aromatic hydrocarbon, e.g. benzene, methyl benzene, dimethyl benzene and the like, a ketone, e.g. 4-methyl-2-pentanone, an ether, e.g. 1,4-dioxane, 1,1'-oxybis-ethane and the like, Ν, Ν-dimethylformamide, nitrobenzene and the like or a mixture of such solvents. Elevated temperatures are suitable for increasing the reaction rate, and preferably the reaction is carried out at the reflux temperature of the reaction mixture.

The compounds of formula (I) may also be prepared by cyclodesul-5 fururization of a suitable thiourea derivative of formula? 2

R 'NH

10 (V)

31 I

* 3

This cyclodesulfurization reaction can be carried out by reacting (V) with a suitable alkyl halide, preferably iodomethane, in a suitable organic solvent for the reaction, e.g. a lower alkanol such as methanol, ethanol, 2-propanol and the like. In addition, the cyclodesulfurization reaction can be carried out by reacting (V) with a suitable metal oxide or salt in a suitable solvent according to the process, e.g. are described in Pharmazie, 31, 348 (1976). For example, the compounds of formula (I) can be readily prepared by reacting (V) with a suitable Hg (11) or Pb (II) oxide or salt, e.g. HgO, HgCl2, HgiOAc ^, PbO or PbtOAcJg. In some cases it may be convenient to supplement the reaction mixture with a little sulfur. Even methanedimines, especially N, N'-methanetretrayl-biscyclohexanamine] can be used as cyclodesulfurizers. Suitable, inert organic solvents which can advantageously be used for the reaction include lower alkanols, e.g. methanol, ethanol, 2-propanol and the like, halogenated hydrocarbons, e.g. dichloromethane and trichloromethane, ethers, e.g. tetrahydrofuran, 2,2'-oxybispropane and the like, and mixtures of such solvents.

For example, amino-substituted compounds can be derived from the corresponding nitro- and cyano-substituted compounds by reducing the latter, e.g. by catalytic hydrogenation in the presence of a suitable catalyst, e.g. Raney nickel and the like.

The amino-substituted compounds can again be N-alkylated or acylated by reaction thereof with a suitable alkylating agent or acylating agent, e.g. a halide, an alkali or acylating agent, e.g. a halide, an alkanoyl halide, an alkoxycarbonyl halide, an isocyanate and the like.

Secondary and tertiary amino-substituted compounds of formula (I) can be prepared by e.g. substitutes an appropriate halogen-substituted compound with the desired primary or secondary amine.

Aminocarbonyl-substituted compounds may conveniently be derived from the corresponding esters by reaction of the latter with ammonia 10 or a suitable primary or secondary amine in a suitable solvent moiety.

Compounds of formula (I) which contain in the structure a sulfonyl group can be readily derived from the corresponding thio compounds by oxidizing the latter with a suitable oxidizing agent, e.g. hydrogen peroxide or the like.

In all the foregoing and subsequent preparations, the reaction products can be isolated from the reaction mixture and, if necessary, further purified in a manner known per se.

The compounds of formula (I) can be converted to the therapeutically active non-toxic acid addition salt by treatment with a suitable acid such as e.g. an inorganic acid such as hydrohalic acid, e.g. hydrogen chloride, hydrogen bromide and the like and sulfuric acid, nitric acid, phosphoric acid and the like, or an organic acid such as e.g. vinegar, propane, 2-hydroxyacetic, 2-hydroxypropane, 2-oxopropane, propanedioin, butanedioin, (Z) -2-butenedioin, (E) -2-butenedioin, 2-hydroxybutanedioin, , 2,3-dihydroxybutanedioin-, 2-hydroxy-1,2,3-propanetricarboxyl-, benzo-, 3-phenyl-2-propane, α-hydroxybenzeneacetic acid, methanesulfone, ethanesulfone, benzenesulphonic acid, methylbenzenesulphonic, cyclohexanesulfame, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acid and similar acids.

Conversely, the salt form can be converted by base treatment to the free base form.

The starting materials of formula (II) can generally be prepared from a thiourea derivative of formula (X) wherein R, R 1, R 2, R 3 and n have the meanings given above, and P represents a suitable protecting group such as e.g. lower alkyloxycarbonyl or phenylmethoxycarbonyl by subjecting (X) a cyclodesulfurization reaction to obtain an intermediate of formula (XI) and then eliminating the protecting group in the usual manner.

R2

5 B NH R

S V-q I

^ Cyclodesulfu- p_ ^ · '\ fr> H3 H ris 10 (x) (xi ·)

Removal of protecting (Π) protecting group 15

The cyclodesulfurization of (X) to obtain (XI) is carried out in the same manner as described herein for the preparation of compounds (I) from (V). For removal of the protective group P can be used in methods known per se. For example, when it is a lower alkyloxycarbonyl group, this group can be removed by basic or preferably acidic hydrolysis using e.g. hydrobromic acid in glacial acetic acid and when the protecting group is a phenylmethoxycarbonyl group is removed by basic or acid hydrolysis or by catalytic hydrogenation using a suitable catalyst such as palladium-on-charcoal.

Intermediates of formula (XI) wherein R2 is different from hydrogen can also be derived from the corresponding compound (XI) wherein R2 is hydrogen by introducing the desired R2 substituent in a manner known per se.

The thiourea derivatives of formula (X) wherein R 1 is hydrogen 30 (Xa) can be prepared by reacting an appropriate 4-isothiocyanato-piperidine of formula (XII) with a suitable benzenediamine or pyridinediamine of formula (XIII), .g. by simply stirring the reactants with each other in a suitable organic solvent, e.g. a lower alkanol, e.g. methanol, ethanol, 2-propanol and the like.

35 DK 171841 B1 P. ^ y ^, - * w »· (XII) (XIII) r2 /

'5 R NH

and fi y%, P-N VnH-C-NhA r3 10 (X-a)

The thiourea derivatives of formula (X) wherein R 1 is as defined above and R 2 is hydrogen (Xb) can be prepared by reacting an appropriate 4-piperidinamine of formula (XIV) with a suitable 1-isothiocyanate-2 nitrobenzene of formula (XV), followed by reduction of the nitro group of the thus obtained compound (XVI) by well known nitro-to-amine reduction methods such as e.g. by reaction of (XVI) with nascent hydrogen or by catalytic hydrogenation using a suitable catalyst such as palladium-on-charcoal, platinum-on-charcoal, and the like or in the presence of more than one such catalyst.

25 j— \ 3

P-N> NH + · -} f- B

\ -VI, S = C = N ^) -5- R1 30 (XV) R O Ν 'Λ n 3 P-N VN-C-NHV / -A- R nitro-to-amine Y-J I. [/ Reduction] R1 (XVI) DK

R Η N

Ηλ FROM 3

p'L / F ^ w "H

5 R

The precursor materials of formula (XIV) can be prepared by methods known per se, e.g. by reductive amination of the corresponding 4-piperidinone. The 4-isothiocyanatopiperidines of formula (XII) can again be prepared from the corresponding compound (XIV), wherein R 1 represents hydrogen according to standard methods for preparing isothiocyanates from primary amines, e.g. by reacting the amine with carbon disulfide in basic medium and subsequently adding to the reaction mixture of a suitable lower alkylcarbon chloride.

The starting materials of formula (XII) wherein P represents a lower alkyloxycarbonyl or phenylmethoxycarbonyl group may also be prepared by reacting a corresponding starting material (XII) wherein P represents phenylmethyl with an appropriate carbon chloride.

The starting materials of formula (V) can be prepared using similar procedures as described above to prepare the 20 thiourea derivatives of formula (X), however, starting from an appropriate 4-piperidinone or 4-piperidinamine in which the L substituent is already present. present on the piperidine nitrogen atom.

The original starting materials for each of the foregoing processes are known compounds, or they can be prepared using methods known per se to produce similar known compounds.

Eg. is the preparation of 4- (haloalkyl) -2H-1,4-benzoxazine-3 (4H) -ones, by N-substitution reaction of 2H-1,4-benzoxazin-3 (4H) -one with a dihalogen lower alkyl group described in Belgian patent no.

30 859.415. 1,3-dihydro-1- (3-oxobutyl) -2H-benzimidazol-2-one (XIX) can be prepared by subjecting 1,3-dihydro-1- (1-methylethenyl) -2H-benzimidazole -2-one (XVII) and 3-butene-2-one a Michael addition in the presence of a base such as Ν, Ν-diethylethanamine and the like and subsequent hydrolysis of 1,3-dihydro-1- (1-methylethenyl) - 3- (3-oxobutyl) -2H-benzimidazole-2-35 one (XVIII).

