US3060089A

US3060089A - Therapeutic lower alkyl esters of alpha-phenyl-alpha-piperidyl-(2)-acetic acid

Info

Publication number: US3060089A
Application number: US846268A
Authority: US
Inventors: Lachman Leon; Malspeis Louis
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1959-10-14
Filing date: 1959-10-14
Publication date: 1962-10-23
Anticipated expiration: 1979-10-23

Description

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The present invention concerns esters of a phenyl-apiperidyl-(2)-acetic acid. In particular, it relates to esters of a racematehereinafter called b-racernate--and the antipodes thereofhereinafter called b -antipode and b -antipodeof u-phenyl-a-(2-piperidyl)-acetic acid of the formula with lower alkanols, said lower 'alkanols having from three to four carbon atoms and being branched at the carbinol carbon atom, or the salts thereof. Such lower alkanols are isopropanol, secondary butanol and tertiary butanol.

Salts of the compounds of this invention are particularly therapeutically acceptable acid addition salts with inorganic acids, such as mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like; other salts may be those with organiccarboxylic acids, such as formic, acetic, prcpionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, hydroxymaleic, dihydroxymaleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic or Z-acctoxybenzoic acid and the like, or with organic sulfonic acids methane sulfonic, ethane sulfonic, 2-hydroxy-ethanesulfonic acid and the like.

It is known that methyl ahenyl-a-(Z-piperidyl)-acetate and salts thereof having stimulating efiects and can be used to overcome states of fatigue and drowsiness. However, this ester has only limited application as it decomposes rapidly in 'a hydrolytic, such as in an aqueous, and especially in an aqueous alkaline medium, as, for example, in the lower gastro-intestinal fluid, and forms the free acid, which no longer exhibits the desirable stimulating effect. This ester can, therefore, not be used in parenterally-applicable solutions containing a hydroly-tic solvent, for example, water and the like, as a vehicle, nor in elixirs for pediatric use, in which water is used as a diluent. Furthermore, the rapid hydrolysis of the ester prevents its use in compositions, which release the active compound in the lower gastro-intestinal tract after having passed through the upper gastro-intestinal tract (e.g. the stomach), and which are particularly suitable to provide a delayed, and, if desired, a sustained therapeutic effect.

It has been found that the compounds of this invention and the salts thereof have stimulating effects and can be used to overcome states of fatigue and drowsiness. In addition, it has also been found that these esters are remarkably stable in hydrolytic, particularly alkaline hydrolytic media and towards hydrolytic, particularly alkaline hydrolytic reagents, and can, therefore, be used in pharmaceutical compositions, which contain such hydrolytic reagents as vehicles. Furthermore, they are especially suitable for pharmaceutical preparations, which provide a delayed and grad al release of the active material in the alkaline medi prevailing in the lower gastro-intestinal tract, thus giving a delayed, and especially a sustained, therapeutic effect.

Apart from any long-acting pharmaceutical prepara- 3,060,089 Patented Oct. 23, 1962 tions, which will be described in detail hereinbelow, the new compounds of this invention may generally be used in the form of pharmaceutical preparations, which contain the new esters and the salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, e.g. oral, or parenteral administration. Such compositions are made according to standard methods used in the pharmaceutical art. As carrier substances there may be employed, for example, water, gelatine, sugars, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, polyalkylene glycols or any other known materials used in carriers. The pharmaceutical preparations may be in solid form, for example, as capsules, tablets or dragees, or in liquid form, for example, as solutions, suspensions or emulsions. If desired, they may contain auxiliary substances, such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain, in combination, other therapeutically useful substances.

The esters of this invention may be prepared according to esterification methods which are known per se.

For example, the isopropyl and secondary butyl esters of the previously described acids may be prepared by treating the b-racemate, the b -antipode or the b -antipode of wphenyl-et-(2-piperidyl)-acetic acid with isopropanol or secondary butanol in the presence of a Lewis acid, and, if desired, converting a resulting salt into the free base, and/ or, if desired, converting a resulting b-racemate into its antipodes and recovering the b antipode and the b antipode, and/or, if desired, converting a free base into a salt thereof.

