N-HETEROCYCLYL-4-PIPERIDINAMINES, METHODS FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS COMPRISING THEM, INTERMEDIATES THEREFOR, AND METHOD FOR THE PREPARATION OF THE INTERMEDIATES

Abstract: Novel N-heterocyclyl-4-piperidinamines wherein said heterocyclic radical is an optionally substituted 1H-benz-imidazol-2-yl or 3H-imidazo[4,5-b]pyridin-2-yl radical, said compounds being useful as antihistaminic agents.

Description: BACKGROUND OF THE INVENTION: In U. S. Pat. No. 2,971,005 there are described 2-(phenyl- methylamino(benzimidazoles having local anaesthetic and antifibrillatory properties and in U. S. Pat. No. 2, 857, 391 there are described a number of 2-(aminomethyl)benzimidazoles The compounds of this invention differ therefrom essentially by the nature of the 4-piperidinyl-group, attached to the amino nitrogen atom and by their unexpected antihistaminic properties. Also known in the art is 1-methyl-N-phenyl-N-phenylmethyl-4- piperidinamine, an antihistaminic compound which is generically designated as Bamipine (see the Merck index, 8th edition (1968) p. 118). The compounds of this invention are structurally different since they invariably contain a lH-benzimidazol-Z-yl or 3H imidazos, 5-bvpyridin-2-yl radical, attached to the amino nitrogen atom. DESCRIPTION OF THS PREFERRED EMBODINSENTS: This invention is concerned with a novel series of N-hetero cyclyl-4-piperidinamines which may structurally be represented by the formula: EMI2.1 and the pharmaceutically acceptable acid addition salts thereof, wherein R is a member selected from the group consisting of hydrogen and tower alkyl; R1 is a member selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryllower alkyl and lower alkanoyl; Rê is a member selected from the group consisting of hydrogen, alkyl having from 1 to 10 carbon atoms, aryl, cycloalkyl and monoand diaryl(lower alkyl); R3 is a member independently selected from the group consisting of halo, lower alkyl, lower alkyloxy and trifluoromethyl; n is an integer of from 0 to 2 inclusive; ; Q is a member selected from the group consisting of CH and N; and L is r member selected from the group consisting of lower alkyl, which is optionally substituted with up to 3 substituents each in dependently selected from the group consisting of halo, cyano, hydroxy, isothiocyanato, lower alkyloxy, aryl, arylosy, arylthior arylsulfonyl, amino; lower alkenyl; aryllower alkenyl; cycloalkyl, being optionally substituted with z cyano and/or an aryl group; l-(aryllower alkyl)-1H-benzimidazol-2-yl; and a radical of the formula Z-Cm-H2m-, wherein m is an integer of from 1 to 6 inclusive; and Z is a member selected from the group consisting of 4, 5 dihydro-5-oxo-1H-tetrazol-1-yl, being optionally substitued in its 4-position by an aryl radical or a lower alkyl radical; 2, 3-dihydro-1, 4-benzodioxin-2-yl; t, 3-dihydro-1, 4-benzo dioxin-6-yl; 2, 3-dihydro-2-oxo-1H-benzimidazol-1-yl; 2, 3 dihydro-3-oxo-4H-benzixazin-4-yl; (10,11-dihydro-5H-di benzo[a,d]cycloheptan-5-ylidene)methyl; 4-morpholinyl; 1 -piperidinyl; 1 -pyrrolidinyl; a radical of the formula T-N(R4)-, wherein R4 is a member selected from the group consisting of hydrogen, lower alkyl and aryllower alkyl; and T is a member selected from the group consisting of lower alkyl, aryl, aryllower alkyl, 1H-benz- imidazol-2-yl; and a radical of the formula EMI3.1 wherein r is the integer 0 or 1; X is a member selected from the group consisting S of O and -N(R5)-, said R5 being a member selected from the group consisting of hydrogen, lower alkyl, aryllower alkyl, lower alkanoyl and aroyl; and W is a member selected from the group consisting of lower alkyl, aryl, aryllower alkyl, amino, aryl amino, mono- and di(lower alkyl)amino, mono- and di(aryllower alkyl)amino, 1-piperidinyl, 1-pyrroli dinyl and 4-morpholinyl; wherein aryl as used in the foregoing definitions, is a member selec- ted from the group consisting of phenyl, substituted phenyl, naphtha- lenyl, thienyl, halothienyl, (lower alkyl)thienyl, pyridinyl, monoand di(lower alkyloxy)pyridinyl, furanyl and 1 lower alkyl)pyrrolyl; wherein said substituted phenyl is phenyl having from 1 to 3 sub stituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyllower alkyl, phenyllower alkylsulfonyl, phenylsulfonyllower alkyl, amino, monoand di-(lower alkyl)amino, lower alkanoyl, a radical of the formula R6-CpH2p-O-, wherein p is an integer of from 1 to 6 inclusive; and R6 is a member selected from the group consisting of hydrogen, amino, cyano, phenyl, aminocarbonyl, mono- and di(lower alkyl)aminocarbonyl, lower alkyl oxycarbonyl, phenyllower alkyloxycarbonyl, 4-morpho linylcarbonyl, 1-piperidinylcarbonyl and I pyrroli dinylcarbonyl, lower alkenyl; and a radical of the formula R -0-, wherein R7 is a member selected from the group consisting of alkanoyl, phenylcarbonyl, phenyllower alkylcarbonyl, lower alkyloxycarbonyl, phenyllower alkoxycarbonyl, aminocarbonyl, phenylaminocarbonyl, mono- and di (lower alkyl)aminocarbonyl; wherein said phenyl in the definition of said R7 may be optionally substituted with up to 3 substituents each independently selected from the group consisting of halo, cyano, nitro, lower alkyl and lower alkyloxy; and wherein said aroyl in the definition of said L represents arylcarbonyl wherein said aryl is as defined hereabove. As used in the foregoing definitions the term "lower alkyl" is meant to include straight and branch chained hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl. ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, a -methylpropyl, butyl, pentyl, hexyl and the like; the term "alkyl" as used in the definition of Rê includes straight and branch chained hydrocarbon radicals having from 1 to 10 carbon atoms, such as, for example, the above-indicated lower alkyls and higher homolog such as heptyl, octyl, nonyl and decyl; the term "lower alkenyl" refers to straight alkenyl radicals having from 3 to 6 carbon atoms wherein the un saturation is preferably located at the p-porition but may also be located at the El, # , or#-position such as for example, 2-propenyl, a -butenyl, 3 -pentenyl, 2-hexenyl and the like; the term "cycloalkyl" refers to cyclic hydrocarbon radicals having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the term "halo" is generic to fluoro, chloro, bromo and iodo. The compounds of formula (I) can generally be derived from a starting material of the formula EMI6.1 wherein R, R1, R2, R3, n and Q are as previously defined by introducing the desired L-substituent onto the piperidine nitrogen by the application of art-known methods. In general the introduction of said L into the intermediate (II) may conveniently be accomplished by the reaction of (II) with an appropriate reactive ester of the formula LV, (III), wherein L is as previously defined and Y is a reactive ester residue such as, for example, halo, preferably chloro or bromo, or a sulfonyloxy residue such as, for example, methylsulfonyloxy or 4-methylphenylsulfonyloxy and the like. The condensation reaction of (II) with (III) is conveniently conducted in an inert organic solvent such as, for example, an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene, 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, 1,1 '-oxybisethane and the like; N,Ndimethylformamide (DMF): nitrobenzene; and the like. The addition of an appropriate base such as, for example, an alkali metal carbonate or hydrogen carbonate, or an organic base such as, for example, N, N-diethylethanamine or N-(1-methylethyl)-2-propanamine may be utilized to pick up the acid that is liberated during the course of the reaction. In some circumstances the addition of an iodide salt, preferably an alkali metal iodide, is appropriate. Somewhat elevated temperatures may be employed to enhance the rate of the reaction. When L in formula(I) represents a (2,3-dihydro-2-oxo-lH- benzimidazol-1-yl)lower alkyl radical it is appropriate to use a reactive ester (III) wherein the nitrogen atom in the 3-position of the 2,3dihydro-2-oxo-1H-benzimidazol-1-yl group is substituted with an appropriate protecting group, preferably a 1-methylethenyl group and removing said protecting group after completion of the condensation reaction. The removal of said protecting group may be accomplished by art-known procedures, such as acid hydrolysis when a 1-methylethenyl group is involved. When L represents a 2-aryl-2-hydroxyethyl or a 2-aryloxy 2-hydroxypropyl radical, the introduction of said aubstituent into the intermediate (II) may conveniently be carried out by reacting (II) at an elevated temperature with an appropriate oxirane ef the formula EMI7.1 wherein m is O or L. The reaction of (II) with (IV) may be carried out in an appropriate organic solvent or, optionally, in the absence of any solvent. Suitable solvents which may be employed include, for example, aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like; halogenated hydrocarbons such as, for example, trichloromethane, dichloromethane and the like; lower alkanols such as, methanol, ethanol, 2-propanol and the like alcohols; and mixtures of such solvents. When the piperidine derivative (Il) is in the form of an acid addition salt it is appropriate to add to the reaction mixture an appropriate base such as, for example, sodium carbonate in order to liberate the free acid from the salt. The compounds of formula (1) wherein L represents a 2-hydrorysthyl radical may be prepared by the reaction of an appropriate piperidine of formula (II) with ozirane, following the same procedure as described for the reaction of (IV) with (II). When L is, at the point of attachment to the piperidine nitrogen atom, a primary or secondary alkyl group, the compounds (I) may also be prepared by the reductive amination of an aldehyde or ketone corresponding with the alcohol L-OH with a piperidine derivative of formula (II) following art-known procedures. In a convenient method of operation a mixture of the aldehyde or ketone and (1I) in an appropriate organic solvent is hydrogenated in the presence of an appropriate catalyst such as, for example, palladium-on- charcoal. Appropriate organic solvents include lower alkanols, such as for example, methanol, ethanol, propanol and the like. The rate of the hydrogenation reaction may be enhanced by carrying out said reaction in the presence of an appropriate weak acid such as, for example, acetic acid. When the piperidine derivative (II) is in the form of an addition salt with a strong acid, e. g., hydrochloric or hydrobromic acid it is appropriate to add thereto a salt of a strong base with a weak acid, e. g., sodium acetate to bind said strong acid. When (11) contains groups that are themselves susceptable to catalytic hydrogenation, e. g. when R2 represents an arylmethyl group, it may be appropriate to add to the reaction mixture an appropriate catalyst poison such as, for example, thiophene. When L represents a radical of formula Z-CmH2m-, wherein m is an integer of from 2 to 6 inclusive and wherein Z is as previously ly defined, the compounds of formula (I) can also be prepared by the reaction of (II) with an appropriate alkenyl derivative, Z-C=H2= 1 according to art-known methods of carrying out similar additionreactions, e.g., by stirring and heating the reactants together in and appropriate reaction-inert organic solvent such as, for example, a lower alkanol such as 2-propanol, butanol and the like. When L represents 8 2-Caroylaniino)ethyl radical or a 2-arylethyl radical the compounds (I) can also be obtained by the reaction of (II) with an appropriate 1-aroylaziridine or an appropriate ethenylarene, respectively. Said reactions are preferably carried out in an appropriate reaction-inert organic solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, butanol and the like alcohols; an aromatic hydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene and the like; a ketone, e.g., 4-methyl-2-pentanone; an ether, e.g., 1,4-dioxane, 1,1'-oxybisethane and the like; N,N-dimethylformamide; nitrobenzene; and the like; or a mixture of such solvents. Elevated temperatures are appropriate in order to enhance the rate of the reaction and preferably the reaction is carried out at the reflux temperature of the reaction mixture. The compounds of formula (I) can also be prepared by the cyclodesulfurization of an appropriate thiourea derivative of the formula EMI9.1 Said cyclodesulfurization reaction may be carried out by the reaction of (V) with an appropriate alkyl halide, preferably iodomethane in an appropriate reaction-inert organic solvent, e.g., a lower alkanol such as methanol, ethanol, 2-propanol and the like. Otherwise, the cyclodesulfurization reaction may be carried out by the reaction of (V) with an appropriate metal oxide or salt in an appropriate solvent according to the procedure described, for example, in Pharmazie, 31, 348 (1976). For example, the compounds of formula (I) can easily be prepared by the reaction of (V) with an appropriate Hg(II) or Pb(II) oxide or salt, such as, for example HgO, HgC12, Hg(OAc)2, PbO or Pb(OAc)2. In certain instances it may be appropriate to supplement the reaction mixture with a small amount of sulfur. Even so methanediimines, especially N,N'-methanetetraylbis(cyclo hexanamine], may be used as cyclodesulfurizing agents. Suitable reaction-inert organic solvents that may advantageously be employed include lower alkanols, e.g., methanol, ethanol, 2-propanol and the like; halogenated hydrocarbonsd, e.g., dichlormethane and trichlormethane; ethers, e.g. tetrahydrofouran, 2,2'-oxybispropane and the like; and mixture of such solvents. The compounds of formula (I) wherein Rê is other than hydrogen, said Rê being represented by Rêa and said compounds by the fools (I-a), can also be prepared starting from z corres ponding compound (I) wherein RZ is hydrogen, (I-b), by introducing said Rêa according to art-known procedures as previously described herein for the introduction of L'into starting materials of formula (II). In a preferred method of operation (I-b ) is reacted with an appropriate reactive ester RêaY, (VI), wherein Rêa and Y are as previously defined. The reaction is charied oat under similar conditions as previously described herein for the reaction of (II) with (m). Since the compounds of formula (I-b) are somewhat less reactive it is advantageous to conduct the alkylation reaction in the presence of a small amount of a strong metal base inch as, for example, sodium hydride. The compounds of formula (I) wherein R1 and ê R are both different from hydrogen, said R1 being represented by R1. and said Rê by Rêa can also be derived from the corresponding compounds wherein R1 is hydrogen by introducing the R1a-group in a similar man ner as described hereinabove for the preparation of compound (I-b) starting from (I-a). Following the procedure, described hereinabove for the preparation of compounds (I) starting from (V), the compounds of formula (I), wherein L represents a (1H-benzimidazol-2-ylamino) lower alkyl radical or a l-(aryllower alkyl)-1H-benzimidazol-2- ylamino)lower alkyl radical (I-c), may even so be derived from the corresponding isothiocyanates (VII) by subjecting the latter to an addition-reaction with a benzenediamine (VIII) and subsequently cyclodesulfuring the intermediately formed thiourca (IX). The isothiocyanate (VII) may be prepared following artknown procedures for the preparation of isothiocyanates Jsee, for example, Saul Patal Ed. "The Chemistry of Cyanates and their Thioderivatives" John Wiley k Sons - Chichester - New York Brisbane - Toronto (1977) p. 1013 - 10523, such as, for example by reacting the corresponding amine (VI) with carbon disulfide, preferably in the presence of alkali .g., sodium hydroxide and the like, and decomposing the intermediately formed dithiocarbamate with for example N,N'-methanetetraylbis [cyclohexanamine], a lower alkyl chlorformate or another appropriate decomposing agent as known in the art. The foregoing reactions are illustrated as follows: EMI11.1 EMI12.1 The compounds of formula (I) wherein L represents a radical Z-CmH2m-, wherein Z represents a radical of the formula W-CO-(X)2-, wherein 5 is 1, X is 0 and W is an optionally substituted amine, a 1-pyrrolidinyl, a 4-morpholinyl or a 1piperidinyl radical, said compounds being represented by the formula (I-d), may be prepared by the reaction of the corresponding amine, pyrrolidiee, morpholine or piperidine with an appropriate N-[1-(halolower alkyl)-4-piperidinyl)]-1H-benzimidazol-2-amine in the presence of an appropriate carbonate, e. g. sodium carbonate and the like. Compounds of formula (I) which contain at least one hydroxyl- group as a substituent can conveniently be derived from the corresponding phenylmethoxy substituted compound by subjecting the latter to 1 catalytic hydrogenation in the presence of an appropriate catalyst, e.g., palladium-on-charcoal and the like. These hydroxyl-derivatives may even so be derived from the corresponding lower alkyloxy substituted analogs by hydrolyzing the latter in acidic medium, using for example hydrogen bromide in acetic acid. The hydroxyl-substituted compounds may in turn be O-aLkylated or acylated by reacting the latter with a halide, an alkanoyl halide, an alkyloxycarbonyl halide, an isocyanate and the like. The hydroxyl-substituted compounds may also be converted into halides by reacting therewith a suitable halogenating agent, e. g. thionyl chloride, phosphor pentabromide and the like in the presence of an appropriate solvent, e.g., a trichloromethane and the like. Amino-ubstituted compounds may, for example, be derived from the corresponding nitro- and cyano-ubutituted compounds by reducing the latter, e. g., by catalytic hydrogenation in the presence of an appropriate catalyst, uch as, for example, Raney-nickel and the like. The amino-substituted compounds may in turn be N-alkylated or acylated by the reaction thereof with an appropriate alkylating agent or acylating agent, e. g., halide, an alkanoyl halide. an alkorycarbonyl halide, an isocyanate and the like. Secondary and tertiary amino-substituted compounds of formula (I) may be prepared by substituting, for example, an appropriate halo-substituted compound with the desired primary or secondary amine. Aminocarbonfl-substituted compounds may conveniently be derived from the corresponding esters by reacting the latter with ammonia or an appropriate primary-or a secondary amine in a suitable solvent. Compounds of formula (I) which contain in their structure a sulfonyl group may easily be derived from the corresponding thio compou:ni5 by oxidizing the latter with an appropriate oxydi- zing agent, e. g. hydrogen peroxide and the like. In all of the foregoing and in the following preparations, the reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art. The compounds of formula (I) may be converted to the therapeutically active non-toxic acid addition salt form by treatment with an appropriate acid, such as, for example, an inorganic acid, such as hydrohalic acid, e. g., hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid, such as, for example, acetic, propanoic, 2-hydroxy acetic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic, (2)-2-butenedioic, (E)-2-butanedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic, &alpha;-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenezenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form. The starting materials of formula (II) herein can generally be prepared starting from a thiourea derivative of the formula (X) wherein R, R1, R2, R3 and n are as previously defined and P is an appropriate protecting group such as, for example, lower alkyloxycarbonyl or phenylmethoxycarbonyl, by subjecting (X) to a cyclodesulfurization reaction to obtain an intermediate of the formula (XI) and thereafter eliminating the protecting group in the usual manner. EMI15.1 The cyclodesulfurization of (X) to obtain (XI) can be carried out in the same manner as previously described herein for the preparation of the compounds (I) starting from (V). In order to remove the protecting group P there may be used art-known procedures. For example, when said group is a lower alkyloxycarbonyl group it may be removed by alkaline or preferably acid hydrolysis, using for example, hydrobromic acid in glacial acetic acid, and when said protecting group is a phenylmethoxycarbonyl group it may be removed by alkaline or acid hydrolysis or by catalytic hydrogenation using an appropriate catalyst such as palladium-on-charcoal. Intermediates of formula (XI) wherein R2 is other than hydrogen can also be derived from the corresponding (XI) wherein R2 is hydrogen by introducing the desired R2-substituent according to artknown methodologies as described hereinabove in connection with the preparation of compounds (I-a) starting form (I-b). The thiourea derivatives of formula (X) wherein R1 represents hydrogen, (X-a), can be prepared by the reaction of an appropriate 4-isothiocyanatopiperidine of formula (XII) with an appropriate benzenediamine or pyridinediamine of formula (XIII), e.g. by simply stirring the reactants together in an appropriate organic solvent such as, for example, a lower alkanol, e.g. methanol, ethanol, 2-propanol and the like. EMI16.1 Thiourea derivatives of formula ( X ) wherein R1 is as previously defined and Rê is hydrogen, (X-b),), can be prepared by the reaction of an appropriate 4-piperidinanine of the formula (XIV) with an appropriate 1-isothiocyanato-2-nitrobenzene of the formula (XV), followed by the reduction of the nitro group of the thus obtained compound (XVI) following well-known nitro-to-amine reduction procedures such as for example by the reaction of (XVI with nascent hydrogen or by catalytic hydrogenation using an appropriate catalyst such as, for example, palladium-on-characoal, platinum-on-charcoal and the like, or in the presence of more than one of such catalysts. EMI17.1 The precursor materials of formula (XIV) herein may be pre pared following methods known in the art, e.g., by the reductive amination of the corresponding 4-piperdininone. The 4-isothiocyanato piperidines of formula (xii) may in turn be prepared starting from the corresponding (xrv) wherein R1 is hydrogen according to standard methods of preparing isothiocyanates starting from primary amines, e.g., by the reaction of the amine with carbon disulfide in alkaline medium and subsequent addition to the reaction mixture of an appropriate lower alkylcarbonochloridate. The starting materials of formula (XII) wherein P represents t lower alkyloxycarbonyl or phenylmethoxycarbonyl group can also be prepared by the reaction of z corresponding starting material QCII.) wherein said P represents phenylmethyl by reacting the latter with a: appropriate carbonochloridate. The starting materials of formula (V) can be prepared wing similar procedures as described hereinabove for the preparation of the thiourea derivatives of formula ( X ) starting however from an appropriate 4-piperidinone or 4-piperidinamine wherein the L-subsituent is already present on the piperidine nitrogen atom. The ultimate starting materials in each of the foregoing preparations are know: compounds or they may be prepared by the application of methodologies known in the art for preparing similar known compounds. The preparation of 4-(haloalkyl)-2H-1,4-benzoxazin-3(4H)-ones, for example, by the N- substitution-reaction of 2H-1, 4-benzoxazin- 3(4H)-one with a dihalolower alkyl group, is described in Belg. Pat. No. 859,415. 1, 3-dihydro-1 -(3-oxobutyl)-2H-benzimidazol-2- one (XIX) can be prepared by subjecting 1,3-dihydro-1-(1-methyl- ethenyl)-2H-benzimidazol-2-one (XVII) and 3-buten-2-one to a Michael-addition procedure in the presence of a base such as, N, N-diethylethanamine and the like, and subsequently hydrolyzing the 1,3-dihydro-1-(1-methylethenyl)-3-(3-oxobutyl)-2H-benzimidazol2-one (XVIII). EMI19.1 The intermediates of the formulae (Il) and (XI) are deemed to be novel and in view of their utility as starting materials in the preparation of the pharmaceutically active compounds of formula (I) they constitute an additional feature of this invention. The compounds of formula (I) and their pharmaceutically acceptable acid addition salts are potent antihistaminic agents and as such they can be used to prepare valuable medicaments for human and animal therapy. The useful antihistaminic properties of the compounds of formula (I) were demonstrated in the following test procedure. PROTECTION OF RATS FROM COMPOUND. 48/80 INDUCED LETHALITY. Compound 48/80, a mixture of oligomers obtained by condensation of p-methoxy-N-methyl-phenylamine and formaldehyde has been described as a potent histamine releasing agent (Int. Arch. Allergy, 13 , 336 (1958)). The protection from compound 48/80-induced lethal circulatory collapse appears to be a simple way of evaluating quantitatively the antihistaminic activity of test-compounds. Male rats of an inbred Wistar strain, weighing 240-260 g were used in the experiment. After overnight starvation the rats were transferred to conditioned laboratories (temp. = 21 + 10c, relative humidity 65 + 5%). Thp rats were treated subcutaneously or orally with a test compound or with the solvent (NaCl solution, 0.9%). One hour after treatment 'more was injected intravenously compound 48/80, freshly dissolved in water, at a dose of 0.5 mg/kg (0.2 my/100 g of body weight). In control experiments, wherein 250 solvent-treated animals were injected with the standard dose of compound 48/80 not more than 2.8S of the animals survived after 4 hours. Survival after 4 hours is therefore considered to be a safe criterion of a protective effect of drug administration. The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof were found very active in the above test, protecting the animals against compound 48/80-induced lethality at oral and subcutaneous dous not higher than 2.5 mg/kg. A number of the subject compounds were found effective even at doses as low as O. 16 mg/kg. In view of their useful antihistaminic activity, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, an effective antihistaminic amount of the particular compound, in base or acid-addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, f6r example, 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, disintegrating agents and the like in the case of powders, pilIs, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most ad vantageous oral dosage unit form, in which case solid pharmaceutical carries are obviously employed. For parenteral compositions, the quarrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example may be prepared in which the carrier comprises saline solution. glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Acid additions salt of (I), due to their increased water solubility over the corresponding base form1 are obviously more suitable in the preparation of aqueous compositions. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete its suitable as unitary dosages, each unit containing a predeter'mined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. E:a=ples of such dosage unit forms are tablets (including scored or coated tablet.), capsules, pills, powder packets, wafers, injectable solutions or suspensions, tenspoonfuls, tablespoonfuls and the like, and segregated multiples thereof. The following examples are intended to illustrate and not to limit the scope of the present invention. Unless otherwise stated all parts therein are by weight. A. PREPARATION OF INTERMEDIATES: Example I A mixture of 102 parts of ethyl 4-oxo-1-piperidinecarboxylate, SO parts of methenamine and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 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, yielding 111 parts of ethyl 4-(methylamino)-1-piperidine- carboxylate as a residue. To z stirred and cooled mixture o± 4 parts of sodium hydroxide in 60 parts of water are added successively 7.9 parts of carbon disulfide and 17.2 parts of ethyl 4-amino-1 -piperidinecarboxylate at a temperature below 10 C. Stirring is continued for 30 minutes at this temperature. Then there are added dropwise 10.9 parts of ethyl carbonochloridate (exothermic reaction: temp. rises to about 35'C). Upon completion, 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. yielding 22 parts (100%) of ethyl 4-isothiocyanato-1-piperidinecarboxylate as a residue. By repeating the procedure of the second step there are also prepared starting from an appropriate amine: 4-isothiocyanato-1-(phenylmethyl)piperidine; and 1-[4,4-bis(4-fluorophenyl)butyl]-4-isothiocyanatopiperidine; mp. 92 C. EXAMPLE II To a stirred solution of 28.4 parts of 4-isothiocyanato-1- (phenylmethyl)piperidine in 315 parts of methylbenzene are added dropwise 41 parts of (phenylmethyl) carbonochloridate at room temperature. Upon completion, the whole is heated to reflux and stirring is continued overnight at reflux temperature. The reaction mixture is cooled and the solvent is evaporated. The residue is pirified by column-chromatography over silica gel using trichloro methane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 32 parts (97%) of (phenylmethyl) 4-isothio- cyanato-1-piperidinecarboxylate as a residue. Example III A mixture of 9.7 parts of 4-fluorobenzenemethanamine hydrochlorid, 9.4 parts of 2-chloro-3-nitropyridine, 10.6 parts of sodium carbonate, 0. 1 parts of potassium iodide and 90 parts of N, N-dimethylformamide is stirred for 1 hour at 90-C. