SK281246B6 - (s)(+)-2-ethoxy-4-(n-(1-(2-piperidino-phenyl)-3-methyl-1- -butyl)amino-carbonylmethyl) benzoic acid, pharmaceutical compositions containing thereof, intermediates for its preparation, and process for its preparation - Google Patents

Abstract

(S)(+)-2-ethoxy-4-(N-1- (2-piperidino-phenyl)- 3-methyl-1-butyl) aminocarbonylmethyl)- benzoic acid (I), and its salts, are new. The intermediate (S)-3-methyl-1- (2-piperdine-phenyl) -1-butylamine (II) and its amide intermediates of formulae (III), (IV) and (VII) are also new. E.g. (either R = Et and A = gp. which can be hydrolysed, thermolysed, hydrogenated or oxidised to carboxy; or R=H and A = carboxy or 1-4C alkyoxy - carbonyl (opt. alkyl substd. by phenyl).

Description

The invention relates to (S) (+) - 2-ethoxy-4- (N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) aminocarbonylmethyl) benzoic acid, pharmaceutical compositions containing the same, methods of its preparation. The invention also provides intermediates for its preparation as well as its use in the manufacture of a medicament for the treatment of diabetes mellitus.

BACKGROUND OF THE INVENTION

EP-B-0147850 discloses, inter alia, the 2-ethoxy-4- (N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) aminocarbonylmethyl) benzoic acid racemate (code no. : AG-EE 388 ZW)

OC ₂ H _S and EP-B-0207331 describes two different polymorphs of the compound. This compound and its physiologically acceptable salts have valuable pharmacological properties, in particular an effect on intermediate metabolism, but particularly a blood sugar lowering effect.

The two enantiomers of this compound, namely (S) (+) - 2-ethoxy-4- (N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl) benzoic acid (code no. : AG-EE 623 ZW) and (R) (-) - 2-ethoxy-4- (N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl) benzoic acid (code No. AG-EE 624 ZW) were tested in female rats for their blood sugar lowering activity.

Surprisingly, the (S) (+) enantiomer (AG-EE 623 ZW) has been found to be a potent enantiomer and lasts for more than 6 hours in rats.

Based on these findings in rats, it appears appropriate in humans to use exclusively AG-EE 623 ZW at a dose reduction of 50% compared to the AG-EE 388 ZW dose. This and also the relatively long period of activity was found in humans. In a human study, it was also found that AG-EE 623 ZW had surprising pharmacokinetic properties that could not be predicted from data on AG-EE 388 ZW. AG-EE 623 ZW then has surprising therapeutic advantages over the AG-EE 388 ZW racemate.

Surprising findings for people are:

(a) AG-EE 623 ZW levels decrease to zero faster than AG-EE 388 ZW levels, even if the dose is exactly the same, which could not be expected due to the long period of activity.

(b) Considering the blood sugar reduction achieved, AG-EE 623 ZW results in significantly lower plasma levels than would be expected when the dose of AG-EE 388 ZW was halved.

(c) Blood glucose lowering activity is apparent after administration of AG-EE 623 ZW rather than administration of AG-EE 388 ZW.

A surprising difference between the two enantiomers is that the active enantiomer, AG-EE 623 ZW, despite its relatively long potency, is surprisingly eliminated rather than the inactive enantiomer AG-EE 624 ZW, as shown in Figures 1 and 2. administration of the racemate is an ineffective enantiomer, therefore AG-EE 624 ZW is present not only as an unnecessary addition to plasma whose concentration is as high as that of the active enantiomer, AG-EE 623 ZW, but is present at unexpectedly high peak and long-term levels. The effect of this, i. j. when administered to a tablet containing 2 mg AG-EE 388 ZW or one tablet containing 1 mg AG-EE 623 ZW to twelve and six test subjects, the maximum concentrations were found to be 84 + 25 and 28 + + 18 ng / ml, concentrations after 4 hours. are 19 + 8 and 0.7 + + 1.0 ng / ml, after 5 hours are 13 + 6 and 0.3 + 0.7 ng / ml, and after six hours are 10 + 6 and 0.3 + 0, 7 ng / ml.

Surprisingly, the rapid onset of blood glucose lowering with AG-EE 623 ZW compared to AG-EE 388 ZW is particularly beneficial for diabetics, as rapid reduction results in optimal treatment of the disease.

Then, compared to the administration of AG-EE 388 ZW, the surprising advantage of administering AG-EE 623 ZW in that unnecessarily high and long-lasting levels of the substance in the body can be avoided, which is extremely important in long-term therapy of a disease such as diabetes mellitus.

Human studies have shown that the (S) -enantiomer, namely, (S) (+) - 2-ethoxy-4- (N- (1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmefyl) acid ) -benzoic, as a means of lowering blood sugar activity, is highly superior to AG-EE 388 ZW because of its surprisingly rapid elimination from the blood, which was unpredictable due to its relatively long duration of activity and these excellent properties far exceed the "normal" advantage of the enantiomer before its racemate, in particular the benefits in halving the dose.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides (S) (+) - 2-ethoxy-4- (N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl) benzoic acid or (S) ( +) - 2-ethoxy-4- (N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl) benzoic acid, which is substantially optically pure, m.p. j. it has an optical purity of at least ee = 95%, preferably 98 to 100%, its physiologically acceptable salts with inorganic or organic acids or bases, pharmaceutical compositions containing the compound or its physiologically acceptable salts, and methods for their preparation.

According to the invention, this novel compound can be obtained by the following methods:

a) reaction of (S) (+) - amine of formula (I)

(I) with a carboxylic acid of formula (II)

SK 281246 Β6

(II), where

W represents a carboxyl group or a carboxyl group protected by a protecting group, or with reactive derivatives thereof, optionally prepared in the reaction mixture and, if necessary, cleavage of the protecting group.

Reactive derivatives of a compound of formula (II) may be, for example, its esters such as methyl, ethyl or benzyl ester, their thioesters such as methylthio or ethylthioesters, their halides such as acid chloride, anhydrides or imidazoles thereof.

The reaction may conveniently be carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a dehydrating agent, for example in the presence of ethyl chloroformate, isobutyl chloroformate, phosphorus trichloride, phosphorus pentoxide, Ν, Ν'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or Ν, Ν'-thionyldiimidazole, or triphenylphosphine / carbon tetrachloride, or reagents which phosphorus pentachloride, 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 simultaneously serve as solvents, at temperatures between -25 and 250 ° C, preferably at temperatures between -10 ° C and the boiling point of the solvent used Stade. The reaction can also be carried out without a solvent, and in addition, any water formed in the reaction can be removed by azeotropic distillation, i. j. by heating with toluene using an aqueous separator or by adding a desiccant such as magnesium sulfate or molecular sieve.

