SK128093A3 - (s) (+)-2 ethoxy-4-(n-(1-(2-(n-piperidinyl)-phenyl)-3-methyl- -1-butyl) aminocarbonylmethyl) benzoic acid - 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

Technical field

The present invention relates to (S) (+) - 2-ethoxy-4- (N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl) benzoic acid, pharmaceutical compositions containing it as well as methods of its preparation.

The state of the art

EP-B-0147850 discloses, inter alia, the 2-ethoxy-4- (N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl) benzoic acid racemate (code no. AG-EE 388 EE) formula 5 ^C / ^ca 3

CH

I

and EP-B-0207331 describes two other polymorphic forms of this compound. This compound and its physiologically acceptable salts have valuable pharmacological properties, in particular an effect on intermediate metabolism, in particular a blood sugar lowering effect.

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

Surprisingly, the (S) -enantiomer (AG-EE 623 ZV) has been found to be a potent enantiomer and its effect 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 ZV at a dose reduction of 50% compared to the AG-EE 388 ZV 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 ZV had surprising pharmacokinetic properties that could not be predicted from data on AG-EE 388 ZV. AG-EE 623 ZV then has surprising therapeutic advantages over the AG-EE 388 ZV racemate.

Surprising findings for people are:

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

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

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

A surprising difference between the two enantiomers is that the active enantiomer, AG-EE 623 ZV, despite its relatively long potency, is surprisingly eliminated rather than the inactive enantiomer AG-EE 624 ZV, as shown in Figures 1a and 2. After racemate administration is an ineffective enantiomer, AG-EE 624 ZV is therefore present not only as an unnecessary addition to plasma, which is as high as the active enantiomer, AG-EE 623 ZV, 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 ZV or one tablet containing 1 mg AG-EE 623 ZV 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 + 8a0.7 +1.0 ng / ml, after 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 ZV compared to AG-EE 388 ZV is particularly beneficial for diabetics, as rapid reduction results in optimal treatment of the disease.

Then, compared to the administration of AG-EE 388 ZV, the surprising advantage of administration of AG-EE 623 ZV is that it is possible to avoid the unrelentingly high and long-lasting levels of the substance in the body, which is extremely important in long-term therapy of a disease such as diabetic mellitus. .

Human studies have shown that the new (S) -enantiomer, namely, (S) (+) - 2-ethoxy-4- (N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl) acid benzoic, a blood glucose lowering agent highly superior to AG-EE 388 ZV due to 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 enantiomeric convenience of its racemate, especially the benefits in halving the dose.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides the 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) aminocarbonylmethyl) benzo, which is substantially optically pure, ie exhibits 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 is a physiologically acceptable salt, and processes for their preparation.

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

(I)

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

CH> H

with a carboxylic acid of formula (II)

where

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

The reactive derivatives of the 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 dehydrating agent, for example in the presence of ethyl chloroformate, isobutyl chloroformate. d, phosphorus trichloride, phosphorus pentoxide, N, N-dicyclohexylcarbodiimide, N, N-dicyclohexylcarbodimide / N-hydroxysuccinimide, N, N-carbonyldiimidazole or N, N-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or an amino group activating agent, e.g. 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 may 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 Tadla. The reaction can also be carried out without a solvent and, in addition, all the water formed in the reaction can be removed by azeotropic distillation, i.e. by heating with toluene using an aqueous separator, or by adding a desiccant such as magnesium sulfate or molecular sieves.

If necessary, the subsequent cleavage of the protecting group may be conveniently 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, i.e. 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 acid. , sulfuric, phosphoric or polyphosphoric.

In addition, the benzyl group as a protecting group may also be hydrogenolytically attached 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.

(III)

b) Attaching the (S) compound of formula (III) wherein

A is a group that 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 group, tetrazolyl group, optionally substituted with 1,3-oxazol-2-yl or 1, The 3-oxazolin-2-yl group and examples of the thermolytically attachable groups include esters with tertiary alcohols, ie, the tertiary butyl ester, and the examples of the 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 by using 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. a butyloxy carbonyl group, e.g. the 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 a temperature of between 20 ° C and the boiling point of the solvent used.

When A in the compound of formula III is a benzyloxycarbonyl group, for example, the benzyl group may 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, ethyl acetate, dioxane, or dimethylformamide, preferably at temperatures between 0 ° C and 50 ° C, for example at room temperature and at a hydrogen pressure of from about 1.10 to about 5.10 Pa.

c) reacting the (S) compound of formula

CH

CH

CH

CO - CH.

