IE43150B1 - N-/(1-piperidinyl)alkyl/arylcarboxamide derivatives - Google Patents

Abstract

A process for the preparation of new arylcarboxamide derivatives of the formula: ** (Formula) ** and its pharmaceutically acceptable salts and acid addition, 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 with 1 to 3 substituents independently selected from the group formed by halogen, lower alkyl, lower alkyloxy, trifluoromethyl, nitro, hydroxy, amino, lower alkylcarbonyloxy and lower alkylcarbonylamino.

Description

The present invention relates to certain N-ZIi-piperidinyl)alkyl/arylcarboxamides which are-useful as antiemetic and psychotropic agents.

In the literature some N-^idialkylamino)alkyl/benzamides, including N-/71-piperidinyl)alkyl/benzamides, and some WZ’(2-pyrrolidinyl)methyl7benzamides are described which have pharmacological properties. Well-known specific examples of such prior art compounds are 4-amino-5-chloro-W-/2-(diethylamino)ethyl7-2-methoxybenzamide, generically designated as metoclopramide and used as an antiemetic agent; and 5aminosulfonyl-N-/~(l-ethyl~2-pyrrolidinyl)methyl7-2-methoxybenzamide, generically designated as sulpiride and used as an antiemetic and neuroleptic agent.

The compounds of the present invention differ from the prior art compounds by the nature of the substituted piperidine nucleus attached to the alkyl side-chain. A number of prior art compounds are described in the following references: Chemical Abstracts, 59, 11358c; United States Patent Wo. 3,342,826; and Chemical Abstracts, 71, P81413c.

The novel W-^l-piperidinyl)alkyl/arylcarboxamide derivatives □f this invention may structurally be represented by the following formula: R ind the pharmaceutically acceptable acid addition salts thereof, /herein: Ar is a phenyl, 2-thienyl, 2-furyl, pyridyl or a 1-methyl2-pvrrolyl group or a phenyl group substituted with from 1 to 3 substituents which are each independently a halogen atom, a lower alkyl, lower alkyloxy, trifluoromethyl, nitro, hydroxy, amino, lower alkylcarbonyloxy or lower alkylcarbonylamino group, provided that when more than one substituent is present only one thereof may be a hydroxy, amino, lower alkylcarbonyloxy or a lower alkylcarbonylamino group; E is a hydrogen atom or a lower alkyl group; n is 2 or 3; and the radical a) a radical having the formula: wherein R1 and Rz are each independently a hydrogen or a halogen atom, a lower alkyl or a trifluoromethyl group; b) a radical having the formula: Y ti 3150 wherein R3 and R* are each independently a hydrogen or halogen atom, a lower alkyl or a trifluoromethyl group; M is a hydrogen atom, a lower alkyl, lower alkylcarbonyl or 2-cyanoethyl group; Y is 0, S or a lower alkylcarbonylimino group; and the dotced line indicates an optional double bond between the 3- and 4-carbon atoms of the piperidine nucleus, provided that when there is a double bond between said 3- and 4-carbon atoms, then said Y is 0 and said M is a hydrogen atom; c) a radical having the formula: or d) a radical having the formula: 7 R is a hydrogen or halogen atom; and R is a hydrogen or halogen atom, a lower alkyl or trifluoromethyl group. _ a 431 As used herein lower alkyl may be straight or branch chained and have from 1 io ahout 5 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl and the like; and the term halo is generic to halogens of atomic weight less than 127, i.e., fluoro, chloro, bromo and iodo.

Compounds of formula (I) wherein Ar and -N A are as previously defined, R is hydrogen and n is 2, (i-a), may generally be prepared by reacting an appropriately substituted 1 -aroylaziridine of formula (II), wherein Ar has tiie previously indicated meaning, with an^ap^ropriate piperidine derivative of formula ( ΠΙ) wherein the -N A group is as previously defined.

(HI) (Π) The foregoing reaction is 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.

In this and following procedures the reaction products are separated from the medium and* if necessary, further purified by the application of methodologies known in the art. -5The compounds of- formula (I), including those wherein R is lower alkyl and those wherein n is 3 may also be prepared by the reaction of a suitable reactive ester of formula (IV ) wherein Ar, R and n are as previously Refined and X is an appropriate reactive ester function derived from the corresponding alcohol, such as, for example, halo, methanesulfonyl, 4-methylbenzenesulfonyl and the like, with an appropriate piperidine derivative of formula (HI).

ArO R £-N-(CH2)a-X d~\ HN A O ——S’ (I> (IV) (ΠΙ ) The foregoing reaction is preferably carried out in a suitable organic solvent such as, for example, Ν,Ν-dimethylformamide, N,Ndimethylacetamide, 4-methyl-2-pentanone, 2-propanol, methanol, ethanol, 2-propanone and the lik'e solvents. The additions of an appropriate base, e. g., an alkali metal or earth alkali metal carbonate or hydrogen carbonate may be utilized to pick up the acid that is liberated during the course of the reaction. Somewhat elevated temperatures are appropriate to enhance the reaction rate and preferably the reaction is carried out at reflux temperature.

Still another method of preparing the compounds of formula (I) consists in reacting an appropriately substituted aroyl halide of formula (V ) with an appropriate amine of formula (VI) according to methodologies generally known in the art for the preparation of amides starting from an aryl halide and an amine, O R _ I Fd Ar-C-halo + ΗΝ-(ΟΗ2)β-Ν^Α ___(I) (V) (VI) . · ' ’ -6431S© ιθ For example, the foregoing reaction may conveniently be carried out by refluxing the reactants together in a suitable reactioninert 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 e.her, 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 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) wherein Ar is a phenyl group having thereon an amino group, alone or together with other substituents, may still be prepared by subjecting the corresponding nitro-subtitutea analogs to a nitro-to-amine reduction reaction according to known procedures, e.g. , by catalytic hydrogenation using, for example, Raney nickel, palladium-on-charcoal or platinium dioxide catalyst or by the treatment of the nitro compounds with iron-ammonium chloride or zinc acetic aci Compounds of formula (I) wherein Ar is a phenyl group having thereon a lower alkylcarbonylamino or lower alkylcarbonyloxy can easily be derived from respectively the corresponding amino or hydroxy substi-. tuted analogs by acylating the latter with an appropriate acylating agent such as, for example a halide or anhydride derived from the appropriate lower alkylcarboxylic acid. The acylation reaction may, e. g., conveniently be carried out by using an appropriate lower alkylcarboxylic acid anhydride in water.

Compounds of formula (I) which may be represented by the formula: (I-b) -7can similarly be prepared, starting from* a corresponding unsubsdtuted compound of the formula: by acylating the latter with an appropriate acylating agent derived from the appropriate lowe'r'alkyicarboxylic acid, e.g., an acyl halide or anhydride. For example, said acylation reaction may conveniently be carried out by using an appropriate anhydride in a suitable organic solvent, such as, for example, benzene, methylbenzene, dimethylbenzene and the like.

Compounds of formula (I) which may be represented by the formula: O R II I , Ar-C-N-(CH.

OH S J NxCXNH R3 R4 (i-d) may also be prepared by subjecting an appropriate diamine of the formula: (VII) to ring closure with an appropriate sulfur containing cyclizing agent such as, for example carbon disulfide, thiourea, carbonothioic dichloride, ammonium thiocyanate and the like.

(VII) ring closure (I-d) -84315u Compounds of formula (I) which may be represented by the iormula: O R - II I Ar-C-N y-\ K S(lower alkyl) R3 R4 (I-e) . may still be prepared .starting from a corresponding compound of formula (I-d), by S-alkylation of the latter according to standard S-alkylating procedures, e.g., by the reaction of (I-d) with an appropriate halolower alkane or with an appropriate di(iower alkyl) sulfate.

The starting materials used in the foregoing preparations may be obtained following the procedures indicated hereinafter.

The aroylaziridine intermediates of formula (II), a number of which are known compounds, can easily be prepared by the application of art-known procedures as described in the literature, e. g., by the reaction of an’aroyl halide ox formula (V ) with aziridine (VIII) in the presence of an appropriate base to neutralize any acid which is liberated during the course of the reaction. The reaction is carried out in an appropriate solvent system, such as, for example, a mixture of water and trichloromethane. The foregoing reaction maybe illustrated as follows. -halo (V) (VIII) N&HCOa / tt ' -> (Π) H,O/CHC1, Z J -93150 The intermediates of formula (IV), some of which are also described in the literature, may conveniently be prepared, for example, by the N-aroylation of an appropriate aminoalkanol of formula (IX) with an appropriate aroyl halide (V) or with an appropriate lower alkylarylcarboxylate of formula (X) according to standard N-aroylating procedures, followed by the conversion of the hydroxyl group on the alkyl side chain of the thus obtained (XI) into a reactive ester group following well-known procedures. In the preparation of halides there may be used common halogenating agents, such as phosgene, sulfinyl chloride, sulfuryl chloride, phosphorous pentachloride, phosphorous pentabromide, and phosphoryl chloride. When the reactive ester is an iodide it is preferably prepared from the corresponding chloride or bromide by the replacement of that halogen with iodine. Other reactive esters such as methanesulfonates and 4-methylbenzenesulfonates are obtained by the reaction of the alcohol with an appropriate sulfonyl halide, such as methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride, respectively. The foregoing reactions are illustrated in the following schematic representation.

(V) + or il Ar-C-0(lower alkyl) (X) R ll I Ar-C-N-(CH-) -OH z n HN-(CH2)n-0H aroylation (IX) reactive ester formation \ (IV) (XI) The intermediates of formula (IV) wherein X is halo, (ΐν-a) may alternatively be obtained in one step by the reaction of an appropriate aroyl halide (V) with an appropriate haloalkanamine (XII) in an appropriate solvent such as N ,N-dimethy If ormamide (DMF) - 10 43150 and N, N-dxmethylacetamide, preferably in the presence of an appropriate base, such as, for example, M, N-dietliylethanamine.

(V (ΧΠ) (ch3ch2)3n -=:-=-s, DMF O R ii : Ar-C-N-(CK,) -halo it XI (IV-a) By carrying out the foregoing reaotion in alkaline medium and using an intermediate of formula (XII) wherein R is hydrogen and n is 2, the corresponding aziridines of formula (II) maybe obtained.

The intermediates of formula (VI) may be prepared as follows. An appropriate lower alkyl N-(haloalkyl)carbamate of formula (XIII) is reacted with an appropriate piperidine derivative of formula (III) according to common N-alkylating procedures, e. g., by heating the reactants together in an appropriate reaction-inert organic solvent, such as, for example, a lower alkanol, e.g., methanol, ethanol and the • like, whereupon there is obtained a carbamate of formula (XIV ).

