IE44611B1 - Piperidine derivatives - Google Patents

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 5 are those compounds of the general formula: {wherein R represents a lower alkoxy or lower alkenyloxy 1 2 group; R and R , which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl TO amino, lower alkylamino, di(1ower)alkylamino, lower alkylsulphony! or lower alkysulphamoyl 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 / being in the 3- or 4-position of the phenyl ring (preferably in the 4-position), with the 1 2 proviso that R and R do not both represent hydrogen 3 atoms; R 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 cycloalkenyl group having from -21 J (ί t ( 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; x represents zero or 1, and W represents a single bond or a lower alkylene (e.g. -CHg- or -CH9-CH,-) or lower alkenylene (e.g. -CH=CH- or - CHg-CH=CH-) group^J and pharmaceutically acceptable acid addition salts and quaternary ammonium derivatives 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 definitions of R3 and R4 may have one, two or three double bonds as is appropriate for the number of carbon atoms in the ring.

The cycloal kenyl groups may be, for example, cyclopentenyl, cyclohexenyl and cycloheptenyl with one double bond present, cyclohexadienyl (preferably cyclohexa - 1,4 dienyl optionally substituted by an alkyl group containing 1 to 3 carbon atoms) and cycloheptatrienyl.

Preferred compounds of general formula 1 are those of the more specific formula: -34 4 611· [wherein R‘ represents a lower alkoxy (preferably methoxy or ethoxy) or allyloxy group, R^ represents a hydrogen atom, or an amino, lower alkylamino (preferably methyl amino), di(1ower)alkylamino (preferably dimethylamino) or a lower acylamino (preferably lower alkanoylamino, e.g. acetamido or trifluoro-acetamido) group, R 1 represents a halogen preferably chlorine or bromine) atom, or an amino, sulphamoyl or lower alkylsulphonyl (preferably methylsulphony!) group, R 1 represents a hydrogen atom or a lower alkyl (preferably methyl )J group and R4' represents a cycloalkenyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms (preferably methyl) and pharmaceutically acceptable acid addition salts thereof.

Other piperidine derivatives of general formula I of interest are those wherein R represents a cyclopentenyl, cyclohexadienyl or cycloheptenyl group, or a cyclohexenyl 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 (CHgJy - wherein y represents zero or an integer from 1 -414 61 t to 5, And R, R1, R‘, RJ and \ are as hereinbcfere defined.

Of outstanding importance are those compounds of general Λ formula II wherein R 1 represents the cyclohexa - 1 ,4 5 dienyl grout optionally substituted by a methyl group and, in particular, N - [Ϊ - cyclohexa - 1 * ,4’ - dienyl”1 methyl piperid - 4 - ylj -2-- methoxy - 4 - amino - 5 chlorobenzamide, N - j? - cyclohexa - I1,4' - dienylmethylpiperid - 4 - ylj - I - methoxy - 4 - methyl ami no 10 5 - chlorobenzamide, N - jj - cyclohexa - l',4‘ dienylmethylpiperid - 4 - yl} - 2 - methoxy - 4 - acetamido - 5 - chlorobenzamide and H -(1-(4- methyleyclohexa 1,4 - dienyl) - methylpiperid - 4 - yj} - 2 - methoxy 4 - amino - 5 - chlorobenzamide, 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 formula:// \-COOH III R 2 (wherein R, R and R are as hereinbefore defined) with a piperidine derivative of the general formula:R3 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 IV 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 hy reductive amination of corresponding piperid - 4 - ones -64 ·ί S 1 1 dissolved in an organic solvent, e.g. an a'.olic-l containing up to 6 carbon atoms, in tne presence of Raney nickel or platinum as catalyst. The piperidine 4 derivatives of general formula IV wherein R and /or R represent(s) a cyclohexadienyl group can be prepared from a correspond!ng phenyl derivative of that formula 3 4 wherein R and /or R represent^; a phenyl group by reduction with lithium in the presence of liquid ammonia or a lower alkylamine. The piperidine derivatives of general formula IV wherein x is 1 can be prepared by known reductive methods starting from corresponding 4 cyanopiperidines.

Halides of the benzoic acids of general formula III can be prepared by reaction of the acid 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 of general formula III can be prepared by the reaction of the acid with, for example, an alkyl chioroformate 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 III which may be employed as starting materials in the -744611 aforementioned process, can be prepared from the benzoic acids by methods known per se, as can also the N imidazolamides or acid azides of the acids.