(IV) ‘OH where

V represents a carboxyl group or an alkoxycarbonyl group having in total 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) where

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 hydride, sodium hydride, 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 V 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 by subsequent hydrogenation in the presence of a hydrogenated catalyst such as palladium / activated carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide at such hydrogen at from 1 to 1 bar.

d) Enantioselective reduction of a compound of formula

where

V 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,

Y represents one of the groups of the formula

CH

CH

CH, CH,

Λ of ^{3 X} CH

I

CH,

-C - NH - C - NHor - C == For subsequent possible hydrolysis.

The reduction is preferably carried out with hydrogen in the presence of a suitable chiral hydrogen chloride 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 10 methanol / water, ethanol, ethanol water, water / dioxane at temperatures between -10 temperatures between room temperature and isopropanol / methylene chloride at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 50 ° C at a hydrogen pressure of between 1 to 1000 bar, preferably between 5 and 100 bar and preferably from 0.1 to 5% by weight, preferably from 0.3 to 1% by weight. 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 Cl ₄ [(S) -BINAP] ₂ x N (C ₂ H ₅ ) ₃ , Rh [ (S) -BINAP-NBD] CL0 ₄ or Rh [(-) - NORPH0S-C0D] BF ₄ .

During catalytic hydrogenation, the benzyloxycarbonyl group may 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, water / isopropanol, or up to 120 ° C, for example at the boiling point of the reaction mixture.

e) oxidizing the (S) compound of formula

CH.

CH.

CH

I

(VII) where

V is a group that can be converted by oxidation to a carboxyl group.

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

The reaction is carried out with an oxidizing agent in a suitable solvent such as acetic, methylene chloride, dioxane water, glacial acid 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 oxide and sodium hydroxide, manganese dioxide and acetone or methylene chloride, a solution of hydrogen peroxide and sodium hydroxide, a solution of bromine or bromine with a solution of sodium or potassium hydroxide, chromium trioxide and pyridine or chlorochromate pyridine.

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

CH ₃ CH ₃

CH l

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

where

V 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, if necessary, followed by hydrolysis or by hydrogenation.

The separation is preferably carried out using a column or column

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 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 / charcoal in a suitable a solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide at a hydrogen pressure of 1 to 1 bar.

The (S) -enantiomer thus obtained having an optical purity, preferably of at least 90%, can be a fractional crystallization of a (S) -enathiomer having an optical purity of at least 95%, preferably 98 to 100

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 such 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, 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 and subsequent salt decomposition, or by HPL chromatography of the chiral phases, optionally in the form of an acyl derivative, or by formation of diastereomeric 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% by weight. titanium isopropoxide, optionally followed by cleavage of the acyl group, such as a forinyl or acetyl group, by diastereoselective reduction of the corresponding ketimine or hydrazine chirally substituted on the nitrogen aroma 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 (S) -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 to nitrogen, 10% by weight. titanium isopropoxide, followed by hydrolysis and optionally separation of the resulting diastereomers and subsequent cleavage of a chiral auxiliary, for example the (R) -phenethyl group by catalytic hydrogenation, if necessary (S) -amine can be obtained in higher enantiomeric purity by salt formation with 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 the formulas III, IV and VII used as starting material are obtained by reacting the (S) -amine with the appropriate carboxylic acid or a reactive derivative thereof, and optionally subsequently removing 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 new (S) -enantiomer is indeed non-toxic, for example after a single administration of 1000 mg / kg p.o. (suspension in 1% methylcellulose) 5 male rats and 5 female rats did not die during the observation period of 14 days.

In view of its pharmacological and pharmacokinexic properties, the (S) -enantiomer prepared according to the invention (AG-EE 623 ZV) and its physiologically acceptable salts are suitable for the treatment of diabetes mellitus. For this purpose, AG-EE 623 ZV or its physiologically acceptable salts, optionally in conjunction with other active ingredients, may be included in conventional galenic formulations such as simple or coated tablets, 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, 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 a novel (S) -amine of formula I which is a valuable intermediate for the preparation of the new (S) -enantiomer and its addition salts with inorganic or organic acids.

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

The examples that follow are intended to illustrate the invention.

EXAMPLES

Example A (S) -1- (2-piperidinophenyl) -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-piperidinophenyl) -3-methyl-1-butylamine as N-acetyl-L-glutamic acid addition salt.

