DE2928352A1 - Hypoglycaemic 2-amino-benzamido-ethyl-benzoic acid derivs. - prepd. e.g. by reaction of 2-amino-benzoic acid derivs. with 4-aminoethyl-benzoic acid derivs. - Google Patents

Abstract

4-(2-(2-Tertiary amino-benzamido) ethyl) benzoic acid derivs. (I) and their salts with organic and inorganic acids and (when R5 is H) bases are new. R1 is H, halogen, NO2, amino, alkanoylamino, alkoxy, CN, COOH, alkoxycarbonyl or dialkylaminosulphonyl (the alkyl residues each being 1-3C); R2 and R3 are 1-7C alkyl or 3-7C cycloalkyl, or N(R2)(R3) is a 3-7C alkyleneimino gp. which is opt. substd. by 1 or 2 1-3C alkyl gps., a 1-3C alkoxy gp., OH, phenyl, COOH or 2-4C alkoxycarbonyl or in which a methylene gp. may be replaced by a 3-4C cyclic ketal gp., an O- or S-atom, a sulphoxide gp. or an imino gp. substd. by phenyl (or pyridyl, or N(R2)(R3) is pyrrolyl, tetrahydro-isoquinolyl or tetrahydro-benzazepinyl; R4 is H or 1-3C alkyl; and R5 is H or 1-4C alkyl. (I) have hypoglycaemic activity, as demonstrated by their effect on blood glucose levels when administered orally to female rats. Thus, 4-(2-(5-chloro-2-dimethylaminobenzamido) ethyl) benzoic acid (mouse LD50 greater than 2000 mg/kg p.o.) in a dosage of 10 mg/kg gives 32%, 18%, 6% and 8% reductions in blood glucose levels 1,2,3 and 4 hrs. after administration.

Description

New aminobenzoic acid amides, their preparation and their

Use as medicaments The present invention relates to new aminobenzoic acid amides of the general formula their physiologically tolerable salts with inorganic or local acids or bases, if R5 represents a hydrogen atom, and processes for their preparation and the use of the new aminobenzoic acid amides and their salts as medicaments.

The new compounds have valuable pharmacological properties on, especially a blood sugar lowering effect.

In the above general formula I, R1 denotes a hydrogen or Halogen atom, a nitro, amino, alkanoylamino, alkoxy, cyano, carboxyl, alkoxycarbonyl or Dialkylaminosulfonyl group, the alkyl part in each case having 1 to 3 carbon atoms may contain R2 and R3, which may be the same or different, alkyl groups having 1 to 7 carbon atoms or cycloalkyl groups having 3 to 7 carbon atoms or R2 and R3 together with the intermediate nitrogen atom form an imino group with 3 to 7 carbon atoms in the imino ring, which is replaced by 1 or 2 alkyl groups with each 1 to 3 carbon atoms, an alkoxy group with 1 to 3 carbon atoms, a hydroxy, phenyl, carboxyl or alkoxycarbonyl group with a total of 2 to 4 carbon atoms can be substituted, or in which a methylene group des Imino rings through a cyclic ketal group with a total of 3 or 4 carbon atoms, by an oxygen or sulfur atom, by a sulfoxide or by an imino group, which is substituted by a shenyl or pyridyl group, can be replaced, a Pyrrolyl, tetrahydroisoquinolyl, tetrahydrobenzazepinyl or 1,4-dioxa-3-azaspiro [4,5] decanyl group, is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and R5 a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, r the The meanings mentioned in the definition of the radicals P1 to R5 thus come for R1 those of the hydrogen, fluorine, chlorine or bromine atom, those of the nitro, amino, formylamino, Acetamino, propionylamino, methoxy, ethoxy, propoxy, isopropoxy, cyano, carboxyl, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycarbonyl, Dimethylamidosulfonyl, diethylamidosulfonyl, ethyl-methylamidosulfonyl, dipropylamidosulfonyl, Methyl-propylamidosulfonyl or ethyl-propylamidosulfonyl group, for R2 and / or 23 those of methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, neopentyl, tert. Pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl or cycloheptyl group, for R2 tind R3 together with the intermediate nitrogen atom that of the trimethyleneimino, pyrrolidino, piperidino, Hexamethyleneimino-, heptamethyleneimino-, methyl-pyrrolidino-, dimethyl-pyrrolidino-, Methyl piperidino, dimethyl piperidino, methyl hexamethyleneimino, methyl ethyl piperidino, Diethylpiperidino-, Dipropylpiperidino-, Methyl-propylpiperidino-, Xthyi-propylpiperidino-, Hydroxy-pyrrolidino-, hydroxypiperidino-, methoxy-pyrrolidino-, methoxy-piperidino-, Ethoxypiperidino, propoxy piperidino, isopropoxy piperidino, phenylpiperidino, Hydroxycarbonyl-pyrrolidino-, hydroxycarbonylpiperidino-, methoxycarbonyl-piperidino-, Ethoxycarbonylpiperidino-, propoxycarbonyl-piperidino-, isopropoxycarbonylpiperidino-, Morpholino, thiomorpholino, thiomorpholino-S-oxide, M-phenyl-piperazino, N-pyridyl-piperazino, 1 -pyrrolyl-, 1,2,3,4-tetrahydroisoquinolin-2-yl-, 1,2,4,5-tetrahydro-3H-3-benzoazepin-3-yl- or 1,4-Dioxo-8-azaspiro [4,5] decan-8-yl group, for .i that of the hydrogen atom, those of the methyl, ethyl, propyl or isopropyl group and 5 those of the hydrogen atom, that of the methyl, ethyl, propyl, iscpropyl, butyl, sec. Butyl-, isobutyl- + or tert.

