CA1225398A - Phenylacetic acid derivatives, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents

Abstract

Abstract New phenylacetic acid derivatives of general formula (I) wherein R1 represents an unbranched alkyleneimino group optionally substituted by one or two alkyl groups, R2 represents a hydrogen or halogen atom or a methyl or methoxy group, R3 represents a hydrogen atom, an alkyl group or a phenyl group optionally substituted by a halogen atom or by a methyl or methoxy group, R4 represents a hydrogen atom, an alkyl group optionally substituted by a phenyl group, or an allyl, acetyl or propionyl group and W represents a methyl, hydroxymethyl, formyl carboxy group or an alkoxycarbonyl group optionally substituted by a phenyl group, and their salts have interesting pharmacological properties, particularly a hypoglycaemic effect.
Processes for preparing these compounds and compositions containing them are described and exemplified

Description

The present invention relates to new phenylacetic acid derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
According to one feature of the present invention there are provided compounds of general formula R2 -H-h~-CO-CH

wherein R1 represents an unbranched alkyleneimino group with 4 to 6 carbon atoms optionally substituted by one or two alkyd groups each having 1 to 3 carbon atoms, R2 represents a hydrogen or halogen atom or a methyl or methoxy group, R3 represents a hydrogen atom, an alkyd group with 1 to 7 carbon atoms or a phenol group optionally substituted by a halogen atom or by a methyl or methoxy group, I represents a hydrogen atom, an alkyd group with 1 to 3 carbon atoms optionally substituted by a phenol group, or an ally, acutely or propionyl group and W represents a methyl, hydroxymethyl, formal or car boxy group or an alkoxycarbonyl group with

2 to 5 carbon atoms and which may be substituted by a phenol group;
and salts thereof.
The compounds according to the invention I 3~3 process interesting pharmacological properties and in particular an effect on the metabolism, especially a hypoglycemic activity It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically acceptable salts but other salts may find use, for example, in the preparation of compounds of general formula I and their physiologically acceptable salts.
Salts may be formed with organic or inorganic acids or, where W represents a car boxy group, with bases.
It will be further appreciated that compounds wherein R3 represents other than a hydrogen atom possess a choral center and may therefore exist in enantiomeric form. Such enantiomeric forms as well as mixtures thereof e.g. race mates are to be considered as within the scope of the present invention.
Al may, for example, represent a pyrrolidino, piperidino, hexamethyleneimino, methyl-pyrrolidino, dimethyl~pyrrolidino, ethyl-pyrrolidino, 2-methyl-piperidino, 3-methyl-piperidino, 4-methyl-piperidino,

3,3-dimethyl-piperidino, cis-3,5-dimethylpiperidino, trans-3,5-dimethyl-piperidino, ethyl-piperidino, diethyl-piperidino, methyl-ethyl-piperidino, propel-piperidino, methyl-propyl-piperidino or isopropyl-piperidino group.
R2 may, for example, represent a hydrogen, fluorine, chlorine or bromide atom or a methyl or methoxy group.
R3 may, for example, represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, n-bottle, isobutyl, sec.butyl, tert.butyl, n-pentyl, 3-methyl-n-butyl, n-hexyl, 4-methyl-n-pentyl, n-hotly, phenol, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl or methoxyphenyl group.
R4 may, for example, represent a hydrogen atom or a methyl ethyl, n-propyl, isopropyl, bouncily, l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, ally, acutely or propionyl group.
W may, for example, represent a methyl, hydroxymethyl, formal, car boxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, l-phenylethoxy-carbonyl, 2-phenylethoxycarbonyl or 3-phenylpropoxy-carbonyl group Preferred compounds according to the invention are those wherein Al represents a pyrrolidino, piperidino,

4-methyl-piperidino, 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, R3 represents a hydrogen atom, an alkyd group with 1 to 6 carbon atoms or a phenol group optionally substituted by a chlorine atom or by a methyl or methoxy group, R4 represents a hydrogen atom, an alkyd group with 1 to 3 carbon atoms or a bouncily, ally or acutely group and W represents a car boxy, methyl, hydroxymethyl, formal or benzyloxycarbonyl group or an alkoxycarbonyl group with 2 to 5 carbon atoms.
More preferred are those compounds wherein Al represents a piperidino group, R2 represents a hydrogen, fluorine or chlorine atom, R3 represents a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or phenol group, R4 represents a methyl or ethyl group and W represents a car boxy, methoxycarbonyl or ethoxycarbonyl group and especially those wherein W represents a car boxy group.
Particularly preferred compounds are the following:

I

2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid try 2-ethoxy-4-[N-(~-phenyl-2-1 ho bouncily)-aminocarbonylmethyl]-benzoic acid and salts thereof The compounds of general formula I may, for example, be prepared by the following processes which processes constitute further features of the present invention:
a) Reaction of an amine of formula 2 (II) ~V--R1 (wherein Al, R2 and R3 are as herein before defined) with a carboxylic acid of formula Jo ~OOC-CH2 \=
(III) OR

(wherein R4 is as herein bore defined and We is as herein before defined for W or represents a protected car boxy group) or with a reactive derivative thereof, optionally prepared in the reaction mixture, followed where necessary by removal of any protecting group.
Examples of reactive derivatives of compounds of general formula III which may be used include esters such as the methyl, ethyl and bouncily esters;
thioesters such as the methylthio and ethylthio esters; halides such as the acid chloride; androids and imidaæolides.
The reaction is appropriately carried out in a solvent such as e.g. ethylene chloride, chloroform, I

carbon tetrachloride, ether, tetrahydrofuran, dioxin, Bunsen, Tulane, acetonitrile or dimethylformamide.
Optionally the reaction may be carried out in the presence of an acid-activating or dehydrating agent, e.g. ethyl chloroform ate, thinly chloride, phosphorus trichloride, phosphorus pent oxide, N,N'-dicyclohexyl-carbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole or N,N'-thionyldi-imidazole or triphenylphosphine/carbon tetrachloride, or in the presence of an amine-activating agent, e.g. phosphorus trichloride. The reaction may also optionally be carried out in the presence of an inorganic base such as e.g. sodium carbonate or a tertiary organic base such as erg. triethylamine or pardon, which bases may simultaneously act as solvent. Temperatures for the reaction are generally from -25 to 250C, preferably from -10C
up to the boiling temperature of the reaction mixture.
The reaction may also be carried out without a solvent. Moreover, any water formed during the reaction may be removed by azeotropic distillation, e.g. by heating with Tulane using a water separator or by adding a drying agent such as e.g. magnesium sulfite or molecular sieve.
Where required the subsequent removal of a protecting group may be carried out by conventional methods, preferably hydrolytic ally. Such a hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric, sulfuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide and in a suitable solvent such as e.g. water, methanol, methanol/water, ethanol, ethanol/water, water/isopropanol or water/dioxan and at temperatures of from -10 to 120C, e.g. ambient temperature up to the boiling temperature of the reaction mixture A tert.butyl group when used as a protecting group may alternatively be split off thermally in an inert solvent such as e.g. ethylene chloride, chloroform, Bunsen, Tulane, tetrahydrofuran or dioxin and preferably in the presence of a catalytic amount of an acid such as ~-toluenesulphonic acid, sulfuric, phosphoric or polyphosphoric acid.
Moreover, a bouncily group when used as a protecting group may alternatively be split off by hydrogenolysis in the presence of a hydrogenation catalyst such as e.g. palladium/charcoal in a suitable solvent such as e.g. methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxin or dim ethyl-formamide.

b) In order to prepare a compound of formula I
wherein W represents a car boxy group:

Hydrolysis, thermolysis or hydrogenolysis of a compound of formula C~-N~-CO-CH A
R2 (IV) I OR

(wherein Al, R2, R3 and R4 are as herein before defined and A represents a group convertible into a car boxy group by hydrolysis, thermolysis or hydrogen-olysis).
Examples of hydrolyzable groups include functional derivatives of the car boxy group such as the unsubstituted and substituted asides, esters, thioesters, orthoesters, iminoethers, amidines and androids thereof, the nitrite group, the tetrazolyl group and an optionally substituted 1,3-oxazol-2-yl or 1,3-oxalin yule group Examples of thermolytically removable groups include esters with tertiary alcohols, e.g. the tert.butyl ester. Examples of hydrogenolytically removable groups include aralkyl groups, erg. the bouncily group.
Hydrolysis is appropriately carried out either in the presence of an acid such as e.g. hydrochloric, sulfuric, phosphoric or trichloroacetic acid or in the presence of a base such as e.g. sodium hydroxide or potassium hydroxide, generally in a suitable solvent such as e.g. water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxan.
Hydrolysis temperatures are generally from -10 to 120C, e.g. ambient temperature up to the boiling temperature of the reaction mixture.
If A in a compound of formula IV represents a nitrite or aminocarbonyl group, conversion into a car boxy group may be carried out by means of 100% phosphoric acid at temperatures of from 100 to 180C, preferably 120 to 160C, or by means of a nitrite, e.g. sodium nitrite, in the presence of an acid such as e.g. sulfuric acid (which may also act as solvent) at temperatures of from 0 to 50C.
If A in a compound ox formula IV represents, for example, the tert~butyloxycarbonyl group, the tert.butyl group may if desired be removed thermally, optionally in an inert solvent such as e.g. ethylene chloride, chloroform, Bunsen, Tulane, tetrahydrofuran or dioxin and preferably in the presence of a catalytic amount of an acid such as e.g. ~-toluenesulphonic acid, sulfuric, phosphoric or polyphosphoric acid, preferably at the boiling temperature of the reaction mixture, e.g. at temperatures of from 40 to 100C.
If A in a compound of formula IV represents, for example, a benzyloxycarbonyl group, the bouncily group may alternatively be removed by hydrogenolysis in the presence of a hydrogenation catalyst such as e.g. palladium/charcoal. Such hydrogenolysis is generally carried out in a suitable solvent such as methanol, ethanol, methanol/water, ethanol/water, glacial acetic acid, ethyl acetate, dioxin or dim ethyl formamide, preferably at temperatures of from 0 to 50C, e.g. at ambient temperature and under a hydrogen pressure of from l to 5 bar. During the hydrogenolysis a halogen-containing compound may simultaneously be dehalogenated.

c) In order to prepare a compound of formula I
wherein R4 represents a hydrogen atom or an alkyd group with l to 3 carbon atoms:

Reaction of a compound of formula OH - I (V) R2 t if (wherein Al, R2 and R3 are as herein before defined) with a compound of formula It _ C - SHEA
(VI) OR

(wherein R4 and W are as herein before defined).
The reaction is generally carried out in the presence of a strong acid, which may simultaneously S~91~

serve as solvent, preferably in concentrated sulfuric acid. Temperatures are generally from 0 to 150C, preferably 20 to 100C.
If in a compound of formula VI R4 represents an azalea, ally or bouncily group, this group may, unless protected, be split off during the reaction or after the reaction when water is added.