Yield: 65.1 g (60.4% of theory),

Melting point: 167-171 ° C

H, 8.56; N, 9.65

Found: 63.64 8.86 9.60 [α] 20 D - ₊ 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, and drying, filtering, and evaporating the extract in vacuo.

The (S) -configuration of the amine 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; [α] D = -2.25 ° (c = 1 in methanol)), crystal growth from 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 the 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 internal diameter 4.6 mm, eluent:

n-hexane / isopropanol (1000/5), flow 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).

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

Melting point: 135-145 ° C

Calculated (x H ₂ 0): C 56.99 H 8.97 N 8.31 Cl 21.02

Found: 56.85 8.93 8.38 21.25 [α] D 2 ° = + 26.1 ° (c = 1 in methanol)

Example B

N-Acetyl-N- [1- (2-piperidino-phenyl) -3-methyl-l-buten-l-phenyl] -amine

To a solution of 20 g (81.8 mmol) of freshly prepared isobutyl- (2-piperidino-phenyl) -ketimine in 200 ml of acetonitrile at room temperature was added 4.7 ml (81.8 mmol) of glacial acetic acid, 25.7 g. (98.2 mmol) of triphenylphosphine, 34.2 mL (245 mmol) of triethylamine and 7.9 mL (81.8 mmol) of carbon tetrachloride and the resulting mixture was stirred at room temperature for 18 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 residue was purified by column chromatography on silica gel (toluene / ethyl acetate = 10/1), eluting first with (E) -form and then with (Z) -form.

(E) -form:

Yield: 6.1 g (26% of theory),

Melting point: 135 to 137 ° C (ethyl acetate / petroleum ether)

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 to 143 ° C (ethyl acetate)

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-yl] -amine ml (0.18 mol) of acetic anhydride is added dropwise at an internal temperature of 0 ° C, 44 g (0.18 mol) of freshly prepared isobutyl- (2-piperidino-phenyl) -ketimine in 440 mL of toluene was added to the stirred solution. The mixture was stirred for an additional three 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 with aqueous sodium bicarbonate solution. The organic phase was dried, filtered and evaporated in vacuo. The evaporated residue was purified by silica gel column chromatography (foluene / 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)

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] -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] (pripra19 vein of [Ru (COD) Cl ₂ with 1 _n (s) -BINAP [= (s) -2,2-bis (diphenylphosphino) -l, l-binaphthyl], triethylamine and sodium acetate). and 3.4 g (0.5 moles) of titanium (IV) isopropoxide in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1). The reaction mixture was placed in an autoclave which was evacuated to 10 mbar. It was purged several times with hydrogen at 4 bar and the mixture was then 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 refluxed with 30 ml of n-hexane and filtered hot to remove undissolved water. Crystallization occurred after cooling the filtrate.

Yield: 0.31 g (54% of theory)

Melting point 127-131 ° C enantiomeric purity: ee = 82% (S) [HPLC method: see Example A].

154 DEG-156 DEG C. is obtained from the insoluble substance 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-piperidinophenyl) -3-methyl-1-butylamine g (3.47 mmol) N-acetyl-N - [(S) -1- (2-piperidinophenyl) -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 a mixture of 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 (m.p.

132 ° C, ee = 99.4%) was obtained by re-acetylation with 0.42 mL (1.3 equivalents) of acetic anhydride in 8.4 mL of glacial acetic acid overnight at room temperature, evaporation in vacuo, separating the evaporation residue between ethyl acetate and saturated aqueous sodium bicarbonate solution, by filtration and evaporation of the organic extract in vacuo.

Example F

Ethyl 2-ethoxy-4- [N-1- (2-piperidinophenyl) -3-methyl-1

-buten-1-yl) aminocarbonylmethyl] -benzoate

Prepared from isobutyl- (2-piperidino-phenyl) -ketimine acid

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

(E) -form:

Yield: 4% of theory,

Melting point: 101-103 ° C

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) Calculated: 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-piperidinophenyl) -3-methyl-1-butyl] -amine g (49 mmol) N - [(S) -1- (2-phenethyl] -isobutyl- (2-piperidinophenyl) ketidine with a boiling point of 150 to 155 ° C / at 40 Pa (prepared from isobutyl- (2-piperidinophenyl) ketone and (S) - of l-fetenylamine (manufactured by 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 and 8 g of Raney were added. 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. The catalyst is filtered off on a pad of Celite over G3-mess and the filtrate is filtered. Evaporate in vacuo.

