GB2044254A

GB2044254A - Novel piperidine derivatives

Info

Publication number: GB2044254A
Application number: GB8001668A
Authority: GB
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1979-01-26
Filing date: 1980-01-17
Publication date: 1980-10-15
Also published as: GB2044254B

Abstract

Compounds of formula: <IMAGE> and pharmaceutically acceptable acid addition or quaternary ammonium salts thereof wherein the piperidine ring is substituted in the 3 or 4 position; X represents =CH- or =N-; Y represents -NR<5>-, -O- or -S- wherein R<5> is hydrogen or lower alkyl; A is lower alkylene or hydroxy lower alkylene, Z and Z<1> independently represent <IMAGE> Z may also represent -CH2-, -(CH2)2-, -CHMe- or -CMe2-; R<1>, R<2>, R<3> independently represent hydrogen, halogen lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, trifluoromethyl, lower-alkanoylamino, hydroxy or aryl lower alkoxy; or R<1> and R<2> when adjacent together with the carbons to which they are attached form a six membered carbocyclic ring; and R<4> represents hydrogen or lower alkyl, are disclosed which possess psychotropic activity and are useful as anti-depressants. Methods of preparation and pharmaceutical compositions comprising compounds of formula I and intermediates therefor are also disclosed.

Description

SPECIFICATION Novel piperidine derivatives This invention relates to new piperdine derivatives, to processes for preparing them and to pharmaceutical compositions containing them.

In our U.K. Patent Specification No. 1,425,578 we have described and claimed compounds of the gen

and their pharmaceutically acceptable acid addition salts, where Ri represents a hydrogen atom, an alkyl group, an aralkyl group or an alkyl group substituted by a heterocyclyl group; R2 and R3, which may be the same or different, represent a hydrogen atom, a halogen atom (for instance, chlorine or bromine), a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxy group, an amino group, a mono-alkylamino group (for instance, a monomethylamino group) or a dialkylamino group (for instance, a dimethylamino or diethylamino group).

According to U.K. Patent Specification No.

1,425,578 the compounds of formula A show anticonvulsant activity and in some cases antiinflammatory activity or anti-arrhythmic activity when tested on warm blooded animals.

We have now suprisingly found that certain compounds falling within the general formula A of U.K.

Patent Specification 1,425,578, but not specifically exemplified form part of a class of compounds exhibiting psychotropic activity as measured by inhibition of uptake of 5 - hydroxytryptamine in brain slices. The compounds are therefore useful as antidepressants. The present invention concerns this new class of compounds and their use.

Accordinglythis invention provides newcom

and their pharmaceutically acceptable acid addition and quaternary ammonium salts, wherein the piperidine ring is substituted in the 3 or 4 position; X represents OH- or =N-; Y represents -NRs-, -O- or -S- wherein R5 is hydrogen or lower alkyl; A is lower alkylene or hydroxy lower alkylene, Z and Z1 independently represent

Z may also repres ent-CH2-, -(CH2)2-, -CHMe- or -CMe2-; R', R2, R3, independently represent hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, trifluoromethyl, lower alkanoylamino, hydroxy or aryl lower alkoxy; or R' and R2 when adjacent, together with the carbons to which they are attached form a six membered carbocyclic ring; and R4 represents hydrogen or lower alkyl.

The term "aryl" as used herein means a carbocyclic ring having aromatic character.

The term "lower" as used herein in connection with such groups as "alkyl" and "alkylene" denotes that the group contains up to 6 carbon atoms, preferably not more than 4 carbon atoms.

Examples of A are straight chain alkylene groups such as -CH2-, -CH2-CH2-, -(CH2)3- and -(CH2)4-, and branched chain alkylene groups such as

Examples of hydroxy lower alkylene groups for A are -CHOH-CH2-, -CH2-CHOH-CH2- and -CHOHCH2CH2-. Preferably A is -CH2- or -CH2CH2-.

Examples of lower alkyl groups for R1, R2, R3, R4 and R5 are methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl and n-hexyl. Preferred lower alkyl groups are methyl and ethyl.

Examples of R', R2 or R3 when halogen are fluorine, chlorine or bromine.

Examples of lower alkoxy groups for R', R2 and R3 are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

Preferred lower alkoxy groups are methoxy and ethoxy. R3 when aryl lower alkoxy is preferably benzyloxy. Preferred values for Z and Z' are -CO-. PreferablyX is =C-. Preferablyy is -NH-. Preferably the piperidine ring is substituted in the 4-position. Preferably R' is H, Cl or NH2.

Preferred compounds of the invention are 2 - (1 [indol - 3 - ylmethyl] piperid - 4 - yl - 1K - isoindole - 1, 3 - (2K) - dione (compound I); 2 - (1 -[2 - (indol - 3 - yl) ethyl] piperid - 4 - yl) - 1K - isoindol - 1,3 - (2K) - dione (compound II), and 5 - amino - 2 - (1 - [2 - (indol - 3 yl) ethyl] piperid - 4 - yl) - 1K - isoindole - 1,3 - (2K) - dione (compound Ill).

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 methanesulphonate and p-toluenesulphonate), acetate, maleate, citrate, fumarate, tartrate, malonate and formate.

The compounds of formula I were tested for the ability to inhibit noradrenaline and 5 - hydroxytryptamine uptake in brain slices in the following standard test: The effects of test compounds on the neuronal uptake of noradrenaline into slices of cerebral cortex prepared from rat brain is determined according to the method described by Snyder, Green and Hendley, Kinetics of H2 - norepinephrine accumulation into slices from different regions of the rat brain (J.