The latter is then subjected to acid or alkaline hydrolysis whereupon decarboxylation occurs, yielding the desired intermediates of formula (VI). '9 a lower alkyl-O-C-N-(CH2)a-halo + (ill) ______> (XIII) O R + lower alkyl-O-C-N-(CH) -ν'A H °g °H_(VI) *31 \__y (XIV) -11431 5 (J In carrying out alkaline hydrolysis, metal bases, such as, sodium and potassium hydroxide may advantageously be employed. Acids to be used in acid hydrolysis include strong mineral acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid.

When -N A in the intermediate (VI) has the formula o it is appropriate to use instead of (XIII) the corresponding phenylmethyl carbamate, in which case the subsequent decarboxylation may be performed by catalytic hydrogenation using an appropriate catalyst, e.g., palladium-on-charcoal.

Intermediates of formula (VII) are conveniently prepared by introducing the aroylaminoalkyl chain into a N-(2-nitrophenyl)-4-piperidinamine of formula (XV) by reacting the latter with an aziridine of formula (II) or reactive ester of formula (IV), and subsequent reduction of the nitro group of the thus obtained (XVI) following standard nitro-to-amine reduction procedures as previously described herein. 4315a (XI ) or (IV) HN /—\ H Ar (XVI) nitro-to-amine -;> reduction (VXI) Starting materials of forrjiula (ill), represented by the formula 'O>0 and methods of preparing the same may be respectively be found in the following references: a) U.S. Fat. No. 3,238,216; b) U.S. Pat. No. 3, 161,645; Belg. Pat. No. 830,403; c) U.S. Pat. No. 3,518,276; and U.S. Pat. No. 3,575,1990.

Starting materials of formula (ill) which Are represented by the formulas; and H S(lower alkyl) (m-e) may generally be prepared starting from an appropriate N-(2-amino e · » phenyl)-4-piperidinamine Of the formula.* (lower alkyl)-O ,NH R· (XVII) -1410 431 5b The starting materials (Ill-d ) are conveniently prepared by the cyclization of ( XVII) with an appropriate cyclizing agent, e.g., carbon disulfide and subsequent removal of the lower alkyloxycarbonyl group of the thus obtained (XVIII) by alkaline hydrolysis.

The starting materials (III-e) can be prepared by S-alkylating (XVIII) as described hereinabove for the preparation of (I~e) starting from (i-d) followed by elimination of the lower alkyloxycarbor yl group of the resulting (XIX).

The N-(2-aminophenyl)-4-piperidinamines of formula (XVII), a number of which are known compounds, may be prepared following the procedures outlined in U. S. Pat. No. 3, 910, 930 and Belg. Pat. No. 830,403.

The foregoing procedures are illustrated in the following schematic representation. (lower a]kyl)-O-C-N Y \_Λ cyclization NH NIL ( xvii ; R3 R4 ρ /—\ 1 (lower alkyl)-O-C-N Y U V/VYh Y OH (IH-d) -3 S R (XVIII) (XVIII) S-alkylation Ψ μ f-\ H S(iower alkyl) (lower a!kyl)-O-C- ' 1 OH (ΠΙ-β) 4.

R R (XIX) The intermediates o£ formula (ill) which are represented by the formula; (m-f) * 9 can be prepared as follows.

An appropriate N-(2-aminophenyl)-l -(phenylmethyl)-4-piperidinamine of formula (XX) is converted into the corresponding 1 -/T-fphenylSnethyl)-4-piperidinyiy-lH-benzimidazol-2-amine (XXI) by the cyclization of (XX ) with an appropriate cyclizing agent as known in the art, e. g., cyanamide. The thus obtained (XXI) is then N-acylated with an appropriate acylating agent derived from the appropriate lower alkylcarboxylic acid, e.g. a halide or anhydride to obtain an intermediate of formula (XXII), -1643150 The desired (ϊϊΐ-ί) are then conveniently obtained by eliminating the phenylmethyl group of (XXII) hy catalytic hydrogenation using an appropriate catalyst such as, for example, palladium-on-charcoal.

The intermediates (XXI) may also be prepared by converting 5 (XX) into a lower alkyl |1, 3-dihydro-l-/l—(phenylmethyl)-4-pxperidinyl7 2H-benzimidazol-2-ylidsne) carbamate (XXIV ) by cyclizing (XX ) with an appropriate cyclizing agent as known in the art for the preparation of 2-benzimidazolecarbamates starting from 1,2-benzenediamines, e. g. with a lower alkyl (iminomsthoxymethyl)carbamate of formula q (XXIII), and thereafter decarboxylating the latter by acid hydrolysis.

The foregoing reactions are illustrated in the following schematic representation.

(XXI) -5 750 (xxi) ο (XXII) Η2_(ΠΙ-f) Pd-on-C Starting materials of formula ( XX) herein may conveniently be obtained by the application of art-known procedures, such as, for example, by the condensation of 1 -(phenylmethyl)-4-piperidinamine with an appropriate 2-halo-nitrobenzene of formula (XXV ) followed by the reduction of the nitro group of the thus obtained ( XXVI) by catalytic hydrogenation using an appropriate catalyst Such as, for example, Raney-nickel. , (XXVI) -1843150 The ultimate starting materials in all of the foregoing procedures are generally known and may be 'prepared according to art-known procedures.

It is obvious that the compounds of formula (I) wherein 5 -N__A has the formula (ΠΙ-c) and wherein R3 stands for methyl have two asymmetric carbon atoms within their structure and consequently such compounds may exist under different stereochemically and optically isomeric forms.

Depending on the relative position· of the methyl and the hydroxy group with respect to the plane of the piperidine nucleus the compounds have the cis or trans configuration and each of these forms further includes two optical isomers. The stereochemical and optical isomers of these compounds, which are naturally intended to be within the scope of this invention, may be prepared following . methodologies known to those skilled in the art. Cis and trans isomers of such compounds and-of precursors therefor may be obtained separately by physical methods, e.g., selective crystallization. Without further reference to their actual stereochemical configuration, the form which is first isolated is herein referred to as the A-form and the remaining as the B-form, Since the compounds involved have basic properties, optically active acids may be employed in the resolution of the racemic cis and trans forms to obtain the optical isomers thereof. -19ϊί 50 The compounds of this invention may be converted to their therapeutically useful acid, addition salts 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-hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic, (Z)-2-butenedioic (E)-2-butenedioic, 2-hydroxybutanedioic, 2, 3-dihydroxybutanedioic, 2-hydroxy-l, 2, 3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic, «-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 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 compounds of formula (I) and the therapeutically active acid addition salts thereof have been found to possess strong antiemetic activity as is evidenced by their ability to block apomorphineinduced vomiting in dogs. The method used is described previously by P.A. J. Janssen and C. J. E. Niemegeers in : Arzneim. -Forsch.

(Drug Res.), 9^.765-767 (1959).

The compounds listed below were administered subcutaneously to beagle dogs at different doses and the animals were challenged 1 hour thereafter with a standard dose of 0. 31 mg/kg (subcutaneous) of apomorphine.

The tables below give the ΕΏ^θ values of a number of the compounds under consideration. As used herein, the ED-. value re50 presents the dose which protects 50% of the animals from emesis.

It is understood that the compounds shown in the tables are not listed for the purpose of limiting the invention thereto, but. only to exemplify the outstanding antiemetic properties of all the compounds within the scope of formula (I). -2043150 ............. ' i— • 1 Ar i ϊ ‘ 1 R1 ! Base or Salt j form i ..... • E1\° m mg/kg s. c. i 1 '-τ-- ! -6 , i H 1 i ι J base 0.10 ί &· i H ? HCl i . 0.06 i -Ο 1 H I j HCl 0.06 1 -o ! H i HCl l· 0.25 I °i>oc2 j H i ί base J. 0..50 Η HCl j ί η ι I i 4-F 4-F 4-F 4-F • 4-F ii HCl. H2O i HCl HCl HCl ! HCl HCl ! base s I 4-F HCl 0.10 0. 004 0.015 0. 002 | ii 0.03 I I 0.20 | 0. 12 0.45 0. 004 3.! TABLE I_(cont'd) Ar R1 Base or Salt formED50 in mg/kg s. c. Cl •0 H . HC1 0.63 P H HC1 0.25 o H base 0.80 •0-n°2 Cl H base >0.63 H base 0.25 Q-f 4-F HC1.H2O 0.002 . H2N H HC1 0.015 Cl - j. SO 4-F HC1 >0.63 Q H?N 4-F' base 0. 008 9, 4-F HC1 0.25 . NH-C0-CH3 4-F base 0.07 -2243150 TABLE -Il Ar-C-NH-CH_-CH~-x. Α 2 2 Η Ar 3 R Base or Salt form ED5o in mg/kg §.c. Ό * Η base 0.20 F Η base 0.50 Η ' base 0.12 η ζ—J c&3 Η base 0.25 -p-F Ο2Ν Η base 0.50 -^^-F 5-C1 base 0.08 Cl 5-C1 base 0.03 ρ-ΓΗ2Ν Η base 0.03 Η base 1.5 Ο 5-C1 base 0.45Ηχ y3 Η . base l/SK^O 0.10 1 η2ν 2343150 TABLE (cont'd. ) Ar R3 Base or Salt form 'ED50 mg/kg s·c -/~Vf H base 0.04 NH-CO-CH^ <>F 5-Cl base 0.06 / NH-CO-CH3 -Qf 5-Cl HCl 0.25 / O2N 24TABLE ΧΠ 315 0 Ο il Ar-C-NH-CH2-CH2-N Ar I R6 Base or Salt form ED_n 50 in mg/kg s. c. -p- 4-Cl 2. HCl 0.70 / nh2 TABLE IV II Ar-C-NH-CK,-CH,-N A 2 v y Compound Base or Salt formED50in mg/kg s.c z—\ π r~\ η θ F-f '§-C-NH-CH,-CH,-N / D \=t/ 2 2 \-WCVcH,-CH,CN \_/ 2 2 base 0.50 \ h Z~~\ N-CO-CH* * f-^Lnh-ch2-ch2-nJ<^ L - ο u base 0.63 i F-^J^-C-NH-CH2-CH2-N^JpN^NH base 0.25 13150 The compounds of formula (I) are potent psychotropic agents and as such they can be used in the treatment of mental disorders such as, for example, personality and psycho-affective disorders and schizophrenia. The psychotropic activity of the subject compounds (I) is strongly evidenced by the experimental data obtained in the apomorphine test in rats, a test which is indicative for central nervous system depressant activity. The test was carried out following the procedure described hereafter and the experimental data which were obtained are summarized in table V wherein the compound numbers refer to the corresponding structures in the tables I to IV.

