NO762781L - - Google Patents

Abstract

Novel N- (T1-piperidinyl) alkyljarylcarboxamide derivatives.

Description

In the literature, some N-(dialkylamino)-alkylbenzamides are described, including N-(T1-piperidinyl)-alkylbenzamides and some N-(T2-pyrrolidinyl)methylbenzamides which have pharmacological properties. Well-known specific examples of such previously known compounds are ^amino^-chloro-H-^2-(diethyllainino)ethyl7-2*methoxybenzamide as generic

is referred to as metoclopramide and is used as a means of

prevent vomiting and 5-aminosulfonyl-K-£tl-ethyl-2-pyrrolidinyl)methyl7-2-methoxybenzamide which is generically designated as sul*pyride and which is used as an agent to prevent vomiting and as a neuroleptic agent.

The compounds according to the present invention differ from the previously known compounds by a difference in the substituted piperidine nucleus which is attached to the alkyl side chain. A number of previously known compounds can be found under the following references: * CX, 59, 11358c, U.S. patent no. 3,342,826, and . ^

CU., 71, P8141C..

The new N-((1-piperidinyl)alkyl-7-arylcarboxamide derivatives according to the present invention can be structurally prepared with the following formula

and the pharmaceutically acceptable acid addition salts thereof wherein '■':*"'"'

Ar is an aryl radical selected from the group consisting of phenyl,

substituted phenyl, 2-thienyl, 2-furanyl, pyridinyl, and 1-methyl-2-pyrrolyl, wherein said substituted phenyl is,phenyl having from 1-3 substituents independently selected from the group consisting of halogen, lower alkyl, lower alc3y, trifluoromethyl, nitro,

hydrokey,. amino, lower alkylcarbonyloxy and lower alkyl>carbonylamino, provided that when more than one of

the said substituents are. present, only one may be selected from the group consisting of hydroxy, amino, lower alkylcarbonyloxy and lower alkylcarbonylamino;

R is a member selected from the group consisting of hydrogen and;

lower alkyl;

n is an integer from 2 3} and

the radical

is a member selected from the group consisting of a) a radical of the formula:

where R and R are each independently selected from group pen consisting of hydrogen, halogen, lower alkyl and trifluoromethylj b) a radical with the formula:

•XA

wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl; M is selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl

and 2-cyanoethyl; Y is selected from the group consisting of O, S and lower alkylcarbonylimino; and the dashed line indicates that the double bond between the 3- and 4-carbon atoms in the piperidine core may possibly be present, and if there is a double bond between the aforementioned 3- and 4-carbon atoms, then Tf is 0 and M is hydrogen,

c) a radical with the formula:

where R . and R is independently selected from the group which

consists of hydrogen, halogen i 'lower alkyl and

trifluoromethyl; and

: d) a radical with the formula:

where R? is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and halogen* and where R is selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl. "Lower alkyl" can be straight or branched and have from 1-5 carbon atoms, such as e.g. methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl, etc. and the term "halogen" refers to halogen of atomic weight less than 127, ie fluorine, chlorine, bromine and iodine. The compounds of formula (I) where. Ar and is as previously defined, R is hydrogen and n is 2 (I-a) can usually be prepared by reacting with a suitable substituted 1-aroylaziridine of the formula (II) where Ar has the previously indicated meaning with a suitable piperidine derivative of the formula (III ) where the group is as previously defined.

The aforementioned reaction is preferably carried out in a suitable reaction-inert organic solvent such as e.g. a lower alkanol, e.g. methanol, ethanol, propanol,

.butanol and similar alcohols; an aromatic hydrocarbon, e.g. e.g. benzene, methylbenzene, dimethylbenzene and the like; a, ketone, fweks. 4-methyl-2-pentanoh; an ether, e.g. 1,4-dioxane, 1^-oxybisethane and the like; N,13-dimethylformamide; nitrobenzene

beer. or a mixture of such solvents. Heating may take place to increase the reaction rate and the reaction is preferably carried out at the reflux temperature for

reaction<mixture.>In this and subsequent methods, the reaction products are separated from the reaction medium and, if necessary, they are subjected to further purification using methods

which in and of itself is known.

The compounds of formula (I), including those where R

is lower alkyl and those where n is 3 can also be prepared by reacting a suitable reactive ester of formula (IV) where Ar, R and n are as previously defined and X is a suitable reactive ester function from the corresponding alcohol, such as halogen, methanesulfonyl , 4-methylbenzenesulfonyl o>l. with a suitable piperidine derivative of formula (III)

The above-mentioned reaction is preferably carried out in a suitable organic solvent such as £, e.g. N,N-dimethyl-, formamide, N,N*dimethylacetamide, 4-methyl-2-pentan6ny 2*propanol, "... methanol, ethanol, 2-propanone and similar solvents. Addition of a suitable base, e.g. An alkali metal or alkaline earth metal carbonate or hydrogen carbonate can be used to absorb the acid released during the reaction. Some heating is necessary to increase the reaction rate or the reaction is preferably carried out at reflux temperature. Another method for preparing the compounds of formula (i) consists in reacting a suitable substituted aroyl halide of formula (V) with a suitable amine of formula (VI) according to methods known per se for the production of amides starting from an aryl halide and an amine

Then the aforementioned reaction can e.g. is suitably carried out by boiling the reactants together under reflux in a suitable inert organic solvent such as e.g. a lower alcohol, e.g. methanol, ethanol, propanol, butanol

and similar alcohols} an aromatic hydrocarbon, for example benzene, methylbenzene, dimethylbenzene etc.; a ketone, e.g. 4-methyl-2-pentanone; an ether, e.g. 1,4-dioxane, l,l<1->oxy-

bisethane and the like N,N-dimethylformamide; nitrobenzene and the like, or a mixture of such solvents. A certain amount of heating is necessary to increase the reaction rate and the reaction is preferably carried out at the temperature of the reaction mixture.

The compounds of formula (I) where Å is a phenyl group to which an amino group is attached, alone or together with other substituents can be prepared by subjecting the corresponding nitro-substituted analogues to a nitro-to-amine reduction according to methods known per se , e.g. by catalytic hydrogenation using e.g. Raney nickel, palladium on*charcoal or platinum dioxide catalyst or by treating the nitro compounds with ferric ammonium chloride or zinc acetic acid. .• .'" The compounds of formula (I) hvpr,Ar is a phenyl group to which is attached a lower alkylcarbonylamino or lower alkylcarbonyloxy can be easily prepared from respectively See corresponding amino- or hydroxy-substituted analogues by acylating the latter with a suitable acylating agent such as eg a halide or an anhydride of a suitable lower alkylcarboxylic acid The acylation reaction can eg conveniently be carried out using a suitable lower alkylcarboxylic anhydride in water.

Compounds of formula (I) having the general formula:

can be similarly prepared starting from a corresponding unsubstituted compound with the formula by acylating the latter with a suitable acylating agent from the appropriate lower alkyl carboxylic acid* for example an acyl halide or anhydride. For example, the aforementioned acylation reaction can be suitably carried out by using a suitable anhydride in a suitable organic solvent such as e.g. benzene, methylbenzene, dimethylbenzene and the like. Compounds of formula (i) of the general formula: V can also be prepared by subjecting a suitable diamine of the formula:

ring closure with a suitable cycling agent containing sulfur such as e.g. carbon disulfide, thiourea, carbon thiodichloride,

ammonium thiocyanate and the like.

Compounds with formula (I) with the general formula!

can be manufactured; starting from the corresponding compound of formula (I-d), S-alkylation of the latter is carried out according to usual S*alkylation methods, e.g. by reacting, (I-d) with a suitable halogen-lower*alkane or with

a suitable di(lower alkyl)sulfate. The materials used in the aforementioned

: reactions can be provided by the methods indicated below.

The aroylaziridine intermediates of formula (II), a number of which are known compounds, can be readily* prepared by <: using known methods as described in the literature, e.g. reacting an aroyl halide of formula (V) with aziridine (VIII) in the presence of a suitable base to neutralize any acid released during the reaction. The reaction out- be entered in a suitable unlocking system, e.g. a mixture of water and trichloromethane. The aforementioned reaction can be illustrated in the following way: •

The intermediates of formula (IV), some of which are also described in the literature, can be suitably prepared by e.g. N-aroylation of a suitable amino alkanol of formula (IX) with a suitable aroyl halide (V) or with a suitable lower alkyl aryl carboxylate of formula (X) according to conventional N-aroylation methods followed by conversion of the hydroxyl group on , the alkyl side chain of it on this way provided compound (XI) to eh reactive ester group according to known methods. , «■,).-.

In the production of the halides, common halogenating agents can be used such as e.g. carbonium dichloride, sul» . f phenyl chloride, sulphuryl chloride, phosphorus pentachloride, phosphorus pentabroride, phosphoryl chloride0*1. When the reactive ester is an iodide, it is preferably prepared from the corresponding chloride or bromide by replacing this halogen with iodine. Other reactive esters such as ethanesulfonates and 4-methylbenzene-,. sulfonates are provided by reacting the alcohol with a suitable sulfonyl halide such as, for example, methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride. The aforementioned reactions can be illustrated with the following reaction nucleus:

The intermediate with formula (IV) where X is halogen (IV-a) can optionally be provided in one step by reacting a suitable aroyl halide (V) with a suitable halogen-alkanamine (XII) in a suitable solvent such as e.g. e.g. N,K-dimethylformamide (DMF) and N,N-dimethylacetamide, preferably in the presence of a suitable base such as e.g. N,N-diethylethane-amine. • ; ■ ..

By carrying out the aforementioned reaction in an alkaline medium and by using an intermediate of formula (XII) where R is hydrogen and n is 2, the corresponding aziridines with . formula (II) is provided* Intermediates of formula (VI) can be prepared in the following manner. A suitable lower alkyl K-(haloalkyl)carbamate of formula (XIII) is reacted with a suitable piperidine derivative of formula (III) according to known H-alkylation methods, e.g. by heating the reactants together in a suitable reaction-inert organic solvent such as e.g. a lower alkanol, e.g. methanol, ethanol etc. after which a carbamate of formula (XIV) is provided. The latter is then subjected to acid hydrolysis or alkaline hydrolysis after which decarboxylation takes place and the Snake intermediates of formula (VI) are provided.