Butyl group into consideration.

Preferred aminobenzoic acid amides of the above general formula 1 3 are the ones in the R1 is a hydrogen, fluorine, chlorine or Bromine atom, a methoxy, nitro, amino, acetamino, cyano, carboxyl, dimethylamidosulfonyl or an alkoxycarbonyl group having a total of 2 or 3 carbon atoms, R2 and R3, which can be the same or different, are alkyl groups: with t to 5 carbon atoms or cyclohexyl groups or R2 and R3 together with the intermediate nitrogen atom a pyrrolyl, pyrrolidino, hexamethyleneimino, heptamethyleneimino, morpholino, Thiomorpholino or thiomorpholino-S-oxide group, optionally by one Hydroxy-methoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl or phenyl group substituted piperidino group, one by 1 or 2 alkyl groups each with 1 or 2 carbon atoms substituted piperidino group, one in the 4-position by one Phenyl, pyridyl (2) or pyridyl (4) group substituted piperazino group, a 1,2,3,4-tetrahydro-isoquinolin-2-yl-, 1,2,4,5-tetrahydro-3H-3-benzoazepin-3-yl- or 1,4-Dioxa-8-aza-spiro [4,5] decan-8-yl group, R4 is a hydrogen atom or the Methyl group and R4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms mean, and their physiologically acceptable salts with inorganic or organic Acids or bases.

Particularly preferred aminobenzoic acid amides of the general above However, formula I are those in which R1 is a fluorine, chlorine or bromine atom, the Cyano or methoxy group, R2 and R3 together with the nitrogen atom the dimethylamino, N-methyl-cyclohexylamino, diethylamino, pyrrolidino, piperidino, hexamethyleneimino, Heptamethyleneimino, 2-methyl-piperidino, 3-methyl-piperidino, 4-methyl-piperidino -, 4-methoxy-piperidino-, 4-ethoxycarbonyl-piperidino-, 3,5-dimethyl-piperidino-, 2-methyl-5-ethyl-piperidino-, Morpholino, 1,4-dioxa-8-aza-spirot4,5Udecan-8-yS, thiomorpholino or thiomorpholino-S-oxide group, R4 is a hydrogen atom or the methyl group and R5 is a hydrogen atom or a Mean alkyl group with 1 to 3 carbon atoms, and their physiologically acceptable Salts with inorganic or organic acids or bases when R5 is a hydrogen atom represents.

According to the invention, the new compounds are obtained by the following processes: a) Reaction of an aminobenzoic acid of the general formula in which R1, R2 and R3 are as defined at the outset, or their reactive derivative, optionally prepared in the reaction mixture, with a phenylalkylamine of the general formula in which R4 and R5 are as defined at the outset, or with its reactive derivative which may be formed in the reaction mixture, if an aminobenzoic acid of the general formula lt is used and R5 represents an alkyl group having 1 to 4 carbon atoms.

The implementation thus relates to the acylation of a phenylalkylnamine of the general formula III with an aminobenzoic acid of the general formula II in the presence of an acid-activating or dehydrating agent or with their functional derivatives or the implementation of an aminobenzoic acid general formula II with a Phenylalkyiamin of the general formula III, in the represents an alkyl group having 1 to 4 carbon atoms, in the presence of one of the Amino group activating agent or with their reactive derivatives.