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off and crystallized from 2 -propanol, yielding 10.5 parts (71 %) of N-(4-fluorophenylmethyl)-3-nitro-2-pyridinamine; mp. 76 C. A mixture of 10.5 parts of N-(4-fluorophenylmethyl)-3nitro-2-pyridinamine and ZOO parts of methanol is hydrogenated at normal pressure and at room temperature witlr Z parts of Raneynickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is altered off and the filtrate is evaporated, yielding 9.3 parts (100%) of Nê-(4-fluorophenylmethyl)-2, 3-pyridinedia=nine as a residue. Following the same procedure and using equivalent amounts of the appropriate starting materials there are also prepared: N1-(phenylmethyl)-4-(trifluormethyl)-1,2-benzenediamine; and 4-chloro-N1-(4-fluorophenylmethyl)-1,2-benzenediamine. Example IV A mixture of 34. 8 parts of 1, 3-dihydro-1-(methylethenyl)- 2H-benzimidazol-2-one, 28 parts of 3-buten-2-one, 20. 2 parts of N, N-diethylethanamine and 270 parts of tetrahydrofuran is stirred and refluxed over week-end. The reaction mixture is evaporated, yielding 48.8 parts (1007) of 1,3-dihydro-1-(1-methylethenyl)-3- (3-oxobutyl)-2H-benzimidazol-2-one as a residue. A mixture of 48. 8 parts of 1, 3-dihydro-1-(1-methylethenyl)- 3-(3-oxobutyl)-2H-benzimidazol-2-one, 12 parts of 2-propanol, saturated with gaseous hydrogen chloride and 240 parts of 2-propanol is stirred for 3 hours at room temperature. The precipitated product is filtered off, washed with 2, 2'-oxybispropane and dried, yielding 30 parts (73.4%) of 1,3-dihydro-1-(3-oxobutyl)-2H- benzimidazol-2-one. Example V To a stirred mixture of 9 parts of 2N-1,4-benzoxazin-3(4H)- one, 0.9 parts of N, N, N-tricthylbenzcnametiranaminium chloride, parts of sodium hydroxide solution 50 % and 24 parts of water are added 10.4 parts of l-bromo-3-chloropropane at 30*C. The whole is heated to 900C and stirring is continued for 3 hours at this temperature. The reaction mixture is cooled to about 70 C, methylbenzene is added and the whole is stirred overnight at room temperature. The organic phase is separated, dried, filtered and evaporated, yielding 10 parts of 4-(3-chloropropyl)-2H-1,4-benzoxazin-3(4H)-one as a residue. Example VI A-mixture of 10.6 parts of ethyl 4-izothiocyanato-I -piperi dinecarboxylate, II.6 parts of 4-chloro-N1-(phenylmethyl)-1,2 benzenediamie and 90 parts of tetrahydrofuran is stirred overnight room temperature. The reaction mixture is evaporated, yielding 21 parts (100%) of ethyl 4-[{[{5-chloro-2-[phenylmethyl)amino] phenyl}amino]thioxomethyl}amino]-1-piperidinecarboxylate; mp 1620C. Example VII Following the procedure of Example VI and using equivalent amounts of the appropriate starting materials there are prepared: ethyl 4-{[(2-amino-5-chlorophenyl)aminothioxomethyl]amino}-1 piperidinecarboxylate; mp. 162.2 C; ethyl 4-{[(2-aminophenyl)aminothioxomethyl]amino}-1-piperidine carboxylate as z residue; ethyl 4-{[(2-amino-5-methylphenyl)aminothioxomethyl]amino}-1 piperidinecarboxylate as a residue; ethyl 4-[{[{2-(phenylmethyl)amino]-3-pyridinyl}amino]thioxo methyl}amino]-1-piperidinecarboxylate; mp. 146.7 C; ethyl 4-[{[{2-(phenylmethyl)amino]-5-(trifluoromethyl)phenyl} amino]thioxomethylamino} - 1- piperidinecarboxylat e as a residue; ethyl 4-[{[(2-amino-4-fluorophenyl)amino]thioxomethyl}amino] 1-piperidinecarboxylate as a residue; ethyl 4-[{[{3-chloro-2-[(4-fluorophenylmethyl)amino]phenyl} amino]thiomethyl} s -piperidinecarboxylate as a residue; (phenylmethyl) 4-[{2-[(4-fluorophenylmethyl)amino]-3-pyridinylamino}thioxomethylamino]-1-piperidinecarboxylate; N-(2-nitrophenyl)-N'-[I-(2-phenylethyl)-4-piperidinyl]-N'-(phenylmethyl)thiourea; mp. 151.1 C; N-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-N'-phenylthiourea; mp. 90'C; ethyl 4-[{[(2-amino-3-pyridinyl)amino]thioxomethyl}amino]-1piperidinecarboxylate; mp. 176. 90C; 4-[{[(2-phenylamino)phenyl]aminothioxomethyl}amino]-1-piperidinecarboxylate; mp. 154.2 C; and ethyl 4-{[{[2-(4-fluorophenylamino)phenyl]amino}thioxomethyl]amino}-1-piperidinecarboxylate as a residue. Example VIII A mixture of 21.6 parts of I-isothiocyanator-2-nitrobenzene and 45 parts of tetrahydrofuran is stirred till all solid enters solution. Then there are added 29. 5 parts of N-(1-methylethyl)-1-(2-phenyl- ethyl)-4-piperidinamine and 160 parts of ethanol 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, yielding 43 parts (84%) of N-(I- methylethyl)-N'-(2-nitrophenyl)-N-[1-(2-phenylethyl)-4piperidinyl]thoiurea; mp. 100.6 C. Example X Following the procedure of Example VIII the following thiourea derivatives are prepared by the reaction of an appropriate 4piperidinamine with an appropriate 1-isothiocyanato-2-nitrobenzene. ethyl 4-[methyl-{[(2-nitrophenyl)amino]thioxomethyl}amino]-1piperidinecarboxylate; ethyl 4-f butyl[(2-nitrophenyl)aminothioxomethyl]amino} -1 -piperidinecarboxylate as a residue; N-ethyl-N'-(2-nitrophenyl)-N-[1-(2-phenylethyl)-4-piperidinyl]thiourea; N-(2-nitrophenyl)-N'-[1-(2-phenylethyl)-4-piperidinyl]-N'-propyl thiourea; mp. 90.30C; N-cyclopropyl-N'-(2-nitrophenyl)-N-[1-(2-phenylethyl)-4-piperidinyl]thiourea; mp. 150.10C; and cistrans-methyl 3-methyl-4-( {[(2-nitrophenyl)amino]thioxomethyl} amino]-1-piperidinecarboxylate; mp. 157.5 C. Example X A mixture of 43 parts of N-(1-methylethyl)-N'-(2-nitrophenyl)- N-[1-(2-phenylethyl)-4-piperdinyl]thiourea and 800 parts of methanol, saturated with ammonia is hydrogenated at normal pressure and at room temperature with 6 parts of palladium-on-charcoal catalyst 10% and 6 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalysts are filtered off over Hyflo and the filtrate is evaporated, yielding 39 parts (100%) of N-(2-aminophenyl)-N'-(1-methylethyl)-N'-[1-(2-phenylethyl)-4-piperi dinyljthiourea as a residue. Example XI Following the procedure of Example X and using an equivalent amount of an appropriate nitro-compound as a starting material, there are prepared: ethyl 4-[{[(2-aminophenyl)amino]thioxomethyl}methylamino]-1piperdinecarboxylate; ethyl 4-[{[(2-aminophenyl)aminothioxomethyl]butylamino}-1-piperidinecarboxylate; N-(2-aminophenyl)-N'-[1-(2-phenylethyl)-4-piperidinyl]thiourea; N-(2-aminophenyl)-N'-[1-(2-phenylethyl)-4-piperidinyl]-N'propylthiourea; N-(2-aminophenyl)-N'-cyclopropyl-N'-[1-(2-phenylethyl)-4piperidinyl]thiourea; methyl 4-{[(2-aminophenyl)amino]thioxomethylamino}-3-methyl1-piperdinecarboxylate; N-(2-aminophenyl)-N'-[1-(2-phenylethyl)-4-piperidinyl]-N' (phenylmethyl)thiourea as a residue. Example X-I - A mixture of 23 parts of (phenylmethyl) 4-[{2-[(4-fluoro- phenylmethyl)amino]-3-pyridinylamino}thioxomethylamino]-1-piperidinecarboxylate, 17 parts of mercury oxide, 0.1 parts of sulfur and 450 parts of tetrahydrofuran is 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-methyl2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 20 parts (93X) of (phenylmethyl) 4-(3-C4-fluoro- phenylmethyl)-3H-imidazo [4,5-b]pyridin-2-ylamino]-1-piperidinecarboxylate; mp. 1300±. Example XIII Following the procedure of Example XII and using equivalent amounts of the appropriate starting materials there are prepared: ethyl 4-[(1H-benzimidazol-2-yl)methylamino]-1-piperidinecarboxylate; ethyl 4-( (1Hbenzimidazol-2-yl)butylamino1-1-piperidinecarboxylate; mp. 225.90C; ethyl 4- C1-(phenylmethyl )-5-(tri fluoromethyl )-1H-benzimidazol- 2-ylamino]-1-piperidinecarboxylate; mp. 200 C; ethyl 4-(5-fluoro-l H-benzimidazol-2-ylamino )-l-piperidine- carboxylate; mp. 227.5 C; ethyl 4-[5-chloro-1-8phenylmethyl)-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-yl amino]-1-piperidinecarboxylate; mp. 215.8 C; methyl 4- (1 H-benzimidazol-2-ylamino) -3-methyl-I -piperidine- carboxylate; mp. 155 C; ethyl 4-[3-(4-fluorophenylmethyl)-3H-imidazo[4,5-b]pyridin-2ylamino]-1-piperidinecarboxylate; mp. 134,4 C; ethyl 4-[(3H-imidazo[4,5-b]pyridin-2-yl)amino]-1-piperidinecarboxylate; mp. 216.1 C; ethyl 4-(1-phenyl-1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate; mp. 137 C; and ethyl 4-[1-(4-fluorophenyl)-1H-benzimidazol-2-ylamino]-1piperidinecarboxylate; mp. 153 C. Example XIV A mixture of 2B parts of ethyl 4-.r C (2-aminophenyl )amino- thioxomethyl]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 whole is alkalized with ammonium 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'-oxybispropane. The product is filtered off and dried, yielding 7 parts (28%) of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate. Following the same procedure and using equivalent amounts of the appropriate starting material there are prepared: ethyl 4- (5-chloro-I H-benzimidazol-2-ylamino)-1-piperidine- carboxylate; mp. 234.1 C; and ethyl 4-(5-methyl-l H-benzimidazol-2-ylamino )-l-piperidine- carboxylate. Exanipib XV A mixture of 19 parts of methyl 4-(1H-benzimidazol-2-ylamino)-3-methyl-1-piperidinecarboxylate, 11 parts of 1-(chloromethyl)-4-fluorobenzene, 6 parts of sodium carbonate and 135 parts of N,N-dimethylformamide is stirred and heated overnight at 700C. The reaction mixture is cooled and poured onto water. The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (96:4 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. The product is filtered off and dried, yielding 8 parts (38%) of methyl 4-[1-(4- fluorophenylmethyl )-1 H-benzimidazol- 2-ylamino ]-3-methyl-1 -piperidine- carboxylate; mp. 172.50C. Example XVI Following the procedure of Example (XIII) the following 4-(1-R2-1H-benzimidazol-2-ylamino)-1-piperidinecarboxylates are prepared by alkylating the corresponding 4-(1H-benzimidazol-2-yl- amino)-1-piperidinecarboxylate with an appropriate chloride, bromide or iodide of the formula R2X: : EMI33.1 EMI33.2 <tb> lower <SEP> alkyl <SEP> R <SEP> R1 <SEP> fl <SEP> CR3) <SEP> melting <tb> point <tb> C2H5 <SEP> H <SEP> H <SEP> CH3 <SEP> H <SEP> 166.7 C <tb> C2H5 <SEP> H <SEP> H <SEP> CH3 <SEP> 5(6)-CH3 <SEP> 142.00C <tb> ±2H5 <SEP> H <SEP> H <SEP> C2Hs <SEP> H <tb> ±2H5 <SEP> H <SEP> H <SEP> n.C3H7 <SEP> H <tb> C2H5 <SEP> H <SEP> H <SEP> i.C3H7 <SEP> H <tb> C2H5 <SEP> H <SEP> H <SEP> n.±4H9 <SEP> H <tb> C2H5 <SEP> H <SEP> H <SEP> niC5H11 <SEP> H <tb> ±2H5 <SEP> H <SEP> H <SEP> n <SEP> C6H13 <SEP> H <tb> C2H5 <SEP> H <SEP> H <SEP> niC7H15 <SEP> H <tb> C2H5 <SEP> H <SEP> H <SEP> z <SEP> H <tb> C2H5 <SEP> H <SEP> H <SEP> 4-Br-C6H4-cH2 <SEP> H <tb> ±2H5 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> 5(6)-CH3 <SEP> 179.30C <tb> C2H5 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <tb> C2H5 <SEP> H <SEP> H <SEP> 2-±16H4-±H2 <SEP> H <SEP> 213.4no <tb> C2H3 <SEP> H <SEP> H <SEP> 4-Cl-C6H4-±H2 <SEP> H <SEP> 202.60C <tb> ±2H5 <SEP> H <SEP> H <SEP> 4 <SEP> CH3C6H4 <SEP> CH2 <SEP> H <SEP> 177.70C <tb> C2H5 <SEP> H <SEP> H <SEP> 4-F-±6H4-CH2 <SEP> H <tb> ±2H5 <SEP> H <SEP> H <SEP> 2-F-C6H4-CH2 <SEP> H <SEP> 176.0 C <tb> C2H5 <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> 5C6)-±H3 <SEP> 173.3 C <tb> C2H5 <SEP> H <SEP> H <SEP> 4-F-±6H4-CH2 <SEP> 5(6)-F <SEP> 182.5 C <tb> <SEP> 2H5 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> 5(6)-F <SEP> 184.0 C <tb> 2H5 <SEP> CH3 <SEP> H <SEP> C6H5-CH <SEP> H <SEP> 191.00C <tb> <SEP> (cisotran8- <SEP> ) <tb> 2H5 <SEP> H <SEP> H <SEP> 4-N02-±6H4-±H2 <SEP> H <tb> 2H5 <SEP> H <SEP> CH3 <SEP> r <SEP> C6H5-CH2 <SEP> ,rU <SEP> H <SEP> 258.00± <SEP> salt) <tb> 2H5 <SEP> H <SEP> I <SEP> H <SEP> 4-F-2-CH3-CgHT- <SEP> H <tb> Example XVII A mixture of 7 parts of ethyl 4-{[5(6)-fluoro-1-(4-fluoro- phenylmethyl)-1H-benzimidazol-2-yl]amino}-1-piperidinecarboxylate and 300 parts of hydrobromic acid solution 48 % in glacial acetic acid is stirred and refluxed for I hour. The reaction Sure is evaporated and the residue is boiled in 2-propanol. 2,2'-Oxybispropane is added and upon cooling, the product is allowed to crystallize. It is filtered off and dried, yielding 7.2 parts (88.2%) of 5(6)-fluoro-l -(4-fluoro- phenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydro bromide: mp. 285.6 C. Example XVIII Following the procedure of Example the following 1-Rê N-(4-piperidinyl)-1H-benzimidazol-2-amines are prepared by hydrolysing the corresponding methyl or ethyl 1 -piperidinecarboxylates. EMI35.1 EMI35.2 <SEP> Base <SEP> or <tb> R <SEP> R1 <SEP> Rê <SEP> (R )n <SEP> O <SEP> Salt <SEP> form <SEP> melting <SEP> point <tb> H <SEP> H <SEP> H <SEP> 5-Cl <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> CH3 <SEP> 5(6)-CH3 <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> H <SEP> 5-CH3 <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> CH3 <SEP> H <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> C2H5 <SEP> H <SEP> CH <SEP> 2HBr.1/2H2O <SEP> 334-338 C <tb> H <SEP> H <SEP> nC3H7 <SEP> H <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> nC5H11 <SEP> H <SEP> CH <SEP> base <SEP> H <SEP> H <SEP> nC7H15 <SEP> H <SEP> CH <SEP> base <SEP> H <SEP> H <SEP> nC4H9 <SEP> H <SEP> CH <SEP> base <SEP> H <SEP> H <SEP> nC6H13 <SEP> H <SEP> CH <SEP> base <SEP> H <SEP> H <SEP> # <SEP> H <SEP> CH <SEP> base <SEP> EMI36.1 <SEP> Base <SEP> or <SEP> Salt <SEP> melting <SEP> point <tb> R <SEP> R1 <SEP> Rê <SEP> (R )n <SEP> O <SEP> form <tb> H <SEP> H <SEP> iC3H7 <SEP> H <SEP> CH <SEP> base <SEP> H <SEP> CH3 <SEP> H <SEP> H <SEP> CH <SEP> 2HBr.H2O <SEP> H <SEP> H <SEP> 2-Cl-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> H <SEP> H <SEP> 4-Cl-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HBr.H2O <SEP> H <SEP> H <SEP> 4-Br-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HBr.H2O <SEP> > 300 C <tb> H <SEP> H <SEP> 4-CH3-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HBr <SEP> H <SEP> nC4H9 <SEP> H <SEP> H <SEP> CH <SEP> 2HBr.H2O <SEP> 223.1 C <tb> H <SEP> H <SEP> 2-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> 5-CF3 <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H-Cl <SEP> CH <SEP> 2HBr <SEP> > 260 C <tb> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> 2HCl.H2O <SEP> 298.1 C <tb> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> 5-Cl <SEP> CH <SEP> 2HBr <SEP> > 260 C <tb> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> 5(6)-CH3 <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> 5(6)-CH3 <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> 5(6)-F <SEP> CH <SEP> 2HBr <SEP> > 260 C <tb> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HBr <SEP> 3-CH3 <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HBr.H2O <SEP> 250.2 C <SEP> (cia+ <tb> <SEP> trans-isomer) <tb> EMI37.1 R <SEP> R1 <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> Salt <SEP> form <SEP> Melting <SEP> point <tb> H <SEP> H <SEP> C6H5 <SEP> H <SEP> CH <SEP> 2HBr <SEP> . <SEP> H2O <SEP> < 300 C <tb> H <SEP> H <SEP> 4-F-C6H4 <SEP> H <SEP> CH <SEP> 2HBr <SEP> > 300 C <tb> H <SEP> H <SEP> 4-NO2-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HBr <SEP> H <SEP> H <SEP> 4-F-2-CH3-C6H3-CH2 <SEP> H <SEP> CH <SEP> 2HBr <SEP> Example XIX A mixture of 20 parts of (phenylmethyl) 4-[3-(4-fluoro- phenylmethyl)-3H-imidazo[4,5-b]pyridine-2-ylamino]-1-piperidinecarboxylate and 160 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on charcoal catalyst 10%. After the calculated amount of hydrogen is <RTI ID=38.10> taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is boiled in Z,2'-cxytispropane. The undissolved product is filtered off and converted into the hydrochloride salt in 2-propanol. The salt is filtered off and dried, yielding 12 parts of 3-(4-fluoro- phenylmethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2 amine dihydrochloride monohydrate; mp. 269. 