IL30528A - Piperidine derivatives,their preparation and pharmaceutical compositions containing them - Google Patents

Description

jniR D"»^»Dan mnpn 'τβοηι' New piperidine derivatives their preparation and pharmaceutical compositions containing them CIBA-GEIGY A.G.

C. 28776 J. R. GEIGY A. G. BAS EL 21 4-2668* PROCESS FOR THE PRODUCTION OF NEW PIPERIDINE DERIVATIVES The present invention concerns new piperidine derivati^s having valuable pharmacological properties, processes for the production of these new compounds, as well as pharmaceutical preparations and application thereof.

Surprisingly, it has been found that piperidine derivatives of the general formula I R 1 rem denotes an alkyl group having at most 9 carbon atoms, a phenylalkyl group having at most 10 carbon atoms, which can be unsubstituted or substituted in the phenyl group by the nitro- or amino group, a halogen atom up to the OB atomic number 35 alkoxy groups o¾—fch-5-3 , A^ma-th l pnp- 44.&ny- £££g) , in which the phenyl group, instead of being bound direct to the alkyl group, can also be bound by way of oxygen, the carbonyl group, hydroxymethylene group, imino group, alkanoyloxymethylene group with at most 4 carbon atoms or alkanoylimino group with at most 3 carbon atoms, or the cinnamyl group, R.2 denotes an alkyl group having at most 2 carbon atoms and denotes hydrogen fe-fee mothyl ffs-oa^, and their addition salts with inorganic and organic acids, exhibit valuable pharmacological properties, in particular antitussive activity with, at the same time, a favourable therapeutic index. With the exception of the compounds of formula I, wherein R-^ represents alkyl, they also exhibit an analgesic activity of average intensity, which can be detected in the case of pain reactions caused both by inflammation and by heat .

The new piperidine derivatives are therefore suitable as active substances for pharmaceutical preparations for reducing tussive irritation, and also for preventing and eliminating pain of various origin, whereby application of these preparations does not give rise to any habituation or addiction effects.

In the compounds of the general formula I and in the appertaining starting materials mentioned below, R^ is embodied, e.g. by alkyl groups, such as the methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, n-heptyl-, n-octyl-, or n-nonyl- group, by the benzyl group, the p-fluorobenzyl , the nitro-, the amino-, p-methoxy-, p-ethoxy-, p-isopropoxy- , or 3 , 4-dimethoxy- , 3 , , 5-trimethoxy- or—3 i ~mothylonod,r»¾ybenzyl group, the phenylethyl- , 3-phenylpropyl- , 4-phenylbutyl- , 2-benzylethyl- . 3-benzoylpropyl- , 2-hydroxy-2-phenylethyl- , 3 -hydroxy-3 -phenylpropy1-4-hydroxy- -phenylbutyl- , 2-ace oxy-2- phenylethyl- , 2-propionoxy-2-phenylethyl- , 3-acetoxy-3-phenyl- propyl-, 3-propionoxy-3-phenylpropyl- or 4-acetoxy-4-phenyl-butyl group which are unsubstituted in the benzene nucleus, or the corresponding groups substituted in the benzene nucleus analogously to the above mentioned benzyl groups; by ethyl-, n-propyl- and n-butyl groups, which are substituted in their -position by the anilino-, m-fluoroanilino- , p-fluoroanilino- , o-chloroanilino- , m-chloroanilino- , p-chloroanilino- , p-bromoanilino- , o-anisidino- , m-anisidino- , p-anisidino- , o-phenetidino- , m-phenetidino- , p-phenetidino- , p-propoxy- anilino-, (N-m-fluorophenyl-acetamido) - , (N-p-fluorophenyl-acetamido) - , (N-o-chlorophenyl-acetamido) - , (N-m-chlorophenyl-acetatnido) - , ( -p-chlorophenyl-acetamido) - , (N-3 , 4-dichloro-phenyl-acetamido) - , (N-p-bromophenyl-acetamido) - , (N-m-methoxyphenyl-acetamido) - , (N-p-methoxyphenyl-acetamido) - , (N-p-ethoxyphenyl-acetamido) -or (N-p-propoxyphenyl.-acetamido) -group or by the cinnamyl group.

To produce the new piperidine derivatives of the general formula I and their acid addition salts, a compound of the general formula II R - CHn - CO wherein R2 and have the meanings given in formula I, is reacted with a reactive ester of a compound of the general formula III Rx - OH (III) wherein has the meaning given in formula I and, if desired, the compound obtained of the general formula I is converted into an addition salt with an inorganic or organic acid. The reaction is performed at room temperature or moderately raised temperature in a suitable organic solvent such as ethanol, acetone, diethyl ketone or dimethyl formamide . If desired, the reaction is accelerated by the addition of acid binding agents such as potassium carbonate, and/ or of catalysts such as potassium iodide. Suitable reactive esters of compounds of the general formula III are, in particular, hydrohalic acid esters such as bromides, chlorides and iodides, also arene sulphonic acid esters, e.g. p-toluene sulphonic acid esters. The starting materials of general formula II , however, are new compounds the production of which will be described below.

According to a second process, compounds of general formula I and their acid addition salts are produced by treating a compound of the general formula IV R - C ≥ C 3 R 1 wherein R^, R2and R^ have the meanings given in formula I, with an aqueous mineral acid containing mercury ions at room temperature to moderately raised temperature and, if desired, converting the compound obtained of general formula I into an addition salt with an inorganic or organic acid. For example, 5-84 % sulphuric acid is suitable as aqueous mineral acid.

The lower the reaction temperature is, the higher the acid concentration; on using 84 % sulphuric acid, the reaction is preferably performed at room temperature, with 5-10% sulphuric acid, it is performed at 50-60°, The compounds of general formula IV required as starting materials for this process are also new. The production thereof will be described after the third process for the production of compounds of general formula I.

A third process for the production of compounds of the general formula I and their acid addition salts consists in reacting, in an inert organic solvent, an isonipecotinic acid ester corresponding to the general formula V X V wherein represents an alkali metal ion, particularly a lithium ion, 1 represents a group corresponding to the definition of with the exception of those groups which contain a carbonyl, hydroxyrnethylene or imino group, and R2 has the meaning given in formula I, with a reactive ester of a compound of the general formula VI .0 - CH - R4 ^ i 2 , \ I (vi) I "0 - CH - R, wherein R^ and R^ represent hydrogen or low alkyl groups, and has the meaning given in formula I, liberating a compound of general formula I from the ketal thereof first obtained, optionally while simultaneously converting an alkylenedioxymethylene group contained in R^' into obtained of general formula I into an addition salt with an inorganic or organic acid.

