IE51707B1 - Piperidine derivatives,their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Piperidine derivatives of the general formula I where R denotes hydrogen, C1-4-alkyl, hydroxy-C1-4-alkyl, C1-4-alkoxycarbonyl, benzyl (optionally substituted with halogen and/or C1-4-alkoxy), phenethyl or 3-phenylpropyl, X denotes one or more hydrogen or halogen atoms or one or more C1-4-alkyl, C1-4-alkoxy, trifluoromethyl or methylenedioxy groups, or X forms, together with the phenyl ring, a naphthyl group, with it not, however, being possible for R and X to be hydrogen simultaneously, and acid addition salts thereof. The compounds are prepared by reacting a compound of the formula II where R' is a protecting group for the nitrogen atom, such as a 4-nitrobenzoyl group, an optionally substituted benzoyl group, an optionally substituted benzyl group or an alkyl group, with a compound of the formula III where Y is a reactive group, such as a chlorine or bromine atom, after which the protecting group R' is removed provided that it does not correspond to the group R, or an optionally substituted benzoyl group which has been used as the protecting group is reduced, or by reacting a compound of the formula I' with a compound of the formula RZ, where Z is a reactive group. The compounds of the formula I and their acid addition salts can be used in medicine as antidepressants.

Description

The present invention relates to new therapeutically useful piperidine derivatives, to a process for their preparation, pharmaceutical compositions containing them and their use in therapy.

The piperidine derivatives of the present invention are those compounds of the general formula: wherein R represents a hydrogen atom, or a alkyl, hydroxyalkyl, or (C^_^)alkoxyc'arbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C1_a)alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl radical, and X represents one or more hydrogen or halogen atoms or (C^ alkyl, alkoxy, trifluoromethyl or methylene15 dioxy radicals, or alternatively X forms with the phenyl nucleus a naphthyl radical, with the proviso that when R represents a hydrogen atom X is other than a hydrogen atom, and,.pharmaceutically acceptable acid - 3 addition salts thereof.

The piperidine derivatives of general formula (I) are therapeutically useful in that they possess antidepressive activity.

Preferred compounds of the invention are those of general formula (I) wherein X represents one or more chlorine atoms, or forms with the phenyl nucleus a naphthyl radical, or represents three methoxy radicals.

Of that class, those piperidine derivatives wherein R represents a hydrogen atom are particularly preferred.

According to a feature of the present invention, the piperidine derivatives of general formula (I) are prepared by the process which comprises the reaction of a compound of the general formula: HON-R1 (XI) (wherein R1 represents a radical within the definition of symbol R, or a nitrogen-protecting radical such as an optionally substituted benzoyl radical, e.g. 4-nitrobenzoyl, or an optionally substituted benzyl or alkyl radical) with a compound of the general formula: (iii) (wherein Y represents a reactive radical such as a chlorine or bromine atom, and X is as hereinbefore defined) and, when R1 in the product obtained of the general formula: \\-ch2-o N-R (IV) is other than a radical R as hereinbefore defined, removing the nitrogen-protecting radical to yield a compound of general formula (I) wherein R represents a hydrogen atom, or reducing by methods known per se an optionally substituted benzoyl radical R3- in the compound of general formula (IV) to a corresponding benzyl radical, as is within the definition of symbol R.

According to a further feature of the invention, a piperidine derivative of the general formula: CH.

(V) X - 5 (•wherein X is as hereinbefore defined) so obtained by the aforedescribed process is converted to another compound of general formula (I) by reaction with a compound of the general formula: Z-R2 (VI) wherein Z represents a reactive atom or group, e.g. a 2 halogen atom, and R represents a (C^_^)alkyl, hydroxy(C1 or (C^_^)alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C^_^)alkoxy radicals, or the phenethyl radical or the 3-phenylpropyl radical.

Pharmaceutically acceptable acid addition salts of the piperidine derivatives of general formula (I), e.g. mandelates, fumarates, citrates and hydrochlorides, may be obtained by methods known per se, for example by treatment of the piperidine base with the appropriate acid in a solvent medium, e.g. an ether or an alkanol.

