BG61690B1 - (s) (+)-2-ethoxy-4-[n-/i-piperidino-phenil)-3-methyl-i-butyl /aminocarbonylmethyl/-benzoic acid - Google Patents

Abstract

The new (S)(+)-2-ethoxy-4-/N-/I-(2-piperidino-phenyl)-3-methyl-I-butyl/aminocarbonylmethyl/benzoic acid and its salts possess valuablepharmacological properties. They affect the intermediatemetabolism, in particular they reduce the blood sugar level. Theinvention also relates to new intermediate compounds havingformulae (1), (III), (IV) and (VII) listed in the description, aswell as to their adjunctive salts. The compounds can be producedby the known methods.11 claims

Description

The present invention relates to (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid.

EP-0147850 is known from the racemate of 2-ethoxy-4- (N-) 1- (2-piperidino-phenyl) -3methyl-1-butyl (aminocarbonylmethyl) -benzoic acid (code number AG-EEZW) of the formula

EP-B-0 207 331 describes two other polymorphic forms of this compound and its physiologically tolerated salts, which show valuable pharmacological properties, namely on intermediate metabolism, in particular the blood glucose-lowering effect.

The two enantiomers of this compound (S) (+) -2-ethoxy-4- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonylmethyl / benzoic acid (code number: AG- EE 623 ZW) and (R) (-) - 2-ethoxy-4- [b] - [1- (2-piperidino-phenyl) -3-methyl-1-butyl (aminocarbonylmethyl / benzoic acid) (code number: AG- EE 624 ZW) have been tested in female rats for their activity in lowering blood sugar.

It is surprisingly found that the (S) enantiomer (AG-EE 623 ZW) is an active enantiomer and that its activity is retained for more than 6 hours.

Based on these results, in the rat, it seems appropriate to use exclusively AG-EE ZW in humans, reducing the dose by 50% compared to AG-EE 388 ZW. This, and the relatively long period of action, is also confirmed in humans. In addition, human studies have found that AG-EE 623 ZW has surprising pharmacokinetic properties that cannot be predicted based on AG-EE 388 ZW. With this, the AG-EE 623 ZW shows surprising curative advantages over the AG-EE 388 ZW racemate.

The surprising findings in humans are:

(a) AG-EE 623 ZW levels drop rapidly to zero from AG-EE 388-ZW-hhboto, up to 5 when the dose is exactly the same, which cannot be expected given the relatively long period of activity.

(b) In connection with the achieved decrease in blood sugar, a significantly lower plasma level of AG-EE 623 ZW appears than is expected with the half-dose of AG-EE 388 ZW.

(c) Blood glucose lowering activity is more rapid after administration of

AG-EE 623 ZW than after the adoption of AG-EE 388 ZW.

The surprising difference between the two enantiomers is that the active enantiomer AG-EE 623 ZW, although having a relatively long period of action, is surprisingly eliminated faster than the inactive enantiomer AG-EE 624 ZW, as shown in Figures 1 and 2. Figure 1 shows the plasma concentrations of AG-EE 623 25 ZW and AG-EE ZW after intravenous administration of 1.0 mg of AG-EE 388 ZW and Figure 2 shows the plasma concentrations of AG-EE 623 ZW and AG-EE 624 ZW after oral administration (as a solution) of AG-EE 388 ZW 30 in each case of 12 male volunteers. After receiving the racemate, the inactive enantiomer AG-EE 624 ZW is not only as unnecessary ballast in the same high plasma concentration as the active enantiomer, AG-EE 623 35 ZW, but is also unexpectedly retained longer with this high plasma level. . This effect can be seen by taking one tablet containing 2 mg of AG-EE 388 ZW or one tablet of 1 mg of AG-EE 623 ZW from 12, 40 and 6 test subjects respectively. The maximum concentration is 84 ± 25, respectively 28 ± 25, respectively 28 ± 18 ng / ml, the concentration after 4 hours 19 ± 8, respectively 0.7 ± 1.0 ng / ml, after 5 hours 13 ± 6, respectively 0. 3 ± 0.7 ng / ml and after 45 6 hours 10 ± 6, respectively 0.3 ± 0.7 ng / ml.

The surprisingly rapid drop in blood sugar in the AG-EE 623 ZW compared to the AG-EE 388 ZW is of great advantage to diabetics, since it can optimally control the disease.

Thus, compared to the use of AGEE ZW, the AG-EE 623 ZW has the surprising advantage of being able to avoid unnecessarily high and prolonged loads of the substance of the body, which is of great importance for long-term treatment, such as diabetes mellitus.

From human studies it has been found that the new (S) -enantiomer, namely (S) (+) - 2ethoxy-4- (N- / 1- (2-piperidino-phenyl) -3-methyl-1-butyl) Aminocarbonylmethyl / -benzoic acid, as a carrier of blood glucose-lowering activity, has a major advantage over AG-EE 388 ZW due to its surprisingly rapid elimination from the blood, something that cannot be predicted due to its relatively long activity. These better properties are well beyond the normal advantages of an enantiomer compared to its racemate, namely the advantage of halving the dose.

It is an object of the present invention to provide the new (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonylmethyl] -benzoic acid, respectively ( S) (+) - 2-ethyl-4- [N- [1- (2-piperidino-phenyl) -3methyl-1-butyl] aminocarbonylmethyl] -benzoic acid, which is practically optically pure, for example having an optical purity of at least 95%, preferably 98 to 100%, of its physiologically acceptable salts with inorganic or organic acids or bases, pharmaceutical compositions containing this compound or its physiologically acceptable salts and methods for preparing them.

According to the invention, the new compound is prepared by the following methods:

a) reacting the (S) -amine with the formula

with carboxylic acid of general formula

wherein W represents a carboxyl group or a carboxyl group protected by a protecting group or by a reactive derivative formed in the reaction mixture and, if necessary, cleaving the protecting group.

Reactive derivatives of a compound of formula II include its esters such as methyl, ethyl or benzyl ester, its thioesters, such as methylthio or ethylthioester, its halides such as its acid chloride, its anhydride or imidazolid.

The reaction is preferably carried out in a solvent medium such as methylene chloride, chloroform, tetrachloromethane, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activating agent or dehydrate, isobutylchloroformian, thionyl chloride, phosphorous trichloride, phosphorous pentachloride, Ν, Ν'-dicyclohexylcarbodiimide, Ν, Ν'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, Ν, Ν'-trifluorocarbamide phosphine / tetrachloromethane, or an agent that activates the amino group, for example 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 can also serve as a solvent, at temperatures between -25 and 250 C, preferably at temperatures between -10 ° C and the reflux temperature of the solvent used. The reaction can also be carried out without solvent and moreover, the water formed during the reaction can be removed by azeotropic distillation, for example by heating with toluene using a water separator, or by adding a drying agent such as magnesium. sulfate or molecular sieve.

If necessary, the subsequent cleavage of the protecting group may be carried out by hydrolysis, expediently or in the presence of an acid such as hydrochloric, sulfuric, phosphoric, trifluoroacetic or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable methanol , methanol / water, ethanol, ethanol / water, water / isopropanol or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between ambient and boiling point of the reaction mixture.

Using a tert-butyl group as a protecting group, it can 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-toluenesulfonic acid, sulfuric, phosphoric or polyphosphoric acid.

