FI83417B - FOERFARANDE FOER FRAMSTAELLNING AV FARMAKOLOGISKT VAERDEFULLA PHENYLETTETYRADERIVAT. - Google Patents

Abstract

1. Phenylacetic acid derivatives of general formula see diagramm : EP0208200,P24,F1 wherein R1 represents a pyrrolidino, piperidino, 4-methylpiperidino, 3-methyl-piperidino, 3,3-dimethyl-piperidino, 3,5-dimethyl-piperidino or hexamethyleneimino group, R2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group, R4 represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an allyl group, R3 represents an alkyl group with 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, in which the cycloalkyl part may contain 3 to 7 carbon atoms, an alkenyl group with 3 to 5 carbon atoms or an alkynyl group with 3 or 4 carbon atoms, and W represents methyl, hydroxymethyl, formyl, carboxy or alkoxycarbonyl group, whilst the alkoxy part may contain from 1 to 4 carbon atoms and may be substituted by a phenyl group, and the enantiomers and salts thereof.

Description

1 83417

The present invention relates to a process for the preparation of pharmacologically valuable phenylacetic acid derivatives of the formula (I): The present invention relates to a process for the preparation of pharmacologically valuable phenylacetic acid derivatives of the formula (I) and to a process for the preparation of pharmacologically valuable phenylacetic acid derivatives.

? CH-NH-CO-CH2-Y-W

^ m

Rl 0R <where

R 1 is a piperidino group, R 4 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an allyl group, R 3 is an alkyl group having 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, wherein the cycloalkyl moiety contains 3 to 7 carbon atoms, 3 to 5 alkyl groups An alkynyl group having 3 or 4 carbon atoms and W is a carboxy or alkoxycarbonyl group, wherein the alkoxy moiety contains 1 to 4 carbon atoms and may be substituted by a phenyl group, their enantiomers and salts thereof.

However, the new compounds have valuable pharmacological properties, in particular an effect on intermediate metabolism, but preferably a blood sugar lowering effect.

The meanings already mentioned in the definitions of the groups R3, R4 and W are, for example, the following: 2 83417

Ra is 1-propen-1-yl, 2-methyl-1-propen-1-yl, 3-methyl-2-buten-1-yl, 2-propen-1-yl, 2-methyl- 2-porpen-1-yl-, 2-buten-1-yl-, 2-methyl-2-buten-1-yl-, 3-methyl-2-buten-1-yl-, 3-buten-1- yl, 2-methyl-2-buten-1-yl, 3-methyl-3-buten-1-yl, 2-hexen-1-yl, 1-propin-1-yl, 2-propyl - 1-yl, 2-butyn-1-yl, 2-Pentin-1-yl, tetrahydrofuran-2-ylmethyl, 2- (terahydrofuran-2-yl) ethyl, tetrahydrofuran-3 -yl-methyl-, tetrahydropyran-2-ylmethyl, 2- (tetrahydropyran-2-yl) -ethyl, tetrahydropyran-3-ylmethyl, cyclopropylmethyl, succiobutylmethyl, cyclopentylmethyl, cyclohexylmethyl- , a cycloheptylmethyl, 2-cyclopropylethyl, 2-cyclobutylethylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl or 2-cycloheptylethyl group and R4 is a hydrogen atom, methyl, ethyl, n-propyl , isopropyl or allyl group, W is carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbon Y1-, n-butoxycarbonyl, sec-butoxycarbonyl, irobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxycarbonyl or 3-phenylpropoxycarbonyl

Preferred compounds of general formula I above are those in which R1 is a piperidino group, R4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

Ra is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl, hydroxymethyl, ethoxymethyl, acetoxymethyl, benzyl or tetrahydrofuranylmethyl group, a cycloalkylmethyl group, a cycloalkylmethyl group in which the cycloalkyl moiety may contain 3 to 7 carbon atoms or an alkyl group having 3 to 7 carbon atoms;

Ra is a cycloalkylmethyl group in which the cycloalkyl moiety may contain 3 to 7 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a propargyl group, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydropyran-2-ylmethyl or a tetrahydropyran-3-ylmethyl group, and W is a carboxy, methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl group, particularly preferred are compounds in which R1 is a piperidino group, R4 is a methyl or ethyl group,

Ra is a cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydrofuran-2-ylmethyl, allyl, methallyl, 2-methylvinyl, 2,2-dimethylvinyl or propargyl group, W is carboxy , a methoxycarbonyl or ethoxycarbonyl group, and in particular those compounds in which

R1 is piperidino R4 ethyl,

Ra is cyclohexylmethyl or cyclopropylmethyl and W is carboxy or ethoxycarbonyl their enantiomers and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

Very particularly preferred compounds of the above general formula I are those in which W is a carboxy group.

4,83417

According to the invention, the novel compounds are obtained by the following methods: a) An amine of the general formula

Ra aCH-NH * where

R1 to Ra are as defined above, reacting a carboxylic acid having the general formula HOOC - CH2 - ^ W (III) OR4 wherein R4 is as defined above and W 'is as defined above with W, or a protected carboxy group or any of the compounds prepared in the reaction mixture. with reactive derivatives and, if necessary, the cleaved protecting group is then cleaved off.

