DE3225155A1 - Novel N-benzylamides and their salts, their preparation and pharmaceuticals containing these compounds - Google Patents

Abstract

Novel N-benzylamides of the general formula <IMAGE> in which R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a nitro group, an alkyl or alkoxy group, R2 denotes an aryl group having 6 to 10 carbon atoms, which is optionally mono- or disubstituted by halogen atoms, by alkyl, hydroxyl, alkoxy, phenylalkoxy, alkylsulphenyl, alkylsulphinyl and/or alkylsulphonyl groups, where the substituents can be identical or different, or a heteroaryl group having 4, 5, 8 or 9 carbon atoms and containing 1 or 2 nitrogen atoms, R3 denotes a hydrogen or halogen atom, A denotes an unbranched alkyleneimino group having 4 to 6 carbon atoms, which can be substituted by one or two alkyl groups, or an octahydroazocino, octahydro-1H-azonino or decahydroazecino group, a dialkylamino group, an allyloxy group or an alkoxy group and W denotes a carboxyl, formyl, hydroxymethyl, nitro, cyano, aminocarbonyl, 2-hydroxycarbonylethylene, 2-hydroxycarbonylethyl or 2,2-bis(hydroxycarbonyl)ethyl group, an alkoxycarbonyl group, an ethylene group which is substituted in the 2-position by an alkoxycarbonyl group or an ethyl group which is substituted in the 2-position by one or two alkoxycarbonyl groups, and their salts which have useful pharmacological properties, in particular a hypoglycaemic action. The compounds of the formula I can be prepared by processes customary for analogous compounds.

Description

New N-benzylamides and their salts, their preparation and medicaments containing these compounds. The present invention relates to new N-benzylamides of the general formula their enantiomers and their salts, in particular their physiologically tolerable salts with inorganic or organic acids and bases, drugs containing these compounds and processes for their preparation.

The new compounds have valuable pharmacological properties on, in particular an effect on the metabolism, but preferably one that lowers blood sugar Effect.

In the above general formula I, R1 denotes a fluorine or bromine atom, a chlorine atom in the 3-, 4- or 6-position, a nitro group, an alkyl or alkoxy group each with 1 to 3 carbon atoms or also a hydrogen atom or a chlorine atom in the 5-position if either A is an unbranched alkyleneimino group with 4 to 6 Carbon atoms replaced by one or two alkyl groups each having 1 to 3 carbon atoms is substituted, an octahydro-azocino, octahydro- 1 H-azonino or decahydro-azecino group, a dialkylamino group having 1 to 5 carbon atoms in each alkyl part, an allyloxy group or an alkoxy group with 1 to 3 carbon atoms and / or R2 is a halogen atom, by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulphinyl and / or Alkylsulfonyl mono- or disubstituted aryl group with 6 or 10 carbon atoms, wherein the alkyl part can each contain 1 to 3 carbon atoms, the naphthyl group or a heteroaryl group containing 1 or 2 nitrogen atoms with 4, 5, 8 or 9 carbon atoms and / or W is a hydroxymethyl, formyl, nitro, cyano, aminocarbonyl, 2-hydroxycarbonylethylene, 2-hydroxycarbonylethyl or 2,2-bis (hydroxycarbonyl) ethyl group, an ethylene group substituted in the 2-position by an alkoxycarbonyl group or an ethyl group substituted in the 2-position by one or two alkoxycarbonyl groups the alkoxycarbonyl group each containing a total of 2 to 4 carbon atoms can, and / or R3 represents a halogen atom, R2 is optionally substituted by halogen atoms, by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulphinyl and / or Mono- or alkylsulfonyl groups disubstituted aryl group with 6 or 10 carbon atoms, the substituents being identical or different can and the alkyl part can each contain 1 to 3 carbon atoms, or one 1 or 2 nitrogen atoms containing heteroaryl group with 4, 5, 8 or 9 carbon atoms, R3 is a hydrogen or halogen atom, A is an unbranched alkyleneimino group 4 to 6 carbon atoms represented by one or two alkyl groups, each with 1 to 3 carbon atoms can be substituted, an octahydro-azocino-, octahydro-1H-azonino- or decahydro-azecino group, a dialkylamino group having 1 to 5 carbon atoms in each alkyl part, an allyloxy group or an alkoxy group having 1 to 3 carbon atoms and W is a carboxy, formyl, hydroxymethyl, nitro, cyano, aminocarbonyl, 2-hydroxycarbonylethylene, 2-hydroxycarbonylethyl or 2,2-bis (hydroxycarbonyl) ethyl group, an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, one in the 2-position through an alkoxycarbonyl group substituted ethylene group or one in the 2-position by one or two alkoxycarbonyl groups substituted ethyl group, the alkoxycarbonyl group in each case from 2 to May contain 4 carbon atoms.

For the meanings mentioned at the beginning in the definition of the radicals come for example for R1 the meaning of hydrogen, fluorine, chlorine or Bromine atom, the nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy group, for R2 that of the phenyl, naphthyl, Fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, isopropylphenyl, Hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl, benzyloxyphenyl, 2-phenylethoxyphenyl-, 3-phenylpropoxyphenyl-, methylsulfenylphenyl-, ethylsulfenyl-phenyl-, Methylsulfinylphenyl, n-propylsulfinylphenyl, methylsulfonylphenyl, ethylsulfonylphenyl, Isopropylsulfonylphenyl, methyl naphthyl, hydroxynaphthyl, methoxy naphthyl, Dichlorophenyl, chloro-bromophenyl-, dimethyl-phenyl-, di-isopropyl-phenyl-, chloromethyl-phenyl-, Dimethoxyphenyl-, methyl-methoxyphenyl-, chloromethoxyphenyl-, bromo-methoxyphenyl-, Pyridyl, pyrimidyl, quinolyl, isoquinolyl or quinazolyl group, for R3 the the hydrogen, fluorine, chlorine or bromine atom, for A the methoxy, ethoxy, Propoxy, isopropoxy, allyloxy, dimethylamino, diethylamino, di-n-propylamino, Di-n-butylamino, di-n-pentylamino, diisobutylamino, N-methyl-ethylamino, N-methyl-n-propylamino, N-5Sethyl-isopropylamino-, N-isopropyl-n-propylamino-, N-isobutyl-n-propylamino-, N-methyl-n-butylamino-, N-ethyln-butylamino-, N-ethyl-isopropylamino-, N-Ä.thyl-n-pentylamino-, N-propyl-n-butylamino-, pyrrolidino-, piperidino-, hexahydro-1H-azepino-, octahydro-azocino-, Octahydro-1H-azonino-, decahydro-azec'ino-, methyl-pyrrolidino-, dimethylpyrrolidino-, Ethyl pyrrolidino, methyl piperidino, ethyl piperidino, diethyl piperidino, Methyl-ethylpiperidino-, propyl-piperidino-, methyl-propyl-piperidino-, isopropyl-piperidino- or dimethyl piperidino group and for W that of the hydroxymethyl, formyl, nitro, Carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, cyano, aminocarbonyl, 2-hydroxycarbonyl-ethylene, 2-methoxycarbonyl-ethylene-, 2-ethoxycarbonyl-ethylene-, 2- Propoxycarbonyl ethylene, 2-hydroxycarbonyl-ethyl, 2-methoxycarbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 2-isoprooxycarbonyl-ethyl, 2,2-bis (hydroxycarbonyl) ethyl, 2,2-bis (methoxycarbonyl) ethyl, 2,2-bis (ethoxycarbonyl) ethyl or 2,2-bis (propoxycarbonyl) ethyl group into consideration.

Preferred compounds of the above general formula I, however, are those in which R1 is a methyl, methoxy or nitro group, a chlorine atom in 3-, 4- or 6-position or also a hydrogen atom or a chlorine atom in the 5-position, when either A is a dialkylamino group having 1 to 3 carbon atoms in each alkyl moiety, a methoxy-, methyl-piperidino-, dimethyl-piperidino-, octahydro-azocino- octahydro-lH-azonino- or decahydro-azecino group and / or R2 one through a fluorine or chlorine atom a methyl, hydroxy, methoxy, benzyloxy, methylsulfenyl, methylsulfinyl or Methylsulfonyl group substituted phenyl group or a pyridyl group and / or W is a hydroxymethyl, formyl, nitro, cyano, aminocarbonyl, 2-hydroxycarbonyl-ethylene, 2-Hydroxycarbonyl-ethyl or 2,2-bis (hydroxycarbonyl) -ethyl group, one in the 2-position ethylene group substituted by an ethoxycarbonyl group or one in the 2-position ethyl group substituted by one or two ethoxycarbonyl groups and / or R3 represents a halogen atom, R2 represents an optionally replaced by a fluorine or chlorine atom, by a methyl, hydroxy, methoxy, benzyloxy, Kethylsulfenyl, Methylsulfinyl or methylsulfonyl group substituted phenyl group or a pyridyl group R3 is a hydrogen or chlorine atom, A is a dialkylamino group with 1 to 3 carbon atoms in each alkyl part, a methoxy, pyrrolidino, piperidino, ~~ methyl piperidino, Dimethyl-piperidino-, hexahydro-1H-azepino-, octahydro-azocino-, octahydro-1H-azonino- or decahydro-azecino group and W is a carboxy, hydroxymethyl, formyl, nitro, Cyano-, aminocarbonyl-, 2-hydroxycarbonyl-ethylene-, 2-hydroxycarbonyl-ethyl-, 2,2-bis- 2,2-bis (hydroxy-carbonyl) -ethyl-, 2-ethoxycarbonyl-ethylene-, 2-thoxycarbonyl-ethyl- or 2,2-bis (ethoxycarbonyl) ethyl group or an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, and their salts, in particular their physiological compatible salts with inorganic or organic acids and bases.

However, particularly preferred compounds are the compounds of the general formula in which A denotes the methoxy, piperidino, methylpiperidino or 3,5-dimethylpiperidino group, R1 denotes a chlorine atom, the methyl or methoxy group and R2 denotes a phenyl group substituted by a methyl group, a fluorine or chlorine atom or a pyridyl group, and their physiologically compatible salts with inorganic or organic bases.

According to the invention, the new compounds are obtained by the following process. a) Acylation of an amine of the general formula in which A, R1 and R2 are as defined at the outset, with a carboxylic acid of the general formula in which R3 is defined as at the beginning and W 'has the meanings mentioned for W at the beginning or represents a carboxyl group protected by a protective radical, or with its reactive derivatives which may have been prepared in the reaction mixture.

As reactive derivatives of a compound of the general formula III come, for example, their esters such as the phenyl ester, their thioesters such as the slethylthio- or ethylthioester, their ttalogenide like the acid chloride, their Anhydrides or imidazolides into consideration.

The reaction is expediently carried out in a solvent such as methylene chloride, Chloroform, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activating agent or a dehydrating agent Means, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, Phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, X, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or an amino group activating agent, e.g., phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic Base such as triethylamine or pyridine, which also serve as solvents can, at temperatures between -25 and 2500C, but preferably at temperatures between -100C and the boiling point of the solvent used. The reaction can also be carried out without a solvent.

If necessary, the subsequent cleavage of a protective residue preferably carried out hydrolytically, expediently either in the presence 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 one Solvents such as water, methanol, ethanol, ethanol / water, water / isopropanol or water / dioxane at temperatures between -10 and 1200C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture.

