IE85730B1 - Benzoic acid derivative - Google Patents

Abstract

ABSTRACT The present invention relates to (S) (+)—2 ethoxyr4—[N- [1-(2—piperidino—phenyl)-3—methyl—1-butyl]amino carbonylmethyl]-benzoic acid, processes for its preparation and pharmaceutical compositions containing this compound.

Description

Benzoic acid derivative The present invention relates to (S) (+)—2 ethoxyr4—[N- [1-(2—piperidino—phenyl)-3—methyl—1-butyl]amino carbonylmethyl]-benzoic acid, processes for its preparation and pharmaceutical compositions containing this compound.

EP-B—147850 describes inter alia the racemate of 2- ethoxy—4—[N—[1-(2—piperidino—phenyl)~3-methylbutyl]- aminocarbonylmethyl]-benzoic acid (Code No.: AG-EE 388 ZW), a compound of formula CH3 cg and EP-B-207331 describes two polymorphous forms of this compound. This compound and the physiologically acceptable salts thereof have valuable pharmacological properties, in particular an effect on the intermediate metabolism, more particularly the effect of lowering the blood sugar level.

We have tested the two enantiomers of this compound, namely (S)(+)ethoxy—4—[N-[1-(2-piperidino-phenyl) methyl-1—butyl]-aminocarbonylmethyl]—benzoic acid (Code No.: AG-EE 623 ZW) and (R)(—)~2-ethoXy-4—[N-[1-(2- piperidino-phenyl)-3—methyl—1—butylJaminocarbonyl methyljbenzoic acid (Code No.: AG-EE 624 ZW), for their blood sugar-lowering effect in female rats and, surprisingly, it was found that the (S)—enantiomer (AG—EE 623 ZW) is the active enantiomer in lowering the blood sugar level and its activity lasts for more than 6 hours in the rat.

On the basis of these findings in the rat, it appears appropriate to use exclusively AG—EE 623 ZW in humans, thereby reducing the dose by 50%, compared with the dose of AG—EE 388 ZW necessary to produce the same effect.

This blood sugar-lowering effect together with a relatively long period of activity has also been found in humans. However, in the human studies it was also found that AG—EE 623 ZW has surprising pharmacokinetic properties which could not have been foreseen on the basis of the AG—EE 388 ZW data.

AG—EE 623 ZW possesses surprising therapeutic advantages over the racemate AG—EE 388 ZW.

Accordingly, The surprising findings in humans included the following: (a) the AG—EE 623 ZW levels fall more rapidly towards zero than the AG—EE 388 ZW levels, even when the dosage is identical, a result which could not have been predicted in view of its relatively long period of activity; V (b) in relation to the lowering of the blood sugar level, substantially lower plasma levels of AG~EE 623 ZW occur than might have been predicted by halving the dosage of AG—EE 388 ZW: and (c) the blood sugar lowering activity occurs more rapidly following the administration of AG—EE 623 ZW than following the administration of AG-EE 388 ZW.

The especially surprising difference between the two enantiomers is the fact that the active enantiomer, AG-EE 623 ZW, period of activity, in spite of having a relatively long is eliminated more rapidly than the inactive enantiomer, AG-EE 624 ZW, as demonstrated by Figures 1 and 2 hereto. These figures provide graphs of the plasma concentrations of AG—EE—624 ZW (filled“ squares) and AG—EE—623 zw (open triangles) against time following 1.0mg i.v. administration of AG-EE-388 ZW to 12 volunteer male test subjects (Figure 1) and after 1.0 mg p.o. (in solution) administration of AG-EE—388 ZW to 12 volunteer male test subjects (Figure 2). Therefore, following the administration of the racemate, the inactive enantiomer, AG—EE 624 ZW, is present not only as an unnecessary additive in plasma concentrations which are just as high as those of the active enantiomer, AG—EE 623 ZW, but indeed and particularly surprisingly achieves higher and longer-lasting levels.

The effect of this, tablet containing 2 mg of AG-EE 388 ZW compared with e.g. following administration of a administration of a tablet containing 1 mg of AG-EE ZW to 12 and 6 test subjects, respectively, is that the maximum concentrations are 84 i 25 and 28 i 18 ng/ml, hours are 19 i 8 and 0.7 t after 5 hours 13 i 6 and 0.3 i and after 6 hours 10 i 6 and 0.3 i 0.7 ng/ml, respectively. respectively, the concentrations after 4 1.0 ng/ml, respectively, .7 ng/ml, respectively, The surprisingly quick onset of the lowering of the blood sugar level by AG—EE 623 ZW, compared with AG—EE .388 ZW, is particularly advantageous for diabetics, since the rapid onset results in optimum control of the disease.

Thus, compared with the administration of AG—EE 388 ZW, the surprising advantage of the administration of AG-EE 623 ZW is that unnecessarily high and long-lasting levels of the substance in the body are avoided, which -4... is of major importance in long term therapy, such as that of diabetic mellitus.

Human studies have shown that the new (S)—enantiomer, namely (S)(+)—2—ethoxy—4—[N—[1—(2—piperidino—phenyl)~3- methyl—l-butyl]aminocarbonylmethyl]-benzoic acid, as a vehicle of blood sugar-lowering activity, is far superior to AG-EE 388 ZW, due to its surprisingly rapid elimination from the blood, which was not foreseeable in View of its relatively long duration of activity. Such superior qualities go far beyond the "normal" advantage of an enantiomer over its racemate, namely that of halving the dose.

Thus, according to one aspect the present invention provides the new compound (S)(+)—2-ethoxy—4-[N—[l—(2— piperidino-phenyl)—3—methyl—l—butyl]— aminocarbonylmethyl]—benzoic acid or an (s)(+)ethoxy- 4—[N—[1-(2-piperidino—phenyl)—3—methyl~l~buty1]— aminocarbonylmethyl]—benzoic acid which is substantially optically pure, e.g. having an optical purity of at %, preferably 98 to 100%, and the addition salts thereof, and more particularly for pharmaceutical least ee = use the physiologically acceptable addition salts thereof with inorganic or organic acids or bases.