If necessary, the subsequent cleavage of the protecting group may preferably be carried out by hydrolysis, suitably 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 or potassium hydroxide in a suitable solvent. such as water, methanol, methanol / water, ethanol, ethanol / water, water / isopropanol or water / dioxane at temperatures of -10 to 120 ° C, m.p. j. temperatures between room temperature and the boiling point of the reaction mixture.

The tertiary butyl group used as a protecting group may also be attached thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid, preferably in the presence of a strong acid such as trifluoroacetic acid, hydrobromic, p- toluenesulfonic, sulfuric, phosphoric or polyphosphoric.

In addition, the benzyl group as a protecting group may also be attached hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / activated carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

b) Attaching (S) (+) - a compound of formula (III)

where

A represents a group which can be converted to a carboxy group by hydrolysis, thermolysis or hydrogenolysis. Examples of hydrolyzable groups include functional groups of carboxy group derivatives such as unsubstituted or substituted amides esters, thioesters, orthoesters, iminoethers, amidines, or anhydrides thereof, nitrile, tetrazolyl, optionally substituted with 1,3-oxazol-2-yl or 1, 3-oxazolin-2-yl and examples of thermolytically attachable groups include esters with tertiary alcohols, i. j. the tertiary butyl ester and examples of hydrogen-attachable groups include aralkyl groups such as a benzyl group.

The hydrolysis may conveniently 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 or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / ethanol , water / isopropanol or water / dioxane at temperatures between -10 to 120 ° C, for example between room temperature and the boiling point of the reaction mixture.

If A in the compound of formula (III) is a nitrile or aminocarbonyl group, then these groups can be converted to the carboxyl group by means of 100% phosphoric acid at temperatures between 100 to 180 ° C, preferably at 120 to 160 ° C, or using a nitrite, for example sodium nitrite, in the presence of an acid such as sulfuric acid, wherein the sulfuric acid can be conveniently used simultaneously as a solvent at temperatures between 0 to 50 ° C.

When A in the compound of formula (III) is ter. butyloxy carbonyl group, for example tert-butyl group, can also be attached thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrhydrofuran, dioxane, glacial acetic acid, preferably in the presence of a strong acid such as trifluoroacetic acid, hydrobromic acid , p-toluenesulfonic, sulfuric, phosphoric 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 the compound of formula (III) is a benzyloxycarbonyl group, for example a benzyl group, it can also be hydrogenated in the presence of a hydrogenation catalyst such as palladium / activated carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, acetate acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50, e.g. at room temperature under a hydrogen pressure of ⁵ 1.I0 to 5.10 Pa ^s.

c) Reaction of (S) (+) - a compound of formula

SK 281246 Β6

where

W 'represents a carboxyl group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl part of the alkoxy group may be replaced by a phenyl group.

With a compound of formula

Z-CH ₂ -CH ₃ (V) wherein

Z represents a nucleophilically exchangeable group such as a halogen atom, a sulfonyloxy group or, together with an adjacent hydrogen atom, a diazo group optionally followed by hydrolysis or hydrogenation.

The reaction is suitably carried out with the corresponding halide, sulfonic acid ester or sulfuric acid diester, for example with ethyl bromide, ethyl iodide, diethyl sulfate, ethyl p-toluenesulfonate or ethyl methanesulfonate, or with diazoethane, optionally in the presence of a base such as sodium, potassium, potassium tert-butoxide or triethylamine, preferably in a suitable solvent such as acetone, diethyl ether, tetrahydrofuran, dioxane, pyridine or dimethylformamide at temperatures between 0 to 100 ° C, preferably at temperatures between 20 to 50 ° C.

When W 'is a carboxyl group in the compound of formula (IV), it can be converted to the corresponding ester compound.

If necessary, the 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 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 to 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture, or subsequent hydrogenation in the presence of a hydrogenation catalyst such as palladium / activated carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide under a hydrogen pressure from 1.10 ⁵ to 1.10 ⁶ Pa.

d) Enantioselective reduction of a compound of formula

where

W 'represents a carboxyl or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl part of the alkoxy group may be replaced by a phenyl group, and

Y represents one of the groups of the formula

R-C-NH-,

and subsequent optional hydrolysis.

The reduction is preferably performed with hydrogen in the presence of a suitable chiral hydrogenation catalyst in the presence of a suitable solvent such as methanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran, methanol / tetrahydrofuran, methanol / methylene chloride, ethanol / methylene chloride or isopropanol / methylene chloride to 100 ° C, preferably at temperatures between 20 and 50 ° C at a hydrogen pressure of between 1 and 1000 bar, preferably between 5 and 100 bar and preferably with an addition of 0.1 to 5% by weight, preferably of 0.3 % to 1 wt. titanium tetraisopropoxide, preferably with the exclusion of oxygen from the air. The reduction can advantageously be carried out with the (Z) form of the compound of formula (VI).

Examples of chiral hydrogenation catalysts are the corresponding metal ligand complexes such as Ru (OCO-CH ₃ ) ₂ [(S) -BINAP], Ru ₂ C ₄ [(S) -BINAP] ₂ x N (C ₂ H ₅ ) ₃ , Rh [(S) -BINAP-NBD] CLO ₄ or Rh [(-) - NORPHOS-COD] BF ₄ .

During catalytic hydrogenation, the benzyloxycarbonyl group can be simultaneously reduced and converted to a carboxyl group.

If necessary, the 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 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, for example at temperatures between room temperature and the boiling point of the reaction mixture.

e) Oxidation of (S) (+) - a compound of formula ch, CH 'X /

where

W represents a group that can be converted by oxidation to a carboxyl group.

An example of an oxidizable group of this kind may be formyl and its acetals, hydroxymethyl and its ethers, unsubstituted or substituted acyl, such as acetyl, chloroacetyl, propionyl, (1) -malonyl or (1) -yl malonyl ester.

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 to 100 ° C, but preferably at temperatures between 20 to 50 ° C. However, this reaction preferably takes place in a solution of silver and sodium hydroxide, manganese dioxide and acetone or methylene chloride, a solution of hydrogen peroxide and sodium hydroxide, a solution of bromine or bro4.

286 mines with sodium or potassium hydroxide solution, chromium trioxide and pyridine or pyridine chlorochromate.

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

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

where

W 'represents a carboxyl group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl part of the alkoxy group may be replaced by a phenyl group, preferably a 50/50 mixture, via diastereomeric adducts, complexes or salts thereof and subsequent hydrolysis or hydrogenation.

