GB2108489A

GB2108489A - Pharmaceutical composition comprising piperidene derivatives

Info

Publication number: GB2108489A
Application number: GB08220042A
Authority: GB
Inventors: John Leheup Archibald; Terence James Ward
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1980-03-01
Filing date: 1982-07-09
Publication date: 1983-05-18
Also published as: GB2108489B

Abstract

The invention concerns pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula <IMAGE> and acid addition and quaternary ammonium salts thereof, wherein the dotted line represents an optional bond, Ar represents a ring system of formula <IMAGE> in which Q is O, S, -CR<7>=CR<8>-, -N=CR<8>- and -N=N-; R<4>, R<5>, R<6>, and R<7> and R<8> when present, each represent hydrogen or defined substituents and additionally either R<4> and R<5> when adjacent or R<6> and R<8> when adjacent, together with the carbon atoms to which they attached also represent a fused five or six membered carbocylic or heterocyclic ring optionally carrying one or more defined substituents; R is an optionally substituted aryl or heteroaryl radical or a cycloalkyl radical containing 5 to 7 carbon atoms; R<1>, R<2>, R<3> and R<9> are each hydrogen or a lower alkyl group; n is 0 or 1; X is =O, =S or =NH; Y is -O- or a direct bond and Z is -CO- or -CH2- with the provisos that (i) when Ar is unsubstituted phenyl and R<9> is hydrogen then Y is -O- and (ii) when Z is -CH2- and Ar is a phenyl or pyridyl group then R<1> is hydrogen. The compounds of formula I exhibit psychotropic activity and are useful as antidepressants.

Description

SPECIFICATION Pharmaceutical compositions comprising piperidine derivatives This invention relates to pharmaceutical compositions comprising new piperidine derivatives.

In our copending UK Patent Application No. 8106044 (Serial No. 2073176A) there are described and claimed piperidino ureas, thioureas and guanidines which exhibit pharmaceutical activity especially psychotropic activity in standard pharmacological test procedures, and are potentially useful as antidepressants. In general the compounds are specific inhibitors or 5-hydroxytryptamine re-uptake in vitro and in vivo, and therefore may also be useful in any other therapeutic applications where such pharmacological specificity may be beneficial.

In detail UK Patent Application No.8106044 (Serial No. 2073176A) provides compounds of formula:

and acid addition and quaternary ammonium salts thereof, wherein the dotted line represents an optional bond, Ar represents a ring system of formula

in which Q is O, S, -CR7=CR8-, -N=CR8- and -N=N-;R4, R5 and R6, and R7 and R8 when present, each represent hydrogen or a substituent selected from lower alkyl, lower alkenyl, lower alkoxy, NO2, NH2, haloloweralkyl, hydroxyloweralkyl, aminoloweralkyl, substituted amino, loweralkoxycarbonyl, cyano, CONY2 and hydroxy; and additionally either R4 and R5 when adjacent or R6 and R8 when adjacent, together with the carbon atoms to which they are attached also represent a fused five or six membered carbocyclic or heterocyclic ring optionally carrying one or more substituents as defined above; R is an optionally substituted aryl or heteroaryl radical or a cycloalkyl radical containing 5 to 7 carbon atoms;R1, R2, R3 and R9 are each hydrogen or a lower alkyl group; n is0 or 1; Xis =O, =S or =NH; Y is -O- or a direct bond and Z is -CO- or -CH2-, with the provisos that (i) when Ar is unsubstituted phenyl and R9 is hydrogen then Y is -0- and (ii) when Z is -CH2- and Ar is a phenyl or pyridyl group either of which may be substituted then R' is hydrogen, and processes for preparing them. The present application is a divisional of UK 8106044 and provides a pharmaceutical composition comprising a compound of formula I above or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof and a pharmaceutical carrier.This invention also provides the compounds of formula I and the pharmaceutically acceptable acid addition or quaternary ammonium salts thereof for use as psychotropic agents.

The term 'lower' as used in connection with alkyl or alkoxy groups means that such groups contain 1 to 6 carbon atoms especially 1 to 4 carbon atoms. 'Substituted amino' includes groups such as alkyl- or dialkyl-amino, acylamino e.g. lower alkylcarbonylamino, ureido or sulphonylamino, e.g. lower alkylsulphonamido or di-lower-alkylsulphonylamino.

Examples of lower alkyl groups are methyl, ethyl n-propyl, isopropyl, t-butyl, neo-pentyl and n-hexyl.

Examples of lower alkoxy groups are methoxy, ethoxy, isopropoxy, butoxy and hexoxy. Examples of cycloalkyl groups are cyclohexyl and cyclopentyl.

'Hydroxyloweralkyl' includes groups such as HO(CH2)rn where m is 1 to 4, e.g. hydroxymethyl or hydroxyethyl.

Examples of lower alkylamino and di-lower-alkylamino groups are MeNH-, EtNH-, dimethylamino, isopropylamino and butylamino.

Examples of lower alkenyl groups are vinyl, propenyl, but-1-enyl and but-2-enyl.

Examples of haloloweralkyl groups are chloroethyl and trifluoromethyl.

'Aminoalkyl' includes groups such as NH2(CH2)rn where m is 1 to 4, e.g. aminomethyl, aminoethyl.

Examples of lower alkoxycarbonyl groups are methoxy-and ethoxycarbonyl.