Moreover, used as a protecting group, the benzyl moiety can be cleaved hydrogenolitically in the presence of a hydrogenation catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

b) Cleavage of (S) compound of general formula

in which A denotes a group which, by hydrolysis, thermolysis or hydrogenolysis, can be converted into a carboxyl group.

Examples of hydrolysable groups are functional derivatives of the carboxyl group, such as unsubstituted or substituted amides, esters, thioesters or orthoesters, iminoeters, amides or anhydrides, nitrile group, tetrazolyl group, optionally substituted 1,3-oxazol-2-yl or 1 , A 3-oxazolin-2-yl group, and thermolytically leaving groups are tertiary alcohol esters, for example tertiary butyl ester. Hydrogenolytic cleavage groups include aralkyl groups, for example a benzyl group.

It is appropriate to carry out hydrolysis either in the presence of an acid such as hydrochloric, sulfuric, 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, for example at temperatures between ambient and reflux temperatures.

If A in a compound of general formula III means a nitrile or aminocarbonyl group, then these groups can be converted to a carboxylic group by 100% phosphoric acid at temperatures between 100 and 180 ° C, preferably at temperatures between 120 and 160 ° C. or when using nitrite, for example sodium nitrite, in the presence of an acid such as sulfuric acid, and it is appropriate to use it at the same time as a solvent at temperatures between 0 and 50 ° C.

If A in the compound of general formula III is a tert-butyloxycarbonyl group, then the tert-butyl group may also be cleaved thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or glacial acetic acid and preferably in the presence of a strong acid such as trifluoroacetic, hydrobromic, p-toluenesulfonic acid, sulfuric, phosphoric or polyphosphoric acid at temperatures between 0 and 100 ° C, preferably at temperatures between 20 ° and that of the solvent used.

If A in a compound of formula III means a benzyloxycarbonyl group, then the benzyl group may be cleaved hydrogenolitically in the presence of a hydrogenating catalyst such as palladium on carbon 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, for example at ambient temperature and hydrogen pressure of 1 to 5 bar.

c) Interaction of the (S) compound of the general formula ^CH 3 CH, \ /

wherein W 'represents a carboxy group or alkoxycarbonyl group containing up to 5 carbon atoms in total, wherein the alkyl moiety of the alkoxy group may be substituted by a phenyl group and Y represents a group of formula in which W' stands for a carboxyl group or alkoxy group containing 2 to 5 carbon atoms, in which the alkyl moiety of the alkoxy group may be substituted by a phenyl group, with a compound of the general formula 5 Z - CH ₂ - CH ₃ (V) in which Z represents a nucleophilic exchange group such as a halogen atom, a sulfonyloxy group or together with sat hydrogen atom, represents a diazo groups, eventual 10 but followed by hydrolysis or hydrogenolysis. It is advantageous to carry out the reaction with a corresponding halide, sulfonic acid ester or sulfuric acid diester, for example ethyl bromide, ethyl iodide, 15 diethyl sulfate, ethyl p-toluylsulfonate or ethyl methanesulfonate, or diazoetrium, even , potassium carbonate, sodium hydroxide, potassium tert-butylate or triethylamine, preferably in a suitable solvent such as acetone, diethyl ether, tetrahydrofuran, dioxane, pyridine or dimethylformamide at temperatures between 20 and 50 ° C.

If W 'in the compound of general formula IV 25 represents a carboxyl group, it can be converted to the corresponding ester compound.

If necessary, the subsequent hydrolysis may be carried out either in the presence of an acid such as hydrochloric, sulfuric, 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 / methanol / methanol , ethanol, ethanol / water, water / isopropanol or water-35 yes / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between ambient and boiling temperatures of the reaction mixture, or subsequent hydrogenolysis is carried out in the presence of Here is a hydrogenation catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide at a hydrogen pressure of 1 to 10 bar. 45

d) Enantioselective reduction of a compound of the general formula

Sun -

- C = ΙΪ and, if necessary, subsequent hydrolysis.

Preferably, the reduction is carried out with hydrogen in the presence of a suitable chiral hydrogenation catalyst in a suitable solvent such as methanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran, methanol / tetrahydrofuran, methanol / methylene chloride, ethanolate or ethanol and 100 °, preferably at temperatures between 20 and 50 ° C, at a hydrogen pressure between 1 and 1000 bar, preferably between 5 and 100 bar, and the addition of 0.1 to 5%, preferably 0.3 to 1% titanium (IV) tetraisopropoxide, and h and preferably when oxygen is removed from the air. The reduction is preferably carried out with the (Z) -form of a compound of general formula VI.

Examples of chiral hydrogenation catalysts include the corresponding metal ligand complexes such as Ru (OCOCH ₃ ) ₂ / (S) -BINAP /, Ru ₂ C1 ₄ / (S) -BINAP / ₂ χ N (C ₂ H ₃ ) ₃ , Rh / (-) - NORPHOS-COD / -BF ₄ or Rh / (S) -BINAP-NBD / ClO ₄ .

In catalytic hydrogenation, the benzyloxycarbonyl group can be simultaneously reduced and converted into a carboxyl group.

If necessary, subsequent hydrolysis is carried out either in the presence of an acid such as hydrochloric, sulfuric, 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 / water, ethanol / water, ethanol / water, ethanol water, water / isopropanol or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between ambient and reflux temperatures.

e) Oxidation of the (S) compound of general formula

in which W 'means a group which, by oxidation, can be converted into a carboxy group.

An example of an oxidizing group is, for example, the formyl group and its acetals, the hydroxymethyl group and its ethers, an unsubstituted or substituted acyl group such as acetyl, chloroacetyl, propionyl, malonic acid (1) -yl group or a molar ester (1) -yl group.

The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxane or glycol dimethyl ether at temperatures between 0 and 100 ° C, however, preferably at temperatures between 20 and 50 ° C. 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 or pyridine.

f) Separation of a mixture consisting of an arbitrary amount of (S) -enantiomer of the general formula

CH I

and an arbitrary amount of the (10-enantiomer of the general formula

CHj _{/ C} H _3-CH

in which W 'means a carboxyl group or an alkoxyl group having a total of 2 to 5 carbon atoms, wherein the alkyl moiety of the alkoxy group may be substituted by a phenyl, preferably 50/50 mixture, by their diastereomeric addition compounds or their salts, and subsequently at the need for hydrolysis or hydrogenolysis.

Separation is preferably carried out using column or high performance liquid chromatography to form diastereomeric coupling compounds or complexes in the chiral phase.

If necessary, subsequent hydrolysis is carried out either in the presence of an acid such as hydrochloric, sulfuric, 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 / water, ethanol / water, ethanol / water, ethanol water, water / isopropanol or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between ambient and reflux temperatures, or subsequent hydrogenolysis is carried out in the presence of hyd. palladium-on-carbon catalyst in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide at a hydrogen pressure of 1 to 10 bar.

The (S) -enantiomer thus obtained according to the present invention, with an optical purity of at least 90%, can be converted into a (S) -enantiomer having an optical purity of at least 95%, preferably 98 to 100%, by fractional crystallization.

The same applies to the (S) compounds of the invention of formulas III, IV and VII, especially their esters.