The esterification may be carried out, for example, by treating a mixture of the acid and the alcohol with a Lewis acid, preferably at an elevated temperature for example, at the boiling temperature of the alcohol. Lewis acids are particularly mineral acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid and the like, whereby gaseous acids may be used in such form; organic sulfonic acids, particularly p-toluene sul-fonie acid, or acid halides, such as thionyl chloride or carboxylic acid chlorides, e.g. 'acetyl chloride, stearoyl chloride and the like, boron tritlluoride, trifluoroacetic acid anhydride, and equivalent Lewis acids may be employed as well. In addition to the alcohols other solvents, such as halogenated lower alkanes, e.g. methylene chloride, ethylene chloride and the like, may serve as diluents. Water, generated during the reaction, may be removed, for example, by azeotropic distillation, etc. Tertiary butanol may also be used in the above reaction, but the yields are quite unsatisfactory.

The starting material used in this reaction may be prepared, for example, by hydrogenating u-phenyl-a-(Z- pyridyD-acetamide in glacial acetic acid in the presence of platinum oxide and treating the resulting mixture of racemates of a-phenyl-a-(2-piperidyl)-acetamide with a concentrated aqueous solution of the alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, in order to convert the a-racemate into the b-racemate. The b-racemate of oephenyl-a-piperidyl-(2)-acetic acid is then formed in almost pure form by hydrolysis with sulfuric acid. The b -antipode and the b -antipode of the starting material is obtained according to known methods, for example, by preparing the salts of the abovedescribed acid with the optically active forms of an acid containing an asymmetric center, e.g. tartaric acid, and isolating the salts of the antipodes of a-phenYl-oc-pipcridyl-(2)-acetic acid with the optically active forms of such acid, e.g. tartaric acid, on the basis of their different solubilities and rate of formation.

The esters of this invention may also be prepared, for example, by treating a metal salt, particularly an alkali metal, e.g. sodium and the like, salt or a silver salt of the b-racemate, the b -antipode or the b -antipode of a-phenyla-(Z- iperidyD-acetic acid in which the secondary amino group may temporarily be protected, with an isopropyl halide or a secondary butyl halide, in which halide stands primarily for the chloride or the bromide, and, if necessary, converting a temporarily protected amino group into the free amino group, and, if desired, carrying out the optional steps.

The reaction may be carried out without protecting the secondary amino group of the piperidyl portion in the a-phenyl-a-(2-piperidyl)-acetic acid, as the ionic reaction may proceed faster than the alkylation of the amino group. If desired, the secondary amino group may be protected temporarily, for example, by an easily removable group, such as an acyl group, e.g. trifluoroacetyl, carbobenzoxy and the like, or by another, easily departing group, e.g. trityl and the like. Such groups may be introduced, and, after completed esterification, removed according to known procedures, e.g. acylation, alkylation and then hydrolysis, hydrogenolysis and the like.

The desired metal salt may be formed according to known procedures, for example, by treatment of a solution of the acid with a metal carbonate, and, if desired, replacing the solvent by another diluent (for example, replacing water by N,N-dimethylforrnamide). Instead of carbonate, a metal hydroxide, particularly an alkali metal hydroxide, may be employed for the salt formation.

The reaction may be performed in the presence of a catalyst, for example, a tertiary amine, e.g. triethylamine and the like, as Well as of an inert solvent. A tertiary butyl halide e.g. chloride and the like, may also be employed, however the yields of the product are quite small and the above modification is not satisfactory for the preparation of the tertiary butyl esters.

In the above modification, the alkyl halides may be replaced by alkyl chlorosulfites (prepared from the corresponding alkanols and thionyl chloride) and reacted with the metal, particularly the alkali metal salts of the b-racemate, b -antipode and b -antipode of u-phenylux- (2-piperidyl)-acetic acid to form the desired esters.