11 DK 171841 B1 H2C o o HC-C-N ^ ffl + CH- = CH-C-CHn Michael addition 3 ^^ 2 3 - * 5 (xvn) H2C o

HjC-IS-N ^ -C ^ -C ^ -C-CHj. hydrolysis _ 1 ° (XVIII) o o CH 2 - CH 2 - C - CH 3 O (XIX)

The compounds of formula (I) and the pharmaceutically acceptable acid additon salts thereof are potent antihistaminic agents and as such can be used to prepare valuable drugs for human and animal therapy.

The valuable antihistaminic properties of the compounds of formula (I) were demonstrated by the following test method.

PROTECTION OF ROTES AGAINST CONNECTION 48/80-INDUCED DEATH.

25

Compound 48/80, which is a mixture of oligomers obtained by condensation of p-methoxy-N-methyl-phenethylamine and formaldehyde, is described as a potent histamine-releasing agent (Int. Arch. Allergy, 13, 336 (1958)). Protection against compound 48/80-induced lethal circuit 30 collapse appears to be a simple method for quantitatively assessing the antihistaminic activity of test compounds. Male rats of an inbred Wistar strain weighing 240-260 gr were used in the experiment. starvation one night, the rats were transferred to conditioned laboratories (temp. = 21 ± 0 ° C, relative humidity = 65 ± 5%).

The rats were treated subcutaneously or orally with a test compound or solvent (NaCl solution, 0.9%). One hour after treatment, intravenous compound 48/80, freshly dissolved in water, was injected at a dose of 0.5 mg / kg (0.2 ml / 100 g body weight).

In control experiments where 250 solvent treated animals were injected with the standard dose of compound 48/80, no more than 5 2.8% of the animals survived after 4 hours. Survival after 4 hours is considered a safe criterion for a protective effect of the administered drug.

The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof were found to be very active in the above tests, protecting the animals from compound 48/80 induced mortality at oral and subcutaneous doses of not more than 2.5 mg / kg. . A number of the compounds of the present invention were even found to be effective at doses as low as 0.16 mg / kg.

Due to the valuable antihistaminic activity of the compounds of the present invention, they can be formulated into various pharmaceutical formulations for administration purposes. To prepare the pharmaceutical compositions, an effective antihistaminic amount of the desired compound in base or acid addition salt form is combined as an active ingredient in intimate admixture with a pharmaceutically acceptable carrier which can take a wide variety of forms depending upon the desired form of administration for administration. . These pharmaceutical compositions are convenient in unit dosage form which is preferably suitable for oral, rectal or parenteral injection. For the preparation of oral dosage form, e.g. any of the usual pharmaceutical media such as e.g. water, glycols, oils, alcohols and the like. in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules and tablets.

Because of the ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are naturally used. For parenteral preparations, the carrier will usually comprise sterile water, at least in large part, although other ingredients, e.g. to facilitate solubility. Injectable solutions may e.g. are prepared wherein the carrier comprises the saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be used. Of course, due to their increased water solubility in relation to the corresponding base form, acid addition salts of (I) are more suitable for the preparation of aqueous preparations.

It is particularly advantageous to formulate the above-mentioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. Unit dosage forms herein refer to physically discrete units suitable as unit doses, each unit containing a predetermined amount of active ingredient intended to produce the desired therapeutic effect, together with the necessary pharmaceutical carrier. Examples of such unit dosage forms are tablets (including slotted or coated tablets), capsules, pills, powder packs, cachets, injectable solutions or suspensions, teaspoon portion balances, tablespoon portion balances and the like. as well as separate multiples thereof.

In the following examples, all parts are parts by weight, unless otherwise stated.

A. Preparation of Intermediate Products Example 1

A mixture of 102 parts of ethyl 4-oxo-1-piperidine carboxylate, 50 parts of 25 methanamine and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off over Hyflo and the filtrate is evaporated to give 111 parts of ethyl 4- (methylamino) -1-piperidine carboxylate as residue.

To a stirred and cooled mixture of 4 parts sodium hydroxide in 60 parts water is added successively 7.9 parts carbon disulfide and 17.2 parts ethyl 4-amino-1-piperidinecarboxylate at a temperature below 10 ° C. Stirring is continued for 30 minutes at this temperature. Then 10.9 parts of ethyl carbon chloridate are added dropwise (exothermic reaction: the temperature rises 35 to about 35 ° C). When this is complete, stirring is continued for 2 hours at 60 ° C. The reaction mixture is cooled and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated to give 22 parts (100%) of ethyl 4-isothiocyanate-1-piperidine carboxylate as residue.

By repeating the process of the second step, a suitable amine can also be prepared from: 4-isothiocyanate-1- (phenylmethylpiperidine) and 1- [4,4-bis (4-fluorophenyl) butyl] -4-isothiocyanate piperidine;

92 ° C.

Example 2

To a stirred solution of 28.4 parts of 4-isothiocyanate-1- (phenylmethyl) pi peri d in n in 315 parts of methylbenzene is added dropwise 41 parts (phenylmethyl) of carbon chloride at room temperature. When this is done, it is all heated to reflux and stirring is continued overnight at ten to 15 reflux temperatures. The reaction mixture is cooled and the solvent is evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated to give 32 parts (97%) (phenylmethyl) -4-isothiocyanate-1-piperine carboxylate as residue.

20

Example 3

A mixture of 9.7 parts of 4-fluorobenzene methamine hydrochloride, 9.4 parts of 2-chloro-3-nitropyridine, 10.6 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of Ν, Ν-dimethylformamide is stirred for 1 hour. 90 ° C. The reaction mixture is cooled and poured into water. The precipitated product is filtered off and crystallized from 2-propanol to give 10.5 parts (71%) of N- (4-fluorophenylmethyl) -3-nitro-2-pyridinamine, m.p. 76 ° C.

A mixture of 10.5 parts of N- (4-fluorophenylmethyl) -3-nitro-2-pyridine-amine and 200 parts of methanol is hydrogenated at normal pressure and room temperature with 2 parts of Raney nickel catalyst. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated to give 9.3 parts (100%) of N2- (4-fluorophenylmethyl) -2,3-pyridinediamine as residue.

By following the same procedure and using equivalent amounts of the appropriate starting materials, N1- (phenylmethyl) -4- (trifluoromethyl) -1,2-benzenediamine can also be prepared, and -N1- (4-fluorophenylmethyl) -1,2-benzenediamine.

Example 4

A mixture of 34.8 parts of 1,3-dihydro-1- (1-methylethenyl) -2H-benz-5-imidazol-2-one, 28 parts of 3-buten-2-one, 20.2 parts of Ν, Ν- diethylethanamine and 270 parts of tetrahydrofuran are stirred and refluxed over a week-end. The reaction mixture is evaporated to give 48.8 parts (100%) of 1,3-dihydro-1- (1-methylethenyl) -3- (3-oxobutyl) -2H-benzimidazol-2-one as residue.

A mixture of 48.8 parts of 1,3-dihydro-1- (1-methylethenyl) -3- (3-oxo-10-butyl) -2H-benzimidazol-2-one, 12 parts of 2-propanol saturated with gaseous hydrogen chloride and 240 parts of 2-propanol are stirred for 3 hours at room temperature. The precipitated product is filtered off, washed with 2,2'-oxybispropane and dried to give 30 parts (73.4%) of 1,3-dihydro-1- (3-oxobutyl) -2H-benzimidazol-2-one.

15

Example 5

To a stirred mixture of 9 parts of 2H-1,4-benzoxazine-3 (4H) -one, 0.9 parts of Ν, Ν, Ν-triethylbenzene methanaminium chloride, 9 parts of sodium hydroxide solution 50% and 24 parts of water are added 10.4 parts of 1- bromo-3-chloropropane at 20 ° C. The whole is heated to 90 ° C and stirring is continued for 3 hours at this temperature. The reaction mixture is cooled to ca. 70 ° C, methyl benzene is added and the whole is stirred overnight at room temperature. The organic phase is separated, dried, filtered and evaporated to give 10 parts of 4- (3-chloropropyl) -2H-1,4-benzoxazin-3 (4H) -one as residue.

25

Example 6

A mixture of 10.6 parts of ethyl 4-isothiocyanate-1-piperidinecarboxylate, 11.6 parts of 4-chloro-N * - (phenylmethyl) -1,2-benzenediamine and 90 parts of tetrahydrofuran is stirred overnight at room temperature. The reaction mixture is evaporated to give 21 parts (100%) of ethyl 4 - [([[5-chloro-2 - [(phenyl methyl) amino] phenyl] amino] thioxomethyl] amino] -1-piperidinecarboxylic acid xylate, mp 162 ° C.

