GB1600970A - Heterocyclic compounds - Google Patents

Description

(54) HETEROCYCLIC COMPOUNDS (71) We, ACF CHEMIEFARMA NV, a Dutch corporate body, of Straatweg 2, Maarssen, The Netherlands, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to novel oxime ether derivatives having anti-gastric ulcer activity, to pharmaceutical compositions containing them and to methods for their preparation.

In J. Org.Chem. 34, 3635 (1969), the preparation of a-methoxyimino and abenzyloxyimino-4-pyridineacetonitrile (O-methyl and O-benzyl 4-pyridine-glyoxylonitrile) and a-methoxyimino-4-pyridineacetamide has been described, but no pharmacological activity was mentioned.

In Dutch patent application 76.09792 the oxime ether a-cyano-methoxyiminophenylacetonitrile has been described as an antagonist of herbicide activity.

We have now found that certain oxime ethers possess anti-ulcer activity in the gastro-intestinal tract, e.g. by inhibition of gastric acid secretion and/or stimulation of mucus formation, and that these compounds and pharmaceutical compositions containing them may be used in the treatment of diseases of the gastro-intestinal tract.

Accordingly, the invention provides a compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein Het is a pyridinyl group (substituted or unsubstituted), X is a group with the formula -C(S)NRLR2, wherein Rl is hydrogen or a C14 alkyl group, R is hydrogen or a C14 alkyl group, or R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring in which another hereto atom may be present; and R is C16 alkyl, C27 carboxyalkyl, C56 cycloalkyl, C58 cycloalkylalkyl, C36 alkenyl, C34 alkynyl, phenyl C1 -3 alkyl, the phenyl group being optionally substituted by one or more C16 alkyl, halogen, C1 -6 alkoxy, nitro, cyano or trifluoromethyl groups, a carbamidoalkyl group with the formula - (CH2)rnCO)NR3R4 wherein m = 1 or 2, R3 is hydrogen or C13 alkyl, R4 is hydrogen or C13 alkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring in which another hetero atom may be present, or cyano C1 -3 alkyl.

The Het group may be optionally substituted by one or more C16 alkyl, halogen or C16 alkoxy groups.

In one sub-class of compounds of the formula (I) R is a C16 alkyl, C5-6 cycloalkyl, C58 cycloalkylalkyl or a phenyl C13 alkyl group.

Examples of Het groups are 2-, 3- or 4-pyridinyl. Preferably, Het is 2- or 4-pyridinyl, of which 2-pyridinyl is especially preferred, Preferably, X is thiocarbamoyl (C-(S)NH2), N,N-diethylaminothiocarbonyl or morpho linothiocarbonyl.

Examples of R groups are methyl, ethyl, n-or iso-propyl, n-or tert-butyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, allyl, propargyl, benzyl, optionally substituted by p-methyl, p-chloro, p-methoxy, p-nitro. p-trifluoromethyl or p-cyano, phenethyl, carbamoylmethyl (CH2C(O)NH2), dimethylaminocarbonylmethyl, and cyanomethyl. Preferably R is methyl, ethyl, allyl, propargyl, benzyl, phenethyl or cyanomethyl, the methyl group being the most preferred.

The pharmaceutically acceptable salts include the therapeutically appropriate acid salts and quaternary addition salts. Among the pharmaceutically acceptable acids, which are suitable for the formation of addition salts, are inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, and organic acids, such as citric acid, acetic acid, oxalic acid, fumaric acid, lactic acid, succinic acid, tartaric acid and methanesulphonic acid, of which hydrochloric acid, sulphuric acid and methanesulphonic acid are preferred.

An example of quaternary addition salts is the methiodide salt of the compounds of formula I.

From the aforesaid it will be seen that one particularly useful class of compounds within formula (I) is of formula (I)':

wherein Het' is 2- or 4-pyridinyl; X' is thiocarbamoyl or morpholinothiocarbonyl; and R' is methyl, ethyl, allyl, propargyl, cyanomethyl, benzyl or phenethyl; and addition salts thereof.

