SI9111136A - (S)-(+)-2-ethoxy-4-/N-/1-(2-piperidino-phenyl)-3-methyl-1-butyl/ aminocarbonylmethyl/-benzoic acid, pharmaceuticals containing this compaund and processes for their preparation - Google Patents

Description

Gesellschaft mit beschriinkter Haftung (S) - (+) - 2-ethoxy-4- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid, medicines containing this and the processes for preparing them

EP-B-0,147,850 discloses, inter alia, the racemate of 2-ethoxy-4- [N- [1- (2-piperidino phenyl) -3-methyl-1-butyl] aminocarbonylmethyl] -benzoic acid (code no .: AG- EE 388 ZW) with the formula

CH

CH

CH

- COOH and in EP-B-0,207,331 two further polymorphic forms of this compound. This compound and its physiologically tolerable salts have valuable pharmacological properties, namely the effect on intermediate metabolism, and in particular the effect of lowering blood sugar.

Both enantiomers of this compound, namely (S) - (+) - 2-ethoxy-4- [N- [1- (2-piperidino-phenyl) 3-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-butyl] -aminocarbonyl methyl-benzoic acid (code no .: AG-EE 624 ZW), we investigated the effect of blood sugar reduction in female rats.

Surprisingly, we found that the (S) -enantiomer (AG-EE 623 ZW) was an effective enantiomer and that its effect on the rat lasted more than 6 hours.

Based on these results, in humans, the exclusive use of AG-EE 623 ZW is offered to humans, thereby reducing the dose compared to the AG-EE 388 ZW dose by 50%. This and the relatively long duration of the effect could be confirmed in humans. In addition, in human studies, AG-EE 623 ZW was again found to have surprising pharmacokinetic properties that could not be predicted on the basis of the data for AG-EE 388 ZW. The AG-EE 623 ZW therefore has surprising therapeutic advantages over the AG-EE 388 ZW racemate.

The surprising findings in humans are:

(a) AG-EE 623 ZW levels fall faster towards zero than AG-EE 388 ZW levels even at the same absolute dose, which was not expected based on the relatively long duration of the effect.

(b) Given the reduction in blood sugar achieved, significantly lower plasma levels of AG-EE 623 ZW than would be expected with the half-dose of AG-EE 388

ZW.

(c) The sugar reduction effect occurs after administration of AG-EE 623 ZW faster than after administration of AG-EE 388 ZW.

The eclatant difference between the two enantiomers is that the effective enantiomer, AG-EE 623 ZW, surprisingly despite its relatively long duration of effect, is eliminated significantly faster than the inefficient enantiomer, AG-EE 624 ZW, as shown in FIG. 1 and 2. After administration of the racemate, the ineffective enantiomer, AG-EE 624 Z \ V, is therefore present not only as unnecessary ballast at the same high plasma concentrations as the effective enantiomer, AG-EE 623 ZW, but at unexpectedly higher maximum and sustained levels. This is reflected e.g. for the administration of 2 mg AG-EE 388 ZW tablets. 1 mg AG-EE 623 ZW tablets at 12 oz. 6 test subjects with maximum concentrations of 84 ± 25 oz. 28 ± 18 ng / ml as well as concentrations after 4 hours 19 ± 8 oz. 0.7 ± 1.0 ng / ml, after 5 hours 13 ± 6 oz. 0.3 ± 0.7 ng / ml and after 6 hours 10 ± 6 oz. 0.3 ± 0.7 ng / ml.

The surprisingly rapid establishment of a reduction in blood sugar with AG-EE 623 ZW compared to AG-EE 388 ZW is particularly advantageous for diabetics because rapid establishment results in optimal disease control.

Compared to the AG-EE 388 ZW application, there is therefore a striking advantage of the AG-EE 623 ZW application in avoiding unnecessarily high and prolonged material loads of the organism, which is of great importance in long-term therapy such as Diabetes Mellitus therapy.

Human studies show that a new (S) -enantiomer, namely (S) - (+) - 2-ethoxy-4- [N- [1- (2-piperidino-phenyl) -3-methyl-1- butyl] aminocarbonylmethyl-benzoic acid as a carrier of blood sugar lowering efficiency due to its surprisingly long-lasting effect of unpredictably rapid blood elimination compared to AG-EE 388 ZW better properties far exceeding the normal advantage of one enantiomer compared to its racemates, namely the advantage of dose administration.

The object of the present invention is therefore a novel (S) - (+) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] -benzoic acid or. (S) - (+) - 2-Ethoxy- 4- [N- [1- (2-piperidino-phenyl) -3-methyl-1-butyl] -aminocarbonyl] methyl-benzoic acid, which is substantially optically pure, e.g. with an optical purity of at least ee = 95%, preferably 98 to 100%, of its physiologically tolerable salts with inorganic or organic acids or bases, medicaments containing this compound or. its physiologically tolerable salts and processes for its preparation.

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

a) Metabolism of (S) -amine by formula

with a carboxylic acid of general formula

HOOC-CH

, (ii) in which it represents

W is a carboxy group or a protected residue protected with a carboxy group, or with its optionally prepared reaction-capable derivative in the reaction mixture and, if necessary, subsequent cleavage of the protective residue.

Reactive derivatives of the compounds of general formula II are suitable, e.g. its esters, such as methyl, ethyl or benzyl ester, its thioesters, such as methylthio or ethylthioester, its halides, such as acid chloride, its anhydrides or imidazolides.

The metabolism is efficiently carried out in a solvent such as methylene chloride, chloroform, tetrachlorocarbon, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or water withdrawal agent, e.g. in the presence of hydrochloric acid ethyl ester, hydrochloric acid isobutyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, Ν, Ν'-dicyclohexylcarbodiimide, Ν, Ν'-dicyclohexylcarbodiimide / N hydroxydisoxide or carboxydiazide, / tetrachlorocarbon, or an agent that activates an 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 solvents, at temperatures between -25 and 250 ° C, and preferably at temperatures between -10 ° C and the boiling point of the solvent used. The metabolism can also be carried out without solvent, further azeotropic distillation can be made between the metabolism and the resulting water, e.g. by heating with toluene on a water separator, or by adding a desiccant such as magnesium sulfate or a molecular sieve.

If necessary, the following cleavage of the protective residue is carried out preferably hydrolytic, preferably either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide, in an appropriate topical , methanol, methanol / water, ethanol, ethanol / water, water / isopropanol or water / dioxane, at temperatures between -10 and 120 ° C, e.g. at temperatures between room temperature and boiling point of the reaction mixture.