70C. B. PREPARATION OF FINAL PRODUCTS: Sample XX A mixture of 2 parts of 2-(bromoethoxy)benzene, 3 parts of 1-(phenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 2 parts of sodium carbonate, 0. 1 parts of potassium iodide and 90 parts of N, N-dimethylformamide is stirred overnight at 700C. The reaction mixture is cooled and poured onto water. The product is extracted with methylbenzenc. The extract is dried, filtered and evaporated. The residue is converted into the hydro. chloride salt in 2-propanone. The salt is filtered off and dried, yielding 3.5 parts (70%) of N-[1-(2-phenoxyethyl)-4-piperidinyl]- 1-(phenylmethyl')-1H-benzimidazol-2-amine dihydrochloride monohydrate; mp. 197.6 C. Example XXI Following the procedure of Example XX and using equivalent amounts of the appropriate starting materials the following compound are prepared in free base form or in the form of an acid addition salt after reacting the free base with an appropriate acid. EMI40.1 EMI40.2 <SEP> L <SEP> R <SEP> R1 <SEP> Rê <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> Salt <tb> <SEP> form <SEP> melting <SEP> point <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> CH3 <SEP> H <SEP> CH <SEP> 2HCl, <SEP> 1/2 <SEP> H2O <SEP> 298.3 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> C2H5 <SEP> H <SEP> CH <SEP> base <SEP> 192.8 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> nC3H7 <SEP> H <SEP> CH <SEP> 2HCl, <SEP> 1/2 <SEP> 278.8 C <tb> <SEP> H2O <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 141.9 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> nC6H11 <SEP> H <SEP> CH <SEP> 2HCl, <SEP> H2O <SEP> 243.5 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> nC7H15 <SEP> H <SEP> CH <SEP> 2HCl, <SEP> H2O <SEP> 212.8 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> nC4H9 <SEP> H <SEP> CH <SEP> 2HCl, <SEP> 1/2 <SEP> H2O <SEP> 274.4 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> nC6H13 <SEP> H <SEP> CH <SEP> 2HCl, <SEP> H2O <SEP> 224.2 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> # <SEP> H <SEP> CH <SEP> 2HCl, <SEP> 1/2 <SEP> H2O <SEP> 285.6 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> iC3H7 <SEP> H <SEP> CH <SEP> 2HCl <SEP> 295.8 C <tb> C6H5-(CH2)2 <SEP> H <SEP> CH3 <SEP> H <SEP> H <SEP> CH <SEP> 2HCl <SEP> 299.6 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> 2-Cl-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HCl, <SEP> 1/2 <SEP> H2O <SEP> 244.4 C <tb> EMI41.1 <SEP> L <SEP> R <SEP> R1 <SEP> Rê <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> Salt <tb> <SEP> form <SEP> melting <SEP> point <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> 4-Br-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HCl, <SEP> H2O <SEP> 251.5 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> 4-CH3-C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HCl.H2O <SEP> 191.4 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> 4-F-C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HCl <SEP> 281.1 C <tb> C6H5-(CH2)2 <SEP> H <SEP> nC4H9 <SEP> H <SEP> H <SEP> CH <SEP> base <SEP> 183.4 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH <SEP> base <SEP> 138.6 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH <SEP> base <SEP> 192.1 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> 5-CF3 <SEP> CH <SEP> 2HCl <SEP> 264.7 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> 5-Cl <SEP> CH <SEP> base <SEP> 168.3 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> 5(6)-CH3 <SEP> CH <SEP> base <SEP> 203-215 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> 5(6)-CH3 <SEP> CH <SEP> base <SEP> 181.9 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> 5(6)F <SEP> CH <SEP> base.1/2H2O <SEP> 146.1 C <tb> C6H5-(CH2)2 <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 193-2 C <tb> C6H5-(CH2)2 <SEP> CH3 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> 5(6)-CH3 <SEP> CH <SEP> base <SEP> 297.9 C <tb> <SEP> (cis+trans <SEP> isomer) <tb> EMI42.1 <SEP> L <SEP> R <SEP> R1 <SEP> Rê <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> Salt <tb> <SEP> form <SEP> melting <SEP> point <tb> C6H5-(CH2)2 <SEP> CH3 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HCl.H2O <SEP> 220.3 C <tb> <SEP> (cis+trans-isomer) <tb> 4-NO2-C6H4-(CH2)2 <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 162.7 C <tb> C6H5-(CH2)3 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HCl.H2O <SEP> 197.1 C <tb> CH2=CH-CH2 <SEP> H <SEP> H <SEP> C2H5 <SEP> H <SEP> CH <SEP> 2HNO3. <SEP> 258.1 C <tb> <SEP> 1/2H2O <tb> CH2=CH-CH2 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HCl.H2O <SEP> 261.9 C <tb> C6H5-O-(CH2)3 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HCl,1/2H2O <SEP> 208.8 C <tb> C6H5-O-(CH2)3 <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 144.5 C <tb> C6H5-O-(CH2)3 <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> N <SEP> base <SEP> 157.6 C <tb> C6H5-O-(CH2)3 <SEP> CH3 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2(COOH)2H2O <SEP> 141.3 C <tb> (C6H5)2CH-(CH2)2 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 173.8 C <tb> nC4H9 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HCl.H2O <SEP> 273.3 C <tb> C6H5-CO-CH2 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HNO3-3H2O <SEP> 135.6 C <tb> (C6H5)2CH <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 203.7 C <tb> C6H5-CH(CH3) <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 154.0 C <tb> C6H5-CH(CH3)-CH2 <SEP> H <SEP> H <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HNO3.H2O <SEP> 159.0 C <tb> C6H5-CH(CH3) <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 170-172.8 C <tb> C6H5-CH(CH3)-CH2 <SEP> H <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> Ch <SEP> 2HNO3-2H2O <SEP> 155.4 C <tb> EMI43.1 EMI43.2 <SEP> L <SEP> Rê <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> salt <SEP> form <SEP> melting <SEP> point <tb> 4-CH3O-C6H4-O-(CH2)3 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <tb> C6H5-CH=CH-CH2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base.H2O <tb> C6H5-CH=CH-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HCl.H2O <tb> C6H5-CH=CH-CH2 <SEP> C2H5 <SEP> H <SEP> CH <SEP> 2HNO3.2H2O <tb> C6H5-CH=CH-CH2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> N <SEP> base <tb> C6H5-O-(CH2)4 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <tb> 4-F-C6H4-CO-(CH2)3 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HCl.1/2H2O <tb> 4-F-C6H4-CO-(CH2)3 <SEP> C2H5 <SEP> H <SEP> CH <SEP> 2HCl <tb> C6H5-CH2 <SEP> CH3 <SEP> H <SEP> CH <SEP> 2HCl.2H2O <tb> C6H5-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HNO3.2H2O <tb> 4-F-C6H4-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> base <tb> C6H5(CH2)2 <SEP> 4-Cl-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HCl.1/2H2O <tb> 4-F-C6H4-(CH2)2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HCl.1/2H2O <tb> 4-F-C6H4-(CH2)2 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> base <tb> 3-CF3-C6H4-(CH2)2 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> base <tb> EMI44.1 <SEP> L <SEP> Rê <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> salt <SEP> form <SEP> melting <SEP> point <tb> (4-F-C6H4)2CH-(CH2)3- <SEP> H <SEP> H <SEP> CH <SEP> 2HCl.1/2H2O <SEP> 279.4 C <tb> (4-F-C6H4)2CH-(CH2)3- <SEP> H <SEP> 5-Cl <SEP> CH <SEP> 2HCl <SEP> 194.8 C <tb> (4-F-C6H4)2CH-(CH2)3- <SEP> H <SEP> 5-CH3 <SEP> CH <SEP> 2HCl.1/2CH3CHOHCH3 <SEP> 171.8 C <tb> (4-F-C6H4)2CH-(CH2)3- <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HNO2.H2O <SEP> 230.9 C <tb> (4-F-C6H4)2CH-(CH2)3- <SEP> CH3 <SEP> H <SEP> CH <SEP> 2HCl.H2O <SEP> 271.7 C <tb> (4-F-C6H4)2CH-(CH2)3- <SEP> CH3 <SEP> 5(6)-CH3 <SEP> CH <SEP> 2HCl.H2O <SEP> 245.8 C <tb> (4-F-C6H4)2CH-(CH2)3- <SEP> C2H5 <SEP> H <SEP> CH <SEP> 2HCl.2H2O <SEP> 208.6 C <tb> <SEP> O <tb> HN#N-(CH2)2 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 237.5 C <tb> <SEP> # <tb> <SEP> O <tb> HN#N-(CH2)2 <SEP> C2H5 <SEP> H <SEP> CH <SEP> base <SEP> 227.0 C <tb> <SEP> # <tb> <SEP> O <tb> CH3-N#N-(CH2)2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> 2HCl.2H2O <SEP> 192.9 C <tb> <SEP> N=N <tb> EMI45.1 <SEP> L <SEP> Rê <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> salt <SEP> form <SEP> melting <SEP> point <tb> <SEP> O <tb> C2H5-N#N-(CH2)2 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2HCl.H2O <SEP> 170.9 C <tb> <SEP> N=N <tb> <SEP> O <tb> C2H5-N#N-(CH2)2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 146.5 C <tb> <SEP> N=N <tb> <SEP> O <tb> C6H5-N#N-(CH2)2 <SEP> CH3 <SEP> H <SEP> CH <SEP> 2HCl1/2H2O <SEP> 279.6 C <tb> <SEP> N=N <tb> <SEP> O <tb> C2H5-N#N-(CH2)2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 143.4 C <tb> <SEP> N=N <tb> EMI46.1 <SEP> L <SEP> Rê <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> salt <SEP> form <SEP> Melting <SEP> point <tb> (4-F-C6H4)2-CH-(CH2)3 <SEP> (4-F-C6H4)2-CH-(CH2)3 <SEP> H <SEP> CH <SEP> base <SEP> 171.1 C <tb> <SEP> ##O#CH2 <tb> <SEP> ##O# <SEP> C2H5 <SEP> H <SEP> CH <SEP> 2HNO3 <SEP> . <SEP> H2O <SEP> 266.5 C <tb> <SEP> ##O#CH2 <tb> <SEP> ##O# <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 210.2 C <tb> <SEP> O <SEP> HOOC-CH <tb> <SEP> O#N-(CH2)3 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2.HOOC <SEP> HC <SEP> 196.2 C <tb> <SEP> # <tb> C6H5-CH2-CH2 <SEP> C6H5-CH2 <SEP> 5-Cl <SEP> CH <SEP> base <SEP> 126.4 C <tb> C6H5-NH-(CH2)3 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 153.1 C <tb> C6H5-O-(CH2)3 <SEP> C6H5 <SEP> H <SEP> CH <SEP> base <SEP> 130.3 C <tb> C6H5-CH2-CH2 <SEP> C6H5 <SEP> H <SEP> CH <SEP> base <SEP> 131.0 C <tb> CH3-(CH2)3 <SEP> C6H5 <SEP> H <SEP> CH <SEP> base <SEP> 125.3 C <tb> C6H5-CH=CH-CH2 <SEP> C6H5 <SEP> H <SEP> CH <SEP> base <SEP> 147.1 C <tb> C6H5-CH2-CH2 <SEP> 4-F-C6H4 <SEP> H <SEP> CH <SEP> base <SEP> 113.8 C <tb> C6H5-O-(CH2)3 <SEP> 4-F-C6H4 <SEP> H <SEP> CH <SEP> base <SEP> 105.6 C <tb> 4-CH3O-C6H4-S-(CH2)3 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 114.5 C <tb> C6H5-CH2-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 153.2 C <tb> EMI47.1 <SEP> L <SEP> Rê <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> salt <SEP> form <SEP> Melting <SEP> point <tb> <SEP> # <tb> <SEP> #=CH-CH2-CH2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 177.6 C <tb> <SEP> # <tb> 4-(CH3-S)-C6H4-(CH2)2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 176.0 C <tb> 4-(CH3-SO2)-C6H4-(CH2)2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> 1/2 <SEP> CH3-CH-CH3 <SEP> 235.8 C <tb> <SEP> OH <tb> (4-F-C6H4)2-CH-(CH2)3 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 131.9 C <tb> CH3-(CH2)3 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 147.5 C <tb> C6H5-O-CH2-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 142.5 C <tb> (C6H5)2-CH-CH2-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 141.4 C <tb> NC-CH2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> CH <SEP> base <SEP> 178.7 C <tb> 4-F-C6H4-CO-(CH2)3 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> N <SEP> base <SEP> 161.5 C <tb> 4-F-C6H4-O-(CH2)3 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 124.9 C <tb> <SEP> ##O#CH2 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 184.7 C <tb> <SEP> ##O# <tb> CH2=CH-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 132.6 C <tb> 2,6-(CH3)2-C6H3-CO-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 176,8 C <tb> O#N-CH2-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> 1/2H2O <SEP> 153.3 C <tb> EMI48.1 <SEP> L <SEP> Rê <SEP> (R )n <SEP> O <SEP> Base <SEP> or <SEP> salt <SEP> form <SEP> Melting <SEP> point <tb> C6H5-CH=CH-CH2 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 124.6 C <tb> 4-F-C6H4-CO-(CH2)3 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 141.0 C <tb> CH3-(CH2)5 <SEP> C6H5-CH2 <SEP> H <SEP> N <SEP> base <SEP> 137.3 C <tb> 3-CN-3,3-(C6H4)2-C-(CH2)2 <SEP> 4-F-C6H4-CH2 <SEP> H <SEP> N <SEP> 2 <SEP> HCl.H2O <SEP> 188.9 C <tb> 3-CN-3,3-(C6H4)2-C-(CH2)2 <SEP> C6H5-CH2 <SEP> H <SEP> CH <SEP> 2 <SEP> HNO3.H2O <SEP> 151.1 C <tb> 3-CN-3,3-(C6H4)2-C-(CH2)2 <SEP> CH3-CH2 <SEP> H <SEP> CH <SEP> 2 <SEP> HNO3.1/2H2O <SEP> 240.5 C <tb> Example XXII A mixture of 2.4 parts of (2-bromoethyl)benzene, 6 parts of 5(6 )-fluoro- I -(4-fluorophenylmethyl) -N-(4-piperidinyl)- I Hbenzimidazol-2-amine dihydrobromide, 4 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl-2-pentanonc is stirred and refluxed overnight using a water-eparator. The reaction mixture is cooted and poured onto 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 collected and the eluent is evaporated. The residue is separated by column-chromato- graphy 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 petroleumether, and dried, yielding 1 part (17.55) of 6-fluoro-1-(4-fluorophenyl- methyl)-N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol2-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 petroleumether, and dried, yielding 1.2 parts of 5-fluoro-l- (4-fluorophenylmethyl) -N - S-(2 -phenylethyl) -4-piperidinyl]-1H- benzimidazol-2-amine monohydrate; mp. 188.8 C. Example XXIII A mixture of 4 parts of 1-(3-chloropropyl)-1,3-dihydro-3- (1-methylethenyl)-2H-benzimidazol-2-one, 7 parts of 1-(phenylmethyl) -N- (4-piperidinyl )-1 H-benzimidazol-2-amine dihydrobromide, 5 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide is stirred and heated overnight at 700C. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol. After stirring for 1 hour, the solvent is evaporated and the residue is taken up in water. The free base is liberated in the conventional manner with ammonium 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, yielding 3.3 parts (45.7S) of 1,3-dihydro1-[3-{4-[1-(phenylmethyl)-1H-benzimidazol-2-ylamino]-1piperidinyl3 propyl ]-2H-benzimidazol-2-one; mp. 243.10±. Following the same procedure and using equivalent amounts of the appropriate starting materials there are prepared: 1-[3-{4-[1-(fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 237.6 C; 1-[7- {4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-3- methyl-1-piperidinyl}-propyl]-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride. 2-propanolate (1:1); mp. 244.1 C; 1-[3-{4-[3-(4-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; mp. 185.3 C; 1-[3-{4-[1-(4-fluorophenyl)-1H-benzimidazol-2-ylamino]-1piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; 188.9 C; and 1,3-dihydro-1-[3-{4-[3-(phenylmethyl)-3H-imidazo[4,5-b]pyridin2-ylamino]-1-piperidinyl}-propyl]-2H-benzimidazol-2-che;mp. 221.7 C. Example XXIV A mixture of 2. 3 parts of 2-(4-methoxyphenyl)ethyl methanesulfonate, 4.9 parts of I-[(4-fluorophenyl)methyl]-N (4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 3,2 parts of sodium carbonate. 