d) In order to prepare compounds of general formula I wherein R4 represents a hydrogen atom:
Deprotection of a compound of formula -NH-CO-CH~ (VII) (wherein Al, R2, R3 and W' are as herein before defined and R5 represents a hydroxy protecting group).
Examples of protected car boxy groups, W', which may be used include alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aminocarbonyl and nitrite groups whilst examples of hydroxy protecting groups R5 include alkyd, aralkyl, trialkylsilyl and azalea groups, e.g. the methyl, ethyl, propel, bouncily, trimethylsilyl, acutely and propionyl groups.
Depending on the protecting group or groups used the deprotection may be carried out, for example by hydrolysis or by hydrogenolysis, optionally in a suitable solvent, and generally at temperatures of from -78 to 250C.
Ether splitting may be carried out, for example, in the presence of an acid such as hydrogen chloride, I

hydrogen bromide, sulfuric acid, boron tribromide, aluminum trichloride or pardon hydrochloride, conveniently in a suitable solvent such as e.g.
ethylene chloride, glacial acetic acid or water or in mixtures thereof and at temperatures of from -78 to 250C. Ether splitting in the presence of a erotic acid is conveniently carried out at temperatures of from 0 to 150C, preferably 50 to 150C whilst when a Lewis acid is used, ether splitting is preferably carried out in a solvent such as e.g. ethylene chloride at temperatures of from -78 to 20C.
Ester splitting may be carried out r for example, in the presence of a base such as e.g. aqueous ammonia, sodium carbonate, potassium carbonate or sodium or potassium hydroxide and in a solvent such as e.g. water, water methanol water/ethanol, water/tetrahydrofuran or water/dioxan. Temperatures are generally from 50 to 100C, preferably the boiling temperature of the reaction mixture Hydrogenolytic removal of a protecting group, such as a bouncily group, may be carried out, for example, with hydrogen in the presence of a hydrogenation catalyst such as e.g. palladium/charcoal generally in a suitable solvent such as e.g. methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxin or dimethylformamide and preferably at ambient temperature and under a hydrogen pressure of from l to 5 bar.

e) In order to prepare compounds of general formula I wherein R4 represents an alkyd group with l to 3 carbon atoms optionally substituted by a phenol group, or an ally, acutely or propionyl group:

Reaction of a compound of formula .. . .

2 R1 OH tVIII) (wherein Al, R2, R3 and W are as herein before defined) with a compound of formula 6 (IX) (wherein R6 represents an alkyd group with 1 to 3 carbon atoms optionally substituted by a phenol group, or an ally, acutely or propionyl group and X represents a nucleophilically exchangeable group such as e.g. a halogen atom or a sulphonyloxy, Aztecs or propionyloxy group or, if I represents an alkyd group with 1 to 3 carbon atoms, together with an adjacent hydrogen atom in R6, represents a dyes group) followed, if required, by hydrolysis of the compound thus obtained.
The reaction is appropriately carried out with a corresponding halide, anhydridef sulphonic acid ester, sulfuric acid divester or diazoalkane, e.g. with methyl iodide, dim ethyl sulfite, ethyl bromide, deathly sulfite, propel bromide, isopropyl bromide, ally bromide, bouncily chloride, bouncily bromide, acutely chloride, acetic android, ethyl p-toluenesulphonate, isopropyl methanesulphonate or diazomethane. Optionally, when X represents a nucleophilically exchangeable group, the reaction is carried out in the presence ox a base such as e.g. sodium hydrides potassium carbonate, sodium hydroxide, potassium tert.butoxide or triethylamine or, in the case of acylation, with an android, in the presence of an acid such as e.g. sulfuric acid. The reaction is preferably canted out in a suitable solvent such as e.g. acetone, deathly ether, tetrahydrofuran, dioxin, pardon or dim ethyl-formamide and at temperatures of from 0 to 100C, most preferably at temperatures of from 20 to 50C.
on android used as assaulting agent may also simultaneously serve as solvent.
If W in the compound of formula VIII represents a car boxy or hydroxymethyl group, this may be converted into the corresponding ester compound. A compound thus obtained may, if required, be converted back into a car boxy or hydroxymethyl compound of formula I by conventional methods e.g. as described hereinafter.
An ester group is preferably split hydrolytic ally, either in the presence of an acid such as e.g.
hydrochloric, sulfuric, phosphoric or trichloroacetic acid or in the presence of a base such as e.g.
sodium hydroxide or potassium hydroxide generally in a suitable solvent such as e.g. water methanol, methanol/water, ethanol, ethanol/water, water/isopropanol or water/dioxan and at temperatures of from -10 to 120C, e.g. at temperatures of from ambient temperature up to the boiling temperature of the reaction mixture.

f) Reduction of a compound of formula R2 --my - C - C~12 W

So wherein Al, I R4 and W are as herein before defined and Y represents a group of formula 7\ / 8 If I
S - C - NH - or - C = N -(wherein R3 is as herein before defined and R7 and R8, together with the carbon atom to which they are attached, represent an alkylidene group with 1 to 4 carbon atoms)].
The reduction is preferably carried out with hydrogen in the presence of a hydrogenation catalyst such as e.g. palladium/charcoal or Rangy nickel and preferably in a suitable solvent such as e.g.
methanol, ethanol, isopropanol, ethyl acetate, dioxin, tetrahydrofuran, dimethylformamide, Bunsen or benzene/ethanol. Temperatures are generally from 0 to 100C, preferably 20C to 50C. A hydrogen pressure of from 1 to 5 bar is also preferred.
If a suitable choral hydrogenation catalyst is used such as a metal ligand complex, erg. a complex of u,u'-dichloro-bis-[1,5-cyclooctadiene rhodium]
and I or (-) O,O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)-butane (= DROP), the addition of hydrogen occurs enantioselectively.
Moreover during catalytic hydrogenation other groups, e.g. a benzyloxy group on a hydroxy group or a formal group on a hydroxymethyl group, may also be reduced or be replaced by hydrogen atoms, e.g.
a halogen atom may be replaced by a hydrogen atom.
The compounds of general formula I may, if desired, be subjected to a number of interconversion steps e.g. as follows:
Thus a compound of formula I wherein I represents a halogen atom and/or R3 represents a halophenyl 5i;3313 group and/or W represents a hydroxymethyl group, which has been converted into a halo methyl group, may if desired be converted by dehalogenation into a corresponding compound of formula I wherein R2 represents a hydrogen atom and/or R3 represents a phenol group and/or W represents a methyl group.
A compound of formula I wherein W represents a car boxy group may if desired be converted by esterification into a corresponding compound of general formula I wherein W represents an alkoxy-carbonyl group with 2 to 5 carbon atoms and which may optionally be substituted by a phenol group.
A compound of formula I wherein W represents a car boxy group or an alkoxycarbonyl with 2 to 5 carbon atoms and which may optionally be substituted by a phenol group may be reduced to give a corresponding compound of formula I wherein W represents a formal or hydroxymethyl group.
A compound of formula I wherein W represents a hydroxymethyl group may be oxidized to give a corresponding compound of formula I wherein W represents a formal or carboxyl group.
A compound of formula I wherein W represents a car boxy group may be converted into the corresponding sulphonic acid hydrazide and then disproportionate to give a corresponding compound of formula I wherein W represents a formal group.
Furthermore compounds according to the invention wherein R3 represents other than a hydrogen atom, when in the form of an enantiomeric mixture, may if desired, be resolved, e.g. via diastereoisomeric adduces, complexes or salts thereof, into enantiomeric form.
Dehalogenation it appropriately carried out using catalytic hydrogenation, e.g. with palladium/
charcoal, generally in a suitable solvent, e.g. methanol, ethanol, tetrahydrofuran, dioxin, dimethylformamide or ethyl acetate and optionally, in the presence of a base such as e.g. triethylamine. Temperatures of from 20 to 100C are generally used, preferably 20 to 50C.
Esterification is appropriately carried out in a suitable solvent, e.g. in the corresponding alcohol, pardon, Tulane, ethylene chloride, tetrahydrofuran or dioxin and in the presence of an acid-activating and/or dehydrating agent such as e.g. thinly chloride, ethyl chloroform ate, carbonyldiimidazole or N,N'-dicyclohexylcarbodiimide or the issuer ethers thereof. A reaction accelerator such as e.g. copper chloride, may also be present if desired Transesterification may alternatively be used if desired e.g. using a corresponding carbonic acid divester. Temperatures are generally from 0 to 100C, preferably from 20C up to the boiling temperature of the reaction mixture.
Reduction is preferably carried out with a metal hydrides e.g. with a complex metal hydrides such as lithium aluminum hydrides lithium bordered or lithium borohydride/trimethylborate, generally in a suitable solvent such as e.g. deathly ether, tetrahydrofuran, dioxin or l,~-dimethoxyethane I and at temperatures of from 0 to 100C, preferably 20C to 60C.
Oxidation of an alcohol is preferably carried out with an oxidizing agent such as pyridinium chlorochromate or manganese dioxide, preferably in a suitable solvent such as e.g. chloroform or ethylene chloride and at temperatures of from -10 and 50C, most preferably 0 to 20C.
Disproportionation of a sulphonic acid hydrazide, obtained by reacting an appropriate hydrazine with a reactive derivative of the acid, is generally carried out in the presence of a base such as ego sodium carbonate and in a solvent such as e.g.

ethylene glycol. Temperatures are generally from 100C to 200C, preferably 160 to 170C.
Resolution of an enantiomeric mixture is preferably carried out using column or HAL chromatography by forming diastereomeric adduces or complexes in a Shari phase.
The compounds of general formula I may also be converted into their salts, especially physiologically acceptable salts by reaction with inorganic or organic acids or, where W represents a car boxy group with bases. Suitable acids include, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, malefic and fumaric acid and suitable bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, cyclohexylamine, ethanol amine, diethanolamine, triethanolamine, ethylenediamine and Lawson.
The compounds of general formulae II to X, used as starting materials are in some cases known from the literature or they may be obtained by methods known pox _ Thus, for example, a compound of formula II may be obtained by reduction of a corresponding nitrite with lithium aluminum hydrides or with catalytically activated hydrogen; by reacting a corresponding nitrite with a suitable Grignard or lithium compound and subsequent lithium aluminum hydrides reduction or subsequent hydrolysis to form the ketimine, which is subsequently reduced with catalytically activated hydrogen, with a complex metal hydrides or with nascent hydrogen; by hydrolysis or hydrazinolysis of a corresponding phthalimido compound; by reacting a corresponding kitten with ammonium format and subsequent hydrolysis or with an ammonium salt in the presence of sodium cinnabar-hydrides by reducing a corresponding oxide with lithium aluminum hydrides with catalytically activated or nascent hydrogen by reduction of a corresponding N-benzyl or N-l-phenylethyl-Schiff's base, e.g.
with a complex metal hydrides in ether or tetrahydro~uran at temperatures of from -78C to the boiling temperature of the reaction mixture and subsequent removal of the bouncily or l-phenylethyl group by catalytic hydrogenation; by a Rotter reaction on a corresponding alcohol with potassium cyanide in sulfuric acid;
or by a Hoffman, Curtis, Losses or Schmidt depredation of a corresponding compound.
A compound of formula II thus obtained with a choral center may, if desirer be resolved into the enantiomers thereof by resolution, e.g. using fractional crystallization of the diastereoisomeric salts with optically active acids and subsequent decomposing of the salts or by column or ILL chromatography, optionally in the form of the azalea derivative, or by forming diastereoisomeric compounds, then separating them and subsequent regeneration of the desired compounds of general formula II.
Moreover, an optically active amine of formula II may also be prepared by enantioselective reduction of a corresponding ketimine using complex boron or aluminum hydrides in which some of the hydrides hydrogen atoms are replaced by optically active alkoxide groups or using hydrogen in the presence of a suitable choral hydrogenation catalyst or analogously starting from a corresponding N-benzyl or N-(l-phenethyl)-ketimine or from a corresponding N-acyl-ketimine or enamide and optionally subsequently splitting off the bouncily, l-phenethyl or azalea group.
Moreover, an optically active amine of formula II may also be prepared by diastereoselective reduction of a corresponding ketimine or hydra zone chorally substituted at the nitrogen atom by means of complex or non-complex boron or aluminum hydrides wherein some of the hydrides hydrogen may optionally be replaced by corresponding alkoxide, phenoxide or alkyd groups, or by means of hydrogen in the presence of a suitable hydrogenation catalyst and where necessary subsequently splitting off the choral auxiliary group by catalytic hydrogenolysis or hydrolysis.
Furthermore, an optically active amine of formula II may also be prepared by diastereo-selective addition of a correspond organometallic compound preferably a Griynard or lithium compound, to a corresponding aldimine chorally substituted at the nitrogen atom, by subsequent hydrolysis and optionally subsequent splitting off the choral auxiliary group by catalytic hydrogenolysis or hydrolysis.
The compounds of general formulae It, VII
and VIII used as starting materials may be obtained by reacting a corresponding amine with a corresponding carboxylic acid or a reactive derivative thereof and optionally subsequently splitting off any protecting group used.
A compound of general formula V used as starting material may be obtained by reducing a corresponding carbonyl compound or by reacting a corresponding carbonyl compound with a corresponding Grignard or lithium reagent.
A compound of formula X used as starting material may be obtained by acylation ox a corresponding amino compound or an organometallic complex thereof with a corresponding carboxylic acid or a reactive derivative thereof and optionally subsequently splitting off an ester group.
As already mentioned herein before, the new compounds according to the invention have interesting pharmacological properties, namely an effect on intermediate metabolism, particularly a hypoglycemic effect.

