EP0506903A1

EP0506903A1 - 4-acetoxy-piperidine derivatives, process for their preparation and use as a muscarinic m3-receptor antagonist

Info

Publication number: EP0506903A1
Application number: EP91917741A
Authority: EP
Inventors: Richard Bawden Ash Lea Cottage Barlow; Mark Anthony 4 Balmoral Close Veale
Original assignee: BTG International Ltd; British Technology Group Ltd
Current assignee: BTG International Ltd
Priority date: 1990-10-23
Filing date: 1991-10-17
Publication date: 1992-10-07
Also published as: AU8714991A; JPH05504578A; GB2249093A; GB9122083D0; WO1992006958A1; ZA918381B; FI922903A; GB9023023D0; PT99299A; CA2072598A1; FI922903A0

Abstract

On décrit des composés de formule (I), dans lesquels R1 et R2 sont chacun séparément choisis à partir d'un alkyle, alcoxy, alkylènedioxy, halogéno, alkyle substitué par halogéno, hydroxy et nitro, R3 et R4 représentent chacun hydrogène ou représentent tous deux un groupe oxo et R5 représente un groupe aromatique, le composé se présentant éventuellement sous forme d'une addition d'acide physiologiquement acceptable ou d'un sel d'ammonium quaternaire. Ces composés sont utiles comme antagonistes sélectifs du récepteur M3 de muscarine.Compounds of formula (I) are described, in which R1 and R2 are each separately chosen from an alkyl, alkoxy, alkylenedioxy, halo, alkyl substituted by halo, hydroxy and nitro, R3 and R4 each represent hydrogen or all represent two an oxo group and R5 represents an aromatic group, the compound possibly being in the form of an addition of physiologically acceptable acid or of a quaternary ammonium salt. These compounds are useful as selective antagonists of the muscarine M3 receptor.

Description

4-acetoxy-p1per1d1ne derivatives, process for their preparation and use as a muscar1n1c M3-receptor antagonist.

This invention relates to esters of N-substituted piperidin-4-ols and to their use as therapeutic agents.

Studies have been reported in the literature on the activity of large numbers of esters of N-substituted piperidin-4-ols as antimuscarinic drugs. Several muscarinic receptors exist, those concerned with actions at atria now being classified as M2 and those concerned with the contraction of ileu now being classified as M3. There is a particular need for compounds which show selective activity between the 2 and 3 receptors in order to provide drugs which have activity at the M3 receptor but with a significantly lower activity at the M2 receptor, thereby reducing the level of undesirable side effects on the heart.

The search for suitable selective antagonists at the M2 and 3 receptors has continued for many years as indicated by Barlow and Shepherd, Br. J. Pharmac, 1986, 89, 837-843, who describe further attempts to produce alternative antagonists to 4-diphenylacetoxy-N- methylpiperidine(4-DAMP) methobro ide. However, it has now been found that a group of N-substituted 4-piperidinol esters possesses fully acceptable levels of antimuscarinic activity and shows enhanced activity for the M3 receptors as compared with the M2 receptors, with a level of selectivity which in general is better than that of 4-ϋAMP methobromide. This group of compounds has never previously been studied as antimuscarinic drugs, although one compound is reported as an intermediate, only, in a patent application relating to such drugs.

A finding in a compound of such selectivity is of greater value than a finding of enhanced, but non-selective, anti-muscarinic receptor activity for a new compound. Thus, the comprehensive literature on antimuscarinic N-substituted piperidin-4-ol esters includes the studies reported by Sugai et aj. (Che . Phar . Bull., 1984, 32(3) . 967 and 977, and Japanese Patent Application Number 27570/1979) on tertiary bases and quaternary ammonium salts which contain a substituted or unsubstituted 1 ,3-dioxolan-4-ylmethyl group substituted on the nitrogen atom of the piperidine ring. Accordingly the present invention compri ses a compound of formula ( I)

in which R and R2 are each separately selected from a phenyl group which is unsubstituted or substituted by one or more groups selected from alkyl, alkoxy, alkylenedioxy, halogeno, halogeno substituted alkyl, hydroxy and nitro, R3 and R4 are each hydrogen or together are an oxo group and R5 is an aromatic group, the compound optionally being in the form of a physiologically acceptable acid addition or quaternary ammonium salt, for use in therapy.