Preferred halogen substituents are chlorine and bromine.

Examples of the group Ar when Q is O or S are

furan-2-yl, thiophen-2-yI, benzo[b]furan-3-yl, benzo[b]-thiophen-3-yl. Examples of Ar when Q is -CR7 = CR8- are

Examples of Ar when Qis -N=CR8- are

When Q is -N=N- examples are

When monosubstituted phenyl or pyridyl the group Ar may be for example 4-t-butylphenyl,4-cumenyl, 4-n-butoxyphenyl, 4-nitrophenyl, 4-dimethylaminophenyl, 3-vinyl phenyl, 3-methylpyrid-2-yl, 4-methylpyrid 2-yl, 4-methyl pyrid-3-yl, 4-chloropyrid-2-yl, 2-methyl pyrid-4-yl or 2-bromopyrid-4-yl.When multi-substituted phenyl or pyridyl the group Ar may be for example 3,4-dichlorophenyl; 3,4,5-trimethylphenyl; 3,4,5trimethoxyphenyl; 3,4-dichloro-2-methylphenyl; 2,3-diethylphenyl, 3-methyl-4-vinylphenyl, 2,4 dichloropyrid-6-yl, 2,4-dimethylpyrid-6-yl. Examples of Ar when phenyl having a fused 5-or 6-membered carbocyclic or heterocyclic ring are naphth-1-yl; naphth-2-yl; benzo[1,4]dioxan-6-yl; 3,4-methylenedioxyphenyl; 1 ,2,3,4-tetrahydrona phth6-yl; 1 ,4-dihydronaphth-6-yl; benzo[b]thiophen-6-yl; indol-6-yl; ben zo[b]furan-6-yl; quinol-6-yl and quinol-5-yl.Examples ofArwhen pyridyl having a fused 5 or 6 membered carbocyclic or heterocyclic ring are quinoi-4-yl, quinol-2-yl, 5,6,7,8-tetrahydro-quinol-4-yl or 5,6,7,8tetrahydro-quinol-2-yl. Examples of such groups when substituted in the fused ring are 6-methoxy-naphth-2yl, 7-methoxynaphth-2-yl and 4-methylnaphth-2-yl. Preferred fused heterocyclic 'Ar' rings have oxygen, nitrogen or sulphur as heteratom(s).

The group R is exemplified by aryl radicals such as phenyl which can be substituted for example by the substituents listed for R4, e.g. methyl (such as 4-methyl) ethyl, propyl, nitro (such as 3- or 4-nitro), hydroxy (such as 4-hydroxy), methoxy, ethoxy, fluorine, bromine, or chlorine (such as 3,4-dichloro). Heteroaryl radicals for R include thienyl (e.g. thien-2-yl), furyl (e.g. fur-2-yl) and pyridyl (e.g. pyrid-2-yl), which radicals may be substituted as described above for the phenyl radical Ar.

Preferred values for Ar are phenyl substituted by one or more alkyl or alkoxy groups of 2 or more carbon atoms, e.g. 4-ethylphenyl, 3,4 dimethylphenyl, 3,4-dimethoxyphenyl; phenyl having a fused 5 or 6 membered carbocyclic ring, e.g. naphth-1-yl, napth-2-yl, such groups being optionally substituted by lower alkyl, lower alkoxy, halogen, nitro, trifluoromethyl, amino, lower alkylamino (e.g. methylamino) diloweralkylamino (e.g. dimethylamino) and cyano.

Preferably n is O, R9 is hydrogen or methyl and R1 is hydrogen. Preferably X is oxygen.

Preferably Z is -CO- and R is phenyl or phenyl substituted in the 4-position by lower alkoxy, e.g.

methoxy.

Y is preferably a direct bond.

When Z is -CH2-, R is preferably phenyl.

Preferred compounds are 1 -benzoyl-3-[1 -(naphth-2-ylmethyl)piperid-4-yljurea; 1 -benzoyl-3-[1 -(naphth-1 ylmethyl)piperid-4-yl]urea; 1 -benzoyl-3-[1 -[4-isopropylbenzyl)piperid-4-yl]urea; 1 -benzoyl-3-[1 -(5,6,7,8 tetrahydronaphth-2-ylmethyl)-piperid-4-yl] urea; 1 -benzoyl-3-[ 1 -(3,4-dimethylbenzyl)piperid-4-yl]urea; 1 benzoyl-3-[1 -(indan-5-ylmethyl)piperid-4-yljurea; 1 -benzoyl-3-[1 -(1 -napth-2-yl)ethyl)piperid-4-yl]urea; and 1 benzoyl-3-[1 -(4-ethyl benzyl)piperid-4-ylJu rea.

Examples of acid addition salts are those formed from inorganic and organic acids and in particular pharmaceutically acceptable acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, sulphonate (such as the methane-sulphonate and p-toiuenesulphonate), acetate, maleate, citrate, fumarate, tartrate, malonate and formate.

Compounds of formula I were tested for psychotropic activity by their ability to inhibit p chloroamphetamine (pCA) induced hyperactivity and/or by their ability to inhibit 5-hydroxytryptamine (5-HT) uptake in brain slices.

The following test procedure was used to test for ability to inhibit p-chloroamphetamine induced hyperactivity.

