CZ280430B6 - (s)(+)-2-ethoxy-4-/n-/1-(2-piperidinophenyl)-3-methyl-1-butyl /aminocarbonylmethyl/benzoic acid, pharmaceutical preparations in which it is comprised, its use and intermediates for preparing such 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

(57)

The invention relates to a novel compound, (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid and its salts. These substances have valuable pharmacological properties, in particular effects on the intermediate metabolism and in particular on the reduction of blood sugar concentration. The invention also relates to novel intermediates for the preparation of the novel compound and its addition salts. The invention also encompasses pharmaceutical compositions comprising the compound and are suitable for use in the treatment of diabetes and the use of novel compounds for the manufacture of such pharmaceutical compositions.

(S) (+) - 2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoic acid, pharmaceutical compositions containing it, its use and intermediates therefor production

Technical field

The invention relates to (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid, pharmaceutical compositions containing the same and are particularly suitable for lowering blood sugar, its use and intermediates for its production.

BACKGROUND OF THE INVENTION

European Patent Specification No. 147,850 discloses, among other compounds, the 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid racemate (code number AG-EE) 388 ZW) of formula

and, in addition, European Patent Specification No. 207 331 describes two other polymorphic forms of this substance. This compound and its salts have valuable pharmacological properties, in particular an effect on the intermediate metabolism and in particular on the reduction of blood sugar concentration.

Two enantiomers of (S) (+) - 2-ethoxy-4- / N- / 1- (2-piperidinophenyl) -3-methyl-1-butyl / aminocarbonylmethyl / benzoic acid (code AG-EE) 623 ZW) and (R) (-) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzo (code number AG-EE 624 ZW), were studied for their blood sugar lowering effect in rats.

The (S) -enantiomer AG-EE 623 ZW has been unexpectedly found to be the active enantiomer, which lasts more than 6 hours in rats.

Based on experiments in rats, it would seem appropriate to use exclusively AG-EE 623 ZW in human medicine, thereby reducing the total dose to 50% compared to the AG-EE 388 ZW racemate dose. A long duration of action has also been shown in human tests in humans, but it has also been found that AG-EE 623 ZW has surprising pharmacokinetic properties that could not be expected from data available for

-1GB 280430 B6 cemát AG-EE 388 ZW. Thus, AG-EE 623 ZW has surprising advantages over therapeutic use over the use of the racemate.

These benefits are:

a) AG-EE 623 ZW values fall to zero faster than AG-EE 388 ZW values even at exactly the same dosage, which could not be expected due to the relatively long duration of action.

(b) With regard to the reduction in blood sugar concentration, the use of AG-EE 623 ZW can result in significantly lower values than would be expected if the dose of AG-EE 388 ZW was halved.

c) Blood sugar levels decrease much more rapidly after administration of AG-EE 623 ZW than after administration of AG-EE 388 ZW.

The surprising difference between the two enantiomers is that the active enantiomer AG-EE 623 ZW, despite its relatively long duration of action, exits much faster than the inactive enantiomer AG-EE 624 ZW, as shown in the accompanying drawings.

Description of the drawings

Figure 1 shows the course of concentrations of AG-EE 623 ZW and AG-EE 624 ZW after administration of 1.0 mg AG-EE 388 ZW intravenously to 12 volunteers, all volunteers were male.

FIG. 2 shows concentrations of AG-EE 623 ZW and AG-EE 624 ZW after administration of 1.0 mg AG-EE 388 ZW as a solution orally to the same volunteers.

These results indicate that the inactive enantiomer of AG-EE 624 ZW is only present as an unnecessary additive since the plasma concentration is as high as the active enantiomer of AG-EE 623 ZW, but the inactive enantiomer has an unexpectedly higher maximum concentration and plasma also lasts longer. That is, for example, after administration of a tablet containing 2 mg AG-EE 388 ZW, or one tablet containing 1 mg AG-EE 623 ZW, to 12 and 6 volunteers, the corresponding maximum concentrations are 84 ± 25 and 28 ± 18 ng / ml, respectively. , after 4 hours these concentrations are 19 ± 8 and 0,7 ± 1,0 ng / ml, after 5 hours 13 ± 6 and 0,3 ± 0,7 ng / ml and finally after 6 hours 10 ± 6 and 0, 3 ± 0.7 ng / ml.

The surprising rapid onset of blood glucose lowering effect of AG-EE 623 ZW compared to AG-EE 388 ZW is particularly advantageous for diabetics, as a rapid onset of effect results in optimal maintenance of blood sugar levels and thus good patient status.

Compared to the administration of AG-EE 388 ZW, the surprising advantage of administering AG-EE 623 ZW is therefore that the active substance does not remain unnecessarily long in the blood at relatively high levels, which is particularly important in long-term treatment, as is currently the case. in the case of diabetes.

Clinical trials have shown that the new (S) -enantiomer, (S) (+) - 2-ethoxy-4- / N- [1- (2-piperidinophenyl) -3-methyl-1-butyl / aminocarbonylmethyl] benzoic acid, is far more advantageous in its effectiveness

-2 AG 280430 B6 for reducing blood sugar concentration than AG-EE 388 ZW, since it is rapidly excreted from the blood, which was not to be expected due to the relatively long efficacy, these more advantageous properties far outweigh the conventional advantages of enantiomers compared to racemates, especially when the dose is halved.

SUMMARY OF THE INVENTION

The present invention provides (S) (+) - 2-ethoxy-4- [N- [1- (2-piperidinophenyl) -3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid as a novel material, preferably in optically pure state. , for example having an optical purity of at least 95, preferably 98 to 100%. The present invention also provides physiologically acceptable salts of this acid with inorganic or organic acids or bases, as well as pharmaceutical compositions containing the compound or physiologically acceptable salts thereof, and processes for their preparation.

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

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

(I) with a carboxylic acid of formula II

HOOG-CH ₂ - / 2 - w (II) OC ₂ H ₅

where

W represents a carboxyl group or a protected carboxyl group, or with a reactive derivative thereof prepared in a reaction mixture, where appropriate, whereupon the protecting group is removed if necessary.

-3GB 280430 B6

Suitable reactive derivatives of the compound of formula (II) are, for example, esters, such as methyl, ethyl or benzyl esters, thioesters, for example methylthioester or ethylthioester, halides, for example acid chloride, furthermore anhydride or imidazolide.

