IE44610B1

IE44610B1 - Piperidine derivatives

Info

Publication number: IE44610B1
Application number: IE327/77A
Authority: IE
Original assignee: Gallardo A Sa
Priority date: 1976-02-17
Filing date: 1977-02-16
Publication date: 1982-01-27
Also published as: BE851508A; ATA98577A; DE2705949A1; AT356106B; FR2342963A1; GB1513631A; IE44611B1; JPS52122378A; NL7701630A; ES455833A1; JPS52122379A; ES455831A1; JPS596851B2; ES455832A1; FR2342963B1; ATA97877A; BE851509A; NL7701631A; DE2705949C2; AU509216B2

Abstract

The piperidine derivative of formula in which the meaning of the symbols appears in Claim 1, is prepared by reacting a benzoic acid of formula with a piperidine derivative of formula in which R, R<1>, R<2>, R<3>, x and W have the same meanings as in formula (I). The piperidine derivative of formula (I) is used in the treatment of nauseas and vomitings and as a neuroleptic or tranquillising agent.

Description

This invention relates to new therapeutically useful piperidine derivatives, to processes for their preparation and pharmaceutical compositions containing them.

The new piperidine derivatives of the present invention are those compounds of the general formula:- {wherein R represents a lower alkoxy or lower alkenyloxy group; R1 and R2, which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl, amino, lower alkylamino, di(lower)alkylamino, loweralkylsulphonyl or lower alkyl sulphamoyl group, or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid,including halogen substituted carboxylic acids such as trifluoroacetic acid (preferably a lower alkanoylamino group), the halogen atom or group represented by the symbol R1 being in the 3- or 4-position of the phenyl ring (preferably in the 4-position), with the proviso that R1 and R2 do not both represent hydrogen atoms; R3 represents a hydrogen atom or a lower alkyl, lower alkenyl or phenyl group or a cycloalkyl or cycloalkenyl group having from 3 to 7 carbon atoms in the ring; R* represents a cycloalkyl group having from 3 to 7 carbon atoms in the ring optionally substituted by an alkyl group containing 1 to 3 carbon atoms or a hydroxy(lower)alkyl or lower alkenyl group, or R1* represents an adamantyl group or a group of the formula: - 2 4 4 610 wherein Rs and R6 each represent a hydrogen atom of a methyl group, or a grouping of formula II or III containing a double bond between two of the carbon atoms in the cyclohexyl ring; x represents zero or 1, and W represents a single bond or a lower alkylene (e.g.

—CH2— or —CH2CH2—) or lower alkenylene (e.g.

—CH=CH— or —CH2—CH=CH—) group with the proviso that when W is a single bond R3 is other than a cycloalkenyl group} and pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides thereof. Preferably x represents zero and W represents a single bond.

The qualification lower as applied in this specification to alkoxy, alkenyloxy, alkyl, acyl, alkanoyl, alkenyl, alkylene and alkenylene groups means that the group in question contains at most 6 carbon atoms. It is to be understood that the cycloalkenyl groups within the definition of R3 may have one, two or three double bonds as is appropriate for the number of carbon atoms in the ring.

Preferred compounds of general formula I are those of the more specific formula: (wherein R' represents a lower alkoxy (preferably methoxy or ethoxy) or allyloxy group, R1' represents a hydrogen atom, or an amino, lower alkylamino (preferably methyl amino), di(lower)alkylamino (preferably dimethylamino) or a lower acylamino (preferably lower alkanoyloxyamino, e.g. acetamido or trifluoroacetamodo) group, R2' represents a halogen (preferably chlorine or bromine) atom, or an amino, sulphamoyl or lower alkyl- 3 44610 sulphonyl (preferably methylsulphonyl) group, R3' represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms (preferably methyl) group, and R*' represents a cycloalkyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms, preferably methyl} and pharmaceutically acceptable acid addition salts thereof.

Another class of compounds of interest is that wherein R* represents a cyclobutyl, cyclopentyl, cycloheptyl or adamantyl group, or a cyclohexyl group optionally substituted in the 4-position by an alkyl group containing 1 to 3 carbon atoms or a hydroxy(lower)alkyl or lower alkenyl group, and W represents a group —(CHz)y— wherein y represents zero or an integer from 1 to 5.

Of outstanding importance are N - (1 - cyclohexylmethylpiperid 4 - yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide, N - (1 - cyclo1,5 hexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 5 - bromobenzamide, N - (1 - cyclohexylmethylpiperid - 4 - yl) -2 - methoxy 4 - methylamino - 5 - chlorobenzamide, N (1 - cyclohexylmethylpiperid 4 - yl) - 2 - allyloxy - 4 - amino - 5 - chlorobenzamide and N - (1 cyclohexylmethylpiperid -4-yl) - 2 - ethoxy - 4 - amino - 5 - chloro20 benzamide, and their pharmaceutically-acceptable acid addition salts.

