DD204478A5 - PROCESS FOR THE PREPARATION OF NEW CARBONIC ACID AMIDES - Google Patents

Abstract

Compounds of general formula I <IMAGE> (wherein, in outline, R1 and R2 represent alkyl or cycloalkyl groups or together with the nitrogen atom to which they are attached, represent a cyclic imino group, R3 represents a hydrogen or a halogen atom, an optionally substituted hydroxy, mercapto, amino, carboxy or aminocarbonyl group, or a nitro, alkanoyl, aminosulfonyl, alkyl, trifluoromethyl or cyano group, R4 represents a hydrogen atom or an alkyl group, R5 represents a hydrogen or a halogen atom or an alkyl group, A represents a bond or an optionally substituted methylene, ethylene, cycloalkylidene or vinylidene group, B represents a methylene or ethylene group optionally substituted by an alkyl group and W represents a hydrogen or a halogen atom, a cyano, alkanoyl or nitro group, an optionally substituted amino or aminocarbonyl group, a carboxy group, or an ester thereof, a formyl group or an acetal thereof or an optionally substituted alkyl or alkenyl group); and salts thereof formed with acids and bases. Processes for the preparation of the new compounds as well as pharmaceutical compositions containing them are also objects of this invention. The new compounds show valuable pharmaceutical properties, especially effects on intermediary metabolism and a blood-sugar lowering activity.

Description

236597 8

Berlin ^ the 28 »5 · 82 AP C 07 D / 236 597/8 60 193 12

Process for the preparation of new carboxylic acid amides Field of application of the invention

The invention relates to a process for the preparation of new carboxamides rait valuable pharmacological properties = ^ in particular with effect on the metabolism ^ but preferably with hypoglycemic effect »

The compounds prepared according to the invention are used as medicaments *

Characteristic of the known technical solutions

In BE-PS 837 311 the most similar known compounds of general formula I are described (see compound IlC page 43 of BE-PS) »

Objective of the invention

The aim of the invention is the provision of new carboxylic acid amides with improved blood sugar lowering effect.

Presentation ¹ -the essence of the invention

The object of the invention is to find new carboxylic acid amides with the desired properties and methods for their preparation.

According to the invention, new carboxylic acid amides of the general formula

236597 8

28, 5. 82

AP C 07 D / 236 597/8

60 193 12

- la -

A -

^R 4

N-CO

R.

and their salts, in particular their physiologically tolerated salts with inorganic or organic acids and bases.

In their synthesis, the novel intermediates of general formula Ia

* (la)

manufactured ^ which also have a lipid-lowering effect *

In the above general formula I mean

RJ and R ₂ , which may be the same or different, are alkyl groups having 1 to 6 carbon atoms or cycloalkyl groups having 5 to 7 carbon atoms or

5R and R ₂ together with the intervening nitrogen atom are a straight-chain alkyleneimino group having 3 to 6 carbon atoms.

atoms which may be substituted by one or two alkyl groups each having 1 to 3 carbon atoms or by a hydroxy group, or in which a methylene group is represented by a carbonyl group, an oxygen or sulfur atom or an imino group represented by an alkyl group having 1 to 3 Carbon atoms, an aralkyl group having 7 to 10 carbon atoms, a phenyl or halophenyl group, or in which an ethylene group may be replaced by an o-phenylene group, an unbranched alkenyleneimino group having 4 to 6 carbon atoms, a saturated or partially unsaturated azabicycloalkyl group having 6 to 10 carbon atoms, an aza-1,4-dioxa-spiroalkyl group ^: having 6 to 8 carbon atoms, a heptamethyleneimino, octaminoimino, nonamethyleneimino or decamethyleneimino group,

R _{3 is} a hydrogen or halogen atom, a trifluoromethyl, alkyl, hydroxy, alkoxy, alkanoyloxy, mercapto, alkylmercapto, nitro, amino, cyano, alkanoyl, carboxy, alkoxy

25 '"oxycarbonyl-> aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulphonyl, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino or alkylsulphonylamino group, wherein each alkyl moiety in the abovementioned groups can contain in each case 1 to 3 carbon atoms Aralkoxy group having 7 to 10 carbon atoms or an arylcarbonylamino group,

236597 8

, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

c represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 3 carbon atoms,

a bond, an optionally substituted by a methyl, ethyl or isopropyl group methylene or ethylene

group, a substituted by two alkyl groups each having 1 to 3 carbon atoms methylene or ethylene group. a methylene group substituted by a cycloalkyl group having 3 to 7 carbon atoms, by a hydroxyalkyl, carboxyl, alkoxycarbonyl or phenyl group, each of the above-mentioned alkyl moieties may contain 1 to 3 carbon atoms, a cycloalkylidene group having 3 to 7 carbon atoms or a vinylidene group of the formula

R, - R_

C Il

- C -, where

R ₁ , and R_ are hydrogen atoms or one of the radicals R, or R-, a methyl or cycloalkyl group having 3 to 7 carbon atoms and the other of the radicals R _g or R _{7 is} a hydrogen atom or R, and R_ together with the intervening

D /

Carbon atom is a cycloalkylidene radical having 5 to 7 carbon atoms,

an optionally substituted by an alkyl group having 1 to 3 carbon atoms methylene or ethylene group and

28iM1983 * 099693

F9T

W is a hydrogen or halogen atom, a nitro group, an optionally substituted by an alkanoyl group having 1 to 3 carbon atoms, an optionally substituted by a hydroxy, carboxy or alkoxycarbonyl group or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms alkyl group having 1 to 3 Carbon atoms, an alkenyl group having 2 to 5 carbon atoms substituted by a carboxy or alkoxycarbonyl group having a total of 2 to 4 carbon atoms, an alkanoyl group having 1 to 3 carbon atoms, a dialkoxymethyl or trialkoxymethyl group having 1 to 3 carbon atoms in each alkyl moiety, a Alkylenedioxymethyl group having 2 or 3 carbon atoms in the alkylene part, a 1,3-oxazolin-2-yl or cyano group, an aminocarbony1 group optionally substituted by one or two alkyl groups each having 1 to 4 carbon atoms in each alkyl part, an unbranched alkyleniminocarbonyl group in total 5 to 8 carbon atoms, a morpholinocarbonyl group, a (dialkyl-dioxolanyl) -alkoxycarbonyl group having a total of 7 to 10 carbon atoms or a carboxy group and esters thereof, wherein alkyl esters having 1 to 6Γcarbon atoms in the alkyl part except for the t ^ -position in each case by a hydroxy, Alkoxy, amino, alkylamino, dialkylamino, 1, S-dimethyl-xanthine-T-yl, alkanoyloxy, aroyloxy, aralkanoyloxy or pyridinecarbonyl or by two hydroxy groups, wherein a methyl or methylene group, each only may be substituted by a Hydröxygruppe, or by a group of the formula

-CO-N-A

736b9 / ö

; in the

; A, B and R ₁ to R _{5 are} as defined above, substituted

wherein each alkyl substituent in the alkyl esters mentioned above may contain from 1 to 3 carbon atoms.

> For the meanings mentioned in the definition of the radicals, for example

for R ₁ and R ₂ together with the nitrogen atom of the dimethylamino, diethylamino, dipropylamino, dibutylamino,

: Diisobutylamino, dipentylamino, dihexylamino, N-methyl) N-ethylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, N-isobutyl-N-propylamino, N-methyl N-isopropylamino, N-methyl-N-butylamino, N-ethyl-N-butylamino, N-ethyl-N-isopropylamino, N-ethyl-N-pentylamino,

^: N-propyl-N-butylamino, N-methyl-N-cyclopentylamino, N

> Ethyl-N-cyclopentylamino, N-methyl-N-cyclohexylamino, N-ethyl-N-cyclohexylamino, N-propyl-N-cyclohexylamino, N-isobutyl-N-cyclohexylamino, pyrrolidino, piperidino, Hexamethyleneimine, heptamethyleneimino, octamethyleneimino, nonamethyleneimino, decamethyleneimino, dimethylazetidino, methylpyrrolidino, dimethylpyrrolidino,

Ethylpyrrolidino-, methyl-piperidino-, dimethyl-piperi-: dino-, ethyl-piperidino-, diethyl-piperidino-, methylethyl-piperidino-, propyl-piperidino-, methyl-propyl-piperidino-, isopropyl-piperidino , cis-S / S-dimethyl-piperidino, trans-3,5-dimethyl-piperidino, morpholino, thiomorpholine, piperazino, N-methyl-piperazino, N-ethyl-piperazino, N-propyl -piperazino, N-isopropyl-piperazino, N-benzyl-piperazino, N- (2-phenyl-ethyl) -piperazino, N- (3-phenylpropyl) -piperazino, N-phenylpiperazino, N-fluorophenyl -piperazino, N-chlorophenylpiperazino, N-bromophenyl-piperazino, hydroxy-pyrrolidino, hydroxy-piperidino, hydroxy-hexamethyleneimino, pyrrolidone-1-yl, piperidone-1-yl, hexahydroazepinone-1-yl , Tetrahydro-isoquinolin-2-yl, octahydro-isoquinolin-2-yl, decahydro-isoquinolin-2-yl, dihydro-isoindole-2-yl

- 6 - 71CK

597 8

yl, hexahydro-isoindol-2-yl, octahydro-isoindol-2-yl, tetrahydro-S-benzazepin-B-yl, decahydro-3-benzazepin-3-yl, S-azabicyclo ^ S ^ cT / heptan-S-yl, 3-azabicyclo- / 3.2.J_7octan-3-yl, 3-azabicyclo / 3. 2. i-nonan-S-yl, 1,4-dioxa-7-aza-spiro-4,4 / nonan-7-yl, 1,4-dioxa-7-azaspiro / 4, 5 / decane 7-yl, 1,4-dioxa-8-aza-spiro / 4,5-decan-8-yl, 1-dioxa-S-aza-spiro / 1-yundecan-5-yl, pyrrolino or tetrahydropyridino group,

for R ₃ those of the hydrogen, fluorine, chlorine, bromine or iodine atom, the - methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, acetoxy , Propionyloxy, mercapto, methylmercapto, ethylmercapto, propylmercapto, isopropylmercapto, tri, fluorine, 1-, nitro, cyano, formyl, acetyl, propionyl, aminosulfonyl, amino, Methylamino, ethylamino, propylamines, dimethylamines, diethylamino, dipropylamino, diisopropylamino, N-methyl-N-ethylamino, N-methyl-N-isopropylamino, N-ethyl-N-propylamino, formylamino, , Acetylamino-propionylamino, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino , isopropylsulfonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, benzoylamino, benzyloxy -, 1-Phenyläthoxy-, 2-phenyl-ethoxy, 3-phenyl-propoxy, aminocarbonyl, Methylaminocarböny1-, Äthy laminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, methyl-ethylaminocarbonyl or methyl-propylaminocarbonyl group,

for R.sup.1 of the hydrogen atom, that of the methyl, ethyl, propyl or isopropyl group,

for R_ that of the hydrogen, fluorine, chlorine, bromine or iodine atom, that of the methyl, ethyl, propyl or isopropyl group,

236597 8 "

A represents the single bond of methylene, x-thylidene, ethylenediamine, isopropylmethylene, dimethylmethylene, diethylmethylene, dipropylmethylene, methylethylmethylene, methylpropylmethylene, Ethyl-propylmethylene, ethyl-isopropyl-methylene, ethylene, methyl-ethylene, ethyl-ethyl, dimethyl-ethyl, cyclopropyl-methylene, cyclobutyl-methylene, cyclopenty-1-methylene, cyclohexyl-methylene, cycloheptyl-methylene , Cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, carboxymethylene, methoxycarbonylmethylene, ethoxycarbonylmethylene, propoxycarbonylmethylene, hydroxymethylmethylene, 1-hydroxyethylmethylene, 2-hydroxyethyl methylene, 1-hydroxypropylmethylene, 3-hydroxypropylene-methylene, phenylmethylene, vinylidene, methylvinylidene, cyclopentyl-vinylidene, cyclohexyl-vinylidene, cyclopropylidene-methylene, cyclopentylidene-methylene, Cyclohexylidene, cyclopropylidene-methylene , cyclopentylidenemethylene, cyclohexylidene-meth ylen or cycloheptylidene ethylene group,

for B, the methylene, ethylene, Xthyliden-, ethyl-methylene-propyl-methylene or isopropy! -Methylengruppe and

3 b 5 9 /

for W that of the hydrogen, chlorine, bromine or iodine atom, the

the methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl , 3-carboxy-propyl, methoxycarbonyl-methyl, ethoxycarbonyl-methyl, propoxycarbonyl-methyl, 2-methoxycarbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 3-ethoxycarbonyl-propyl, bis (methoxycarbonyl) - methyl, bis {ethoxycarbonyl) -methyl, 2,2-bis (ethoxycarbonyl) -ethyl, carboxy-vinyl-1, carboxy-propenyl, carboxypentenyl, methoxycarbonyl-vinyl, ethoxycarbonyl-vinyl, Propoxycarbonyl-vinyl, forinyl, acetyl, propionyl, dimethoxymethyl, diethoxy-methyl, dipropoxy-methyl, trimethoxymethyl, triethoxy-methyl, 1,2-ethylenedioxy-methyl, 1,3-propylenedioxy methyl, cyano, nitro, "amino, formylamino, acetamino, propionylamino, 1,3-oxazolin-2-yl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,. propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl -, Dimethylaminocarbonyl -, _r Diäthylaminocarbonyl- Dipropylaminocarbonyl-, Dibutylaminocarbonyl-, pyrrolidinocarbonyl, Piperidinocarbony1-, Hexämethyleriiminocarbonyl-, Heptamethyleniminocarbonyl-, morpholinocarbonyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Butoxycarbony1-, tert-butoxycarbonyl, Pentoxycarbonyl, hexoxycarbonyl, heptoxycarbonyl, octoxycarbonyl, allyloxycarbonyl / butenyloxycarbonyl, benzyloxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 2-hydroxyethoxycarbonyl, 2-hydroxypropoxycarbonyl, 3-hydroxypropoxycar -.

~ $ Q bonyl-i. 2-methoxyethoxycarbonyl> 2-ethoxyethoxycarbonyl, (2,2-dimethyl-dioxolan-4-yl) -methoxycarbonyl, 2- (2,2-dimethyl-dioxolan-4-yl) -ethoxycarbonyl-, (2,2 Diethyl-dioxolan-4-yl) -methoxycarbonyl, 2- (2,2-diethyl-dioxolan-4-yl) -ethoxycarbonyl, 3- (2,2-dimethyl-dioxolan-4-yl) - propoxycarbonyl, 2-amino-ethoxycarbonyl, 2-dimethylaminoethoxycarbonyl, 2-diethylamirio-ethoxycarbonyl, 2- (1,3-dimethyl-xanthine-7-yl) -ethoxycarbonyl, 2-acetoxy-ethoxy

236597 8

carbonyl, 2-benzoyloxy-ethoxycarbonyl, 2-phenylacetoxyethoxycarbonyl, 2-pyridinecarbonyloxy-ethoxycarbonyl, 2,3-dihydroxy-propoxycarbonyl, 3,4-dihydroxy-butoxycarbonyl, 2 -ε- 4-yl (2 -Piperidino-phenyl) -ethyl) -aminocarbonylmethyl-benzoyloxy-athoxycarbonyl or 3- / 4- / 7i- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoyl-propoxycarbonyl group.

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

) R. and R- together with the intervening nitrogen atom, a dialkylamino or N-alkyl-cyclohexylamino group, in which each alkyl moiety may contain 1 to 4 carbon atoms, an optionally substituted by one or two methyl groups unbranched Alkyleniminogruppe 3-6

j is carbon atoms, a hydroxypiperidino, piperidone-1-yl, tetrahydro-pyridino, morpholino, thiomorpholine, N-methylpiperazino, N-benzyl-piperazino, N-chlorophenyl-piperazino, heptamethylenesimino or octamethyleneimino group, a saturated or partially unsaturated azabicycloalkyl group having 7 to 9 carbon atoms, an unbranched Alkyleniminogruppe having 4 to 6 carbon atoms, in which one Äthy- lengruppe is replaced by an o-phenylene group, or a ^: 1,4-dioxa-aza-spiro-alkyl group with 7 or 8 carbon atoms,

5R- is a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, trifluoromethyl, hydroxy, methoxy, benzyloxy, acetoxy, mercapto, methylmercapto, nitro, amino, dimethylamino , Acetylamino, methylsulfonylamino, benzoylamino, ethoxycarbonylamino, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, acetyl or aminosulfonyl group,

R. is a hydrogen atom or a methyl group,

^ 236597 8

a hydrogen atom, a chlorine atom or a methyl group,

IA is a bond, a methylene, optionally substituted by a methyl, ethyl, isopropyl, phenyl, cyclohexyl, carboxy, Methoxycarbonylodör hydroxymethyl group, a dimethyl-methylene, cyclopropylidene or ethylene group or a vinylidene group of the formula

Il

- C -, where R and R_

D /

Hydrogen atoms or one of the radicals R, or R _{n is} a methyl group and the other of the radicals R, or R-, a water

D /

Substance or R, and R_ together with the intervening carbon atoms mean a cycloalkylidene radical having 5 or 6 carbon atoms,

B is a methylene, ethylidene or ethylene group and

W is a hydrogen atom, a methyl, ethyl, hydroxymethyl, cyano or carboxyvinylene group, one represented by a carboxy

  'group or by one or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms substituted alkyl group having 1 to 3 carbon atoms, one by a

, Hydrogen atom, a methyl; Ethyl, hydroxy, alkoxy, (2,2-dimethyl-dioxolan-4-yl) -methoxy, benzyloxy, pyridyl

: methoxy-> amino-> alkylamino, dialkylamino, piperidino.

or morpholino group-substituted carbonyl group, wherein each alkyl moiety in the above-mentioned group may contain 1 to carbon atoms, or a group of the formula

- 0 - (CH_) - R ₀ in which ζ η ο

η is the number 2, 3 or 4 and

236597 8

a hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy, pyridinecarbonyloxy, a dialkylamino group having 1 to carbon atoms in each alkyl moiety, a 1,3-dimethylxanthine-7-yl group or a group of the formula

-CO-N-A

in the

A, B and R to R ₅ are defined as mentioned above,

represent

but especially those compounds in which the

Rest - N

in position 2 and the rest W in 4'-position

R-

tion, and, if they contain an asymmetric carbon atom, their optically active antipodes and their salts.

However, particularly preferred compounds are those of the general formula

A - N-CO

- CH,

(Ia)

7 "8

in the

R. and R_ together with the intervening nitrogen atom are a dimethylamines, pyrrolidino, methylpyrrolidino,

: Piperidino, methylpiperidino, dimethylpiperidino, tetrahydro-pyridino, 2-octahydroisoindolo- or hexamethylene

: imino group,

R _{3 is} a hydrogen, fluorine or chlorine atom or a methyl group,

an optionally substituted by a cyclohexyl, phenyl, meth oxycarbonyl, ethoxycarbonyl, methyl, ethyl or isopropyl group substituted methylene, a dimethylmethylene or a vinylidene group of the formula

C II

C, where R _c and R_

each represent a hydrogen atom or, together with the intervening carbon atom, a cyclohexylidene group, and

a methyl ,. Hydroxymethyl or carboxymethyl group, a group represented by a hydrogen atom, a methyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, 2-hydroxyethoxy, 2-methoxyethoxy, (2,2-dimethyl-dioxolan-4-hydroxy) yl) methoxy- or 2-diethylaminatoethoxy group substituted carbonyl group mean? their optically active antipodes and their physiologically acceptable salts with inorganic or organic acids or bases.

3 6 5 9 7 8

a) Acylation of an amine of the general formula

(II)

in the

A and R. to R, as defined above, or, if A is one of the above-mentioned vinylidene groups, its tautomers or its lithium or magnesium halide complex with a carboxylic acid of the general formula

HOOC-B-C 1 -), (III)

in the

R ₁ . and B are as defined above and W has the meanings mentioned for W or represents a carboxyl group protected by a protective group,

or with their optionally reactive derivatives prepared in the reaction mixture.

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

3 6 b9 7 B

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or one of Amino group activating agent, eg Phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may serve as a solvent at temperatures between -25 and 250 C, but preferably at temperatures between -10 C and the boiling temperature of the used Solvent, performed. The reaction may also be carried out without solvent, further, water formed during the reaction may be removed by azeotropic distillation, e.g. be separated by heating with toluene on a water separator, or by adding a desiccant such as magnesium sulfate or molecular sieve.

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

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

Furthermore, a benzyl radical used as a protective radical can also be removed by hydrogenolysis in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

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

Cleavage of a compound of the general formula

A-N-CO-B

in the

R ₁ to R-, A and B are as defined above and D represents a by hydrolysis, thermolysis or hydrogenolysis into a carboxy group convertible group.

Suitable hydrolyzable groups are, for example, functional derivatives of the carboxy group, such as their unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides, the nitrile group, a malonic group.

2 Ό. Q Γ Q Π «ο>? % JJJJ /

ester (1) -yl group, the tetrazolyl group, an optionally substituted 1,3-oxazol-2-yl or 1,3-oxazolin-2-yl group and

as thermally cleavable groups, for example, esters with tertiary alcohols, e.g. the tert-butyl ester, and

as hydrogenolytically cleavable groups, for example, aralkyl groups, e.g. the benzyl group, into consideration.

The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / ethanol, water / isopropanol or water / dioxane at temperatures between -10 and 120 C, eg at temperatures between room temperature and the boiling temperature of the reaction mixture, carried out.

If D in a compound of the general formula IV denotes a nitrile or aminocarbonyl group, these groups may also be reacted with a nitrite, e.g. Sodium nitrite, in the presence of an acid such as sulfuric acid, which is suitably used simultaneously as a solvent, at temperatures zw:

be guided.

Temperatures between 0 and 50 ° C into the carboxy group über-

If D in a compound of general formula IV, for example, the tert.Butyloxycarbonylgruppe, so the tert-butyl group may also be thermally optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such P-toluenesulfonic acids sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, for example, be cleaved.

Solvent, e.g. at temperatures between 40 and 100 C,

If D in a compound of general formula IV, for example, the benzyloxycarbonyl group, the benzyl group may also be hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 C, eg at room temperature and at a hydrogen pressure of 1 to 5 bar.

the. In the hydrogenolysis, other groups may be co-reduced at the same time, e.g. a halogen compound is dehalogenated, a nitro group converted into the corresponding amino group and a vinylidene group in the corresponding alkylidene group.

c) reaction of a compound of the general formula which may be formed in the reaction mixture

A-N-CO-B

R.

in the

R ₃ to R ₁ -, A, B and W are as defined above, R- ^{1 represents} a hydrogen atom or has the meanings mentioned above for R ₂ , with a compound of general formula

- E

, (VI)

"2 3 6 ^ Q 7 ft"

in the

R ^ 'has the meanings mentioned for R ₁ or, together with the radical R ₂ ' of the formula V, a straight-chain alkylene group having 4 to 6 carbon atoms optionally substituted by one or two alkyl groups with 1 to 3 carbon atoms each, or an Pentylene group in which the 3rd methylene group is replaced by an oxygen or sulfur atom, and ..- E is a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, for example a chlorine, bromine or iodine atom, a Methansulfonyloxy- or p-toluenesulfonyloxy or a hydrogen atom, if in R 'a methylene group is replaced by an aldehyde or ketone carbonyl group, if necessary in the presence of a reduction

^ by means of and optionally subsequent hydrolysis »

Thus, suitable alkylating agents of Formula VI are, for example, the corresponding halides or sulfates, such as methyl iodide, ethyl iodide, propyl bromide, dimethyl sulfate or diethyl sulfate.