Suitable reactive derivatives of the compound of the general formula III are, for example, their esters, such as methyl, ethyl or benzyl ester, their thioesters, such as methyl thio or ethyl thioester, their halides, such as acid chloride, their anhydrides or imidazolides.

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, 5,83417 in toluene, acetonitrile or dimethylformamide. azide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N-carbonsyldiimidazole or Ν, Ν'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride and optionally in the presence of an inorganic base such as triethylamine or pyridine, which can simultaneously act as solvents, at temperatures between -25 ° C and + 25 ° C, most preferably at temperatures between -10 ° C and the boiling point of the solvent used. However, the reaction can be carried out without a solvent, and the water formed during the reaction can be separated by azeotropic distillation, e.g. by heating with toluene in a water separator, or by adding a desiccant such as magnesium sulfate or a molecular sieve.

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

The tert-butyl group used for the protecting group may also be cleaved off by heat, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and most preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, phosphoric acid, sulfuric acid, sulfuric acid.

6,83417

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

b) For the preparation of compounds of general formula I in which W represents a carboxy group.

The compound of general formula IV is hydrolysed, thermolysed, hydrogenolysed or alcoholized

_ / "V

aCH - NH - CO - CH2 — V XV-A

\ = <

R10R4 where

R 1, R 5 and R 4 are as defined above, A is a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis.

Suitable hydrolyzable groups are, for example, functional derivatives of the carboxy group, such as their unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides, nitrile group, tetrazolyl group, optionally substituted 1,3-oxazole or 1,3-oxazolin-2-yl group, suitable thermolytically cleavable groups are, for example, esters with tertiary alcohols, e.g. tert-butyl ester, hydrogenolytically cleavable suitable are, for example, aralkyl groups, e.g. benzyl group, and 7,83417 .

The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / ethanol, water / isopropanol or water / diol. 10 and 120 ° C, e.g. at room temperature to the boiling point of the reaction mixture, and the alcoholysis of the cyano group is best carried out in excess of the corresponding alcohol such as methanol, ethanol or propanol or at elevated temperatures in the presence of an acid such as hydrogen chloride, e.g.

If A in a compound of general formula IV represents a nitrile or aminocarbonyl group, these groups can be converted into the corresponding carboxy compound with 100% phosphoric acid at temperatures between 100 and 180 ° C, preferably at temperatures between 120 and 160 ° C, or also with nitrite, e.g. sodium nitrite. , in the presence of an acid such as sulfuric acid, which is suitably used simultaneously as a solvent, at temperatures between 0 and 50 ° C.

If A in a compound of general formula IV represents e.g. a tert-butyloxycarbonyl group, then the tert-butyl group can also be cleaved off by heat in a potentially inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalyst such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, most preferably at the boiling point of the solvent used, e.g. at temperatures between 40 and 100 ° C.

8 83417

If A in a compound of general formula IV represents e.g. a benzyloxycarbonyl group, the benzyl group can also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, methanol / water, dimethylformate, ethanol / water, glacial acetic acid, acetic acid, acetic acid 0 and 50 ° C, e.g. at room temperature, and at a hydrogen pressure of 1 to 5 bar. In hydrogenolysis, the halogen-containing compound can be simultaneously dehalogenated, the double or triple bond present can be hydrogenated, and the benzyloxycarbonyl group present can be converted to a carboxy group.

c) For the preparation of compounds of general formula I in which R 1 is an alkyl group having 1 to 3 carbon atoms or an alkyl group:

Compound of general formula VI

aCH - NH - CO - CH2-V y-W

N = <<VI>

R1 OH

where

R 1, R 5 and W are as defined above, are reacted with a compound of general formula VII X - Re, (VII) - wherein

Re is an alkyl group having 1 to 3 carbon atoms or an allyl group, and X is a nucleophilically exchangeable group such as a halo-Sene atom, a sulfonyloxy group or also, together with an adjacent - hydrogen atom, a diazo group when R «is an alkyl group having 1 to 3 carbon atoms, followed by hydrolysis if necessary.

9,83417

The reaction is conveniently carried out with the corresponding halide, sulfonic acid ester, sulfuric acid diester or diazoalkane, e.g. methyl iodide, dimethyl sulphate, ethyl bromide, diethylsulphonate sulphonylate, propyl bromide, isopropyl bromide, isopropyl bromide. isopropyl ester or diazomethane 11a, optionally in the presence of a base such as sodium hydride, potassium carbonate, sodium hydroxide, potassium tert-butylate or triethylamine in a suitable solvent such as acetone, diethyl ether, tetrahydrofuran, dioxane or dimethylformamide at 100 ° C and 50 ° C.

If W in the compound of general formula VI is carboxy, then this compound can be simultaneously converted into the corresponding ester compound. The compound thus obtained is converted, if necessary, by cleavage of the ester group into the desired compound of general formula I.