A tert-butyl radical used as a protective radical can also be used thermally optionally in an inert solvent such as methylene chloride, chloroform, benzene, Toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic one Amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid, or polyphosphoric acid be split off.

Furthermore, a benzyl radical used as a protective radical can also be split off 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. b) To prepare a compound of the general formula I in which W represents a carboxy group: cleavage of a compound of the general formula in which R1 to R3 and A are as defined at the outset and B represents a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis.

Functional derivatives, for example, can be used as hydrolyzable groups the carboxy group such as their unsubstituted or substituted amides, esters, thioesters, Orthoesters, imino ethers, amidines or anhydrides, the nitrile group, a malonic ester - (1) -yl group, the tetrazolyl group, an optionally substituted 1,3-oxaz41-2-yl or 1,3-oxazolin-2-yl group and as thermolytically 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, can be considered.

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

If B in a compound of the general formula IV is a nitrile or aminocarbonyl group, these groups can also be combined with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulfuric acid, which is expediently carried out simultaneously is used as a solvent, at temperatures between 0 and 50 0C in the carboxy group be transferred.

If B in a compound of the general formula IV is, for example the tert-butyl carbonyl group, the tert-butyl group can optionally also be used thermally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, Tetrahydrofuran or dioxane and preferably in the presence of a catalytic constriction an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling point of the solvent used, e.g. at temperatures be split off between 40 and 1000C.

If B in a compound of general formula IV is, for example, the benzyloxycarbonyl group, the benzyl group can 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 be split off at temperatures between 0 and 50 °, for example at room temperature, and a hydrogen pressure of 1 to 5 bar. During the hydrogenolysis, other groups can be reduced at the same time, for example a halogen compound can be anhalogenously frozen and a nitro group can be converted into the corresponding amino group. c) For the preparation of a compound of the general formula I in which W represents the carboxy group: Oxidation of a compound of the general formula in which R1 to R3 and A are as defined at the outset and D represents a group which can be converted into a carboxy group by oxidation.

An example of such an oxidizable group is the formyl group and their acetals, the hydroxymethyl group and their ethers, an unsubstituted one or substituted acyl groups such as cetyl, chloroacetyl, proponyl, walonic 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, methylene chloride, dioxane or glycol dimethyl ether at temperatures between 0 and 100.degree. C., but expediently at temperatures between 20.degree. And 50.degree. 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 hydroxide or potassium hydroxide solution or chromium trioxide / pyridine. d) Reduction of an imino compound of the general formula in which R1 to R3, A and are defined as 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 10,000, but preferably at temperatures between 20 and 5000, and a hydrogen pressure of 1 to 5 bar. When using a suitable chiral hydrogenation catalyst such as a metal ligand complex, for example a complex of rhodium chloride and (+) - or (-) O, O-isoropylidene-2,3-hydroxy-1,4-bis (diphenylphosphino) butane (= DIOP ), the hydrogen addition can take place enantioselectively. Furthermore, other reducible groups can also be reduced in the catalytic hydrogenation, for example a nitro group to the amino group or a chlorine or bromine atom to the hydrogen atom. e) Implementation of a compound of the general formula in aer R1, R2 and A are as defined at the outset, with a compound of the general formula in which R3 and W are as defined at the beginning.

The reaction is carried out in the presence of a strong acid, which at the same time can serve as a solvent, preferably in concentrated sulfuric acid Temperatures between 20 and 1500C, preferably at temperatures between 20 and 600C.

According to the invention, a compound of the general formula is obtained I, in the ': represents the Garboxygruppe, this can, if desired, by means of Esterification or kmidation into a corresponding compound of the general formula I are converted and / or a compound of the general formula I in which R1 represents a nitro group, this can be converted into a corresponding one by means of reduction Compound of the general formula I in which R 1 represents an amino group, converted and a compound obtained in this way via a corresponding diazonium salt in a corresponding compound of the general formula I, in which R1 is a hydrogen, Represents fluorine, chlorine or bromine atom or a hydroxyl group, are converted, wherein a compound of the general formula I, optionally obtained in this way, is in the R1 represents the hydroxyl group, then converted into a corresponding one by means of alkylation Compound of the general formula I can be converted in which R1 is an alkoxy group represents, and / or a compound of the general formula I in which W is a nitro group represents, this can be converted into a corresponding compound of the general formula I, in which W represents an amino group, are converted and a compound obtained in this way via a corresponding diazonium salt into a corresponding one Compound of the general formula I, in which W represents the cyangrupne, converted are, and / or a compound of the general formula I in which R1 is a chlorine or Represents bromine atom, by means of dehalogenation into a corresponding compound of general formula I, in which R1 represents a hydrogen atom, can be converted and or a compound of the general formula I in which ri a Represents carboxy or alkoxycarbonyl group, so this can by means of reduction in a corresponding compound of the general formula I in which W is a rormyl or Is hydroxymethyl group, are converted and / or a compound of the general Formula I, in which W represents a hydroxymethyl group, this can, after conversion into a corresponding halomethyl compound by reaction with a malonic acid diester into a corresponding compound of the general formula I, in which W one through two Represents alkoxycarbonyl groups substituted ethyl group, are converted and / or a compound of the general formula I in which W represents a formyl group, so this can by means of condensation and, if appropriate, subsequent hydrolysis and / or Decarboxylation into a corresponding compound of general formula I in which W is a vinyl group substituted by a hydroxycarbonyl or alkoxycarbonyl group represents, are converted and / or a compound of the general formula I, in which W represents an ethyl group substituted by two alkoxycarbonyl groups, this can be converted into a corresponding compound of the general by means of hydrolysis Formula I, in which W represents an ethyl group substituted by two carboxy groups, be converted and / or a compound of the general formula I in which W is a is ethyl group substituted by two alkoxycarbonyl groups, this can by means of hydrolysis and decarboxylation into a corresponding compound of the general Formula 1, in which 1 'represents a 2-hydroxycarbonylthyl group, can be converted and or a compound of the general formula I, in which W the Carboxo group, this can be converted into a SulLonsäurehydrazid and subsequent disproportionation into a corresponding compound of the general Formula I, in which represents the formyl group, can be converted and / or a compound of the general formula I, in which R2 is a mono- or disubstituted by a 3enzyloxy radical Aryl radical, this can be converted into a corresponding hydroxy compound by means of ntbenzylation of the general formula I are converted and / or a compound of the general Formula I, in which R2 is a mono- or disubstituted by an alkylsulfenyl radical Represents aryl radical, this can be converted into a corresponding alkylsulfinyl compound by means of oxidation be converted and / or a compound of the general formula I in which R2 one mono- or disubstituted by an alkylsulfenyl or alkylsulphinyl radical If aryl radical is represented, this can be converted into a corresponding alkylsulfonyl compound by means of oxidation be converted and / or a compound of the general formula I in which W is a Aminocarbonyl group represents, this can by means of dehydration in a corresponding Compound of the general formula I, in which W represents a cyano group, converted will.

The subsequent esterification is expediently carried out in a suitable Solvent, e.g. in an appropriate alcohol, pyridine, toluene, methylene chloride, Tetrahydrofuran or dioxane, in the presence of an acid-activating and / or dehydrating one Means such as thionyl chloride, ethyl chloroformate, Garbonyldlimidazol or N, N-dicyclohexylcarbodiimide, optionally in the presence of a reaction accelerator such as Nuufer chloride, or by transesterification, e.g. with an appropriate Carbonic acid diester, at temperatures between 0 and 1000C, but preferably at temperatures between 200C and the boiling point of the solvent in question.

The subsequent amidation is expediently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, Dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence an acid activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, Phosphorus pentoxide, N, N1-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole, N, N1-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or an amino group activating agent, e.g., phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic Base such as triethylamine or pyridine, which also serve as solvents can, at temperatures between -25 and 2500C, but preferably at temperatures between -100C and the boiling point of the solvent used. The reaction can also be carried out without a solvent.

Post reduction of the nitro compound is preferred in a solvent such as water, water / ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, expediently with hydrogen in the presence of a hydrogenation catalyst like Raney nickel, platinum or palladium / carbon, with metals like iron, or tin Zinc in the presence of an acid, with salts such as iron (II) sulfate, tin (II) chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50 ° C, but preferably at room temperature, carried out.

The subsequent conversion of a diazonium salt, e.g. the fluoroborate, the hydrosulphate in sulfuric acid or the hydrochloride, if necessary in Presence of copper or a corresponding copper (I) salt such as copper (I) chloride / hydrochloric acid, Copper (I) bromide / hydrobromic acid or trisodium copper (I) tetracyanide pH 7, becomes at slightly elevated temperatures, e.g. at temperatures between 15 and 100 C, performed; the subsequent reaction with hypophosphorous acid is preferably carried out at -5 to OOC. The diazonium salt required for this is expediently in a suitable solvent, z.3. in s * 7asser / hydrochloric acid, Methynol / hydrochloric acid, ethanol / hydrochloric acid or dioxane / hydrochloric acid, by diazotization a corresponding amino compound with a nitrite, e.g. sodium nitrite or a Esters of nitrous acid, at lower temperatures, e.g. at temperatures between -10 and 5 ° C.

The subsequent dehalogenation or debenzylation is expedient 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 750C, preferably but carried out at room temperature and at a hydrogen pressure of 1-5 bar.

The subsequent O-alkylation is expediently carried out with a corresponding Ualogenide, 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, ethanol, ethanol, pyridine or dimethylformamide at temperatures between 0 and 750 ° C., but preferably at room temperature.

The subsequent reduction is preferably carried out with a metal hydride, for example with a complex metal hydride such as lithium aluminum hydride in a suitable Solvents such as diethyl ether, tetrahydrofuran or dioxane at temperatures between 0 and 100 ° C., but preferably at temperatures between 20 and GOOC.

The subsequent conversion of a hydroxymethyl group into a halomethyl group is 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, e.g. with an alkali salt of the diethyl balonate, at temperatures between 0 and 1000 ° C., but preferably at temperatures between 50 and 80 ° C.

Post condensation of a formyl compound is expedient in a solvent such as pyridine or tetrahydrofuran with malonic acid, with a Malonic acid ester, with a dialkyl phosphonoacetic acid ester or an alkoxycarbonyl triphenyl phosphonium methylide, optionally in the presence of a base as a condensing agent, e.g. in the presence of piperidine, potassium tert-butoxide or nitrium hydride, at temperatures between 0 and 100 ° C carried out; by subsequent acidification, e.g. with hydrochloric acid or Sulfuric acid, or by subsequent alkaline hydrolysis, one obtains the desired Acid.

Post hydrolysis or hydrolysis and decarboxylation will expediently 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, Nfasser / isopropanol or water / dioxane at elevated temperatures, e.g. carried out at the boiling point of the reaction mixture.

The subsequent disproportionation of a sulfonic acid hydrazide, which one by reacting a corresponding hydrazine with a corresponding reactive carboxylic acid derivative is obtained in the presence of a base such as sodium carbonate in a solvent such as ethylene glycol at temperatures between 100 and 2000C, but preferably carried out at 160-170 ° C.