Yield: 13.1 g (76.6% of theory),

Melting point: 152 ° C / 26.7 Pa

Calcd: C 82.23 H 9.78 N 7.99

Found: 82.00 10.03 7.74 [α] ρ ² θ = -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 gm. Eluant: methanol / dioxane f 0.1% aqueous sodium acetate solution, 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 dn = 97, Dissolve 0% (S, S) in 125 ml of water and 3.6 ml of concentrated hydrochloric acid. 1.3 g (10%) of palladium / activated carbon were added to the mixture, and the mixture was hydrogenated at 50 ° C and 50 mm Hg. After the uptake of hydrogen (10 hours), the mixture was filtered through a pad of celite to remove the catalyst. The filtrate was basified with concentrated ammonia with ice and extracted with ethyl acetate. The organic extract was dried, filtered and evaporated in vacuo.

Yield: 6.7 g (72.1% of theory)

Boiling point: 115 to 117 ° C / 53.33 Pa

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-piperidinophenyl) -3-methyl-1-butyl] -amine

A solution of 2 g (6.84 mmol) of N - [(R) -1-phenethyl] - (2-piperidinobenzimidimine) [prepared from equimolar amounts of 2-piperidino-benzaldehyde and (R) -1-phenethyleimine by standing overnight followed by ethereal drying solution of 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.

Observed: 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 base and a total of 6 equivalents of isobutyl magnesium bromide in toluene / tetrahydrofuran solution (4/1) and addition of 5% titanium isopropoxide heated at 100 ° C for 60 hours in a glass vessel yielded 5% de = 97.6% (S, R).

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 under a pressure of 3.4 bar of hydrogen. . The mixture was filtered through diatomite, made alkaline with 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 (according to previous acetylation): see Example A].

Example 1

Ethyl (S) -2-ethoxy-4- [N-1- (2-piperidinophenyl) -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 triethanolamine and 0.18 ml (1.91 mmol) of carbon tetrachloride are 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 for 20 hours at room temperature. It is then evaporated in a bag 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: 110-112 ° C

H, 8.39; N, 5.83

Found: 72.29 8.42 5.80

Enantiomeric purity was determined by HP1LC on a Baker chiral phase column 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 N, N-dicyclohexylcarbodiimide are then added and the mixture is stirred at room temperature. After 24 hours an additional 0.54 g (2.14 mmol) was added.

Of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.48 g (2.33 mmol) of N, N-dicyclohexylcarbodiimide 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 was maintained. 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; melting point)

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. it is cooled with ice and the crystals are suction filtered and dried at 75 ° C / 4 torr.

Yield: 3.93 g (74.3% of theory).

Melting point: 117-118 ° C

Calcd: 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 p

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 ethyl (S) -2-ethoxy-4- [N-1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate (ee) = 99.9%) in 37 ml of ethanol is stirred in a bath at 60 ° C 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 1N hydrochloric acid are added while warming 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 to 131 ° C (high temperature modification)

H, 8.02; N, 6.19

Found: 71.48 7.87 6.39 [α] D ² = + 7.45 ° (c = 1.06 in methanol)

Enantiomeric purity was determined by HPLC on a chiral phase HPLC column, manufactured by ChromTech (Sweden) with an AGP (α1-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:

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 infra red spectra in KBr but not in their infra red 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 using Differential Scanning Calorimetry (DSC) [Mett27 ler, TA-3000; measuring cell: DSC 20; manufacturer Metxler, CH-8380 Greifensee, Switzerland] and the following results were obtained:

compound of Example 3 Heating rate 10 ° K / min Heating rate 3 ° K / min Vysokotep- Uniform melting peak Uniform melting peak lotná forma with melting point 133 [deg.] C .; melting enthalpy 100 J / g and melting point 132 [deg.] C .; melting enthalpy 99.1 J / g Nízkoteplot- 1st peak at 57 ° C 1st peak at 54 ° C form ...... '(Very weak) (very weak; ........... 2nd peak at 78 ° C (weak) 3. endoxermic peak at 107 ° C; melting enthalpy: 55 J / g 4. Endothermic peak at 132 ° C melting enthalpy: 25 J / g endoxermický) 2. endothermic peak at 104 ° C. melting point 102 ° C, melting enthalpy: 55 J / g 3. endothermic footprint of the baseline in the crystals of the substance melting at 104 ° C

4. endoxermic peak at 131 ° C, melting point 130 ° C melting enthalpy of 52 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- [N-1- (2-piperidinophenyl) -3-methyl-1-buten-1-yl) aminocarbonylmethyl] -benzoate with mp 124-127 ° C is dissolved in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1) under argon and added to the solution of 17 mg NOYORI Ru (O-acetyl) 2 ((S) -BINAP) catalyst] (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 reaction mixture is placed in an autoclave evacuated to 10 millibars and the mixture is purged 5 times with hydrogen at 5 bar and finally hydrogenated at 30 ° C and 100 bar until The red-brown solution was evaporated in vacuo, the evaporation residue was dissolved in sodium sulfate, filtered from undissolved brown flakes with activated carbon and the resulting clear, bright yellow filtrate was evaporated. 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 to 133 ° C (after sintering at 120 ° C)

Enantiomeric purity: ee = 39% (S) uHPLC method: see Example 1].