The tert.butyl residue used as a protective residue can also be cleaved thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial, and preferably in the presence of a strong acid such as trifluoroacetic acid, hydrobromic acid, hydrobromic acid toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid.

Further, the benzyl residue used can also be cleaved as a protective residue by hydrogenolytic in the presence of a hydration catalyst, such as palladium / charcoal, in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

bj Cleavage (Sj-spoiine of general formula

CH

in which he represents

But by hydrolysis, thermolysis or hydrogenolysis into a carboxy group a translatable group.

As hydrolysable groups, e.g. functional derivatives of a carboxy group such as unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoeters, amidines or anhydrides, nitrile group, tetrazolyl group optionally substituted 1,3-oxazol-2-yl or 1,3-oxazoline- 2-yl group, and as thermolytically cleavable groups e.g. esters with tertiary alcohols, e.g. tert.butyl ester, and as hydrogenolytically cleavable groups e.g. aralkyl groups, e.g. benzyl group.

Hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid 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, ethanol, ethanol / ethanol, water / isopropanol or water / dioxane, at temperatures between -10 and 120 ° C, e.g. at temperatures between room temperature and boiling point of the reaction mixture.

If A in the compound of general Formula III is a nitrile or aminocarbonyl group, these groups may be converted using 100% phosphoric acid at temperatures between 100 and 180 ° C, preferably at temperatures between 120 and 160 ° C, or with nitrite, e.g. sodium nitrite, in the presence of acid, as sulfuric acid, where appropriate simultaneously used as a solvent, at temperatures between 0 and 50 ° C in the carboxy group.

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

If A in a compound of general formula III, e.g. benzyloxycarbonyl group, the benzyl group can also be cleaved hydrogenolitically in the presence of a hydration 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 pri 0 and 50 ° C, e.g. at room temperature, and a hydrogen pressure of 1 to 5 bar.

c) Metabolism of (S) compounds of general formula

in which it means

A W 'carboxy group or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl moiety of the alkoxy group may be substituted by a phenyl group, with a compound of the general formula

Z - CH ₂ - CH ₃ (V) in which it represents

With a nucleophilic exchangeable group, such as a halogen atom, a sulfonyloxy group, or also together with an adjacent hydrogen atom a diazo group, and subsequent hydrolysis or hydrogenolysis, if necessary.

The metabolism is efficiently carried out with a suitable halide, a sulfonic acid ester or a sulfuric acid diester, e.g. with ethyl bromide, ethyl iodide, diethylsulfate, p-toluenesulfonic acid ethyl ester or methanesulfonic acid ethyl ester, or diazoethane, optionally in the presence of a base such as sodium hydride, potassium carbonate, sodium hydroxide, potassium tertiaryl methyl, or triethylbutyrate or triethylbutyrate such as acetone, diethyl ether, tetrahydrofuran, dioxane, pyridine or dimethylformamide, at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 50 ° C.

If W 'in a compound of general formula IV is a carboxy group, this can be converted to the corresponding ester compound.

If necessary, the following hydrolysis is carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid 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. at temperatures between room temperature and the boiling point of the reaction mixture, or subsequent hydrogenolysis in the presence of a hydration catalyst, such as palladium / charcoal, in a suitable solvent, such as methanol, ethanol, ethanol / water, ice, ethyl acetate, dioxane or dimethylformamide at hydrogen pressure 1 to 10 bars.

d) Enantioselective reduction of a compound of the general formula

W ', <vi) in which it represents

A W 'carboxy group or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl portion of the alkoxy group being substituted by a phenyl group, and

Y group of formula / ^CH CH

H / ^ CH

C

CH

CH

CH.

CH.

CH.

CH

I

CH.

-C - NH- C - NH ^or - C = Nin further hydrolysis if necessary.

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

Suitable metal Ugandan complexes such as Ru (OCO-CH ₃ ) ₂ [(S) -BINAP], Ru ₂ Cl ₄ [(S) -BINAP] ₂ x N (C ₂ H ₅ ) _{3 are} suitable as chiral hydration catalysts , Rh [(S) -BINAP-NBD] C10 ₄ or Rh [(-) - NORPHOS-COD] BF ₄ ((S) -BINAP = (S) 2,2'-bis (diphenylphosphino) -l, l '-binaftyl; BND = 2,5-norbornadiene; (-) - NORPHOS = (-) - 2,3-bis (diphenylphosphino) -5-norbornene; COD = 1,5-cyclooctadiene).

In catalytic hydrogenation, the benzyloxycarbonyl group can be simultaneously co-treated and converted into a carboxy group.

If necessary, the following hydrolysis is carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid 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 , ethanol, ethanol / water, water / isopropanol or water / dioxane, at temperatures between -10 and 120 ° C, e.g. at temperatures between room temperature and boiling point of the reaction mixture.

e) Oxidation of (S) -compounds of the general formula ch ₃ ch ₃

, (villas) in which it represents

W by oxidation to the carboxy group translatable group.

As such, the oxidizable group is suitable e.g. a formyl group and its acetals, a hydroxymethyl group and its ethers, an unsubstituted or substituted acyl group, such as an acetyl, chloroacetyl, propionyl, malonic acid- (l) -yl group or malonester (l) -yl group.

The metabolism is carried out with an oxidizing agent in a suitable solvent, such as water, ice, methylene chloride, dioxane or glycoldimeter, at temperatures between 0 and 100 ° C, and preferably at temperatures between 20 ° C and 50 ° C. The metabolism is preferably carried out with silver oxide / sodium hydroxide, manganese dioxide / acetone or methylene chloride, hydrogen peroxide / sodium hydroxide, bromine or chlorine / sodium or potassium alkali, chromium trioxide / pyridine or pyridinium.

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

CH.

CH

and any amount of (R) -enantiomer of the general formula

, (IX) in which it means

A W 'carboxy group or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl portion of the alkoxy group being substituted by a phenyl group, preferably 50/50, via its diastereomeric adducts, complexes or salts, and, if necessary, subsequent hydrolysis or hydrogenolysis .

Separation is preferably carried out by column or HPL chromatography to form diastereomeric adducts or chiral phase complexes.

If necessary, the following hydrolysis is carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid 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. at temperatures between room temperature and the boiling point of the reaction mixture, or subsequent hydrogenolysis in the presence of a hydration catalyst, such as palladium / charcoal, in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl ester acetic acid, dioxane or dimethylformamide, to hydrogen pressure 10 bars.

Thus, according to the invention, the resulting (S) -enantiomer with an optical purity of at least 90% can be converted by fractional crystallization to the (S) -enantiomer with an optical purity of at least 95%, preferably 98 to 100%.