By the term 'methods known per se1 as used in this specification is meant methods heretofore used or described in the literature. - 6 The following Examples illustrate the preparation of piperidine derivatives of the present invention and acid addition salts thereof by the hereinbefore described process. The analyses and the IR and NMR spectra confirm the structure of the compounds.

EXAMPLE 1 4-(4-Fluorobenzyloxy)-piperidine and its mandelate 1(1) 1-(4-Nitrobenzoyl)-4-(4-fluorobenzyloxy)-piperidine A mixture of 1.6 g of a 50% aqueous sodium hydroxide solution, 10 ml of methylene chloride, 2 g (0.008 mol) of l-(4-nitrobenzoyl)-4-hydroxypiperidine, 2.32 g (0.012 mol) of 4-fluorobenzyl bromide and 0.15 g -4 .... (4 x 10 mol) of tetrabutylammonium iodide is stirred for 5 hours at 50°C. After dilution of the reaction medium with 20 ml of water and 30 ml of methylene chloride, the organic phase is decanted, washed with water until the washings are neutral, dried (MgSO^) and evaporated in vacuo. The residual oil obtained crystallises on stirring in diethyl ether. This yields 2.23 g of a product which is purified by dissolving it in 11 ml of dimethylformamide (DMF) and reprecipitating it by the dropwise addition of 11 ml of water, whilst stirring. After washing with water and drying in vacuo, l-(4-nitrobenzoyl)-4-(4-fluorobenzyloxy)51707 - 7 piperidine, m.p. 120°C, is obtained. 1(2) 4-(4-Fluorobenzyloxy)-piperidine (mandelate) A mixture of 11.48 g (0.032 mol) of the product obtained under 1(1), 192 ml of 96° ethanol and 48 ml of 10M aqueous potassium hydroxide solution is stirred under nitrogen and heated for 4 hours at 50°C. The alcohol is driven off in vacuo and the residue is taken up in 200 ml of water, 72 g of sodium chloride and 200 ml of diethyl ether. After filtration, the aqueous phase is extracted twice with 200 ml of diethyl ether and the total organic phase is dried (MgS04) and evaporated in vacuo.

This yields an oil which is converted to the d,l-mandelate by dissolving it in 100 ml of diethyl ether and adding 4.57 g (0.03 mol) of d,l-mandelic acid.

The salt obtained is filtered off and recrystallised from isopropanol. Its melting point is 146°C.

EXAMPLE 2 4-(3,4,5-Trimethoxybenzyloxv)-piperidine and its mandelate 2(1) 1-(4-Nitrobenzoyl)-4-(3,4,5-trimethoxybenzyloxy)piperidine A mixture of 0.8 g of 50% aqueous sodium hydroxide solution, 5 ml of methylene chloride, 1 g (0.004 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine, 1.30 g (0.006 mol) of 3,4,5-trimethoxybenzyl chloride - 8 -4 and 0.08 g (2 x 10 mol) of tetrabutylammonium iodide is stirred for 5 hours at 50°C. After dilution with 10 ml of water and 15 ml of methylene chloride, the organic phase is decanted, washed with water until the washings are neutral, dried (MgS04) and evaporated in vacuo. The residual oil obtained crystallises on stirring in diethyl ether. This yields 1.36 g (79%) of a product which is purified by dissolving it in 7 ml of DMF and slowly reprecipitating it with 7 ml of water.

After washing with water and drying in vacuo, 1-(4-nitrobenzoyl)-4-(3,4,5-trimethoxybenzyloxy)piperidine, m.p. 124°C, is obtained. 2(2) 4-(3,4,5-Trimethoxybenzyloxy)-piperidine (mandelate) A mixture of 12 g (0.028 mol) of the product obtained under 2(1), 168 ml of 96° ethanol and ml of 10M aqueous potassium hydroxide solution is stirred under nitrogen and heated for 4 hours at 50°C.

The alcohol is driven off in vacuo and the residue is taken up in 70 ml of water, 25.2 g of sodium chloride and 70 ml of chloroform. After filtration, the aqueous phase is extracted twice with 70 ml of chloroform and the total organic phase is dried (MgSO^) and evaporated in vacuo. This yields a pasty solid which is converted to the d,l-mandelate by dissolving it in 120 ml of methanol, adding 4.26 g (0.028 mol) of d,l-mandelic acid and filtering the medium after it has - 9 been stirred overnight at ambient temperature. The precipitate obtained is recrystallised from methanol. The product crystallises with half a molecule of water. Its melting point is 114°c.