The subsequent oxidation of a compound of the general formula I, in which R2 is a mono- or by an alkylsulfenyl or alkylsulfinyl radical represents disubstituted aryl radical, is preferably in a solvent or Solvent mixture, e.g. B. in water, water / pyridine, acetone, glacial acetic acid, dilute Sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used expediently carried out at temperatures between -80 and 1000C. For the production an alkanesulfinylmethyl compound of the general formula I, this is expediently carried out with one equivalent of the oxidizing agent used, e.g. B. with hydrogen peroxide in glacial acetic acid or trifluoroacetic acid at 0 to 200C or in acetone at 0 to 600C, with a peracid such as peracetic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20 to 60 ° C, with sodium metaperiodate in aqueous ethanol or ethanol at 15 to 250C or with bromine in glacial acetic acid or aqueous acetic acid and for the preparation of an alkanesulfonylmethyl compound the general formula I, this oxidation is expediently with a or with carried out two or more divalents of the oxidizing agent used, e.g. 3. with hydrogen peroxide in glacial acetic acid or trifluoroacetic acid at 20 to 1000C or in acetone at 0 to 60 ° C, with a peracid such as peracetic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform Temperatures between 0 and 600C, with nitric acid in glacial acetic acid at 0 to 200C, with chromic acid or potassium permalcanate in glacial acetic acid, water / sulfuric acid or in acetone at 0 to 20 ° C.

The subsequent dehydration is done with a dehydrator Agents such as phosphorus pentoxide, sulfuric acid or p-toluenesulfonic acid chloride, if appropriate in a solvent such as methylene chloride or pyridine at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C carried out.

The compounds of the general formula I obtained can also be used separate into their enantiomers by conventional methods. This separation is preferably done by fractional crystallization of their diastereomeric derivatives or salts.

The compounds of general formula I obtained can also be used in their addition salts, especially in their physiologically acceptable salts transferring inorganic or organic acids or bases. Come as acids here, for example, 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 into consideration.

The compounds of the general formulas used as starting materials II to VIII are partly known from the literature or are obtained according to known ones Procedure.

For example, a compound of the general formula is obtained in this way II by reacting a corresponding nitrile with a corresponding aryl magnesium halide or a corresponding aryl-lithium compound and subsequent reduction of the intermediately obtained ketimine with catalytically excited or nascent hydrogen or with a complex metal hydride, by implementing a corresponding Ketones with hydroxylamine and reduction of the oxime obtained in this way with catalytically activated or nascent hydrogen or with a complex metal hydride, by reaction a corresponding acetone with formamide at temperatures between 150 and 250 C, by reductive amination using Av2.0nium salts in the presence of formic acid or by means of ammonium salts in the presence of sodium cyanoborohydride, by treatment a corresponding 2-halo-benzophenone with a corresponding secondary Amine, optionally with copper catalysis and subsequent conversion of the carbonyl group into the amino group, by alkylating corresponding 2-amino-benzophenones with %, w-dihaloalkanes and subsequent conversion of the carbonyl group into the amino group, by alkylating a corresponding 2-hydroxy-benzophenone with alkyl halides in the presence of a base and subsequent conversion of the carbonyl group into the amino group, by reducing a corresponding N-3enzyl- or N-acyl-ketimine compound with a complex metal hydride or with catalytically excited hydrogen, whereby here in the case of the benzyl protective group, its simultaneous cleavage takes place, by Curtius, Lossen or Schmidt degradation of a corresponding carboxylic acid derivative, by Ritter reaction of a corresponding alcohol with potassium cyanide in sulfuric acid and subsequent hydrolysis or by reaction of a corresponding halide with Phthalimide potassium and subsequent hydrolysis or hydrazinolysis of the corresponding Phthalimido compound.

An amine of the general formula II obtained in this way with a chiral one The center can be achieved by resolution, e.g. by means of fractional crystallization of the diastereomeric salts with optically active traces and subsequent decomposition of the salts or by the formation of diastereomeric compounds, their separation and subsequent cleavage are separated into their enantiomers. Furthermore, a Optically active amine of the general formula II also by enantioselective reduction a corresponding ketimine using complex boron or aluminum hydrides, in which part of the hydride hydrogen atoms through optically active alcoholate residues is replaced, or by means of hydrogen in the presence of a suitable chiral Hodrierunosatalysators are prepared, with a corresponding N-acyl, N-benzyl or optionally optically active N-1-phenethyl-ketimine can be assumed and if necessary, the splitting off of the benzyl or 1-phenethyl radical is then carried out will.

-The compounds of the general formulas used as starting materials IV and V are obtained by reacting a corresponding amine with a corresponding one Carboxylic acid or its reactive derivatives and, if appropriate, subsequent hydrolysis.

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

As already mentioned at the beginning, the new compounds have the general Formula I on valuable pharmacological properties, namely an effect on the intermediate metabolism, but especially a blood sugar lowering effect.

For example, the compounds A = 4- / hr- / r, - (4-methylphenyl) -2-piperidino-benzyl / carbamoylmethyl-benzoic acid, B = 4 - / - / x- (3-methyl-phenyl) -2-piperidino-benzyl / carbamoylmethyl / benzoic acid, C = 4- / Ñ- / K- (4-fluoro-phenyl) -2-piperidino-benzyl-carbamoylmethyl / benzoic acid, D = 4- / N-7- (2-fluorophenyl) -2-piperidino-benzyl / carbamoylmethyl / benzoic acid, E. = 4- [N- [α- (4-chlorophenyl) -2-piperidino-benzyl] carbamoyl meth / benzoic acid, F = 4 »- / X- (3-chloro-» henyl) -2-piperidino-benzyl / carbamoylmethyl] benzoic acid, G. = 4- [N- [2-piperidino-α- (2-pyridyl) benzyl] carbamoylmethyl] benzoic acid H = 4- [N- [2-piperidino-α- (4-pyridyl) benzyl / carbamoyl meth / benzoic acid, I = 4- [N- (4-chloro-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] benzoic acid, K. = 4- [N- (6-chloro-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] benzoic acid, L = 4- [N- (6-methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] benzoic acid M = 4- [N- (4-methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl-7 benzoic acid and N = 4- [N- (2-methoxy-α-phenyl-benzyl) carbamoylmethyl] benzoic acid on their own Blood sugar lowering properties were studied as follows: 1. Hypoglycemic l7irkun: The blood sugar-lowering effect of the substances to be examined was on female rats of our own breeding with a weight of 180-220 g tested, which 24 Hours before the start of the experiment. The substances to be examined were suspended in 1.5% methyl cellulose immediately before the start of the experiment and applied by gavage.

The blood was taken immediately before the substance was administered, as well 1, 2, 3 and 4 hours later from the retroorbital venous plexus. Of this 50 μl each were deproteinized with 0.5 ml of 0.33 N perchloric acid and centrifuged. In the supernatant, glucose was determined by the hexokinase method with the aid of an analytical photometer certainly. The statistical evaluation was carried out using the Student's t-test p = 0.05 as the limit of significance.

The following table contains the values found in percent compared to controls: Table 1 Sub- 25 mg / kg 10 mg / kg 5 5 mg / kg punch 1 2 3 4 1 2 3 4 1 2 3 4 Hours hours hours A | -41 -44 -26 -31 -30 -33 -14 ns B -43 -36 -35 -28 -43 -38 -36 -27 C -44 -39 -38 -43 -36 -37 -36 -33 D -30 -28 -29 -23 -28 -32 -27 -28 E -30 -38 -39 -36 FF -36 -30 -30 -26 -43 -39 -30 -26 G -49 -50 -36 -31 H -41 -37 -20 ns I -34 -35 -32 -29 K -39 -35 -32 -38 -43 -41 -42 -41 -44 -40 -39 -40 L -43 -42 -40 -38 M -37 -34 -32 -31 N -46 -40 -36 -31 -39 -31 -27 -20 -28 -11 nsns ns = not statistically significant 2. Acute toxicity: In female and male mice of our own breeding, weighing 20-26 g, the toxic effects after oral cabe (suspension in 1% ethyl cellulose) of a single dose with a follow-up period of 14 days were tested .

The following table contains the values found: substance orienting toxicity A> 1000 mg / kg p.o. (0 out of 10 animals died) B> 1000 mg / kg p.o. (0 out of 10 animals died) C> 1000 mg / kg p.o. (0 out of 10 animals died) D) 1000 mg / kg p.o. (0 out of 10 animals died) E> 1000 mg / kg p.o. (0 out of 10 animals died) G) 1000 mg / kg p.o. (0 out of 10 animals died) Due to their pharmacological properties The compounds of the general properties prepared according to the invention are suitable Formula I and their physiologically tolerable salts for the treatment of diabetes mellitus. For this purpose, they can be used, if necessary in combination with other active substances, in the usual galenic preparation forms such as tablets, coated tablets, capsules, Incorporate powder or suspensions. The single dose for adults is here 1-50 mg, but preferably 2.5-20 mg, 1 or 2 times a day.

The following examples are intended to explain the invention in more detail: example 1 ethyl 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] carbamoylmethyl] benzoate To 4.2 g (15 mmol) of α- (4-methylphenyl) -2-piperidino-benzylamine and 3.4 g (16.5 mmol) of 4-ethoxycarbonyl-phenylacetic acid, dissolved in 40 ml of acetonitrile, are added one after the other 4.7 g (18 mmol) triphenylphosphine, 3 g (30 mmol) triethylamine and 1.5 ml (15 mbNol) Carbon tetrachloride. The reaction mixture is stirred at 50 ° C. for 2 hours, then concentrated and, after acidification with 6N hydrochloric acid, extracted with ethyl acetate. The acidic aqueous phase is then extracted several times with methylene chloride. The methylene chloride extracts are washed with sodium bicarbonate solution over magnesium sulfate dried and concentrated. The residue is triturated with ethanol and sucked off.

Yield: 4.55 g (65% of theory), melting point: 177-178 ° C, calc .: C 76.57 H 7.28 N 5.95 Found: 76.19 7.16 5.82 The following were prepared in the same way as in Example 1: Ethyl 4- / N- / W- (3-methyl-phenyl) -2-piperidino-benzyl / carbamoyl meth- yl / benzoate Yield. 48 90 of theory, melting point: 159-1600C, calc .: C 76.57 H 7.28 N 5.95 Found: 76.80 7.35 5.76 Ethyl 4- [N- [α- (2-methyl-phenyl) -2-piperidino-benzyl] carbamoylmethyl] -benzoate Yield: 35.4 l of theory, melting point: 196-1980C Calc .: C 76.57 H 7.28 N 5.95 Found: 76.65 7.35 5.90 Ethyl 4- [N- [α- (4-methoxyphenyl) -2-piperidino-benzyl] carbamolymethyl] -benzoate Yield: 45% of theory, melting point: 167-1680C.

Calc .: C 74.05 H 7.04 N 5.76 Found: 73.72 6.99 5.62 4- [N- [α- (4-Benzyloxyphenyl) -2-piperidino-benzyl] carbamoylmethyl ] ethyl benzoate Yield: 96% of theory, melting point: 154-1550C.

Calc .: C 76.84 H 6.81 N 4.98 Found: 76.82 6.68 5.03 4- [N- [α- (4-fluorophenyl) -2-piperidino-benzyl] carbamoylmethyl] -benzoic acid ethyl ester Yield: 58% of the Theory, melting point: 174-176 ° C.

Calc .: C 73.40 H 6.58 N 5.90 Found: 73.55 6.72 5.91 4- [N- [α- (2-fluoro-phenyl) -2-piperidino-benzyl] carbamoylmethyl ] ethyl benzoate Yield: 83% of theory, melting point: 173-175 ° C.

Calc .: C 73.40 H 6.58 N 5.90 Found: 73.61 6.62 5.85 Ethyl 4- [N- [α- (4-chloro-phenyl) -2-piperidino-benzyl] carbamoylmethyl] -benzoate Yield: 57% of theory, melting point: 178-181 ° C.