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

Thus, according to the invention, the (S) -enantiomer obtained can be converted into its salts, in particular for pharmaceutical use, into its physiologically acceptable salts with inorganic or organic acids or also bases. The acids, for example, come in handy for example. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid, and as bases sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexaminolamine, ethanol, ethanolamine, ethanol, ethanol, ethanol ethylenediamine or lysine.

The compounds of formulas I to IX used as starting materials are known in part from the literature and the art. they are obtained by known methods.

The (S) -amine of formula I can be obtained from the corresponding racemic amine by cleavage of the racemate, e.g. by fractional crystallization of diastereomeric salts with suitable optically active acids, preferably N-acetyl-L-glutamic acid, and if necessary by recrystallization as well as subsequent degradation of salts, by column or HPL chromatography on chiral phases, optionally in the form of acyl derivatives, or by formation of diastereomeric compounds, their separation and subsequent cleavage.

Furthermore, the (S) -amine of formula I can be obtained in high enantiomeric purity by enantioselective reduction with hydrogen in the presence of a suitable chiral hydration catalyst from the corresponding N-acyl-ketimine or. of the enamide, optionally with the addition of 0.1 to 5% titanium tetraisopropylate, and optionally by further cleaving the acyl residue as a formyl or acetyl residue, by diastereoselective reduction of the corresponding, chiral substituted ketimine or hydrazine nitrogen atom in the presence of hydrogen in the presence of hydrogen in the presence of hydrogen catalyst, preferably with the addition of 0.1 to 5% titanium tetraisopropylate, and optionally by further cleavage of the chiral auxiliary residue, e.g. (S) -phenylphenyl residue, by catalytic hydrogenolysis, or by diastereoselective addition of a suitable metallogenic compound, preferably Grignard or lithium compound, to the corresponding chiral substituted aldimine on the nitrogen atom, optionally with the addition of 0.1 to 10% titanium tetraisopropylate, hydrolysis and optionally separation of the diastereomers obtained and subsequent cleavage of the chiral auxiliary residue, e.g. (R) -l-phenethyl residue, by catalytic hydrogenolysis, and optionally by forming salts with suitable optically active acids, preferably N-acetyl-L-glutamic acid and, if necessary, single or multiple recrystallization as well as subsequent degradation of the salt.

Compounds of the general formulas III, IV and VII are used as starting materials by the reaction of (S) -amine I with the corresponding carboxylic acid or. its reactive derivatives and optionally the subsequent cleavage of the protective residue used.

The starting material of the compound of the general formula VI is obtained by acylation of the corresponding imino compound or its metalloorganic complexes with the corresponding carboxylic acid or its reactive derivatives with any subsequent cleavage of the ester group.

The new (S) -enantiomer is practically non-toxic; e.g. after a single application of 1000 mg / kg p.o. (suspension in 1% methylcellulose), each animal in five male and five female rats was not killed in the subsequent observation period of 14 days.

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

A further object of the present invention is a novel (S) -amine of formula I, which is a valuable intermediate for the preparation of a novel (S) -enantiomer as well as its addition salts with inorganic or organic acids.

It is a further object of the present invention to provide novel compounds of general formulas III, IV and VII, which are valuable intermediates for the preparation of a novel (S) enantiomer, as well as their addition salts with inorganic or organic acids.

The following examples further illustrate the invention.

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

To a stirred solution of 122 g (0.495 mol) of racemic 1- (2-piperidino-phenyl) -3-methyl-butylamine in 1000 ml of acetone was added 93.7 g (0.495 mol) of N-acetyl-L-glutamic acid. Reflux the steam bath and add methanol (about 80 ml in total) until a clear solution is reached. After cooling and condition at room temperature overnight, the resulting crystals were sucked off, washed twice with 200 ml of cold acetone (-15 ° C) and dried. Obtained product [98.9 g; mp: 163-166 ° C; [a ^ p = + 0.286 ° (c = 1 in methanol)] was recrystallized from 1000 ml of acetone with the addition of 200 ml of methanol to give (S) -1- (2-piperidino-phenyl) 3-methyl-1-butylamine as the N-acetyl-L-glutamic acid addition salt.

Yield: 65.1 g (60.4% of theory), melting point: 168-171 ° C calc .: C 63.42 H 8.56 N 9.65 found: 63.64 8.86 9.60 [α] β ° = 0.357 ° (c = 1 in methanol)

The free amine is obtained as an oil by the release of e.g. with sodium hydroxide or ammonia solution, by extraction, e.g. with toluene, ether, ethyl acetate or methylene chloride, as well as by drying, filtering and evaporating the extract in vacuo.

The (S) amine configuration is proved as follows:

Metabolism of an amine with (S ') - l-phenethylisocyanate in ether into the corresponding urea derivative [mp: 183 to 184 ° C; [α] ² θ = -2.25 ° (c = 1 in methanol)], ethanol / water crystal growth (8/1) and subsequent X-ray structural analysis to give the (S, S ') - configuration for the urea derivative and thus the (S) -configuration for the amine used.

The enantiomeric purity is determined as follows:

1. Acetylation of an amine sample with 1.3 equivalents of acetic anhydride in freezing at 20 ° C overnight.

2. Examination of the N-acetyl derivative (mp 128 to 132 ° C) by HPLC on chiral-phase HPLC chiral gauze columns of (S) -N- (3,5-dinitrobenzoyl) -2-phenyl-glycine covalently bound to an aminopropyl silica gel (grain size: 5 μτη, spherical, pore width 6 nm; column length: 250 mm at an internal diameter of 4.6 mm; elution agent: N-hexane / isopropanol (100/5); elution rate : 2 ml / min; 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).

Hydrochloric acid solution can be used to convert (S) -amine to its dihydrochloride hydrate.

