BG61519B2 - New derivatives of phenylacetic acid, medicamentous compositions containing these compounds, and method for their preparation - Google Patents

Abstract

New derivatives of phenyacetic acid, medicamentous compositions containing them and methods for their preparations are proposed. The compounds have the general formula and differ from the so far known drivatives of the phenylacetic acid by the -OR4 radical. They have improved prarmacological properties, and have particularly great effect on metabolism and in particular on the reduction of the blood sugar level. The medicamentous forms containing these compounds are used for the treatment of diabetis mellitus.

Description

(54) NEW PHENYLACETIC ACID PRODUCTS, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS,

AND METHODS FOR THEIR PREPARATION

Background of the invention - Phenylacetic acid derivatives will be used in the pharmaceutical industry

Prior art

EP-A-0 058 779 and EP-A-0 099 017 describe phenylacetic acid derivatives that affect metabolism.

D substances, and in particular lower blood sugar levels _;

........... ..... * ....... ς

SUMMARY OF THE INVENTION

The novel phenylacetic acid derivatives of the general formula were discovered

which differ from the previously described phenylacetic acid derivatives of the -OEC radical possess valuable properties. Thus, the compounds of general formula I in which R ₄ represents a methyl, ethyl or allyl group exhibit superior pharmacological properties, especially having a profound effect on metabolism, and in particular on lowering blood sugar. The compounds of general formula I wherein R ₄ is hydrogen are valuable intermediates for the preparation of the aforementioned compounds.

It is an object of the present invention to provide novel phenylacetic acid derivatives of the above general formula I, their enantiomers and salts, especially the physiologically tolerated salts obtained with inorganic or organic acids or bases, drugs containing these compounds, and methods for their preparation.

In the above general formula I means;

- pyrrolidino-, piperidino-, hexamethyleneimino-, methylpyrrolidino-, dimethylpyrrolidino, 2-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 3,3-dimethylpiperidino, cis-

The 3,5-dimethylpiperidino- or trans-3,5-dimethylpiperidino group,

R _o is a hydrogen or halogen atom, a methyl or methoxy group,

R1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a n-phenyl or 3-methyl-n-butyl group, or one optionally substituted by a halogen atom, a methyl or a methoxy group phenyl group,

R ₄ is a hydrogen atom, a methyl, ethyl or allyl group and

W is a methyl, hydroxymethyl, formyl, carboxy or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl moiety of the alkoxy group being substituted by a phenyl group.

For the meanings of the radicals R ₂ to R ₄ and W mentioned above in their definition, cc is meant e.g. the following atoms and groups;

for R ₂ is a hydrogen, fluorine, chlorine or bromine atom, methyl or methoxy group, for R ₂ is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, p-butyl, isobutyl, sec-butyl, tert-butyl, p-pentyl, 3-methyl-p-butyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl or methoxyphenyl group, for W - methyl, hydroxymethyl, formyl, carboxy, methoxycarbonyl, ethoxycarbonyl, p-propoxycarbonyl, isopropoxycarbonyl, isopropoxycarbonyl, isopropoxycarbonyl , benzyloxycarbonyl, 1-phenyl ethoxycarbonyl, 2-phenylethoxycarbonyl or 3-phenylpropoxycarbonyl group.

However, preferred compounds of the above general formula I are those in which

R ₂ and R ₄ are defined as in the beginning,

R1 represents pyrrolidino-, piperidino-, 4-methylpiperidino-, 3-methylpiperidino-, 3,3-dimethylpiperidino-,

3,5-dimethylpiperidino- or hexamethyleneimino group,

R ₂ represents a hydrogen, fluorine or chlorine atom, a methyl or methoxy group, and

W represents a carboxy, methyl, hydroxymethyl, formyl or benzyloxycarbonyl group or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, especially those compounds in which

R 1 represents a piperidino group,

R ₂ represents a hydrogen, fluorine or chlorine atom,

R ₂ represents a methyl, ethyl, n-propyl, n-butyl, isobutyl, n-pentyl or phenyl group.

R4 represents a methyl or ethyl group and

W represents a carboxy, methoxycarbonyl or ethoxycarbonyl group.

their enantiomers or salts, especially their physiologically tolerated salts obtained with inorganic or organic acids or bases.

Particularly preferred compounds of the above general formula I are those compounds wherein W represents a carboxyl group.

According to the invention, novel compounds are prepared by the following methods:

a) reacting an amine of the general formula

(Ii) in which

Rj go R ₃ are as hereinbefore defined, with a carboxylic acid of the general formula

(III) as defined in the beginning,

W 'has the meanings mentioned at the beginning of W, or represents a carboxyl group protected by a protective radical, or optionally derived reactive derivatives in the reaction mixture, and, if necessary, further cleavage of the protected radical used.

As reactive derivatives of a compound of the formula (II) is dissolved, e.g. their esters such as methyl, ethyl or benzyl ester, their thioesters such as methylthio 5 or ethylthioester, their halides as acid chloride, their anhydrides or imidazolides.

The reaction is conveniently carried out in any solvent such as methylene chloride, chloroform, tetrachloromethane, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activating or dehydrating agent. ethyl chloride, thiol chloride, phosphorus trichloride, phosphorus pentoxide; an amino group activating agent, e.g. phosphorus trichloride and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which can serve simultaneously as solvents, at temperatures of -25 and 250 ° C, but preferably at temperatures between -10 ° C and temperatures of -10 ° C. boiling the solvent used. The conversion may also be carried out in the absence of a solvent, and further the water obtained during the reaction may be removed by azeotropic distillation, e.g. by heating with toluene, in a water separator or by adding a desiccant such as magnesium sulfate, or by molecular sieving.

If necessary, the subsequent cleavage of the protective radical is preferably hydrolytic, as appropriate, or 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 / water, ethanol. ethanol-water, water / isopropanol or water / dioxane at temperatures between -10 ° C and 120 ° C, e.g. at temperatures between room temperature and the reflux temperature of the reaction mixture.

A tert-butyl radical used as a protective radical can be cleaved and thermally optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluene acid phosphoric or polyphosphoric acid.

Further, the benzyl radical used as the protecting radical may be cleaved and hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide.

b) for the preparation of a compound of general formula I in which W represents a carboxyl group:

Cleavage of a compound of the general formula

(Iv) in which

BCs go R ₄ are defined as in the beginning and

A represents a group which can be converted into a carboxyl group by hydrolysis, thermolysis or hydrogenolysis.

As hydrolysable groups are meant e.g. functional derivatives of the carboxyl group, such as unsubstituted or substituted, amides, esters, thioesters, orpesters, 11 ν ί and n - 'C' t with pi. amidines or anhydrides, nitrile group, meinpmy.'lil apvna, one e (5einnca.uio substituted co-oxazol-A yl or 1.3-oxazolin-2-yl group and cat. 'thermally leaving groups, e.g. ester is tertiary alcohol , e.g., tert-butyl ester, and as hydrogenolytic cleavage groups, e.g. aralkyl groups, e.g., benzyl group.

Is hydrolysis carried out as appropriate, either in the presence of an acid such as hydrochloric, sulfuric, phosphoric or trichloroacetic acid, or in the presence of a droplet base? sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / ethanol, water / isopropanol or water / dioxane at temperatures between -10 and 120 ° C, e.g. at temperatures between room temperature and the reflux temperature of the reaction mixture.

If A, in a compound of general formula IV, denotes a nitrile or aminocarbonyl group, then these groups can be converted to a carboxylic group using 100% phosphoric acid at temperatures between 100 and 180 ° C, preferably at temperatures between 120 and 160 ° C or with nitrite, e.g. sodium nitrite, in the presence of an acid such as sulfuric acid, the acid being suitably used as solvent, at temperatures between 0 and 50 ° C.

If A, in a compound of general formula IV means e.g. tert-butyloxycarbonyl group, the tert-butyloxy group can also be cleaved thermally, optionally in an inert solvent such as methylene chloride. chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric, phosphoric or polyphosphoric acid, preferably at the reflux temperature of the solvent used, e.g. at temperatures between 4 <I and (ι η ι%

Aku A in a compound of general formula IV means the benzyloxycarbonyl group, then the benzyl group. It can also be cleaved hydrogenolitically in the presence of a hydrogenation catalyst such as palladium / charcoal in a suitable solvent such as methanol, ethanol, methanol / water, ethanol / water, ice. acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ^with C, for example. at room temperature and hydrogen pressure from 1 to 5 bar. In hydrogenolysis, a halogen-containing compound can be dehalogenated simultaneously.

(c) for the preparation of a compound of general formula I wherein R ₄ represents a hydrogen atom, a methyl or ethyl group:

A compound of the general formula

R ₃

CH-OH (V) \ in which

Rj go R ₃ are as hereinbefore defined, with a compound of general formula

OR ₄ (VI) in which

R ₄ and W are defined as β onset.

The reaction is carried out in the presence of a strong acid which

concentrated sulfuric acid, at temperatures between 0 and 150 ^with C. preferably at temperatures between 20 and 100 ° C.

If, in a compound of general formula VI, R ₄ is an alkyl group, it is cleaved off during or after the end of the reaction by the addition of water.

d) for the preparation of a compound of general formula I in which R ₄ represents a hydrogen atom:

The protective radical of a compound of the general formula

c • 2

(VII)

V, in which

Rj go are defined as in the beginning,

W has the meanings of W mentioned in the beginning or represents a group which can be converted into a carboxyl group and

R ₅ represents a protecting radical for the hydroxyl group, cleaves.

As a group which can be converted into a carboxyl group, it is considered e.g. for W '- aryloxycarbonyl, aralkoxycarbonyl, aminocarbonyl or nitro, and as a protecting group for R' alkyl. an aralkyl, trialkylsilyl or acyl group, e.g. methyl, ethyl, propyl, benzyl, trimethylsilyl, acetyl or propionyl.

The cleavage of the aforementioned protecting radical is carried out according to the protecting radical used either by hydrolysis or by hydrogenolysis, optionally in a suitable solvent at temperatures between -78 and 2cB ° C. For example, ether cleavage is carried out in the presence of an acid such as hydrochloric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, boron tribromide, aluminum trichloride or pyridine hydrochloride, optionally in a suitable solvent such as methylene chloride, glacial acetic acid or water, or in mixtures at -78 ° C and at 250 ° C. The ether cleavage is carried out in the presence of protic acids, preferably at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 150 ° C, or with Lewis acid, preferably in a solvent such as methylene chloride at temperatures between -78 and 20 ° C.

The ester cleavage is carried out e.g. in the presence of a base such as aqueous ammonia solution, sodium carbonate, potassium carbonate, sodium or potassium hydroxide, in a solvent such as water, water / methanol, water / ethanol, water / tetrahydrofuran or water / dioxane at temperatures between 50 and 100 ° C, preferably at the temperatures of the solvent used.