Pharm. exp. Therap. 164: 90-102) (1968). The effects of test compounds on the uptake of 5 - hydroxytryptamine is obtained in a similar manner except that H25- hydroxytryptamine is used in place of H3noradrenaline. Concentration-response curves are obtained both for the test compound and for the standard agent, imipramine. The potency of each test compound is expressed in proportion to that of imipramine. Thus, the potency ratio for the test compound = Compound

Thus both compounds I, II and III are potent nhibitors of 5-HT (hydroxytryptamine) uptake and sery weak inhibitors of noradrenaline uptake. The compound 2 - (1 - benzylpiperid - 4 - yl) - 1H - isoindol - 1,3 - - (2K) - dione was inactive in the test.

Compounds of formula I were also tested for their ability to inhibit p-chloroamphetamine induced hyperactivity. The following procedure was used: Three groups of 4 female mice (20-24 g) received 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 sre placed immediately in square plastic cages in 3activity monitors and their motor activity recorded overthe period 10-30 minutes post pCA.This procesure is repeated three more times so that four Compound 2-(1 -[indol-3-ylmethy(j piperid 4-yl)-1H-isoindole-1,3-(2H)-dione 2-(1 -[indol-3-ylmethy(i piperid 4-yI) - 1,2 - benzisothiazolin -3 one-1,1-dioxide 5-chloro-2-(1 -[2-(indol-3-yI)- ethyl piperid - 4 - yl) - 1H - isoindole 1,3- (2H) - dione 5-chloro-2-[1-(indol-3-ylmethyl) piperid -4-yl-1H - isoindole - 1,3- (2H) dione This invention also provides processes for preparng compounds of formula I or acid addition or quaternary ammonium salts thereof.In general the compounds of formula are prepared by building up he molecule from the appropriate starting materials Molar concentration of imipramine giving 50% inhibition of NA (or 5HT-) uptake Molar concentration of test drug giving 50% inhibition of HA (or 5HT) uptake Compounds not achieving 50% inhibition are considered inactive.

In such a test the compounds I, II and Ill above and a compound from U.K. Patent Specification No.

1,425,578, namely 2 - (1 - benzylpiperid -4 - yl) - 1H isoindol - 1,3 - . (2K) - dione (B) gave the following results: Potency Ratio (imipramine = 1.0) Noradrenaline 5-hydroxytryptamine 0.01 9.5 0.06 8.3 inactive 11.0 inactive inactive groups of mice are used pertreatmentand each activity monitor is used with all treatments in turn.

The inhibition of pCA induced hyperactivity is calculated thus: O-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: %Inhibition of pCA induced hyperactivity 53% 56% 94% 63% by known reactions.

Accordingly a first process for preparing a compound of formula I comprises reacting a compound of formula Il

wherein R', R2, Z and Z1 are as defined in connection with formula I, with a compound of formula Ill

wherein R3, R4, A, X and Y are as defined above and W represents a leaving group, such as halogen (e.g.

chlorine, bromine or iodine), an organic sulphonyloxy radical (e.g. tosyloxy, mesyloxy), a disubstituted amino radical (such as dimethylamino), a trisubstituted ammonium radical (such as trimethyl ammonium, QN+Me2). Where the leaving group is a halogen or an organic sulphonyloxy radical the reaction is preferably carried out in the presence of base, e.g. potassium carbonate, triethylamine; otherwise the reaction may be carried out by heating in the presence of an inert solvent, e.g. toluene.

A second general process for preparing compounds of formula I (wherein Z is -CO-, -COCH2-, -SO2- or-CO(CH2)2-) comprises reacting a compound of formula IV

wherein R3, R4, A, X and Y are as defined above, with an acid of formula

or a reactive derivative thereof, wherein Z', R' and R2 are as hereinbefore defined and Z is as defined immediately above. Examples of reactive derivatives of the acid of formula (V) are di-acid halides (e.g.

chloride) and acid anhydrides. Such reactions may be brought to completion by employing a dehydrating agent (e.g. acetic anhydride). Other examples of reactive derivatives are alkoxycarbonylimides of general formula:

A further process for preparing a compound of formula I comprises reducing a compound of formula VI or VII

wherein R', R2, R3, R4, X, Y, Z and Z1 are as hereinbefore defined and B5)represents an anion, e.g. a halide ion, for example by catalytic hydrogenation, e.g. in the presence of Raney nickel or platinum catalyst. The reduction may also be effected by a process described and claimed in our U.K. Patent Specification No. 1542137. Such a reduction process employs an alkali metal borohydride in a secondary alkanol having 3-5 carbon atoms, e.g. isopropanol.

Yet a further process for preparing a compound of formula I comprises reacting a compound of formula VIII

wherein X, Y, A, R3 and R4 are as hereinbefore defined with a compound of formula II, in the presence of a catalyst, e.g. Raney nickel.

Compounds of formula I wherein the piperidine ring is substituted in the 4-position may also be prepared by a process which comprises reacting a compound of formula

with an alkali metal salt of a compound of formula

in which formulae A, X, Y, Z, Z', R', R2, R3 and R4 are as hereinbefore defined.

Examples of halogen in the compound of formula IX are chlorine and bromine. Examples of alkali metal salts of the compound of formula X are the potassium and sodium salts.