As reactive esters of alkyl-substituted 1 , 3-dioxolan-2-methanols of general formula VI, in particular their halides such as bromides, iodides and chlorides, also alkane and arene sulphonic acid esters such as methane sulphonic acid esters or p-toluene sulphonic acid esters are used.

A suitable reaction medium for the main reaction is, e.g. a mixture of abs . diethyl ether or tetrahydrofuran with 1,2-dimethoxyethane (ethylene glycol dimethyl ether) . The alkali metal compounds of general formula V are produced in situ from other suitable alkali metal compounds. Triphenylmethyl lithium, which is particularly suitable, is preferably also formed in situ from another organic lithium compound such as phenyl lithium by, e.g., adding a solution of triphenylmethane in 1 , 2-dimethoxy-ethane to the phenyl lithium, which has been produced in the known way, in diethyl ether. As the triphenylmethyl lithium produces intensively coloured solutions, its formation as well as the amount consumed thereof can easily be followed by the isonipecotinic acid ester subsequently added.. Instead of triphenylmethyl lithium, also, e.g., triphenylmethyl sodium or potassium can be used. The steps in the processes according to the invention are generally slightly exothermic and can be performed at room temperature or at a slightly raised temperature. The reaction mixture must also be cooled if necessary, depending on the starting materials and amounts used thereof.

The subsequent liberation of the compound I can be per corresponding products of the main reaction with dilute, e.g., 6N, aqueous hydrochloric acid at room temperature to the boiling temperature of the acid, or by transketalisation , e.g. the reaction with acetone in the presence of a catalyst such as p-toluene sulphonic acid, at room temperature or moderately raised temperature.

A number of 1-substituted isonipecotinic acid alkyl esters, which form the basis of the alkali metal compounds of general formula V, is known and others can be produced analogously in a simple manner. For example, such starting materials are obtained by quaternisation of low isonicotinic acid alkyl esters with halogen compounds of the general formula VII R1' - Hal (VII) wherein Hal represents chlorine, bromine or iodine, and R-^' has the meaning given in formula V, followed by catalytic hydrogenation , e.g. in the presence of rhodium-aluminium oxide catalysts. More generally useful, i.e. also for starting materials wherein R^ is an aliphatically unsaturated group, is the reaction of a low isonipecotinic acid alkyl ester with a halide of the general formula VII or with a corresponding methane or p-toluene sulphonic acid ester.

Starting materials for the second process mentioned which contain a radical R^ ' as 1-substituent , can be produced analogously to the main reaction of the previous process by reacting alkali metal compounds of general formula V with a the general formula VIII R3 - C = C - CH2 - OH (VIII) •wherein has the meaning given in formula I . The same compounds , and also those having a 1-substituent corresponding to the broader definition of R^, are obtained by analogously reacting an alkali metal compound of a low 1-benzyl-oxycarbonyl isonipecotinic acid alkyl ester with a reactive ester of a compound of the general formula VIII, splitting off the benzyloxy-carbonyl group of the l-benzyloxycarbonyl-4- (2-alkinyl) -isonipecotinic acid alkyl ester obtained, e.g., with hydrogen bromide in glacial acetic acid, and reacting the 4- (2-alkinyl) -isonipecotinic acid alkyl ester formed with a reactive ester of a compound of the general formula III analogously to the first process mentioned for the production of compounds of general formula I .

Certain starting materials of general formula II for the first process for the production of compounds of general formula I are obtained, e.g., by hydration of the lov; 4-(2-alkinyl) -isonipecotinic acid alkyl esters mentioned above analogously to the second process mentioned for the production of compounds of the general formula I. The same starting materials of the general formula II can also be produced by reaction of alkali metal compounds of low 1-benzyloxycarbonyl isonipecotinic acid alkyl. esters with reactive esters of compounds of the general formula VI followed by liberation of the keto group and splitting off of the benzyloxycarbonyl group as Further possibilities for the production of compounds of general formulae II and IV are given following the next process .

Compounds of the general formula I and their acid addition salts are produced according to a fourth process by alcoholysing a compound of the general formula IX, Rl wherein R^ and R^ have the meanings given in formula I, in the known way and, if desired, converting the compound obtained of the general formula I into an addition salt with an inorganic or organic acid. The alcoholysis is performed by the action, simultaneously or one after the other, of a mineral acid, a low alkanol and, optionally, water. For example, the nitriles of the general formula IX are refluxed in low alkanols in the presence of a concentrated mineral acid, particularly sulphuric acid, for several hours. According to another embodiment of the process, a nitrile of the general formula IX is reacted in the cold with hydrogen chloride, the imide chloride-hydrochloride formed is reacted with a low anhydrous alkanol to rr in imidoalk l e ter h drochloride and the latter is decomposed with water to form the alkyl ester of the general formula I or its hydrochloride.

The nitriles of general formula IX required as starting materials for this process are produced in their turn, e.g., starting from isonipecotamide . This is first reacted with a halogen compound of the general formula VII to form the corresponding 1- substituted isonipecotamide and the latter is converted into the corresponding nitrile, e.g. by boiling with thionyl chloride in benzene or chloroform. The alkali metal compounds of the 1-substituted isonipecotonitriles so obtained can be reacted with reactive esters of compounds of general formula VI or VIII analogously to the alkali metal compounds of general formula V. The reaction products directly obtained are finally subjected to ketal splitting or hydration. Nitriles of general formula IX having other 1-substituents corresponding to the definition of are obtained by reacting an alkali metal compound of 1-benzyl-oxycarbonyl-isonipecotonitrile with a reactive ester of a compound of the general formula VI or VIII, splitting off the benzyloxycarbonyl group by means of hydrogen bromide in glacial acetic acid either before or after the ketal splitting or hydration or splitting it off hydrogenolytically before the ketal splitting, and then reacting the 4-(2-oxo-alkyl) -isonipecotonitrile obtained with a reactive ester of a compound of general formula III analogously to the process first mentioned for the production of compounds of the general formula I. However, if the 4- (2-oxoalkyl) -isonipecotonitriles still un-substituted in the 1-position mentioned above are subjected to i.e. starting materials for the first process mentioned for the production of compounds of general formula I, whilst starting materials of the general formula IV for the second production process are obtained if the reaction products of the alkali metal compounds of 1-substituted isonipecotonitriles mentioned above are subjected to alcoholysis with reactive esters of compounds of the general formula VII instead of being hydrated.