The (S) -enantiomer thus obtained according to the invention can be converted into its salts, in particular for pharmaceutical use, in its pharmacologically acceptable salts with inorganic or organic acids or bases. Examples of such acids are hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acids, such as bases of sodium hydroxide, potassium hydroxide, calcium hydroxylamine, cyclohelaminamylamine, cyclohelaminylamine,

The compounds of formulas I to IX used as starting materials are known in the literature or prepared by known methods.

The (8) -amine of formula I can be obtained from the corresponding racemic amine:

- by racemic cleavage, for example by fractional crystallization of the diastereomeric salts with suitable optically active salts, preferably with N-acetyl-L-glutamic acid and, if necessary, recrystallization and subsequent decomposition of the salts,

- by column or high performance liquid chromatography on chiral phases, optionally in the form of an acyl derivative,

- by forming diastereomeric compounds, the separation of which and subsequently cleavage yields the above compound.

In addition, the (3) -amine of formula I can be obtained by enantioactive reduction using hydrogen in the presence of a suitable chiral hydrogenation catalyst, starting from the corresponding N-acylene-ketamine or enamide, where appropriate, from 0 , 1 to 5% titanium tetraisopropylate, optionally followed by cleavage of the acyl group as a formyl or acetyl group;

- by diastereoselective reduction of the corresponding ketamine or hydrazine, which are chiral substituted on the nitrogen atom, using hydrogen in the presence of a suitable hydrogenation catalyst. It is advisable to add 0.1 to 5% titanium tetraisopropoxide and then cleave the chiral auxiliary group, for example to the (S) -1-phenethyl group, by catalytic hydrogenolysis, or

- by diastereoselectively adding the corresponding ORGANOMETALLIC compound, preferably Grignard or lithium compound, to the corresponding chiral substituted at the aldimine nitrogen atom, optionally by the addition of 0.1 to 10% titanium tetraisopropoxide, then hydrolyzing and eventually diamethanol cleavage of the chiral auxiliary group, for example the (R) -I-phenethyl residue by catalytic hydrogenolysis, and, if necessary, the (S) -amino to be obtained with a higher enantiomeric purity, it is formed and a salt with suitable optically active acids, preferably with C-acetyl-L-glutamic acid, and, if necessary, single or multiple recrystallization and subsequent decomposition of the salt.

The compounds of formulas III, IV and VII used as starting materials are prepared by reacting (S) -amino I with the corresponding carboxylic acid or its reactive derivatives and optionally subsequently cleaving the protecting groups used.

The compound of general formula VI used as the starting material is obtained by acetylation of the corresponding imino derivatives or their organometallic complexes with the corresponding carboxylic acids or derivatives thereof, which are reactive and possibly subsequent cleavage of an ester group.

The new (S) enantiomer is practically non-toxic. For example, after single administration of 1000 mg / kg orally (suspension in 1% methylcellulose) to 5 male and 5 female rats, none of them died within the 14-day observation period.

Based on its pharmacological and pharmacokinetic properties, the (3) -enantiomer obtained according to the invention (AG-EE 623 ZW) and its physiologically tolerated salts are suitable for the treatment of diabetes mellitus. For this purpose, AG-EE 623 ZW or its physiologically acceptable salts, optionally in combination with other active substances, is formulated in conventional galenic forms such as tablets, dragees, capsules, powders, suppositories or suspensions and injectable solutions. The single adult dose is 0.1 to 20 mg, preferably 0.25 to 5 mg, in particular 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3 , 0 or 5.0 once, twice or thrice, daily.

The present invention is also novel (Sl-amine of formula I, which is a valuable intermediate in the preparation of the new (S) -enantiomer, as well as its addition salts with inorganic or organic acids.

Another object of the invention is the novel compounds of general formulas III, IV and VII, which are valuable intermediates in the preparation of the new (S) enantiomer as well as their addition salts with inorganic or organic acids.

The following examples illustrate the invention:

Example A. (S) -1- (2-Piperidino-phenyl) 3-methyl-1-butylamine

A solution of 122 g (0.495 mol) of racemic 1- (2-piperidino-phenyl) -3-methyl-1-butylamine in 1000 ml of acetone was reacted with stirring with 93.7 g (0.495 mol) of N-acetyl-1-glutamic acid . When heated under reflux, methanol (about 80 ml total) is added portionwise until a clear solution is obtained. Cool and allow to stand at room temperature overnight. The crystals obtained are filtered off in vacuo, washed twice with 200 ml each, cooled to -15 ° C with cold acetone and dried. The resulting product (98.9 g; mp 163-166 ° C; (a / _D ²⁰ = + 0.286 (C = 1 in methanol)) was recrystallized from acetone 1000 ml, in which 200 ml of methanol were added at which yields (S) -1- (2-piperidino-phenyl) -3-methyl-butylamine as the acetyl-1-glutamic acid addition salt.

Yield: 65.1 g (60.4% of theory), m.p. Mp 168-171 ° C

Calculated: C 63.42 H 8.56 N 9.65 Found: C 63.64 H 8.86 N 9.60 / a / p ²⁰ = + 0.357 ° (c = 1 in methanol) The free amine can be obtained in the form of an oil, treated with sodium hydroxide or ammonia solution, extracted with toluene, ether, ethyl acetate or methylene chloride, followed by drying, filtration and evaporation of the extract in vacuo.

The (S) -configuration of the amine is proved as follows:

The amine is reacted with (8 ') - 1-phenethylisocyanate in ether to give the corresponding urea derivative / mp. 183184 ° C; (a / _D ²⁰ = -2.25 ° C (c = 1 in methanol) /, the crystals are grown in ethanol / water (8/1) and subsequent X-ray analysis of their structure shows (S, S ') - the configuration of the urea derivative and thus (S) -configuration of the amine used.

Enantiomeric purity is determined as follows:

1. Acetylation of a sample of amino with 1.3 equivalents of acetic anhydride in glacial acetic acid at 20 ° C overnight.

2. Investigation of the N-acetal derivative (mp 128-132 ° C) by high performance liquid chromatography on a Baker chiral-phase high performance liquid chromatography column in which (S) -N- (3,5-nitrobenzoyl) -2-Phenyl-glycine is covalently bound to aminopropyl silica gel (particle size 5 gm, spherical, pore size 6θΑ: column length: 250 mm at an internal diameter of 4.6 mm; eluent: n-hexane / isopropanol (100 (5); flow rate 2 ml / min; temperature: 20 ° C; UV detection at 254 µm).

Found: peak 1 (R): peak 2 (S) = 0.75%; 99.25% ee (enantiometric excess) = 98.5% (S).

By using an ethereal hydrogen chloride solution, the (S) -amine can be converted to its dihydrochloride hydrate.