Following the procedure of Example 6 and using 35 equivalent amounts of the appropriate starting materials, it is possible to prepare: 1-ethyl-4 - {[(2-amino-5-chlorophenyl) aminothioxomethyl] amino} -1-piperidine. dincarboxylat; mp. 162.2 ° C, ethyl 4 - {[(2-aminophenyl) aminothioxomethyl] amino} -1-piperidinecarboxylate as residue, ethyl 4 - {[(2-amino-5-methylphenyl) aminothioxomethyl] amino} -1-piperidinecarboxylate as residue, ethyl 4 - [{[{2- (phenylmethyl) amino] -3-pyridinyl) amino] thioxomethyl} amino] -1-piperidinecarboxylate; mp. 146.7 ° C, ethyl 4 - {[{2 - [(phenylmethyl) amino] -5- (trifluoromethyl) phenyl) amino] thioxomethylamino} -1-piperidinecarboxylate as residue, ethyl 4 - [{[( 2-amino-4-fluorophenyl) amino] thioxomethyl} amino] -1-piperidincarboxylate as residue, ethyl 4 - [{[{5-chloro-2 - [(4-fluorophenylmethyl) amino] phenyl} amino ] -15 thioxomethyl} amino] -1-piperidinecarboxylate as residue, (phenyl methyl) -4 - [{2- [4-fluorophenylmethyl) amino] -3-pyridinylamino) thioxomethylamino] -1-piperidinecarboxylate, N - (2-nitrophenyl) -N '- [1- (2-phenylethyl) -4-piperidinyl] -N' - (phenylmethyl) thiourea; mp. 151.1 ° C, 20 N- (1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl} -N'-phenylthiourea; mp 90 ° C; ethyl -4 - [{ [(2-amino-3-pyridinyl) amino] thioxomethyl} amino] -1-piperidinecarboxylate; mp 176.9 ° C, 4 - [{[(2-phenylamino) phenyl] amine nothioxomethyl} amino] -1-piperidinecarboxylate; mp 154.2 ° C and ethyl 4 - {[{[2- (4-fluorophenylamino) phenyl] amino) thioxomethyl] amino] -1-piperidinecarboxylate as residue.

Example 8 A mixture of 21.6 parts of 1-isothiocyanate-2-nitrobenzene and 45 parts of tetrahydrofuran is stirred until all solids have dissolved. Then, 29.5 parts of N- (1-methylethyl) -1- (2-phenylethyl) -4-piperidinamine and 160 parts of ethanol are added and the whole is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is crystallized from 2-propanol. The product is filtered off and dried to give 43 parts (84%) of N- (1-methylethyl) -Ν '- (2-nitrophenyl) -N- [1- (2-phenylethyl) -4-piperidinyl] th i o- urea; mp. 100.6 ° C.

Example 9

Following the procedure of Example 8, the following thiourea derivatives can be prepared by reacting an appropriate 4-piperidinamine with an appropriate 1-isothiocyanate-2-nitrobenzene.

ethyl 4- [methyl - {[(2-nitrophenyl) amino] thioxomethyl} amino] -1-piperidinecarboxylate, ethyl 4- {butyl [(2-nitrophenyl) amine nothioxomethyl] amino} -1-piperidine hydrochloride carboxylate as residue, N-ethyl-N '- (2-nitrophenyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -thiourea, N- (2-nitrophenyl) -Ν' - [1 - (2-phenylethyl) -4-piperidinyl] -Ν'-propyl-thiourea; mp. 90.3 ° C, N-cyclopropyl-Ν '- (2-nitrophenyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -thiourea; mp. 150.1 ° C and cis + trans-methyl-3-methyl-4 - [{[(2-nitrophenyl) amino] thioxomethyl} amino] -1-piperidinecarboxylate; mp. 157.5 ° C.

20

Example 10

A mixture of 43 parts of N- (1-methylethyl) -N '- (2-nitrophenyl) -N- [1-2-phenylethyl) -4-piperidinyl] thiourea and 800 parts of methanol is saturated with ammonia, hydrogenated at normal pressure and at room temperature with 6 parts 25 palladium-on-charcoal catalyst 10% and 6 parts platinum-on-charcoal catalyst 5%. After taking up the calculated amount of hydrogen, the catalysts are filtered off over Hyflo and the filtrate is evaporated to give 39 parts (100%) of N- (2-aminophenyl) -N '- (1-methylethyl) -N' [1- (2-phenylethyl) ) -4-pi peri di nyl] thiourea as residue.

30

Example 11

Following the procedure of Example 10 and using an equivalent amount of a suitable nitro mixture as starting material, it is possible to prepare: ethyl -4 - [{[(2-aminophenyl) amino] th in oxomethyl} methylamino] -1-piperidine B1 dincarboxylate, ethyl -4 - {[(2-aminophenyl) amine nothioxomethyl] butyl amine} -1-pi peridinecarboxylate, N- (2-aminophenyl) -Ν '- [1- (2 -phenyl ethyl) -4-piperidinyl] thiourea, 5 N- (2-aminophenyl) -Ν '- [1- (2-phenylethyl) -4-piperidinyl] -N'propyl - thiourea, N - (2-Aminophenyl) -Ν'-cyclopropyl-N '- [1- (2-phenylethyl) -4-piperidin-yl] thiourea, methyl-4 - {[(2-aminophenyl) amino] thioxomethylamino } -3-methyl-1-pipe-pyridinecarboxylate, N- (2-aminophenyl) -Ν '- [1- (2-phenylethyl) -4-piperidinyl] -Ν' (phenyl methylthiourea as residue.

Example 12 A mixture of 23 parts (phenylmethyl) -4 - [{2 - [(4-fluorophenylmethyl) amino] -3-pyridinylamino} thioxomethylamino] -1-piperidinecarboxylate, 17 parts mercuric oxide, 0.1 part sulfur and 450 parts tetrahydrofuran are stirred and refluxed for 1 hour. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2-oxybispropane. The product is filtered off and dried to give 20 parts (93%) of (phenylmethyl) -4- [3- (4-fluorophenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinecarboxylate; mp. 130 ° C.

Example 13 By following the procedure of Example 12 and using equivalent amounts of the appropriate starting materials, ethyl 4 - [(1H-benzimidazol-2-yl) methylamino] -1-piperidinecarboxyl, 30 ethyl 4 - [(1H-benzimidazol-2-yl) butylamino] -1-piperidinecarboxylate; mp. 225.9 ° C, ethyl 4- [1- (phenylmethyl) -5- (trifluoromethyl) -1H-benzimidazol-2-yl-amino] -1-piperidinylcarboxylate; mp. 200 ° C, ethyl 4- (5-fluoro-1H-benzimidazol-2-ylamino) -1-piperidinecarboxylate; 35 m.p. 227.5 ° C, ethyl 4- [5-chloro-1- (phenyl methyl) -1H-benzimidazol-2-ylamino] -1-piperidinecarboxylate; mp. 211.9 ° C, ethyl 4- [3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinecarboxylate; mp. 148.6 ° C, ethyl 4- [5-chloro-1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinecarboxyl; mp. 215.8 ° C, methyl 4- (1H-benzimidazol-2-ylamino) -3-methyl-1-piperidinecarboxylate; mp. 155 ° C, ethyl 4- [2- (4-fluorophenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] piperidinecarboxylate; mp. 134.4 ° C, ethyl 4 - [(3H-imidazo [4,5-b] pyridin-2-yl) amino] -1-piperine carboxylate; mp. 216.1 ° C, ethyl 4- (1-phenol-ΙΗ-benzimidazol-2-ylamino) -1-piperidinecarboxylate; mp. 137 ° C and ethyl 4- [1- (4-fluorophenyl) -1H-benzimidazol-2-ylamino] -1-piperidine carboxylate; mp. 153 ° C.

Example 14

A mixture of 28 parts of ethyl 4 - {[(2-aminophenyl) aminothioxomethyl] amino} -1-piperidinecarboxylate, 112 parts of iodomethane and 240 parts of ethanol is stirred and refluxed for 8 hours. The reaction mixture is evaporated and the residue is taken up in water. The entire al potassium is extracted with ammonia hydroxide and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol and 2,2'-oxobispropane. The product is filtered off and dried to give 7 parts (28%) of ethyl 4- (1H-benzimidazol-2-ylamio) -1-piperidinecarboxylate.