If desired, the piperidine derivatives of the general formula I obtained by the processes according to the invention are then converted into their addition salts with inorganic and organic acids in the usual way. For example, the acid desired as salt component or a solution thereof is added to a solution of a piperidine derivative of the general formula I in an organic solvent such as diethyl ether, methanol or ethanol, and the salt which precipitates either direct or after addition of a second organic liquid, e.g. diethyl ether to methanol, is isolated .

For use as active substances for medicaments, pharmaceutically acceptable acid addition salts can be used instead of free bases, i.e. salts with those acids the anions of which have no pharmacological action or which in themselves have a desired pharmacological action. In addition, it is of advantage if the salts' to be used as active substances crystallise well and are not or are only slighlty hygroscopic. Hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, 3-hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid or 1 , 5-naphthalene disulphonic acid, for example, can be used for salt formation with piperidine derivatives of the general formula I .

The new piperidine derivatives of the general formula I and their salts are administered orally, rectally or parenterally . The daily dosages of free bases or of pharmaceutically acceptable salts thereof vary between 5 and 600 mg for warm-blooded animals. Suitable dosage units such as dragees (sugar coated tablets) , capsules, tablets, suppositories or ampoules, preferably contain 5-200 mg of a piperidine derivative of the general formula I or of a pharmaceutically acceptable salt thereof.

Dosage units for oral administration preferably contain between 17» and 907o of a piperidine derivative of general formula I or of a pharmaceutically acceptable salt thereof as active substance. They are produced by combining the active substance with, e.g., solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to form tablets or dragee cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active sub are hard gelatine capsules and also soft, closed capsules made of gelatine and a softener such as glycerin. The former preferably contain the active substance as a granulate in admixture with lubricants such as talcum or magnesium stearate and, optionally, stabilisers such as sodium metabisulphite or ascorbi acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols to which stabilisers can also be added.

Also, particularly for the treatment of coughs, e.g. lozenges as well as forms not made up into single dosages can be used for oral administration, e.g. cough syrups or drops prepared with the usual auxiliaries.

Dosage units for rectal administration are, e.g. suppositories which consist of a combination of a piperidine derivative of the general formula I or a suitable salt thereof with a neutral fatty foundation, or also gelatine rectal capsules which contain a combination of the active substance with polyethylene glycols .

Ampoules for parenteral, particularly intramuscular, also intravenous, administration preferably contain a water soluble salt of a piperidine derivative of the general formula I as active substance in a concentration of, preferably, 0.5-57o, in aqueous solution, optionally together with suitable stabilisers and buffer substances.

The following prescriptions further illustrate the production of forms for administration according to the invention: acetonyl-isonipecotinic acid ethyl ester hydrochloride, 550 g of lactose and 292.0 g of potato starch are mixed, the mixture is moistened with an alcoholic solution of 8.0 g of gelatine and granulated through a sieve. The granulate is dried and carefully mixed with 60.0 g of potato starch, 60.0 g of talcum, 10.0 g of magnesium stearate and 20 g of highly dispersed silicon dioxide. The mixture is pressed into 10,000 tablets each weighing 200 mg and containing 100 mg of active substance, which can be grooved for better adaption of the dosage. b) From 500 g of active substance, e.g. 1- (3-phenylpropyl) -4-acetonyl-isonipecotinic acid ethyl ester hydrochloride, 175.9 g of lactose and the alcoholic solution of 10 g of stearic acid is produced a granulate which is dried, and carefully mixed with 56.6 g of highly dispersed silicon dioxide, 165.0 g of talcum, 20.0 g of potato starch and 2.5 g of magnesium stearate The mixture is pressed into 10,000 dragee cores. These are then coated with a concentrated syrup made from 502.28 g of crystallised saccharose, 6.0 g of shellac, 10.0 g of gum arable, 1.5 g of titanium dioxide and 0.220 g of dyestuff, and dried. The dragees obtained each weigh 145 mg and contain 50 mg of active substan ce . c) 1,000 capsules each containing 100 mg of active substance are produced as follows: 100 g of l-cinnamyl-4-acetonyl-isonipecotinic acid ethyl ester hydrochloride are mixed with 173.0 g of lactose. The mixture is evenly moistened with an aqueous solution of 2 g of gelatine and granulated through a suitable sieve (e.g. sieve III, Ph. Helv. V), The granulate d) A cough .syrup containing 0 . 5% active substance is prepared as follows: 1 . 5 litres of glycerin, 42 g of p-hydroxy-benzoic acid methyl ester, 18 g of p-hydroxybenzoic acid n-propyl ester and, while slightly warming, 50 g of l-benzyl-4-acetonyl isonipecotinic acid ethyl ester hydrochloride are dissolved in 3 litres of distilled water. 4 litres of 707o sorbitol solution, 1 , 000 g of crystallised saccharose, 350 g of glucose and a flavouring, e.g. 250 g of "Orange Peel Soluble Fluid" produced by Eli Lilly & Co., Indianapolis, or 5 g of natural lemon flavouring and 5 g of "Halb und Halb" essence both produced by Haarmann und Reimer, Holzminden, Germany, are added. The solution obtained is filtered and the filtrate is made up to 10 litres with distilled water. e) A cough syrup containing 0 . 25% of active substance is produced as follows: 25 g of l-methyl-4-acetonyl isonipecotinic acid ethyl ester hydrochloride is dissolved by warming in a mixture of 2 . 5 litres of water and 0 . 5 litres of 96%, ethanol. Also, a syrup is made from 30 litres of water, 1 litre of 70% sorbitol solution, 3 , 000 g of crystallised saccharose, 42 g of p-hydroxybenzoic acid methyl ester and 18 g of p-hydroxybenzoic acid n-propyl ester, and this syrup is carefully mixed with the solution of active substance. After the addition of flavourings, e.g. those mentioned under d) and, if necessary, filtration, the syrup obtained is made up to 10 litres with distilled water. f) For the treatment of coughs, drops containing 2 . 5%. of active substance are prepared by dissolving 250 g of 1-n-heptyl-4-acetonyl isonipecotinic acid ethyl ester hydrochloride and and .1 litre of propylene glycol. Also, 3.5 litres of 70% sorbitol solution are mixed with 1 litre of water and this mixture is added to the above solution of active substance. A flavouring, e.g. 5 g of coughdrop aroma or 30 g of grapefruit essence, both produced by Haarmann und Reimer, Holzminden,' Germany, is added, the whole is well mixed, filtered and made up to 10 litres with distilled water. g) A mass for suppositories is made from 7.5 g of l-(2-phenoxy ethyl) -4-acetonyl isonipecotinic acid ethyl ester hydrochloride and 161.0 g of Adeps solidus and 100 suppositories are filled therewith. Each contains 75 mg of active substance. h) 2 g of 1- (3-hydroxy-3-phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester hydrochloride and 2.2 g of glycerin are dissolved in distilled water up to 100 ml and the solution is filled into 100 ' ampoules . Each contains 1 ml and 20 mg of active substance .