According to a further aspect the invention also provides a process for the preparation of the compound of the invention, said process comprising at least one of the following steps: a) reacting the (S)—amine of formula I (I) with a carboxylic acid of formula II W ”°°CC”2 OCH2CH5 (II) (wherein W represents an optionally protected carboxy group) or with a reactive derivative thereof, optionally prepared in the reaction mixture and, if necessary, subsequently _ cleaving any protecting group used; b) cleaving an (S)-compound of formula III (III) (wherein A represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis); c) reacting an (S)—compound of formula IV (IV) (wherein W’ represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and in which the_ J alkoxy group may additionally be substituted by a phenyl group) with a compound of formula V z — CH2 — CH3 (V) (wherein Z represents a nucleophilic leaving group such as a ...7_ halogen atom or a sulphonyloxy group, or, together with the adjacent hydrogen atom represents a diazo group) optionally followed by hydrolysis or hydrogenolysis; d) enantioselectively reducing a compound of formula VI w' :%: ‘Y ocazcus C] (VI) (wherein W‘ represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and in which the alkoxy group may additionally be substituted by a phenyl group, and Y represents a group of formula cu, °“: °”3 NH/’ NH/’ ”// V optionally followed by hydrolysis: e) oxidising an (S)-compound of formula VII (VII) (wherein W" represents a group which may be converted into a carboxy group by oxidation); f) separating a mixture comprising an amount of the (S)- .enantiomer of formula VIII (VIII) and an amount of the (R)—enantiomer of formula (IX) CHs\\c|.‘/EH3 W w- _H c”. . \ [:::]:: "“ ocuzcns {::] (IX) (wherein W‘ represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and in which the___ alkoxy group may additionally be substituted by a phenyl group), preferably a 50/50 mixture thereof, via the diastereomeric adducts, complexes or salts thereof, and followed if necessary by hydrolysis or hydrogenolysis; g) converting an (S)-enantiomer thus obtained, having an optical purity of, preferably, at least 90%, into an (S)-enantiomer having an optical purity of at least 95%, preferably 98 to 100%, by fractional crystallisation; and h) converting an (S)—enantiomer thus obtained into an addition salt thereof or an addition salt of the (S)- enantiomer into the free (S)-enantiomer. ' Reactive derivatives of a compound of formula II include, for example, the esters thereof such as the methyl, ethyl and benzyl esters, the thioesters thereof such as the methylthio and ethylthioesters, the halides as acid chloride, and the anhydrides and thereof. thereof such imidazolides (a) may conveniently be carried out The reaction of step in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid—activating agent or a dehydrating agent, e.g. in the presence of ethylchloro—formate, isobutylchloroformate, thionylchloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'- dicyclohexylcarbodi—imide/N-hydroxysuccinimide, N,N'- carbonyldiimidazole, N,N'-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine which may simultaneously serve as solvent, at temperatures between -25 and 250“C, preferably at temperatures between ~10°C The reaction may also be carried out without a solvent and and the boiling temperature of the solvent used. moreover any water formed during the reaction may be removed by azeotropic distillation, e.g. by heating with toluene using a water separator, or by the addition of a drying agent such as magnesium sulphate or a molecular sieve.

If necessary, the subsequent cleaving of a protecting group used in step (a) is preferably carried out by hydrolysis, conveniently either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trifluoroacetic or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as water, methanol, methanol/water, ethanol, ethanol/water, water/isopropanol or water/dioxane at temperatures between -10 and 120°C, e.g. ambient temperature and the boiling temperature of the at temperatures between reaction mixture.

A tert.—butyl group used as protecting group may also be cleaved thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid and preferably in the presence of a strong acid such as trifluoroacetic, hydrobromic, p—toluenesu1phonic, sulphuric, phosphoric or polyphosphoric acid.

A benzyl group used as protecting group may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

For reagents of formula III used in step (b), examples of hydrolysable groups include functional derivatives of the carboxy group such as optionally substituted amides, esters, thioesters, orthoesters, iminoethers, amidines and anhydrides, nitrile and tetrazolyl groups, and -11.. optionally substituted 1,3—oxazol—2-yl and 1,3-oxazolin- 2-yl groups, examples of thermolytically cleavable groups include esters with tertiary alcohols, e.g. tert.butylester, and examples of hydrogenolytically cleavable groups include aralkyl groups, e.g. a benzyl group.

The hydrolysis of step (b) may conveniently be carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trifluoroacetic or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10 and 120°C, preferably at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

If A in a compound of formula III represents a nitrile or aminocarbonyl group, these groups may be converted into a carboxy group by means of 100% phosphoric acid at temperatures between 100 and 180°C, preferably at temperatures between 120 and 160°C, or using a nitrite, e.g. sulphuric acid, whilst the latter may conveniently be sodium nitrite, in the presence of an acid such as used as solvent at the same time, between 0 and 50°C. at temperatures If A in a compound of formula III represents, for example, a tert.butyloxycarbonyl group, the tert.butyl_ . group may also be cleaved thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid and preferably in the presence of a strong acid such as trifluoroacetic acid, hydrobromic acid, p- toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, at temperatures between 0 and °C, preferably at temperatures between 20°C and the boiling temperature of the solvent used.

If A in a compound of formula III represents, for example, a benzyloxycarbonyl group, the benzyl group may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, methanol/water, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. at ambient temperature and under a hydrogen pressure of from 1 to bar.

The reaction of step (c) may conveniently be carried out with a corresponding halide, sulphonic acid ester or sulphuric acid diester, e.g. with ethyl bromide, ethyl iodide, diethylsulphate, ethyl p-toluenesulphonate or ethyl-methanesulphonate, or with diazoethane, optionally in the presence of a base such as sodium hydride, potassium carbonate, sodium hydroxide, potassium tert.butoxide or triethylamine, preferably in a suitable solvent such as acetone, diethylether, tetrahydrofuran, dioxane, pyridine or dimethylformamide at temperatures between 0 and 100°C, preferably at temperatures between and 50°C.

If W’ in a compound of formula IV represents a carboxy group, this can be converted into the corresponding ester compound.

If necessary, the subsequent hydrolysis of step (c) is carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trifluoroacetic or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol/water, -13.. ethanol, ethanol/water, water/isopropanol or water/dioxane at temperatures between -10 and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. _ The subsequent hydrogenolysis may also be carried out in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide under a hydrogen pressure of from 1 to 10 bar.

The reduction of step (d) is preferably carried out with hydrogen in the presence of a chiral hydrogenation catalyst in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran, methanol/tetrahydrofuran, methanol/methylene chloride, ethanol/methylene chloride of isopropanol/methylene chloride at temperatures between 0 and 100°C, but preferably at temperatures between 20 and 50°C, under a hydrogen pressure of between 1 and 1000 bar, preferably between 5 and 100 bar, and conveniently with the addition of 0.1 to 5%, preferably 0.3 to 1%, of titanium(IV)tetraisopropoxide, preferably with the exclusion of oxygen from the surrounding atmosphere.

The reduction is preferably carried out with the (Z)- form of a compound of formula VI.

Examples of chiral hydrogenation catalysts which may be used in step (d) include the corresponding metal ligand _ NORPHOS —COD] BF . benzyloxycarbonyl group may simultaneously be reduced During the catalytic hydrogenation, a and converted into the carboxy group.

If necessary, the subsequent hydrolysis of step (d) may ._l4._ be carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trifluoroacetic or tri-chloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol/water,f ethanol, ethanol/water, water/isopropanol or" water/dioxane at temperatures between -10 and 120’C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

For the reagent of formula VII used in step (e), examples of oxidisable W" groups include the formyl group and the acetals thereof, the hydroxymethyl group and the ethers thereof, and optionally substituted acyl groups such as acetyl, chloroacetyl, propionyl, malonic acid-(1)—yl and malonic ester-(1)-yl groups.

The reaction of step (e) may be carried out with an oxidising agent in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxane or glycoldimethylether at temperatures between 0 and 100°C, preferably at temperatures between 20°C and 50°C.

However, the reaction is preferably carried out with silver oxide/sodium hydroxide solution, manganese dioxide/acetone or methylene chloride, hydrogen peroxide/sodium hydroxide solution, bromine or chlorine/sodium or potassium hydroxide solution, chromium trioxide/pyridine or pyridinium chlorochromate.