Mp .: 135-145 ° C (dec) Calcd. (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 + 26.1 ° (c = 1 in methanol)

EXAMPLE B

N-acetyl-N-flu- (2-piperidino-phenyl) -3-methyl-1-buten-1-yl] amine

To a solution of 20 g (81.8 mmol) of freshly prepared isobutyl- (2-piperidino-phenyl) ketimine in 200 ml of acetonitrile was added at room temperature 4.7 ml (81.8 mmol) of ice, 25.7 g (98.2) of triphenylphosphine, 34.2 ml (245 mmol) of triethylamine and 7.9 ml (81.8 mmol) of tetrachlorocarbon and stirred for 18 hours at room temperature. It was then evaporated in vacuo and partitioned between 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), calc .: 135-137 ° C (ethyl acetate / petroleum ether) calc .: 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) calcd .: C 75.48 H 9.15 N 9.78 found: 75.56 9.30 9, 79

EXAMPLE C

N-acetyl-N- [1- (2-piperidino-phenyl) -3-methyl-1-butene-1-yl-amine

To a stirred solution of 44 g (0.18 mol) of freshly prepared isobutyl- (2-piperidinophenyl) -ketimine in 440 ml of toluene was added dropwise at an internal temperature of 0 ° C 17 ml (0.18 mol) of acetanhydride. The mixture was stirred for 3 hours at 0 ° C and for 15 hours at room temperature, then evaporated in vacuo, dissolved by evaporation in ethyl acetate and shaken several times with aqueous sodium hydrogen carbonate. The organic phase was dried, filtered and evaporated in vacuo. The evaporation 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),

Mp .: 139-141 ° C (ethyl acetate) calcd .: C 75.48 H 9.15 N 9.78 Found: 75.68 8.99 9.86

EXAMPLE D

N-acetyl-N - [(S) -1- (2-piperidino-phenyl) -3-methyl-1-butyl-1-amine

0.57 g (1.99 mmol) of (Z) -N-acetyl-N- [1- (2-piperidino-phenyl) -3-methyl-1-buten-1-yl] 17 amine, m.p. 139 to 141 ° C was dissolved in 10 ml of a degassed solvent mixture (methanol / methylene chloride = 5/1) under an argon atmosphere, and a solution of 16.8 mg (1 mol%) of the NOYORI catalyst Ru (O-acetyl) ₂ [(S ) -BINAP] (prepared from [Ru (COD) Cl ₂ ] _n with (S) -BINAP [= (S) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl], triethylamine and sodium acetate ) and 3.4 mg (0.5 mol%) of titanium tetraisopropylate in 10 ml of a degassed solvent mixture (methanol / methylene chloride = 5/1). The reaction mixture was placed in an autoclave evacuated at 10 ' ² mbar. It is repeatedly washed with 4 bars of hydrogen and then hydrated at 30 ° C and 100 bars until the end of the hydrogen uptake (170 hours). Then, evaporate the brown red solution in vacuo, boil the evaporation residue with 30 ml of N-hexane at reflux and filter hot with undissolved. Crystallization occurs when the filtrate is cooled.

Yield: 0.31 g (54% of theory),

Mp .: 127-131 ° C

Enantiomeric purity: ee = 82% (S) [PHLC method: see example Aj.

From undissolved obtained by boiling with 30 ml of N-hexane, 14% racemic N-acetyl-amine from the soil can be obtained by further boiling with N-hexane, filtration and crystallization from hexane solution. Mp 154-156 ° C.

EXAMPLES (S) -1- (2-Piperidino-phenyl) -3-methyl-1-butylamine

Heat 1 g (3.47 mmol) of N-acetyl-N - [(S) -1- (2-piperidino-phenyl) -3-methyl-1-butyl) amine (mp: 128-133 ° C; ee = 99.4%) in 10 ml of concentrated hydrochloric acid for 5.5 hours at reflux, cooled and poured into a mixture of concentrated ammonia and ice. It is extracted twice with ethyl acetate, the organic phase is washed with water, dried and filtered and evaporated in vacuo.

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

By back acetylation with 0.42 ml (1.3 equivalents) of acetanhydride in 8.4 ml of ice overnight at room temperature, evaporation in vacuo, distribution of the evaporation residue between ethyl acetate and saturated aqueous sodium bicarbonate solution as well as drying, filtration and evaporation of the organic extract in vacuo gave 0.83 g (84.7% of theory) of N-acetyl-N - [(S) -1- (2-piperidino-phenyl) -3-methyl-1-butyl] -amine (m.p. .: 130-132 ° C; ee = 99.4%).

EXAMPLE F

2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-buten-1-yl) -aminocarbonylmethyl-benzoic acid ethyl ester

Prepared from isobutyl- (2-piperidino-phenyl) -ketimine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid analogous to example B. Purification by silica gel column chromatography (toluene / acetone = 10/1), eluting first (E) -form and then (Z) -form.

(E) -form:

Yield: 4% of theory,

Mp .: 101-103 ° C Calc .: C 72.77 H 8.00 N 5.85 Found: 72.74 7.78 5.86 (Z) -form:

Yield: 28.1% of theory, mp .: 124-127 ° C (petroleum ether / toluene = 5/1) calc .: C 72.77 H 8.00 N 5.85 found: 72.90 7.86 5.83

EXAMPLE G

N - [(S ') - 1-phenethyl] -Nf (S) -1- (2-piperidino-phenyl) -3-methyl-1-butyl-amine g (49 mmol) N - [(S') - of 1-phenethyl] -isobutyl- (2-piperidino-phenyl) -cetimine by boiling. 150-155 ° C / 0.4 mbar [prepared from isobutyl- (2-piperidino-phenyl) -ketone and (S ') 19

Of 1-phenethyl-amine (Fluka, ee = 99.6%) in toluene + triethylamine by dissolving a solution of titanium tetrachloride in toluene] was dissolved in 170 ml of anhydrous ethanol. 1.7 g of titanium tetraisopropylate and 8 g of Raney nickel were added and hydrogenated at 50 ° C and 200 bars of hydrogen. After 20 hours a further 8 g of Raney nickel was added and hydrated under the same conditions for another 52 hours. It was filtered through a pad of celite on a G3-frit from the catalyst and the filtrate was evaporated in vacuo.

Yield: 13.1 g (76.6% of theory), boiling point: 152 ° C / 0.27 mbar calc .: C 82.23 H 9.78 N 7.99 found: 82.00 10.03 7.74 [a] _D ² ^ -55.3 ° (c = 1.1 in methanol)

Diastereomeric purity was determined by HPLC on a Lichrosorb RP18-HPLCcolumn from E. Merck (Germany); column length: 250 mm at 4 mm internal diameter, particle size: 7 gm; elution agent: methanol / dioxane / 0.1% aqueous sodium acetate solution, adjusted with acetic acid to pH = 4.05 (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 (diastereomeric excess) = 97.0% (S, S ') ·

EXAMPLE H (S) -1- (2-Piperidino-phenyl) -3-methyl-1-butylamine

12.5 g (36 mmol) of N - [(S ') - 1-phenethyl] -N - [(S) -1- (2-piperidino-phenyl) -3-methyl-butyl] -amine with de = 97 , 0% (S, S ') is dissolved in 125 ml of water and 3.6 ml of conc. hydrochloric acids. 1.3 g of palladium / charcoal (10%) was added and hydrated at 50 ° C and 5 bars of hydrogen. After the uptake of hydrogen (10 hours), the catalyst was filtered off through a celite layer. The filtrate was basified with concentrated ammonia with ice and extracted with ethyl acetate. The organic extract was dried and filtered and evaporated in vacuo. Yield: 6.4 g (72.1% of theory), boiling point: 115-117 ° C / 0.53 mbar enantiomeric purity: ee = 93.5% (S) [HPLC method (by preliminary acetylation): see Example A].