The following examples illustrate the production of the new compounds of general formula I but in no way limit the scope of the invention. The temperatures are given in degrees Centigrade.

Example 1 (i) 2.13 g of 4-acetonyl isonipecotinic acid ethyl ester, 3 g of 2-phenylethyl bromide, 6 g of sodium carbonate and 0.2 g of potassium iodide in 50 ml of acetone are refluxed for 16 hours. The reaction mixture is then filtered, the residue is washed with acetone, the filtrate is concentrated and the residue is distilled under high vacuum. The 1- (2-phenylethyl) -4-acetonyl isonipecotinic acid ethyl ester boils at 140-146° /0.08 Torr. The hydrochloride prepared with ethereal hydrogen chloride solution melts at 199-200° .

The following compounds are obtained in an analogous manner (ii) l-methyl-4-acetonyl-isonipecotinic acid methyl' ester , B.P. 134-136°/12 Torr, citrate M.P. 177-178° (produced with citric acid in acetone, recrystallised from methanol dimethyl-formamide) ; (iii) l-methyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 130-136°/12 Torr, citrate M.P. 172-173°; (iv) l-ethyl-4-acetonyl-isonipecotinic acid ethyl ester, B.P. 138-151°/12 Torr, hydrochloride, M.P. 177-178°; (v) l-n-heptyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 170-190°/0.05 Torr (air bath), fumarate M.P. 108-110°; (vi) 1- (3-phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester B.P. 150-164° /0.01 Torr, hydrochloride M.P. 165°; (vii) l-n-octyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 123-125°/0.02 Torr, hydrochloride M.P. 108-111°; (viii) l-benzyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 143-152° /0.06 Torr, hydrochloride M.P. 183-184°; (x) 1- (2-phenoxyethyl) -4-acetonyl isonipecotinic acid ethyl ester, B.P. 172-179/0.1 Torr, hydrochloride M.P. 164-165°; (xi) l-cinnamyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 170-175°/0.01 Torr, hydrochloride M.P. 166-168°; (xii) l-n-nonyl-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 104-106°; (xiii) 1- [ 2- (N-phenyl proprionamido) -ethyl ] -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 109-110°; (xiv) 1- [2-anilinoethyl ] -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 134-137°; (xv) 1- (3-hydroxy-3-phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 133-135°; (xvi) 1- (3-propionoxy-3-phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 120°; (xvii) 1- (2-benzoylethyl) -4-acetonyl isonipecotinic ethyl ester, fumarate, M.P. 139-142°; (xviii) 1- (3-acetoxy-3-phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 132-133°; (xix) 1- [ 2- ( -phenyl-acetamido) -ethyl ] -4-acetonyl isonipecotinic acid ethyl ester, hydrochloride, M P. 81-82°; (xx) 1- f2- (4-methoxyphenyl) -ethyl ] -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 139-140°; (xxi) 1- [3- (4-nitrophenyl) -propyl ] -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 208-209°; (xxii) 1- [3- (4-aminophenyl) -propyl ] -4-acetonyl isonipecotinic acid ethyl ester, B.P. 0.01 Torr, 180-190°; (xxiii) 1- [ 2- (4-chlorophenyl) -ethyl ] -4-acetonyl isonipecotinic (xxiv) 1- [3- (4-methoxyphenyl) -propyl ] -4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 128-130°.

The 4-acetonyl isonipecotinic acid ethyl ester required as starting material is produced as follows: a) 22.8 g of bromobenzene in 180 ml of abs. ether are placed in a 750 ml four-necked flask and, while stirring under an atmosphere of nitrogen, 3.03 g of lithium wire, which has been cut into small pieces and washed with petroleum ether, are added, whereupon the ether begins to boil. After the reaction has subsided, the mixture is refluxed for another 2 1/2 hours. 35.4 g of triphenylmethane in 150 ml of abs. 1 , 2-dimethoxy-ethane are added all at once to the solution of phenyl lithium obtained, whereupon, due to the formation of the triphenylmethyl lithium, the solution becomes deep red coloured and gently boils. After stirring for 20 minutes at room temperature, 42.3 g of 1-benzyloxycarbonyl isonipecotinic acid ethyl ester, (produced by reaction of isonipecotinic acid ethyl ester with chloroformic acid benzyl ester in the presence of IN sodium bicarbonate solution), in 50 ml of abs. ether are added at 28°. The solution loses its deep red colour and the temperature slightly rises. It is stirred for 10 minutes at room temperature and then 18 g of propargyl bromide (3-bromopropine) in 50 ml of abs. ether are added all at once. The mixture is stirred for 2 1/2 hours at room temperature whereupon it turns yellowish and lithium bromide precipitates. 40 ml of water are then added to the reaction mixture which is then evaporated almost to dryness in a rotary evaporator. The residue is taken up in acid. The ether solution is dried and concentrated and the residue is left to stand overnight whereupon the triphenyl-methane crystallises out. The whole mixture is then suspended in cold methanol, the triphenylmethane is filtered off under suction, the filtrate is concentrated and the residue is distilled under high vacuum. The l-benzyloxycarbonyl-4- (2-propinyl) -isonipeco-tinic acid ethyl ester passes over at 170-192° /0.07 Torr . b) 8 g of l-benzyloxycarbonyl-4- (2-propinyl) -isonipecotinic acid ethyl ester and 40 ml of a 25-307o solution of hydrogen bromide in glacial acetic acid and 9 ml of abs. ether are stirred for 2 hours in a round flask by means of a magnetic stirrer. The initial strong development of carbon dioxide gradually diminishes. The reaction solution is then evaporated in a rotary evaporator and the residue is taken up in 6N hydrochloric acid. The hydrochloric acid is extracted with ether, then made alkaline with concentrated ammonia while cooling well and extracted with chloroform. The chloroform solution is dried, concentrated and the resultant 4- (2-propinyl) -isonipecotinic acid ethyl ester is further reacted immediately.