The reaction proceeds well 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 such as ethyl chloroformate, isobutyl chloroformate, thionyl chloride , phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, a mixture of N, N'-dicyclohexylcarbodiimide and N-hydroxysuccinimide, in the presence of N, N'-carbonyldiimidazole, N, N'-thionyldiimidazole or a mixture of triphenylphosphine and carbon tetrachloride, or activates an amino group, for example phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as a solvent, the reaction being carried out at -25 to 250 ° C; preferably from -10 ° C to the boiling point of the solvent used. The reaction may also be carried out without solvent and any water formed during the reaction may also be removed by azeotropic distillation, for example by heating with toluene using a water separator or by a water scavenger such as magnesium sulfate or molecular sieves.

If desired, the subsequent cleavage of the protecting group is preferably carried out by hydrolysis, either in the presence of an acid such as hydrochloric, sulfuric, phosphoric, trifluoroacetic or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water. methanol, a mixture of methanol and water, ethanol, a mixture of ethanol and water, water and isopropanol or water and dioxane at a temperature in the range of -10 to 120 ° C, for example at room temperature to the boiling point of the reaction mixture.

The tert-butyl group which is used as a protecting group can also be cleaved by the action of heat, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid, and preferably in the presence of a strong acid, e.g. trifluoroacetic, hydrobromic, p-toluenesulfonic, sulfuric, phosphoric or polyphosphoric.

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

b) The novel compound can also be obtained by cleavage of the (s) compound of formula III

-4GB 280430 B6 (III)

where

A is a group which can be converted to a carboxyl group by hydrolysis, heat treatment or hydrogenolysis.

Examples of hydrolyzable groups include functional derivatives of a carboxyl group, for example unsubstituted or substituted amides, esters, thioesters, orthoesters, imino ethers, amidines or anhydrides, nitrile, tetrazolyl or 1,3-oxazol-2-yl or 1,3-oxazoline- 2-yl optionally substituted. Examples of heat-cleavable groups are esters with tertiary alcohols, for example tert-butyl ester, and examples of groups which can be cleaved by hydrogenolysis are aralkyl groups, for example benzyl.

Hydrolysis is conveniently carried out in the presence of an acid such as hydrochloric, sulfuric, phosphoric, trifluoroacetic or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol or a mixture water and ethanol, a mixture of water and isopropanol, or a mixture of water and dioxane at a temperature in the range of -10 to 120 ° C, for example at room temperature to the boiling point of the reaction mixture.

When A in the compound of formula III is a nitrile or aminocarbonyl group, these groups can be converted to the carboxyl group by treatment with 100% phosphoric acid at a temperature in the range 100-180 ° C, preferably 120-160 ° C, or a nitrite such as sodium nitrite can be used in the presence of an acid such as sulfuric acid which can also serve as a solvent at a temperature of 0 to 50 ° C.

When A in the compound of formula III is a tert-butyloxycarbonyl group, the tert-butyl group can also be cleaved by heat treatment, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid, with benefit

In the presence of a strong acid such as trifluoroacetic acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid at a temperature of 0 to 100 ° C, preferably at a temperature of 20 ° C to the boiling point of the solvent used.

When in the compound of formula III A is a benzyloxycarbonyl group, the benzyl group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst, for example palladium on activated carbon in a suitable solvent, for example methanol, ethanol, methanol / water or ethanol / water, in glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at 0 to 50 ° C, for example at room temperature and at a hydrogen pressure of 1 to 5 bar.

c) The resulting product can also be obtained by reacting the (S) compound of formula IV

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 is optionally substituted by a phenyl radical, with a compound of formula V

Z - ch ₂ - ch ₃ (E) where

Z represents a nucleophilically exchangeable group, for example a halogen atom, a sulfonyloxy group, or forms Z together with the adjacent hydrogen atom a diazo group, optionally followed by hydrolysis or hydrogenolysis.

The reaction is readily carried out using the corresponding halide, sulfonic acid ester or sulfuric acid diester, for example ethyl bromide, ethyl iodide, diethyl sulfate, ethyl p-toluenesulfonate or ethyl methanesulfonate, or also diazoethane, optionally in the presence of a base such as sodium hydride

Potassium carbonate, sodium hydroxide, potassium tert-butoxide or triethylamine, preferably in a suitable solvent such as acetone, diethyl ether, tetrahydrofuran, dioxane, pyridine or dimethylformamide at a temperature of 0 to 100, preferably 20 to 50 ° C.

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

If desired, the subsequent hydrolysis is carried out in the presence of an acid such as hydrochloric, sulfuric, phosphoric, trifluoroacetic or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol / water, ethanol , a mixture of ethanol and water, water and isopropanol or water and dioxane at a temperature in the range of -10 to 120 ° C, for example at room temperature to the boiling point of the reaction mixture, or subsequent hydrogenolysis may be carried out in the presence of a hydrogenation catalyst such as palladium on charcoal in a suitable solvent such as methanol, ethanol, a mixture of ethanol and water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide at a hydrogen pressure of from 1 to 10 bar.

d) The desired product can also be obtained by enantioselective reduction of a compound of formula VI

(VI) where

W 'represents a carboxyl group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl part of the alkoxy group being optionally substituted by a phenyl group; and

Y represents one of the groups

CH.

/

H CH \ / \ ch ₃

It

- C - NH -,

CH

CH H / \ /

CH. C ^J II

- C - NH or

CH. CH->

</ CH I ch ₉ I

- C = N

-7EN 280430 B6 followed by hydrolysis.

The reduction is preferably carried out by treatment with hydrogen in the presence of a suitable chiral hydrogenation catalyst in a suitable solvent such as methanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran, a mixture of methanol and tetrahydrofuran, methanol and methylene chloride, ethanol and methylene chloride or isopropanol and methylene chloride. to 100, preferably 20 to 50 ° C at a hydrogen pressure of 0.1 to 100, preferably 0.5 to 10 MPa, preferably 0.1 to 5, preferably 0.3 to 1% titanium tetraisopropoxide is added and the reaction is preferably carried out with the exclusion of air oxygen. The reduction is preferably carried out using the (Z) form of the compound of formula VI.

Examples of chiral hydrogenation catalyst may be some metal complexes, e.g., Ru (OCO-CH _{3) 2} / (S) -BINAP / Ru ₄ C 1 ₂ / (S) -BINAP / ₂ x N (C ₂ H _{5) 3,} Rh / (S) -BINAP-NBD / C10 ₄ or Rh / (-) - NORPHOS-cod / bf ₄ .