Following the same procedure and using equivalent amounts of the appropriate starting materials can be prepared; ethyl 4- (5-chloro-ΙΗ-benzimidazol-2-ylamino) -1-piperidinecarboxylate; 30 m.p. 234.1 ° C and ethyl 4- (5-methyl-ΙΗ-benzimidazol-2-ylamino) -1-piperidinecarboxylate. Example 15

A mixture of 19 parts of methyl 4- (ΙΗ-benzimidazol-2-ylamino) -3-methyl-1-piperidinecarboxylate, 11 parts of 1- (chloromethyl) -4-fluorobenzene, 6 parts of sodium carbonate and 135 parts of Ν, Ν-Dimethylformamide is stirred and heated overnight at 70 ° C. The reaction mixture is cooled and poured onto water. The product is extracted three times with methyl benzene. The combined extracts are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96: 4 by volume) as eluent. The pure fractions are combined and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried to give 8 parts (38%) of methyl 4- [1- (4-fluorophenylmethyl) -ΙΗ-benzimidazol-2-ylamino] -3-methyl-1-piperidinecarboxylate; mp. 172.5 ° C.

10

Example 16

Using the procedure of Example 13, the following 4- (1-R2-1H-benzimidazol-2-ylamino) -1-piperidinecarboxylates can be prepared by alkylating the corresponding 4- (1H-benzimidazol-2-ylamino) -1-piperidine -15 carboxylate having a suitable chloride, bromide or iodide of the formula R2X:

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Example 17

A mixture of 7 parts of ethyl 4 - {[5 (6) -fluoro-1- (4-fluorophenylmethyl) -1H-benzimidazol-Z-yl] amino} -1-piperidinecarboxylate and 300 parts of hydrobromic acid 48% in ice cold acetic acid is stirred and refluxed for 1 hour. The reaction mixture is evaporated and the residue is boiled in 2-propanol, 2,2'-oxy-bispropane is added and after cooling the product is allowed to crystallize. It is filtered off and dried to give 7.2 parts (88.2%) of 5 (6) -fluoro-1- (4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide; mp. 285.6 ° C.

10

Example 18

By analogy to the foregoing examples, the following 1- R2-N- (4-piperidinyl) -1H-benzimidazole-2-amines can be prepared by hydrolysis of the corresponding methyl or ethyl-1-piperidinecarboxylates.

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Example 19

A mixture of 20 parts (phenylmethyl) -4- [3- (4-fluorophenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinecarboxylate and 160 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts 5 palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is boiled in 2,2'-oxobispropane. The undissolved product is filtered off and converted to hydrochloride salt in 2-propanol. The salt is filtered off and dried to give 12 parts of 3- (4-fluorophenylmethyl) -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine dihydrochloride monohydrate; mp. 269.7 ° C.

B. PREPARATION OF FINAL PRODUCTS Example 20 A mixture of 2 parts of 2- (bromethoxy) benzene, 3 parts of 1- (phenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine, 2 parts of sodium carbonate, 0.1 part potassium iodide and 90 part Ν, Ν-dimethylformamide are stirred overnight at 70 ° C. The reaction mixture is cooled and poured into water. The product is extracted with methyl benzene. The extract is dried, filtered and evaporated.

The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 3.5 parts (70%) of N- [1- (2-phenoxyethyl) -4-piperidinyl] -1- (phenylmethyl) -1H-benzimidazole-2-amine dihydrochloride monohydrate; mp. 197.6 ° C.

Example 21

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Example 22

A mixture of 2.4 parts (2-bromethyl) benzene, 6 parts 5 (6) fluoro-1- (4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide, 4 parts sodium carbonate, 0.2 parts potassium iodide and 240 parts 4-methyl-2-5 pentanone are stirred and refluxed overnight using a water separator. The reaction mixture is cooled and poured onto cold water. The layers are separated and the aqueous phase is extracted three times with trichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. The pure fractions are combined and the eluent is evaporated. The residue is separated by column chromatography over silica gel using a mixture of ethyl acetate and methanol (93: 7 by volume) as eluent. The first fraction (A isomer) is collected and the eluent is evaporated. The residue is washed with a mixture of 2,2'-oxybispropane and petroleum ether and dried to give 1 part (17.5%) of 6-fluoro-1- (4-fluorophenylmethyl) -N- [1- (phenylethyl) -4 piperidinyl] -LH-benzimidazol-2-amine; mp. 178.1 ° C.

The second fraction (B isomer) is collected and the eluent is evaporated. The residue is washed with a mixture of 2,2'-oxybispropane and petroleum ether 20 and dried to give 1.2 parts of 5-fluoro-1- (4-fluorophenylmethyl) -N- [1- (2-phenylethyl) -4-piperidinyl ] -1H-benzimidazole-2-amine monohydrate; mp.

188.8 ° C.

Example 23 A mixture of 4 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methyl-ethenyl) -2H-benzimidazol-2-one, 7 parts of 1- (phenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide, 5 parts sodium carbonate, 0.1 parts potassium iodide and 135 parts N, N-dimethyl formamide are stirred and heated overnight at 70 ° C. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in 2-propanol. After stirring for one hour, the solvent is evaporated and the residue is taken up in water. The free base is conventionally released with ammonia hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried to give 3.3 parts (45.7%) of 1,3-dihydro-1- [3- {4- [1- (phe-nylmethyl) -1H-benzimidazole-2 ylamino] -l-piperidinyl} propyl] -2H-benzimi-imidazole-2-one; mp. 243.1 ° C.

Following the same procedure and using equivalent amounts of the appropriate starting materials, it is possible to prepare: 1- [3- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-pipe ridinyl} propyl] -l, 3-dihydro-2H-benzimidazol-2-one; mp. 237.6 ° C.

L- [3- {4- [L- (4-fluorophenylmethyl) benzimidazole-2-ylamino] -3-me-thyl-l-piperidinyl} propyl] -l, 3-dihydro-2H-benzimidazol-2 -on dihydrochloride. 2-propanolate; mp. 244.1 ° C, 1- [3- {4- [3- (fluorophenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinyl} propyl] -1,3-dihydro -2H-benzimidazol-2-one; mp. 202.4 ° C, 1,3-dihydro-1- {3- [4- (1-phenyl-1H-benzimidazol-2-ylamino] -1-piperidinyl] propyl} -2H-benzimidazol-2-one; .l85,3 ° C.

1- [3- {4- [1- (4-fluorophenyl) -1H-benzimidazol-2-ylamino] -1-piperidin-yl] propyl} -2H-benzimidazol-2-one; mp. 188.9 ° C and 1,3-dihydro-1- [3- (4- [3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinyl} propyl] -2H-benzimidazol-2-one, mp 221.7 ° C.

Example 24

A mixture of 2.3 parts of 2- (4-methoxyphenylethylmethanesulfonate, 4.9 parts of 1 - [(4-fluorophenyl) methyl] -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide, 3.2 parts Sodium carbonate, 0.1 part potassium iodide and 90 parts Ν, Ν-dimethylformamide are stirred overnight at 70 ° C. The reaction mixture is poured onto water. The product is extracted with methyl benzene. The extract is washed with water, dried, filtered and evaporated. over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are combined and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane to give 2.2 parts (48%) of (4-fluorophenylmethyl) -N- (1- [2- (4-methoxy-phenyl) ethyl] -4-piperidinyl) -1H-benzimidazol-2-amine; mp 172.9 ° C.

Example 25

Following the procedure of Example 24 and using 35 equivalent amounts of the appropriate starting materials, the following mixtures can be obtained in free base form or in the form of an acid addition salt after reacting the free base with a suitable acid.

R

at71- (chu-fyimJ 'T)] * \ _ /' N ^ 'Q> i2 2 Base-el-melt

Aryl R R Q clay sait_ point ___, ____; __- forju__ 3.4- (CH30) -C6H3 H 4-F-C6H4-CH2 CH base 69.3 * C.