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide is stirred overnight at 70 C. The reaction mixture is poured onto water. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using z mirrire of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent Ls evaporated. The residue is crystallized from t, 2'- oxybispropane, yielding 2.2 parts (48 %) of 1-(4-fluorophenylmethyl)-N-{1-[2-(4-methoxyphenyl)ethyl]-4-piperidnyl}-1H-benzimidazol-2-amine; mp. 172. 9C. Example XXV Following the procedure of Example XXIV and using equi valent amounts of the appropriate starting materials the following compounds are obtained in free base form or in the form of an acid addition salt after reacting the free base with an appropriate acid. EMI52.1 EMI52.2 <tb> <SEP> Base <SEP> or <SEP> melting <tb> Aryl <SEP> R <SEP> Rê <SEP> O <SEP> salt <tb> <SEP> form <SEP> point <tb> <SEP> 3,4-(CH3O)2-C6H3 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> CH <SEP> base <SEP> 69.3 C <tb> <SEP> 2,5-(CH3O)2-C6H3 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> CH <SEP> base <SEP> 127.9 C <tb> <SEP> 4-(C2H5O)-C6H4 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> CH <SEP> base <SEP> 152.3 C <tb> <SEP> 4-(CH3O)-C6H4 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> N <SEP> base <SEP> 149.1 C <tb> <SEP> 3-(CH3O)-C6H4 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> CH <SEP> 2HCl.1/2 <SEP> 242.4 C <tb> <SEP> H2O <tb> <SEP> 2-(CH3O)-C6H4 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> CH <SEP> base <SEP> 158.1 C <tb> <SEP> 4-(CH3O)¯C6H4 <SEP> CH3 <SEP> 4-F-C6H4-CH2 <SEP> CH <SEP> 2HCl <SEP> 184.0 C <tb> <SEP> (cis+trans <tb> <SEP> isomer) <tb> <SEP> 3,4,5-(CH3O)-C6H2 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> CH <SEP> 2HCl.1/2 <SEP> 260.2 C <tb> <SEP> H2O <tb> <SEP> 3,4-(CH3O)2-C6H3 <SEP> H <SEP> C6H5-CH2 <SEP> CH <SEP> base <SEP> 149.8 C <tb> <SEP> 4-(CH3O)-C6H4 <SEP> CH3 <SEP> C6H5-CH2 <SEP> CH <SEP> 2HClH2O <SEP> 198.4 C <tb> <SEP> (cis+trans <tb> <SEP> isomer) <tb> <SEP> 3-(CH3O)-C6H4 <SEP> H <SEP> C6H5-CH2 <SEP> CH <SEP> base <SEP> 128.6 C <tb> <SEP> 4-(C2H5O)-C6H4 <SEP> H <SEP> C6H5-CH2 <SEP> CH <SEP> base <SEP> 128.5 C <tb> <SEP> 2-(CH3O)-C6H4 <SEP> H <SEP> C6H5-CH2 <SEP> CH <SEP> 2HCl <SEP> 186.1 C <tb> <SEP> 2H2O <tb> <SEP> 3-(CH3)-C6H4 <SEP> H <SEP> C6H5-CH2 <SEP> CH <SEP> 2HCl.H2O <SEP> 235.7 C <tb> <SEP> 4-(CH3O)-C6H4 <SEP> H <SEP> C6H5-CH2 <SEP> CH <SEP> 2HCl.H2O <SEP> 274.7 C <tb> 4-Cl-C6H4 <SEP> H <SEP> C6H5-CH2 <SEP> CH <SEP> base <SEP> 183.9 C <tb> 3,4,5-(CH3O)3-C6H2 <SEP> H <SEP> C6H5-CH2 <SEP> CH <SEP> base <SEP> 156.6 C <tb> <SEP> 4-(C6H5CH2O)-C6H4 <SEP> H <SEP> 4-F-C6H4-CH2 <SEP> CH <SEP> base <SEP> 155.4 C <tb> <SEP> 4-CH3O-C6H4 <SEP> H <SEP> C6H5 <SEP> CH <SEP> base <SEP> 157.8 C <tb> <SEP> 4-CH3O-C6H4 <SEP> H <SEP> 4-F-C6H4 <SEP> CH <SEP> base <SEP> 167.4 C <tb> <SEP> 4-CH3O-C6H4 <SEP> H <SEP> 4-NO2-C6H4-CH <SEP> CH <SEP> base <SEP> 200.1 C <tb> EMI53.1 <tb> <SEP> Base <SEP> R <SEP> R2 <SEP> Q <SEP> Best <SEP> or <SEP> Melting <tb> <SEP> Aryl <SEP> R <SEP> R2 <SEP> Q <SEP> Salt <SEP> Point <tb> <SEP> Form <tb> 2'4-(CH30)2-C6H3 <SEP> H <SEP> 4-F-C,H4'CH2 <SEP> CH <SEP> 2 <SEP> H±1 <SEP> 190.40C <tb> <SEP> 1/2H20 <tb> 4-CH3C-C6H4 <SEP> H <SEP> 4-F-2-CH3- <SEP> CH <SEP> 2 <SEP> HBr <SEP> 264.80C <tb> <SEP> C6H3-CH2 <tb> 4-CH30-C6H4 <SEP> H <SEP> C6H5-CH2 <SEP> N <SEP> base <SEP> 124.10C <tb> 64 <tb> (C6H5-CH2-0) <SEP> C6H3 <SEP> H <SEP> 4-F-±6H4-±H2 <SEP> CH <SEP> base <SEP> 145.60C <tb> <SEP> H <SEP> 4-F-C6H4-±H2 <SEP> CH <SEP> 2 <SEP> HC1. <SEP> 264.60C <tb> <SEP> HO <tb> <SEP> l <tb> Example XXVI A mixture of 2.8 parts of [2-(2-thienyl)ethyll 4-methylbenzenesulfonate, 4.9 parts of 1-[4-fluorophenyl)methylj-N-C4- piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 2.1 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,Ndimethylformamide is 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, yielding 2.3 parts (534 of l-(4-fluorophenylmethyl)-N-1-C2-(2- thienyl)ethyl l4piperidinylJ -1H-benzimidazol-2-amine; mp. 131.6 C. Following the same procedure and using equivalent amounts of the appropriate starting materials there are prepared: 1-(phenylmethyl)-N-{1-[2-(2-thienyl)ethyl]-4-piperidinyl}-1Hbenzimidazol-2-amine dihydrochloride. monohydrate; mp. 259-2730C; 1-(4-fluorophenylmethyl)-N-{1-[2-(1-naphthalenyl)ethyl]-4-piperi dinyl -1 H-bc?nzimidazol-2-amine ; mp. 143.10C; and 3-(4-fluorophenylmethyl)-N-{1-[2-(2-thienyl)ethyl]-4-piperidinyl}3H-imidazo[4,5-b]pyridin-2-amine; mp. 176.2 C. Example XXVII A mixture of 2.1 parts of 2-(ethenyl)pyridine, 3.25 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidninyl)-1H-benzimidazol-2amine and 80 parts of 1-butanol is stirred and refluxed overnight. The reaction mixture is evaporated. The residue is purified by columnchromatography 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 crystallized from 2,2'-oxybispropane, yielding 1 part (23S) of 1-[(4-fluorophenyl)methyl]-N-{1-[2-(2-pyridinyl)ethyl-4-piperidinyl}-1Hbenzimidazol-2-amine; mp. 133.40±. Following the same procedure and using equivalent amounts of the appropriate starting material there are also prepared: 4-[1-(4-fluorophenylméthyl)-1H-benzimidazol-2-ylamino]-1piperidinepropanenitrile; mp. 166.5 C; 1-(4-fluorophenylmethyl)-N-{1-[2-(4-pyridinyl)ethyl]-4-piperidinyl} lH.benzimidazol-2-amine; mp. 158.2 C; and 3-(4-fluorophenylmethyl)-N-{1-[2-(2-pyridinyl)ethyl]-4-piperidinyl}3H-imidazo[4,5-b]pyridin-2-amine; mp. 157.2 C. Example XXVIII To 3. 96 parts of 1-(4-fluorogbenzoyl)aziridine, dissolved in 16 parts of benzene, are added 3.25 parts of 1-[(4-fluorophenyl)- methyy-N- (4- piperid inyl) -1 H-benzimidazol- 2 - amine, 90 parts of benzene and 45 parts of N, N-dimethylfortamide. The whole is 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 methylbenzene. The combined organic phases are dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2, 2'-oxybispropan., yielding 1 part (19%) of 4-fluoro-N-[2-{4-[1-(4-fluorophenyl- methyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]benzamide; mp.193.7 C. Starting from 3 -(phenylmethyl) N- (4- piperidinyl) - 3H- imidazo [4, 5-b]pyridin-2-amine and following the same procedure there is also prepared: 4-fluoro-N-[2-{4-[3-(phenylmethyl)-3H-imidazo[4,5-b]pyridin2-ylamino]-1-piperidinyl}ethyl]benzamide; mp. 187.5 C. Example XXIX A mixture of 3.6 parts of [(4-methoxyphenoxy)methyl] oxirane, 4.9 parts of 1-[(4-fluorphenyl)methyl]-N-(4-piperidinyl)-1Hbenzimidazol-2-amine dihydrobromide, 2.1 parts of sodium carbonate, 40 parts of methanol and 90 parts of benzene is stirred and refluxed overnight. The reaction mixture is filtered and the filtrate is eva ponted. The reside is crystallized from z pure of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 2.6 parts (51 %) of 4[1-(4-fluorphenylmethyl)-1H-benzimidazol-2 ylamino]-&alpha;-(4-methoxyphenoxymethyl)-1-piperidineethanol;mp. 174.5 C. Example XXX Following the procedure of Example XXIX and using equivalent amounts of the appropriate starting materials there are also prepared: &alpha;-(phenoxymethyl)-4-{[I-(phenylmethyl)-1H-benzimidazol-2-yl]- amino}-1-piperidineethanol; mp. 146.6 C; 4-[1-(4-fluorphenylmethyl)-1H-benzimidazol-2-ylamino]-&alpha;- (phenoxymethyl)-1-piperidineethanol; mp. 181.3 C; 4-[1-(4-fluorphenylmethyl)-1H-benzimidazol-2-ylamino]-3 methyl-&alpha;-(phenoxymethyl)-1-piperidineethanol dihydrochloride. monohydrate; mp. 163.3 C; &alpha;-(4-methoxyphenoxymethyl)-4-[1-(phenylmethyl)-1H-benzimidazol-2- ylamino]-1-piperifineethanol; mp. 162.7 C; &alpha;-(2-butoxyphenoxymethyl)-4-[1-(4-fluorophenylmethyl)-1H-benz- imidazol-2-ylamino]-1-piperidineethanol; mp. 138.7 C; &alpha;-(2,6-dimethoxymethyl)-4-[1-(4-fluorphenylmethyl)-1H- benzimidazol-2-ylamino]-1-piperidineethanol; mp. 140 C; 4-[1-(4-fluorphenylmethyl)-1H-benzimidazol-2-ylamino]-&alpha;- (2-methoxyphenoxymethyl)-1-piperidineethanol; mp. 174 C; 1- -14- [1-(4-fluorphenylmethyl)- I H-benzimidazol- 2 - ylamino- 1-piperidinyl }-2-hydroxypropoxy]phenyl} ethanone; mp. 174. 7-C; -&alpha;(2,6-dimethoxymethyl)-4-[1-(phenylethyl)-1H-benz- imidazol-2-ylamino]-1-piperidineethanol; mp. 122.2 C; 4-[1-(4-fluorophenylmethyl)- 1 H-benzimidazol-2 -ylaming7- - phenyl-l-piperidineetbanol; mp. 184.1 C; and &alpha;-(phenoxymethyl)-4-[3-(phenylmethyl)-3H-imidazo[4,5-b]pyrimidin- 2-ylamino]-1-piperidinnethanol; mp. 136.6 C. Example XXXI To a stirred mixture of 40. 4 parts of 1-(4-fluorophenylmethyl)- N-(4-piperidinyl)-1H-benzimidazol-2-amine hydrobromide and 400 parts of methanol are 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, yielding 29 parts (647.) of4-[1- (4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinoethanol monohydrobromide; mp. 248.2 C. Example: XXX To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol, are added 1.5 parts of formaldehyde solution 37%, 3 parts of 1-(phenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-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 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 alkalized with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol. The salt is filtered off and dried, yielding 1.5 parts (36.6t) of N-(1-methyl-4- piperidinyl)-1-(phenylmethyl)-1H-benzimidazol-2-amine dihydrochloride monohydrate; mp. 1919.1 C. Following the same procedure and using equivalent amounts of the appropriate starting materials there are also prepared: 1-(4-fluorophenylmethyl)-N-(1-methyl-4-piperidinyl)-1H-benzimidazol2-amine; mp. 145.50Ci N-Cl-cyclohexyl-4-piperidinyl )-1-(4-fluorophenylmethyl)-lH- benzimidazol-2-amine; mp. 1680C; 1-(4-fluorophenylmethyl)-N-[1-C1-methyl-2-phenylethyl)-4 piperidinyl]-1H-benzimidazol-2-amine; mp. 182.40C; 1-methyl-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine dihydrochloride dihydrate; 300.60C; 1-ethyl-N-[1-methylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 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 XXXIII To 1 part of t solution of 2 parts of thiophene in 40 parts of ethanol, are added 2 parts of cyclohexanone, 3 parts of 1-(phenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-am,ine, 1 part of acetic acid and 120 parts of mathmol 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 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 aiali:ed with sodium hydroxide. The product is errracted with tetrahydrofuran. The extract is dried, altered and evaporated. The residue is crystallized from a mixture of 2,2'-axybispropane and 2-propanol, yielding 1.5 parts (38.5%) of N-(1-cyclohexyl-4-piperidinyl)-1- (phenylmethyl)-1H-benzimidazol-2-amine; mp. 143 C. Following the same procedure and using equivalent amounts of the appropriate starting materials there are also prepared: 1-phenyl-4-{4-[1-(phenylmethyl)-1H-benzimidazol-2-ylamino]-1piperidinyl}cyclohexanecarbonitrile; mp. 106-017 C; 4-{4-[1-(4-fluorophenylm,ethyl)-1H-benzimidazol-2-ylamino]-1 piperit3inyl S -1 . phenylcyclohexanecarbonitrile dihydrochloride; mp. 275 C; 1-[3-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1piperidinyl}butyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 234.8 C; N-(1-cyclohexyl-4-piperidinyl)-3-(phenylmethyl)-3H-imidazo[4,5-b]pyridin-2-amine, mp. 129.2 C; N-F1-( 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}-4piperidine]-1H-benzimidazol-2-amine; mp. 135.6 C; Example XXXIV A mixture of 39.8 parts of N-(2-aminophenyl)-N'-ethyl-N'- [1-(2-phenyslethyl)-4-piperidinyl]- 15 parts of mercury oxide, 0.1 parts of sulfur and 400 parts of methanol is stirred and refluxed overnight. The reaction mixture is filtered hot over Hyflo and the filtrate is evaporated. The residue is crystallized from 4methyl-2-pentanone. The product is filtered off and dried, yielding 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 there are also prepared: N-[1-(2-phenylethyl)-4-piperidinyl]-N-propyl-1H-benzimidazol-2amine; N-Cl -methyl ethyl-N-Fl - (2-phenylethyl ) -4-piperidinyl J-1 H-benzimida- zol-2-amine; mp. 228.4 C; N-cyclopropyl-N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol2-amine; "'p. 193.50±; N-[1-(2-phenylethyl)-4-piperidinyl]-N-(phenylmethyl)-1Hbenzimidazol-2-amino; mp. 191.5 C. Example XXXV To a stirred and cooled (below S-C) mixture of 3. 3 parts of N-methyl-N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol2-amine, 100 parts of dimethylsulfoxide and 90 parts of benzene are added 0.5 parts of sodium hydride dispersion 50%. After stirring for 30 minutes, 1.5 parts of l-(chloromethyl)-4-fluoro- benzene rfcia8dbd and stirring is continued overnight while the mixture is allowed to reach room temperature. The reaction mixture is poured onto water and the product t extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from 2-propanol, yielding 2.8 parts (54.4%) of 1-[(4-fluorophenyl)metyhl]-N-methyl-N- [1(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amine dihydrochloride; mp. 246.6 C. Following the same procedure and using equivalent amounts of the appropriate starting materials there are also prepared: 1-[(4-chlorphenyl)methyl]-N-[1-(2-phenylethyl)-4-piperidinyl] N-(phenylmethyl)-1H-benzimidazol-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)methyl]-N[1-(2-phenylethyl)-4-piperidinyl] N-(pehnylmethyl)-1H-benzimidazol-2-amine; mp. 122.4 C; 1-[(4-fluorophenyl)methyl]-N-[1-(2-phenylethyl)-4-piperidinyl] N-(phenylmethyl)-1H-benzimidazol-2-amine; mp. 108.5 C; 1-(4-bromophenylmethyl)-N-[1-(2-phenylethyl)-4-piperidinyl]-N (phenylmethyl)-1H-benzimidazol-2 -amine; mp. 139.30 C; 1-[(4-methylphenyl)methyl]-N-[1-(2-phenylethyl)-4.-piperidinyl] N-(phenylmethyl)-1H-benzimidazol-2-amine; mp. 123.4 C; 1-(2-chlorphenylmethyl]-N-[1-(2-phenylethyl)-4.-piperidinyl]-N (phenylmethyl)-1H-benzimidazol-2-amine; mp. 123.4 C; 1-butyl-N[1-(2-phenylethyl)-4-piperidinyl]-N-(phenylmethyl)-1H be-zimidazol-2-atine; mp. 76.5 C; and 1-ethyl-N-[1-(2-phenylethyl)-4.-piperidinyl]-N-(phenylmethyl) lH-benzimidazol-2-amine dihydrochloride, dihydrate; mp. 157. 