the hollowing compounds, for example:
A = 2-methoxy-4-[N-(1-(2-piperidino-phenyl)~l-ethyl)-aminocarbonylmethyl]-benzoic acid, B = 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-5butyl)-aminocarbonylmethyl]-benzoic acid, -C = 2-methoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid, D = 2-ethoxy-4-[N-(-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-ben~oic acid, 0 E = (-~)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid, F = 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid, G = sodium 2-ethoxy-4-[N-(1-(2-pyrrolidino-phenyl)-15l-butyl)-aminocarbonylmethyl]-benzoate, H = 2-ethoxy-4-[N-(1-(2-hexamethylenimino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid, I = 2-methoxy-4-[N-(1-~2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid, 0 K = 2-n-propoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl) aminocarbonylmethyl]-benzoic aria, L = 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl]-benzoic acid and 5 M = 2-ethoxy-4-1N-(4-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid were tested for their hypoglycemic properties as follows:
0 ~y~oqlycaemic Effect The hypoglycemic effect of the test substances was tested on female rats of a particular strain weighing from 180-220 g which had been fasted for 24 hours before the start of the test. The test substances were suspended in 1.5% methyl cellulose immediately before the start of the test and administered by esophageal tube.

Blood samples were taken immediately before the administration of the substance and 1, 2, 3 and 4 hours afterwards, in each case from the retroorbital Venous plexus. 50 I of each sample were deprotenated with 0.5 ml of 0.33 N perchloric acid and centrifuged.
The glucose in the supernatant was measured using the hexokinase method with the aid of an analytical photometer. The statistical evaluation was made using the t-test according to Student with p = 0.05 as the limit of significance.
The following table shows the values found in percent compared with the control:

1 mg/kg 0.5 mg/kg 15 Substance 1 2 3 4 h 1 2 3 4 h H -42 -34 -18 no K -34 -36 -24 no __ no = not statistically significant 53~

In the tests for hypoglycemic activity of the substances, no toxic side effects were observed even at a dosage of 10 mg/kg pro.
The new compounds are virtually non-toxic;
fox example, after a single dose of 2,000 mg/kg pro. (suspension in 1% methyl cellulose) of substances B and D to 5 male and 5 female mice, only one animal in this group died during the observation period of 14 days.
In the light of their pharmacological properties the compounds of general formula I according to the invention and the physiologically acceptable salts thereof are suitable for the treatment of diabetes Maltese.
According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of formula I as herein before defined or a physiologically acceptable salt thereof in association with a pharmaceutical carrier or excipient.
For pharmaceutical administration the compounds of general formula I and their physiologically acceptable salts may be incorporated into the conventional preparations in either solid or liquid form, optionally in combination with other active ingredients.
The compositions may, for example, be presented in a form suitable for galenic administration.
Preferred forms include, for example plain tablets, coated tablets, capsules, powders and suspensions.
The active ingredient may be incorporated in recipients customarily employed in pharmaceutical compositions such as, for example, talc, gum Arabic lactose, starch, magnesium Stewart, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents b I I

and/or preservatives.
Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults contain from 1 to 50 my, preferably from 2.5 to 20 my of active ingredient.
The following non-limiting examples serve to illustrate the present invention.

.. , Example 1 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoate To a solution of 1.84 9 (7.9 Molly) of 1-(2-piperidinophenyl)-l-butylamine in 19 ml of acetonitrile, are added 2 g (7.9 Molly) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 2.46 9 (9.38 Molly) of triphenyl-phosphine, 1.7 ml (12.3 Molly) of triethylamine and 0.76 ml (7.9 Molly) of carbon tetrachloride and the mixture it stirred for two days at ambient temperature. It is then evaporated in vacua and the residue is distributed between ethyl acetate and water. The organic extract is dried and filtered and evaporated in vacua. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 5/1).
Yield: 39 ~81% of theory), My: 113-115C (petroleum ether) Calculated: C 72.07 H 8.21 N 6.00 20 Found: 72.18 8.27 6.16 The following compounds were obtained analogously to Example 1:
a) Methyl 2-methoxy-4-[N-(1-(2_piperidino-phenyl)-l-ethyl)aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-ethylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Yield: 78% of theory, My: 82-85C
Calculated: C 70.22 H 7.37 N 6.82 30 Found: 70.54 7.49 6.75 b) Ethyl 2-ethoxy-4-[N-~a-phenyl-2-piperidino-_enzyl)-aminocarbonYlmethYl]-benzoate Prepared from ~-phenyl-2-piperidino-benzylamine and 3 ethoxy-4-ethoxycarbonyl-phenylacetic acid.
yield 77~ of theory, My: 149-151C

Calculated: C 74.37 H 7.25 N 5060 Found: 74.69 7~44 5.59 c) Matthew 2-methoxy-4-[N-(~-phenyl-2-_iperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from ~-phenyl-2-piperidino-benzylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Yield: 65% of theory, My: 189-190C
Calculated: C 73.70 H 6.83 N 5.93 10 Found: 73.51 6.75 5.86 d) Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-ethyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl) l-ethylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 69% of theory, My: 92-93C
Calculated: C 71.21 H 7.81 N 6.36 Found: 71.29 8.03 6.58 e) Ethyl 2-ethoxy-4-[N-(l-(S-chloro-2-~peridino-phenyl)-l-propyl)-aminocarbonylmethyl]-ben20ate Prepared from 1-(5-chloro-2-piperidino-phenyl)-l-propylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 80~ of theory, 25 up: 110-112C
Calculated: C 66.58~ 7.24 N 5.75 Of 7.28 Found: 66~61 7.34 5.86 7.3 5 f) Ethyl 2-ethoxy-4-[N-(2-piperidino-phenyl?-l-pentyl1-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-pentylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 63~ of theory, My: 113-115C
35 Calculated: C 72.47 H 8.39 N 5.83 Found: 72.568.265.99 g) Ethyl 2~ethoxy-4-[N~ (2-pyrrolidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-pyrrolidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 50~ of theory, My: 85-87C
Calculated: C 71.65 H 8.02 N 6.19 Found: 71.90 8.37 6.34 h) Ethyl 2-ethoxy-4-[N-(1-(2-(4-methyl-piperidino)-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2~(4-methyl-piperidino)-phenyl)-l-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 44% of theory, 15 My: 127-128C
Calculated: C 72.47H 8.39N 5.83 Found: 72.20 8.23 5.69 i) Ethyl 2-ethoxy-4-[N~ (2-hexameth~leneimino-phenyl)-l~butyl)-aminocarbonylmethyl]-benzoa~e Prepared from 1-(2-hexamethyleneimino~
phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 44~ of theory My: 97-100C
25 Calculated: C 72.47 H 8.39 N 5.83 Found: 72.41 8.50 5.66 k) Ethyl 2-ethoxy-4-[N-(1-(4-methyl-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from l-t4-methyl-2-piperidino-phenyl)-l-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 68~ of theory, My: 113-114C
Calculated: C OWE H 8.39 N 5.83 35 Found: 72.368.315.91 1) Ethyl 2-ethoxy-4-tN-~1-(6-methyl-2-piperidino-phenyl~-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-~6-methyl-2-piperidino-phenyl)-l-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic

5 acid.
Yield: 62~ of theory, My: 20C
Calculated: C 72.47H 8.39N 5.83 Found: 72.30 8.50 5.72 m) Ethyl 2-ethoxy-4-[N-(1-(6-chloro-2-piperidino-phenvl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(6-chloro-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid 15 Yield: 85~ of theory, My: 20C
Calculated: C 67.12H 7.44N 5.50 Of 7.08 Found: 67D607.77 5.92 7.24 n) Ethyl 2-ethoxy-4-[N-(1-(4-metho~y-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(4-methoxy-2-piperidino-phenyl)-l-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 65% of theory, 25 My: 109-110C
Calculated: Mol. peak m/e = 496 Found: Mol. peak m/e = 496 o) Ethyl 2-ethoxy-4-[N-(1-(5-methoxy-2-piperidino-ehenyl)-l-butyl)-aminocarbonylmethyl~-benzoate Prepared from 1-(5-methoxy-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 31% of theory, My: 117-120C

Calculated: mow peak m/e = 496 Found: mow peak m/e = 496 p) Ethyl 2-hydroxy-4-[N-(1-(2-pi~eridino-~enyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 4-ethoxycarbonyl-3-hydroxy-phenylacetic acid.
Yield: 46% of theory, My: 133-134C
Calculated: C 71.21 H 7.81 N 6.39 10 Found: 7i.08 7.91 6.45 q) Methyl 2-methoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzo lo Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Yield: 67% of theory, My: 128-131C
Calculated C 71.21 H 7.81 N 5.39 Found: 71.46 7.80 6.07 r) n-Propyl_2-n-propoxy-4-[N-(l-t2-piEeridino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-n-propoxy-4-n-propoxycarbonyl-phenylacetic acid.
Yield: 56% of theory, 25 Mop.: 88-89C
Calculated C 72.84 H 8.56 N 5.66 Found: 72.80 8.78 5.78 s) Ethyl 2-ethoxy-4-[N-(5-chloro-2-piperidino-benzyl)-aminocarbony~lmethyl]-benzoate Prepared from 5-chloro-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 65% of theory, up: 106-108QC