Cleavage of the ester group hydrolytically takes place, as appropriate, either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, methanol / water, ethanol / water, ethanol, ethanol, ethanol, ethanol at temperatures between -10 and; + 120 ° C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture.

d) For the preparation of compounds of general formula I in which; R1 and R3 have the same meaning as above, and. R 1 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, ίο 8341 7 f W is a carboxy or alkoxycarbonyl group, wherein the alkoxy moiety may contain 1 to 4 carbon atoms, a compound of general formula VIII t

Rs

? CH-OH

„Where

R 1 and R 5 are as defined above, are reacted with a compound of general formula IX

NsC-CH 2 - ^ (IX) OR 4 r. wherein R 4 is as defined above and W "is a carboxy or alkoxycarbonyl group, wherein the alkoxy moiety may contain 1 to 4 carbon atoms.

The reaction is carried out in the presence of a strong acid which can simultaneously act as a solvent, preferably in concentrated sulfuric acid, at temperatures between 0 and 150 ° C, preferably at temperatures between 20 and 100 ° C.

.'e) For the preparation of compounds of general formula I in which R 4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 3 is substituted by tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl. A 2-carbon alkyl group 11 8341 7 in which the cycloalkyl moiety may contain 5 to 7 carbon atoms and W is a carboxy or alkoxycarbonyl group in which the alkoxy moiety may have 1 to 4 carbon atoms is reduced by a compound of general formula X

aD - C - CH 2 · - ^ 7 — W

(X)

R10R4 where

R1 / R4 and W have the same meaning as above and D is a group of formula R7. Re n

C

NH- wherein R7 and Re together with the carbon atom between them are an alkydene group having 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, wherein the cycloalkyl moiety may contain 5-7 carbon atoms. e

The reduction is best performed with hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon or Raney nickel in a suitable solvent such as methanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide and benzene / benzene, benzene or benzene, benzene or benzene. ° C, preferably at temperatures between 20 and 50 ° C, at a hydrogen pressure of 1-5 bar. When using a suitable chiral hydrogenation catalyst such as a metal ligand complex, e.g. [(2S), (4S) -1-tert-butoxycarbonyl] 83417-yl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidin-rhodium-cyclooctadiene (1,5)] perchlorate, the incorporation of water occurs enantioselectively. In addition, other groups may be involved in the catalytic hydrogenation, e.g. a benzyloxy group to a hydroxy group or a formyl group to a hydroxymethyl group, or replaced by hydrogen atoms, e.g. a halogen atom to a hydrogen atom.

If, according to the invention, a racemic compound of the general formula I is obtained in which Ra has the same meaning as above, with the exception of hydrogen, this can be separated into its enantiomers via its diastereomeric adducts, clots, salts or derivatives.

Post-racemate cleavage is best performed by column or HPL chromatography to form diastereomeric adducts or complexes in the chiral phase.

The compounds of the general formula I obtained according to the invention can be further converted into their salts and, for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids or also with bases. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, etharic acid oxide, calendoxic acid, glutamic acid, glutamic acid, glutamic acid, sodium hydroxide, -amine, lysine or arginine.

The compounds of the general formulas II to X used as starting materials • are known in part from the literature or are obtained by methods known per se.

is 8341 7

Thus, e.g. , hydrolyzing or hydrazinolysing the corresponding talimido compound, reacting the corresponding ketone with ammonium formate and then hydrolyzing or with the ammonium salt in the presence of sodium cyanoborohydride, reducing the corresponding oxime with lithium aluminum hydride, catalytically activated, catalytically activated or n-phenylethyl shiffine base, e.g. with a complex metal hydride in ether or tetrahydrofuran at temperatures between -78 ° C and the the boiling point of the solvent followed by cleavage of the benzyl or 1-phenylethyl group by catalytic hydrogenation, lithium treatment with the corresponding benzylidene imidobenzyl compound, e.g. lithium diisopropylamide at temperatures between -78 and + 20 ° C, followed by reaction with the corresponding halogen. e.g. sodium cyanide ammonium carbonate in ethanol / water to the corresponding hydantoin derivative, by hydrolysis and, if necessary, subsequent esterification and, if necessary, subsequent reduction, e.g. with a complex metal hydride in ether or tetrahydrofuran.

The amine of general formula II thus obtained, which has a chiral center, can be separated into its enantiomers by racemate cleavage, e.g. diastereomeric compounds, separating these and then cleaving.

Furthermore, the optically active amine of general formula II can also be prepared enantio-selectively by reduction of the corresponding ketimine with a complex boron or aluminum hydride having hydride hydrogen atoms replaced by optically active alcoholate groups, or hydrogen in the presence of a suitable Chiral hydrogenation catalyst or N - (1-phenethyl) -ketimine or N-acyl-ketimine or enamide, respectively, and optionally thereafter by cleavage from benzyl, 1-phenethyl or acyl groups.

Furthermore, the optically active amine of the general formula II can also be prepared diastereo-selectively by reducing the corresponding ketimine or hydrazone substituted on the nitrogen atom by a chiral group with a complex or also a non-complex boron or aluminum hydride, in which some hydrides are optionally replaced by corresponding alcohol, phenolate or phenate. also with alkyl groups, or with hydrogen in the presence of a suitable hydrogenation catalyst and optionally thereafter by cleavage of the chiral auxiliary group by catalytic hydrogenolysis or hydrolysis.