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

If desired, the subsequent hydrolysis may be carried out in the presence of an acid such as hydrochloric, sulfuric, phosphoric, trifluoroacetic or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol and water. ethanol, a mixture of ethanol and water, water and isopropanol, or water and dioxane at a temperature in the range of -10 to 120 ° C, for example at room temperature to the boiling point of the reaction mixture.

e) The product can also be obtained by oxidation of the (S) compound of formula VII with CH 3 CH ³ X / CH

(VII) where

W '' is a group by which oxidation can be converted to a carboxyl group.

-8EN 280430 B6

Examples of an oxidizable group of this type are formyl and its acetals, hydroxymethyl and its ethers, unsubstituted or substituted acyl, such as acetyl, chloroacetyl, propionyl or (1) -yl, such as a malonic acid residue or ester thereof.

The reaction is carried out by treatment with an oxidizing agent in a suitable solvent, for example water, glacial acetic acid, methylene chloride, dioxane or glycol dimethyl ether at a temperature of 0 to 100, usually 20 to 50 C. Preferably, the reaction is carried out using a mixture of silver oxide and sodium hydroxide solution. a mixture of manganese dioxide and acetone or methylene chloride, a mixture of hydrogen peroxide and a sodium hydroxide solution, a mixture of bromine or chlorine and a solution of sodium or potassium hydroxide, or a mixture of chromium oxide and pyridine or pyridinium chlorochromate.

f) The resulting product can also be obtained by separating a mixture containing any desired amount of the (S) -enantiomer of Formula VIII

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

(IX) where

W 'represents a carboxyl group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl part of the alkoxy group being optionally substituted by a phenyl group,

Preferably, in a 50:50 mixture via diastereomeric addition products, complexes or salts with optional subsequent hydrolysis or hydrogenolysis.

Separation is preferably performed by column chromatography or high pressure liquid chromatography by formation of diastereomeric addition products or complexes on a chiral phase.

If desired, the subsequent hydrolysis is carried out in the presence of an acid such as hydrochloric, sulfuric, phosphoric, trifluoroacetic or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol and water, ethanol , a mixture of ethanol and water, water and isopropanol or water and dioxane at a temperature in the range of -10 to 120 ° C, e.g. at room temperature to the boiling point of the reaction mixture, or subsequent hydrolysis is carried out in the presence of a hydrogenation catalyst such as palladium on charcoal. a suitable solvent such as methanol, ethanol, a mixture of ethanol and water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide at a hydrogen pressure of 1 to 10 bar.

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

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

The (S) -enantiomer thus obtained according to the invention can be converted into salts, especially in the case of pharmaceutical use, into physiologically acceptable salts with inorganic or organic acids or bases. Examples of such acids include hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartar, succinic, maleic or fumaric acids, examples of which may be sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine or ethylenediamine .

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

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

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

- column chromatography or chiral phase high-pressure liquid chromatography, optionally in the form of an acyl derivative, or

- formation of diastereomeric compounds followed by their separation and resolution.

-10GB 280430 B6

In addition, the (S) -amine of formula (I) may be prepared

- by enantioselective reduction using hydrogen in the presence of a suitable chiral hydrogenation catalyst, starting from the corresponding N-acylketimine or enamide and adding 0.1 to 5% of titanium tetraisopropoxide, optionally followed by cleavage of an acyl group, for example 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, suitably by adding 0.1 to 5% titanium tetraisopropoxide with optional subsequent cleavage of a chiral auxiliary, for example a (S) -1-phenethyl group by catalytic hydrogenolysis, or

- diastereoselective addition of the corresponding organometallic compound, preferably the Grignard compound or lithium compound, to the corresponding aldimine, chirally substituted on a nitrogen atom, optionally adding 0.1 to 10% titanium tetraisopropoxide followed by hydrolysis and optional resolution of the resulting diastereomers and subsequent cleavage of the chiral auxiliary , for example, (R) -1-phenylethyl groups by catalytic hydrogenolysis,

and, if desired, the (S) -amine of higher enantiomeric purity can be obtained by salt formation with suitable optically active acids, preferably N-acetyl-L-glutamic acid, and if necessary recrystallization is performed one or more times with subsequent salt decomposition.

The compounds of formulas III, IV and VII which are starting materials can be obtained by reacting the (S) -amine of formula I with the corresponding carboxylic acid or reactive derivative thereof, followed by optional cleavage of any protecting group used.

The compounds of formula (VI) which are used as starting materials can be obtained by acylating the corresponding imino compound or one of its organometallic complexes by treatment with the corresponding carboxylic acid or its reactive derivative, followed by subsequent cleavage of the ester group.

The novel (S) -enantiomer of the invention is practically non-toxic. For example, after a single administration of 1000 mg / kg orally as a suspension in 1% methylcellulose to five male rats and five female rats, none of these test animals died within a 14-day observation period.

Due to its pharmacological and pharmacokinetic properties, the (S) -enantiomer AG-EE 623 ZW, transported by the method of the invention, is suitable for the treatment of diabetes mellitus, including its physiologically acceptable salts. For said therapeutic purposes, AG-EE 623 ZW or a physiologically acceptable salt thereof, optionally in admixture with other active ingredients, may be formulated as conventional galenic dosage forms, for example, conventional or coated tablets, powders, suppositories, suspensions or solutions. for injection use. An intended single dose for an adult human is in the range of 0.1 to 20 mg, preferably 0.25

280430 B6 to 5 mg, in particular 0.25, 0.5, 1.0, 1.5, 2.0,

2.5, 3.0, or 5.0 mg, may be administered once, twice or three times daily.

The invention also relates to a novel (S) amine of formula I which is a valuable intermediate for the preparation of the novel (S) -enantiomer of the invention, as well as addition salts thereof with inorganic or organic acids.

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

DETAILED DESCRIPTION OF THE INVENTION

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

A stirred solution of 122 g (0.495 mol) of 1- (2-piperidino-phenyl) -3-methyl-1-butylamine racemate in 1000 ml of acetone is mixed with 93.7 g (0.495 mol) of N-acetyl-L-glutamic acid . The mixture was refluxed in a steam bath, and methanol (about 80 mL total) was added in portions until a clear solution was obtained. The solution was allowed to cool and allowed to stand overnight at ambient temperature. The obtained crystals were removed by suction filtration, washed twice with 200 ml of cold acetone at -15 ° C and then dried. The product thus obtained / 98.9 g, mp: 163-166 ° C // // ct ² ° _D = + 0.286 ° / c = 1 in methanol / / is recrystallised from 1000 ml of acetone with the addition of 200 ml of methanol , the (S) -1- (2-piperidino-phenyl) -3-methyl-1-butylamine thus obtained as a supplement to the N-acetyl-L-glutamic acid salt.