The hydrogenolytic cleavage of the protecting radical used as the benzyl group is carried out e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium / charcoal in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide, preferably e.g. at room temperature and hydrogen pressure from 1 to 5 bar.

(e) for the preparation of compounds of general formula I in which R ₄ represents a methyl, ethyl or allyl group:

Compound of general formula

(Viii) which

Rj go Rj u W are defined as initially reacted with a compound of general formula (IX) in which

R ' ₄ with the exception of the hydrogen atom has the meaning defined at the beginning and

X represents a nucleophilic, substituent group such as a halogen atom or a sulfonyloxy group or together with the adjacent hydrogen atom denotes a dia group when R ₁₄ represents a methyl or ethyl group and, if necessary, is finally hydrolyzed.

The reaction is suitably carried out with a suitable halide, anhydride, sulfonic acid ester or diazoalkane, e.g. with methyl iodide, ethyl bromide, propyl bromide, isopropyl bromide, ethyl ester of cauliflower in the case of acylation with anhydride, also in the presence of an acid such as sulfuric acid, preferably in the presence of a suitable solvent such as acetone, diethyl ether, tetrahydrofuran, dioxane, pyridine or dimethylfor mamide at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 50 ° C, wherein the agent used for acylation may also serve as a solvent.

If W, in a compound of general formula VIII. means a carboxyl or hydroxymethyl group, it may be converted to 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 is carried out hydrolytically, optionally 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 / water, ethanol , ethanol / water, water / isopropanol or water / dioxane at temperatures between -10 and 120 ° C, e.g. at temperatures between room temperature and the reflux temperature of the reaction mixture.

f) Reduction of a compound of the general formula

wherein

Rp R ₂ , R ₄ and W are as defined at the beginning and

Y represents a group of formula

In

-C-NH- or -C = When R ₃ is as defined at the beginning and and R- together with the carbon atom between them represents an alkylidene group of 1 to 4 carbon atoms.

The reduction is preferably carried out with hydrogen in the presence of a hydrogenation catalyst such as palladium / charcoal or Raney nickel in a suitable solvent such as methanol, ethanol, isopropanol, acetic acid ethyl ester, dioxane. tetrahydrofuran. dimethylformamide. benzene or benzene / ethanol at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 ° C and 50 ° C and a hydrogen pressure of 1 to 5 bar. Using a suitable chiral hydrogenation catalyst as a metal ligand complex, e.g. complex of l, l'-dichloro-bis- [1,5-cyclooctadienrodium] and (+) or (-) O, O-isopropylidene-2,3-dihydroxy) -1,4-bis (diphenylphosphino) butane (= DIOP), the addition of hydrogen becomes enantioselective. In catalytic hydrogenation other groups may also be reduced, e.g. a benzyloxy group to a hydroxyl group or a formyl group to a hydroxymethyl group or to be replaced by hydrogen atoms, e.g. a halogen atom with a hydrogen atom.

If a compound of general formula I is prepared according to the invention, which means: R _{2 is a} halogen atom and / or R ₂ is a halogenphenyl group and / or a W-hydroxymethyl group which is converted into a halogenmethyl group, it can be enthalogenated in a corresponding compound of general formula I, in which R ₂ is hydrogen and / or R ₂ is a phenyl group, and / or W is a methyl group, and / or a compound of general formula I, in which W is a carboxyl group, may, optionally to be converted by esterification into a corresponding compound of general form la, in which W represents an alkoxycarbonyl or phenylalkoxycarbonyl group, and / or a compound of general formula I in which W represents a carboxylic, alkoxycarbonyl or phenylalkoxycarbonyl group, may, by reduction, be converted to a corresponding compound of general formula I, in which W represents a formyl or hydroxymethyl group, and / or sipipe with the general formula

I in which W is converted into a corresponding compound of the general formula I. 15 which λλ represents formyl or carboxy. a group, or compound of general formula I in which W represents a carboxylic group, may be converted to a corresponding compound of general formula I in which W represents a formyl group, by conversion to a sulphonic acid hydrazide, and subsequently disproportionately / or a racemic compound of general formula I wherein R _; , with the exception of the hydrogen atom, defined as in the beginning, may be separated into the enantiomers through its diastereomeric adducts, complexes or salts.

The additional dehalogenation is suitably carried out by catalytic hydrogenation, e.g. of palladium / charcoal, in a suitable solvent, e.g. methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide or acetic acid ethyl ester, optionally in the presence of an acid such as triethylamine at temperatures between 20 and 100 ° C, preferably at 20 to 50 ° C

Further esterification is conveniently carried out in a suitable solvent, e.g. in an appropriate alcohol, pyridine, toluene, methylene chloride, tetrahydrofuran or dioxane, in the presence of an acid activator or a water-absorbing agent such as thionyl chloride, hydrochloric acid ethyl ester, carbonyl diimidazole, or cyclohexyl ether, of reaction accelerators such as copper chloride or by transesterification, e.g. with a corresponding carbonic acid diester at temperatures between 0 and 100 ^L , but preferably at temperatures between 2 and C and the reflux temperature of the solvent in question.

The final reduction is preferably a metal hydtad. e.g. is a complex metallic hydride cath lithiumN. yptdichev xugpuq. Aumudx6opcii xugpug or lithium-free xugpug, · a tri-methyl ester of ooric acid, in a suitable solution. \ As diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane at temperatures between 0 and 100 ° C, preferably at temperatures between 20 ° C. and 60 ° C.

The additional oxidation of an alcohol is preferably carried out with an oxidizing agent, e.g. with pyridinium chlorochromate or manganese dioxide, in a suitable solvent such as chloroform or methylene chloride at temperatures between -10 and 50 ° C, but preferably at temperatures between 0 and 20 ° C.

The additional disproportionation of a sulfonic acid hydrazide obtained by reacting the corresponding hydrazine with a corresponding reactive carbonic acid derivative is carried out in the presence of a base such as sodium carbonate, in a solvent such as ethylene glycol, at temperatures between 100 ° C and 200 However, preferably at 160-170 ° C.

The additional separation of racemates is carried out preferably by column or high performance liquid chromatography (HPL) by forming diastereomeric adducts or complexes in the chiral phase.

The compounds of general formula I obtained can be further converted into their salts, especially the physiologically tolerated salts obtained with inorganic or organic acids or even bases. As acids are meant e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid or fumaric acid and as their bases sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanolamine or triethylamine .

Compounds of the general formula II to X used as starting materials are known in the literature in part, respectively they can be prepared by known methods.

For example, a compound of general formula I is obtained by reduction of the corresponding nitrile with lithium aluminum hydride or with catalytically activated hydrogen, by reaction of the corresponding nitrile with the corresponding Grignard or lithium compound, and further reduction with lithium aluminum hydride, or by additional hydrolysis to ketamine, which is ketyl, this is reduced by catalytically activated hydrogen, complex metal hydride or by saturated hydrogen, by hydrolysis, respectively, by hydrazinolysis of the corresponding phthalimido compound, by reacting respectively en ketone with ammonium formate and additional hydrolysis, respectively with ammonium salt in the presence of sodium cyanoborohydride, by reduction of the corresponding oxime with lithium aluminum hydride, with catalytically activated or saturated hydrogen, by reduction of the corresponding N-benzyl or N-1-phenyl e.g. with complex metal hydride in ether or tetrahydrofuran at ₍ temperatures between -78 ° C and the reflux temperature of the solvent used and subsequent cleavage of the benzyl or 1-phenylethyl group by catalytic hydrogenation by reaction of the Ritter of the corresponding alcohol with potassium cyanide in sulfuric acid , or by decomposing a corresponding Hoffman, Kurtius, Losen, or Schmidt compound.

The thus obtained amine of general formula II with a chiral center can be separated into its enantiomers by separation of racemates, e.g. by fractional crystallization of the diastereomeric salts with optically active acids and subsequent decomposition of the salt, either by column or HPL chromatography, optionally as its acyl derivative, or by formation of diastereomeric compounds, their separation and subsequent cleavage.

Further, an optically active amine of the general formula II can be obtained by enantioselective reduction of the corresponding ketimine by boron or aluminum hydride, in which part of the hydride hydrogen atoms is replaced by optically active alcoholic radicals, or by hydrogen in the presence of a suitable chiral hydrogenation catalyst, respectively, proceeding analogously from the corresponding N-benzyl or N (1-phenethyl) ketimine or from the corresponding N-acylketimine, respectively the enamide and any subsequent cleavage of the benzyl, 1-phenethyl or acyl radical.

In addition, an optically active amine of the general formula II may also be obtained by diastereoselective reduction of a corresponding ketimine, chiral substituted on nitrogen, or of hydrazone by complex or non-complex boron or aluminum hydrides, in which one part of the hydrides the hydrogen is substituted with the corresponding alcoholate, phenolate or alkyl radicals, or · via hydrogen in the presence of a suitable hydrogenation catalyst and any subsequent cleavage of the chiral auxiliary radical by catalytic hydrogenol or hydrolysis.

In addition, an optically active amine of the general formula II can also be obtained by diastereoselectively attaching a corresponding organometallic compound, preferably a Grignard or lithium compound, to a corresponding chiral nitrogen substituted aldimine by subsequent hydrolysis and optionally subsequent cleavage of the chiral auxiliary radical by catalytic hydrogenolysis or hydrolysis.

The compounds of general formula IV, VII and VIII used as starting materials were prepared by reacting the corresponding amine with the corresponding carboxylic acid, resp. its reactive derivatives and any subsequent cleavage of a protecting radical used.

A compound of general formula V used as starting material is obtained by reducing the corresponding carbonyl compound or by reacting the corresponding carbonyl compound with a corresponding Grignard or lithium radical.

A compound of general formula X used as starting material is prepared by acylating the corresponding imino compound or its organometallic complex with the corresponding carboxylic acid or its reactive derivatives and optionally further cleaving an ester group.

As mentioned in the beginning, the new compounds of general formula I, in which R ₄ represents an alkyl group or an alkyl group of 1 to 3 carbon atoms, exhibit valuable pharmacological properties, namely affecting the intermediate metabolism, but in particular, lowering the level of the blood sugar.

For example, the compounds A = 2-methoxy-4- [X- (1- (2-piperidinophenyl) -1-ethylaminocarbonylmethyl] benzoic acid,

B = 2-ethoxy-4- [X- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid,

C = 2-methoxy-4- [X- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] 6-enzyme with eline,

D = 2-ethoxy-4- [X- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid,

E = (+) - 2-emoxy-4- [N- (1- (2-piperidinophenyl-1-butyl) aminocarbonylmethyl] benzoic acid,

F = 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -1-ethyl) amino arbonylmethyl] benzoic acid.