The piperidine derivatives of general formula 1 are 5 also prepared, according to a further feature of the invention, by the direct reaction of a benzoic acid of general formula III with a piperidine derivative of general formula IV in the presence of an appropriate dehydrating agent. Such agents are silicon tetrachloride, a mono-, di- or trialkyl - silyl chloride, titanium tetrachloride, N,N' - dicyclohexyl - carbodiimide, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene - p - 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 ' 2 I wherein the symbol(s) R and/or R represents(s) an amino group by the aforementioned processes, it is sometimes advisable to protect the amino group(s) of the acid of general formula III or derivative thereof before reacting the compound with the piperidine derivative of general formula IV. In this case an N - acyl derivative -84 4 611 of the amino - substituted benzoic acid of general formula III 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 III, or reactive derivative thereof, the piperidine derivative of general formula IV, the correspond!ng 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 R and/or R 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 aqueous - alcoholic 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 -g. effects 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 tranquillizing agents. They may be useful for the treatment of nausea and vomiting resulting from gastrointestinal disorders, congestive heart failure, post-operative 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 supressant is warranted.

For therapeutic purposes the piperidine derivatives of general formula I may be employed in the form of nontoxic pharmaceutically-acceptable inorganic or organic acid addition salts such a sulphates, hydrohalides, phosphates, lower alkanesulphonates, arylsulphonates, salts or aliphatic mono, di- or tri-basic acids of from 1 to 20 carbon atoms which may contain one or more double bonds, an aryl nucelus or other functional group such as hydroxy, amino or keto; salts of aromatic acids in -104 4611 which the aromatic nucleus may optionally be substituted by groups such as hydroxy, lower alkoxy, anrino, mono·or di - (lower)alkylamino and sulphonamido groups.

They may also be employed in the form of pharmaceutically5 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.

The pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives of the piperdine 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 thereof, in association with a pharmaceutically-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 -114461k per se and the actual excipients used 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 compositions 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 ammonia derivative thereof.

The liquid compositions adapted for oral use may be in the form of solutions or suspensions. The solutions may be acqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspension may comprise a water insoluble active compound of the -1244611 invention or an acid addition salt or quaternary ammonium derivative thereof in association with water, together with a suspending agent and flavouring agent.

Compositions for parenteral injection may be prepared 5 from water-soluble salts, which may or may not be freezedried, 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 compounds of the present invent!on.

REFERENCE EXAMPLE A solution of lithium (5 g; 0.7 g.at.) in liquid ammonia (250 ml.) was added little by little to another solution of 1 - benzyl - 4 - aminopiperidine (50 g.; 0.264 moles) in anhydrous diethyl ether (100 ml.) After stirring for half an hour, absolute ethanol (180 ml.) was added little by little, the solvent removed in vacuo and the residue -134 4 611 taken up with water. The aqueous solution was extracted with diethyl ether and the organic layers dried and distilled in vacuo to give 1 - cyclohexa I1,4' - dienylmethyl - 4 - aminopiperidine (48 g.), b.p. 117° - 118°C./0.5 mm. Hg.

Also prepared in a similar manner were: 1-(4- methylcyclohexa - 1,4 - dienyl) - methyl 4 - aminopiperidine, b.p. 104° - 106°C./0.07 mm. Hg.; 1-(1- cyclohexa - 11,41 - dienyl - ethyl) - 4 - amino10 piperidine, b.p. 103° - 105°C./0.08 mm. Hg. and - cyclohex - 3' - en - ylmethyl - 4 - aminopiperidine, b.p. 101° - 103°C./0.05 mm. Hg.

EXAMPLE 1 Triethylamine (7.0 ml.; 0.05 moles) and ethyl chloroformate 15 (4.8 ml.; 0.05 moles) were added successively to a stirred suspension of 2 - methoxy - 4 - amino - 5 chlorobenzoic acid (10.1 g.; 0.05 moles) in 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 cyclohexa - 1*,4’ - dienylmethyl - 4 - aminopiperidine -144 4 611 (9.6 g.; 0.05 moles) in anhydrous tetrahydrofuran (50 ml.) was added; the temperature was maintained at -5° to -10°C. for i hour and then the resat ion ii\ture was allowed to stand overnight at room temperature.

The solvent was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layers washed with water. The chloroform solution was dried (NagSO^) and the solvent removed in vacuo to give a solid which was triturated with a mixture of methanol and diethyl ether, N - (1 - cyclohexa - 1', 4' dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino 5 - chlorobenzamide (12.2 g.) was obtained.