When it is desired to prepare a compound of formula I wherein A is methylene and Y is -NR5- as defined above then such a compound can be prepared by reacting a compound of formula

with formaldehyde and a piperidine derivative of formula Il

in which formulae X, Z, Z1, R', R2, R3, R4 and R5 are as hereinbefore defined. The formaldehyde used in the above reaction may be in the form of a solution in an inert solvent as paraformaldehyde.

Once a compound of formula I has been prepared then that compound may be converted in known manner to other compounds of formula I. For example when R5 is hydrogen then that compound may be alkylatedto produce a compound of formula I wherein R5 is lower alkyl e.g. using sodium hydride and methyl iodide. When R3 is lower alkoxy or aryl lower alkoxy dealkylation produces a corresponding compound of formula I wherein R3 is hydroxy. When any of R', R2 and R3 is nitro then reduction (e.g.

catalytic hydrogenation) will convert the nitro group to an amino group.

Compounds of formula I wherein Z is -OH2- or -(CH2)2- may be prepared by reducing, e.g. using zinc dust in glacial acetic acid, a corresponding com pound of formula I wherein Z is -CO- or -COCH2-.

The aforementioned processes may also include the step of conversion of an acid addition salt into the free base form or vice versa. Quaternisation of the tertiary nitrogen of the piperdine ring may be included as an optional after step, e.g. using alkyl or aryl lower alkyl halides, e.g. methyl iodide, benzyl chloride.

Starting materials used in the above mentioned processes are known compounds or may be prepared by analogous processes. For example, a compound of formula il may be prepared by reducing the corresponding compound of formula XII

using for example catalytic hydrogenation. Compounds of formula XII may be prepared by reacting a 4-halopyridine with an alkali metal salt of compound of formula X, or by reacting a 3-or 4-aminopyridine with a di-acid or reactive derivative of formula V.

Compounds of formula VII may be prepared by reacting a compound of formula III wherein W is halogen, especially bromine, with a compound of formula XII.

Compounds of formula VI may be prepared by reducing, e.g. using sodium borohydride in methanol, a compound of formula VII.

Compounds of formula II wherein Z is -CO- or -COCH2- may be reduced, e.g. using zinc dust in glacial acetic acid, to give corresponding compounds of formula II wherein Z is -OH2- or -(CH2)2-.

If necessary, in any of the reactions herein described, reactive substituent groups may be blocked during a reaction and released at a later stage. For example an amino substituent may be protected by a benzyloxy-carbonyl group which is removable using H2/Pd atthe end of a reaction.

A further aspect of this invention includes a method of treating depression in animals which comprises administering an effective amount of a compound of formula I as hereinbefore defined.

This invention also includes pharmaceutical compositions containing 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, ortablet-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 formation of an active ingrediet 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 elix irs. The active ingredient can be dissolved or sus pended in a pharmaceutically acceptable sterile liquid carrier, such as sterile water, sterile organic solvent or a mixture of both. Preferably a liquid car rier 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 suit able organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aque- ous 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 carboxy-methyl cellulose solution or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized 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 subdivided 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.

This invention also includes compounds of formula VI and VII as hereinbefore defined which are intermediates to compounds of formula I.

The following examples illustrate the invention: EXAMPLE 1 2-(I-Elndol-3- ylmethyl] piperid -4-yl)- 1H- isoindole-1,3-(2H)-dione Formaldehyde (0.84cm , 40% aq. W/v, 11.3mmol) was added to a stirred and cooled mixture of indole (1.32g,11.3mmol),2 - (piperid - 4 - yl) - 1H - isoindol - 1,3 - (2K) - dione, hydrochloride (3.0g, 11.3mmol), and sodium acetate (0.93g, 11.3mmol) in glacial acetic acid (10cm3). The suspension was stirred at room temperature for 5 hours, then poured into water and a gummy precipitate filtered off. The mother liquors were basified by addition of 0.880 ammonia to precipitate the title compound, which was collected and dried (2.52g, 62.4%).

The hydrochloride was precipitated from a suspension of the base in hot ethanol by addition of ethanolic HCI. Two recrystallisations from ethanol gave the hydrochloride as pale pink crystals, m.p.

171-174 C.

Analysis Found: C,63.39; H,5.67; N,10.37%; C22H2, N2O2.HCl.1 .25H2O requires C,63.15; H, 5.90; N, 10.04%.

EXAMPLE2 2 - {1- [2 - {Indol -3 - ylJ ethyl] piperid - 4 - ylJ - 1H - isoindol - 1,3- (2H) - dione Phthalic anhydride (2.96g, 0.02mol, finely ground) and 4 - amino - 1 -[2 - (indol - 3 - yl) ethyl] piperidine (4.86g,0.02mol) were suspended in chloroform (40cm3) and the suspension stirred at room temperature overnight. The solvent was then evaporated and acetic anhydride (40cm3) added to the residue. This mixture was heated on a steam bath for 2 hours then the solvent removed in vacuo to give a glassy solid which was dissolved in very dilute aqueous acetic acid.Basification of the solution with 0.880 ammonia gave the title compound as a gum which solidified on trituration with methanol. (4.319, 57.8%). A sus pension of the base in ethanolic HCI was stirred overnight to give the hydrochloride, mp. 252-260 after extensive decomposition above 240 C.

Analysis: Found: C, 66.65; H, 6.06; N, 10.10%, C33H23N3O2.HCl.1/4H2O requires C,66.66; H, 5.90; N, 10.14%.