EXAMPLE 3 1-Ethoxycarbonyl—4-benzyloxypiperidine (θ)- COOC2H5 3,4 g (0.033 mol) of ethyl chloroformate are added dropwise to a stirred mixture of 6.83 g (0.03 mol) of 4-benzyloxypiperidine hydrochloride, 7.74 g (0.056 mol) of dry Κ,ΟΟ^, 26 ml of water and 26 ml of chloroform. After stirring for 1 hour, the organic phase is decanted after dilution with 54 ml of chloroform, and washed 3 times with 20 ml of water and dried (MgSO^). Evaporation of the solvent in vacuo gives a liquid, which is distilled in vacuo.

Boiling point (0.4 mm Hg): 149-151°C; n21 = 1.5178.

EXAMPLE 4 l-Methyl-4-(4-chlorobenzyloxy)-piperidine and its hydrochloride In a 500 ml three-necked round-bottomed flask placed under an argon atmosphere, 4.4 g (0.1 mol) of a - 10 55% suspension of sodium hydride in oil are washed 3 times with petroleum ether. 10.1 g (0.1 mol) of l-methyl-4-hydroxypiperidine, dissolved in 100 ml of DMF, are then added. The mixture is stirred for 1 hour at ambient temperature and then cooled with a bath of iced water, and 19.3 g (0.12 mol) of p-chlorobenzyl chloride, dissolved in 50 ml of DMF, are added. Once the introduction has ended, the mixture is stirred for 4 hours at ambient tenperature and left to stand overnight. The reaction medium is poured into iced water and extracted 3 times with diethyl ether. The organic phase is washed once with water and then extracted with dilute HCl (1-2 N).

The aqueous phase is then rendered alkaline with NaOH.

It is extracted with diethyl ether and the ether extract is then washed 4 times with water. It is dried over magnesium sulphate, filtered and concentrated. The oil obtained is distilled twice and the fraction passing over at 94-98°C/0.04 mm Hg is collected.

This yields an oil, which is taken up in diethyl ether, and the hydrochloride is precipitated by adding hydrogen chloride. The hydrochloride is filtered off and rinsed with diethyl ether. It is taken up in the minimum amount of hot isopropanol, 5 times the volume of ethyl acetate is then added and the compound is left to recrystallise. The hydrochloride melts at 149-151°C. - 11 EXAMPLE 5 l-Benzyl-4-(3,4,5-trimethoxybenzvloxy)piperidine and its fumarate In a 250 ml three-necked round-bottomed flask placed under a nitrogen atmosphere, 2.2 g (0.05 mol) of a 55% suspension of sodium hydride in oil are washed 3 times with petroleum ether. 9.6 g (0.05 mol) of l-benzyl-4-hydroxypiperidine, dissolved in 30 ml of DMF* are then introduced. Once the addition has ended/ the mixture is stirred for 1 hour at ambient temperature. 13 g (0.06 mol) of 3,4,5-trimethoxybenzyl chloride in 30 ml of DMP are then added, whilst cooling with a bath of iced water. The mixture is stirred for 5 hours at ambient temperature and then left to stand overnight. The reaction medium is poured into iced water and then extracted with diethyl ether.

The product is then extracted with dilute HCl. The aqueous phase is rendered alkaline with NaOH and then extracted with diethyl ether, and the ether extract is washed with water, dried over MgSO^, filtered and concentrated. The oil obtained is taken up in hot pentane. The product crystallises. It is filtered off and recrystallised from isopropanol. This yields the base, which is dissolved in 70 ml of ethanol, and a filtered solution of 2.9 g (0.025 mol) of fumaric acid in 140 ml of ethanol is added. The fumarate salt formed is filtered off and dried. Its melting point is 160-161°C.