As functional derivatives optionally produced in the reaction mixture an aminobenzoic acid of the general formula II, for example, its alkyl, Aryl or aralkyl esters or thioesters such as the methyl, ethyl, phenyl or benzyl esters, their imidazolides, their acid halides such as the acid chloride or bromide, their O-acyl derivatives such as an O-acyl hemiacetal or ketal, their anhydrides, their mixed Anhydrides with aliphatic or aromatic carbon-j; Sulfenic, sulphinic or sulphonic acids or carbonic acid esters, e.g. acetic acid, propionic acid, p-toluenesulfonic acid or of ethyl carbonate, their acyloxytriphenylphosphonium salts, their N-acyloxyimides, their carboxylic acid azides or nitriles or the corresponding thio-aminobenzoic acid derivatives and as reactive derivatives optionally produced in the reaction mixture of a phenylalkylamine of the general formula III when R5 is an alkyl group with R represents 1 to 4 carbon atoms, consider their phosphazo derivatives as Dehydrating and / or acid-activating agents are, for example, a chloroformic acid ester such as ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, N, N'-thionyldiimidazole or Boron trifluoride etherate into consideration.

The reaction is expediently carried out in a solvent such as methylene chloride, Chloroform, carbon tetrachloride, ether; Tetrahydrofuran, dioxane, benzene, toluene or dimethylformamide, optionally in the presence of an inorganic base such as Sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which can serve as solvents at the same time, and optionally in the presence an acid-activating agent at temperatures between -25 and 250 ° C., preferably but at temperatures between -1OOC and the boiling point of the solvent used, led by +. In this case, a possibly formed in the reaction mixture needs functional derivative of a compound of: general formula II or III not to be isolated, furthermore, the reaction can also be carried out without a solvent will. Furthermore, water formed during the reaction can be azeotroped Distillation, e.g. by heating with toluene on a water separator, or by adding a desiccant such as magnesium sulfate or molecular sieve are separated.

b) To prepare a compound of the general formula I in which R1 represents the nitro group: Reaction of a nitrobenzamide of the general formula in which R4 and R5 are as defined at the outset and X represents a halogen or pseudohalogen, with an amine of the general formula in which R2 and R3 are as defined at the beginning.

Below that used in defining the interchangeable radical X The term "a halogen or a pseudohalogenZ is in particular a fluorine, chlorine- or bromine, the nitrile or rhodanide group.

The reaction is conveniently carried out in a solvent such as water, Water / methanol, water / ethanol, water / isopropanol, dimethylformamide or in one Excess of the amine of the general formula V used, if appropriate in the presence an inorganic or tertiary organic base and optionally in one Pressure vessel at temperatures between 20 and 1500C, but preferably at the boiling point of the reaction mixture carried out. However, the reaction can also be carried out without a solvent be performed.

c> For the preparation of compounds of the general formula I in which R5 represents a hydrogen atom: Oxidation of a compound of the general formula in which R1 to R4 are as defined at the outset and A denotes a group which can be converted into a carboxyl 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 the acetyl, chloroacetyl, propionyl or malonic acid (1) -yl group or a malonic ester- (1) -yl- resp.

Malonic ester (2) -yl group into consideration.

The reaction is carried out with an oxidizing agent such as chromium trioxide, potassium permanganate or with chlorine or bromine in the presence of an inorganic base such as sodium or Potassium hydroxide in a suitable solvent such as glacial acetic acid, water / glacial acetic acid or Water at temperatures between 0 and 1000C, but preferably at temperatures between 20 and 500C.

d) For the preparation of compounds of the general formula I in which R5 represents a hydrogen atom: hydrolysis of a compound of the general formula in which R1 to R4 are as defined at the outset and B represents a group which can be converted into a carboxyl group by hydrolysis.

As such a hydrolyzable group, for example, comes Nitrile group, a functional derivative of the carboxyl group like its unsubstituted one or substituted amides, esters, thioesters, orthoesters, imino ethers, amidines or Anhydrides, a malonic ester (1) -yl group, a malonic acid (2) -yl group, the tetrazolyl group, an optionally substituted 1,3-oxazole- (2) -yl or dihydro-1,3-oxazole- (2) -yl group into consideration.

The hydrolysis is expediently either in the presence of a Acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in Presence of a base such as sodium hydroxide or potassium hydroxide in a suitable one Solvents such as ethanol, water / ethanol, water / isopropanol or water / dioxane at elevated temperatures, e.g. at the boiling point of the reaction mixture, carried out.