Yield: 65.1 g (60.4% of theory), Melting point: 168-171 ° C.

Analysis: Calculated: C 63.42%, H 8.56%, N 9.65%. Found: C 63.64%, H 8.86%, N 9.60%.

[ _.alpha. ] _D @ ²⁰ = + 0.357 DEG (c = 1 in methanol).

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

The (S) -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), [α] _D = -2.25 (c = 1 in methanol), crystal growth from ethanol / water (8/1) and subsequent X-ray structural analysis showed

-12GB 280430 B6 / S, S '/ - the urea derivative configuration and, consequently, the / S / configuration for the amine used.

The enantiomeric purity was determined as follows:

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

2. Analysis of the N-acetyl derivative (melting point: 128-132 ° C) by HPLC on an HPLC column phase manufactured by Baker, in which [S] -N- (3,5-dinitrobenzoyl) -2-phenyl-glycine is bound by covalent bonding to aminopropyl silica gel / particles of 5 μιη size, spherical, pore size 60. 10 cm, column length: 250 mm, 4.6 mm ID, eluent: n-hexane / isopropanol / 100/5 /, 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 (excess enantiomer) = 98.5% (S).

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

Melting point: 135 - 145 ° C (with decomposition).

Calculated (H ₂ O): C 56.99%, H 8.97%, N 8.31%, Cl 21.02%.

Found: C 56.85%, H 8.93%, N 8.38%, Cl 21.25%.

[ _.alpha. ] _D @ ²⁰ = + 26.1 DEG (c = 1 in methanol).

Example B

N-Acetyl-N - [1- (2-piperidin-phenyl) -3-methyl-1-buten-1-yl] -amine

Ambient temperature, 4.7 mL (81.8 mmol) glacial acetic acid, 25.7 g (98.2 mmol) triphenylphosphine, 34.2 mL (245 mmol) triethylamine and 7.9 mL (81.8 mmol) of carbon tetrachloride is added to a solution of 20 g (81.8 mmol) of freshly prepared isobutyl- (2-piperidinophenyl) ketidine in 200 ml of acetonitrile and the resulting mixture is stirred for 18 hours at ambient temperature. The mixture is then evaporated in vacuo and partitioned between ethyl acetate and water. The organic extract is dried and filtered and evaporated in vacuo. The residue is purified by column chromatography over silica gel (toluene / ethyl acetate = 10/1), eluting first with (E) -form, then with (Z) -form.

/ E / -form:

Yield: 6.1 g (26% of theory), Melting point: 135-137 DEG C. (ethyl acetate / petroleum ether), Calculated: C 75.48%, H 9.15%, N 9.78%, Found: C 75.47%, H 9.35%, N 9.70%.

/ Z / -form:

Yield: 3.1 g (13% of theory), Melting point: 140-143 ° C, (ethyl acetate), Calculated: C 75.48%, H 9.15%, N 9.78%, Found: C 75 % H, 9.30%; N 9.79%.

-13GB 280430 B6

Example C

N-Acetyl-N - [1- (2-piperidin-phenyl) -3-methyl-1-buten-1-yl] -amine ml (0.18 mol) of acetic anhydride at an internal temperature of 0 ° C 44 g (0.18 mol) of freshly prepared isobutyl- (2-piperidinophenyl) ketidine in 440 ml toluene was added dropwise to a stirred solution. The mixture is stirred at 0 ° C for a further 3 hours and then at ambient temperature for 15 hours. It is then evaporated in vacuo, the residue is taken up in ethyl acetate and extracted several times with aqueous sodium bicarbonate solution. The organic phase is dried, filtered and evaporated in vacuo. The residue is purified by silica gel column chromatography (toluene / ethyl acetate = 5/1), first eluting the E-form and then the Z-form.

E-form:

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

Yield: 17.8 g (34.5% of theory), Melting point: 139-141 ° C (ethyl acetate), Calculated: C 75.48%, H 9.15%, N 9.78%, Found: C 75.68%, H 8.99%, N 9.86%.

Example D

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

0.57 g (1.99 mmol) of (Z) -N-acetyl-N - [1- (2-piperidinophenyl) -3-methyl-1-buten-1-yl] -amine, m.p. 141 ° C, is dissolved in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1) under argon and is added to a solution of 16.8 mg (1 mol%) of Noyori catalyst Ru / O-acetyl / ₂ // / s / -BINAP // / // prepared from Ru / COD / Cl // _{n 2} s / s / -BINAP // = / s / 2,2'-bis / diphenylphosphine / -l, 1 ' -binaphthyl), triethylamine and sodium acetate (and 3.4 mg (0.5 mol%)) of titanium tetraisopropoxide in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1). The reaction mixture is drawn into an autoclave which is evacuated to 10 Pa. It is purged several times with hydrogen at 0.4 MPa and the mixture is then hydrogenated at 30 ° C and 10 MPa until saturated with hydrogen (170 hours). The red-brown solution is evaporated in vacuo, the residue is heated to reflux with 30 ml of n-hexane and the insoluble particles are filtered off while hot. Once the filtrate has cooled, crystallization occurs.

Yield: 0.31 g (54% of theory), m.p. 127-131 ° C, enantiomeric purity: ee = 82% (S) // HPLC method: see Example

AND//.

154-156 ° C can be obtained from the insoluble particles obtained by boiling with 30 ml of n-hexane, further boiling with n-hexane, filtering and crystallizing from a hexane solution.

-14GB 280430 B6

Example E (S) -1- (2-Piperidino-phenyl) -3-methyl-1-butylamine g (3.47 mmol) of N-acetyl-N - [(S) -1- (2-piperidinophenyl)] - 3-methyl-1-butyl-N-amine (melting point: 128-133 ° C, ee = 99.4%) is heated under reflux 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 portion is washed with water, dried and filtered and then evaporated in vacuo.