The hydrochloride monohydrate was prepared by addition of a saturated ethanolic solution of hydrogen chloride to a solution of the base in ethanol. Recrystallization of the precipitate from ethanol gave a while solid, m.p. 226° - 227°C. (dec.) Also prepared in a similar manner were: N - (1 - cyclohexa - l',4' - dienylmethyl - piperid ZO 4 - yl) - Z - methoxy - 5 - methyl - sulphonyl benzamide hydrochloride, m.p. Z09° - 211°C. (dec.); N - (1 - cyclohexa - 1' ,4* - dienylmethyl piperid - 4 yl) - 2 - methoxy - 5 - chiorcbenzamide hydrochloride, -154 4 61 1 m.p. 231° - 233°C.; N - (1 - cyclohexa - l',4‘ - dienylmethyl - piperid 4 - yl) - 2 - methoxy - 4 - amino - 5 - bromobenzamide hydrochloride, m.p. 215°C. (dec.); N - (1 4 cyclohexa - I1,4' - dienylmethyl - piperid 4 - yl) - 2 - methoxy - 5 - sulphamoylbenzamide hydrochloride, m.p. 230° - 231°C. (dec.); N - (1 - cyclohexa - T, 4' - dienylmethyl-piperid - 4 yl) - 2 - methoxy - 4 - acetamido - 5 - chlorobenzamide hydrochloride monohydrate, m.p. 193 - 195°C.; N - (j - (4 - methylcyclohexa - 1,4 - dienyl) methylpiperid - 4 - ylj - 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride, m.p. 246° - 248°C. (dec.); N - [l - (1 - cyclohexa - l1,4' - dienylethyl)piperid 15 4 - yll - 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride, m.p. 241° - 242°C.(dec.); N - [l - (1 - cyclohexa - 1' ,4' - dienylethyl )piperidy 4 - yl] - 2 - ethoxy - 4 - acetamido - 5 - chlorobenzamide, the fumarate of which melts at 171° - 173°C.; N - Π - (1 - cyclohexa -1^41 - dienylethyl )piperid - 4 -164 4 6 1 1 ylj · 2 - ethoxy - 4 - amino - 5 - chlorobenzamide hydrochloride, m.p. 264° - 266°C.; N - (1 - cyclohexa - l',4‘ - dienylmethylpiperid 4 - yl) - 2 - methoxy - 4,5 - diaminobenzamide dihydrochloride monohydrate m.p. 240° - 24Z°C.; N - (1 - cyclohexa - 11,4' - dienylmethylpiperid - 4 yl) - 2 - methoxy - 4 - dimethyl ami no - 5 - chlorobenzamide, the fumarate of which melts at 182° - 184°C.; N - (1 - cyclohexa - l',4' - dienylmethylpiperid - 4 10 yl) - 2 - methoxy - 4 - methylamino - 5 - chlorobenzamide, the fumarate of which melts at 203° - 205°C.; N - (1 - cyclohexa - 1' ,4' - dienylmethylpiperid - 4 yl) - 2 - allyloxy - 4 - amino - 5 - chlorobenzamide hydrochloride, m.p. 180°-l82°C.; N - (1 - cyclohexa - l',4' - dienylmethylpiperid - 4 yl) - 2 - ethoxy - 4 - amino - 5 - chlorobenzamide hydrochloride, m.p. 247°-249°C.; N - (1 - cyclohexa - l',4' - dienylmethylpiperid - 4 yl) - 2 - ethoxy - 4 - acetamido - 5 - chlorobenzamide, the fumarate of which melts at 17 3° -1 75° C., and -174 4 6.11 Ν - (1 - cyclohex - 3' - en - ylmethyl - piperid 4 - yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide, m.p. 189 - 191°C.

The fumarates of the piperidine derivatives mentioned 5 above were obtained by adding fumaric acid to a hot ethanolic solution of the piperidine base, the amount of added acid being substantially equimolecular to that of the piperidine base present, stirring the hot mixture until dissolution, and then cooling the resulting solution to crystallize the fumarate.

EXAMPLE 2 To a warm solution of N - (1 - cyclohex - 3' - en ylmethylpiperid -4-yl) - 2 - methoxy - 4 - amino 5 - chlorobenzamide (3.5 g; 0,0093 moles) in acetone (75 ml.) a solution of methyl iodide (2.63 g.; 0.0185 moles) in acetone (25 ml.) was slowly added. The mixture was stirred at room temperature for 12 hours and then heated under reflux for 4 more hours. The mixture was then concentrated in vacuo to a small volume 20 and the residue filtered off to give N - (1 - cyclohex 3' - enylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - chlorobenzamide methyl iodide (4 g.), m.p. 231 - 233°C. (dec.) after recrystallization from a mixture of ethanol-water. -184 1611 The following Examples illustrate pharmaceutical compositions according to the present invention and procedures for their prepareation.