Other low alkyl esters of 4- (2-propinyl) -isonipecotinic acid can also be produced analogously to a) and b) . c) The crude 4- (2-propinyl) -isonipecotinic acid ethyl ester is hydrated at 60° analogously to example 2 by heating for 3 hours with ten times the amount of IN sulphuric acid which contains VL of mercury- (II) sulphate, and the 4-acetonyl isonipecotinic acid ethyl ester formed is isolated analogously to example 2 and is further reacted as crude product.

Example 2 (i) 15.7 g of 1- (3 -phenylpropyl) -4- (2-propinyl) -isonipecotinic acid ethyl ester, 150 ml of IN sulphuric acid and 1.5 g of mercury- (II) sulphate are heated for 3 hours while stirring at 60-70° . The suspension is then filtered, the filtrate is made alkaline with concentrated aqueous ammonia solution while cooling and extracted twice with chloroform. The combined chloroform solutions are washed with sodium chloride solution, dried and evaporated and the residue is distilled under high vacuum. The 1- (3-phenylpropyl) -4-acetonyl-isonipecotinic acid ethyl ester boils at 150-164° /0.01 Torr . The hydrochloride is produced therefrom with ethereal hydrogen chloride solution and it is recrystallised from acetone, M.P 165°.

The following compounds are produced in an analogous way: (ii) l-methyl-4-acetonyl isonipecotinic acid methyl ester, B.P. 134-136°/12 Torr, citrate M.P. 177-178° (produced with citric acid in acetone, recrystallised from methanol/dimethyl formamide) ; (iii) l-methyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 130-136°/12 Torr, citrate M.P. 172-173°; (iv) l-ethyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 138-151°/12 Torr, hydrochloride M.P. 177-178°; (v) l-n-heptyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 170-190°/0.05 Torr (airbath) , fumarate M.P. 108-110°; (vi) 1- (3 -phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester, B.P. 150-164° /0.01 Torr, hydrochloride M.P. 165°; (vii) l-n-octyl-4-acetonyl isonipecotinic acid ethyl ester, (viii) l-benzyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 143-152°/0.06 Torr, hydrochloride M.P. 183-184°; (ix) 1- (4-phenylbutyl) -4-acetonyl isonipecotinic acid ethyl ester, B.P. 170-195°/0.1 Torr, hydrochloride M.P. 192-193°; (x) 1- (2-phenoxyethyl) -4-acetonyl isonipecotinic acid ethyl ester, B.P. 172-179°/0.1 Torr, hydrochloride M.P. 164-165°; (xi) l-cinnamyl-4-acetonyl isonipecotinic acid methyl ester, B.P. 170-175°/0.01 Torr, hydrochloride M.P. 166-168°; (xii) l-n-nonyl-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 104-106°; (xiii) 1- (2-anilinoethyl) -4-acetonyl isonipecotinic ethyl ester, M.P. 134-137°; (xiv) 1- (2-benzoylethyl) -4-acetonyl isonipecotinic acid ethyl ester, M.P. 139-142°; (xv) 1- [ 2- ( -phenyl-propionamido) -ethyl ] -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 109-110°; (xvi) 1- (3-hydroxy-3-phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 133-135°; (xvii) 1- (3-propionoxy-3-phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 120°; (xviii) 1- (3-acetoxy-3-phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 132-133°; (xix) 1- [2- (N-phenyl-acetamido) -ethyl ] -4-acetonyl isonipecotinic acid ethyl ester, hydrochloride, M.P. 81-82°; (xx) 1- [2- (4-methoxyphenyl) -ethyl ] -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 139-140°; (xxi) 1- ( 3 - (4-nitrophenyl) -propyl ] -4-acetonyl isonipecotinic (xxii) 1- [3- (4-aminophenyl) -propyl ] -4-acetonyl isonipecotinic acid ethyl ester, B.P. 180-190° /0.01 Torr ; (xxiii) 1- [2- (4-chlorophenyl) -ethyl ] -4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 158-160°; and (xxiv) 1- [3- (4-methoxyphenyl) -propyl ] -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 128-130°.