E, 5- (CH30) 2-C6H3 H 4-F-C6H4-CH2 CH base 127.9 ° C

4- (C, H_0) C, H. H 4-F-C, H -CH, CH base 152.3 * C

4- (CH30) -C6H4 H 4-F-C6H4-CH2 N base 149.1 ° C

3- (CH10) -C, H H 4-F-C, H -CH, CH 2HC1.1 / 2 242.4 * C

3 64 ___. 6 4 2 H ^ Q

2- (CH30) -C6H4 H 4-F-C6H4-CH2 CH base 153, 1 * C

4- (CH, O) -C, H. CH, 4-F-C, H -CH, CH 2HC1 184, 0eC

3 6 4 3 6 4 2 [cis + trans isomer)

3.4 * 5- (CH, O), - C, H, H 4-F-C, H-CH, CH 2HC1.1 / 2 260.2 * C

3 3 6 2 6 4 ώ H20

3.4- (CH30) 2-C6H3 H 'C6H5-CH2 CH base 149, 8 ° C

4. (CHO) -C, H CH3 C6H5-CH2 CH ZHCLH2O 198, 4 * C

(0 cis + txans isomer)

3- (CH30) -C6H4 H C6H5-CH2 CH base 128, 6 ° C

4- (C2H.O) -C6H4H C6H5-CH2 CH base 128, 5 ° C

2- (CH2 O) -C, H. . H C, H -CH, CH 2 HCl. 186, 1 ° C

3.64 65 2 2H ^ 0

3- (CH3) -C6H4 H C6H5-CH2 CH 2HC1.H2O 235.7 ° C

4- (CH30) -C6H4 H C6H5-CH2 CH 2HC1.H20 274, 7 * C

4-Cl-C6H4 H C6H5-CH2 CH base 183, 9 ° C

3,4,5- (CH30) 3-C6H2 H C6H5-CH2 CH base 156,6 ° C

4 - (<3 HCl 2 O) -C6H4 H 4-F-C6H4-CH2 CH base 155, 4 * C

4-CH30-C6H4 H C6H5 CH base 157, 8 ° C

4-CH30-C6H4 H 4-F-C6H4 CH base 167, 4eC

4: -CH30-C6H4H 4-NO2-C6H4-CH2 CH base 200, leC

39 DK 171841 B1

Aryl R R2 Q? Jreia! T: Melt _________ (glue point

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.. 3 2 6 3 · 6 4 2 .1 / 2H20

4-CH-O-C / Η. H 4-F-2-CH, - CH 2 HBr 264.8 ° C

3 6 4 3 · c6h3-ch2

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3-CH3-4-

(C6H5-CH2-O) -C6H3 H 4-F-C6H4-CH2 CH base 145.6 ° C

15 H CH 2 HCl * 264.6 ° C

Example 26

A mixture of 2.8 parts of [2- (2-thienyl) ethyl] -4-methylbenzenesulfonate, 4.9 parts of 1- [4-fluorophenyl) methyl] -N- (4-piperidinyl) -1H-benzimidazole -2-amine dihydrobromide, 2.1 parts sodium carbonate, 0.1 parts potassium iodide and 90 parts N, N-dimethyl formamide are stirred overnight at 70 ° C. The reaction mixture is cooled and poured onto water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried to give 2.3 parts (53%) of 1- (4-fluorophenylmethyl) -N- {1- [2- (2-thienyl) ethyl] -4-piperidin-yl) -1H-benzimidazole -2-amine; mp. 151.6 ° C.

Following the same procedure and using equivalent amounts of the appropriate starting materials, it is possible to prepare: 1- (phenylmethyl) -N- {1- [2- (2-thienyl) ethyl] -4-piperidinyl} -1H- benzimidazole-2-amine dihydrochloride monohydrate; snip.259 273 ° C, 1- (4-fluorophenylmethyl) -N- {1- [2- (1-napthienyl) ethyl] -4-piperidin-yl} -1H-benzimidazol-2-amine; mp. 143.1 ° C and 3- (4-fluorophenylmethyl) -N- {1- [2- (2-thienyl) ethyl] -4-piperidinyl} -5H-imidazo [4,5-b] pyridin-2 amine; smp.l76,2 ° C.

Example 27

A mixture of 2.1 parts of 2- (ethenylpyridine, 3.25 parts of 1 - [(4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine and 80 parts of 10-butanol is stirred and refluxed The reaction mixture is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as the eluent. The pure fractions are collected and the eluent is evaporated. to give 1 part 15 (23%) of 1 - [(4-fluorophenyl) methyl) -N- {1- [2- (2-pyridinyl) ethyl] -4-piperidinyl} -1H-benzimidazole-2 amine, mp 133.4 ° C.

Following the same procedure and using equivalent amounts of the appropriate starting materials, it is also possible to prepare: 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidine-propannitrile; mp. 166.5 ° C, 1- (4-fluorophenylmethyl) -Ν- {1 - [- [2- (4-pyridinyl) ethyl] -4-piperidin-1-yl} -1H-benzimidazol-2-amine; mp. 158.2 ° C and 3- (4-fluorophenylmethyl) -N- (1- [2- (2-pyridinyl) ethyl] -4-piperidinyl) -3H-imidazo [4,5-b] pyridine-2 amine; mp. 157.2 ° C.

Example 28

To 3.96 parts of 1- (4-fluorobenzoyl) aziridine, dissolved in 16 parts of benzene, are added 3.25 parts of 1 - [(4-fluorophenyl) methyl] -N- (4-piperidinyl) -1H-benz-30 imidazole-2-amine, 90 parts of benzene and 45 parts of N, N-dimethyl formamide. It is all stirred and refluxed for 5 hours. The reaction mixture is cooled and poured onto water. The layers are separated and the aqueous phase is extracted with methyl benzene. The combined phases are dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane to give 1 part (19%) of 4-fluoro-N- [2- (4- [1- (4-fluorophenylmethyl) -1H) benzimidazole-2-ylamino] -1-piperidinyl) ethyl] benzamide; mp. 193.7 ° C.

41 DK 171841 B1

Starting from 3- (phenylmethyl) -N- (4-piperidinyl) -3H-imidazo [4,5- b] pyridin-2-amine and using the same process, 4-fluoro-N- [2- {4- [3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinyl} ethyl] benzamide; mp. 187.5 ° C.

Example 29

A mixture of 3.6 parts of [(4-methoxyphenoxy) methyl] oxirane, 4.9 parts of 10 - [(4-fluorophenyl) methyl] -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide, 2.1 parts of sodium carbonate, 40 parts of methanol and 90 parts of benzene are stirred and refluxed overnight, the reaction mixture is filtered and the filtrate is evaporated, the residue is crystallized from a mixture of 2-propane and 2,2'-oxybispropane. The product is filtered off and dried to give 2.6 parts (51%) of 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -a- (4-methoxyphenoxymethyl) -1-piperidinethanol; mp 174.5 ° C.

Example 30

Following the procedure of Example 29 and using 20 equivalent amounts of the appropriate starting materials, it is also possible to prepare: α- (phenoxymethyl) -4 - {[1- (phenylmethyl) -1H-benzimidazol-2-yl] amino} - 1-piperidineethanol; mp. 146.6 ° C, 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -t- (phenoxymethyl) -1-piperidinethanol; mp. 181.3 ° C, 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -3-methyl-ar- (phenoxymethyl) -1-piperidinethanol dihydrochloride monohydrate; mp.

163.3 ° C, or- (4-methoxyphenoxymethyl) -4- [1- (phenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol; mp. 162.7 ° C, α- (2-butoxyphenoxymethyl) -4- [1- (4-fluorophenyl methyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol; mp. 138.7 ° C, α- (2,6-dimethoxyphenoxymethyl) -4 - [(4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol; mp. 140 ° C, 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -α- (2methoxy-phenoxymethyl) -1-piperidinethanol; mp. 174 ° C, 1- {4- [3- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} -2-hydroxypropoxy] phenyl} ethanone; mp. 174.7 ° C, α- (2,6-dimethoxyphenoxymethyl) -4- [1- (phenylmethyl) -ΙΗ-benzimidazol-2-ylamino] -1-piperidinethanol; mp. 122.2 ° C, 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -α-phenyl-1-piperidinethanol; mp. 184.1 ° C and α- (phenoxymethyl) -4- [3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinethanol; mp. 136.6 ° C.

10

Example 31

To a stirred mixture of 40.4 parts of 1- (4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine hydrobromide and 400 parts of methanol is added 8.8 parts of oxirane and stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is taken up in water.

The precipitated product is filtered off and dried to give 29 parts (64%) of 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidine-ethanol monohydrobromide; mp. 248.2 ° C.

Example 32

To 1 part solution of 2 parts thiophene in 40 parts ethanol is added 1.5 parts formaldehyde solution 37%, 3 parts 1- (phenylmethyl) -N- (4-piperidin-yl) -1H-benzimidazole-2-amine and 120 parts methanol . It is all hydrogenated at normal pressure and at room temperature with two parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over Hyflo and the filtrate is evaporated. The residue is taken up in water and the whole is potassized with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in 2-propanol. The salt is filtered off and dried to give 1.5 parts (36.6%) of N- (1-methyl-4-piperidinyl) -1- (phenylmethyl) -1H-benzimidazole-2-amine dihydrochloride monohydrate; mp. 191.1 ° C.

Following the same procedure and using equivalent amounts of suitable starting materials, it is also possible to prepare: 1- (4-fluorophenylmethyl) -N- (1-methyl-4-piperidinyl) -1H-benzimidazole-2 amine; mp. 145.5 ° C, N- (1-cyclohexyl-4-piperidinyl) -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine; mp. 168 ° C, 1- (4-fluorophenyl methyl) -N- [1- (1-methyl-2-phenylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 182.4 ° C, 1-methyl-N- (1-methyl-4-piperidinyl) -1H-benzimidazole-2-amine dihydrochloride dihydrate; mp. 300.6 ° C, 1-ethyl-N- [1-methylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; 10 m.p. 156.6 ° C.