It will be realized that the compounds with formula (I) may exist in two different forms, E and Z isomers (i.e. cis and trans isomers, respectively). All such forms are included within this invention.

The compounds of formula (I) (by which, hereinafter, we include the pharmaceutically acceptable salts) can be prepared according to methods which are known per se for the preparation of this type of compound, or methods analogous thereto.

A suitable method for the preparation of a compound of formula (I) comprises the reaction of a compound of formula (II):

wherein Het and X are as defined in relation to formula (I) and M is a hydrogen or an alkali metal atom, with a compound of formula (III): R-Y (III) wherein R is as defined in relation to formula (I) and Y is a suitable leaving group, such as a chloride, bromide, iodide or a tosyloxy group.

The reaction may be carried out in a solvent, such as methanol, ethanol, acetone, methyl ethyl ketone, dioxane, dimethylglycol ether or dimethyl formamide. If, in formula (II), M represents a hydrogen atom, it may be useful to add an acid binding agent to the reaction mixture. Suitable acid binding agents are, for example, alkali metal hydrides, hydroxides, carbonates and alkoxides, tertiary amines, and pyridine. The reaction conditions are as commonly used for this type of reaction. Usually, the reaction temperature will be between room temperature and boiling temperature of the reaction mixture.

The conversion of the oxime compound (II) into compound (I) is usually effected by alkylation with an alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, phenylalkyl, carbamidoalkyl, carboxyalkyl or cyanoalkyl halide, such as the chloride, bromide or iodide, in the presence of, for instance, sodium hydride, or an alkali metal hydroxide or alkoxide, preferably sodium methoxide, dissolved in a suitable solvent, preferably dimethyl formamide or methyl alcohol.

The compounds of the formula (I) may also be prepared by reacting a corresponding compound wherein X is cyano so as to convert the cyano to thioamide; or by reacting a corresponding compound wherein X is carboxamide (suitably prepared from the X is cyano compound) so as to convert the carboxamide to thioamide. Suitably, such-as cyano group can be converted to a thioamide group by treating the compound with hydrogen sulphide; and such a carboxamide may be converted to thio amide by treatment with phosphorus pentasulphide; the thus formed thioamides can then be alkylated if desired with for example a dialkyl sulphate. The cyano intermediates mentioned in the preceding paragraph may be prepared in analogous manner to the compounds of this invention.

The conversion of the obtained compound of formula (I), wherein R is carboxyalkyl, into the compound in which R is carbamidoalkyl may take place by conventional methods.

The pharmaceutically acceptable salts can be prepared in conventional manner.

The separation of the E and Z isomers may be effected by conventional methods, preferably by column chromatography.

The preparation of the intermediate oxime compounds of formula (II) and their salts may occur by methods which are known for the preparation of this type of compound and methods analogous thereto.

A preferred method for the preparation of a compound of formula (II) comprises the reaction of a compound of formula (IV): Het - CH2 - X (IV) with a suitable nitrite compound.

Suitable nitrite compounds include nitrous acid-generating salts or esters. If the methylene group of the starting compound (IV) is relatively active, the conventional and preferred nitrite compounds are alkali metal nitrates, preferably sodium nitrite, the conventional and preferred solvent being glacial acetic acid.

When the methylene group of the starting compound (IV) is relatively less active, eg if Het is a 3-pyridyl group, suitable nitrite compounds for the conversion of compound (IV) into compound (II) include alkyl nitrites, preferably n-butyl nitrite, in a suitable solvent, preferably methyl alcohol, in the presence of an alkali metal alkoxide, preferably sodium methoxide. After acidifying, e.g. with acetic acid, compound (II) may be isolated.