When the alkaline hydrolysis is carried out, metal bases such as sodium and potassium hydroxide are advantageously used. Acids used in the acid hydrolysis include strong mineral acids such as hydrochloric acid, hydrobromic acid, solubilic acid, phosphoric acid and the like.

When

in the intermediate (VI) has the formula

it is appropriate instead of (XIII) to use the corresponding .phenylmethyl carbamate and in this case the subsequent decarboxylation can be carried out by catalytic hydrogenation using a suitable catalyst t - e.g. palladium-on-coal.

Intermediates of formula (VI) are believed to be new and

as useful intermediates for the preparation of the compounds

with formula (I) they constitute a further aspect of the invention. Intermediates of formula (VII) are conveniently prepared by infecting the aroylaminoalkyl chain 1 with an R-(2-nitrophenyl)*4-piperidinamine of formula (XV) by reacting the latter

with an aziridine of formula (II) or a reactive ester with

formula (IV) with subsequent reduction of the nitro group of the thus obtained compound (XVI) followed by a conventional nitro-to-amine reduction as previously described.

Starting materials of formula (III) with the formulas:

and methods for producing these can be found respectively in the aforementioned references:

a) U.S. patent no. 3,238,216,

b) U.S. patent no. 3,161,645, Belgian Pat. No. 830.403, e) U.S. pat. No. 3,518,276 and U.S. Pat. pat. No. 3,575,990.

Starting materials of formula (III) which have the formulas: can generally be prepared starting from a suitable N-(2-aininophenyl)-4-pyr<p>eridinamine of the formula: The starting materials (III-d) are suitably prepared by cyclization of (XVII ) with a suitable cycling agent, e.g. carbon disulfide dg subsequent removal of the lower alkyloxycarbonyl group of the provided (XVIII) by alkaline hydrolysis.

The starting materials (III-e) can be prepared by S-alkylation (XVIII) as described above for the preparation of (I-e) starting from (I-d) followed by elimination of the lower alkyloxycarbonyl group in the resulting (XIX).

N-(2-aminophenyl)-4-piperidinamines of formula (XVII), a number of which are known compounds, can be prepared by following the methods described in U.S. Pat. Patent No. 3,910,930 and Belgian Patent No. 830,403.

The aforementioned methods are illustrated by the following reaction cores.

Intermediate substance of formula (III) with formula; can be produced in f Telling way. ■■ : An appropriate N-(2-aminophenyl)-1-(phenylmethyl)-4-piper&-dynamln of formula (XX) is converted to the ^corresponding 1-^I*(phenylmethyl)-4-piperidinyl7-1H- ben2imidazol-2-amine (XXI) by cyclization of (XX) with a suitable cyclization agent as recognized, e.g., cyanamide. The thus obtained (XXI) is then N-acylated with a suitable acylating agent of a suitable lower alkyl carboxylic acid, e.g. a halide or anhydride to obtain the intermediate of formula (XXII). The Snakede (III-f) is conveniently provided by eliminating the phenylmethyl group in (XXII) by catalytic hydrogenation using a suitable catalyst such as e.g. palladium-on-coal. Intermediate (XXI) : can also be prepared by converting (XX) to a lower alkyl ^1,3-dihydro-1-^I-(phenylmethyl)-4-piperidinyl7*2H-behzimida2ol-2-ylidene}. carbamate (XXIV) by cyclizing (XX) with a suitable cyclization agent known for the preparation of 2*benzimidazole carbamates starting from 1,2-benzenediamines, e.g. medium lower alkyl (iminomethoxymethyl)carbamate of the formula (XXIII) and then decarboxylate the latter by acid hydrolysis. The aforementioned reactions are illustrated by the following schematic representation.

tft<g>an<g>s materials with formula (XX) can conveniently be provided by using known methods such as

e.g. by condensing 1-(phenylmethyl)-4rp4Per*a'inamine with a suitable 2-halogeh-nitrobenzene of formula (XXV) followed by reduction of the nitro group of the provided (XXVI) by catalytic hydrogenation using a suitable catalyst such as e.g. e.g. Raney nickel.

The final starting materials in all the above-mentioned types are known and can be produced by known methods.

It is obvious that compounds of formula (I) wherein

has the formula (Ill-c) and where B? is methyl has two asym-

tric carbonate<p>mers in their structure and that the compounds can thus be found with different stereochelic and optical isomeric forms.

Depending on the relative position of the methyl and the hydroxy group in relation to the plane of the piperidine nucleus, the compounds have cis- or trans-figurations and each of these forms also includes two optical isomers. The stereochemical and optical isomers of these compounds, which of course lie within the scope of the present invention, can be prepared using known methods. Cis- and trans-isomers of these compounds and of their predecessors can therefore be obtained separately by physical methods* e.g. selective crystallization. Without further indication of their actual stereochemical configuration, the form which is further isolated will be called the A-form and the remaining one will be called - the B-form* Since the compounds in question have basic properties, optically active acids can be used to dissolve them rapemic cis and trans forms to provide the optical isomers.7 The compounds of the present invention can be converted into their therapeutically useful acid addition salts by treatment with a suitable acid such as e.g. an inorganic acid such as a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid etc. and sulfuric acid, nitric acid, phosphoric acid and the like, or an organic acid such as e.g. acetic acid, propanoic acid, 2-hydroxyacetic acid, 2-hydroxypropanonic acid, 2-oxopropanonic acid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2- butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenionic acid,.a-hydroxybenzeneacetic acid, methanesul- phonic acid, methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and similar acids. .' The salt form can be converted to the free base by treatment with alkali. Compounds of formula (I) and the therapeutically active acid addition salts thereof have strong antiemetic properties which is demonstrated by their ability to block apomorphine-induced ; severe vomiting 1 dogs. The method used was previously described by P*A.J. Janssen and C*J.E*Niemegeers in: Yearly. -Research. (Drug Res.), 9*765-767 (1959).

The compounds given below were administered subcutaneously to beagle dogs at various doses and 1 hour later the animals were administered a standard dose of 0.31 mg/kg (subcutaneous) apomorphine.

The tables below give the ED^Q values for the number of compounds that were evaluated. The ED^ value represents the dosage that protects 50% of the animals from vomiting.

It is understood that the compounds in the tables do not limit the invention to these, but are only used to exemplify the excellent antiemetic properties of all compounds within the scope of formula (I).

The compounds of formula (I) are strong psychotropic agents and can therefore be used in the treatment of mental disorders such as e.g. personality disorders and psycho* affective disorders and schizophrenia. The psychotropic activity of the compounds of formula (I) emerges through experimental data from apomorphine samples in rats, a sample which is indicative of the depressant effect on the central nervous system. The test was carried out using the method described in the following and experimental data are reproduced in table V where the number indicating the compound refers to corresponding structures in tables I - IV. The compounds which are reproduced in table V do not limit the invention to these, but are given as examples of the useful psychotropic properties of all compounds which lie within the framework of formula (i). Apomorphine 1 rats. The experimental animals used were adult male Wistar rats (weight 240 - 10 g). After fasting overnight, the animals were treated subcutaneously (1 ml/100 g) with an aqueous solution of the compound to be examined and transferred to isolated observation cages. 30 minutes later, 1.25 mg/kg of apomorphine hydrochloride was injected intravenously and the rats were observed during 1 hour for the presence or absence of the following apomorphine-induced phenomena: arousal and sterotype chewing. Table V gives the lowest effective dose (LED), i.e. the dosage level at which the effect was statistically significantly different from that observed in the corresponding untreated control samples (Fisher exact probability test).

Considering their antiemetic and psychotropic properties, the compounds according to the invention can be added to various pharmaceutical preparations. To prepare the pharmaceutical preparations according to the invention, an effective antiemetic or psychotropic amount of the particular compound in the form of a base or acid addition salt as the active ingredient with a pharmaceutically acceptable carrier and this carrier can have a wide range of forms depending on the preparation and the administration desired" These pharmaceutical preparations are preferably produced in unit doses and then preferably for oral administration, for administration through the rectum or by parenteral injection. To prepare preparations to be administered orally, a number of applicable pharmaceutical media can be used, such as e.g. water, glycols, oils, alcohols, etc. and when it comes to liquid preparations such as syrups, elixirs and solutions, or solid carriers such as starches, sugars, kaolin, lubricants* agents, binding agents, disintegrating agents, etc. when it comes to powders, pills, capsules and tablets. Because of the ease of administration, tablets and capsules represent the most appropriate dosage unit for oral administration and in this case obviously solid tar substances are used. For parenteral preparations, the carrier usually comprises sterile water, although other ingredients e.g. to aid solubility, may be added. Injectable solutions can e.g. are produced where the carrier consists of a salt solution, glucose solution or mixtures of salt and glucose solutions. Injectable suspensions can also be prepared and in this case suitable liquid carrier* substances, suspending agents and the like are used. Acid addition salts of (I) are, due to their increased water solubility compared to the corresponding base form, obviously more suitable when it comes to preparing aqueous preparations. It is particularly appropriate to prepare the above-mentioned pharmaceutical preparations in unit dosages for easy administration and consistency in dosage. Unit dosages as used in the following specifications and requirements refer to physically separated units that are suitable for unit dosages where

Each unit contains a predetermined amount of the active ingredient intended to produce the desired therapeutic effect together with the necessary pharmaceutical carrier*

Examples of such unit dosages are tablets (including coated or scored tablets), caps, pills, powder packets, thin discs, injectable solutions or suspensions, an amount equivalent to a teaspoon, a tablespoon, etc. and multiple units thereof.

- The amount of active ingredient per dosage unit for both antiemetic and psychotropic purposes will be from approx. 1 - approx. 200 mg and preferably from approx. 5 to approx. 100mg*

The following preparations are examples of typical antiemetic and psychotropic pharmaceutical preparations in unit doses suitable for systemic administration to animals and humans in accordance with the invention.

Oral drops: The following preparation provides 10 liters of a solution for oral drops consisting of . 5-mg N-£ 2-/5-(5*chloro-2,3-dihydro-2-oxo-1H-benziinidazol-1-yl)-1-piperidinyl-4-fluorobenzamide as the active ingredient per ml.

The methyl and propyl*4-hydroxybenzoates dissolve in approx. 5 liters of boiling, pyrogen-free water. After cooling to approx. 50°C, 2-hydroxypropanone acid is then added with stirring, then the active ingredient. The solution is cooled to room temperature and pyrogen-free water is added to the desired 1 volume. The solution is sterilized by filtration (U.S.P. XVII page 811) and filled into sterile containers. In. readable resolution: The resolution for. oral drops described above can be used as an injectable solution.