EXAMPLE 6 1-(4-Chlorobenzyl)-4-(3,4,5-trimethoxybenzyloxy)5 piperidine and its fumarate 6(1) 1-(4-Chlorobenzoyl)-4-hydroxyplperidine g (0.296 mol) of 4-hydroxypiperidine, 260 ml of CHC1, ι 57.3 g (0.414 mol) of K^CO, an<^ 260 ml of water are placed in a one litre Erlenmeyer flask. 51.8 g (0.296 mol) of p-chlorohenzoyl chloride, dissolved in ml of CHC1,, are added in the course of 15 minutes, whilst cooling with a bath of iced water. The mixture is stirred overnight at ambient temperature. The organic phase is decanted, the aqueous phase is extracted with' CHCl, and the CHCl, extract is washed with water until the pH is 6-7. It is dried oyer MgSO^, filtered and concentrated.

The product is reerystallised from ethyl acetate. 6(2) 1- (4-Chlorobenzoyl)-4- (3,4,5-trimethoxybenzyl oxy) piperidine In a three-necked round-bottomed flask, under a nitrogen atmosphere, 0.96 g (0.022 mol) of a 55% suspension of sodium hydride in oil is washed 3 times with petroleum ether. 4.8 g (0.02 mol) of l-(4-chlorobenzoyl)-4-hydroxypiperidine obtained as described in 6(1), dissolved in 50 ml of DMF, are then added. After the addition has ended, the mixture is stirred for 1 - 13 hour at ambient temperature. It is then cooled with a bath of iced water, and 5.4 g (0.025 mol) of 3,4,5-trimethoxybenzyl chloride, dissolved in 10 ml of DMF, are added. The mixture is stirred for 3 hours at ambient temperature and then left to stand overnight. It is poured into iced water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over MgS04, filtered and concentrated. The oil obtained is taken up in diethyl ether and the solution is then filtered. The filtrate is concentrated and passed through an alumina column (eluant: CHClj). The product does not crystallise and is used as such in the following step. 6(3) 1-(4-Chlorobenzyl)-4-(3,4,5-trimethoxybenzyloxy)piperidine and its fumarate In a round-bottomed flask under a nitrogen atmosphere, 7 g (0.0167 mol) of the product obtained under 6(2), dissolved in 70 ml of dry diethyl ether, are added at ambient temperature to a suspension of 0.38 g (0.01 mol) of AlLiH^ in 30 ml of dry diethyl ether. The mixture is heated for 3 hours at the reflux temperature. It is hydrolysed with 2.6 ml of isopropanol and 3.3 ml of a saturated aqueous solution of NaCl.

The mixture is filtered and the material on the filter is rinsed with diethyl ether. The product is extracted into dilute hydrochloric acid and the reaction mixture 5170 7 - 14 is then rendered alkaline with NH^OH and extracted with diethyl ether. The ether extract is washed with water, dried over MgSO^, filtered and concentrated. This yields an oil, which is dissolved in 30 ml of ethanol and the solution is added to a filtered solution of 1.2 g (0.0105 mol) of fumaric acid in 60 ml of ethanol. The fumarate precipitates gradually. It is filtered off, rinsed with a small amount of ethanol and then with diethyl ether, and dried. Its melting point is 178-180°C.

The compounds of the invention prepared by procedures described in the foregoing Examples are shown in the following Table. Ρί I Ζ - 15 TABLE ο I Melting point ( °C ) of salt Vir'SftMOA'Cor.oi'n rH r-)r—(rHr-Ir-li—1 r~ Salt ΦΦΦΦΦΦΦΦΦΦ ρ+)+)+ι+)+)Ό+>+,+> ι8(8ΦΦ(ΰΚ!·ΗΠΐ(0Φ r4 r-l r-l ι-i r-ί (Η Μ ι-l r-f r-l ΦΦΦΦΦΦΟΦΦΦ Ό'Ο'άΌ'ΟΌι-ΙΌ'ΟΌ β.ββρββ,αβββ enjnjieioioogeg Η 5 Η 5 S Η f r-jj-jf-jr-Jr-JHOHr-lH ΌΌΡΌΌΌΛ'ΰ'Ο'ϋ X KKKffiKffiKWWW X (Ό Φ ι ι 2 ο Ο Ο <Ό φ Φ Φ 4J \ 7 Φ Φ fe § 5 £ Η fe\/l SSUOOOO ι ιη ι ι ι ι ι ι ι <ψΐ - oa m oj ω οι μ· Ο> Π7 ts § 0 o HfMD'iinvor'COffiO - if.