The reaction is conveniently carried out in a solvent such as acetone, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide, optionally in the presence of an inorganic base such as sodium carbonate, potassium carbonate or potassium tert-butylate or a tertiary organic base such as pyridine, at temperatures between 0 and 150 C, but preferably at temperatures between 20 and 75 C performed. Substituting a compound of the general formula V, in which W represents a carboxyl group, this carboxyl group can, depending on the. reaction conditions used, e.g. at temperatures above room temperature and in the presence of a suitable base, for example of sodium carbonate, are converted simultaneously into the corresponding ester.

 ff

The methylation may also be carried out by reacting a compound of general formula V with formalin in the presence of a reducing agent, e.g. Formic acid or hydrogen in the presence of a hydrogenation catalyst, e.g. Palladium .or platinum, optionally in a solvent such as formic acid or glacial acetic acid is reacted at temperatures up to the boiling temperature of the reaction mixture.

Further, the alkylation may also be carried out with a corresponding carbonyl compound in the presence of a hydride such as sodium cyanoborohydride in a suitable solvent such as acetonitrile / acetic acid or dimethylformamide / acetic acid preferably at pH = 7 and at temperatures between 0 and 50 ° C.

The optionally subsequent hydrolysis is preferably carried out in an aqueous solvent such as water / methanol, water / - ethanol or water / dioxane in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of a base such as sodium or potassium hydroxide at temperatures between 50 and 100 ⁰ C. ,

2Od) For the preparation of a compound of the general formula I in which W is a carboxy group, an alkanoyl group having 1 to 3 carbon atoms or an alkyl group having 1 to 3 carbon atoms:

Reaction of a compound of the general formula

R ₄

A - N - CO - B - // \), (VII)

"23 6.5 9 7 ~ 8

in the

R ₁ to R ₁ -, A and B are as defined above, with phosgene, an oxalyl halide, an alkyl or alkanoyl halide having in each case 1 to 3 carbon atoms in the alkyl moiety or with hydrogen cyanide / hydrogen halide, but preferably hydrogen chloride, in the presence of a Lewis acid ,

Here come as halides in particular the chlorides and

Bromides and as Lewis acid, in particular aluminum chloride into consideration.

The reaction is preferably carried out in a solvent such as methylene chloride, nitrobenzene, chlorobenzene, dichlorobenzene, tetrachloroethane or carbon disulfide or in polyphosphoric acid at temperatures between 0 and 120 C, but preferably at temperatures between 20 and 80 C. In this case, in a compound of the general formula VII R ₃ denotes a hydrogen atom, it may at the same time be replaced by a corresponding alkyl or acyl radical.

e) For the preparation of a compound of general formula I in which W represents the carboxy group:

, 20 Reaction of a compound of the general formula

A-N-CO-B

COCH ₃

R _c

, (VIII)

in the

R ₁ to R ₁ -, A and B are as defined above, with an optionally prepared in the reaction mixture hypohalite.

2O Γ Γ Λ \ \ 7 η w 'U w ^J ö / Q

The reaction is conveniently carried out in a solvent such as water / tetrahydrofuran or water / dioxane and in the presence of a base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 80 C, but preferably at temperatures between 25 and 50 C.

f) For the preparation of a compound of general formula I in which W represents the carboxy group:

Oxidation of a compound of the general formula

R ₄

AN-CO-BC ' ^X >, (IX)

f T

in the

^ ₁ to R _g , A and B are as defined above and

G is a convertible by oxidation in a carboxy group

Group represents.

As such an oxidizable group, for example, the formyl group and its acetals, the hydroxymethyl group and their ethers, an unsubstituted or substituted acyl group such as the acetyl, chloroacetyl, propionyl, the malonic acid (1) -yl group or a malonic ester ( 1) -yl group into consideration.

The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, pyridine or carbon tetrachloride at temperatures between 0 and 100 C, but expediently at temperatures between 20 and

5Ο C, performed. However, the reaction is preferably carried out with silver oxide / sodium hydroxide solution, manganese dioxide / acetone or methylene chloride, hydrogen peroxide / sodium hydroxide solution, bromine or chlorine / sodium or potassium hydroxide solution or chromium trioxide / pyridine.

g) For the preparation of a compound of general formula I in which R _{3 is} a nitro group:

Reaction of a compound of the general formula

A-N-CO-B

in the

R ₄ / R ₅ / R & ^{B u} nd W are as hereinbefore defined, R ₃ is a nitro group and

Y represents a nucleophile-exchangeable radical such as a halogen atom, with an amine of the general formula

H- N

, (XI)

in the

R-j and R_ are as defined above, and optionally subsequent hydrolysis.

The term "a halogen atom" used in the definition of the exchangeable radical Y is in particular to be understood as meaning a fluorine, chlorine or bromine atom, but preferably in the o- or p-position to the nitro group.

The reaction is conveniently carried out in a solvent such as water, water / methanol, water / ethanol, water / isopropanol, water / dioxane, methanol, ethanol, dimethylformamide or in an excess of the amine of general formula XI and / or its N-formyl Optionally in the presence of an inorganic or tertiary organic base, optionally in. Presence of a reaction accelerator such as copper or a copper salt and optionally in a pressure vessel at temperatures between 20 and 150 ° C, but preferably at the boiling temperature of

Reaction mixture, e.g. at 100 ° C, performed. However, the reaction can also be carried out without a solvent.

The optionally subsequent hydrolysis is conveniently carried out in an aqueous solvent such as methanol / water, ethanol / water or dioxane / water in the presence of an acid such as hydrochloric acid or sulfuric acid or a base such as sodium or potassium hydroxide at temperatures between 50 and 100 C.

h) For the preparation of a compound of the general formula I in which A is a group of the formula

- CH -, where R- and R-

D /

as defined above: Reduction of an enamide of the general formula

'χ

C-N-CO-B

(XII)

  in the

: R ₁ to R_, B and W are as defined above. ,

^! The reduction is preferably carried out with hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon or platinum in a suitable solvent such as methanol, ethanol, isopropanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide, benzene or benzene / ethanol at temperatures between 0 and 100 C, but preferably carried out at temperatures between 20 and 50 C, and a hydrogen pressure of 1 to 5 bar. When using a suitable chiral hydrogenation catalyst such as a Metalligandenkpmplex, eg a complex of rhodium chloride and (+) - or (-) 0,0-isopropylidene-2,3-dihy-

, droxy-1,4-bis (diphenylphosphino) butane (= DIOP), takes place

^: hydrogenation is enantioselective. Furthermore, other reducible groups can be mitreduziert in the catalytic hydrogenation, for example, a nitro group to the amino group or a chlorine or bromine atom to the water

; atom.

(ji) for the preparation of a compound of general formula (I) in which R. is a hydrogen atom and A is optionally substituted by a methyl, ethyl or isopropyl group.

236597 8

methylene or ethylene group, a methylene or ethylene group substituted by two alkyl groups each having 1 to 3 carbon atoms, a methylene group substituted by a cycloalkyl group having 3 to 7 carbon atoms, a carboxyl, alkoxycarbonyl or phenyl group, wherein each of the above-mentioned alkyl moieties 1 may contain up to 3 carbon atoms, or a cycloalkylidene group having 4 to 7 "carbon atoms:

Reaction of a compound of the general formula

A '- OH

(XIII)

in the

to R _{3 are} as defined above and one optionally substituted by a methyl, ethyl or isopropyl group methylene or ethylene 'group, one by two alkyl groups each having 1 to

3-carbon substituted methylene or ethylene group, a substituted by a cycloalkyl group having 3 to 7 carbon atoms, a carboxyl , _ alkoxycarbonyl or phenyl group-substituted methylene group, each of the above-mentioned alkyl moieties may contain 1 to 3 carbon atoms, or a cycloalkylidene group

4 to 7 carbon atoms, with a compound of the general formula

"3 6 δ S T

in the

R_, B and W are as defined above.

The reaction is carried out in the presence of a strong acid, which may also serve as a solvent, preferably in concentrated sulfuric acid, at temperatures between 20 and 150 ° C, preferably at temperatures between 80 and 100 ⁰ C.

If, according to the invention, a compound of the general formula I in which W represents the carboxy group is obtained, this can, if desired, be converted into a corresponding compound of the general formula I by means of esterification or amidation, and / or

a compound of general formula I in which R ₃ and / or W represent a nitro group, this can be converted by reduction into a corresponding compound of general formula I in which R_ and / or W represent an amino group, and / or

a compound of the general formula I in which R ₃ and / or W is an amino group, this may be converted via a corresponding diazonium salt into a corresponding compound of the general formula I in which R-, a hydrogen or halogen atom, a hydroxy group , Alkoxy-, mercapto, Alky! Mercapto, chlorosulfonyl or cyano group and / or W is a hydrogen or halogen atom or a cyano group, to be converted, wherein a

thus optionally obtained compound of the general formula I in which R _{3 represents} the hydroxy group, can then be converted by alkylation into a corresponding compound of the general formula I in which R ₁ represents an alkoxy group, or a compound of the general formula I thus obtained, in the R-. represents the chlorosulfony! group, then, by means of ammonia, into a corresponding compound of the general formula I in which R, the aminosulfonyl group, can be converted, and / or

a compound of general formula I in which R-. represents the amino group, it may be converted by acylation into a corresponding compound of general formula I in which R represents an alkanoylamino, aroylamino, alkoxycarbonylamino or alkylsulfonylamino group, and / or

a compound of the general formula I in which R- represents an amino group, it may be converted by alkylation into a corresponding compound of the general formula I, in which R _{3 is} an alkylamino or dialkylamino group, and / or

a compound of the general formula I, in which R _{3 is} a chlorine or bromine atom, is converted by means of dehalogenation into a corresponding compound of the general formula I, in which R _{3 represents} a hydrogen atom, and / or

a compound of general formula I, in which R represents the nitrile group, it may be prepared by hydrolysis or alcoholysis into a corresponding compound of general formula I, in the R-. represents an aminocarbonyl, carboxy or Alkoxycarbony! group, be converted, and / or

a compound of the general formula I in which R _{3 is} a carboxy- or alkoxycarbonyl group and / or W is an optionally esterified carboxy group, this can be converted by reduction into a corresponding compound of the general formula

3 " C Γ * Π T" 6 ό 9 7

mel I, in which R ₃ and / or W represent a formyl or hydroxymethyl group, are converted, and / or

a compound of general formula I in which W is a group of the formula -COO- (CH ₂ J ^ -OH, so this can be prepared by acylation in a corresponding compound of the general

Formula I, in which W represents a group of the formula -COO- (CH ₂ ) -Rg, • converted, and / or

a compound of the general formula I in which W represents a hydroxymethyl group, this may, after conversion into - a corresponding halomethyl compound by reaction with a Malonsäurediester into a corresponding compound of the general formula I ', in which W represents a substituted by two alkoxycarbonyl ethyl group , be transferred and / or

a compound of the general formula I in which W represents a formyl group, this may be obtained by condensation and. optionally subsequent hydrolysis and / or decarboxylation into a corresponding compound of general formula I, in which W represents a vinyl group substituted by a hydroxycarbonyl or alkoxycarbonyl group, and / or

a compound of the general formula I in which W is an ethyl group substituted by two alkoxycarbonyl groups may be converted by hydrolysis and decarboxylation into a corresponding compound of the general formula I in which W represents an ethyl group substituted by a carboxy group and /or

a compound of the general formula I in which W represents the carboxyl group, this can be converted by means of conversion into a Sulfonsäurehydrazid and subsequent disproportionation into a corresponding compound of the general formula I in which 'W represents the formyl group, and / or

- »- 236 59 7

a compound of the general formula I in which R ₁ and R together with the intervening nitrogen atom represent an aza-1,4-dioxa-spiro-alkyl group having 6 to 8 carbon atoms, this can by hydrolysis in the presence of an acid in a corresponding A compound of the general formula I in which R ₁ and R ₃ together with the intervening nitrogen atom are a straight-chain alkyleneimino group having 4 to 6 carbon atoms in which a methylene group is replaced by a carbonyl group, and / or

a compound of the general formula I in which R.sup.1 and R.sup.1, together with the intervening nitrogen atom, represent an unbranched alkylenimino group having 4 to 6 carbon atoms in which one methylene group has been replaced by a carbonyl group, this can be converted by reduction into a corresponding hydroxyalkyleneimino compound converted general formula I, and / or

a compound of the general formula I in which W represents an aminocarbonyl group, this can be converted by dehydration into a corresponding compound of the general formula I in which W represents a cyano group.

236597 8

The subsequent dehydration is carried out with a dehydrating agent such as phosphorus pentoxide, sulfuric acid or p-toluenesulfonyl chloride optionally in a solvent such as methylene chloride or pyridine at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.

The subsequent esterification is expediently carried out in an _x suitable solvent, eg in a corresponding alcohol, pyridine, toluene, methylene chloride, tetrahydrofuran or dioxane, in the presence of an acid-activating and / or dehydrating agent such as thionyl chloride, ethyl chloroformate, carbonyldiimidazole or Ν, Ν'-dicyclohexylcarbodiimide or its Isoharnstoffäthern, optionally in the presence of a reaction accelerator such as copper chloride, or by transesterification, eg ^ 5 with a corresponding carbonic acid diester, at temperatures. • between 0 and 100 C, but preferably at temperatures between 20 C and the boiling temperature of the solvent in question, carried out.

The subsequent amidation is' conveniently in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a hydrophilic agent, for example in the presence of ethyl chloroformate, thionyl chloride , phosphorus trichloride, phosphorus pentoxide, N, N ¹ -dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole, N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or an amino group activating agent, for example phosphorus trichloride , and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which can simultaneously serve as a solvent, at temperatures between -25 and 250 C, preferential

However, at temperatures between -10 C and the boiling point of the solvent used, carried out. The reaction may also be carried out without a solvent, further, water formed during the reaction may be removed by azeotropic distillation, e.g. by heating with toluene on a water separator, or by adding a desiccant such as magnesium sulfate or molecular sieve.

The subsequent reduction of the nitro compound is preferably carried out in a solvent such as water, water / ethanol, methanol.

TO nol, glacial acetic acid, ethyl acetate or dimethylformamide expediently with hydrogen in the presence of a hydrogenation catalyst such as Rähy nickel, platinum or palladium / carbon, with me- .tallen such as iron, tin or zinc in the presence of an acid, with salts such as iron (II) sulfate , Tin (II) chloride or sodium dithlonite, or hydrazine in the presence of Raney nickel at temperatures between-0 ratur, performed.

between-0 and 50 C ,. but preferably at room tempera-

Subsequent reaction of a diazonium salt, e.g. of the fluoroborate, of the hydrosulfate in sulfuric acid, of the hydrochloride or of the hydroiodide, if necessary in the presence of copper or a corresponding copper (I) salt, such as copper (I) chloride / hydrochloric acid, copper (I) bromide / hydrobromic acid, trisodium copper (I) -tetracyanide at pH 7 or a Alkalixanthogenats, "or of copper (II) chloride / sulfur dioxide in glacial acetic acid, optionally with the addition of magnesium chloride, at slightly elevated temperatures, for example at temperatures between 15 and 100 [deg.] C., the subsequent reaction with hypophosphorous acid is preferably carried out at -5 to 0 C. The diazonium salt required for this purpose is expediently dissolved in a suitable solvent, for example in water / hydrochloric acid, methanol / hydrochloric acid, ethanol / hydrochloric acid or dioxane Hydrochloric acid, by diazotization of a corresponding amino compound with a nitrite, for example sodium nitrite or an ester of nitrous acid, at low temperature For example, at temperatures between -10 and 5 C, produced.

The subsequent acylation is conveniently carried out in a solvent such as methylene chloride, ether, tetrahydrofuran or in an excess of the acylating agent used, e.g. Formic acid, acetic acid or propionic acid or their anhy-

Acid radicals or esters, if appropriate in the presence of an inorganic or a tertiary organic base, which can simultaneously also serve as a solvent, and optionally in the presence of an acid activating or dehydrating agent at temperatures between -25 and

10150 C, but preferably at temperatures between -10 C and the boiling temperature of the reaction mixture, carried out.

The "post N" alkylation is conveniently carried out with a corresponding halide or sulfonic acid ester, for example "methyl iodide, dimethyl sulfate, ethyl bromide or p-toluenesulfonic acid.

15säureäthylester, optionally in the presence of a base such as sodium hydride, potassium hydroxide or potassium tert.butylat and preferably in a solvent such as diethyl ether, tetrahydrofuran, dioxane, ethanol, pyridine or dimethylformamide at temperatures between 0 and 75 C, but preferably in Raum-

20 temperature, performed. Methylation may be further conveniently carried out with formaldehyde / formic acid at the boiling temperature of the reaction mixture and alkylation with a corresponding carbonyl compound in the presence of a hydride such as sodium cyanoborohydride in a solvent such as acetonitrile / acetic acid or .dimethylformamide / acetic acid ^: preferably at pH = 7 and Temperatures between 0 and 50 C are performed.

The subsequent dehalogenation is expediently carried out in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide by means of catalytically excited hydrogen, e.g. with hydrogen in the presence of platinum or palladium / carbon, at temperatures between 0 and 75 C, but preferably at room temperature, and carried out at a hydrogen pressure of 1-5 bar. '

23-6 59 7 8

The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, ethanol, water / ethanol, water / isopropanol or water / dioxane elevated temperatures, eg at the boiling temperature of the reaction mixture, performed. However, it can also be treated with a nitrite, e.g. Sodium nitrite, in the presence of an acid such as sulfuric acid, which is suitably used simultaneously as a solvent, be carried out at temperatures between 0 and 50 C. The subsequent alcoholysis is conveniently carried out in the presence of hydrogen halide, preferably hydrogen chloride, at temperatures between 20

15 Alcohols performed.

temperatures between 20 C and the boiling point of the used

The subsequent reduction is preferably carried out with a metal hydride, e.g. with a complex metal hydride such as lithium aluminum hydride, in a suitable solvent such as diethyl ether, tetrahydrofuran or dioxane at temperatures between 0 and 100 C, but preferably at temperatures between 20 and 60 C.

Subsequent O-alkylation is conveniently effected with a corresponding halide, sulfonic acid ester or diazoalkane, e.g. with methyl iodide, dimethyl sulfate, ethyl bromide, p-toluenesulfonic acid ethyl ester, methanesulfonic acid isopropyl ester or diazomethane, if appropriate in the presence of a base such as sodium hydride, potassium hydroxide or potassium tert-butylate and preferably in a solvent such as diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, Pyridine or dimethylformamide at temperatures between 0 and 7 5 C, but preferably at room temperature performed.

236597 8

The subsequent conversion of a hydroxymethyl group into a halomethyl group is carried out with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene and their subsequent reaction with a malonic acid ester, for example with an alkali metal salt of Malonsäurediäthylester, at temperatures between 0 and 100 ⁰ C, but preferably at temperatures between and .50 ° C performed.

The subsequent condensation of a formyl compound is conveniently carried out in a solvent such as pyridine or tetrahydrofuran with malonic acid / with a malonic acid ester, with a dialkylphosphonoacetic acid ester or an alkoxycarbonylmethylene-triphenylphosphone, optionally in the presence of a base as condensing agent, e.g. in the presence of piperidine, potassium tert-butylate or sodium hydride, carried out at temperatures between 0 and 100 ° C; by subsequent acidification e.g. with hydrochloric acid or sulfuric acid, or by subsequent alkaline hydrolysis gives the desired acid.

The subsequent hydrolysis and decarboxylation is conveniently carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid or trifluoroacetic acid in a suitable solvent such as water, ethanol, water / ethanol, water / isopropanol or water / dioxane at elevated temperatures, e.g. carried out at the boiling point of the reaction mixture.

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

236597 8

The resulting compounds of general formula I can be further converted into their addition salts, in particular in their physiologically acceptable salts with inorganic or organic acids or bases. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid and, as bases, sodium hydroxide, potassium hydroxide or cyclohexylamine.

The compounds of the general formulas II to XIV used as starting materials are known from the literature in some cases or are obtained by processes known per se.

Thus, for example, a compound of the general formula II in which A represents a bond is obtained by reduction of a corresponding nitro compound, for example by means of catalytically excited or nascent hydrogen or by means of sodium dithionite or by Hofmann, Curtius, Lossen or Schmidt degradation corresponding connection.

For example, a compound of general formula II in which A is a vinylidene group, or their tautomeric ketimine by reacting a corresponding nitrile with a corresponding Grignard or lithium compound and subsequent hydrolysis or by reacting a corresponding ketone with a corresponding amine in Presence of titanium tetrachloride. For further reaction with a compound of general formula III or their reactive derivatives, especially their acid chlorides, the organometallic ketimine complex can also be used.

A compound of general formula II, in which A is not a bond and no vinylidene group, is obtained, for example, by reduction of a corresponding nitrile with lithium aluminum hydride, by reacting a corresponding nitrile with a corresponding Grignard or lithium compound and optionally subsequent lithium aluminum hydride.

236597 8

Reduction or subsequent hydrolysis to ketimine, which is subsequently reduced with catalytically-promoted hydrogen, with a complex metal hydride or with nascent hydrogen, by hydrolysis or by hydrazinolysis of a corresponding phthalimido compound, by reacting a corresponding ketone with ammonium formate and subsequent hydrolysis or with an ammonium salt in the presence of sodium cyanoborohydride, by reduction of a corresponding oxime with lithium aluminum hydride, with catalytically-excited or nascent hydrogen, by reduction of a corresponding N-benzyl or N-1-phenylethyl Schiff base, for example with a complex metal hydride in ether or tetrahydrofuran Temperatures between -78 ° and the boiling point of the solvent used and subsequent cleavage of the benzyl or 1-Phenyläthy! Group by catalytic hydrogenation, by Ritter reaction of a corresponding alcohol with potassium cyanide in sulfur lauric acid, or by Hofmann, Curtius, Lossen or Schmidt degradation, a corresponding compound. A resulting amine of general formula II with a chiral center can be obtained by racemate resolution, for example by means of fractional crystallization of diastereomeric salts with optically active acids and subsequent decomposition of the salts, or by formation of diastereomeric compounds with separation and subsequent ^Cleavage be separated into its enantiomers. Furthermore, an optically active amine of the general formula II can also be prepared by enantio-selective reduction of a corresponding ketimine by means of complex boron or aluminum hydrides in which part of the hydride hydrogen atoms is replaced by optically active alcohol radicals or by means of hydrogen in the presence of a suitable chiral hydrogenation catalyst or analogously starting from a corresponding N-benzyl or optionally optically active N-1-Phenäthyl Schiff' see base and optionally subsequent cleavage of the benzyl or 1-Phenäthylrestes.

"236 59 7

A compound of general formula II in which R. represents a lower alkyl radical is obtained by reduction of a corresponding N-acyl compound, e.g. by means of lithium aluminum hydride.