The compounds listed in table V are not given for the purpose of limiting the invention thereto but only in order to exemplify the useful psychotropic properties of all the compounds within the scope of formula (I).

The apomorphine test in rats .

The experimental animals used in this test were adult male Wistar rats ( weight 240 + 10 g.). After an overnight fast, the animals were treated subcutaneously (lml/lOOg) with an aqueous solution of the compound under investigation and put into isolated observation cages. Thirty minutes thereafter, 1.25 mg/kg of apomoiphine hydrochloride •was injected intravenously and the rats were observed over a 1 hour period for the presence or absence of the following apotnorphine-induced phenomena: agitation and stereotypic chewing.

Table V gives the lowest effective dose (LED), i. e., the dose level, the effect of which is.statistically significantly different from that observed in the corresponding untreated controls (Fisher exact probability test). -264 315 0 TABLE V: Anti-apamorphine activity of the compounds (I} in rats, Compound no, LED in mg/kg s. c. 2 5 I 3 0,31 4 2,5 6 2.5 7 2.5 8 10 9 0.63 Π 10 14 ' 0.63 16 1.25 ί 20 5 21 2, 5 23 2.5 24 10 25 ' 5 27 5 31 5 32 1.25 33 5. 34 - 5- 36 >10 37 10 38 10 40 5 -2750 In. view of their useful antiemetic and psychotropic activity, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical, compositions of this invention, an effective antiemetic or psychotropic 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 desirable 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, for 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, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier 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 salts of (I), due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions. -2843150 It is especially advantageous tc 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 units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions.

The amount of active ingredient per dosage unit for either antiemetic or psychotropic purposes will be from about 1 to 200 mg and, preferably from 5 to 100 mg.

The following formulations exemplify typical antiemetic and psychotropic pharmaceutical compositions in dosage unit form suitable for systemic administration to animal and human subjects in accordance with the instant invention.

Oral drop : The following formulation provides 10 liters of an oral-drop solution comprising 5 milligrams of N-^2-^T-(5-chloro2, 3-dihydro-2-oxo-lH-benzimidazol-l -ylj-l-piperidinyl/ethyl J4-fluorobenzamide as the active ingredient per ml.

A, I, ---------------------------50 grams 2-Hydroxypropanoic acid—------- 2.5 milliliters Methyl 4-hydroxybenzoate ----13 grams -Propyl 4-hydroxybenzoate------- 2 grams Pyrogen-free water q. s. ad 10 liters -293150 The methyl and propyl 4-hydroxybenzoates are dissolved in.. . . about 5 liters of boiling pyrogen-free water. After cooling to about 50°C there are added while ..tirring the 2-hydroxypropanoic acid and thereafter the A.l.. The solution is cooled to room temperature and supplemented with pyrogen-free water ad volume. The solution is sterilized by filtration (U.S. Ρ. XVII ρ. 811) and filled in sterile containers.

Injectable' solution: The oral drop solution described herebefore may be used as an injectable solution.

Capsules: 10,000 Hard gelatine capsules, each containing as the active ingredient (A.X.) 20 milligrams of N- |2-/4-(5-chloro-2, 3dihydro-2-oxo-lH-benzimidazol-l -yl)-l -piperidinyl/ethylj-4-fluoro benzamide, are prepared from the following composition.

. · ' Grams A.l. -------------- 200 Lactose-------------------1000 Starch --------------------*300 Talc....................— 300 Calcium stearate ------ 10 An uniform mixture of the active and supplementary ingredients is prepared and filled into two-piece hard gelatine· capsules.

Tablets: 5000 Compressed tablets, each containing as the active ingredient (A.l.) 25 milligrams of N- ^2-^-(5-chloro-2, 3-dihydro2-oxo-lH-benzimidazol-l -yl)-l -piperidinyl/ethyl J -4-fluorobenzamide, are prepared from the following formulation. -304 315 0 A. I. ——.......................... 125 Starch ------------------ 150 •Dibasic calcium phosphate hydrous----- 650 Calcium stearate --------------------- 35 The finely powdered, ingredients are mixed well and granulated with 10% starch paste. The granulation is dried and compressed into tablets.

Oral suspension: The following formulation provides 5 liters of an Oral suspension comprising as an active ingredient (A. I.) 15 milli10 grams of N- |2-^-(S-chloro-2, 3-dihydro-2-oxo-lH-benzimidazol-l -yl)· l-piperidinyl/ ethyl > -4-fIuorcbenzamide per teaspoonfull (5 milliliters).

Grams A. I................................15.0 Sucrose -------------------i----------- 300. 0 Dioctyl sodium sulfo succinate ----------- 0. 5 « Bentonite--------------------22.5 Methyl paraben ------------------------ 7.5 Propylparaben----------------------— 1.5 Antifoam A. F. Emulsion---------------- 0.15 Propylene Glycol---------------------- 52. 0 FD&C Yellow jr^5..................... 0. 1 Sodium cyclamate —------------------ 50.0 Sodium saccharin --------------------- 5. 0 Orange Flavor------------------------ 7,5 Filtered purified water, q, s., ad 5 liters -3143150 Dissolve the parabens in the propylene glycol and add this solution to a solution of the sodium cyclamate, sodium saccharin and sucrose in half the water. Suspend the bentonite in hot (about 85°C) water and stir for 50 minutes. Add the bentonite solution to the former solution. Dissolve the sulfosuccinate in some water and suspend the A.I. in the resulting solution. Add the Antifoam A.F. Emulsion which has been diluted to a lotion consistency with a minimum amount of water and mix well. Add the latter suspension of A.I. to the former mixture and mix well. Add the FD & C Yellow -//- 5 dissolved in a small amount of water. Add the orange flavor, g.s. to volume with water, and stir to a homogeneous mixture. Pass the mixture through a colloid mill and fill into suitable containers.

In view of the antiemetic activity of the subject compounds, it is evident that the present invention provides a method of inhibiting emesis in non-human warm-blooded animals affected by emesis, by the systemic administration of an effective antiemetic amount of a compound of formula (j) and the pharmaceutically acceptable acid addition salts thereof in admixture with a pharmaceutical carrier. In addition, in view of the psychotropic activity of the subject compounds, the present invention also provides a method of treating mental disorders in non-human warm-blooded animals affected by such disorders, by the systemic administration of an effective psychotropic inhibiting amount of a compound of formula (I) and the pharmaceutically acceptable acid addition salts thereof in admixture with a pharmaceutical carrier.

The following examples are intended to illustrate but not to limit the scope of the present invention. Unless otherwise stated all parts therein are by weight. Examples I to XI illustrate the preparation of starting materials.

Example I To a stirred mixture of 76 parts of 4-fluoro-2-nitrobenzoic acid and 225 parts of benzene are added dropwise 71 parts of sulfinyl chloride. Upon completion, stirring is conS tinued first for 5 hours at reflux and further overnight at room temperatue. The reaction mixture is evaporated. The residue is taken up twice in benzene and the latter is evaporated each time, yielding 85 parts of 4-fluoro-2-nitrobenzoyl chloride as a residue. IH Example II To 231 parts of a aziridine solution 0. 95M in water are added 16 parts of sodium hydrogen carbonate while stirring vigorously at O'C. Then there is added dropwise, during a 45 minutes-period, a solution of 36 parts of 4-fluoro-2-methoxy 15 benzoyl chloride in 150 parts of trichlorom ethane while still cooling at O'C. Upon completion, stirring is continued for 30-45 minutes without cooling. The reaction mixture is adjusted to pH 8 with a diluted 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, yielding 40, 5 parts of 1-{4-fluoro-2-methoxyb'enzoyl)aziridine as a residue. . 13150 Example III Following the procedure of Example II and using an equivalent amount of an appropriate arylcarbonyl chloride in place of the 4-fl.uoro-2-methoxybenzoyl chloride used therein, the following 1 -(arylcarbonyl)aziridines are prepared: l-(2-hydroxybenzoyl)aziridine as a residue II 1-(4-£luoro-2-nitrobenzoyl)aziridine as a residue III, u l-(2-thienylcarbonyl)a2iridine as a residue; and IV -(5-chloro-2-methoxy-4-nitrobenzoyi)aziridine. LIII Example IV A mixture of 12.94 parts of ethyl (2-bromoethyl)carbamate, 13.51 parts of 1,3-dihydro-l-(4-piperidinyl)-2H-benzimidazoi-2-one, .1 parts of sodium hydrogen carbonate and 160 parts of ethanol is stirred and refluxed overnight. The reaction mixture is cooled, filtered over hyflo and the filtrate is evaporated. Th'e residue is purified by- column-chromatography over silica gel using a mixture of trichloromethane, 10% of methanol and. one drop of ammonium hydroxide, as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4.4 parts of ethyl 2-^-(2,3-dihydro>-2-oxo-lH-benzi»iidazoll„yij_l_piperidinyl7ethylcarbamate as a residue. y 315 0 A mixture oi 0.333 parts of ethyl 2-/5-(2,3-dihydro-2-oxoIH-benzimidazol-I-ylJ-l-piperidinyl/ethylcarbamate, 1.65 parts of hydrobromic acid solution 43¾ and 0.11 parts of water is stirred and refluxed for 2 hours. The hydrobromic acid and water are evaorated. The residue is taken up three times in benzene, while each, time the latter is evaporated. The oily residue is crystallized from 2- propanol. The product is filtered ai£ and recrystallized from a small amount of ethanol, yielding 0.27 parts of 1-^5.(2-aminoethyl)-. 4-piper idinyl/-1,3-dxhydro-2H-benzimidazol-2-one dihydrobromide; mp. + 300*C (dec.).

Example V * To a stirred and cooled (ice-bath) mixture of 87 parts of 2-chloroethanj.mine hydrochloride and 300 parts of trichloromethane are added 224.2 parts of N, N-dxethylethanamine. After the addition of another 300 parts of trichloromethane, there is added dropwise, during a 1,50 hours period, a solution of 96 parts of 2-furancarbonyl chloride in 300 parts of trichlcromeshane at a temperature below 5 °C.

Upon completion, stirring is continued overnight at room temperature.

The reaction mixture is poured onto water and the layers are separated.

The aqueous phase is extracted with trichloromethane. The combined organic phases are washed with water, with a diluted, hydrochloric acid solution and again twice with water, dried, filtered and evaporated.

The residue is purified by column-chromatography over silica gel using a mixture of trichloromeihane and 2¾ of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 95 parts of N-(2-ehloroethyl)-2-furaEcarboxamide as a residue.