EXAMPLE 3 100,000 Tablets each containing 2 mg. of N - (1 cyclohexa - 1' ,4' - dienylmethyl - piperid - 4 - yl) 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride monohydrate were prepared from the following formulation: N - (1 - cyclohexa - 11,41 10 dienylmethylpiperid - 4 yl) - 2 - methoxy - 4 amino - 5 - chlorobenzamide hydrochloride monohydrate 200 g. microcrystalline cellulose 1870 g. lactose spray dried 9880 g. carboxymethyl starch 430 g. sodium stearyl fumarate 60 g. colloidal silicon dioxide 60 g.

Procedure: All the powders were passed through a screen with an opening of 0.6 mm. They were then all mixed in a suitable mixer for 20 minutes and compressed into 125 mg. tablets -1944611 using 6 mm. discs and flat bevelled punches. The disintegration time of the tablets was about 60 seconds.

EXAMPLE 4 100,000 Capsules each containing 1 mg. of N - (1 cyclohexa - I1,4' - dienylmethyl - piperid - 4 - yl) 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride monohydrate were prepared from the following formulation: N - (1 - cyclohexa - l',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride monohydrate 100 9 lactose 9000 g 15 sodium lauryl sulphate 370 g corn starch 8000 g alpine talc 530 g Procedure The above ingredients were sieved through a 40 mesh 20 sieve, then mixed in a suitable mixer and distributed into 100,000 gelatine capsules (180 mg). -20•ϊ J 6 1 1 ,000 Suppositories each containing 5 mg. of N - (1 cyclohexa - 1 1,4’ - dienylmethyl-piperid - 4 - yl) 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydro5 chloride monohydrate were prepared as follows: N - ( 1 - cyclohexa - 1' ,4‘ dienylmethylpiperid -4-yl) 2 - methoxy - 4 - amino - 5 chlorobenzamide hydrochloride monohydrate 50 g. theobrome oil 19950 g.

Procedure The theobroma oil was melted and the N - (1 - cyclohexa l',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 15 amino - 5 - chlorobenzamide hydrochloride monohydrate suspended in it. The mixture was then poured into appropriate suppository moulds to make 2.0 g. suppositories.

EXAMPLE 6 50,000 Ampoules each containing 2 mg. of N - (1 - cyclohexa 1' ,4* - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino 5 - chlorobenzamide hydrochloride monohydrate were prepared from the following formulation. -214 4 6 11 Ν - (1 - cyclohexa - 1' ,4' dienylmethylpiperid - 4 yl) - 2 - methoxy - 4 amino - 5 - chlorobenzamide hydrochloride monohydrate 100 g sodium chloride 500 g water injectable grade q.s. 100 litres Procedure The N - (1 - cyclohexa - 11,4' - dienylmethylpiperid 10 4 - yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride monohydrate 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 filler ampoules.

EXAMPLE 7 1,000 Bottles of 150 ml. each containing 75 mg. of N (1 - cyclohexa - 1‘,4' - dienylmethylpiperid - 4 - yl) 2 - methoxy - 4 - amino - 5 - chlorobenzamide hydrochloride monohydrate were prepared as follows: -2244611 N - (1 - eye 1 ohe\a - 1 1 ,·ί dienylmethylpiperid - 4 yl) - 2 - methoxy - 4 - amino 5 - chlorobenzamide hydrochloride monohydrate 75 9 · sorbi tol 70000 g· sorbic acid 125 g· citric acid 125 g. disti1 led water q.s. 150 1i tres flavouring agent q.s.

Procedure The N - (1 - cyclohexa - 1 1 ,4' - dienylmethyl pi perid 4 - yl) - 2 - methozy - 4 - amino - 5 - chlorobenzamide hydrochloride monohydrate 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 3 to 7 can be prepared having as the active ingredient piperidine derivatives of general formula I other than N - (1 - cyclohexa - 1 ' ,4' - dienylmethylpiperid - 4 yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide, for example other products conforming to that formula mentioned in Example 1. -2344611 The piperidine derivatives of general formula IV are new compounds and as such constitute another feature of the present invention.