Three groups of 4 female mice (20-24 g) receive the test compounds (50 mg/kg po) and a fourth group the requisite volume of vehicle. Thirty minutes later all the animals are given 20 mg/kg p-chloroamphetamine (pCA) ip. The grouped mice are placed immediately in square plastic cages in activity monitors and their motor activity recorded over the period 10-30 minutes post pCA. This procedure is repeated three more times so that four groups of mice are used per treatment and each activity monitor is used with all treatments in turn. The inhibition of pCA induced hyperactivity is calculated thus: C-T 100% C where C = mean activity of control groups 10-30 minutes post pCA.

T = mean activity of treated groups 10-30 minutes post pCA.

This test is used as an in vivo screen for detection of 5-hydroxytryptamine uptake inhibitors.

Compounds giving < 50% inhibition are considered of special interest. In such a test the following compounds were particularly active: Compound % Inhibition of pCA induced hyperactivity 1 -Benzoyl-3-[1 -(naphth-2-ylmethyl) piperid-4-yl]urea 67.5% 1-Benzoyl-3-[1-(naphth-1-ylmethyl)- piperid-4-yl]urea 56.4% 1 -Benzoyl-3-[1 -(4-isopropylbenzyl) piperid-4-yl]urea 49% 1-Benzoyl-3-[1 -(5,6,7,8-tetrahydro naphth-2-ylmethyl)piperid-4-yl]urea 69.4%, 73.5% 1 -Benzoyl-3-[1 -(3,4-dimethyl benzyl)- 68.9% piperid-4-yl]urea 1-Benzoyl-3-[1-(indan-5-ylmetbyl)- piperid-4-yl]urea 59.3% l-Benzoyl-3-[l-(l-naphth-2-yl)ethyl]- piperid-4-yl]urea 71.7% 1 -Benzoyl-3-[1 -(4-ethylbenzyl)- piperid-4-yl]urea 72.9% Compounds of formula I were tested for ability to inhibit 5-hydroxytryptamine (5-HT) uptake in brain slices using the following procedure: The effects of test compound on the neuronal uptake of 5-hydroxytryptamine into slices of cerebral cortex prepared from rat brain is determined according to the method described by Snyder, Green and Hendley, Kinetics of H3-norepinephrine accumulation into slices from different regions of the rat brain (J.Pharm. exp.

Therap, 164: 90-102) (1968). Concentration-response curves for the test compound and for the standard agent, imipramine, are obtained. The potency of the test compound is expressed in proportion to that of imipramine. Thus, the potency ratio for the test compound Molar concentration of imipramine giving 50% inhibition of 5HT uptake Molar concentration of test drug giving 50% inhibition of 5HT uptake Compounds not achieving 50% inhibition are considered inactive.

In such a test the compound 1-benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea above was particularly active having a potency ratio of 8.8 (imipramine = 1.0).

In vivo 5-HT uptake inhibition was also demonstrated for compounds of the invention by a procedure involving 5-hydroxy-L-tryptophan (5-HTP) induced behavioural syndrome. Mice given a high dose of 5-HTP exhibit a behavioural syndrome consisting of tremor, hind limb abduction, lateral head weaving and forepaw treading. In addition to these signs rats also exhibit head twitching and circling behaviour. In the following experiments the syndrome was said to be present if mice exhibited at least 3 and rats at least 4 of these signs. When animals are given a low dose of 5-HTP, which does not itself produce the syndrome, it can be produced by pretreatment with 5-HT uptake inhibitors. Thus, this test can be used as an indication of in vivo 5-HT uptake inhibition.

aj Doselresponse study in mice Groups of 12 (2 subgroups of 6) female mice (18-22g) were used per dose, each group being housed in a separate cage for the duration of the experiment. Mice were dosed p.o. with either test compound or vehicle (0.5% HPMC) and 30 minutes later received a threshold dose of 5-HTP (80 mg/kg i.p.) and were placed in "Perspex (RTM) cylinders (12" diameter). After a further 20 minutes the mice were observed for 5 minutes for the presence or absence of the syndrome. The dose that produced the syndrome in 50% of the mice was calculated using the method of Litchfield and Wilcoxon, J. Pharm. Exp. Ther. 96,99-113 (1949).

b) Dose/response study in rats Groups of 6 male rats (150 g) were dosed with test compound suspended in HPMC. Thirty minutes later 5-HTP (70 mg/kg i.p.) was given and the number of signs/rat recorded between 20 and 35 minutes post 5-HTP. Linear regression analysis of the results was performed and the ED50 calculated from this.

The results found for l-benzoyl3-[l -(naphth-2-ylmethyl)-piperid-4-yl]urea (A) and for the antidepressant clomipramine are shown below: ED50 values for potentiation of 5-HTP syndrome in: Compound Mice lmglkg po) Rats rmglkg ip) A 7.2 5.3 clomipramine 18 39.2 The pharmaceutical compositions contain as active ingredient an active compound of formula I as above defined. The active compound may be finely comminuted if desired. In addition to the active ingredient, the compositions also contain a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules.A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient.

Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier, such as sterile water, sterile organic solvent or a mixture of both. Preferably a liquid carrier is one suitable for parenteral injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it is too insoluble for this it can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable.In other instances composition can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilised by intramuscular, intraperitoneal or subcutaneous injection. In many instances, a compound is orally active and can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form. In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredients; the unit dosage form can be a packaged composition, the package containing specific quantities of composition, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in package form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 5 mg or less to 500 or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.