These compounds are novel apart from the disclosure of l-benzyl-4-diphenylacetoxypiperidine hydrochloride as an intermediate in Example 5 of European Patent Application A-0309424. The present invention therefore further comprises a compound of formula (I)

in which R] and R2 are each separately selected from a phenyl group which is unsubstituted or substituted by one or more groups selected from alkyl, alkoxy, alkylenedioxy, halogeno, halogeno substituted alkyl, hydroxy and nitro, R3 and R4 are each hydrogen or together are an oxo group and R5 is an aromatic group, the compound optionally being in the form of a physiologically acceptable acid addition or quaternary ammonium salt thereof, but excluding the compound in which R-| = R2 = R5 = phenyl and R3 = R4 = hydrogen and physiologically acceptable acid addition salts thereof. Particularly suitable substituents on a substituted phenyl group R-| or R2 are Cη— alkyl groups, for example methyl, ethyl, propyl and isopropyl, C _ alkoxy groups, for example methoxy and ethoxy, C-j_3 alkylenedioxy groups, for example methylenedioxy, fluoro, chloro, bro o and iodo groups, C-_j— alkyl groups substituted by one or more halogeno groups, for example three fluoro groups as in trifluoromethyl , hydroxy and nitro. Although various numbers of substituents may be present, for example 1 , 2 or 3 monovalent substituents, preferably such substituted phenyl groups contain no more than one substituent (including one alkylenedioxy group) and conveniently the groups R_] and R are identical, especially with each being an unsubstituted phenyl group.

Although the grouping -C(R3)(R4)-Rs may be an acyl group it is preferred that R3 and R₄ are each hydrogen rather than together being an oxo group. The aromatic group R5 may be carbocyclic or heterocyclic and unsubstituted or substituted, suitable heterocyclic groups consisting of a 5- or 6-membered ring system which contains one or two hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur. Although suitable carbocyclic groups R5 are both phenyl and naphthyl, it is generally preferred that R5 is monocyclic. Moreover, it is further preferred that R5 is a non-basic aromatic group so that among the heterocyclic groups thienyl is of greater interest than basic groups such as pyridyl, pyrimidyl, oxazolyl and thiazolyl, although such groups can be used as evidenced by the data presented herein on the compound containing a 2-pyridyl group R5. Preferred groups R5 are thus 2- or 3-thienyl (thienyl indicates the univalent radical^"i{^" Jjderived from thiophene) and especially phenyl.

Such aromatic groups R5 may be substituted by one or more substituents but preferably no more than one substituent, especially in the case of naphthyl and particularly of phenyl groups. Suitable substituents are broadly as described above for the substituted phenyl groups R- and R , for example methyl, methoxy, fluoro and nitro. However, in the case of R5, halogeno and especially fluoro substituents are of the greatest interest. Substitution may be present at various positions in the ring but in the case of substituted phenyl groups there is particular interest in substitution at the ortho and especially the para positions, substitution at the meta position being less preferred, especially in the case of a nitro group. Unsubstituted groups R5 are, however, generally preferred.

Specific compounds (I) according to the present invention are 4-diphenylacetoxy-l-phenacylpiperidine (R-j = R₂ = R5 = C6H5, R3 + R4 = 0) , l-benzyl-4-diphenylacetoxypiperidine

(R-| = R₂ = R5 = C₅H₅, R₃ = R₄ = H), 4-diphenylacetoxy-l- (2-thienylmethyl)-ρiρeridine (R-_| = R₂ = C6H5, R₃ = R₄ = H, R5 = 2-C4H3S) and 4-diphenylacetoxy-l-(3-thienylmethyl)-piperidine (R-| = R₂ = C₆H₅, R₃ = R₄ = H, R₅ = 2-C4H3S) . As indicated, the tertiary bases (I) can be used in the form of physiologically acceptable salts which may be formed with various suitable inorganic and organic acids. Examples of such inorganic acids are phosphonic acid, nitric acid, sulphuric acid and particularly the hydrohalic acids hydrochloric acid, hydrobromic acid and hydroiodic acid. Examples of such organic acids are citric acid, oxalic acid, fumaric acid, maleic acid, lactic acid, succinic acid, malic acid, tartaric acid and methane sulphonic acid.