In a number of cases, certain reaction steps described may be carried out in a different sequence or simultaneously or without insolating intermediates, and these possibilities are all included in the invention. If, for example, the introduction of the oxime group in a compound of formula (IV) is carried out with an alkyl nitrite, the following alkylation step can also be performed without isolating the oxime compound (II), by omitting the acidifying step and adding the alkyl, cycloalkyl, etc. halide to the reaction medium, the medium being made weakly alkaline for the latter reaction.

The invention also provides a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or dilutent therefor.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

Clearly the formulation of the said pharmaceutical composition will depend on the nature of the activity shown by the chosen compound of the formula (I), and on other factors such as a preference in a particular area of therapy for a particular mode of administration.

Tablets and capsules for oral administration may be in unit dose presentation form, and may 'contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstruction with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents. emulsifying agents, non-aqueous vichicles (which may include edible oils), preservatives, and if desired conventional flavouring or colouring agents.

For the parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

When appropriate the compositions of this invention may be presented as an aerosol for oral administration, or as a microfine powder for insufflation.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

It will of course be realized that the precise dosage used in the treatment of any of the hereinbefore described disorders will depend on the actual compound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated.

Broadly, the dose may vary from about 100 mg up to about 25 g per day per patient.

The following Examples illustrate the preparation of compounds of the formula (I) and their pharmacological properties (Examples 3(c), (d), (e), 4 and 6), and the preparation of certain other compounds not in accordance with the invention (Examples 1, 2, 3(a), 3(b) and 5).

EXAMPLE la a-Hydroxyiminopyrazineaceton itrile (model compound) Pyrazineacetonitrile (32 g), prepared as described in British Patent Specification 1 021 397, was dissolved in glacial acetic acid (250 ml). The solution was stirred and 1.2 equivalents of sodium nitrite (22.3 g) were added in small portions, while the temperature was kept under 20"C. After the addition, the reaction mixture was stirred at room temperature for another two hours. The title compound separated partly from the reaction mixture. On evaporation of the solvent under reduced pressure, a solid was obtained which on recrystallization from hot water yielded a-llydroxyiminopyrazineacetonitrile (35 g, 88%). Melting point > 192"C (dec.).

EXAMPLE l b a-Hvdroxyhnho-2-pyridhieacetoninlle (intermediate compound) In a manner identical to that described in Example la, but starting from 2pyridineacetonitrile, the title compound was obtained in a yield of 80%. Melting point 209go (dec.) after crystallization from methanol/water.

EXAMPLE 2 a. ct-Hvdroxvitiino-N, N-diinetkvI-2-pyndinedioacetamide (intermediate compound) In a manner similar to that described in Example la. but starting from N,N-dimethyl 2-pyridinethioacetamide instead of pyrazineacetonitrile. the title compound was obtained, m.p. 120-121"C. The starting compound can be obtained in several ways. see for instance German Offenlegungsschrift 20 32 738, Organic Reactions III chapter 2 and R. Wegler et al in "Neuere Methoden der Praparativen Organischen Chemie".

Band III chapter 1 (p. 31).

In the same manner the following compounds were obtained: b. x-hydixyi'nino-N.N-diethyl-2-pyridinethioacetamide c. a-hydroxyimino-4-(2-pyridinylthioacetyl)morpholine (m.p. 213-214"C dec.).

Not purified. Crude product was directly used in the next reaction.

EXAMPLE 3a (model compound) a-Methoxviminop vrazineacetonitrile a-Hydroxyiminopyrazineacetonitrile (35 g), prepared as described in Example 1, was added to 1.1 equivalents of sodium methoxide in methanol (300 ml) and the mixture was refluxed for two hours. The sodium salt of the oxime separated as a cream coloured solid.