Separation is preferably performed using column or HPL chromatography by formation of diastereomeric adducts or complexes on the chiral phase.

If necessary, the 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 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 to 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture, or subsequent hydrogenation is carried out in the presence of a hydrogenation catalyst such as palladium / animal coal 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 ⁵ bar.

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

The same procedure can be applied according to the invention to the (S) (+) - compounds of formulas (III), (IV) and (VII), and in particular to their esters.

The (S) (+) - enantiomer thus obtained according to the invention can be converted into its salts especially for pharmaceutical use into its physiologically acceptable salts with inorganic or organic acids or bases. Examples of these acids include hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acids, and examples of bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, ethylenediamine, triethylamine, triethylamine, triethylamine, triethylamine, triethylamine.

The compounds of formulas (I) to (IX) used as starting materials are in some cases known from the literature or can be prepared by known methods.

The (S) (+) - amine of formula (I) can be obtained from the corresponding racemic amine by racemate resolution, for example, by fractional crystallization of diastereomeric salts with suitable optically active acids, preferably N-acetyl-L-glutamic acid and, if necessary, recrystallization followed by recrystallization by salt decomposition, column or HPL chromatography of the chiral phases, optionally in the form of an acyl derivative, or by formation of diasteromeric compounds, their separation and their subsequent resolution.

In addition, the (S) (+) - amine of formula (I) may be prepared by enantioselective reduction using hydrogen in the presence of suitable chiral hydrogenation catalysts, starting from the corresponding N-acyl-ketimine or enamide, suitably with an addition of 0.1 to 5 wt. titanium isopropoxide, optionally followed by cleavage of the acyl group, such as a formyl or acetyl group, by diastereoselective reduction of the corresponding ketimine or hydrazine chirally substituted on a nitrogen atom using hydrogen in the presence of a suitable hydrogenation catalyst, preferably with an addition of 0.1 to 5%. titanium isopropoxide and optionally subsequent cleavage of a chiral auxiliary, for example a (SX +) - 1-phenethyl group by catalytic hydrogenation, or by diastereoselective addition of the corresponding organometallic compound, preferably a Grignard or lithium compound to the corresponding aldimine-optionally substituted chiral-substituted amide; 10 wt. titanium isopropoxide, followed by hydrolysis and optionally separation of the resulting diastereomers and subsequent cleavage of a chiral auxiliary, for example a (R) -phenethyl group by catalytic hydrogenation, if necessary (S) (+ O-amine can be obtained in higher enantiomeric purity by salt formation using a suitable optically active acid, preferably with N-acetyl-L-glutamic acid, and if necessary by simple or multiple recrystallization and subsequent salt decomposition.

The compounds of formula (III), (IV) and (VII) used as starting material are obtained by reacting (S) (+) - amine with the appropriate carboxylic acid or a reactive derivative thereof and optionally cleaving each protecting group used.

The compound of formula (VI) used as the starting material is obtained by acylating the corresponding imino compound or its organometallic complexes with the appropriate carboxylic acid or reactive derivatives thereof, optionally followed by cleavage of the ester group.

The (S) (+) enantiomer is indeed non-toxic, for example after a single administration of 1000 mg / kg p. about. (suspension in 1% methylcellulose) 5 male rats and 5 female rats did not die during the observation period of 14 days.

Owing to its pharmacological and pharmacokinetic properties, the (S) (+) enantiomer prepared according to the invention (AG-EE 623 ZW) and its physiologically acceptable salts are suitable for the treatment of diabetes mellitus. To this end, AG-EE 623 ZW or its physiologically acceptable salts, optionally in combination with other active substances, may be

Included in conventional galenical preparations such as simple or coated tablets, capsules, powders, suppositories, suspensions or injectable solutions. A single dose for an adult 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 mg, once, twice or three times a day.

The present invention further relates to the (S) (+) - amine of formula (I), which is a valuable intermediate for the preparation of the (S) (+) - enantiomer and its addition salts with inorganic or organic acids.

The present invention also relates to compounds of formulas (III), (IV) and (VII), which are valuable intermediates for the preparation of the (S) (+) - enantiomer and its addition salts with inorganic or organic acids.

The examples that follow are intended to illustrate the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph illustrating plasma concentrations of AG-EE 623 ZW and AG-EE 624 ZW following administration of 1.0 mg i. in. AG-EE 388 ZW to male volunteers (n = 12).

Figure 2 is a graph illustrating plasma concentrations of AG-EE 623 ZW and AG-EE 624 ZW following administration of 1.0 mg p. about. (solution) AG-EE 388 ZW to volunteer male test subjects (n = 12).

DETAILED DESCRIPTION OF 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 mixed with 93.7 g (0.495 mol) of N-acetyl-L-glutamic acid with stirring. . The mixture was refluxed on a water bath and methanol (about 80 mL total) was added in portions until a clear solution was obtained. After cooling and standing overnight at room temperature, the crystals obtained are collected by suction, washed twice with 200 ml of cold acetone at -15 DEG C. and dried. The product obtained (98.9 g, melting point: 163 DEG -166 DEG C.; [.alpha.] _D @ ²⁰ = + 0.286 DEG (c = 1 in methanol) is recrystallized from 1000 ml of acetone with 200 ml of methanol to give (S). -1- (2-piperidino-phenyl) -3-methyl-1-butylamine as N-acetyl-L-glutamic acid addition salt Yield: 65.1 g (60.4% of theory); 171 DEG C. Calculated: C63,42 H 8.56 N 9.65 Found: 63.64 8.86 9.60 [?] ^_D20 = + 0.357 ° (c = 1 in methanol)

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

(Sj-Amine configuration was demonstrated as follows:

Reaction of the amine with (S ') -1-phenethylisocyanate in ether to give the corresponding urea derivative (melting point: 183-184 ° C; [.alpha.] _D @ ²⁰ = -2.25 DEG (c = 1 in methanol); crystal growth from a mixture of ethanol and water (8/1) followed by X-ray. structural analysis showed the (S, S ') - configuration of the urea derivative followed by the (S) - configuration of the amine used.

The enantiomeric purity was determined as follows:

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

2. Determination of N-acetyl derivative (melting point: 128-132 ° C) by HPLC on a chiral phase HPLC column manufactured by Baker, in which (S) -N- (3,5-dinitrobenzoyl) -2-phenyl-glycine is covalently bound for aminopropyl silica gel (particle size 5 µm, spherical particles, pore size 60A, column length: 250 mm with an inner diameter of 4.6 mm, eluent: n-hexane / isopropanol (1000/5), flow rate: 2 ml / minute , temperature: 20 ° C, UV detection at 254 nm.)