Afurther aspect of this invention includes a method of alleviating depression in a warm blooded animal afflicted with depression, which method comprises administering to said animal an effective amount of a compound of formula I as defined above.

The amount of compound used will depend on the compound employed, the severity and nature of the depression and the animal being treated. With large animals (about 70 kg body weight) by the oral route the dose is preferably from about 5 to about 75 mg and most preferably from about 10 to about 25 mg every four hours or as needed. By the parenteral route the dosage is preferably from about 2 to about 35 mg as needed.

Ideally therapy should be initiated with lower dosages, the dosage thereafter being increased until the desired anti-depressive effect is obtained.

The following examples illustrate the preparation of compounds of formula I: EXAMPLE 1 1-Benzo yI-3-Jl-(naph th-2-ylmeth yI)piperid-4-yljurea 4-Benzoylureidopiperidine (1.289, 0.005m), 2-(bromomethyl)naphthalene (1.1g, 0.005m) and triethylamine (0.6g, 0.006m) in dimethylformamide (25 cm3) were stirred at room temperature for 23 hours. Water was added and the precipitated solid filtered off and washed well with water. The solid was suspended in warm ethanol, acidified with ethanolic HCI and then heated until all the solid had dissolved. The title compound crystallised and was collected as the hydrochloride salt, hemihydrate (1.6g), m.p. 232-234"C.

Analysis: C24H25N302.HCI.-H2O requires: C, 66.58; H, 6.29; N, 9.70%.

Found: C, 66.57; H, 6.43; N, 9.45%.

EXAMPLE 2 t-Benzoyl-3-[1-{naphth- 1-ylmethyl)piperid-4ylYurea 1-Chloromethyinaphthalene (0.88g, 0.005m), 4-benzoylureidopiperidine (1.28g, 0.005m) and triethylamine (0.6g) in dimethylformamide (25 cm3) were stirred at room temperature for 24 hours. Water was added and the precipitated solid filtered off. The solid was suspended in isopropylalcohoi and acidified with ethanolic HCI. The title compound was filtered off and dried as the hydrochloride salt, hemihydrate (1.29), m.p.

185-186"C.

Analysis: C24H25N302.HCI.2H2O requires: C, 66.58; H, 6.29; N, 9.70%.

Found: C, 66.19; H, 6.52; N, 9.72%.

EXAMPLE 3 1-Benzoyl-3-fl-(4-isoprnp ylbenzyl)piperid-4-yljurea 4-lsopropylbenzyl chloride (0.84g, 0.005m), 4-benzoylureidopiperidine (1.28g, 0.005m) and triethylamine (0.69) in dimethylformamide (25 cm3) were stirred at room temperature for 24 hours. Water was added and the precipitated solid filtered off. The solid was suspended in isopropylalcohol and acidified with ethanolic HCI. The title compound was filtered off and dried (1.2 g), m.p. 240-242"C as the hydrochloride salt, hemihydrate.

Analysis: C23H29N302.HCI.2H2O requires: C, 65.01; H, 7.35; N, 9.89%.

Found: C, 65.24; H, 7.66; N, 9.67%.

EXAMPLE 4 1-Benzo yl-3-fl-(6-meth oxynaphth-2-ylmethyl)piperid-4-ylj-urea 6-Methoxynaphth-2-ylmethanol (0.94g, 0.005m) in dry benzene (10 cm3) was refluxed with thionyl chloride (3 cm3) for 3 hours. The solvent was evaporated and the residue treated with benzene (3 x) and evaporated.

4-Benzoylureido-piperidine (1.289, 0.005m), triethylamine (1.5g, 0.015m) and dimethylformamide (25 cm3) was added to the residue and the reaction mixture stirred at 500C for 2 hours. The solution was filtered and then diluted with water. The precipitated solid was washed with water, dissolved in chloroform and the chloroform extract washed with water and dried (MgSO4). Evaporation gave a solid which was suspended in ethanol, acidified with ethanolic HCI and heated until all the solid had dissolved. On cooling the title compound crystallised and was filtered and dried as the hydrochloride, hemihydrate (1.3 g), m.p. 243-244"C.

Analysis: C25H27N303.HCI.2H2O requires: C, 64.85; H, 6.31; N, 9.07%.

Found: C, 64.59; H, 6.40; N, 8.90%.

EXAMPLE 5 3-Benzoyl- 1-[7-( 4-benzodioxan-6-ylmeth yllpiperid-4-yll-urea 1,4-Benzodioxan-6-ylmethanol (1.55g, 9.34 mmol) and thionyl chloride (1.7g,14.29 mmol) were refluxed in sodium-dried diethyl ether (30 cm3) for 3 hours then the solvent and excess thionyl chloride evaporated. The residue was dissolved in toluene (20 cm3), thionyl chloride (1.7g,14.29 mmol) was added and the solution heated and stirred at 800C for 3 hours. Evaporation of the solvent gave a residue. 4-Benzoylureidopiperidine (2.0g, 8.1 mmol) and triethylamine (1.09g, 10 mmol) were added to the residue and refluxed in isopropyl alcohol overnight. The isopropyl alcohol was evaporated and the residue triturated with water.The water was decanted and the residue crystallised from isopropyl alcohol (1.649).