Calc .: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 71.10 6.56 5.56 7.11 4- [N- [α- (3-chloro-phenyl) - 2-piperidino-benzyl] carbamoylmethyl] -benzoic acid ethyl ester Yield: 71% of theory, melting point: 153-1560C.

Calc .: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 70.86 6.26 5.65 7.25 4- / N Ethyl (2-chloro-phenyl) -2-piperidino-benzyl7carbamoylmethy17-benzoate Yield: 66% of theory, melting point: 196-1980C.

Calc .: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 70.90 6.30 5.61 7.10 4- [N- [α- (4-methylmercapto-phenyl) - 2-piperidino-benzyl] carbamoylmethyl7benzoic acid ethyl ester Yield: 84% of theory, melting point: 173-1750C.

Calc .: C 71.68 H 6.82 N 5.57 S 6.38 Found: 71.92 6.97 5.45 6.21 Ethyl 4- [N- [5-chloro-α- (2-chlorophenyl) -2-piperidino-benzyl] carbamoylmethylZbenzoate Yield: 92% of theory, melting point: 213-215 ° C.

Calc .: C 66.28 H 5.75 N 5.33 Cl 13.49 Found: 66.45 5.86 5.25 13.51 -4- [N- [2-piperidino-α- (2- pyridyl) benzyl] carbamoylmethyl] benzoic acid ethyl ester Yield: 51% of theory, melting point: 158-1590C.

Calc .: C 73.50 H 6.83 N 9.18 Found: 73.40 6.95 9.10 4- [N- [2-piperidino-α- (3-pyridyl) -benzyl] carbamoylmethyl] benzoic acid ethyl ester Yield: 85% of theory, melting point: 1720C.

Calc .: C 73.50 H 6.83 N 9.18 Found: 73.42 6.76 9.25 4- [N- [2-piperidino-α- (4-pyridyl) -benzyl] carbamoylmethyl] benzoic acid ethyl ester Yield: 20% of theory, melting point: 150-1520C.

Calc .: C 73.50 H 6.83 N 9.18 Found: 73.61 6.91 9.15 4- [N- (6-chloro-α-phenyl-2-piperidino-benzyl) carbamoylmethy] - ethyl benzoate Yield: 12% of theory, melting point: oil Ber .: Molpeak m / e = 490/492 Found: Molpeak m / e = 490/492 Ethyl 4- [N- (4-chloro-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoate Yield: 37% of theory, melting point: 148-1500C, calc .: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 70.81 6.25 5.61 7.12 Ethyl 4- [N- (3-chloro-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoate Yield: 74% of theory, melting point: 176-178 ° C. Calc .: C 70.94 H 6.36 N 5.71 Cl 7.22 Found: 70.59 6.25 5.68 7.16 Ethyl 4- [N- (6-Methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoate Yield: 65 t of theory, melting point: oil.

Calc .: Molpeak m / e - 470 Found: Molpeak m / e = 470 Ethyl 4- [N- (5-methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoate Yield: 48 40 of theory, melting point: 171-173 ° C.

Calc .: C 76.57 H 7.28 N 5.95 Found: 76.75 7.35 5.72 Ethyl 4- [N- (4-methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoate Yield: 76 e of theory, melting point: 133-1350C.

Calc .: C 76.57 H 7.28 N 5.95 Found: 76.51 7.16 5.83 -4- [N- (5-Methoxy-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoic acid ethyl ester Yield: 10% of theory, melting point: 122-1250C.

Calc .: Mol peak m / e = 486 Found: Mol peak m / e = 486 Ethyl 4- [N- (6-methoxy-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoate Yield: 97% of theory, melting point: oil.

Calc .: Mol peak m / e = 486 Found: Mol peak m / e = 486 ethyl 4- [N- (2-methoxy-α-phenyl-benzyl) carbamoylmethyl] benzoate Yield: 67% of theory, melting point: 129 C.

Calc .: C 74.41 H 6.24 N 3.47 Found: 74.52 6.30 3.25 4- [N- [α- (4-chloro-phenyl) -2-methoxy-benzyl] carbamoylmethyl ] ethyl benzoate Yield: 68% of theory, melting point: 154-155 ° C, Ber .: C 68.56 F 5.52 N 3.20 Cl 8.10 Found: 6S, 71 5.63 3.19 8.02 3-chloro-4- [N- (α-phenyl-2-piperidino-benzyl ) carbamoylmethyl] Ethyl benzoate Yield: 42 8 of theory, melting point: 175-1760C Calc .: C 70.93 H 6.36 N 5.71 Cl 7.22 Found: 70.65 6.36 5.50 7.29 4- [N- (2-Dimethylamino-α-phenyl-benzyl) carbamoylmethyl] Ethyl benzoate Yield: 67.9 of theory, melting point: 116-118 ° C. Calc .: C 74.97 H 6.77 N 6.73 Found: 75.13 6.60 6.78 4- [N- (2-Di-n-propylamino-α-phenyl-benzyl) carbamoylmethyl] ethyl benzoate Yield: 76 ° 6 of theory, melting point: 138-1390C, Ber. : C 76.24 H 7.68 N 5.93 Found: 76.41 7.79 5.81 4- [N- [2- (Octahydro-1H-azonino) -α-phenyl-benzyl] carbamoylmethyl] benzoic acid ethyl ester Yield: 71% of theory, melting point: oil ber. : Mol peak m / e = 498 found: Mol peak m / e = 498 4- [N- [5-chloro-2- (2-methyl-piperidino) -α-phenyl-benzyl] carbamoylmethyl] benzoic acid ethyl ester Yield: 36.5% of theory, melting point: 171-173 ° C, calc .: C 70.64 H 6.75 N 5.68 Cl 7.19 found: 70.45 6.68 5.59 7.20 4- [N- [2- (3 , 3-dimethyl-piperidino) -α-phenyl-benzyl] carbamolymethyl-benzoic acid ethyl ester Yield: 91% of theory, melting point: 146-1480C, calc .: C 76.82 H 7.49 N 5.78 Found: 76.91 7.55 5.61 Example 2 4- [N- [α- (4-Methylsulfinyl-phenyl) -2-piperidino-benzyl] carbamoylmethyl / benzoic acid ethyl ester 3 g (6 mmol) of 4- [N- [α- (4-methylmercapto-phenyl) -2-piperidinobenzyl] carbamoylmethyl / benzoic acid ethyl ester are dissolved in 50 ml of glacial acetic acid and, while stirring, with 0.7 g of 30% water peroxide solution added. After 90 minutes of stirring at 50 ° C. there is no starting material more detectable in the thin-layer chromatogram. It is poured into ice water and extracted with chloroform.

After drying over magnesium sulfate, the residue is concentrated rubbed with ethyl acetate and sucked off the crystals.

Yield: 2.6 g (72! Of theory).

Melting point: 190-1920C.

Calc .: C 69.47 H 6.61 N 5.40 S 6.18 Found: 69.56 6.73 5.25 6.05 example 3 Ethyl 4- [N- [α- (4-methylsulfonyl-phenyl) -2-piperidino-benzyl] carbamoylmethyl] benzoic acid, dihydrate 2.6 g (5.17 nq4ol) 4-LS α- (4-methylmercapto-phenyl) -2-piperidinobenzyl] carbamoylmethyl] benzoic acid ethyl ester are dissolved in 50 ml of isessic and after adding 6 ml of 30% hydrogen peroxide solution Heated to 500C for 4 hours. Then you pour on water, suck off the failed Precipitate and crystallizes from ethanol.

Yield: 2.2 g (75% of theory), melting point: 190-1920C (decomp.).

Calc .: C 63.14 H 6.71 N 4.91 S 5.62 Found: 63.49 6.43 5.02 6.01 Example 4 Ethyl 4- [N- [5-chloro-2- (3-methyl-piperidino) -α-phenyl-benzyl] carbamoylmethyl] benzoate To a solution of 7.9 g (25 mmol) of 5-chloro-2- (3-methylpiperidino) - P (-phenyl-benzylamine) and 3.7 ml (26 mmol) of triethylamine in 50 ml of chloroform are added dropwise under lighter Ice cooling a solution of 6.0 g (26.5 mmol) of 4-ethoxycarbonyl-phenylacetyl chloride in 20 ml of chloroform. The mixture is stirred for two hours at room temperature, then poured into water and extracted with chloroform. The extracts are dried and concentrated and the residue on silica gel with toluene / ethyl acetate 5: 1 as the mobile phase chromatographed.

Yield: 6.6 a (54 U of theory), melting point: 178-1800C.

Ber. : C 70.64 H 6.75 N 5.68 Cl 7.19 Found: 70.51 6.64 5.75 7.01 example 5 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] carbamoylmethyl] -benzoic acid 4.4 g (9.35 mmol) of ethyl 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -carbamoylmethyl] benzoate are dissolved in 150 ml of ethanol with warming. Then 20 ml of 1N are added Sodium hydroxide solution is added and the mixture is stirred at 50 ° C. for 3 hours. According to the thin-layer chromatogram, there is no Source material more detectable. 20 ml of 1N are then added to the reaction mixture Hydrochloric acid and removes excess ethanol by concentrating on a rotary evaporator.

The remaining aqueous suspension is filtered and the precipitate washed well with water. It is then recrystallized from acetonitrile.

Yield: 2.45 g (59.3% of theory), melting point: 226-228 ° C.

Calc .: C 75.99 H 6.83 N 6.33 Found: 75.60 6.75 6.29 Analogous to the example 5 were prepared: 4- [N- [α- (3-methyl-phenyl) -2-piperidino-benzyl] carbamoylmethyl] -benzoic acid Yield: 72% of theory, melting point: 202-203 ° C.

Calc .: C 75.99 H 6.83 N 6.33 Found: 75.64 6.91 6.37 4- / N- / - (2-methyl-phenyl) -2-piperidino-benzyl7carbamoylmethyl7-benzoic acid Yield: 42.6 90 of theory, Melting point: 285-290 ° C. Calc .: C 75.99 H 6.83 N 6.33 Found: 76.05 6.98 6.25 4- [N- [α- (4-methoxyphenyl) -2-piperidino-benzyl] carbamoylmethyl] Benoic acid yield: 72.4% of theory, melting point: 228-2300C.

Calc .: C 73.34 H 6.59 N 6.11 Found: 73.22 6.61 6.13 4- / N- / 7 \ - (4-benzyloxyphenyl) -2-piperidino-benzyl / carbamoylmethyl7benzoic acid Yield: 57% of theory, melting point: 219-221 ° C.

Calc .: C 76.38 H 6.41 N 5.24 Found: 76.05 6.44 5.24 4- [N- [α- (4-fluoro-phenyl) -2-piperidino-benzyl] carbamoylmethyl ] benzoic acid Yield: 75.8 of theory, melting point: 238-2400C.

Calc .: C 72.63 H 6.09 N 6.27 Found: 72.98 6.29 6.32 4- [N- [α- (2-fluoro-phenyl) -2-piperidino-benzyl] carbamoylmethyl ] benzoic acid Yield: 87% of theory, melting point: 280-2830C.

Calc .: C 72.63 H 6.09 N 6.27 Found: 72.70 6.10 6.37 4- [N- [α- (4-chloro-phenyl) -2-piperidino-benzyl] carbamoylmethyl] -benzoic acid Yield: 89% of theory, melting point: 241-242 ° C.