Calculated C 65~41 H 6.81 N ~.10 Of 7,73 Found: 65~81 6.89 6.11 7.62 t) Ethyl (-)-2-ethoxy-4-[N-(a-~henyl-2-pi~eridino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from (-)--phenyl-2-piperidino-phenyl)-l-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 87% of theory, My: 110-111C
Calculated mow peak m/e = 500 Found: mow peak m/e = 500 Specific rotation: [aye = -6.3 (c = 1, methanol) u) Ethyl 2-ethoxy-4-[N-(6-methyl-a-phenyl-2-piperidino-benz~l)-aminocarbonylmethyl]-benzoate Prepared from 6-methyl-a-phenyl-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 39% of theory My: 20C
Calculated: C 74.68 H 7.44 N 5.44 Found: 74.81 7.56 5.32 v) Ethyl 2-ethoxy-4-~N-(a-(4-methyl-phen~l)-2-~iperidino-benzyl)-aminocarbonylmethyl]-bonniest Prepared from a-(4-methyl-phenyl)-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 34% of theory, My: 150-152C
Calculated C 74.68 H 7.44 N 5.44 30 Found: 74.71 7.51 5.29 we Ethyl 2-ethoxy-4-[N-(~-phenyl-2-~rrolidino~
benzyl)-aminocarbonylmethyl]-benzoate Prepared from a-phenyl-2-pyrrolidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

I

Yield: 45~ of theory, My- 85-87C
Calculated C 74.05 H 7.04 N 5.76 Found: 73.95 7.07 5.70 x) Methyl 2-methoxy-4-[N (2-hexamethylenimino-~-phenyl-benzyl)-aminocarbonylmethyl]-benzoate Prepared from 2-hexamethyleneimino-~-phenyl-benzylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
10 Yield: 45~ of theory, My: 181-183C
Calculated: C 74.05H 7.04 N 5.74 Found: 74.096.62 5~74 y) Ethyl 2-ethoxy-4-[N-(2-hexamethyleneimino-lo ~-phenyl-benzyl)-aminocarbonylmethyl]-benzoate Prepared from 2-hexamethyleneimino-~-phenyl-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 41% of theory, My: 140-141C
Calculated: C 74.68H 7.44 N 5.44 Found: 74.467.62 5.45 z) 2-Ethoxy-4-[N-(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-methyl-phenylacetic acid.
Yield: 55~ ox theory, My: 107-108C
Calculated- C 76.43 H 8.88 N 6.86 30 Found: 76.38 8.99 6.97 a) Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-heptyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-heptylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

I

Yield: 79~ of theory, Mop.: 101-104C
Calculated: C 73.19 H 8.72 N 5.51 Found: 73.00 8.90 5.28 Example 2 Ethyl (+)-2-ethoxy=4-lN-(1-(2-piperidino-~henyl)-l-butyl)-aminocarbonylmethyl]-benzoate 0.90 g (3.57 Molly) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.61 g (3.73 Molly) of NOAH
carbonyldiimidazole are reflexed for 5 hours in 9 ml of absolute tetrahydrofuran. Then a solution of 0.85 g (3.67 Molly) of (~)-1-(2-piperidino-phenyl)-1-butylamine Lee = 94.2) in g ml of absolute tetrahydro-Furman is added and the mixture is reflexed for hours. It is concentrated in vacua and the evaporation residue is distributed between chloroform and water.
The organic phase is dried, filtered and evaporated in vacua. The evaporated extract is purified by column chromatography on silica gel (toluene/acetone =
10:1) .
Yield: 0.85 g (51.2~ of theory), My: 118-119C (petroleum ether/toluene = 50/2) Calculated: C 72.07 H 8.21 N 5.00 Found: 72.43 8.34 6.00 Specific rotation: [Audi = 7.1 (c = 1.06 in methanol) The following compounds were obtained analogously to Example 2:

a) Methyl 3-meth~-4-[N-(1-(2-piperidino-phenyl _butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl-1-butylamine and 2-methoxy-4-methoxycarbonyl-phenylacetic acid.
Yield: 89~ of theory, My: 102-105C

~2~398 Calculated: C 71.20 H 7.81 N 6.39 Found: 71.20 8.02 6.27 b) Ethyl 3-ethoxY-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 2-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 73% of theory, My: 136-138~C
Calculated: C 72.07 H 8.21 N 6.00 Found: 71.50 8.33 5.95 c) Ethyl 3-ethoxy-4-[N-(1-(4-methyl-2-~iperidino phenyl)-l-buty~)-aminocarbonylmethyl]-benzoate Prepared from 1-(4-methyl-2-piperidino-phenyl-l-butylamine and 2-ethoxy-4-ethoxycarbonyl-phenylacetic 15 acid.
Yield: 61% of theory, My: Luke Calculated: C 72.46H 8.39 N 5.83 Found: 72.508.46 5.92 d) Ethyl 3-ethox~-4-[N-(1-(6-methyl-2-piperidino~
phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(6-methyl-2-piperidino-phenyl)-l-butylamine and 2-ethoxy-4-ethoxycarbonyl phenylacetic acid.
Yield: 90% of theory, My: 20~C
Calculated: C 72.46 H 8.39 N 5.83 Found: 72.868.20 5.50 e) Methyl 3-methoxy~4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from a-phenyl-2-piperidino-benzylamine and 2-methoxy-4-methoxycarbonyl-phenylacetic acid.
Yield: 86% of theory, My: 144-148C
Calculated: C 73.70 H 6.83 N 5.93 Found: 73.70 6.85 5.84 f) Ethyl 3-ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from ~-phenyl-2-piperidino-benzylamine and 2-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Yield: 77% of theory, My: 112-115C
15 Calculated: C 74.37H 7.25 N 5.60 Found: 74.69 7.29 5.75 Example 3 Ethyl 2-ethoxy-~-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate To a mixture of 30 ml of concentrated sulfuric acid and 30 ml of o-dichlorobenzene, a solution of 4.7 g (20 Molly) of ethyl 2~ethoxy-4-cyanomethyl-bonniest and 5.3 g (20 Molly) of a-phenyl-2-piperidino-bouncily alcohol in 30 ml of 0-dichlorobenzene is added drops at 32-25C. The mixture is stirred for 2 hours at ambient temperature. Then the o-dichlorobenzene phase is separated off and the residue is added to ice. After it has been made alkaline with soda solution, it is extracted with chloroform. The extracts are dried over magnesium sulfite and concentrated by evaporation. The residue is trituated with petroleum ether (30-60), filtered off and purified on silica gel (toluene/ethyl-acetate = 5.1) by column chromatography Yield 5.6 g (56~ of theory), My: 150-151C

I

- I -Calculated: C 74.37 H 7.25 N 5.6 Found: 74.59 7.41 5.45 The following compounds were obtained analogously to Example 3:

a) Methyl 2-methoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from ~-phenyl-2-piperidino-benzyl alcohol and methyl 4-cyanomethyl-2-methoxy-benzoate.
Yield: 34% of theory, Mop.: 189-191C
Calculated: C 73.70 H 6.83 N 5.93 Found: 73.63 7.05 5.95 b) 2-Ethoxy-4-[N-(a-phenyl-2-pi~eridino-benzyl)-aminocarbonylmethyl]benzoic acid 15 Prepared from a-phenyl-2-piperidino-benzyl alcohol and 2-ethoxy-4-cyanomethyl-benzoic acid.
Extraction at pi 5.
Yield: 47~ of theory, Mop.: 154-155C
Calculated: C 73.70 H 6.83 N 5.93 Found: 73.61 6.72 5.65 c) 2-Methoxy-4-[N-(~-phenyl-2-piperidino-benz~1)-aminocarbonylmethyl]-benzoic acid Prepared from ~-phenyl-2-piperidino-benzyl alcohol and 4-cyanomethyl-2-methoxy-benzoic acid.
Extraction at pi 5.
Yield: 30% of theory, Mop.: 202-204C
Calculated: C 73.34 H 6.59 N 6.11 30 Found: 73.17 6.41 6.05 d) Ethyl 2-ethoxy-4-[N-(1-(2 piperidino-phenYl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-butanol and ethyl 2-ethoxy-4-cyanomethyl-benzoate.
Yield: 5% of theory, Mop.: 112-114C
Calculated: C 72.07 H 8.21 N 6.00 Found: 72.29 8.46 6.31 e) Methyl 2-methoxy-4-~N-(1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl~-benzoate Prepared from 1-(2-piperidino-phenyl~ ethanol and methyl 4-cyanomethyl-2-methoxy-benzoate.
Yield: 18~ of theory r Mop.: 83-85C
Calculated: C 70.22 H 7.37 N 6.82 Found: 70.60 7.29 6.97 f) 2-Methoxy-4-[N-(1-(2-piperidino-phenyl)-1-ethY1)-aminocarbonylmeth~l]-benæoic acid Prepared from 1-(2-piperidino-phenyl)-1-ethanol and 4-cyanomethyl-2-methoxy-benzoic acid. Extraction at pi 5.5.
Yield: 21% of theory Mop.: 118-120C
Calculated: m/e = 396 Found: m/e = 396 g) Ethyl 2-ethoxy-4-[N-(4-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from 4-methyl-~-phenyl-2-piperidino-bouncily alcohol and ethyl 2-ethoxy-4-cyanomethyl-bonniest.
Yield: 46% of theory, Mop.: 124-125C
Calculated: C 74.68 H 7.44 N 5.44 Found: 74.81 7.56 5.32 h) Methyl 2-methoxy-4-[N-(~-(4-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-bonniest Prepared from a-(4-chlorophenyl)-2-piperidino-bouncily alcohol and methyl 2-methoxy-4-cyanomethyl-bonniest.
Yield: 47~ of theory, Mop.: 176-178C
Calculated: C 68.70 6.17 N 5.53 Of 6.99 Found: 69.05 5.93 5.76 7.10 i) Ethyl 2-hydroxy-4-[N-(~-phenyl-2-piperidino~
benzyl)-aminocarbonylmethyl]-benzoate Prepared from a-phenyl-2-piperidino-benzyl alcohol and ethyl 4-cyanomethyl-2-hydroxy-benzoate.
Yield: 78~ of theory, Mop.: 172-174C
Calculated: C 73.70 H 6.83 N 5.93 Found: 73.80 6.81 5.83 5 k) n-Propyl 2-n-propoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from a-phenyl-2-piperidino-benzyl alcohol and n-propyl 4-cyanomethyl-2-n-propoxy-benzoate.
Yield: 52~ of theory, Mop.: 119-120C
Calculated: C 74.97 H 7.63 N 5.30 Found: 74.91 7.72 5.25 I

Example 4 2-Ethoxy-4-[N~ (2-piperidino-phenyl)-1-but~l)-aminocarbonylmethyl]-benzoic acid A mixture of 2 g (4.3 Molly) of ethyl ethics-5 4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonnil-methyl]-benzoate and 5.3 ml of lo sodium hydroxide solution in 20 ml of ethanol is stirred for 3 hours at 60C, then neutralized with 5.3 ml of lo hydrochloric acid and the ethanol is evaporated off in vacua.
The residue is distributed between ethyl acetate and water; the organic extract is dried and filtered and evaporated in vacua. The evaporation residue is crystallized from petroleum ether with the addition of ethanol.
Yield: 1.3 g (69~ of theory), Mop.: 88-90~C
Calculated- C 71.21 H 7.81 N 6.39 Found: 71.62 OWE 6.54 The following compounds were obtained analogously to Example 4:

a) 2-Methoxy-4-[N-(1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonylmethyl]-benzoic acid x 0.67 HO
Prepared from methyl 2-methoxy-4-[N-(1-(2-piperidino-phenyl)-l-ethyl)-aminocarbonylmethyl]-bonniest.
Yield: 60% of theory, Mop.: 116-120C
Calculated: C 67.62 H 7.07 N 6.85 30 found: 67.60 6.87 6.55 b) 2-Ethoxy-4-[N-(~-phen~1-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatee.
Yield: 89% of theory, Jo I