The base was suspended in refluxing isopropyl alcohol, ethanolic HCI was added and the mixture filtered.

The filtrate was cooled at 5 C overnight and the title compound collected and dried as the hydrochloride, quarterhydrate (1.46g), m.p. 231 -2350C.

Analysis: C22H25N304.HC1.1/4H2O requires: C, 60.55; H, 6.12; N, 9.63%.

Found: C, 60.74; H, 6.27; N, 9.38%.

EXAMPLE 6 1-Benzo yl-3-f 1- (3,4-dimeth ylbenzyl)piperid-4-yljurea 3,4-Dimethylbenzyl alcohol (0.68g, 0.005m) in dry benzene (10 cm3) was trdated with thionyl chloride (3 cm3) and refluxed for 3 hours. The solvent was evaporated and the residue treated with benzene (3 times) and evaporated. 4-Benzoylureidopiperidine (1.28g,0.05m), triethylamine (1.5 g, 0.015m) and dimethylformamide (25 cm3) were added to the residue and the reaction mixture stirred at 50"C for 2 hours. The solution was filtered and the filtrate diluted with water. The precipitated solid was filtered, dissolved in chloroform and washed well with water, dried (MgSO4) and evaporated to give a solid.The solid was suspended in ethanol and acidified with ethanolic HCI to give the title compound, which was recrystallised from ethanol as the hydrochloride, quarterhydrate, m.p.239-240 C.

Analysis: C22H27N302.HCI.1/4H2O requires: C, 65.01; H, 7.07; N, 10.34%.

Found: C, 64.62; H, 7.05; N, 10.15%.

EXAMPLE 7 1-Benzo-yl-3-[1-{3-aminobenzyl)piperid-4yl]urea 1-Benzoyl-3-[1-(3-nitrobenzyl)piperid-4-yl]urea 4.479 (from Example 13) was hydrogenated with 5% Pd/C (0.5g) at atmospheric pressure and room temperature until no more hydrogen was taken up. The catalyst was filtered and the filtrate evaporated. The residue was dissolved in water and basified with .880 ammonia.

The precipitated solid was filtered, washed well with water, dried, treated with charcoal, and evaporated to give the title compound, (1.9 gms). This was recrystallised from ethanolic HCI to give the dihydrochloride salt, monohydrate, m.p.194-195 C.

EXAMPLE 8 1-Benzoyl-3-[1-(3-dimethanesulphonylaminobenzyl)piperid-4-yl]urea Methanesulphonyl chloride (0.55g) was added at room temperature to a stirred solution of the product of Example 7 (1.69g) and triethylamine (0.5g) in chloroform (10 cm3). After addition was complete the solution was allowed to stir for 3 hours, then washed with water, dried, and evaporated. The residue was purified by trituration with ethanol at reflux. The product was suspended in ethanol, acidified with ethanolic HCI, heated for 5 minutes, cooled, and the title hydrochloride collected by filtration (0.5g), m.p. 189-91 "C.

Analysis: C22H28N406S2.HCI.2H2O requires: C, 47.69; H, 5.46; N, 10.11%.

Found: C, 47.56; H, 5.25; N, 9.74%.

EXAMPLES 9 to 35 Using the procedure of Example 1 the following compound of formula I are obtained by reacting the appropriate compound of formula Ill wherein W is chlorine or bromine with 4-benzoylureidopiperidine: EXAMPLE NO. Compound 9. 1 -Benzoyl-3-[1 -(2-[naphth-1 -yloxyjethyl)-piperid-4-yl]urea (m.p. of HCI, quarter hydrate salt = 226-229"C).

10. 1-Benzoyl-3-[1-(3,4-dichlorobenzyl)-piperid-4-yljurea (m.p. of HCI, hemihydrate salt = 244-245"C).

11. 1 -Benzoyl-3-[1 -(4-t-butylbenzyl)piperid-4-yl]urea, (m.p. of HCI, quarterhydrate salt = 202-204"C).

12. 1 -Benzoyl-3-[1 -(4-n-butoxybenzyl)-piperid-4-yl]urea, (m.p. of HCI, hemihydrate salt = 214-217"C).

13. 1-Benzoyl-3-[1-(3-nitrobenzyl)piperid-4-yl]urea, (m.p. of HCI, quarterhydrate salt = 255-257"C).

14. 1 -Benzoyl-3-[1 -(5,6,7,84etrahydronaphth-2-ylmethyl)piperid-4-yl]urea (m.p. of HCI salt = 233-5"C).

15. l-Benzoyi-3-[l -(4-ethylbenzyl)piperid-4-yl]urea, (m.p. of HCI salt = 234-236"C).

16. 1-Benzoyl-3-[1-(3,4-dibromobenzyl)-piperid-4-yl]urea, (m.p. of HCI salt = 228-230"C).

17. 1-Benzoyl-3-[1-(2,5-dimethylbenzyl)-piperid-4-yljurea, (m.p. of HCI salt = 231-232"C).

18. 1 -Benzoyl-3-[1 -(4-n-propoxybenzyl)-piperid-4-yl]urea, (m.p. of HCI salt = 232-234"C).

19. 1 -Benzoyl-[1 -[2-(naphth-2-oxy)ethylj-piperid-4-yl]urea (m.p. of HCI salt = 215-218"C).