UV ο Example VI To a stirred and cooled mixture of 32 parts of 2-bromoethanamine hydrobromide in 150 parts of water is added a solution of 23.5 parts of 4-fluoro-2-nitrobenzoyl chloride in 54 parts of benzene. While cooling to 0-5°C and while stirring vigourously, there is added dropwise a solution of 13 parts of sodium hydroxide in 200 parts of water (exothermic reaction). Upon completion, stirring is continued for 2 hours at 0-10°C. The precipitated product is filtered off, washed with water and dried, yielding 30 parts (93.6%) of N-(2-bromoethyl)4-£luoro-2-nitrobenzamide.

Example VII To a stirred solution of 21 parts of sodium hydroxide in 75 parts of water is added a solution of 29 parts of 2-chloroethanamine hydrochloride in 75 parts of water. The whole is stirred and heated for 10 minutes at 90°C. After cooling to 0°C, 19 parts of sodium hydrogen carbonate are added. While stirring vigourously, there is added dropwise, during a 45 minutes-period, a solution of 49 parts of 2,5-dichlorobenzoyl chloride in 75 parts of trichloromethane at a temperature below 0°C. Upon completion, stirring is continued for 30 minutes without cooling. The reaction mixture is 'warmed to 25°C and adjusted to pH 8 with a diluted sodium hydroxide solution. The product is extracted three times with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated, yielding 62 parts of 1-(2, 5-dichlorobenzoyl)aziridine as a residue. . j · LVI 43130 Example VIII A mixture of 72 parts of methyl 2-pyridinecarboxylate and 32 parts of 2-aminoethanol is stirred and refluxed carefully for 2 hours. The reaction mixture is cooled and poured onio water. The product is extracted five times with trichloromethane. The combined extracts are dried, filtered and evaporated, yielding 49 parts of N-(2-hydroxyethyl)-2-pyridinecarboxamide as a residue.

• LVII1 To 49 parts of N-(2-hydroxyethyl)-2-pyridinecarboxamide are added dropwise 80 parts of sulfinyl chloride while stirring· vigourously. Upon completion, stirring is continued first for 3 hours at reflux and further for 2 hours at room temperature. The excess of sulfinyl chloride is evaporated and the residue is poured onto hot methanol. After cooling, the precipitated product is filtered off (the filtrate is set aside) and washed thoroughly with 2, 2'-oxybispropane, yielding a first fraction of 14 parts of N-(2-chloroethyl)-2pyridinecarboxamide hydrochloride.

The filtrate (see above), which was set aside, is stirred with 2,2’» oxybispropane. The precipitated product is filtered off and dried, 2o yielding a second fraction of 30 parts of N-(2-chloroethyl)-2-pyridineearboxamide hydrochloride. lvii2 I 150 Example IX A mixture of 5.5 parts o£ methyl 1-methyl-lH-pyrrole2-carboxylate and 2.4 parts of 2-aminoethanol is stirred and refluxed for 2 hours. The reaction mixture is evaporated till dry. Benzene is added twice to the residue and evaporation is continued each time till dry. 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 taken up in petroleumether and upon scratching, the product solidifies. It is filtered off and dried, yielding 1.9 parts of N-(2-hydroxyethyl)-l-methyl-lH-pyrrole-2-carboxamide; mp. 78.1 °C. LVIIIj To a stirred Solution of 40 parts of N-(2-hydroxyethyl)-l methyl-lH-pyrrole-2-carboxamide in 450 parts of trichloromethane is added one drop of pyridine. Then there are added dropwise, during a 30 minutes-period, 28.3 parts of sulfinyl chloride (slightly exothermic reaction: temp, rises from 15 to 25°C). Upon completion, 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 (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 15 parts of N-(2-chloro- LVIIIj ehyl)-1 -methyl-lH-pyrrole-2-carboxamide. 315 0 Example X A mixture ox 12.94 parts of ethyl (2-bromoethyl)carbamate, 15.63 parts of 5-chloro-l,3-dihydro-l-(4-piperidinyl5-2H-benzimidazol2-one, 10. OS parts of 3odi«m hydrogen carbonate and 160 parts of ethanol is 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 (90:10 by volume} as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethanol 70%. The product is filtered off and dried, yielding 6.5 parts of ethyl ^2-/4(S-chloro-2, 3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinyl7ethyl', carbamate; mp. 187·. 7°C.

A mixture of 6.6 carts of ethyl LK dihydro-2-oxo-lK-benzimidazol-l-yl)-l-piperidinyl/ethylj carbamate, 60 parts of a hydrobrorfiic acid solution 48% in water and 4 parts of water is stirred and refluxed for 2. 50 hours. After cooling, the· precipitated product is filtered off and crystallised from water, yielding 5.5 parts of l-/T-(2-aminoethyl)-4-piperidinyj7-5chloro-1,3-dihydro-2H-benzimidazol-2-one dihydrobromide; mp. } ,300*C.

LIX. '2 Example XI A mixture of 38 parts of I-(phenylmethyl)-4-piperidinamine, 40 parts of 2chloronitrobenzene, 32 parts ox sodium carbonate, a few crystals of potassium iodide in 320 parts of cyclohexanol is stirred and refluxed for 22 hours. After cooling, 300 parts of water are added. 150 he whole is washed.three times with 150 parts of water; the organic .ayer is dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in a mixture of 40 parts of 2,2'-oxybispropane md 160 parts of hexane. After cooling to -15°C, the precipitate is altered off and the filtrate is set aside. The precipitate is recrystallized rom 160 parts of 2, 2’-oxybispropane and filtered off, yielding 18.5 arts of W-(2-nitrophenyl)-l-(phenylmethyl)-4-piperidinamine; mp. >3.4-94. 6°C.

Che combined mother liquors are diluted with 2,2’-oxybispropane and Iry gaseous hydrogen chloride is introduced into it. The precipitated lydrochloride salt is filtered off. This crop is washed with 120 parts >f water and the undissolved part is dried, yielding 18 parts of ¢-(2-nitrophenyl)-l -(phenylmethyl)-4-piperidinamine hydrochloride; np. 206-220°C (dec).

A solution of 31 parts of N-(2-nitrophenyl)-l -(phenylmethyl)t-piperidinamine in 160 parts of tetrahydrofuran is hydrogenated at lormal pressure and at a temperature of 40°C, with 20 parts of Raney dckel catalyst. After the calculated amount of hydrogen is taken up 3 moles) hydrogenation is stopped. The catalyst is filtered off and rom the filtrate the solvent is evaporated. The solid residue is sashed with 160 parts of 2,2'-oxybispropane, to yield 22 parts of LX2 ’ . - 40 i 315u A mixture of 5 parts of N-,/i-{phenylmeihyl)-4-piperidiny]/-!, 2benzenediamine, 2.35 parts of methyl (iminomethoxymethyl)carbamate, parts of acetic acid and 75 parts of trichloromethane is stirred and refluxed for 48 hours. The reaction mixture is evaporated and the residue is taken up in water. The solution is neutralized with ammonium hydroxide solution. The precipitated product is purified by columnchromatography over silica gel using a mixture ox trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected’ and the eluent is evaporated, yielding 1.75 parts of methyl ,3-dihydro-l -/f-(phenylmethyl)-4-piperidinyl7-2H-benzimidazQl-2ylidene ^carbamate; mp. 169. 7*C.

A mixture of 3.64 parts of methyl (2, 3-dihydro-l-/1(phenylmethyi)-4-piperidinyl7-lH-benzimidazol-2-ylidenej carbamate, 24 parts of a hydrochloric acid solution and 40.parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is dissolved in water. This solution is alkalized with a 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 l-/T-(phenylmethyl)-4-piperidinyl7-lH-benzimidazol-2~amine as a residue.

LX4 A mixture of 2 parts of l-/T-(phenylmethyl)-4-piperidinyj7'-beazimidazol-2-amine, 3 parts of acetic acid anhydride and 45 its of methylbenzene is stirred and refluxed, for 3 hours. The iction mixture is evaporated and water is added to the residue. a whole is alkalized with a concentrated ammonium hydroxide Lution. The precipitated product is filtered off, washed with water ί dissolved in trichloromethane. The solution is dried, filtered 3 evaporated. The residue is crystallized from 2,2*-oxybispropane, 3-dihydro-l ~/T-(phenyl- LXE A mixture of 12 parts of N-J 1, 3-dihydro-l-^T-(phenyliHethyl)th 5 parts of palladium-on-charcoal catalyst 10%. After the calculated aount of hydrogen is taken up, the catalyst is filtered off over hyflo d the filtrate is evaporated. The residue is crystallized from a mixture 2t 2’-oxybispropane and 2-propanol. The, product is filtered off and crystallized from a mixture of ethanol and 2, 2'-oxybispropane, yielding 6 parts of Ν-/Ϊ, 3-dihydro-l-(4-piperidinyl)-2H-benzimidazol-2idene/acetamide; mp. 164. 5°C.

LX, ’δ 3150 Example ΧΐΓ A mixture cf 1.-58 parts oi l-(4-fluorobenzoyl)azixidine, 2.5 parte oi i-(4-2.ucraphcnyl)-l, 3, S-trinzaspiro/4. 5/decan—4-one, 10.8 parts of benzene and 1.6 parts of methanol is Stirred and refluxed for 1.50 hours. The reaction, mixture is cooled and acidified with. 2-propanol, previously saturated with gaseous hydrogen chloride. The formed hydrochloride salt is filtered off * and crystallized fram a mixture of ethanol and water (8:2 by volume), yielding, after drying, 2,4 parts of 4-fluoro-N-|22T-(4-fluorophenyl)-4-oxo-1,3, S-triasaspiro/4, c/dec-S-yl/ethyl jbenzamide hydrochloride; mp. 279. 6’C, XI Example XIII A mixture of 0. 74 parts of l-(benzoyl)aziridine, 1.16 parts of 1-phenyl-l, 3, S-triazaspiro^f, 57decan~4-one, 7.2 parts of benzene and 0.3 parts of methanol is stirred and refluxed for hours. The reaction mixture is cooled, 1,1 '-oxybisethane is added and the whole is boiled in ethyl acetate. After cooling, the precipitated product is filtered off and crystallized from ethanol 70%, yielding, after arying in vacuo at 80’C, 0.67 parts of N-^-(4-oxo- 1-phenyl-l, 3, 8-triasaspiro^? S/dec-S-yQethyl/benzamide; mp. 198.4’C.