According to a feature of the present invention, the piperidine derivatives of general formula I are prepared by the process which comprises reacting a reactive derivative of a benzoic acid of the general foraiula:- COOH - 4 44610 (wherein R, R1 and Rz are as hereinbefore defined) with a piperidine derivative of the general formula: wherein the various symbols are as hereinbefore defined. The reactive derivative of the said benzoic acid may be a halide (preferably chloride), an alkyl ester (preferably methyl ester), anhydride or a mixed anhydride, the N-imidazolamide or acid azide.

The reaction is preferably carried out in the presence of an inert organic solvent, for example benzene, toluene, chloroform, tetrahydrofuran or dioxan, at a temperature between -5° and 120°C.

The piperidine derivatives of general formula VI wherein x is zero can be prepared by reduction of corresponding piperid - 4 - one oximes with lithium aluminium hydride in the presence of diethyl ether or tetrahydrofuran, or by reductive amination of corresponding piperid 4 - ones dissolved in an organic solvent, e.g. an alcohol containing up to 6 carbon atoms, in the presence of Raney nickel or platinum as catalyst. The piperidine derivatives of general formula VI wherein R3 represents a cyclohexadienyl group can be prepared from a corresponding phenyl derivative of that formula wherein R3 represents a phenyl group by reduction with lithium in the presence of liquid ammonia or a lower alkylamine. The piperidine derivatives of general formula VI wherein x is 1 can be prepared by known reductive methods starting from corresponding 4 - cyanopiperidines.

Halides of the benzoic acids of general formula V can be prepared by reaction of the acids with thionyl chloride or a phosphorus halide in the presence of an inert organic solvent such as benzene, toluene or a halogenated hydrocarbon. Mixed anhydrides of the benzoic acids - 5 446ΐθ of general formula V can be prepared by the reaction of the acid with, for example, an alkyl chloroformate in the presence of an organic nitrogen-containing base, e.g. triethylamine, in an inert organic solvent, e.g. tetrahydrofuran or methylene chloride and at a temperature between -20° and +25°C. Esters and anhydrides of the benzoic acids of formula V, which may be employed as starting materials in the aforementioned process, can be prepared from the benzoic acids by methods known per se, as can also the N - imidazolamides of acid azides of the acids.

The piperidine derivatives of general formula I are also prepared, according to a further feature of the invention, by the direct reaction of a benzoic acid of general formula V with a piperidine derivative of general formula VI in the presence of an appropriate dehydrating agent. Such agents are silicon tetrachloride, a mono-, di- or tri alkyl-silyl chloride, titanium tetrachloride, N,N' - dicyclohexyl - carbodiimide, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene £ - sulphonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent. The reaction is carried out in an inert organic solvent, e.g. methylene chloride, acetone, pyridine, ethyl acetate or dioxan, at a temperature between 20° and 110°C.

In the preparation of those compounds of general formula I wherein the symbol(s) R1 and/or R2 represent(s) an amino group by the aforementioned processes, it is sometimes advisable'to protect the amino group(s) of the acid of general formula V or derivative thereof before reacting the compound with the piperidine derivative of general formula VI. In this case an N-acyl derivative of the amino-substituted benzoic acid of general formula V is initially prepared, the acyl protecting group preferably being acetyl, chloroacetyl, trifluoroacetyl or phthalimido. After the reaction between the N-acylated compound of general formula V, or reactive derivative thereof, with the piperidine derivative - 6 44610 of general formula VI, the corresponding N-acyl derivative of the compound of general formula I is obtained and that compound is then subjected to acid or alkaline hydrolysis to give the corresponding compound of general formula I in which R1 and/or R2 represent(s) an amino group. Acid hydrolysis of the N-acylated compound may be carried out by heating with dilute hydrochloric acid, preferably at the boiling point of the reaction mixture, while alkaline hydrolysis is preferably carried out at room temperature with sodium or potassium hydroxide in an aqueousalcoholic solution.

The piperidine derivatives of general formula I have as one of their principal pharmacological properties the ability to antagonise the effects of dopamine or dopaminergic agents of endogenous or exogenous origin. They have exhibited activities which may be considered beneficial in the treatment of gastrointestinal and cerebral malfunction in mammals, including man. They have also been shown to be capable of exerting anorectic properties. Their characteristic properties are an antagonism of the effect of the dopaminergic agent, apomorphine, in animals, local anaesthetic activity and the ability to induce catatonia in rats and mice. Consequently, they may be useful in the treatment of nausea and vomiting of diverse origin and as neuroleptic or tranquilising agents. They may be useful for the treatment of nausea and vomiting resulting from gastrointestinal disorders, congestive heart failure, postoperative conditions, other gastrointestinal disorders such as dyspepsia, flatulance, bile regurgitations, hiatus hernia, peptic ulcer, reflux oesophagitis, gastritis, duodenitis and cholelithiasis, and a variety of conditions affecting the central nervous system such as acute and chronic psychosis, manical psychosis, schizophrenias, serious disturbances of behaviour and non-melancholic depressive states and migraine. They may also be useful in the treatment of obesity and allied conditions where the administration of an appetite - 7 44610 suppressant is warranted.