Calc .: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 69.74 6.05 6.01 7.64 4- [N- [α- (3-chloro-phenyl) - 2-piperidino-benzyl] carbamoylmethyl] benzoic acid Yield: 53% of theory, melting point: 223-2250C.

Calc .: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 70.28 5.98 5.78 7.84 4- [N- [α- (2-chlorophenyl) - 2-piperidino-benzyl] carbamoylmethyl] benzoic acid Yield: 98 t of theory, melting point: 303-3050C.

Calc .: C 70.05 k 5.88 N 6.05 Cl 7.66 Found: 69.88 6.05 5.87 7.74 4- [N- [α- (4-methylmercapto-phenyl) - 2-piperidino-benzyl] carbamoylmethyl / benzoic acid Yield: 84.6% of theory, melting point: 225-227 ° C.

Calc .: C 70.86 H 6.37 N 5.90 S 6.75 Found: 70.34 6.37 5.68 6.82 4- [N- [α- (4-methylsulfinyl-phenyl) - 2-piperidino-benzyl] carbamoylmethyl] benzoic acid Yield: 62% of theory, melting point: 232-234 ° C.

Calc .: C 68.55 H 6.16 N 5.71 S 6.53 Found: 68.39 6.27 5.79 6.42 4- [N- [5-chloro-α- (2-chloro-phenyl) -2-piperidino-benzyl] carbamoylmethyl / benzoic acid Yield: 90-90 of theory, melting point: 317-3200C.

Ber. : C 65.19 H 5.27 N 5.63 Cl 14.25 Found: 64.87 5.34 5.69 14.22 4- [N- [2-piperidino-α- (2-pyridyl) benzyl] carbamoylmethyl] benzoic acid Yield: 81% of theory, melting point: 160-161 ° C.

Calc .: C 72.71 H 6.34 N 9.78 Found: 72.43 6.39 10.00 4- [N- [2-piperidino-α- (3-pyridyl) -benzyl] carbamoylmethyl] benzoic acid Yield: 72.8 of theory, melting point: 252-2530C, calc .: C 72.71 H 6.34 N 9.78 Found: 72.56 6.53 9.60 4- [N- [2-piperidino-α- (4-pyridyl) benzyl] carbamoylmethyl] benzoic acid Yield: 68.5% of theory, melting point: from 260 ° C. (decomposition).

Calc .: C 72.71 H 6.34 N 9.78 Found: 72.31 6.29 9.63 4- [N- (6-chloro-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] - benzoic acid Yield: 82% of theory, melting point: 91-940C.

Calc .: C 70.04 H 5.88 N 6.05 Cl 7.66 Found: 69.61 5.77 5.96 7.78 4- [N- (4-chloro-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] benzoic acid Yield: 61% of theory, melting point: 221-223 ° C., calc .: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 69.73 6.89 5.87 7.52 4- [N- (3-Chloro-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoic acid Yield: 83 t of theory, melting point: 210-2130C.

Calc .: C 70.05 H 5.88 N 6.05 Cl 7.66 Found: 70.31 6.03 5.90 7.79 4- [N- (6-methyl-α-phenyl-2- piperidino-benzyl) carbamoylmethyl] benzoic acid Yield: 64% of theory, melting point: 165-1700C (sintering from 1500C), calc .: C 75.99 H 6.83 N 6.33 Found: 75.73 6.96 6.14 4- [N- (5-Methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoic acid Yield: 97% of theory, melting point: 243-2450C.

Calc .: C 75.99 H 6.83 N 6.33 Found: 75.60 7.01 6.31 4- [N- (4-methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] - benzoic acid Yield: 96% of theory, melting point: 202-203 ° C.

Ber. : C 75.99 H 6.83 N 6.33 Found: 76.04 6.78 6.23 4- [N- (5-Methoxy-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoic acid Yield: 27% of theory, melting point: 217-220 ° C. (sintering from 203 ° C.).

Ber. : C 73.34 H 6.59 N 6.11 Found: 72.92 6.68 5.99 4- [N- (6-Methoxy-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoic acid Yield: 51.5% of theory, melting point: 90-950C.

Ber. : C 73.34 H 6.59 N 6.11 Found: 73.03 6.42 5.86 4- [N- (2-methoxy-α-phenyl-benzyl) carbamoylmethyl] benzoic acid Yield: 82% of theory, melting point: 184-185 ° C.

Ber. : C 73.58 H 5.64 N 3.73 Found: 73.85 5.75 3.59 4- [N- (5-chloro-2-methoxy-α-phenyl-benzyl) carbamoylmethyl] benzoic acid Yield: 87 l of theory, melting point: 191-193 ° C.

Ber. : C 67.40 H 4.92 N 3.42 Cl 8.65 Found: 67.16 4.78 3.49 8.90 4- [N- [α- (4-chloro-phenyl) -2-methoxy-benzyl] carbamoylmethyl] benzoic acid yield: 63.5 e of theory, melting point: 192-194 ° C.

Calc .: C 67.40 H 4.92 N 3.42 Cl 8.65 Found: 67.13 5.01 3.61 8.48 4- [N- (2-dimethylamino-α-phenyl-benzyl) carbamoylmethyl] benzoic acid Yield: 83 t of theory, melting point: 183-184 ° C.

Calc .: C 74.20 H 6.23 N 7.21 Found: 74.31 6.27 7.16 4- [N- (2-Di-n-propylamino-α-phenyl-benzyl) carbamoylmethyl] - benzoic acid Yield: 79% of theory, melting point: 202-204 ° C.

Calc .: C 75.64 H 7.26 N 6.30 Found: 75.74 7.31 6.15 4- [N- [5-chloro-2- (2-methyl-piperidino) -α-phenyl benzyl] carbamoylmethyl] benzoic acid Yield: 52% of theory, melting point: 280-2820C.

Calc .: C 70.50 H 6.13 N 5.87 Cl 7.43 Found: 70.14 6.10 5.75 7.45 4- [N- [5-chloro-2- (3-methyl -piperidino) -α-phenyl-benzyl] -carbamoylmethyl / benzoic acid Yield: 66 E dr of theory, melting point: 246-2480C.

Calc .: C 70.50 H 6.13 N 5.87 Cl 7.43 Found: 70.16 6.07 5.87 7.30 4- / N- / 2- (3,3-DimethSl-piyJeridino) - A-phenyl-benzylJ carbamoylmethyl] benzoic acid Yield: 59 8 of theory, melting point: 238-240 ° C.

Calc .: C 76.28 H 7.07 N 6.14 Found: 76.38 7.28 6.11 3-chloro-4- [N- (α-phenyl-2-piperidino-benzyl) carbamoylmethyl] - benzoic acid Yield: 56% of theory, melting point: 236-2390C.

Calc .: C 70.04 H 5.88 N 6.05 Cl 7.66 Found: 69.88 5.77 5.86 7.81 4- [N- [2- (3,5-cis-dimethyl -piperidino) -5-nitro-α-phenyl-benzyl] -carbamoylmethyl / benzoic acid Yield: 81% of theory, melting point: from 2550C decomposition).

Calc .: C 69.44 H 6.23 N 8.38 Found: 68.95 6.44 8.53 4- [N- [2- (Octahydro-1H-azonino) -α-phenyl-benzyl] carbamoylmethyl ] benzoic acid Yield: 62.5 t of theory, melting point: 235-237 ° C.

Calc .: C 76.56 H 7.28 N 5.95 Found: 76.50 7.30 5.94 example 6 4- [N- [α- (4-Hydroxyphenyl) -2-piperidino-benzyl] carbamoylmethyl] benzoic acid 1.1 g (2 mmoles) of 4- [N- [α- (4-benzyloxyphenyl] -2-piperidino-benzyl] -carbamoylmethyl] benzoic acid are suspended in 200 ml of ethanol and at 50 ° and a hydrogen pressure of 5 bar in the presence of 0.4 g of 10% palladium / carbon catalytically debenzylated. The catalyst is then filtered off, concentrated and recrystallized from acetonitrile.

Yield: 720 mg (66.7 g of theory), melting point: 202-204 ° C.

Calc .: C 72.95 H 6.35 N 6.30 Found: 72.65 6.17 6.20 Example 7 4- [N- ( α-Phenyl-2-pipiridino-benzyl) carbamoylmethyl] benzyl alcohol 3 g (6.57 mmol) 4-LN- (α-phenyl-2-piperidino-benzyl) carbamoylmethyl-benzoic acid ethyl ester are added in portions to a suspension of 0.5 g (13.2 mmol) of lithium aluminum hydride given in 50 ml of absolute tetrahydrofuran. The mixture is stirred for a further 30 minutes at room temperature, decomposed by the dropwise addition of 4 N sodium hydroxide solution and the sodium aluminate formed is filtered off away. The filtrate is concentrated and the residue is recrystallized from a little toluene.

Yield: 0.85 g (31.5% of theory), melting point: 143-1450C.

Calc .: C 78.23 H 7.2 ° N 6.76 Found: 78.13 7.30 6.62 example 8 4- [N- (α-Phenyl-2-piperidino-benzyl) -carbamoylmethyl] benzaldehyde 8.6 g (20 mmol) 4- [N- (α-phenyl-2-piperidino-benzyl) carmoyl meth / benzoic acid and 3.25 g (20 mmol) of carbonyldiimidazole are in 100 ml of absolute tetrahydrofuran for 2 hours heated to reflux. It is then concentrated and, after the addition of 50 ml of pyridine and 3.7 g (20 mmol) of 4-toluenesulfonic acid hydrazide refluxed for a further 2 hours. It is then poured into ice water, filtered off with suction and the precipitate is purified Column chromatography on silica gel with chloroform / methanol 10: 1 as the mobile phase. 4 g (33.6 t of theory) of the toluene sulfonic acid hydrazide used are obtained Carboxylic acid.

Melting point: 167-169 ° C.

Ber. : C 68.43 H 6.08 N 9.39 Found: 68.70 6.34 9.23 600 mg (1 mmol) of the hydrazide obtained and 1.8 g of anhydrous sodium carbonate are in 20 ml Ethylene glycol heated to 170 ° C for 2 hours. It is then poured into water and extracted with chloroform. The concentrated extracts are on silica gel with Toluene / ethyl acetate 5: 1 as a mobile phase purified by column chromatography.

Yield: 120 mg (29% of theory), melting point: 168-1700C.

Calc .: C 78.61 H 6.84 2 6.79 Found: 78.60 7.00 6.72 example 9 4- [N- (α-Phenyl-2-piperidino-benzyl) carbamoylmethyl] benzaldehyde 0.5 g (1.2 mmol) 4- [n- (α-Phenyl-2-piperidino-benzyl) carbamoylmethyl / benzyl alcohol to a suspension of 399 mg (1.5 mmol) of pyridinium chlorochromate in 2 ml of chloroform. After 12 hours at room temperature, ether is added, the mixture is filtered and the concentrated The filtrate was purified by column chromatography on silica gel (eluent toluene / ethyl acetate = 5: 1).

Yield: 0.2 g (40% of theory), melting point: 170 ° C.