EXAMPLE I

N - [(R ^, ) -fluorophenyl-N -] (S) -1-f2-piperidino-phenyl) -3-methyl-1-butyl] -amine

A solution of 2 g (6.84 mmol) of N - [(R ') - l-phenethyl] - (2-piperidino) was added dropwise in a 60 ° C mixed solution of 27.4 mmol (4 equivalents) isobutylmagnesium bromide in 22 ml of anhydrous tetrahydrofuran. -benzaldimine) [prepared from equimolar amounts of 2-piperidino-benzaldehyde and (R ') - l-phenethylamine with standing at room temperature overnight, followed by drying with sodium sulfate in ether solution] in 20 ml of anhydrous tetrahydrofuran. After 18 hours, increase the bath temperature to 80 ° C and add another two equivalents of isobutylmagnesium bromide in 11 ml of tetrahydrofuran. After stirring at 80 ° C for 12 hours each time, 2 equivalents of isobutylmagnesium bromide solution are added again. After about 90 hours at 80 ° C, cool, add excess hydrochloric acid and evaporate to dryness in a water-jet vacuum. The evaporation residue was dissolved in water and basified with concentrated ammonia. It was extracted with ether, the organic extract was dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue was purified by silica gel column chromatography (toluene / acetone = 95/5).

Yield: 0.20 g (8.3% of theory),

Melting point: <20 ° C

The diastereomeric purity was determined as 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 ').

An analogous continuation of 2.0 g of Schiff base and a total of 6 equivalents of isobutylmagnesium bromide in toluene / tetrahydrofuran (4/1) as well as the addition of 5% titanium (IV) tetraisopropylate and 60 hours of heating at 100 ° C in a glass bomb yielded 5 % z de = 97.6% (S, R ') ·

EXAMPLE K (S) -1- (2-Piperidino-phenyl) -3-methyl-1-butylamine

Hydrate a solution of 0.15 g (0.428 mmol) of 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 in the presence of 20 mg of palladium / charcoal (10%) for 5 hours at 50 ° C and 3.4 bars of hydrogen. It was filtered through Kieselgur, 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),

Melting point: <20 ° C

Enantiomeric purity: ee = 87.6% (S) [HPLC method (after preliminary acetylation): see Example A].

EXAMPLE 1

(S) -2-Ethoxy-4-N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl-benzoic acid ethyl ester

To a solution of 0.47 g (1.91 mmol) (S) -3-methyl-1- (2-piperidino-phenyl) -1-butylamine (ee = 98.5%) in 5 ml of anhydrous acetonitrile was added successively 0, 48 g (1.91 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 0.60 g (2.29 mmol) of triphenylphosphine, 0.80 ml (5.73 mmol) of triethylamine and 0.18 ml (1, 91 mmol) of tetrachlorocarbon and stirred at room temperature for 20 hours. It was then evaporated in vacuo and partitioned between 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).

Yield: 0.71 g (77.3% of theory),

Mp = 110-112 ° C Calc .: C 72.47 H 8.39 N 5.83 Found .. 72.29 8.42 5.80

The enantiomeric purity is determined by HPLC on a Baker chiral phase HPLC column in which (S) -N-3,5-dinitrobenzoyl-leucine is covalently bound to an aminopropyl silica gel. Grain size: 5 / im, spherical, pore width, 60 nm; column length: 250 mm with an inside diameter of 4.6 mm; elution agent: n-hexane / tetrahydrofuran / methylene chloride / ethanol (90/10/1/1); elution 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

(S) -2-Ethoxy-4-N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl-benzoic acid ethyl ester

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 was added at room temperature 2.77 g (11 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and stirred until a solution is formed. 2.38 g (11.55 mmol) of N, N'-dicyclohexylcarbodiimide are then added and stirred at room temperature. After 24 hours, another 0.54 g (2.14 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.48 g (2.33 mmol) of N, N, cyclohexyl-carbodiimide were added and stirred overnight. It is then cooled to an internal temperature of +5 ° C and the separated precipitate is filtered off, washed once with 5 ml of toluene. The combined toluene filtrates were evaporated in vacuo to a volume of about 10 ml. The solution thus obtained is heated in a steam bath and petroleum ether (55 ml total) is added in portions until it is cloudy. Cool in ice, causing crystallization. It is filtered off and dried at 75 ° C / 5.3 mbar. The resulting product (4.57 g; mp 111-112 ° C; ee = 98.9%) was suspended in 50 ml of light petroleum. Heat in a steam bath and add as much toluene (8 ml in total) until a solution is formed. It was then cooled in ice and the crystallizate was dried, which was dried at 75 ° C / 5.3 mbar.

Yield: 3.93 g (74.3% of theory), mp: 117-118 ° C calc .: C 72.47 H 8.39 N 5.83 found: 72.44 8.43 5.93 [α] ² - + 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) of (S) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid was stirred. of acid (ee = 99.9%) in 37 ml of ethanol in a bath of 60 ° C and 10 ml (10 mmol) of sodium hydroxide is added. After stirring at 60 DEG C. for 4 hours, 10 ml (10 mmol) of 1 N hydrochloric acid were added in heat and allowed to cool to room temperature. After separation and condition overnight, cool for another 1 hour with stirring in ice. The crystallite was filtered off and washed twice with 5 ml of water each. It is then dried at 75 ° C to a final 100 ° C / 5.3 mbar in a vacuum oven over phosphorus pentoxide.

Yield: 3.13 g (87.7% of theory), mp .: 130-131 ° C (high melting point) calc .: C 71.64 H 8.02 N 6.19 found: 71.48 7.87 6.39

Μθ- + 7.45 ° (c = 1.06 in methanol)

The enantiomeric purity was determined by HPLC on a ChromTech HPLC column of ChromTech (Sweden) with an AGP (al-acid glycoprotein) phase; inside diameter: 4.0 mm; length: 100 mm; particle diameter: 5 μτη. Temperature: 20 ° C; elution agent: 0.1% aqueous solution of KH ₂ PO ₄ (= A) + 20% acetonitrile (= B), gradient rise in 4 minutes to 40% (B); elution rate: 1 ml / min; UV detection at 240 nm. Retention time (S) -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 ethanol / water sample (2/1) does not change the melting point.