The compounds of the general formulas IV, V and VII to X used as starting materials are obtained by reacting a corresponding amine with a corresponding carboxylic acid or its reactive derivatives and optionally subsequent hydrolysis. A compound of general formula VIII is also obtained by Friedel-Crafts acetylation of a corresponding compound.

A compound of the general formula XII used as starting material is preferably obtained by acylation of a corresponding ketimine with a corresponding carboxylic acid or its reactive derivatives with tautomerization.

A compound of general formula XIII used as starting material is obtained by reduction of a corresponding carbonyl compound or by reacting a corresponding carbonyl compound with a corresponding Grignard or lithium reagent.

As already mentioned, the novel compounds of the general formula I have valuable pharmacological properties, namely an effect on the intermediary metabolism, but in particular a blood glucose lowering effect.

For example, the compounds were

A = 4- (2-pyrrolidino-benzyl) -aminocarbonyl-methyl-benzoic acid,

B = 4- (1- (2-pyrrolidino-phenyl) -ethyl) -aminocarbonyl-methyl / -benzoic acid,

- ^3S - 2 j 6 5 9 7

C = 4- (1- (5-chloro-2-pyrrolidino-phenyl) -ethyl) -aminocarbonyl, methyl / benzoic acid,

D = 4 - </ (2-piperidinobenzyl) aminocarbonylmethylZ-benzoic acid,

E = 4 - / _ (1- (2-piperidino-phenyl) -äthenyl) -aminocarbonylmethy1 / benzoic acid,

F = 4 - / _ (1- (6-chloro-2-piperidino-phenyl) -äthenyl) - aminocarbonylmethylbenzoic acid,

G = 4- (1- (6-methyl-2-piperidino-phenyl) -äthenyl) -aminocarbonyl-

methyl / - benzoic acid,

-] 0H = 4- / (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl-benzoic acid,

I = 4- (II-piperidino-phenyl) -ethyl) -aminocarbony-1-methyl-V-benzoate,

K = (+) ethyl 4- ^ J1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoate,

L = 4 - ^ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid (2,2-dimethyl-dioxolan-4-yl) -methyl ester,

M = 4- / 71- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethy1 / -toluene,

2QN = 4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethy.1 / -benzyl alcohol,

0 = 4-? -1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / benzaldehyde,

P = 4-T-ti- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl-phenylacetic acid,

Q = 4- (1- (4-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid,

R = 4 - / _ (1- (5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid,

S = 4 - / _ (1 ~ (6-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / -benzoic acid ethyl ester,

T = 4 - ^ (1- (5-fluoro-2-piperidino-phenyl) -ethyl) -aminocarbonyl-ethyl-benzoic acid,

U = 4 - / (1- (4-methyl-2-piperidino-phenyl) -ethyl) -aminocarbonylmethylZ-benzoic acid,

V = 4 - / _ (1- (5-methyl-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid, '

W = 4- / 72- (2-piperidino-phenyl) -2-propyl) -incinocarbonyl methyl / benzoic acid,

X = 4 - ^ (1- (2-piperidino-phenyl) -2-methyl-propyl) -aminocarbonyl-methyl / benzoic acid,

Y = 4- (2-piperidinobenzhydryl) -aminocarbonylmethyl-1-benzoic acid,

Z = 4 - / _ (1- (2- (1,2,3,6-tetrahydropyridino) -phenyl) -ethyl) -aminocarbonyl-methyl-benzoic acid,

AA = 4-, / (1- {2- (3-methyl-piperidino) -phenyl) -ethyl) -aminocarbonyl-methyl / -benzoic acid,

AB = 4- / JI- (2-hexahydroazepino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid,

- 4ο - ~~ 2 3 fi 5 9 Ί

may ^ c / \ j? K * J% ^ /

AC - 4 - / (1- (2-octahydroisoindolo-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid,

AD = 4 - / ^ (K, -methoxycarbonyl-2-piperidino-benzyl) -aminocarbonylmethyl / -benzoic acid ethyl ester and

AE = (+) -4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid

on their hypoglycemic properties examined as follows: 1. Hypoglycemic effect:

The hypoglycemic effect of the substances to be tested was tested on female rats of their own breed weighing 180-220 g, which were fasted 24 hours before the start of the experiment. The substances to be investigated were suspended immediately before the start of the test in 1.5% methyl cellulose and applied by gavage.

The blood was taken immediately before administration of the substance, as well as 1, 2, 3 and 4 hours after each from the retroorbital venous plexus. Of these, 50 μl each were de-infected with 0.5 ml of 0.33N perchloric acid and centrifuged. In the supernatant, glucose was determined by the hexokinase method using an analysis photometer. The statistical evaluation was carried out according to the student t-test with ρ = 0.05 as the significance limit.

The following table contains the values found in percent over control:

table

Sub 25 mg / kg 1 2 3 -26 4 1 10 mg / kg 3 -14 4 5 mg / kg 2 3 4 -10 n.s. punching hours 2 hours -31 1 hours n.s. n.s. -36 -23 N.s n.s. n.s. A -38 -42 -35 -25 -13 -22 -18 -11 -13 B -40 -30 -22 -26 -17 -34 n.s. -38 -36 -21 C -45 -38 -36 -32 -14 -16 -26 n.s. D -42 -39 -32 -27 -41 n.s. n.s. e -45 -42 -32 -44 -39 -3 5 -24 -45 -33 -36 -32 F -17 -47 -15 n.s. n.s. G -40 -43 -38 -38 -45 -38 -30 -31 -45 -31 -22 H -24 -27 -32 -13 -45 -22 -29 -19. I -37 -22 -42 K -39 -37 -30 -24 -47 -34 n.s. n.s. L -45 -44 -32 -39 -43 -26 -23 M -34 -40 -40 -19 -31 -29 n.s. n.s. N -46 -47 -39 -36 -46 -41 -33 -35 -35 -35 O -41 -26 -26 n. s. -43 -18 -11 n.s. P -35 -39 -30 -27 - Q -36 -36 -25 -28 -36 -34 -46 -20 -18 -29 -29 R -44 -46 -37 N.s -17 n.s. n.s. S -43 -49 -47 -46 -36 T -41 + -37 -18 -27 n.s. -43 -15 -16 n.s. U -28 -23 -20 -36 -42 -32 -32 V -32 -34 -20 -24 -41 -37 W -46 -45 -36 -43 -41 -28 -19 -40 -35 -31 X -44 + -44 ⁴ -42+ -36 -38 Y -44 -39 Z -45

Continuation Table 1

10

Sub 1 2S 2 ) mg / kg -46 -38 -44 4 1 1C 2 ) mg / kg -26 -35 5 1 mg / kg -33 4 punching 3 -45 -46 -39 3 4 -24 -17 2 3 n. s. hours -41 -44 -32 -46 -42 hours -48 hours -20 AA -34 -41 -32 -31 -17 -29 -36 n. s. FROM -26 -35 -18 -20 AC -40 AD -32 -41 n.s. AE ⁺⁺ -34

Dose: 20 mg / kg

Dose: 1 mg / kg n.s. = not statistically significant

2. Acute toxicity:

In female urid male mice of their own breed weighing 20-26 g, the toxic effects of the substances H, R and Y after oral administration (suspension in 1% methyl cellulose) of a single dose at a follow-up period of 14 days was tested. The following table contains the .. · .. found values:.

20

substance

orienting toxicity

H R Y

y 2,000 mg / kg po (1 of 10 animals died)> 2 0OO mg / kg po (0 of 10 animals died)> 2,000 mg / kg po (0 of 6 animals died)

23 6 5 9

Because of their pharmacological properties, the compounds of the general formula I and their physiologically tolerated salts according to the invention are suitable for the treatment of diabetes mellitus. For this they can be incorporated, if appropriate in combination with other active substances, into the customary pharmaceutical preparation forms such as tablets, dragees, capsules, powders or suspensions. The single dose in adults is 1-50 mg, but preferably 2.5-20 mg, 1 or 2 times daily.

The following examples are intended to explain the invention in more detail:

236 59 7 8

example 1

Methyl 4- (1- (5-chloro-2-dimethylamino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid

To a solution of 2.00 g (0.0103 mol) of 4-methoxycarbonyl-phenyl acetic acid in 13.5 ml of absolute tetrahydrofuran is added at 20 ° C with stirring 1.67 g (0.0103 mol) of carbonyldiimidazole and then heated with exclusion of moisture for 45 minutes at reflux. After cooling to room temperature, 2.05 g (0.0103 mol) of 1- (5-chloro-2-trimethylamino-phenyl) -ethylamine in 7 ml of absolute tetrahydrofuran are added and the mixture is stirred overnight at 20.degree. It is evaporated in vacuo and the evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/1). Yield: 2.6 g (66.7% of theory), m.p .: 153-155 ° C (from ether).

15Ber .:. C 64.08 H 6,18 Cl. 9,46 N 7,47 Found: 64,30 6,04 9,70 7,39 "

The following compounds were prepared analogously to Example 1:

4-_ (1- (5-chloro-2-dipropylamino-phenyl) -ethyl) -aminocarbonyl- methyl-7-benzoic acid methyl ester

Yield: 42% of theory,

Melting point: 135-137 ° C (aus'Äther / petroleum ether): Calc .: C 66.83 H 7,25 Cl 8,23 N 6,50 Gef .: 66,95 7,35 '8,35 6,05

4-__ (1- (5-chloro-2-dibutylamino-phenyl) -ethyl) -aminocarbonyl- methyl-benzoic acid methyl ester.

Yield: 64.8% of theory,

Melting point: 110-112 ° C.

Calc .: C, 68.03, H, 7.69, Cl, 7.72, N, 6.10, Found: 67.86, 7.61, 7.73, 6.17

J 6 D 9 7

4- / J1- (S-chloro-N-cyclohexyl-N-methylamino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid methyl ester.

Yield: 63.9% of theory, melting point: 152-153 ° C (ether).

5s .: C 67.78 H 7.05 Cl 8.00 N 6.32 Found: 67.70 6.92 8.24 6.46

4- / (5-chloro-2-pyrrolidino ~ benzyl) aminocarbonylmethyl / -benzoe acid methylester

Yield: 68.1% of theory, m.p .: 139-14.1 ° C (methanol)

Calc .: C 65.19 H 5.99 Cl 9.17 N 7.24 Found: 65.46 5.91 9.26 7.41

A- (J, 1- (5-chloro-2-pyrrolidino-phenyl) -ethyl) -amino-carbonyl. methyl / benzoic acid methy he reads

Built: 58.3% of theory,

Melting point: 133-135 ° C (methanol) Calc .: C 65.91 H 6,29 Cl 8,84 N 6,99 Found: 66,24 6,19 8,75 7,13

4 - / _ (5-chloro-2-piperidino-benzyl) -aminocarbonylmethyl / -benzoic acid methyl ester

Yield: 75.1% of theory,. Melting point: 123-125 ° C (ether)

Calc .: C, 65.91, H, 6.29, Cl, 8.84, N, 6.99, Found: 66.05, 6.13, 8.86, 7.21

4 - / _ (1- (5-chloro-2-piperidino-benzyl) aminocarbony 1) -ethyl ^ / - benzoic acid methyl ester

Yield: 70.4% of theory, melting point: 142-144 ° C (ether).

2-3 6 b y "/

Ber. : C 66 , 57 H 6 , 56 Cl 8th , 55 N 6 75 Gef .: 66 50 6 , 49 8th , 44 6 , 86

4- {1- (5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl-7- benzoic acid methyl ester.

Yield: 69.5% of theory, melting point: 147-149 ° C (ether)

-Ber .: C 66.57 H 6.56 Cl 8.55 N 6.75 F .: 66.33 6.54 8.67 6.85

4 -, / JI- (5-chloro-2- (3-methyl-piperidino) -phenyl) -ethyl) -aminocar bonyimethyl-7-benzoic acid methyl ester

Yield: 54.3% of theory,

Melting point: 16O-162 ° C (methanol)

Calcd .: C, 67.20, N, 6.81, Cl, 8.27, N, 6.53, F, 67, 67, 6.81, 8.13, 6.45

4- (1- (5-chloro-2- (3,5-cis-dimethyl-piperidino) -phenyl) -ethyl) -aminocarbonylmethyl-benzoic acid methyl ester

Yield: 44% of theory, melting point: 19O-19 3 ° C (methanol) Calc .: C 67.78 H 7.05 Cl 8.00 N 6.32 V, 67.50 7.05 8.25 6 > 48

Methyl 4- / J 1 - (5-chloro-2-piperidino-phenyl) -propyl) -aminocarbonyl -methyl / benzoate;

Yield: 65.9% of theory, melting point: 142-144 ° C (ether).

Calc .: C, 67.20, H, 6.81, Cl, 8.26, N, 6.53, Found: 67.45, 6.63, 8.38, 6.63

- 47 - ~ ζττΒ ~ 5

4- (1- (5-chloro-2-piperidino-phenyl) -2-methyl-propyl) -aminocarbene

bonylmethy / - benzoic acid methyl ester-!

Yield: 61.4% of theory, melting point: 156-158 ° C. (ether)

5Ber .: C 67.78 H 7.05 Cl 8.00 N 6.32

Gef .: 67.80 7,17 7,89 6,28

"4 ^ = Z ₁ (1- (5-chloro-2-morpholino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid methyl ester

Yield: 69.8% of theory, melting point: 156-158 ° C (ether) Calc .: C 63.38 H 6.04 Cl 8.50 N 6.72 V .: 63.24 6.12 8.70 6.85

4 - </ _ (1- (5-Chloro-2-thiomorpholino-phenyl) -ethyl) -aminocarbonyl- methyl / -benzoic acid methyl ester

Yield: 68.2% of theory, melting point: 167-169 ° C (ether) Calc .: C 61.03 H 5.82 Cl 8.19 N 6.47 S 7.41 Found: 60.83 5 / 77 8.33 6.49 7.39.

4 - ^ (1- (5-chloro-2- (hexahydro-1H-azepino) -phenyl) -ethyl) -aminocar bony lme thy! / - benzoic acid methyl ester

Yield: 41.7% of theory, melting point: 146-147 ° C. (methylene chloride / petroleum ether) Calc .: C 67.19 H 6.81 Cl 8.27 N 6.53 F .: 66.90 6.66 8 , 30 6,39

4 - / _ (1- (5-chloro-2-octahydroazocino-phenyl) -ethyl) -aminocarbonyl methyl / benzoic acid methyl ester

Yield: 30% of theory, melting point: 154-156 ° C.

/ -, - ^ - ^% -T

- ^4S - 16 bba /

Example: Molepeak m / e = 442/444 (1 chlorine) JGef .: m / e = 442/444 (1 chlorine)

j 4 -, / JI- (5-chloro-2- (octahydro-iH-azonino) -phenyl) -ethyl) -amino

| carbonylmethyl / benzoic acid methylester

Yield: 38% of theory, Melting point: 184-185 ° C (chloroform / toluene) rBer. C 68.32 H 7.28 N 6.13

JGef .: 68.10 7.30 6.28

O ί _.

j 4 - ^ (2- (5-chloro-2-piperidino-phenyl) -2-propyl) aminocarbonyl

10 ^j methyl / -benzoic acid methylester

Yield: 84.4% of theory, Melting point: 162-164 ° C. Example: Molpeak m / e = 428/430 (1 chlorine)

iGef .: m / e = 428/430 (1 chlorine)

4-__ (1- (5-nitro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid methyl ester

Yield: 68.3% of theory, (melting point: 178-18O ° C (toluene) 3er .: C 64.93 H 6,40 N 9,88 Gef .: 65,05 6,43 9,87

4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid methyl ester ' - - - -

Yield: 59.1% of theory, melting point: 145-147 ° C

25Ber .: C 72.61 H 7.42 N 7.36 F .: 72.35 7.39 7.40

* · «Ο ο ο

4- / 5-methyl-2-piperidino-benzyl) aminocarbonylmethyl / benzoic acid methyl ester

Yield: 32.9% of theory,

Melting point: 124-126 ° C (petroleum ether / acetone) 5Ber ·: Molepak m / e = 380

Gef .: m / e = 3 80

N - (4-nitrophenacetyl) -N- / J (2-piperidino-phenyl) -äthy ^ -amine

Yield: 62.4% of theory, m.p .: 165-167 ° (ether) 10 μs .: C, 68.64, H, 6.86, N, 11.44, viz., 68.73, 6.88, 11.63

N- (4-acetyl-phenacetyl) -N- ^ J- (2-piperidino-phenyl) ethyl / amine

Yield: 32.4% of theory, m.p .: 162-164 ° C (ether)

15s .: C 75.79 H 7.74 N 7.69

Gef .: 75.51 7.86 7.3 8

N- (4-acetyl-phenacetyl) -N - / _ 1- (5-chloro-2-piperidino-phenyl) -ethyl 3-ethylamine

Yield: 50.3% of theory, Melting point: .162-163 ⁰ C (ether) Calcd. : C 69.24 H 6.82 N 7.02 Found: 68.88 6.63 6.70

2 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid methyl ester ;

Yield: 82% of theory, melting point: 10 -108 ° C. Calc .: C 72.60 H 7.42 N 7.36 F .: 72.79 7.38 7.53

236597

3 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethylj-benzoic acid ethyl ester _t

Yield: 47% of theory, melting point: 155 ° C

Re: C 73.07 H 7,67 N 7,10 F .: 73,30 7,58 7,17

-3 = X-chloro-4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid ethyl ester _.

Yield: 63% of theory, melting point: 123-124 ° C

Ber. : C 67.20 H 6,81 Cl 8,27 N 6,53 V: 67,28 6,84 8,36 6,50

4- (2- (1,2,3,4-Tetrahydro-isoquinolin-2-yl) -phenyl) -ethyl) -aminocarbonyl-methyl-benzoic acid ethyl ester

Yield: 43% of theory, m.p .: 142-144 ° C. Calc .: C, 75.99, H, 6.83, N, 6.33, Found: 75.64, 6.75, 6.35

4 IS 1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethy / - toluene

Yield: 59% of theory, melting point: 136-138 ° C. Calc .: C, 78.53, H, 8.39, N, 8.33, Foth .: 78.58, 8.16, 8.26

4- / l5-chloro-2-piperidino-anilino) -carbonylmethyl-benzoic acid methyl ester

Yield: 40.3% of theory, melting point: 156-158 ° C (methanol / toluene)

-236597

Ber. : C 65.19 H 5.99 Cl 9.16 Found: 65.20 6.15 9.40

4- [2- (2-piperidino-anilino-carbonyl) -äthyiy-benzoic acid methyl ester

Yield: 26.9% of theory,

Melting point: 71-73 ° C (petroleum ether)

Calc .: C 72 10 H 7 15 N 7 65 Gef .: 72 00 7 , 09 7 , 94

4- / J1- (2- (1,2,3,6-tetrahydropyridino) -phenyl) -ethyl) -amino- carbonyl-1-methyl-benzoate;

Yield: 63.4% of theory, m.p .: 125-127 ° C (ether) calc .: C, 73.44, H, 7.19, N, 7.14, v: 73.38, 7.13, 7.13

4- / J 2 - (5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid ethyl ester

Yield: 68% of theory, m.p .: 95-97 ° C (ethanol)

Calc .: C 67.20 H 6.81 Cl 8.27 N 6.53 V: 67.75 6.76 8.22 6.24

4 -Ethyl (1- (5-fluoro-2-piperidino-phenyl) -ethyl) -aminocarbonyl -methylbenzoate

Yield: 47 3% of the Theory, (Ether) 6 , 79 melting point : 138-140 ° C , 09 N 6 , 87 25 Ber .: C 69, 88 H 7, 10 Gef .: 70 10 7,

59 7 8

4 - / _ (1- (5-nitro-2-piperidino-phenyl) -ethyl) -aminocarbonyl methyl / -benzoic acid ethyl ester . '

Yield: 56.5% of theory, melting point: 144-147 ° C (ethanol) Calc .: C 65.59 H 6.65 N 9.56 V .: 65.78 6.56 9.73

4 = · - / (2- (1- (2-piperidino-phenyl) -ethyl) -aminocarbony 1) -ethyl / -benzoic acid methyl ester

C) 10 Yield: 90 % the Theory, N 7 10 Melting point: 129-1 31 ° C 7 , 52 Ber .: C 73 , 06 H 7,67 Gef .: 72 , 61 7.77

• 4 - / (2-Hydroxy-1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-1 -methylbenzoic acid ethyl ester

Yield: 4%, 4% of theory,

Melting point: 132-135 ° C (petroleum ether / acetone) Calc .: C 70.22 H 7.37 N 6.82 m / e = 410 V: 70.02 7.25 6.77 m / e = 410

.4 - ^ (1- (5-Hydroxy-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl ^ -benzoic acid ethyl ester

Yield: 64.2 % of Theory, 6 , 82 m / e = 4 10 Melting point: 150-15 1 ° C (ether) 6 , 81 m / e = 4 10 Ber .: C 70, 22 H 7,37 N Gef .: 70, 37 7.17

^ -1_ { CC-methoxycarbonyl-2-piperidinobenzyl) aminocarbony! Methyl / benzoic acid ethyl ester

Yield: 59% of theory,

Melting point: 11O-112 ° C (petroleum ether / acetone)

Ber. : C 68 , 47 H 6 90 N 6 , 39 m / e = 438 Gef .: 68 , 57 6 , 64 6 , 46 m / e = 438

4 -, / JI- (5-chloro-2- (2-methyl-piperidino) -phenyl) -ethyl) -amino carbonylmethyl · / -benzoic acid ethyl ester

Yield: 71.3% of theory, melting point: <"20 ° C. Calc .: m / e = 442/444 (1 chlorine) F: m / e = 442/444 (1 chlorine)

4- (1- (2-hexahydroazepino-phenyl) -ethyl) -aminocarbonyl-methyl / -benzoic acid ethyl ester

Yield: 68% of theory, melting point: 145-148 ° C (toluene) calc .: C 73.50 H 7.90 N 6.86. 73.35 8.04 6.89

4- (1- (2- _< / T, 4-dioxa-8-azaspiro £ 4, j-decyl- (827-phenyl) -ethyl) -aminocarbonylmethylZ-benzoic acid ethyl ester

Yield: 64.3% of theory, melting point: 143-145 ° C (petroleum ether / acetone) Calc .: C 69.01 H 7.13 N 6.19 F .: 69.30 7.38 6.21

4 - ^ _ (1 - (2- (2-methyl-pyrrolidino) phenyl) ethyl) aminocarbonyl me thy \ J -benzoic acid ethyl ester

Yield: 72.0% of theory, melting point: 94-97 ° C

Calc .: C 73.07 H 7.66 N 7.10 F .: 73.25 7.67 7.11

4 - / _ (1- (3-methyl-2-piperidine-phenyl) -ethyl) -aminocarbonylmethyl / benzoic acid e-ethylhyd

Yield: 39.5% of theory, calc .: m / e = 408 Gef .: m / e = 408

4 -, /. U- (3-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonyl- methyj-benzoic acid ethyl ester

Yield: 52.6% of theory, calc .: m / e = 428/430 (1 chlorine) F: m / e = 428/430 (1 chlorine)

Example 2

<+) 4- / J1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl- J- benzoic acid ethyl ester _;

To a solution of 290.9 mg (1.40 mmol) 4-Äthoxycarbonylphenylessigsäure in 6 ml of tetrahydrofuran is added 231.4 mg (1.43 mmol) of carbonyldiimidazole and then heated under exclusion of moisture for 1.5 hours at reflux. After cooling to room temperature, 0.385 ml (= 2.78 mmol) of triethylamine (dried over potassium hydroxide) and 3.60 mg (1.30 mmol) of (+) - 1- (2-piperidino-phenyl) -ethylamine-dihydrochloride / melting point / 242 :. C (Zers.); _0 </ ~ = + 14.8 (c = 1; methanol) 7 together with 2 ml of tetrahydrofuran. Stir in a 50 C oil bath for 4 hours. It is evaporated in vacuo and the evaporation residue is partitioned between chloroform and water. The chloroform extract is dried over sodium sulfate, filtered through a G3 glass frit and evaporated to dryness in vacuo. The residue obtained is purified by column chromatography on silica gel (chloroform / methanol = 6: 1).