VI L50 Example XIV Following the procedure of Example XIII and using squivalent amounts of the appropriate starting materials, the ollowing compounds are prepared in free base form or iri' the 'orm of an acid addition salt after reaction of the base with an Ar R1 - Base.or Salt form Melting Point °C;-ci-c6h4 H base 200.6 -NO2-C6H4 H base 225.7 :-{OCH3)-C6H4 H base 200.9 ,4-Cl2-C6ii3 H base 205.7 -(oc2h5)-c6h4 H base 205.8 -(och3)-c6h4 H base 195 -(OCHx)-4-NO?-C6H, H base 205.8 -Cl-4-NO2-C6H3 H base 190 -thienyl H base 194 -NO2-4-F-C6H3 H base 160:6H5 H HCt , 259.4 -f-c6h4 H HCl , 266.4 -ci-c6h4 H HCl 256.6 -ch3-c6h4 4-F HCl 261.2 -f-c6h4 H HCl 242. 8 -Cl-4-F-C6H3 H HCl 263.8 -Cl-4-F-C6H3 4-F HCl 269.8 VII VIIIj viii2 vni3 VIIIvm6 VIII? IX X XII3 xn2 xiiXII4 XIII XIV, XIV„ 4443150 r............-.....- Ar -U Base or Salt form Melting Point °C 2-Cl-C^H4 a.K HCl 252.6 XIV3 2-Br-C,K 61 H HCl 260.6 XIV, he 2-01,-0¾ H HCl 251.9 XIV- 52-n-o2-c0h4 • 4-F HCl 267.2 XV |2-OH-C6H4 4-F HCl 279.4 XVI 4-CH3-C6H4 H (COOH)2 229.8 XVII 4-f-c6h4 4-F HCl 271.3 XVIII 3-Cl-C6H4 H HCl 263.4 LXI 3-CF3-C6H4 H HCl 262 ΗΧΠχ 3-F-C6H4 H HCl 248.5 LXII2 3,4,5-(001,),-0¾ H HCl 271.6 lxii3 2,5-0,-0¾ 4-F HCl 234.8 lxii4 3-(OCH3)-C6H4 4-F HCl 243.2 lxii5 2,5-0,-0¾ H HCl 249.8 LXII6 2-(OCH,)-4-F-0¾ H base 193.8 lxii? 2-(OCH3)-4-NO2-5-Ci- H HC1.1/2H-0. 176.5 LXIIgC6H2 1/2 C?HqOH 3-ΟΗ3-Ο6Η4 H (cooh)2 225.3 • LXIIg 3-01,-0¾ 4-F (cooh)2 225.6 LXII10 2-(OCH,)-5-0-0,. H, 4-F base 242.2 2-(OCH3)-4-NO2-5-Cl 4-F HCl. 1/21^0 226.2 lxii12C6K2 • 3-(OCH3)-C6H4 H HCl 251 * lxii13 Sxample XV A mixture of 1.2 parts of N-(2-bromoethyl)-2-nitrobenzamide, 1,15 parts of 1-phenyl-1,3, 8-triazaspiro/X i£7decan-4-one and 45 parts of N, N-dimethylformamide is stirred and refluxed for 3 hours. After stirring is continued overnight at room temperature, Ν,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-propanol is added to the concentrate.

The precipitated product is filtered off and dried, yielding 7 parts of 2-nitro-N-/2-(4-oxo-l-phenyl-1,3, 8-triasaspiro^ 5j7dec-8-yl)ethyl/benzamide hydrobromide; mp. 259.4°C„ .

XIX Example XVI A mixture of 6. 9 parts of N-(2-chloroethyl)-2-furancarboxamide, 9.2 parts of 1-phenyl-1,3, 8-triazaspiro/4, Sjdecah4-oae, 6.6 parts of potassium iodide and 135 parts of Ν, N-dimethylformamide is stirred first for 3 hours at reflux and further over-. night at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The whole is alkalized and the product i& extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel .using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent ia evaporated. The solid residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 1.9 parts of N-/2-(4-oxo=l -phenyl-λ, 3, S-iriazaspiro/4, 57dec-8-yl)ethyl72-furancarboxamide; mp. 196.3°C. LXIII 3150 Example XVE Eollowing the procedure of Example XVI there is prepared N- |2-2T~'4-fluorophenyl)-4-oxo-I,3, 8-triazaspiro i -yj7-ethylJ-2-iuraacarboxamiae hydrochloride; mp. 254.2eC by the reaction of N-(2-chloroethyl)-2-furancarboxamide with 1 -{4-fluorophenyl)-l ,3,8-triazaspiro/4, o/decan-4-one, LXIV Example XVIII A mixture of 4.4 parts of N-(2-chloroethyi)-2-pyridine10 carboxamide, 13.3 parts of 1-phenyl-1,3, 8-triazaspiro/4, S/decan4—one, 3, 3 parts of potassium iodide and 200 parts of 4-methyl-2pentanone is stirred and refluxed 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 (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 crystallized from ethanol, yielding 1.1 parts cf N-/2-(4-oxo-l-phenyl-1,3, 8-triazaSpiro/4,5j7dec -8 -yljethyi/-2 -pyridinecarboxamide dihydrochloride .20 hydrate; mp. 250.5° C.

LXV Example XIX A mixture of 3.75 parts of N-(2-chloro ethyl)-1 -rnethyllH-pyrrole-2-carboxamide, 5 parts of l-(4-fluorophenyl)-l, 3, 8triazaspiro/ϊ) 57decan-4-one, 1, 7 parts of sodium hydrogen· car25 bonate, 0.1 parts of potassium iodide and 160 parts of 4-methyl2-pentanone is stirred and refluxed for 48 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 (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-propanol and 2,2’-oxybispropane. The salt is filtered off and crystallized from methanol, yielding 0.8 parts of N-^2-/l-(4-fluorophenyl)-4-oxo1,3, 8-triazaspiro^l, 5/dec-8-yl/ethyl j-l-methyl-lH-pyrrole-2carboxamide hydrochloride; mp. 273.4°C.

LXVI Example XX A mixture of 8 parts of 4-fluoro-2-nitro-N-/2-(4-'oxo-l phenyl-1,3, 8-triazaspiro^,57dec-8-yl)ethy]7benzamide, 40 parts Of methanol and 90 parts of tetrahydrofuran 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 eatalyst is filtered off and the filtrate is evaporated. The residue is converted into the hydrochloride salt in 2,-propanol. The salt is filtered off and crystallized from ethanol, yielding 1 part of / 2-amino-4-fluoro-N-22-(4-oxo-l -phenyl-1,3, 8-triazaspiro/4, 5/dec-8-yl)ethyl7benzamide hydrochloride hydrate; mp. 167. 3°C.

XX Example XXI A mixture of 8 parts of 4-fluoro-N-^ 2-/T-(4-fluorophenyl)4-oxo-l, 3, S-triazaspiro/T, 57dec-8-y£7ethyl J-2-nitrobenzamide hydrochloride, 120 parts of methanol and 25 parts of water is hydrogenated at normal pressure and at room temperature with 5 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 crystallized from methanol. The product is filtered off and recrystallized from ethanol, yielding 1 part of 2-amino-4-fluoro-N-^2-/T-(4-fluorophenyl)-4-oxo-l, 3,8triazaspiro/T,57dec-8-yl7ethylJbenzamide hydrochloride hydrate; XXI mp. 223. 5°C.

Example XXII A mixture o£ 6 pasts of 5-cftioro-2-methoxy-4-aitro-N/§-(4-oxo-l -phenyl-1,3, 3-triazaspiro^i, S/dec-S-ylJethyl/benzamide in 150 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 1 part 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 taken up in water and the whole is alkalized. The precipitated product is filtered off and crystallized fwiee from ethanol, yielding 1.7 parts of 4-amino-5chloro-2-methoxy-N-/2-(4-oxo-l -phenyl-1,3, 8-triazaspiro^i, 57dec-8-yl)ethyl7benzamide; mp. 247.4’C.

LXVII Example XXIII Following the procedure of Example XXII and using therein and after converting the product thus obtained into a hydrochloride salt there is prepared: 4-amino-5-chloro-N-}2-/T-(4-fluoropheayl)LXVIII Example XXIV chloride in 150 parts of acetic acid 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 whole is alkalized with ammonium hydroxide. The product is extracted twice with trichloromethane. The combined extracts are wahsed twice 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 vacuo, yielding S parts of 2-amino-N- j 2-/T-(4-flucrophenyl)-4-oxo- LXIX >150 Example XXV for 30 minutes in a water-bath at about 80°C. The reaction mixture is cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The aqueous phase is separated and ejstracted with trichloromethane. The combined 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-/T(4-£luorophenyl)-4-oxo=l, 3, 8-triazaspiro^, 5/dec-8 amide; mp. 195.1°C. ’ ' benzLXX Example XXVI A mixture of 1.68 parts of 1-(4-flLuorobenzoyl)aziridine, 2,53 parts of 5-chloro-l, 3i-dihydro-l-(4-piperidinyl)2H-benzimidazol-2-one, 10.8 parts of benzene and 1.6 parts of methanol is stirred and refluxed for 1.50 hours. The precipitated product is sucked off and washed with 2-propanone. The product is crystallized from 2-propanol, yielding, after drying, 2, 47 parts of N-{2-/4-(5-chloro-2, 3-dihydro-2-oxo-lH-benzimidazol-l-yl)- •XXIV 431 5C Example XXVII Following the procedure cf Example XXVI and using equivalent amounts of the appropriate starting materials, the following compounds are obtained in free base form, or aeid addition salt form after reaction of the free base with an appropriate acid.

Ar-B-NH-CH -CH- V li 2 4 Ar R3 Base or Salt form Melting Point •c C,He 0 5 H base 223.9 XXII 24OC2h5)-c6h4 K base 192.8 XXIIIj 4-F-C6H4 H base 231 XXIII2 2-Br-C6H4 H base 204.4 XXIII3 2-F-C6H4 H base 197.3 χχνχ 4-Cl-C6H4 •H base 236.9 XXV2 2-Cl-C6H4 H base .196.4 XXV., 4-(OCH3)-C6H4 H base 259.2 XXV. 42-ch3-c6h4 H base 217.2 XXVg 2-C1-4-F-CzH o 3 5-C1 base 225 XXV6 2-(OCH,)-4-NO?-CaH3 K base 243. S XXV7 2-Cl-4-NO--C,H„ e 6 o base,H2O 208.8-209.9 XXVg 2-NO2-4-F-C6H3H base 196.8 xxv9 2-OK-CzH. 6 4H i HCl. 1/2CH, CKOH-CH, 206.2χχν10 2-CH-C6H4 5-C.l ECI. l/2H,d .........21 296.6 XXVn - 51 50 Ar s3 Base or · Salt form Melting Point °C 2-(OCH3)-4-F-C6H3 H base 197.3 XXVI 2-(OCH,)-4-F-CaH, 5-Cl base 227.3 XXVIX 2 -thienyl H base + 300°C (dec.) XXV III 2-NO2-C6H4 H HCl 263.6-265 XXIX 4-CH3-C6H4 5-.Cl (COOH)2 230.9 XXX 4-CH3-C6Ha H (COOH)2 227.6 XXXI 2-(.OCH3)-C6H4 H (COOH)2 217.4 - XXXII 3-F-C6H4 H base 226. 3 LXXI 2,6-(CH3)2-C6H3 H base 208.1 ’ L3iXlX1 3-Cl-C^ H _ ' base.G^fLOK 226.5 LXXII. ώ 3-CF3-C6H4 H · · base 225. 7 LXXII3 3,4,5-(ΟΟΗ3)3-ΟήΗζ H . base 248.1 LXXII, 4 2-(OCH3)-5-Cl-C6H3 5-C1 ' base 241.8 LXXIIg 3-CH3-C6H4 . H (COOH)2 228.8 lxxxi6 3-(OCH3)-C6H4 H (COOH)2 220 lxxii? 2,5-CL,-CaH, H - · HCl 245.6-250.2 LXXIIg 3-(OCH3)-C6H4 5-C1 HCl 236.3 LXXIIg- 2-(OCH3M-NO2-5-Cl- c6H2 H base 266 LXXil10 2 -(OCK3)-4-N02-5 -ClC6H2 5-Cl base 223.6 LXXII, „ 12 Example XXVIS Ν-/Γ, 3-dihydro-1 -(4»piperidinyl)-2E-ben3imidazol-2-yIideae7acetamide.