P I-1 rt (0 4-1 -P +> rH 0) -P rt rH Φ Ό C rt TABLE (continued) Φ 4J rt rH Φ Ό C rt S ι r—1 •H O Φ •H k H a ,α φ -P rt -P •H □ •P g OJ (V w OJ Φ P o’ -P •P OJ ffi S w g w . w o U •w* OJ •s*· OJ OJ O OJ X o K O o E a u υ a o o Ol cn CO z”'. z->. Φ Φ .3 s rO E g co co o PM o o Pm 3 Pm O X-* «_· U E υ Ύ E ffi ! | 1 I 1 1 CO «Φ CO in in co co ro CO ΓΩ 4,5-(OMe)~ Me citrate rt rt o u rO rH m io > co σι o i*H rH i—J rH rH rH OJ TABLE (continued) Ό Φ α c •Η •Ρ C ο ϋ CQ Η S1707 - 19 Cn C •rl +1 f—I 4J +» d β , —1 •3 •ri ϋ in P·» ϋ o • CM o £ ft u p co σ» r-| tP o £ o ε 1 t ω | β CO tP m G r* 4J (0 Γ>· co rH in •ri H u 1 o c to Tt 1 1 H O •ri co co CM o in •ri VO O •ri co o | o M-l CO CM 0 rH • •ri rH o in ft 0 ι—1 I-) O 0 rQ II o o CM TABLE (continued) 4J f-i (0 w H •ri Ή W rH Λ W Λ fl) 0) £ § O o H < l U 1 in 1 in .» x* •a <3· CO CO Φ CM »ri CM rH S υ υ o 1 | 1 <* xt * «. co CM g & cm co xtf in r· xt xt tn -m* CO cn - 20 The piperidine derivatives of general formula (I) of the present invention were subjected to pharmacological experiments which demonstrated their antidepressive activity.

The toxicity of the compounds was determined on mice by intraperitoneal administration. The LD50 varies from 30 to 1000 mg/kg animal body weight.

The antidepressive activity was determined by the test for the antagonism towards the ptosis caused by reserpine (C. Gouret et al., J. Pharmacol. (Paris) 8, 333-350 (1977)).

Mice (male, CD1 Charles River, France, 18-22 g) simultaneously receive the products to be studied or the solvent (administered intraperitoneally) and reserpine (4 mg/kg animal body weight, administered subcutaneously).

Sixty minutes later, the degree of palpebral ptosis is estimated by means of a rating scale (0 to 4) for each mouse.

For each dose, the average rating and the percentage variation, compared with the control batch, are calculated.

For each product, the AD 50, or the dose which reduces the average ptosis score, compared with the controls, by 50%, is determined graphically. - 21 The AD 50 varies from 4 to 10 mg/kg animal body weight, administered intraperitoneally.

The antidepressive activity was also determined by the test for potentiation of the head twitches caused by L-5-hydroxytryptophan (H. Van Riezen (1972) Arch.

Int. Hiarmacology, 198, 256-269).

The procedure is as follows: hours before the experiment, the animals are placed in the laboratory in which the operation is to be carried out. On the day of the experiment, the mice are weighed and put to sleep.

The products to be tested are then injected intraperitoneally before L5-HTP is injected subcutaneously in an amount of 125 mg/kg animal body weight as a suspension in Tween. 30 minutes after the injection of L5-HTP, the number of head twitches is counted for 60 seconds.

For each dose, the average number of head twitches and the percentage variation, relative to the control animals, are calculated. The 50% active dose is established from a curve.

The AD 50 varies from 0.1 to 5 mg/kg animal body weight, administered intraperitoneally.

The pharmacological results show that the piperidine derivatives of the present invention can be useful for the treatment of depression.

S1707 - 22 The compounds of the invention can he presented in any form suitable for oral or parenteral administration, for example in the form of tablets, coated tablets, capsules, solutions to be taken orally or injected, and the like, in association with any suitable excipient.