The separation of step (f) is preferably carried out using column or HPL chromatography by forming the diastereomeric adducts or complexes on a chiral phase.

If necessary, the subsequent hydrolysis of step (f) may be carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trifluoroacetic or trichloroacetic acid or in the presence of a base such ._.l5_ as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol/water, ethanol, ethanol/water, water/isopropanol or water/dioxane at temperatures between -10 and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture;" The subsequent hydrogenolysis may also be carried out in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide under a hydrogen pressure of from 1 to 10 bar.

A compound obtained in step (f) may, if necessary, be "converted by recrystallisation into a compound with a higher enantiomeric purity, crystallisation from ethanol/water (2/1 by volume) producing the high melting form with a melting point of 130~131°C, and crystallisation from petroleum ether/toluene (5/3 by volume) producing the low-melting form with a melting point of 99-101°C.

The (S)—enantiomer obtained according to the invention may, if desired, be converted into the addition salts thereof, more particularly, for pharmaceutical use, into the physiologically acceptable salts thereof with inorganic or organic acids or bases. Examples of suitable acids for this purpose include hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, tartaric, succinic, maleic and fumaric acids and examples of suitable bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine and lysine. some of the compounds of formulae I to IX used as ._]_6_ starting materials are known from the literature.

Otherwise these compounds may be obtained by methods known per ge.

The (S)—amine of formula I may, for example, be obtained from the corresponding racemic amine: by racemate cleaving, e.g. by means of fractional crystallisation of the diastereomeric salts with suitable optically active acids, preferably with N- acety1—L-glutamic acid, and if necessary recrystallisation and subsequent decomposition of the salts, or by column or HPL—chromatography on chiral phases, optionally in the form of an acyl derivative, or‘ by forming diastereomeric compounds, then separating and subsequently cleaving them.

Additionally, the (S)—amine of formula I may be prepared: by enantioselective reduction using hydrogen in the presence of a suitable chiral hydrogenation catalyst, starting from a corresponding N—acyl-ketimine or enamide, conveniently with the addition of 0.1 to 5% titanium tetraisopropoxide, optionally with subsequent cleaving group , of the acyl group such as the formyl or acetyl by diastereoselective reduction of a corresponding ketimine or hydrazine chirally substituted at the nitrogen atom, using hydrogen in the presence of a suitable hydrogenation catalyst, conveniently with the addition of 0.1 to 5% titanium tetraisopropoxide, and optionally followed by cleaving of the chiral auxiliary group, e.g. the (S)phenethyl group, by catalytic hydrogenolysis, or by diastereoselective addition of a corresponding organometallic compound, preferably a Grignard or. lithium compound, to a corresponding aldimine chirally substituted at the nitrogen atom, optionally with the addition of 0.1 to 10% titanium tetraisopropoxide, subsequent hydrolysis and optional separation of the resulting diastereomers and subsequent cleaving of the chiral auxiliary group, e.g. the (R)phenethyl group by catalytic hydrogenolysis, and if necessary the (S)—amine may be obtained in a higher enantiomeric purity by salt formation with suitable optically active acids, preferably with N- acetyl-L-glutamic acid, and if necessary single or multiple recrystallisation and subsequent decomposition of the salt.

Compounds of formulae III, IV and VII used as starting materials may be obtained by reacting the (S)—amine of formula I with a corresponding carboxylic acid or a reactive derivative thereof and optionally subsequently splitting off any protecting group used.

The compounds of formula VI used as starting materials may be obtained by acylating corresponding imino compounds or the organometallic complexes thereof with a corresponding carboxylic acid or with a reactive derivative thereof with optional subsequent cleaving of an ester group.

The new (S)-enantiomer is virtually non-toxic; for example, after a single administration of 1000 mg/kg p.o. (suspension in 1% methylcellulose) to 5 male and 5 female rats, no animals died within the observation period of 14 days.

In View of its pharmacological and pharmacokinetic properties, the (S)—enantiomer prepared according to the invention (AG—EE 623 ZW) and the physiologically." acceptable salts thereof are suitable for the treatment For this purpose, AG-EE 623 ZW or the physiologically acceptable salts thereof, optionally of diabetes mellitus. combined with other active substances, may be incorporated in conventional galenic preparations such as plain or coated tablets, capsules, powders, suppositories, suspensions or injectable solutions. The single dose for adults is 0.1 to 20 mg, preferably 0.25 to 5 mg, especially 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 or 5.0 mg, once, twice or three times a day.

Thus in a further aspect the present invention provides a pharmaceutical composition comprising as active ingredient the (S)-enantiomer or a physiologically acceptable addition salt thereof together and at least substantially free from other isomers of said active ingredient with at least one pharmaceutical carrier or excipient.

In a still the use of further aspect the present invention provides the (S)—enantiomer or a physiologically acceptable addition salt thereof for the manufacture of a therapeutic agent for the treatment of diabetes mellitus.

In a still yet further aspect the present invention provides a method of treatment of the human or non—human animal body to combat diabetes mellitus, said method comprising administering to said body the (S)—enantiomer or a physiologically acceptable addition salt thereof.

In another aspect the present invention provides new _]_9... compounds of formulae I, III, IV and VII which are valuable intermediate products for preparing the new (S)-enantiomer, and the addition salts thereof with inorganic or organic acids. — The following non—1imiting Examples are provided to illustrate the invention. Unless otherwise specified all percentages and ratios given are by weight.

Example A (S)—1—(2—Piperidino—phenyl)—3—methyl—1-butylamine Yield: 65.1 g (60.4% of theory), Melting point: l68~l71°C Calculated: C 63.42 H 8.56 N 9.65 Found: 63.64 8.86 9.60 The free amine is obtained as an oil by liberation, for example, with a sodium hydroxide or ammonia solution, extraction with, for example, toluene, ether, ethylacetate or methylene chloride, and drying, filtering and evaporation of the extract in vacuo.

Enantiomeric purity was determined as follows: . Acetylation of a sample of the amine with 1.3 equivalents of acetic anhydride in glacial acetic acid at 20°C overnight.

. Investigation of the N-acetyl derivative (melting 128—132°C) by HPLC on a chiral phase HPLC column made by Baker, in which (S)-N-(3,5-dinitrobenzoyl) point: phenyl—glycine is covalently bonded to aminopropyl silica gel (particle size 5 pm, spherical, pore size 60 A; column length: 250 mm with internal diameter .6 mm; eluant: n-hexane/isopropanol (100/5 by volume); flow rate: 2 ml/minute; temperature: 20°C; UV-detection at 254 nm.) Found: peak 1(R): peak 2(S) = 0.75%: 99.25%, ee (enantiomeric excess) = 98.5% (S).

The (S)—amine may be converted into the dihydrochloride hydrate thereof using ethereal hydrogen chloride solution. .02 21.25 1 in methanol) Example B N-Acetyl—N—[l—(2-piperidino—phenyl)methyl—1—buten—1- y1]—amine ~ At ambient temperature, 4.7 ml (81.8 mmol) of glacial acetic acid, 25.7 g (98.2 mMol) of triphenylphosphine, 34.2 ml (245 mMol) of triethylamine and 7.9 ml (81.8 mMol) of carbon tetrachloride are added to a solution of 20 g (81.8 mMol) of freshly prepared isobutyl-(2-piperidino-phenyl)-ketimine in 200 ml of acetonitrile and the resulting mixture is stirred for 18 -hours at ambient temperature. It is then evaporated down in vacuo and distributed between ethyl acetate and water. The organic extract is dried and filtered and evaporated down in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1 by volume), eluting first the (E)-form and then the (Z)-form.