Example 10 [4- [N- (α-Phenyl-2-piperidino-benzyl) carbamoylmethyl] benzyl] -malonic acid diethyl ester 1 g (2.4 mmol) 4- [N- (α-phenyl-2-piperidino-benzyl) carbamoylmethyl / benzyl alcohol are dissolved in 20 ml of chloroform and after adding 1 ml of thionyl chloride for 2 hours stirred at room temperature. It is then concentrated in vacuo. The constriction residue is dissolved in absolute ethanol with an alcoholic solution of 5 mmoles of sodium malonic acid diethyl ester added and refluxed for 2 hours. It is then concentrated, and water is added and extracted with ethyl acetate. The extracts are concentrated and the residue column chromatography on silica gel with toluene / ethyl acetate 5: 1 as the mobile phase cleaned.

Yield: 0.83 g (62.5% of theory), melting point: 85-87 ° C.

Calc .: Mol peak m / e = 556 Found: Mol peak m / e = 556 example 11 [4- [N- (α-Phenyl-2-piperidino-benzyl) carbamoylmethyl] benzyl] malonic acid Manufactured from / 4- / N α-phenyl-2-piperidino-benzyl) carbamoylmethyl] benzyl] malonic acid diethyl ester by alkaline saponification as in Example 5.

Yield: 78% of theory, melting point: 120 ° C. (decomp.).

Ber. : C 71.98 H 6.44 N 5.60 Found: 71.61 6.28 5.39 Example 12 3- / 4- / N- (t-Phenyl-2-piperidino-benzyl) carbamoylmethyl / phenyl / -propionic acid 1.85 g (3.7 mnlol) / 4- / N- (α-phenyl-2-piperidino-benzyl) carbamoylmethyl / benzyl / malonic acid are heated for 30 minutes in a hot oil bath at 1500C. The residue is after dissolving in Toluene / ethyl acetate 2: 1 chromatographed on silica gel.

Yield: 0.6 g (36% of theory), melting point: 96-980C.

Ber. : C 76.59 H 6.82 N 6.09 Found: 76.29 7.06 6.14 Example 13 4- / N- (\\ - Phenyl-2-piperidino-benzyl) carbamoylmethyl7cinnamic acid ethyl ester 412 mg (1 mmol) 4- [N- (α-phenyl-2-piperidino-benzyl) carbamoylmethyl / benzaldehyde become an ethereal solution of 450 mg (2 melol) diethyl phosphonacetic acid ethyl ester and 100 mg (2 mmol) of 50% sodium hydride added. After stirring It is decomposed overnight with water and extracted with chloroform and on silica gel Purified by column chromatography with toluene / ethyl acetate 5: 1 as the mobile phase.

Yield: 100 mg (28.6% of theory). Melting point: 159-161 ° C.

Calc .: C 77.14 H 7.10 N 5.80 Found: 77.28 7.21 5.65 Example 14 4-EN- (f-Phenvl-2-piperidino-benzylWcarbamovlmethyl | cinnamic acid Manufactured by alkaline Saponification of ethyl 4-tN- (A-phenyl-2-piperidino-benzyl) carbamoylmethyllcinnamate analogous to example 5.

Yield: 75% of theory, melting point: 177-180 ° C.

Calc .: C 76.62 H 6.65 N 6.16 Found: 76.75 6.57 6.07 Example 15 4- [N- (5-chloro-2-methoxy-α-phenyl-benzyl) carbamoylmethyl ] benzoic acid ether ester To a solution of 0.9 g (4.2 mmol) of 4-ethoxycarbonyl-phenylacetic acid in 20 ml 0.68 g (4.2 mmol) of carbonyldiimidazole are added to absolute tetrahydrofuran at 200 ° C. with stirring and then heated to reflux for 45 minutes with exclusion of moisture. To Cooling to room temperature gives 1.05 a (4.2 mmol) of 5-chloro-2-methoxy-α-phenyl-benzylamine and heated to reflux for a further 3 hours. Then one concentrates in a vacuum, gives on water and extracted with methylene chloride. The dried extracts will chromatographically after concentration on trickle gel with toluene / ethyl acetate as the mobile phase cleaned.

Yield: 1.5 g (81.6% of theory), melting point: 153-1550C.

Calc .: C 68.56 H 5.52 N 3.20 Cl 8.10 Found: 68.77 5.63 3.05 7.95 Example 16 Ethyl 4- [N- [α- (3-methyl-phenyl) -2-piperidino-benzyl] carbamoylmethyl] -benzoate 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated sulfuric acid are added dropwise Room temperature a mixture of 0.22 g (0.8 mmol) of α- (3-methyl-phenyl) -2-piperidino-benzyl alcohol and 0.15 g (0.8 mmol) of ethyl 4-cyanomethyl-benzoate in 2 ml of o-dichlorobenzene. After stirring for 2 hours, the mixture is poured into ice water and made up with dilute sodium hydroxide solution alkaline and extracted with chloroform. The extracts are concentrated and the residue recrystallized from ethanol.

Yield: 0.22 g (60% of theory). Melting point: 158-1590C.

Calc .: C 76.57 H 7.28 N 5.95 Found: 76.41 7.39 5.76 Analogous to the example 16 the following compound was prepared: ethyl 4- [N- [2- (3,5-cis-dimethyl-piperidino) -5-nitro-α-phenylbenzyl] carbamoylmethyl] benzoate Yield: 57 t of theory, melting point: 170-1730C.

Calc .: C 70.30 H 6.66 N 7.93 Found: 70.05 6.68 7.81 example 17 4- [N- [2- (2-methyl-piperidino) -α-phenyl] carbamoylmethyl] -benzoic acid 238 mg (5 mblol) 4- [N- [5-chloro-2- (2-methyl-piperidino) - t -phenylbenzyl] carbamoylmethyl] benzoic acid are in 80 ml of ethanol / dioxane 1: 1 in the presence of 0.1 g of palladium on carbon (10%) Catalytically dehalogenated at 500C and a hydrogen pressure of 5 bar. To the catalyst is filtered off after cooling.

The filtrate is concentrated and the residue is recrystallized from ethanol.

Yield: 150 mg (68% of theory). Melting point: 246-2480C.

Calc .: C 75.99 H 6.83 N 6.33 Found: 75.57 7.10 6.44 Analogous to the example 17 was prepared: 4- [N- [2- (3-methyl-piperidino) -α-phenyl-benzyl] carbamoylmethyl] -benzoic acid Yield: 43% of theory, melting point: 228-2300C.

Calc .: C 75.99 H 6.83 N 6.33 Found: 75.91 6.82 6.33 Example 18 4- [N- [α- 4-methyl-phenyl) -2-piperidino-benzyl] carbamoyl meth / benzoic acid ether ester Solution of 2.78 g (10 mmol) of freshly prepared (4-'ethylphenyl) - (2-piperidino-phenyl) ketimine in 50 ml of methylene chloride, 1.5 ml (11 mmol) of triethylamine are added and then while cooling with ice, dropwise with a solution of 2.5 g (11 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 20 ml Methylene chloride. There after 1 hour at room temperature it is poured onto ice water and extracted with methylene chloride. The extracts are dried and concentrated and the concentration residue was purified by column chromatography on silica gel (Mobile phase toluene / ethyl acetate 10: 1). The crude acylimine is made in dimethylformamide dissolved unc after the addition of 0.5 g of palladium (10% on carbon) at 5 bar wet substance pressure hydrogenated at room temperature.

After the calculated amount of hydrogen has been taken up, the catalyst filtered off, concentrated and the residue recrystallized from a little alcohol.

Yield: 2.8 g (60% of theory), melting point: 175-1770C.

Calc .: C 76.57 H 7.28 N 5.95 Found: 76.41 7.19 5.76 Example 19 4- [N- (α-Phenyl-2-piperidino-benzyl) carbamoyl-methyl] benzamide 4.3 grams (10 mils) of 4-LN- (α-phenyl-2-piperidino-benzyl) carbamoylmethyl] benzoic acid are suspended in 30 ml of chloroform and after adding 5 ml of thionyl chloride 30 Stirred minutes at room temperature. Then it is concentrated in vacuo and the residue is dissolved in 50 ml of glycol dimethyl ether and then added with stirring to concentrated aqueous Ammonia solution. After stirring for 1 hour, it is filtered off with suction, the precipitate with 1 N hydrochloric acid is added and, after neutralization with dilute ammonia solution, with Chloroform extracted. The chloroform extracts are concentrated and the concentration residue recrystallized from ethanol.

Yield: 2.2 o (51.5 90 of theory). Melting point: 237-2400C.

3rd: C 75.84 ia 6.84 N 9.83 Found: 75.60 6.74 9.69 example 20 4- [N- (α-Phenyl-2-piperidino-benzyl) carbamoylmethyl] benzonitrile 427 mg (1 mmol) 4- [N- (α-phenyl-2-piperidino-benzyl) carabmoylmethylffibenzamide suspended in 3 ml of absolute pyridine and at room temperature with 210 mg (1.1 mmol) 4-toluenesulfonic acid chloride was added. The mixture is then stirred at 50 ° C. for 1 hour lets stand overnight. Then you add to water, make with concentrated ammonia strongly alkaline and extracted with chloroform. The extracts are dried and concentrated and chromatographed on silica gel for purification (mobile phase = toluene / ethyl acetate 5: 1).

Yield: 216 mg (53% of theory), melting point: 178-181 ° C.

Calc .: C 79.18 H 6.65 N 10.26 Found: 78.84 6.55 10.24 Example 21 4-EN- ((-Phenyl-2-pineridino-benzyl) carbamoyl-methyl-benzaldehyde 0.207 g 0.5 mmol 4- [N- ( α-Phenyl-2-piperidino-benzyl) carbamoylmethyl / benzyl alcohol in 50 ml Dissolved methylene chloride and after adding 2 g of active manganese dioxide for 3 hours Room temperature stirred. It is then filtered and the filtrate is concentrated. Of the Concentration residue is over silica gel with toluene / ethyl acetate (10: 1) as Eluent purified by chromatography.

Yield: 50 mg (25% of theory) Melting point: 168-169 ° C., calc .: C 78.61 F. 6.84 N 6.79 Found: 78.54 6.61 6.57 Example 22 4- [N- (5-Methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl] -benzoic acid 0.43 g (1 mmole) 4- [N- (5-methyl-α-phenyl-2-piperidino-benzyl) -carbamoylmethyl / benzaldehyde are dissolved in 25 ml of glycol dimethyl ether and after adding 2 g of silver oxide and Heat 5 ml of 1 N sodium hydroxide solution on the steam bath for 30 minutes. After adding 5 ml 1 N sulfuric acid is filtered through kieselguhr, the filtrate is concentrated and the residue crystallized from ethanol.

Yield: 53 mg (12% of theory), melting point: 244-2450C.

Calc .: C 75.99 H 6.83 N 6.33 Found: 75.81 6.79 6.21 Example 23 4- [N- (5-Methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl ] benzoic acid ether ester 0.42 g (1 mmol) 4- [N- (5-methyl-α-phenyl-2-piperidino-benzyl) carbamoylmethyl / benzonitrile are refluxed with 50 ml of ethanolic hydrochloric acid for 24 hours. Afterward if the mixture is concentrated, aqueous sodium bicarbonate solution is added to the concentration residue and extracted with chloroform. The chloroform extract is concentrated and the residue triturated with ethanol and suctioned off.

Yield: 270 mg (57.4% of theory), melting point: 170-1730C.