Chancellor: 10,000 Hard gelatin capsules, each containing as the active ingredient (A.§) 20 mg K- { 2-^5-(5-chloro-2T3-dihydro-2-oxo-1H-benzlmidazol-1-yl) -1-piperidinyl-7-ethyl-4-fluorobenzamide is prepared from the following composition.

A uniform mixture of the active ingredient and the other ingredients is prepared and filled into two-part, hard gelatin capsules.

Pills; 5,000 compressed tablets each containing

as the active ingredient (A.B.) 25 mg N-^2*^5-(5-chloro-2,3-dihydro-2*oxo-1H*benzimidazol-yl)-1-piperidiny^/ethylj-4*

fluorobenzamide is prepared with the following composition.

The finely divided ingredients are mixed well and granulated with 105S starch paste. The granulate is dried and pressed

to tablets.

Oral sussens. lon: The following preparation provides 5 liters of an oral suspension which as the active ingredient (A.B.) contains. 15 mg of N-2-(5-chloro-2n3-dihydrob-2-oxo-1H-benzimi-dazol-1-yl)-1-piperidinyl-7-ethyl-4-fluorobenzamide per teaspoon (5ml).

^»ara^ in propylene glycol and of this solution-'

a solution of sodium cyclamate, sodium saccharin and sucrose in half the water is added* The Bentohit is suspended in warm (approx. 85°C) water and stirred for 60 minutes. The ben* tonite solution is added to the first solution. The sulfosuccinate is dissolved in some water and the active ingredient is suspended in the resulting solution. The solution is added to Antifoåm A.F. emulsion that has been diluted into a lotion

with a minimal amount of water and it all mixes well. The , aimed at the suspension of A.B. is added to the first mixture and

.the whole thing is stirred well. Then add FD&C Yellovr No. 5 dissolved in 1 a small amount of water. The orange flavor is added, and diluted to the required volume with water and the mixture

■ Stir until it becomes homogeneous. The mixture is passed through one colloid mill and transferred to suitable containers.

Considering the antiemetic activity of the compounds according to the invention, it is obvious that the present invention provides a method for inhibiting vomiting in warm-blooded animals suffering from such vomiting by systemic administration of an effective antiemetic amount

ay the compound of formula (I) and pharmaceutically acceptable acid addition salts thereof together with a pharmaceutical carrier.,': In view of the psychotropic activity of the compound according to the invention, the invention also provides a method for treating mental disorders in warm-blooded animals having such disorders upon systemic administration of an effective psychotropic inhibitory amount of a compound

of formula (I) and a pharmaceutically acceptable acid addition salt ay this together with a pharmaceutical carrier.

The following examples illustrate; but does not limit the present invention. Unless otherwise stated, all parts are parts by weight.

Example I

...... To a stirred mixture of 76 parts of 4-fluoro-2-nitrobenzoic acid and 225 parts of benzene, 71 parts of sulfinyl chloride are added dropwise. After completion of the addition, the stirring continues first for 5 hours at reflux temperature and then overnight at room temperature. The reaction mixture

evaporates. The residue is taken up twice in benzene and the latter is evaporated each time, giving 85 parts of 4-fluoro-2-nitrobenzoyl chloride as a residue.

Eczema! II '(<:>To 231 parts of æiridine solution 0.95M in water, 16 parts of sodium hydrogencarbonate are added with vigorous stirring at 0°C. Then add dropwise over the course of 45 minutes

a solution of 36 parts of 4-fluoro-2-methoxy-benzoyl chloride in 150 parts of trichloromethane while cooling to 0°C continues. After completion of the addition, stirring is continued for 30 - 45 minutes without cooling. The reaction mixture is adjusted to pH 8 with dilute sodium hydroxide solution and the product is extracted three times with trichloromethane. The combined extracts are washed three times with water* dried, filtered and evaporated to give 40.5 parts of 1-(4*fluoro-2-methoxybenzoyl)-aziridine as a residue.

Eczema! III

Using the procedure of Example II and using equivalent amounts of an appropriate arylcarbonyl chloride in place of 4-fluoro-2-methoxybenzyl chloride, the following 1-(arylcarbonyl)aziridines are prepared: 1-(2-hydroxybenzoyl)zirlidine as a residue 1-(4-fluoro-2-nitrobenzoyl)aziridine as a residue 1-(2-thienylcarbonyl)aziridine as a residue; and

1-(5-klbr*2-methoxy-4-nitrobenzoyl)aziridine

Example IV

A mixture of 12.94 parts ethyl*(2-bromomethyl)carba*

food, 13.51 parts 1,3-dlhydro»l-(4-piperidinyl)-2H*benzimidazol-2«*one, 10.1 parts sodium bicarbonate and 160 parts

ethanol is stirred and boiled under reflux overnight. The reaction mixture is cooled, filtered over hyflo and the filtrate

evaporates. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane, 10% methanol and a drop of ammonium hydroxide as eluent. The pure fractions are collected and the eluent is evaporated, giving 4.4 parts of ethyl 2'^-(2,3-dihydro^2'-oxo-1H-benz-imidazol-1-yl)-l -piperidinyl-7-ethylcarbamate.as a residue. A mixture of 0.333 parts of ethyl 2*^^(2,3-α^hyro*2-oxo-1H-benzimid^ol-1-yl)*1-piperidinyl-7ethylcarbamate, 1.65 parts of hydrobromic acid solution 48?£ and 0 ,11 parts of water are stirred - and boiled under reflux for 2 hours. The hydrobromic acid and the water are ■ evaporated. The residue is taken up three times in benzene, while the last* mentioned is evaporated each time. The oil-active residue is crystallized from 2-propanol. The product is filtered off and recrystallized from a small amount of ethanol, which gives 0.27 parts

1-[1-(2-aminoethyl)-4-piperidinyl-7-1,3-dihydro-2H-benzi^2-one-dihydropyramide with melting point 300°C (decomposition). Example V To a stirred and cooled (ice bath) mixture of 87 parts of 2-chloroethanamine hydrochloride and 300 parts of trichloromethane is added 224.2 parts of N,H-diethylethanamine* After the addition of a further 300 parts of trichloromethane, is added dropwise

in the course of 1.5 hours a solution of 96 parts of 2-furancarbonyl chloride in 300 parts of trichloromethane at a temperature of

below 5°C. After the addition has ended, stirring* is continued overnight at room temperature. The reaction mixture is poured into water and the layers are separated. The water phase is extracted with trichloromethane. The combined organic phases are washed with water, with dilute hydrochloric acid solution and again twice with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and 2% methanol as eluent. The pure fractions are collected and the eluent is evaporated, giving 95 parts of H-(2-chloroethyl)-2-furancarboxamide as a residue. Example VI A solution of 23.5 parts of 4-fluoro-2-nitrobenzoyl chloride in 454 parts of benzene is added to a stirred and cooled mixture of 32 parts of 2-bromomethanamine hydrobromide in 150 parts of water. While the mixture is cooled to 0 - 5°C and stirred vigorously, a solution of 13 parts sodium hydroxide in 200 parts water is added dropwise (exothermic reaction). After the addition has ended, stirring is continued for 12 hours at 0 - 10°C. ^ The precipitated product from raf is drained, washed with water and dried,

giving 30 parts (93.650 H-(2-bromomethyl)-4-fluoro-2-nitro-benzamide.

Example VII

A solution of 29 parts 2-chloroethanamine hydrochloride in 75 parts water is added to a stirred solution of 21 parts sodium hydroxide in 75 parts water. The whole is stirred and heated for 10 minutes to 90°C. After cooling to 0°C,

19 parts of sodium bicarbonate are added. While stirring continues vigorously, a solution of 49 parts of 2,5-dichlorobenzoyl chloride in 75 parts of tri-

chloromethane at a temperature below 0°C. After the addition is finished, stirring is continued for 30 minutes without cooling.

The reaction mixture is heated to 25°C and adjusted to pH 8 with dilute sodium hydroxide solution. The product is extracted three times with trichloromethane. The combined extracts* are washed three times with water* dried, filtered and evaporated to give 62 parts of 1-(2,5-dichloroben2oyl)-aziridine as a

residue.

;. Example VIII

A mixture of 72 parts methyl-2-pyridinecarboxylate and 32 parts 2-aminoethanol is stirred. and boiled under reflux

gently for 2 hours. The reaction mixture is cooled and poured into water. The product is extracted five times with trichloromethane. The combined extracts are dried, filtered and evaporated to give .49 parts of N-(2-hydroxyethyl)-2-pyridinecarboxamide as a residue.

To 49 parts of N-(2-hydroxyethyl)-2-pyridinecarboxamide, 80 parts of sulfinyl chloride are added dropwise with vigorous stirring. After the addition has ended, stirring is continued for 3 hours at reflux temperature and then 12 hours at room temperature. Excess sulfinyl chloride is evaporated and the residue is poured into hot methanol. After off*

the cooling from The precipitated product is filtered off (the filtrate is set aside) and washed carefully with 2,2,»oxybis*propane, which gives a first fraction of 14 parts of W-(2-chloroethyl)-2-pyridinecarboxamide hydrochloride d.

The filtrate which was set aside is stirred with 2,2<!>- voxybispropane. hydrochloride.

Example IX

A mixture of 5.5 parts methyl-1-methyl-1H-pyrrole-2-carboxylate and 2.4 parts 2-aminoethanol is stirred and boiled

under reflux for 2 hours. The reaction mixture is evaporated

to dryness. Benzene is added twice to the residue and evaporation is continued each time to dryness. The residue is purified by column chromatography over silica gel using v

. a mixture of trichloromethane and methanol (95:5 in volume ratio)

as eluent. The pure fractions are collected and the eluent is evaporated. The residue is taken up in petroleum ether and after scraping the product precipitates. It is filtered and dried, which gives 1.9 parts of N-(2-thihydroxyethyl)-1-methyl-1H-pyrrole-2-carboxamide with a melting point of 78.1°C.