Furthermore, the optically active amine of general formula II can also be prepared diastereo-selectively by adding the corresponding organo metal compound, preferably a Grignard or lithium compound, to the corresponding nitrogen-substituted chiral aldimine, followed by hydrolysis and optionally hydrogenation of the chiral apyrolysis group. or by hydrolysis.

The compounds of the general formulas IV, V and VI used as starting materials are obtained by reacting the corresponding amine with the corresponding carboxylic acid or its reactive derivatives and, if appropriate, subsequently cleaving off the protecting group used.

The starting compound of general formula X is obtained by reducing the corresponding carbonyl compound, reacting the corresponding carbonyl compound with the corresponding Grignard or lithium reagent, and hydrolyzing or alcoholizing the corresponding cyanohydride, followed, if necessary, by esterification.

The compound of general formula X used as starting material is obtained by acylation of the corresponding ketimine or a metallo-organic complex thereof with the corresponding carboxylic acid or with its reactive derivatives, optionally by tautomerization.

It has already been mentioned above that the new compounds of the general formula I and their physiologically acceptable salts have valuable pharmacological properties, namely an effect on intermerium-terminal metabolism, in particular, however, a hypoglycemic effect. For example, the hypoglycemic property of the following compounds was studied and compared with each other as follows: A = 2-Ethoxy-4- [N-cyclohexylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl] benzoic acid (e.g. 2)

Av = 4 - [(α-cyclohexyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid (Compound 32 in Example 9, EP-A-0.058.799), i.e. 8341 7 B1 = 2-ethoxy-4- [ N- (1- (2-piperidino-phenyl) -4-penten-1-yl) -aminocarbonylmethyl} -benzoic acid (e.g. 24), B2 = 2-ethoxy-4- [N- (1- (2-piperidinophenyl)) -3-buten-1-yl) aminocarbonylmethyl] benzoic acid (e.g. 16) and B3 = 2-ethoxy-4- [N- (α: -cyclopropylmethyl-2-piperidino-benzyl) aminocarbonylmethyl] benzoic acid hemihydrate ( eg 4)

Bv = 4 - [(1- (2-piperidinophenyl) -4-penten-1-yl) aminocarbonylmethyl] benzoic acid x 0.67 H2O (Compound 18 in Example 3, DE-A-3,225,188 = e.g. 26f, EP-A-0.099.017),

Cv = 4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzonitrile (e.g. 13a, EP-A-0.099.017) and

Dv = 4 - [(2-phenyl-1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl] -methyl] -benzoic acid (Compound 9, in Example 3, DE-A-3,255,188 = Example 26c EP-A-0099017).

Blood glucose lowering effect

The hypoglycemic effect of the test substances was studied in self-reared female rats weighing 180 to 220 g and fasted for 24 hours before the start of the experiment. The test substances were suspended in 1.5% methylcellulose immediately before the start of the experiment and administered by gavage.

11 I, 83417

Blood was drawn immediately before and 1, 2, 3, and 4 hours after application, respectively, retro-orbitally from the venous plexus. In each case, 0.5 ml of 0.33 N perchloric acid was deproteinized from 50 microliters and centrifuged. Glucose was determined from the supernatant by the hexokinase method using an analytical totometer. Statistical evaluation was performed by t-test (student) using significance limits p = 0.05.

The following tables show the values obtained as a percentage of the control: TABLE a) 1 mg / kg 0.5 mg / kg

Compound 1234 1234 te_hour__hour_ A was not studied -22 -47 -45 -45

Av -27 -14 n.s. socalled not studied B1 not studied -44 -37 -28 -27 B2 not studied -42 -39 -28 -35 B3 not studied -45 -45 -36 -36

Bv -42 -35 -28 -18 was not studied

Cv * _not studied_ * no significant activity could be detected at a dose of 10 mg / kg n.s. = not statistically significant TABLE b) 1 mg / kg 0.5 mg / kg

1234 1234 te_hour_hour_

Pv_-24_-27 -13 -18 -19 -21 -11 n.s._ ie 83 41 7

When studying the hypoglycemic effect of the compounds, no toxic side effects could be observed even at 10 mg / kg p.o. dose.

Due to their pharmacological properties, the compounds of the general formula I according to the invention and their physiologically acceptable salts are suitable for the treatment of diabetes mellitus. For this purpose, they can be processed, optionally in combination with other active ingredients, into customary galenic formulations, such as tablets, granules, capsules, powders or suspensions. The single dose for adults is then 1-50 mg, preferably 2.5-50 mg, 1 or 2 times a day.