The isopropyl and isobutyl esters of the b-racemate, the b -antipode or the b antipode of a-phenyl-a(2-pyridyl)- acetic acid may also be obtained by reacting the free carboxylic acids or the acid addition salts thereof, with diazoisopropane or with diazoisobutane, and, if desired, carrying out the optional steps.

This esterification may be carried out according to known methods; for example, a solution of the free acid or an acid addition salt thereof in an inert solvent, such as an ether, e.g. diethylether and the like, or a halogenated lower alkane, e.g. methylene chloride and the like, is

treated with a solution of the diazo compound in an inert solvent, particularly diethylether, under cooling or at room temperature, until no further nitrogen evolution can be observed. The desired ester is then isolated from the reaction mixture, for example, by evaporating the solvent and crystallizing the residue, etc.

The esters may also be obtained'by treating the bracemate, the b -antipode or the b -antipode of tat-phenyla.-(2-piperidyl)-acetonitrile with an alkanol, containing from three to four carbon atoms and being branched at the carbinol carbon atom, in the presence of an acid and hydrolyzing any intermediarily formed imino ester salt, and, if desired, carrying out the optional steps.

The reaction may be carried out according to known methods; for example, a solution of the substituted acetonitrile in the alkanol may be heated in the presence of an acid, particularly a mineral acid, e.g. hydrochloric, sulfuric acid and the like. Under anhydrous conditions, the intermediary imino ester salt may be isolated, which upon contact with an aqueous reagent, e.g. water and the like, is hydrolized to the desired ester.

The starting material used in this reaction may be obtained from the b-racemate, the b -antipode and the b -antipode of or-phenyl-a-(2-piperidyl)-acetamide by de hydration, for example, by treatment with phosphorous pentoxide and the like.

The compounds of the present invention may also be formed, for example, by reacting the b-racemate, the b antipode or the b -antipode of a-phenyl-u-(2-piperidyl)- acetic acid with an alkene containing from three to four carbon atoms, and, if desired, carrying out the optional steps.

The above reaction is preferably carried out under anhydrous conditions, and may be catalyzed by the presence of a Lewis acid, e.g. sulfuric acid, borontrifluoride and the like. Addition across the double bond of the alkene compound, particularly propene, butene and isobutylene, is advantageously performed under cooling or at room temperature, preferably in a closed vessel under pressure and in the presence of an inert solvent, such as, for example, chloroform, diethyleneglycol dimethylether, dioxane and the like.

A further procedure for the manufacture of the compounds of this invention comprises reacting the b-racemate, b -antipode or b -antipode of an u-phenyl-a-(2- piperidyl)-acetic acid halide, in which the secondary amino group of the piperidyl portion is temporarily protected, with an alkanol containing from three to four carbon atoms and being branched at the carbinol carbon atom, and, if desired, carrying out the optional steps.

The starting materials used in the above procedure may be prepared according to procedures known in themselves. Thus, the secondary amino group in the tut-phenyla-(Z- iperidyD-acetic acid compounds is temporarily protected, for example, by an easily removable acyl group, e.g. carbobenzoxy, trifluoroacetyl and the like, or by another, readily departing group, e.g. trityl and the like. Such groups may be introduced according to known methods, e.g. acylation and the like. Protection for the amino group may also be ofllered by salt formation; thus, an acid addition salt, for example, with a mineral acid, e.g. hydrochloric acid and the like, of the acid may be converted to the acid halide. The b-racemate, the b antipode or the b -antipode of the u-phenyl-a-(2-piperidyl) -acetic acid, having a temporarily protected secondary amino group, is reacted with a reagent capable of converting a carboxylic acid into a carboxylic acid halide, for example, with a thionyl halide, e.g. thionyl chloride and the like, and the resulting carboxylic acid halide is then treated with the desired alkanol. The reaction may be carried out in the presence of a hydrogen halide absorbent, e.g. pyridine, N,N-dimethylaniline, and, if desired, in the presence of an additional solvent, e.g. toluene, N,N-dimethylforrnamide and the like. The temporarily protected amino group is then liberated, for example, by hydrolysis or hydrogenolysis.