To a stirred mixture of 40 parts of H-(2-hydroxyethyl)-1-methyl-1H-pyrroic-2-carboxainide in 450 parts of trichloromethane is added one drop of pyridyl. Then, 28.3 parts of sulfinyl chloride are added dropwise over 30 minutes (slightly exothermic reaction, the temperature rises from 15 to 25°C). After the addition has ended, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (volume ratio: 96:4) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2*-6xybis- , propane. The product from Is drained and dried, which gives 15 parts , K-(2*chloroethyl)-1-methyl-1H-pyrrole-2-carboxamide.

Example X A mixture of 12.94 parts of ethyl-(2-br©methyl)carbamate, 15.68 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidalzol-2-one , 10.08 parts sodium bicarbonate and 166 parts ethanol are stirred and refluxed overnight. The formed precipitate is filtered off and washed with trichloromethane. The layers from the filtrate are separated. The organic phase is dried, filtered and evaporated. The residue is stirred in 2-propanone. The unreacted starting material is filtered off and the filtrate is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (in the volume ratio 90:10).

as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethanol 70%. The product is filtered and dried, yielding 6.5 parts of ethyl-

nyl7ethyl} *carbamate with melting point 187.7°C.

A mixture of 6.6 parts ethyl-f 2-^5-(5-chloro^-2,3''•di-.hydro-2-oxo-^^-carbamate, 60 parts. hydrobromic acid solution 48?6 in water and 4 parts of water are stirred and refluxed for 2.5 hours. After cooling, the precipitated product is filtered off and crystallized, i from water, which gives 5.5 parts of i-^l-(2-aminoethyl^)*4 *pipe 5-chloro-1,3-dihydro-2H-benziraidazol-2-one-d^ with a melting point above 300° C. Example XI

A mixture of 38 parts of 1-(phenylmethyl)-4*piperidinamine, 40 parts of 2-chloronitrobenzene, 32 parts of sodium carbonate, some crystals of potassium iodide in 320 parts of cyclohexanol is stirred and refluxed for 22 hours. After cooling, 300 parts of water are added. The organic layer is separated, diluted with 160 parts of benzene and the whole is washed three times with 150 parts of water after which the organic layer is dried over magnesium sulphate, filtered and evaporated. The residue is dissolved in a mixture of 40 parts of 2,2T-oxybispropane and 160 parts of hexane. After cooling to -15°C, the precipitate is filtered off and the filtrate is set aside. The precipitate is recrystallized from 160 parts of 2,2•-oxybispropane and extracted from ra-f, which gives 18.5 parts of K-(2-nitro.phenyl)-1-(phenylmethyl)-4*piperidlamine with a melting point of 93.4 - 94 .6°C.

The combined mother liquors are diluted with 2,2<*>-oxybispropane and dry, gaseous hydrogen chloride is added to the mixture. The precipitated hydrochloride salt is filtered off. The yield is washed with 120 parts of water and the undissolved part is dried, something V

which gives 18 parts of N-(2-nitrophenyl)-1-(phenylmethyl)*4-piperidln-;:T;; amine hydrochloride with melting point 206 - 220°C (decomposition).

A solution of 31 parts of H-(2-nitrophenyl)-1*(phenylmethyl)-4-piperidineamine in 160 parts of tetrahydrofuran is hydrogenated

under normal pressure and a temperature of 40°C with 20 parts Raney nickel*catalyst. After the calculated amount of hydrogen has been taken up (3 mol), the hydrogenation is stopped. The catalyst is filtered off and the solvent. f or is evaporated from the filtrate. The solid residue is washed with 160 parts of 2,2f<->oxybispropane and this gives. 22 parts N-^1-(phenylmethyl)-4-piperidihyl7*1»2-benzenedianine with melting point 112 - 113°C.. After the filtrate is concentrated to approx. a quarter of its volume provides another yield of 2.5 parts N-^1-(phenylmethyl)-4-piperidinyl7-1,2-benzenediamine with melting point 108 - 109°C*'"• A mixture of 5 parts N- £I-(phenylmethyl)*4~piperidi-

Nyl7-1,2-benzenedamine, 2.35 parts of methyl(imine-6-methoxymethyl)-carbamate, 5 parts of acetic acid and 75 parts of trichloromethane are stirred and refluxed for 8 hours. The reactive ion mixture evaporates when the residue is taken up in water. The solution is neutralized with ammonium hydroxide solution. The precipitated product is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (in the volume ratio 95:5) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1.75 parts of methyl£1*3-dihydroch*l-^1-(phenylmethyl)-4-piperidinyl7-2H-benzimidazol-2*ylidenej-carbamate of m.p. 169.7 °C.

A mixture of 3.64 parts methyl f 2,>dihydro-l-£- .

(phenyl)-4-piperidinyl 7-1H-benzimidazol-2-ylidene} carbamate, 24 parts hydrochloric acid solution and 40 parts ethanol are stirred and refluxed overnight. The reaction mixture is evaporated

and the residue is dissolved in water. This solution is made alkaline with concentrated ammonium hydroxide solution. The precipitated product is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated, yielding 2.1 parts of 1-(phenylmethyl)-4-piperldinyl-7-1H-benzimidazol-2-amine as a residue. .: . A mixture of 2 parts 1-^1-(phenylmethyl)-4-piperidin-ny 17-1H-benz 1 ro t dazol-2-aminy 3 parts acetic acid anhy dr i d and 45 parts methylbenzene is stirred and boiled under.back-open 13 hours . The reaction mixture is evaporated and water is added to the residue.

The mixture is made alkaline with concentrated ammonium hydroxide solution. The precipitated product is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 2,2*-oxybispropane* which after drying gives 0.8 parts of N-£lt3-dihydro-1*/I-(phenylmethyl)-4-plperidinyl7-2H-benzimidazol-2-ylidene ^ acetamide with melting point 189.2°C.

A mixture of 12 parts of N-(1,>dihydro-1-£I-(phenyl-methyl)-4-;piperidinyl7-2H-benzimidazol-2i-ylideneJ-acetamide and 120 parts of methanol is hydrogenated at normal pressure and room temperature with 5 parts palladium-on-charcoal tough catalyst 10%, After the calculated amount of hydrogen has been taken up, the catalyst is filtered over hyflo and the filtrate is evaporated. The residue crystallizes from a mixture of 2,2'-oxybispropane and 2-propanol. The product is filtered off and recrystallized from a - mixture of ethanol and 2* 2 *-oxybispropane, which gives 2.6 parts of N-£1,3-dihydro-1(4-piperidinyl)-2H-^den7acetamide with melting point 164.5° C Example XII - A mixture of 1.68 parts of 1-(4-fluorobenzoyl)-aziridine, 2.5 parts of 1-(4-fluorophenyl)-1,3,8-triazaspiro^5.57*decane-4-6n , 10.8 parts of benzene and 1.6 parts of methanol: stirred and refluxed for 1.5 hours" The reaction mixture is cooled and acidified with 2-propanol which has previously been saturated with gaseous hydrogen chloride. The hydrochloride salt formed is filtered off and NOK is crystallized from a mixture of ethanol and water

(in the volume ratio 8:2), which after drying gives 2.4 parts of 4-fluoro-N* 2*^1-(4-fluorophenyl)-4*dxo~1,3T8-triazaspiro<£54 57-dec -8-yl-7-ethyl-4-benzamide hydrochloride with a melting point of 2-9.6°C. Example XIII

A mixture of 0.74 parts of l-(benzoyl)aziridine, 1.16

parts of 1-phenyl-1,3,8-tr&azaspiro/5,£7decan-A-one, 7.2 parts of benzene and 0.8 parts of methanol are stirred and refluxed for 2 minutes. The reaction mixture is cooled, 1,1<1>-oxybisethane is added and the mixture is boiled in ethyl acetate. After cooling from* the precipitated product is filtered and crystallized from ethanol 70%, which after drying in vacuum at 80°C gives 0.67 parts of N-£2-(4-oxo-l-phenyl-i,3,8- ^^ with

melting point 198.4°C, ... v.Vv.

Example XIV Using the procedure of Example XIII and using equivalent amounts of suitable starting materials, the following compounds are prepared either in the form of free base or in the form of acid addition salts after reaction of the base with a suitable acid.

Example XV

Eti mixture of 1.2 parts N-(2-bromomethyl)-2-nitrobenz-amide, 1.15 parts 1-phenyl-1,3,8-triazaspiro^5,57decan-4-one and 45 parts H,N -dimethylformamide is stirred and boiled under reflux

for 3 hours. After the stirring is continued overnight at room temperature, N,N-dimethylformamide is evaporated in vacuo at 80°C. The residue is boiled in a mixture of 2-propanone and water and the unreacted starting material is filtered off. The filtrate is concentrated to half its volume and 2-propanoyl is added to the concentrate. The precipitated product is filtered off and dried, which gives 7 parts of 2-nitro-N-^2-(4-oxo-1-phenyl-1,5,8-triazaspiro-4^»57<iec-8*yl)-ethyl7benzamide- hydrobromide with a melting point of 259.4°C. Example XVI A mixture of 6.9 parts of K-(2-chloroethyl)-2-furancarboxamide, 9.2 parts of 1-phenyl-1,3t8-triazaspiro/5,§7decan-4-one, 6.6 parts potassium iodide and 135 parts of N,N-dimethylformamide are first stirred for 3 hours at reflux temperature and then overnight at room temperature. The reactive ion mixture is evaporated and the residue is taken up in water. The mixture is made alkaline and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (in the volume ratio 96:4) as eluent. The.;

pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2-propanone. The product is filtered and dried, yielding 1.9 parts of K-^2-(4-oxo-1-phenyl-1,3,8-triazaspiro^,§7dec-8-yl)ethyl7*2- furancarboxamide, melting point 19#,3°CY

Example XVII

Using the process from example XVI, N-£ 2-^1-(4-fluorophenyl)-4-oxo-1, 3,8-triazaspiro/5, §7<iec*8*y|7-ethylJ'-2 *furancarboxamide hydrochloride with melting point 254.2°C by reacting N-(2-chloroethyl)-2-furancarboxamide with 1-(4-fluorophenyl)-1*3»8-trilazaspiro^5,§7 -<iecan-4-on. Example XVIII A mixture of 4.4 parts of N-(2-chloroethyl)-2-pyridih-carboxamide, 13.8 parts of 1*phenyl-1>3»8-triazapro^,5/decah-4-one, 3, 3 parts potassium iodide and 200 parts 4-methyl-2-pentanoh are stirred and boiled at reflux for 24 hours. The reaction mixture is evaporated and the residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (in the volume ratio 98:2) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanol. The salt is filtered off and crystallized from ethanol, giving 1.1 parts

(4*oxo-1-phenyl)-1,3»6-triazaspiro^5,£7dec-8-yl)ethyl 7-2-pyrl-(Uncarboxamide dihydrochloride hydrate with melting point 250.5°C.