20. 1 -Benzoyl-3-[1 -(indan-5-ylmethyl)-piperid-4-yl]urea, (m.p. of HCI salt 253-6"C).

21. 1 -Benzoyl-3-[1 -(1 -(naphth-2-yl)ethyl)-piperid-4-yljurea, (m.p. of HCI salt = 1 72-4"C).

22. 1 -Benzoyl-3-[1 -(4-methyl-3-nitrobenzyl)-piperid-4-yl]urea, (m.p. of HCI salt 232-234"C).

23. 1 -Benzoyl-3-[1 -(3-bromo-4-methyl benzyl)-piperid-4-yl]urea.

24. 1 -Benzoyl-3-[1 -(quinol-4-ylmethyl)-piperid-4-yl]urea, (m.p. of sesquihydrochloride salt = 21 1-213"C).

25. 1 -Benzoyl-3-[1 -(quinol-2-ylmethyl)-piperid-4-yljurea, (m.p. of di-HCI salt = 213-215 C).

26. 1-Benzoyl-3-[1-(3,5-dimethylbenzyl)-piperid-4-yl]urea, (m.p. of HCI, quarterhydrate salt = 248-252"C).

27. 1 -Benzoyl-3-[1 -(2,4-dimethylbenzyl)-piperid-4-yl]urea, (m.p. of HCI, quarterhydrate salt = 230-232"C).

28. 1-Benzoyl-3-[1-(3-bromobenzyl)piperid-4-yl]urea (m.p. of HCI, quarterhydrate salt = 222-224"C).

29. 1-Benzoyl-3-[1-(3-iodobenzyl)piperid-4-yl]urea (m.p. of HCI salt = 217-219"C).

30. 1-Benzoyl-3-[1-(pyrid-4-ylmpiperid-4-yl]urea (m.p. of di-HCI salt = 236-238"C).

31. 1-Benzoyl-3-[1-(3-trifluoromethylbenzyl)-piperid-4-yl]urea (m.p. of HCI salt = 241 243"C).

32. 1-Benzoyl-3-[1-(4-methoxycarbonyl-benzyl)piperid-4-yl]urea (m.p. of HCI salt = 247 249"C).

33. 1 -Benzoyl-3-[1 -(6-methylnapthth-2-yl-methyl)piperid-4-yl]urea (m.p. of HCI, hemi hydrate salt = 250-253"C).

34. 1-Benzoyl-3-[1-(1-[benzofuran-2-yl]-ethyl)piperid-4-yl]urea (m.p. of HCI salt = 148 149"C).

35. 1-[1-(S-Acetamido-2-hydroxybenzyl)-piperid-4-yl]-3-benzoylurea (m.p. of HCI, 3/4 hydrate salt = 230-232"C).

EXAMPLE 36 1-Benzoyl-3-fl-(naphth-2-ylm eth yl)piperid-4-yljthiourea 4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0g, 0.0042m) and benzoylisothiocyanate (0.69 g, 0.0042m) in toluene (120 cm3) was stirred at room temperature for 6 hours. The solvent was evaporated and the gum dissolved in isopropyl alcohol and acidified with ethanolic HCI. The solvent was evaporated and the residue dissolved in ethyl acetate. The title compound crystallised and was filtered and dried as the monohydroch chloride quarterhydrate salt, m.p. 212-214"C.

EXAMPLE 37 1-f1-(Naphth-2-ylmeth yl)piperid-4-ylj-3-(then-2-oyl)urea 4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g 0.0047m) and 1-(then-2-oyl)urea (0.65g, 0.0042m) in pyridine (5 cm3) was refluxed for 9.5 hours. The solvent was evaporated, water added, and the precipitated title compound filtered and washed well with water. This was recrystallised from ethanol, converted to the hydrochloride salt in ethanol with ethanolic HCI, and recrystallised from ethanol,0.5g, at the hydrochloride, m.p.217-219"C.

EXAMPLE 38 1-Benzoyl-3-f1-(naphth-2-ylm ethyl)piperid-4-yljquanidine 4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0g, 0.0042m) and benzoyl cyanamide (0.67g, 0.0042m) in toluene (100 cm3) were refluxed for 15 hours. The solvent was evaporated and the residue recrystallised from the minimum amount of isopropyl alcohol and recrystallised twice more from ethanol to give 0.65 g of the title compound, m.p. dihydrochloride quarter hydrate, m.p. 260-262"C.

EXAMPLES 39-42 Using a procedure analogous to Example 37 4-amino-1-(naphth-2-ylmethyl)piperidine is reacted with each of the following ureas: 3,4-dimethylbenzoylurea, 3-trifluoromethylbenzoylurea, 4-nitrobenzoyl urea and 1-(pyrid-4-oyl)urea to give the following compounds: EXAMPLE NO. Compound 39. 1 -(3,4-Dimethylbenzoyl)-3-[1 -(naphth-2-ylmethyl)piperid-4-yl]urea (m.p. of HCI, quarterhydrate = 223-226"C).

40. 1 -(1 -(Naphth-2-ylmethyl)piperid-4-yl]-3-(3-trifluoromethylbenzoyl)urea (m.p. 251 253"C).

41. 1-[1-(Naphth-2-ylmethyl)piperid-4-yl]-3-(4-nitrobenzoyl)urea (m.p. of HCI salt = 264 5"C).