N- (1-methyl-4-piperidinyl) -1-phenyl-1H-benzimidazol-2-amine; mp.

128.5 ° C.

3- (4-fluorophenylmethyl) -N- (1-methyl-4-piperidinyl) -3H-imidazo [4,5- b] pyridin-2-amine; mp. 153.4 ° C and N- (1-methyl-4-piperidinyl) -3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-amine; mp. 141.4 ° C.

Example 33

To 1 part solution of 2 parts thiophene in 40 parts ethanol are added 2 20 parts cyclohexanone, 3 parts 1- (phenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine, 1 part acetic acid and 120 parts methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off over Hyflo and the filtrate is evaporated. The residue is taken up in water and the whole is alkalized with sodium hydroxide. The product is extracted with tetrahydrofuran. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol to give 1.5 parts (38.5%) of N- (1-cyclohexyl-4-piperidinyl) -1- (phenylmethyl) -LH-benzimidazol-2-amine; mp. 143 ° C.

Following the same procedure and using equivalent amounts of the appropriate starting materials, it is also possible to prepare: 1-phenyl-4- {4- [1- (phenyl methyl) -ol-benzimidazol-2-ylamino] -1 piperidinyl} cyclohexanecarbonitrile; mp. 106-107 ° C, 4- {4- [1- (4-fluorophenylmethyl] -1H-benzimidazol-2-ylamino] -1-piperidinyl) -1-phenylcyclohexanecarbonitrile dihydrochloride; mp. 275 ° C, DK 171841 B1 44 1- [3- {4- [1- (4-Fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} butyl] -1,3-dihydro-2H benzimidazole-2-one; mp. 234 ° C, N- (1-cyclohexyl-4-piperidinyl) -3- (phenylmethyl) -3H-imidazo [4,5- b] pyridin-2-amine; mp. 129.2 ° C, 5 N- [1- (1-methylethyl) -4-piperidinyl] -3- (phenylmethyl) -3H-imidazo- [4,5-b] pyridin-2-amine; mp. 136.4 ° C and 1- (4-fluorophenylmethyl) -N- [1- (2 - [(phenylmethyl) amino] ethyl) 4-piperidine] -1H-benzimidazol-2-amine; ° C.

Example 34

A mixture of 39.8 parts of N- (Z-aminophenyl) -N'-ethyl-N '- [1- (2-phenylethyl) -4-piperidinyl] thiourea, 15 parts of mercuric oxide, 0.1 part of sulfur and 400 parts of methanol are stirred and refluxed overnight. The reaction mixture is filtered hot over Hyflo and the filtrate is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried to give 14.5 parts (43%) of N-ethyl-N- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 204.9 ° C.

Following the same procedure and using equivalent amounts of the appropriate starting materials, 20 N- [1- (2-phenyl ethyl) -4-piperidinyl] -N-propyl-1H-benzimidazole-2-amine can also be prepared. , N- (1-methylethyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 228.4 ° C, N-cyclopropyl-N- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 193.5 ° C, N- [1- (2-phenyl ethyl) -4-piperidinyl] -N- (phenyl methyl) -1H-benzimidazol-2-amine; mp. 191.5 ° C.

Example 35

To a stirred and cooled mixture (below 5 ° C) of 3.3 parts of N-methyl- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazole-2-amine, 100 parts of dimethylsulfoxide and 90 part of benzene is added 0.5 part of sodium hydride dispersion 50%. After stirring for 30 minutes, 1.5 parts of 1- (chloromethyl) -4- 35 fluorobenzene are added and stirring is continued overnight while allowing the mixture to reach room temperature. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in 2-propanone.

The salt is filtered off and crystallized from 2-propanol to give 2.8 parts (54.4%) of 1 - [(4-fluorophenyl) methyl] -N-methyl-N- [1- (2-phenylethyl) -4- 5-piperidinyl] -1H-benzimidazole-2-amine dihydrochloride; mp. 246.6 ° C.

Following the same procedure and using equivalent amounts of the appropriate starting materials, it is also possible to prepare: 1 - [(4-chlorophenyl) methyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -N -10 (phenylmethyl) -1H-benzimidazole-2-amine; mp. 138 ° C, 1 - [(2-methoxyphenyl) methyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; mp. 148.3 ° C, 1 - [(4-methoxyphenyl) methyl3-N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; mp. 122.4 ° C, 1 - [(4-fluorophenyl) methyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; 108.5 ° C, 1- (4-bromophenylmethyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; mp 139, 3 ° C, 1 - [(4-methylphenyl) methyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -N-20 (phenylmethyl) -1H-benzimidazole-2-amine; 123.4 ° C, 1- (2-Chlorophenylmethyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; mp 105.5 ° C, 1-butyl-N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine, mp 76.5 ° C and 1-ethyl- N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazole-2-amine dihydrochloride dihydrate, mp 157.2 ° C.

Example 36

A mixture of 1.6 parts of 1- (1-chloroethyl) -4-fluorobenzene, 3.2 parts of N-30 [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazole-2-amine, 1 part sodium carbonate, 0.1 part potassium iodide and 120 parts 4-methyl-2-pentanone are stirred and refluxed overnight with water separator. The reaction mixture is cooled, poured into water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over 35 silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. Oe pure fractions are collected and the eluent is evaporated.

46 DK 171841 B1

The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried to give 1.8 parts (40.7%) of 1- [1- (4-fluorophenyl) ethyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -1H- benzimidazol-2-amine; mp.

161.7 ° C.

5

Example 37

Following the procedures of Examples 35 and 36 and using equivalent amounts of the appropriate starting materials, the following compounds are obtained in free base form or in the form of an acid addition salt 10 after reacting the free base with an appropriate acid (

R

DK 171841 B1 47 R * R2 Base or salt forerene Melting point

H C ^ Hg-iCH ^ base 136tl * C

H 4-F-C6H4- (CH2) 2 base 151.5 * 0

H (4-F-C6H) -CH (C6iy2HCLH2O 239.6 ° C)

H 144 - CH 2 base 127.6 * 0 H C 6 H 5 -CH (CH 3) 2 H C 1 H 2 O 239.9 * 0 H - (4-F-C 6 H 4) 2CH base * 172.5 * 0 H 2- (CH30) -C6H4-CH2 base 128.5 * 0

CH3 2- (CH30) -C6H4-CH2 2HNO3 169.7 ° C

CH3. 2-C1-C6H4-CH2 2HC1 251.2 * C

CH3 4-Br-C6H4-CH2 .2HCLHzO 187.1 * 0 CH3 4- (CH30) -C6H4-CH2 2HNO3 163.5 * 0

CH3 C&H -CH2 2HC1 243.1 * C

CH3 4- (CH3) -C6H4-CH2 2HNO3 175.3 * 0 CH, 4-Cl-C, H-CH, 2HC1 251.3 * 0 3 6 4 2 * CH3 a-c4H9 2HC1 257.9 * 0 CH3 C2H5 2HC1.H2O 243.1 * 0 C2H5 C6H5-CH2 base 115.8 * 0

C2H5 C2H5 base 93.2 ° C

"ϊθ3Η? C6" H -CH2 2HC1.H20 159.4 * 0 nC3H7aC4H * (COOH) 2 177.5 * 0 nC3H7C2H5 2HC1 160.7 * 0 iC3H? C2H5 2HC1.1AH20 206.8 * 0

iC3H? C 6 H 5 -CH 2 CCOOH) 215.6 ° C

1C3H7 nC4H9 (COOH) 2 198.0 * 0 nC.H-C, H_-CH_ 2HC1.2H, 0 160.0 * 0 4 9 o 5 c. U aC4H9 4 "Br-c6Ii4-CH2 2HC1.2H ^ O - 137.2 * 0 nC.H nC.Hn 2HCL2H, 0 138.7 * 0 4 9 4 9 2 '

nC.Hn 4-F-C, H-CH 2HC1.2H, 0 135 5 * C

4 9 o 4 Z Z · - <^ J 21101.21 ^ 0 123.8 * 0 48 DK 171841 B1

Example 38

A mixture of 3.2 parts of N- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazole-2-amine, 2.9 parts of [2- (2-thienyl) ethyl] -4-methylbenzenesulfonic acid overnight, 1 part sodium carbonate and 135 parts of 4-methyl-2-pentanone are stirred and refluxed overnight with water separator. The reaction mixture is poured into water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanone to give 1 part (23.2%) of N- [1- (2-phenylethyl) -4-piperidinyl] -1- [2 - (2-thienyl) ethyl] -LH-benzimidazol-2-amine; mp. 118.3 ° C.