Example XIX

A mixture of 3»75 parts of N-(2-chloroethyl)-1-methyl-1H-pyrroic*2-carboxamide, 5 parts of 1-(4-fluorophenyl)*1,3,8-triazaspiro^5,§7< iecan-4-one, 1.7 parts sodium bicarbonate,

0.1 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone are stirred and refluxed for 48 hours. The react ion mixture is cooled and the solvent is evaporated. The residue is purified by column chromatography over silica gel using a

mixture of trichloromethane and methanol (in the volume ratio 95:5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanol and 2,2,-oxyblspropane. The salt is filtered off and crystallized from methanol and this yields 0.8 parts of N- [2-^1-(4-fluorophenyl)-4-oxo-1,3»8-triazaspiro^4# 0dec-8-yl7ethyl 3 -1- inethyl-1H-pyrrole-2*carboxayl hydrochloride with a melting point of 273.4°C. ■ ' ■ 'V ■ V .

Example XX '- u: A mixture of 8 parts of 4-fluoro-2-nitro(4-oxo-l-phenyl*1,3,S-triazaspiro^S* £7<iec-8*yl)ethyl7benzamide, 40 parts

methanol and 90 parts of tetrahydrofuran are hydrogenated at normal pressure, and at room temperature with 3 parts of Raney nickel catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is converted to the hydrochloride salt in 2-prdpanol. The salt is filtered off and crystallized from ethanol, giving 1 part of 2*amino*4-fluoro-N-(2-(4*oxo*1-phenyl-1,3,8-triazaspiro^5,57-dec-8- yl)ethylbenzamide hydrochloride hydrate with melting point 167.3°C., Example XXI A mixture of 8 parts of 4-fluoro-N-£2-^1-(4-fluoro-phenylJ-4-oxo-1,3,8- triazaspiro^5,§7dec*8-yjl£éthyl|£ -2-nitrobenz*

amide hydrochloride, 120 parts methanol and 25: parts water are hydrogenated at normal pressure and at room temperature with 5 parts Raney nickel catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated ♦ The residue is crystallized from methanol* The product from^

filtered and recrystallized from ethanol, yielding 1 part

2*amino-4~fluoro-N-£2-££-(4-fluorophenyl)-4-oxo-1|3^i8-triaza-spirp^5,5Zdec*8-yl7ethyl3 benzamide hydrochloride hydrate with. melting point 223.5°C

Example XXII • ;.s „ u;-' A mixture of 6 parts of 5-chloro*2-methoxy-4-nitro-N* £2-(4-oxo-l-phenyl-1,3,S-triazaspiro^ 5,g7dec*8*yl)ethyl7benzamide in 15P parts acetic acid is hydrogenated at normal pressure and

room temperature with 1 part Raney nickel*catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated*, the R§§ide is taken up in

water bg the mixture is made alkaline. The precipitated product is filtered off and crystallized twice from ethanol, which gives 1.7 parts of 4-aminop-5-chloro-2-methoxy-N-^2-(4-oxo-1-phenyl-1,3, g- triazaspiro^S, 57*dec-8-yl)ethyl7benzamide with melting point 247.4°C.

Example XXIII Using the method of Example XXII

and using 5-chloro-N-12-[I-(4-fluorophenyl)-4-oxo-1,3,8-tri-8^aspiro^5,£7~dec«8-yl7ethyl J *2 -methoxy-4-nitrobenzamide as the starting point and after converting the product provided* to the hydrochloride salt is prepared: 4-amino-5-chloro-H-

{, (4-fluorineyl)-4-oxo-1,3»8-triazaspiro^5,57dec*8-yl7-ethyl^-2-methoxybehzaiide hydrochloride of melting point 259.8°C.

Example XXIV

A mixture of 9 parts of N-[2-[1-(4-fluorophenyl)-4-oxo-1,3#8-triazaspiro^5»^j>7dec-8-yl7ethylJ-2*nitrobenzamide hydrochloride in 150 parts Acetic acid is hydrogenated at normal pressure and room temperature with 2 parts palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water bg the mixture is made alkaline with ammonium hydroxide. The product is extracted twice with trichloromethane. The combined extracts are washed two ••■f§^pL. with water, dried, filtered and evaporated. The solid residue is boiled in 2-propanol and filtered. The product is allowed to crystallize from the filtrate. It is filtered off and dried in vacuum, which gives 5

parts 2-amino-N-12-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro-§7<lec-8*yl7ethyl}-benzamide with melting point 194.9°C. Example XXV A mixture of 9 parts of 2-amino-4-fluoro-N-£2-^1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro^5,57dec-8-yl7ethyl}- -

benzamide, 8.5 parts acetic anhydride and 85 parts water are stirred for 1 30 minutes in a water bath at approx. 80°C. Reaction no

the mixture is cooled and made alkaline, with ammonium hydroxide.

The product is extracted with trichloromethane. The water phase is separated and extracted with trichloromethane. The merged organic . phases are washed three times with water, dried, filtered and evaporated; The residue is crystallized from 2*propanol. The product is filtered off; and dried, yielding 5.2 parts of 2*(acetylamino)-4-fluoro-N-[2-(1*(4-fluoro[enyl)-4-oxo-1,3#8-triazaspiro^,). §7-dec-8-yl7ethyl3-benzamide with melting point 195.1°C,

• 'Example XXVI A mixture of 1.68 parts of 1-(4-fluorobenzoyl)-aziridine, 2.53 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazbl-2-one , 10.8 parts of benzene and 1.6 parts of methanol are stirred and refluxed for 1.5 hours. The precipitated product is filtered off with suction and washed with 2-propanone. The product is crystallized from 2-propanol, which after drying gives 2.47 parts of W-£ 2-^5-(5-chloro-2,3-dlhydro-2-oxo*1H-benzimidazol-1-yl)-1-

piperidlnyl7 ethyl-4-fluorobenzamide with melting point 239.6°C.

Example XXVII Using the procedure of Example XXVI and using equivalent amounts of the appropriate raw materials, the following compounds are prepared in the form of

their free bases or acid addition salts after reacting the free base with a suitable acid.

Example XXVIII

Using the method from Example XXVI, H*/2-f4-/5*(acetylimino)»2»3^2ol-1-yl7-1*piperidinyl/ethyl7-4-fluorobenzamide is prepared with melting point Jr 216.9°G at reaction of (1-aziridinyl)(4*fluorophenyl)methanone with N*£C, 3-dihydro*1*(4-piperidinyl)-2H-benzimlidazol-2-ylidene/-acetamide. Example XXIX A mixture of 1.5 parts of N-(2-bromomethyl)-2-nitrobenzramide, 1.55 parts of 5*cldr-1,3-dihydro-1-(4-piperidinyl)-2H-benz-imidazbl- 2-one and 27 parts of N,W-dimethylformamide are stirred and refluxed for 5 hours. The reaction mixture is evaporated and the oily residue is crystallized from ethanol. The product

filtered off and dried, yielding 2.2 parts (6790 N-J^..^.

( 5~chloro-2, 3-(IIhydrQ-2-oxo-^

ethyl j -2-nitroben2amide hydrobromide.hemihydrate with melting point .

273.2°C.

Example XXX

A mixture of 8.7 parts of 4-fluoro.-rN- ^2-^5-(2,3-dihydro-2*oxo-1H-benzlmidazol-1*yl)-1-piperldinyl7 ethyl J-2- nine trobenzamide and 120 parts methanol are hydrogenated at normal pressure and room temperature with 2 parts Raney-Hickel catalyst.

after the calculated amount of hydrogen has been taken up£ is filtered

the catalyst from and the filtrate is evaporated. The residue is crystallized from a mixture of methanol and 2-propanol. The product is filtered off and dried, yielding 4.5 parts of 2-amino-N-2-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-ethyl-4-fluorobenzamide with melting point 229.3°C;

Example XXXI ,.,„

Using the method from example XXX, 2*amino-N-[2-[5-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-1-piperidinyl-7ethyl) is prepared -fluorobenzamld-hydrochloride,dlhydrate with Melting point*t"250°i? by hydrogenating N-f 2*

{%~ (5-Chloro-2,3-dihydro-2-bxo-1H-benzimidazol*1-yl)-1-piperidinyl7ethyl}-U-£fluoro-2-nitrobenzamide and converting the product thereof into a hydrochloride salt with hydrochloric acid.,,,, Example XXXII A mixture of 16 parts N-^2-^5-(5-chloro-2,3-dihydro-2-bkao-fH-benzimldaZol.1-yl)-1-plperldinyl7ethyl; -2-nitrobenzamide in 90 parts tetrahydrofuran and 40 parts methanol is hydrogenated at normal pressure and at room temperature with 3 parts Ranéy*nickel catalyst. After the calculated amount of hydrogen has been taken up, a reading of methanol which has previously been saturated with gaseous ammonia is added. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in acidified water and the mixture is washed twice with trichloromethane.

The water phase is separated and made alkaline with dilute sodium hydroxide solution. The product is extracted twice with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated. The residue is triturated

with 2,2<*>-oxybispropane. The product is filtered off and crystallized from a mixture of ethanol and a small amount of water, yielding 2 parts of 2-amino-N-12-^5*(5-chloro*2,3-dihydro-2-oxo-1H-benzimidazole- i-yl)-l-piperidiny^ benzamide-with melt-

point 226.8°C.

Example XXXIII

Using the method from Example XXXII, the following compounds are prepared from the corresponding nitro compounds: 4-amino-N-2-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-,1 -piperidinyl-7-ethyl-2-methoxybenzamide hydrate with a melting point of 220.6°C and 2-amino-N-{2-[5-(2,3:fdihydro-2-oxo-1H-benzimlidazol-1-yl)-1- piperidinyl-7-ethyl-benzamide-hemihydrate with a melting point of 219.2°C.