For the therapeutic purposes the piperidine derivatives of general formula I may be employed in the form of non-toxic pharmaceuticallyacceptable inorganic or organic acid addition salts such as sulphates, hydrohalides, phosphates, lower alkanesulphonates, arylsulphonates, salts of aliphatic mono- di- or tri-basic acids of from 1 to 20 carbon atoms which may contain one or more double bonds, an aryl nucleus or other functional group such as hydroxy, amino or keto; salts of aromatic acids in which the aromatic nucleus may optionally be substituted by groups such as hydroxy, lower alkoxy, amino, mono- or di(lower)alkylamino and sulphonamido groups. They may also be employed in the form of pharmaceutically-acceptable quaternary ammonium salts such as those salts formed by reaction of the piperidine derivatives of general formula I with lower alkyl halides or sulphates, or in the form of oxygenated derivatives in which oxygen is attached to the nitrogen atom of the piperidine nucleus, viz. the N-oxides.

The pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides of the piperidine derivatives of general formula I may be prepared by methods known per se.

Also included within the scope of the present invention are pharmaceutical compositions which comprise, as active ingredient, at.least one piperidine derivative of general formula I, or a non-toxic pharmaceutically-acceptable acid addition salt or quaternary ammonium derivative or N-oxide thereof, in association with a pharmaceutically25 acceptable carrier or diluent. Preferably the compositions are made up in a form suitable for oral, topical, percutaneous or parenteral administration.

The pharmaceutically-acceptable carriers or diluents which are admixed with the active compound, or compounds, to form the compositions of this invention are well known per se and the actual excipients used - 8 44610 depend inter alia on the method of administering the compositions. Compositions of this invention are preferably adapted for administration per os. In this case, the compositions for oral administration may take the form of tablets, capsules, lozenges or effervescent granules or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing one or more compounds of the invention; such preparations may be made by methods well known in the art.

The diluents which may be used in the preparation of the composition include those liquid and solid diluents which are compatible with the active ingredient, together with, if desired, colouring or flavouring agents. Tablets or capsules may conveniently contain between 0.1 and 20 mg of active ingredient or the equivalent amount of an acid addition salt or quaternary ammonium or N-oxide derivative thereof.

The liquid compositions adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise a water-insoluble active compound of the invention or an acid addition salt or quaternary ammonium or N-oxide derivative thereof in association with water, together with a suspending agent and flavouring agent.

Compositions for parenteral injection may be prepared from watersoluble salts, which may or may not be freeze dried and which may be dissolved in water or an appropriate parenteral injection fluid.

In another aspect of the invention, the compounds may be mixed with other active anti-acid and anti-ulcer agents (excluding anticholinergic agents) for oral or, in appropriate cases, for parenteral use.

The following Reference Example and Examples illustrate the preparation of piperidine derivatives of general formula I. - 9 44610 REFERENCE EXAMPLE (a) A solution of 1 - cyclohexylmethyl piperid - 4 - one oxime (37.8 g;) 0.18 moles) dissolved in anhydrous diethyl ether (250 ml) was added little by little to a suspension of lithium aluminium hydride (14,04 g; 0.36 moles) in anhydrous diethyl ether (200 ml). On completion of the addition, the resultant mixture was heated to the boiling point and maintained there under reflux for 12 hours, and then thoroughly cooled whilst water (14 ml), 15%(w/v) aqueous sodium hydroxide solution (14 ml) and water (42 ml) were added successively. The mixture was filtered and the ethereal solution was dried (Na2SOu) and the solvent removed in vacuo. The product 1 - cyclohexylmethyl - 4 - aminopiperidine (31 g) was isolated as a viscous liquid, b.p. 105°—110°C/0.3 mm Hg.