Example 5

Ethyl (S) -2-ethoxy-4- [N-1- (2-piperidino-phenyl) -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- [N1- (2-piperidinophenyl) (3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate (m.p. 125-126 ° C); [α] _D ²⁰ = + 12.87 ° (c = 1.01 in methanol)] in 5 mL of anhydrous dimethylformamide and stirred for 0.5 h. 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 extralt, filter and evaporate in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene / ethyl acetate = 10/1).

Yield: 0.48 g (67% of theory),

Melting point: 110-112 ° C

Calcd: 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-exoxy-4- [N-1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate

Prepared from (S) -2-exoxy-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: 110-112 ° C

Calcd: 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-piperidinophenyl) -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-dinitrobenzoylleucine is covalently bound to a silica aminopropyl gel (particle size: 40 nm, column length 250 mm with an inner diameter of 20 mm; eluant: n-hexane / tetrahydrofuran / ethanol / methylene chloride ( Flow rate: 21.25 ml / min; temperature: 27 ° C; UV detection at 285 nm) at which the (R) (-) enantiomer (peak 1) is eluted first and then (S) (+) - enantiomer (peak 2). Evaporation in vacuo gave the following results based on the collected and collected fractions:

Peak 1 fraction (R): 423 mg (gross)

Peak 2 fraction (S): 325 mg (coarse) z- _and - for the purpose of ..... or

2,6-di-tert-butyl-4-methylphenol 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)

Calcd: C 72.47 H 8.39 N 5.83

Found: 72.40 8.18 5.71 [α] D ² = - 8.3 ° (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) Calculated: C 72.47 H 8.39 N 5.83 Found: 72.28 8.44 5.70 [α] ^^ θ = + 8.3 ° (c = 1 in methanol)

For separation of enantiomers, the chiral cell OD column of 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 0

Prepared from 150 mg (0.312 mmol) of ethyl (R) (-) - 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 a 1N solution of sodium hydroxide in ethanol analogously to Example 3.

Yield: 95.8 mg (66.7% of theory),

Melting point: 103 to 105 ° C (toluene / petroleum ether)

Calculated (x 0.4 h ₂ 0) : C 70.51 H, 8.01 N, 6.09 'Detected: ......... ....... ~ 7O78’8 - · ₇ γ ₇₉ ' ......... 5.81 Molecular peak M ⁺ : counted: 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-, 0

Prepared from 89 mg (0.198 mmol) of ethyl (S) (+) - 2-ethoxy-4- [N1 (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoate [m.p. 124 [deg.] C .;

[α] _D = + 8.3 ° (c = 1 in methanol)] by saponification with 1 N sodium hydroxide in ethanol analogously to Example 3. Yield: 44.5 mg (48.8% of theory),

Melting point: 102 to 103 ° C (toluene / petroleum ether)

Calcd (x 0.4 H ₂ O): C 70.51 H 8.01

Found: 70.80 8.06 [α] ζ | 2θ = + 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- [N 1 - (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] -benzoate (m.p. 91-92 °) C;

[α] D 20 + 9.5 °; c = 1 in methanol) was hydrogenated in 10 ml of ethanol using 0.12 g (10%) of palladium / charcoal at 50 ° C and a hydrogen pressure of 5 bar. 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 to 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) tert. butyl (S) -2-ethoxy-4- [N1- (2-piperidino-phenyl) -3-methyl-1-butyl) aminocarbonylmethyl] -benzoate (m.p. 122-123 ° C; [α] ^ ² θ = + 8.7 ° (c = 1 in methanol) is refluxed for half a day in 5 ml of benzene along with several crystals of p-toluenesulfonic acid hydrate. The desired product was obtained by thin layer chromatography, based on Rf value and mass spectrum.