(E)—form: Yield: 6.1 g (26% of theory), Melting point: 135—137°C (ethylacetate/petroleum ether) Calculated: C 75.48 H 9.15 N 9.78 Found: 75.47 9.35 9.70 (Z)-form: Yield: 3.1 g (13% of theory), Melting point: 140—143°C (ethylacetate) Calculated: C 75.48 H 9.15 N 9.78 Found: 75.56 9.30 9. -22..

Example C N-Acetyl-N-[1-(2—piperidino—phenyl)methyl—1—buten—1- yl]-amine — ml (0.18 mol) of acetic anhydride are added dropwise, at an internal temperature of 0°C, to a stirred solution of 44 g (0.18 mol) of freshly prepared isobutyl-(2- piperidino—phenyl)—ketimine in 440 ml of toluene. The mixture is stirred for a further 3 hours at 0°C and for hours at ambient temperature, then evaporated down in vacuo, the evaporation residue is dissolved in ethyl acetate and extracted several times with aqueous sodium hydrogen carbonate solution. The organic phase is dried, filtered and evaporated down lg vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 5/1 by volume), eluting first the (E)—form and then the (Z)-form.

(E)-form: Yield: 3.0 g (5.8% of theory), (Z)-form: Yield: 17.8 g (34.5% of theory), Melting point: 139-141“C (ethyl acetate) Calculated: C 75.48 H 9.15 N 9.78 Found: 75.68 8.99 9.86 Example D N-Acetyl—N—[(S)(2—piperidino—phenyl)-3—methy1 butyl]-amine .57 g (1.99 mMol) of (Z)—N—acetyl—N—[1-(2-piperidino- phenyl)—3—methylbutenyl]—amine, melting point 139-141°C, are dissolved in 10 ml of degassed solvent mixture (methanol/methylene chloride = 5/1 by volume) under an Argon atmosphere and added to a solution of 16.8 mg (1 mol %) of the NOYORI—catalyst Ru(0— acetyl)2[(S)—BINAP] (prepared from [Ru(C0D)Cl2L1with (S)-BINAP [= (S)—2,2'—bis(diphenylphosphino)—l,l1— binaphthyl], triethylamine and sodium acetate), and 3.4 mg (0.5 mol %) of titanium tetraisopropoxide in ml of degassed solvent mixture (methanol/methylene /1 by volume). drawn into an autoclave which is evacuated at 10* mbar. chloride = The reaction mixture is It is flushed several times with hydrogen at 4 bar and the mixture is then hydrogenated at 30°C under 100 bar Then the reddish—brown solution is evaporated down in vacuo, until the hydrogen uptake has ceased (170 hours). the evaporation residue is refluxed with 30 ml of n- hexane and filtered hot to remove any insoluble matter. when the filtrate cools, crystallisation occurs.

Yield: 0.31 g (54% of theory), Melting point: 127—131°C enantiomeric purity: ee = 82% [HPLC method: see (5) Example A]. % of the racemic N—acetyl—amine of melting point 154-156°C can be obtained from the insoluble matter obtained when boiling with 30 ml of n-hexane, by further decoction with n—hexane, filtration and crystallisation from the hexane solution.

Example E (S)(2—Piperidino-phenyl)—3—methyl—1-butylamine g (3.47 mMol) of N-acetyl-N-[(S)-l-(2-piperidino- phenyl)methyl—1-butyl]—amine (melting point: 128-133°C; 99.4%] are refluxed in 10 ml of concentrated hydrochloric acid for 5.5 hours, then cooled and poured into a mixture of concentrated ammonia and ice. The mixture is extracted twice with ethyl acetate, the organic phase is washed with water, dried ...24_ and filtered and then evaporated down in vacuo.

Yield: 0.84 g (98.8% of theory) oily amine.

By re—acetylation with 0.42 ml (1.3 equivalents)—of acetic anhydride in 8.4 ml of glacial acetic acid“ overnight at ambient temperature, evaporation'in vacuo, distribution of the evaporation residue between ethyl acetate and saturated aqueous sodium bicarbonate solution then drying, filtering and evaporation of the organic extract in vacuo, 0.83 g (84.7% of theory) of N- acetyl—N—[(S)—1—(2—piperidino-phenyl)-3—methyl—1-butyl]- amine are obtained (melting point: 130-132°C; ee = 99.4%).

Example F Ethyl 2—ethoxy—4—[N-(1-(2—piperidino~phenyl)—3—methy1 buten—1—yl)—aminocarbonylmethyl]-benzoate Prepared from isobutyl—(2—piperidino—phenyl)-ketimine and 3—ethoxy-4—ethoxycarbonyl-phenylacetic acid analogously to Example B. Purification by column chromatography on silica gel (toluene/acetone = 10/1 by volume), eluting first the (E)-form and then the (Z)- form.

(E)-form: Yield: 4% of theory, Melting point: 101-103°C Calculated: C 72.77 H 8.00 N 5.85 Found: 72.74 7.78 5.86 (Z)-form: Yield: 28.1% of theory, Melting point: 124—127°C (petroleum ether/toluene = 5/1 by volume) Calculated: C 72.77 H 8.00 N 5.85 Found: 72.90 7.86 5. _25..

Example G N-[(S‘)-1—phenethyl]—N—[(S)—1—(2—piperidino—phenyl)-3— methyl-1—butyl]—amine — g (49 mMol) of N—[(S')—1—phenethyl]-isobutyl-(2- piperidino-phenyl)—ketimine, boiling point 150- 155°C/0.3 torr [prepared from isobutyl-(2-piperidino— phenyl)—ketone and (S')—1—phenethy1-amine (made by Fluka, dropwise addition of a solution of titanium ee = 99.6%) in toluene + triethylamine by tetrachloride in toluene] are dissolved in 170 ml of anhydrous ethanol. 1.7 g of titanium tetraisopropoxide and 8 g of Raney nickel are added and the mixture is After hours a further 8 g of Raney nickel are added and the hydrogenated at 50°C under 200 bar of hydrogen. mixture is hydrogenated for a further 52 hours under the same conditions. The catalyst is filtered off over a layer of Celite on a G3—frit and the filtrate is evaporated down in vacuo.

Yield: 13.1 g (76.6% of theory), Boiling point: 152°C/0.2 torr The diastereomeric purity is determined by HPLC on a Lichrosorb RP18 HPLC column made by E. Merck (Germany); column length: 250 mm with an internal diameter of 4 mm;” particle size: 7 pm. Eluant: methanol/dioxane/0.1% aqueous sodium acetate solution, adjusted to pH 4.05 with acetic acid (135/60/5 by volume); temperature: 23°C; UV-detection at 254 nm.

Found: peak 1(S,S'): peak 2(R,S') de (diastereomeric excess) .49: 1.4%, 97.0% (s,s'). -26..