Methyl iodide (1.5 eq. 52 g) was added and the reaction mixture was refluxed until the solid disappeared and a dark brown solution was obtained. Methanol was evaporated under reduced pressure and the residue was shaken with water and ethyl acetate. The organic layer was separated and dried over magnesium sulphate. Evaporation of the solvent vielded a dark residue, which was distilled under reduced pressure and recrystallised from petroleum ether (b.p. 40-60"C), containing about 10sic of ether. or purified by chromatography (SiO2) column, cyclohexane-ethyl acetate 2: 1) and then crystallized from petroleum ether (b.p. 40-60"C), containing about 10% of ether. The amethoxyiminopyrazineacetonitrile was obtained in a 75% yeild (29 g), m.p. 63-64"C. From NMR-spectra this compound appeared to be the Z-isomer. The E-isomer was obtained by photochemical isomerization in benzene, followed by column chromatography of the obtained mixture (silica gel with cyclohexane-ethyl acetate 3 : 1 as the eluent). Melting point 64-65"C after recrystallization from petroleum ether (40-60"C).

EXAMPLE 3b (intermediate compound) a-Methoxyimino-2-pyridineacetonitrile In a similar manner to that described in Example 3a, but starting from a-hydroxyimino-2pyridineacetonitrile, prepared as described in Example 1B, the title compound was prepared in a yield of 90%. Melting point after crystallization from petroleum ether (b.p.

40-60"C) 68-69"C.

In the same manner the following oxime ethers of the formula (I) were obtained.

Het X R Y m.p. "C c. 2-pyridinyl N,N-dimethylaminothiocarbonyl methyl iodide 121-124 d. 2-pyridinyl N,N-diethylaminothiocarbonyl methyl iodide oil e. 2-pyridinyl thiocarbonylmorpholide methyl iodide 142-144 EXAMPLE 4 a-Methoxyimino-2-pyridinethioacetamide (Z-isomer) A solution of 1.23 g of hydrogen sulphide and 5.86 g of a-methoxyimino-2pyridineacetonitrile in 50 ml of pyridine was stirred in a closed vessel for 17 hours. The reaction mixture was then concentrated under reduced pressure and the residue crystallized from a mixture of methanol and ether. Yield 0.6 g, m.p. 155-156"C.

EXAMPLE 5 a. a-Methoxyiminopyrazineacetamide (Z-isomer) (model compound) a-Methoxyiminopyrazineacetonitrile Z-isomer (6.0 g) was dissolved in 35 ml of methanol. A solution of potassium hydroxide (4 g) in 10 ml of water was added and the dark reaction mixture was stirred for 1 hour at a temperature of 40"C. The greater part of the methanol was evaporated at reduced pressure. Acidification and successive filtration of the precipitate afforded Z-a-methoxyiminopyrazineacetamide which was recrystallized from water. M.p. 188-190"C, yield 3.1 g.

In the same way was obtained: b. a-methoxyimino-2-pyridineacetamide, Z-isomer, m.p. 147-148"C (intermediate com pound) EXAMPLE 6 a-Methoxyimino-2-pyridinethioacetamide (Z-isomer) The same compound as described in Example 4 was obtained by treating the corresponding carboxamide (Example Sb) with P2S5 in pyridine (cf. German Offenlegungsschrift 20 32 738).

PHARMACOLOGICAL DATA 1. Anti-ulcer Activity This was assessed by the inhibition of indomethacin-induced gastric damage in the rat according to the method of Elegbe (Israeli J. Med. Sci. (1974), 10, 1451).

Rats were starved overnight, given indomethacin subcutaneously (15 mg/kg) and sacrificed 5 hours later. Stomachs were inflated with 0.9% saline, cut along the greater curvature, pinned out and scored for gastric damage by the following system: Score 1-3 according to the degree of erythema and slight haemorrage.

Score 4-6 according to the degree of mucosal erosion.

Score 7-9 according to depth of gastric damage.

Groups of 7 rats were used for each treatment level of compound, and a similar group receiving vehicle only was set up on each occasion of testing. Compound or vehicle was administered orally 30 minutes prior to, and at 2 hours post, dosing with indomethacin. Mean values per treatment were obtained using the above scoring system and the Mann Witney test applied for significance between such values. The mean inhibition of gastric damage from a number of experiments is shown in the following Table 1; the dosage being 100 mg/kg orally.