The following examples further illustrate the invention:

Example 1 2-Ethoxy-4- [N- (o-cyclohexylmethyl-2-piperidino-benzyl] aminocarbonylmethyl] -benzoic acid ethyl ester

To a solution of 1.13 g (3.96 mmol) of α-cyclohexylmethyl-2-piperidinobenzylamine and 11 ml of acetonitrile is added successively 1 g (3.96 mmol) of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid, 1.25 g (4.76 mmol) of triphenylphosphine, 1.11 ml (7.92 mmol) of triethylamine and 0.38 ml (3.96 mmol) of carbon tetrachloride and stirred for 15 hours at room 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. Evaporation-.; the residue is purified by flash chromatography on silica gel (toluene / acetone 10/1). Yield: 1.4 g (68% of theory), m.p .: 95-97 ° C (petroleum ether / cyclohexane = 1/1) ·: · Calculated: C 73.81 H 8.52 N 5.38. Found: 73.98 8.49 5.61 i9 8341 7

Example 2 2-Ethoxy-4- [N- (α-cyclohexylmethyl-2-piperidinobenzyl) -eminocarbonylmethyl] -benzoic acid

1.15 g (2.21 mmol) of 2-ethoxy-4- [N- (α-cyclohexylmethyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester are mixed together in 12 ml of ethanol and 3.3 ml of 1N sodium hydroxide for 2 hours at 50 ° C. 3.3 ml of 1N hydrochloric acid are then added and the mixture is cooled on ice. The precipitate formed is filtered off, washed with a small amount of ice-cold ethanol and dried in vacuo at 100 ° C.

Yield: 0.9 g (82% of theory), m.p .: 153-156 ° C Calculated: C 73.14 H 8.18 N 5.69

Found: 73.30 8.17 5.66

Example 3 2-Ethoxy-3- [N- (α-cyclopropylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Prepared according to Example 1 from g-cyclopropylmethyl-2-piperidino-benzylamide and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 29.5% of theory,

M.p .: 126-127 ° C

Calculated: C 72.77 H 8.00 N 5.85

Found: 72.85 7.74 5.84

Example 4 4-Ethoxy-4- [4- (cyclopropylmethyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid semihydrate

Prepared according to Example 2 by alkaline saponification of 2-ethoxy-4- [N- (g-cyclopropylmethyl-2-piperidinobenzyl) -208 3 4 1 7 aminocarbonylmethyl] -benzoic acid ethyl ester.

Yield: 88% of theory, m.p .: 103-104 ° C Calculated (x 0.5 H 2 O): C 70.55 H 7.86 N 6.10 70.67 7.67 6.37

Example 5 2-Ethoxy-4- [N- (α-cyclobutyl-1-methyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Prepared according to Example 1 from α-cyclobutylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 14% of theory,

M.p .: 116-118 ° C

Calculated: C 73.14 H 8.18 N 5.69

Found: 73.14 8.32 5.64

Example 6 2-Ethoxy-4- [3- (α-cyclobutylmethyl-2-piperidinobenzyl) aminocarbonylmethyl 1-benzoic acid

Prepared according to Example 1 by alkaline saponification of 2-ethoxy-4- [N- (α-cyclobutylmethyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 33% of theory, m.p .: 140-142 ° C Calculated: C 72.39 H 7.81 N 6.03

Found: 72.15 7.79 5.97

Example 7 2-Ethoxy-4- [4- (α-cyclopentylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Prepared according to Example 1 α-cyclopentylmethyl-2-

II

2i 83417 from piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 36.8% of theory,

M.p .: 120-121 ° C

Calculated: C 73.49 H 8.36 N 5.53

Found: 73.31 8.55 5.39

Example 8 2-Ethoxy-4- [4- (α-cyclopentylmethyl-2-piperino-dino-benzyl) -aminocarbonylmethyl] -benzoic acid

Prepared according to Example 2 by alkaline saponification of 2-ethoxy-4- [N- (α-cyclopentylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ether.

Yield: 75% of the heretic,

M.p .: 85-88 ° C

Calculated: C 72.77 H 8.00 N 5.85

Found: 72.50 8.02 6.03

Example 9 • 2-Ethoxy-4- [2- (2-piperidino-o-tetrahydrofuran-2-ylmethyl) -benzyl) -aminocarbonyl] -methyl-1-benzoic acid ethyl 2 · psUp

Prepared according to Example 1 from 2-piperidino-o- (tetrahydrofuran-2-ylmethyl) -benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 38% of theory M.p .: 111-113 ° C

Calculated: C 70.84 H 7.93 N 5.51

Found: 70.76 7.73 5.51 22 8341 7

Example 10 2-Ethoxy-4- [N- (2-piperidino-α - ('tetrahydrofuran-2-ylmethyl) -benzyl) -aminocarbomylmethyl] -benzoic acid

Prepared according to Example 2 by alkaline saponification of 2-ethoxy-4- [N- (2-piperidino-α- (tetrahydrofuran-2-ylmethyl) -benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 75% of theory, m.p .: 121-123 ° C Calculated: C 69.98 H 7.55 N 5.83

Found: 69.90 7.78 5.71

Example 11 2-Ethoxy-4- [N- (α-cycloheptylmethyl-2-piperidinobenzyl) aminocarbonyl] methyl] -benzoic acid ethyl ester

Prepared according to Example 1 from α-cycloheptylmethyl-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid. Yield: 48% of theory, m.p .: 96-98 ° C

Calculated: C 74.12 H 8.67 N 5.24

Found: 74.40 8.87 5.39

Example 12 2-Ethoxy-4- [N- [Q-cyclopentylmethyl] -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Prepared according to Example 2 by alkaline saponification of 2-ethoxy-4- [N- (α-cycloheptylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester.