Found: peak 1 (R): peak 2 (S) = 0.75%: 99.25%, ee (enantiomeric excess) = 98.5% (S). (S) -Amin can be converted to its dihydrochloride hydrate using ethereal hydrogen chloride solution. Melting point: 135-145 ° C Calculated (x II ₂ O): C 56.99 H 8.97 N 8.31 Cl 21.02 Found: 56.85 8.93 8.38 21.25 [δ ^{20 =} + 26, Γ (c = 1 in methanol)

Example B

N-Acetyl-N- [1- (2-piperidino-phenyl) -3-methyl-1-buten-1-ynyl] -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 4.7 ml (81.8 mmol) of glacial acetic acid, 25.7 g at normal temperature. (98.2 mmol) triphenylphosphine, 34.2 mL (245 mmol) triethylamine and 7.9 mL (81.8 mmol) carbon tetrachloride and the resulting mixture was stirred at room temperature for 18 h. It was then evaporated in vacuo and partitioned between ethyl acetate and water. The organic extract was dried, filtered and evaporated in vacuo. The residue after drying was purified by silica gel column chromatography (toluene / ethyl acetate = 10/1), eluting first with (E) -form and then with (Z) -form.

Yield: 6.1 g (26% of theory) Melting point: 135 DEG-137 DEG 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) Melting point: 140 DEG-143 DEG C. (ethyl acetate). Calculated: 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-buten-1-ynyl] -amine (0.18 mol) acetic anhydride was added dropwise at an internal temperature of 0 ° C, to a stirred solution was added 44 g (0.18 mol) of freshly prepared isobutyl- (2-piperidino-phenyl) -ketimine in 440 mL of toluene. The mixture was stirred for an additional 3 hours at 0 ° C and 15 hours at room temperature, then evaporated in vacuo, the residue was dissolved in ethyl acetate and extracted several times.

286 aqueous sodium bicarbonate solution. The organic phase was dried, filtered and evaporated in vacuo. The evaporated residue was purified by silica gel column chromatography (toluene / ethyl acetate = 5/1), eluting first with (E) -form and then with (Z) -form.

(E) -form:

Yield: 3.0 g (5.8% of theoretical) (Z) -form:

Yield: 17.8 g (34.5% of theory) Melting point: 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) -l- (2-piperidino-phenyl) -3-methyl-butyl] -amine

0.57 g (1.99 mol) of (Z) -N-acetyl-N- [1- (2-piperidino-phenyl) -3-methyl-1-buten-1-yl] -amine, m.p. 141 ° C was dissolved in 10 ml of argon degassed solvent mixture (methanol / methylene chloride = 5/1) and added to a solution of 16.8 mg (1 mol%) of NOYORI catalyst RU (O-acetyl) ₂ [(S) -BINAP] (prepared from [Ru (COD) C1 _2] "with (s) -BINAP [= (s) -2,2'-bis (diphenylphosphino) -l ' binaphthyl], triethylamine and sodium acetate). and 3.4 g (0.5 mol) of titanium (IV) isopropoxide in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1). The mixture was placed in an autoclave which was evacuated to 10 ^"2 mbar. It was purged several times with hydrogen at 4 bar and then the mixture was hydrogenated at 30 ° C at 100 bar until hydrogen uptake was complete (170 hours). The red-brown solution was then evaporated in vacuo, the evaporated residue was re-refluxed with 30 ml of n-hexane and filtered hot to remove insoluble water. Crystallization occurred upon cooling of the filtrate.

Yield: 0.31 g (54% of theory) Melting point: 127-131 ° C enantiomeric purity: ee = 82% (S) [HPLC method: see Example I].

154 DEG-156 DEG C. is obtained from the insoluble material obtained by boiling with 30 ml of n-hexane, further boiling with n-hexane, filtering and crystallizing from a hexane solution.

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

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

0.83 g (84.7% of theory) of N-acetyl-N - [(S) -1- (2-piperidino-phenyl) -3-methyl-1-butyl] -amine (melting point: 130-132) ° C, ee = 99.4%) was obtained by reacetylation with 0.42 mL (1.3 equivalents) of acetic anhydride in 8.4 mL of glacial acetic acid overnight at room temperature, evaporation in vacuo, partitioning the evaporation residue between ethyl acetate. and a saturated aqueous sodium bicarbonate solution, filtering and evaporating the organic extract in vacuo.

Example F

Ethyl 2-ethoxy-4- [N-1- (2-piperidino-phenyl) -3-methyl-1-buten-1-yl) -aminocarbonylmethyl] -benzoate

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

(E) -form:

Yield: 4% of theory Melting point: 101-103 ° C Calculated: C 72.77 H 8.00 N 5.85 Found: 72.74 7.78 5.86 (Z) -form:

Yield: 21.1% of theory. Melting point: 124-127 ° C (petroleum ether / toluene = 5/1) Calcd: C 72.77 H 8.00 N 5.85 Found: 72.90 7.86 5.83

Example G

N - [(S ') -1-Phenethyl] -N - [(S) -1- (2-piperidino-phenyl) -3-methyl-1-butyl] -amine g (49 mmol) N - [(S) 1-) - 1- (2-phenethyl] -isobutyl- (2-piperidino-phenyl) -ketimine, boiling point 150-155 ° C / at 40 Pa [prepared from isobutyl- (2-piperidino-phenyl) -ketone and ( S ') - 1-fetenylamine (product Fluka, ee = 99.6%) in toluene + triethylamine by dropwise addition of a solution of titanium tetrachloride in toluene] was dissolved in 170 ml of anhydrous ethanol and 1.7 g of titanium isopropoxide added. and 8 g of Raney nickel and the mixture is hydrogenated at 50 ° C and 200 bar of hydrogen After 20 hours an additional 8 g of Raney nickel is added and the mixture is hydrogenated for an additional 52 hours under the same conditions. -mess and the filtrate was evaporated in vacuo.

Yield: 13.1 g (76.6% of theory) Melting point: 152 DEG C./0.7 mbar

calculated; C 82.23 H 9.78 N 7.99 Found: 82.00 10.03 7.74 [] _d ²⁰ = - 55.3 ° (c = 1.1 in methanol)

Diastereomeric purity was determined by HPLC on a Lichrosorb RP18 column, manufactured by E. Merck (Germany), column length: 250 mm with an inner diameter of 4 mm, particle size: 7 µm. Eluant: 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 (diastereomeric excess) = 97.0% (S, S ').