20C. Example XXXVI A mixture of 1.6 parts of I -(I -chloroethyl)-4-fluorobenzene, 3.2 parts of N-[1-(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2 amine, I part of sodium carbonate, O. I parts of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred and refluxed over night with water-separator. The reaction mixture is cooled, poured onto water and the layers are separated. The organic phase is dried, filtred and evaporated. The residue is purified by column-chromato- graphy 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 it crystallized from 2,2' -oxybis- propane. The product is filtered off and dried, yielding 1.8 parts (40.7%) of 1-[1-(4-fluorophenyl)ethyl]-N-[1-(2-phenylethyl)-4 piperidinyl]-1H-benzimidaziol-2-amine; mp. 161.7 C. Example XXXVII Following the procedures of Example XXXV and XXXVI 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 after reacting the free base with an appropiate acid EMI63.1 EMI63.2 <SEP> 2 <SEP> BI <SEP> or <SEP> SI <SEP> torm <SEP> maltingpoint <tb> R <SEP> R <tb> H <SEP> C,HiC4 <SEP> bru <SEP> 136.rC <tb> <SEP> C6H4-(CR2)2 <tb> R <SEP> (4-F-C6H5)-CR(C6H5) <SEP> ZHCLH2O <SEP> 239.6'C <tb> H <SEP> C6H;;,CR(CH3)-CE2 <SEP> base <SEP> 144.50C <tb> H <SEP> . <SEP> cH2 <SEP> base <SEP> 127.60C <tb> H <SEP> c6H5-CH(CH3) <SEP> INCI. <SEP> HzO <SEP> 239. <SEP> 90C <tb> H <SEP> (4-F-C6H4)2CH <SEP> base' <SEP> 17Z. <SEP> 5-C <tb> H <SEP> 24CH30)-C6B <SEP> Cz2 <SEP> base <SEP> 128. <SEP> S-C <tb> cH3 <SEP> ZCH3O)-C6H+-C <SEP> 2HNO3 <SEP> 169. <SEP> 7'C <tb> CE3 <SEP> - <SEP> 2-Cl-C6H4-Ch <SEP> 2HC1 <SEP> 251.ZC <tb> CR3 <SEP> 4-flr-%H4-CH1 <SEP> z-Cf <SEP> 2XCL <SEP> qO <SEP> l87.l0C <tb> <SEP> a <tb> CH3 <SEP> 4-(CR3O)-C6H4CH <SEP> ZN3 <SEP> 163. <tb> <SEP> 3 <SEP> o <SEP> fHN03 <SEP> l63.50C <tb> ca3 <SEP> C6B5-Ca2 <SEP> Z C1 <SEP> 243. <SEP> 1-C <tb> CH3 <SEP> 4¯(CH3)-C6R4-CR2 <SEP> 2HN03 <SEP> 175. <SEP> 3'C <tb> CHI <SEP> 4-CI-C6H-cH2 <SEP> 2HC1 <SEP> 151. <SEP> 30C <tb> a3 <SEP> n.C4H9 <SEP> 2XC1 <SEP> 257.9'C <tb> CH3 <SEP> C2H5 <SEP> 2HC1. <SEP> 243.1C <tb> C2H5 <SEP> C6H5-CH1 <SEP> base <SEP> 1l5.80C <tb> CZH5 <SEP> C2H5 <SEP> base <SEP> 93. <SEP> 2-C <tb> EMI64.1 <tb> <SEP> t <SEP> R2 <SEP> Base <SEP> or <SEP> Salt <SEP> form <SEP> melting <SEP> point <tb> aC3H, <SEP> . <SEP> C6HS-CHZ <SEP> 2HCLO <SEP> l59.4-C <tb> nC3H <SEP> aC4H9 <SEP> (COUCH)2 <SEP> I77.50C <tb> nC3H <SEP> C2R5 <SEP> 2HC1 <SEP> 160. <SEP> rc <tb> iC3H7 <SEP> C2H5 <SEP> 2HC1. <SEP> 1 <SEP> H20 <SEP> 206. <SEP> 8 <SEP> C <tb> iC3H7 <SEP> C6H5-C <SEP> (CoCH)z <SEP> 215.6'C <tb> 1C3R7 <SEP> aC4H9 <SEP> (COOT)2 <SEP> 198.O'C <tb> aC4H9 <SEP> C6 <SEP> 5 <SEP> HZ <SEP> 2HCL2H20 <SEP> 160.0-C <tb> nCHq <SEP> 4-Br-C6fl4-CH2 <SEP> z-C, <SEP> 2HCL <SEP> 137.20C <tb> aC4H9 <SEP> nC4H9 <SEP> 2HCL <SEP> 2X20 <SEP> I38 <SEP> . <SEP> 7-C <tb> 4;F16:sffr <SEP> FIZZ4-F-C6H4- <SEP> 135.5'C <tb> < 1 <SEP> C2Hs <SEP> 2HCI. <SEP> 2H20 <SEP> 123.80C <tb> Example XXXVm A mixture of 3.2 parts of -N-[1-(2-phenylethyl)-4.-piperidinyl]1H-benzimidazol-2-amine; 2.9 parts of [2-(2-thienyl)ethyl] 4methylbenzenesulfonate, I part of sodium carbonate and 135 parts of 4-methyl-2-pentanona is stirred and refluxed ovgernight with water separator. The reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by columm-chromatography over silica gel using z mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is eva porated. The residue is crystallized from a mixture of 2, 2'-oxybis- propane and 2-propoone, yielding I part (23.2 %) of phenylethyl)-4-piperidinyl]-I-[2-(2-thienyl)ethyl]-1H-benzimidazol2-amine; mp. 118.3 C. Example XXXIX To a stirred and cooled (below 5-C) mixture of 4 parts of N- [I-(2-phenylethyl)-4-piperidinyl]- I -(phenylmethyl) - I H-benz imidazol-2-amine, 100 parts of 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 of (chromethyl)benzene are added and stirring is continued for 4 hours while the mixture is allowed to reach room temperature. The reaction mixture is poured onto water and 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 trichlormethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent t evaporated. The residue is converted into the nitrate salt in 2-propanone. The salt is filtered off and dried, yielding 1.5 parts (24%) of N{1-(2-phenylethyl)-4-piperidinyl]-N, 1-bis- (phenylmethyl)-1H-benzimidazol-2-amine dinitrate; mp. 156.9 C; Example XL To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol are added 3.3 parts of 1 -(4-fluorophenylmethyl)-N- [2-(4-nitrophenyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-oncharcoal 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 silica gel using a mixture of methylbenzene and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 1.3 parts (42%) of N-{1-[2-(4-aminophenyl) ethyl]-4-piperidinyl}-1-(14-fluorophenylmethyl)-1H-benzimidazol 2-amine; mp. 195.4 C. Following the same hydrogenation procedure and starting from the corresponding flitro-compound there is also prepared: 1-[(4.-aminophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl] 4-piperidinyl}-1H-benzimidazol-2-amine monohydrate; mp. 142.6 C. Example XLI A mixture of 7.5 parts of 1-(4-nuorophenylmethyl)-N- [1-{2-[4-(phenylmethoxy)phenyl]ethyl}-4-piperidinyl]-1H benzimidazol-2-amine and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 part of 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'-oxybis- propane. The product is filtered off and dried, yielding 5.5 parts (88.5 %) of 4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol2-ylamino]-1-piperidinyl}ethyl]phenol hemihydrate; mp. 111.6 C. Following the same hydrogenation procedure and starting from 1-(4-fluorophenylmethyl)-N-[1-{2-[3-methyl-4-(phenylmethoxy)phenyl]ethyl}-4-piperidinyl -1 H-ben:imidazol- 2-amine there is also prepared 4-{2-[4-{[1-(4-fluorophenylmethyl)-1H benzimidazol-2-yl]amino}-1-piperidinyl]ethyl}-2-methylphenol dihydrochloride monohydrate; mp. 277.8 C. A mixture of 8 parts of 1 -(4-fluorophenylmethyl)-N- {1- [2-(3-methoxyphenyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2amine and 225 parts of a hydrobromic acid solution 48 S in acetic acid is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is taken up in water. The free base is liberated in the conventional manner 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 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and dried, yielding 0. 8 parts (9%) of 3-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl amino I-piperidinyl}ethyl/phenol dihydrochloride. monohydrate; mp. 209.8 C. Example XLII A mixture of 1.2 parts of 3-bromo-l-propene, 4 parts of 4[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]1-piperidinyl} ethyl]phenol, 1.4 parts of potassium carbonate and 160 parts of 2-propanone is 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 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 into the hydrochloride salt in 2-propanone. The salt is filtered off and dried, yielding 1 part (19.9 %) of 1-(4-fluorophenylmethyl)-N-[1-{2-[4-(2propenyloxy)phenyl]ethyl}-4-piperidinyl]-1H-benzimidazol 1-2amine dihydrochloride; mp. 224. 70C. Example XLII A mixture of 15 parts of thionyl chloride, 4 parts of 4 J1-(4-fluorophenylmethyl)- 1 H-benzimidazol-2 -ylamino]- 1- piperidinnethanol dihydrochloride and 375 parts of trichloromethane is stirred and refluxed overnight. The precipitated product is filtered off and dried. yielding 13 parts (835) of N-[1- (2-chloroethyl)-4-piperidinyl]-1(4-fluorophenylmethyl)-1H-benzimidazol2-amine dihydrochloride; mp. > 260 C. Example XLIV A mixture of 0. 9 parts of morpholine, 4.8 parts of N-[1- (2 - chloroethyl) -4-piperidinyl]- 1 -(4-fluorophenylmethyl) - I H benzimidazol-2-amine dihydrochloride, 3 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N, N-dimethylform- amide is stirred and heated overnight at 70 C. The reaction mixture is poured onto water and 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 a mixture of 2-propanone and 2,2'-oxybeispropane, yielding 0.6 parts (12.5 %) of [2-{4-[1 (4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl] 4-morpholinecarboxylate; mp. 144.8 C. Example XLV A mixture of 3.6 parts of morpholine, 4.8 parts of N-[1-(2- chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol2-amine dihydrochloride 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide is strirred and heated overnight at 70 C. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in methanol. The salt is filtered off and dried, yielding I part (18.3%) of 1-(4-fluorophenylmethyl)-N-{1.-[2-(4-morpholinyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine trichloride; mp. + 300 C. Example XLVI To a stirred mixture of 4. 4.5 parts of 4-[1-(4-fluorophenyl- methyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol, 2 parts of N,N-diethylethanamine and 195 parts of dichloromethane is added dropwise a solution of 1.7 parts of 4-methozybenzoyl chloride in dichloromethane. Upon 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 trichioromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and dried, yielding 2.5 parts (43.5 %) of [2-{4-(4-fluorophenylmethyl)-1H-benz imidazol-2-ylamino]-1-piperidinyl}ethyl] 4-methoxybenzoate; dihydrochloride. hemihydrate; mp. 189.2 C. Following the same procedure and using equivalent amounts of the appropriate starting materials there are also prepared: {4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino] 1-piperidinyl}ethyl} benzeneacetate; mp. 135.1 C; {4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino] 1 piperidinyl ethyl]phenyl} 4-methoxybenzoate; mp. 157.10C; {4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino] 1-piperidinyl}ethyl}methyl carbonate; mp. 134.5 C; and {4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1 piperidinyl}ethyl}(phenylmethyl) carbonate; mp. 147.8 C; and Example XLVII A mixture of 1.2 parts of chloracetonitrile, 6. 7 parts of 4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]1-piperidinyl}ethyl]phenol, 2.8 parts of potassium carbonate and 160 part of 2-propanone is stirred and refluxed overnight. The reaction mixture is poured onto water and the product is extracted with methylbenzene, The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filered off and dired, yielding 7.4 parts (78.6 %) of {4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino] 1-piperidinyl}ethyl]acetonitrile dihydrochloride, monohydrate; mp. 224.6 C. Following the same procedure and using equivalent amounts of the appropriate starting materials there are prepared: ethyl 2-{4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol2-ylamino]-1-piperidinyl}ethyl]phenoxy}acetate; mp. 109.1 C; methyl 2-{4-[2-{4-[1-[4-fluorophenylmethyl)-1H-benzimidazol 2-ylamnoj-l -piperidinyl}ethyl]phenoxy} acetate; mp. 109. 8iC; and 1-[2-{4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2ylaming]-1-piperidinyl}ethyl]piperidine dihydrochzloride; mp. 247 C. Examtle XLVIII A mixture of 0.5 parts of isocyanatomethyne, 4.5 parts of 4-[1-(4-fluorophenylmethyl]-1H-benzimidazol-2-ylamino]1-piperidinyl}ethyl]phenol. and 135 parts of tetrahydrofuran is 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. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 1 part (20 %) of {4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol2-ylamino]-1-piperidinyl}ethyl]phenyl} methylcarbamate; mp. 172.2 C. By the addition-reaction of {4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]. phenol to I -isocyanatobutane there is also prepared: {4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino] 1-piperidinyl {ethyl]phenyl} butyl carbonate; mp. 142. 50C. Example IL A mixture of 9 parts of 4-[1-(4-fluorophenylmethyl)-1H- benzimidazol-2-ylamino]-1-piperidineacetonitrile and 200 parts of methanol, saturated with ammonia, is hydrogenated at normal pressure and at room temperature with 3 parts of Raney-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 into the hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from a mixture of 2-propanone and methanol, yielding 11 part of N-[1-(2-aminoethyl)-4-piperidinyl]1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine trihydrochloride; mp. 292.9 C. Following the same hydrogenation procedure and starting from 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]1-piperidinepropanonitrile there is also prepared: N.[1-(3-amino propyl) -4-piperidinyg7- 1 -(4-fluorophenylmethyl)- I H- benzimidazol- 2 - amine trihydrochloride. monohydrate; mp. 239. 3-C. Exemple 1 A mixture of 1.8 parts of 1-isothiocyanato-2-nitrobenzene, 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenyl- methyl)-1H-benzimidazol-2-amine and 135 parts of tetrahydrofuran is stirred overnight at room temperature. The reaction mixture i8 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, yielding 3.7 parts (67 ó) of N-F2-f4-F1-(4- fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl] N'-(2-nitrophenyl)thiourea as a residue. A mixture of 3.7 parts of N-F 2-f 4-t1-(4-fluorophenyl- methyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl] N'-(2-nitrophenyl)thiourea, 7 parts of iron-powder, 0.25 parts of concentrated hydrochloric acid, 48 parts of ethanol and 15 parts of water is stirred and refluxed for 1 hour. The reaction mixture is alkalized with methanol saturated with ammonia. The whole is filtered and the filtrate is evaporated, yielding 3.5 parts of N (2-aminophenyl)-N'-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimi dazol-2-ylaminol-l-piperidinyllr -ethyl]thiourea as a residue. A mixture of 3.5 parts of N-(2-aminophenyl)-N'-[2-{ 4 [1-)4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1 piperidinylJ ethyl]thiourea, 2.2 parts of mercury (II) oxide, 0.1 parts of sulfur and 80 parts of ethanol is 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 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 2propanone, yielding 1.5 parts (44.4%) of N-{1-[2-(1H-benz- imidazol-2-ylamino-ethyl]-4-piperidinyl} -1-(4-fluorophenyl- methyl)-1H-benzimidazol-2-amine; mp. 253.4 C. Example LI A solution of 4.77 parts of N-[1-(2-aminoethyl)-4-piperi- dinyl]-1 -(4-fluorophenylmethyl)- I H-benzimidazol-2 -amine trihydro - chloride in methanol saturated with ammonia is stirred for 1 hour at room temperature. The solvent is evaporated and the residue is taken up in 135 parts of tetrahydrofuran. Then there are added 6 parts of isocyanatomethane and the whole is stirred overnight at room temperature. The precipitated product is filtered off and dried, yielding 3 parts (70.7%) of N-[2-{4-[1-(4-fluorophenylmethyl) 1H-benzimidazol-2-ylamino]-1-piperidinyl}-ethyl]-N'-methylurea. homihydrate; mp. 231.4-C. Example LII To a stirred mixture of 3.8 parts of N-[I-(2-aminoethyl)4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2amine, 1 part of N,N-diethylamine and 195 parts of dichloromethane is added dropwise a solution of 1.7 parts of 4-methoxy- benzoyl chloride in dichloromethane. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto 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 converted into the hydrochloride salt in 2-propanol. The salt is filtered off and dried, yielding 1 part of N-[2-{ 4-g- (4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]-4-methoxy-N-(4-methoxybenzoyl)benzamide dihydrochloride. dihydrate; mp. 161.50C. Example LIII To I part of a solution of 2 parts of thiophene in 40 parts of ethanol are added I part of paraformaldehyde, 3.5 parts of (2- aminoethyl)-4-piperidinyl]-1 -(4-fluorophenylmethyl) - H- benzimidazol-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 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'-oxybispropane, yielding 1.5 parts (42 %) of N-{1-[2-(dimethylamino)ethyl]-4-piperidinyl}-1 (4-fluorophenylmethyl)-1H-benzimidazol-2-amine; mp. 166.10 C. example LIV To 1 part 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-g- (2-aminoethyl)-4-piperidinyl]-1-(4-flourophenylmethyl)-1H-benz imidazol-2-amine and 120 parts of methanol. The whole is hydro genated at normal pressure and at room temperature with 2 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 converted into the hydrochloride salt in 2-propanone. The salt is filtered off and taken up in water. The free base is liberated in the conventional manner with ammonium hydroxide and extracted with dicllloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 212'-oxybispropane, yielding 1.5 parts (27.5%) of N-[1-{2-[bis (phenylmethyl)aminvethyl3 -4- piperidinyjl 1- (4-fluorophenylmethyl)-1H-benzimidazol-2 -amine; mp. 116.40 C. Example LV A mixture of 5.5 parts of N-[1-(1H-benzimidazol-2-yl) 4-piperidinyl] -(phenylmethyl) - I H-benzimidazol-2 -amine dinitrate, 1.5 parts of 1-(chloromethyl)-4-fluorobenzene, 5 parts of sodium carbonate, 0. 