In a similar manner, using appropriate oximes as starting materials, there were also prepared: 1 - cyclopentylmethyl - 4 - aminopiperidine, b.p. 90°—92°C/0.45 mm Hg; - cyclobuetylmethyl - 4 - aminopiperidine, b.p. 70°—71°C/0.05 nm Hg; 1-(1- adamantylmethyl) - 4 - aminopiperidine, m.p. 75°—79°C, and 1-(4- methyl cyclohexylmethyl) - 4 - ami nopiperidine, b.p. 127°— 130°C/4 mm Hg. (b) A solution of 1 - cyclohexylmethyl piperid - 4 - one (65 g; 0.33 moles in a saturated ethanolic solution of ammonia (350 ml) was hydrogenated in the presence of Raney nickel catalyst (6.5 g) at 75°C and 13 atmospheres for 3.5 hours. The mixture was cooled, the catalyst filtered off and the solvent removed by distillation in vacuo. The residue was treated with a saturated ethanolic solution of hydrogen chloride, and the insoluble dihydrochloride was filtered off, treated with an aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was dried (Na2S0[J and the solvent removed i£ vacuo giving 1 - cyclohexylmethyl - 4 - aminopiperidine (45.5 g) as a - 10 44610 viscous liquid, b.p. 105°—110°C/0.3 mm Hg.

Also prepared in a similar manner were: - cycloheptylmethyl - 4 - aminopiperidine, b.p. 101°—102°C/0.15 mm Hg, and 1 - cyclobutylmethyl - 4 - aminopiperidine, b.p. 70°—71°C/0.05 mm Hg.

EXAMPLE 1 Triethylamine (5.6 ml; 0.04 moles) and ethyl chloroformate (3.84 ml; 0.04 moles) were added successively to a stirred suspension of - methoxy - 4 - amino - 5 - chlorobenzoic acid (8 g; 0.04 moles) in 10 anhydrous tetrahydrofuran (300 ml) whilst maintaining the temperature between -5° and -10°C. After stirring at this temperature for 0.5 hours, a solution of 1 - cyclohexylmethyl - 4 - aminopiperidine (7.85 g; 0.04 moles) in anhydrous tetrahydrofuran (50 ml) was added, the temperature was maintained at --5° to -10°C for 1 hour and then allowed over15 night to reach room temperature. The solvent of the mixture was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layers washed with water. The chloroformic solution was dried (Na2S04) and the solvent removed in vacuo to give a solid which was triturated with a mixture of methanol and diethyl ether. N 20 (1 - Cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 5 chlorobenzamide (8 g) was thus obtained.

The hydrochloride was prepared by addition of a saturated ethanolic solution of hydrogen chloride to a solution of the base in ethanol. Recrystallization from ethanol gave a white solid, melting point 225°— 227°C (dec.).

Also prepared in a similar manner were: N - (1 - cyclopentylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino 5 - chlorobenzamide hydrochloride, m.p. 226°—227°C; N - (1 - cyclobutylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 11 44610 - chlorobenzamide hydrochloride, m.p. 240°—242°C; N - {1 - (1 - adamantyl)methylpiperid - 4- yl} - 2- methoxy - 4 amino - 5 - chlorobenzamide hydrochloride, m.p. 259°—260°C; N - (1 - cycloheptylmethylpiperid -4-yl) - 2 - methoxy - 4 - amino 5 5 - chlorobenzamide hydrochloride, m.p. 218°—220°C; N - (1 - cyclohexylmethylpiperidin -4-yl) - 2 - methoxy - 4 - amino 5 - bromobenzamide hydrochloride, m.p. 229—230°C; N - (1 - cyclohexylmethylpiperid -4-yl) - 2 - methoxy - 4 - acetamido - 5 - chlorobenzamide hydrochloride monohydrate, m.p. 219— 221°C; N - (1 - cyclohexylmethylpiperid -4-yl) - 2 - methoxy - 5 - chlorobenzamide hydrochloride, m.p. 231°—233°C; N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 5 - sulphamoylbenzamide hydrochloride, m.p. 237°—238°C; N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - trifluoroacetamido - 5 - chlorobenzamide hydrochloride, m.p. 218°—220°C (dec); N - (1 - cyclohexylmethylpiperid -4-yl) - 2 - methoxy - 5 - methylsulphonylbenzamide hydrochloride, m.p. 215°—218°C (dec); N - {1 - (4 - methyl cyclohexylmethylpiperid - 4-yl}-2 - methoxy 4 - amino - 5 - chlorobenzamide hydrochloride, m.p, 229°—230°C; N - {1 - (1 - cyclohexyl)ethylpiperid - 4- yl} - 2- methoxy - 4 amino - 5 - chlorobenzamide hydrochloride, m.p. 225°—227°C; N - (1 - cyclohexylmethylpiperid -4-yl) - 2 - ethoxy - 4 - acetamido 25 5 - chlordbenzamide, the fumurate of which melts at 189°—191°C; N - (1 - cyclohexylmethylpiperid - 4- yl) - 2 - ethoxy - 4 - amino 5 - chlorobenzamide hydrochloride, m.p. 242°—243°C; N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4,5 - diaminobenzamide dihydrochloride, m.p. 270°—272°C (dec); N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - dimethyl- 12 44610 amino - 5 - chlorobenzamide, the fumarate of which melts at 187— 188°C; N - ( 1 - cyclohexylmethylpiperid -4-yl) - 2 - methoxy - 4 - methylamino - 5 - chlorobenzamide, the fumarate of which melts at 216°— 218°C, and N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - allyloxy - 4 - amino 5 - chlorobenzamide hydrochloride, m.p. 212°—214°C.