G = 2-Ethoxy-4- [X- (1- (2-pyrrolidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid sodium salt,

N = 2-ethoxy-4- [N- (1- (2-hexamethyleneiminophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid,

I = 2-methoxy-4- [X- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid,

N = 2-ethoxy-4- [L- (1- (2-piperidinophenyl) -1-phenyl) aminocarbonylmethyl] benzoic acid and

L = 2-Ethoxy-4- [X- (4-methyl-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid are tested for their ability to lower blood sugar levels as follows:

The effect of the test substances on lowering blood sugar levels was tested on female rats raised by us weighing 180-220 g, which were kept fasted for 24 hours before the start of the experiment. The test substances were suspended immediately before testing in 1.5% methylcellulose and fed with a gastric tube.

Blood samples were taken each time from the retro-orbital venous plexus just before the substance was administered, and 1, 2, 3, and 4 hours thereafter. 50 μΐ of each sample was treated with 0.5 ml of 0.33 N perchloric acid to remove protein and centrifuged. The protein-free liquid phase was examined for glucose by the hexokinase method using an analytical photometer. The statistical calculation is made according to the Student's t-test with a limit of significance p = 0.05.

The following table shows the values found as a percentage of control:

Substance 1 mg / kg 0.5 mg / kg

2 3 4h 1 2 3 4h

A -37 -46 -23 -14 -------------------------------------------------- -------------------------------------------------- ------ 1 IN -38 -49 -38 -33 -43 / H -Yes -34 -35 p -38 -41 -38 -34 D -42 -54 -37 -34 Well -40 -39 -36 -36 F -44 -44 -40 -30 Mr -40 -33 -30 -17 N. -42 -34 -18 n.s. I -42 -39 -37 -30 K. 'h -41 -45 -38 -39 L -44 -41 -35 -27

n.s. = statistically irrelevant

No toxic side effects were observed when testing substances for their effect on lowering blood sugar, even at a dose of 10 mg / kg p.o.

The new compounds are practically non-toxic; e.g. after a single dose of 2000 mg / kg p.o. (suspension in 1% methylcellulose) of your substance D given to 5 male and 5 female mice over a 14-day observation period, only one animal in this group died.

On the basis of their pharmacological properties, the compounds of general formula I wherein R ₄ is a methyl, ethyl or allyl group, as well as their physiologically tolerated! salts are suitable for combination with diabetes mellitus treatment. They can be processed, possibly into other active substances. in the usual dosage forms, such as tablets, dragees, or suspensions. Single dose for adults with 1- / T pharmaceutical capsules, powders

Γ | ΊΙ- ηρρ · ΊΙΙΜΗ '·' COMIC, l- ^! And I j'jL '. ί 1] A'tl 5 inine capsules, powders or suspensions. The single dose for adults is 1-2 mg. however, preferably 2.5-20 mg. 1 or 2 times a day.

The following examples explain the invention in more detail:

An exemplary embodiment of the invention

Example 1

2-Ethoxy-4- [N ^m - (1- (2-piperidinophenyl-1-butyl) amino-carbonylmethyl] benzoic acid ethyl ester

To a solution of 1.84 g (7.9 mmol) of 1- (2-piperidinophenyl) -1-butylamine in 19 ml of acetonitrile was added successively 2 g (7.9 mmol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid, 2.46 g (9.38 mmol) of triphenylphosphine, 1.7 ml. (12.3 mmol) triethylamine and 0.76 ml (7.9 mmol) tetrachloromethane and stirred for 2 days at room temperature. It was then evaporated in vacuo and partitioned between ethyl acetate and water. The organic extract was dried, filtered and evaporated in vacuo. The evaporation residue was purified by silica gel column chromatography (toluene / acetone = 5/1).

Yield: 3 g (81% of theory)

Melting point: 113-115 ° C (petroleum ether).

Calculated: C 72.07 H 8.21 N 6.00

Found: C 72.18 H 8.27 N 6.16

Like Example 1, the following compounds are obtained:

a) 2-Methoxy-4- [N ^1- (1- (2-piperidinophenyl) -1-ethyl) aminocarbonylmethyl] benzoic acid methyl ester

Prepared from 1- (2-piperidinophenyl) -1-ethylamine and 3-methoxy-4methoxycarbonylphenylacetic acid.

Yield: 78% of theory. value

Melting point :: 82-85 ^With S. t Ί t Ί - - \ ί 1h seal: ν. ,· in —1Ί /.? Mr And with me ·>: C 7 ' 1 tu Η, 40 X 22

b) ethyl 2-ethoxy-4 - [^ ^T - (a-phenyl-2-piperidinooenzil / aminocarbonylmethyl] benzoic acid

Prepared from α-phenyl-2-piperidinobenzylamine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: 77% of theory. value

Melting point: 149-151 ° C

Calculated: C 74.37 H 7.25 N 5.60

Found: C 74.69 H 7.44 N 5.59

c) 2-Methoxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid methyl ester

Obtained from cs-phenyl-2-piperidinobenzylamine and 3-methoxy-4 labels to the arb they are enylacetic acid.

Yield: 65% of theory. value

Melting point: 189-190 ° C

Calculated: C 73.70 H 6.83 N 5.93

Found: C 73.51 H 6.75 N5.86

d) 2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -1ethyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (2-piperidinophenyl) -1-ethylamine and 3-ethoxy-4 'ethoxycarbonylphenylacetic acid.

Yield: 69% of theory. value

Melting point: 92-93 ° C

Calculated: C 71.21 H 7.81 N 6.39

Found: C 71.29 H 8.03 N 6.58

e) 2-Ethoxy-4- [N- (1- (5-chloro-2-piperidinophenyl) -1propyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (5-chloro-2-piperidinophenyl) -1-propylamine and 3-ethoxy-4-ethoxycyclohexylacetate with eline.

Yield: 80% of theory. value

Melting point: 92-93 ° C

Calculated: C, 66.58; H, 7.24; N, 5.75;

Found: C 66.61 H 7.34 N 5.86 Cl 7.35

f) 2-Ethoxy-4- [H '- (1- (2-piperidinophenyl) -1pentyl) amino arbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (2-piperidinophenyl) -1-pentylamine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: 63% of theory. value

Melting point: 113-115 ° C

Calculated: C 72.47 H 8.39 N 5.83

Found: C 72.66 H 8.26 N5.99

g) 2-Ethoxy-4- [N- (1- (2-pyrrolidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (2-pyrrolidinophenyl) -1-butylamine and 3-ethoxy-4 * ethoxycarbonylphenylacetic acid.

Yield: 50% of theory. value

Melting point: 85-87 ° C

Calculated: C 71.65 H 8.02 N6.19

Found: C 71.90 H 8.37 N6.34

h) 2-Ethoxy-4- [N- (1- (2- (4-methylpiperidino) phenyl) 1-butyl) amino arbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (2- (4-methylpiperidino) phenyl) -1-butylamine and 3ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: 44% of theory. value

Melting point: 127-128 ° C

Calculated: C 72.47 H 8.39 N5.83

Found: C 72.20 H 8.23 N 5.69

i) 2-Ethoxy-4- [N- (1- (2-hexamethyleneiminophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (2-hexamethyleneiminophenyl) -1-butylamine and 3ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: 44% of theory. value

Melting point: 97-100 ° C

Calculated: C 72.47 H 8.39 N 5.83

Found: C 72.41 H 8.50 N 5.66

k) 2-Ethoxy-4- [N- (1- (4-methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Obtained from 1- (4-methyl-2-nineridinophenyl) -1-butylamine and 3-ethoxy-4-ethane sic arb onyl phenylacetic acid.

Yield: 68% of theory. value

Melting point: 113-114 ° C

Calculated: C 72.47 H 8.39 N 5.83

Found: C 72.36 H 8.31 N 5.91

(l) 2-Ethoxy-4- [N- (1- (6-methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (6-methyl-2-piperidinophenyl) -1-butylamine and 3ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: 62% of theory. value

Melting point: 113-114 ° C

Calculated: C 72.47 H 8.39 N 5.83

Found: C 72.30 H 8.50 N5.72

m) 2-Ethoxy-4- [N- (1- (6-chloro-2-piperidinophenyl) -1 'butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Obtained from 1- (6-chloro-2-piperidinophenyl) -1-butylamine and 3ethoxy-4-ethoxycarbonylphenyloic acid.

Yield: 85% of theory. value

Melting point: 113-114 ° C

Calculated: C 67.12 H 7.44 N 5.50 Cl 7.08

Found: C 67.60 H 7.77 N5.95 C17.24

n) 2-Emoxy-4- [N- (1- (4-Memoxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Obtained from 1- (4-methoxy-2-piperidinophenyl) -1-butylamine and 3ethoxy-4-ethoxycarbonylphenyloic acid.

Yield: 65% of theory, value

Melting point: 109-110 ° C

Calculated: molpeak m / e = 496

Found: molpeak m / e = 496

o) 2-Ethoxy-4- [N- (1- (5-methoxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (5-methoxy-2-piperidinophenyl) -1-butylamine and 3ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: 31% of theory. value

Melting point: 117-120 ° C

Calculated: molpeak m / e = 496

Found: molpeak m / e = 496

n) 2-hydroxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (2-piperidinophenyl) -1-butylamine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: 46% of theory. value

Melting point: 133-134 ° C

Calculated: C 71.21 H 7.81 N6.39

Found: C 71.08 H 7.91 N 6.45

p) 2-Methoxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl] benzoic acid methyl ester

Prepared from 1- (2-piperidinophenyl) -1-butylamine and 3-methoxy-4methoxycarbonylphenylacetic acid.

Yield: 67% of theory. value

Melting point: 128-131 C ^with

Calculated: C 71.21 H 7.81 N 6.39

Found: C 71.46 H 7.80 N 6.07

c) 2-Ethoxy-4- [N- (1- (5-chloro-2-piperidinobenzyl) amino arbonylmethyl] benzoenacin and selina ethyl ester

Obtained from 5-: oro-2-piperidinobenzylamine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: b5% om theory. value

Melting point: 106-108 C ^with

Calculated: C 65.41 and 6.81 N6.10 Cl 7.73

Found: C 65.81 H 6.89 N6.11 C17.62

m) (-) - 2-Ethoxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonyl-methyl] benzoic acid ethyl ester

Obtained from (-) -? - phenyl-2-piperidinobenzylamine and 3-ethoxy-4-ethoxy-arbonylphenylacetic acid.