Example XXIX A mixture oi 1.5 parts of K-(2-bromoethyl)-2-nitrobenzamide, 1.55 parts of 5-chloro-l, 3-dihydro-l-(4-piperidinyl)2H-benzimidazol-2-one and 27 parts of N, N-dimethyl£ormamide ' is stirred and refluxed for 5 hours. The reaction mixture is evaporated and the oily residue is crystallized from ethanol.

The product is filtered off and dried, yielding 2.2 parte (67%) of N-j2-/4-(5-chloro-2, 3-dihydro-2-oxo-lH-benzimidazol-l -yl)LXXII. of N-|2-/4-(5-chlorc-2, 3-dihydro-2-oxo-lH-benzimidazol-l -yl)1 ~piperidinyf7ethyl ( -2-nitrobensamide hydrobromide. hemihydrate; mp. 273,2*C, J XXXIII Example XXX A mixture oi 8. 7 parts of 4-fluoro-iV-y 2-/^-(2,.3-dihydroroom temperature with 2 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 crystallized from a mixture of methanol and 2-propanol. The product is filtered off and XXXIV 150 Example XXXI Following the procedure of Example XXX there io prepared 2-amino-N- ^2-/4-(5-chloro-2, 3-dihydro-2-oxoIH-bensimidazol-l -yl)-l -piperidinyl/ethyl ^-4-fluorobensamide hydrochloride, dihydrate; mp. 250°C, by hydrogenating N- ^2/4-(5-chloro-2, 3-dihydro-2-oxo-lH-bensimidazol-l -yl)-I -piperidinyl/ethyl j -4-fhioro-2 -nitrobenzamide and converting the product thereof in a hydrochloride salt with hydrochloric acid LXXXUI Example XXXII A mixture of 16 parts of N-^2-^f-(5-chloro-2, 3-dihydro2-oxo- lH-benzimidazol-1 -yl)-l -piperidinyl/ethyl j -2-nitrobenzamide in 90 parts of tetrahydrofuran and 40 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of Raneynickel catalyst. · After the calculated amount of hydrogen is taken up,' there is added a solution of methanol, previously saturated with gaseous ammonia. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in acidified water and the whole is washed twice with trichloromethane. The aqueous phase is separated and alkalized with a diluted 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 in 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-aminoN- j/-/4-(5-chloro-2, S-dihydro-B-oxo-lH-benZimidazol-l-yl)-! piperidinyl/ethyl^ benzamide; mp. 226, 8° C.

XXXV Example XX'.III Following the procedure c£ Example XXXII, the following compounds are derived from the corresponding nitro compounds: LXXXI Example XXXIV A mixture of 4.2 parts of 5-chloro-N-J 2-/^-(2, 3-dihydro2-oxo-lH-benzimidazol~l -yl)-l -piperidinyl7ethyl| -2-methoxy-4nitrobenzamide in 150 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 1 part of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrateds evaporated. Water is added to the residue and the whole is alkalized with a diluted 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, yielding benzamide; mp, 230.i’C.

The filtrate, which was set aside, is concentrated. A second fraction is filtered off, yielding· 1.6 parts of 4-amino-5-chloro-N-^2-/4(2, 3-dihydro-2-oxo-lH-benzimidasol-l-yl)-l -piperidinyf7ethyljL-2methoxybenzamide; mp. 232.5°C.

LXXX 315 0 Example XXXV A mixture of 1.68 parts of 1-(4-fluorobenzoyl)aziridine, 2. Ιό parts of 1, 3-dihydro-l-(3, 6-dihydro-l-(ZH)pyridinyl)-2Hbeazimidazol-2-on.e, 10.8 parts of benzene and 1.6 parts of methanol is stirred and refluxed for 1.50 hours. After cooling, the precipitated product is filtered off, washed with 2-propanone and crystallized from ethanol, yielding 1.76 parts of N-)2-/4-(2,3-dihydro-2-oxo1 H-benzimidazol-l -yl)-3 benzamide: mp. 202. 7° C, •4-fluoroXXXVII Example XXXVI A mixture of 1.68 parts of 1-(4-fluorobenzoyl)aziridine, 3.07 parts of2,3-dihydro-2-oxo-3-(4-piperidin.yl)-lH-benzimidazole1-propanenitrile hydrochloride, 1.65 parts of N, N-diethylethanamiae, .8 parts of benzene and 1.6 parts of methanol is stirred and refluxed for 1,50 hours. The reaction mixture is cooled and poured onto 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, yielding benzimida- LXXIII Example XXXVH ' , .

A mixture of 5.6 parts of N-(2-chloroethyl)-l-methyl-lHpyrr-ile-2-carboxamide, 6.52 parts of 1,3-dihydro-1-(4-piperidinyl)2H-benzimidazol-2-one, 2.52 parts of sodium, hydrogen, carbonate, 0,1 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed for 62 hours. The reaction mixture is cooled and the solvent 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 converted into the hydrochloride salt in ethanol, 2-propanol and 2,2'-oxybispropene. The salt is filtered off and crystallized from a mixture of ethanol and 2, 2r-oxybispropane, yielding 0.6 parts of N-J 2-/4(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l -piperidinyl/ethyl^ l-methyl-lH-pyrrole-2-carboxamide hydrochloride hydrate; mp. 237.7* G.

LXXIV Example XXXVIII Following the procedure of Example XXXVII there is prepared: r N-{2 -/4-(2, 3-dihydro-2-oxo-lH-benzimidazoI-l -yl)-l -piperidinyl/. ethyl j-3-pyridinecarboxamide dihydrochloride, hydrate; mp. 214.l’C by the reaction of Nl(2-chloroethyl)-3-pyridinecarboxamide hydrochloride with 15 3-dihydro-l-(4-piperidinyl)-2H-benzimidazol-2-one; and LXXV I N- |2»^-(5-chloro-2, 3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l piperidinyl/ethyl i-4-flucro-2-nitrobenzamide by the. reaction of N-(2-bromoethyl)-4-fluoro-2-nitrobenzamide with 5-chlore-i, 3dihydro-1 -(4-piperidinyl)-2H-ben.zimidazol-2-one. LXXVI - 57 i 5150 Luoro-2-nxtrobenzamide hydrochloride; mp. 276.8°C.

Sample XXXIX A mixture of 16 parts of N-(Z~bromoethyl)-4-fluoro-2itrobenzamide, 12.6 parts of 5-chloro-l, 3-dihydro-l-(4-piperidinyl)H-benzimidazol-2-one and 216 parts of N, N-dimethylformamide is tirred and refluxed for 3 hours. The Ν,Ν-dimethylformamide is vaporated and the residue is purified by column-chromatography ver silica gel using a mixture of trichloromethane and methanol 95:5 by volume) as eluent. The pure fractions are collected and the luent is evaporated. The residue is converted into the hydrochloride alt in 2-propanone and 2-propanol. The salt is filtered off and rystallized from methanol, yielding 1.5 parts of N- ^2-/4-(5-chloro, 3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinyi/ethylJ^-4LXXVH Example XL A mixture of 2.2 parts of N-(2-chloroethyl)-2-pyridine• -a :arboxamxde hydrochloride, 6.6 parts of 1, 3-dihydro-l-(4-piperidinyl):H-benzimidazol-2-one, 1.66 parts of potassium iodide and 120 parts if 4-methyl-Z-pentanone is stirred and refluxed overnight. After :ooling, the precipitated product is filtered off and dissolved in water.

Che solution is alkalized with sodium carbonate and the product is attracted three times with 4-methyl-2-pentanone. The combined attracts are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using t mixture of trichloromethane and methanol (95:5 by volume) as eluent, rhe pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone and ’-propanol. The salt is filtered off and crystallized from a mixture if ethanol and 2, 2'-oxybispropane (1:1 by volume), yielding 2 parts if N-^2-/4-(2, 3-dihydro-Z-oxo-lH-benzimidazol-l -yl)-1 - piper idinyl/ithyl^-2-pyridinecarboxamxde dihydrochloride dihydrate; mp. .65.7°C.

LXXVIII Example XL1 Following the procedure of Example XL and using N, Ndimethylformamide as a solvent there is prepared N- -/T(2, 3-dihydro-2-oxc-lH-benzimidasol-l-yl)-l-piper 2-furancarboxamide; mp. 231.7’G, by the reaction cf N-(2chloroethyl)-2«furancarboxamic.e with 1,3-dihydro-l-(4-piperidinyl)-2H-bea2imidazol-2-one.

LXXIX Example XL1I' part of acetic acid anhydride and 15 parts of water is stirred for 30 minutes in a water-bath at 80-90°C. The reaction mixture is cooled and alkalized with an ammonium hydroxide solution. The product is extracted with trichioromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl2-pentanone. The product is filtered off and dried, yielding 0.5 parts ' of 2-(acetylamino)-N- ^2-/4*-(2, 3-dihydro-2-oxo-lH-benzimidazoll-yl)-l-piperidinyX7ethylJ-4-fiuorobenzamide; mp. 210’C.

LXXXII Example XL1II oxo-lH-benzimidaaci-1 -yl)-l -piperidinyl/ethylj -4-fhiorobenzamide; mp. 196.5’C startingfrom2-amino-N-^2-/4-(5-chloro-2,3-dihydro2-oxo-lH-benzimidazol-l -yl)-i-piperidinyl/ethyl J-4-fluorobenz» amide.