The 1-substituted 4- (2-propinyl) -isonipecotinic acid alkyl esters required as starting materials for the production of the above compounds can be produced, e.g. as follows: a) 20 g of isonicotinic acid ethyl ester and 75.5 g of 3-phenylpropyl bromide in 100 ml of diethylketone are refluxed for 5 hours. The diethylketone is then evaporated under vacuum, the residue is dissolved in water and the aqueous solution is extracted three times with ether. On evaporating the aqueous solution under vacuum and, finally, high vacuum, the ethyl ester of 4-carboxyl-l- (3-phenylpropyl) -pyridinium bromide remains. b) 24.1 g of the above quaternary salt in 200 ml of ethanol are hydrogenated at room temperature and 3-4 atm. ' pressure in the presence of rhodium/aluminium oxide catalyst (5% Rh) . The catalyst is then filtered off and the filtrate is concentrated. The residue is covered with chloroform and made alkaline with concentrated sodium hydroxide solution. The chloroform is removed and the aqueous phase is exhaustively- extracted with chloroform. The combined chloroform solutions are washed with saturated sodium chloride solution, dried and concentrated and the residue is distilled under high vacuum. The 1- (3-phenylpropyl) -isonipecotinic acid ethyl ester boils at 130-132° /0.08 The following compounds are obtained analogously to a) and b) (quaternisation being performed in each case in the alkanol used as ester component) : 1-methyl isonipecotinic acid methyl ester, B.P. 73-75° /12 Torr; 1-methyl isonipecotinic acid ethyl ester, B.P. 78-80° /ll Torr; 1-ethyl isonipecotinic acid ethyl ester, B.P. 100-107°/12 Torr; 1-n-heptyl isonipecotinic acid ethyl ester, B.P. 120°/0.01 Torr; 1-n-octyl isonipecotinic acid ethyl ester, B.P. 130-135°/0.1 Torr; 1-benzyl isonipecotinic acid ethyl ester, B.P. 110-115°/0.2 Torr; 1- (2-phenylethyl) -isonipecotinic acid ethyl ester, B.P. 140-146°/ ,0.08 Torr; 1- (4-phenylbutyl) -isonipecotinic acid ethyl ester, B.P. 142-153°/ 0.01 Torr; 1- (2-phenoxyethyl) -isonipecotinic acid ethyl ester, B.P. 143-148°/0.03 Torr; 1-cinnamyl isonipecotinic acid ethyl ester, B.P. 150-160° /0.01 Torr; -n-propyl isonipecotinic acid ethyl ester, B.P. 107-110°/0.5 Torr ; -n-nonyl isonipecotinic acid ethyl ester, B.P. 150-160° /0.001 Torr ; - (3-phenylpropyl) -isonipecotinic acid methyl ester, B.P. 115-118°/0.01 Torr; - (2-phenylpropyl) -isonipecotinic acid ethyl ester, B.P. 130-145°/0.01 Torr; - [ 2- (N-phenyl-propionamido) -ethyl ] -isonipecotinic acid ethyl ester, B.P. 190-216° /0.01 Torr; ' " c) 11 g of bromobenzene in 100 ml of abs. ether are placed in a 350 ml four-necked flask and, while stirring under an atmosphere of nitrogen, 0.98 g of lithium wire, which has been cut into small pieces and washed with petroleum ether, are added, whereupon the ether begins to boil. After the reaction has subsided, the mixture is refluxed for another 2 1/2 hours. 17.1 of triphenylmethane in 80 ml of abs. 1 , 2-dimethoxyethane are added all at once at 30° to the solution of phenyl lithium obtained. Due to the formation of the triphenyl lithium, the solution becomes dark red coloured and gently boils. After stirring for 20 minutes at room temperature, 18.3 g of l-(3-phenylpropyl) -isonipecotinic acid ethyl ester in 20 ml of abs. ether are added at 28° whereupon the solution loses its dark red colour and the temperature rises slightly. The solution is stirred for 10 minutes at room temperature and then 8 g of prop-argyl bromide (3 -bromopropine) in 20 ml of abs. ether are added all at once. The mixture is stirred for 2 1/2 hours at room temperature whereupon it turns yellowish and lithium bromide precipitates. 10 ml of water are then added to the reaction mixture which is then evaporated in a rotary evaporator.

Methylene chloride is added to the residue and the methylene chloride solution obtained is extracted four times with 6N hydrochloric acid. The acid extracts are made alkaline and extracted exhaustively with chloroform. The chloroform extracts are dried and concentrated. The residue is taken up in ether, the ether solution is dried and concentrated and the residue is distilled . The 1- (3-phenyl-propyl) -4- (2-propinyl) -isonipecotinic dissolved in ether and 95% of the theoretical amount of fumaric acid is added. The fumarate is filtered off under suction and recrystallised from isopropanol. The 1- (3-phenylpropyl) -4- (2-propinyl) -isonipecotinic acid ethyl ester fumarate melts at 153° The following compounds are produced analogously: l-methyl-4- (2-propinyl) -isonipecotinic acid methyl ester, B.P. 100-102°/12 Torr, citrate M.P. 167-168°; l-methyl-4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 112°/35 Torr, citrate M.P. 169-170°; l-ethyl-4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 117-119°/12 Torr; l-n-heptyl-4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 130-135°/0.01 Torr, fumarate 118-120°; l-n-octyl-4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 128-135°/0.02 Torr, fumarate M.P. 119-120°; l-benzyl-4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 131-159°/0.05 Torr, fumarate M.P. 157-158°; 1- (2-phenylethyl) -4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 139-143° /0.08 Torr, hydrochloride M.P. 212-213°; 1- (4-phenylbutyl) -4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 165-185° /0.01 Torr, fumarate M.P. 117-118°; 1- (2-phenoxyethyl) -4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 168-169°/1 Torr, fumarate M.P. 138-139°; l-cinnamyl-4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 170-178°/0.02 Torr, fumarate 164-165°; l-n-propyl-4- (2-propinyl) -isonipecotinic acid ethyl ester, B.P. 112-ll4°/2. Torr , hydrochloride M.P. 168-169°; 1- (3-phenylpropyl) -4- (2-propinyl) -isonipecotinic acid methyl ester, B.P. 134-139° /0.01 Tor'r, fumarate M.P. 153-154°; 1- (2-phenylpropyl) -4- (2-propinyl) -isonipecotinic acid ethyl ester ; 1- [2- (N-phenyl-propionamido) -ethyl ] -4- (2-propinyl) -isonipecotinic acid ethyl ester . d) 1 g of 1- [3- (4-nitrophenyl) -propyl ] -4- (2-propinyl) isonipecotinic acid ethyl ester is dissolved in glacial acetic acid while stirring at 50°. A solution of 3.5 ml of cone, hydrochloric acid and 2.5 g of tin chloride is then added drop-wise over a period of 2 minutes and heated over 30 minutes to 90°. It is then cooled, adjusted to p^ 3.5 with 2 ml cone, sodium hydroxide solution, separate from the sediment, and washed well with water. The acid solution is made alkaline with cone, ammonia and extracted with ether. The ethereal solution is dried and evaporated. The 1- f3- (4-aminophenyl) -propyl ] -4- (2-propinyl) -isonipecotinic acid ethyl ester is distilled in a bulb tube at B.P. 180-190° under 0.01 Torr.

Example 3 0.64 g of lithium and 7.4 g of bromobenzene in 32 ml of abs . ether are reacted in a 350 ml sulfonating flask while stirring and under nitrogen, and subsequently refluxed for two hours. 11.4 g of triphenylmethane in 65 ml of dimethoxyethane are then added at 30° and stirred for a further 30 minutes, whereby a red solution is obtained. 6.5 g of 1- (3-phenylpropyl) -isonipecotinic acid ethyl ester in 32 ml of abs. ether are then added dro wise with 7 minutes stirrin at 30°. 8.5 of 2-meth l subsequently added so that refluxing occurs. The solution is refluxed for 2 hours, decomposed with 30 ml of water, the ether phase separated off, the aqueous phase extracted twice with ether and the combined ether extracts evaporated in vacuum. The residue is dissolved in alcohol with warming. On cooling, the triphenyl-m ethane crystallises out, is filtered off, washed with alcohol and the filtrate evaporated. The residue is taken up in 6N hydrochloric acid and heated for 4 hours at 70° . The solution is cooled, made alkaline with ammonia, and extracted exhaustively with ether, dried and evaporated. The residue is distilled in a bulb tube at B.P. 160-180° and 0.01 Torr, the hydrochloride being produced from that in the normal manner. The l-(3-phenylpropyl) -4-acetonyl isonipecotinic acid ethyl ester hydrochloride melts at 165° and is identical to a sample produced in another way.