Mop.: 155-156C
Calculated: C 73.70 H 6 83 N 5.93 found: 73.60 6.96 6.12 c) 2-Methoxy-4-[N-(~-phenyl-2 piperidino-benzY1)-5 aminocarbonylmethyl]-benzoic acid Prepared from methyl 2-methoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatee.
Yield: 68~ of theory, Mop.: 202-204C
Calculated: C 73.34 En 6.59 N 6.11 Found: 73.60 6.77 6.20 d) 2-Ethoxy-4-[N-(1-(5-chloro-2-piperidino-phenyl)-l-propyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(5-chloro-15 2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyll]-bonniest.
Yield: 74% of theory, Mop.: 115-118C
Calculated: C 65.42 H 6.81 N 6.10 Of 7.72 20 Found: 65.54 6.94 5.81 7.89 e) 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-yl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-propyl)-aminocarbonylmethyl]-benzoate.
Yield: 73% of theory, Mop.: 81-83C
Calculated: C 70.73 H 7.60 N 6.60 Found: 70.90 7.47 6.77 f) 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-30 E~entyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-pentyl)-aminocarbonylmethyl]-benzoate.
Yield: 92% of theory, Mop.: 82-85C

3~3~3 Calculated: C 71.65 H 8.02 N 6.19 Found: 71.45 8.01 6.13 g) 2-Ethoxy-4-[N-(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-pyrrolidino-phenyl)-l-butyl)-aminocarbonylmethyl]~benzoate.
Yield: 77% of theory, Mop.: 120-123C
Calculated: C 70.33 H 7.60 N 6.60 Found: 70.71 7.44 6.33 h) 2-Ethoxy-4-[N-(1-(2-(4-methyl-piperidino)-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4~[N-(1-(2-(4-15 methyl-piperidino)-phenyl)-l-butyl)-aminocarbonylmmethyl]-bonniest.
Yield: 71~ of theory, Mop.: 83-85C
Calculated: C 71.65 H 8.02 N 6.19 20 Found: 71.60 7.94 6.09 i) 2-Ethoxy-4-[N-(1-(2-hexamethyleneimino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-hexa-methyleneimino-phenyl)-l-butyl)-aminocarbonylmethyyule-benzoate.Yield: 81% of theory, Mop.: 101-105~C
Calculated: C 71.65 Al 8.02 N 6.19 Found: 71.31 7.79 6.18 0 k) 2-Ethoxy-4-[N-(1-(6-chloro-2-piperidino-phen~
l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(6-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]]-bonniest.

91~
-- ~10 --Yield: 82~ of theory, Mop.: 133-136C
Calculated: C 66.02 H 7.03 N 5.92 Of 7.50 Found: 66.48 7.47 5.98 7.88 1) 2-Ethoxy-4-[N-(1-(4-methoxy-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(4-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]]-bonniest.
Yield: 81~ of theory, Mop.: 98-100C
Calculated: C 69.21 H 7.74 N 5.98 Found: 69.12 7.62 5.78 m) 2-Ethoxy-4-[N-(l-(S-methoxY-2-piperidino-~henyl)-1-butyl)-aminocarbonylmeth~l]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(5-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]]-bonniest.
Yield: 74~ of theory, Mop.: 145-148C
Calculated: C 69.21 H 7.74 N 5.98 Found: 69.00 7.65 5.83 n) 2-Methoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from methyl 2-methoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-bonniest.
Yield: 86% of theory, Mop.: 140-143C
Calculated: C 70.73 H 7.60 N 6.60 Found: 70.49 7.58 6.31 -I

o) 2-n-Propoxy-4-~N-(1-(2~piperidino-~henyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from n-propyl 2-n-propoxy-4 No (2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyll]-bonniest.
Yield: 89% of theory, Mop.: 128-132C
Calculated: C 71.65 H 8.02 N 6.19 Found: 71.40 7.90 6.47 p) 2-Ethoxy-4-[N-(5-chloro-2~piperidino-benzyl)-aminocarbonylme~hyl]-benzoic acid x 0.5 HO
Prepared from ethyl 2-ethoxy-4-[N-(5-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoateen Yield: 93% of theory, 15 Mop.: 153-155C
Calculated: C 62.79 H 6.41 N 6.36 Of 8.06 Found: 63.21 6.34 5.89 8.46 q)2-Ethoxy-4-[N-(2-pi~eridino-benzyl)-aminocarbonyl--methyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.
Yield: 77% of theory, Mop.: 108-109C
Calculated: C 69.68 H 7.12 N 7.07 25 Found: 70.00 7.99 7.31 r) 2-Hydroxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-bonniest.
Yield: 61% of theory, Mop.: 136-138C
Calculated: C 70.22 H 7.37 N 6.82 Found: 70.40 7.64 6.60 ~Z~39~

s) 2-Isopropoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-isopropoxy-4-[N-(l-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyll]-bonniest.
Yield: 67% of theory, Mop.: 115-118C
Calculated: C 71.65 H 8.02 N 6.19 Found: 71.94 7.96 6.04 0 t) 2-Allyloxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-allyloxy-4-1N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-bonniest.
Yield: 92~ of theory, Mop.: 110-112C
Calculated: C 71.97 H OWE N 6.22 found: 71.90 7.62 6.21 u) 2-Benzyloxy-4-1N=(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-benzyloxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl) aminocarbonylmethyl~-bonniest.
Yield: 95% of theory, 25 Mop.: 161-163C
Calculated: C 74.37 H 7.25 N 5.60 Found: 74.40 7.44 5.64 v) -ethics -[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl (+)-2-ethoxy-4-[N-(l-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyll]-bonniest.
Yield: 81% of theory, Mop.: 122-123C

I

Calculated: C 71.21 I 7.81 N 6.39 Found: 71.19 7.77 6.~9 Specific rotation [~]20 = + OWE lo = 1.03 in methanol) I) 3-Methoxy-4-[N-(1-(2-piperidino-pheny~
butyl)-aminocarbonylmethyl]-benzoic acid Prepared from methyl 3-methoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-bonniest.
Yield: 64~ of theory, Mop.: 188-191C
Calculated: C 70.73 H 7.60 N 6.60 Found: 70.88 7.56 6~59 x) 3-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-15 utyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 3-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate.
Yield: 79% of theory, Mop.: 159-165C
Calculated: C 71.21 H 7.81 N 6.39 Found: 71.32 7.62 6.24 y) 3-Ethoxy-4-[N-(1-(4-methyl-2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 3-ethoxy-4-[N-(1-(4-methyl-25 2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]]-bonniest.
yield: 71% of theory, Mop.: 186-188C
Calculated: C 71.65 H 8.02 N 6.1~
30 Found: 71.70 7.86 6.26 z) 3-EthoxY-4-[N-(1-(6-methyl-2-piperidino-phenyl) l-butyl)-aminocarbonvlmethyl]-benzoic acid Prepared from ethyl 3-ethoxy-4-[N-(1-(6-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]]-bonniest.

539~3 - I -Yield: 65~ of theory, up.: 174-176C
Calculated C 71.65 8.02 N 6.19 Found: 72.00 8.10 5.91 a) 2-Ethoxy-4-[N-(4-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(4-methyl-a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]]-bonniest Yield: 41% of theory, Mop.: 127-129C
Calculated: C 74.05 H 7.04 N 5.76 Found: 73.80 7.09 5.74 Abe 2-Ethoxy-4-[N-(6-methyl-~-phenyl-2-piperidino-bouncily) aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(6-methyl-~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]]-bonniest.
Yield: 40~ of theory, Mop.: 118-121C
Calculated: C 74.05 H 7.04 N 5.76 Found: 73.71 6.92 5.76 act 2-Ethoxy-4-[N-(~-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(~-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]--bonniest.
Yield: 94~ of theory, Mop.: 148-151~C
30 Calculated: C 74.05 H 7.04 N 5.76 Found: 74.20 7.15 5.81 ad) 2-Methoxy-4-[N-(~-(4-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from methyl 2-methoxy-4-[N-(~-(4-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmmethyl]-bonniest.
Yield: 77~ of theory, pi 177-180C
Calculated: C 68.21 H 5.93 N 5.68 Of 7.19 Found: 68.10 5.78 5.53 7.43 a) 2-Ethoxy-4-[N-(~-phenyl-2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzolc acid Prepared from ethyl 2-ethoxy-4-[N-(~-phenyl-10 2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzoatlo.
yield: 67% of theory, up.: 141-143C
Calculated: C 73.34 H 6.59 N 6.11 Found: 73.3~ 6.74 6.02 aft 2-Methoxy-4-N-(2-hexamethyleneimino-~-phenyl-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from methyl 2-methoxy-4-N-(2-hexamethylene-imino-~-phenyl-benzyl)-aminocarbonylmethyl]-benzoaate.
Yield: 90~ of theory, 20 Mop.: 154-156C
Calculated: C 73.70 H 6.83 N 5.93 Found: 73.70 7.00 5.95 ago 2-Ethoxy-4-[N-(2-hexamethyleneimino-a-phenyl-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(2-hexamethylene-imino-a-phenyl-benzyl)-aminocarbonylmethyl]-benzoaate.
yield: 75% of theory, Mop.: 139-141~C
Calculated: C 74.05 H 7.04 N 5.76 30 Found: 73.90 7.14 5.79 ah) 2-Hydroxy-4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-hydroxy-4-~N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatee ~53~

by saponification with 4 equivalents of lo sodium hydroxide solution in ethanol/dioxan.
Yield: 35~ of theory, pi 222-224C
Calculated: C 72.95 H 6.35 N 6 . 30 Found: 73.00 6.64 6.28 at) 2-n-Propoxy-4-[N-(~-phenyl-2-piperidino-benzyl) aminocarbonylmethyl]-benzoic acid Prepared from n-propyl 2-n-propoxy-4-[N-(~
phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-bonniest.
Yield: 41% of theory, Mop.: 168-170C
Calculated: C 74.05 H 7.04 N 5.76 15 Found: 74.20 7.19 5.57 a) 2-Allyloxy-4-[N-(~-phen~1-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-allyloxy-4-1N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl~-benzoatee.
Yield: 69~ of theory, Mop.: 172-173C
Calculated: C 74.35 H 6.66 N 5.78 Found: 74.11 6.S0 5.74 at) 2-Benzyloxy-4-[N-(~-phenyl-2-piperidino-benzyl)-25 aminocarbonylmethYl]-benæoic acid Prepared from ethyl 2-benzyloxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatee.
Yield: 72% of theory, M up.: 214-215C