Example XXXIV

A mixture of 4.2 parts of 5-chloro-N-(2-(5-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-ethyl)-2-methoxy-4- Nitrobenzamide in 150 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 1 part of Rånéy-nickel-catar

illuminator. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. Water is added to the residue and the mixture is made alkaline with dilute sodium hydroxide solution. The precipitated product is filtered off and crystallized from methanol. The product is filtered off (the filtrate is set aside) and dried, giving a first fraction of 0.8 parts of 4-amino-5~chloro-N- 2-(5-(2,3-dihydro-2-oxo-1H- benzimidazol-1-yl)-1-piperidinyl-7-ethyl-2-methoxy-benzamide, melting point 230.1°C. r

The filtrate which was set aside is concentrated. Another fraction is filtered off and this gives 1.6 parts of 4-amino*5-chloro-N-2-[5-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperifedinyl]ethyl -2-Methoxybenzamide with melting point 232.5°C.

Example XXXV

A mixture of 1.68 parts of 1-(4-fluorobenzoyl)aziridine, 2.16 parts of 1,3-dihydro-1-(3,6-dihydro-1-(2H)pyridihyl)-2H-ben2imidazol-2-one , 10.8 parts of benzene and 1.6 parts of methanol are stirred and refluxed for 1.5 hours* After cooling the precipitated product is filtered, washed with 2-propanone and crystallized from ethanol, which gives 1, 76 parts of N-[2-(5-(2,3-dihydro-2-6xo-1H-benzimidazol-1-yl)-3''-6-dihydro-1-(2H)-pyridinyl-7-ethyl-/-4-fluorobenzamide of m.p. 202.7°C. .'Example XXXVI A mixture of 1.68 parts of 1-(4-fluorobenzoyl)aziridine, 3.07: parts of 2,3~dihydro-2-o^^

zol*1-propanenitrile hydrochloride, 1.65 parts N,N-diethylethanamine,

10.8 parts of benzene and 1.6 parts of methanol are stirred and refluxed for 1.5 hours. The reaction mixture is cooled and poured into water. The product is extracted with trichloromethane.

The extract is dried, filtered and evaporated. The residue is crystallized from 2*propanol. The product is filtered off and recrystallized from 2-propanol, which gives 1 part of N-[2-f-4*]-3-(2-cyanoethyl)-2,3-dihydro-2-oxo-1H-benzimidol- 1-yl7-1-piperidinyl

ethyl 7-4-fluorobenzamide with melting point 172.2°C. f in Example XXXVII

A mixture of 5.6 parts of N-(2-chloroethyl)-1-methyl-1H-pyrrole*2-carboxamide, 6.52 parts of 1,3-dihydro*1-(4-piperldinyl)~2H-benzimidazole-2 -one, 2.52 parts sodium bicarbonate, 0.1 parts potassium iodide and 240 parts 4-methyl-2-pentanone are stirred and refluxed for 62 hours. The reaction mixture is cooled and the solvent is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (in the volume ratio 95:5)

as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt

in ethanol, 2-propanol and 2,2*-oxybispropane. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane which gives 0.6 parts of N-£ 2-[5-(2,3-dihydro-2-oxo-1H*benzimidazol-1- yl)-1-piperidinyl-7-ethyl-1-methyl-1H-pyrrole-2-carboxamide hydrochloride hydrate with melting point 237.7°C.

Example XXXVIII Using the method from Example XXXVII is prepared: K-f 2-(5-X2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-ethyl-3-pyridinecarboxamide dihydrochloride* hydrate with a melting point of 214.1°C by reaction of N-(2-chloroethyl)-3-pyridinecarboxamide*hydrochloride with 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, and f 2-[5-(5-chloro-2,3-dihydro-2-oxo*1H-benzimidazol-1-yl)-1-piperidinyl-7-ethyl]-4-fluoro-2*-nitrobenzamide by reaction of N-(2- bromomethyl)-4-fluoro-2-nitrobenzamide with 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol*2-one.

Example XXXIX

A mixture of 16 parts N-(2-bromomethyl)-4-fluoro-2-nitrobenzamide, 12.6 parts 5-chloro-1,3-dihydro*1-(4-piperldinyl)-2H-phenzimidazol-2-one and 216 parts of N,<N>-dimeth<y>lformamide are stirred and refluxed for 3 hours. The N,N-dimethylformamide<r>is evaporated and the residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methane (in the volume ratio 95:5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanone and 2-propanol. The salt is filtered off and crystallized from methanol, which gives 1.5 parts N- f 2-/5-(5-chloro-2,3-dihydro-2-qkso- 1H-Benzinidazol-1-yl)-1-piperidinyl-7-ethyl-4-fluoro-2*nitrobenzamide hydrochloride with a melting point of 276.8°C.

Example XL

A mixture of 2.2 parts of N-(2-chloroethyl)-2-pyridine-carboxamide hydrochloride, 6.6 parts of 1,3*dihydro-1-(4-piperidinyl)-2H*benzimidazole -2*one, 1.66 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone are stirred and refluxed overnight. After cooling, the precipitated product is filtered off and dissolved in water. The solution is made alkaline with sodium carbonate and the product is extracted three times with 4-methyl-2-pentanone. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (in the volume ratio 95:5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanone and 2-propanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2,-oxybispropane (in the ratio of 1:1 by volume), which gives 2 parts of N-f 2-[5-(2*3-dihydro-2-oxo-1H-benzimidazole) -1-yl)-1-piperidinyl-7-ethyl-2-pyridinecarboxamide di*hydrochloride dihydrate with melting point 165.7°C. Example XLI

Using the procedure from Example XL and using K,H-dimethylformamide as solvent, N-t2-[5-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1- piperidinyl-7-ethyl-2-furancarboxamide with melting point 231.7°C by reaction of N-(2-chloroethyl)-2-furancarboxamide with 1,3-dihydro-1-(4-piperidinyl)-2H-benzlmidazol-2-one. Eczema! XLII

A mixture of 1 part 2-amino-N-[2-(5-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-ethyl-4-fluorobenzamide, 1 part acetic anhydride and 15 parts of water are stirred for 30

minutes in a water bath at 80 - 90°C. The react ion mixture is cooled and made alkaline with ammonium hydroxide solution. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, which gives 0.5 parts of 2-acetylamino)-N-[2-(2,3-dihydro-2-oxo-1H*benz-imidazol-1-yl)-1-piperidinyl]ethyl -4-fluorobenzamide with melting point 210°C. Example XLIII

Using the procedure from Example XLII, 2-(acetylamino)-N-f 2-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl7ethyl3- 4-Fluorobenzamide with melting point 196.5°C starting from 2-amino-N-<T 2-/5-(5-chloro*2,3-dihydro-2-oxo-1H-benzimldazol-1-yl)- 1-piperi-dlnyl/ethylj Example XLIV

A mixture of 1.68 parts of A-fluorobenzbyl chloride, 4.22 parts of ((1-C2-aminoethyl)-4-piperidinyl7-1,3*dihydro-2H-benz-imidazol-2-one-dihydrobromide, 4 .83 parts potassium carbonate and 18

parts H,N-dimethylformamide is stirred overnight at 90°C. The reaction mixture is cooled, filtered over hyflo and the filtrate is washed with a small amount of N,N-dimethylformamide. The N,H-dimethylformamide is removed in vacuo<p>g water is added to the residue» The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2-propanol, which gives 2.5 parts of N*f 2-(2,3-dihydro-2-oxo-1H*benzimidazol-

1*yl)-i-piperidinyl-7ethyl? -4-Fluorobenzamide with melting point 23i°c. r:,,

Example XLV

A mixture of 0.74 parts of 1-(benzoyl)azlridine, 1.06 parts of 4-(4-chlorophenyl)-4-piperidihol, 5.4 parts of benzene and 0.4 parts of methanol is refluxed with stirring for 2 hours.

The reaction mixture is cooled. After addition of 1,1*-oxybis-ethane, the product precipitates. After stirring for 15 minutes, the product is filtered off and dried, which gives 1.1 parts of N-2-[Zf-(4-.chlorophenyl)-4*hydroxy-1-piperidinyl-7ethyl benzamide with a melting point of 169°C.

Example XLVI

Using the method 1 example XLV and using equivalent amounts of suitable starting materials, the following compounds are prepared in the form of their free bases or in the form of acid addition salts after treatment (of the base with a suitable acid.

Example XLVII

A mixture of 5.8 parts of 2-amino-N-jf2-[5-(4-chloro-phenyl)-4-hydroxy-1-piperldinyl7ethylj? *4-fluorobenzamide, 5.5 parts acetic anhydride and 55 parts water are stirred and boiled for 30 minutes in a water bath at approx. 80°C. The reaction mixture is cooled and made alkaline with ammonium hydroxide. The product is extracted with trichloromethane. The water phase is separated and extracted with trichloromethane. The combined organic phases are washed three times with water, dried, filtered and evaporated.

The oily residue is crystallized from 4-methyl-2-penta*none. The product is filtered off and dried, which gives 4.5 parts of 2-(acetylamino)-M-{^2-(5-(4-chlorophenyl)-4-hydroxy-1*piperidinyl-7-ethyl-7-4-fluorobenzamide with a melting point of 175 .1°C. Example XLVIII

A mixture of 10.6 parts of M-(2-bromomethyl)-2-nitrobenzamide, 9.2 parts of A(*)-4-(4-chlorophenyl)-3-methyl-4-piperidinol and 270 parts H*N-dimethylformamide is stirred and refluxed for 4 hours. The react ion mixture is evaporated to dryness. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol

(1 volume ratio 95:5) as eluent* ^s^^t fractions are collected and the eluent is evaporated* The residue is converted to the hydrochloride salt with 2-propanol^ The salt is filtered off and crystallized from a mixture of ethanol and 2,2,*oxybispropane (in the volume ratio 1:1). The product is filtered off and dried overnight at 60°C, which gives 4.5 parts of A-(-)*N-f 2-(5-(4-chlorophenyl)-4-hydroxy-3-iBethyl-1-piperidinyl7ethyl^ - 2 -nitrobenzamide hydrochloride, with a melting point of 228°C.

Example IL

Using the method from Example XLVIII, A-(-)-N-[alpha]-[5-(4-chlorophenyl)-4-hydroxy-3-methyl-1-piperidylethyl]-4-fluoro-2-nitrobenzamide hydrochloride is prepared by reaction of N-(2-bromomethyl)-4-fluoro-2-nitrobenzamide with A-(-)-4-(4-chlorophenyl)-3-methyl-4-piperidinol.