Example 4 a) 5.5 g of bromobenzene in 50 ml of abs . ether are placed in a 200 ml four-necked flask and, while stirring under an atmosphere of nitrogen, 0.49 g of lithium wire, which has been cut into small pieces and washed with petroleum ether, are added, whereupon the ether commences to boil. After the reaction has subsided, the mixture is refluxed for a further 2 1/2 hours. 7.6 g of triphenylmethane in 25 ml of abs. 1 , 2-dimethoxyethane are added all at once to the obtained solution of phenyllithium, whereupon, due to the formation of triphenylmethyl lithium, the solution turns deep red and gently boils. After 20 minutes stirring at room temperature, 6.4 g of 1- (2-phenylethyl) -isonipecoto- loses its deep red colour with a slight increase in temperature occurring. It is stirred for 10 minutes at room temperature and then mixed all at once with 4.0 g of propargyl bromide (3- bromopropine) in 20 ml of abs . ether. The mixture is stirred for 2 1/2 hours at room temperature, whereby it turns yellowish and lithium bromide precipitates. The reaction mixture is then mixed with 20 ml of water and evaporated in a rotary evaporator. Ether is added to the residue and the obtained ether solution is extracted four times with dilute hydrochloric acid. The acid extracts are made alkaline and exhaustively extracted with chloroform, the chloroform extracts being dried and evaporated. The residue is taken up in ether, the ether solution dried and evaporated and the residue distilled. The 1- (2-phenylethyl) -4- (2-propinyl) -isonipecotonitrile passes over at 141-170° /0.05 Torr . b) 12.6 g of 1- (2-phenylethyl) -4- (2-propinyl)- isonipecotonitrile with 150 ml of IN sulphuric acid and 1.5 g of mercury (II) sulphate are heated while stirring for 3 hours at 60-70°. The suspension is then filtered, the filtrate made alkaline with concentrated aqueous ammonia solution while cooling and extracted twice with chloroform. The combined chloroform solutions are washed with sodium chloride solution, dried and evaporated, and the residue distilled in high vacuum. The 1- (2-phenylethyl) -4-acetonyl isonipecotonitrile boils at 140-150° /0.01 Torr. c) 2.7 g of 1- (2-phenylethyl) -4-acetonyl isonipecotonitrile with 10 ml of abs. ethanol and 2.3 ml of cone, sulphuric acid are refluxed for 11 hours. The reaction mixture is then made chloroform. The extract is dried, the chloroform evaporated and the residue distilled. The 1- (2-phenylethyl) -4-acetonyl isonipecotinic acid ethyl ester boils at 140-156° /0.07 Torr. The hydrochloride produced with ethereal hydrochloric acid has a.M.P. of 199-200°.

Claims (33)

i What we claim is:

1. Piperidine derivatives of the general formula I R, CH, CO CH, CO R, wherein R^ represents an alkyl group having at most 9 carbon atoms, or a phenylalkyl group having at most 10 carbon atoms wherein the phenyl moiety may be unsubstituted or substituted by, independently, a nitro group, an amino group, a halogen atom or by up to the atomic number 35 ( one or two alkoxy groups having 1 or 2 carbon atoms each, by tha—S-T^watbylaa-a-AA-Jxy-^r-aip , and wherein the phenyl moiety, instead of being bound directly to the alkyl moiety, may be bound thereto by way of oxygen, the carbonyl group, the hydroxymethylene group, the imino group , an alkanoyloxymethylene group having at most 4 carbon atoms or an alkanoylimino group having at most 3 carbon atoms, or the cinnamyl group, R£ represents an alkyl group having at most 2 carbon atoms and and their pharmaceutically acceptable addition salts with acids , - 32 - GB etc .

2. Piperidine derivatives of the general formula I - wherein R^ represents an alkyl group having at most 9 carbon atoms; or a phenylalkyl group having at most 10 carbon atoms, wherein the phenyl moiety may be unsubstituted or substituted by or by a halogen atom up to the atomic number 35 ,/ an alkoxy group having 1 or 2 carbon atoms, e¥-ky-^.«-^^me£¾yl-e¥¾edio¾y •g-*--©^ , and wherein the phenyl moiety, instead of being bound directly to the alkyl moiety, may be bound thereto by way of oxygen, the carbonyl group, the hydroxymethylene group, the imino group, an alkanoyloxymethylene group having at most 4 carbon atoms or an alkanoylimino group having at most 3 carbon atoms or the cinnamy1. group , R2 represents an alkyl group having at most 2 carbon atoms, and R^ represents hydrogen fcfee—»efcky.i-g¾?««e , and their pharmaceutically acceptable addition salts with acids-

3. Piperidine derivatives of the general formula la CH, CO I CH wherein represents an alkyl group having at most 8 carbon atoms; or a phenylalkyl group having at most 9 carbon atoms wherein the phenyl moiety, instead of being bound directly to the alkyl moiety, may be bound thereto by way of oxygen or. the imino group, or the cinnamyl group, and their pharmaceutically acceptable addition salts with acids .

4. 1- (3-phenylpropyl) -4- (2-acetonyl) -isonipecotinic acid ethyl e.ster .

5. 1- (2-phenoxyethyl) -4- (2-acetonyl) -isonipecotinic acid ethyl ester .

6. l-cinnamyl-4- (2- acetonyl) - isopecotinic acid ethyl ester.

7. 1- (2- anilinoethyl) -4- (2- acetonyl) - isopecotinic acid ethyl ester .

8. l-methyl-4- (2-acetonyl) -isopecotinic acid ethyl ester.

9. l-n-octyl-4- (2- acetonyl) - isonipecotinic acid ethyl ester .

10. l-benzyl-4- (2-acetonyl) -isonipecotinic acid ethyl ester .