Calculated: C 76.38 H 6.41 N 5.24 Found: 76.18 6.39 5.36 am) (-)-2-Ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl (-)-2-ethoxy-4-[N-(~-~S3~8 - I -phenyl-2-piperidino-benzyl)-aminocarbonylmethyl~-bonniest.
Yield: 89% of theory, Mop.: 90-95C
Calculated: C 73.70 H 6.83 N 5.93 Found: 73.59 6.81 5.83 Specific rotation: [aye = -2.2 (c = 1 in methanol) an) 3-Methoxy-4-[N-(~-Phenyl-2-piperidino-benzyl) aminocarbonylmethyl~-benzoic acid Prepared from methyl 3-methoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatee.
Yield: 72% of theory, Mop.: 220-221C
Calculated: C 73.34 H 6.59 N 6.11 Found: 73.36 6.46 5.85 a) ethics ~N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 3-e~hoxy-4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatee.
Yield: 70~ of theory, Mop.: 199-201C
Calculated: C 73.70 H 6.83 N 5.93 Found: 73.50 6.74 5.94 apt _-Ethoxy-4-[N-(1-(2-piperidin~phenyl) hePtYl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-heptyl)-aminocarbonylmethyl]-benzoate.
Yield: 88% of theory, Mop.: 71-73C
30 Calculated: C 72.47 H 8.39 N 5.83 Found: 72.28 8.56 5.82 5i3~

example 5 Sodium salt of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-ethyl)-aminocarbonylmethyl]-benzoic acid x 1.5 Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-ethyl)-aminocarbonylmethyl]-benzoate analogously to Example 4. After purification by column chromatography the evaporation residue obtained is dissolved in ethanol and mixed with 1 equivalent of lo sodium hydroxide solution. By evaporation in vacua and trituration with acetone, the crystalline sodium salt is obtained.
Yield: 76~ of theory, Mop.: 242-244C
Calculated: C 62.73 H 7.01 N 6.01 Found: 62.74 7.17 6.05 The following compounds were obtained analogously to Example 5:

a) Sodium salt of 2-ethoxy-4-[N-(1-(4-methyl-2-piperidino-~henyl)-1-butyl)-aminocarbonylmethyl]]-benzoic acid x 0.5 HO
Prepared from ethyl 2-ethoxy-4-[N-(1-(4-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]]-bonniest.
Yield: 72% of theory, Mop.: 255-260C
Calculated: C 67.06 H 7.50 N 5.79 Found: 66.94 7.285.50 b) Sodium salt of 2-ethoxy-4-[N-(1-(6-methyl-2-piperidino-phenyl)-1-butyl~-aminocarbonylmethyl]]-benzoic acid x 2.5 H O
_ _ _ - 2---Prepared from ethyl 2-ethoxy-4-[N-(1-(6-methyl-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]]-bonniest.
Yield: 81% of theory, Mop.: 232-240C

. .

~2'~3 Calculated C 62.39 7.75 N 5.39 Found: 62.22 7.46 5.61 c) Sodium salt of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate.
Yield: 87~ of theory, Mop.: 250-258C
Calculated: C 67.79 H 7.22 N 6.08 Found: 67.60 7.37 6.04 d) Sodium salt of 2-ethoxy-4-[N-(~-phen~1-2-piperidino-benzyl)-aminocarbon~lmethyl]-benzoic acid Prepared from ethyl 2-etho~y-4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoateeon Yield: 89~ of theory, Mop.: 233-235C
Calculated: C 70.42 H 6.32 N 5.67 20 Found: 70.~0 6.41 5.49 Example 6 Ethyl 2-hydroxy-4-[N-(~-phenyl-2-piper_dino-benzyl)-aminocarbonylmethyl]-benæoate To a stirred solution of 2 g (4 Molly) of ethyl 2-ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate in 20 ml of 1,2-dichloro-ethanes 1 ml (10.4 Molly) of boron tribromide is added drops at -20C under an hydrous conditions.
The mixture is allowed to reach ambient temperature and then stirred for a further 17 hours. It is then poured into ethanol, evaporated on vacua, ice is added and the resulting mixture is distributed between chloroform and water. The organic extract is dried, filtered and evaporated in vacua.
The evaporation residue is purified by column cremate-~33~

graph on silica gel (toluene~ethyl acetate = 5/1).
Yield: 0.37 g (21% of theory), Mop.: 172-173C
Calculated: C 73.70 H 6.83 N 5.93 Found: 73.95 7.05 6.12 The following compounds were obtained analogously to Example 6:

a) 2-Hydroxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Prepared from 2-ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid.
Yield: 40% of theory, Mop.: 221-223C
Calculated: C 72.95 H 6.35 N 6.30 Found: 72.68 6.45 6.49 b) ethyl 2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 19% of theory, Mop.: 132-134C
Calculated: C 71.21 H 7.81 N 6.39 Found: 71.43 7.91 6.55 c) 2-Hydroxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Yield: 42% of theory, Mop.: 136-137C
30 Calculated: C 70.22 H 7.37 N 6.82 Found: 70.19 7.39 6.99 I

Example 7 tert.Butyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate A mixture of 1.98 g (9.6 Molly) of ~,N-dicyclohexyl-carbodiimidel 1.06 ml (11.2 Molly) of absolute tert.butanol and 0.020 g (0.20 Molly) of copper chloride is stirred for 60 hours at ambient temperature, then

6.6 ml of ethylene chloride are added and the resulting solution is added drops to a solution of 0.44 g (1 Molly) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid in 15 ml of ethylene chloride. After 60 hours' stirring at 20C, the precipitate is filtered off, washed with ethylene chloride and the ethylene chloride solution is evaporated in vacua. The evaporation residue is purified by column chromatography on silica gel (chloroform/ethyl acetate = 9/1).
Yield: 0.30 g (60% of theory), Mop.: 74-77C (from petroleum ether) Calculated: C 72.84 H 8.S6 N 5.66 Found: 73.00 8.65 5.79 Example 8 Ethyl 2-benzyloxy-4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate To a solution of 1.1 g (2.3 Molly) of ethyl 2-hydroxy-4-[N-(a-phenyl-2-piperidino-benzyl)-aminno-carbonylmethyll-benzoate in 10 ml of an hydrous dimethylformamide are added 0.10 g (2.3 Molly) of sodium hydrides (55% in oil) and the resulting mixture is stirred for 0.5 hours at ambient temperature.
Then a solution of 0.27 ml (2.3 Molly) of bouncily bromide in 5 ml of an hydrous dimethylformamide is added drops and the mixture is stirred for 5 hours at ambient temperature. It is evaporated _ vacua, the residue is distributed between dilute sodium hydroxide solution and chloroform and the organic extract is dried, filtered and evaporated in vacua.

The evaporation residue is recrystallized from acetonitrile.
Yield: 0.9 g (69.5% of theory), Mop.: 156-157C
Calculated: C 76.84 H 6.81 N 4.98 Found: 76.94 6.95 4.87 The following compounds were obtained analogously to Example 8:

a) Ethyl 2-allyloxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-hydroxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatee using ally bromide.
Yield: 46% of theory, Mop.: 117-119C
Calculated: C 74.97 7.08 N 5.47 Found: 74.90 7.14 5.38 b) Ethyl 2-isopropoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl~-aminocarbonylmethyl]-bonniest using 1.5 equivalents of isopropyl bromide at 150C.
Yield: 56~ of theory, 25 Mop.: 98-99C
Calculated: C 72.47 H 8.39 N 5.83 Found: 72.60 8.60 5.75 c) Ethyl 2-allyloxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-bonniest using ally bromide.
Yield: 72% of theory, Mop.: 105-106C
35 Calculated: C 72.77 H 8.00 N 5.85 Found: 72.90 7.90 5.87 d) Ethyl 2-benzyloxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-bonniest using bouncily bromide.
Yield: 80% of theory, Mop.: 135-136C
Calculated: C 74.97 H 7.63 N 5.30 10 Found: 75.20 7.78 5.59 Example 9 n-Propyl 2-n-propoxy-4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate 15 Prepared from 2-hydroxy-4-[N-(~ phenol-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid analogously to Example 8 using 2 equivalents of sodium hydrides and 2 equivalents of n-propyl bromide.
Yield: 45% of theory, Mop.: 118-120C
Calculated: C 74.97 H 7.63 N 5.30 Found: 75.20 7.80 5.41 The following compound was obtained analogously to Example 9:

a) n-Propyl 2-n-propoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonYlmethyl]-benzoate Prepared from n-propyl 2-hydroxy-4-[N-(l-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyll]-bonniest.
Yield: 39% of theory, Mop.: 89-90C
Calculated: C 72.84 H OWE N 5.66 Found: 72.95 8.77 5.59 So - I -Example 10 Ethyl2~ethoxy-4-[N-(2-piperidino-benzyl)-aminocarbonyl--methyl]-benzoate 1.0 9 (2.18 Molly) of ethyl ethics [N-5 (5-chloro-2-piperidino-benzyl)-aminocarbonylmethyll]-bonniest is hydrogenated in 20 ml of ethanol with 0.5 g of 10~ palladium/charcoal at 50C under 1 bar of hydrogen for 45 minutes. It is filtered over kieselguhr, evaporated in vacua and purified by column chromatography on silica gel (chloroform/meth-anon = 10/1).
yield: 0.71 g (77~ of theory), My 83-84C from petroleum ether) Calculated: C 70.73 H 7.60 N 6.60 15 Found: 70.89 7.66 6.76 The following compound was obtained analogously to Example 10:

a) Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phen~
l-propyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-ethoxy-4-lN-(1-(5-chloro-2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyll]-bonniest.
Yield: 74% of theory, Mop.: 115-117C
25 Calculated: C 71.65 8.02 N 6.19 Found: 71.47 8.11 6.25 Example 11 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l-butyl)-aminocarbonylmethyl]-benzoic acid a) 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-l-buten-l-yl)-aminocarbonylmethyl]-benzoic acid Prepared from ethyl 2 ethoxy-4-[N-(1-(2-piperidino-35 phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethy]]]-bonniest Yield: 85~ of theory, Mop.: 110~113C
Calculated: C 71.97 H 7.61 N 6.2~
Found: 71.92 7.80 5.98 b) 0.21 g (0.39 Molly) of 2-ethoxy-4-[N (1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyll]-benzoic acid are hydrogenated in 10 ml of absolute ethanol with 0.10 g of 10~ palladium/charcoal at 50C under 1 bar of hydrogen for 7 hours. The mixture is filtered over kieselguhr, evaporated in vacua and the residue is purified by column chromatography on silica gel (chloroform/methanol = 10/1).
Yield: 0.10 9 (47% ox theory), Mop.: 90-92C
Calculated: C 71.65 El 8.02 N 6.19 Found: 71~50 8.12 6.45 The following compound was obtained analogously to Example 11:

a) Ethyl 2-ethoxy~4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyll]-bonniest, melting point 125-126C [prepared from (2-piperidino-phenyl)-isobutyl-ketimine and ethics-4-ethoxycarbonyl-phenyl-acetic acid analogously to Example 1].
Yield: 51~ of theory, Mop.: 139-141C
Calculated: C 72.47 H 8.39 N 5.83 Found: 72.30 8.20 5.87 Example 12 2-Ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminoo-carbonylmethyl]-benzyl alcohol ~,ZS~3~