The compounds of this invention may be obtained in the form of the free bases or as the salts thereof. A salt may be converted into the free base, for example, by reaction with an aqueous basic reagent, such as an alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide, an alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate, or ammonia. A free base may be converted into its therapeutically useful acid addition salts by reaction With one of the inorganic or organic acids outlined hereinbefore; this may be carried out, for example, by treating a solution of the free base in a solvent, such as a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol and the like, or in an ether, e.g. diethylether and the like, or in any other suitable solvent or solvent mixture, with the acid or a solution thereof, and isolating the desired salt.

If desired, the b-racemate of the resulting compounds of this invention may be resolved into the b -antipode and b -antipode according to procedures known for the resolution of racemic compounds. For example, the

free base of a b-racemate may be dissolved in a solvent, such as a lower alkanol, e.g. methanol, ethanol and the like, and one of the optically active forms of an acid containing an asymmetric carbon atom, or a solution thereof, for example, in the same lower alkanol, is then added, whereupon a salt can be isolated, which is formed by the optically active acid with one of the optically active forms of the base. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atoms are D- and L-tartaric acid; the optically active forms of dibenzoyl-tartaric, di-p-toluyl tartaric, malic, mandelic, -camphor sulfonic, quinic acid and the like may also be employed. The resolution may also be carried out by biochemical methods. From a resulting salt, the free and optically active base may be obtained according to processes known for the conversion of a salt into a base, for example, as outlined hereinbefore. If desired, such an optically active base may be converted into a therapeutically acceptable acid addition salt with one of the acids mentioned hereinbefore.

This is a continuation-in-part application of our application Serial No. 774,098, filed November 17, 1958, now abandoned.

The following examples illustrate the invention; temperatures are given in degrees centigrade.

Example 1 Dry hydrogen chloride gas is passed through a solution of the b-racemate of ot-phenyl-u-(2-piperidyl)-acetic acid in a four-fold molar excess of isopropanol. The resulting clear solution is heated on a water bath for two to three hours and then evaporated to dryness. The crude isopropyl a-phenyl-ix-(2-piperidyl)-acetate hydrochloride is triturated with ether, water is added and the solution is basified with aqueous sodium hydroxide. The organic material is extracted with ether, the ether solution dried over anhydrous calcium sulfate and hydrogen chloride gas is passed through the solution. The b-racemate of isopropyl a-phenyl-a-(2-piperidyl)-acetate hydrochloride is filtered off, washed with ether and recrystallized from ethanol, M.P. 227-228".

The starting material used in the above reaction may be prepared as follows: A solution of 75 g. of a-phenyla-(Z-pyridyD-acetamide in glacial acetic acid is hydrogenated in the presence of 1 g. of platinum oxide at 40 C. The acetic acid is evaporated, water is added and the basic material is precipitated with aqueous sodium hydroxide. The mixture of the band the a-racernates of a-phenyl-a-(2-piperidyl)-acetarnide is recrystallized from ethyl acetate, M.P. 173 C.

25 g. of the crude a-phenyl-ot-(2-piperidyl)-acetarnide, with a content of about 30 percent of the b-racemate, is refluxed for ten hours with 25 g. of potassium hydroxide dissolved in 50 ml. of water. After cooling, a mixture of the two racemates of a-phenyl-a-(Z-piperidyl)-acetamide with an increased content of the b-racemate precipitates, which mixture is filtered off (23.5 g.), washed with a little cold water and hydrolyzed to a-phenyl-u- (2-piperidyl)-acetic acid by boiling with 47 ml. of a 40 percent aqueous solution of sulfuric acid. The hydrolysis solution is brought to pH 6.0 with aqueous potassium hydroxide and upon dilution with water to a total of 400 ml., 19 g. of the b-racemate of a-phenyl-a-(2-piperidyl) -acetic acid precipitates.

Example 2 By substituting secondary butanol for the isopropanol used in Example 1 the b-racemate of secondary butyl a-phenyl-a-(2-piperidyl)-acetate hydrochloride can be obtajned, which, after recrystallization from isopropanol, melts at 208-209.