Formation of such an acid addition salt provides a particularly suitable method of formulating the basic compounds (I). In addition, however, it is possible to prepare quaternary ammonium salts in which the nitrogen atom of the piperidine ring is substituted by an additional group R to provide a salt as shown below in which a cation (la) is associated with one of various physiologically acceptable anions X^~.

da) The quaternary salts may contain a variety of groups RX but particularly preferred are those which contain a group R which is an alkyl group substituted by a phenyl group which may optionally itself be substituted, for example as described in relation to the groups R-| and R2, and particularly those which contain a group R which is an alkyl group. Such alkyl groups R may conveniently be as described hereinbefore in relation to alkyl substituents on substituted phenyl groups R- and Rg, for example being isopropyl, propyl, ethyl or particularly methyl. The group X may be of a variety of types, for example corresponding to the anions present in the acid addition salts described hereinbefore. Preferred groups X are however the halogeno groups, for example bromo or chloro.

The compounds of formula (I) are most conveniently prepared by reaction of a compound of formula (II)

in which R-| and R2 are as defined for the compound of formula (1) or are groups convertible thereto, with a compound of formula (III).

?3

Y— C—R5 (III)

I R₄

in which R3 and R4 are as defined for the compound of formula (I) and R5 is as defined for the compound of formula (I) or is a group convertible thereto, and Y is a suitable leaving group, in particular a halogeno group, for example a chloro or especially a bromo group. The reaction is conveniently effected in solution in a suitable organic solvent such as chloroform using an appropriate temperature and time, for example at room temperature over a period of up to 24 hours. An alternati ve route to the compounds of formula ( I ) i nvol ves reacti ng a compound of formula ( IV)

CHCOY ( IV)

/ R2

in which R- and R2 are as defined for the compound of formula (I) or are groups convertible thereto, and Y is a suitable leaving group, with a compound of formula (V)

in which R3 and R4 are as defined for the compound of formula (I) and R5 is as defined for the compound of formula (I) or is a group convertible thereto. Y is in particular a halogeno group, for example a bromo or especially a chloro group, or alternatively an alkoxy group, for example one containing an alkyl group as described hereinbefore in relation to alkyl substituents on substituted phenyl groups R-| and R2, such as methoxy. The reaction, is conveniently effected in solution in a suitable organic solvent such as toluene using an appropriate temperature and time, for example at 80°C over a period of up to 24 hours.

The free bases (I) often do not form crystalline solids and it is therefore usually convenient to isolate the compound (I) in the form of an acid addition salt by reaction with an acid, for example a monobasic acid. It is also usually preferable to .formulate the compound (I) as a salt, for example with one of the acids described hereinbefore, for example HBr or HC1, and in such an instance the compound may suitably be isolated directly in the form of the acid addition salt which is to be used therapeutically. As an alternative to the use of the compounds (I) as the free base or an acid addition salt they may be formulated as a quaternary ammonium salt containing a cation (la) as indicated hereinbefore, although such salts do have disadvantages in terms of oral absorption and ability to cross the blood brain barrier. Such salts may conveniently be formed in several ways. Firstly the compound (1) may be reacted with a compound RX in which R is the additional group present on the nitrogen atom in the quaternary ammonium salt and X~ is the anion present therein. Alternatively a compound of formula (Ha)

in which R] and R2 are as defined above for formula (II) and R is the additional group present in the quaternary ammonium salt may be reacted with a compound of formula (Ilia)

X— C— R5 (Ilia)

R4

in which R3, R4 and R5 are as defined above for formula (III) and X provides the anion present in the quaternary ammonium salt.