To 0.28 g (7.4 Molly) of lithium aluminum hydrides in 50 ml of absolute tetrahydrofuran, a solution of 1.8 g ~3.6 Molly) of ethyl ethics-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmmethyl]-bonniest in 20 ml of absolute tetrahydrofuran are added drops at -5C and the mixture is stirred for 3 hours at 0C. It is then diluted with absolute ether and ON sodium hydroxide solution is added.
The mixture is filtered over kieselguhr, the residue is concentrated by evaporation in vacua and purified by column chromatography on silica gel (toluene/ethyl acetate = 2/1).
Yield: 0.51 g (31% of theory), Mop.: 133-135C
Calculated: C 75.95 H 7.47 N 6.11 Found: 75.97 7.55 5~95 The following compound was obtained analogously to Example 12:

a) 2~Ethoxy-4-[N-(1-(2-piperidino-pheny~
but~l)-aminocarbonylmethyl3-benzyl alcohol Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate by reduction with lithium bordered in boiling tetrahydrofuran with the addition of 10~ of trim ethyl borate.
Yield: 68% of theory, Mop.: 112-115C
Calculated: C 73.55 H 8.55 N 6.60 Found: 73.60 8.38 6.69 Example 13 _Ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-amino--carbonylmethyl]-benzaldehyde -To a stirred solution of 0.28 g (1.3 Molly) of pyridinium chlorochromate in 5 ml of chloroform, a solution of 0.4 g (0.87 Molly) of 2-ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyll]-I

bouncily alcohol is added drops at ambient temperature.
The mixture is stirred overnight at ambient temperature, evaporated in vacua, mixed with ether, filtered, evaporated in vacua and purified by column chromatography on silica gel (toluene/ethyl acetate = 2/1).
Yield: 0.16 g (40% of theory), Mop 154-156C
Calculated: C 76.29 H 7.06 N 6.1~
Found: 76.30 7.15 6.10 The following compound was obtained analogously to Example 13:

a) 3-EthoxY~-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehyde Prepared from 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzyl alcohol.
Yield: 47% of theory, Mop.: 109-111C
Calculated: C 73.90 H 8.11 N 6.63 Found- 74.22 8.14 6.73 Example 14 2-Ethoxy-4-[N-(a-phenyl~2-piperidino-benzyl)-aminoocarbonyl-methyl]-benzaldehyde 0.67 g (5.6 Molly) of sodium carbonate are heated together with 6 ml of ethylene glycol in a bath at 170C and then, with rapid stirring, 0.70 g (1.1 Molly) of Nl-[2-ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoyl]]-N2-tosyl-hydrazine are added thereto within a minute, and a violent evolution of gas is observed. Then the mixture is heated for a further 2 minutes at 170C and poured immediately onto ice. It is extracted with ether, dried, filtered and the ether solution is evaporated in vacua. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 2/1).
Yield: 0.25 g (50% of theory), Mop.: 153-156C
Calculated: C 76.29 H 7.06 N 6.14 Found: 76.42 7.33 6.28 The following compound was obtained analogously to Example 14:

a) 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethYl]-benzaldehyde Prepared from Nl-[2-ethoxy-4-[N~ (2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl~-benzoyl]-10 N2-tosyl-hydrazine.
Yield: 51~ of theory, Mop.: 108-111C
Calculated: C 73.90 H 8~11 N 6.63 Found: 73.79 8.29 6.75 Example 15 ensoul 2-ethoxy-4-[N-(1-(2-piperi.dino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate 0.35 g (3.8 Molly) of 2-ethoxy-4-lN-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid are reflexed together with 0.15 g (0.9 Molly) of N,NI-carbonyldiimidazole in 15 ml of absolute tetrahydrofuran for 2 hours. Then 1.03 ml (10 Molly) of bouncily alcohol are added and the mixture is reflexed for 3.5 hours. It is evaporated in vacua and purified by column chromatography on silica gel (chloroform/acetone = 9/1).
Yield: 0.10 g (23.6% of theory), Mop.: 20C
Calculated: Mow peak m/e = 528 Found: Mow peak m/e = 528 Example 16 Ethyl (+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate and I

Ethyl (-) 2-ethoxy-4-[N-~1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate 28 my of ethyl (~)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl] bonniest are added in single doses of 0.02 my to a choral phase HPLC column made by Messrs. Baker, in which (R)-N-3,5-dinitrobenzoyl-phenylglycine is covalently bound to aminopropyl-silica gel (5 sum particle size, spherical, pore size 60R; 4.6 mm internal diameter, 25 cm in length).
Flow agent: hexane/ethanol = 100/5;
Flow rate: 0.75 ml/minute;
Temperature: 22C.
The fractions eluded at 31.2 minutes and at 32.9 minutes (US detection at 254 no) are separately recovered, collected and evaporated in vacua.

The following is obtained from the 31.2 minute equate:

7.5 my of ethyl (+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Mop.: 117-119C
Specific rotation: ED = + 7-0 (C = 1.03 in methanol) The following is obtained from the 32.9 minute equate:
9.4 my of ethyl (-)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoate Mop.: 11~-117C
Specific rotation: Do = + 6.9 (c = 1.02 in methanol) Analogously to Example 16 a) ethyl (-)-2-ethoxy-4-[N-(~-Phenyl-2-pi~eridino-enzyl)-aminocarbonylmethyl]-benzoate can be resolved into its (+) enantiomer and its I

I-) enantiomer.

Ethyl 2-acetoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate A mixture of 0.20 g (0.46 Molly) of ethyl 2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate, 0.34 ml ~3.65 Molly) of acetic android and 20 us of concentrated sulfuric acid is stirred for 40 hours at 70C. The mixture is then evaporated in vacua, distributed between water and ether and neutralized with sodium carbonate.
The ethereal phase is separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are dried, filtered and evaporated in vacua. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).
Yield: 50~ of theory), Mop.: 133-135C (from petroleum ether) Calculated: C 69.98 H 7.55 N 5.83 Found: 69.75 7.32 5.74 The following compound were obtained analogously to Example 17:
5 a) 2-Acetoxy-4-[N-(1-(2-piperidino-phenyl)-1~
butyl)-aminocarbonylmethyl]-benzoic acid Prepared from 2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid.
Yield: 12~ of theory, Mop.: 125-127C
Calculated: Mow peak m/e = 452 Found: Mow peak m/e = 452 b) Ethyl 2-acetoxy-4-[N (a-phenyl~2-piperidino-benyl)-aminocarbonylmeth~_]-benzoate Prepared from ethyl 2-hydroxy-4-[N-(a-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatee.

Yield: 23.5% of theory, up.: 163-166C
Calculated: C 72.35 H 6.66 N 5.44 Found: OWE 6.75 5.31 c) 2-Acetoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-l-aminocarbonylmethyl]-benzoic acid Prepared from 2-hydroxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid.
Yield: 17~ of theory, Mop.: 126-128C
Calculated: C 71.58 H 6.21 N 5.76 Found: 71.77 6.57 5.81 Example 18 2-Ethoxy-~-[N-(1-(2-piperidino-pheny~ -bottle) aminocarbonyl]-tolue~e 0.54 g (1.2 Molly) of 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-bouncily chloride [melting point 114-115C, prepared from 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzyl alcohol using thinly chloride in chloroform] in 10 ml of absolute dioxin are hydrogenated for 3 hours at 20C and under 5 bar of hydrogen. The mixture is evaporated in vacua and the residue is distributed between ethyl acetate and aqueous sodium carbonate solution.
The organic extract is dried, filterer and evaporated in vacua. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone 19/1 ) -Yield: 0.23g (47% of theory), Mop.: 107-108C
Calculated: C 76.43 H 8.88 N 6.86 35 Found: 76.~0 8.88 6.90 I

Example 19 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethvl]-benzoic acid 100 my (0.20 Molly) of tert.butyl ethics-5 4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonnil]-bonniest are reflexed in 5 ml of Bunsen together with a few crystals of p-toluenesulphonic acid hydrate for half a day. Then the desired product is obtained, according to a thin layer chromatography by the Of value and mass spectrum.
Mop.: 87-89C
Calculated: m/e = 438 Found: m/e = 438 .

Example 20 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl-aminocarbonylmethyl]-benzoic acid 0.25 g (0.47 Molly of bouncily 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl-aminocarbonylmethHal]-bonniest are hydrogenated in 10 ml of ethanol with 0.12 g of 10~ palladium/charcoal at 50C under 5 bar of hydrogen. After 5 hours the catalyst is filtered off over kieselguhr and the filtrate is evaporated in vacua. The evaporation residue is crystallized from petroleum ether/ethanol.
Yield: 0.14 g (70% of theory), Mop.: 87-90C
Calculated: C 71.21 7.81 N 6.39 Found: 71.46 7.95 6.51 Example 21 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-n-hexyl)-aminocarbonylmethyl-benzoate Prepared from 1-(2-piperidino-phenyl)-1-n-hexylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogously to Example 1.
Yield: 43% of theory, Mop.: 101-105C

Calculated: C 72.84 HI 8.56 N 5.66 Found: 72.72 8.52 5.63 Example 22 5 2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-n-hexyl)--aminocarbonylmethyl-benzoic acid Prepared from ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-l-n-hexyl)-aminocarbonylmethyl]-benzoate analogously to Example 4.
10 Yield: 77% of theory, Mop.: 117-120C
Calculated: C 72.07 H 8.21 N 6.00 Found: 72~00 8.06 5.90 So Example A
Tablets containing 5 my of 2-ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid 5 Composition:
1 tablet contains:
Active substance I 0 my Corn starch (2)62.0 my Lactose (3)48.0 my 10 Polyvinylpyrrolidone (4)4.0 my Magnesium Stewart (5)1.0 my 120.0 my Method of preparation:
1, 2, 3 and 4 are mixed together and moistened with water. The moist mixture is passed through a 1.5 mm mesh screen and dried at about 45C.
The dry granulate is passed through a 1.0 mm mesh screen and mixed with 5. The finished mixture is compressed in a tablet press with 7 mm diameter punches including a dividing slot, to form tablets.
Weight of tablet: 120 my Example B
Coated tablets containing 2.5 my of ethics-[No Phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-bunk acid 1 tablet core contains:
Active substance (1)2.5 my 30 Potato starch (2)44.0 my Lactose (3)30.0 my Polyvinylpyrrolidone (4)3.0 my Magnesium Stewart (5) 80.0 my I

Method 1, 2, 3 and 4 are thoroughly mixed and moistened with water. The moist mass is passed through a 1 mm mesh screen, dried at about 45C and the granulate is then passed through the same screen. After 5 has been added, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine.
The tablet cores thus produced are covered in known manner with a coating consisting essentially of sugar and talc. The finished tablets are polished with wax.
Weight of coated tablet: 120 my Example C
Tablets containing 10 my of 2-ethoxy-4-[N-(~-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid Composition:
1 tablet contains:
20 Active substance 10.0 my Powdered lactose 70.0 my Corn starch 31.0 my Polyvinylpyrrolidone8.0 my Magnesium Stewart 1.0 my 120.0 my method:
-The mixture of active substance, lactose and corn starch is moistened with a 20~ solution of polyvinylpyrrolidone in water. The moist mass is passed through a 1.5 mm mesh screen and dried at 45C. The dried granulate is passed through a 1 mm mesh screen and homogeneously mixed with magnesium Stewart.
Weight of tablet: 120 my Punch: 7 mm diameter with dividing slot.

so Example D
Coated tablets containing 5 my of 2-ethoxy-4-[N-(~-phenyl-2-piperidino-ben~yl)-aminocarbonylmethyll]-benzoic acid 5 1 tablet core contains:
Active substance 5.0 my Secondary calcium phosphate 70.0 my Corn starch 50.0 my Polyvinylpyrrolidone 4.0 my 10 Magnesium Stewart 1.0 my 130.0 my Method:
The mixture of active substance, calcium phosphate and corn starch is moistened with a 15%
solution of polyvinylpyrrolidone in water. The moist mass is passed through a 1 mm mesh screen, dried at 45C and then rubbed through the same screen. After being mixed with the stated quantity of magnesium Stewart, tablet cores are compressed from the mixture.
Weight of core: 130 my Punch: 7 mm in diameter A coating of sugar and talc is applied to the cores thus produced in known manner. The finished coated tablets are polished with wax.
Weight of coated tablet: 180 my