Yield: 83% of theory, m.p .: 127-130 ° C Calculated: C 73.49 H 8.36 N 5.53

Found: 73.54 8.62 5.47

II

23 8341 7

Example 13 2-Ethoxy-4- [N- (α-cyclohexylmethyl-2-piperidinobenzyl) aminocarbonylmethyl] -1-benzoic acid ethyl ester a) 2-Ethoxy-4- [N- (α-cyclohexylmethylidene) -2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Prepared according to Example 1 from α-cyclohexylmethyl- (2-piperidino-phenyl) -ketimine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 25% of theory,

M.p .: 85-88 ° C

Calculated: C 74.10 H 8.16 N 5.10

Found: 74.37 8.00 5.45 Based on 80 MHz 1 H-NMR spectrum (CDCl 3), mixture E / Z = 1/2. [Olefinic H: (E) D 6.26, (Z) 5.42 ppm].

b) 2-Ethoxy-4- [N- (α-cyclohexylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Prepared according to Example 12 by catalytic hydrogenation of 2-ethoxy-4- [N- (α-cyclohexylmethylidene) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester. Yield: 61% of theory, m.p .: 95 - 97®C Calculated: C 73.81 H 8.52 N 5.82

Found: 73.92 8.74 5.29

Example 14 2-Ethoxy-4- [3- (α-cyclohexylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid a) 2-Ethoxy-4- [N- (α- (cyclohexylmethylidene) -2-piperidino-benzyl) ) -aminocarbonylmethyl] -benzoic acid 24,83417

Prepared according to Example 2 by alkaline saponification of 2-ethoxy-4- [N- (α- (cyclohexylmethylidene) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester. Yield: 87% of theory, m.p .: 95 - 100 ° C Calculated: C 73.44 H 7.81 N 5.71

Found: 73.38 7.73 5.75 b) 2-Ethoxy-4- [N- (α-cyclohexylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid

Prepared according to Example 13 by catalytic hydrogenation of 2-ethoxy-4- [N- (α-cyclohexylmethylidene) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid.

Yield: 52% of theory, m.p .: 154-156 ° C Calculated: C 73.14 H 8.18 N 5.69

Found: 73.31 8.25 5.71

Example 15 2-Ethoxy-4- [1- (1- (2-piperidino-phenyl) -3-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Prepared according to Example 1 from 1- (2-piperidino-phenyl) -3-buten-1-ylamine and 3-ethoxy-4-ethoxycarbonyl-enyl-acetic acid. Yield: 32.7% of theory, m.p .: 110-112 ° C Calculated: C 72.39 H 7.81 N 6.03

Found: 72.10 7.66 5.94

Example 16 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-buten-1-yl) -1 '- aminocarbonylmethyl] -benzoic acid

Prepared according to Example 2 by alkaline saponification of 2-ethoxy-4- [N- (2- (2-piperidinophenyl) -3-buten-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 68% of theory, m.p .: 92-95 ° C Calculated: C 71.53 H 7.39 N 6.42

Found: 71.27 7.42 6.42

Example 17 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-3-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Prepared according to Example 1 from 3-methyl-1- (2-piperidino-phenyl) -3-buten-1-yl) -amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 33.6% of toeretic,

M.p .: 126-128 ° C

Calculated: C 72.77 H 8.00 N 5.85 72.82 8.22 5.78

Example 18 2-Ethoxy-4- [1- (1- (2-piperidino-phenyl) -3-methyl-3-buten-1-yl) -aminocarbonylmethyl] -benzoic acid

Prepared according to Example 2 by alkaline saponification of 2-ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-3-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 74% of theory, m.p .: 64-66 ° C Calculated: C 71.97 H 7.61 N 6.22

Found: 71.70 7.50 5.98

Example 19 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-methyl-2-buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester [containing 25% 2-ethoxy-4- [ N- (1- (2-Piperidinophenyl) -3-methyl-26 8341 7 1-butyl) aminocarbonylmethyl 1-benzoic acid ethyl ester!

Prepared according to Example 1 from 3-methyl-1- (2-piperidinophenyl) -2-buten-1-ylamine [with 25% 3-methyl-1- (2-piperidinophenyl) -1-butylamine] and 3-ethoxy-3-etoksikar-carbonyl-phenylacetic acid. Yield: 37% of theory,

M.p .: 141-142 ° C

Calculated: C 72.77 H 8.00 N 5.85

Found: 72.60 7.77 5.73

The mixture ratio of 75/72 is obtained from the corresponding ratio of the intensities of the particularly characteristic signals in the 400 MHz-1 H-NMR spectrum of CDCl 3. The signal location is: 3-methyl-2-buten-1-yl compound: olefinic H: 5.25 (d), CHa: 1.64 (s) and 1.77 (s), benzyl> CH. 6.00 (t), benzyl -CH 2 -: 3.25 ppm (s).