Particularly where the quaternary ammonium salts contain an anion which is not a halogeno anion, it may be convenient to prepare the salt by reaction of a quaternary ammonium salt containing such a halogeno anion with an alkali metal salt, for example a sodium or potassium salt, containing the alternative anion which it is desired to introduce.

Most commonly R- , R2 and R5 in the compounds of formulae (II), (IV), (V), (III), (Ila) and (Ilia) are identical with those groups in the compound of formula (I) but in some instances it may be convenient for this not to be the case, particularly where these groups are substituted groups and the compounds (II) to (V), (Ila) and (Ilia) contain a substituent or substituents convertible to those present in (I) .

It will be appreciated that the invention encompasses compounds (I) in the various stereochemical forms in which they exist, certain of which may be of particular value by virtue of their level of therapeutic activity and/or physical properties such as greater aqueous solubility, etc. In particular, when R- and R2 are different the compounds will contain at least one asymmetric carbon atom and will be resolvable into optically active iso ers. Moreover the quaternary ammonium salts can exist in different stereoisomeric forms depending on the relative orientation of the groups -C(R3)(R4)-Rs and R to the rest of the molecule. Such stereochemistry is described in detail by Sugai et al_, ibid, particularly in the Japanese patent application. It will be appreciated, however, that the absence of stereoisomerism in a compound (I) can simplify synthetic procedures and for that reason free bases and acid addition salts (I) in which R- and R2 are identical and which do not contain other asymmetric carbon atoms have an advantage.

The antagonist activity of the compounds of the present invention against the uscarinic receptors, particularly against the M3 receptor, renders them of value as spasmolytics (or antispasmodics) which may be used in the treatment of patients with various conditions in which smooth muscle is in spasm. Such conditions include gastrointestinal motility disorders such as the spastic condition of the gut, functional diarrhoea, irritable bowel syndrome, cardiospas , pylorospasm, gastro-oesophaegeal reflux, gastric and duodenal ulcers and also spasm of the bilary and particularly urinary tracts and urinary incontinence. In addition the compounds are of interest in the control of bronchospasm as M3 receptors are involved in cholinergic-induced bronchoconstriction. The particular value of the compounds is their ability to block effects on M3 receptors in concentrations which do not have substantial effects on the beating of the heart. The compounds are of further interest for their anti-secretory activity and in addition to their effects on gastric and intestinal secretion therefore have potential for use in reducing nasal secretion in colds, in reducing sweating and for reducing excessive excretions in conjunction with operative procedures. Thus there is a role for cardiac-sparing substitutes for atropine as pre-operative medication, particularly in the elderly, and in preparations for suppressing nasal secretions and for reducing sweating.

It should also be noted that other antimuscarinics have been shown to be of value by virtue of a centrally acting effect in the treatment of defects of the central nervous system where the cholinergic or muscarinic mechanisms are malfunctioning, for example Parkinson's and Alzheimer's diseases and other conditions involving cognitive deficiencies. The compounds of the present invention thus have further potential in this area.

The compounds (I) may be formulated with a physiologically acceptable diluent or carrier for use as pharmaceuticals for veterinary, for example in an avian or especially a mammalian context, and particularly for human use by a variety of methods. For instance, they may be applied as a composition incorporating a liquid diluent or carrier, for example an aqueous or oily solution, suspension or emulsion, which may often be employed in injectable form for parenteral administration and therefore may conveniently be sterile and pyrogen free. Oral administration may also be used, particularly in the case of the free bases and their acid addition salts, and indeed is preferred. Although compositions for this purpose may incorporate a liquid diluent or carrier, it is more usual to use a solid, for example a conventional solid carrier material such as starch, lactose, dextrin or magnesium stearate. Such solid compositions may conveniently be of a formed type, for example as tablets, capsules (including spansules), etc. Other forms of administration than by injection or through the oral route may also be considered in both human and veterinary contexts, for example the use of suppositories or pessaries. Another form of pharmaceutical composition is one for baccal or nasal administration, for example lozenges, nose drops or an aerosol spray, or alternatively drops for administration into the eye which may conveniently contain a sterile liquid diluent or carrier.