Claims (43)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a phenylacetic acid compound of general formula (I) wherein R1 represents an unbranched alkyleneimino group with 4 to 6 carbon atoms which is unsubstituted or is substituted by one or two alkyl groups each having 1 to 3 carbon atoms, R2 represents a hydrogen or halogen atom or a methyl or methoxy group, R3 represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoms or a phenyl group which is unsubstituted or is substituted by a halogen atom or by a methyl or methoxy group, R4 represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms which is unsubstituted or is substituted by a phenyl group, or an allyl, acetyl or propionyl group, and W represents a methyl, hydroxymethyl, formyl or carboxy group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms and in which the alkyl part of the alkoxy group is unsub-stituted or is substituted by a phenyl group, an enantiomers or a salt thereof, which process comprises a) reacting an amine of general formula (II) wherein R1 to R3 are defined as above, with a carboxylic acid of general formula (III) wherein R4 is defined as above and W' has the meanings given for W above or represents a carboxy group protected by a protecting group, or with a reactive derivative thereof, followed where necessary by removal of any protecting group used, or b) in order to prepare a compound of general formula I where-in W represents a carboxy group, subjecting to hydrolysis, thermolysis or hydrogenolysis a group A in a compound of general formula wherein R1 to R4 are defined as above and A represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, c) in order to prepare a compound of general formula I where-in R4 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, reacting a compound of general formula (V) wherein R1 to R3 are defined as above, with a compound of general formula (VI) wherein R4 and W are defined as above, or d) in order to prepare compounds of general formula I where-in R4 represents a hydrogen atom, splitting off a protecting group from a compound of general for-mula (VII) wherein R1 to R3 are defined as above, W' has the meanings given for W above or represents a group which can be converted into a carboxy group and R5 represents a protecting group for a hydroxy group, or e) in order to prepare compounds of general formula I
wherein R4 represents an alkyl group with 1 to 3 carbon atoms which is unsubstituted or is substituted by a phenyl group, or an allyl, acetyl or propionyl group, reacting a compound of general formula (VIII) wherein R1 to R3 and W are defined as above with a compound of general formula R6 - X (IX) wherein R6 represents an alkyl group with 1 to 3 carbon atoms which is unsubstituted or is substituted by a phenyl group, or an allyl, acetyl or propionyl group and X represents a nucleophilically exchangeable group or, if R6 represents an alkyl group with 1 to 3 carbon atoms, together with an adjacent hydrogen atom, represents a diazo group, and subsequently, if necessary, hydrolysing a compound thus obtained, or f) reducing a compound of general formula (X) wherein R1, R2, R4 and W are defined as above and Y represents a group of formula wherein R3 is defined as above and R7 and R8 together with the carbon atom to which they are attached represent an alkylidene group with 1 to 4 carbon atoms, and subsequently, if required, dehalogenating a compound of general formula I thus obtained wherein R2 represents a halogen atom or R3 represents a halophenyl group or W represents a hydroxy-methyl group which has been converted into a halomethyl group, to obtain a corresponding compound of general formula I wherein R2 represents a hydrogen atom or R3 represents a phenyl group or W represents a methyl group, or esterifying a compound of general formula I obtained wherein W
represents a carboxy group to obtain a corresponding compound of general formula I wherein W represents an alkoxycarbonyl or phenyl-alkoxycarbonyl group, or reducing a compound of formula I obtained wherein W represents a carboxy, alkoxycarbonyl or phenylalkoxycarbonyl group to obtain a corresponding compound of general formula I wherein W represents a formyl or hydroxymethyl group, or oxidising a compound of general formula I obtained wherein W
represents a hydroxymethyl group to obtain a corresponding compound of general formula I wherein W represents a formyl or carboxy group, or converting, via a sulphonic acid hydrazide and subsequent dis-proportionation, a compound of general formula I obtained wherein W represents a carboxy group, into a corresponding compound of general formula I wherein W represents a formyl group, or resolving a racemic compound of general formula I obtained wherein R3 has the meanings given above with the exception of the hydro-gen atom, into its enantiomers by chromatography on chiral phases, or converting a compound of general formula I obtained into a salt thereof particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases.

2. A process as claimed in claim 1(a), characterised in that the reaction is carried out in a solvent.

3. A process as claimed in claim 1(a) or 2, characterised in that the reaction is carried out in the presence of an acid-activating or a dehydrating agent optionally in the presence of an inorganic or tertiary organic base.

4. A process as claimed in claim 1(a) or 2, characterised in that the reaction is carried out in the presence of an agent which activates the amine, optionally in the presence of an in-organic or tertiary organic base.

5. A process as claimed in claim 1(a) or 2, characterised in that the water formed during the reaction is removed by azeo-tropic distillation or by the addition of a drying agent.

6. A process as claimed in claim 1(a), 2 or 3, character-ised in that the reaction is carried out at temperatures of between -25 and 250°C.

7. A process as claimed in claim 1(a), 2 or 3, characterised in that the reaction is carried out at temperatures of between -10°C and the boiling temperature of the solvent used.

8. A process as claimed in claim 1(b) or 2, characterised in that the hydrolysis or thermolysis is carried out in the pre-sence of an acid or base at temperatures of between -10 and 180°C.

9. A process as claimed in claim 1(b) or 2, characterised in that the reaction is carried out in the presence of a nitrite, e.g. sodium nitrite, and in the presence of sulphuric acid at temperatures of between 0 and 50°C when A represents a nitrile or aminocarbonyl group.

10. A process as claimed in claim 1(b) or 2, characterised in that the reaction is carried out using 100% phosphoric acid at temperatures of between 100 and 180°C, when A represents a nitrile or aminocarbonyl group.

11. A process as claimed in claim 1(b) or 2, characterised in that the reaction is carried out using 100% phosphoric acid at temperatures of between 120 and 160°C, when A represents a nitrile or aminocarbonyl group.

12. A process as claimed in claim 1(c), characterised in that the reaction is carried out in concentrated sulphuric acid.

13. A process as claimed in claim 1(c), 2 or 12, character-ised in that the reaction is carried out at temperatures of between 0 and 150°C.

14. A process as claimed in claim 1(c), 2 or 12, character-ised in that the reaction is carried out at temperatures of between 20 and 100°C.

15. A process as claimed in claim 1(d) or 2, characterised in that the reaction is carried out in the presence of an acid at temperatures of between 0 and 150°C.

16. A process as claimed in claim 1(d) or 2, characterised in that the reaction is carried out with boron tribromide at temperatures of between -78 and 20°C.

17. A process as claimed in claim 1(e) or 2, characterised in that the reaction is carried out at temperatures of between 0 and 100°C.

18. A process as claimed in claim 1(e) or 2, characterised in that the reaction is carried out at temperatures of between 20 and 50°C.

19. A process as claimed in claim 1(e) or 2, characterised in that the reaction is carried out in the presence of a base when X represents a nucleophilic leaving group.

20. A process as claimed in claim 1(f) or 2, characterised in that the reduction is carried out with hydrogen in the presence of a hydrogenation catalyst.

21. A process as claimed in claim 1(f) or 2, characterised in that the hydrogenation is carried out at temperatures of between 0 and 100°C.

22. A process as claimed in claim 1(f) or 2, characterised in that the hydrogenation is carried out at temperatures of between 20 and 50°C.

23. A process as claimed in claim 1, wherein R1 represents a pyrrolidino, piperidino, 4-methyl-piperidino, 3-methyl-piperidino, 3,3-dimethylpiperidino, 3,5-dimethyl-piperidino or hexamethyleneimino group, R2 represents a hydrogen, fluorine or chlorine atom or a methyl or methoxy group, R3 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or a phenyl group optionally substituted by a chlorine atom or by a methyl or methoxy group, R4 represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or a benzyl, allyl or acetyl group, and W represents a carboxy, methyl, hydroxymethyl, formyl or benzyloxycarbonyl group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms.

24. A process as claimed in claim 1, where R1 represents a piperidino group, R2 represents a hydrogen, fluorine or chlorine atom, R3 represents a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or phenyl group, R4 represents a methyl or ethyl group and W represents a carboxy, methoxycarbonyl or ethoxycar-bonyl group.

25. A process as claimed in claim 1, wherein R1 to R4 are defined as in claim 24 and W represents a carboxy group.

26. A process as claimed in claim 1(b) wherein in the compound of formula IV A represents an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, in which the alkyl part of the alkoxy group is unsubstituted or is substituted by a phenyl group, and the compound of formula IV is obtained by process (a), (c), (d), (e) or (f) as defined in claim 1.

27. A process as claimed in claim 1 wherein the compound of formula I is obtained in the form of a physiologically acceptable salt thereof with an organic or inorganic acid or base.

28. A compound of formula I as defined in claim 1 or a salt thereof when prepared by a process of claim 1 or an obvious chemical equivalent thereof.

29. A physiologically acceptable salt of a compound as defined in claim 1 with an inorganic or organic acid or, if it con-tains a carboxy group, a base when prepared by the process of claim 27 or an obvious chemical equivalent thereof.

30. A process as claimed in claim 1 wherein R1 represents a piperidino group, R2 represents a hydrogen atom, R3 represents an n-propyl group, R4 represents an ethyl group and the ethoxy group is in the 2 position of the phenyl ring and W represents a carboxy group.

31. A process for preparing 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or its sodium salt which comprises subjecting ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate to hydrolysis to obtain the required acid and, if required, convert-ing the acid to the sodium salt.

32. A process for preparing 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or its sodium salt which comprises subjecting tert.butyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate to hydrolysis to obtain the required acid and, if required, convert-ing the acid to the sodium salt.

33. A process for preparing 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid or its sodium salt subjecting benzyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate to hydrogenolysis in the presence of a palladium/charcoal catalyst to obtain the required acid and, if required, converting the acid to the sodium salt.

34. The compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid or its sodium salt when prepared by a process according to claim 31, 32 or 33 or an ob-vious chemical equivalent thereof.

35. A process according to claim 1 wherein R1 represents a piperidino group, R2 represents a hydrogen atom, R3 represents a phenyl group, R4 represents an ethyl group and the ethoxy group is in the 2-position of the phenyl ring and W represents a carboxy group.

36. A process for preparing 2-ethoxy-4-[N-(.alpha.-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid or its sodium salt which comprises reacting .alpha.-phenyl-2-piperidino-benzyl alcohol with 2-ethoxy-4-cyanomethyl-benzoic acid to obtain the required acid and, if required, converting the acid to the sodium salt.

37. A process for preparing 2-ethoxy-4-[N-(.alpha.-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid or its sodium salt when hydrolysing ethyl 2-ethoxy-4-[N-(.alpha.-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate to obtain the required acid and, if required, converting the acid to the sodium salt.

38. The compound 2-ethoxy-4-[N-(.alpha.-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid or its sodium salt when prepared by a process according to claim 36 or 37 or an obvious chemical equivalent thereof.

39. A process for preparing (+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid which comprises hydrolysing ethyl (+)-2-ethoxy-4-[N-(1-(2-piperi-dino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate.

40. The compound (+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid when prepared by a process according to claim 39 or an obvious chemical equivalent thereof.

41. A process according to claim 1 wherein R1 represents a piperidino group, R2 represents a hydrogen atom, R3 represents a 2-methyl-propyl group, R4 represents an ethyl group and the ethoxy group is in the 2-position of the phenyl ring and W re-presents a carboxy group.

42. A process for preparing 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid which comprises hydrogenating 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid.

43. The compound 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid when prepared by a process according to claim 42 or an obvious chemical equivalent thereof.