23659 7 8

Yield: 229 mg (44.7% of theory), m.p .: 89-9O ° C (ether) / Jk] ² ^ = + 8.2 ° (c = 1, methanol)

Calc .: C 73.07 H 7.66 N 7.10 m / e = 394 F .: 73.20 7> 68 7.14 m / e = 394

Analogously to Example 2 was prepared:

- (-) -4 - / (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -

benzoic acid ethyl ester ;

from (-) - 1- (2-piperidino-phenyl) ethylamine dihydrochloride / m.p .: 239-242 ° (dec.); ? / '4 / ° ^"19/6 ° (c = 1; methanol] /

Yield: 4 1, 1% of theory, ° C (ether / cyclohexane) = 394 melting point • 77-79 methanol) = 394 / "^ ₀ = -6,2 O (c = 1; 7.66 N 7.10 m / e Ber .: C 73 , 07 H 7.75 6.82 m / e 15. Gef .: 72 , 67 Example 3

4 - / _ (1- (4-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyjL / - benzoic acid ethyl ester

To a solution of 5.5 g (0.023 mol) of 1- (4-chloro-2-piperidinophenyl) ethylamine, 4.8 g (0.023 mol) of 4-ethoxycarbonyl-phenylacetic acid, 7.3 g (0.028 mol) of triphenyl! Phosphine and 3.2 ml (0.023 mol) of triethylamine in 50 ml of acetonitrile are added 2.3 ml (0.023 mol) of carbon tetrachloride and stirred for 24 hours at room temperature. Then it is evaporated in vacuo and distributed ^ 5 between 100 ml of water and ethyl acetate. The combined, dried over sodium sulfate organic extracts are filtered, evaporated in vacuo and the evaporation residue purified by column chromatography on silica gel (toluene / acetic acid ethyl ester _e = 4/1).

Yield: 6.1 g (62% of theory), m.p .: 12 6-128 ° C

Ber. : C 67 20 H 6 , 81 Cl 8th , 27 N 6 , 53 Gef .: 67 , 43 6 97 8th , 16th 6 40

The following compounds were obtained analogously to Example 3:

4- (1- (4-Methyl-2-piperidino-phenyl) -ethyl) -aminocarbonyl- methyl / -benzoic acid ethyl ester

Yield: 48.2% of theory, melting point: 12O-122 ° C

Calc .: C 73 50 H 7 , 89 N CTI 86 Gef .: 73 , 61 7 95 6 73

A- ( 1 , 1- (2- (4-Methyl-piperidino) -phenyl) -ethyl) -aminocarbonyl-methyl-benzoic acid ester

Yield: 55.8% of theory, m.p .: 125-128 ° C (ether)

Ber. : -C 73 50 H 7 90 N 6 , 86 Gef .: 73 30 7 99 7 20

A- / Ji 1- (2-piperidino-phenyl) -ethyl) -aminocarbphenylmethyl / benzoic

^ acid ethyl ester '..--. -

Yield: 71% of theory, melting point: 147-148 ° C

(__) Calc .: C 73.06 H 7.67 N 7.10 F .: 73.54 8.04 6.95

A- / J 1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -phenyl-

acetic acid . · , - '

Prepared from 1- (2-piperidino-phenyl) -ethylamine and p-phenylene-diacetic acid

 Yield: 27% of theory, melting point:. 186-189 ° C Ber ,: C 72.60 H 7.42 N 7.36 F .: 72.75 7.65 7.11

9

-P = - fs - *

- 57 - I ; j 6 5 9

4 - ^ {2-piperidino-benzhydryl) -aminocarbonylmethyl-benzoic acid ethyl ester

Yield: 87.4% of theory, melting point: 16O-162 ° C calc .: C 76.29 H 7.06 N 6.14 V .: 76.44 7.08 6.17

^ -IS 5-chloro-2-piperidino-benzhydry1) -aminocarbonylmethy1 / -benzoic acid ethyl ester

Yield: 78% of theory, melting point: 2O2-2O4 ° C calc .: C 70.93 H 6.36 Cl 7.22 N 5.71 V .: 70.85 6.40 .7.11 5.45

4- ^ J 1- (4-piperidino-phenyl) ethyl) aminocarbonylmethyl _ / - benzoic acid ethyl ester ·.

Yield: 39% of theory, m.p .: t18-12O ° C calc .: C, 73.07, H, 7.67, N, 7.10, F .: 73.20, 7.78, 7.11

4 -, / _ (1- (2- (4-methyl-piperazino) -phenyl) -ethyl) -aminocarbonyl-methyl -ethylbenzate

Yield: 53% of theory, melting point: 13O-13 2 ° C calc .: C 70.38 H 7.63 N 10.26 F .: 70.41 7.53 10.13

4 - / _ (1- (2- (4-Benzyl-piperazino) -phenyl) -ethyl) -aminocarbonyl- methyl / -benzoic acid-ethyl ester

Yield: 75% of theory, melting point: 13 5-136 ° C

36 59 7

Calc .: C 74.20 H 7.26 N 8.66 F .: 74.45 7.34 8.54

Ethyl 4- [ 4- (2- (4-p-chlorophenyl-piperazino) -phenyl) -aminocarbonyl-ethylbenzoate] __ ^ _

Yield: 48.5% of theory, melting point: 178-18O ° C

Calc .: C, 68.83, H, 6.37, Cl, 7.01, N, 8.30, V, 68.71, 6.22, 6.82, 8.41

4 -, / _ (g, -cyclohexyl-2-piperidinc-benzyl) -aminocarbonylmethy l / ~ benzoic acid ethyl ester.

Yield: 75.0% of theory, melting point: 135 ° C

Calc .: C 75.29 H 8.28 N 6.06 Found: 75.11 8.13 5.99

N- (4-chloro-phenacetyl) -N - /. 1- (2-piperidino-phenyl) -ethyl / -amine

Yield: 79% of theory,

Melting point: 15O-152 ° C

Calc .: C 70.67 H 7.06 Cl 9.93 N 7.85 Found: -70.94 7.84 10.09 7.90

4 - / (2-pyrrolidinobenzhydryl) aminocarbonylmethy] _; / -benzoic

ethyl ester ..., .... ....

Yield: 57% of theory,

 Melting point: 163-165 ° C

Calc .: C, 75.99, H, 6.83; N, 6.33, Found: 75.45, 6.52, 6.10

- ^5S - / 3

4 - ^ _ (2-hexamethyleneimino-benzhydryl) -aminocarbonylmethyl / -benzoic acid ethyl ester

Yield: 68% of theory,

Melting point: 151-154 ° C

Calc .: C 76.56 H 7.28 N 5.95

Gef .: 76.43 7.19 6.01

Example 4

4- / J1- (2-piperidino-phenyl) -äthenyl) -aminocarbonylmethylj benzoic acid ethyl ester

To a solution of 10.9 g (0.0539 mol) of freshly prepared (2-piperidinophenyl) -methyl-ketimine in 110 ml of acetonitrile, 11.2 g (0.0539 mol) of 4-ethoxycarbonyl-phenylacetic acid are added successively with stirring, 17 g (0.0647 mol) of triphenylphosphine, 22.6 ml '(0.162 mol) of triethylamine and 5.2 ml (0.0539 mol) of tetra-

^ 5 chlorocarbon. The solution which is clear after a short time is stirred for 20 hours at 20.degree. C. The precipitated precipitate (triethylamine hydrochloride) is filtered off and the filtrate is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/1). Yield: 15 g (70.1% of theory), mp: 112-115 ° C (ether)

Ber. : C 73 , 44 H 7 19 N 7 , 14 Gef .: 73 , 28 7 , 32 6 96

The following compounds were obtained analogously to Example 4:

4 - / _ (& - cyclohexylidene-2-piperidinobenzyl) aminocarbonylmethyl / benzoic acid ethyl ester

Yield: 24% of theory, m.p .: 131-133 ° C

Ber. C, 75.62, H, 7.88, N, 6.08

Gef .: 75.59 7.47 6.01

^ -Li 1 ~ '(2-piperidino-phenyl) -propenyl) -aminocarbonylmethyl / -benzoic acid ethyl ester

Yield: 55.0% of theory (mixture of E and Z isomers) Melting point of the polar isomer: 82-84 C Calc .: C, 73.86, H, 7.44; N, 6.89, Found: 73.73 7, 57 7.01

Example 5 '.

4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-y-benzoic acid ethyl ester

To a stirred solution of 4.9,6 g (0.243 mol) of 1- (2-piperidone · dino-phenyl) -ethylamine / Kp _g _: 100-107 ° C; Melting point of the dihydrochloride: 234-237 ° C (Zers.f / and 37.3 ml (0.267 mol) of triethylamine in 245 ml of methylene chloride, is added dropwise with gentle ice cooling at an internal temperature of 20-30 C, the solution of 60.6 g (0.267 mol) of 4-ethoxycarbonyl-phenacetyl chloride in 120 ml of methylene chloride, followed by stirring at room temperature for 2 more hours ... The precipitate which has precipitated is filtered off, washed once with methylene chloride and the combined methylene chloride phases are shaken successively twice with water , once with 10% aqueous ammonia, twice with water, once with 100 ml of 3% hydrochloric acid and twice with water, the methylene chloride phase is dried over sodium sulphate, filtered and evaporated in vacuo, the residue is crystallized from ether ,

Yield: 88.8 g (92.7% of theory), m.p .: 148-15O ° C

The following compounds were obtained analogously to Example 5:

4- _i / _ {5-Methyl-2-piperidino-benzyl) -aminocarbonylmethyl-benzoic acid ethyl ester

Yield: 22.5% of theory,

Melting point: 116.5-117 ° C (ethanol / petroleum ether) Calc .: C 73.07 H 7.66 N 7.10 J Fe: 73.48 7.62 7.15

A-IS "*" (5-Methyl-2-piperidino-phenyl) -ethyl) -aminocarbonyl- methyl / -benzoic acid ethyl ester

Yield: 20.2% of theory,

Melting point: 132-132.5 ° C (ethanol) Ber ..: C 73.50 H 7.90 N 6.86 F .: 73.49 7.74 6.94

Ethyl 4 - / (1- (5-methoxy-2-piperidino-phenyl) -ethyl) -aminocarbonyl- methyl / ~ -benzoate __J

Yield: 35.8% of theory, m.p .: 131-132 ° C (ethanol) Calc .: C 70.73 H 7.60 N 6.60 Found: 70.98 7.59 6.38

A-Ij, 1- (2-piperidino-phenyl) -ethyl) -N- methyl-amino -carbonyl- methy! / - benzoic acid ethyl ester

Yield: 65.2% of theory, melting point: 20 ^° C.

Calc .: C 73.50 H 7.9 N 6.86 F .: 72.99 7.60 6.87

* "% Λ Λ ρ- f * s C-) -.

4- / JI- (2- (decahydro-isoquinolin-2-yl) -phenyl) -ethyl) -aminocarbonylmethyl / benzoic acid ethyl ester _;

Yield: 44% of theory, melting point: 159 ° C

5Ber .: C 74 96 H 8th , 08 N 6 24 Gef .: 75 , 09 8th , 01 6 , 01

4-Bis- (2- (1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl) -phenyl) ethyl) -amino-carbonyl-methyl-7-benzoic acid ethyl ester

Yield: 35% of theory, melting point: 115-117 ° C

Calc .: C, 75.30, H, 7.67, N, 6.27, Gef .: 75.18, 7.37, 5.89

Ethyl 4- (4- (1- (2- (Octahydroisoindol-2-yl) -phenyl) -aminocarbonyl- methyl / -benzoic acid)

15 Yield: 36% of theory, melting point: 141 ° C

Calc .: C 74 , 62 H 7 , 88 N 6 , 44 Gef .: 74 70 7 97 6 , 42

A-IJ. 1- (3-piperidino-phenyl) -ethyl) - aminocarbony lmethy 3 ^ ¹ -benzoe

acid ethyl ester ' . ·. ·

Yield: 24% ^; of theory / melting point: 164 ° C

Calc .: C 73.07 H 7.66, N 7.10. Gef .: 72,80 7,48 7,13

4- / J1- (6-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / · benzoic acid ethyl ester

Yield: 17% of theory, · m.p .: <20 ° C

JO · _ ~

j 3 /

Ber. : C 67, 20 H 6 , 81 Cl 8th , 26 N 6 , 53 m / e = 428/30 Gef .: 67, 96 6 , 56 8th 80 6 , 67 m / e = 428/30

20 ° C 7 , 89 N 6 85 m / e = 408 H 7 , 61 7 , 01 m / e = 408

4- £ _ (1- (6-methyl-2-piperidino-phenyl) ethyl) aminocarbonylmethyl / - benzoic acid ester äthy!

Yield: 3.5% of theory, melting point: ^ -Ber .: C 73.49 Gef .: 73.80

4- / L (1- (2- (3-Azabicyclo / 1,2,2-nanoan-3-yl) -phenyl) -ethyl) -amino- carbonylmethyl-benzoic acid ethyl ester

Yield: 0.5% of theory, melting point: <20 ° C Ber. ·: "M / e = 43 4 Gef .: m / e = 434

15 N - /. 1- (5-Chloro-2-piperidino-phenyl) -ethyl-N-phenacetyl-amine

Yield: 53.5% of theory, Melting point: 134-136 ° C (ethanol) 'Calc .: C 70.67 H 7.06 Cl 9.94 N 7.85 Found: 70.40 7.32 9, 77 7.68

Example 6

4 - ^. (1- (2-piperidino-phenyl) -äthenyl) -aminocarbonylmethyV- benzoic acid ethyl ester

To a stirred solution of 2.02 g (0.010 mol) of freshly prepared methyl (2-piperidino-phenyl) -ketimin and 1.53 ml (0.011 mol) of triethylamine in 10 ml of methylene chloride is added dropwise with ice cooling at an internal temperature of 1 to 6 C inside

"- 64 -

TS 597 8

The solution of 2.49 g (0.011 mol) of 4-ethoxycarbonylphenacetyl chloride in 10 ml of methylene chloride for 15 minutes. The mixture is stirred for another hour at 20 ° C and the reaction mixture is poured into cold sodium bicarbonate solution. It is extracted several times with methylene chloride, the organic extract is washed once with water, dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 50/1). Yield: 1.86 g (47.7% of theory), m.p .: 113-116 ° C (ethanol)

Calc .: C 73.44 H 7,19 N 7,14 m / e = 392 F .: 72,95 6,98 7,22 m / e = 392

The following compounds were prepared analogously to Example 6:

4 - ^ (1- (6-chloro-2-piperidino-phenyl) -äthenyl) aminocarbonyl methyl thybenitic acid ethyl ester

Yield: 37% of theory, melting point: calc .: C 67.51 Gef .: 67.86

4- (1- (6-Methyl-2-piperidino-phenyl) -äthenyl) -aminocarbonyl- methy! / - benzoic acid ethyl ester

Yield:. .41% of theory, melting point: 116-1-18 ⁰ C.

Calc .: C 73.86 H 7.43 N 6.89 F .: 73.75 7.43 6.77

102-105 ° C Cl 8th 30 N 6 , 56 • m / e = 426/28 H 6 , 37. 8th , 58 6 , 23 m / e = 426/28 6 , 39

73 6 5 9 7

Example 7

4 - / _ (1- (2-piperidino-phenyl) -äthenyl) -aminocarbonylmethylZ-benzoic acid ethyl ester __

To a suspension of 2.20 g (6.24 mmol) of iodomagnesium / methyl- (2-piperidino-phenyl) -ketimino7 complex in 15 ml of methylene chloride is added dropwise with stirring, the solution of 1.55 g (6.86 mmol ) 4-Ethoxycarbonyl-phenacetyl chloride in 5 ml of methylene chloride. There-. when the internal temperature rises from 20 C to 30 C. The mixture is stirred for a further 2 hours at room temperature, treated with water and extracted several times with methylene chloride The methylene chloride solution is washed three times with water, dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 50/2).

Yield: 1.1 g (45.8% of theory), m.p .: 115-118 ° C (ethanol) Calc .: C, 73.44, H, 7.19; N, 7.14, Found: 73.30, 7.06 7 16

Analogously to Example 7, the following compound was obtained:

4-Ethyl-1-chloro-2-piperidino-phenyl-4-phenyl- aminocarbonyl-methylbenzoate

Yield: 39.5% of theory, 'Melting point: 14 2-1 4 5 ° C (ethanol) _x

Calc .: C 67.51 H 6.37 Cl 8.30 N 6.56 V: 67.51 6.37 8.36 6.49

- 66 - ZTooyγτ

Example 8

I- (5-chloro-2-dimethylamino-phenyl) -ethyl) -aminocarbonyl- methyl-benzoic acid

A solution of 2.0 g (0.00534 mol) of methyl 4- (di (2-dimethylamino-phenyl) -ethyl) -aminocarbonylmethylZ-benzoate, 2.0 g (0.00534 mol), and 0.32 g (0.00801 mol Sodium hydroxide in 23 ml of ethanol and 7 ml of water is stirred for 2 hours at 50 ° C. It is evaporated in vacuo, taken up in water, adjusted to pH 6 with 2N hydrochloric acid and extracted with ethyl acetate The organic phase is shaken with water, dried over sodium sulphate, filtered and evaporated in vacuo, the residue from evaporation is recrystallised from ether

 Yield: 1.7 g (88% of theory), m.p .: 19O-192 ° C

Calc .: C 63.24 H 5.8.7 Cl 9.83 N 7.76 F .: 62.90 '5.81 10.02 7.90

The following compounds were prepared analogously to Example 8:

4 - </ _ (1- (5-chloro-2-dipropylamino-phenyl) -ethyl) -aminocarbonyl- methyl-benzoic acid

Yield: 87.6% of theory, melting point: 2O3-2O5 ° C

Calc .: C 66.25 H 7.01 Cl B, 50 N 6.72 V .: 65.97 6.96 8.52 6.55

^1- JS ¹ - (5-chloro-2-dit) utyl-amino-phenyl) -ethyl) -aminocarbonyl- methyl-benzoic acid _:

Yield: 77.3% of theory,

Melting point: 2OO-2O2 ° C

Calc .: C, 67.47, H, 7.48, Cl, 7.97, N, 6.30, F, 67.45, 7.60, 8.28, 6.44

36 59 7 8

4 - ^ _ (1- (S-chloro-N-cyclohexyl-N-methylamino-phenyl) -ethyl) aminocarbonylmethyl / benzoic acid

Yield: 88.2% of theory, melting point: 198-200 ° C (ether).

5 parts: C 67.20 H 6.81 Cl 8.27 "N 6.53 F: 67.10 6.73 8.16 6.47

4 - / _ (5-chloro-2-pyrrolidino-benzyl) -aminocarbonylmethyl / -benzoic acid

Yield: 84.2% of theory, melting point: 2O8-21O ° C (ethyl acetate). Calc .: C 64.42 H 5.68 Cl 9.51 N 7.51 V .: 64.70 5.68 9.58 7.60

4 ~ l_ { 1- (5-chloro-2-pyrrolidino-phenyl) -ethyl) -aminocarbonyl- methyl / benzoic acid

Yield: 81.1% of theory, melting point: 2O2-2O4 ° C (ethyl acetate). Calc .: C 65.20 H 5.99 Cl 9.17 N 7.24 F .: 65.02 6.12 9.32 7.10

4 - / _ (5-chloro-2-piperidinobenzyl) aminocarbonylmethyl / benzoic acid

Yield: 78% of theory, m.p .: 164-166 ° C.