Claims (39)

1. WHAT WE CLAIM IS:5 1. Piperidine derivatives of the general formula:- 0herein R represents a lower alkoxy or lower alkenyloxy group; R 1 and R 2 , which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl, amino, lower alkylamino, di(lower) 10 alkylamino, lower alkylsulphonyl 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 the 3- or 4-position of the phenyl ring, with the proviso 1 2 15 that R and R do not both represent hydrogen atoms; -24R 3 represents a hydrogen atom or a lower alkyl, lower alkenyl, or phenyl group, or a c.vcloalkyl or ι \ ν 1 oal krin 1 group having from 3 to 7 carbon atoms in the ring; R* 1 represents a cycloalkenyl group having from 3 to 7 carbon 5 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; x represents zero or 1, and W represents a single bond or a lower alkylene or lower alkenylene groupj and pharmaceutically-acceptable acid addition salts 10 and quaternary ammonium derivatives thereof.

2. Piperidine compounds according to claim 1 wherein x represents zero and W represents a single bond.

3. Piperidine compounds according to claim 1 or 2 in which R 1 represents a halogen atom, or a group as specified 15 in claim 1, attached to the 4-position of the phenyl ring.

4. Piperidine derivatives according to claim 1, 2 or 3 wherein i/ represents the cyclohexa - 1,4 - dienyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms. 20 5. Piperidine derivatiaves of the general formula:-2544611 [wherein R‘ represents a lower alkoxy or allyloxy group, I 1 R represents a hydrogen atom, or an amino, lower alkylamino, 2 1 di-(lower)alkylamino or a lower acylamino group, R represents

5. A halogen atom, or an amino, sulphamoyl or lower alkylsulphonyl group, R represents a hydrogen atom or a lower 4 1 alkyl group and R represents a cycloalkenyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms] and pharmaceutically-acceptable acid addition 10 salts thereof.

6. Piperidine derivatives according to claim 5 wherein R 1 when a lower alkoxy group represents methoxy or ethoxy; 1 I R (i) when a lower alkylamino group represents methylamino, (ii) when a di(lower)alkylamino group represents 15 dimethylamino, or (iii) when a lower acylamino group 2 1 represents a lower alkanoylamino group; R (i) when a halogen atom represents chlorine or bromine, or (ii) when a lower alkylsulphony! group represents methylsulphonyl; 3* 4' R when a lower alkyl group represents methyl, and R 20 represents a cycloalkenyl group optionally substituted by -264461 1 a methyl group, and pharmaceutically-acceptable acid addition salts thereof.

7. Piperidine derivatives according to claim 5 or 1 « 6 wherein R represents the acetamido or trifluoro5 acetamido group.

8. Piperidine derivatives according to claim 5, 6 or 7 wherein R represents the cyclohexa - 1,4 - dienyl group optionally substituted by a methyl group.

9. Piperidine derivatives according to claim 1 10. Wherein R 4 represents a cyclopentenyl, cyclohexadienyl or cycloheptenyl group, or a cyclohexenyl 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 -(CH 2 ) y - wherein 15 y represents zero or an integer from 1 to 5.

10. N -[l - Cyclohexa - l',4' - dienylmethylpiperid 4 - yl] - 2 - methoxy - 4 - amino - 5 - chlorobenzamide.

11. N - [l - Cyclohexa - l',4' - dienylmethylpiperid 4 - yTj - methoxy - 4 - acetamido - 5 - chlorobenzamide. 20

12. 'N -£l - (4 - Methylcyclohexa - 1,4 - dienyl) methylpiperid -4-yl] - 2 - methoxy - 4 - amino - 5 -2744611 chlorobenzamide.

13-, N -[l - Cyclohexa - 1',4' - dienylmethyl piperid 4 - yTj - 2 - methoxy - 5 - methylsulphonylbenzamide.

14. N - (1 - Cyclohexa -1^4 1 - dienylmethylpiperid 5 4 - yl) - ,2 - methoxy - 5 - chlorobenzamide.

15. N - (1 - Cyclohexa - 1 * ,4’ - dienylmethylpiperid 4 - yl) - 2 - methoxy - 4 - amino - 5 - bromobenzamide.

16. N - (1 - Cyclohexa - 1 1 ,4' - dienylmethylpiperid 4 - yl) - 2 - methoxy - 5 - sulphamoylbenzamide. 10

17. 'N -£ 1 -(1- Cyclohexa - l',4' - dienylethyl) piperid - 4 - yl] - 2 - methoxy - 4 - amino - 5 chlorobenzamide.