Yield: 87% of theory, value

Melting point: 110-111 ° C

Calculated: molpeak m / e = 500

Found: molpeak m / e = 500

Specific rotation: [a] _D ²⁰ = 6.3 ° (c = 1, methanol)

(y) 2-Ethoxy-4- [N- (6-methyl-a-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 6-methyl-? -Phenylbenzylamine and 3-ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: 39% of theory, value

Melting point: <20 ° C

Calculated: C 74.68 H 7.44 N 5.44

Found: C 74.81 H 7.56 N5.32

u) 2-Ethoxy-4- [N- (α- (4-methylphenyl) -2-piperidinobenzyl) amino arbonylmethyl] benzoic acid ethyl ester

Prepared from α- (4-methylphenyl) -2-piperidinobenzylamine and 3ethoxy-4-ethoxycarbonylphenylacetic acid.

Yield: 34% of theory, value

Melting point: 150-152 ° C

Calculated; C, 74.68; H, 7.44; N, 5.44

Found: C 74.71 H 7.51 N 5.29

x) 2-Ethoxy-4- [N- (α-4-enyl-2-pyrrolidinobenzylT · ak11.] styrene ester of nocarbonylmethyl | benzoic acid style ester

The resultant α-phenyl-2-pyrrolidinobenzylamine in 3-enocucu-4emoccucarbonylphenylacetic acid.

Yield: 45% of theory. value

Melting point: 85-87 ° C

Calculated: C 74.05 H 7.04 N 5.76

Found: C 73.95 H 7.07 N 5.70

w) 2-methoxy-4- [N- (2-hexamethyleneimino-phenylbenzyl) aminocarbonylmethyl] benzoic acid methyl ester

Prepared from 2-hexamethyleneimino-? -Phenylbenzylamine and 3methoxy-4-methoxy arbonylphenylacetic acid.

Yield: 45% of theory. value

Melting point: 481-183 ° C

Calculated: C 74.05 H 7.04 N 5.74

Found: C 74.09 H 6.62 N5.74

h) 2-Ethoxy-4- [N- (2-hexamethyleneimino-phenylbenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 2-hexamethyleneimino-α-phenylbenzylamine and 3ethoxy-4-ethoxy arbonylphenylacetic acid.

Yield: 41% of theory. value

Melting point: 140-141 ° C

Calculated: C 74.68 H 7.44 N 5.44

Found: C 74.46 H 7.62 N 5.45 si) 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) -amino arbonylmethyl] toluene

Prepared from 1- (2-piperidinophenyl) -1-butylamine and 3-ethoxy-4methylphenylacetic acid.

Yield: 55% of theory. value

Melting point: 107-108 ° C

Calculated: C 76.43 H 8.88 N 6.86

Found: C 76.38 And 8.99 Ν 6.T '

Example 2

(+) - 2-Emoxy-4- [N- (1- (2-nitrophenyl) butyl] aminocarbonyl-methyl] benzoic acid ethyl ester

0.90 g (3.57 mmol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid and 0.61 g (3.73 mmol) of N, N -carbonyldiimidazole are heated in 9 ml of absolute tetrahydrofuran for 5 hours under reflux. A solution of 0.85 g (3.67 mmol) (+) - 1- (2-piperidinophenyl) -1-butylamine (ee = 94.2) in 9 ml of absolute THF was then added and refluxed for 3 hours. It was evaporated in vacuo and the residue after evaporation was partitioned between chloroform and water. The organic phase is dried, filtered and evaporated in vacuo. The evaporated extract was purified by ~ column chromatography over silica gel (toluene / acetone = 10/1).

Yield: 0.85 g (51.2% of theory),

Melting point: 118-119 ° C (petroleum ether / toluene = 50/2)

Calculated: C 72.07 H 8.21 N 6.00

Found: C 72.43 H 8.34 N 6.00

Specific rotation: [cx] p ²⁰ = +7.1 ° (c - 1.06 in methanol)

Example 3

2-Ethoxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

To a mixture of 30 ml of concentrated sulfuric acid and 30 ml of odichlorobenzene, a solution of 4.7 g (20 mmol) of 2-ethoxy-4-cyanomethylbenzoic acid ethyl ester was added dropwise at 23-25 ° C and

5.3 g (20 mmol) of [alpha] -phenyl-2-piperidinobenzylal ¹ pan in 30 nil odihorobenzene. Stirred for 2 hours at room temperature. The o-dichloro-benzene phase was then separated and poured completely on C.-lcc '| alkalysed with sodium xuapoio solution. is the value of j.

you think and concentrate. The residual tar is triturated with petroleum fl. The filtrate was filtered off and purified over silica gel (toluene ethyl acetate = 5/1) by column chromatography.

Yield: 3.6 g ι5b ^; '/ <:> by Theor.

Melting point: 150-151 ° C

Calculated: C 74.37 H 7.25

Found: C 74.59 H 7.41 g *

Like Example 3, the following compounds were prepared:

a) 2-Methoxy-4- [X- (α-phenyl-2-piperidinobenzyl; aminocarbonylmethyl] benzoic acid methyl ester

Prepared from α-phenyl-2-piperidinobenzyl alcohol and 4-cyanomethyl-2-methoxybenzoic acid methyl ester.

Yield: 34% of. theor. value

Melting point: 1S9-191 ^with C

Calculated: C 73.70 H 6.88 N 5.93

Found: C 73.63 H 7.05 N 5.95

b) 2-ethoxy-4- [X- (α-phenyl-2-piperidinobenzyl) aminocarbonyl. methyl] -benzoic acid

Prepared from α-phenyl-2-piperidinobenzyl alcohol and 2-ethoxy-4 cyanomethylbenzoic acid. Extraction at pH 5.

Yield: 47% of theory. value

Melting point: 154-155 ° C

Calculated: C 73.70 H 6.83 \ 3.93

Found: C, 73.61; H, 6.72; N, 5.65

c) 2-methoxy-4DM- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -bepzoic acid

Made from i.-Phenyl-Achsperidinooenzyl.shthol and 4 plexi-benzoic acid. Extraction at pH 5.

'ΊΊ ι schl. \ AnyH'j'i'i ·, 1 U V. AC i. and 'k .... ,? ..? 4 lI χ N). i 1 Found ·. ': Hl ^- Η 6.4 !. \ m * 5

Na ::: λι. \ '· Ο c..arp na 2 <niokcu-4- [N- <T- <D -piperidinophenyl? -1butyl »aminocap-6t,) nor. \ Methyl] benzoic acid

Obtained from 1- (2-piperidinophenyl / -1-butano) and ethyl ester 2 - methylpiperidine and 4 - cyanomethylbenzene and selina.

Yield: 5% of theory. value

Melting point: 112-114 ° C Calculated: C 72.07 N 8.21 N B.o.

Found: C 72.29 H 8.46 N 6.31

e) 2-Methoxy-4- [X- (1- (2-piperidinophenyl / -1ethyl) aminocarbonylmethyl] benzoic acid methyl ester

Prepared from 1- (2-piperidinophenyl) -1-ethanol and 4-cyanomethyl-2-methoxybenzoic acid methyl ester.

Yield: 18% of theory. value.

Melting point: 83-85 ° C Calculated: C 70.22 H 7.37 N 6.82

Found: C 70.60 H 7.29 N 6.97

e) 2-methoxy-4- [N- (1- (2-piperidinophenyl) -1-ethyl) aminocarbonylmethyl] 6-enoic acid

Obtained from 1- (2-piperidinophenyl) -1-ethanol and 4-cyanomethyl 2-methoxybenzoic acid. Extraction at pH 5.5.

Yield: 21% of theory. value

Melting point: 118 -120 ° C Calculated: C 70.22 H 7.37 N 6.82

Found: C 70.60 H 7.29 N 6.97 Calculated: they are ~ 396

Found: t / e = 3%

g) 2-Ethoxy-4- [N- (4-methyl-a-phenyl-2-methyl-a-phenyl-2-methyl-a-phenyl) -amino aroonylmethyl] -enzoic acid ethyl ester

Prepared from 4-methyl-.alpha.-phenyl-2-piperidinobenzylbenzyl. 2-ethoxy-4-cyanomethylbenzoic acid ethyl ester.

Yield: 46% of theory. value

Melting point: 124-125 ° C Calculated: C 74.68 H, 7.44 N, 5.44 Found: C, 74.81 H, 7.56 N, 5.32 methyl ester on 2-Methyl - 4 - [N - (α- (4-Chloro-phenyl)

piperidinobenzyl) aminocarbonylmethyl] -benzoic acid

Prepared from? 4-chlorophenyl) -2-piperidinobenzyl alcohol and 2-methoxy-4-cyanomethylbenzoic acid methyl ester.

Yield: 47% of theory. value.

Melting point: 176-178 ° C

Calculated; C 68.70 H 6.17 N5.53 C1 6.99

Found: C 69.05 H 5.93 N5.76 C17.10

i) 2-hydroxy-4- [N- (o-phenyl-2-piperidinobenzyl) amino arbonylmethyl] benzoic acid ethyl ester

Prepared from α-phenyl-2-piperidinobenzyl alcohol and 4-cyanomethyl-2-hydroxybenzoic acid ethyl ester.

Yield: 78% of theory. value.

Melting point: 172-174 C ^with

Calculated: C 73.70 H 6.83 N 5.93

Found: C 73.80 H 6.81 N5.83

Example 4

2-Ethyl-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid

Mixture of 2g (4.3 mmol) 2-emoxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester and

5.3 ml of IN sodium hydroxide solution in 20 mJ. The ethanol was stirred for 3 hours at 60 ^° C, then neutralized with 0.3 ml of 1N hydrochloric acid and the styrene evaporated in vacuo. Distributes. between ethyl acetate and the slurry.

the organic extract was dried, filtered and evaporated in vacuo. The evaporated residue was crystallized from petroleum ether with the addition of ethanol.

Yield: 1.3 g (69% of theory).

Melting point: 88-90 ° C

Calculated: C 71.21 H 7.81 N 6.39

Found: C 71.62 H 7.73 N 6.54 Similar to Example 4, the following compounds were obtained:

a) 2-methoxy-4- [N- (1- (2-piperidinophenyl) -1-ethyl) aminocarbonylmethyl] benzoic acid x 0.67 H ₂ O

Obtained from 2-Memokcu-4- [N- (1- (2-piperidinophenyl) -1-ethyl) aminocarbonylmethyl] benzoic acid methyl ester.

Yield: 60% of theory. value.