Calc .: C 65.19 H 5.99 Cl "9.17 N 7.24 V .: 65.50 5.76 9.24 7.36

4- / J 1 - (5-chloro-2-piperidino-benzyl) -aminocarbonyl) -äthyj-Z-benzoic acid

Yield: 81.1% of theory, melting point: 213-216 ° C. (acetone / ether)

Calc .: C 65.90 H 6.29 Cl 8.84 N 6.99 F .: 66.30 6.40 9.00 7.04

4- (1- (5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl- benzoic acid

Yield: 84.9% of theory, melting point: 213-215 ° C (ether)

Calc .: C, 65.91, H, 6.29, Cl, 8.85, N, 6.99, Found: 66.18, 6.19, 8.88, 7.12

4-_J 1- (5-Chloro-2- (3-methyl-piperidino) -phenyl) -ethyl) -aminocar bony! Methyl / benzoic acid

Yield: 69 2 % the Theory, 6 (Ethyl acetate), N 6 75 Melting point: 208-210 ° C 6 , 56 Cl 8,55 6 80 Ber .: C 66 , 57 H , 77 8:58 Gef .: 66 , 36

4 - / (1- (5-chloro-2- (3,5-cis-dimethyl-piperidino) -phenyl) -ethyl) -aminocarbonylmethyl-benzoic acid

Yield: 82.2% of theory, melting point: 212-214 ° C. (ether)

Ber.:- C 67,20 H 6,81 Cl 8,26 N 6,53 Gef .: ⁶⁶ '? ^{5 β '69 8} ' ^{43 β '68}

4 - / _ (1- (5-chloro-2-piperidino-phenyl) -propyl) -aminocarbonyloxyethyl / benzoic acid ..., .. ... ·. ..- .. · ...... -:

Yield: '81, 5% of theory, melting point: 2OO-2O3 ° C (ether)

Calc .: 66.74, 6.35, 8.59, 6.45, C, 66.57, H, 6.56, Cl, 8.55, N, 6.75;

- 69 - 2 3 fi S Q

fe-W LJ vJ _Jf /

4- / 1- (1- (5-chloro-2-piperidino-phenyl) -2-methyl-propyl) -aminocarbonylmethylbenzoic acid

Yield: 82 , 7% of Theory, 27 N 6 , 53 Melting point: 236-240 ⁰ C (ethyl acetate) 14 6 , 39 VJL Ber .: C 67.20 H 6.81 Cl 8, Gef .: 67.19 6.56 8,

4 - / _ (1- (5-chloro-2-morpholino-phenyl) ethyl) aminocarbonylmethyl / -

benzoic acid ;

Yield: 85.6% of theory, melting point: 2O1-2O3 ° C (ether) Calc .: C 62.60 H 5.75 Cl 8.80 N 6.95 F .: 62.30 5.82 8.83 6.85

4- / J 1 - (5-chloro-2-thiomorpholino-phenyl) -ethyl) -aminocarbonyl- methyl / benzoic acid

Yield: 87.6% of theory, melting point: 216-217 ° C (ether) Calc .: C 60.20 H 5.53 Cl 8.46 N 6.69 F .: 59.90 5.51 8.61 6.53

4-__ (1- (5-chloro-2- (hexahydro-1H-azepino) -phenyl) -ethyl) -aminocarbonylmethyl / benzoic acid

Yield: 81.2% of theory, melting point: 2O2-2O4 ° C. (Chloroform / toluene) Calc .: C 66.58 H 6.56 Cl 8.55 N 6.75 V .: 66.60 6.37 8.50 6.59

 - 70

2 ^) < »J

4-yl _ (1- (5-chloro-2-octahydroazocino-phenyl) -ethyl) -arainocarbonyl- methyl / benzoic acid

Yield? 44.4% of theory, melting point: 19 6-197 ° C (chloroform / petroleum ether) 5Ber .: C 67.19 H 6.81 N 6.53 Found: 67.10 6.97 6.37

4- / J1- (5-chloro-2- (octahydro-iH-azonino) -phenyl) -ethyl) -aminocarboxylic- methyl-benzoic acid '

Yield: 74.7% of theory,

10Melting point: 2O4-2O6 ^Ö C (ethyl acetate / petroleum ether) Ber. : C 67,7g "H 7,05 N 6,32 Found: 67,50 7,03 6,04

4-'l-2- (5-chloro-2-piperidino-phenyl) -2-propyl) -aminocarbonyl- methyl / benzoic acid . '

15 Yield: 82.9% of theory, Melting point: 227-229 ° C (acetone) Calc .: C 66.57 H 6.56 Cl 8.55 N 6.75 V: 66.03 6.66 8.67 "6:59

4 -, / _ (ϊ- (5-nitro-2-piperridino-phenyl) -ethyl) - aininpcarbpny line thy 1 / -20 benzoic acid · - · '· ^; - · '- · · -' - - '-. - - ^ v.-r, '-. ... »---, -... -; -. - ·, -: - -

Yield: 9 5.6% of theory, melting point: 252-254 ° C (ether) Calc .: C 64.22 H 6.12 N 10.21

Gef .:. 64,20 6,17 10,12

~ 71 *) ^ C t ^ Q

tea »%«? \ J ttj ^ J

i- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl.Z-benzoic acid

acid

Yield: 85% of theory, melting point: 17O-172 ° C

5 Ber. : C 72 , 11 H 7 15 N 7 , 64 Gef .: 71 , 94 7 , 03 7 72

- (2-piperidino-phenyl) -2-propyl) -aminocarbonylmethyl / -benzoic acid ._

Yield: 72.7% of theory, 10 melting point: 213-215 ° C

Calc .: C 72.61 H 7.42 N 7.36 F .: 72.52 7.31 7.4 5

4- (5-methyl-2-piperidino-benzyl) -aminocarbonyl-methyl-benzoic

acid ; _i ;

15 Yield: 64.6% of theory, melting point: 120-12 2 ° C

Ber .: C 72.11 H 7.15 N 7.64 H 6.76 Cl 8,80 m / e = 366 ) Found .: 72.42 7.38 7.45 6.62 9.40 m / e = 366 6.95 melting point of the hydrochloride: 266 ° C (Dec. 7.00 20 days: C 65.58 N Gef .: 65,00

4 - / - (2-piperidino-anilino) carbonylmethylbenzoic acid χ 0.25 HCl

Yield: 72 5% of the O Theory, 69.11 H melting point : 216-217 C C 69,40 25 Ber .: (χ Ο 25 HCl) Gef .:

6.45 Cl 2.55 N 8.06 6.32 3.08 8.37

4-_ (5-chloro-2-piperidino-anilino) -carbonylmethyl_ / -benzoic acid hydrochloride

Yield: 51.3% of theory, melting point: 232 ° C. (dec.)

Calcd .: C, 58.68, H, 5.42, Cl, 17.32, N, 6.84, Found: 58.26, 5.44, 17.97, 6.74

4-__ 2- (2-piperidino-anilino-carbonyl) -ethyl / benzoic acid semiprene

hydrate . _ _:

Yield: 69.9% of theory,

10. Melting point: 151-1 53 ° C (petroleum ether / acetone) Calc .: (x 0.5 H ₂ O) C 69.78 H 6.97 N 7.75 Found: 69.30 6.82 7, 46

4- (2- (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl) -ethyl- benzoic acid χ 0.2 H ^ O.

Yield: 71.4% of theory,

Melting point: 171-172 ° C (acetone / petroleum ether) Calc .: (x 0.2 H ₂ O) C 71.91 H 7.45 N 7.29 F .: 71.90 7.30 7.03

Example 9

4 - / _ (1- (5-benzyloxy-2-piperidino-phenyl) -ethyl) -amino-carbony-1- methyl-benzoic acid '''''

244 mg (0.487 mmol) of ethyl 4-_ (1- (5-benzyloxy-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-benzoate in 2.5 ml. Ethanol is heated with stirring with 0.73 ml of 1N sodium hydroxide solution in a bath of 50 ° C until (after 3 hours) thin-layer chromatography is no longer detectable ester. Add 0.7 3 ml of 1N hydrochloric acid, evaporate in vacuo and partition between ethyl acetate and water. The organic extract is dried

9 7 8

over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is recrystallized from methanol. Yield: 191 mg (83% of theory), m.p .: 22O-222 ° C Calc .: C 73.71 H 6.83 N 5.93 F .: 73.21 6.67 5.80

The following compounds were obtained analogously to Example 9:

i ~ l_ { 1- (2-hexahydroazepino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid .

Yield: 68.5% of theory, m.p .: 174-176 ° C (ethyl acetate) Calc .: C, 72.61, H, 7.42, N, 7.36, F, 72.36, 7.34, 7.38

4 -, / _ (1- (2- (1,2,3,6-Tetrahydropyridino) phenyl) ethyl) amino, carbonylmethyl / benzoic acid

Yield: 68.2% of theory, melting point: 158-160 ° C (ethyl acetate) Calc .: C 72.51 H 6.64 N 7.69 F .: 72.20 6.66 7.74

4- (2-piperidino-2-phenyl) -ethyl) -aminocarbonyl- methyl / benzoic acid

Yield: 75% of theory, m.p .: 192-195 ° C (ethyl acetate) Calc .: C, 65.91, H, 6.29, Cl, 8.84, N, 6.99, Found: 66.39, 6.17, 8.45 , 78

236597 8

4 - / _ (1- (5-fluoro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl- benzoic acid . ,

Yield: 52.9% of theory, melting point: 174-176 ° C (ethyl acetate) 5Ber .: C 68.73 H 6,55 N 7,29 Gef .: 68,30 6,48 7,45

4 - / (5-methyl-2-piperidino-benzyl) -aminocarbonyl-methyl-benzoic acid .

Yield: 53.9% of theory, m.p .: 12O-122 ° C (ethanol)

Calc .: C 72.11 H 7.15 N 7.64 m / e = 366 GefI: 72.45 7.04 7.64 m / e = 366

4 - / _ (1- (5-cyano-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid ; · '-. "

Yield: 71.6% of theory, - * Melting point: 198-200 ° C (ether) Calc .: C 70.57 H 6.44 N 10.73 Found: 70.17 6.38 11.00

4 - ^ (1- (5-carboxy-2-piperidino-phenyl) -ethyl) -aminocarbonyl-1- methyl-benzoic acid

Prepared from the corresponding diethyl ester by saponification with 2.5 equivalents of sodium hydroxide. Yield: 73.5% of theory, melting point: 26 ° C. (dec.)

Calc .: C, 67.30; H, 6.38; N, 6.82; Found: 67.76, 6.62, 6.85

36 59 / .0

4-_1- (2-__ 1,4-dioxa-8-azaspiro ¼ 4.5 / decan-8-yl / -phenyl) -ethyl) aminocarbonylmethylbenzoic acid semihydrate

Yield: 85.7% of theory, melting point: 13O-135 ° C. (petroleum ether / acetone) calc .: (x 0.5 H 2 O) G 66.49 H 6.74 N 6.46 Gef .: 66.56 6,65 6,46

^ \ _ 2-Hydroxy-1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl -benzoic acid _;

Yield: 65% of theory,

Melting point :. 155-157 ° (dec.) (Petroleum ether / + acetone) Ber- »: m / e = 382 Gef .: m / e = 382

4-__ (1- (5-chloro-2- (2-methyl-piperidine-o-phenyl) -ethyl) -amino- carbony-1-yl-benzoic acid

Yield: 64.1% of theory,

Melting point: 195-198 ° C (ethyl acetate) Calc .: C 66.57 H 6.56 Cl 8.54 N 6.75 V: 66.01 6.25 8.32 6.90

4-__ (1- (5-aminocarbonyl-2-piperidino-phenyl-1-yl) -ethyl) -aminocar bony lme thy!. / Benzoic acid

Yield: 86% of theory, m.p .: 231-235 ° C (ethyl acetate) Calc .: C 67.46 H 6.65 N 10.26 Found: 67.96 6.68 10.11

12 6 5 9 7 ~ B

A ~ l_ { 1- (2- (4-methyl-piperidino) -phenyl) -ethyl) -aminocarbony-1-methyl- benzoic acid

Yield: 67.7% of theory, - - "

Melting point: 1.73-175 ° C (chloroform) 5Ber .: C 72.61 H 7.42 N 7.36 F .: 72.20 7.36 7.45

4 ^^ / j 1- (2-piperidino-phenyl) -ethyl) -N-methylamino-carbonylmethyl - 1- benzoic acid hydrochloride

( ') Transfer of the viscous betaine (72% crude) into the hydrochloride using hydrogen chloride in an isopropanolic solution Yield: 32% of theory, m.p .: 222-23 ° C. (dec) (ethanol) Calc .: C 66.25 H 7 , 01 Cl 8.50 N 6.71 Found .: '66.07 6.96 · 8.37 \ 6.58 *

2- (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-t-benzoic acid

Yield: 7% of theory, m.p .: 135 ° C (dec.) Calcd .: C, 72.10, H, 7.15, N, 7.64; 20Gef .: 72.29, 7.03, 7.37

3 - ^ (1- (-2-piperidino-phenyl) -ethyl) - aminocarbonylmethyl- 1- benzoic acid -.-- ". · ... ............. ·. .. - .. .. .., .. · .. ..., -.-

Yield: 86% of theory,.

, Melting point: 2O5-2O7 ° C

Calc .: C 72.11 H 7,15 N 7,64 F .: 72,30 7,29 7,71

3-chloro-4 -, / J 1 - (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / -benzoic acid _a

Yield: 38% of theory,

Melting point: from 175 ° C sintering, from 190 ° C clear melt Ber .: C Gef.

65 91 H 6 , 29 Cl 8th , 84 N 6 99 65 , 42 6 , 32 9 , 05 6 77

4- (1- (2- (1,2,3,4-Tetrahydro-isoquinolin-2-yl) -phenyl) -ethyl) -aminocarbonylmethyl / benzoic acid

Yield: 59% of theory, melting point: 2O7-2O9 ° C

Calc .: C 75.34 H 6.32 N 6.76 V .: 75.30 6.29 6.67

4 - ^ _ (1- (3-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / -benzoic acid _i __ '

Yield: 33% of theory, melting point: 2O6-2O8 ° C

Calc .: C 72.09 H 7,15 N 7,6 4 Found: 72,04 7,14 7,57

4- / J 1- (6-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl- benzoic acid

Yield: 35% the -Theory, Cl 8 , 84 N 6 , 98 Melting point: 148-1 50 ° C 9 , 63 6 , 84 Re: C 65 91 H 6,28 Gef .: 65 45 6.36

236 5 9 '/

4 - (/ _ {1- (6-Methyl-2-piperidinyl-phenyl) -ethyl) -aminocarbonyl- methyl / benzoic acid

Yield: 33% of theory, melting point: 170 ° C

5Ber .: C 72.60 H 7.41 N 7.36 F .: 72.45 7.34 7.32

4-1-1- (2- (octahydro-isoindol-2-yl) -phenyl) -ethyl) -aminocarbonyl- methyl-benzoic acid

Yield: 64% of theory, melting point: 130 ° C

Ber. C 73.86 H 7.43 N 6.89 F .: 73, SO 1.41-6.72

4-__ (1- (2- (Decahydro-isoquinoline-2-yl) -phenyl) -ethyl) -aminocarbonyl methyl / benzoic acid

Yield: 71% of theory, m.p .: Ber .: C Gef .:

4- / 71- (2- (1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl) phenyl) - ethyl) -aminocarbony .lmethyl / -benzoesä _ι acid semihydrate '

Yield: 99% of theory

Melting point: 70 ^Q C (dec.)

Ber. (x 0.5 'H ₂ O): C 73.05 H 7.30 N 6.54 m / e = 418

Gef .: 73.00 7.16 5.98 m / e = 418

220-221 ° C 7 , 66 N 6 , 66 m / e = 420 , 25 H -7 50 6 , 58 m / e = 420 45

- 79 - 23 6 δ S

4-chloro-1-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid

Yield: 82.1% of theory, melting point: 2OO-2O2 ° C

5Ber .: C 65.91 H 6,29 Cl 8,84 N 6,99 Found: 66,06 6,40. 9.01 '6.93

4- / ti- (4-methyl-2-piperino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid \ _

Yield: 66.5% of theory, melting point: 11O-115 ° C calc .: C 72.60 H 7.42 N 7.36 F .: 72.50. 7.52 7.46

4 - / _ (2-piperidinobenzhydryl) aminocarbonylmethyl / benzoic acid

Yield: 88% of theory, Melting point: 232-234 ⁹ C Calc .: C 75.68 H 6.59 N 6.54 Found .: 75.16 6.52 6.74

4 - / _ (5-chloro-2-piperidinobenzhydryl) aminocarbonylmethyl / '- benzoic acid

" ²⁰ Yield: 78.5% of theory, m.p .: 255-26O ° C

Calc .: C 70.05 H 5.88 Cl 7.66 N 6.05

G .: 70,50 5,76 7,36 6,06

4 - / _ (1- (4-piperidino-phenyl) -ethyl) -aminocarbonylmethyl-1-benzoic acid

Yield: 81% of theory, melting point: 2O8-21O ° C

5s .: C 72.11 H 7,15 N 7,64 F .: 72,24 7,26 7,54

4 -, / _ (1- (2- (4-Methyl-piperazino) -phenyl) -ethyl) -aminocarbonyl- methyj-benzoic acid

Yield: 65 % 1 the theory r 11 , 02 10 Melting point: 69 50-1 53 ° C 10 , 64 Ber.,: C 69 , 27 H 7, 13 N Gef .: , 62 7, 65 ..

4 -, / J 1- (2- (4-benzyl-piperazino) -phenyl) -ethyl) -a'- minocarbonyl-methyl-benzoic acid hydrochloride ;

Yield: 32% of theory, melting points. 1 80? C *. Calc .: C, 68.07, H, 6.53, Cl, 7.18, N, 8.51, Found: 67.85 '. 6.56 7.18 8.51

4-U 1- (2- (4-p-chlorophenyl-piperazino) -phenyl) -ethyl) -aminocarbonylmethyl / ^ -benzoic acid , - ^ y ^ y. * - ^^^ -: - <ά > ,,. · · · · ,. , _; , v ^. ", .... - ..

Yield ": 75% of theory, melting point: 212 ° C (dec.) Calc .: C 67.84 H 5.90 Cl 7.42" N 8.79 F .: 67.74 6.22 7.59 ^Ί 8.82

-si - -π

4 - / _ ( K-cyclohexyl-2-piperidinobenzyl) aminocarbonylmethyl

benzoic acid ,

Yield: 33% of theory, melting point: 199-2O2 ° C Calc .: C 74.62 H 7.89 N 6.45 V .: 74.60 7.54 6.66

(-κ) -4-__ (1- (2-piperidino-phenyl) -ethyl) -aminacarbonylmethyl / -benzoic acid χ 0.3 H O _________ "__

Yield: 40 % of theory,

Melting point: 107 ° C (dec.) (Isopropanol / ether) ZÄ7n ° ⁼ + 7.3 ° '(C = ¹ l; methanol)

Calc .: (x 0.3 H ₃ O) C 71.02 H 7.25 N 7.52 m / e = Gef .: 70.90 7.22 7.42 m / e =

(-) - 4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid sodium salt

Crude yield of betaine: 77% of theory, ref .: m / e = 366 Gef .: m / e = 366

conversion into the sodium salt by means of 1 equivalent of sodium hydroxide solution in ethanol.

Melting point of the sodium salt: 190 (dec.)

4- / J 1 - (2-piperidino-phenyl) -äthenyl) -aminocarbonylmethyl / - benzoic acid

Yield: 53.6% of theory, m.p .: 158-160 ° C (ethanol)

Calc .: C 72.51 H 6.64 N 7.69 F .: 72.40 6.34 7.51

23b b37

4- ^ J 1- (5-chloro-2-piperidino-phenyl) -äthenyl) -aminocarbonyl methyl / L-benzoic acid

Yield: 78.7% of theory, m.p .: 198-200 ° C (acetone)

5Ber .: C 66.24 H 5.81 Cl 8.88 N 7.02 Gef .: 65.74 5.72 9.37 7.10

4 = - ^ _ (^, - Cyclohexylidene-2-piperidino-benzyl) -aminocarbonylmethyV · benzoic acid

Yield: 21% of theory, m.p .: 213-216 ° C

Calc .: C 74.97 H 7.46 N 6.48 F .: 74.73 7.52 6.48

4 -, / JI- (6-chloro-2-piperidino-phenyl) -äthenyl) -aminocarbonyl- methyl-7-benzoic acid _;

15 Yield: 39% of theory, melting point: 162 ° C

Calc .: C 66.24 H 5.81 Cl 8.88 N 7.02 m / e = 398/400 V: 66.48 5.84 8.88 6.85 m / e = 398/400

- 4 - (/ JI- (6-methyl-2-piperidino-phenyl) -äthenyl) -aminocarbonyl-

methyiy-benzoic acid, ...... ..... '. " , ... .., ...

Yield: 49% of theory, melting point: 128-130 ° C Calc .: m / e = 378 F: m / e = 378

4- ^ J 1- (2-piperidino-phenyl) -propenyl) -aminocarbonylmethyl / benzoic acid .

Yield: 65% of theory, m.p .: 185-187 ° C (ethyl acetate)

236 59

Calc .: C 72.99 H 6.92 N 7.40

Gef .: 73.10 6.99 7.56

4-__ (1- (5-Hydroxy-2-piperidino-phenyl) -ethyl) -aminocarbonyl- methyl / -benzoic acid semihydrate

Saponification with 2.5 equivalents of sodium hydroxide. Yield: 55.9% of theory, foam (from ether)

Calc .: (x 0.5 H ₃ O) C 67.50 H 6.95 N 7.16 Gef .:. 67.11 7.15 6.87

4-_1- (2- (2-methyl-pyrrolidino) -phenyl) -ethyl) -aminocarbonyl-methyl- benzoic acid

Yield: 62% of theory, melting point: 169-172 ° C

Calc .: C 72.11 H '7.15 N 7.64 F .: 71.96 6.82 7.51

4-__ <1- (5-aminosulfonyl-2-piperidino-phenyl) -ethyl) -, aminocarbonylmethyl / benzoic acid

Yield: 19.2% of theory, melting point: 21O ° C (dec.) Calc .: C 59.30 H 6.11 N 9.43 m / e = Gef .: 58.80 5.87 9.06 m / e =

4-___ (1- (2-piperidino-phenyl) -propyl) -aminocarbonyl-methyl-benzoic acid

acid

Yield: 71.4% of theory, m.p .: 208-210 ° C (ethanol) Calc .: C, 72.61, H, 7.42; N, 7.36, Found: 72.30, 7.44, 7.45

236 59 7 8

Example 10

4- / J 1 - (2-piperidino-phenyl) -ethyl) -aminocarbonylmethylZ-benzoic acid

A solution of 13.5 g (0.338 mol) is added to 88.8 g (0.225 mol) of ethyl 4- (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl-1-benzoate in 890 ml of ethanol. Sodium hydroxide in 50 ml of water and stirred at an internal temperature of 60 ° C until thin-layer chromatography no more starting material is detectable (about 45 minutes). 400 ml of water are then added and the mixture is adjusted to pH = 5.8 with half-concentrated hydrochloric acid under pH-metric control at <25 ° C. After a short time, crystallization starts. After standing overnight at 20 ° C is filtered off, ® the crystals washed several times with water, the crystals are dissolved in methylene chloride and separated from the aqueous phase. The

The solution is dried over sodium sulphate, filtered, and evaporated in vacuo to give 57.5 g of solid evaporation residue.

The ethanol-hydrochloric acid filtrate (pH = .5,8) is adjusted to pH = 5.0 with half-concentrated hydrochloric acid, then distilled

The ethanol in vacuum largely off and cools the concentrated solution in ice. The resulting precipitate is filtered off, dissolved in methylene chloride, separated from the aqueous phase, the methylene chloride solution is dried, filtered and evaporated in vacuo. The solid evaporation residue is ..

2513.0 g. The two evaporation residues (together 70.5 g) are recrystallized from 5 to 6 times the amount of ethanol / water (80/20) with addition of activated charcoal

 Yield: 62% of theory, melting point: 163-164 ° C

Calc .: * C 72.11 H 7,15 N 7,64 F .: 72,13 7,25 7,75

If, after completion of the saponification, after addition of water and cooling to 25 ° C., the pH is equal to 5.0, the result obtained is as described above, but without working up the ethereal solution.

JU J j / Ö

nolic-hydrochloric filtrate - 75.9% dried evaporation residue, which provides a proper elemental analysis even before the final recrystallization.

 Melting point: 172-176 ° C

 Calc .: C 72.11 H 7.15 N 7.64 F .: 71.90 7.08 7.52

The following compounds were obtained analogously to Example 10:

4-p-jl- (5-methyl-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl- benzoic acid

Yield: 56.6% of theory,

Melting point: 215-217 ° C (ethanol) Calc .: C 72.61 H 7.42 N 7.36 F .: 72.71 7.49 7.25

4- (C 1 -C 4 -carboxy-2-piperidinobenzyl) aminocarbonylmethylbenzoic acid χ 0.66 Η _; 0

Prepared by saponification of the 4- ((3-methoxycarbonyl-2-piperidino-benzyl) -aminocarbonylmethyl / benzoic acid ethyl ester with 2.5 equivalents of sodium hydroxide

 Yield: 72.2% of theory,

Melting point: 235-24O ° C (dec.) (Methanol / chloroform) Calc .: (x 0.66H ₃ O) C 64.69 H 6.33 N 6.85 Found: 64.64 6.23 6 , 61

Example 11

A-l-1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / L-benzoic acid sodium salt monohydrate

The mixture is stirred 500 mg (1.26 mmol) 4- / J2-piperidino-phenyl) -ethyl) -aminocarbonylmethyiy-benzoic acid ethyl ester in 5 ml of ethanol together with 1.26 ml of 1N sodium hydroxide solution for 1 hour at 50 ° C. Then cool

It is on ^{0 0} C, filtered from the precipitated crystals and washed with cold ethanol and ether. Yield: 238 mg (48.6% of theory), m.p .: 245-25 ° C '

Ber. (x 1 H-O): C 65.01 H 6/69 N 6.89 Cf. 65.40 6.83 6.72

The following compound was obtained analogously to Example 11:

4 - / _ (1- (5-methoxy-2-piperidino-phenyl) -ethyl) -aminocarbonyl-

methyiy-benzoic acid sodium salt monohydrate

Yield: 17.5% of theory, melting point: 212-215 ° C

Ber. (x 1 H ₂ O): C 63.28 H 6.70 N 6.42 V .: 63.20 6.82 6.51

From this sodium salt is obtained analogously to Example 9, the corresponding acid as a monohydrate:

Melting point: 187-89 ° C (ethanol / water) Ber. (x 1 H ₂ O): C 66.40 H 7,29 N 6,76 Vessel: 66,87 6,97 6,80

Example 12

4- (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-benzoic acid sodium salt χ 0.6 H _? 0 .. ..... .