Example 39 To a stirred and boiled mixture (below 5 ° C) of 4 parts of N- [1- (2-phenylethyl) -4-piperidinyl] -1- (phenylmethyl) -1H-benzimidazole-2-amine, 100 parts dimethyl sulfoxide and 90 parts of benzene are added 0.5 parts of sodium hydride dispersion 50%. After stirring for 30 minutes at a temperature below 5 ° C, 1.3 parts (chloromethyl) benzene are added and stirring is continued for 4 hours while allowing the mixture to reach room temperature. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to nitrate salt in 2-propanone. The salt is filtered off and dried to give 1.5 parts (24%) of N- [1- (2-phenylethyl) -4-piperidinyl] -N, 1-bis- (phenylmethyl) -1H-benzimidazole -2- amine dinitrate; mp. 156.9 ° C.

Example 40

To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol is added 3.3 parts of 1- (4-fluorophenylmethyl) -N- {1- [2- (4-nitrophenyl) ethyl] -4-piperidinyl} - 1H-benzimidazole-2-amine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column chromatography over sieve in cage! using a mixture of methylbenzene and methanol (95: 5 by volume) saturated with ammonia as eluent. t) e pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol to give 1.3 parts (42%) of N- {1- [2-5 (4-aminophenylethyl] -4-piperidinyl) -1- (4-fluorophenylmethyl) -1H-benzimidazole -2-amine; mp. 195.4 ° C.

Following the same hydrogenation process and starting with the corresponding nine faith compound, it is also possible to prepare: 1 - [(4-aminophenyl) methyl] -N- [1- [2- (4-methoxyphenyl) ethyl] -4-piperidine - dinyl] -1H-benzimidazole-2-amine monohydrate; mp. 142.6 ° C.

Example 41

A mixture of 7.5 parts of 1- (4-fluorophenylmethyl) -N- [1- {2- [4 (phenyl-methoxy) phenyl] ethyl) -4-piperidinyl] -1H-benzimidazole-2-amine and 120 parts of methanol are hydrogenated at normal pressure and at room temperature with 2 parts palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is suspended in 2,2'-oxybispropane. The product is filtered off and dried to give 5.5 parts (88.5%) of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamine] -1-piperidinyl} ethyl] phenolhemihydrat; mp.

111.6 ° C.

Following the same hydrogenation process and starting with 1- (4-fluorophenylmethyl) -N- [1- {2- [3-methyl-4- (phenylmethoxy) phenyl] ethyl] -4-piperidinyl] -1H- benzimidazol-2-amine may also be prepared 4- (2- [4 - {[1- (4-fluorophenylmethyl) -1H-benzimidazol-2-yl] amino) -1-piperidin-yl] ethyl} -2-methylphenol dihydrochloride monohydrate; mp. 277.8 ° C.

A mixture of 8 parts of 1- (4-fluorophenylmethyl) -N- {1- [2- (3-methoxy-phenyl) ethyl] -4-piperidinyl) -1H-benzimidazole-2-amine and 255 parts of a hydrobromide acetic acid solution 48% in acetic acid is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is taken up in the water.

The free base is conventionally released with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol (98: 2 by volume) and then a mixture of trichloromethane and methanol (95: 5 50 DK 171841 B1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 0.8 part (9%) of 3- [2- {4- [1- (4-fluoro-phenylmethyl) -1H-benzimidazol-2-ylalimino] -1-piperidinyl) ethyl] phenol Dihydrochloride monohydrate; mp. 209.8 ° C.

Example 42

A mixture of 1.2 parts of 3-bromo-1-propene, 4 parts of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] pheanol, 1.4 parts potassium carbonate and 160 parts 2-propanone are stirred and refluxed overnight. The reaction mixture is filtered and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent.

The pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 1 part (19.9%) of 1- (4-fluorophenylmethyl) -N- [1- {2- [4- (2-propenyloxy) phenyl] ethyl} -4-piperidinyl] -1H-benzimidazole-2-amine dihydrochloride; mp. 224.7 ° C.

Example 43

A mixture of 15 parts of thionyl chloride, 4 parts of 4- [1- (4-fluorophenyl-methyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol dihydrochloride and 375 parts of trichloromethane is stirred and refluxed overnight. The precipitated product is filtered off and dried to give 13 parts (83%) of N- [1-25 (2-chloroethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine dihydrochloride; mp. > 260 ° C.

Example 44

A mixture of 0.9 parts of morpholine, 4.8 parts of N- [1- (2-chloroethyl) -4-30 piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine dihydrochloride, 3 parts sodium carbonate , 0.1 part potassium iodide and 135 parts N, N-dimethylformamide are stirred and heated overnight at 70 ° C. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane to give 0.6 part (12.5%) of [2 {4- [1- (4-fluorophenylmethyl) -1H-benzimidazole-2 -ylamino] -1-piperidinyl] ethyl] -4-morpholinecarboxylate; mp. 144.8 ° C.

5

Example 45

A mixture of 3.6 parts of morpholine, 4.8 parts of N- [1- (2-chloroethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine dihydrochloride, 1 part potassium iodide and 135 parts N, N, -dimethylformamide are stirred and heated overnight at 70 ° C. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in methanol. The salt is filtered off and dried to give 1 part (18.3%) of 1- (4-fluorophenylmethyl) -Ν- {1- [2- (4-morpholinyl) ethyl] -4-piperidinyl) -1H-benzimidazole 2-amine trihydrochloride; mp. + 300 ° C.

Example 46

To a stirred mixture of 4.5 parts of 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol, 2 parts of N, N-diethylethanamine 20 and 195 parts of dichloromethane is added dropwise to a solution of 1.7 parts of 4-methoxybenzoyl chloride in dichloromethane. After completion, stirring is continued overnight at room temperature. Water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent.

The pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 2.5 parts (43.5%) of [2- {4- [1- (4-fluorophenylmethyl) -1H-benz-imidazol-2-ylamino] -1-piperidinyl) ethyl] -4-methoxybenzoate dihydrochloride hemihydrate; mp. 189.2 ° C.

By following the same procedure and using equivalent amounts of the appropriate starting materials, it is also possible to prepare: (4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-yl amino] -1- (piperidinyl) ethyl] phenyl) benzeneacetate; mp. 135.1 ° C, (4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl] ethyl] phenyl} 4-methoxybenzoate; 157.1 ° C, {4- [2- {4- [1- (4-fluorophenylmethyl} -1H-benzimidazol-2-ylamino] -1-piperidinyl) ethyl] phenyl} methyl carbonate; mp 134, 5 ° C and {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenyl} - (phenylmethyl) carbonate; 147.8 ° C.

Example 47

A mixture of 1.2 parts of chloroacetonitrile, 6.7 parts of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl] ethyl] phenol, 2 , 8 parts potassium carbonate and 160 parts 2-propanone are stirred and refluxed overnight. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 7.4 parts (78.6%) of {4- [2- {4 [1- (4-fluoro-phenylmethyl) -1H-benzimidazol-2-ylamino] -1- piperidinylethylphenoxyJ-acetonitrile dihydrochloride monohydrate; mp. 224.6 ° C.

By following the same process and using equivalent amounts of the appropriate starting materials, it is possible to prepare; Ethyl 2- {4- [2- {4- [1- (4-fluorophenyl methyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenoxy} acetate; mp. 109.1 ° C, methyl 2- {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenoxy} acetate; mp 109.8 ° C, 1- [2- {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -25-piperidinyl} ethyl] phenoxy} acetyl ] piperidine dihydrochloride; mp. 247 ° C.

Example 48

A mixture of 0.5 parts of isocyanatomethane, 4.5 parts of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenol and 135 parts of tetrahydrofuran are stirred overnight at room temperature. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, which gives 1 part (20%) of {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazole]. 2-ylamino [1-pi peridinyl] ethyl] phenyl] methyl carbamate; mp. 172.2 ° C.

53 DK 171841 B1

By addition reaction of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] -phenol to 1-isocyanobutane can also be prepared: 5 {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenyl} butylcarbamate; mp. 142.5 ° C.

Example 49

A mixture of 9 parts of 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidine acetonitrile and 200 parts of methanol, saturated with ammonia, is hydrogenated at normal pressure and at room temperature with 3 parts of Ra ney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from a mixture of 2-propanone and methanol to give 11 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole -2-amine trihydrochloride; mp. 292.9 ° C.