Melting point: 129-131 ° C

Molecular peak M ⁺ : Calculated: 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) tert. butyl (S) -2-ethoxy-4- [N 1 - (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoate (m.p. 122-123 ° C; ² θ = ₊ 8.7 °, c = 1 in methanol) was mixed in 2 ml of methylene chloride together with 0.45 g (3.95 mmol) of trifluoroacetic acid over: night at ordinary temperature. The mixture was evaporated in vacuo and the residue was partitioned between aqueous sodium bicarbonate 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 to 128 ° C

H, 8.02; N, 6.19

Found: 71.39 7.91 6.06 = + 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 ZV

Each tablet contains:

0.250 mg of active substance 0.125 mg of N-methylglucamine 0.038 mg of polyvinylpirolidone

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 ZV

Each tablet contains:

0.500 mg of active substance 0.250 mg of N-methylglucamine 0.075 mg of polyvinylpirolidone

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 ZV

Each tablet contains:

1.00 mg of active substance 0.50 mg of N-methylglucamine 0.15 mg of polyvinylpirolidone

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 of 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 ZV

Each tablet contains:

1.500 mg of active substance 0.750 mg of N-methylglucamine 0.225 mg of polyvinylpirolidone

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 ZV

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

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 ZV

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 ZV

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 operated in a spray drier. The following ingredients are then added to each tablet:

21.5 mg microcrystalline cellulose

21.0 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.

Example 20

Tablets containing 5 mg AG-EE 623 ZV

Each tablet contains:

5.0 mg of active substance

2.5 mg of L-lysine

2.5 mg polyvinylpirolidone

2.5 mg of polyoxyethylene polyoxypropylene polymer

Preparation:

The active ingredients and excipients are dissolved in water at 90 ° C and the solution is operated 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.

I

B / h 7 /ng/ml./

II / _ng / m /

κι ω

m

K) (M!

CC m

ΤΓ f-?

CM

ABOUT

CM

Fig

- 40 pl /

Claims (11)

PATENT CLAIMS 1. (S) (+) - 2-Ethoxy-4- [N1- (2-piperidino-phenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] -benzoic acid and its salts with inorganic or organic acids and bases . A compound according to claim 1 which is substantially optically pure. A compound according to claim 2 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 4 with organic or inorganic acids or bases. Pharmaceutical compositions comprising a compound according to claims 1 to 4 or physiologically acceptable salts according to claim 5 together with one or more internal carriers and / or diluents. Use of a compound according to claims 1 to 4 or is a physiologically acceptable salt according to claim 5 for the treatment of diabetes mellitus A process for the preparation of pharmaceutical compositions according to claim 6, characterized in that the compound according to claims 1 to 4 or its physiologically acceptable salts according to claim 5 is incorporated into one or more inert carriers and / or diluents in a non-chemical manner. A process for the preparation of a) (S) -amine of formula I of a novel compound according to claims 1 to 5, characterized in that (I) is reacted with a carboxylic acid of formula II (II) wherein: V represents a carboxy group or a carboxy group protected by a protecting group. or with a reactive derivative thereof, optionally prepared in the reaction mixture and subsequently, if necessary, by cleavage of each protecting group, or b) The (S) compound of formula III ^! 3 CH, CH. \ / CH I CO - (III) where A represents a group which is converted to a carboxyl group by hydrolysis, thermolysis or cleavage, or (IV) where c) (S) of formula IV V 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) where 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 V 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 represents a group of formula CHCH H CH / CH CH _n k. CH - C - NHCH. \ / c It -C-NHCH-, CH 3 / CH 3 CH_ or Is reduced enantioselectively and, if necessary, the compound so obtained is hydrolysed or e) (S) -compound of formula VII CH ₃ CH ₃ wherein WITH V is a group that can be converted to a carboxy group by oxidation, is oxidized or f) a mixture consisting of any desired amount of the (S) -enantiomer of the formula ^{C 13} from ^CH 3 and any desired amount of the (R) -enantiomer of the formula wherein (ix) V 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, is separated and the compound thus obtained is converted, if necessary, by recrystallization to a high enantiomerically pure compound by crystallization from 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 to give the compound is converted to its salts, preferably to its physiologically acceptable salts, by inorganic or organic acids and bases. (S) -3-Methyl-1- (2-piperidinophenyl) -1-butylamine and its acid addition salts. 11. New compounds of formulas III, IV, VII (III) (IV) (VII) wherein A represents a group which is converted to a carboxyl group by hydrolysis, thermolysis or hydrogenolysis, V 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 V is a group that can be converted by oxidation to a carboxyl group and its addition salts.