Dissolve 8.4 gi (0.0229 mol) of 4- (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethylZ-benzoic acid at 60 to 65 ° C in 80 ml of ethanol, added with stirring 22.9 ml 1N sodium hydroxide solution and stirred for 30 minutes. Then allowed to cool to 20 C, wherein a precipitate fails. It is cooled to 0 ° C, filtered and the precipitate is washed with cold ethanol and ether. The resulting precipitate of enamel; Ethanol / water (7/3) around.

Precipitate of melting point 250-251 ° C mashed out

236697 8 ~

Yield: 7.2 g (78.6% of theory) Melting point: 253-255 ° C

Ber. (x 0.6 K ₂ O): C 66.18 H 6.61 N 7.02

Gef.: 66.10 6.64 7.13

Example 13

4 - (/ _ {1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-1-benzoic acid

100 mg (0.237 mmol) of tert-butyl 4- / (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / benzoate in 5 ml of benzene together with a few crystals of p-toluenesulphonic acid hydrate are refluxed for half a day , Then, according to thin-layer chromatogram, no starting product is left, but instead the desired product has formed according to R _f value and mass spectrum.

Melting point: 16.3-1 65 ° C Calc .: m / e = 366 Gef .: m / e = 366

Example 14

4- / J 1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / '- benzoin-

acid

Hydrogenated 0.4 6 g (1 mmol) of benzyl 4 - / (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethylbenzoate in 20 ml of ethanol over 0.25 g of pallaidum / carbon (10% strength by weight) at 50 ° C and 5 bar hydrogen pressure. After 5 hours, the catalyst is filtered through Celite and evaporated in vacuo. The evaporation residue is crystallized from ethanol / water (8/2).

Yield: 0.26 g (71% of theory), m.p .: 163-165 ° C

C 72, 11 H 7 - 88 - 7, 7 1 72 30 7 , 15 N 7, Ber. : 25 64 Gef .: 81 Example 15

4-_J 1 - (5-Chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid

In a stirred solution of 3.57 g (0.01 mol) of Ν- / Ί- (5-chloro-2-piperidino-phenyl) -äthy _ / - N-_phenacety_V-ainine in 16 ml of carbon disulfide at 0 to 5 ° C. 2.54 g (0.02 mol) of oxalyl chloride were added dropwise, followed by the introduction of 2.67 g (0.02 mol) of aluminum chloric acid. After one hour, the same quantities of oxalyl chloride and aluminum chloride are added, and the mixture is heated for 3 hours at 50 ° C. It is cooled, mixed with ice-water and hydrochloric acid, and extracted with chloroform.The organic extract is dried, filtered, and concentrated by evaporation Vacuum and the evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 10/1). Yield: 0.60 g (15% of theory), m.p .: 213-214 ° C (ether) calc .: C, 65.91, H, 6.29, Cl, 8.85, N, 6.99, found: 66.13 6, 05 8.97 7.25

Example 16

N- _/ 4-acetyl-phenoxy-JL / -N -, _ 1- (5-chloro-2-piperidino-phenyl) ethyl-7'-amine '' -. '- -''' '' - '''' * '- - - ^":" ________

To 1.12 g (8.43 mmol) of aluminum chloride in 10 ml of methylene chloride are added at an internal temperature of 0 to 5 C, the solution of 0.6 ml (8.43 mmol) of acetyl chloride in 5 ml of methylene chloride. The solution of 1 g (2.81 mmol) of N-_J- (5-chloro-2-piperidino-phenyl) ~ ethyl-N-N-phenacetyl / - min in 5 ml of methylene chloride is then added dropwise with stirring at 0 to 5 C to. One stirs one

J /

Hour at 3 ° C and 2 days at 20 ° C. It is decomposed with cooling with ice water and hydrochloric acid, the methylene chloride phase is separated off and extracted with chloroform. The combined organic phases are dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 4/1). Yield: 0.28 g (25% of theory), Melting point: 160-161 ⁰ C.

Ber. C 69.24 H 6.82 Cl 8.89 N 7.02 m / e = 398/400 V: 69.55 6.99 9.45 6.85 m / e = 398/400

Example 17

4- ^ Λ (1- (5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid

To a stirred sodium hypobromite solution prepared from 1.84 g (0.046 mol) of sodium hydroxide dissolved in 9 ml of water and 0.72 ml (0.014 mol) of bromine under ice-cooling. Is added dropwise within 15 minutes at 35-4O ° C, the solution of 1.23 g (0.0031 mol) of N- / T-acetyl-phenacetyl-7-N- / T- (5-chloro-2-piperidino-phenyl) - ethyl / amine in 12 ml dioxane. After 40 minutes at 35-4O ° C are added aqueous sodium bisulfite solution and water and evaporated • the mixture in vacuo. The residue is dissolved in water, acidified under cooling with 2N hydrochloric acid and extracted with ether / ethyl acetate. The organic phase is dried, filtered and evaporated in vacuo. The evaporation residue is crystallized from ether.

Yield: 0.14 g (11% of theory), m.p .: 213-215 ° C Calc .: C, 65.91, H, 6.29, Cl, 8.85, Found: 65.78, 5.98, 8.95

6 / 9.9 7.17

TTT ^ S

The following compound was obtained analogously to Example 17:

4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid

Yield: 15% of theory, Melting point: 170-171 ⁰ C Calc .: C 72.11 H 7.15 N 7.64 Found .: 72.45 7.01 7.48

Example 18

4 -__ (1- (2-piperidino-phenyl) ethyl) aminocarbonylmethyl / benz aldehyde

Prepared from 4 -_ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl ". Methylp-benzyl alcohol by oxidation with active manganese dioxide in absolute acetone and subsequent purification by column chromatography on silica gel (chloroform / acetone = 20/1). Yield: 4% of theory, melting point: 159 ° C

Ber. : C 75 40 H 7 48 N 7 99 Gef .: 75 , 05 7 , 18 7 , 67 example 19

4 - / _ (1- (2-Piperidiho-phenyl) ethyl) aminocarbonylmethyl / <- benzoic acid: '

Prepared from 4 - / (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethoxy / -benzaldehyde by heating with silver oxide in the presence of 1N sodium hydroxide solution for 20 minutes on the steam bath, then acidifying with 2N Sulfuric acid at pH = 5, extraction with ethyl acetate and purification by column chromatography on silica gel (toluene / acetone = 1/1).

7 8

Yield: 3% of theory, melting point: 168-170 ° C Calc .: m / e = 366 F: m / e = 366

Example -20

4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-benzoic acid ethyl ester -

Hydrogenated 5.5 g (0.014 mol) of 4- / Ji- (2-piperidino-phenyl) -äthenyl) -aminocarbonylmethyl / benzoic acid ethyl ester in * 110 ml

1 ° ethanol on 1.5 "g of palladium / carbon (10%) at 20 ° C. and 5 bar of hydrogen After 30 minutes, the mixture is filtered off from the catalyst over Celite and the filtrate is evaporated off in vacuo Yield: 4.7 g (85.5% of theory), m.p .: 152-154 ° C (ethanol / petroleum ether) Calc .: C, 73.07, H, 7.66, N, 7.10, F, 72.80, 7.63, 7.08

The following compound was obtained analogously to Example 20:

4 -, / J- (2-piperidino-phenyl) -propyl) -aminocarbonylmethyl / -benzoic acid ethyl ester

Yield: .70.8% of theory,

Melting point: 1 3 2-1 34 ° C (Ether) 86 Re: C 73 50 H 7 90 N 6, 77 Gef .: 73 , 71 7 , 88 6

⁹² : 236 59 7 8

Example 21

4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid; _:

Hydrogenated 100 mg (0.2744 mmol) of 4- / di- (2-piperidino-phenyl) -äthenyl) -aminocarbonylmethyl / benzoic acid in 5 ml of absolute ethanol to 50 mg of palladium / carbon (10%) at 20 ° C. and 1 bar. • Hydrogen with shaking. After 1.5 hours, filtered and evaporated in vacuo. ,

__ Yield: 91% of theory, -

^v - .- 10 melting point: 17O-171 ° C

Ber. : m / e = 366 Gef .: m / e = 366 example 22

4 - / __ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid semihydrate ^; '''·' - ^: - '- - · · - ·' ·

Hydrogenated 200 mg (0.5014 mmol) 4- / 71- (5-chloro-2-piperidinophenyl) -äthenyl) -aminocarbonylniethyl / benzoic acid in 10 ml of absolute ethanol to 100 mg of palladium / carbon (10%) at 50 C and 1 bar of hydrogen with shaking. After 5 hours, the mixture is filtered, 5.5 ml of water are added, and the pH is adjusted to 6 with 1N-N-nitronate, and the mixture is evaporated off in vacuo from ethanol. It's falling.

a colorless precipitate: _v , which can be filtered off after cooling.

Yield: 100 mg (53.1% of theory), m.p .: 135 ° C

Ber. (x 0.5 H ₂ O): C Gef.

70 , 36 H , 7 24 N 7 , 46 m / e = 366 70 , 31 7 , 44 7 , 78 m / e = 366

~ ^ ~ 9T ~ - / 1 hh Q 7

Example 23

4-J1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl. -Benzoic acid ether

To a mixture of 2 g (9.74 mmol) of 1- (2-piperidino-phenyl) -ethanol and 4 g (21.1 mmol) of 4-cyanomethyl-benzoic acid ethyl ester is added with stirring and cooling with ice 1.6 ml conc. Sulfuric acid in small drops so that the internal temperature does not exceed 3 5 to 40 ° C. The mixture is then heated for 2.5 hours in the bath of 80 ° C, then more 2g (10.5 mmol) of ethyl 4-cyanomethylbenzoate and 0.8 ml of conc. Sulfuric acid and heated for a further hour at 80 ° C and 3 hours at 100 C. Then, no starting alcohol can be detected by thin-layer chromatography

 After cooling to 20 ° C is covered with ethyl acetate and

Ί5 is added with stirring and cooling ice water. It is extracted several times with ethyl acetate, the organic extract is dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/1). From the prefractions is isolated 0, -5 g of 2-piperidino-styrene.

Yield: 0.66 g (17.4% of theory), m.p .: 147-15O ° C (ethanol) Calc .: C, 73.07, H, 7.66, N, 7.10, F .: 73.26, 7.55 90

Example 24

4 -, / J 1- (5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbony-1-methyl- benzoic acid

To a stirred solution of 1 g (5.55 mmol) of 4-carboxyphenylacetic acid and 1.32 g (5.55 mmol) of 1- (5-chloro-2-piperidino-O-phenyl) -ethylamine in 10 mL absolute pyridine is added dropwise 0.4 ml (5.55 mmol) of thionyl chloride, the internal temperature of 20 C

rises to 35C. The deep brown reaction mixture is stirred for another 3 hours at 20 ° C and then evaporated in vacuo. The evaporation residue is partitioned between water (at pH = 3 after addition of 2N hydrochloric acid) and chloroform. The organic extract is dried, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 10/1). Yield: 1.06 g (48% of theory), m.p .: 212-214 ° C (ether)

Re: C 65.91 H 6.29 Cl 8.85 N 6.99 F .: 65.79 6.01 8.69 6.87

The following compounds were obtained analogously to Example 24:

4- / J1 (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyj./-benzoesäure · \

15 Yield: 52% of theory, melting point: 169-171 ° C. Calc .: C 72.11 H 7.15 N 7.64 F .: 71.84 6.87 7.72

4- / J 1 - (2- (4-oxo-piperidino) -phenyl) -ethyl) -aminocarbonyl-methyl- benzoic acid _t

Yield: 32% of theory,

Melting point: 177-180 ° C (dec.) (Acetone / petroleum ether)

Calc .: C 69.46 H 6.36 N 7.36

G .: 69.62 6,41 7,50

AM 1- (2- (4-hydroxy-piperidino) -phenyl) -ethyl) -aminocarbonyl- methyl / benzoic acid χ 0.6 6 H 2 O ',

Yield: 23.5% of theory,

Melting point: 17 6-179 ° C (dec.) (Acetone / petroleum ether) Ber. (x 0.66 H ₂ O): C 66.97 H 6.81 N 7.10 30Gef. : 67.12 6.78 7.26

4-_1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethy / benzo- nitrile . '

Made with 4-cyano-phenylacetic acid. Yield: 51% of theory, m.p .: 155-157 ° C (ethyl acetate) Calc .: C 76.05 H 7,25 N 12,09 Found: 76,41 7,10 12,20

Example 25

A-IS 1 - (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / benzyl alcohol

Prepared from 4 - / (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / -benzoic acid ethyl ester by lithium aluminum hydride reduction in. Tetrahydrofuran

 Yield: 39% of theory, melting point 15: 1O4-1O6 ° C.

Calc .: C 74.96 H 8,00 N 7,94 F .: 74,80 7,80 7,80

Example 26

4 -_ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / benzyl malonic acid diethyl ester

To a solution of sodium malonic acid diethyl ester / prepares from 0.7 g (30 mmol) of sodium in 25 ml of absolute ethanol and 4.8 g (30 mmol) of malonic acid diäthyles'ter / is added dropwise a solution of 3.7 g ( 10 mmol) 4-_ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / -benzyl chloride / m.p .: 123-125 ° C; prepared from the alcohol described in Example 25 using thionyl chloride in chloroform / in 35 ml of absolute ethanol. You bet

236 59 7 8

added a catalytic amount of potassium iodide and heated to reflux for 16 hours. Then concentrated in vacuo, neutralized with hydrochloric acid and extracted with methylene chloride. The organic extract is dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 6/1). Yield: 3.0 g (60% of theory), m.p .: K 20 ° C calc .: m / e = 494 10Gef. : m / e = 494

Example 27

3- / 4 - / (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -phenyl / -propionic acid . ,

To a solution of 0.85 g {1.7 mmol) of 4 - / (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / benzylmalonic acid diethyl ester in 18 ml of ethanol are added 5 ml of 1N sodium hydroxide solution and stirred 2 hours at 50 C, then concentrated in vacuo, water and 5 ml of 1N hydrochloric acid to. The precipitate formed is filtered off, dried in vacuo and then heated for 30 minutes at 120 C, with splits off carbon dioxide. It is then purified by column chromatography on silica gel (chloroform / methanol = 20/1).

Yield; 0.15 g (22.4% of theory), mp: 68-70 ° C

 Re: C Gef.:

73 , 06 H 7 , 67 N 7 10 m / e = 394 72 , 64 7 , 42 6 , 81 m / e = 394

- 97 Example 28

4 - ^ / _ (1 - (2-piperidino-phenyl) -ethyl) - aminocarbony lmethy__7-benz aldehyde

Prepared by heating crude N - / 1 "- / ti- (2-piperidinophenyl) ethyl) -aminocarbony lmethy_L / benzoyl-7-N-tosyl hydrazine / Prepared from 4- / 1- (2-piperidino-phenyl) - ethyl) aminocarbonylmethyl / benzoic acid and tosylhydrazine with carbonyldiimidazole in tetrahydrofuran ^ with anhydrous sodium carbonate at 16O-17O ° C in ethylene glycol

 Yield: 10% of theory, melting point: 159 ° C

Calc .: C, 75.40, H, 7.48, N, 7.99, F .: 74.99, 7.24, 7.60

Example-29

4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethylj-benzoic acid

Hydrogenated 0.50 g (1.247 mmol) of 4- (7-chloro-2-piperidinophenyl) -ethyl) -aminocarbonylmethy / benzoic acid in 20 ml of absolute ethanol over 0.25 g of palladium / carbon (10%) at 50 ° C and 5 bar hydrogen pressure. After 2 hours, the catalyst is filtered through Celite and evaporated in vacuo. The evaporation residue is distributed at pH = 6 between water and ethyl acetate. The organic extract is washed with water, dried and filtered and evaporated in vacuo. Yield: 0.31 g (67% of theory), m.p .: 170-172 ° C (ether) Calc .: C, 72.11, H, 7.15, N, 7.64, F, 71.76, 6.98, 7.51

<κ η U / 5 * J KJ -J Ό ί C

The following compounds were prepared analogously to Example 29

4 - ^ (2- (2-piperidino-phenyl) -2-propyl) -aminocarbonyimethyl / -benzoic acid

Yield: 68.5% of theory, melting point: 213-215 ° C

Calc .: C 72.61 H 7.42 N 7.36 F .: 72.43 7.25 7.40

4 - / _ (1- (2-dimethylamino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid

1.0 Yield: 53.3% of theory,

Melting point: 165-168 ° C (acetone / petroleum ether) Calc .: C 69.92 H 6.79 N 8.59 Gef .:. 69.88 6,83 8,49

4-Z- (2-pyrrolidino-benzyl) aminocarbonylmethyl / benzoic acid

Yield: 55% of theory,

Melting point: 212-215 ° C (methanol) Calc .: C 70.99 H 6.55 N 8.28 Found: .70.97 6.91 8.15

4- / J 1- (2-pyrrolidino-phenyl) -ethyl) -aminocarbonylmethyl_ / -ben. acid

Yield: 25% of theory, Melting point: '155-157 ⁰ C (acetone / ether) Calc .: C 71.57 H 6.86 N 7.95 Found .: 71.22 6.75 8.42

9 7 8

4 - / _ (2-piperidinobenzyl) aminocarbonylmethyl / benzoic acid

Yield: 60.4% of theory, m.p .: 175-177 ° C (acetone) Ber. : C 71.57 H 6.86 N 7.95 5 parts: 71.48 7.00 8.09

4 - / _ (2- (2-piperidiho-phenyl) -ethyl) -aminocarbony lme thy / benzoic acid

Yield: 60.4% of theory, m.p .: 164-166 ° C (ethyl acetate) 10 bp .: "C 72.11 H 7.15 N 7.64" "Gef .: 72.35 7.18 7.76

4- (1- (2- (2-Methyl-piperidino) -phenyl) -ethyl) -aminocarbonyl-1-methyl- benzoic acid

Yield: 90.9% of theory, 'Melting point: 171-173 ° C (petroleum ether / acetone) Calc .: C 72.61 H 7.42 N 7.36 F .: 72.30 7.39 7.43

4 - / _ (1- (2- (3-Methyl-piperidino) -phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid

Yield: 86.3% of theory, m.p .: 17O-17 3 ° C (petroleum ether / acetone) Calc .: C, 72.61, H, 7.42, N, 7.36, F: 72.20, 7.28, 7.12

4 - / _ (1- (2-dipropylamino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid

Yield: 51.1% of theory, m.p .: 175-178 ° C (ethyl acetate)

⁹ H - 100 -

236597 R

* "" Ww W * J / Q

Ber. C 72.22 H 7.91 N 7.32

Gef .: 72.10 8.05 7.69

4 - / _ (1 - {2-piperidino-phenyl) -2-methyl-propyl) -aminocarbonyl-methyl- benzoic acid

Yield: 68% of theory, m.p .: 215-217 ° C (acetone) calc .: C, 73.06, H, 7.67, N, 7.10, viz., 73.10, 7.55, 6.99

4 - / (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl methyl / benzoic acid methyl ester

Prepared from 4 - / (1- (5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl-V-benzoic acid methyl ester. Yield: 37.2% of theory, melting point: 145-147 ° C

Calc .: C 72.61 H 7.42 N 7.36 '* F .: 72.47 7.30 7.56

4- £ J2-piperidino-anilino) -carbonylmethylZ-benzoic acid-methyl-

ester

Prepared from 4- (5-chloro-2-piperidino-anilino) -carbonylmethyl-benzoic acid methyl ester. Yield: 60% of theory, melting point: 85-86 ° C (toluene / petroleum ether) Calc .: C 71.57 H 6.86 N 7.9 6 Found: 71.48 6.92 8.39

N-phenacetyl-N-ZJ- (2-piperidino-phenyl) -äthyiy-amine

Prepared from N- £ J- (5-chloro-2-piperidino-phenyl) -ethyl _ / - N-phenacetyl-amine.

Yield: 54.6% of theory,

Melting point: 120-121 ° C (petroleum ether / acetone)

236b97 8

Calc .: C 78.22 H 8,13 N 8,69 F .: 77,90 8,24 8,75

Example 30

4 - / _ (1- (5-amino-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid methyl ester

Hydrogenated 2.0 g (0.0047 mol) of 4 - / (1- (5-nitro-2-piperidinophenyl) ethyl) aminocarbonylmethyl-benzoic acid methyl ester in 20 ml of dimethylformamide on 0.2 g of palladium / carbon (10 %) in a Parr apparatus at 20 C and 1 bar hydrogen pressure. After the end of the hydrogen uptake (2 hours), the catalyst is filtered through Celite and evaporated to dryness in vacuo. Yield: 1.8 g (95% of theory), m.p .: 14O-142 ° C (toluene)

The following compounds were prepared analogously to Example 30:

4- / J1- (5-amino-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / - benzoic acid ethyl ester

Yield: 97.8% of theory, m.p. 148-1 49.5 ° C (cyclohexane) Calc .: C 70.39 H 7.63 N 10.26 Found: 70.20 7.67 '9.60

4- / J 1- (5-amino-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid

Prepared from 4- (1- (5-nitro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethy1 / benzoic acid.

Yield: 85.7% of theory, m.p .: 223-225 ° C (ether) Ber. : C 69.27 H 7,13 H 11,02 F: 69,18 7,04 11,35

N- / 4-amino-phenacetyl / -N - / _ 1- (2-piperidino-phenyl) -ethyl-amine dihydrochloride-semicl hydrate

Prepared from N- 4-nitro-phenacetyl-N- / - (2-piperidinophenyl) -ethyl-amine. Transfer of the crude amino compound i dihydrochloride in ethanol by means of ethereal hydrochloric acid. O 10 Yield: 17.5% of theory, melting point: 238 ° C. (dec.)