11. Pharmaceutically acceptable addition salts of any one of the compounds claimed in claims 4 to 10, with acids.

12. Process for 'the production of piperidine derivatives of the general formula I as defined in claim 1, and their pharmaceutically acceptable addition salts with acids, which process comprises reacting a compound of the general formula II R„ - CH, CH, wherein R2 and R^ have the meanings given in claim 1, with a reactive ester of a compound of the general formula III R-_ - OH (III) wherein R^ has the meaning given in claim 1 and, if desired, converting a compound thus obtained of the general formula I, into a pharmaceutically acceptable addition salt thereof with an acid.

13. Process as claimed in claim 12, wherein R^ has the meaning given in claim 2, whereby a compound of the general formula I as defined in claim 2 , or a pharmaceutically acceptable addition salt thereof with an acid, is produced.

14. Process as claimed in claim 13, wherein R^ has the meaning given in claim 3, R2 represents the ethyl group and R^ represents hydrogen, whereby a compound of the general formula la as defined in claim 3 , or a pharmaceutically acceptable addition salt thereof with an acid, is produced.

15. Process for the production of piperidine derivatives o the general formula I as defined in claim 1, and their pharma ceutically acceptable addition salts with acids, which process comprises treating a compound of the general formula CH2 wherein R-^, R2 and R^ have the meanings given in claim 1 with an aqueous mineral acid containing mercury ions and, if desired, converting a compound thus obtained of the general formula I into a pharmaceutically acceptable addition salt thereof with an acid.

16. Process as claimed in claim 15, wherein R^ has the meaning given in claim 2, whereby a compound of the general formula I as defined in claim 2, or a pharmaceutically acceptable addition · salt thereof with an acid, is produced.

17. Process as claimed in claim 16, wherein R^ has the meaning given in claim 3, R2 represents the ethyl group and R^ represents hydrogen, whereby a compound of the general formula la as defined in claim 3, of a pharmaceutically acceptable addition salt thereof with an acid, is produced.

18. Process for the production of piperidine derivatives of the general formula lb R3 - CH2 - CO CH I V wherein R^1 has the meaning given for R^ in claim 1, with the exception that it may not represent those groups containing a carbonyl , hydroxymethylene or imino group, and R2 and R^ have the meanings given in claim 1 , and their pharmaceutically acceptable addition salts with acic which process comprises reacting, in an inert organic solvent, an alkali metal derivative of an isonipecotinic acid ester of the general formula V X wherein X ® represents an alkali metal ion, R^ 1 has the meaning given above under formula lb, and R2 has the meaning given in claim 1, with a reactive ester of a compound of the general formula VI CH 0 CH R, 2\ / (VI) C / \ CH9 0 - CH - R, OH - 37 - GB etc . wherein and R^. individually represent hydrogen or low alkyl groups, and has the meaning given in claim 1, and liberating a compound of the general formula lb from the ketal thus obtained and, if desired, converting a compound thus obtained of the general . formula lb into a pharmaceutically acceptable addition salt thereof with an acid.

19. Process as claimed in claim 18, wherein the alkali metal ion X® is a lithium ion.

20. Process as claimed in claim 18 or claim 19, wherein R^' has the meaning given for R^ in claim 2 with the exceptions indicated in claim 18, whereby a compound of the general formula lb wherein R^ 1 has the meaning given above, or a pharmaceutically acceptable addition salt thereof with an acid, is produced.

21. Process as claimed in claim 20, wherein R^ 1 has the meaning given for R^ in claim 3 with the exception of those groups containing an imino group, R2 represents the ethyl group and R^ represents hydrogen, whereby a compound of the general formula lb wherein R^ '. , R and R^ have the meanings given above, or a pharmaceutically acceptable addition salt thereof with an acid,. is produced.

22. Process for the production of piperidine derivatives of the general formula I as defined in claim 1, and their pharmaceutically acceptable addition salts with acids, which process comprises subjecting a compound of the general formula IX - CO R3 " CH2 CH wherein and have the meanings given in claim 1 to ethanolic or methanolic alcoholysis and, if desired, converting a compound thus obtained of the general formula I into a pharmaceutically acceptable addition salt thereof with an acid .

23. Process as claimed in claim 22, wherein has the meaning given in claim 2, whereby a compound of the general formula I as defined in claim 2 , or a pharmaceutically acceptable addition salt thereof with an acid, is

24. Process as claimed in claim 23, wherein has the meaning given in claim 3, R^ represents hydrogen and ethanol is used for the alcoholysis, whereby a compound of the general formula la as defined in claim 3 , or a pharmaceutically acceptable addition salt thereof with an •acid, is produced.

25. A piperidine derivative of the general formula I as defined in claim 1 or . a pharmaceutically acceptable addition salt thereof with an acid, whenever prepared by a process as claimed in any one of claims 12, 15, 18, 19 and 22.

26. A piperidine derivative of the general formula I as defined in claim 2 or a pharmaceutically acceptable addition salt thereof with an acid, whenever prepared by. a process as claimed in any one of claims 13, 16, 20 and 23.

27. A piperidine derivative of the general formula la as defined in claim 3 or a pharmaceutically acceptable addition salt thereof with an acid, whenever prepared by a process as claimed in any one of claims 14, 17, 21 and 24. for the' prodaction of piperidine derivatives according to Claim 1

28. Process/substantially as hereinbefore described with reference to any one of the Examples 1 (i) , (vi) , (xiii) (xvi) and (xvii) ; and 2 (i) to (v) , (vi) to (xii) and (xv) .

29. A piperidine derivative of the general formula I as defined in claim 2 or a pharmaceutically acceptable addition salt thereof with an acid, whenever prepared by a process as claimed in claim 28. for the production of piperidine derivatives according to Claim 1

30. Process/substantially as hereinbefore described with reference to any one of the Examples 1 (ii) to (v) , (vii) to (vii) , (xv) and (xviii) to (xxiv) ; 2 (vi) , (xiii) , (xiv) and (xvi) to (xxiv) ; 3 and 4.

31. A piperidine derivative of the general formula 1 as defined in claim 1 or a pharmaceutically acceptable addition salt thereof with an acid, whenever prepared by a process as claimed in claim 30.

32. A pharmaceutical composition comprising a piperidine derivative or a pharmaceutically acceptable addition salt thereof with an acid as claimed in claim 2, together with a pharmaceutically acceptable diluent or carrier therefor. V

33. A pharmaceutical composition comprising a piperidine derivative or a pharmaceutically acceptable addition salt thereof with an acid as claimed in claim 1, together with a pharmaceutically acceptable diluent or carrier therefor. 23.7.68/Sa/GSG/ml/dZ