Example 3 By refluxing the b -antipode of u-phenyl-a-(2-piperidyD-acetic acid hydrochloride with isopropanol in the presence of hydrogen chloride according to the procedure described in Example 1 the b -antipode of isopropyl uphenyl-a-(2-piperidyl)-acetate hydrochloride can be obtained.

The starting material may he prepared as follows: 500 g. of crude a-phenyl-a(2-piperidyl)-acetamide with a 68 percent content of the a-racemate is dissolved in 2000 ml. of absolute ethanol; the solution is treated with dry hydrogen chloride gas and allowed to stand for two hours at 5l0. 425 g. of nearly pure a-racemate of zit-phenyla-(2-piperidyl)-acetamide hydrochloride crystallizes. It can be converted to the free a-racemate of a-phenyl-ix- (2piperidyl)-acetamide by treatment with aqueous ammonia, and the free base is used without further purification.

To a boiling solution of 109 g. of the a-racemate of a-phenyl-a-(Z-piperidyD-acetamide in 2500 ml. of ethanol is added a hot solution of 75 g. of l-tartaric acid in 2500 ml. ethanol. The mixture is allowed to stand at 20 for 15 hours during which 112 g. of the u-phenyl-a-(Z- piperidyl)-acetamide tartrate crystallizes; this salt contains a large amount of the a -antipode. The separated salt is dissolved in 500 ml. of water and the amide is precipitated with 1.1 equivalents of 10 N aqueous sodium hydroxide. The preparation and crystallization of the salt by the same procedure is repeated twice by using correspondingly smaller amounts of l-tartaric acid and solvent. The crude material is recrystallized from ethyl acetate to yield 35 g. of the pure a -antipode of ot-phenyl-a-(2-piperidyl)-acetamide, M.P. 162463"; specific rotation: 68 (as a 1 percent solution in 60 percent ethanol); solubility: 20.5 g./ 1000 ml. ethyl acetate (25).

11 g. of the a -antipode of a-phenyl-a-(Z-piperidyl)- acetamide is refluxed for six hours with a solution of 12 g. potassium hydroxide in 12 ml. of water. After cooling, 10.5 g. of a mixture of a -antipode and b -antipode of the a-phenyl-ot-(2-piperidyl) -acetamide precipitates. The precipitate is filtered oft, washed with a small amount of cold water, and dried for half an hour at 70 under reduced pressure. The material then has a specific rotation [M +41. (as a 1 percent solution in 60 percent ethanol). By recrystallization from 350ml. of ethyl acetate there is obtained as a first crop 4.9 of the b -antipode, specific rotation: +65 (as a 1 percent solution in 60 percent ethanol); solubility: 8.7 grams per liter/ 1000 ml. of ethyl acetate (25). By systematic fractional crystallization it is possible to regenerate from the mother liquors further quantities of the b -antipode, in addition to 2.5 g. of recovered starting material. Yet it is preferable to subject the combined mother liquor products of the first b -antipode crystallization to a further alkaline treatment, whereupon an additional crop of pure b -antipode can be separated again by a single crystallization operation from ethyl acetate. This procedure is repeated until practically the entire quantity of the a antipode is converted into the b -antipode of the oi-phenyla-(2-piperidyl)-acetamide, M.P. -171.

From 4.5 g. of the b -antipode of a-phenyl-a-(2-piperidyl)-acetamide there are obtained by refluxing for six hours With 14.5 g. of 6 N hydrochloric acid and subsequent crystallization 5.0 g. of the b -antipode of a-phenyla-(2-piperidyl)-acetic acid hydrochloride, M.P. 207-2082 specific rotation: +63 (as a 1 percent solution in water).

Example 4 A solution of the b -antipode of a-phenyI-ix-(Z-piperidy1)-acetic acid in isopropanol, when treated with hydrogen chloride gas according to the procedure of Example 1, yields the desired b -antipode of isopropyl a-phenyl-oi- (2-piperidyl) -acetate hydrochloride.

The starting material may be prepared according to the procedure given in Example 3 by using d-tartaric acid for the resolution of the zi-racemate of ot-PhBIlYl-oc- 2-pip eridyl) -acetamide.