LXXXIV 3150 A mixture of 1,68 parts oi 4-fluorobenzoyl chloride, 4.22 parts of 1 -/j--(2-aminoethyl)-4-piperidinyf7"1,3-dihydro-2H-benzimidazol~ 2-one dihydrobromide, 4.83 parts of potassium carbonate and 18 parts of N, 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 Ν', N-dimethylformamide. The N, N-dimethylformamide la removed in vacuo and water is added to the residue. The product is sxtracted with trichloromethane. The extract is dried, filtered and evaporated. Tie residue is crystallized from 2-propanol, yielding 2. 5 parts of N--|_2-/4-(2, 3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l- -4-fluorobenzamide. mp. 231’C» xxxvni Example XLV A mixture of 0, 74 parts of 1 -(benzoyl)aziridine, 1, 06 parts if 4-{4-chlorophenyl)-4-piperidinol, 5. 4 parts of benzene, and 0. 4 parts of methanol is stirred and refluxed for 2 hours. The reaction mixture is cooled. Upon the addition of 1,1 '-oxybisethane, the product is precipitated. After stirring for 15 minutes, the product is filtered off and dried phenyl)-4-hydroxy-1 -pi XXXIX I 315C Example XLVI Following the procedure of Example XLV and using equivalent amounts of the appropriate starting materials, the following compounds are prepared in free base form or in acid addition salt form after treatment of the base with an appropriate acid. ίϊ Ar-C-NH-CH.,-CH,-N y OH Ar |r6,s7 Base or Salt form Melting Point •c 4-F-C6H4 I 4-Cl ί base 168. 7 2-(OC2Hs)-C6H4 4-Cl base 171-173 2 -thienyl ! 4-Cl » base 153 4-CH3-C6H4 ! 4-Cl hci.h2o 232.6 2-Ν°2-Ο6Η4 4-Cl Her 174.12.NO2-4-F-C6H3 ! 4-ci. base 144. 3 2-Br-C6H4 4-CI i base 120.6 2-(OCH3)-4-F-C6H3 4-Cl base 156. 7 2,6-{CH3)2-C6H3 4-Cl i /h^nh-so^h 236-280(dec.) 3-CH3-C6H4 4-Cl ;cooh) 181.2 2, S-CLj-C^H^ 4-Cl HC1.H2O 187.5 3-(OCH3)-C,H4 4-Cl ’ (cooh)2 183.4 2-(OCH3)-4-NC2-5-Cl- 4-CI 1/2 CHj-CKOH •6h3 CH„OH o . 163.1 C,H 4-F-C6H4 3-C3\-4-Cl 2.^Η^ΓΗ-ΞΟ3Η - XL XLI XLII XLIII XLIV XLV XLVI XLVI1 ’ LXXXV LXXXVIj lxxxvi2 LXXXVI3 lxxxvi4 LXXXVI.

Ixample XLVII A mixture of 5.8 parts of 2-amino-N- ^2-/4-(4-chlorophenyl)i-hydroxy-l -piperidinyl/ethyl J-4-£luorobenzamide, 5.5 parts of acetic leid anhydride and 55 parts of -water is stirred and heated for 30 minutes in a water-bath at about 80 °C. The reaction mixture is cooled and ilkalized with ammonium hydroxide. The product is extracted with trishloromeihane. The aqueous phase is separated and extracted with dichloromethane. The combined organic phases are washed three tim.-es vith water, dried, filtered and evaporated. The oily residue is crystalized from 4-methyl-2-pentanone. The product is· filtered off and dried, fielding 4.5 parts of2-(acetylamino)-N-^2-/4-(4-chlorophenyl)-4tydroxy-1-piper idinyl/ethyl^ -4-fluorobenzamide; mp. 175.1 °C. LXXXVII Sample XLVIII · A mixture of 10.6 parts of N-(2-bromoethyl)-2-nitrobenzamide, 9.2 parts of A (+)-4-(4-chlorophenyl)-3-methyl-4»piperidinol and 270 parts of N, N-Himethylformamide is stirred and refluxed for 4 hours. The reaction mixture is evaporated till dry. 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 converted into the hydrochloride salt is 2-propanol. The salt is Sltered off and crystallized from a mixture of ethanol and 2, 2'-oxybispropane (l :1 by volume). The product is filtered off and dried overnight at 60°C, yielding 4.5 parts of A-(+)-N- |2-/4-(4-ehlorophenyl)-4-hydroxy-3-methyl-l -piperidinyl/ethyl) -2-nitrobenzamide hydrochloride; mp. 228°C.

LXXXVIIX 31 ίίβ Example IL Following the procedure of Example XLVIil there is prepared A-(+)-N-$ 2-^-(4-chlorophenyl)-4-hydroxy-3-methyl-lpiperidinyl7ethylJ-4-fluoro-2-nitrobenzamide hydrochloride, by the reaction of N-(2-bromoethyl)-4-iluoro-2-nitrobenzamide with A-(+)-4-(4-chloropheayl)«3-methyl-4-piperidinol. LXXXIX Example L A mixture of 2.8 parts of A-(+)-N-^2-/4-(4-chlorophenyl}-4·· hydroxy-3-methyl-l -piperidinyl7ethylj -4-fluoro-2 -nitrobenzamide hydrochloride in 160 parts of methanol is hydrogenated, at normal pressure and at room temperature with 2 parts of Saney-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 and 2-propanol, The salt is filtered off and crystallized from 2-propanol, yielding part of A-(+)-2-amino-N-|2-/4-{4-chlorophenyl)-4-hydroxy-3methyl-1-plperidinyl/ethyli -4-fluorobenzamide dihydrochloride 2-propanolate; mp. 135aC, n.-.

Example LI 2o Following the procedure of Example L there is prepared A-(+)-2-amino-N-^ 2-23"(‘i'-ohiorophenyl)«4-hydroxy-3-meth.yl-l · piperidinyl/ethyl j benzamide dihydrochloride; mp. 190. 5’C, . ' by hydrogenating A-(+)-N-^2-/4-(4-chlorophenyl)-4-hydroxy-3methyl-ϊ -piperidinyl/ethyij-i-nitrobenzamide.

XCI - 63 I LSO Example LII · A mixture oi 3.5 parts of N-[2-/3-(4-chlorophenyl)-4hydroxy-1 -piperidinyl/ethyl]-2-nitrobenzamide hydrochloride, parts of tetrahydrofuran and 40 parts of methanol is hydrogenated at normal pressure and at room temperature with 0.2 parts of platinium dioxide. 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-propanol and 2’, 2'-oxyhiSpropane. The salt is filtered off and dried, yielding 2.6 parts of 2-amino-N-^2-^t-(4-chlorophenyl)-4-hydroxy-Ipiperidinyl/ethylj benzamide dihydrochloride hemihydrate; mp. 195. 7"C.

XLVIII Example LIII .

A mixture of 4. 5 parts of N- £2-/4-(4-chlorophenyl)-4hydroxy-1 -piper idinyl/ethylJ-4-fluoro-2-nitrobenzamide, 40 parts of methanol and 90 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 2 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-propanol. The salt is filtered off and dried, yielding 2 parts of 2-amino-N-j2-/4-(4-chlorophenyl)-4-hydroxy-lpiperidinyl/ethyl^-4-fluorobenzamide dihydrochloride; mp. 210, 7°C.

XLIX Example L1V Following the procedure of Example XILand using therein equivalent amounts of the appropriate starting materials, the following compounds are obtained in hydrochloride salt form: N-|2-/T-(4-chloraphenyl)-4-oxo-I, 3,S-triazaspiro/iTij/dec8-yj/ethyl J-4-fluorobenzamide; Γ N-p-J -(4-chlorophenyl)-4-oxo-l, 3, S-triazaspiro/9l, 5/dec-8- yVethylj benzamide; N- j2-/T-(4-bromephenyl)-4-cxa-i, 3, 8-triazaspiro/J, 5/dec-Syl/ethylj-4-fluorobenzamide; 2-chloro-N-^2-/l-(4-chlorophenyl)-4-oxo-l, 3, 8-triazaspiro/4, 5/dec-8-yl7ethyl J -4-fluorobenzamide; 2-amino-N-^.2-^-(4-chlarophenyl)-4-oxo-l, 3, 8-triazaspiro^, 5/dec-8-yl/ethylJ -4-£iuorobenzamide; and 2-amino-N-j2-/F-(4-bromophenyl,5-4-oxo-l, 3, 8-triazaspiro^, 5/dec-8-yl/ethyl -4-fluorobenzamide.' JiSO Example LV .Following the procedure of ExampleXXVI and using equivalent amounts of the appropriate starting materials, the -following compounds of formula (i) are still prepared: N- -^-(5 -bromo - 2, 3 -dihydro -2 -oxo - Lff-benzimidazol-1 -yl)1- piperidinyl/ethyl^-4-fl.uorobenzamide;.

N- ^2-/4-(2,3-dihydro-5-methyl -2-oxo- lH-benzimidazol-1 -yl)1 -piper idinyl/ethyl J -4-fluorobenzamide; N- ^2-/4-(5, 6-dichloro-2, 3-dihydro-2-oxo-lH-benzimidazol-l-yl)2 -piperidinyf/ethyl ^-4-fluorobenzamide; 2- chloro-N- ^2-/4^(5, 6-dichloro-2, 3-dihydro-2-oxo*l Hbensimidazol-l-yl)-l-piperidinyl/ethylj -4-lluorobenzamide; 2-amino-N- ^2-'/4-(5-bromo-2, 3-dihydro-2-oxo-lH-benzimidazol~ 1-ylJ-l -piperidinyl/ethylJ-4-fl.uorobenzamide; N- ^2-/T, 6-dihydro-4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)1- (2H)-pyr idinyl/ethyl J-benzamide,· 2- amino-N-^ 2- /3.6 -dihydro-4-(2, 3-dihydro-2-oxo-lH-benzimidazol-1 -yl)-l-(2H)-pyridinyi/ethyl J-4-fluorobenzamide; 2-chJ.oro-N-^2-/3, 6-dihydro-4-(2, 3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l-(2H)-pyridinyl/ethyl ^-4-fluorobenzamide; and N- ^2-/j-(5-chloro-?, 3-dihydro -2-oxo-lH-benzimidazol-l-yl)l-(2H)-pyr idinyl/ethyl j-4-fluorobenzamide. ..

Example LVT Following tho procedure of ExampleXLVand using therein equivalent amounts of the appropriate starting materials, the ' following compounds are still obtained: ' .