EXAMPLES 2-(1-[Indol-3-ylmethyl]piperid-4-yl)-1,2benzisothiazolin - 3 - one - 1, 1- dioxide Formaldehyde (0.4cm3, 40% aqu.soln.) was added to a mixture of indole (0.6g, 0.005 mol), 2 - (piperid - 4 - yl) - 1,2 - benzisothiazoline - 3 - one - 1, 1 - dioxide, hydrochloride (1.5g,0.005mol) and methanol (10 cm3). The mixture was warmed sufficiently to give a clear solution and then allowed to stand with out further heating for 2 hours. The clear solution was then evaporated, and the residual water removed by successive evaporation of the residue with ethanol to give a gum. The gum was dissolved in methanol and allowed to stand in ice whereupon the crystalline title compound separated (1.7g, 79%) as the hydrochloride.Recrystallisation twice from aqueous methanol (80% methanol) gave 1.3g of the title compound as the hydrochloride hemihydrate, m.p.214-215 C.

Analysis: Found: C,57.63; H, 5.18; N,9.24.

C21H21N3O3S.HCl.0.5H2O requires C, 57.20; H, 5.26; N, 9.53%.

EXAMPLE4 2.[1.(2.[lndol-3-yl]ethyl)piperid-4-yl]-113- (2H, 4H) - iso - quinolinedione 4 - Amino - 1 -[2 - (indol - 3 - yl) ethyl] piperidine (2.43g, 0.01 mol) and homophthalic acid (1.80g, 0.01 mol) were heated at 1600 (external temperature) for3 hours then cooled to room temperature, giving a glass. This was dissolved in refluxing methanol and a small quantity of ethanol then cooled at 5 C over night. The title compound was deposited as a tacky solid which was colleced and dried (0.82g, 21.2%).

The hydrochloride was formed by treatment of the baseovernightwith ethereal HCI, m.p. 186-188 .

Analysis: Found: C,64.84; H,6.18; N,9.15.

024H22N2O2.HOI. 114H2O requires C,64.57; H, 6.43; N, 9.41%.

EXAMPLES 2,3-Dihydro-2-[1-(indol-3-ylmethyl)piperid-4 yl]. 1H - isoindol - 1- one a) Indole (0.51 g, 4.36 mmol) and 4 - (2 phthalimidino) - piperidine acetate (1.2g,4.35mmol) were suspended in glacial acetic acid (5cm3) and aqueous formaldehyde (0.33cm , 40% aq w/v, 4.35 mmol) was added at room temperature with stirring.

The reaction mixture was stirred until homogeneous then allowed to stand. After 5 hours the solution was poured into water and filtered. The filtrate was basified by addition of conc. ammonia to precipitate the title compound. This was collected and dried.

(1.30g, 86.7%).

The hydrochloride was formed by trituration of the base overnight with ethereal hydrogen chloride, m.p. softens above 19000.

Analysis: Found C, 65.93; H, 6.47; N, 10.68%.

C22H23N3O.HCI.H2O requires C,66.07; H6.55; N, 10.51%.

b) 4 - (2 - Phthalimidino) piperidine acetate was prepared by the following procedure: 4-(2-Phthalimido)piperidine, hydrochloride (2.67g 0.01 mol) was dissolved in glacial acetic acid (25cm ) at 70 C. Zinc dust (3.5g, 0.055 g atoms) was added all at once, with stirring, and the reaction mixture heated to reflux. Refluxing was continued for 5 hours, then unchanged zinc filtered off and the reaction mixture left overnight Acetic acid was evapo- rated off leaving a solid which was dissolved in water. Addition of aqueous sodium bicarbonate precipitated4 - {2 - phthalimidinoj piperidine acetate which was collected and dried (1.54 g).

EXAMPLE 6 5,6-Benoz-2-(1-[2-(indol-3-yl)ethyl]piperid-4 -yl)-1H-isoindol-1,3-(2H)-dione, An intimate mixture of 4-amino-1-[2-(indol-3yl) - ethyl] piperidine (1.21 g, 5 mmol) and naphthalene-2,3-dicarboxylic acid (1.08 g, 5mmol) was heated at 175 C for 2 hours. The melt was then extracted under reflux with ethanol (15cm ) until the product formed a crystalline solid. The extract was coaled and the solid coilected by filtration to give the title compound 1.6g (80%). The base was dissolved in warm dimethylformamide and acidified with ethanolic hydrogen chloride to precipitate the hydrochloride, which was recrystallised twice from aqueous DMF (1:1) to give 0.8g (36.4%), m.p.

280-84 C.

Analysis: Found: C,68.46; H,5.89; N,8.55%.

C27H25N3O2.HCl.1/4H2O requires C, 68.49; H, 5.85; N, 8.87 EXAMPLE 7 2-[1-[3-[(Indol-3-yl]propyl)piperid-4-yl]-1H Jsoindo'e - 1,3- H) - dione 3-Tesyloxypropylindole (1.65g, 5mmol), 4 phthalimido-piperidine, hydrochloride (1.33g, 5mmol) and potassium carbonate (1.5g, 10.9mmol) were ground together and then heated at 11 0C for 2 hours. The mixture was triturated twice with water under reflux followed by ethanol, giving the title compound as a pale brown solid (0.39g, 20%), m.p.

187-190 C.

The base was suspended in boiling ethanol and ethanolic HCl added to give an acidic solution. This crystailised on cooling in ice. The hydrochloride was collected and recrystallised from aqueous ethanol, giving pale brown shiny plates m.p. 255-260 C, with extensive decomposition above 220 C.

Analysis: Found: C, 67.98; H, 6.42; N, aS8%.

C24H25N3O2.HCl requires C, 68.00; H,6.18; N, 9.91.