Example Parenteral solutions, elixirs or tablets of the compounds of this invention may be prepared according to standard procedures. For example, aqueous solution for parenteral use, containing from 0.1 to percent of the active material may be illustrated by a parenteral solution containing 3 percent of the b-racemate of isopropyl m-phenyl-m- (2-piperidyl)-acetate hydrochloride which is prepared as follows. Ingredients:

b-Racemate of isopropyl u-phenyLa-(2-piperidyl)-acetate hydrochloride g 30.00 Potassium acid phthalate g 7.67 Hydrochloric acid (37 percent) ml 1.43 Benzyl alcohol rn1 10.00

Water for injection, q.s. 1000.00 ml.

The potassium acid phthalate is dissolved in 800 ml. of Water for injection, the hydrochloric acid is added to the solution, which is then mixed with the b-racernate of isopropyl a-phenyl-a-(2-piperidyl)-acetate hydrochloride. The benzyl alcohol is added and the volume is brought to 1000 ml. with water for injection. The solution is filtered through a medium porosity filter and a pre-determined amount of filtrate is filled into vials or ampules, which are subsequently sterilized in an autoclave at 115 for 30 minutes An elixir for oral administration, containing 0.5 percent of the b-racemate of isopropyl a-phenyl-a-(Z-piperidyl)-acetate hydrochloride may be prepared as follows (for 1000 1111.).

Ingredients:

b-Racemate of isopropyl Q-phenyl-a-(Z- Distilled water, q.s. 1000.000 ml.

The b-racemate of isopropyl a-phenyI-u-(Z-piperidyl)- acetate hydrochloride is dissolved in distilled Water and the citric acid, the sor-bitol and the glycerin are added in succession and mixed Well. The benzoic acid is dissolved in ethanol and then given to the parent solution while stirring constantly. The color solution and the flavor are added to the solution and the volume is brought to 1000 ml. with water. The finished elixir is filtered and bottled.

Tablets, which contain from about 0.015 g. to about 0.150 g. of the active ingredient may be prepared according to standard procedures. For example, tablets (of 0.150 g. total weight) containing 0.030 g. of the b-racemate of isopropyl u-phenyl-a-(IZ-piperidyl)-acetate may be prepared as follows (for 1,000,000 tablets).

Ingredients:

b-Racemate of isopropyl a-phenyl-a-(Z-piperidyU-acetate hydrochloride g 30,000 Lactose, U.S.P g.. .98,997 Tragacanth BC, U.S.P g 3,000 Talcum, U.S.P g.. 7,500 Magnesium stearate g 750 Sucrose g 2,250 Carbowax 6000 g 7,500 Purified water ml 1,200 3A alcohol, 50% ml 9,000 FD & C Blue No. 2 ..g 3

The tragacanth BC, the lactose, the talcum, the magnesium stearate and the b-racemate of isopropyl a-phenyla-(Z-piperidyD-acetate hydrochloride is placed in a mixer 8 and mixed for thirty minutes at slow speed. The color is dissolved in 500 ml. of water, the sucrose in 15 ml. of Water and the car-bowax 6000 in 3500 ml. of water, by applying heat it necessary. To the carbowax solution is added 4000 ml. of 3A alcohol and mixed Well. The color, sucrose and carbowax solutions are blended and used to granulate the powder mix. Additional quantities of 500 ml. of 3A alcohol and 200 ml. of water are used to rinse the container that held the granulating solution and the rinsings are added to the mixer. The granulation is allowed to mix for twenty minutes and is then passed through a No. 10 screen. After drying to a moisture content of about 1 to 2 percent, the dried granulation is rescreened through a No. 16 screen and compressed into tablets by using 2/ of punches and dies.