By heating the sample in petroleum ether / toluene (5/3), filtration of the undissolved portion (mp .: 130-131 ° C) and rapid cooling of the filtrate, the title compound is obtained with a low

boiling point 99-101 ° C. Calc .: Found: C71.64 71,66 H, 8.02 7.97 N, 6.19 6.44 Shapes with low acreage and shape high melting points differ in their

infrared KBr spectra but not in its infrared solution spectra (methylene chloride).

If we heat the sample with a low melting point above its melting point, a second melting point is observed at 127-130 ° C.

Recrystallizing the sample from the low melting point and from ethanol / water (2/1) gives the high melting point.

High melting and low melting forms are examined using Differential Scanning Calorimetry (DSC) [Mettler apparatus, ΤΑ-300-system; measuring cell: DSC 20; Mettler, CH-8306 Greifensee, Switzerland] with the following result:

The compound of Example 3 Warm-up speed 10 ° K / Min. Warm-up speed 3 ° K / Min. Form with Single melting peak with melting point Single melting peak with melting point high temperature 133 ° C; smelters temperature 132 ° C; smelters melting point enthalpy: 100 J / g enthalpy: 99.1 J / g Form with 1. Peak at 57 ° C 1. Peak at 54 ° C low (very weak) (very weak; endotherm) melting point 2. Peak at 78 ° C (weak) 3. Endothermic Peak at 107 ° C; melting enthalpy: 55 J / y 4. Endothermic Peak at 132 ° C melting enthalpy: 25 J / y 2. endothermic Peak at 104 ° C, melting temperature 102 ° C, melting enthalpy 52 J / y 3. exothermic course of the baseline with crystallization at 104 ° C molten dreams

4th endothermic Peak at 131 ° C, melting point: 130 ° C melting enthalpy 52 J / g

EXAMPLE 4

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

0.79 g (1.65 mmol) ethyl (Z) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-buten-1-yl) -aminocarbonylmethyl] -benzoic acid from the soil. 124-127 ° C was dissolved in 10 ml of a degassed solvent mixture (methanol / methylene chloride = 5/1) under an argon atmosphere and added to a solution of 17 mg NOYORI catalyst Ru (O-acetyl) ₂ [(S) -BINAPj (prepared from [ Ru (COD) Cl ₂ ] _n with (S) -BINAP [= (S) -2,2'-bis- (diphenylphosphino) -1,26 binaphthyl], triethylamine and sodium acetate) and 3 mg of titanium tetraisopropylate in 10 ml of gaseous solvent mixture (methanol / methylene chloride = 5/1). The reaction mixture was placed in an autoclave evacuated at 10 ' ² mbar. Wash 5 times with hydrogen at 5 bar and then hydrate at 30 ° C and 100 bar until the end of the hydrogen uptake (154 hours). The brown red solution was evaporated in vacuo, the evaporation residue was dissolved in 80 ml of ether, filtered undissolved brown flakes using activated charcoal and the resulting clear light yellow filtrate was evaporated in vacuo. The evaporation residue (0.60 g) was boiled in 60 ml of N-hexane at reflux and filtered undissolved. The filtrate was allowed to stand overnight at room temperature. The separated crystals are filtered off.

Yield: 0.45 g (56.7% of theory),

Melting point: 131-133 ° C (after sintering above 120 ° C)

Enantiomeric purity: ee = 39% (S [HPLC method: see Example 1].

EXAMPLE 5

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

To a solution of 0.68 g (1.15 mmol) of (S) -2-hydroxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester mp: 125-126 ° C; [α] θ ^ = + 12.87 ° (c = 1.01 in methanol)] in 0.05 ml of anhydrous dimethylformamide was added 0.05 g (1.15 mmol) of sodium hydride / 55% in oil and stirred 0. 5 hours at room temperature. A solution of 0.12 ml (1.15 mmol) of ethyl iodide in 2.5 ml of anhydrous dimethylformamide is then added dropwise and stirred at room temperature for 5 hours. Evaporated in vacuo, partitioned between diluted sodium hydroxide and chloroform, the organic extract was dried, filtered and evaporated in vacuo. The evaporation residue was purified by silica gel column chromatography (toluene / ethyl acetate 10/1).

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

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

Prepared from (S) -2-hydroxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl-benzoic acid analogous to Example 5 with 2 equivalents of sodium hydride and 2 equivalents of ethyliodide.

Yield: 42% of theory, mp .: 110-112 ° C Calc .: 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

(S) (+) - 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) aminocarbonylmethyl-benzoic acid ethyl ester (R) (-) - 2 -Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid

920 mg of (±) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl-benzoic acid ethyl ester was separated in 10 mg individual doses at preparative HPLC -columns of Baker chiral phases in which (S) -N-3,5dinitrobenzoyl-leucine is covalently bound to an aminopropyl-silica gel. (Grain size: 40 / an; column length: 250 mm at an inner diameter of 20 mm; eluent: N-hexane / tetrahydrofuran / ethanol / methylene chloride (180/20/3/2); elution rate: 21.25 ml / min ; temperature: 27 ° C; UV detection at 285 nm), eluting first the (R) (-) - enantiomer (Peak 1) and then the (S) (+) enantiomer (Peak 2).

From properly cut and collected fractions, after evaporation under vacuum:

Peak fraction 1 (R): 423 mg (crude),

Peak fraction 2 (S): 325 mg (crude).

To separate the impurities (including, for example, the 2,6-di-tert.butyl-4-methylphenol stabilizer contained in tetrahydrofuran), both fractions were purified by column chromatography on silica gel (toluene / acetone = 10/1).

(R) (-) - Enantiomer:

Yield: 234.5 mg (51% of theory), mp .: 122-124 ° C (petroleum ether + acetone) calcd .: C 72.47 H 8.39 N 5.83 found: 72.40 8.18 5.71 [a] _D ² - -8.3 ° (c = 1 in methanol) (S) -enantiomer:

Yield: 131.2 mg (28.5% of theory), mp .: 122-124 ° C (petroleum ether / acetone = 8/1) calcd .: C 72.47 H 8.39 N 5.83 found: 72.28 8.44 5.70 [a] _D ² - + 8.3 ° (c = 1 in methanol)

The Chiralcel OD-column of Daicel is also suitable for the separation of enantiomers. On a column with a length of 250 mm and an inside diameter of 4.6 mm (eluant: absolute ethanol / (N-hexane + 0.2% diethylamine) = 5/95; temperature: 40 ° C; UV detection at 245 nm) elute The (R) -enantiomer after 6.8 minutes and the (S) -enantiomer after 8.5 minutes.