M.P. 135-145 ° C (decomposition)

Calculated: (x H ₂ O): C 56.99 H 8.97 N 8.31 Cl 21.02

Found: 56.85 8.93 8.38 21.25 / a / _D ² ° = + 26.1 ° (c = 1 in methanol) Example B. N-acetyl-N- [1- (2-piperidino- phenyl) -3-methyl-1-buten-1-yl) -amine

To a solution of freshly prepared isobutyl- (2-piperidino-phenyl) -ketimine (20 g, 81.8 mmol) in 200 ml of acetonitrile, 4.7 ml (81.8 mmol) of glacial acetic acid were added at room temperature. , 7 g (98.2 mmol) triphenylphosphine, 34.2 ml (245 mmol) triethylamine and 7.9 ml (81.8 mmol) tetrachloromethane and stirred for 18 h at room temperature. It was then evaporated in vacuo and taken up in ethyl acetate and water. The organic extract was dried and filtered and evaporated in vacuo. The evaporation residue was purified by silica gel column chromatography (toluene / ethyl acetate = 10/1), eluting first the (E) form and then the (Z) form.

(E) -form

Yield: 6.1 g (26% of theory)

mp 135-137 ° C (ethyl acetate / 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)

mp 140-143 ° C (ethyl acetate) Calculated: C 75.48 H 9.15 N 9.78 Found: 75.56 9.30 9.79

Example B. N-acetyl-N- [1- (2-piperidino-phenyl) -3-methyl-1-buten-1-yl] -amine

To a solution of 44 g (0.18 mol) of freshly prepared isobutyl- (2-piperidino-phenyl) -ketimine in 440 ml of toluene was added dropwise at 0 ° C to 17 ml (0.18 mol) of acetic anhydride in the reaction medium. It was then stirred for another 3 h at 0 ° C and 15 h at room temperature. It was concentrated in vacuo, the residue was dissolved in ethyl acetate and the solution was washed several times with aqueous sodium bicarbonate solution. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (toluene / ethyl acetate = 5/1), 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), m.p. 139-141 ° C (ethyl acetate) Calculated: C 75.48 H 9.15 N 9.78 Found: C 75.68 H 8.99 N 9.86 Example D. N-acetyl-N - / (S) - 1- (2-Nneridino-phenyl) -3-methyl-1-butyl] -amine

0.57 g (1.99 mmol) (Z) -N-methyl-N- [1- (2-piperidin-phenyl) -3-methyl-1-buten-1-yl] -amine, m.p. 139-141 ° C was dissolved in 10 ml of a degassed solvent mixture (methanol / methylene chloride = 5/1) under argon and added to a solution of 16.8 mg (1 mol%) of NOYORI catalyst Ru (0- acetyl) ₂ / (S) BINAP / (obtained from / Ru (COD) Cl ₂ / _n with (S) BINAP / = (S) -2,2'-bis (diphenylphosphino) -1, Gbinaftyl), triethylamine and sodium acetate), and 3.4 mg (0.5 mol%) of titanium tetraisopropoxide in 10 ml of a degassed solvent mixture (methanol / methylene chloride = 5/1). The reaction mixture was transferred to an autoclave evacuated with 10 ' ¹ mbar. Rinse repeatedly with hydrogen at 4 bar and then the mixture was hydrogenated at 30 ° C and 100 bar until hydrogen absorption (170 h) ceased. The brown-red solution was then concentrated in vacuo, the residue boiled with 30 ml of n-hexane at reflux and hot filtered to remove the undissolved portion. Crystals are obtained by cooling the filtrate.

Yield: 0.31 g (54% of theory), m.p. 127-131 ° C.

Enantiomeric purity: ee = 82% (S) / By HPLC method: see Example A /.

14% of the racemic N-acetal-amine with mp. Is obtained by boiling the n-hexane moiety undissolved by boiling with 30 ml of n-hexane, filtration and crystallization from hexane solution. Mp 154-156 ° C.

Example D. (S) -1- (2-Piperidino-phenyl) 3-methyl-1-butylamine g (3.47 mmol) N-acetyl-N - [(S) -1- (2-piperidino-phenyl) -Z -methyl-1-butyl] -amine (mp 128-133 ° C; ee = 99.4%) in 10 ml of concentrated hydrochloric acid was heated at reflux for 5.5 h. It is cooled and poured into a mixture of concentrated ammonia and ice. The mixture was extracted twice with ethyl acetate, the organic phase was washed with water, dried, filtered and concentrated 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 room temperature, concentrating in vacuo and taking up the residue in ethyl acetate and saturated aqueous sodium bicarbonate solution, then this drying, filtration, and concentration of the organic extract in vacuo afforded 0.83 g (84.7% of theory) of N-acetyl-N- (S) -1- (2-piperidino-phenyl) -3-methyl- 1-butyl / amine (mp 130-132 ° C; ee = 99.4%).

Example E. Ethyl-2-ethoxy-4- (N- (1- (2-piperidino-phenyl) -3-methyl-1-buten-1-yl) aminocarbonylmethyl) -benzoate

Prepared from isobutyl- (2-piperidino-phenyl) -ketimine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, analogously to Example B. Purified by silica gel column chromatography (toluene / acetone = 10/1), first eluting the (E) -form and then the (Z) -form.

(E) -form:

Yield: 4% of theory, mp: 101103 ° C.

Calculated: C 72.77 H 8.00 N 5.85 Found: C 72.74 H 7.78 N 5.86 (Z) -form:

Yield: 28.1% of theory, m.p. 124127 ° C (petroleum ether / toluene = 5/1)

Calculated: C 72.77 H 8.00 N 5.85

Found: 72.90 7.86 5.83

Example G. N - [(5 ') -1-phenethyl] -N - [(5) 1- (2-piperidino-phenyl) -3-methyl-1-butyl] amine g (49 mmol) N - / ( 8 ') - 1-phenethyl] -isobutyl- (2-piperidino-phenyl) -ketimine, m.p. 150-155 ° C (0.3 Torr) obtained from isobutyl- (2-piperidino-phenyl) -ketone and (8 ') - 1-phenethylamine (fluka produced, ee = 99.6%) in toluene + triethylamine by dropwise addition. a solution of titanium tetrachloride in toluene / was dissolved in anhydrous ethanol (170 ml). 1.9 g of titanium tetraisopropylate and 8 g of Raney Nickel were added and the mixture was hydrogenated under the same conditions for a further 52 h. The catalyst was filtered through a pad of Celite on a G 3 frit and the filtrate was concentrated in vacuo.

Yield: 13.1 g (76.6% of theory). 152 ° C / 0.2 Torr

Calculated: C 82.23 H 9.78 N 7.99 Found: 82.00 10.03 7.74 / α / p ²⁰ = -55.3 ° C (C = 1.1 in methanol) Diastereomeric purity. Determined by HPLC Liquororb RP 18-HPLC column from Merck (Germany); column length: 250 mm and inside diameter 4 mm; particle size: 7 µm. Eluent: methanol / dioxane / 0.1% aqueous sodium acetate, adjusted to pH 4.05 with acetic acid (135/60/5); temperature: 23 ° C; UV detection at 254 nm.

Found: peak 1 (S, S '): peak 2 (R, S') = 98.4%: 1.4%, de (diastereometric excess) - 97.0% (S, S ').

Example 3. (S) -1- (2-piperidino-phenyl) 3-methyl-1-butylamine

12.5 g (36 mmol) of L1 - [(8 ') -1-phenethyl] -N- (S) -1- (2-piperidinophenyl) -3-methyl-1-butyl] -amine with de = 97, Dissolve 0% (S, S ') in 125 ml of water and 3.6 ml of concentrated hydrochloric acid. 1.3 g of palladium on carbon (10%) were added and hydrogenated at 50 ° C and 5 bar of hydrogen. After stopping the absorption of hydrogen (10 h), the catalyst was filtered through a pad of Celite. The filtrate was basified with concentrated ammonia with ice added and extracted with ethyl acetate. The organic extract was dried, filtered and evaporated in vacuo.