3-methyl-1-butyl compound: CH 3: 90.90 (d), benzyl> CH-5.35 (m), benzyl -CH 2 -: 3.54 ppm (s).

Example 20 2-Ethoxy-4- [1- (1- (2-piperidino-phenyl) -3-methyl-2-buten-1-yl) -aminocarbonylmethyl] -benzoic acid [with 25% 2-ethoxy-4- [N - (L- (2-piperidino-phenyl) -3-methyl ~ 1-butyy1i) -aminokarbonyylimetyyli1-benzoic acid

Prepare according to Example 2 by alkaline saponification of the corresponding ethyl ester mixture from Example 68.

Yield: 91% of theory,

M.p .: 154-156 ° C

Calculated: C 71.97 H 7.61 N 6.22: ·. Found: 71.80 7.57 5.98

Example 21 27 8341 7 2-Ethoxy-4- [1- (1- (2-piperidino-phenyl) -3-butyn-1-yl) -amino] -carbonylmethyl T-benzoic acid ethyl ester

Prepared according to Example 1 from 1- (2-piperidinophenyl) -3-butyn-1-ylamine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid. Yield: 52% of theory, m.p .: 86-90 ° C Calculated: C 72.70 H 7.41 N 6.06

Found: 72.60 7.40 6.04

Example 22 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -3-butyn-1-yl] -aminocarbonylmethyl] -benzoic acid

Prepared according to Example 2 by alkaline saponification of 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3-butyn-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 68% of theory, m.p .: 66-69 ° C Calculated: C 71.87 H 6.96 N 6.45

Found: 71.60 6.95 6.38

Example 23 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl) -4-penten-1-yl] -aminocarbonylmethyl-1-benzoic acid ethyl ester

Prepared according to Example 1 from 1- (2-piperidino-phenyl) -4-penten-1-ylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid. Yield: 58% of theory,

M.p .: 117-102 ° C

Calculated: C 72.77 H 8.00 N 5.85

Found: 72.73 7.97 6.07

Example 24 28 8341 7 2-Ethoxy-4- [N- (1- (2-piperidino-phenyl-4-penten-1-yl) -aminocarbonylmethyl] -benzoic acid

Prepared according to Example 2 by early saponification of 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -4-penten-1-yl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 61% of theory, m.p .: 82 - 85 ° C Calculated: C 71.91 H 7.61 N 6.22

Found: 71.97 7.59 5.98

Example 25 2-Ethoxy-4- [N- (1- (2-piperidino-α- (tetrahydropyran-2-yl) methyl) benzyl] aminocarbonylmethyl] benzoic acid ethyl ester

Prepared according to Example 1 from 2-piperidino-α- (tetrahydropyran-2-ylmethyl) -benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 29% of theory, m.p .: 82 - 85 ° C Calculated: C 71.24 H 8.10 N 5.36

Found: 71.28 7.96 5.29

Example 26 2-Ethoxy-4- [N- (1- (2-piperidino-q- (tetrahydropyran-2-ylmethyl) -benzyl) -aminocarbonylmethyl] -benzoic acid

Prepared according to Example 2 by alkaline saponification

2-Ethoxy-4- [N- (1- (2-piperidino-α- (tetrahydropyran-2-ylmethyl) benzyl) aminocarbonylmethyl] benzoic acid ethyl ester Yield: 85% of theory, m.p .: 140 - 142 ° C

29 8341 7 (sintered from 70 ° C; partially softens at 105 ° C) Calculated: C 70.42 H 7.74 N 5.66

Found: 70.15 7.88 5.40

Example 27 2-Ethoxy-4- [N- (α-cyclohexylmethyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester

To a mixture of 15 ml of concentrated sulfuric acid and 15 ml of o-dichlorobenzene at 23-25 ° C is added dropwise a solution of 2.35 g (10 mmol) of 2-ethoxy-4-cyanomethyl-benzoic acid ethyl ester and 2 .88 g (10 mmol) of g-cyclohexylmethyl-2-piperidinobenzyl alcohol in 15 ml of o-dichlorobenzene. Stir for an additional 2 hours at room temperature. The o-dichlorobenzene phase is then separated and the residue is added to ice. It is made with sodium hydroxide solution and then extracted with chloroform. The extracts are dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel 1 (toluene / acetone = 10/1).

Yield: 1.1 g (21% of theory), m.p .: 95-97 ° C Calculated: C 73.81 H 8.52 N 5.38

Found: 73.95 8.64 5.42

Example 28 2-Ethoxy-3-CN- (g-cyclohexylmethyl-2-piperidinobenzyl) aminocarbonylmethyl 11-benzoic acid ethyl ester

To a solution of 0.113 g (0.23 mM) of 2-hydroxy-4- [N- (g-cyclohexylmethyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester having a melting point of 140-142 In 1 ml of anhydrous dimethylformamide, 0.01 g (0.23 mM) of sodium hydride (55% as an oil) was added and stirred for 30 minutes. A solution of 0.018 ml (0.23 mM) of ethyl iodide in 0.5 ml of anhydrous dimethylformamide was then added and stirred for 5 hours at room temperature. Evaporated in vacuo, dissolved in dilute sodium hydroxide and chloroform, dried the organic extract, filtered and evaporated to dryness in vacuo.