Using the same hydrogenation process and starting with 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinopropanitrile, N- [1- (3-aminopropyl) can also be prepared ) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine trihydrochloride monohydrate; mp. 239.3 ° C.

Example 50 A mixture of 1.8 parts of 1-isothiocyanato-2-nitrobenzene, 3.7 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimida -zol-2-amine and 135 parts of tetrahydrofuran are stirred overnight at room temperature. The reaction mixture is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated to give 3.7 parts (67%) of N- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] -N / - (2-nitrophenyl) thiourea as residue.

A mixture of 3.7 parts of N- [2- {4- [1- (4-fluorophenylmethyl) -1Hbenz-imidazol-2-ylamino] -1-pioeridinyl} ethyl] -N '- (2-nitrophenyl) thi 7 parts of iron powder, 0.25 parts of concentrated hydrochloric acid, 48 parts of ethanol and 15 parts of water are stirred and refluxed for 1 hour. The reaction mixture is alkalized and the filtrate is evaporated to give 3.5 parts of N- (2-aminophenyl) -N '. [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] - 1-piperidinylethyl) thiourea as residue.

A mixture of 3.5 parts of N- (2-aminophenyl) -N '- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinylethyl] thi our nitrogen, 2.2 parts of mercuric (II) oxide, 0.1 parts of sulfur and 80 parts of ethanol are stirred and refluxed for 1 hour. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is purified by column chromatography over si 1 in -10 cage! using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanone to give 1.5 parts (44.4%) of N- {1- [2- (1H-benzimidazol-2-ylamino) ethyl] -4-piperidinyl} -1- (4 -fluorphenylmethyl) -LH-benzimidazol-2-amine; mp. 253.4 ° C.

15

Example 51

A solution of 4.77 parts of N- [1-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine trihydrochloride in methanol saturated with ammonia is stirred for 1 hour at room temperature. The solvent 20 is evaporated and the residue is taken up in 135 parts of tetrahydrofuran. Then 6 parts of isocyanatomethane are added and the whole is stirred overnight at room temperature. The precipitated product is filtered off and dried to give 3 parts (70.7%) of N- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl } ethyl] -Ν'-methyl urea hemi hydrate; mp.

231.4 ° C.

Example 52

To a stirred mixture of 3.8 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine, 1 part N, N-diethyl -30 ethanamine and 195 parts of dichloromethane are added dropwise to a solution of 1.7 parts of 4-methoxybenzoyl chloride in dichloromethane. When done, stirring is continued overnight at room temperature. The reaction mixture is poured into water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel 35 using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride salt in 2-propanol. The salt is filtered off and dried to give 1 part of N- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] -4-methoxy-N- (4-methoxybenzoyl) benzamide dihydrochloride di hydrate; mp. 161.5 ° C.

5

Example 53

To a mixture of 2 parts of thiophene in 40 parts of ethanol is added 1 part of paraformaldehyde, 3.5 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluoro-phenylmethyl) -1H-benzimidazole 2-amine and 120 parts of methanol. The entire hy-10 is dehydrated at normal pressure and at room temperature with 2 parts of pal ladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxobispropane to give 1.5 parts (42%) of N- {1- [2- (dimethylamino) ethyl] -4-piperidinyl) -L- (4-fluorophenylmethyl) -1H-benzimidazol-2-amine; mp. 166.1 ° C.

Example 54 To 2.5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol are added 2.5 parts of benzaldehyde, 3.7 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4- fluorophenylmethyl) -1H-benzimidazole-2-amine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen 25 is taken up, the catalyst is filtered off over Hyflo and the filtrate is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and taken up in water. The free base is conventionally released with ammonium hydroxide and extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane to give 1.5 parts (27.5%) of N- [1- {2- [bis (phenylmethyl) amino] ethyl} -4-piperidinyl] -L- (4-fluorophenyl-methyl) -LH-benzimidazol-2-amine; mp. 116.4 ° C.

Example 55 A mixture of 5.5 parts of N- [1- (1H-benzimidazol-2-yl) -4-piperidinyl] -1- (phenylmethyl) -1H-benzimidazole-2-amine dinitrate, 1.5 parts of 1- (chloromethyl) -4-fluorobenzene, 5 parts sodium carbonate, 0.1 parts potassium iodide and 120 parts 4-methyl-2-pentanone are stirred and refluxed overnight using a water separator. The reaction mixture is poured into water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried to give 1.5 parts (28.3%) of N- {1-10 [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-yl] -4-piperidinyl} -1 - (phenyl-methyl) -1H-benzimidazole-2-amine; mp. 163.9 ° C.

Example 56

A mixture of 3.7 parts of 1- (4-fluorophenylmethyl) -N- {1- [3- (4-methoxy-phenylthio) propyl] -4-piperidinyl} -1H-benzimidazole-2-amine, 2.42 parts of hydrogen peroxide solution 30% and 20 parts acetic acid are stirred and refluxed for 1 hour. The reaction mixture is cooled and poured into ice water. The entire alkali is extracted with 50% sodium hydroxide solution and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to ethanedioate salt in methanol and 2-propanol. The salt is filtered off and dried to give 0.8 part (16%) of 1- (4-fluorophenylmethyl) -N- {1- [3- (4-methoxyphenylsulfonyl) propyl] -4-piperidinyl} -1H-benz -imidazole-2-aminethanedioate (1: 2); mp. 213.1 ° C.

Example 57

A mixture of 5 parts of ethyl 2- {4- [2- 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenoxy acetate, 70 parts of ethanamine solution 50% and 40 parts of methanol are stirred for 3 hours at room temperature. The reaction mixture is evaporated and the residue is crystallized twice from 2-propanol to give 1 part (19%) of N-ethyl-2- {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazole-2 -ylamino [1-piperidinyl} -35-ethyl] -phenoxy} -acetamide; mp. 160.9 ° C.

57 DK 171841 B1

Example 58

A mixture of 3.5 parts of methyl 2- {4- [2- 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenoxy acetate, 90 parts concentrated ammonium hydroxide and 40 parts of methanol are stirred for 4 hours at 5 room temperature. The reaction mixture is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol to give 1 part (28.5%) of 2- {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1 piperidinyl) ethyl] phenoxy} acet-amido; mp. 180.4 ° C.

Example 59

To a stirred and cooled mixture (below 10 ° C) of 5.04 parts of carbon disulfide, 2.06 parts of N, N'-methantetraylbis [cyclohexamine] and 45 parts of tetrahydrofuran is added dropwise to a solution of 3.7 parts. N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine in tetrahydrofuran. When done, stirring is continued overnight while the mixture is allowed to reach room temperature. The reaction mixture is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated to give 4 parts (100%) of 1- (4-fluorophenylmethyl) -N- [1- (2-isothiocya-natoethyl) -4-piperidinyl] -1H-benzimidazole-2-amine as residue.

A mixture of 2.1 parts of N- (4-fluorophenylmethyl) -1,2-benzenediamine, 4 parts of 1- (4-fluorophenylmethyl) -N- [1- (2-isothiocyanatoethyl) -4-piperidinyl ] -1H-benzimidazole-2-amine and 90 parts of tetrahydrofuran are stirred and refluxed for 2 hours. The reaction mixture is evaporated to give 6 parts (100%) of N- {2 - [(4-fluorophenylmethyl) amino] phenyl} -N '- [2- {4- [1- (4fluorophenylmethyl) -1H-benzimidazole 2-ylamino] -1-piperidinyl} ethyl] thiourea as residue.

A mixture of 6 parts of N- {2 - [(4-fluorophenylmethyl) amino] phenyl} -N '- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1 -piperidinyl] ethyl) thiourea, 3.2 parts of mercuric (II) oxide, 0.1 parts of sulfur and 90 parts of tetrahydrofuran are stirred and refluxed for 3 hours. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane to give 1.2 parts (20%) of 1- (4-5 fluorophenylmethyl) -N- [1- (2- (1-fluorophenylmethyl) - 1H-benzimidazol-2-yl-amino] ethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 196.9 ° C.

Claims (1)

10 R1 L. R * wherein L 1 is hydrogen, lower alkyloxycarbonyl or phenylmethoxycarbonyl, 15. is hydrogen or methyl, R 1 is hydrogen or lower alkyl of 1 to 6 carbon atoms, R 2 is hydrogen, alkyl of from 1 to 10 carbon atoms, aryl, cycloal alkyl of 3 to 6 carbon atoms, mono- or diphenyl-Cj-lower alkyl, wherein the phenyl group is optionally substituted with 1 to 2 identical or 20 different substituents which are halogen atoms or methyl or nitro groups, R 3 is hydrogen, halogen, methyl or trifluoromethyl, and Q is CH or N.