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

Reacetylation with 0.42 ml (1.3 equivalents) of acetic anhydride in 8.4 ml of glacial acetic acid overnight at ambient temperature, evaporation in vacuo, partitioning the residue between ethyl acetate and saturated sodium bicarbonate solution, then drying, filtering and evaporating of organic extract in vacuo yields 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%).

Example F

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

Prepared from isobutyl- (2-piperidin-phenyl) -ketimine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid in a manner similar to that described in Example B. Purification by column chromatography over silica gel (toluene / acetone = 10/1) , the (E) -form eluted first, then the (Z) -form.

/ E / -form:

Yield: 4% of theory. Melting point: 101 - 103 ° C.

Calculated: C 72.77%, H 8.00%, N 5.85%, Found: C 72.74%, H 7.78%, N 5.86%.

/ Z / -form:

Yield: 28.1% of theory,

Melting point: 124 - 127 ° C (petroleum ether / toluene = 5/1),

Calculated: C 72.77%, H 8.00%, N 5.85%, Found: C 72.90%, H 7.86%, N 5.83%. Example G

N - [(S ') -1-phenethyl] - N - [(S) -1- (2-piperidinophenyl) -3-methyl-1-butyl] -amine g (49 mmol) N- // (S ') -1-phenethyl // isobutyl- (2-piperidin-phenyl) -ketimine, boiling point 150-155 ° C (0.3 torr) prepared from isobutyl- (2-piperidin-phenyl) ketone and (S ') - 1-phenethylamine (manufactured by Fluka, ee = 99.6%) in toluene + triethylamine, a solution of titanium tetrachloride in toluene is added dropwise // is

280430 B6 dissolved in 170 ml of anhydrous ethanol. 1.7 g of titanium tetraisopropoxide and 8 g of Raney nickel are added and the mixture is hydrogenated at 50 DEG C. under 20 MPa 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. The catalyst is filtered through a pad of Celite on G3 and the filtrate is evaporated in vacuo.

Yield: 13.1 g (76.6% of theory), Boiling point: 152 ° C / 0.2 torr,

Calculated: C 82.23%, H 9.78%, N 7.99%, Found: C 82.00%, H 10.03%, N 7.74%.

[ _.alpha. ] _D @ ²⁰ = -55.3 DEG (c = 1.1 in methanol).

Diastereomeric purity is determined by HPLC on a Lichosorb RP18 HPLC column, manufactured by E. Merck (Germany), column length: 250 mm, 4 mm ID, particle size: 7 µιη. Elution: methanol / dioxane / 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-Piperidin-phenyl) -3-methyl-1-butylamine

12.5 g (36 mmol) of N - [(S) -1-phenethyl] - N - [(S) -1- (2-piperidinophenyl) -3-methyl-1-butyl] - of the amine with de 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 on charcoal is added and the mixture is enriched with hydrogen at 50 ° C at 0.5 MPa of hydrogen. After hydrogen saturation (10 hours) the mixture is filtered through a pad of celite to filter out the catalyst. The filtrate was basified with concentrated ammonia with ice and extracted with ethyl acetate. The organic layer is dried, filtered and evaporated in vacuo.

Yield: 6.4 g (72.1% of theory), Boiling point: 115-117 ° C / 0.4 torr,

Enantiomeric purity: ee = 93.5% (S) (HPLC method (after 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-piperidinobenzaldimine) // prepared from an equimolar amount of 2-piperidine-benzaldehyde and (R') -1- Phenethylamine standing overnight at ambient temperature followed by drying with sodium sulfate in ether solution // in 20 ml of anhydrous tetrahydrofuran is added dropwise to a solution of 27.4 mmol (4 equivalents) of isobutylmagnesium bromide in 22 ml of anhydrous tetrahydrofuran stirred in a bath. at 60 ° C. After 18 hours the temperature of the bath was raised to

280430 B6 ° C and an additional 2 equivalents of isobutyl magnesium bromide in 11 mL of tetrahydrofuran are added. After stirring for 12 hours, 2 equivalents of isobutyl magnesium bromide are added at 80 ° C. After about 90 hours at 80 ° C, the mixture is cooled, excess concentrated hydrochloric acid is added, and the resulting mixture is evaporated to dryness in a water pump. The residue is dissolved in water and made alkaline with concentrated ammonia. It is extracted with ether, the organic extract is dried over sodium sulfate, filtered and evaporated in vacuo. The residue is purified by column chromatography over silica gel (toluene / acetone = 95/5).

Yield: 0.20 g (8.3% of theory),

Melting point: <20 ° C, Diastereomeric purity determined by HPLC, as in Example G. Found: peak 1 (R, R '): peak 2 (S, R') = 4.4%: 95.6%, de (diastereomeric excess) = 91.2% (S, R ').

In a similar mixture with 2.0 g of Schiff's base and a total of 6 equivalents of isobutylmagnesium bromide in toluene / tetrahydrofuran / 4/1 / and with the addition of 5% titanium (IV) -tetraisopropoxide and heating for 60 hours at 100 ° C in a glass vial a yield of 5% with de 97.6% (S, R ') was obtained.

Example K (S) -1- (2-Piperidin-phenyl) -3-methyl-1-butylamine

A solution of 0.15 g (0.428 mmol) of N - [(R ') -1-phenethyl] - N - [(S) -1- (2-piperidinophenyl) -3-methyl-1-butyl] (amide / de = 91.2%),

0.47 ml (0.47 mmol) of 1N hydrochloric acid and 1.5 ml of water are hydrogenated in the presence of 20 mg of 10% palladium on charcoal for 5 hours at 50 ° C at 50 psi hydrogen. The mixture is filtered through diatomaceous earth, basified with concentrated ammonia and extracted with ethyl acetate. The extract is dried, filtered and evaporated in vacuo.

Yield: 0.066 g (62.8% of theory), Melting point: less than 20 ° C,

Enantiomeric purity: ee = 87.6% (S) (HPLC method) (after 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 triethylamine and 0.18 ml) 1.91 mmol) of carbon tetrachloride was added sequentially to a solution of 0.47 g (1.91 mmol) of (S) -3-methyl-1- (2-piperidinophenyl) -1-butylamine (ee = 98.5%). in 5 ml of anhydrous acetonitrile and the resulting mixture is stirred for 20 hours at ambient temperature. It is then evaporated in vacuo and partitioned between ethyl acetate and water. The organic extract is dried and filtered and evaporated in vacuo. The residue is purified by column chromatography over silica gel (toluene / ethyl acetate = 10/1).