1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight using a water-separator. The reaction mixture is poured onto 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 t evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2, 2'-oxybispropane. The product is filtered off and dried, yielding 1.5 parts (28.37.) of [1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-4-piperidinyl}1-(phenylmethyl)-1H-benzimidazol-2-amine; mp. 163.9 C. example LVI A mixture of 3.7 parts of 1-(4-nuorophenylmethyl)-N- {1-[3- (4-methoxyphenylthio)propyl]-4-piperidinyl}-1H-benzimidazol-2amine, 2.42 parts of hydrogen peroxide sol ion 30% and 20 parts of acetic acid is stirred and refluxed for 1 hour. The reaction mixture is cooled and poured ontoice-water. The whole is alkalized with sodium hydroxide solution 50% 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 trichioromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the ethanedioate salt in methanol and 2-propanol. The salt is filtered off and dried, yielding 0. 8 parts (165) of I-(4-fluorophenylmethyl)-N- {1-[3-(4-methoxyphenylsulfonyl)propyl]-4-piperidinyl}-1H-benzimidazol-2-amine ethanedioate (1:2); mp. 213.1 C. Example LVII A mixture of 5 parts of ethyl 2-{4-[2-{4-[1-(4-fluoro- phenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl] phenoxy3acetate, 70 parts of ethanamine solution 50% and 40 parts of methanol is stirred for 3 hours at room temperature. The reaction mixture is evaporated and the residue is crystallized twice from 2-propanol, yielding 1 part (19%) of N-ethyl-2-{4-[2-{4 [1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]phenoxy} acetamide; mp. 160. 90C. Example LVIII A mixture of 3.5 parts of methyl 2- {4-[2-{4-[1-(4-fluoro- phenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]phenoxy acetate, 90 parts of concentrated ammonium hydroxide and 40 parts of methanol is stirred for 4 hours at room temperature. The reaction mixture is evaporated. The residue is purified by columnchromatography 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, yielding 1 part (28.57) of 4-{4-[2-{4-[1-[4- f?uorophenylmethyl)- I H-benzimidazol-2 -ylamino]-1-piperidinyl}- ethyl]-phenoxy}acetamide; mp. 180.4 C. Example LIX To a stirred and cooled (below lOZC) mixture of 5.04 parts of carbon disulfide, 2. 06 parts of N, N'-methhetetrayThisJcyclo hexamino]and 45 parts of tetrahydrofuran is added dropwise a solution of 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1 (4-Suorophenylmethyl)- I H-benzimidazol- -amine in tetrahydro furan. Upon completion, stirring is continued overnight while the mixture is allowed to reach room temperature. The reaction mixture is evaporated. The residue is purified by columnchromatography over silica gel using a moisture of trichlorome thane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent t evaporated, yielding 4 parts (100 %) of 1-(4-fluorophenylmethyl)-N-[1-(2-isocyanatoethyl)-4piperidinyl]-1H-benzimidazol-Z-amine as a residue. A mixture of 2.1 parts of N-(4-fluorophenylmethyl)-1,2- benzenediamine, 4 parts of 1-(4-fluorophenylmethyl)-N-[1- (2-isocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran is stirred and refluxed for 2 hour..' The reaction mixture is evaporated, yielding 6 parts (1005) of N-{2-[(4-fluorophenylmethyl)amino]phenyl}-N'-[2-{4-[1-(4 fluorophenylmethyl)- 1 H -benzimidazol -2 -ylamino7- 1.- piperidinyl} ethyl thiourea as a 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 mercury (II) oxide, 0. 1 parts of sulfur. and 90 parts of tetrahydrofuran is stirred and refluxed for 3 hours. The reaction mixture is filtered over Hyno and the filtrate 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 purse fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2propanone and 2,2'-oxybispropane, yielding 1.2 parts (20%) of 1 -(4-fluorophenylmethyl)-N- J- 2 -j-(4-fluorophenylmethyl) - 1 H- benzimidazol-2-ylamino]ethyl}-4-piperidinyl]-1H-benzimidazol2-amine; mp. 196.9 C.

Claims: Claims: 1. A chemical compound selected from the group consisting of a N-heterocyclyl-4-piperidinamine having the formula EMI78.1 and the pharmaceutically acceptable acid addition salts thereof, wherein R is a member selected from the group consisting of hydrogen and lower alkyl; R1 is a member selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryllower alkyl and lower alkanoyl; R2 is a member selected from the group consisting of hydrogen, alkyl having from 1 to 10 carbon atoms, aryl, cycloalkyl and mono- and diaryl(lower alkyl); R3 is a member independently selected from the group consisting of, halo, lower alkyl, lower alkyloxy and trifluoromethyl; n is an integer of from 0 to 2 inclusive; Q is a member selected from the group consisting of CH and N; and L is a memeber selected from the group consisting of lower alkyl, which is optionally substituted with up to 3 substituents each independently selected from the group consisting of halo, cyano, hydroxy, isothiocyanato, lower alkyloxy, aryl, aryloxy, arylthio, arrylsulfonyl, amino; lower alkanyl; aryllower alkanyl; cycloalkyl, being optionally substituted with a cyano and/or an aryl group; 1- (aryllower alkyl)-1H-benzimidazol-2-yl; and a radical of the formula Z-CmH2m-, wherein m is an integer of from 1 to inclusive: and Z is a member selected from the group consisting of 4,5- dihydro-5-oxo-1H-tetrazol-1-yl, being optionally substituted in its 4-position by an aryl radical or a lower alkyl radical; 2, 3-dihydro-1 , 4-benzodiorin-2-yl; 2, 3-dihydro-l, 4-benzodioxin-6-yl; 2,4-dihydro-2-oxo-1H-benzimidazol-1-yl; 2,3dihydro-3-oxo-4H-benzoxazin-4-yl; (10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5-ylidene)methyl; 4-morpholinyl; 1-piperidinyl; 1-pyrrolidinyl; a radiacal of the formula T-N(R4)-, wherein R4 is a member selected from the group consisting of hydrogen, lower alkyl and aryllower alkyl; and T is a member selected from the group consisting of lower alkyl, aryl, aryllower alkyl, lH-benz imidazol-2-yl; and a radical of the formula EMI79.1 wherein 5 is the integer 0 or 1; X is r member selected from the group consisting of O and -N(R5)-, said R5 being z member selected from the group consisting of hydrogen, lower alkyl, aryllower alkyl, lower alkanoyl and uoyl; ; and W is a member selected from the group consisting of lower alkyl,. aryl, aryllower alkyl, amino, arylamino, mono- and di(lower alkyl)amino, mono- and di(arryllower alkyl)amino, 1-piperidinyl, 1-pyrroli vinyl and 4-morpholinyl; wherein aryl as used in the foregoing definitions, is a member selected from the group consisting of phenyl, substituted phenyl, naphthalenyl, thienyl, halothienyl, (lower alkyl)thienyl, pyridinyl, monoand di(lower alkyloxy)pyridinyl, furanyl and 1-(lower alkyl)pyrrolyl; wherein said substituted phenyl is phenyl having from 1 to 3 substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyaso, trifluoromethyl, lower alkyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyllower alkyl, phenyllower alkylsulfonyl, phenylsulfonyllower alkyl, amino, mono- and di- (lower alkyl)anino, lower alkanoyl, a radical of the formula R6-CppH2p-O-, wherein p is an integer of from 1 to 6 inclusive; ; and R6 is z member selected from the group consisting of hydrogen, amino, cyano, phenyl, aminocabonyl, mono- and di(lower a1ky1)a:dnocarbonyl, lower alkyloxycarbonyl, phenyllower aIkylox:ycarbonyl, 4-morpholinylcarbonykl, 1-piperidinylcarbonyl and 1-pyrrolidinylcarbonyl, lower alkenyl and a radical of the formula R7. wherein is is z member selected from the group consisting of alkanoyl, phenylcarbonyl, phenyllower alkylcarbonyl, lower alkyloxycarbonyl, phenyllower alkyloxycarbonyl, amino carbonyl, phenylamno carbonyl, mono - and di - (lower alkyl)aminocarbonyl. wherein said phenyl in the definition of said R 7 may be optionally substituted with up to 3 eubstituents each independently selected from the group consisting of halo, cyano, nitro, lower alkyl and lower alkyloxy: and wherein said aroyl in the definition of said X represents arylcarbonyl wherein said aryl is as defined hereabove. 2. A chemical compound selected from the group consisting of 1-(4-fluorophenylmethyl)-N-{1-[2-(4 methoxyphenyl) ethyl 1 -4-piperidinyl -lH-benzimidazol-2- amine and the pharmaceutically acceptable acid addition salts thereof. 3. A chemical compound selected from the group consisting of 4-[2-{4-[1-(4-fluorophenylmethyl)-1Hbenzimidazol-2-ylamino ]-1-piperidinyl}ethylphenol and the pharmaceutically acceptable acid addition salts thereof. 4. A chemical compound selected from the group consisting of 4-[2-{4-[1-(4-fluorophenylmethyl)-1Hbenzimidazol-2-ylamino ]-1-piperidinyl}ethylphenyl} benzeneacetate and the pharmaceutically acceptable acid addition salts thereof. 5. A chemical compound selected from the group consisting of {4-[2-{4-[1- (4-fluorophenylmethyl) -lH- benzimidazol-2-ylaminho]-1-piperidinyl}ethyl]phenoxy acetonitrile and the pharmaceutically acceptable acid addition salts thereof. 6. A chemical compound selected from the group consisting of N- tl- (2-phenylethyl) -4-piperidinyl] -1- (phenylmethyl)-1H-benzimidazol-2-amine and the pharmaceutically acceptable acid addition salts thereof. 7. An antihistaminic pharmaceutical composition comprising an inert carrier material and as an active ingredient an effective antihistaminic amount of a chemical compound selected from the group consisting of a N-heterocyclyl-4-piperidinamine having the formula EMI82.1 as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof. 8. A method to prevent the release of histamine in wariblooded animals, which comprises the systemic administration to said animals of an effective anti histaminic amount of a chemical compound selected from the group consisting of a N-heterocyclyl-4- piperidinamine having the formula EMI83.1 and the pharmaceutically acceptable acid addition salts thereof, as defined in claim 1. 9. A chemical compound having the formula EMI83.2 wherein: L1 is a ether selected from the group consisting of hydrogen, lower alkyloxycarbonyl and phenylmethoxycarbonyl; R is a member selected from the group consisting of hydrogen and lower alkyl R1 is a member selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryllower alkyl and lower alkanoyl; R2 is a memeber selected from the group consisting of hydrogen, alkyl having from 1 to 10 carbon atoms, aryl, cycloalkyl and sono- and diaryl (lover alkyl); R3 is a memeber independently selected from the group consisting of, halo, lower alkyl, lower alkyloxy, tri fluoroxethyl s n is an integer of from 0 to 2 inclusive; ; Q is a member selected from the group consisting of CH and N; and wherein aryl as used in the foregoing definitions, is a .ember selected from the group consisting of phenyl, substituted phenyl, naphthalenyl, thienyl, halothienyl, (lower alkyl)thienyl, pyridinyl, mono-and di (lower alkyloxy) pyridinyl, furanyl and 1 (lower alkyl)pyrrolyl; wherein said substituted phenyl is phenyl having from 1 to 3 substituents each inde pendently selected from the group consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkylthio, lower alkylsulfonyl, lower alkyl sulfonyllower alkyl, phenyllower alkylsulfonyl, phenylsulfonyllower alkyl, amino, mono- and di- (lower alkyl)amino, lower alkanoyl, a radical of the formula R6-CpH2p-O-, wherein p is an integer of from 1 to 6 inclusive; and R6 is member selected form the group consisiting of hydrogen, amino, cyano, phenyl, a carbonyl, mono- and di(lower alkyl)aminocarbonyl, lower alkyl oxycarbonyl, phenyllower alkyloxycarbonyl, 4-morpho linylcarbonyl, 1 -piperidinylcarbonyl and 1 -pyrroli dinylcarbonyl, lower alkenyl; and a radical of the formula R-O-, wherein R7 7 is a member selected from the group consisting of alkanoyl, phenylcarbonyl, phenyllower alkylcarbonyl, lower alkyloxycarbonyl, phenyllower alkyloxycarbonyl, aminocarbonyl, phenylaminocarboyl, and mono- and di (lower alkyl)aminocarbonyl, wherein said phenyl in the definition of said R7 may be optionally substituted with up to 3 substituents each independently selected from the group consisting of halo, cyano, nitro, lower alkyl and lower alkyloxy. 