EXAMPLE 8 5-Chloro-2-(1-[2-(indol-3-yl)ethyl]piperid-4yl)-1H-isoindole-1,3-(2H)-dione.

4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (3.86g, 15.9mmol) was dissolved in warm methyl cyanide 150 cm ) and a solution of 4 - chlorophthalic anhydride (2.9g, 15.9mmol) in methyl cyanide (20cm ) was added dropwise with stirring, to precipi tate a solid. The suspension was stirred at room temperature overnight then cooled briefly in ice and the solid collected. This crude material was heated in acetic anhydride (70cm ) for 2 1/2 hours then the sol vent was evaporated. The residue was dissolved in methanol, to destroy excess acetic anhydride, then the methanol was evaporated.The residue was dis solved in very dilute aqueous acetic acid and the solution was basified by addition of conc. ammonia to precipitate a gum. The supematent layer was decanted and the gum triturated with boiling ethanol and cooled in iceto give crystals of the title com- pound (2.82g, 43.6%), m.p. 188-190 C.

The base was suspended in boiling ethanol, acidified by addition of ethanolic HCI, filtered and cooled in ice, giving a gum. This was recrystallised twice from ethanol to give the pure hydrochloride salt, m.p. 274-277 C (dec).

Analysis: Found: C, 62.14; H, 5.31; N, 9.76%.

C23H22N3O2Cl.HCl requires C,62.17; H,5.22; N,9.46%.

EXAMPLE 9 2-[1-(2-[Indol-3-yl]ethyl)piperid-4-yl]-5 methyl-1H-isoindole-1,3-(2H)-dione.

4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (1.22g, 5mmol) was dissolved in warm methyl cyanide (50cm ) and a solution of 4-methylphthalic anhydride (0.81g, 5mmol) in methyl cyanide 510 cm3) was added dropwise with stirring to precipitate a while solid. The suspension was stirred overnight then the solid collected and heated in acetic annydride (40cm ) for2 hours on a steam bath. The acetic anhydride was evaporated. The residue was dissel- ved in very dilute aqueous acetic acid and the solu- tion basilied by addition of conc. ammonia to give a gum. The mother liquer was decanted and the gum recrystallised from ethanol to give crystals of the title compound (0.53g, 27.3%).

The base was suspended in refluxing propan - 2- cl, and the suspension acidified with ethanolic HCl to give a solution. Coclingin ice gave the hydroch- loride as a gum. This was recrystallised from ethanol m.p. 160-183 C as the monohydrate.

Analysis: Found: C, 65,50; H, 610; N, 9.13%.

C24H25N3O2.HCl.H2O requires C, 65.23; H, 6.39; N, 9.51%.

EXAMPLE 10 2-[1-(2-[Indol-3-yl]ethyl)piperid-4-yl]-5nitro-1H-isoindole-1,3-(2H)-dione.

4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (1.22g, 5mmol) was dissolved in refluxing acetonitrile (20cm )and a solution of 4-nitrophthalic anhydride (0.96g, 5mmol) in acetonitrile (10cm ) was added dropwise with stirring to precipitate a yellow gum.

The mixture was refluxed for a further 2-3 minutes then cooled in ice. The precipitated material was col ected and heated in acetic anhydride on a steam bath for 1/2hour. The solvent was evaporated.

Methanol was added to the residue and evaporated to destroy excess acetic anhydride. The residue 'as then dissolved in very dilute aqueous acetic acid and insoluble material filtered off. The filtrate was basified by addition of conc. ammonia to precipitate a gum, which was triturated with methanol under reflux to give the title compound as a bright range solid (0.44g, 21%).

The base was suspended in hot ethanol and the mixture acidified with ethanolic HCl, filtered and cooled in ice to give the hydrochloride 11.4 hydrate.

m.p. 194-195 C.

Analysis: Found: C, 57.46; H, 5.02; N, 11 11.93%.

C23H22N6O4.HCl.11/4H2O requires C, 57.86; H, 5.38; N, 11.74% EXAMPLE 11 5-Amino -2- (1 -[2- (indol-3-yl)ethyl] - piperid - 4 -yl)-1H-isoindole-1,3-(2H)-dione.

The title compound of Example 10 (0.99g, 2.37mmol) was dissolved in ethanol/acetic acid and hydrogenated over 5% Pd/C at 20 C and 40 psi.

Uptake ceased after 6 hours. The catalyst was fil tered off and the filtrate evaporated. The oily residue was dissolved in water and basified by addition of conc. ammonia to give a mixture of solid and gum.

The gum was removed by hand and the solid col lected and dried (0.54g, 58.7%).

The base was suspended in refluxing ethyl acetate and isopropanol was added dropwise until most of the material has dissolved. The mixture was filtered and ethereal HCI added to the filtrate, which crystal lised at once. Further ethyl acetate was added until the suspension was mobile, then the pH was checked to be 1 and the suspension stirred overnight at room temperature. The title compound as the dihydrochloride salt was collected and dried, m.p.

180-183 C(dec).

Analysis: Found: C,60.17; H, 5.95; N, 11.97% C23H24N4O2.2HCl requires C, 59.87; H, 5.68 ; N, 12.14%.

EXAMPLE 12 2- (1- [Benzo [b] thiophen - 3- ylmethyl] piperid - 4 - yl)-1H-isoindole-1,3-(2H)-dione.

4-Phthalimidopiperidine, hydrochloride (1.339, Smmol) was suspended in dimethylformamide (12cm3) andtriethylamine (1.5g, 14.8mmol) was added with stirring, followed by 3-bromoethylbenzo[b]thiophene (1 .2g, 5.3mmol).