Yield: 0.061 g (51% of theory), m.p .: 95-97 ° C [petroleum ether / cyclohexane = 1: 1]

Calculated: C 73.81 H 8.52 N 5.38

Found: 73.75 8.62 5.54

Example 29 2-Ethoxy-4- [N- (o-cyclohexylmethyl-2-piperidino-benzyl) -aminocarbonyl] -methyl] -benzoic acid ethyl ester

Prepared from 2-hydroxy-4- [N- (α-cyclohexylmethyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid according to Example 28 with 3 equivalents of sodium hydride and 2 equivalents of ethyl iodide. Yield: 38% of theory,

M.p .: 94-97 ° C

Calculated: C 73.81 H 8.52 N 5.38

Found: 73.99 8.75 5.52

Claims (2)

3i 8341 7 A process for the preparation of pharmacologically valuable phenylacetic acid derivatives of the formula (I) aCH-NH-CO-CH 2 - (X y - W 1 = <(I) R 10 R 4 wherein R 1 is a piperidino group, R 4 is a hydrogen atom, 1 to 3 carbon atoms an alkyl group or an allyl group, R 5 is an alkyl group having 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, wherein the cycloalkyl moiety contains 3 to 7 carbon atoms, an alkenyl group having 3 to 5 carbon atoms or an alkynyl group having 3 or 4 carbon atoms or alkoxy , wherein the alkoxy moiety contains 1 to 4 carbon atoms and may be substituted by phenyl, their enantiomers and salts thereof, characterized in that a) an amine of the general formula R 5 aCH - NH 2 in which R 1 and R 5 are as defined above is reacted with a carboxylic acid, with the general formula 32 8341 7 HOOC - CH2— <ryW. (III) R 4 wherein R 4 is as defined above and W is as defined above for W, or a protected carboxy group or reactive derivatives thereof optionally prepared in the reaction mixture and optionally cleaving the spent protecting group, if necessary, or b) for the preparation of compounds of general formula I, wherein W represents a carboxy group, is hydrolysed, thermolysed, hydrogenolysed or alcoholized with a compound of general formula IV f * aCH - NH - CO - CH2-XV and Uv, R1 OR4 wherein R1, R3 and R4 are as defined above, A is by hydrolysis, thermolysed 1a or by hydrogenolysis to a group convertible to a carboxy group, and c) for the preparation of compounds of general formula I in which R 4 is an alkyl group or an allyl group having 1 to 3 carbon atoms: a compound of general formula VI 11 33 8341 7 aCH-NH-CO-CH 2 - (f 'V-W wherein Ri, Rs and W have the same meaning as above, placed in rea with a compound of general formula VII X - Re (VII) in which Re is an alkyl group or an allyl group having 1 to 3 carbon atoms and X is a nucleophilically exchangeable group such as a halogen atom, a sulfonyloxy group or also together with an adjacent hydrogen atom a dia group when Re is 1 to 3 carbon atoms an alkyl group followed, if necessary, by hydrolysis of the compound thus obtained, or d) for the preparation of compounds of general formula I in which R 1 and R 5 are as defined above and R 4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, W is a carboxy or alkoxycarbonyl group, the alkoxy moiety may be contains 1 to 4 carbon atoms, a compound of general formula VIII Rs aCH-OH wherein R1 and R3 are as defined above, 34 8341 7 is reacted with a compound of general formula IX N5C-CH2-Qw · (ix) OR4 wherein R4 is as defined above and W "is a carboxy or alkoxycarbonyl group, wherein the alkoxy moiety may contain 1- 4 carbon atoms, or e) for the preparation of compounds of general formula I in which R 4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 3 is a tetrahydrofuranyl, tetrahydropyranyl * or cycloalkyl-substituted alkyl group having 1 or 2 carbon atoms, wherein the cycloalkyl moiety may contain 5- 7 carbon atoms, and W is a carboxy or alkoxycarbonyl group, wherein the alkoxy moiety may have 1 to 4 carbon atoms, a compound of general formula X is reduced? f / ao-c - CH2— (fy — w K <x) R1 OR4 where R1, R4 and W are as defined above and D is a group of formula R7 ^ ^ Re CH • V 35 8341 7 where R7 and Re together with the intervening carbon atom are a alkylidene group having 1 or 2 carbon atoms substituted by a tetrahydrofuranyl, tetrahydropyranyl or cycloalkyl group, in which the cycloalkyl moiety may contain 5 to 7 carbon atoms, and then, if desired, the racemic compound of general formula I is chromatographically separated in a chiral phase , and / or the compound of the general formula I thus obtained is converted into its salts, in particular into its physiologically acceptable salts with inorganic or organic acids or bases. Process according to Claim 1, characterized in that the compound of the general formula I 2-ethoxy-4- [N- (α-cyclohexylmethyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid, its enantiomer or a salt thereof is prepared . 36 8341 7