The fumarates of certain piperidine derivatives indicated above were prepared by the procedure described in subsequent Example 9 illustrating the preparation of the fumarate of fi - (1 - cyclohexylmethylpiperid -4-yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide.

EXAMPLE 2 To a solution of 1 - cyclohexylmethyl - 4 - aminopiperidine (9.8 g; 0.05 moles) in methyl ethyl ketone (100 ml), a solution of 2 - methoxy - 4 - acetamido - 5 - chlorobenzoyl chloride (14.4 g, 0.055 moles) in methyl ethyl ketone (100 ml) was slowly added at a temperature between 0° and 5°C. The mixture was stirred at the same temperature for 1 hour followed by 4 hours at room temperature. The precipitated solid was filtered off, washed with methyl ethyl ketone and recrystallized from a mixture of ethanol-water to give N - (1 - cyclohexylmethylpiperid 4-yl) - 2 - methoxy - 4 - acetamido - 5 - chlorobenzamide hydrochloride monohydrate (21 g), m.p. 219—221°C.

Also prepared in a similar manner was N - (1 - cyclohexylmethylpiperid -4-yl) - 2 - methoxy - 4 - trifluoroacetamido - 5 - chlorobenzamide hydrochloride, m.p. 218°—220°C (dec).

EXAMPLE 3 A mixture of N - (1 - cyclohexylmethylpiperid -4-yl) - 2 methoxy - 4 - acetamido - 5 - chlorobenzamide hydrochloride monohydrate (10 g; 0.02 moles), concentrated hydrochloric acid (6 ml) and water - 13 446i° (20 ml) was boiled under reflux for 1.5 hours. The solution was then made alkaline with sodiun hydroxide solution and extracted with chloroform. The organic solution was dried (Na2S0i,) and the solvent removed in vacuo to give N - (1 - cyclohexylmethylpiperid -4-yl) - 2 methoxy - 4 - amino - 5 - chlorobenzamide (7.1 g), m.p. 213°—215°C after recrystallization from methanol.

The base was converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride. The solid obtained melted at 225&—227°C (dec).

EXAMPLE 4 A mixture of N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 methoxy - 4 - trifluoroacetamido - 5 - chlorobenzamide (8.1 g; 0.017 moles), ethanol (25 ml), water (15 ml) and 8N sodium hydroxide aqueous solution (25 ml) was stirred for 12 hours at room temperature. After dilution with water, the mixture was extracted with chloroform and the chloroformic solution dried (Na2SOiJ and evaporated in vacuo. N - (1 Cyclohexylmethyl - pi peri d -4-yl) - 2 - methoxy - 4 - amino - 5 chlorobenzamide (5 g) was obtained. It was converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride; the hydrochloride melted at 225°·—227°C (dec).

EXAMPLE 5 A mixture of methyl 2 - methoxy - 4 - acetamido - 5 - chlorobenzoate (25.7 g; 0.1 moles), xylene (80 ml), 1 - cyclohexylmethyl - 4 aminopiperidine (21.6 g; 0.11 moles) and aluminium isopropoxide (5 g) was heated to the boiling point whilst methanol was distilled off as it was formed. When the theoretical quantity of methanol was removed, the xylene was distilled off and the residue was dissolved in 2N hydrochloric acid (200 ml). The aqueous solution was made alkaline with sodium hydroxide solution, extracted with chloroform and the chloro- 14 formic layer evaporated to dryness to give N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - acetamido - 5 - chlorobenzamide (27 g). Its hydrochloride monohydrate was prepared by the procedure described in Example 1, m.p. 219°— 221°C.

EXAMPLE 6 N,N' - dicyclohexylcarbodiimide (10.3 g; 0.05 moles) and 1 cyclohexylmethyl - 4 - aminopiperidine (9.8 g; 0.05 moles) were added successively to a solution of 2 - methoxy - 4 - acetamido - 5 - chlorobenzoic acid (12.1 g; 0.05 moles) in methylene chloride (250 ml).

After stirring overnight at room temperature, the insoluble N.hT - dicyciohexyl urea was filtered off, the solution was washed with water, dried (NaaSOj and the solvent removed in vacuo. The residue was recrystallized and the product converted into its hydrochloride to give 14.2 g of N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy 4 - acetamido - 5 - chlorobenzamide hydrochloride monohydrate, m.p. 219°—221 °C.