Melting point: 116-120 ° C

Calculated: C 67.62 H 7.07 N 6.85

Found: C 67.60 H 6.87 N 6.55

b) 2-ethoxy-4- [N- (a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid

Prepared from 2-ethoxy-4 - [] 5k (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 89% of theory. value

Melting point: 155-156 ° C

Calculated: C 73.70 H 6.83 N 5.93

Found: C 73.60 H 6.96 N 6.12

c) 2-methoxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethylfbenzoic acid

Obtained from 2-methoxy-4- [N- (α-phenyl-2-piperidinobenzyl) amino ester and pb onylmethyl] b enzone. ki with ellin a

Yield: 68% of theory. value

Melting point: 202-204 ° C

Calculated: C 73.34 N 6.? 9 N 6.1 AND

Found: C 73.60 H 6.77 N 6.20

d) 2-Emoxy-4- [N- (1- (5-XAop-2-nunepuguHo4'eHUA) -1-nitrocarbonylmethyl] benzoic acid

Obtained from 2-emoxy-4- [N- (1-5-X-op-2-piperidinophenyl) -1-propyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 74% of theory. value.

Melting point: 115-118 ° C

Calculated: C 65.42 H 6.81 N6.10 C17.72

Found: C 65.54 H 6.94 N 5.81 Cl 7.89

e) 2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -1-propyl) aminocarbonylmethyl] benzoic acid

Prepared from 2-emoxy-4- [N- (1- (2-piperidinophenyl) -1-propyl) aminocarbonylmethyl] benzoic acid ethyl ester Yield: 73% of theory. value.

Melting point: 81-83 ° C

Calculated: C 70.73 H 7.60 N 6.60

Found: C 70.90 H 7.47 N 6.77

e) 2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -1-phenyl) aminocarbonylmethyl] benzoic acid

Prepared from 2-emoxy-4- [N- (1- (2-piperidinophenyl) -1-phenyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 92% of theory. value.

Melting point: 82-85 ° C

Calculated: C 71.65 H 8.02 N6.19

Found: C 71.45 H 8.01 N6.13

g) 2-ethoxy-4- [N- (1- (2-pyrrolidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Prepared from 2-emoxy-4- [N- (T - ('2-pyrrolidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 77% of theory. value.

Melting point: J20-123 ° C

Calculated: C 70.33 H 7.60 N 6.60

Found: C 70.71 H 7.44 N 6.33

h) 2-Emoxy-4- [N- (1- (2- (4-methylpiperidino) phenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Prepared from 2-emoxy-4- [N- (1- (2- (2- (4-methylpiperidino) phenyl) -1-butyl) -amino] -bonylmethyl] -benzoic acid ethyl ester

Yield: 71% of theory. value.

Melting point: 83-85 ° C

Calculated: C 71.65 H 8.02 N 6.19

Found: C 71.60 H 7.94 N 6.09

i) 2-ethoxy-4- [N - (. 1- (2-hexamethyleneiminophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Obtained from 2-emoxy-4- [N- (1- (2-hexamethyleneimino phenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 81% of theory. value.

Melting point: 101-105 ° C

Calculated: C 71.65 H 8.02 N 6.19

Found: C 71.31 H 7.79 N6.18

k) 2-ethoxy-4- [N- (1- (6-chloro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Prepared from 2-ethoxy-4- [N- (1- (6-chloro-2-piperidinophenyl) -1-butyl) amino-carbonylmethyl] benzoic acid ethyl ester

Yield: 82% of theory. value.

Melting point: 133-136 ° C

Calculated: C 66.02 H 7.03 N 5.92 Cl 7.50

Found: C 66.48 H 7.47 N 5. ° 8 C17.88

l) 2-epoxy-4- [N- (1- (4-methoxy-2-piperidinophenyl) -1-butyl) aminocarboylmethyl] benzoic acid

Obtained from 2-Emoxy-4- [N- (1- (4-Memoxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 81% of theory. value.

Melting point: 98-100 ° C

Calculated: C 69.21 H 7.74 N5.98

Found: C 69.12 H 7.62 N 5.78 m; 2-Emoxy-4- [N- (1- (5-methoxy-2-piperidinophenyl) -1-butyl) amino arbonylmethyl] benzoic acid

Obtained from 2-Emoxy-4- [N- (1- (5-Memoxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 74% of theory. value.

Melting point: 145-148 ° C

Calculated: C 69.21 H 7.74 N 5.98

Found: C 69.00 H 7.65 N 5.89

n) 2-methoxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Obtained from 2-Memokec-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid methyl ester.

Yield: 86% of theory, value.

Melting point: 140-143 ° C

Calculated: C 70.73 H 7.60 N 6.60

Found: C 70.49 H 7.58 N 6.31

o) 2-Ethoxy-4- [N- (5-chloro-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid x 0.5 N? O

Prepared from 2-ethoxy-4- [N- (5-chloro-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester x 0.5 N _? Oh

Yield: 93% of theory, value.

Melting point: 153-155 C ^with

Calculated: C 62.79 H 6.41 N 6.36 C.1 8.06

Found: C 63.21 H 6.34 N 5.S9 Cl 8.46

n) 2-ethoxy-4- [N- (2-piperidinobenzyl / 1, 5-chromocarbonylAmethyl] benzoic acid

Prepared from 2-emoxy-4- [N- (2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 77% of theory, value.

Melting point: 108-109 ° C

Calculated: C 69.68 H 7.12 N7.07

Found: C 70.00 H 7.99 N 7.31

p) 2-hydroxy-4- [N- (1- (2-piperidinophenyl) -1-biphenyl) aminocarbonylmethyl] benzoic acid

Prepared from 2-hydroxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 61% of theory. value.

Melting point: 136-138 ° C

Calculated: C 70.22 H 7.37 N 6.82

Found: C 70.40 H 7.64 N 6.60

c) 2-Allyloxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Prepared from 2-allyloxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 92% of theory. value.

Melting point: 110-112 ° C

Calculated: C 71.97 H 7.61 N 6.22

Found: C 71.90 H 7.62 N 6.21

m) (+) - 2-ethoxy-4 - [N - (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Prepared from (+) - 2-ethoxy -4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester. Yield: 81% of theory. value.

Melting point: 1.22-123 ^with C

Calculate C'_ / 1.21 H 7.7.1 N e l '

Found: C, 1.19 N @ 0. Specific rotation: [o.D, = + 4., O ° (c = 1.1'3 in met.c.

y) 2-ethoxy-4- [N- (4-methyl-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Prepared from 2-ethoxy-4- [N- (4-methyl-α-phenyl2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 41% of theory. value.

Melting point: 127-129 C ^with

Calculated: C 74.05 H 7.04 N 5. ”6

Found: C 73.80 H 7.09 N5.74

u) 2-Ethoxy-4- [N- (6-methyl-a-phenyl-2-piperidinobenzyl) amino arbonylmethyl] benzoic acid

Prepared from 2-ethoxy-4- [N- (6-methyl-1-phenyl2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 40% of theory. value.

Mp 118-121 ^{with a} 'C

Calculated: C 74.05 H 7.04 N5.76

Found: C 73.71 H 6.92 N 5.76

x) 2-ethoxy-4- | N- (α- (4-methylphenyl) -2-piperidinobenzyl) amino aminobenzylamine] benzoic acid

Obtained from 2-emoxy-4- [N- [alpha] (4-methylphenyl) -2-piperidinobenzyl) amino arbonylmethyl] benzoic acid ethyl ester.

Yield: 94% of theory. value.

Melting point: 148-151 ^C C

IT Number: With /4.0 Η, .04 .ό., Ό

Found: C 74.20 H 7.15 N5.81 ι ί. ι 2-'M <;'IΊ'1 »К-, 1-4- (, Л - I (X- ^J 4-Х. \: РЛОСН UA j-2-П I! NCpLK; ί1 'ί · л: <_ · · ΛίΛ; ЗМ ί iH ¹ ? 38

Obtained osh mci ι iu.v C ecnic: ··· on 2-Mcmumu - r-ι \ - ·.

x a? 'p ·.' 'ei ii ι a ι-2-nunepi.iquH ·. > 6ei -kil j -imui ·· '8: n''Alnylmethyl Ή:' * e! and a <Ula. \ u1! a.

. b; |: v 77 7,. and met'p. moons *. · ..m.

Melting point: 177-ISO ^c C

Calculated: C 68.21 7λ. ^; N5.68 Cl 7.1 °

Found; ^{C 68.11 'H 5.78 N5x3 Cl -} .-Ο

h) 2-ethoxy-4- [X- (α-phenyl-2-pyrrolidinobenzyl) aminocarbonylmethyl] -acetic acid

Prepared from 2-ethoxy-4 - [N - [α-phenyl-2-pyrrolidinobenzyl · amino arbonylmethyl] benzoic acid ethyl ester.

Yield: 67 Ά from Theop. value.

Point pa point: 141-143 C ^with

Calculated: C 73.34 and 6.59 N6.11

Found: C, 73.33; 6.74; N 6 .- / 2 m 2 -methyl-4- | N l-hex a.Mei 1ι ilsnim n · '- (l-phenyl <.> En.-: il j amine * * * to a p} smlmethyl] benzoic acid

Obtained from methyl cvmcp of 2-methoxy-4- | \ -'._ hexamethane.ke11 and \ psho-a-phenylbenzyl. \ - amino-cross> nit.-and \ 1ethyl] benzoic acid

.Nobiv: 91. »A in theory. magazine <·. > ΗΗ · '! 11. Melting point: 154-166 ° C 1 1 t ·. -t ·. . With '3.7 ^1. ' And As XA ^! U ί-б t А трпгм - а '(·· ι ι Н. Co! * \ A A MS ' ^T Ί ¹ 1 - Lil ,; A-ei AAOM. and - -4 -1 - (_.- XCiv C3R; 11.U ALLlUM-ll-Ht i-iA-'K CHUAOC Η. in. \ / <1 a; u'tο 'iivi.AMemu \ iotara' s whale. a u ι m -.- Mr ../ ...... ..... -1 ..... t. . . , " _ j. t A A.i - .. 1.1 A.A .., \.? A. ... _t .. X. A Λ, .. ... Λ *. I \ C k v. 3 K'j 1 i.'J AC i Η.! 7 1 ί TH '^<and Λ- · ρ пИ4 ίΐ A * -A Hi nA Λ AA'AiloX Apt>. ΧΑιΛΜό /ΑΧ AH / H 4

Calc .: C .4 / .6 N /.04 Νθ · -ό

Found: C 73.H 7.14 N5.79 a a; 2-Hydroxy 1-4- [H-1a-phenyl-2-pyridinobenzylamino] carbonyl is 1 j 1 and l | b e n y. »is ι ί а к ιι е е л и н а

Obtained from 2-ethylpiperazole-4- [N- [alpha] -phenyl] -2-piperidobenzene / paminocarbonyl-methylbenzoic acid ethyl ester by esterification with 4 equivalents of 1N sodium hydroxide in ethanol / decan.

Yield: 35% of theory. value.