After stirring for 4 < hours at room temperature a further small quantity of 3-bromoethylbenzo [b] thiophene was added. Stirring was continued for 2 hours then the reaction mixture was poured into water and the precipitated solid collected and dried (1.65g, 87.8%).

The base was suspended in isopropyl alcohol, ethanolic HCI was added and the mixture stirred at room temperature overnight. The solid was collected, triturated with methanol under reflux and undissolved material filtered off. The filtrate was diluted with water until just turbid, then the methanol evaporated to give solid material suspended in water. The title compound as the mono hydrochloride salt was collected and recrystallised from ethanol, then ethanol/methanol. (m.p. = 163-168 C).

Analysis: Found C, 62.21; H, 5.75; N, 6.00%.

C22H20N202S.HCI. 3/4H2O requires C, 61.96; H, 5.32; N, 6.57%.

EXAMPLE 13 2 -(1 - [s - Methoxyindol - 3 - ylmethyl] piperid - 4 - yl) - 1H-isoindole- 1,3-(2H)-dione 5 - Methoxyindole (1.0g, 6.73 mmol) was dissolved in glacial acetic acid (8cm3). 4-phthalimidopiperidine hydrochoride (1.799, 6.72mmol), sodium acetate (0.59 g, 7.2 mmol) and formaldehyde (0.5 cm3, 40% aq w/v, 6.7 mmol) were added in that order to the stirred mixture. Stirring was continued at room temperature for 5 hours, then the mixture was poured into water, filtered, and the filtrate basified by addition of conc.ammonia. The precipitated solid was collected and dried(1.07 g, 41%).

The base was suspended in a small volume of boiling ethanol, and ethanolic HCI added to give a solution. Cooling overnight at 5 C gave a gum. The mother-liquors were decanted and maintained at 5 C for 3 weeks to give title compound as the hydrochloride, m.p. 178-180 C.

Analysis: Found: C,62.98; H,5.73; N, 9.22%.

C23H23N3,HCI.3/4 H2O requires C, 62.87; H, 5.85; N, 9.57%.

EXAMPLE 14 Repeating the procedure of Example 2 the following indolyl derivatives of formula I may be prepared according to the reaction scheme:

R1 R2 R3 R4 R5 A a) 5-trifluoro- H H H H CH2 methyl b) 5-acetamido H H H H CH2 c) 5-methoxy H H H H CH2 d) 5-methyl- H H H H CH2 amino e) 5-chloro H H Me H (CH2)2 f) 5-chloro H H H Me (CH2)2 g) H H 5-chloro H H CH2 h) H H 5-methyl H H CH2 i) H H H H H -CH2CH(Me) EXAMPLE 15 5, 6-Dichloro -2 - (1 - [2 - (indol-3 - ylJ ethyl] piperid 4-yl)-1H isoindole-1,3-(2H)-dione 4 - Amino - 1 -[2 - (indol 3 - yl) ethyl] piperidine (3.64 g, 15 mmol) was dissolved in hot methyl cyanide (50 cm3) and 4, 5-dichlorophthalic anhydride (3.25 g, 15 mmol) in hot methyl cyanide (30 cm3) was added dropwise with stirring to precipitate a solid.

The mixture was stirred overnight. The solid was collected by filtration, pressed dry on a filter, and suspended in acetic anhydride (70 ml). The mixture was heated on a steam bath for 3 hours then the solvent was evaporated to give a bright yellow solid residue.

Ethanol was added and evaporated twice to remove acetic anhydride. The solid was dissolved in very dilute aqueous acetic acid and re-precipitated as a gum by addition of conc. ammonia. The gum hardened on standing in ice.

The crude material (1 g) was suspended in ethanol (15 cm3) and methanesulphonic acid (0.15 cm3, 2.31 mmol) was added. The mixture was heated and stir red under reflux for 2 hours. The suspension was cooled briefly in ice and the solid collected. This was triturated at reflux with 9:1 ethanol:water then 9:1 methanol:waterto give the title compound as the methanesulphonate salt, m.p. > 270 C (dec.) Analysis: Found: C,52.72; H, 5.03; N, 7.38%; C22H21Cl2N3O2.CH3SO3H1/2H2O requires: C, 52.65; H, 4.79; N, 7.67%.

EXAMPLE 16 5-Chloro-2-[1-(indol-3-yimethyl)piperid-4 yl] - 1H - isoindole - 1,3- (2H) - dione A solution of 5 - chloro - 2 - ethoxycarbonyl - 1H isoindole - 1,3 - (2H) - dione (1.27 g, 5.01 mmol) in hot ethanol (20 cm3) was added rapidly with stirring to a solution of 4 - amino - 1 - [1 - indol - 3 - ylmethyl] piperidine (1.15 g, 5.02 mmol) in ethanol (10 cm3), giving a clear solution. This was refluxed for 3 hours, cooled overnight and the solid collected and dried.

The mother-liquors were refluxed for a further 1.8 hours and a further crop of product recovered.

The product was suspended in isopropyl alcohol at reflux and acidified with ethanolic HCI, filtered, and the filtrate cooled in ice to give the title compound as the hydrochloride, m.p. 188-190'O.

Analysis: Found: C,59.95; H, 5.20; N, 9.33%; C22H20CIN3O2.HCl1/2H2O requires: C, 60.15; N, 5.05; N, 9.56%.