Ber. (x 2 HCl χ ο, 5H ₂ O ): C 60 12 H 7 , 21 Cl 1 6 91 Gef .: 60 52 7 , 52 1 7 , 05 example 31 -

15. 4 - / _ (1-, (5-bromo-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl, benzoic acid ,, · _; ;

To 0.40 g (1.05 mmol) of 4 - / _ ( 1- (5-amino-2-piperidino-phenyl) ethyl) -aminocarbonylmethyiy-benzoic acid in 2 ml of half-concentrated aqueous hydrobromic acid is added dropwise at an internal temperature of 0 to 5 The solution of 0.072 g (1.05 mM sodium nitrite in 0.5, ml water.) The diazonium salt solution thus obtained is then added dropwise to 0.196 g of copper (I) bromide in 2 ml of 48% hydrobromic acid, with vigorous evolution of gas The mixture is stirred for a further 1.5 hours at an internal temperature of 45-50 ° C., cooled and adjusted to pH 4 with 4N sodium hydroxide solution, extracted with warm ethyl acetate, washed with water, dried and filtered Vacuum is purified, the residue obtained by Säulenchromatograplan silica gel (chloroform / methanol = 7/1).

i h * -) Μ / η

<± JS _x J * eJ <* J f \ J

Yield: 0.08 g (17% of theory), m.p .: 212-213 ° C (ethyl acetate / petroleum ether) Ber. C 59.32 H 5.66 Br 17.94 N 6.29 F .: 59.30 5.71 x 17.85 6.48

The following compound was prepared analogously to Example 31:

4 - / (1- (5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid

Prepared by diazotization of 4 - ^ (1- (5-amino-2-piperidinophenyl) ethyl) aminocarbonylmethyl / benzoic acid in conc. HCl and Sandmeyer reaction with copper (I) chloride. Yield: 25.2% of theory, m.p .: 213-215 ° C

Ber. : C 65 91 H 6 29 Cl 8th 85 N 6 99 Gef .: 66 20 6 31 8th , 87 6 , 82

If the reaction is carried out in hydrochloric acid without copper (I) chloride, the yield is 19% of theory. In addition, 9% of the corresponding 5-hydroxy compound is formed.

Example 32

4 - / _ (1- (5-iodo-2-piperidino-phenyl) -ethyl) -aminocarbonylmethy1 / - benzoic acid ethyl ester

To 1.0 g (2.44 mmol.) A - / { 1- (5-amino-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-benzoic acid ethyl ester in 1.9 ml of half-concentrated hydroiodic acid is added dropwise with stirring slowly at 0 to 5 C, the solution of 0.17 g (2.44 mmol) of sodium nitrite in 0.52 ml of water and then allowed to warm to 20 ⁰ C within one hour. It is then heated for 2 hours at 100 ° C. After cooling, the mixture is extracted with ethyl acetate, the organic phase is washed with dilute sodium bicarbonate solution and then with water, dried over sodium sulphate, filtered and evaporated in vacuo.

Matography on silica gel (toluene / acetone = 5/1). Yield: 0.011 g (0.93% of theory) Melting point: 145-147 ° C (ether)

Calc .: C 55.39 H. 5.62 N 5.38 m / e = 520

5gf .: 55,95 5,53 5,05 m / e = 520

Example 33

A- (J ₁ 1- (5-Cyanc-2-piperidino-phenyl) -ethyl.) -Aminocarbony methyl / - benzoic acid ester äthy '!

To 2.0 g (4.88 mmol) of ethyl 4- ( 1- { 5-amino-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl-benzoate in 4.0 ml of water + 3.5 ml of concentrated Hydrochloric acid is added dropwise with stirring at -5 to 0 ^ C, the solution of 0.34 g (4.88 mmol) of sodium nitrite in 2.3 ml of water. It is stirred for 15 minutes and then neutralized with 1.1 g of calcium carbonate. The resulting suspension is rinsed with the aid of 2 × 15 ml of water into a 0 ⁰ C cold solution, consisting of 0.568 g (6.34 mmol) of copper (I) cyanide, 1.24 g (19 mmol) of potassium cyanide and 5.8 ml of water has prepared / It immediately precipitates a red-colored precipitate. With stirring, the reaction mixture is heated for 30 minutes at an internal temperature of 4 5 C, then 30 minutes at 70 ° C and 60 minutes at 9 5 ° C. In Dünnschichchromatogramin missing now the red-colored spot, which was previously present. It is cooled to 20 C and extracted with ethyl acetate. The organic extract is dried over sodium sulfate, filtered and evaporated in vacuo. The Sindampfrückstand purified by two column chromatograms on gravel silica gel ((a) toluene / acetone = 10/1, (b) methylene chloride / acetonitrile / glacial acetic acid = 10/1 / 0.05). In addition to the corresponding 5-C1 and 5-H compounds, the desired 5-cyano compound is obtained.

Yield: 0.186 g (9% of theory), m.p .: 16 5-167 ° C (ether)

Calc .: C 71.58 H 6.97 N 10.02 m / e = 419 V: 71.64 6.94 '9.72 m / e = 419

236b9T

Example 34

4- (1- (5-Aminosulfonyl-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl- 7-benzoic acid ethyl ester ...

a) To a suspension of 2.0 g (4.88 mmol) of ethyl 4 - </ _ (1- (5-amino-2-piperidino-phenyl-aminocarbonyl-methyl / benzoate) in 2.02 ml of half-concentrated Hydrochloric acid is added dropwise

with stirring at 4 to 6 ° C, the solution of 0.37 g (5.36 mmol) of sodium nitrite in 0.7 ml of water. Subsequently, 0.37 g (3.89 mmol) of magnesium chloride are added. The mixture thus obtained

Is then added dropwise at 30 ⁰ C to a solution which has been prepared from 4.9 ml of glacial acetic acid (saturated with sulfur dioxide) and 0.27 g of copper (II) chloride dihydrate. The internal temperature rises to 40 C, and it develops lively nitrogen. The mixture is stirred for 15 minutes in the bath of 50 ⁰ C, then added 7.5 ml of water and extracted with chloroform. The organic extract is dried over sodium sulfate, filtered and evaporated in vacuo. "The viscous, reddish brown evaporation residue (2.7 g, still chloroform-containing) contains the desired 4 -, / _ (1 - (5-20 chlorosulfonyl-2-piperidino-phenyl) -ethyl) -aminocarbonylmethylT? - benzoic acid ethyl ester.

b) The solution of the evaporation residue obtained in a) in 10 ml of chloroform is added dropwise at 2 ° C with stirring to 50 ml of conc. Ammonia. 30 minutes later, saturated saline solution is added to achieve phase separation. It is extracted again with chloroform, dried and filtered, the organic extract and evaporated it in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 10/1). In addition to 55% of the corresponding 5-chloro compound, the desired 5-aminosulfonyl compound is obtained as a foam. Yield: 32% of theory, Ber .: m / e = 473 Gef .: m / e = 473

JS ψί l · * ^. $ 9Μ * 1_ * JL.

Z ^ JQ J y 7

Example 35

4 -. ^ J 1- (5-Dimethylamino-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl- / benzoic acid

To a stirred solution of 0.20 g (0.5242 mmol) of 4- / ~ 1- (5-amino-2-piperidine-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid and 0.45 ml of 40% formalin in 2 ml of acetonitrile + 1 ml of absolute dimethylformamide is added at 20 ° C 0.10 g (1.589 mmol) of sodium cyanoborohydride and after 2 minutes 0.056 ml of glacial acetic acid. After 1.5 hours, evaporate in vacuo. The evaporation residue is dissolved in water with the addition of hydrochloric acid at pH 2-3. After repeated extraction with chloroform, the aqueous phase is adjusted to pH 6 to 7 with saturated sodium bicarbonate solution and extracted several times with chloroform. This organic extract is dried and filtered. After evaporation in vacuo, the evaporation residue is recrystallized from isopropanol. The colorless crystals are washed with absolute ether.

Yield: 0.09 g (42.8% of theory), melting point: 185 ° C. (decomposed from 175 ° C.)

20 Ber. : C 70 39 H 7, 63 N 10 26 Gef .: 70 10 7, 63 10 47

Example 36

A- ( 1- (5-acetylamino-2-piperidino-phenyl) -ethyl) -aminocarbonyl- methyl / benzoic acid

Then, 0.10 g (0.262 mmol) of A- ( 1- (5-amino-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid in 1 ml of acetic anhydride is stirred for 6 hours at 20 ° C., then it is evaporated in vacuo , distilled several times with toluene and crystallized the evaporation residue from ether.

OCC η -g

Yield: 0.08 g (72.7% of theory), m.p .: 241-243 ° C

Calc .: C 68.07 H 6.90 N 9.92 F .: 67.53 6.83 9.72

Example 37

4 - ^. (1- (5-Benzoylamino-2-piperidino-phenyl) -ethyl) -aminocarbonyl- methyl / benzoic acid

To dissolve 1 g (2.62 mmol) of 4- (1- (5-amino-2-piperidinophenyl) ethyl) aminocarbonylmethylbenzoic acid and 0.37 ml

10 (2.62 mmol) of triethylamine in 10 ml of anhydrous dimethylformamide is added dropwise 0.30 ml (2.62 mmol) of benzoyl chloride. The mixture is stirred for 2 hours at 2O-3O ° C, evaporated in vacuo and partitioned between water and ethyl acetate. The organic phase is dried and.filtered and evaporated in vacuo. The evaporation residue

15 (1.12 g) is recrystallized from ethanol with activated charcoal addition.

Yield: 0.5 g (39.4% of theory), mp: 225-227 ° C calc .: C, 71.73, H, 6.43, N, 8.65

Gef .: 71.70 6.50 8.66

The following compound was prepared analogously to Example 37:

4- [1- (5-ethoxycarbonylamino-2-piperidino-phenyl) -ethyl) -amino- carbonylmethyl-benzoic acid

Yield: 34.2% of theory, melting point: 22 ° C. (dec.)

Calc .: C 66.21 H 6.89 N 9.26 F .: 65.97 6.83 9.57

-108 - 23 6 5 9 7 8

Example 38

4- (1- (5-Methylsulfonylamino-2-piperidino-phenyl) -ethyl) -amino- carbonylmethyl / benzoic acid

To the solution of 0.10 g (0.262 mmol) of 4- (1- (5-amino-2-piperidinophenyl) ethyl) aminocarbonylmethoxybenzoic acid in 1 ml of anhydrous pyridine is added 0.20 ml (0.262 mmol) mesyl. After the exothermic reaction has subsided, the mixture is allowed to stand for a further 4 hours at 20 ° C. The mixture is then concentrated by evaporation in vacuo and the residue is partitioned between water and chloroform at pH 2 to 3. The acidic aqueous phase is adjusted to pH with sodium bicarbonate solution 6 to 7 and extracted with chloroform, this chloroform extract is dried and filtered, and the residue obtained by evaporation in vacuo is purified by column chromatography on silica gel (chloroform / methanol = 4/1). Yield: 0.03 g (25%). of theory), melting point: 21O-22O ° C (dec.) (ether) Ber .: Molpeak m / e = 459 Gef .: m / e = 459

Example 39

A- / J 1- (S-acetoxy-2-piperidino-phenyl) -ethyl) -aminocarbonyl- methyl / benzoic acid

0.35 g (0.915 mmol) of 4-bis (5-hydroxy-2-piperidinophenyl) -ethyl) -aminocarbonylmethyl / benzoic acid are heated on the steam bath together with 0.1.03 ml (1.098 mmol) of acetic anhydride stand for 4 days at 20 ° C. It is crystallized from methanol

Yield: 0.16 g (41.2% of theory), m.p .: 213-221 ° C

Calcd .: C, 67.91, H, 6.65, N, 6.60

Found: 67.70 6.95 6.55

-109 - 13 6 5 9 7 8 -

Example 40

4 - / _ (1 - (5-methoxy-2-piperidino-phenyl) -ethyl) -aminocarbonylmethy U 'benzoic acid methylester

A solution of 60 mg (0.157 mmol) 4- (1- (5-hydroxy-2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid in 1 ml of methanol (+ 1 drop of water) is added dropwise added to an ethereal diazomethane solution until no gas evolution occurs. To destroy excess diazomethane, add 2N-acetic acid. Then it is evaporated in vacuo. The evaporation residue is partitioned between toluene / ether and dilute sodium hydroxide solution. After drying, filtration and evaporation of the organic phase in vacuo, the evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 5/1).

Yield: "27% of theory, melting point: foam Ber .: Molpeak m / e = 410 Gef .: m / e = 410

Example 41

4 - / _ (1- (5-Benzyloxy-2-piperidino-phenyl) -ethyl) -aminocarbonyl- methy! / - benzoic acid ethyl ester

To a suspension of 1.353 mmol of sodium hydride (32.5 mg of a 50% suspension in oil) in 2 ml of anhydrous dimethylformamide is added dropwise the solution of 0.50 g (1.218 mmol) of 4- (1- (5-hydroxy) 2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / benzoic acid ethyl ester in 10 ml of anhydrous dimethylformamide. After 1.5 hours of stirring at 20 ° C is added dropwise 0.16 ml (1.353 mmol) of benzyl bromide, dissolved in 2.3 ml of anhydrous dimethylformamide and stirred for 16 hours at 20 ° C. After evaporation in vacuo, partition between water and ether. The organic extract

3 6 5 9 7 8

dried, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/1).

 Yield: 0.34 g (55.7% of theory) Melting point: 155-157 ° C (ether)

Ber. : C 74 , 37 H 7 25 N 5 60 Gef .: 74 , 11 7 , 41 5 , 39 example 42

Ethyl 4-__ (1- (5-aminocarbonyl-2-piperidino-phenyl) -ethyl) -aminocarbonyl] -ethyl-benzoate

Are stirred 3.8 g (9.06 mmol) of ethyl 4-_ ~ (1- (5-cyano-2-piperidino-phenyl) -aminocarbonylmethy! / - benzoate and 38 g of polyphosphoric acid for 2.5 hours at 8O -9O ° C. While cooling with ice, carefully add water. It is overlaid with ethyl acetate and concentrated with conc. Ammonia alkaline. The organic phase is washed with water, dried and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 20/1). Yield: 1 g (25.2% of theory)

Melting point: 188-189 ° C (ethanol) Calc .: c 68.63 H 7,14 N 9,60 Found: 68,42 6,95 9,46

Example 43 '..

He read A- (J, 1- (5-ethoxycarbonyl-2-piperidino-phenyl) -ethyl) -aminocar bony-imethyl-7-benzoic acid ether .

In a refluxed solution of 1.1 g (2.62 mmol) of 4-__ (1- (5-cyano-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl, / -benzoic acid ethyl ester in 22 ml of absolute ethanol Initiate dry hydrogen chloride until after 4 hours no Nitrii 30.mehr verifiable. It is evaporated in vacuo, mixed with

236597

Water and ether, and make alkaline with sodium bicarbonate solution. The separated ether phase is shaken once with water, - dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (methylene chloride / acetonitrile / glacial acetic acid = 10/1 / 0.05). Yield: 0.6 g (49.2% of theory), melting point: 136-138 ° C. (ether)

Calc .: C 69 , 51 H 7 35 N 6 00 Gef .: 69 , 28 7 , 34 5 , 83 example 44

4- / J 1- (2- (4-Oxopiperidino) -phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid

A solution of 2.9 g (6.86 mmol) of 4- / Ti (2-1,4-dioxa-8-azaspiro ^ 4.5ydecan-8-yl / phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid Semihydrate in. 40 ml of acetone is adjusted to pH = 2 by addition of 2N hydrochloric acid. After stirring for 6 hours at 50 ° C, 5 drops of concentrated. Hydrochloric acid and allowed to stand for 16 hours at 20 ° C. It is concentrated by evaporation in a vacuum, water and ethyl acetate are added and the pH is adjusted to 6 by addition of 2N ammonia. It is shaken out several times with ethyl acetate, the combined organic extracts are washed with water, dried and filtered and evaporated in vacuo. The evaporation residue is recrystallized from acetone / petroleum ether

 Yield: 1.9 g (73.1% of theory),

Melting point: 177-18O ° C (decomp.)

Calc .: C 69.46 H 6.36 N 7.36 F .: 69.75 6.33 7.29

¹¹² - 236597 8

Example 45

4-./1- (2- (4-Hydroxy-piperidino-phenyl) -ethyl) -aminocarbonyl, methyl / benzoic acid x 0.66H.sub.10

To a solution of 1 g (2.63 mmol) of 4- (Ί- (2- (4-oxo-piperidino) phenyl) -ethyl) -aminocarbonylmethy! / - benzoic acid in 20 ml of absolute ethanol is added with stirring in portions 0.244 g (7T, 92 mmol) sodium borohydride. After stirring for 1.5 hours at room temperature, the mixture is initially made acidic with 2N hydrochloric acid, evaporated in vacuo, water and ethyl acetate are added and adjusted with 2N sodium hydroxide solution to pH = 6. It is extracted several times with ethyl acetate, dried and filtered, the extract and evaporated it in vacuo. The evaporation residue is crystallized from petroleum ether. ' Yield: 0.78 g (75% of theory),

Melting point: Ber. (x 0.66 Gef.

Example 46

4- / J 1 - (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-yl-benzoic acid propyl ester

To a solution of 2 g (5.46 mmol) of 4- (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid in 20 ml of absolute tetrahydrofuran is added 0.94 g (5.80 mmol). Carbonyl-diimidazole and heated for 30 minutes under exclusion of moisture to reflux Then set to 1.64 ml (22 mmol) of 1-propanol, stirred for 18 hours at 20 ° C and heated for 8 hours at reflux. It is then evaporated in vacuo and the evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/1).

1 75- 1 80 ° C (Dec.) 97 H 6 ,8th 1 N 7 10 H 2 ⁰⁾ • C 66 72 6 , 6 2 6 , 98 66

& ο D b 9 /

Yield: 1.3 g (58.3% of theory), m.p .: 150-151 ° C {ethyl acetate) Calc .: C 73.51 H 7.90 N 6.86 F .: 73.70 7.78 ' 6.92

Analogously to Example 46, the following compounds were obtained:

4 - ^ _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-benzoic acid isopropyl ester

Yield: 45 % the Theory, (Ether) 6 , 86 Melting point: 141-1 43 ° C , 90 N 6 70 10 Re: C 73 , 51 H I ₁ , 79 Gef .: 73 20 I ₁

A- ( 1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid butyl ester .

Yield: 49% of theory, melting point: 148 ° C. (ether / toluene)

Calc .: C 73.90 H 8.11 N 6.63 F .: 74.10 7.99 6.70

- 4 -, / J 1 - (5-chloro-2-piperidino-phenyl-1-ethyl) -aminocarbonylmethyl / benzoic acid ethyl ester .

Yield: 41% of theory,

Melting point: 13O-133 ° C (ether)

Ber. : C 67 , 21 H 6 , 81 Cl 8th , 26 N 6 , 53 Gef .: 66 90 6 65 8th , 32 6 , 67

4- / J 1 - (5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid butyric ester

Yield: 30.7% of theory, melting point: 115-118 ° C

C 68 , 33 H 7 - 114 - 7 75 I J b Ber. : 68 20 7 , 27 Cl 7 , 68 N 6 12 Gef .: , 23 5 95

4- / J 1 - {5-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid-tert. buty! ester

Yield: 1% of theory, calc .: Molpeak m / e = 456/8 F: m / e = 456/8

4-__ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl-y-benzoic acid (2-methoxy-ethyl ester) _;

Yield: 56% of theory,

Melting point: 155-157 ° C (ethyl acetate) Calc .: C 70.74 H 7.60 N 6.60 Found: 70.55 7.38 6.47

4-1- {1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl -methyl-L- benzoic acid Zj2,2-dimethyl-dioxolan-4-yl) -methyl7-este'r

Yield: 30.5% of theory,

Melting point: 11O-112 ° C (ether)

Calc .: C 69.98 H 7.55 N 5.83 m / e = 480 F: 69.80 7.50 5.76 m / e = 480

4-__ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl- _1- benzoic acid benzyl ester ν ... · .. ·; - · ·. - ,,. · ...

Yield: 73.7% of theory, m.p .: 126-128 ° C (ethyl acetate) Calc .: C 76.28 H 7.06 N 6.14 F .: 76.33 7.20 6.03

~ 2T5 ~ 5 ~ 9 7 8

4 - ^ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl -methyl-1-yl-benzoic acid (2-hydroxy-ethyl) -ester

It was heated to reflux for 17 hours after the addition of 10 equivalents of ethylene glycol

 Yield: 71.4% of theory,

Melting point: 128-129 ° C (ethyl acetate / ether) Calc .: C 70.21 H 7.36 N 6.82 m / e = 410 V: 70.14 7.42 6.70 m / e = 410

1,2-Bis / 4 - / _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoyloxy7-ethane

It was refluxed for 17 hours after addition of 0.5 equivalent of ethylene glycol

 Yield: 43.5% of theory, m.p .: 188-191 ° C (toluene)

Calc .: C 72.80 H / 7.17 N 7.38 'm / e = 758 F: 72.85 7.07 7.37 m / e = 758'

4- _jf 1 - (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl-k ⁰²¹²⁰⁰ " acid (2-diethylaminoethyl) ester

Yield: 56.7% of theory, melting point: 99-101 ° C (petroleum ether)

Calc .: C 72.23 H 8.44 N 9.03 Found: 72.40 8.37 8.95

4-__ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethy / benzoic acid / J2- ( 1,3 -dimethyl-xanthine-7-yl) -äthy! / - ester

The solvent used was absolute pyridine. After addition of 1 equivalent of 7- (2-hydroxyethyl) -theophylline and after addition of a tiny piece of metallic sodium was stirred for 4 hours in the bath of 130.degree. **

Yield: 40.9% of theory,

Melting point: 121-123 ° C (ether)

Calc .: C 65.01 H 6.34 N 14.68 m / e = 572 F .: 64.78 6.38 14.90 m / e = 572

Example 47

T-ZJ1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl_ / -benzoic acid methyl ester

The mixture is heated with 2 g (5.46 mmol) of 4 - / (1- (2-piperidinophenyl) -ethyl) -ajttinocarbonylmethyl / benzoic acid, 0.53 g of methanol.

10nol, 0.38 ml conc. Sulfuric acid and 1.65 ml of 1,2-dichloroethane for 24 hours at reflux, evaporated in vacuo, dissolved in chloroform and extracted with dilute sodium bicarbonate solution. The organic phase is washed with water, dried and filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 5/1).

Yield: 0.93 g (44.8% of theory), melting point: 146-147 ° C. Calc .: C 72.60 H 7.42 N 7.36 F .: 72.19 7.33 7.01

Example 48

4 -, / J 2- (2-piperidino-phenyl) -2-propyl) -aminocarbonylmethyl / -benzoic acid ethyl ester

0.20 g (0.526 mmol) of A- / J 2 - (2-piperidino-phenyl) -2-propyl-aminocarbonyl-methylene / benzoic acid and 2 ml of 4N-ethanoic acid hydrochloric acid are stirred at 20 ° C. After 36 hours, the mixture is evaporated in vacuo and distributes the evaporation residue between water (at pH = 8 by adding 10% ammonia) and ethyl acetate. you

"23 6 b 9 ΤΎ

The organic phase is washed with water, dried, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/1).

Yield: 0.079 g (36.7% of theory) Melting point: 151-153 ° C (ether)

Ber. : C 49 73 50 H 7 90 N 6 , 86 Gef .: 73 40 7 95 6 96 example

4 - / _ {1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethylZ-benzoic acid-tert. buty! ester

The mixture is stirred from 3.60 g (17.4 mmol) of Ν, Ν'-dicyclohexylcarbodiimide, 1.9 ml (20.4 mmol) of t-butanol and 0.036 g (0.36 mmol) of copper (I) chloride 3 Days at room temperature, then 12 ml of methylene chloride and the resulting solution is added dropwise to the solution of 2 g (5.46 mmol) of 4-__ (1- (2-piperidino-phenyl) -ethyl) aminocarbony line thy! / - benzoic acid in 80 ml of methylene chloride. After 16 hours of stirring at 20 ° C is filtered from the precipitate, washed with methylene chloride and the methylene chloride solution is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 15/1).