Melting point: 222-224 ° C

Calculated: C 72.95 H 6.35 N b

Found: C 73.00 H 6.64 N 6.28 ab) 2-allyloxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl · benzo] benzoic acid

Obtained from ethyl 2-allyloxy-4 - [\ ^T - (a-phenyl-2piperis | inoben.zil'aminokarboni ₂ \ methyl] benzoic acid.

Yield: 69% of theory. value.

Melting point: 172-173 ° C

Calculated: C 74.35 H 6.66 N5.78

Found: C 74.11 H 6.50 N 5/74 av) (-) - 2-ethoxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzene and selina

Prepared from (-) - 2-emoxy-4- [N- [cs-phenyl-2-piperidinobenzylminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 89% of theory. value.

Melting point: 90-95 C ^with

Calculated: C 73.70 H 6.83 N 5.93

Found: C 73.59 But. 81 N 5.83

Specific rotation: ~ -2.2 ° <c = 1 in methanol?

Example 5

2-Emokcu-4- [N- (1-2-piperidinophenyl-1-yl) aminocarbonylmethyl] benzoic acid sodium salt x 1.5 IU

Obtained from 2-emoxy-4- [N- (1- (2-piperidinylphenyl) -1-ethyl) aminocarbonylmethyl] benzoic acid ethyl ester like Example 4, After purification by column chromatography. The evaporated residue is dissolved in ethanol and mixed with 1 equivalent of 1 N sodium hydroxide. Evaporation in vacuo and stirring with acetone yields the crystalline sodium salt.

Yield: 76% of theory. value.

Melting point: 242-244 ° C

- Calculated: C 62.73 and 7.01 N 6.01

Found: C 62/74 H 7.17 N6.05

Similar to Example 5, the following compounds were obtained:

(a) 2-Ethoxy-4- [N- (1- (4-methyl-2-piperidinophenyl) -1-butyl) alnocarbonylmethyl] benzoic acid sodium salt x 0.5 IU

Prepared from 2-ethoxy-4- [N- (1- (4-methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 72% of theory. value.

Melting point: 255-260 ° C

Calculated: C 67.06 H 7.50 N 5.79

Found: C 66.94 H 7.28 N 5.50

b) 2-Ethoxy-4- [N- (1- (6-methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid sodium salt x 2.5 IO

Prepared from 2-ethoxy-4- [N- (1- (6-methyl-2-piperidinophenyl) -1-butyl) amino arbonylmethyl] benzoic acid ethyl ester.

1. · .'6υΙ \ 81% of theory. value.

Melting point: 232-240 ° C

Calculated: C 62.39 H 7.75 N 5.39

Nimepeno: ('62.22 H 7.46 N 5.61

6; 2-Ethoxy-4- [N- (1- \ 2-niperidinophenylC1-methyl-aminocarbonylacetyl] benzoic acid sodium salt

Prepared from 2-emoxy-4- [N- (1-, 2- piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 87% of theory. value.

Melting point: 250-258 ° C

Calculated: C 67.79 H 7.22 N 6.08

Found: C 67.60 H 7.37 N 6.04

d) 2-Ethoxy-4- [N- (α-phenyl-2-piperidinobenzyl) amino arbonylmethyl] benzoic acid sodium salt

Prepared from 2-ethoxy-4- [N- (? -Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 89% of theory. value.

Melting point: 233-235 ° C

Calculated: C 70.42 H 6.32 N 5.67

Found: C 70.20 H 6.41 N5.49

Example 6

2-Hydroxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

To a solution of 2 g (4 mmol) of 2-emoxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoene ethyl ester. acid in 20 ml of 1,2-dichloroethane, with stirring and isolation from moisture and -20 ^: C, was added dropwise 1 ml (10.4 mmol) of boron tribromide. Allow to reach room temperature and stir for a further 17 hours. It was then poured into ethanol, concentrated in vacuo, ice added and partitioned dried and purified between chloroform and water.

is filtered off and evaporated in vacuo. The residue was obtained by column chromatography over silica

The organic extract

-> · '- - * ··

CC cc (m.p. oog / ethyl acetate = 7 / D).

SUN: 037 and <21% of theory. spawn

Melting point: 172-173 C ^with

Calculated: C 72.70 H 6.83 N 5.93

Found: C 73.95 H 7.05 N6.12

Like Example 6, the following compounds were prepared:

a) 2-hydroxy-4- [N (a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoic acid

Prepared from 2-ethoxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid.

Yield: 40% of theory. value.

Melting point: 221-223 ° C

Calculated: C 72.95 H 6.35 N 6.30

Found: C 72.68 H 6.45 N 6.49

b) 2-hydroxy-4- [No. (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 2-emoxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 19% of theory. value.

Melting point: 132-134 ° C

Calculated: C 71.21 H 7.81 N6.39

Found: C 71.43 H 7.91 N 6.55

c) 2-hydroxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) amino arbonylmethyl] benzoic acid

Obtained from 2-ethoxy-4- [N- (1- (2-piperinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid

Yield: 42% of theory, value.

Point of. mp: 136-137 ° C

Calculated: C 70.22 H 7.3 / N 6.82

Found: C 70.19 H 7.39 N 6.99

Butyl ester of 2-emokcu-4- [N- (1- (2-piperidinophenyl) 1-butyl> ami a p b onylmethyl] benzoenic and selin a

A mixture of 1.98 g (9.6 mmol) of N, N-dicyclohexylcarbodiimide, 1a. temperature, then 6.6 ml of methylene chloride are added and the solution thus obtained is added dropwise to a solution of 0.44 g (1 mmol) of 2-emoxy-4- [N- (1 (2-piperino-phenyl) -1-butyl) -amino arbonylmethyl] benzoic acid in 15 ml of methylene chloride. After stirring for 60 hours at 20 ° C, the precipitated precipitate was filtered off, washed with methylene chloride and the methylene chloride solution was evaporated in vacuo. The evaporated residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 9/1).

Yield: 0.30 g (60% of theory, value).

Melting point: 74-77 ° C

Calculated: C, 72.84; 8.56; N 5.66

Found: C 73.00 H 8.65 N 5.79

Example 8

2-Allyloxy-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonyl-methyl-benzoic acid ethyl ester

Go to solution 1.1. 2-Hydroxy-4 [N- (? -phenyl-2-piperidinobenzyl) amino] tribonylmethyl] -benzoic acid (2.3 mmol) ethyl ester in 1.0 ml of anhydrous dimethylformamide was added 0.10 g (2.3 mmol) of sodium hydride (55% -en in oil) and stirred for 0.5 h at room temperature, then a solution of 0.2 was added dropwise

ml (2.3 type'Ί) allyl bromide in 5 ml of anhydrous dimethylformamide and se stirred for 5 hours at room temperature. Evaporates in vacuo. distributes ss between times regular chromatography with chloroform and chloroform. the organic ckcninakng is .1 .1. f ί ¹ -cvuiaoa. gnici η i'vIm -π ημμοηΚ 'gn-r

vacuum. The evaporated residue was recrystallized from acetonitrile and then from ethanol.

Yield: 0.55 g (46% of theory).

Melting point: 117-119 ° C

Calculated: C 74.97 H 7.08 N 5.47

Found: C 74.90 H 7.14 N 5.38

Like Example 8, the following compound was obtained:

a) 2-Allyloxy-4- [X- (1H-2-piperidinophenyl .'-1-butyl) amino arbonylmethyl] benzoic acid ethyl ester

Prepared from 2-hydroxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester and allyl bromide.

Yield: 72% of theory. value.

Melting point: 105-106 ° C

Calculated: C 72.77 H 8.00 N 5.85

Found: C 72.90 H 7.90 N 5.87

Example 9

2-Ethoxy-4- [N- (2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

1.0 g (2.18 mmol) of 2-ethoxy-4- [N- (5-chloro-2-pyridinyl benzyl) amino arbone and lmethyl] ethylbenzoate is hydrogenated in 20 rnl. ethanol with 0.5 g palladium / carbon (10%) at 50 ^; 1 C, and a hydrogen pressure of 1 bar for 45 minutes, was filtered through silica gel, evaporated in vacuo and purified by silica gel column chromatography (chloroform / methanol = 10.1).

Yield: 0.71 s (77

Melting point

Accrued: C 70

And aternes: With Ό>

to

1N

Like Example 9, the following compound was obtained:

a) 2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -1-pentyl] aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 2-emoxy-4- [N- (1- (5-hydroxy-2-piperidinophenyl) 4 H -propyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 74% of theory. value.

Melting point: 115-117 ° C

Calculated: C 71.65 H S.02 N 6.19

Found: C 71.47 H 8.11 N 6.25

Example 10 2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) -aminocarbonylmethyl] benzoic acid (i) 2-emoxy-4- [N- (1- (2 -piperidinophenyl) -3-methyl-1-buten-1-yl) -amino arbonylmethyl] benzoic acid

Prepared from 2-emoxy-4- [N- (1-piperidinophenyl) -3-methyl-1-buten-1-yl) -aminocarbonylmethyl] benzoic acid ethyl ester.

Yield: 85% of theory. value.

Melting point: 110-113 ° C

Calculated: C 71.97 H 7.61 N 6.22

Found: C 71.92 H 7.80 N5.98 (j) · 0.21 g (0.39 mmol) of 2-ethoxy-4- [N- (1- (2-piperidinophenyl) -3 acid with 0.10 g of palladium / wool (1 and 1 bar) for 7 hours, vacuum and purify,, I ..., ... ... 4 .. \. .... .. „.,. _____ methyl-1-butene-1- il) -aminocarbonylmethyl] benzoic acid hydrate in 1.0 ml absolute ethanol) at 50 ^{; 1} C through filtrate and hydrogen pressure over kieselguhr evaporated χρ ·. Tp Theoretical Suspension

o> h1: a on 'lpll · A> .chn. ^g pgprsp

Over night of Example 1, a fusion compound was obtained:

a) Art. ··· '!? 2-epoxy-4 - [(1- (2-piperidinophenyl) -1-ethyl-1-butyl-1-aminocarbonyl) methylmethyl] benzoic acid ester

Obtained from 2-emoxy-4- [N- (1 H -piperidinophenyl; -3-methyl-1-buten-1-yl) Daminocarbonylmegpyl] benzoic acid ethyl ester, mp 125-126 C | , 2-piperidinofepylisobutylketeticht and 3-ethoxy-4emokcukapoi nylphenylacetic acid, similar to example 1f

Yield: 51 5 ¹ of theory. value.

Melting point: 139-141 ° C

Calculated: C 72.4'7 H <8.39 N 5.83

Found: C 72.30 H 8.20 N 5.87

Example II

2-Stoxy-4- [N-1a-phenyl-2-piperidinobst: yl ') amsulfarbonylmethyl

Ο'.ίγ alcohol

To '728 mmol lithium aluminum aluminide hydrochloride tetrahydrofuran was added dropwise at -5 ^: With solubility and feathers and not, μηήιλ ¹ aminocaroonylmethyl.