-17GB 280430 B6

Yield: 0.71 g (77.3% of theory),

Melting point: 110 - 112 ° C,

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

Enantiomeric purity is determined by HPLC on a Baker phase HPLC column in which / S / -N-3,5-dinitrobenzoyl-leucine is covalently bound to aminopropyl silica gel / particle size: 5 μιη, spherical, pore size 60 A, column length: 250 mm, 4.6 mm ID, eluent: n-hexane / tetrahydrofuran / methylene chloride / ethanol / 90/10/1/1 /, flow rate 2 ml / min, temperature: 20 ° C, UV detection at 242 nm /.

Found: peak 1 (R): peak 2 (S) = 0.75%: 99.25%, ee = 98.5% (S) -.

Example 2

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

2.77 g (11 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid is added to a solution of 2.71 g (11 mmol) of anhydrous (S) -3-methyl-1- (2-piperidine) at ambient temperature. phenyl (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 is then added and the mixture is stirred at ambient temperature. After 24 hours, 0.54 g (2.14 mmol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid and 0.48 g (2.33 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred overnight. It is then cooled to an internal temperature of + 5 ° C and the precipitate is collected by suction filtration and washed once with toluene. The combined toluene filtrates are evaporated in vacuo to a volume of approximately 10 mL. The resulting solution is heated in a steam bath and petroleum ether (55 ml total) is added in portions until turbidity remains. It is cooled in ice, where crystallization occurs. It is filtered with suction and dried at 75 ° C at 4 torr. The product obtained (4.57 g, m.p. 111-112 ° C, ee = 98.9%) is suspended in 50 ml of petroleum ether. The mixture is heated in a steam bath and sufficient toluene is added in portions (total 8 ml) to form a solution. It is then cooled in ice and filtered with suction until crystals are separated which are dried at 75 ° C and 530 Pa.

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

Calculated: C 72.47%, H 8.39%, N 5.83%, Found: C 72.44%, H 8.43%, N 5.93%, // a // ² % = + 9 4 ° (c = 1.01 in methanol). Enantiomeric purity: ee = 99.9% (HPLC method: see Example 1).

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

-18GB 280430 B6

A solution of 3.79 g (7.88 mmol) of ethyl (S) -2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] - of benzoate (ee = 99.9%) in 37 ml of ethanol is stirred in a 60 ° C bath and 10 ml of 1N sodium hydroxide solution is added. After stirring at 60 ° C for 4 hours, 10 ml (10 mmol) of 1N hydrochloric acid are added warm and the mixture is allowed to cool to ambient temperature. After inoculation and standing overnight, the mixture is cooled in the ice for an additional hour with stirring. The crystals are 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 at 350 Pa in a vacuum drying apparatus over phosphorus pentoxide.

Yield: 3.13 (87.7% of theory), Melting point: 130-131 ° C (high melting form), Calculated: C 71.64%, H 8.02%, N 6.19%.

Found: C 71.48%, H 7.87%, N 6.39%, [α] ²⁰ _D = + 7.45 ° (c = 1.06 in methanol).

Enantiomeric or made by ChromTech / Sweden / glycoprotein / phase, internal dimension: 4.0 particle size: 5 μιη.

Temperature: 20 ° C, eluent: 0.1% purity is determined by HPLC on an AGP phase HPLC / alpha-acidic mm, length: 100 mm, KH ₂ PO ₄ / = A / + 20% acetonitrile / = B), the gradient is increased to 40% (B) over 4 minutes, flow rate: 1 ml per minute, 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 ethanol / water (2/1), the melting point does not change. When the sample is heated in a mixture of petroleum ether / toluene (5/3), the undissolved portion is filtered (melting point: 130-131 ° C) and the filtrate is quenched to give a lower melting form of the title compound, mp 99-101 Deň: 32 ° C.

Calculated: C 71.64%, H 8.02%, N 6.19%. Found: C 71.66%, H 7.97%, N 6.44%.

The lower melting and higher melting forms differ from each other in their infrared KBr spectrum, but not in their infrared spectrum in solution (methylene chloride).

If the lower melting sample is heated beyond its melting point, a second melting point is observed at 127-130 ° C.

When the lower melting point sample is recrystallized from ethanol / water (2/1), a higher melting point form is obtained.

High melting and lower melting molds were examined by differential calorimetry (DSC) / Mettler apparatus, TA-300 system, measuring cell: DSC 20, manufactured by Mettler, CH-8306 Greifensee, Switzerland / with the following results:

-19GB 280430 B6

Example 3 compound Heating rate 10 ”K / min Heating rate 3 ° K / min Form Uniform peak of melting Uniform peak of melting with higher heat- with a melting point of 133 ° C, melting point 132 by melting enthalpy of melting enthalpy of melting: 100 J / g 99.1 J / g Form 1st peak at 57 ° C 1st peak at 54 ° C with lower heat- / very weak /, very weak by melting 2nd peak at 78 ° C endothermic /, /weak/ 2. endothermic 3. endothermic melting point 102 ° C, peak at 107 ° C, enthalpy of melting enthalpy of melting 52 J / g 55 J / g 3. exothermic pathway 4. endothermic zákl. line using peak at 132 ° C, crystallization of the substance, enthalpy of melting melting at 104 ° C, 25 J / g. 4. endothermic peak at 131 ° C melting point 130 ° C, melting enthalpy 52 J / g.

Example 4

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

0.79 g (1.65 mmol) of ethyl (Z) -2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-buten-1-yl) aminocarbonylmethyl) 124 DEG-127 DEG C. is dissolved in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1) under argon and this is added to a solution of 17 mg NOYORI catalyst Ru (O-acetyl). ₂ // (S) -BINAP // / prepared from / Ru / COD / Cl ₂ // _n s / S / -BINAP // = / S / -2,2'-bis- / diphenylphosphino / 1,1 ' -binafyl], triethylamine and sodium acetate (and 3 mg of titanium tetraisopropoxide in 10 ml of degassed solvent mixture (methanol / methylene chloride = 5/1)). The reaction mixture is drawn into an autoclave evacuated at 10 ^-2 mbar. This is five times saturated with hydrogen at 0.5 MPa and finally enriched with hydrogen at 30 ° C and 10 MPa until saturated with hydrogen (154 hours). The red-brown solution is evaporated in vacuo, the residue is dissolved in 80 ml of ether, the insoluble brown flakes are filtered off with activated charcoal and the resulting clear, clear yellow filtrate is evaporated in vacuo. The residue (0.60 g) is heated under reflux in 60 ml of n-hexane and the insoluble particles are filtered off while hot. The filtrate is allowed to stand overnight at ambient temperature. The crystals which precipitated are filtered off.