2. Effects on Gastric Secretion, in the Pyloric Ligated Rat The method described by Shay, et al. (gastroenterol (1945) 26, 906) was used. After overnight starvation the pylorus of a rat was ligated under halothane anaesthesia, the Compound vehicle only administered intraduodenally and the rats allowed to recover.

They were sacrificed 3 hours later and the gastric juice removed. After measurement of the volume of secretion, its hydrogen ion concentration, [H+] was determined by titration with 0.05N NaOH to pH 7. Groups of 4-6 animals were used for each treatment and the inhibitory effect of the compound was ascertained by comparison of the mean values obtained with those from a simultaneously set up control group of animals which received vehicle only. Students 't' test was applied for significance between groups. The mean values for % inhibition obtained for a number of experiments are shown in the following Table 2, the dosage being 100 mg/kg i.d.

Compound No. * Table 1 Table 2 % Inhibition % Inhibition Volume [H+] 3d 83 90 56 3e 96 46 38 4 (and 6) 74 32+ 24+ * The compound number is identical with the number of the Example wherein the preparation of the said compound is described.

+ 50 mg/kg Compounds of formula I in which Het is a substituted or unsubstituted heteroaromatic groups other than pyridyl are described and claimed in our copending application No.

624/77 (Serial No. 1600969).

WHAT WE CLAIM IS: 1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof. wherein Het is a substituted or unsubstituted pyridinyl group, X is a group with the formula -C(S)NR1R-, wherein R1 is hydrogen or a C14 alkyl group, R is hydrogen or a C14 alkyl group or Rl and R2 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring in which another hetero atom may be present; and

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (22)

**WARNING** start of CLMS field may overlap end of DESC **. Score 1-3 according to the degree of erythema and slight haemorrage. Score 4-6 according to the degree of mucosal erosion. Score 7-9 according to depth of gastric damage. Groups of 7 rats were used for each treatment level of compound, and a similar group receiving vehicle only was set up on each occasion of testing. Compound or vehicle was administered orally 30 minutes prior to, and at 2 hours post, dosing with indomethacin. Mean values per treatment were obtained using the above scoring system and the Mann Witney test applied for significance between such values. The mean inhibition of gastric damage from a number of experiments is shown in the following Table 1; the dosage being 100 mg/kg orally. 2. Effects on Gastric Secretion, in the Pyloric Ligated Rat The method described by Shay, et al. (gastroenterol (1945) 26, 906) was used. After overnight starvation the pylorus of a rat was ligated under halothane anaesthesia, the Compound vehicle only administered intraduodenally and the rats allowed to recover. They were sacrificed 3 hours later and the gastric juice removed. After measurement of the volume of secretion, its hydrogen ion concentration, [H+] was determined by titration with 0.05N NaOH to pH 7. Groups of 4-6 animals were used for each treatment and the inhibitory effect of the compound was ascertained by comparison of the mean values obtained with those from a simultaneously set up control group of animals which received vehicle only. Students 't' test was applied for significance between groups. The mean values for % inhibition obtained for a number of experiments are shown in the following Table 2, the dosage being 100 mg/kg i.d. Compound No. * Table 1 Table 2 % Inhibition % Inhibition Volume [H+] 3d 83 90 56 3e 96 46 38 4 (and 6) 74 32+ 24+ * The compound number is identical with the number of the Example wherein the preparation of the said compound is described. + 50 mg/kg Compounds of formula I in which Het is a substituted or unsubstituted heteroaromatic groups other than pyridyl are described and claimed in our copending application No. 624/77 (Serial No. 1600969). WHAT WE CLAIM IS:

1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof. wherein Het is a substituted or unsubstituted pyridinyl group, X is a group with the formula -C(S)NR1R-, wherein R1 is hydrogen or a C14 alkyl group, R is hydrogen or a C14 alkyl group or Rl and R2 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring in which another hetero atom may be present; and