Thus, the invention further includes a pharmaceutical composition comprising a compound (I) as defined hereinbefore together with a physiologically acceptable diluent or carrier.

Compositions may be formulated in unit dosage form, i.e. in the form of discrete portions each comprising a unit dose, or a multiple or sub-multiple of a unit dose. Whilst the dosage of active compound given will depend on various factors, including the particular compound which is employed in the composition and the condition treated, it may be stated by way of guidance that a satisfactory spasmolytic effect will often be achieved using a daily dosage of about 0.05 to 40 mg/kg, particularly of about 0.1 to 10 or 20 mg/kg, for example about 1 or 1.5 mg/kg. However, it will be appreciated that it may be appropriate under certain circumstances to give daily dosages either below or above these levels. Where desired, more than one compound (I) may be administered in the pharmaceutical composition or, indeed, other active compounds may be included in the composition.

The present invention therefore includes a compound of formula (I) as defined hereinbefore for use in therapy and also a method for the treatment of a patient in need of anti-spasmodic treatment which comprises administering to said patient a therapeutically effective amount of a compound of formula (I) as defined hereinbefore. The invention is illustrated by the following Examples.

EXAMPLES Example 1 : Preparation of compounds (I) (A) The compounds are prepared by reacting equimolar amounts of the appropriate unsubstituted or substituted 4-diphenylacetoxy- piperidine free base and the appropriate bromo compound Br-C(R3)(R4)-R5. The reactants are dissolved in chloroform and stirred at room temperature overnight. The solution is then washed with saturated aqueous sodium carbonate and the chloroform layer is dried with magnesium sulphate. After filtration, the solvent is distilled off, the last traces of chloroform being removed by evaporation with ethanol. The residue is triturated with ether and this often yields the base as a white powder. The product from the trituration is dissolved in a mixture of acetone and ether (3:1 by volume) and a slight excess of 5056 aqueous HBr is added with stirring. Stirring of the mixture is continued overnight, the hydrobro ide of the base often appearing after only about 5 minutes as a white solid. The mixture is then filtered and the solid washed with ether and recrystallized usually from butanone or mixtures of butanone and ethanol with the addition of ether if necessary.

Details of the crystallization solvent and melting point for fourteen compounds (I) prepared in this way are given in Table 1. These contain as R5 a substituted or unsubstituted phenyl group, an a- or β-naphthyl group or a 2- or 3-thienyl group. In addition similar data on a fifteenth compound containing a 2-pyridyl group R5 prepared as described under (B) below is also given in the table. In the case of compound 7 the free base was obtained by crystallization from ethanol/water of the product obtained by trituration of the reaction residue. In the case of compound 2 the methobromide was formed by reaction of the free base in butanone with an excess (>1 equivalent) of methyl bromide. (B) The above procedure can be varied slightly so that in the case of the compound containing a 2-pyridyl group R5 the reactant 2-chloromethylpyridine may be used as follows.

4-(ϋiphenylacetoxy)piperidine (2.37 g, 8.03 mmol), potassium carbonate (2.222 g, 16.1 mmol), 2-(chloromethyl)pyridine hydrochloride (1.31 g, 7.99 mmol) and catalytic sodium iodide (65 mg) are stirred together in boiling acetonitrile (30 ml) for 15 hours. The solvent is evaporated under reduced pressure. The residue is partitioned between water (30 ml) and chlorofom (3 x 50 ml). The combined organic portions are dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is "flash" chromatographed on silica eluting with acetone-petrol (bp 40-60°C) 1/1 to give the free base as a pale yellow solid. This is dissolved in acetone (20 ml) and treated with 48% HBr aqueous solution (1 ml). The solvents are evaporated under reduced pressure and the residue is co-evaporated under reduced pressure with toluene (30 ml). The residue is recrystallised from ethanol to give the 4-(diphenylacetoxy)-l-(2- pyridylmethyl)piperidine bis-hydrobromide salt as a white powder (2.15 g).