42. (1 -(Pyrid-4-oyl)-3-[1 -(naphth-2-ylmethyl)-piperid-4-yl]urea (m.p. 254-255"C) EXAMPLE 43 1-r4-Methoxybenzoyl)-3-[1-{naphth-2-ylmethyl)piperid-4yllurea 1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (prepared according to Example 1) is hydrolysed by refluxing in 2N sodium hydroxide to give [1 -(naphth-2-ylmethyl)piperid-4-yl]urea(m.p. 1 83-5"C). The product is acylated by reaction with 4-methoxybenzoyl chloride to give the title compound, m.p. of HCI, quarterhydrate = 193-193.5"C).

EXAMPLES 44-45 In a manner analogous to Example 1, 2-bromomethyl-naphthalene was reacted with the following compounds of formula II: 4-benzylureidopiperidine, 4-(p-fluorobenzoyl)ureidopiperidine to give the following compounds of formula I: EXAMPLE NO. Compound 44. 1-Benzyl-3-[1-(naphth-2-ylmethyl)-piperid-4-yl]urea (m.p. of HCI, 1/4 hydrate salt = 243-247"C (dec)).

45. 1-(p-Fluorobenzoyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (m.p. of HCI, 1/4 hy drate salt = 242-245"C(dec)).

EXAMPLES 46-54 Using a procedure analogous to Example 1, 4-benzoylureidopiperidine is reacted with the following compounds: 2-(naphth-2-yl)ethyl tosylate, 6-cyanonaphth-2-ylmethyl bromide, 6-fluoronaphth-2-ylmethyl bromide, 6-bromonaphth-2-ylmethyl bromide, 1-(naphth-2-yl)propyl chloride, di-(naphth-2-ylmethyl)sulphate, 6-chloromethylquinoxaline, 3-chloromethylcinnoline, 6-chloromethylisoquinoline, to give the following compounds EXAMPLE NO. Compound 46. 1-Benzoyl-3-[1-(2-[naphth-2-yl]ethyl)-piperid-4-yl]urea, (m.p. of HCI salt = 230-232"C).

47. 1 -Benzoyl-3-[1 -(6-cyanonaphth-2-ylmethyl)piperid-4-yl]urea, (m.p. of HCI, hemi hydrate salt = 264-266"C).

48. 1 -Benzoyl-3-[1 -(64luoronaphth-2-ylmethyl)piperid-4-yl]urea.

49. 1 -Benzoyl-3-[1 -(6-bromonaphth-2-ylmethyl)piperid-4-yl]urea.

50. 1-Benzoyl-3-[1-[1-(naphth-2-yl)propyl]-piperid-4-yl]urea.

51. 1-Benzoyl-3-[1-(naphth-2-ylmethyl)-piperid-4-yl]urea, m.p. of HCI, hemihydrate salt = 232"-234"C).

52. 1 -Benzoyl-3-[1 -(quinoxalin-6-ylmethyl)-piperid-4-yl]urea.

53. 1-Benzoyl-3-[1-(cinnolin-3-ylmethyl)-pipend-4-yljurea.

54. 1 -Benzoyl-3-[1 -(isoquinol in-6-yl methyl )-piperid-4-yl]urea.

EXAMPLE 55 1-Benzo yl-3-J1-(naphth-2-ylmeth yl)piperid-4-yljurea 2-Bromomethylnaphthalene is heated with 4-benzoyl-ureidopyridine in acetonitrile solvent to give 1-benzoyl-3-[1-(naphth-2-ylmethyl)-4-pyridinium urea bromide m.p. 247-8"C. This compound is reduced by refluxing with sodium borohydride in isopropyl alcohol solvent to give the title compound, m.p. of HCI hemihydrate salt = 232-234"C.

Alternatively 1-benzoyl-3-[1-(naphth-2-ylmethyl)-4-pyridinium]urea bromide is reduced with sodium borohydride in methanol solvent to give 1 -benzoyl-3-[1 -(naphth-2-ylmethyl)-3,4-dehydropiperid-4-ylju rea.

This compound may then be reduced by refluxing with sodium borohydride in isopropyl alcohol to give the title compound.

EXAMPLE 56 1-Benzo yl- 1-methyl-3-f1-(naphth-2-ylmeth yl)piperid-4-yljurea 1-Methyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (1.4 g.) (prepared by reacting 4-amino-1-(naphth-2- ylmethyl)-piperidine with methyl isocyanate) in toluene (30cm3) was acylated using benzoyl chloride (0.92g) in presence of pyridine (0.6g) to give the title compound: m.p. of HCI, hemihydrate salt = 164-1 66"C.

Analysis: Found: C 67.37; H, 6.58; N, 9.45; C25H27N302.HCI2H2O requires C 67.18; H, 6.54; N, 9.40%.

EXAMPLE 57 1-Benzo yl-3-meth yl-3-fl-(naphth-2-ylmethyl)pip erid-4-yljurea Using a procedure analogous to Example 37, 4-methylamino-1-(naphth-2-ylmethyl)piperidine was reacted with benzoyl-urea to give the title compound. m.p. of HCI, quarterhydrate=207-209"C.