Yield: 6.4 g (72.1% of theory)

Since 115-117 ° C / 0.4 Torr

Enantiomeric purity: ee = 93.5% (S) (HPLC method described in Example A (after pre-acetylation)).

Example 1. N - ((D ') - 1-phenethyl) -N - (S) 1- (2-piperidino-phenyl) -3-methyl-1-butyl / amine

A solution of 2 g (6.84 mmol) of N - ((R ') 1-phenethyl) was added dropwise to a solution of 27.4 mmol (4 equivalents) isobutyl-magnesium bromide in 22 ml of anhydrous tetrahydrofuran in a water bath at 60 ° C. - (2-Piperidino-benzaldimine) / obtained from equimolar amounts of 2-piperidino-benzaldehyde and (K ') - 1-fetethylamine overnight at room temperature, dried with sodium sulfate in ether solution / in 20 ml of anhydrous tetrahydrofuran. After 18 h, the bath temperature was raised to 80 ° C and another 2 equivalents of isobutylmagnesium bromide in 11 ml of tetrahydrofuran were added. After stirring for 12 hours at 80 ° C, a further 2 equivalents of isobutyl magnesium bromide were added to the solution. After about 90 hours at 80 ° C, the mixture was cooled, excess hydrochloric acid was added and evaporated to dryness in vacuo obtained from a water jet. The evaporation residue was dissolved in water and made basic with concentrated ammonia. It is extracted with ether, the organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (toluene / acetone = 95/5).

Yield: 0.20 g (8.3% of theory), m.p. below 20 ° C.

Diastereomeric purity was determined as described in Example G by HPLC.

Found: Peak 1 (R, R '): Peak 2 (S, R') = 4.4%: 95.6%, de (diastereomeric excess) = 91.2% <S, R ').

In an analogous mixture with 2.0 g Schiff base and a total of 6 equivalents of isobutyl magnesium bromide in toluene / tetrahydrofuran (4/1) and with the addition of 5% titanium (IV) -tetraisopropylate and 60 h heating at 100 ° C in a glass container , a 5% yield was obtained with de = 97.6% (S, R *).

Example I. (5) -1- (2-Piperidino-phenyl) -3-methyl-1-butylamine

A solution of 0.15 g (0.428 mmol) N - ((R ') 1-phenethyl) -N- (S) -1- (2-piperidino-phenyl) 3-methyl-1-butyl] -amine (de = 91.2%), 0.47 ml (0.47 mmol) of 1 N hydrochloric acid and 1.5 ml of water are hydrogenated in the presence of 20 mg of 10% palladium-on-charcoal for 5 hours at 50 ° C. and 3.4 bar hydrogen. The mixture was filtered through diatomaceous earth, basified with concentrated ammonia and extracted with ethyl acetate. The extract was dried, filtered and evaporated in vacuo.

Yield: 0.066 g (62.8% of theory). below 20 ° C enantiomeric purity: ee = 87.6% (S) / HPLC method (after pre-acetylation): see Example A).

Example 1. Ethyl (S) -2-Ethoxy-4- [N- (1 (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate

To a solution of 0.47 g (1.91 mmol) (S) -3methyl-1- (2-piperidino-phenyl) -1-butylamine (ee = 98.5%) in 5 ml of anhydrous acetonitrile was added sequentially 0, 48 g (1.91 mmol) 3-ethoxy-4 ethoxycarbonyl-phenylacetic acid, 0.60 g (2.29 mmol) triphenylphosphine, 0.80 ml (5.73 mmol) triethylamine and 0.18 ml (1.91 mmol) ) tetrachloromethane and stirred for 20 h at room temperature. It was then concentrated in vacuo and taken up in ethyl acetate and water. The organic layer was dried, filtered and concentrated in vacuo. The residue obtained after evaporation was purified by column chromatography on silica gel (toluene-ethyl acetate = 10/1). Yield: 0.71 g (77.3% of theory), m.p. 1 ΙΟΙ 12 ° C.

Calculated: C 72.47 H 8.39 N 5.83 Found: 72.29 8.42 5.80

Enantiomeric purity was determined by high performance liquid chromatography (HPLC) on a Baker chiral phase HPLC column in which (S) -N-3,5-4Hhtrobenzoyl-leucine was covalently bound to aminopropyl silica gel (particle size: 5 gm, spherical, 60 A pore width; column length: 250 mm with an internal diameter of 4.6 mm; eluent: n-hexane / tetrahydrofuran / methylene chloride / ethanol (90/10/1/1); flow rate: 2 ml / min; temperature: 20 ° C; UV detection at 242 nm).

Found: peak 1 (R): peak 2 (S) = 0.75%:

99.25%, ee = 98.5% (S).

Example 2. Ethyl (S) -2-ethoxy-4- [N- (1 (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate

To a solution of 2.71 g (11 mmol) of anhydrous (S) -3-methyl-1- (2-piperidino-phenyl) -1-butylamine (ee = 98.5%) in 30 ml of absolute toluene at room temperature and stirring 2.77 g (11 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid are added. Stirring is continued until a solution is obtained. 2.38 g (2.14 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.48 g (2.33 mmol) of N, N-dicyclohexyl-carbodiimide were then added and stirred overnight. It is then cooled to internal temperature + 5 ° C and the resulting precipitate is filtered off and washed once with 5 ml of toluene. The toluene filtrates collected were concentrated in vacuo to about 10 ml and the solution thus obtained was heated in a steam bath. Petroleum ether (about 55 ml total) was added in portions until constant turbidity. It is cooled in ice to give crystals. The crystals were filtered off and dried at 75 ° C / 4 Torr. The product obtained (4.57 g; mp 111-112 ° C; ee = 98.9%) was suspended in petroleum ether. It was heated in a water bath and toluene (8 ml total) was added portionwise until a solution was obtained. It was cooled in ice and the crystals were filtered under vacuum and dried at 75 ° C / 4 Torr.

Yield: 3.93 g (74.3% of theory). 117-118 ° C

Calculated: C 72.47 H 8.39 N 5.83 Found: 72.44 8.43 5.93 / a / _D ²⁰ = + 9.4 ° (c = 1.01 in methanol) enantiomeric purity: ee = 99.9% / HPLC method: see Example 1 /

Example 3 (S) -2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid

A solution of 3.79 g (7.88 mmol) 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 1 N sodium hydroxide solution are added. After stirring at 60 ° C for 4 h, 10 ml (10 mmol) of 1 N hydrochloric acid were added to the warm mixture and allowed to cool to room temperature. After inoculating and standing overnight, the mixture was cooled in ice for another hour with stirring. The crystals were filtered off, washed twice with 5 ml of water each, first dried at 75 ° C and then at a final temperature of 100 ° C / 4 Torr in a drying chamber over phosphorus pentoxide.