A similar variation may be used with other compounds.

Table 1

Compounds of formula

Example 2 : Comparison of activity of compounds (I) against guinea-pig isolated atria and ileum The procedures used were essentially those described by Barlow and Shepherd, Br. J. Pharmac, 1986, 89., 837-843 as indicated below. (a) Guinea-pig isolated ileum

The guinea-pig ileum responses were recorded isotonically with a load of about 0.5 g. The agonist, carbachol , was allowed to act for 30 seconds and added once every 90 seconds by relays controlled from a PET microcomputer. The tissue was suspended in Krebs solution aerated with a mixture of 95% O2 and 5% CO2, usually containing 5 yM norphenylephrine and experiments were carried out at 29.8 ± 0.3°C.

Alternate small and large control responses were obtained, usually to 0.1 and 0.2 y carbachol. When these were regular the tissue was exposed to a solution of the antagonist and the concentration of agonist was increased to try to obtain responses which roughly matched the controls. When these were regular the approximate dose-ratio was given by the ratio of the concentrations of agonist used in the presence and in the absence of the antagonist and an exact dose-ratio was calculated from the size of the responses by a calculation similar to a 4-point assay, (b) Guinea-pig isolated atria

The atria were set up in Krebs solution aerated with a mixture of 95% O2 and 5% CO2, usually containing 5 yM norphenylephrine (the same solution as was used for the ileum). The temperature was 29.8 ± 0.3°C and the spontaneous contractions were recorded isometrically with a load of about 0.2 g, action potentials also being recorded.

The agonist, carbachol, was added by relays operated from a Commodore 128 microcomputer and allowed to act for 5 minutes. Doses were given once every 15 minutes with a second wash 10 minutes from the start of the cycle. The effects of the agonist were expressed as the percentage inhibition of the force of the contraction. As in the experiments on the ileum, the control responses were usually obtained with 0.1 and 0.2 μM carbachol. The tissue was then exposed to the antagonist and the experiment continued as with the ileum. The data obtained for the fourteen compounds (I) of Example 1 is given in Table 2. The dose-ratios obtained are used to calculate the affinity constants which are shown in log form. In some cases the mean estimate of log affinity constant, K, is shown (± s.e.) with the number of experiments carried out indicated in brackets. In the other cases only one experiment was carried out. It will be seen that for every compound there is a selective M3 receptor antagonist effect with the effect against the atria being less than that against the ileum. On the basis of these results the highest level of selectivity was shown by l-benzyl-4-diphenyl- acetoxypiperidine hydrobromide but nearly similar levels were shown by the hydrobromides of l-(3-thienylmethyl)-4-diphenyl- acetoxypiperidine and particularly l-(2-thienylmethyl)-4- diphenylacetoxypiperidine (compounds 1, 6 and 5 respectively).

Table 2 Atria and ileum log affinity constants for compounds (I)

Claims

in which R-_| and R2 are each separately selected from a phenyl group which is unsubstituted or substituted by one or more groups selected from alkyl, alkoxy, alkylenedioxy, halogeno, halogeno substituted alkyl, hydroxy and nitro, R3 and R4 are each hydrogen or together are an oxo group and R5 is an aromatic group, the compound optionally being in the form of a physiologically acceptable acid addition or quaternary ammonium salt, for use in therapy.

2. A compound of formula (I)

in which R-| and R2 are each separately selected from a phenyl group, which is unsubstituted or substituted by one or more groups selected from alkyl, alkoxy, alkylenedioxy, halogeno, halogeno substituted alkyl, hydroxy and nitro, R3 and R4 are each hydrogen or together are an oxo group and R5 is an aromatic group, the compound optionally being in the form of a physiologically acceptable acid addition or quaternary ammonium salt thereof, but excluding the compound in which R-| = R2 = R5 = phenyl and R3 = R4 = hydrogen and physiologically acceptable acid addition salts thereof.