:! 'Н ch mein' seni r · e i. ¹ a φνρηπ and cc is confused 3 time / 1 at ^{! 1} ( (ip.i t ··, H ' ⁴ - - - B) * .. · .1 e. . · , · X J ri ΛΛ'Λψι c, lxx>, h) w sn ether and ss pr i.b> 1 4? \ Sodium c1? <1 '<4f. / n 'F. t -, I t-all is ere.- · is _AND 'H · \: t. evaporate g. ίύ 45 ivi ιΚννχΐ and Se prn ucrnr ^v

. , 1am1 rp. C 75.9 ”: 4/57 and 5.95 ! .. cool bnp for the prize 1 <p And be n ·. 'Treats ssmdns? compound: and ι 2-ei ιι · '7.ι ·! · [-, .2- ( and, perdig. goals 1l | benzyl! 5 horror. klllchsn YAN SPY 2-Stoxy-4- [6- <alpha] ester ptzeg idiophenes. m-1-butyl minylcarb. \ methyl] 0enz <'en acid through erection <. : lithium borohydride in boiling tetrachlorodrofur, ar: nmie on ί T-three baric acid bird ester. 21 b: 68 7 2 of Theop 1 . value.

They> TC and mp 112-115 ^with C

Calculated: C 73.55 and 8.55 N bNi

Found: C, 73.60; H, 8.38; N, 6.69

Example 12

2-methyl-4- [N- (α-phenyl-2-piperidinoethyl) aminocarbonyl acetyl] benzaldehyde

To a solution of 0.28 g (1.3 .mu.l> pyridinium chlorochromate in 5

ml of chloroform, a dropwise solution of stirring and room temperature is added to: 0.4 g (0.87 mmol) of 2-ethoxy-4- [X- (α-phenyl-2 a nd p e r d i n <'b en z a l 1 a m ι .gnocarbonylmethyl] benzyl alcohol .. Mix with <

overnight at room temperature, evaporates in station !. ether was collected, filtered, evaporated in vacuo and purified by column chromatography over silica gel (toluene / ether. acetate =

Yield: 0.16 g 14 * j% of theory. value !.

Melting point: 154-156 ° C

Calculated: C7o.29H7l7 Νή14

Found: (2 /6.30 Η /.Ιό· X ή ίυ a / 2-ernokcu-4-i N-t 1- · 3-piperidinophenyl) - 1-butyl schinocarb ·. -nilme til] b is and z a lu is hi y

Obtained from 2-emoxy-4- [N- (1- (2-piperuinophenyl) -1-butyl a minocarbonylmethyl] benzenyl in alk.

Yield: 47% of theory. value.

Melting point: 109-111 ° C

Calculated: C 73.90 H 8.11 N 6.63

Found: C 74.22 H 8.14 N 6.73

Example 13

2-Ethoxy-4- [N- (α-phenyl-2-piperuinobenzyl) aminocarbonylmethyl] benz aldehyde

0.67 g (5.6 mmol) of sodium carbonate are heated together with 6 ml of ethylene glycol in a bath of 170 ° C and, with rapid stirring, 0.70 g (1.1 mmol) of H ¹ '[2-ethoxy-4- [H-] (α-Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -benzoyl] -B [ ^2- tosylhydrazine, resulting in rapid gas evolution. It is then heated for another 2 minutes at 170 ° C and immediately poured onto ice. It is extracted with ether, dried, filtered and the ether solution is evaporated in vacuo. The residue was purified by silica gel column chromatography (toluene / ethyl acetate = 2/1).

Yield: 0.25 g (50% of theory).

Melting point: 153-156 C ^with

Calculated: C 76.29 H 7.06 N 6.14

Found: C 76.42 H 7.33 N 6.28

Similar to Example 13, the following compound was obtained:

a) 2-ethoxy-4- 1 H- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzene aldehyde

No results from N ¹ - [2-emokcu-4- [N- · '1 -D-nippers in the inferior I- - o bvrnu l 'ami And aroons lmeti a {benzoyl P.N „-t o -: and lhh κι oazin.

Yield: 51 76 Theory. value.

Melting point: 11'8-111 ° C

Calculated: C 73.90 H 8.11 N6.63

Found; C, 73.79; H, 8.29; N, 6.75

Example 14

2-Emoxy-4- [N - ('1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid benzyl ester

0.35 g (0.8 mmol) of 2-ethoxy-4- [1H- (1- (2-piperidinophenyl-1-butyl) -aminocarbonylmethyl] benzoic acid were heated together with 0.15 g (0.9 mmol) of N, N'-carbonyldiimidazole in 15 ml. absolute tetrahydrofuran at reflux for 2 hours.Then, 1.03 ml (10 mmol) of benzyl alcohol are added and heated at reflux for 3.5 hours. / 1).

Yield: 0.10 g (23.6% of theory).

Melting point: <20 ° C

Calculated: C 76.29 H 7.06 N 6.14

Found: C 76.42 H 7.33 N 6.28

Calculated: molpeak m / e = 528

Found: molpeak t / e - 528

Example 15

(+) -2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -1-butyl] -N-inocarbonylmethyl] benzoic acid ethyl ester and (-) - 2-ethoxy-4- | N- (1- (2-piperidinophenyl) -1-butyl) acetic acid carbonylmethyl-dibenzoic acid mg of (±) -2-emoxy-4- [N- (1- ', 2-piperidinophenyl-1-butyl) aminocarbonyl ethyl ester .beta. methyl benzoic acid is supplied in unit doses at i.02 mg of our Baker Chiral Phase IV column. in which · R) -SS-3,5dinitrobenzoylphenylglycine is covalently linked to aminopropylsilica gel (grain size 5 μηι , circular, is a pore size of 60 A: 4.6 min inner diameter, 25 cm long liar).

Eluent: hexane: ethanol = 100/5;

Flow rate: 0.75 ml / min;

Temperature: 22 ° C

The fractions eluted after 31.2 minutes and after 32.9 minutes (detection with ϋλ ⁷ at 254 pt) were captured and collected separately and evaporated in vacuo.

From the 31.2 minute eluate the following is obtained:

7.5 mg of (+) - 2-emoxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester Melting point: 117-119 ° C.

Specific rotation: [cx] _D ²⁰ = + 7.0 ° (c = 1.03 in methanol)

From the 32.9 minute eluent the following is obtained:

9.4 mg of (-) - 2-emoxy-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid ethyl ester

Melting point: 115-117 ° C.

Specific rotation: [a] _D ²⁰ = -6.9 ° (c = 1.02 in methanol)

Like example 15

(a) (±) -2-ethoxy-4- [N- (a-phenyl) -2-piperidinobenzyloxy amine arb onylmethyl] benzoic acid ethyl ester can be separated into its (+) - enantiomer and its (-) enantiomer.

Example 16

2-Ethoxy-4- [N- (1- (2-11-piperidinophenyl) -1-butyl) -benzylmethyl] -toluene

Hydrogenation was 0.54 g (1.2 mmol) 2-eiiiokcu-4-j ^r N- (l-! 2R 'ιπο:'·> and ¹ 'mahhei; ί d ί -ΰνι and! Ιl> amsh rock detention center \ [ethyl | bench · · υλ · .anno ί mm

114-115 ^with C; obtained from 2-ethoxy-4- [N- (2- (2-piperidinophenyl) butyl) aminocarbonyl] methyl] benzyl- copolymer with thionyl chloride in chloroform] in 10 ml absolute dioxane for 3 hours at 20 ° C and pressure at hydrogen 5 bar. It was evaporated in vacuo and partitioned between ethyl acetate and aqueous sodium carbonate solution. The organic residue was dried, filtered and evaporated in vacuo. The evaporation residue was purified by silica gel column chromatography (chloroform / acetone = 19/1).

Yield: 0.23 g (47% of theory).

Melting point: 107-108 ° C

Calculated: C 76.43 H 8.88 N 6.86

Found: C 76.40 H 8.884 N 6.90

Example 17

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

Heat 100 mg (0.20 mmol) of 2cmokcu-4- [N- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid tert-butyl ester in 5 ml of benzene together with several crystals of p-toluenesulfonic hydrate acid for. half day under reflux. Then the desired product is obtained, according to R _{f the} value of the thin layer chromatogram and mass spectrum.

Melting point: 87-89 ° C.

Calculated: m / e - 438

Found: mc = 438

Example 18

2-emokcu-4- [N- {1-dipiperidinophenyl) -1butyl] aminoacarboxybenzyl] 40a: acetic acid / 1H. ί | 'U i 3 .I And A D.C-r? i 1 1 ii 1. ti '· - 1 ii U ¹ <L ii H h t ¹ Ij H · <Li ivkl · 11' LL, j 'n-to'-J. μ !! p _; - the J-thrush crushed-toothed pellet can be filled with <7 acid in 10 ml of ethanol is 0.12 g of palladium, carbon (10 7-eiij, at 5 and C and a hydrogen pressure of 5 bar. After 5 hours, the catalyst is removed by filtration through diatomaceous earth and the solution was evaporated in vacuo.

The evaporation residue was crystallized from petroleum ether / ethanol.

Yield: 0.14 g (70% of theory).

Melting point: 87-90 ° C

Calculated: C 71.21 H 7.81 N 6.39

Found: C 71.46 H 7.95 N 6.51

Example 19

2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -1-hexyl) aminocarbonylmethyl] benzoic acid ethyl ester

Prepared from 1- (2-piperidinophenyl) -1-n-hexyl and 3-ethoxy-4-ethoxycarbonylphenylacetic acid similar to Example 1.

Yield: 43% of theory. value.

Melting point: 101-105 ° C

Calculated: C 72.84 H 8.56 N 5.66

Found: C 72.72 H 8.52 N 5.63

Example 20

2-Ethoxy-4- [N- (1- (2-piperidinophenyl) -1-n-hexyl) aminocarbonylmethyl] benzoic acid.

Obtained from 2-emoxy-4- [N- (1-piperidinophenyl) -1-n-hexyl) aminocarbonylmethyl] benzoic acid ethyl ester like Example 4.

Yield: 77% of theory. value.