Yield: 3.13 g (87.7% of theory)

M.P. 130-131 ° C (high melting form)

Calculated: C 71.64 H 8.02 N 6.19 Found: 71.48 7.87 6.39 / α / p ²⁰ = + 7.45 ° (c - 1.06 in methanol) The enantiomeric purity was determined by HPLC on a chiral phase HPLC column from Hromteh (Sweden) with AGP (α 1-acid glycoprotein) -phase; Inner Diameter: 4.0 mm; length 100 mm; particle size - diameter: 5 µg; temperature: 20 ° C, eluent: 0.1% aqueous KH ₂ PO ₄ (= A) + 20% acetonitrile (= B), gradient increase for 4 min to 40% (B); flow rate: 1 ml / min; UV detection at 240 nm. Retention time of the (3) -enantiomer: 2.7 min; retention time (R) -enantiomer: 4.1 min.

Found: (S): (R) = 99.85%: 0.15%. ee = 99.7% (S).

Recrystallization of the sample in eth15 nol / water (2: 1) did not change the mp.

Upon heating the sample in petroleum ether / toluene (5: 3), the insoluble portion was filtered (mp 130-131 ° C) and rapid cooling of the 5 filtrates gave the low-melting title compound of mp. 99-101 ° C.

Calculated: C 71.64 H 8.02 N 6.19

Found: 71.66 7.97 6.44

The low-melting form and the high-melting form differ in their infrared spectra -KBr- but not in their infrared spectra of their solutions (methylene chloride).

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

Recrystallization of a sample of the low-melting form into ethanol / water (2: 1) then yields the high-melting form.

The high melting form and the low melting form were examined using a Differential Scanning Calorimeter (DSC) (Metler Apparatus, TA-300-system; measuring cell: DSC 20; Metler production, CH-8306 Greifensee, Switzerland), yielding the following results :

Compound of Example 3 Speed of heating 10 ° K / min Heating speed 3 ° K / min high melting- uniform melting peak uniform melting peak and get in shape with the temperature of with the temperature of mp 133 ° C; mp of 132 C; melting enthalpy: melting enthalpy: 100 J / g 99.1 J / year low-melting- 1. Peak at 57 ° C 1. Peak at 54 ° C and get in shape (very weak) (very weak; 2. Peak at 78 ° C endothermic) (weak) 2. Endothermic peak 3. Endothermic peak at 104 ° C, at 107 ° C; temperature at melting enthalpy mp 102 ° C 55 J / y melting enthalpy 4. Endothermic peak 52 J / y at 132 ° C 3. Exothermic anti- melting enthalpy: the basic li- 25 J / y by crystallization

wound of the substance melted at 104 ° C

4. Endothermic peak at 131 ° C, melting point 130 ° C, melting enthalpy:

J / y

Example 4. Ethyl (S) -2-Ethoxy-4- [N- (1 (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate

0.79 g (1.65 mmol) (S) -2-eroxy-4- [N- (1 (2-piperidino-phenyl) -3-methyl-1-buten-1-yl) aminocarbonylmethyl] -benzoate with mp 124-127 ° C were dissolved in 10 ml of a degassed solvent mixture (methanol / methylene chloride = 5/1) under argon and added to a solution of 17 mg NOYORI catalyst Ru (0-acetyl) ₂ - / (S) -BINAP / (obtained from / Ru (COD) Cl ₂ / _n with (S) BINAP / = (S) -2,2'-bis- (diphenylphosphino) -1, Gbinaftyl), triethylamine and sodium acetate) and 3 mg titan tetraisopropylate in 10 ml of a degassed solvent mixture (methanol / methylene chloride 2 5/1). The reaction mixture was transferred to a 10 * ^g mbar evacuated autoclave. It was rinsed five times with 5 bar hydrogen and then hydrogenated at 30 ° C and 100 bar until hydrogen absorption (154 h) ceased. The red-brown solution was concentrated in vacuo, the residue was dissolved in 80 ml of ether, the undissolved brown rags were filtered through charcoal and the resulting clear light yellow filtrate was concentrated in vacuo. After evaporation (0.60 g), the residue was refluxed with 60 ml of n-hexane and the undissolved particles were hot-filtered. The filtrate was allowed to stand overnight at ambient temperature. The resulting crystals were filtered off.

Yield: 0.45 g (56.7% of theory), m.p. 131-133®C (120 ° C sintering begins) 40 Enantiomeric purity: ee = 39% (S) / HPLC method: see Example 1 /.

Example 5. Ethyl (S) -2-ethoxy-4- [N- (1 (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl) -benzoate 45

To a solution of 0.68 g (1.15 mmol) of ethyl (S) -2-hydroxy-4- (N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) aminocarbonylmethyl (benzoate) mp 125-126 ° C; (a / _D ^M + 12.87 ° (c = 1.01 in methanol) / in 5 ml of anhydrous dimethylfor-50 mamide was stirred at room temperature for 0.5 h after 0.05 g (0.05 g) were added to the solution. 1.15 mmol) sodium hydride (as a 55% oil dispersion). Then a solution of 10.12 of 0.12 ml (1.15 mmol) of ethyl iodide in 2.5 ml of anhydrous dimethylformamide was added and stirred for 5 hours at room temperature. It is concentrated in vacuo, the residue partitioned between dilute sodium hydroxide and chloroform, the organic extract is dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (toluene / ethyl acetate = 10/1).

Yield: 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- (125 (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate

Prepared in analogy to Example 5 of (S) -2-hydroxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] 30-benzoic acid with 2 equivalents of sodium hydride and 2 equivalents of ethyl iodide.

Yield: 42% of theory, m.p. 1 ΙΟΙ 12 ° 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) -3-methyl-1-butyl) aminocarbonylmethyl) -benzoate and ethyl (R) (-) -2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate

920 mg of ethyl (±) -2-ethoxy-4- (N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl) -benzoate are divided into single doses of 10 mg per preparative chiral-phase HPLC column of the Baker company in which (S) -N-3,5-dinitrobenzoyl-leucine is covalently bound to aminopropyl silica gel (particle size: 40 pm; column length: 250 mm at inner diameter 20 mm; eluent: n13 hexane / tetrahydrofuran / ethanol / methylene chloride (180/20/3/2); mobile phase flow rate: 21.25 ml / min; temperature: 27 ° C; Y-detection at 285 nm) first eluting the (R) (-) enantiomer ( peak 1) and then the (S) (+) enantiomer (peak 2).

From the respective separated and collected fractions, after concentration in vacuo, the following are obtained:

peak 1 fraction (R): 423 mg (crude) peak 2 fraction (S): 325 mg (crude).

To remove the impurities (among other things contained in the tetrahydrofuran stabilizer 2,6-di-tert-butyl-4-methylphenol), the two fractions were independently purified by column chromatography on silica gel (toluene / acetone = 10/1).

(R) (-) -enantiomer:

Yield: 234.5 mg (51% of theory); 122-124 ° C (petroleum ether + acetone)

Calculated: C 72.47 H 8.39 N 5.83 Found: C 72.40 N 8.18 N 5.71 / α / p “= -8.3 ° (c = 1 in methanol) (S) - enantiomer:

Yield: 131.2 mg (28.5% of theory)

M.P. 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 / and / _v ^m - + 8,3 ° (c - 1 in methanol)

For the separation of the enantiomers, a chiral target OD column of the company Ditzel is also suitable. On a 250 mm long column and 4.6 mm internal diameter (eluent: absolute ethanol / (n-hexane + 0.2% diethylamine) = 5/95; temperature: 40 ° C; UV detection at 245 nm) (R The) enantiomer was eluted after 6.8 min and the (S) enantiomer after 8.5 min.