Example H (S) -1- (2-Piperidinophenyl) -3-methyl-1-butylamine

12.5 g (36 mmol) of N - [(S ') - 1-phenethyl] -N - [(S) -1- (2-piperidinophenyl) -3-methyl-1-butyl] -amine with g. = 97.0% (S, S ') is dissolved in 125 ml of water and 3.6 ml of concentrated hydrochloric acid. 1.3 g (10%) of palladium / activated carbon are added to the mixture and the mixture is hydrogenated at 50 ° C and

5.10 ^with hydrogen Pa. After the uptake of hydrogen (10 hours), the mixture was filtered through a pad of celite to remove the catalyst.

SK 281246 Β6

The filtrate was basified with concentrated ammonia with ice and extracted with ethylacetate. The organic extract was dried, filtered and evaporated in vacuo.

Yield: 6.7 g (72.1% of theory) Boiling point: 115 DEG-117 DEG C./53 mm Hg

Enantiomeric purity: ee = 93.5% (S) [HPLC method (according to previous acetylation): see Example A].

Example I

N - [(R ') -1-Phenethyl] -N - [(S) -1- (2-piperidino-phenyl) -3-methyl-1-butyl] -amine

A solution of 2 g (6.84 mol) of N - [(R ') -1-phenethyl] - (2-piperidino-benzaldimine) [prepared from equimolar amounts of 2-piperidino-benzaldehyde and (R') -1-phenethylamine by standing through overnight followed by drying with ethereal sodium sulfate] in 20 mL of anhydrous tetrahydrofuran was added dropwise to a solution of 27.4 mmol (4 equivalents) of isobutyl magnesium bromide in 22 mL of anhydrous tetrahydrofuran, which was stirred in a bath at 60 ° C. After 18 hours, the bath temperature was raised to 80 ° C and an additional 2 equivalents of isobutyl magnesium bromide in 11 mL of tetrahydrofuran were added. After stirring at 80 ° C for 12 hours, 2 equivalents of isobutyl magnesium bromide solution are added again. After approximately 90 hours at 80 ° C, the mixture is cooled, excess concentrated hydrochloric acid is added and the resulting mixture is evaporated to dryness by means of a water pump. The evaporation residue was dissolved in water and basified with concentrated ammonia. Extract with ether, dry the organic extract over sodium sulfate, filter and concentrate in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 95/5).

Yield: 0.20 g (8.3% of theory) Melting point: <20 ° C

Diastereomeric purity was determined by HPLC as in Example G.

Found: peak 1 (R, R '): peak 2 (S, R') = 4.4%: 95.6%, de (diasteromeric excess) = 91.2% (S, R ').

In an analogous mixture with 2.0 g of Schiff's base and a total of 6 equivalents of isobutyl magnesium bromide in toluene / tetrahydrofuran solution (4/1) and the addition of 5% titanium isopropoxide heated at 100 ° C for 60 hours in a glass vessel yielded a 5% yield. de = 97.6% (S, R &apos;).

Example K (S) -1- (2-Piperidinophenyl) -3-methyl-1-butylamine

A solution of 0.15 g (0.428 mmol) of N - [(R ') -1-phenethyl] -N - [(S) -1- (2-piperidino-phenyl) -3-methyl-1-butyl] -amide ( dn = - 91.2%) and 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 / activated carbon catalyst for 5 hours at 3.4 pressure bars of hydrogen. The mixture was filtered through diatomite, made alkaline with ammonia and extracted with ethylacetate. 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 (according to previous acetylation): see Example A].

Example 1

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

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 trictanolamine and 0.18 ml (1.91 mmol) of carbon tetrachloride is gradually added to a solution of 0.7 g (1.91 mmol) of (S) -3-methyl-1- (2-piperidinophenyl) -1-butylamine (en = 98, 5%) in 5 ml of anhydrous acetonitrile and the resulting mixture was 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, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel / toluene / ethyl acetate = 10/1). Yield: 0.71 g (77.3% of theory) Melting point: 110 to 112 ° C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.29 8.42 5.80

Enantiomeric purity was determined by Baker chiral phase HPLC, in which (S) -N-3,5-dinitrobenzoyl-leucine is covalently bound to a silica aminopropyl gel (particle size: 5 nm, spherical particles, 60 A pore size; column length 250 mm with 4.6 mm ID; eluant: 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

2.77 g (11 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid is added at room temperature to a solution of 2.71 g (11 mmol) of anhydrous (S) -3-methyl-1- (2-piperidinophenyl) 1-butylamine (ee = 98.5%) in 30 ml of absolute toluene and the mixture is stirred until dissolved. 2.38 g (11.55 mmol) of Ν, Ν-dicyclohexylcarbodiimide are then added and the mixture is stirred at room temperature. After 24 hours an additional 0.54 g (2.14 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.48 g (2.33 mmol) of N, N'-dicyclohexylcarbodiimide were added and the mixture was stirred overnight . It is then cooled to an internal temperature of +5 ° C and suction filtered to remove the precipitate which is washed once with 5 ml of toluene. The combined toluene filtrates were evaporated in vacuo to a volume of approximately 10 ml. The resulting solution was heated in a steam bath and petroleum ether (55 mL total) was added in portions until turbidity remained. It is then cooled in ice, whereupon crystallization occurs. The product is suction filtered and dried at 75 ° C / 4 torr. The product obtained (4.57 g; mp 111-112 ° C; ee = 98.9%) is suspended in 50 ml of petroleum ether. The mixture was heated on a steam bath and sufficient toluene (8 mL total) was added in portions until a solution was formed. This was cooled with ice and the crystals were suction filtered and dried at 75 ° C / 4 torr.

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

Calculated: C 72.47 H 8.39 N 5.83 Found: 72.44 8.43 5.93 [+ 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-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoyl acid

SK 281246 Β6

A solution of 3.79 g (7.88 mmol) of ethyl (S) -2-ethoxy-4- [N1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] -benzoate (ee = 99) (9%) in 37 ml of ethanol is stirred in a bath at 60 ° C with the addition of 10 ml (10 mmol) of 1N sodium hydroxide solution. After stirring at 60 ° C for 4 hours, 10 ml (10 mmol) of 1 N hydrochloric acid are added warmly and the mixture is allowed to cool to ambient temperature. After seeding and standing overnight, the mixture was further cooled in ice for 1 hour with stirring. The crystals were collected by suction filtration and washed twice with 5 ml of water. They are then dried at 75 ° C to a final temperature of 100 ° C / 4 torr in a vacuum drier over phosphorus pentoxide.