Example L A mixture of 2.8 parts of A-(-)-N-£2-(4-chlorophenyl)-4-hydroxy-3-methyl-1-piperidinyl-7-ethyl-3-4-fluoro-2-nitrobenz-amide -hydrochloride in 160 parts methanol is hydrogenated at normal pressure and room temperature with 2 parts Raney nickel catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is converted to the hydrochloride salt in 2-propanone and 2-propahol. The salt is filtered off and crystallized from 2-propanol, which gives 1 part of A-(i)-2-amino-N-^2-/5-(4-chlorophenyl)-4-hydroxy-3-methyl-1-piperidinyl-7-ethylj - 4-fluorobenzamide dihydrochloride-2-propanolate with melting point 185°C. Example Li

Using the method from Example L, A-(-)-2-amino-N-2-(4-chlorophenyl)-4-hydroxy-3-methyl-1-piperidinyl-7-ethyl-benzamide dihydrochloride is prepared with melting point 190.5°C by hydrogenating N-(-)-N-(2-(4-chlorophenyl)-4-hydroxy-3-methyl-1-piperidinyl-7-ethyl)-2-nitrobenzamide. Example LII

A mixture of 3.5 parts of N-2-[5-(4-chlorophenyl)-4-hydroxy-1-piperidinyl-7-ethyl]-2-nitrobenzamide hydrochloride, 90 parts of tetrahydrofuran and 40 parts of methanol is hydrogenated at normal pressure and room temperature with 0.2 parts platinum dioxide. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is converted to the hydrochloride salt in 2-propanol and 2,2*-oxybispropane. The salt is filtered off and concentrated, yielding 2.6 parts of 2-amino-N-r2-[5-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl-benzamide dihydrochloride hemihydrate, m.p. 195.7° C. Example LIII

A mixture of 4.5 parts of N-{2-(5-(4-chlorophenyl)-4-hydroxy-1-piperidinyl-7-ethyl-7-4-fluoro-2-nitrobenzamide, 40 parts of methanol and 90 parts of tetrahydrofuran is hydrogenated at normal pressure and room temperature with 2 parts Raney nickel analyzer. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is converted to the hydrochloride salt in 2-propanol. The salt is filtered off and dried, yielding 2 parts of 2-amino-N-jC2-[5-(4-chloro-phenyl)-4-hydroxy-1-piperidinyl-7-ethyl]-4-fluorobenzamide dihydrochloride of melting point 210.7°C .

Example LIFE

Using the method of Example XII

and using equivalent amounts of suitable starting materials, the following compounds are prepared in the form of their hydrochloride salts;

N-(2-[1-(4-Chlorophenyl)-4-oxo-1,3»8*triazaspiro/5,57dec-8-yl7-ethyl}-4-fluorobenzamide, N-1 2-[1^4afchloropheyl )-4-oxo-1,3,8-triazaspiro[2f,§7deo-8-yl7-ethyl£benzamide,.

N-(2-(1-(4-brylphenyl)-4-oxo-1,3-8-triazaspiro[5415]dec-8-yl7•,• ethyl)-4-fluorobenzamide,

2-chloro-N-f 2-(1-(4-chlorophenyl)-4-oxo-1,3*8-triazaspiro/5,§7*

dec-8-yl/ethylX/-4-fluorobenzamide, 2-amino-N-[2-/I-(4-chlorophenyl)-4-oxo-1,3,8-triazaspiro/5,£7-dec- 8-yl7ethylJ -4-fluorobenzamide and 2-amino-N- i 2-/I-(4-bromophenyl)-4-oxo-1, 3,8-triazasplro/5, §7** dec-8-yl7ethyljf - 4-fluorobenzamide. Example LV Using the procedure of Example XXVI and using equivalent amounts of suitable starting materials, the following compounds of formula (I) are prepared: N-2-(5-(5-bromo-2,3*-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl7ethyl3-4-fluorobenzamide, N-C 2-(5-(2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl)-1-piperdinyl7ethyl3 -4-Fluorobenzamide, ..... N- 1 2-/5-( 5»6-dichloro-2, 3-<ii^hydro-2-oxo-1H-benzimidazol-1-yl) * 1-pipertdinyl /ethylj -4-fluorobenzamide, ,2-chloro-N- i2 -/§-(5,6-dichloro-α,3-dlhydro-2-oxo-1H-benzlmidazol-1-yl)-1-piperidinyl-7ethylj -4 -fluorobenzamide, 2-amino-N-X. 2-(5-(5-bromo-2,3-dihydro-2-oxd-1H-benzimidazpl-1-

yl)-1-piperidinyl-ethyl-4-fluorobenzamide, N-£2-[3»6-dihy<*o-4-(2,3-dihydro-2-oxp-^

1-(2H)-pyridinyl-7-ethyl-benzamide, 2-amino-N-{2-(3,6-dihydro-4-(2,3*dihydro-2-oxo-1H-benzamidazol-1-yl) -1-(2H)-pyridinyl-yl}-4-fluorobenzamide,

2-Chloro-N-• 2-[3,6-dihydro-4~(2,3-dihydro-2-oxo-1H-benzimidat-z©1-1-yl)-1-(2H)-pyridlnyl7ethylJ'- 4-fluorobenzamide and

N-{2-(5-(5-Chloro[2,3-dihydro-2-oxo-1H-benziinidazol-1-yl)-1-(2H)-pyridinylethyl-4-fluorobenzamide.

Example LVI

Using the procedure of Example XLV and using equivalent amounts of the appropriate starting materials, the following compounds are prepared.

N-/2-^ 4-/5-chloro-3-(trifluoroTOethyl)phenyl7^4-liydroxy-1-piperidinylj ethyl7-4-fluorobenzamide 2- amino-/2- i 4-/5-chloro-3 -(trifluoromethyl)phenyl7-4-hydroxy-1-piperidinyl J ethyl7-4-fluorobenzamide 2-chloro-/2- i4-/5-chloro-3-(trifluoromethyl)phenyl7-4-hydrx3r-1-piperidinyl^ethyl7- 4-fluorobenzamide,

N-(2-(4-bromophenyl)-4-hydroxy-1-piperidinyl-7-ethyl)-4-fluorobenzamide

2-Amino-N-[2-(4-bromophenyl)-4-hydroxy-1-piperidinyl-7-ethyl]-4[fluorobenzamide].

Claims (1)