Example 8. (R) (-) - 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid x 0.4 H ₂ O

Obtained from 150 mg (0.312 mmol) of ethyl (R) (-) -2-eroxy-4- [N- (1- (2-piperidinophenyl) 3-methyl-1-butyl) -aminocarbonylmethyl) -benzoate / m. t. 122-124 ° C; (a) p ²⁰ = -8.3 ° (c = 1 in methanol) / by saponification with 1 N sodium hydroxide solution in ethanol, analogous to example 3.

M.P. 103-105 ° C (toluene / petroleum ether) Yield: 95.8 mg (66.7% of theory) Calculated (x 0.4 H ₂ O): C 70.51 H 8.01 N 6.09

Found: 70.88 7.79 5.81

Molecular M ⁺ peak: calculated: 452 found: 452 / α / p ²⁰ = -6.5 ° (c = 1 in methanol)

Enantiomeric purity: ee = 99.7% (R) / HPLC method: see Example 3 /.

Example 9. (S) (+) - 2-Ethoxy-4- / N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl) -benzoic acid x 0.4 H ₂ O

Obtained from 89 mg (0.198 mmol) of ethyl (S) (+) -2-ethoxy-4- [N - (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate / mp 122-124 ° C; (a) _D ^M = + 8.3 ° (c = 1 in methanol) / by saponification in 1 N ethanol sodium hydroxide solution, analogous to example 3.

Yield: 44.5 mg (48.8% of theory), m.p. 102-103 ° C (toluene / petroleum ether)

Calculated: (x 0.4 H ₂ O) C 70.51 N 8.01 Found: 70.80 8.06 / α / p ²⁰ = + 6.7 ° (c = 1 in methanol)

Enantiomeric purity: ee = 99.6% (S) / HPLC method: see Example 3 /.

Example 10 (S) -2-Ethoxy-4- [N- (1- (N -peridino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid

0.26 g (0.47 mmol) benzyl (S) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonyl-methyl] -benzoate ( mp 91-92 ° C; / α / p ²⁰ = + 9.5 °; c = 1.05 in methanol) are hydrogenated in 10 ml of ethanol using 0.12 g (10%) palladium on carbon at 50 ° C and 5 bar hydrogen. After 5 h, the catalyst was filtered off with kieselguhr and evaporated in vacuo. After evaporation, the residue was crystallized from ethanol / water (2/1).

Yield: 0.15 g (70% of theory), m.p. 130-131 ° C.

Calculated: C 71.64 H 8.02 N 6.19

Found: 71.76 8.12 6.05

Enantiomeric purity: ee = 99.6% (HPLC method: see Example 3).

Example 11 (S) -2-Ethoxy-4- [N- (1- (2-N -peridino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid

102 mg (0.20 mmol) tert-butyl (S) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate (m.p. 122-123 ° C; (a / ^g - + 8.7 °; c = 1 in methanol) was refluxed for half a day together with several crystals of p-toluenesulfonic acid hydrate. The desired product was obtained by tan14 chromatography according to the R _f value and mass spectrum.

M.P. 129-131 ° C

M ⁺ Molecular Peak: calculated: 452 found: 452

Example 12 (S) -2-Ethoxy-4- [N- (1- (2-N -peridino-phenyl) -3-methyl-1-butyl) aminocarbonylmethyl] -benzoic acid

200 mg (0.395 mmol) tert-butyl (S) -2-ethoxy-4- N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl) -benzoate (m.p. 122 -123 ° C; (a / _D ²⁰ = + 8.7 °; c = 1 in methanol) was stirred in 2 ml of methylene chloride together with 0.4 g (3.95 mmol) of trifluoroacetic acid overnight at room temperature. The mixture was evaporated in vacuo and the residue partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic extract was dried, filtered and evaporated in vacuo. The residue was crystallized in ethanol / water (2/1).

Yield: 115 mg (64.7% of theory), m.p. 126-128 ° C

Calculated: C 71.64 H 8.02 N 6.19 Found: 71.39 7.91 6.06 / a / _D ^M = 6.97 ° (c = 0.975 in methanol) enantiomeric purity: ee = 99.8 % (HPLC method: see Example 3).

Example 13. Tablets containing 0.25 mg AG-EE 623 ZW

One tablet contains, in mg: 0.250 active substance, 0.125 N-methylglucamine, 0.038 polyvinylpyrrolidone, 0.075 polyoxyethylenepolyoxypropylenepolymer and 0.150 microcrystalline cellulose.

Preparation: The active substance and the auxiliary materials are dissolved in water at 90 ° C or the microcrystalline cellulose is suspended and the dispersion is evaporated in vacuo. The dry mass is sieved through a 1 mm mesh screen.

The following ingredients were added to the granular active ingredient for each tablet in mg: 24,862 sodium carboxymethyl starch, 24,000 microcrystalline cellulose, 0,500 magnesium stearate. The total amount is 50,000 mg.

From this mixture are compressed round, biplanar tablets of 50 mg and 5 mm diameter.

Example 14. Tablets containing 0.5 mg AG-EE 623 ZW

One tablet contains, in mg: 0.500 active substance, 0.250 N-methylglucamine, 0.075 polyvinylpyrrolidone, 0.150 polyoxyethylene polyoxypropylene polymer and 0.300 microcrystalline cellulose.

Preparation: The active substance together with the adjuvants are dissolved in water at 90 ° C, respectively, the microcrystalline cellulose is suspended therein and the dispersion is evaporated in vacuo. The dry mass is sieved through a 1 mm mesh screen.

The following ingredients in mg are added to the granulated active substance per tablet: 24,225 sodium carboxymethyl starch, 24,000 microcrystalline cellulose and 0,500 magnesium stearate. The total amount is 50,000 mg.

From this mixture are compressed round, biplanar tablets of 50 mg with a diameter of 5 mm.

Example 15. Tablets containing 1.0 mg AG-EE 623 ZW

One tablet contains, in mg: 1.00 active substance, 0.50 N-methylglucamine, 0.15 polyvinylpyrrolidone, 0.03 polyoxyethylenepolyoxypropylene polymer and 0.60 microcrystalline cellulose.

Preparation: The active substance, together with the adjuvants, is dissolved in water at 90 ° C, respectively, the microcrystalline cellulose is suspended and the dispersion is evaporated in vacuo. The dry mass is sieved through a 1 mm mesh sieve.

The following ingredients in mg are added to the granular active substance per tablet: 23.22 sodium carboxymethyl starch, 24.00 microcrystalline cellulose and 0.50 magnesium stearate. The total amount is 50.00 mg.

From this mixture are compressed round, biplanar tablets of 50 mg and a diameter of 5 mm.

Example 16. Tablets containing 1.5 mg AG-EE 623 ZW

Each tablet contains, in mg: 1,500 active substance, 0.750 N-methylglucamine, 0.225 polyvinylpyrrolidone, 0.045 polyoxyethylenepolyoxypropylene polymer and 0.900 microcrystalline cellulose.