3. A compound according to Claim 1 or 2, in which R5 is a phenyl or thienyl group which is unsubstituted or substituted by one or more groups selected from alkyl, alkoxy, alkylenedioxy, halogeno, halogeno substituted alkyl, hydroxy and nitro.

4. A compound according to Claim 3, in which R5 is phenyl, 2-thienyl or 3-thienyl.

5. A compound according to any of Claims 1 to 4, in which R- and R are each phenyl .

6. A compound according to any of Claims 1 to 5, in which R3 and R4 are each hydrogen.

7. A compound according to Claim 1, which is l-benzyl-4-diphenyl- acetoxypiperidine, 4-diphenylacetoxy-l-(2-thienylmethyl)-piperidine or 4-diphenylacetoxy-l-(3-thienylmethyl)-piperidine.

8. A compound according to Claim 2, which is l-(2-thienylmethyl-4- diphenylacetoxypiperidine or l-(3-thienylmethyl)-4-diphenylacetoxy- piperidine.

9. A compound according to any of the preceding claims, which is in the form of the free base or an acid addition salt.

10. A compound according to any of Claims 1 to 8, which is in the form of a quaternary ammonium salt wherein the additional group substituted on the nitrogen atom of the ring is an alkyl group.

11. A compound according to Claim 1 or 2, which is a quaternary ammonium salt of l-benzyl-4-diphenylacetoxypiperidine, 4-diphenylacetoxy-l-(2-thienylmethyl)-piperidine or

4-diphenylacetoxy-l-(3-thienylmethyl)-piperidiπe having an additional methyl group substituted on the nitrogen atom of the ring.

12. A process for the preparation of a compound of formula (I) as defined in Claim 1 which comprises:

(1) reacting a compound of formula (II)

in which R- and R2 are as defined for the compound of formula (I), or are groups convertible thereto, with a compound of formula (III) Y — C— R5 ( III)

I

R₄

in which R3 and R4 are as defined for the compound of formula (I), R5 is as defined for the compound of formula (I) or is a group convertible thereto, and Y is a suitable leaving group, and where appropriate in either order converting one or more of R- , R and R5 to the groups present in the compound (I) and/or converting the compound to an acid addition or quaternary ammonium salt: (2) reacting a compound of formula (IV)

(IV)

in which R- and R2 are as defined for the compound of formula (I), or are groups convertible thereto, and Y is a suitable leaving group, with a compound of formula (V)

in which R3 and R4 are as defined for the compound of formula (I) and R5 is as defined for the compound of formula (I), or is a group convertible thereto, and where appropriate in either order converting one or more of R-| , R2 and R5 to the groups present in the compound (I) and/or converting the compound to an acid addition or quaternary ammonium salt; or in the case of the preparation of a quaternary ammonium salt: (3) reacting a compound of formula ( Ila)

^Rl

CHCOO— N-R ( Ila)

in which R- and R2 are as defined above for formula (II) and R is the additional group present in the quaternary ammonium salt with a compound of formula (Ilia)

X—C—R5 (Ilia)

R₄

in which R3, R4 and R5 are as defined above for formula (III) and X provides the anion present in the quaternary ammonium salt, and where appropriate converting one or more of R~ , R2 and R5 to the groups present in the compound (I); or (4) reacting a quaternary ammonium salt produced by any of the three procedures with an alkali metal salt to replace the anion present in the quaternary ammonium salt by that present in the alkali metal salt and where appropriate converting one or more of R-| , R2 and R5 to the groups present in the compound (I).

13. A process according to Claim 12, in which the procedure (1), (3) or (4) is used.

14. A pharmaceutical composition comprising a compound of formula (I) as defined in any of Claims 1 to 11 , together with a physiologically acceptable diluent or carrier.

15. A method for the treatment of a patient in need. of anti-spasmodic treatment which comprises administering to said patient a therapeutically effective amount of a compound of formula (I) as defined in any of Claims 1 to 11.