EXAMPLE 17 5-Nitro -2-[1 - (indol-3- ylmethyl)piperid-4- yl] - 1H-isoindole-1,3-(2H)-dione 2 - Ethoxycarbonyl -5 - nitro - 1H - isoindole - 1,3- (2H)-dione (1.32 g, 5.00 mmol) in boiling ethanol (12 cm3) was added to 4 - amino - 1 -[1 - indol - 3 ylmethyl] piperidine (1.15 g, 5.02 mmol) in ethanol (10cm3) and the resulting bright orange suspension refluxed for 3 hours. After cooling overnight the product was filtered off. The filtrate was refluxed over nightto give asecond crop of the title compound m.p.195-197 C.

Analysis: Found: C,65.10; H,5.18; N, 13.81% C22H20N4O4 requires: C, 65.34; H, 4.99; N, 13.85%.

EXAMPLE 18 5-Amino -2 -[1 - (indol-3 - ylmethyl)piperid-4 - yl] -1H-isoindole-1,3-(2H)-dione 5 - Nitro - 2 -[i - (indol - 3 - ylmethyl) piperid - 4 - yl] - 1H - isoindole - 1,3 - (2K) - dione (0.8 g, 1.98 mmol) was hydrogenated in methanol over Pd/C (5%, 0.15 g) at atmospheric pressure. The catalyst was filtered off and the filtrate evaporated. The solid product was recrystallised from chloroform to give the title compound.

Claims

1 A rnmnniind nffnrmiiln:

or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof, wherein the piperidine ring is substituted in the 3 or4 position; X represents OH- or =N-; Y represents -NR5-, -O- or -S- wherein R5 is hydrogen or lower alkyl; A is lower alkylene or hydroxy lower alkylene, Z and Z' independently represent O -C-, -SO2-, -COCH2- or -CO(CH202-;Z may also represent -CH2-, -(CH2)2-, -CHMe- or-CMe2-; R1, R2, R3 independently represent hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, trifluoromethyl, lower-alkanoylamino, hydroxy or aryl lower alkoxy; or R1 and R2 when adjacent together with the carbons to which they are attached form a six membered carbocyclic ring; and R4 represents hydrogen or lower alkyl.

2. A compound as claimed in Claim 1 wherein A represents -CH2-, -CH2CH2-, -CH2CH2CH2- or -(CH2)4-.

3. A compound as claimed in Claim 1 or Claim 2 wherein X represents OH- and Y represents -NH-.

4. A compound as claimed in any one of Claims 1 to 3 wherein Z represents -CO- and Z1 represents -CO- or -SO2-.

5. A compound as claimed in any one of Claims 1 to 4 wherein R' is chlorine or amino.

6. 2 - (1 -[Indol -3 - ylmethyl] piperid-4-yl)- ill isoindole - 1,3 - (2K) - dione.

7. 2-(1 -[2-(Indol-3-yl) ethyl] piperid-4-yl) 1H - isoindol - 1,3 - (2K) - dione.

8. 2-(1 -[lndol-3-ylmethy] piperid-4-yl)- 1, 2 - benzisothiazolin - 3 - one -1, 1 - dioxide.

9. 2-[1-(2-[Indol-3-yl]ethyl)piperid-4-yl] 1,3 - (2H, 4H) - isoquinolinedione.

10. 2,3-Dihydro-2-[1-(indol-3-ylmethyl) piperid - 4 - y] - 1H- isoindol - 1 - one.

11. 5,6-Benzo-2-(1-[2-(indol-3-yl)ethyl] piperid - 4 - yl) - 1H- isoindol - 1,3 - (2K) - dione.

12. 2-[1-(3-[Indol-3-yl] propyl) piperid-4-yl] -1H-isoindole-1,3-(2H)-dione.

13. 5-Chloro-2-(1-[2- (indol-3-yl) ethyi] piperid - 4 - yl) - 1H- isoindole - 1,3 - (2H) - dione.

14. 2-[1-(2-[lndol-3-yl]ethyl)piperid-4-yl]5-methyl-1H-isoindole-1,3-(2H)-dione.

15. 2-[1-(2-[Indol-3-yl]ethyl)piperid-4-yl]5-nitro-1H-isoindole-1,3-(2H)-dione.

16. 5-Amino-2-(1-[2-(indol-3-yl)ethyl]piperid - 4 - yl) - 1H - isoindole - 1,3 - (2H) - dione.

17. 2 - (1 -[Benzo [b] thiophen - 3 - ylmethyl] piperid - 4 - yl) - 1H- isoindole - 1,3 - (2H) - dione.

18. 2 - (1 -[s - Methoxyindol - 3 - ylmethyl] piperid-4-yl)-1H-isoindole-1,3-(2H)-dione.

19. 5,6-Dichloro-2-(1-[2-(indol-3-yl)ethyl] piperid - 4 - yl) - 1H - isoindole - 1,3 - (2H)- dione.

20. 5-Chloro-2-[1- (indol-3-ylmethyl) piperid -4-yl]-1H-isoindole-1,3-(2H)-dione,

21. 5-Nitro-2-[l-(indol -3-ylmethyl) piperid- 4 - yl] - 1H- isoindole - 1,3 - (2H) - dione.

22. 5 - Amino - 2 - [1 - (indol - 3 - ylmethyl) piperid - 4 - yl] - 1H-isoindole-1,3-(2H)-dione.

23. A compound of formula I as claimed in any one of Claims 1 to 22 when in the form of a phar maceutically acceptable acid addition salt.