Calc .: C 76.57 H 7.28 N 5.95 Found: 76.41 7.19 5.68 example 24 Ethyl 4- [N- [5-chloro-2- (3-cis-dimethyl-piperidino) -α-phenyl-benzyl] -carbamoylmethyl] benzoate 2.65 g (5 mmol) of ethyl 4- [N- [2- (3,5-cis-dimethyl-piperidino) -5-nitro-α-phenyl-benzylcarbamoylmethyl-benzoate] are dissolved in 20 ml of dimethylformamide and after adding 0.2 g of palladium (10% on charcoal) hydrogenated at a hydrogen pressure of 1 bar at room temperature. Afterward the catalyst is filtered off, the filtrate is concentrated, and the residue consists from 4- [N- [5-amino-2- (3,5-cis-dimethyl-piperidino) -α-phenyl-benzyl] -carbamoylmethyl] ethyl benzoate, dissolved in 50 ml of concentrated hydrochloric acid. With ice cooling a solution of 0.5 g (7.0 mmol) of sodium nitrite in 5 ml of water is now added and stirred at 0-5 ° C. for 1 hour. The reaction mixture is then added dropwise to a solution of 1.5 g of copper (I) chloride in 25 ml of concentrated hydrochloric acid. To Stirring for 1 hour is made alkaline with sodium hydroxide solution and extracted with chloroform. The concentrated chloroform extracts are purified by column chromatography on silica gel.

(Mobile phase: toluene / ethyl acetate 5: 1).

Yield: 0.75 g (28% of theory), melting point: 188-191 ° C.

Calc .: C 71.72 H 6.80 N 5.40 Cl 6.83 Found: 71.95 6.85 5.35 6.77 Example 25 4- [N- [5-chloro-2- (3,5-cis -dimethyl-piperidino) -α-phenyl-benzyl] -carbamoylmethyl / benzoic acid Manufactured by alkaline saponification of 4-EN-ES-chloro-2- (3,5-cis-dimethyl-piperidino) -α-phenyl-benzyl] carbamoylmethyl] -benzoic acid ethyl ester analogous to example 5.

Yield: 81% of theory, melting point: 253-2550C.

Ber. : C 70.93 H 6.36 N 5.71 Cl 7.22 Found: 70.68 6.51 5.73 7.36 Example 26 4- [N- (α-Phenyl-2-piperidino-benzyl) carbamoylmethyl] nitrobenzene Prepared from S-phenyl-2-piperidino-benzylamine and 4-nitrophenylacetic acid analogous to the example 1.

Yield: 67% of theory, melting point: 193-1950C.

Calc .: C 72.70 H 6.34 N 9.78 Found: 72.80 6.49 9.80 Example 27 4-t (-Phenvl-2-tiDeridino-benzvl) carbamoyl meth / benzonitrile 4.29 g (10 mmol) 4- [N- ( α-Phenyl-2-piperidino-benzyl) carbamoylmethyl] nitrobenzene in 50 ml Dissolved dimethylformamide and after adding 0.5 g of palladium (10% on activated carbon) hydrogenated under a hydrogen pressure of 1 bar at room temperature. One sucks off Catalyst from, evaporates and takes the remaining residue of 4- [N- (α-phenyl-2-piperidino-benzyl) -carbamoylmethyl] aniline in 25 ml of 4 N hydrochloric acid. A solution of 0.77 g (11th mmol) of sodium nitrite in 2 ml of water. The mixture is stirred for a further 30 minutes and neutralized then the reaction mixture carefully by adding solid soda and then gives on a solution of trisodium-tetracyano-copper-I-complex (made by loosening of 2.0 g (20 mmol) of copper-I chloride in a solution of 4.0 g (81.6 mmol) of sodium cyanamide in 50 ml of water). After the evolution of nitrogen has ended will rit Chloroform extracted. The extracts are concentrated and placed on silica gel in a mobile phase Toluene / ethyl acetate 5: 1 purified by column chromatography.

Yield: 86 mg (21% of theory), melting point: 179-181 ° C.

Example A Tablets with 5 mg 4- [N- (6-chloro-α-phenyl-2-piperidino-benzyl) carbamovlmethv1Jbenzoic acid Composition: 1 tablet contains: active substance (1) 5.0 mg corn starch (2) 62.0 mg lactose (3) 48.0 mg polyvinylpyrrolidone (4) 4.0 Magnesium Stearate mg (5) 1.0 mg 120.0 mg Manufacturing process: 1, 2, 3 and 4 will be mixed and moistened with water. The wet mixture is passed through a sieve with 1.5 mm mesh size pressed and dried at approx. 45 ° C. The dry granules is passed through a sieve with a mesh size of 1.0 mm and mixed with 5. the the finished mixture is pressed on a tablet press with punches 7 mm in diameter, which are provided with a partial notch into tablets.

Tablet weight: 120 mg example B coated tablets with 2.5 mg 4- / N- (6-chlorine- -phenyl-2-piperidino-benzyl) -carbamovlmethyl / benzoic acid 1 tablet core contains: active substance (1) 2.5 mg potato starch (2) 44.0 mg lactose (3) 30.0 mg Polyvinyl pyrrolidone (4) 3.0 mg flagnesium stearate (5) 0.5 mg 80.0 mg Manufacturing process: 1, 2, 3 and 4 are mixed well and moistened with water.

The moist mass is pressed through a sieve with 1 mm mesh size, dries at approx. 45 ° C and then passes the granulate through the same sieve. After adding 5, curved tablet cores are made on a tablet machine pressed with a diameter of 6 mm. The tablet cores produced in this way are coated in a known manner with a layer consisting essentially of sugar and Talc is composed. The finished coated tablets are polished with wax.

Dragee weight: 120 mg Example C tablets with 10 mg 4- / N- (6-chlorine- ; C-phenyl-2-piperidino-benzyl) -carbamoylmethyl7benzoic acid Composition: 1 tablet contains: active substance 10.0 mg elk sugar powder. 70.0 mg corn starch 31.0 mg polyvinylpyrrolidone 8.0 mg magnesium stearate 1.0 mo 120.0 mg Manufacturing process: The Mixture of the active ingredient, milk sugar and corn starch is made with a 20% strength Solution of polyvinylpyrrolidone moistened in water. The wet mass is through granulated a sieve with a mesh size of 1.5 mm and dried at 45 °. The dried one Granules are rubbed through a sieve with 1 mm mesh size and covered with magnesium stearate mixed homogeneously.

Tablet weight: 120 mg Punch: 7 mm with dividing notch Example D coated tablets with 5 mg of 4-8N- (6-chloro-K-phenyl-2-piperidino-benzyl) -carbamovlmethv / benzoic acid 1 tablet core contains: Active ingredient 5.0 mg calcium phosphate secondary 70.0 mg corn starch 50.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 1.0 mg 130.0 mg Manufacturing process: The mixture of the active ingredient, calcium phosphate and corn starch is made with a Moistened 15% solution of polyvinylpyrrolidone in water. The wet mass is beaten through a sieve with 1 mm mesh size, dried at 45 ° C and then Rub through the same sieve. After mixing with the specified amount of magnesium stearate are pressed from it tablet cores.

Core weight: 130 mg Stamp: 7 mm # On the tablet cores produced in this way a layer of sugar and talc is applied in a known way. The finished Dragees are polished with wax.

Drage weight: 180 mg

Claims (22)