Yield: 0.45 g (56.7% of theory),

Melting point: 131 - 133 ° C (after sintering from 120 ° C), Enantiomeric purity: ee = 39% (S) // HPLC method: see example

1 // ·

-20GB 280430 B6

Example 5

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-) - -piperidine-phenyl / -3-methyl-1-butyl / -aminocarbonylmethyl // benzoate / melting point: 125-126 ° C, [α] ²⁰ _D = + 12.87 ° / c = 1.01 % methanol / 5 ml of anhydrous dimethylformamide and the mixture is stirred for 0.5 hour at ambient temperature. A solution of 0.12 ml (1.15 mmol) of ethyl iodide in 2.5 ml of anhydrous dimethylformamide is then added dropwise and the mixture is stirred for 5 hours at ambient temperature. Evaporate in vacuo, partition the residue between dilute sodium hydroxide solution and chloroform. The organic extract is dried, filtered and evaporated in vacuo. The residue is purified by column chromatography over silica gel (toluene / ethyl acetate = 10/1).

Yield: 0.48 g (67% of theory), m.p. 110-112 ° C,

Calculated: C 72.47%, H 8.39%, N 5.83%, Found: C 72.61%, H 8.54%, N 5.97%, Enantiomeric purity: ee = 98.5% / HPLC method: see Example 1 //.

Example 6

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

Prepared from (S) -2-hydroxy-4- [N- (1- (2-piperidine phenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoic acid in a manner similar to that described in Example 5 using 2 equivalents of sodium hydride with 2 equivalents of ethyl iodide.

Yield: (42% of theory),

Melting point: 110 - 112 ° C,

Calculated: C 72.47%, H 8.39%, N 5.83%,

Found: C 72.61%, H 8.54%, N 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- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoate is divided in 10 mg doses per preparative a chiral phase HPLC column manufactured by Baker in which is [S] -N-3,5-di

-21EN 280430 B6 nitrobenzoyl-leucine covalently bound to aminopropyl-silica gel / particle size: 40 μιη, column length: 250 mm, internal dimension 20 mm, eluent: n-hexane / tetrahydrofuran / ethanol / methylene chloride / 180/20/3 (2), flow rate: 21.25 ml per minute, temperature: 27 ° C, UV detection at 285 nm, in which the (R) - (enantiomer) peak 1 is first followed by (S) / + The (-enantiomer) peak 2) eluted. After evaporation in vacuo, the following consistently separated fractions are obtained:

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

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

To remove any impurities (including the 2,6-di-tert-butyl-4-methylphenol stabilizer contained in tetrahydrofuran), the two fractions are each separately purified on a chromatography column over silica gel (toluene / acetone = 10/1).

(R) / - / - enantiomer:

Yield: 234.5 mg (51% of theory),

Melting point: 122 - 124 ° C (petroleum ether + acetone),

Calculated: C 72.47%, H 8.39%, N 5.83%,

Found: C 72.40%, H 8.18%, N 5.71%, [α] ²⁰ _D = -8.3 ° (c = 1 in methanol).

(S) -enantiomer:

Yield: 131.2 mg (28.5% of theory);

Melting point: 122 - 124 ° C (petroleum ether / acetone = 8/1),

Calculated: C 72.47%, H 8.39%, N 5.83%,

Found: C 72.28%, H 8.44%, N 5.70%, [α] ²⁰ _D = + 8.3 ° (c = 1 in methanol).

An OD column made by Daicel is also suitable for the separation of enantiomers. The (R) -enantiomer is eluted after 6.8 minutes and the (S) -enantiomer after 8.5 minutes on a 250 mm long 4.6 mm internal column (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-piperidinophenyl) -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, [α] ²⁰ _D = -8.3 ° (c = 1 in methanol), by saponification with solution

1N sodium hydroxide in ethanol in a manner similar to that described in Example 3.

Yield: 95.8 mg (66.7% of theory),

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

Calculated: / x 0.4 H ₂ 0 / C 70.51%, H 8.01%, N 6.09%;

Found: C 70.88%, H 7.79%, N 5.81%,

-22GB 280430 B6

Molecular peak M ⁺ : Calculated: 452,

Found: 452, [?] ²⁰ _D = -6.5 ° (c = 1 in methanol),

Enantiomeric purity: ee = 99.7% (R) // HPLC method: see example

3 // ·

Example 9 (S) [+] - 2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -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 / melting point: 122-124 ° C, // and // ² ° _D = + 8.3 ° (c = 1 in methanol) by saponification with a 1N solution of sodium hydroxide in ethanol in a manner similar to that described in 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: C 70.80%, H 8.06%, [α] ²⁰ _D = + 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-piperidinophenyl) -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 (melting point: 91-92 ° C, // α // ²⁰ ° = + 9.5 °, c = 1.05 in methanol) is hydrogenated in 10 ml of ethanol using 0.12 g (10%) of palladium on activated carbon at 50 ° C and 0.5 MPa of hydrogen. After 5 hours, the catalyst is filtered through diatomaceous earth and evaporated in vacuo. The residue is 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: C 71.76%, H 8.12%, N 6.05%, Enantiomeric purity: ee = 99.6% / HPLC method: see Example 3).

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

-23GB 280430 B6

102 mg (0.20 mmol) of tert-butyl (S) -2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoate (melting point: 122-123 DEG C., [ _.alpha. ] _D @ ²⁰ = + 8.7 DEG, c = 1 in methanol) is heated under reflux in 5 ml of benzene together with a few crystals of p-toluenesulfonic acid hydrate for a period of time. mid-day. The desired product is then obtained by thin layer chromatography, 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-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoic acid

200 mg (0.395 mmol) of tert-butyl (S) -2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoate / temperature mp: 122-123 "C, // and // ² ° _D = + 8.7 °, c = 1 in methanol / is mixed into 2 ml of methylene chloride together with 0.45 g / 3.95 mmol / trifluoroacetic acid during night at ambient temperature. The mixture is evaporated in vacuo and the residue is partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic extract is dried, filtered and evaporated in vacuo. The residue is 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: C 71.39%, H 7.91%, N 6.06%, // α // ² θβ = + 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 ingredient

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 ingredient and excipients are dissolved in water at 90 ° C or in microcrystalline cellulose, suspended, and the dispersion is evaporated in vacuo. The dry mass is forced through a 1 mm sieve.