Example 6 In view of the enhanced stability towards alkaline reagents the compounds of this invention and the salts thereof are particularly suitable in certain tablet preparations which due to their slow disintegration in the lower gastro-intestinal tract provide for a prolonged and sustained efiect. Such formulations contain from about 0.050 g. to about 0.2 g. of the active compound. For example, the b-racemate of isopropyl a phenyl-a-(Lpiperidyl)-acetate hydrochloride may be utilized in tablets which, due to their particular composition and manufacture, provide for an intermediate as well as a prolonged and sustained stimulating eitect. Such a tablet (total weight 0.480 g.), containing 0.09 g. of isopropyl a-phenyla-(Z-piperidyD-acetate hydrochloride in the core and 0.015 g. of the same active ingredient in the coating, may be prepared as follows (for 20,000 tablets).

Ingredients for core:

b-Ra'cemate of isopropyl a-phenyl-a-(Z- piperidyl)-acetate hydrochloride 1800.00 Carnauba wax 1050.00 Stearic acid 357.00 Stearyl alcohol 357.00 Magnesium stearate 36.00

g. core with 05, punches and dies.

The core may also have the following ingredients:

G. b-Racemate of isopropyl et-phenyl-a-(2apiperidyl)-acetate hydrochloride 1800.00 Castor wax 1050.00 Stearic acid 714.00 1 Magnesium stearate V 36.00

and may be prepared according to the previously-given procedure.

Ingredients for coating: G.

b-Racemate of isopropyl a-phenyl-a-(Z- piperidyl)-acetate hydrochloride 300.00 Tragacanth BC 120.00 Acacia 120.00 Carbowax 6000 150.00 Confectioners sugar 900.00

Lactose 4349.10 FD & C Blue No. l 0.90 Magnesium stearate 60.00 Alcolol, 25%, q.s.

The b-racemate of isopropyl a-phenyl-u-(2-piperidyl) acetate hydrochloride, the tragacanth, the acacia, the confectioners sugar and the lactose are mixed in a mixer. The Carbowax 6000 and the FD 8: C Blue No. l are dissolved in 200 ml. of alcohol and given to the mix to granulate. The damp mass is passed through a No. 10

screen and then dried to a moisture content of about 1 to 2 percent. The dried granulation is passed through a No. 16 screen and 0.3 g. of this coating material is compressed around the previously-described core on a Manesty Dry- Cota machine with punches and dies.

The b-racemate of isopropyl oc-phenyl-a-(Z-piperidyl)- acetate hydrochloride in the coating may be replaced by another lower alkyl a-phenyl-a-(2'piperidyl)-acetate, which does not necessarily have to be resistant towards hydrolytic media, such as the lower gastro-intestinal fluid. For example, the b-racemate of methyl a-phenyla-(Z-piPcridyD-acetate hydrochloride may be used in the coating.

Ingredients for coating: G.

b-Racemate of methyl a-phenyl-a-(Z-piperidyl)-acetate hydrochloride 100.00 Tragacanth BC 120.00 Acacia 120.00 Carbowax 6000 150.00 Confectioners sugar 900.00 Lactose 4549.10 FD & C Blue No. 1 0.90 Magnesium 'stearate 60.00

Alcohol, 25%, q.s.

The coating may be prepared as previously shown and be compressed around one of the above-described cores.

Instead of the b-racemate of isopropyl a-phenyl-a-(2- piperidyl-acetate the corresponding b -antipode or b antipode or salts thereof or the b-racemate, the b -antipode or the b -antipode of secondary or tertiary butyl a-phenyl-a-(2-piperidyl)-acetate or the salts thereof may be formulated into the above pharmaceutical compositions.

Example 7 To a solution of 0.5 g. of the b-racemate of a-phenyla-(Z- iperidyD-acetic acid in 10 ml. of methylene chloride is added rapidly a solution of diazo-isopropane in ether until the nitrogen evolution ceases. After standing in the cold overnight, the solution is gassed hydrogen chloride and evaporated to dryness under reduced pressure. The residue is crystallized and recrystallized from ethanol to yield the desired b-racemate isopropyl of u-phenyl-u-(2-piperidyl)-acetate hydrochloride which is identical with the product obtained according to the procedure of Example 1.