Claims 1. N-Benzylamides of the general formula in which R1 is a fluorine or bromine atom, a chlorine atom in the 3-, 4- or 6-position, a nitro group, an alkyl or alkoxy group each with 1 to 3 carbon atoms or a hydrogen atom or a chlorine atom in the 5-position, if either A is an unbranched alkyleneimino group with 4 to 6 carbon atoms which is substituted by one or two alkyl groups each with 1 to 3 carbon atoms, an octahydro-azocino, octahydro-1H-azonino or decahydro-azecino group, a dialkylamino group with 1 to 5 carbon atoms in each alkyl part, an allyloxy group or an alkoxy group with 1 to 3 carbon atoms and / or R2 an aryl group with 6 mono- or disubstituted by halogen atoms, by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulfinyl and / or alkylsulfonyl groups ocer 10 carbon atoms, where the alkyl part can each contain 1 to 3 carbon atoms, the naphthyl group or a heteroaryl group containing 1 or 2 nitrogen atoms 4, 5, 8 or 9 carbon atoms and / or a hydroxymethyl, formyl, nitro, then, aminocarbonyl, 2-hydroxycarbonylethylene, 2-hydroxycarbonylethyl or 2, 2-bis (hydroxycarbonyl) ethyl group, one in 2-position ethylene group substituted by an alkoxycarbonyl group or an ethyl group substituted in 2-position by one or two alkoxycarbonyl groups, where the alkoxycarbonyl group can each contain a total of 2 to 4 carbon atoms, and / or R3 represents a halogen atom, R2 represents one, optionally with halogen atoms, with alkyl -, Hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulphinyl and / or alkylsulphonyl groups, mono- or disubstituted aryl groups with 6 or 10 carbon atoms, where the substituents can be identical or different and the alkyl part can each contain 1 to 3 carbon atoms a heteroaryl group containing 1 or 2 nitrogen atoms with 4, 5, 8 or 9 carbon atoms, R3 a hydrogen or halogen atom, A a u nbranched alkyleneimino group with 4 to 6 carbon atoms, which can be substituted by one or two alkyl groups each with 1 to 3 carbon atoms, an octahydro-azocino, octahydro-1H.-azonino or decahydro-azecino group, a dialkylamino group with 1 to 5 Carbon atoms in each alkyl part, an allyloxy group or an alkoxy group having 1 to 3 carbon atoms and a carboxy, formyl, hydroxymethyl, nitro, cyano, aminocarbonyl, 2-hydroxycarbonylethylene, 2-hydroxycarbonylethyl or 2,2-bis - (hydroxycarbonvl) ethyl group, an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, an ethylene group substituted in the 2-position by an alkoxycarbonyl group or an ethyl group substituted in the 2-position by one or two alkoxycarbonyl groups, the alkoxycarbonyl group each containing a total of 2 to 4 carbon atoms can mean their optically active antipodes and their salts, in particular their physiologically acceptable salts mi t inorganic - or organic acids or bases. 2. N-benzylamides of the general formula I according to claim 1, in which R1 is a methyl, methoxy or nitro group, a chlorine atom in the 3-, 4- or 6-position or also a hydrogen atom or a chlorine atom in the 5-position when either A a dialkylamino group with 1 to 3 carbon atoms in each alkyl part, a methoxy, Methyl-piperidino-, dimethyl-piperidino-, octahydro-azocino-, octahydro- 1H-azonino- or decahydro-azecino group and / or R2 one through a fluorine or chlorine atom a methyl, hydroxy, methoxy, benzyloxy, methylsulfenyl, methylsulfinyl or Methylsulfonyl group substituted phenyl group or a pyridyl group and / or W is a hydroxymethyl, formyl, nitro, cyano, aminocarbonyl, 2-hydroxycarbonyl-ethylene, 2-hydroxycarbonyl-ethyl or 2, 2-ice (hydroxycarbonyl) ethyl group, one in 2-position substituted by an ethoxycarbonyl group or an ethylene group ethyl group substituted in the 2-position by one or two ethoxycarbonyl groups and / or R3 represents a halogen atom, R2 one through if necessary a fluorine or chlorine atom, through a methyl, hydroxy, methoxy, benzyloxy, ttethvlsulfenvl-, Bethvlsulfinyl- or methylsulfonyl group or a substituted phenyl group Pyridyl group, R3 is a hydrogen or chlorine atom, A is a dialkylamino group 1 to 3 carbon atoms in each alkyl part, a methoxy, pyrrolidino, piperidino, Methyl piperidino, dimethyl piperidino, hexahydro-1H-azepino, octahydro-azocino, Octahydro-1H-azonino or decahydro-azecino group and W is a carboxy, hydroxymethyl, Formyl, nitro, cyano, aminocarbonyl, 2-hydroxycarbonyl-ethylene, 2-hydroxycarbonyl-ethyl, 2,2-bis (hydroxy-carbonyl) -ethyl-, 2-ethoxycarbonyl-ethylene-, 2-ethoxycarbonyl-ethyl- or 2,2-bis (ethoxycarbonyl) ethyl group or an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, their optically active antipodes and their salts, in particular their physiologically compatible salts with inorganic or organic Acids or bases. 3. N-benzylamides of the general formula I according to claim 1, in which R1 to R3, A and W are as defined in claim 2 and the radical A is in the 2-position stands, their optically active antipodes and their physiologically acceptable acid addition salts with inorganic or organic acids or bases. 4. N-Benzylamides of the general formula in which A denotes the t5ethoxy, piperidino, methylpiperidino or 3,5-dimethylpiperidino group, R1 denotes a chlorine atom, the methyl or methoxy group and R2 denotes a phenyl group substituted by a methyl group, a fluorine or chlorine atom or a pyridyl group, their optical active antipodes and their physiologically compatible acid addition salts with inorganic or organic acids or bases. 5. 4- / N- (6-chloro-A-phenyl-2-piperidino-benzyl) carbamoylmethyl / benzoic acid, their optically active antipodes and their salts. 6. 4- / N- rA- (4-fluorophenyl) -2-piperidino-benzyl / carbamoylmethylJ-benzoic acid, their optically active antipodes and their salts. 7. 4- [N- (4-Methyl-α-phenyl-2-piperidino-bezyl) carbamoylmethyl] -benzoic acid, their optically active antipodes and their salts. 8. Medicament containing a compound according to claims 1 to 7 in addition to one or more inert carriers and / or diluents. 9. Medicament according to claim 8 with a blood sugar lowering effect. 10. Process for the preparation of new N-benzylamides of the general formula in which Ri is a fluorine or bromine atom, a chlorine atom in the 3-, 4- or 6-position, a nitro group, cinc Alyl- o5er: NlkOXV group with 1 to 3 carbon atoms or a hydrogen atom or a chlorine atom in the 5-position, if either A is an unbranched alkyleneimino group with 4 to 6 carbon atoms, which is substituted by one or two alkyl groups each with 1 to 3 carbon atoms, an octahydro-azocino, octahydro-1H-azonino or decahydro-azecino group, a dialkylamino group with 1 to 5 Carbon atoms in each alkyl part, an allyloxy group or an alkoxy group with 1 to 3 carbon atoms and / or R2 is an aryl group mono- or disubstituted by halogen atoms, by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulphinyl and / or alkylsulphonyl groups with 6 or 10 carbon atoms, where the alkyl part can each contain 1 to 3 carbon atoms, the naphthyl group or a heteroaryl group containing 1 or 2 nitrogen atoms mi t 4, 5, 8 or 9 carbon atoms and / or W is a hydroxymethyl, formyl, nitro, cyano, aminocarbonyl, 2-hydroxycarbonylethylene, 2-hydroxycarbonylethyl or 2,2-bis (hydroxycarbonyl) -äthylgruppe, an ethylene group substituted in the 2-position by an alkoxycarbonyl group or an ethyl group substituted in the 2-position by one or two alkoxycarbonyl groups, the alkoxycarbonyl group in each case containing a total of 2 to 4 carbon atoms, and / or R3 represents a halogen atom, R2 optionally by halogen atoms, by alkyl, hydroxy, alkoxy, phenylalkoxy 'alkylsulfenyl, alkylsulphinyl and / or alkylsulphonyl groups mono- or disubstituted aryl group with 6 or 10 carbon atoms, the substituents can be the same or different and the alkyl part in each case 1 to May contain 2 carbon atoms, or a 1 or 2 nitrogen atoms containing heteroaryl group with 4, 5, 8 or @ carbon atoms, a hydrogen or halogen atom, A is a un branched alkyleneimino group with 4 to 6 carbon atoms which can be substituted by one or two alkyl groups each with 1 to 3 carbon atoms, an octahydro-azocino, octahydro-1H-azonino or decahydro-azecino group, a dialkylamino group with 1 to 5 carbon atoms in each Alkyl part, an allyloxy group or an alkoxy group with 1 to 3 carbon atoms and W a carboxy, formyl, hydroxymethyl, nitro, cyano, aminocarbonyl, 2-hydroxycarbonylethylene, 2-hydroxycarbonylethyl or 2,2-bis ( hydroxycarbonyl) ethyl group, an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, an ethylene group substituted in the 2-position by an alkoxycarbonyl group or an ethyl group substituted in the 2-position by one or two alkoxycarbonyl groups, the alkoxycarbonyl group each containing a total of 2 to 4 carbon atoms, mean, as well as their optically active antipodes and their salts, in particular of their physiologically ve Compatible salts with inorganic or organic acids or bases, characterized in that a) an amine of the general formula in which A, R1 and R2 are as defined at the outset, with a carboxylic acid of the general formula in which R3 is defined as above and W 'has the meanings mentioned for W at the beginning or represents a carboxyl group protected by a protective radical, or is reacted with any reactive derivatives thereof prepared in the reaction mixture and, if necessary, a protective radical used is cleaved off, or b) to produce a Compound of the general formula I in which W represents a carboxy group, a compound of the general formula in which R1 to R 3 and A are as defined at the outset and B represents a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, is cleaved hydrolytically, thermolytically or hydrogenolytically, or c) for the preparation of a compound of the general formula I in which W represents the carboxy group, a compound of the general formula in which R1 to R3 and A are as defined at the outset and D represents a group which can be converted into a carboxy group by oxidation, is oxidized, or d) a compound of the general formula in which to 23, A and tf are as defined at the outset, is reduced with hydrogen in the presence of a hydrogenation catalyst, or e) a compound of the general formula in which R1, R2 and A are as defined at the outset, with a compound of the general formula in which R3 and W are as defined at the outset, is reacted in the presence of a strong acid and, if desired, a compound of general formula I obtained in this way, in which W represents the carboxy group, is converted into a corresponding compound of general formula I by esterification or amidation and / or a compound of the general formula I obtained in which R1 represents a nitro group is converted by means of reduction into a corresponding compound of the general formula I in which R1 represents an amino group, and a compound of the general formula I obtained in this way is converted into the R1 represents an amino group, is converted via a corresponding diazonium salt into a corresponding compound of the general formula I in which R1 represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl group, a compound of the general formula obtained in this way, if appropriate I, in which R1 represents the hydroxyl group, by means of alkylation g can be converted into a corresponding compound of the general formula I, in which R1 represents an alkoxy group, and / or a compound of the general formula I obtained, in which W represents a nitro group, by means of reduction into a corresponding compound of the general formula I, in which W represents an amino group, is converted and a compound of the general formula I obtained in this way, in which W represents an amino group, is converted via a corresponding diazonium salt into a corresponding compound of the general formula I in which the cyano group is and / or an obtained compound of the general formula I in which R1 represents a chlorine or bromine atom is converted by means of dehalogenation into a corresponding compound of the general formula I in which R1 represents a hydrogen atom, and / or a obtained compound of the general formula I, in which a carboxy or Al}; o.xvcarbonylgruppe represents, by means of reduction into a corresponding A specific compound of the general formula I in which is a formyl or hydrosymethyl group is converted and / or a compound of the general formula I in which W is a hydroxymethyl group is converted into a corresponding compound by halogenation and subsequent reaction with a malonic acid diester of the general formula I, in which N is an ethyl group substituted by two alkoxycarbonyl groups, is converted and / or a compound of the general formula I in which W is a formyl group obtained is converted into a corresponding compound by means of condensation and, if appropriate, subsequent hydrolysis and / or decarboxylation of the general formula I, in which W represents a vinyl group substituted by a hydroxycarbonyl or alkoxycarbonyl group, is converted and / or a compound of the general formula I in which W represents an ethyl group substituted by two alkoxycarbonyl groups is converted into e by means of hydrolysis A corresponding compound of the general formula I, in which W is an aryl group substituted by two carboxy groups, is converted, and / or a compound of the general formula I obtained, in which W is an ethyl group substituted by two alkoxycarbonyl groups, into one by means of hydrolysis and decarboxylation corresponding compound of general formula I, in which W represents a 2-hydroxycarbonylethyl group, is converted and / or a compound of general formula I obtained in which W represents a garboxy group, by means of conversion into a sulfonic acid hydrazide and then disproportionation into a corresponding compound of the general Formula I, in which it represents elne formyl group, is converted, and / or a compound of the general formula I obtained, in which R2 represents an aryl radical mono- or disubstituted by a benzyloxy radical, into a corresponding hydroxy compound of the general form by means of debenzylation el I is converted and / or a compound of the general formula I obtained in which R2 represents an aryl group mono- or disubstituted by an alkylsulfenyl group, is converted into a corresponding alkylsulfinyl compound by means of oxidation and / or a compound of the general formula I obtained in which R2 represents an aryl radical mono- or disubstituted by an alkylsulfenyl or alkylsulphinyl radical, is converted into a corresponding alkylsulphonyl compound by means of oxidation and / or a compound of the general formula I obtained is separated into its enantiomers by means of racemate resolution and / or a compound of the general formula I obtained is converted into their salts, in particular into their physiologically acceptable salts with inorganic or organic acids or bases. 11. The method according to claim 10, characterized in that the implementation is carried out in a solvent. 12. The method according to claims 10a and 11, characterized in that that the reaction in the presence of an acid activating or a dehydrating Means optionally in the presence of an inorganic or tertiary organic Base is carried out. 13. The method according to claims 10a and 11, characterized in that that the reaction in the presence of an amine-activating agent, if appropriate is carried out in the presence of an inorganic or tertiary organic base. 14. The method according to claims 10a and 11 to 13, characterized in that that the reaction at temperatures between -25 and 250 ° C, but preferably at Temperatures between -100C and the boiling point of the solvent used, is carried out. 15. The method according to claims 10b and 11, characterized in that that the hydrolysis or thermolysis is carried out in the presence of an acid or base will. 16. The method according to claims 10b and 11, characterized in that that the reaction takes place in the presence of a nitrite, e.g. sodium nitrite, and in the presence an acid such as sulfuric acid when B is the nitrile or aminocarbonyl group represents. 17. The method according to claims 1Ob, 11 and 15, characterized in that that the reaction at temperatures between -10 and 1200C, preferably at temperatures between room temperature and the boiling point of the reaction mixture carried out will. 18. The method according to claims 10c and 11, characterized in that that the reaction at temperatures between 0 and 1000C, but preferably at Temperatures between 20 and 50cd. 19. The method according to claims 10d and 11, characterized in that that the reaction at temperatures between 0 and 1000C, preferably at temperatures between 20 and 500C, and a hydrogen pressure of 1 to 5 bar. 20. The method according to claim 10e, characterized in that the Reaction is carried out in the presence of sulfuric acid. 21. The method according to claims 10e, 11 and 20, characterized in that that the reaction at temperatures between 20 and 1500C, preferably at temperatures between 80 and 1000C. 22. Use of a compound according to claims 1 to 7 for the preparation a drug with blood sugar lowering properties by non-chemical means.