Example H (S)—1~(2—Piperidino—pheny1)—3—methyl—1—butylamine .5 g (36 mMol) of N—[(S')phenethyl]-N-[(S)—l;(2— piperidino—phenyl)-3—methyl-l—butyl]—amine with a de of 97.0% of conc. hydrochloric acid.

(S,S') are dissolved in 125 ml of water and 3.6 ml 1.3 g of (10%) palladium/charcoal are added and the mixture is After the has ended (10 hours) the mixture is hydrogenated at 50°C under 5 bar of hydrogen. hydrogen uptake filtered over a The filtrate is the addition of The organic extract is dried and filtered and evaporated layer of Celite to remove the catalyst. made alkaline with conc. ammonia with ice and extracted with ethyl acetate. down ig vacuo.

Yield: 6.4 g (72.1% of theory), Boiling point: 115—117°C/0.4 torr .5% (5) [HPLC method previous acetylation): see Example A].

Enantiomeric purity: ee = (after Example I N-[(R‘)phenethyl]—N—[(S)(2—piperidino-phenyl) methylbutyl]—amine A solution of 2 g (6.84 mMol) of N—[(R')—l—phenethyl}— (2-piperidino-benzaldimine) [prepared from equimolar amounts of 2-piperidino—benzaldehyde and (R')—l- phenethylamine by standing overnight at ambient temperature and subsequent drying with sodium sulphate in ether solution] in 20 ml of anhydrous tetrahydrofuran is added dropwise to a solution of 27.4 mMol (4 equivalents) of isobutyl—magnesium bromide in 22 ml of anhydrous tetrahydrofuran, which is stirred in a bath at °C. After 18 hours the bath temperature is increased _2'7._ to 80°C and a further 2 equivalents of isobutyl— magnesium bromide in 11 ml of tetrahydrofuran are added.

After 12 hours stirring at 80°C 2 equivalents of isobutyl—magnesium bromide solution are added onee After about 90 hours at 80°C the mixture_is hydrochloric acid is added and the again. cooled, excess conc. resulting mixture is evaporated to dryness in a water The evaporation residue is dissolved in It is the organic extract is dried over The jet vacuum. water and made alkaline with cone. ammonia. extracted with ether, sodium sulphate, filtered and evaporated in vacuo. evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 95/5 by volume).

Yield: 0.20 g (8.3% of theory), Melting point: < 20°C The diastereomeric purity is determined by HPLC as in Example G. peak 1(R,R'): peak 2(S,R') = de (diastereomeric excess) .4%:95.6%, 91.2% (S,R').

Found: In an analogous mixture with 2.0 g of the Schiff's base and a total of 6 equivalents of isobutyl-magnesium bromide in toluene/tetrahydrofuran (4/1 by volume) and with the addition of 5% titanium(IV)-tetraisopropoxide and heating for 60 hours at 100°C in a glass tank, a yield of 5% was achieved with a de of 97.6% (S,R').

Example K (S)(2-Piperidino—phenyl)—3—methyl—1—butylamine A solution of 0.15 g (0.428 mMol) of N-[(R') phenethyl]-N-[(S)—l—(2—piperidino—phenyl)—3—methyl butyl]—amide (de = 91.2%), 0.47 ml (0.47 mMol) of 1N- hydrochloric acid and 1.5 ml of water is hydrogenated in the presence of 20 mg of 10% palladium/charcoal for 5 hours at 50°C under 3.4 bar of hydrogen. The mixture -28.. filtered over kieselguhr, made alkaline with cone. ammonia and extracted with ethyl acetate. The extract is dried, filtered and evaporated in vacuo.

Yield: 0.066 g (62.8% of theory), ~ Melting point: < 20°C _ 1 Enantiomeric purity: ee = 87.6% (S) [HPLC method (after previous acetylation): see Example A}.

Example 1 Ethyl (S)ethoxy—4~[N—(1—(2—piperidino-phenyl) methyl-l—butyl)—aminocarbonylmethyl]—benzoate .48 g (1.91 mMol) of 3—ethoxy—4—ethoxycarbonyl— phenylacetic acid, 0.60 g (2.29 mMol) of triphenyl- phosphine, 0.80 ml (5.73 mMol) of triethylamine and .18 ml (1.91 mMol) of carbon tetrachloride are added successively to a solution of 0.47 g (1.91 mMol) of (S)- 3-methyl—1—(2—piperidino—phenyl)-1—butylamine (ee = 98.5%) in 5 ml of anhydrous acetonitrile and the resulting mixture is stirred for 20 hours at ambient I It is then evaporated down in vacuo and The organic extract is dried and filtered and evaporated temperature. distributed between ethyl acetate and water. down in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1 by volume).

Yield: 0.71 g (77.3% of theory), Melting point: 110-112°C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.29 8.42 5.80 The enantiomeric puritv is determined by HPLC on a chiral phase HPLC column made by Baker, in which (S)-N- 3,S-dinitrobenzoyl—1eucine is covalently bound to aminopropyl silica gel (particle size: 5 pm, spherical, A pore size; column length: 250 mm with an internal diameter of 4.6 mm: eluant: n-hexane/tetrahydro— furan/methylene chloride/ethanol (90/10/1/1 by volume); flow rate: 2 ml per minute; temperature: 20°C; UV detection at 242 nm). — Found: peak l(R): peak 2(8) = 0.75%: 99.25%, ee = 98.5% (3).

Example 2 Ethyl (S)ethoxy—4—[N—(1—(2—piperidino—phenyl)~3- methylbutyl)-aminocarbonylmethyl]-benzoate .77 g (11 mMol) of 3—ethoxy—4—ethoxycarbonyl- phenylacetic acid are added at ambient temperature to a solution of 2.71 g (11 mMol) of anhydrous (S)-3—methyl- 98.5%) in ml of absolute toluene and the mixture is stirred Then 2.38 g (11.55 mMol) of N,N'- dicyclohexyl—carbodiimide are added and the mixture is stirred at ambient temperature. After 24 hours a further 0.54 g (2.14 mMol) of 3—ethoxyethoxycarbony1- phenylacetic acid and 0.48 g (2.33 mMol) of N,N'— dicyclohexylcarbodiimide are added and the mixture is -(2-piperidino-phenyl)~l—butylamine (ee = until dissolved. stirred overnight. It is then cooled to an internal temperature of +5°C and suction filtered to separate the precipitate, which is washed once with 5 ml of toluene.

The combined toluene filtrates are evaporated down ip vacuo to a volume of about 10 ml. The resulting solution is heated over the steam bath and petroleum ether is added in batches thereto (total of 55 ml) until It is cooled in ice, whereupon the turbidity remains. crystallisation takes place. It is suction filtered and dried at 75°C/4 torr. The product obtained (4.57 g; melting point 111—112°C; ee = 98.9%) is suspended in ml of petroleum ether. The mixture is heated over the steam bath and sufficient toluene is added in batches (8 ml in total) until a solution is obtained.

This is then cooled in ice and suction filtered to separate the crystals, which are dried at 75°C/4 torr.