18. N -£l .- (1 - Cyclohexa - 1' ,4' - dienylethyl) piperid - 4 - ylj - 2 - ethoxy - 4 - acetamido - 5 15 chlorobenzamide.

19. 'N -[l -(1 - Cyclohexa - 1 1 ,4' - dienylethyl) piperid - 4 - ylj - 2 - ethoxy - 4 - amino - 5 chlorobenzamide.

20. N - (1 - Cyclohexa - l',4' - dienylmethylpiperid -2844611 4 - yl) - 2 - methoxy - 4,5 - diaiiiinobenzamidt’.

21. N - (1 - Cyclohexa - l',4' - dienylmethylpiperid 4 - yl) - 2 - methoxy - 4 - dimethylamino - 5 - chlorobenzami de. 5

22. N - (1 - Cyclohexa - 1 ' ,4' - dienylmethylpiperid 4 - yl) - 2 - methoxy - 4 - methylamino - 5 - chlorobenzamide.

23. N - (1 - Cyclohexa - l',4' - dienylmethylpiperid 4 - yl) - 2 - allyloxy - 4 - amino - 5 - chlorobenzamide. 10

24. N - (1 - Cyclohexa - τ',4' - dienylmethylpiperid 4 - yl) - 2 - ethoxy - 4 - amino - 5 - chlorobenzamide.

25. N - (1 - Cyclohexa - 1' ,4' - dienylmethylpiperid 4 - yl) - 2 - ethoxy - 4 - acetamido - 5 - chlorobenzamide.

26. N - (1 - Cyclohex - 3' - enylmethylpiperid - 4 15 yl) - 2 - methoxy - 4 - amino - 5 - chlorobenzamide.

27. Pharmaceutically-acceptable acid addition salts of a compound claimed in any one of claims 10 to 26.

28. Pharmaceutically-acceptable quaternary ammonium -2944611 derivatives of a compound claimed in any one of claims 10 to 26.

29. A process for the preparation of a piperidine derivative as claimed in claim 1 which comprises reacting 5 a reactive derivative of a benzoic acid of the general formula:- 12. 1 2 (wherein R, R and R are as defined in claim 1) with a piperidine derivative of the general formula:R 3 H 2 N-(CH 2'x N - CH-W-R 4 IV 10 wherein the various symbols are as defined in claim 1. -30J 4 β 2 i

30. A process according to claim 29 in which the reactive derivative of the benzoic acid is a halide, an alkyl ester, anhydride, a mixed anhydride, the N imidazolamide or acid azide. 5

31. A process according to claim 29 or 30 in which the reaction is carried out in an inert organic solvent at a temperature between -5° and 120°C.

32. A modification of the process claimed in claim 29 in which the benzoic acid of general formula III is 10 reacted with the piperidine derivative of general formula IV in the presence of a dehydrating agent.

33. A process according to claim 32 in which the dehydrating agent is silicon tetrachloride, a mono-, di- or trialkyl-silyl chloride, titanium tetrachloride, 13. 15 N,N' - di- cyclohexyl - carbodiimide, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene - p sulphonyl chloride, acetone, di-methyl acetal or a polymeric dehydrating agent.

34. A process according to calim 32 or 33 in which 14. 20 the reaction is carried out in an inert organic solvent at a temperature between 20° and 110°C.

35. A process for the preparation of a piperidine -314 4 614 derivative of the general formula specified in claim 1 or an acid addition salt or quaternary ammonium derivative substantially as hereinbefore described with especial reference to Example 1.

36. Pharmaceutical compositions which comprise, as active ingredient, at least one piperidine derivative as claimed in any one of claims 1 to 26, or a non-toxic pharmaceutically-acceptable acid addition salt or quaternary ammonium derivative thereof, in association with a pharmaceutically-acceptable carrier or diluent.

37. Pharmaceutical compositions according to claim 36 substantially as hereinbefore described with especial reference to any one of Examples 3 to 6.

38. Piperidine derivatives of the general formula:- wherein R 3 , r\ χ and W are as defined in claim 1

39.' 1 - Cyclohexa - l',4‘ - dienylmethyl - 4 -3214611 aminopiperidine, 1-(4- methylcyclohexa - 1 ,4 dienyl)methyl - 4 - aminopiperidine, 1-(1cyclohexa - l',4' - dienyl - ethyl) - 4 aminopiperidine and 1 - cyclohexen - 3' - ylmethyl - 4 - aminopiperidine.