Yield: 3.13 g (87.7% of theory) Melting point: 130-131 ° C (high temperature modification) Calculated: C 71.64 H 8.02 N 6.19 Found: 71.48 7.87 6, [.Alpha.] _D @ ²⁰ = + 7.45 DEG (c = 1.06 in methanol)

Enantiomeric purity was determined by HPLC on a chiral phase HPLC column manufactured by ChromTech (Sweden) with AGP (1-glycoproteinic acid) phase; inside diameter: 4.0 mm; length: 100 mm; particle size: 5 µm. Temperature: 20 ° C; eluent: 0.1% aqueous KH ₂ PO ₄ (= A) + 20% acetonitrile (= B). Gradient increase over 4 minutes to 40% (B); flow rate: 1 mL / min; UV detection at 240 nm. Retention time of the (S) -enantiomer: 2.7 minutes; retention time of the (R) -enantiomer: 4.1 minutes.

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

When the sample is recrystallized from water-ethanol (2/1), its melting point does not change. When the sample is heated in a mixture of petroleum ether and toluene (5/3), the insoluble portion is filtered off (melting point: 130-131 ° C) and the filtrate is cooled rapidly to give a low temperature modification of the title compound with a melting point of 99-101 ° C. H, 8.02; N, 6.19. Found: 71.66, 7.97, 6.44

The low temperature and high temperature forms differ in their infrared spectra in KBr, but not in their infrared spectra in solution (methylene chloride).

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

If a sample of the low temperature form is recrystallized from a mixture of ethanol and water (2/1), a high temperature form is obtained.

The high temperature form and the low temperature form were studied by differential scanning calorimetry (DSC) [Mettler instrument, TA-3000; measuring cell: DSC 20; manufacturer Mettler, CH-8380 Greifensee, Switzerland] and the following results were obtained:

Compound of Example 3 10K / rrin heating rate. Response rate 3 KMn.

High temperature form Uniform melting peak e, melting point 133 ° C; entalpla melting 100 µg Uniform pk melting at 132 ° C; enthalpy of melting 99.1 J / g Low temperature refraction 1.plk at ST Xívehri weak) 2nd plk at 78 X (weak) 3. endothermic peak at 10 7 X: enthalpy of melting: 55 µl 4. Endothermic plk at 132 X; melting enthalpy: 25 J / p 1st peak at 54 C (very weak endotorm) 2. endothermic peak at 104 C. mp 102 ° C. melting enthalpy: 55 J / q (3) the endotophic trace of the baseline in cryptation of toptoce] at 104 ° C 4. endothecmic peak at 131 Ό, melting point 130 C melting enthalpy 62 J / g

Example 4

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

0.79 g (1.66 mmol) of ethyl (Z) -2-ethoxy-4- [N1- (2-piperidinophenyl) -3-methyl-1-buten-1-yl) aminocarbonylmethyl] - the benzoate, m.p. 124-127 ° C, is dissolved in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1) under argon and added to a solution of 17 mg NOYORI Ru (O-acetyl) ₂ [(S) - BINAP] (prepared from [Ru (COD) Cl ₂ ] _n with (S) -BINAP [= (S) -2,2-bis- (diphenylphosphino) -1,1'-binaphthyl], triethanolamine and sodium acetate) and 3 mg of titanium isopropoxide in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1). The mixture was placed in an autoclave evacuated to 10 ^"2 mbar. The mixture was purged 5 times with hydrogen at 5.10 ⁵ Pa and finally hydrogenated at 30 ° C and 100.10 ⁵ Pa until hydrogen uptake ceased (154 hours). The red-brown solution is evaporated in vacuo, the residue is dissolved in 80 ml of ether, filtered from undissolved brown flakes with activated carbon and the resulting clear, bright yellow filtrate is evaporated in vacuo. The evaporation residue (0.60 g) was refluxed in 60 mL of n-hexane and filtered hot to separate from the insoluble material. The filtrate is allowed to stand overnight at room temperature. The precipitated crystals are filtered off. Yield: 0.45 g (56.7% of theory) Melting point: 131-133 ° C (after sintering at 120 ° C) Enantiomeric purity: ee = 39% (S) HPLC method: see Example 1],

EXAMPLE 5 _t i

Ethyl (S) -2-ethoxy-4- [N-1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] -benzoate;

/

0.05 g (1.15 mmol) of 55% sodium hydride in oil is added 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 [m.p. 125-126 ° C; [.alpha.] _D @ ²⁰ = + 12.87 DEG (c = 1.01 in methanol)] in 5 ml of anhydrous dimethylformamide and the mixture is stirred for 0.5 hour. at ordinary temperature. A solution of 0.12 ml (1.15 mmol) of ethyl iodide in 2.5 ml of anhydrous dimethylformamide was added dropwise and the mixture was stirred at room temperature for 5 hours. Evaporate in vacuo and partition the residue between dilute sodium hydroxide solution and chloroform, dry the organic extract, filter and evaporate 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

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

Prepared from (S) -2-ethoxy-4- [N 1 - (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid analogously to Example 5 using 2 equivalents of sodium hydride and 2 equivalents ethyl iodide.

Yield: 42% of theory

Melting point: 110 to 112 ° C Calculated: C 72.47 H 8.39 N 5.83 Found: 72.61 8.54 5.99

Enantiomeric purity: ee = 98.3% (S) [HPLC method: see Example 1].

Example 7

Ethyl (S) -2-ethoxy-4- [N-1- (2-piperidinophenyl) -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- [N1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate are separated in portions of 10 mg each on a preparative chiral phase column for HPLC fy. Baker in which (S) -N-3,5-dinitrobenzoyl-leucine is covalently bound to a silica aminopropyl gel (particle size: 40 nm, column length 250 mm with an inner diameter of 20 mm; eluent: n-hexane / tetrahydrofuran / ethanol / methylene chloride (180/20/3/2); flow rate: 21.25 ml / min; temperature: 27 ° C; UV detection at 285 nm) at which the (R) (-) enantiomer ( peak 1) and then the (S) (+) enantiomer (peak 2). Evaporation in vacuo gave the following results based on the collected and collected fractions:

Peak 1 fraction (R): 423 mg (coarse) Peak 2 fraction (S): 325 mg (coarse)

To remove impurities (including the 2,6-di-tert-butyl-4-methylphenol stabilizer present in tetrahydrofuran), each of the two fractions was purified by silica gel column chromatography (toluene / acetone = 10/1).

(R) (-) - Enantiomer:

Yield: 234.53 g (51% of theory) Melting point: 122 to 124 ° C (petroleum ether + acetone) Calculated: C 72.47 H 8.39 N 5.83 Found: 72.40 8.18 5.71 [.alpha.] D @ ^{20 =} -8.3 DEG (c = 1 in methanol) (S) -Enantiomer:

Yield: 131.2 g (28.5% of theory) Melting point: 122 to 124 ° C (petroleum ether / acetone = 8/1) Calcd: C 72.47 H 8.39 N 5.83 Found: 72.28 8.44 5.70 [?] ^D20 = + 8.3 ° (c = 1 in methanol)

For separation of enantiomers, the chiral cell of an OD column fy. Daicel. The (R) -enantiomer elutes after 6.8 minutes and the (S) -enantiomer after 8.5 minutes on a 250 mm long column with 4.6 mm internal diameter (eluent: absolute ethanol / (n-hexane + 0.2) % diethylamine) = 5/95; temperature: 40 ° C; UV detection at 245 nm).