Yield: 3.93 g (74.3% of theory), — Melting point: 117—l18°C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.44 8.43 5.93 {a]?==+-9.4° (c = 1.01 in methanol) Enantiomeric purity: ee = 99.9% [HPLC method: see Example 1] Example 3 (S)Ethoxy—4—[N—(1—(2~piperidino—phenyl)—3—methyl-l- butyl)-aminocarbonylmethyl]—benzoic acid A solution of 3.79 g (7.88 mMol) of ethyl (S)ethoxy— 4—[N~(1—(2—piperidino-phenyl)—3—methyl-1—butyl)— aminocarbonylmethyl]—benzoate (ee = 99.9%) in 37 ml of ethanol is stirred in a bath at 60°C and 10 ml (10 mMol) of 1N sodium hydroxide solution are added. After 4 ml (10 mMol) of 1N- hydrochloric acid are added in the warm and the mixture After inoculation and standing overnight, the mixture is hours stirring at 60°C, is left to cool to ambient temperature.

The crystals are separated by suction filtering and washed They are then dried at 75°C cooled for a further hour in ice, with stirring. twice with 5 ml of water. up to a final temperature of 100°C/4 torr in a vacuum drying cupboard over phosphorus pentoxide.

Yield: 3.13 g (87.7% of theory), Melting point: 130—131°C (high-melting form) Calculated: C 71.64 H 8.02 N 6.19 Found: 71.48 7.87 6.39 The enantiomeric purity is determined by HPLC on a _3:}__ chiral phase HPLC column made by ChromTech (Sweden) with an AGP(al—acid glycoprotein) phase; internal diameter: .0 mm: length: 100 mm; particle diameter: 5 pm.

Temperature: 20°C; eluant: 0.1% aqueous Kngxr solution (=A) + 20% acetonitrile (=B), gradient increase within 4 minutes to 40% (B); detection at 240 nm. flow rate: 1 ml per minute; UV Retention time (S)—enantiomer: 2.7 minutes; retention time (R)—enantiomer: 4.1 minutes.

(S):(R) = 99.85%: 0.15%, .7% (s).

When a sample is recrystallised from ethanol/water (2/1 Found: ee = by volume) the melting point does not change. when a sample is heated in petroleum ether/toluene (5/3 by volume) the undissolved portion is filtered (melting point: 130—131°C) and the filtrate is rapidly cooled, the low melting form of the title compound is obtained, melting point 99~101°C.

Calculated: C 71.64 H 8.02 71.66 7.97 N 6.19 Found: 6.44 The low melting form and the high melting form differ in their infra—red KBr spectra but not in their infra-red solution spectra (methylene chloride).

If a sample of the low melting form is heated beyond its melting point a second melting point is observed at 127- 130°C.

If a sample of the low—melting form is recrystallised from ethanol/water (2/1 by volume), the high melting form is obtained.

The high melting form and the low melting form were investigated by Differential Scanning Calorimetry (DSC) [Mettler apparatus, TA-300 system; measuring cell: DSC 20; made by Mettler, CH—8306 Greifensee, Switzerland] with the following results: _32.— Compound of Example 3 Heating rate 10°K/min.

Heating rate 3°K/min.

High melting form Uniform melting peak with melting tempera- ture of 133°C; melting enthalpy: J/g Uniform melting peak with melting tempera- of 132°C; melting enthalpy: 99.1 J/g Low melting form lst peak at 57°C (very weak) nd peak at 78°C (weak) rd endothermic peak at 107°C; melting enthalpy: J/g . th endothermic peak at 132°C melting enthalpy: J/g lst peak at 54°C (very weak; endothermic) nd endothermic peak at 104"C. melting temperature 102°C, melting enthalpy J/g rd exothermic path of the base line by crystallisation of the substance melting at 104°C th endothermic peak at 131°C, melting temperature 130°C melting enthalpy J/g Example 4 Ethyl (S)-2—ethoxy[N-(1-(2—piperidino—phenyl) methy1—1—buty1)—aminocarbonylmethyl]—benzoate .79 g (1.65 mMol) of ethyl (Z)—2—ethoxy—4—[N—(1-(2- piperidino—phenyl)—3—methy1—1—butenyl)-aminocarbony1— methyl]-benzoate, melting point 124-127°C, are dissolved in 10 ml of degassed solvent mixture (methanol/methylene chloride = /1) under an Argon atmosphere and added to a solution of 17 mg of the NOYORI—catalyst Ru(0— _33_ acetyl)2[(S)-BINAP] (prepared from [Ru(COD)Cl2L‘with (S)—BINAP [= (S)—2,2'-bis~(diphenylphosphino)—1,1'— binaphthyl], triethylamine and sodium acetate) and 3 mg of titanium tetraisopropoxide in 10 ml of degassed solvent mixture (methanol/methylene chloride =_5/1 by volume). The reaction mixture is drawn into an autoclave evacuated at 10* mbar. This is flushed five times with hydrogen at 5 bar and finally hydrogenated at °C and 100 bar until the hydrogen uptake has ceased (154 hours). The reddish—brown solution is evaporated down in vacuo, the evaporation residue is dissolved in 80 ml of ether, flakes by means of activated charcoal and the resulting filtered off from the undissolved brown clear, bright yellow filtrate is evaporated down in vacuo. The evaporation residue (0.60 g) is refluxed in 60 ml of n~hexane and filtered hot to separate it from The filtrate is left to stand The crystals which the insoluble matter. overnight at ambient temperature. are precipitated are filtered off.

Yield: 0.45 g (56.7% of theory), Melting point: 131—133°C (after sintering from 120°C) (S) [HPLC method: Enantiomeric purity: ee = 39% see Example 1].

Example 5 Ethyl (S)ethoxy—4—[N—(1~(2—piperidino-phenyl) methylbutyl)-aminocarbonylmethyl]—benzoate ml of anhydrous dimethylformamide and the mixture is stirred for 0.5 hours at ambient temperature. Then a solution of 0.12 ml (1.15 mMol) of ethyliodide in 2.5 ml ._34.. of anhydrous dimethylformamide is added dropwise thereto and the mixture is stirred for 5 hours at ambient temperature. It is evaporated down in vacuo, the residue is distributed between dilute sodium hydroxide solution and chloroform, the organic extract is dried, filtered and evaporated down in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1 by volume).

Yield: 0.48 g (67% of theory), Melting point: 110—112“C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.61 8.54 5.97 Enantiomeric purity: ee = 98.5% (S) [HPLC method: see Example 1].

Example 6 Ethyl (S)—2—ethoxy—4—[N—(1—(2—piperidino—phenyl) methyl—1—buty1)-aminocarbonylmethyl]-benzoate Prepared from (S)—2-hydroxy—4—[N—(1-(2-piperidino- phenyl)methyl—1—butyl)-aminocarbonylmethylj—benzoic acid analogously to Example 5 using 2 equivalents of sodium hydride and 2 equivalents of ethyl iodide.

Yield: 42% of theory, Melting point: 110—112°C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.61 8.54 5.99 Enantiomeric purity: ee = 98.3% (S) [HPLC method: see Example 1].