Claims

1. A pharmaceutical composition comprising a compound of formula I

or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof, in which the dotted line represents an optional bond, Ar represents a ring system of formula

in which Q is O, -CR7=CR8-, -N=CR8- and -N=N-;R4, R5 and R6, and R7 and R8 when present, each represent hydrogen or a substituent selected from lower alkyl, lower alkenyl, lower alkoxy, NO2, NH2, halo-lower alkyl, hydroxyloweralkyl, aminolower alkyl, substituted amino, lower alkoxycarbonyl, cyano, CONH2 and hydroxy; and additionally either R4 and R8 when adjacent or R6 and R8 when adjacent, together with the carbon atoms to which they are attached also represent a fused five or six membered carbocyclic or heterocyclic ring optionally carrying one or more substituents as defined above; R is an optionally substituted aryl or heteroaryl radical or a cycloalkyl radical containing 5 to 7 carbon atoms; R1, R2, R3 and R9 are each hydrogen or a lower alkyl group; n is0 or 1; Xis =0, =S or =NH;Y is -O- or a direct bond and Z is -CO- or -CH2-, with the provisos that (i) when Ar is unsubstituted phenyl and R9 is hydrogen then Y is -0- and (ii) when Z is -CH2- and Ar is a phenyl or pyridyl group either of which may be substituted then R is hydrogen, and a pharmaceutically acceptable carrier.

2. A pharmaceutical composition as claimed in Claim 1 wherein Ar represents phenyl substituted by one or more groups selected from lower alkyl, halogen or lower alkoxy or a naphthyl, benzofuranyl, benzothiophenyl, tetrahydronaphthyl, indanyl, benzodioxanyl, quinolinyl, isoquinolinyl, cinnolyl, or 4-, 5-, 6- or 7-indolyl group, each optionally substituted by one or more groups selected from halogen, lower alkyl, lower alkoxy and cyano.

3. A pharmaceutical composition as claimed in Claim 1 or Claim 2 wherein Y is a direct bond, n represents 0 and Z represents -CO-.

4. A pharmaceutical composition as claimed in any one of Claims 1 to 3 wherein R is phenyl, phenyl substituted by one or more groups selected from halogen, lower alkyl, lower alkoxy, hydroxy or nitro, or a thienyl or pyridyl group.

5. A pharmaceutical composition as claimed in Claim 1 in which the compound of formula I is 1-benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea, or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

6. A pharmaceutical composition as claimed in Claim 1 in which the compound of formula I is 1-benzoyl-3-[1-(pyrid-4-ylmethyl)piperid-4-yl]urea or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

7. A pharmaceutical composition as claimed in Claim 1 in which the compound of formula I is selected from 1 -benzoyl-3-[1 -(4-isopropylbenzyl)piperid-4-yl]urea, 1 -benzoyl-3-[1 -(5,6,7,84etrahydronaphth-2-ylmethyl)-piperid-4-yl]urea, 1 -benzoyl-3-[1 -(3,4-dimethylbenzyl)piperid-4-yl]urea, 1 -benzoyl-3-[1 -(indan-5-ylmethyl)piperid-4-yl]urea, 1 -benzoyl-3-1 -[1 -(naphth-2-yl)ethyl]-piperid-4-yl}urea, 1 -benzoyl-3-[1 -(4-ethyl benzyl)piperid-4-yl]urea, 3-benzoyl-1 -[1 -(1 ,4-benzodioxan-6-ylmethyl )piperid-4-yl]urea, 1 -benzoyl-3-[1 -(6-methoxynaphth-2-ylmethyl)piperid-4-yljurea, 1 -benzoyl-3-[1 -(2-[naphth-1 -yloxy]ethyl )piperid-4-yl] urea, 1-benzoyl-3-[1-(3,4-dibromobenzyl)piperid-4-yl]urea, 1-benzoyl-3-[1-(4-n-propoxybenzyl)piperid-4-yljurea, 1 -benzoyl-3-[1 -(3-amino-4-methylbenzyl)piperid-4-yl]-urea, 1-benzoyl-3-[1 (quinol-2-ylmethyl)piperid-4-yl]urea, 1 -[1 -(naphth-2-ylmethyl)piperid-4-yl]-3-(then-2-oyl)-u rea, 1 -benzoyl-3-[1 -(naphth-2-ylmethyl)piperid-4-yl]-guanidine, 1 -(4-fluorobenzoyl-3-[1 -(naphth-2-ylmethyl)piperid-4-yljurea, 1-benzyl-3-[1 -(naphth-2-ylmethyl)piperid-4-yl]urea, 1-benzoyl-3-[1 -(2-naphth-2-ylethyi)piperid-4-yl]urea, 1 -benzoyl-3-] 1 -(6-cyanonaphth-2-ylmethyl)piperid-4-yl]urea, and 1 -benzoyl-3-[1 -(6-fluoronaphth-2-ylmethyl)piperid-4-yl]urea; or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

8. A pharmaceutical composition as claimed in any one of Claims 1 to 7 in which the salt is the hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, methanesulphonate, ptoluenesulphonate, acetate, maleate, citrate, furmarate, tartrate, malonate orformate.

9. A pharmaceutical composition as claimed in any one of Claims 1-8 which is in unit dosage form.

10. A process for preparing a therapeutic composition exhibiting psychotropic activity characterised in that a compound of formula I or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof as defined in any one of Claims 1 to 7 is brought into a form suitable for therapeutic administration.

11. A compound of formula I as defined in any one of Claims 1 to 8 for use as a psychotropic agent.