Example 8

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

Prepared from 150 mg (0.312 mmol) of ethyl (R) (-) - 2-ethoxy-4- [N-1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoate [melting point] : 122-124 ° C;

[] D ^{= 2} ° - 8.3 ° (c = 1 in methanol)] hydrolysis with sodium hydroxide solution in ethanol analogously to Example 3rd

Yield: 95.8 mg (66.7% of theory) Melting point: 103-105 ° C (toluene / petroleum ether) Calculated (x 0.4 H ₂ O): C 70.51 H 8.01 N 6.09 Found: 70.88 7.79 5.81

Molecular peak M ⁺ : Calculated: 452

Found: 452 [α] D ^{20 =} * 6.5 ° (c = 1 in methanol) Enantiomeric purity: ee = 99.7% (R) [HPLC method: see Example 3],

Example 8

(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 ethyl (S) (+) - 2-ethoxy-4- [N-1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] -benzoate [item] mp: 122-124 ° C; [.alpha.] _D @ ²⁰ = + + 8.3 DEG (c = 1 in methanol)] by saponification with 1N sodium hydroxide solution in ethanol analogously to Example 3. Yield: 44.5 mg (48.8% of theory) Melting point: 102-103 ° C (toluene / petroleum ether) Calculated (x 0.4 H ₂ O): C 70.51 H 8.01 Found: 70.80 8.06 [] _d 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- (2-piperidino-phenyl) -3-methyl-1-butyl] -aminocarbonylmethyl] -benzoic acid

0.26 g (0.47 mmol) of benzyl (S) -2-ethoxy-4- [N1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] -benzoate (m.p. 92 ° C; [] _d ²⁰ = + 9.5 °; c = 1 in methanol) is hydrogenated in 10 ml ethanol using 0.12 g (10%) palladium / charcoal at 50 ° C and hydrogen pressure 5.10 ⁵ Pa. After 5 hours, the catalyst was filtered off with diatomaceous earth and evaporated in vacuo. The evaporation residue was crystallized from ethanol / water (2/1). Yield: 0.15 g (70% of theory) Melting point: 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-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid

102 mg (0.20 mmol) of tert-butyl (S) -2-ethoxy-4- [N1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoate (point m.p .: 122-123 ° C; [ _α ] _D ²⁰ = + 8.7 °; c = 1 in methanol) is refluxed for half an day in 5 ml of benzene along with several crystals of p-toluenesulfonic acid hydrate. The desired product was obtained by TLC on the basis of the value of _Rf and mass spectra.

Melting point: 129 to 131 ° C Molecular peak M ': Calculated: 452

Found: 452

Example 12

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

SK 281246 Β6

200 mg (0.395 mmol) of tert-butyl (S) -2-ethoxy-4- [N1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate (melting point: 122 to 123) ° C; [.alpha.] _D @ ²⁰ = + 8.7 DEG; c = 1 in methanol) was stirred into 2 ml of methylene chloride together with 0.45 g (3.95 mmol) of trifluoroacetic acid overnight at room temperature. The mixture was evaporated in vacuo and the residue was partitioned between aqueous sodium bicarbonate solution 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 Calculated: C 71.64 H 8.02 N 6.19 Found: 71.39 7.91 6.06 [] d20 ⁼ + 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 Each tablet contains: 0.250 mg of active substance

0.125 mg of N-methylglucamine

0.038 mg of polyvinylpyrrolidone

0.075 mg of polyoxyethylene polyoxypropylene polymer 0.150 mg of microcrystalline cellulose

preparation

The active ingredients and excipients are dissolved in water at 90 ° C, in which microcrystalline cellulose is suspended and the dispersion is evaporated under vacuum. The dry matter is sieved with a 1 mm sieve.

For each tablet, the following ingredients are added to the granulated active ingredient:

24.225 mg of carboxymethyl starch sodium 24.000 mg of microcrystalline cellulose

0.500 mg magnesium stearate _________

50,000 mg

Round, biplanar tablets having a weight of 50 mg and a diameter of 5 mm are compressed from this mixture.

Example 14

Tablets containing 0.50 mg AG-EE 623 ZW

Each tablet contains:

0.500 mg of active substance

0.250 mg of N-methylglucamine

0.075 mg of polyvinylpyrrolidone

0.150 mg of polyoxyethylene polyoxypropylene polymer 0.300 mg of microcrystalline cellulose

preparation

The active ingredients and excipients are dissolved in water at 90 ° C, in which microcrystalline cellulose is suspended and the dispersion is evaporated under vacuum. The dry matter is sieved with a 1 mm sieve.

For each tablet, the following ingredients are added to the granulated active ingredient:

24.225 mg of carboxymethyl starch sodium 24.000 mg of microcrystalline cellulose

0.500 mg magnesium stearate _________

50,000 mg

Round, biplanar tablets having a weight of 50 mg and a diameter of 5 mm are compressed from this mixture.

Example 15

Tablets containing 1.0 mg AG-EE 623 ZW

Each tablet contains:

1.00 mg of active ingredient

0.50 mg of N-methylglucamine

0.15 mg of polyvinylpyrrolidone

0.03 mg of polyoxyethylene polyoxypropylene polymer

0.60 mg of microcrystalline cellulose

preparation

The active ingredients and excipients are dissolved in water at 90 ° C, in which microcrystalline cellulose is suspended and the dispersion is evaporated under vacuum. The dry matter is sieved with a 1 mm sieve.

For each tablet, the following ingredients are added to the granulated active ingredient:

23.22 mg carboxymethyl starch sodium 24.00 mg microcrystalline cellulose

0,50 mg magnesium stearate __________

50,00 mg

Round, biplanar tablets having a weight of 50 mg and a diameter of 5 mm are compressed from this mixture.

Example 16

Tablets containing 1.5 mg AG-EE 623 ZW

Each tablet contains:

1,500 mg of active substance

0.750 mg of N-methylglucamine

0.225 mg of polyvinylpyrrolidone

0.045 mg of polyoxyethylene polyoxypropylene polymer

0.900 mg of microcrystalline cellulose

preparation

The active ingredients and excipients are dissolved in water at 90 ° C, in which microcrystalline cellulose is suspended and the dispersion is evaporated under vacuum. The dry matter is sieved with a 1 mm sieve.