EXAMPLE 7 To a warm solution of N - (1 - cyclohexylmethylpiperid - 4 - yl) 2 - methoxy - 4 - acetamido - 5 - chlorobenzamide (10 g; 0.023 moles) in diethyl ether (300 ml) a solution of methyl iodide (1.8 ml; 0.033 moles) in diethyl ether (25 ml) was added. The mixture was stirred at room temperature for 1 hour and then heated under reflux for 2 hours. An additional amount of methyl iodide (1 g; 0.0023 moles) was added and the reflux of the mixture was kept up for 3 more hours. The mixture was then evaporated in vacuo and the residue recrystallized from a mixture of diethyl ether-ethanol. N - (1 - Cyclohexylmethylpiperid 4 - yl) - 2 - methoxy - 4 - acetamido - 5 - chlorobenzamide methyl iodide (10.5 g), m.p. 209°—211°C, was thus obtained. - 15 44610 EXAMPLE 8 To a solution of N - (1 - cyclohexylmethylpiperid -4-yl) - 2 methoxy - 4 - acetamido - 5 - chlorobenzamide (lOg; 0.023 moles) in glacial acetic acid (50 ml) a 30% hydrogen peroxide solution (6 ml) was added. The mixture was heated for 8 hours at a temperature between 70° and 80°C. Afterwards the solvent was evaporated in vacuo, and N - (1 cyclohexylmethylpiperid - 4- yl) - 2 - methoxy - 4 - acetamido - 5 chlorobenzamide N - oxide was obtained as a viscous liquid. After recry stall is ation from a mixture of acetone and diethyl ether, there was obtained 7.3 g of the N-oxide, melting at 206°—208°C.

EXAMPLE 9 To a hot solution of N - (1 - cyclohexylmethylpiperid -4-yl) 2 - methoxy - 4 - amino - 5 - chlorobenzamide (5 g; 0.013 moles) in ethanol (30 ml) there was added fumaric acid (1.7 g; 0.014 moles). The hot mixture was stirred until complete dissolution. After cooling N (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 5 chlorobenzoic fumarate crystallized: yield 6.3 g, m.p. 229°—231°C.

The following Examples illustrate pharmaceutical compositions accord ing to the present invention and procedures for their preparation.

EXAMPLE 10 100,000 Tablets each containing 2 mg of N - (1 - cyclohexylmethy1piperid -4-yl) - 2 - methoxy - 4 - amino - 4 - chlorobenzamide hydrochloride were prepared from the following formulation: N - (1 - cyclohexylmethylpiperid - 4- yl) - 2 25 methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride 200 microcrystalline cellulose 1870 lactose spray dried 9880 carboxymethyl starch 430 sodium stearyl fumarate 60 colloidal silicon dioxide 60 - 16 44610 Procedure: All the powders were passed through a screen with an opening of 0.5 nan. They were then all mixed in a '.uitable mixer for i’ll minute·, and compressed into 125 mg cablets using 6 mm. discs and flat bevelled punches. The disintegration time of the tablets was about 60 seconds.

EXAMPLE 11 100,000 Capsules each containing 1 mg of N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride were prepared from the following formulation: N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride 100 g lactose 9000 g sodium lauryl sulphate 370 g corn starch 8000 g alpine talc 530 g Procedure: The above ingredients were sieved through a 40 mesh sieve, then mixed in a suitable mixer and distributed into 100,000 gelatine capsules (180 mg).

EXAMPLE 12 ,000 Suppositories each containing 5 mg of N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride were prepared as follows: N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 methoxy - 4 - amino - 5 - chlorobenzamide hydrochibri de 50 g theobroma oil 19950 g - 17 44610 Procedure: The theobroma oil was melted and the N - (1 - cyclohexylmethylpiperid - 4 - yl) - Z - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride suspended in it. The mixture was then poured into appropriate suppository moulds to make 2.0 g suppositories.

EXAMPLE 13 50,000 Ampoules each containing 2 mg of N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride were prepared from the following formulation: N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride 100 g sodium chloride 500 g water injectable grade q.s. 100 litres.

Procedure: The N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - chlorobenzamide hydrochloride and the sodium chloride were dissolved in approximately 80 litres of water with slight heating. The solution was diluted with water to 100 litres, passed through a bacteria retaining filter and filled into 2 ml glass ampoules in known manner.

The production of the injectable solution can take place under sterile conditions. It is also possible to work under normal conditions and then to heat-sterilize the filled ampoules.

EXAMPLE 14 1,000 Bottles of 150 ml each containing 75 mg of N - (1 - cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride were prepared as follows: N - (1 - cyclohexylmethylpiperid - 4 - yl) 2 - methoxy - 4 - amino - 5 - chlorobenz- 18 amide hydrochloride sorbitol sorbic acid citric acid distilled water q.s. flavouring agent g 70000 g 150 litres q.s.