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

-24GB 280430 B6

24.862 mg of sodium carbonylmethyl starch

24,000 mg microcrystalline cellulose

0.500 mg magnesium stearate

50,000 mg

Round, biplanar tablets weighing 50 mg and 5 mm in diameter are extruded from this mixture.

Example 14

Tablets containing 0.5 mg AG-EE 623 ZW

Each tablet contains:

0.500 mg of active ingredient

0.250 mg of N-methylglucamine

0.075 mg of polyvinylpyrrolidone

0.150 mg of polyoxyethylene polyoxypropylene polymer

0.300 mg microcrystalline cellulose.

Preparation:

The active ingredient and excipients are dissolved in water at 90 ° C, to which microcrystalline cellulose is suspended and the dispersion is evaporated in vacuo. The dry mass is passed through a sieve with a mesh size of 1 mm.

The following ingredients are added to the granulated active ingredient for each tablet:

24.225 mg of sodium carboxymethyl starch

24,000 mg microcrystalline cellulose

0.500 mg magnesium stearate

50,000 mg

Round biplanar tablets of 50 mg in weight and 5 mm in diameter are extruded from this mass.

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 ingredient and excipients are dissolved in water at 90 ° C, to which microcrystalline cellulose is suspended and the dispersion is evaporated in vacuo. The dry mass is passed through a sieve with a mesh size of 1 mm.

-25GB 280430 B6

The following ingredients for each tablet are added to the granulated active ingredient:

23.22 mg of sodium carboxymethyl starch

24.00 mg of microcrystalline cellulose

0.50 mg of magnesium stearate

50,00 mg

From this mixture, round biplanar tablets, weighing 50 mg, of 5 mm diameter are formed.

Example 16

Tablets containing 1.5 mg AG-EE 623 ZW

Each tablet contains:

1,500 mg of active ingredient

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 ingredient and excipients are dissolved in water at 90 ° C, to which microcrystalline cellulose is suspended and the dispersion is evaporated in vacuo. The dry mass is passed through a sieve with a mesh size of 1 mm.

The following ingredients for each tablet are added to the granulated active ingredient:

23.080 mg of sodium carboxymethyl starch

23,000 mg microcrystalline cellulose

0.500 mg magnesium stearate

50,000 mg

Round biplanar tablets of 50 mg in weight and 5 mm in diameter are extruded 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.

Preparation:

The components are dissolved in water at a temperature of 90 ° C, to which is dissolved

Microcrystalline cellulose is affected and the dispersion is further processed. The following ingredients are then added to each tablet:

20.35 mg of microcrystalline cellulose

20.00 mg of sodium carboxymethyl starch

0.65 mg of magnesium stearate

50,00 mg

Round biconvex tablets weighing 50 mg and 5 mm in diameter are extruded from this mixture and are flavored on the surface with hydroxypropyl methylcellulose.

Example 18

Tablets containing 2.5 mg AG-EE 623 ZW

Each tablet contains:

2.50 mg of active ingredient

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 ingredients are dissolved in water at 90 ° C, into which microcrystalline cellulose is dispersed and the dispersion is further processed in a spray-drying apparatus. The following ingredients are then added to each tablet:

19.50 mg microcrystalline cellulose

19.50 mg of sodium carboxymethyl starch

0.65 mg of magnesium stearate

50,00 mg

Round biconvex tablets weighing 50 mg and 5 mm in diameter are extruded from this mixture and are flavored on the surface with hydroxypropyl methylcellulose.

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 polyoxymethylene polyoxypropylene polymer.

Preparation:

The ingredients are dissolved in water at 90 ° C and the solution is further processed in a spray-drying apparatus. The following substances are then added for each tablet:

-27GB 280430 B6

21.5 mg of microcrystalline cellulose

21.00 mg of sodium carboxymethyl starch

50,00 mg

Round biconvex tablets weighing 50 mg and 5 mm in diameter are extruded from this mixture and are flavored on the surface with hydroxypropyl methylcellulose.

Example 20

Tablets containing 5 mg AG-EE 623 ZW

Each tablet contains:

5.0 mg of active ingredient

2.5 mg of L-lysine

2.5 mg of polyvinylpyrrolidone

2.5 mg of polyoxyethylene polyoxypropylene polymer.

Preparation:

The ingredients are dissolved in water at 90 ° C and the solution is further processed.

The following substances are then added for each tablet:

19.0 mg microcrystalline cellulose

18.5 mg of sodium carboxymethyl starch

50,00 mg

From this mixture, round biconvex tablets with a weight of 50 mg and a size of 5 mm in diameter are formed and are surface-treated with hydroxypropyl methylcellulose.

Claims (8)

PATENT CLAIMS (S) (+) - 2-ethoxy-4- / N / 1- (2-piperidinophenyl) -3-methyl-1-butyl / aminocarbonylmethyl / benzoic acid and its salts with inorganic or organic acids or bases. The acid of claim 1, having an optical purity of at least 95%. The acid of claim 1, having an optical purity of at least 98%. The acid of claim 1, in the form of physiologically acceptable salts with organic or inorganic acids or bases. Pharmaceutical composition for the treatment of diabetes, characterized in that it comprises, as its active ingredient, an acid according to claims 1 to 3, or a physiologically acceptable salt thereof according to claim 4, together with one or more inert carriers and / or diluents. Use of an acid according to claims 1 to 3, or a physiologically acceptable salt thereof according to claim 4, for the manufacture of a pharmaceutical composition for the treatment of diabetes mellitus. (S) -3-methyl-1- (2-piperidinophenyl) -1-butylamine and its acid addition salts as an intermediate for the preparation of an acid according to claim 1. 8. New piperidine derivatives of formulas III, IV and VII, (III), (IV) -29EN 280430 B6 (VII) PH CH3 ^CH3 _X / CH where A represents an alkoxycarbonyl group having a total of 2 to 5 carbon atoms in which the alkyl part of the alkoxy group is optionally substituted by a phenyl radical, W 'represents a carboxyl group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl part of the alkoxy group being optionally substituted by a phenyl group; and W '' represents a formyl or hydroxymethyl group, as well as addition salts of these compounds as intermediates for the production of the acid according to claim 1.