For each tablet, the following ingredients are added to the granulated active ingredient:

23.080 mg carboxymethyl starch sodium 23.000 mg microcrystalline cellulose

0.500 mg magnesium stearate _________

50,00 mg

Round, biplanar tablets having a weight of 50 mg and a diameter of 5 mm are compressed from this mixture.

Example 17

Tablets containing 2.0 mg AG-EE 623 ZW

Each tablet contains:

2.00 mg of active ingredient

1.00 mg of L-lysine

1.00 mg of polyvinylpyrrolidone

1.00 mg of polyoxyethylene polyoxypropylene polymer

4.00 mg of microcrystalline cellulose

SK 281246 Β6

preparation

The active ingredients and excipients are dissolved in water at 90 ° C, in which microcrystalline cellulose is suspended and the dispersion is processed in a spray drier. The following ingredients are added to each tablet: 23.35 mg microcrystalline cellulose 20.00 mg carboxymethyl starch sodium

0,65 mg magnesium stearate ___________

50,00 mg

Round, biconvex tablets weighing 50 mg and 5 mm in diameter are compressed from this mixture and covered with a scent masking coating of hydroxypropylmethylcellulose.

Example 18

Tablets containing 2.5 mg 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 of polyoxyethylene polyoxypropylene polymer

4.10 mg of microcrystalline cellulose

preparation

The active ingredients and excipients are dissolved in water at 90 ° C, in which microcrystalline cellulose is suspended and the dispersion is processed in a spray drier. The following ingredients are then added to each tablet:

19.50 mg microcrystalline cellulose

19.50 mg of sodium starch glycolate

0,65 mg magnesium stearate __________

50,00 mg

Round, biconvex tablets weighing 50 mg and 5 mm in diameter are compressed from this mixture and covered with a scent masking coating of hydroxypropylmethylcellulose.

Example 19

Tablets containing 3.0 mg AG-EE 623 ZW

Each tablet contains:

3.0 mg of active substance

1.5 mg of L-lysine

1.5 mg of polyvinylpyrrolidone

1.5 mg of polyoxyethylene polyoxypropylene polymer

4.10 mg of microcrystalline cellulose

preparation

The active ingredients and excipients are dissolved in water at 90 ° C and the solution is processed in a spray drier. The following ingredients are then added to each tablet:

21.5 mg microcrystalline cellulose 21.0 mg carboxymethyl starch sodium 50.00 mg

Round, biconvex tablets weighing 50 mg and 5 mm in diameter are compressed from this mixture and covered with a scent masking coating of hydroxypropylmethylcellulose.

Example 20

Tablets containing 5 mg AG-EE 623 ZW

Each tablet contains:

5.0 mg of active substance

2.5 mg of L-lysine

2.5 mg of polyvinylpyrrolidone

2.5 mg of polyoxyethylene polyoxypropylene polymer

preparation

The active ingredients and excipients are dissolved in water at 90 ° C and the solution is processed in a spray drier. The following ingredients are then added to each tablet: 19.0 mg microcrystalline cellulose

18.5 mg of carboxymethyl starch sodium

50,00 mg

Round, biconvex tablets weighing 50 mg and 5 mm in diameter are compressed from this mixture and covered with a scent masking coating of hydroxypropylmethylcellulose.

Claims (9)

(S) (+) - 2-ethoxy-4- [N-1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoic acid and its salts with inorganic or organic acids and bases. A compound according to claim 1 having an optical purity of ee = 95%. A compound according to claim 2 having an optical purity of at least ee = 98%. Physiologically acceptable salts of a compound according to claims 1 to 3 with organic or inorganic acids or bases. Pharmaceutical compositions comprising a compound according to claims 1 to 3 or physiologically acceptable salts according to claim 4 together with one or more internal carriers and / or diluents. Use of a compound according to claims 1 to 3 or a physiologically acceptable salt thereof according to claim 4 for the manufacture of a medicament for the treatment of diabetes mellitus. A process for the preparation of a compound according to claims 1 to 4, characterized in that a) (S) (+) - amine of formula (I) ^cb / CH ₃ is reacted with a carboxylic acid of formula (II) '(II), wherein: W represents a carboxy or a protected carboxy group, Or a reactive derivative thereof, optionally prepared in the reaction mixture and subsequently, if necessary, by cleavage of each protecting group, or b) (S) (+) - a compound of formula (III) wherein A is a group which is converted to a carboxyl group by hydrolysis, thermolysis or cleavage, or c) (S) (+) - a compound of formula (IV) wherein W 'represents a carboxyl or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl portion of the alkoxy group may be replaced by a phenyl group, reacts with a compound of formula (V) Z-CH ₂ -CH ₃ (V) wherein Z represents a nucleophilically exchangeable group or, together with an adjacent hydrogen atom, represents a diazo group and, if necessary, the compound thus obtained is hydrolyzed or hydrogenolyzed, or d) a compound of formula (VI) (VI) wherein W 'represents a carboxyl or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl moiety of the alkoxy group may be replaced by a phenyl group; and Y is a group of the formula is enantioselectively reduced and, if necessary, the compound so obtained is hydrolyzed or e) (S) (+) - a compound of formula (VII) wherein W represents a group which can be converted to a carboxy group by oxidation, is oxidized or f) a mixture consisting of any desired amount of the (SX +) enantiomer of the general formula: h, ch Λ / CH and any desired amount of the (R) -enantiomer of the formula wherein W 'represents a carboxyl or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl part of the alkoxy group can be replaced by a phenyl group, is separated and the compound thus obtained is converted by recrystallization to a high enantiomerically pure compound by crystallization from the mixture ethanol / water (2/1) to give its high-temperature form with a melting point of 130-131 ° C and crystallization from petroleum ether / toluene (5/3) to give a low-temperature form with a melting point of 99-101 ° C, and the compound thus obtained is converted to its salts, preferably to its physiologically acceptable salts, by inorganic or organic acids and bases. (S) -3-Methyl-1- (2-piperidino-phenyl) -1-butylamine and its acid addition salts as an intermediate for the preparation of a compound according to claim 1. Compounds of formulas (III), (IV), (VII) SK 281246-6 (III), -O- uu N / / 3 \ b I kde A is a group which is converted to a carboxyl group by hydrolysis, thermolysis or hydrogenolysis, W 'represents a carboxyl or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, wherein the alkyl part of the alkoxy group may be replaced by a phenyl group; and W represents a group which can be converted by oxidation to a carboxyl group and their addition salts as intermediates for the preparation of a compound according to claim 1.