Procedure; The N - (1 - cyclohexylmethylpiperid -4-yl) - 2 - methoxy 4 - amino - 5 - chlorobenzamide hydrochloride and the sorbic acid were dissolved in 100 litres of water and then the sorbitol, citric acid and flavouring agent were added with stirring until dissolution. The mixture was diluted to 150 litres and divided amongst the bottles.

Similar compositions to those described in Examples 10 to 14 can be prepared having as the active ingredient piperidine derivatives of general formula I other than N - (1 - cyclohexylmethylpiperid - 4- yl) 2 - methoxy - 4 - amino - 5 - chlorobenzamide, for example other products conforming to that formula mentioned in Examples 1, 2 and 5 to 8.

The piperidine derivatives of general formula VI are new compounds and as such constitute another feature of the present invention. - 19 •14 610

Claims

1. Piperidine derivatives of the general formula:- {wherein R represents a lower alkoxy or lower alkenyl oxy group; R 1 and

2. Piperidine compounds according to claim 1 wherein v represents it'ro omt W represent·· a single bend.

3. Piperidine compounds according to claim 1 or 2 in which R 1 re5 presents a halogen atom, or a group as specified in claim 1, attached to the 4-position of the phenyl ring.

4. Piperidine derivatives of the general formula: IV {wherein R' represents a lower alkoxy or allyloxy group, R 1 ' represents 10 a hydrogen atom, or an amino, lower alkylamino, di(lower)alkyl ami no or a lower acylamino group, R 2 ' represents a halogen atom, or an amino, sulphamoyl or lower alkylsulphonyl group, R 3> represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, and R 4 ' represents a cycloalkyl group optionally substituted by an alkyl group containing 15 1 to 3 carbon atoms} and pharmaceutically-acceptable acid addition salts thereof. 5. Cyclohexyl group optionally substituted in the 4-position by an alkyl group containing 1 to 3 carbon atoms or a hydroxy(lower)alkyl or lower alkenyl group, and W represents a group —(CH2)y— wherein y represents zero or an integer from 1 to 5. 10

5. Piperidine derivatives according to claim 4 wherein when a lower alkoxy group represents methoxy or ethoxy; R 1 (i) when a lower alkylamino group represents methylamino, (ii) when a di(lower)alky1amino 20 group represents dimethyl amino, or (III) when a lower acylamino group represents a lower alkanoylamino group; R 2 (i) when a halogen atom represents chlorine or bromine, or (II) when a lower alkylsulphonyl group represents methylsulphonyl; R 3 when an alkyl group represents methyl, and R 4 represents a cycloalkyl group optionally substituted by 25 a methyl group, and pharmaceutically-acceptable acid addition salts thereof. - 21 44610 5 R z , which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl, amino, lower alkylamino, di(lower)alkylamino, lower alkyl sulphonyl or lower alkylsulphamoyl group, or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid, the halogen atom or group represented by the symbol R 1 being in 10 the 3- or 4-position of the phenyl ring, with the proviso that R 1 and R z do not both represent hydrogen atoms; R 3 represents a hydrogen atom or a lower alkyl, lower alkenyl or phenyl group, or a cycloalkyl or cycloalkenyl group having from 3 to 7 carbon atoms in the ring; R 1 * represents a cycloalkyl group having from 3 to 7 carbon atoms in the ring 15 optionally substituted by an alkyl group containing 1 to 3 carbon atoms or a hydroxy(lower)alkyl or lower alkenyl group, or R 1 * represents an adamantyl group or a group of the formula:- II ΠΙ wherein R 5 and R 6 each represent a hydrogen atom or a methyl group, or 20 a grouping of formula II or III containing a double bond between two of the carbon atoms in the cyclohexyl ring; x represents zero or 1, and W represents a single bond or a lower alkylene or lower alkenylene group with the proviso that when W is a single bond R 3 is other than a cycloalkenyl group} and pharmaceutically-acceptable acid addition salts and - 20 ϊ 4 6 1 ο quaternary amsonium derivatives and N-oxides thereof.

6. Piperidine derivatives according to claim 4 or t> wherein R 1 ' represents the acetamido or trifluoroacetamido group.

7. Piperidine derivatives according to claim 1 wherein R* represents a cyclobutyl, cyclopentyl, cycloheptyl or adamantyl group, or a

8. , N - (1 - Cyclohexylmethylpiperid) - 4 - yl) - 2 - methoxy - 4 amino - 5 - chlorobenzamide.