EXAMPLE 8 (R) (-) - 2-Ethoxy-4-N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] benzoic acid x 0.4 H _; Q

Prepared from 150 mg (0.312 mmol) of (R) (-) - 2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester [m.p. .: 122124 ° C;

[a] 20 = -8.3 ° (c = 1 in methanol)] by saponification with 1 N sodium hydroxide in ethanol analogous to Example 3.

Yield: 95.8 mg (66.7% of theory),

Tak: 103-105 ° C (toluene / petroleum ether) calcd: (x 0.4 H ₂ O); C 70.51 H 8.01 N 6.09 found: 70.88 7.79 5.81 molar peak M ⁺ : calc .: 452 found: 452 [α] 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

Prepared from 89 mg (0.198 mmol) of (S) (+) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester [m.p. .: 122124 ° C; [c% = + 8.3 ° (c = 1 in methanol)] by saponification with 1 N sodium hydroxide in ethanol analogous to Example 3.

Yield: 44.5 mg (48.8% of theory), mp: 102-103 ° C (toluene / petroleum ether) calc .: (x 0.4 H ₂ O) C 70.51 H 8.01 found. : 70.80 8.06 [a] ^ + 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- ('2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] benzoic acid

Hydrogenated 0.26 g (0.47 mmol) of (S) -2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid benzyl ester (m.p. .: 91-92 ° C;

[α] ^ θ = + 9.5 °; c = 1.05 in methanol) in 10 ml of ethanol per 0.12 g of palladium / charcoal (10%) at 50 ° C and 5 bars of hydrogen. After 5 hours, the catalyst was filtered off through Kieselgur and evaporated in vacuo. The evaporation residue was crystallized from ethanol / water (2/1). Yield: 0.15 g (70% of theory), mp 130-131 ° C calcd .:

found:

C 71.64 H 8.02 N 6.19 71.76 8.12 6.05

Enantiomeric purity: ee = 99.6% [HPLC method: see Example 3j.

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

102 mg (0.20 mmol) (S) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) 3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid tert-butyl ester (m.p. .: 122-123 ° C; [a] 2O = + 8.7 °; c = 1 in methanol) was refluxed in 5 ml of benzene for half a day, together with a few crystals of p-toluenesulfonic acid hydrate. Then, by thin layer chromatogram, the desired product is obtained by the value of R _p and the mass spectrum.

Mp: 129-131 ° C molar peak M ⁺ : calcd: 452 found: 452

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

200 mg (0.395 mmol) of (S) -2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3methyl-1-butyl) -aminocarbonylmethyl-benzoic acid tert-butyl ester (m.p .: 122- 123 ° C; [α] ^ θ = + 8.7 °; c = 1 in methanol) was stirred overnight at room temperature in 2 ml of methylene chloride together with 0.45 g (3.95 mmol) of trifluoroacetic acid. It is evaporated in vacuo and the evaporation residue is partitioned between aqueous sodium hydrogen carbonate and ethyl acetate. The organic extract was dried, filtered and evaporated in vacuo. The evaporation residue was crystallized from ethanol / water (2/1).

Yield: 115 mg (64.7% of theory), melting point: 126-128 ° C calc .: C 71.64 H 8.02 N 6.19 found: 71.39 7.91 6.06 [α ] 20 = + 6.97 ° (c = 0.975 in methanol)

Enantiomeric purity: ee = 99.8% [HPLC method: see Example 3].

EXAMPLE 13

0.25 mg tablets AG-EE 623 ZW

One table contains:

0.250 mg of the active substance

0.125 mg N-methylglucamine

0.038 mg of polyvinylpyrrolidone

0.075 mg polyoxyethylenepolyoxypropylene polymer

0.150 mg microcrystalline cellulose

Preparation:

The active substances and excipients are dissolved in water at 90 ° C or. the microcrystalline cellulose was suspended and the dispersion was evaporated in vacuo. The dry mass is sieved to a width of 1 mm.

The active ingredient granules are added to the tablet with the following ingredients:

24.862 mg sodium carboxymethyl starch

24,000 mg of microcrystalline cellulose 0,500 mg of magnesium stearate 50,000 mg

Compressed round planparallel tablets of 50 mg and 5 mm in diameter are squeezed from this mixture.

EXAMPLE

0.5 mg tablets AG-EE 623 ZW

Each tablet contains:

0.500 mg of the active substance

0.250 mg N-methylglucamine

0.075 mg of polyvinylpyrrolidone

0.150 mg polyoxyethylenepolyoxypropylene polymer

0.300 mg of microcrystalline cellulose

Preparation

The active substances and excipients are dissolved in water at 90 ° C or. the microcrystalline cellulose was suspended and the dispersion was evaporated in vacuo. The dry mass is sieved to a width of 1 mm.

The active ingredient granules are added to the tablet with the following ingredients:

24.225 mg sodium carboxymethyl starch

24,000 mg of microcrystalline cellulose

0.500 mg magnesium stearate

50,000 mg

Compressed round planparallel tablets of 50 mg and 5 mm in diameter are squeezed from this mixture.

EXAMPLE 15

1.0 mg tablets AG-EE 623 ZW

Each tablet contains:

1.00 mg of the active substance

0.50 mg N-methylglucamine

0.15 mg polyvinylpyrrolidone

0.03 mg polyoxyethylenepolyoxypropylene polymer

0.60 mg microcrystalline cellulose

Preparation:

The active substances and excipients are dissolved in water at 90 ° C or. the microcrystalline cellulose was suspended and the dispersion was evaporated in vacuo. The dry mass is sieved to a width of 1 mm.

The active ingredient granules are added to the tablet with the following ingredients:

23.22 mg sodium carboxymethyl starch

24.00 mg microcrystalline cellulose

0.50 mg magnesium stearate

50.00 mg

Compressed round planparallel tablets of 50 mg and 5 mm in diameter are squeezed from this mixture.

EXAMPLE 16

1.5 mg tablets AG-EE 623 ZW

Each tablet contains:

1,500 mg of active substance

0.750 mg N-methylglucamine

0.225 mg of polyvinylpyrrolidone

0.045 mg polyoxyethylenepolyoxypropylene polymer

0.900 mg microcrystalline cellulose

Preparation:

The active substances and excipients are dissolved in water at 90 ° C or. the microcrystalline cellulose was suspended and the dispersion was evaporated in vacuo. The dry mass is sieved to a width of 1 mm.