R is C16 alkyl, C21 carboxyalkyl, C56 cycloalkyl, C58 cycloalkylalkyl, C3-6 alkenyl, Q,-4 alkynyl, phenyl C13 alkyl, phenyl C13 alkyl, the phenyl group being optionally substituted by one or more C16 alkyl, halogen, C16 alkoxy, nitro, cyano or trifluoromethyl groups, a carbamidoalkyl group with the formula (CR2)rnC(O)NR3R4 wherein m = 1 or 2, R3 is hydrogen or C13 alkyl, R4 is hydrogen or C13 alkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring in which another hetero atom may be present, or cyano C13 alkyl.

2. A compound according to claim 1, wherein the Het pyridyl group may be optionally substituted by one or more C16 alkyl, halogen or C16 alkoxy groups.

3. A compound according to claim 1 or claim 2, wherein R is a C16 alkyl, C56 cycloalkyl, C5g cycloalkylalkyl or a phenyl C13 alkyl group.

4. A compound according to claim 3, wherein Het is 2- or 4- pyridinyl; X is thiocarbamoyl or morpholinothiocarbonyl; and R is methyl, ethyl, allyl, propargyl, cyanomethyl, benzyl or phenethyl.

5. A compound according to any one of the preceding claims, wherein Het is 2-pyridinyl.

6. A compound according to any one of the claims 1 to 3 and 5, wherein Rl and R2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring in which another hetero atom may be present.

7. A compound according to any one of the claims 1 to 3 and 5, wherein R1 is hydrogen or a C14 alkyl group and R2 is hydrogen or a C14 alkyl group.

8. A compound according to claim 7, wherein R is hydrogen, methyl or ethyl and R2 is hydrogen, methyl or ethyl.

9. A compound according to any one of the preceding claims, wherein R is methyl.

10. A compound according to claim 1, wherein Het is 2-pyridyl, R1 is hydrogen, methyl or ethyl, R2 is hydrogen, methyl or ethyl, and R is methyl.

11. a-Methoxyimino-2-pyridinethioacetamide, or a pharmaceutically acceptable salt thereof.

12. α-Methoxyimino-2-pyridine-N,N-dimethylthioacetamide, or a pharmaceutically acceptable salt thereof.

13. α-Methoxyimino-2-pyridine-N,N-diethylthioacetamide, or a pharmaceutically acceptable salt thereof.

14. The compound of formula I as defined in claim 1, wherein Het is 2-pyridinyl, X is thiocarbonylmorpholide, and R is methyl, or a pharmaceutically acceptable salt thereof.

15. A compound according to any one of the preceding claims, which is substantially entirely in the form of the E or the Z isomer.

16. A process for preparing a compound as claimed in claim 1, which comprises reacting a compound of formula (II):

wherein Het and X are as defined in claim 1 and M is a hydrogen or an alkali metal atom, with a compound of formula (III): R - Y (III) wherein R is as defined in claim 1 and Y is a leaving group.

17. A process according to claim 1, wherein T is a chloride, bromide, iodide or a tosyloxy group.

18. A process for preparing a compound as claimed in claim 1 wherein X is a thioamide group, which comprises treating a compound of formula I wherein X is a cyano group with hydrogen sulphide to convert the cyano group to a thioamide group.

19. A process for preparing a compound as claimed in claim 1 wherein X is a thioamide group, which comprises treating a compound of formula I in which X is a carboxamide group with phosphorus pentasulphide to convert the carboxamide group to a thioamide group.

20. A process according to any of claims 16 to 19, which includes the step of forming a pharmaceutically acceptable acid or quaternary addition salt as claimed in claim 1.

21. A process according to any of claims 16 to 20, which also includes the step of separating individual E and Z isomers from a mixture of isomers.

22. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 15, together with a pharmaceutically acceptable carrier or diluent thereof.