Example 7 Ethyl (S)(+)-2—ethoxy—4—[N—(1—(2-piperidino-phenyl) methyl—1—butyl)-aminocarbonylmethyl]-benzoate and Ethyl (R)(~)—2—ethoxy~4-[N-(1-(2—piperidino-phenyl)F3- methyl—1-butyl)—aminocarbonylmethyl]—benzoate' mg of ethyl (1)-2—ethoxy—4—[N-(1-(2-piperidino- phenyl)—3~methylbutyl)~aminocarbonylmethyl]-benzoate are separated, in single doses of 10 mg, on a preparative chiral phase HPLC column made by Baker, in which (S)—N—3,5—dinitrobenzoyl~1eucine is covalently bonded column length: to aminopropyl—silica gel (particle size: 40 pm; 250 mm with an internal diameter of mm; eluant: n—hexane/tetrahydrofuran/ethanol/ methylene chloride (180/20/3/2 by volume): flow rate: 21.25 ml per minute; temperature: 27°C: UV—detection at 285 nm), in which first the (R)(—)-enantiomer (peak 1) and then the (S)(+)—enantiomer (peak 2) is eluted.

After evaporation in vacuo, the following are obtained from the correspondingly cut and collected fractions: Peak 1 fraction (R): 423 mg (crude), Peak 2 fraction (8): 325 mg (crude).

In order to remove any impurities (including the stabiliser 2,6-di-tert.butyl:4—methyl—phenol contained in the tetrahydrofuran) the two fractions are each purified by column chromatography on silica gel o/1). (toluene/acetone (R)(—)—enantiomer: Yield: 234.5 mg (51% of theory), Melting point: 122-124°C (petroleum ether + acetone) (S)—enantiomer: Yield: 131.2 mg (28.5% of theory), Melting point: 122—124°C (petroleum ether/acetone = 8/1) Calculated: C 72.47 H 8.39 N 5.83 Found: 72.28 8.44 5.70 A chiral cell OD column made by Daicel is also suitable for separating the enantiomers. The (R)—enantiomer is eluted after 6.8 minutes and the (S)—enantiomer after 8.5 minutes on a column 250 mm long with an internal absolute ethanol/(n-hexane + {)"C; diameter of 4.6 mm (eluantz 0.2% diethylamine = UV—detection at 245 nm). /95 by volume); temperature: Example 8 (R)(-)Ethoxy[N-(1—(2—piperidino-phenyl)methyl- 1-butyl)—aminocarbonylmethyl]—benzoic acid X 0.4130 Prepared from 150 mg (0.312 mMol) of ethyl (R)(—) ethoxy—4-[N-(1-(2-piperidino-phenyl)methylbutyl)- aminocarbonyl-methyl]-benzoate [melting point: 122- 124°C? in methano1)] by saponification with Example 3.

Yield: 95.8 mg (66.7% of theory), Melting point: 103—105°C (toluene/petroleum ether) Example 3]. _3'7...

Examgle 9 (S)(+)Ethoxy[N-(1—(2~piperidino—phenyl)methyl~ 1—butyl)-aminocarbonylmethyl]—benzoic acid x 0.4-H5) Yield: 44.5 mg (48.8% of theory), Melting point: 102-103°C (toluene/petroleum ether) Calc.: (X 0.4 Hgfl C 70.51 H 8.01 Found: 70.80 8.06 [a]fi°= + 6.7° (c = 1 in methanol) Enantiomeric purity: ee = 99.6% (S) [HPLC method: see Example 3].

Example 10 (S)Ethoxy—4—[N-(1—(2—piperidino—phenyl)—3—methy1-l- butyl)-aminocarbonylmethyl]-benzoic acid .26 g (0.47 mMol) of benzyl (S)—2-ethoxy—4~[N-(1—(2— pipieridino—phenyl)-3—methyl—1~butyl)-aminocarbonyl- methyl]-benzoate (melting point: 91-92°C; Yield: 0.15 g (70% of theory), Melting point: 130-131°C Calculated: C 71.64 H 8.02 N 6.

Found: 71.76 8.12 6.05 Enantiomeric purity: ee = 99.6% [HPLC method: see Example 3].

Example 11 (S)Ethoxy—4—[N—(l—(2—piperidino—phenyl)—3—methy1 butyl)-aminocarbonylmethyl]—benzoic acid + 8.7“; c = 1 in methanol) are refluxed in 5 ml of benzene together with a few crystals of p- toluenesulphonic acid hydrate, for half a day. The desired product is then obtained, according to thin layer chromatography, according to the RF value and mass spectrum.

Melting point: 129-13 1 ° c Molecular peak M‘: Calc.: 452 Found: 452 Examgle 12 (S)Ethoxy~4—[N—(l—(2—piperidino-phenyl)methyl butyl)-aminocarbonylmethyl]—benzoic acid mg (0.395 mMol) of tert.butyl (S)—2-ethoxy-4—[N—(1- (2-piperidino~phenyl)—3~methy1—1—butyl)—aminocarbonyl—" " methyl]-benzoate (melting point: 122—123°C: acetate. The organic extract is dried, filtered and evaporated down in vacuo. The evaporation residue is crystallised from ethanol/water (2/1).

Yield: 115 mg (64.7% of theory), — Melting point: 126—128°C _ i Calculated: C 71.64 H 8.02 N 6.19 Found: 71.39 7.91 6.06 Example 13 Tablets containing 0.25 mg of AG—EE 623 ZW Each tablet comprises: (1) 0.250 mg of (2) 0.125 mg of (3) 0.038 mg of (4) 0.075 mg of (5) 0.150 mg of (6) 24.352 (7) 24.000 (8) 0.500 .000 mg active substance N—methy1g1ucamine polyvinylpyrrolidone polyoxyethylenepolyoxypropylene polymer microcrystalline cellulose mg of sodium carboxymethyl starch mg of microcrystalline cellulose mg of magnesium stearate Total weight The active substance and excipients (2) to (4) are dissolved in water at 90°C and the microcrystalline cellulose (5) is suspended therein. The dispersion is evaporated down in vacuo and the dry mass is screened to a mesh size of 1 mm. Ingredients (6) to (8) are then added to the dried granules.

Round, biplanar tablets weighing 50 mg and measuring mm in diameter are compressed from this mixture.

Example 14 Tablets containing 0.5 mg of AG—EE 623 _4o_ Each tablet comprises: (1) (2) (3) (4) (5) (6) (7) (3) .500 0.250 0.075 0.150 0.300 mg mg mg mg mg .225 mg of 24.000 mg of .500 mg of of of of of of .000 mg active substance N—methylg1ucamine polyvinylpyrrolidone polyoxyethylenepolyoxypropylene polymer microcrystalline cellulose sodium carboxymethyl starch microcrystalline cellulose magnesium stearate Total weight Round, biplanar tablets weighing 50 mg and measuring mm in diameter are produced analogously to those of Example 13.

Example 15 Tablets containing 1.0 mg of AG—EE 623 ZW Each tablet comprises: (1) (2) (3) (4) (5) (6) (7) (3) .00 0.50 0.15 0.03 mg 0.60 mg 23.22 mg 24.00 mg .50 mg 50.00 mg mg mg mg of of of of of active substance N—methylglucamine polyvinylpyrrolidone polyoxyethylenepolyoxypropylene polymer microcrystalline cellulose " sodium carboxymethyl starch microcrystalline cellulose magnesium stearate Total weight Round, biplanar tablets weighing 50 mg and measuring mm in diameter are produced analogously to those of Example 13.