Melting point: 117-120 ^° C

Accrued: (; L..O / bl s. And oil

Found: ('' TcO ¹ H forehead And ~ _? N

Example A

Tablets are 5 mg of 2-ethoxy-4- [N- (α-phenyl-2-piperidino-benzyl) amine.

carbonylmethyl] benzoic acid

Composition:

tablet contains:

active substance (1) 5.0 mg cornstarch (2) 62.0 mg milk sugar (3) 48.0 mg poly wines and lpyrrolidone And) 4.0 mg magnesium stearate (5) 1.0 me _

120.0 mg

Method of production:

1,2,3 and 4 are mixed and moistened with water. Wet the wet mixture through a sieve with a mesh size of 1.5 pat and dry at about 45 ^Q C. Dry the granulate through a sieve with a mesh size of 1.0 pat and mix with 5. The finished mixture is compressed into tablets with a matrix tablet press. with a diameter of 7 mm, which has a split cut.

Tablet weight: 120 mg

Example B

Dragees with 2.5 mg 2-ethoxy-4- [X- (α-phenyl-2-piperidinobenzyl) amino to arbonylmethyl] benzoic acid Selected core consists of:

a tively wei i, e c mBo (1) 2.5 mg potato starch (2) 44.0 mg milky fever 1 j 30.0 mg N o vinshi r olid he t 4; 3.0 mg magnesium stearate ί -3 0.5 me χί! N. mg

Mem ·. > g on receipt:

1,2.3 and 4 are thoroughly mixed and moistened with water. The wet mass was poured through a sieve with a mesh size of 1 mt, dried at 45 ° C and then the granulate was passed through the same sieve. 5. Add the rounded cores of dragees with a diameter of 6 mm by the addition of a tablet machine. The cores thus obtained are coated in a known manner with a coating consisting essentially of sugar and drink. The finished dragees are polished with wax.

Dragee weight: 120 mg

Example B

10 mg tablets of 2-ethoxy-4 - [(1- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Composition:

active substance 10. 0 they with .. · ' milk sugar on 70. 0 mg powder and you are us and you are 31. 0 they C. ·· polyvinylpyr ι> li don 8. 0 mg m a g n e z i e s s t e a r at Lu mg

120.0 mg

Method of production:

(..places of the active substance. milk sugar and nougat starch are moistened with a 20M solution of polyoinimmurolidoids all over the body. The blah mass is granulated through ciHTr 'apertures 1.? mm and dried at · ...

lazy. a. ri j is pressurized through a session with g <\\ szpn1g evil op n - ·· ip. and inc ί 'I ίι Ί j and l are homogeneous <. cjOHicjiic '.' st.

Η ···. ··,>;;'j -, Μ-,' · ί 'Η ·' ·, '' ί Ή PL ¹

Matrix: / mm gjj. '. Ic;,] ϊκρ · ν gc. \ Umc.uiu sharp.

The 5 is the 2-epoxy-4 - [N-phenyl-2-piperidino-oenzyl] amine.

ca ··· 'ni lk 1stil] b en c o e ι of acid The core of 1 dra / ; is c i; active substances' hours and mg calcium phosphate J 1 .and nig Tue < cornstarch Si. i. 0 mg polyvinylpyrrolidone 4. 0 mg magnesium stearate 1. ^{n nI} S 13 and .0 mg Receiving Mood:

The active substance, calcium phosphate and corn starch are moistened with a 15% aqueous solution of polyvinylpyr. The wet mass passing through the sieve is the size of the opening I m. dried at 45 ' C then rubbed _; the same screen. After mixing with the given amount of magnesium, they are tightened. you are the mixture you press the cores of the dragees.

Weight: 130 mg

Matrix: 7 mm diameter

The so-called dragee cores of the dragees are applied in a known manner to the lM sugar and melt. Temp dragees with w>. \ Ir ir with

Claims (11)

1 ju V. i D1 1 fl Uk 1.1 · B To:? ' chat R | - pyrrolidino-. nunepuguiio-, hexamethyleneimino-, methyl-pyrrolidino-, dimethylshyrrolidino, 2-methyl-piperidino. 3-methylpiperidino, 4-methylpiperidino, 3,3-dimethyl-piperidino, cis- 3,5-dimethylpiperidino- or trans-3C-dimethylpiperidino group. R _? - a hydrogen or halogen atom, a methyl or methoxy group, R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a n-phenyl or 3-methyl-n-butyl group, or optionally substituted by a halogen atom, with a methyl or methoxy group phenyl group, R ₄ is a hydrogen atom, a methyl, ethyl or allyl group and W is methyl, hydroxymethyl. formyl. a carboxy or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, the alkyl moiety of the alkoxy group being substituted by a phenyl group, their enangiomers and their salts. 2. Phenylacetic acid derivatives of general formula I. according to claim 1. in which means R ·} and R ₄ are as defined in claim 1, m * * * ...... 1. . ,. · XeivC jaicjituacliun ι w ι ρνη- ·. Rn is a hydrogen, fluorine or chlorine atom, a methyl or methoxy group. W is a carboxy, methyl, hydroxymethyl, formyl or benzyloxycarbonyl, or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, their enantiomers and their salts. 3. Derivatives of. phenylacetic acid of the general formula I according to claim 1, in which: R j is a piperidine group, R _? - a hydrogen, fluorine or chlorine atom, R4 is a methyl, ethyl, p-propyl, p-butyl, isobutyl, p-pentyl or phenyl group, R ₄ is a methyl or ethyl group and W is a carboxy-, mepuxycarbonyl or ethoxycarbonyl group, their enantiomers or their salts. 4. Phenylacetic acid derivatives of general formula I according to claim I, in which they are denoted R1 go R ₄ . as in claim 3 and W is a carboxyl group, their enantiomers and their salts. 5. 2-Ethoxy-4- [N - (1- (2-pyridyl-phenyl) -1-butyl) aminocarbonylmethyl] benzoic acid, its enantiomers and its salts. 6. 2-Emoxy-4- [N- (1- (2-piperidinophenyl) -3-methyl-1-butyl) aminocarbonylmethyl] benzoic acid, its enantiomers and its salts. 7. The physiologically tolerated salts of the compounds according to claims 1 to 6, inorganic or organic acids or bases are obtained if these compounds contain a carboxy group. 8, A medicament comprising a compound according to claims 1 to 6, wherein [1 represents a methyl, ethyl or allyl group. or a physiologically tolerated coa .. together with one. 1 ..- .. 11 several inert Ilkisli sewed with Use of the compounds of claims 1 to 6, wherein R ₄ represents a methyl, ethyl or allyl group, or a physiologically tolerated salt thereof, for the preparation of a medicament suitable for the treatment of Diabetes mellitus. A method for the preparation of a medicament according to claim 8, characterized in that in a non-chemical way a compound according to claims 1 to 6, in which R ₄ represents a methyl, ethyl or allyl group, or a physiologically tolerated salt thereof, is added to one or more inert carriers and / or diluents. 11. A process for the preparation of new phenylacetic acid derivatives according to claims 1 to 7, characterized in that (a) an amine of the general formula CH-NH ₂ (I) in which R _{2 and} R ₂ are as defined in claims 1 to 6, reacted with a carboxylic acid of the general formula HOOC-CH ₂ - <f 3 5 \ / or ₄ (W) in which R ₄ is as defined in claims 1 to 6 and W 'has the meanings of Claims 1 to 6, or W means a karaoxyl group protected by a protected radical, or optionally derived b-reaction mixture of readily capable derivatives and, if necessary, cleavage of the protected radical used, or b) to obtain a compound of general formula I in which W represents a carboxyl group, group A in a compound of general formula / / --t (Iv) in which R 1 and R ₄ are as defined in claims 1 to 6 and A represents a group which can be converted into a carboxyl group by hydrolysis, thermolysis or hydrogenolysis, converted into a carboxyl group c) to obtain a compound of general formula I wherein R ₄ represents a hydrogen atom, methyl or ethyl group, a compound of general formula c-Jun R ₂ 4 in which R _{3 and} R ₃ are as defined in claims 1 to 6. it is reacted with a compound of the general formula OR ₄ 6 which R ₄ and AV are as defined in claims 1 to 6, or d) in order to obtain compounds of general formula I in which R ₄ represents a hydrogen atom, a protective radical is cleaved from a compound of general formula in / SNUTSZ-SWF-f * 2 X \\ X \ / ----- / W-W '/ ^x or ₅ Ri (VII) in which Rj to R- are as defined in claims 1 to 6, W has the meanings of W mentioned in claims 1 to 6 or represents a group which can be converted into a carboxyl group R- represents a protecting radical for a hydroxyl group, or e) to give a compound of general formula I wherein R ₄ represents a methyl, ethyl or allyl group, a compound with R ·, R. I ^J SNSh-SSKN l /! // -e \ \% · W / / HE 1 <1 (VIII) Rj go R- u W are defined as in claims 1 to 6. Interacts with a compound of the general formula R ' ₄ -X (IX) in which R ₁₄ except the hydrogen atom has the meaning defined in claims 1 to 6 and X represents a nucleophilic, substitutable group, or together with the adjacent hydrogen atom, means a diazo group when R ₁₄ represents a methyl or ethyl group and, if necessary, the resulting compound is hydrolyzed, or f) a compound of general formula (X) wherein Rp R. _? , R ₄ and W are as defined in claims 1 to 6 and Y represents a group of formula R ^ Le \ _ / in R · / ί -C-ΝΉ- or -C = X as R- is as defined in claims 1 to 6 and R ₆ and R ₇ together with the carbon atom present in them represent an alkylidene group of 1 to 4 carbon atoms, and, if desired, a compound of the general formula I is obtained at this end, in which means: 15 -: a halogen atom and / or K; ha loghenphenyl! The b group, and / or the Vv-hydroxygmg and hunting group, is conveniently converted to a halosmgpyl group, by dehalogenation it is converted to a corresponding compound of the general formula I, in which Ro is hydrogen and / or represents a phenyl group, and / or W means a methyl group, and / or one compound thus obtained of general formula I in which W is a carboxyl group is converted by esterification to a corresponding compound of general formula I in which W is an alkoxycarbonyl or phenylalkoxycarbonyl group and / or one so obtained a compound of general formula I, c which W represents a carboxyl, alkoxycarbonyl or phenylalkoxycarbonyl group, by reduction, is converted into a corresponding compound of general formula I, in which W represents a formula or hydroxymethyl group, and / or a compound of the general formula I thus obtained, in which W represents a hydroxymethyl group, by oxidation, it is converted to a corresponding compound of general formula I, in which W represents a formyl or carboxyl group, and / or the compound thus obtained is general formula I, in which W represents a carboxyl group, It is converted to the hydrazide of sulfonic acid and by subsequent disproportionation - one corresponding compound of the general formula I, wherein W represents a formyl group, and / or so-obtained rac, emich.no compound of general formula I, in which the atom. is defined R .; except for the hydrogen claims 1 to 6, the enantiomers are separated by chromatography of the chiral phases, and / or the compound of formula I thus obtained is n; its salts, especially in the physiologically acceptable salts used with inorganic or organic acids or bases.