The active ingredient granules are added to the tablet with the following ingredients:

23,080 mg of sodium carboxymethyl starch

23,000 mg of microcrystalline cellulose

0.500 mg magnesium stearate

50,000 mg

From this mixture, a 50 mg, 5 mm round, parallel tablets were squeezed.

EXAMPLE 17

2.0 mg tablets AG-EE 623 ZW

Each tablet contains:

2.00 mg of the active substance

1.00 mg of L-lysine

1.00 mg of polyvinylpyrrolidone

1.00 mg polyoxyethylenepolyoxypropylene polymer

4.00 mg of microcrystalline cellulose

Preparation:

The ingredients are dissolved in water at 90 ° C or. the microcrystalline cellulose is suspended and the dispersion is processed in a spray dryer. The following ingredients are then added to the tablet:

20.35 mg microcrystalline cellulose

20.00 mg sodium carboxymethyl starch

0.65 mg of magnesium stearate

50.00 mg

Compressed round biconvex tablets of 50 mg and 5 mm in diameter are coated from this mixture and coated to cover the taste with hydroxypropylmethylcellulose.

EXAMPLE 18

2.5 mg tablets AG-EE 623 ZW

Each tablet contains:

2.50 mg of active substance

1.25 mg of L-lysine

1.25 mg of polyvinylpyrrolidone

1.25 mg polyoxyethylenepolyoxypropylene polymer

4.10 mg microcrystalline cellulose

Preparation:

The ingredients are dissolved in water at 90 ° C or. the microcrystalline cellulose is suspended and the dispersion is processed in a spray dryer. The following ingredients are then added to the tablet:

19.50 mg microcrystalline cellulose

19.50 mg sodium carboxymethyl starch

0.65 mg of magnesium stearate

50.00 mg

Round biconvex tablets of 50 mg and 5 mm in diameter are compressed from this mixture and coated with hydroxypropylmethylcellulose to cover the taste.

EXAMPLE 19

3.0 mg tablets AG-EE 623 ZW

Each tablet contains:

3.0 mg of the active substance

1.5 mg of L-lysine

1.5 mg of polyvinylpyrrolidone

1.5 mg polyoxyethylenepolyoxypropylene polymer

Preparation:

The ingredients were dissolved in 90 ° C water and the solution was processed in a spray dryer. The following ingredients are then added to the tablet:

21.5 mg microcrystalline cellulose

21.0 mg sodium carboxymethyl starch

50,0 mg

Round biconvex tablets of 50 mg and 5 mm in diameter are compressed from this mixture and coated with hydroxypropylmethylcellulose to cover the taste.

EXAMPLE 20

5 mg tablets AG-EE 623 ZW

Each tablet contains:

5.0 mg of the active substance

2.5 mg of L-lysine

2.5 mg of polyvinylpyrrolidone

2.5 mg polyoxyethylenepolyoxypropylene polymer

Preparation

The ingredients were dissolved in 90 ° C water and the solution was processed in a spray dryer. The following ingredients are then added to the tablet:

19.0 mg of microcrystalline cellulose

18.5 mg sodium carboxymethyl starch

50,0 mg

Round biconvex tablets of 50 mg and 5 mm in diameter are compressed from this mixture and coated with hydroxypropylmethylcellulose to cover the taste.

Claims (11)

PATENT APPLICATIONS 1. (S) (+) - 2-Ethoxy-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 substantially optically pure. A compound according to claim 2 having an optical purity of at least ee = 95%. A compound of claim 2 having an optical purity of at least ee = 98%. The physiologically acceptable salts of the compound of claims 1 to 4 with inorganic or organic acids or bases. A medicament comprising a compound of claims 1 to 4 or a physiologically acceptable salt of claim 5 in addition to one or more inert carriers and / or diluents. Use of a compound according to claims 1 to 4 or its physiologically tolerable salts according to claim 5 for the preparation of medicaments for the treatment of Diabetes mellitus. Method for the preparation of medicaments according to claim 6, characterized in that the compound according to claims 1 to 4 or the physiologically acceptable salt according to claim 5 is incorporated in one or more inert carriers and / or diluents in a non-chemical way. A process for the preparation of a new compound according to claims 1 to 5, characterized in that a) The (S) -amine of the formula is reacted with a carboxylic acid of the general formula HOOC-CH, (II) in which it represents W is a carboxy group or a protected residue protected with a carboxy group, or optionally in the reaction mixture prepared reaction-capable derivatives and if necessary then the protective residue used is cleaved off or b) cleave the (S) compound of the general formula in which it represents A by hydrolysis, thermolysis or hydrogenolysis into a carboxy group a translatable group, or c) an (S) compound of the general formula C «'C H CH Mr CO - CH 'OH, (IV) in which: The W 'carboxy group or alkoxycarbonyl group together with 2 to 5 carbon atoms, wherein the alkyl moiety of the alkoxy group may be substituted by a phenyl group, is reacted with a compound of the general formula Z - CH ₂ - CH ₃ (V) in which it represents With the nucleophilic interchangeable group or together with the adjacent hydrogen atom a diazo group, and if necessary then the compound thus obtained is hydrolyzed or hydrogenolized or d) a compound of the general formula (VI) in which it represents A W 'carboxy group or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl portion of the alkoxy group being substituted by a phenyl group, and A Y group of formula 'C / CH. CH / ^ CH. CH CH-C-NH-, CH CH ^ \ CH CH C - NH- or - C = Non-nantioselectively reduced and, if necessary, the resulting compound hydrolyzed or e) oxidize the (S) compound of the general formula CH ₃ CH ₃ in which it represents W 'for the oxidation to the carboxy group of a translatable group, or f) separate the mixture consisting of any amount of (S) -enantiomer of the general formula CH ₃ CH ₃ and any amount of (R) -enantiomer of the general formula ^C \ ^H 3 / ^CH 3 with (ix) in which The W 'carboxy group or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl moiety of the alkoxy group may be substituted by a phenyl group, and the compound thus obtained is recrystallized, if necessary, into a compound of higher enantiomeric purity, by crystallization from ethanol / water (2/1) is obtained in the form of high melting point 130 to 131 ° C and by crystallization from petroleum ether / toluene (5/3) the form with low melting point 99 to 101 ° C, and thus the resulting compound is converted into its salts, especially in its physiologically tolerable salts with 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, (111) V CH ₃ CH ₃ CH, (IV) und, (VII) in which they represent And by hydrolysis, thermolysis or hydrogenolysis into a carboxy group a translatable group, A W 'carboxy group or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl portion of the alkoxy group being substituted by a phenyl group, and W by the oxidation to the carboxy group of the translatable group, and their addition salts.