Yield: 0.45 g (19.7% of theory), m.p .: 125-127 ° C (ether)

25 Ber. : 50 C 73 90 H 8th , 11 N 6 , 63 Gef.-: 74 20 8th , 09 6 77 BeiSDiel

4- / J1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid (2-nicotinoyloxy-ethyl) -ester

To the solution of 0.45 g (T, 10 mmol) 4- / 71- (2-piperidino-phenyl) -

236597 8

Ethyl) -aminocarbonylmethyl / benzoic acid (2-hydroxyethyl) ester and 0.16 ml (1.16 mmol) of triethylamine in 10 ml of methylene chloride is added dropwise rapidly the solution of 0.16 g (1.13 mmol) of nicotinic acid chloride in 5 ml of methylene chloride. After stirring for 4 hours at 20 ° C., it is shaken out with water, dried and filtered, the methylene chloride solution and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel -formeroform / acetone = 3/1)

 Yield: 0.34 g (60% of theory), m.p .: 1O3-1O5 ° C (ether)

Calc .: C 69.88 H 6,45 N 8,15 Found: 70,13 6,55 8,13

Example 51

4-Ζ_ΠΠ · ·-piperidine-phenyl) -ethyl) -aminocarbonylmethyl / -benzamide

To 4.76 g (0.013 mol) of 4-11- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethylbenzoic acid in 60 ml of absolute pyridine is added 2.3 g (0.0142 mol) of carbonyldiimidazole and then heated to 50 ° C for 45 minutes. After cooling in a carbonic-methanol bath, 7 ml of liquid ammonia are added and heated in

Autoclave for 20 hours at 80 ° C. Thereafter, the reaction mixture is cooled, and from. T evaporated in vacuo. The residue is dissolved in 50 ml of hot methanol, 200 ml of water are added and allowed to stand overnight. The crystalline precipitate is filtered off and recrystallized from methanol with addition of activated carbon. Yield: 3.5 g (73.6% of theory), m.p .: 197-199 ° C

Ber. : C 72 30 H 7 45 , N 11 50 Gef .: 72 30 7 45 11 , 32

- 119 Example 52

236597 8

4 - ^ _ (1- (2-piperidino-phenyl) -ethyl) -aminocarbony lme thy 1 / -N- methyl-benzamide

Heat 2 g (5.46 mmol) of 4-ol ~ (1- (2-piperidino-phenyl) -ethyl) -aminocarbonyl-methyl / benzoic acid and 0.94 g (5.80 mmol) of carbonyl diimidaz oil in 20 ml absolute pyridine one hour on reflux. Subsequently, 0.41 g (6.07 mmol) of methylamine hydrochloride are added and the mixture is stirred at 20 C for 1 hour and under reflux for 2 hours. It is evaporated in vacuo, distributed between water

and methylene chloride, drying and filtering the organic extract and evaporating it in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol / concentrated ammonia = 10/1 / 0.05).

 Yield: 1.7 g (82% of theory),

Melting point: 218-22O ° C (isopropanol) Calc .: C 72.77 H 7.70 N 11.07 F .: 72.88 7.67 10.91

The following compound was prepared analogously to Example 52:

4- (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -N, N-di- methylbenzamide

Yield: 52.5% of theory, melting point: 148-15O ° C (ethyl acetate) Calc .: C 73.26 H 7.94 N 10.68 F .: 73.60 7.85 10.73

25 Example 53

4- / J 1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl? N-butyl benzamide ·

To dissolve 2 g (5.46 mmol) of 4- / J 1 - (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / benzoic acid in 20 ml of absolute water.

- ™ - 236 59 7 8

Trahydrofuran is added 0.94 g (5.80 mmol) of carbonyldiimidazole. The mixture is heated for 30 minutes at reflux, 0.44 g (6.1 mmol) of 1-butylamine is added and heated for 2 hours at reflux. It is evaporated in vacuo and the evaporation residue is purified by column chromatography on silica gel (chloroform / acetone = 6/1). Yield: 1.65 g (71.7% of theory) Melting point: 178-181 ° C (ethyl acetate) Calc .: C 74.09 H 8.37 N 9.97 F .: 74.34 8.26 9 95

Analogously to Example 5 3, the following compounds were obtained:

4 - ^, (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid-piperidide

Yield: 73.8% of theory, m.p .: 131-133 ° C (toluene)

15Ber .: C 74,79 H 8,14 N 9,69 m / e = 433 Gef .: 75,13 7,99 9,48 m / e = 433

4- / J 1 - (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl / -benzoic acid morpholide .

Yield: 60.5% of theory, melting point: 148-15O ° C (ethyl acetate / ether) Calc .: C 71.69 H 7.64 N 9.65 F .: 71.60 7.80 9.57

Example 54

4- / J1 (2-piperidino-phenyl) ethyl) aminocarbonylmethyl / -benzo

nitrile

To a mixture of 2.19 g (6 mmol) of 4 - / (1- (2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl-1-benzamide and 1.07 g (13.5 mmol) of absolute pyridine are added at room temperature with stirring 1.14 g

59 7 8

(6 mmol) p-toluenesulfonyl chloride in 2 portions. The mixture is stirred for 15 minutes at 20 ° C and then for 2 hours at 50 ° C. After cooling, it is mixed with water, made alkaline with concentrated ammonia and extracted 3 times with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / ethyl acetate = -4 / 1).

 Yield: 1.15 g (55.3% of theory),

melting point: 155-157 ° C (ethyl acetate) calc .: C 76.05 H 7.25 N 12.09 g .: 76.30 7.07 11.90

Claims (23)

in the R. and R2S "which may be the same or different ^ alkyl groups having 1 to 6 carbon atoms or cycloalkyl groups having 5 to 7 carbon atoms or R. and R" together with the intervening nitrogen atom is an unbranched Alkyleniminogruppe having 3 to 6 carbon atoms? which may be substituted by one or two alkyl groups each having 1 to 3 carbon atoms or by a hydroxy group or in which a methylene group is represented by a carboxyl group durch by an oxygen or sulfur atom or by an imino group which is substituted by an alkyl group having from 1 to 3 carbon atoms , an aralkyl group having 7 to 10 carbon atoms, a phenyl or halogen phenyl group, or in which an ethylene group may be replaced by an o-phenylene group, an unbranched alkenyleneimino group having 4 to 6 carbon atoms, a saturated or partially unsaturated azabicycloalkyl group: with 6 to 10 carbon atoms, an aza-1,4-di oxa-spiroalkyl group having 6 to 8 carbon atoms, a heptamethyleneimino, octamethyleneimino, nonamethyleneimino or decamethyleneimino group, R- a hydrogen or halogen atom, a trifluoromethyl, alkyl, hydroxy, alkoxy, alkanoyloxy, mercapto, alky! mercapto, nitro, amino, cyano, alkanoyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arainosulphonyl, alkynamino, dialkylamino, alkanoylamino, alkoxycarbonylamino or alkylsulphonylamino groups, wherein each alkyl portion each of the above-mentioned groups may contain 1 to 3 carbon atoms, an aralkoxy group having 7 to 10 carbon atoms or an arylcarbonylamine group, R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R5 is a hydrogen atom, a halogen atom or an alkyl group having 1 to 3 Carbon atoms, A is a bond, an optionally substituted by a methyl, ethyl or isopropyl group methylene or Äthylengru ppe, a methylene or ethylene group substituted by two alkyl groups each having 1 to 3 carbon atoms, a methylene group substituted by a cycloalkyl group having 3 to 7 carbon atoms, by a hydroxyalkyl, carboxyl, alkoxycarbonyl or phenyl group, each of the above-mentioned alkyl moieties 1 to 3 carbon atoms, a Cycloalkylidengruppe having 3 to 7 carbon atoms or a vinylidene group of the formula II - C, wherein Rg and R7 are hydrogen atoms or one of Rg or R7 is a methyl or cycloalkyl group having 3 to 7 carbon atoms and the other of the radicals R, or R7 represents a hydrogen atom or Rr and R- together with the intervening O / represents a cycloalkylidene radical having 5 to 7 carbon atoms, B represents a methylene or ethylene group optionally substituted by an alkyl group having 1 to 3 carbon atoms and W represents a hydrogen - or halogen atom, a nitro group, an optionally d An amino group substituted by an alkanoyl group having 1 to 3 carbon atoms, an optionally substituted by a hydroxy, carboxy or alkoxycarbonyl group or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms alkyl group having 1 to 3 carbon atoms, one by a carboxy or alkoxycarbonyl group with a total of 2 alkenyl group having 2 to 5 carbon atoms substituted by 4 carbon atoms, an alkanoyl group having 1 to 3 carbon atoms, a dialkoxymethyl or trialkoxymethyl group having 1 to 3 carbon atoms in each alkyl part, an alkylenedioxymethyl group having 2 or 3 carbon atoms in the alkylene part, a 1,3-oxazoline 2-yloder-., Cyano group, an optionally substituted by one or two alkyl groups each having 1 to 4 carbon atoms in each alkyl moiety substituted aminocarbonyl group, an unbranched Alkyleniminocarbonylgruppe having a total of 5 to 8 carbon atoms, a morpholinocarbonyl group, a (dialkyl-dioxolane -yl) alkoxycarbonyl group having a total of 7 to 10 carbon atoms or a carboxy group and their esters, wherein alkyl esters having 1 to 6 carbon atoms in the alkyl part except the $. Each position by a hydroxy-% alkoxy ~ <% araino-i »alkylaraino-vy dialkylaraino-r * dJ ^ 3-dimethyl-xanthine-7-yl-1»; Alkanoyloxy-% arylcarbonyloxy-fi Aralkanoyloxy- or Pyridincarbonyloxygruppe or by two hydroxy groups ^ wherein a Methylbzw, methylene group may be substituted in each case only by a hydroxy group% or by a group of the formula B-CO-NA R. in the Ail B and R1 to R5 where each alkyl substituent in the abovementioned alkyl esters can contain 1 to 3 carbon atoms, as well as their optically active antipodes and their salts, in particular their physiologically tolerated salts with inorganic or organic radicals Acids or bases, characterized in that a) is an amine of the general formula 236597 8 in the A and R 1 to R 4 as defined above, or if A represents one of the abovementioned vinylidene groups whose tautomer, its lithium or magnesium halide Complex with a carboxylic acid of the general formula HOOC-B, (in) in the R1 and B as defined above and W has the meanings mentioned for W or represents a carboxyl group protected by a protecting group, or reacted with their reactive derivatives optionally prepared in the reaction mixture and, if necessary, a protective residue used is cleaved, or b) for preparing a compound of general formula I, in W is a carboxy group, a compound of the general formula AN-CO-B- in which R1 to Rj-, A and B are as defined above and D is a compound obtained by hydrolysis, thermolysis or hydrogenolysis in represents a carboxy group convertible group, hydrolytically, thermolytically or hydrogenolytically cleaved, or c) a compound optionally formed in the reaction mixture of the general formula -N-CO-B v in the R3 to Rj- / A, B and W are as defined above and R- 'represents a hydrogen atom or has the meanings mentioned for R--, with a connec tion of a the general formula - E, (VI) in which R1 'has the meanings mentioned for R1 or, together with the radical R-' of the formula V, a straight-chain alkylene group with 4 to 6 which is unsubstituted or substituted by one or two alkyl groups each having 1 to 3 carbon atoms Carbon atoms or an n-pentylene group in which the third methylene group is replaced by an oxygen or sulfur atom, and E is a nucleophilic leaving group or a hydrogen atom, if in R .. 'a methylene group is replaced by an aldehyde or Ketoncarbonylgruppe, if necessary, alkylated in the presence of a reducing agent and optionally subsequently hydrolyzed, or d) for preparing a compound of the general formula I in which W represents a carboxy group, an alkanoyl group having 1 to 3 carbon atoms or an alkyl group having 1 to 3 carbon atoms Compound of the general formula R4 AN-CO-B, (VI) in the R1 to R5, A and B as in angs are defined, is reacted with phosgene, an oxalyl halide, an alkyl or Alkanoy! halide having in each case 1 to 3 carbon atoms in the alkyl moiety or with hydrogen cyanide / hydrogen halide in the presence of a Lewis acid, or e) for preparing a compound of general formula I. in which W represents the carboxy group, a compound of the general formula -i-25 AN-CO-B 1 ^l 2 COCH3 , (VIII) in the to R ,, A and B are as defined above, with an optionally prepared in the reaction mixture hypohalite in the presence of an alkali metal base
is implemented, or. , , f) for the preparation of a compound of the general formula I in which W represents the carboxy group, a compound of the general formula A-N-CO-B , (Ix) in the R ₁ to R-, A and B are as defined above and
G represents a group convertible by oxidation into a carboxy group,
is oxidized, or r η _η ο 9 / g) for the preparation of a compound of the general formula I in which R, the nitro group, is a compound of the general formula A-N-CO-B in the R- / Rj., A, B and W are as defined above, R _{3 is} a nitro group and Y represents a nucleophilically exchangeable residue, with an amih. the general formula H-N , (XI) in the R ₁ and R are as defined above, reacted and optionally subsequently hydrolyzed, or h) for preparing a compound of general formula I, in which A is a group of formula R _c R _n ⁶ X / ⁷ - CH - represents where R and R ₇ as are defined at the outset, a compound of the general formula - A4-3 · * / 3 '/ - B in the R ₁ to R_, B and W are as defined above, is reduced with hydrogen in the presence of a hydrogenation catalyst, or i) for the preparation of a compound of the general formula I in which R. is a hydrogen atom and A is a Ge optionally substituted by a methyl, ethyl or isopropyl group substituted methylene or ethylene group, a substituted by two alkyl groups each having 1 to 3 carbon atoms methylene or ethylene group, one by a cycloalkyl group having 3 to 7 carbon atoms, a carboxyl, alkoxycarbonyl or phenyl group substituted methylene group, wherein each of the. The above-mentioned alkyl moieties may contain 1 to 3 carbon atoms, or a cycloalkylidene group having 4 to 7 carbon atoms, a compound of the general formula 732nd 236 59 7 8 A ¹ - OH in the R ₁ to R _{3 are} as defined above and A 'is an optionally substituted by a methyl, ethyl or isopropyl group methylene or ethylene group, a substituted by two alkyl groups each having 1 to 3 carbon atoms methylene or ethylene group. a methylene group -substituted by a cycloalkyl group having 3 to 7 carbon atoms, a carboxyl, alkoxycarbonyl or phenyl group, wherein each of the above-mentioned alkyl moieties may contain 1 to 3 carbon atoms, or a cycloalkylidene group having A to 7 carbon atoms,
with a compound of the general formula N = C-B (XIV) DZ) 236597 8 in the R _1. , B and W are as defined above, is reacted in the presence of a strong acid and, if desired, subsequently a compound of the general formula I obtained in which W represents the carboxy group, by esterification or amidation into a corresponding compound tion of general formula I is converted and or an obtained compound of the general formula I, in which R ₃ and / or W represent a nitro group, are converted by reduction into a corresponding compound of the general formula I, in which R ₃ and / or W is an amino group, and / or a compound of the general formula I in which R and / or W represents an amino group, via a corresponding diazonium salt, into a corresponding compound of the general formula I in which R _{3 is} a hydrogen or halogen atom, a Hydroxy, alkoxy, mercapto, alkylmercapto, chlorosulfonyl or cyano group and / or W is a hydrogen or halogen atom or a cyano group, is converted, wherein a compound thus obtained optionally of the general Formula I, in which R _{3 represents} the hydroxy group, by alkylation in a corresponding compound of general formula I, in which R _{3 represents} an alkoxy group or a compound optionally obtained in such a general formula I, in the R-, which represents chlorosulfonyl group, can be converted by means of ammonia into a corresponding compound of general formula I in which R _{3 represents} the aminosulfonyl group, and / or ζ- η η ο g 7 a compound of the general formula I _{1 obtained} . in the R-. represents an amino group, by acylation in a corresponding compound of the general formula I, in which R., an alkanoylamino, aroylamino, alkoxycarbonylamino or alkylsulfonyl represents fonyiaminogruppe, is transferred, and / or an obtained compound of the general formula I ₁ in dej ^ R, an amino group, by alkylation in a corresponding compound of general formula I, in which R _{3 represents} an alkylamino or dialkylamino group, is converted and / or a compound of the general formula I in which R _{3 represents} a chlorine or bromine atom, with delta dehalogenation in a corresponding compound 'of the general formula I, in which R _{3 represents} a hydrogen atom, transferred., Is, and / or an obtained compound of general formula I, in which R _{3 represents} a nitrile group, is converted by hydrolysis or alcoholysis into a corresponding compound of the general formula I in which R _{3 represents} an aminocarbonyl, carboxy or alkoxycarbonyl group, and / or a compound of general formula I in which R _{3 represents} a carboxy or alkoxycarbonyl group and / or W represents an optionally esterified carboxy group, by reduction to a corresponding compound of the general formula mel I, in which R ₃ and / or W represent a formyl or hydroxymethyl group, is converted and / or a compound of general formula I in which W represents an alkoxycarbonyl group in which the alkoxy group may contain from 2 to 6 carbon atoms and is substituted by a hydroxy group except for the ^ -position; Acylation is converted into a corresponding compound of general formula I and / or a compound of the general formula I in which W represents a hydroxymethyl group, by means of halogenation and subsequent reaction with a Malonsäurediester in a corresponding compound of the general formula I, in which W represents an ethyl group substituted by two Aikoxycarbonylgruppen, is converted and / or 'an obtained compound of general formula I, wherein W represents a formyl group, by condensation and optionally subsequent hydrolysis and / or decarboxylation in a corresponding compound of general formula I, in the W by a hydroxycarbonyl or Alk represents oxycarbonyl substituted vinyl group, is converted and / or an obtained compound of the general formula I in which W represents an ethyl group substituted by two alkoxycarbonyl groups, by means of Hy drolyse and decarboxylation in a corresponding compound of general formula I, in which W represents an ethyl group substituted by a carboxy group, is converted, and / or a compound of the general formula I in which Vi is a carboxy group, by conversion into a sulfonic acid hydrazide and then disproportionation into a corresponding compound of the general formula I, in which W represents a formyl group, is converted, and / or an obtained compound of general formula I, in the R- and R-, together with the intervening nitrogen atom, an aza-1,4-dioxa-spiro Alkyl group having 6 to 8 carbon atoms, by hydrolysis -in a corresponding compound of general formula I, in the R .. and R_ together with the intervening nitrogen atom, an unbranched Alkyleniminogruppe with 4 to 6 carbon atoms, in which a methylene group is replaced by a carbonyl group, is converted, and / or an obtained compound of the general formula I in which R ₁ and R "together with the intervening lying nitrogen atom represent an unbranched Alkyleniminogruppe with 4 to 6 carbon atoms, in which a methylene group is replaced by a carbonyl group, by reduction to a corresponding hydroxy-alkylene-imioverbindung the general formula I is converted, and / or a compound of general formula I in which W represents an aminocarbonyl group, by dehydration into a corresponding compound Compound of the general formula I in which W represents a cyano group is converted, and / or , 236597 8 28, 5, 82 AP C 07 D / 236 597/8 - 14T - 60 193 12 a compound of the general formula I obtained is converted into its salts, in particular into its physiologically tolerated salts with inorganic or organic acids and bases. 2 # Procedure according to item 1 / * characterized in that the reaction is carried out in a solvent * 3 * Process according to items 1 and 2 ', characterized in that the reaction is carried out in the presence of an acid-activating or dehydrating agent, if appropriate in the presence of an inorganic or tertiary organic base, 4 # Process according to items 1 and 2%, characterized in that the reaction is carried out in the presence of an amine-activating agent, if appropriate in the presence of an inorganic or tertiary organic base, 5 * Process according to items 1 and 2s »characterized by?« That the water formed during the reaction is removed by azeotropic distillation or by adding a T.rockan agent * 6, method according to the points ja and 2 to 5e-, characterized in that the reaction at temperatures between -25 and 250 ⁰ Cf ^, but preferably at temperatures between -10 ⁰ C and the boiling temperature of the solvent used ^ is carried out « Γ Λ Π ο 9 7 28. 5 * 82 AP C 07 D / 236 597/8 60 193 12 7 "The procedure according to the points Ib and 2u characterized ^ that the hydrolysis or thermolysis in the presence
an acid or base is carried out « 8 * Method according to items Ib and 2fc, characterized in that the reaction is carried out in the presence of a nitrite E *
z * B, sodium nitrate '* and in the presence of an acid such as
Sulfuric acid is carried out? »- when D represents the nitrile or aminocarbonyl group * 9 * Method according to points Ib ^ 2 and 7%. marked
in that the reaction is carried out at temperatures between -10 and 120 ° C%, preferably at temperatures between room temperature and the boiling point of the reaction mixture. 10 · Method according to the points Ic and ZV ₉ characterized dadurchsi. that the reaction is carried out in the presence of an inorganic or tertiary organic base * 11 · Process according to the items Ic and 2f, characterized in that the methylation with formaldehyde in the presence of formic acid or hydrogen in the presence of a
Hydrogenation catalyst is carried out * 12. Procedure according to points IcE ^ 2 ^ 10 and 11 !; dadurchi in 'that the reaction is carried out at temperatures between ο I5o and O, but preferably at temperatures between 20 and 75 ⁰ Qy * 13.The method according to items Ic and 2 >> is characterized by the fact that the alkylation is carried out with a corresponding car- 236597 8 28, 5. 82 AP C 07 D / 236 597/8 60 193 12 bonyl compound is carried out in the presence of a hydride such as sodium cyanoborohydride at pH 7 and at temperatures between 0 and 50 ° C, 14 "Processes according to points Id and 2i> characterized in that the Lewis acid used is alufinium chloride, Characterized in that the reaction is carried out at temperatures between 0 and 120 Ci, but preferably at temperatures between 20 and 80 ° Cfi. 16 · Process according to items Ie and 2 », characterized in that the reaction is carried out in the presence of an alkali metal base and at temperatures between 0 and 80 CSi but preferably at temperatures between 25 and 50 ° C. 17 * Process according to the points If and Z%, characterized in that the reaction is carried out at temperatures between 0 and 100 Ct, but preferably at temperatures between 20 and 50 ⁰ CJg, 18 * Procedure according to points Ig and Zr ₉ . characterized by !! that the reaction is carried out in the presence of an excess of the amine used of the general formula XI and / or its N-formyl derivative 19 »method according to the points Igr» 2 and Ι8ί> characterized in that the reaction in the presence of an inorganic or tertiary organic base * in the presence 28. 5 · 82 AP C 07 D / 236 597/8 - Π52Τ - 60 193 12 a reaction accelerator such as copper or a copper salt and / or carried out in a pressure vessel. Process according to the items Igfg 18 and I9> j characterized in that the reaction takes place at temperatures between 20 and 150 ° C but preferably at the boiling temperature of the Reaktionsgemischesfi z. 8 »is carried out at 100 ⁰ C ^« Process according to items 1h and 2S3: characterized in that the reaction is carried out at temperatures between 100 and 100 ° C, preferably at temperatures between 20 and 50 ° C. and aa hydrogen pressure of 1 to 5 bar is performed. 22 * Method according to item lir * characterized by ^; that the reaction is carried out in the presence of sulfuric acid. 23 * A process according to points Ii "in 2 ?, and 221 dadurchfv that the reaction is carried out at temperatures between 20 and 15o C ⁰ ?, preferably at temperatures between 80 and ⁰ 1Ö0 Ci performed.