N-^- j4-/4-chloro-3-(trisluoromethyl)pheny^-4-hydroxy-l -piperi

Claims (5)

1. CLAIMS:1. An Ν- £(l-piperidinyl)alkylJ arylcarboxamide derivative having the general formula: 0 R ( 1 ) II I Ar-C—N-(CH-) - N A 2. N whereih Ar is a phenyl, 2-thienyl, 2-furyl, pyridyl or a l-methyl-2pyrrolyl group or a phenyl group substituted with from 1 to 3 substituents which are each independently a halogen atom, a lower alkyl, lower alkyloxy, trifluoromethyl, nitro, hydroxy, amino, lower alkylcarbonyloxy or lower alkylcarbonylamino group, provided that when more than one substituent is present only one thereof may be a hydroxy, amino, lower alkylcarbonyloxy or a lower alkylcarbonylamino group; R is a hydrogen atom or a lower alkyl group; 3. Is 2 or 3; and the radical S~X -N A o is a) a radical having the formula: 1 2 'herein R and R are each independently a hydrogen or a alogen atom, a lower alkyl or a trifluoromethyl group; b) a radical having the formula: wherein R and S' are each independently a hydrogen or halogen atom, a lower alkyl or a trifluoromethyl group; M is a hydrogen atom, a lower alkyl, lower alkylcarbonyl or 2-cyanoethyl group; Y is 0, S or a lower alkylcarbonylimino group; and the dotted line indicates an optional double bond between the 3- and 4-earbon atoms of the piperidine nucleus, provided that when there is a double bond between said 3- and 4. -earbon atoms, then said Y is 0 and said M is a hydrogen atom; c) a radical having the formula: /—\.H S(lower alkyl) 3 d wherein R and R' are each as defined above; or d) a radical having the formula: wherein R 3 is a hydrogen atom or a methyl group; 6 7 R is a hydrogen or halogen atom: and & is a hydrogen or halogen atom, a lower alkyl or trifluoromethyl group. 1150

2. 4 - fluoro - Ν - {2 - [l - (4 - fluorophenyl) - 4 oxo - 1,3,8 - triazaspiro [4,5] - dec - 8 - yl] ethyl}benzamide.

3. 2 - Amino - 4 - fluoro - N -fe - (4 - oxo - 1 - phenyl 1,3,8 - triazaspiro-[4,5] dec - 8 - yl)ethyl] benzamide.

4. 2 - Chloro - N - {2 - - (4 - fluorophenyl) - 4 Dxo - 1,3,8 - triazaspiro-[4,5] dec - 8 - yl] ethyl}benzamide. 3. 2 - Chloro - 4 - fluoro - N - {2 -[l -(4- fluorophenyl) - 4 - oxo - l,3,8-triazaspiro^4,5]dec - 8 - yl] ethyl}benzamide. ί. N - {2 -[4 -(5- Chloro - 2,3 - dihydro - 2 - oxo _H - benzimidazol - 1-yl) - 1 - piperidinyl] ethyl} - 4 :luorobenzamide. ’. 2 - Chloro -N- {2-[4- (4- chloro - 2,3 - dihydro : - oxo - IH - benzimidazol - 1 - yl) - 1 - piperidinyl] ethyl} - fluorobenzamide. 2 - Amino -N-{2-[4- (2,3- dihydro - 2 - oxo - IH enzimidazol - 1-yl) - 1 - piperidinyl] ethyl} - 4 - fluorobenzamide A pharmaceutically acceptable acid addition salt of compound as claimed in any one of claims 1 to 8. 0. A process for preparing a N-£(l-piperidinyl)alkyl] rylcarboxamide derivative of formula I as defined in claim 1, tich process comprises: a) reacting a compound of the formula 11 -Ί Ar-C-N I (II) 4 315 0 wherein Ar is a: formula defined in claim 1 th a compound of the (XII) wherein the radical -N A is as defined in claim 1 in order to prepare a compound of the formula (I-a) Ar-C- NH CH,-CH,-N A 2 2 the reaction being carried out in an appropriate, reaction inert, organic solvent; or b) reacting a compound of the formula 0 R !! I Ar—C—N—(CH,) —X (XV) wherein Ar, R and n are as defined in claim 1 and X is an appropriate reactive ester function derived from the corresponding alcohol, with a compound of the formula (III) HN a o wherein the radical is as defined in claim 1 in a suitable organic solvent, in order tc prepare a ccmpound of the formula (I) (CH,) 2 n 5150 or c) reacting a compound of the formula II Ar-C—halo (V) wherein Ar is as defined in claim 1 with an appropriate amine of the formula R I M HN“(CH 2 ) n -N A (VX) wherein R, n and the radical dd -N A are as defined in claim 1 in a suitable reaction inert organic solvent, or d) subjecting a compound of formula 1 wherein Ar is a nitro-substituted phenyl group, to a nitro-to-amine reduction reaction according to known techniques, in order to prepare a compound of formula (I), wherein Ar is an aminesubstituted phenyl group, or e) preparing a compound of the formula (I) wherein Ar is a phenyl group substituted by a lower alkyl carbonyl amino group or a lower alkyl carbonyloxy group, by acylating the corresponding amino or hydroxy substituted derivative by known techniques, or f) acylating a compound of the formula (I-c) 4 315 0 3 4 wherein Ar, R, n, 3. and R are as defined in claim 1 with an appropriate acylating agent derived from the appropriate lower alkyl carboxylic acid in order to prepare a compound of the formula 11 I ira ·, Ar~C-N -,Lli 2 } n· /-\ (I-b) alkyl) or g) subjecting a compound of the formula (VII) r-ii-N - (CH n ) -N NH. NH 3 4 wherein Ar, R, n, R and R are as defined in claim 1 to ring closure with an appropriate sulfur containing cyclizing agent in order to prepare a compound of the formula or h) S-alkylating a compound of the formula (I-d) defined above by standard S-alkylating procedures in order to prepare a compound of the formula (I-e) 0 R II ! Γ Ar-C-N-(CH_) -N 11 \_ H S(lower alkyl) ! - C *N 3150 and, if desired, preparing pharmaceutically acceptable acid addition salts of the products of steps I-a to I-h and, further, if desired, preparing different stereochemical or optically isomeric forms thereof, by known methods. 11. A process for preparing 4 - fluoro - N- {2 -£l (4 - fluorophenyl) - 4-oxo - 1,3,8 - triazaspiro[4,s] dec - 8 yl] ethyljbenzamide or a pharmaceutically acceptable acid addition salt which comprises reacting 1 - (4 - fluorobenzoyl) aziridine with 1 - (4 - fluorophenyl) - 1,3,8 - triazaspiro £4,5] decan - 4 - one, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof. 12. A process for preparing 2 - amino - 4 - fluoro - N [2 - (4 - oxo - 1 - phenyl- 1,3,8 - triazaspiro £4,5jdec -8yl)ethyi[ benzamide or a pharmaceutically acceptable acid addition salt thereof which comprises hydrogenating the corresponding 2-nitro benzamide, and, if desired, preparing a pharmaceutically acceptcible acid addition salt of the product thereof. 13. A process for preparing 2 - chloro - N - {2 - £l (4 - fluorophenyl) - 4 - oxo - 1,3,8 - triazaspiro £4,5] dec 8 - yl]ethyljbenzamide or a pharmaceutically acceptable acid addition salt thereof which comprises reacting 1-(2chlorobenzoyl)aziridine with 1-(4- fluorophenyl) - 1,3,8 triazaspiro[4,5] decan - 4 - one and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof. 14. A process for preparing 2 - chloro - 4 - fluoro - N {2 -£l - (4 - fluorophenyl) - 4 - oxo - 1,3,8 - triazaspiro [4,5] dec - 8 - yl] ethyljbenzamide or a pharmaceutically acceptable acid addition salt thereof which comprises reacting 1-(2- chloro - 4 - fluorobenzoyl)aziridine with 1-(474 4 315 0 fluorophenyl·} - 1,3,8 - triazaspiro[4,5] decan - 4 - one and, if desired, preparing a pharmaceutically acceptable acid addition salt ox the product thereof. 15. A process for preparing H - {2 -[4 -(5- chloro 2,3 - dihydro - 2 - oxo - IH - benzimidazol - 1 - yl) - 1 piperidinylj ethyl} - 4 - fluorobenzamide or a pharmaceutically acceptable acid addition salt thereof which comprises reacting 1-(4- fluorobenzoyl)aziridine with 5 - chloro -1,3dihydro - 1 - (4 - piperidinyl) - 2H - benzimidazol - 2 - one and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof. 16. A process for preparing 2 - chloro -11-(2-^4(5 - chloro - 2,3 - dihydro - 2 - oxo - IH - benzimidazol - 1 - yl) - 1 - piperidinyl] ethyl} - 4 - fluorobenzamide or a pharmaceutically acceptable acid addition salt thereof which comprises reacting 1-(2- chloro - 4 - fluorobenzoyl)aziridine with 5 - chloro - 1,3 - dihydro - 1 - (4 - piperidinyl) - 2H benzimidazol - 2 - one and, if desired, preparing a pharmaceutically acceptable addition salt of the product thereof. 17. A process for preparing 2 - amino - N - {2 -^4 (2,3 - dihydro - 2 - oxo - IH - benzimidazol - 1 - yl) -1piperidinyl]ethyl} - 4 - fluorobenzamide or a pharmaceutically acceptable acid addition salt thereof v/hich comprises hydrogenating the corresponding 2-nitro substituted benzamide, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof. 18. A process as claimed in claim 10 substantially as hereinbefore described with reference to any one of Examples XII to LVI. 150 19. A pharmaceutical composition, which comprises an N- [(1-piperidinyl)alkylj- arylcarboxamide derivative having the formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, in admixture with a pharmaceutical carrier. 20. A pharmaceutical composition as claimed in claim 19 wherein the pharmaceutical carrier is a solid, ingestible carrier. 21. A pharmaceutical composition as claimed in claim 19 wherein the pharmaceutical carrier is a liquid, ingestible carrier. 22. A pharmaceutical composition as claimed in claim 19 wherein the pharmaceutical carrier is a sterile liquid suitable for parenteral use. 23. A pharmaceutical composition as claimed in claim 22 which is in unit dosage form. 24. A pharmaceutical composition as claimed in any one of claims 19 to 23 which comprises N - {2 -[4 - (5- chloro 2,3 - dihydro - 2 - oxo - IH - benzimidazol - 1 - yl) - 1piperidinyl] ethyl} - 4 - fluorobenzamide or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutical carrier. 25. A pharmaceutical composition as claimed in claim 19 substantially as hereinbefore described. 25. A method of inhibiting emesis or a mental disorder which comprises the systemic administration to a non-human warm-blooded animal of an effective anti-emetic or psychotropic amount of an N-[{1-piperidinyl)alkyl] arylearboxamide derivative of formula (I) as claimed in any one of claims 1 to 8, or 19, or of a pharmaceutically acceptable salt as claimed in claim 9, or of a pharmaceutical composition as claimed in any

5. One of claims 19 to 25.