10. A process for preparing a chemical compound selected from the group consisting of a N-hetero cyclyl-4-piperidinamine having the formula EMI85.1 and the pharmaceutically acceptable acid addition salts thereof, wherein R is a member selected from the group consisting of hydrogen and lower alkyl; R1 is a member selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryllower alkyl and lower alkanoyl; R2is a member selected from the group consisting of hydrogen, alkyl having from 1 to 10 carbon atoms, aryl, cycloalkyl and mono-and diaryl(lower alkyl); R3 is a member independently selected from the group consisting of, halo, lower alkyl, lower alkyloxy and trifluoromethyl; n is an integer of from 0 to 2 inclusive; Q is a member elected from the group consisting of CH and N; ; and L is a member selected from the group consisting of lower alkyl, which is optionally substituted with up to 3 substituents each independently selected from the group consisting of halo, cyano, hydroxy, isothiocycanato, lower alkyloxy, aryl, aryloxy, arylthio, arylsulfonyl, amino; lower alkenyl; aryllower alkenyl; cycloalkyl, being optionally substituted with a cyano and/or an aryl group; 1-(aryllower alkyl)-lH-benzi- imidazol-2-yl; and a radical of the formula Z-Cm-H2m-, wherein -= is an integer of from 1 to 6 inclusive; and Z is z member selected from the group consisting of 4,5- dihydro-5-oxo-1H-tetrasol-1-yl, being optionally substituted in its -porition by an aryl radical or z lower alkyl radical; 2,3-dihydro-1,4-benzodioxin-2-yl; 2,3-dihydro-1,4-benzodioxin-6-yl; 2,3-dihydro-2-oxo-1H-benzimidazol-1yl; 2,3dihydro-3-oxo-4H-benzioxazin-4-yl; (10,11-dihydro-5H-dibenzo[a,d]cylcoheptan-5-ylidene)methyl; 4-morpholinyl; 1-piperidinyl; 1-pyrrolidinyl; a radical of the formula T-N(R4)-, wherein is r member selected from the group consisting of hydrogen, lower alkyl and arryllower alkyl; and T is z member selected from the group consisting of lower alkyl, aryl, aryllower alkyl. lH-benz imidazol-2-yl; and a radical of the formula EMI87.1 wherein 5 is the integer 0 or I; X is a member selected from the group consisting of O and -N(R5)-; said H being z member selected from the group consisting of hydrogen, lower alkyl, aryllower alkyl, lower alkanoyl and uoyl; and W is z member selected from the group consisting of lower alkyl, - aryl, aryllower alkyl, amino, aryl- amino, mono- and di(lower alkyl)amino, mono- and di(aryllower alkyl)amino, 1-piperidinyl, 1-pyrrolidinyl and 4-morpholinyl: wherein aryl as used in the foregoing definitions, is a member selected front the group consisting of phenyl, substituted phenyl, naphthalenyl, thienyl, halothienyl, (lower alkyl)thienyl, pyridinyl, monoand di (lower alkyloxy)pyridinyl, furanyl and 1- (lower alkyl ) pyrrolyl wherein said substituted phenyl is phenyl having from 1 to 3 substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyllower alkyl, phenyllower alkylsulfonyl, phenylsulfonyllower alkyl, amino, mono- and di- (lower alkyl)amino, lower alkanoyl, a radical of the formula R6-CpH2p-O-, wherein p is an integer of from 1 to 6 Inclusive; and R6 is z member selected from the group consisting of hydrogen, amino, cyano, phenyl, aminocarbonyl, mono- and di(lower alkyl)aminocarbonyl, lower alkyl oxycarbonyl, phenyllower rlkylorycrrbonyl, 4-morpholinylcarbonyl, 1-piperidinylcarbonyl and 1-pyrrolidinylcarbonyl, lower alkenykl; and a radical of the formule R7-O-, wherein is b member selected from the group consisting of alkanoyl, phenylcarbonyl, phenyllower alkylcarbonyl, lower alkyloxycarbonyl, phenyllower alkyloxycarbonyl, aminocarbonyl, phenylaminocarbonyl, mono- and di (lower alkyl) aminocarbonyl, wherein said phenyl in the definition of said R7 may be optionally susbstituted with up to 3 substituents sach independently selected from the group consisting of halo, cyano, nitro, lower alkyl and lower alkyloxy; ; and wherein said aroyl in the definition of said X represents arylcarbonyl wherein said aryl is as defined hereabove, characterized by a) introducing onto a starting material of the formula EMI88.1 wherein R, R1, R2, R3, n and Q are as previously defined, the desired L-substituent onto the piperidine nitrogen by the application of art-known methode; ; i) preferably the introduction of said L into the intermediate (11) may be accomplished by the reaction of (II) with an appropriate reactive ester of the formula L Y, (III), wherein L is as previously defined and Y is a reactive ester residue such as, for example, halo, preferably chloro or bromo, or a sulfonyloxy residue such as, for example, methylsulfonyloxy or 4methylphenylsulfonyloxy, said condensation reaction preferably being conducted in an inert solvent with the addition of an appropriate base, at elevated temperatures; ii) when L in formula (I) represents a (2,3-dihydro-2oxo-lH-benzimidazol-l-yl)lower alkyl radical it is appropriate to use a reactive ester (III) wherein the nitrogen atom in the 3-position of the 2,3-dihydro-2oxo-lH-benzimidazol-l-yl group is substituted with an appropriate protecting group, preferably a l-methylethenyl group and removing said protecting group preferably by acid hydrolysis after completion of the condensation reaction; iii) when L represents a 2-aryl-2-hydroxyethyl or a 3-aryloxy 2-hydroxypropyl radical, the introduction of said substituent into the intermediate (11) may conveniently be carried out by reacting (II) at an elevated temperature with an appropriate oxirane of the formula EMI89.1 wherein m is O or 1; iv) or compounds of formula (I) wherein L represents a 2-hydroxyethyl radical may be prepared by the reaction of an appropriate piperidine of formula (II) with oxirane, following the same procedure as described for the reaction of (IV) with (II)t v) when L is, at the point of attachment to the piperidine nitrogen atom, a primary or secondary alkyl group, the compounds (I) may also be prepared by the reductive amination of an aldehyde or ketone corresponding with the alcohol L-OH with a piperidine derivative of formula (II) following art-known procedures, preferably, a mixture of the aldehyde or ketone and (11) in an appropriate organic solvent is hydrogenated in the presence of an appropriate catalyst such as, for example, palladium-on-charcoal; ; when the piperidine derivative (II) is in the form of an addition salt with a strong acid, e.g., hydrochloric or hydrobromic acid, it is appropriate to add thereto a salt of a strong base with a weak acid, e.g., sodium acetate to bind said strong acid, and when (II) contains groups that are themselves susceptable to catalytic hydrogenation, e.g. when R2 represents an arylmethyl group, it is appropriate to add to the reaction mixture an appropriate catalyst poison, such as, for example, thiophene; vi) when L represents a radical of formula Z-Cm-X12m-, wherein m is an integer of from 2 to 6 inclusive and wherein Z is as previously defined, the compounds of formula (I) can also be prepared by the reaction of (II) with an appropriate alkenyl derivative. Z-C H2m 1' according to art-known methods of carrying out similar addition-reactions, e.g.,by stirring and heating the reactants together in and appropriate reaction-inert organic solvent; vii) when L represents a 2-(aroylamino)ethyl radical or a 2-arylethyl radical the compounds (I) can also be obtained by the reaction of (II) with an appropriate l-aroylaziridine or an appropriate ethenylarene, respectively, said reactions being preferably carried out in an appropriate reaction-inert organic solvent, at elevated temperatures, or b) preparing compounds of formula (I) by the cyclodesulfurization of an appropriate thiourea derivative of the formula EMI91.1 i) said cyclodesulfurization reaction being preferably carried out by the reaction of (V) with an appropriate alkyl halide, prefeeably iodomethane in an appropriate reaction-inert organic solvent; ii) said cyclodesulfurization reaction may be also carried out by the reaction of (V) with an appropriate metal oxide or salt in an appropriate solvent, preferably preparing the compounds of formula (I) by the reaction of (V) with an appropriate Hug (11) or Pb(II) oxide or salt, such as, for example, HgO, HgCl2, Hg(OAc)2, PbO or Pb(OAc)2, or iii) utilizing methanediimines, especially N,N'methanetetraylbis[cyclo-hexanamine] as cyclodesulfurizing agents in suitable reaction-inert organic solvents; or c) preparing compounds as formula (I) wherein R9 is other thas hydrogen, said R8 being represented by R2 and said compounds by the formula (I-a), a -2 starting from a corresponding compound (I) wherein R is hydrogen, (I-b), by introducing said R2a according to art-known procedures; i) preferably said compound (I-b) is reacted with an appropriate reactive ester R2aY, (VI), wherein R a and Y are as defined above, the reaction being carried out under similar conditions as previously described herein for the reaction of (II) with (III) as described in step a) i); or d) preparing compounds of the formula (I) wherein R1 and R2 are both different from hydrogen, said R1 being represented by RÚ, and said R by R a, form the corresponding compounds wherein R1 is hydrogen by introducing the Rla- group in a similar manner as described hereinabove in step c) for the preparation of compound (I-b) starting from (I-a); or e) preparing a compound of the formula EMI93.1 by subjecting an isothiocyanate of the formula EMI93.2 to an addition reaction with a benzene diamine of the formula EMI93.3 and subsequently cyclodesulfurizing the intermediately formed thiourea of the formula EMI94.1 as described in steps b) i),b) ii),or b) iii)above; or f) preparing compounds of formula (I) wherein L represents a radical Z-CmH2m-, wherein Z represents a radical of the formula W-CO-(X)5-, wherein s is 1, X is 0 and W is an optionally substituted amine, a l-pyrrolidinyl, a 4-morpholinyl or a l-piperidinyl radical, said compounds being represented by the formula (I-d), by the reaction of the corresponding -amine, pyrrolidine, morpholine or piperidine with an approprisse N-11-[belolower alkyl)-4-piperidinyl)-inbenzimidazol-2-amine in the presence of an appropriate carbonate; or g) preparing compounds of formula (I) which contain at least one hydroxyl-group as a substituent, from the corresponding phenylmethoxy substituted compounds by subjecting the latter to a catalytic hydrogenation in the presence of an appropriate catalyst, or deriving said hydroxyl-derivatives from the corresponding lower alkyloxy substituted analogs by hydrolyzing the latter in acidic medium, using for example hydrogen bromide in acetic acid, and, if desired, said hydroxyl-sub stituted compounds may in turn be O-aLylated or acylated by reacting the latter with a halide, an alkanoyl halide, an alkyloxycarbonyl halide, or an isocyanate, or said hydroxyl-substituted compounds may also be converted into halides by reacting therewith a suitable halogenating agent or h) deriving amino-substituted compounds from the corresponding nitro- and cyano-substituted compounds by reducing the latter, e.g., by catalytic hydrogenation in the presence of an appropriate catalyst, and, if desired, said amino-substituted compounds may in turn be N-alkylated or acylated by the reaction thereof with an appropriate alkylating agent or acylating agent; or i) preparing secondary and tertiary amino-substituted compounds of formula (I) by substituting, for example, an appropriate halo-substituted compound with the desired primary or secondary amine; or j) deriving aminocarbonyl-substituted compounds from the corresponding esters by reacting the latter with anunonia or an appropriate primary- or a secondary amine in a suitable solvent; or k) deriving compounds of formula (I) which contain in their structure a sulfonyl group from the corresponding thio compounds by oxidizing the latter with an appropriate oxydizing agent; and, if desired, converting the compounds of formula (I) to the therapeutically active non-toxic acid addition salt form by treatment with an appropriate acid, or the salt form can be converted by treatment with alkali into the free base form. 11. A process for preparing a chemical compound selected from the group consisting of 1-(4- fluorophenylmethyl)-N-tl-12-(4-methoxyphenyl)ethyl]- 4-piperidinyl t- lH-benzimidazol-2-amine and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting l-[(4-fluoro- phenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol2-amine dihydrobromide with 2-(4-methoxyphenyl) ethylmethanesulfonate. 12. A process for preparing a chemical compound selected from the group consisting of 4-[2-{ 4 [1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1piperidinyl { ethyl 1 phenol and the pharmaceutically acceptable acid addition salts thereof, characterized by hydrogenating 1- (4-fluorophenylmethyl) -N- 11-+ 2 [4-(phenylmethoxy)phenyl]ethyl}-4-piperidinyl]-1H benzimidazole-2-amine. 13. A process for preparing a chemical compound selected from the group consisting of + 4-12- 4 [1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]l-piperidinyl + ethyl]phenyl} benzeneacetate and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperi dinylethyl] -phenol with benzeneacetylchloride. 14. A process for preparing a chemical compound selected from the group consisting of [1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]1-piperidinyl}ethyl]phenoxy}acetonitrile and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 4-[2-f4-(l-(4-fluoro- phenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]phenol with chloroacetonitrile. 15. A process for preparing N-[1-(2-phenylethyl)-4- piperidinyl}-1-(phenylmethyl)-1H-benzimidazol-2amine, characterized by reacting l-(phenylmethyl)-N (4-piperidinyl)-1H-benzimidazol-2-amino dihydrobromide with (2-bromoethyl)benzene. 16. A process for preparing a chemical compound having the formula EMI97.1 wnerein: L1 is a member selected from the group consisting of hydrogen, lower alkyloxycarbonyl and phenylmethoxycarbonyl; R is member selected from the group consisting of hydrogen and lower alkyl; R1 is a ember selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryllower alkyl and lower alkanoyl; R2 is a ;seeber selected from the group consisting of hydrogen, alkyl having from 1 to 10 carbon atoms, aryl, cycloalkyl and mono- and diaryl(lower alkyl); R3 is a isznber independently selected from the group consisting of, halo, lower alkyl, lower alkyloxy, trifluoromethyl; n is an integer of from 0 to 2 inclusive; Q is a member selected from the group consisting of CH and N; and wherein aryl as used in the foregoing defintions, is a umber selected from the group consisting of phenyl, substituted phenyl, naphthalenyl, thienyl, halothienyl, (lower alkyl)thienyl, pyridinyl, mono-and di(lower alkyloxy)pyridinyl, furanyl and i- (lower alkyl)pyrrolyl; wherein said substituted phenyl is phenyl having from 1 to 3 substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyllower alkyl, phenyllower alkylsulfonyl, phenylsulfonyllower alkyl, amino mono- and di-(lower alkyl)amino, lower alkanoyl, a radical of the fromula R6-CpH2p-O-, wherein p is an integer of from 1 to 6 inclusive; and 16 is r member selected from the group consisting of hydrogen, amino, cyano, phonyl, aminocarbonyl, mono- and di(lower alkyl)aminocarbonyl, lower alkyl- oxycarbonyl, phenyllower alkyloxycarbonyl, 4-morpholinylcarbonyl, 1-piperidinylcarbonyl and 1-pyrrolidinylcarbonyl, lower alkenyl; and a radical of the form,ula R7-O-, wherein R7 is a member selected from the group consisting of alkanoyl, phenylcarbonyl, phenyllower alkylcarbonyl, lower alkyloxycarbonyl, phenyllower alkyloxycarbonyl, aminocarbonyl, phenylaminocarbonyl, and mono- and di (lower alkyl) aminocarbonyl wherein said phenyl in the definition of said H be optionally substituted with up to 3 substituents each independently selected from the group consisting of halo, cynno, nitro, lower alkyl and lower alkylory, characterized by cyclodesulfurizingl by known methods, a compound of fbrmula EMI99.1 in order to prepare a compound of the formula EMI100.1 wherein P is lower alkoxycarbonyl or phenylmethoxy carbonyl, and, if desired, eliminating said group P in order to prepare the compound in which L' is hydrogen, when said group P is a lower alkyloxycarbonyl group it may be removed by alkaline or acid hydrolysis, using for example, hydrobromic acid in glacial acid, and when said protecting group is a phenylmethoxy carbonyl group it may be removed by alkaline or acid hydrolysis or by catalytic hydrogenation using an appropriate catalyst such as palladium-on-charcoal. 17. An antihistaminic pharmaceutical composition comprising an in ert carrier material and as an active ingredient an effective antihistaminic amount of a compound as claimed in any one of Claims 2 to 6. 18. Use of a compound as claimed in any one of Claims 1 to 6 as an antihistaminic agent.

Inventors: JANSSENS, FRANS, LUYCKX, MARCEL, STOKBROEKX, RAYMOND, TORREMANS, JOSEPH
Applicants: JANSSEN PHARMACEUTICA N.V.
Application year: 1979
Main classification: C07D471
IPC codes: A61K31, C07D235, C07D213, C07D211, A61P1, C07D413, C07D265, A61P43, C07D409, C07D401, C07D471, C07D405