9. N - (1 - Cyclohexylmethylpiperid) -4-yl) - 2 - methoxy - 4 acetamido - 5 - chlorobenzamide. 10. N - (1 - Cyclohexylmethylpiperid) -4-yl) - 2 - methoxy - 4 15 trifluoroacetamido - 5 - chlorobenzamide. 11. N - (1 - Cyclohexylmethylpiperid - 4 - yl) - 2 - ethoxy - 4 amino - 5 - chlorobenzamide. 12. N - (1 - Cyclopentyl methyl pi peri d -4-yl) - 2 - methoxy - 4 amino - 5 - chlorobenzamide. 20 13. N - (1 - Cyclobutylmethylpiperidin - 4- yl) - 2 - methoxy 4 - amino - 5 - chlorobenzamide. 14. N - {1 - (1 - Adamantyl)methylpiperid - 4-yl}-2 - methoxy 4 - amino - 5 - chlorobenzamide. 15. N - (1 - Cycloheptylmethylpiperid -4-yl) - 2 - methoxy 25 4 - amino - 5 - chlorobenzamide. 16. N - (1 - Cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy 4 - amino - 5 - bromobenzamide. 17. N - (1 - Cyclohexylmethylpiperid -4-yl) - 2 - methoxy - 5 chlorobenzamide. 30 18. N - (1 - Cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 5 - 22 ^4610 sulphonami dobenzami de. 19. N - (1 - Cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 5 methylsulphonylbenzamide. 20. N - {1 - (4 - Methylcyclohexyl)methylpiperid - 4 - yl} - 2 methoxy - 4 - amino - 5 - chlorobenzamide. 21. N - {1 - (1 - Cycl ohexyl ethyl) piperid -4-yl}-2- methoxy 4 - amino - 5 - chlorobenzamide. 22. N - (1 - Cyclohexylmethylpiperid - 4 - yl) - 2 - ethoxy - 4 acetamido - 5 - chlorobenzamide. 23. N - (1 - Cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy 4,5 - di aminobenzamide. 24. N - (1 - Cyclohexylmethylpiperid -4-yl) - 2 - methoxy - 4 dimethylamino - 5 - chlorobenzamide. 25. N - (1 - Cyclohexylmethylpiperid - 4 - yl) - 2 - methoxy - 4 methylamino - 5 - chlorobenzamide. 26. N - (1 - Cyclohexylmethylpiperid - 4 - yl) - 2 - allyloxy - 4 amino - 5 - chlorobenzamide. 27. Pharmaceutically-acceptable acid addition salts of a compound claimed in arty one of claims 8 to 26. 28. Pharmaceutically-acceptable quaternary ammonium derivatives of a compound claimed in any one of claims 8 to 26. 29. The N-oxide of a compound claimed in any one of claims 8 to 26. 30. A process for the preparation of a piperidine derivative as claimed in claim 1 which comprises reacting a reactive derivative of a benzoic acid of the general formula:Ό0Η (wherein R, R 1 and R 2 are as defined in claim 1) with a piperidin deri- 23 vative of the general formula: H 2 N-(CH 2 } x N-CH-W-R 4 VI wherein the various symbols are as defined in claim 1. 31. A process according to claim 30 in which the reactive derivative of the benzoic acid is a halide, and alkyl ester, anhydride, a mixed anhydride, the N - imidazolamide or acid azide. 32. A process according to claim 30 or 31 in which the reaction is carried out in an inert organic solvent at a temperature between -5° and 120°C. 33. A modification of the process claimed in claim 30 in which the benzoic acid of general formula V is reacted with the piperidine derivative of general formula VI in the presence of a dehydrating agent. 34. A process according to claim 33 in which the dehydrating agent is silicon tetrachloride, a mono-, di- or trialkyl-silyl chloride, titanium tetrachloride, Ν,γΓ - dicyclohexyl - carbodiimide, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene -£- sulphonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent. 35. A process according to claim 33 or 34 in which the reaction is carried out in an inert organic solvent at a temperature between 20° and 110°C. 36. A process for the preparation of a piperidine derivative of the general formula specified in claim 1 or an acid addition salt or quaternary airenonium derivative or N-oxide thereof substantially as hereinbefore described viith especial reference to any one of Examples 1 to 9. 37. Pharmaceutical compositions which comprise, as active ingredient, at least one piperidine derivative as claimed in any one of claims - 24 1 to 26, or a non-toxic pharmaceutically-acceptable acid addition salt or quaternary ammonium derivative or N-oxide thereof, in association with a pharmaceutically-acceptable carrier or diluent. 38. Pharmaceutical compositions according to claim 37 substantially 5 as hereinbefore described with especial reference to any one of Examples 10 to 14. 39. Piperidine derivatives of the general formula:h 2 n-(ch 2 ) x / wherein R 3 , R 1 *, x and W are as defined in claim 1.

10. 40. 1 - Cyclohexyl methyl - 4 - aminopiperidine, 1 - cyclopentylmethyl - 4 - aminopiperidine, 1 - cyclobutylmethyl - 4 - aminopiperidine, 1-(1- adamantylmethyl) - 4 - aminopiperidine, 1-(4- methylcyclohexylmethyl) - 4 - ami nopiperidine and 1 - cycloheptylmethyl - 4 aminopiperidine.