Example 16 Tablets containing 1.5 mg of AG~EE 623 ZW _ __ Each tablet comprises: (1) (2) (3) (4) (5) (5) (7) (8) .500 0.750 0.225 0.045 0.900 mg mg mg mg mg of active substance N—methylglucamine polyvinylpyrrolidone polyoxyethylenepolyoxypropylene polymer microcrystalline cellulose .080 mg of sodium carboxymethyl starch .000 mg of microcrystalline cellulose .500 mg of magnesium stearate .000 mg Total weight Round, biplanar tablets weighing 50 mg and measuring mm in diameter are produced analogously to those of Example 13.

Example 17 Tablets containing 2.0 mg of AG—EE 623 ZW Each tablet comprises: (1) (2) (3) (4) (5) (5) (7) (8) .00 1.00 1.00 1.00 4.00 mg mg mg mg mg of active substance of L-lysine of polyvinylpyrrolidone of polyoxyethylenepolyoxypropylene polymer of microcrystalline cellulose .35 mg of microcrystalline cellulose .00 mg of sodium carboxymethyl starch .65 mg of magnesium stearate .00 mg Total weight _42_ The ingredients (1) to (4) are dissolved in water at 90°C and the microcrystalline cellulose (5) is suspended therein. The dispersion is processed in a spray dryer and ingredients (6) to (8) are then added. — Round, biconvex tablets weighing 50 mg and measuring mm in diameter are compressed from this mixture and are given a flavour—masking coating of hydroxypropy1- .methylcellulose.

Example 18 Tablets containing 2.5 mg of AG—EE 623 zw Each tablet comprises: (1) 2.50 mg of active substance (2) 1.25 mg of L—lysine (3) 1.25 mg of polyvinylpyrrolidone (4) 1.25 mg of polyoxyethylenepolyoxypropylene polymer (5) 4.10 mg of microcrystalline cellulose (6) 19.50 mg of microcrystalline cellulose (7) 19.50 mg of sodium carboxymethyl starch _(8) 0.65 mg of magnesium stearate .00 mg Total weight Round, biconvex tablets weighing 50 mg and measuring mm in diameter are produced analogously to those in Example 17 and given a flavour—masking coating of hydroxypropylmethyl cellulose.

Example 19 Tablets containing 3.0 mg of AG—EE 623 ZW Each tablet comprises: (1) 3.0 mg of active substance .5 mg of L—lysine l.5 mg of polyvinylpyrrolidone .5 mg of polyoxyethylenepolyoxypropylene polymer 21.5 mg of microcrystalline cellulose — .0 mg of sodium carboxymethyl starch .0 mg Total weight The ingredients (1) to (4) are dissolved in water at 90°C and the solution is processed in a spray dryer.

Then, ingredients (5) and (6) are added.

Round, biconvex tablets weighing 50 mg and measuring mm in diameter are compressed from this mixture and [given a flavour-masking coating of hydroxypropylmethyl cellulose.

Example 20 Tablets containing 5 mg of AG—EE 623 ZW Each tablet (1) 5.0 (2) 2.5 (3) 2.5 (4) 2.5 (5) 19.0 mg of microcrystalline cellulose comprises: of active substance of Lvlysine of polyvinylpyrrolidone of polyoxyethylenepolyoxypropylene polymer .5 mg of sodium carboxymethyl starch 50.0 mg Total weight Round, biconvex tablets weighing 50 mg and measuring mm in diameter are produced analogously to those in Example 19 and given a flavour—masking coating of hydroxypropylmethyl cellulose.

Claims (6)

Claims:

1. (S)(+)~2-Ethoxy—4—[N—[1—(2—piperidino—phenyl) methyl-1—butyljaminocarbonylmethylj—benzoic acid-in at least substantially optically pure form salt thereof. or an_addition

2. A compound as claimed in claim 1 which is substantially optically pure.

3. A claimed in claim 2 having an optical purity compound as of at least

4. A purity compound as of at least ee =

5. A compound as claimed in any one of claims 1 to 4 being a physiologically acceptable addition salt.

6. A process for the preparation of a compound as claimed in claim 1, said process comprising at least one of the following steps: a) reacting the (S)~amine of formula I 2 (I) with a carboxylic acid of formula II W HOOCCH2 ocH2cH3 (II) (wherein 5 W represents an optionally protected carboxy group) or with a reactive derivative thereof, optionally prepared in the reaction mixture, and subsequently, if necessary, cleaving any protecting group used; 10 b) cleaving an (S)—compound of formula III (III) (wherein A represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis); c) reacting an (S)—compound of formula IV CH3 CH3 cu O W. C ‘W X 0 (wherein W‘ represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and in which the alkoxy group may additionally be substituted by a phenyl group) with a compound of formula V (IV) 2 — ca? — CH3 (V) (wherein 2 represents a nucleophilic leaving group or, together with the adjacent hydrogen atom represents a diazo group) and subsequently, if necessary, hydrolysing or hydrogenolysing a compound thus obtained; d) enantioselectively reducing a compound of formula VI ij 1 n Y ocuzcus " [:5;) (VI) 5 (wherein W‘ represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and in which the alkoxy group may additionally be substituted by a phenyl group, and 10 Y represents a group of formula cu, 9“: C”: tn NH// NH// ' “”’( and subsequently, if necessary, hydrolysing a compound thus obtained; 15 e) oxidising an (S)-compound of general formula VII (VII) (wherein W" represents a group which can be converted into a -48.- carboxy group by oxidation); f) separating a mixture comprising an amount of the (S)-enantiomer of formula VIII — (VIII) and an amount of the (R)~enantiomer of formula IX CH\3\ /CH3 cu 0 W, \| SH 0” \ £::;]:: N“ ocazcu, N 0 (IX) (wherein W‘ represents a carboxy group or an alkoxycarbonyl group 10* having a total of 2 to 5 carbon atoms and in which the alkoxy group may additionally be substituted by a phenyl group); g) converting an (S)~enantiomer obtained in any one of steps (a) to (f), having an optical purity of at least 15" 90%, into an (S)—enantiomer having an optical purity of at least 95% by fractional crystallisation; and h) converting an (S)—enantiomer thus obtained into an addition salt thereof or an addition salt of the (S)- 10 7 Compounds of formulae I, ...49._. enantiomer into the free (S)—enantiomer. III, IV and VII -50.. CHKCH/CH3 fl flex“ (I) [ (S) —3—Methyl—1_-(2—piperidino-phenyl) butylamine] (III) (IV) 14:“ JOL/CC“ ocnzcus (VII) (wherein A represents a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis; W‘ represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms and in which the alkoxy group may additionally be substituted by a phenyl group; and W" represents a group which may be converted by oxidation into a carboxy group) and the addition salts thereof. _ 8 A compound as claimed in any one of claims 1 to 4 or a pharmaceutical composition thereof substantially as herein disclosed in any one of the Examples. 9 Each and every novel compound, composition, process, use and method as herein disclosed. 10 A process for.the preparation of a compound as claimed in claim l substantially as described herein with reference to the Examples and/or the accompanying drawings. ‘ 11 A compound as claimed in.claim 1 whenever prepared by_a process as claimed in claim 6 or 10 _ ix TOMKINS & C0.