1. A process for the preparation of a chemical compound selected from the group consisting of an N-((X1-piperidinyl)-alkyl7arylcarboxamide derivative of the formula and pharmaceutically acceptable acid addition salts thereof where : Ar is an aryl radical selected from the group consisting of phenyl* substituted phenyl, 2-thienyl, 2-furanyl, pyridinyl and 1-methyl-2-pyrrolyl, wherein said substituted <1> phenyl is phenyl with 1-3 substituents independently selected from the group consisting of halogen, lower alkyl, xl ; lower alkyloxy, trifluoromethyl, nitro, hydroxy, amino, lower alkylcarbonyloxy and lower alkylcarbonylamino, provided that when more than one of those said substituents are present, only one is selected from the group consisting of hydroxy, amino, lower alkylcarbonyloxy and lower alkylcarbonylamino; R is a member selected from the group consisting of hydrogen and lower alkyl; n is a whole number from 2-3 including these: and the radical is a member selected from the group consisting of | a; a radical with the formula: 12 where R and R are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl; b) a radical with the formula: wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl; M is selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl and 2-cyanobutyl; Y is selected from the group that be» stands for 0, S and lower alkylcarbonylimino; and. the dashed line indicates that the double bond between the 3- and 4-carbon atoms in the piperidine iron may possibly be present, provided that when there is a double bond between the said 3- and 4-carbon atoms, then said Y is equal to 0 and said M is equal to hydrogenj c ) a radical with the formula: wherein R-* and R** are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl; and >v«^d) a radical with the formula: wherein R" is selected from the group consisting of hydro gen and methyl; R6 is selected from the group consisting of, aV hydrogen and halogen; and R 7- is selected from group», t pen consisting of hydrogen, halogen* lower alkyl and trifluoromethyl characterized by a) reacting a compound with the formula with a compound with the formula to produce a compound with the formula wherein said reaction is carried out in a suitable organic solvent which is inert to the reaction* preferably under heating} or by manb) reacting a compound with the formula where X is a suitable reactive ester function from the corre- reacting alcohol with a compound of the formula in a suitable organic solvent, preferably in the presence of a suitable base, under heating to prepare a connection with the formula or <..>c) reacts a compound of the formula with a suitable amine of the formula in a suitable organic solvent which is inert to the reaction, preferably under heating or by d) subjecting compounds of formula I, where Ar is a phenyl group to which a nitro group is attached, alone or together with other substituents, to a nitro-to-amine reduction reaction according to known methods for preparing a compound of formula (I) where Ar is a phenyl group to which an amino group is attached, alone or together with other substituents; or by e) preparing a compound of formula (I) where Ar is a phenyl group to which a lower alkyl carbo- nylamino group or one lower alkylcarbonyloxy group at to acylate the corresponding amino- or hydroxy-substituted! analog by known methods* or by f) acylating a compound of formula with a suitable acylating agent from a suitable lower alkyl- carboxylic acid to produce a compound of the formula or by yoke) submit to a compound with the formula cyclization with a suitable sulfur-containing cyclizing agent to produce a compound of the formula or by h) S-alkylating a compound of formula (I-d) above by usual S-alkylation methods to produce : make a connection with the formula b g, if desired, prepare pharmaceutically acceptable acid addition salts of the products from steps I-a to I-h and, further, if desired, prepare various stereochemical or optical isomeric forms of <y> these compounds others by known methods. ' V . i. Method of preparing a chemical compound selected from the group consisting of 4-fluoro-N* 1 -2-/Lr(4- f fluoro enyl) *4»oxo-I,3 »8*triazaspiro/5t J57dec-8-yl7ethyl/. benzamide and pharmaceutically acceptable acid addition salts thereof, characterized by reacting l-(4-fluoro-benzoyl)aziridine with 1-(4-fluorophenyl)-1,3,8-triazaspiro/5,f>7-decan-4-one and, if desired, prepares pharmaceutically acceptable acid addition salts of the product" 3": Process for preparing a chemical compound else selected from the group consisting of 2-amino-4-fluoro-N-(2-(4-oxo-1-phenyl-1,3,8-triazaspiro[5,7dec-8-yl)ethyl]benzamide and pharmaceutically acceptable acid addition salts thereof, characterized by hydrogenating the cor- reacting 2-nitrobenzamide and, if desired, preparing pharmaceutically acceptable acid addition salts of the product. , , 4. Process for preparing a chemical compound selected from the group consisting of 2-chloro-N-[2-(4-fluoro-phenyl)-4-oxo-1,3-8-triazaspiro/3,§ 7dec-.%yi7© ty^ benzamide and pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1-(2-chloro-benzoyl)aziridine with 1-(4-fluorophenyl) with 1-(4-fluorophenyl)- 1,3,8-triazaspird/5,57decan-4-one and, if desired, prepare pharmaceutically acceptable acid addition salts. of the product. 5» Process for preparing a chemical compound selected from the group consisting of 2-chloro-4-fluoro-N-^2-(1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro/5 ,§7dec-8-yi/ethyl^ benzamide and pharmaceutically acceptable acid addition salts thereof, characterized in that 1-(2-chloro-4-fluorobenzoyl)-azirldine is reacted with 1-(4-fluorophenyl)-1,3 # 8 -tri- azaspiro/5,57decan-4-one and, if desired, preparing pharmaceutically acceptable acid addition salts of the product. 6. Process for preparing a chemical compound selected from the group consisting of N-1-2-[5-(54-dor-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl a <y>l ^ - 4-fluorobenzamide and pharmaceutically acceptable acid addition salts thereof, characterized in that one reacts 1-(4-fluorobenzoyl)aziridine with 5-chloro-1,3-dihydro-1- (4-piperidinyl)-2H-benzimldazol-2-one and, if desired, prepares pharmaceutically acceptable acid addition salts of '•; r the product.,. 7. Process' for preparing a chemical compound selected from the group consisting of 2-chloro-N-[2-[2r*(5-chloro-2,3-<iihydr-2-oxo-1H-benzimidazol-1 -yl)-1-piperidinyl-7-ethyl-4-fluorobenzamide and pharmaceutically acceptable acid addition salts thereof, characterized in that 1-(2-chloro-4-fluorobenzoyl)aziridine is reacted with 5-chloro-1,3-dihydro*l- (4*piperidinyl)»2H-benzimidazol-2-one Ag,, if this is desired, prepares pharmaceutically acceptable acid addition salts of the products. %. Process for preparing a chemical compound selected from the group consisting of 2'*amino-N-£2-(2,3* dihydro-2-oxo-1H-benzimidazol-1-yl)-1- piperidinyl7ethylJ -4-fluorobenzamide and pharmaceutically acceptable acid addition salts thereof, characterized in that one hydrogenates the corresponding 2-nitro-substituted benzamide and, if desired, prepares pharmaceutically acceptable acid addition salts of the product. , 9. Procedure for preparing a chemical compound with the formula: where the group is a member selected from the group consisting of:a) a radical of the formula: where R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl;b) a radical with the formula wherein and R 1 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl; M is selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl and 2-cyanoethyl; Y is selected from the group consisting of 0, S and lower alkylcarbonyliminoj, and the dashed line indicates that a double bond between the 3- and 4-carbon atoms of the 1 piperidine ring may optionally be present, provided | that when there is a double bond between the aforementioned 3- and 4- carbon atoms, then Y equals 0 and the aforementioned M is hydrogen; c) a radical with the formula: wherein R-' and R are each independently selected from the group consisting of <y> hydrogen, halogen, lower alkyl and, trifluoromethyl; and d) a radical of the formula: wherein fr 5 is selected from the group consisting of hydrogen and methyl; R^ is selected from the group consisting of hydrogen and halogen, and where R^ is selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl, characterized in that mana) undergoes a compound of the formula to acid or alkaline hydrolysis whereby decarboxylation takes place; or by manb) subjecting a connection with the formula to catalytic hydrogenation using a suitable catalyst to produce a compound of the formula? 10. Procedure to prevent vomiting or mental ■■ - ■ '7 disturbances, character! serted by systemic administration to warm-blooded animals of an effective antiemetic or psychotropic amount of a compound selected from the group consisting of N((1-piperidinyl)alkyl-7-arylcarboxamide derivative of formula (I). 11. Procedure to inhibit vomiting or mental disorders* characterized by systemic administration to warm-blooded animals of an effective antiemetic or pycotropic amount of N-f2-(5-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazole-1- <y>l )-1- <pi>perldin <y>I7 et <y>l )-4-fluorobenzamide and pharmaceutically acceptable acid addition salts thereof, in mixture with a pharmaceutical carrier. 12. Chemical compound, characterized in that it is selected from the group consisting of N-((T1-piperidinyl)alkyl7arylcarboxamide derivative with the formula: and pharmaceutically acceptable acid addition salts thereof, wherein: Ar is an aryl radical selected from the group.. $o.m consists of f phenyl, substituted phenyl, 2-thienyl, 2-furanyl, pyrldinyl and 1-methyl-2-pyrrolyl, wherein said substituted phenyl is phenyl mad from.1 - 3 substituents uav optionally selected from the group consisting of halogen, lower alkyl, lower alkyloxy, trifluoromethyl, nitro, hydroxy, amino, lower alkylcarbonyloxy and lower alkylcarbonylamino, provided that when,mer than. one of said substituents is present, only one is selected from the group consisting of hydroxy, amino, lower alkylcarbonyloxyb g lower alkylcarbonylamino; .As R is a member selected from the group consisting of hydrogen and lower alkyl; n is one goat number from 2-3 Including these; and the radical is a member selected from the group consisting of a) a radical of the formula: 12 wherein R and R are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl; b) one radical with the formula: • x h wherein R-^ and R are each independently selected from the group > <■ consisting of hydrogen, halogen, lower alkyl bg trifluoromethyl; M is selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl and 2-cyanoethyl; Y is selected from the group s>m consists of 0, S and lower alkylcarbonylimino;. and the dashed line indicates that the double bond between the 3- and 4-carbon atoms in the piperidine nucleus may possibly be present, provided that when there is a double bond between the said 3- and 4-carbons bon atoms, then said Y is b and said M is hydrogen; c) a radical with the formula: "=5 4 where R <r> and R where are independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl; andd) a radical of the formula; where R^ is. selected from the group consisting of hydrogen and methyl; R 1 is selected from the group consisting of hydrogen and halogen; and where R^ is chosen from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl. 13. Chemical compound, characterized in that it is selected from the group consisting of aV 4-fluoro-N-^~ 2-/I-(4-fluorophenyl)-4-oxo-1,3 *8-triazaspiro/5, §7dec-8-yl7-ethyl} benzamide and pharmaceutically acceptable acid addition salts thereof. 14. Chemical compound, characterized in that it is selected from the group consisting of 2-amino-4- fluoro-N-(2-(4-oxo-1-phenyl-1,3,8-triazaspiro/5,^7dec-8-yl)-ethyl7benzamide and pharmaceutically acceptable acid addition salts of this one. 15. Chemical compound, characterized . in that it is selected from the group consisting of 2-chloro-N-^2- /1-(4-fluorophenyl)•4-oxo-1,3♦8-triazaspiro/5 r£7dec-8-yl7ethyl£ ■-benzamide and pharmaceutically acceptable acid addition salts thereof. 16. Chemical compound, characterized in that it is selected from the group consisting of 2-chloro-4-fluoro-N-2-11-(4-fluorophenyl)-4-oxo-1,3, 8-triazaspiro[5,7-dec-8-yl]ethyl} benzamide and pharmaceutically acceptable addition salts thereof. 17. Chemical compound, vessel ac' terized in that it is selected from the group consisting of N-[2-(5-(5-chloro-2,3-dihydro-2-oxo-1H-benzindazol-1-yl)-1-piperi- dinyl-7-ethyl-3-4-fluorobenzamide and pharmaceutically acceptable acid addition salts thereof. 18. Chemical compound, characterized in that it is selected from the group consisting of 2-chloro-N-2-[5-(5^chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl-7-ethyl-4-fluorobenzamide and pharmaceutically acceptable acid addition salts thereof. 19. Chemical compound, characterized . in that it is selected from the group consisting of 2-amino-N-(2-(5-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-ethyl)-4- fluorobenzamide and pharmaceutically acceptable acid addition salts thereof.20. ..,■■ \ J- Chemical compound, characterized by having the formula: where the group is a member selected from the group consisting of a) a radical of the formula: ; • 1 P where R and R are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl;b) a radical of the formula; : •: -z A V wherein R-' and R are each independently selected from the group consisting of hydrogen, halogen* lower alkyl and trifluoromethyl; M is selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl and 2-cyanoethyl; Y is selected from the group consisting of O, S and lower alkylcarbonylimino; and the dashed line indicates that the double bond between the 3* and 4-carbon atoms in the piperidine nucleus may optionally be present, provided that when there is a double bond between the mentioned 3- and 4-carbon atoms, then the mentioned Y is 0 and the mentioned M is hydrogen; c) a radical with the formula: wherein R<3> and R<*> are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl; andd) a radical with the formula: wherein R 5 is selected from the group consisting of hydrogen and methyl; R^ is selected from the group consisting of hydrogen and halogen; and where R^ is selected from the group consisting of hydrogen, halogen, lower alkyl and trifluoromethyl. 21. Pharmaceutical preparation in the form of unit doses, characterized by the fact that they per . dosage unit contains an effective antiemetic or psychotropic amount of a compound selected from the group consisting of an N-/t-piperidinyl>-alkyl/arylcarboxamide derivative of the formula (I) and pharmaceutically acceptable acid addition salts thereof, in admixture with a pharmaceutical carrier. 22. Pharmaceutical preparation according to claim 21, character* i s e r t in that the said pharmaceutical carrier is a solid, swallowable carrier. 23* Pharmaceutical preparation for alcohol; claim 21 é characterized in that the pharmaceutical carrier is a liquid, swallowable carrier. 24. Pharmaceutical preparation according to claim 21, characterized in that said pharmaceutical carrier is a sterile liquid suitable for parenteral use. '25. Pharmaceutical preparation in the form of unit dosages, cure act 1 s e r t in that it per dosage unit contains an effective antiemetic or psychotropic amount of N-[2-(5-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl-7-ethyl]-4-fluorobenzamide and pharmaceutically acceptable acid addition salts thereof in admixture with a pharmaceutical carrier.