Example 8 A solution of the b-racemate of a-phenyl-a-(2-piperidyl)-acetonitrile in dry isopropanol is gassed with hydrogen chloride. The reaction mixture is heated on the steam bath for two hours and is then evaporated. The residue, representing the isopropyl imino-ester of the b-racemate of a-phenyl-a-(2-piperidyl)-acetic acid, is taken up in water, acidified to pH to 6 with hydrochloric acid and heated on the steam bath for one hour. The solution is cooled, acidified to pH 3 with hydrochloric acid, and evaporated to dryness under reduced pressure. The resulting b-racemate of isopropyl a-phenyl-a-(2-piperidyl)- acetate hydrochloride is recrystallized from ethanol and is identical with the product obtained according to the procedure of Example 1.

The starting material may be obtained by heating the b-racemate of a-phenyl-a-(2-piperidyl) -acet-amide with phosphorous pentoxide, pouring the reaction mixture on ice, extracting the organic material with ether and isolating the desired b-racemate of uhenyI-a-(Z-piperidyl)- acetonitrile.

Example 9 To a suspension of 22 g. of the b-racemate of a-phenyla-(Z-pi eridyD-acetic acid in ml. of diethyleneglycol dimethylether is added 6.5 ml. of concentrated sulfuric acid. After cooling to 12 in a pressure vessel, 112 g. of liquid isobutylene is given to the mixture and the vessel is closed and shaken for twelve hours at room temperature.

The reaction mixture is cooled to l0, the excess of isobntylene is allowed to evaporate and the residue is dissolved in ice water and immediately made basic. The free base is extracted with ether, the ether solution is washed neutral with water, dried over magnesium sulfate and evaporated. The resulting b-racemate of tertiary butyl a-phenyl-u-(2-piperidyl)-acetate is dissolved in acetone, an equivalent amount of hydrogen chloride in ethyl acetate is added and the resulting hydrochloride of the b-racemate of tertiary butyl oL-PhGIlYl-a-(Z-PiPClidYl)- acetate is recrystallized from isopropanol, M.P. 204205 What is claimed is:

l. A member of the group consisting of the b-racemate, the b -antipode and the b -antip-ode of esters of a-phenylu-(2-piperidyl)-acetic acid with isopropanol and therapeutically acceptable acid addition salts thereof.

2. The b-racem-ate of isopropyl a-phenyl-a-(2-piperidyl)-acetate.

3. The b-racemate of isopropyl u-phenyl-a-(2-piperidyl) acetate hydrochloride.

4. The b -antipode of isopropyl oz-phenyl-a-(2-piperidyl) -acetate.

5. The b -antipode of isopropyl a-phenyl-a-(2-piperidyl) -acetate.

6. A solid, orally applicable dosage unit consisting essentially of from about 0.015 g. to about 0.2 g. of a member of the group consisting of the b-racemate, the b antipode and the b -antipode of esters of a-phenyI-a-(Z- piperidyl)-acetic acid with isopropanol and therapeutically acceptable acid addition salts thereof together with a solid pharmaceutically acceptable carrier.

7. A liquid, aqueous pharmaceutical composition consisting essentially of from about 0.1 percent to about 10 percent of a member of the group consisting of the b-racemate, the b -antipode and the b -antipode of esters of a-phenyl-a-(2-piperidyl)-acetic acid with isopropanol and therapeutically acceptable acid addition salts thereof together with an aqueous, pharmaceutically acceptable carrier.

References Cited in the file of this patent UNITED STATES PATENTS 2,507,631 Hartmann May 16, 1950 2,774,789 Tullar Dec. 18, 1956 2,838,519 Rometsch June 10, 1958 2,957,880 Rometseh Oct. 25, 1960 OTHER REFERENCES Pyribenzamine Lontabs, Pamphlet 3-9145, Ciba, Summit, New Jersey.

Claims

1. A MEMBER OF THE GROUP CONSISTING OF THE B-RACEMATE, THE B1-ANITIPODE AND THE B2-ANTIPODE OF ESTERS OF A-PHENYL A-(2-PIPERIDYL)-ACETIC ACID WITH ISOPROPANOL AND THERAPEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.