The daily posology can range from 5 to 200 mg 81707

Claims (12)

1. l.A piperidine derivative of the general formula: X' / A-ch 2 -o N - R (I) 5 wherein R represents a hydrogen atom, or a (C^_ 4 )alkyl, hydroxy(Cj alkyl, or (Cj_ 4 )alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C^ 4 )alkoxy radicals, or the phenethyl radical, or the 3-phenylpropyl 10 radical, and X represents one or more hydrogen or halogen atoms or (C^ alkyl, (C^ alkoxy, trifluoromethyl or methylenedioxy radicals, or alternatively X forms with the phenyl nucleus a naphthyl radical, with the proviso that when R represents a hydrogen atom 15 X is other than a hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof.
2. 2.a piperidine derivative according to claim 1 wherein X represents one or more chlorine atoms, or forms with the phenyl nucleus a naphthyl radical, or 20 represents three methoxy radicals, or a pharmaceutically acceptable acid addition salt thereof. - 24
3. 3. A piperidine derivative according to claim 1 or 2 wherein R in the general formula depicted in claim 1 represents a hydrogen atom or a (C,_^) alkoxycarbonyl radical or a pharmaceutically acceptable acid addition salt thereof.
4. 4. A piperidine derivative according to claim 1 identified by reference to the general formula depicted in claim 1 and the simultaneous significances of the symbols R and X in the Table by the Compound numbers 1 to 49 in said Table.
5. 5. A process for the preparation of a piperidine derivative as claimed in claim 1 which comprises the reaction of a compound of the general formula: (wherein R^ represents a radical within symbol R as defined in claim 1, or a nitrogen-protecting radical such as an optionally substituted benzoyl radical, or an optionally substituted benzyl or alkyl radical) with a compound of the general formula: 81707 (III) (wherein Y represents a reactive radical such as a chlorine or bromine atom, and X is as defined in claim 1) and, when R 1 in the product obtained of the general formula: ch 2 -o N-R (IV) is other than a radical R as defined in claim 1, removing the nitrogen-protecting radical to yield a piperidine derivative of general formula (I) depicted in claim 1 wherein R represents a hydrogen atom, 10 or reducing by methods known per se an optionally substituted benzoyl radical R 1 in the compound of general formula (IV) to a corresponding benzyl radical, as is within the definition of symbol R.
6. 6. A process for the preparation of a piperidine 15 derivative as claimed in claim 1 wherein R represents a (C 1 _ 4 )alkyl, hydroxy(C 1 _ 4 )alkyl or (C 1-4 )alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C 1 _ 4 )alkoxy radicals, or the phenethyl radical or the 3-phenylpropyl 5 J 707 - 26 radical, and X is aa defined in claim 1. wiiich comprises the reaction of a piperidine derivative ot the general formula: CH. -0-/ N-f (V) x (wherein X is as defined in claim 1) with a compound of the general formula; Z-R (VI) wherein Z represents a reactive atom or group such as a 2 halogen atom, and R represents a (C^_^)alkyl, hydroxy10 (C^ 4)alkyl or (C^_ i |) alkoxycarbonyl radical, or a benzyl radical optionally carrying a substituent selected from halogen atoms and (C^_^)alkoxy radicals, or the phenethyl radical or the 3-phenylpropyl radical.
7. 7. A process according to claim 5 or 6 15 followed by the step of converting by methods known per se a piperidine derivative of the general formula depicted in claim 1 so obtained into an acid addition salt.
8. 8. A pharmaceutical composition which comprises, 20 as active ingredient, at least one piperidine derivative as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof, in association with any suitable excipient. 81707 - 27
9. 9. A piperidine derivative of the general formula depicted in claim 1, wherein R and X are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, for use as a medicament 5 and, more particularly, as an antidepressant.
10. 10. A process for the preparation of a piperidine derivative of the general formula (I) given and defined in Claim 1 or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with 10 particular reference to the accompanying Preparation Examples.
11. 11. A piperidine derivative of the general formula (I) given and defined in Claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever prepared 15 by a process claimed in a preceding claim.
12. 12. A pharmaceutical composition according to Claim 8, substantially as hereinbefore described.