24. A compound of formula I as claimed in Claim

1 which is a salt formed with hydrochloric, hydrob romic, hydroiodic, sulphuric, nitric, phosphoric, methanesulphonic, p-toluenesulphonic, acetic, maleic, citric, fumaric, tartaric, malonic or formic acid.

25. A process for preparing a compound of for mula las claimed in any one of Claims 1 to 5 which comprises reacting a compound of formula II

with a compound of formula III

In which formulae R1, R2, R3, R4, A, Z, Z', X and Y are as defined in any one of Claims 1 to 5, any reactive substituent group being protected where necessary, and W represents a leaving group, an organic sulphonyloxy radical, a disubstituted amino radical, a trisubstituted ammonium radical; and deprotecting any protected substituent group and, if desired, converting a free base form of a compound having formula I into a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof or an acid addition salt of a compound having formula I into the free base form.

26. A process as claimed in Claim 25 wherein W is chlorine or bromine.

27. A process for preparing a compound of for- mula I as claimed in any one of Claims 1 to 5 wherein Z is -00-, -COCH2-, -SO2- or-CO(CH2)- which comprises reacting a compound of formula IV

with an acid of formula

or a reactive derivative thereof, in which formulae R1, R2, R3, R4, A, X, Y and Z' are as defined in any one of Claims 1 to 5, Z is as defined immediately above, any reactive substituent groups being protected where necessary, and deprotecting a protected substituent group and, if desired, converting a free base form of a compound having formula I into a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof or an acid addition salt of a compound having formula I into the free base form.

28. A process as claimed in Claim 27 in which the reactive derivative of the acid of formula V is the diacid halide acid anhydride or alkoxycarbonylimide.

29. A process for preparing a compound of formula I as claimed in any of Claims 1 to 5 which comprises reducing a compound of formula VI or VII

in which formulae R', R2, R3, R4, X, Y, Z and Z1 are as hereinbefore defined and BGrepresents an anion and, if desired, converting a free base form of a compound having formula I into a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof or an acid addition salt of a compound having formula I into the free base form.

30. A process as claimed in Claim 29 which is effected using an alkali metal borohydride in a secondary alkanol having 3-5 carbon atoms.

31. A process for preparing a compound of formula I as claimed in any one of Claims 1 to 5 which comprises reacting a compound of formula VIII

with a compound of formula II

in which formulae R1, R2, R3, R4, X, Y, Z and Z' are as defined in any one of Claims 1 to 5, reactive substituent groups being protected where necessary; in the presence of a Raney nickel catalyst; and, if desired, converting a free base form of a compound having formula I into a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof or an acid addition salt of a compound having formula I into the free base form.

32. A process for preparing a compound of for- mula I as claimed in any one of Claims 1 to 5 wherein the piperidine ring is substituted in the 4 position which comprises reacting a compound of formula

with an alkali metal salt of a compound of formula

in which formulae A, X, Y, Z, Z1, R', R2, R3 and R4 are as hereinbefore defined, any reactive substituent groups being protected where necessary; and, in any order, deprotecting a protected group and, if desired, converting a free base form of a compound of formula I into a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof or an acid addition salt to the free base.

33. A process as claimed in Claim 32 wherein halogen is chlorine or bromine and the alkali metal salt of the compound of formula X is the potassium or sodium salt.

34. A process for preparing a compound of formula I as defined in any one of Claims 1 to 5 wherein A is methylene and Y is -NR5- which comprises reacting a compound of formula

with formaldehyde and a piperidine derivative of

in which formulae R', R2, R3, R4, Rq X, Z and Z1 are as defined in any one of Claims 1 to 5, reactive substituent groups being protected where necessary, and deprotecting any protected groups and, if desired, converting a free base form of a compound of formula I to a pharmaceutically acceptable acid addition salt to the free base.

35. A process for preparing a compound of formula I as defined in Claim 1 which comprises a) alkylating a compound offormula I wherein R5 is hydrogen to give a compound of formula I wherein R5 is lower alkyl; or b) dealkylating a compound offormula I wherein R3 is lower alkoxy or aryl lower alkoxy to give a compound of formula I wherein R3 is hydroxy; or c) reducing a compound of formula I wherein any one of R1, R2 and R3 is nitro to give a compound of formula I wherein any one of R', R2 and R3 is amino; or d) reducing a compound of formula I wherein Z is -CO- or -COCH2- to give a compound of formula I wherein Z is -OH2- or-(CH2)2-; or e) acylating a compound of formula I wherein any one of R', R2 and R3 is amino to give a compound of formula I wherein any one of R', R2, R3 is lower alkanoylamino.

36. A compound of formula I whenever prepared by a process as claimed in any one of Claims 25 to 35.

37. A compound offormula I as claimed in any one of Claims 1 to 24 for use as a pharmaceutical

38. A pharmaceutical composition comprising a compound of formula I as claimed in any one of Claims 1 to 24 and a pharmaceutically acceptable carrier.

39. A pharmaceutical composition as claimed in Claim 38 when in unit dosage form.

in which formulae R', R2, R3, R', X, Y, Z and Z' are as defined in Claim 1, B#is an anion and the pyridine and tetrahydropyridine rings are substituted in position 3 or position 4.

41. A process for preparing a compound of formula VI or VII as defined in Claim 40 which comprises reacting a compound of formula

with a compound of formula

in which formulae R1, R2, R3, R4, X, Y, Z and Z1 are as defined in Claim 40 and W is a leaving group, to give a compound of formula Vli and if desired reducing to give a compound of formula VI, reactive substituent groups being blocked where necessary and released subsequently.