Preparation: The active substance and the adjuvants are dissolved in water at 90 °, respectively the microcrystalline cellulose is suspended and the dispersion is evaporated in vacuo. The dry mass is sieved through a 1 mm mesh sieve.

The following ingredients in mg were added to the granular active ingredient for each tablet: 23,080 sodium carboxymethyl starch, 23,000 microcrystalline cellulose and 0.500 magnesium stearate. The total amount is 50,000 mg.

From this mixture are compressed round, biplanar tablets of 50 mg and 5 mm diameter.

Example 17. Tablets with 2.0 mg content of AG-EE 623 ZW

Each tablet contains, in mg: 2.00 active substance, 1.00 L-lysine, 1.00 polyvinylpyrrolidone, 1.00 polyoxyethylenepolyoxypropylene polymer and 4.00 microcrystalline cellulose.

Preparation: The ingredients were dissolved in water at 90 ° C, respectively, the microcrystalline cellulose was suspended and the dispersion was dried in an air dryer. The following components were then added to each tablet in mg: 20.35 microcrystalline cellulose, 20.00 sodium carboxymethyl starch and 0.65 magnesium stearate. The total amount is 50.00 mg.

From this mixture, round, biconvex 50 mg tablets with a diameter of 5 mm are compressed and coated with a taste-enhancing hydroxypropyl methylcellulose coating.

Example 18. Tablets containing 2.5 mg AG-EE 623 ZW

Each tablet contains in mg: 2.5 active substance, 1.25 L-lysine, 1.25 polyvinylpyrrolidone, 1.25 polyoxyethylenepolyoxypropylene polymer and 4.10 microcrystalline cellulose.

Preparation: The ingredients were dissolved in water at 90 ° C, respectively the microcrystalline cellulose was suspended and the dispersion was air-dried. The following substances were then added to each tablet in mg: 19.50 microcrystalline cellulose, 19.50 sodium carboxymethyl starch and 0.65 magnesium stearate, the total amount being 50.00 mg.

From this mixture, round, biconvex tablets of 50 mg and 5 mm in diameter are compressed and coated with hydroxypropyl methylcellulose to improve taste.

Example 19. Tablets containing 3.0 mg AG-EE 623 ZW

Each tablet contains, in mg: 3.0 active substance, 1.5 L-lysine, 1.5 polyvinylpyrrolidone and 1.5 polyoxyethylenepolyoxypropylene polymer.

The ingredients were dissolved in water at 90 ° C and the solution was evaporated in an air dryer. The following substances are then added to the tablet in mg: 21.5 microcrystalline cellulose and 21.0 sodium carboxymethyl starch. The total amount is 50.0 mg.

From this mixture, round, biconvex 50 mg tablets and 5 mm diameter are compressed and coated with hydroxypropyl methylcellulose to improve taste.

Example 20. Tablets containing 5 mg of AG-EE 623 ZW

Each tablet contains, in mg: 5.0 active substance, 2.5 L-lysine, 2.5 polyvinylpyrrolidone and 2.5 polyoxyethylenepolyoxypropylene polymer.

The ingredients were dissolved in water at 90 ° C and the solution was air-dried. 19.0 mg of microcrystalline cellulose and 18.5 mg of sodium carboxymethyl starch were then added to each tablet, the total amount being 50.0 mg.

The mixture is pressed round, biconvex 50 mg and 5 mm diameter tablets and coated with hydroxypropyl methylcellulose to improve taste.

Claims (11)

1. (S) (+) -2-eroxy-4- (N-) 1- (2-piperidino-phenyl) -3-methyl-1-butyl (aminocarbonylmethyl) -benzoic acid and its salts with inorganic or organic acids or bases. A compound according to claim 1 which is practically optically pure. A compound according to claim 2, with an optical purity of at least ee = 95%. The compound of claim 2, with an optical purity of at least ee = 98%. 5. Physiologically tolerated salts of a compound according to claims 1 to 4 with inorganic or organic acids or bases. Medicaments characterized in that they contain a compound according to claims 1 to 4 or a physiologically acceptable salt according to claim 5 together with one or more inert carriers and / or diluents. Use of a compound according to claims 1 to 4 or its physiologically tolerated salts according to claim 5 for the treatment of Diabetes mellitus. A method for the preparation of medicaments according to claim 6, characterized in that in a non-chemical way the compound according to claims 1 to 4 or the physiologically tolerated salt thereof according to claim 5 is mixed with one or more carriers and / or diluents. A method for the preparation of a new compound according to claims 1 to 5, characterized in that a) (5) -amine of formula wherein W 'represents a carboxyl group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms in which the alkyl moiety of the alkoxy group may be 5 substituted by a phenyl group is reacted with a compound of the general formula Z is CH ₂ - CH ₂ (V) in which Z is a nucleophilically substituted group or together with the adjacent water10 parent atom means a dia group, and then, if necessary, the compound thus obtained is hydrolyzed or hydrogenated, or d) a compound of the general formula is reacted with a carboxylic acid of the general formula _2- axis ₅ in which W 'represents a carboxyl group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl moiety of the alkoxy group may be replaced by a phe25-nyl group and Y represents a group of formula wherein W is a carboxyl group or a carboxyl group protected with a protecting group or with its reactive derivative optionally obtained in the reaction mixture and subsequently, if necessary, cleavage of the protecting group or b) (S) compound of general formula CH, CH, L / CH in which A denotes a group which may be converted to a carboxyl group by hydrolysis, thermolysis or hydrogenolysis, or c) the (S) compound of general formula (IV) is enantioselectively reduced and, if necessary, the compound thus obtained is hydrolyzed or e) (S) compound of general formula CH, CH, \ ^3/5 CH wherein W "represents a group that can by oxidation to convert into carboxyl group, is oxidised or f) a mixture consisting of an arbitrary amount of (S) -enantiomer of general formula and an arbitrary amount of (R) -enantiomer of general formula in which W 'denotes a carboxyl group or alkoxycarbonyl group containing a total of 2 to 5 carbon atoms, wherein the alkyl the residue may be substituted by a phenyl group, separated and the compound thus obtained 30 recrystallized, if necessary, to give a compound of greater enantiomeric purity, whereby crystallization is carried out by ethanol / water (2/1 ) and the higher melting form is obtained, m.p. 130-131 ° C, 35 and recrystallization from petroleum ether / toluene (5/3) gave the low-melting form of m.p. 99-101 ° C and the compound thus obtained is converted into its salts, in particular physiologically tolerated salts with the help of ₄ q inorganic or organic acids or bases. 10. (S) -3-methyl-1- (2-piperidino-phenyl) -1-butylamine and its acid addition salts. 11. New compounds of general formulas in which A represents a group which, by hydrolysis, thermolysis or hydrogenolysis, can be converted into a carboxyl group; W 'denotes a carboxyl group Or an alkoxycarbonyl group containing a total of 2 to 5 carbon atoms in which the alkyl moiety in the alkoxy group may be substituted by a phenyl group, and W' represents a group which, by oxidation, can be converted to a carboxyl group, and their addition salts. Expert: R. Jovovich Publication of the Patent Office of the Republic of Bulgaria 1113 Sofia, 52-B Dr. GM Dimitrov Blvd. Editor: E. Sinkova Cf. № 38971 Circulation: 40 MB