In a compound of the general formula VII, B means the cyano group, the reaction is expediently carried out in the presence of ethanol / hydrogen chloride carried out, this forms the corresponding orthoester in the reaction mixture, j which is hydrolyzed after adding water.

e) For the preparation of compounds of general formula I, in which R2 and R3, which can be the same or different, alkyl groups with 1 to 7 carbon atoms or cycloalkyl groups with 3 to 7 carbon atoms or R2 and R3 together with the intermediate nitrogen atom a ge. in the case of 1 or 2 alkyl groups each having 1 to 3 carbon atoms substituted imino ring with 3 to 7 carbon atoms represents conversion of a compound of the general formula in which R1, R4 and R5 are as defined at the beginning and R3 'represents a hydrogen atom or has the meanings mentioned above for R3, with a compound of the general formula R' - X, fIX) in which R2 'has the meanings mentioned for R2 at the beginning or together with the radical R3 'of the formula VIII is a straight-chain alkylene group having 3 to 7 carbon atoms, which can be substituted by 1 or 2 alkyl groups each having 1 to 3 carbon atoms, and X is a nucleophilic leaving group such as a halogen atom or a sulfonic acid group, e.g. Means chlorine, bromine or iodine atom, a methanesulphonyloxy or p-toluenesulphonyloxy group.

An example of an alkylating agent of the formula IX is thus the corresponding halides or sulfates such as methyl iodide, ethyl iodide, propyl bromide, Dimethyl sulfate or diethyl sulfate into consideration, the reaction is expedient in a solvent such as acetone, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or Hexamethylphosphorsäuretriamid, optionally in the presence of an alaorqanischen Base such as sodium carbonate, potassium carbonate, or potassium -tert.butylate or a tertiary organic base such as pyridine, at temperatures between 0 and 1500C, but preferably at temperatures between 20 and 75 0C carried out. If a compound of the general formula VIII is used in which R5 is a hydrogen atom represents, this can depending on the reaction conditions used, e.g. at Temperatures above room temperature and in the presence of an alcoholate as base, are simultaneously converted into the corresponding ester.

-The methylation can also be carried out in such a way that a compound of the general formula VIII with formalin in the presence of a reducing agent, e.g. formic acid or catalytically excited hydrogen such as hydrogen in the presence a hydrogenation catalyst, e.g. palladium or platinum, optionally in one Solvents such as formic acid or glacial acetic acid at temperatures up to the boiling point of the reaction mixture is converted. According to the invention, an aminobenzoic acid amide is obtained of the general formula I, in which R5 represents a hydrogen atom, this can by means of esterification into a corresponding ester of the general formula I in which R5 represents an alkyl group having 1 to 4 carbon atoms, can be converted and / or an aminobenzoic acid amide of the general formula 1 in which R1 is the nitro group represents, this can be converted into a corresponding compound of the general formula I, in which R1 represents the amino group, can be converted and / or an aminobenzoic acid amide of the general formula I in which R1 represents the amino group, so this can be converted into a corresponding connection of the general by means of the Sandmeyer reaction Formula I, in which R1 represents a fluorine, chlorine or bromine atom or the cyano group, be converted and / or an aminobenzoic acid amide of the general formula 1, in the R1 represents the amino group, this can be converted into a corresponding one by means of acylation Compound of the general formula I in which R1 is an alkanoylamino group with 1 bs Represents 3 carbon atoms in the alkanoyl part, are converted and / or a Aminobenzoic acid amide of the general formula I, in which R1 represents the cyano group, by means of alcoholysis into a corresponding compound of the general formula I, in the R1 represents an alkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy part, be converted and / or an aminobenzoic acid amide of the general formula I, in the R1 is an alkoxycarbonyl group and / or R2 and R3 together with the intermediate Nitrogen atom with an imino group substituted by an alkoxycarbonyl group Represents 3 to 7 carbon atoms with the alkoxy portion each having 1 to 3 carbon atoms may contain, by means of hydrolysis into a corresponding compound of the general Formula I, in which R1 is the carboxyl group and / or R2 and R3 together with that in between Nitrogen atom is an imino group with 3 to substituted by a carboxyl group 7 represents carbon atoms in the imino ring.

The subsequent esterification is expediently carried out in a corresponding Alcohol of the general formula R50H as a solvent in the presence of an acid-activating agent and / or dehydrating agents such as thionyl chloride, N, N'-dicyclohexylcarbodiimide or carbonyldiimidazole at temperatures between 0 and 50 ° C., but preferably at room temperature.

Post reduction of the nitro compound is preferred in a solvent such as water, water / ethanol, methanol, glacial acetic acid or ethyl acetate expediently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium / carbon, with metals such as iron, tin or zinc in the presence of an acid, with salts such as iron (II) sulfate, tin (II) chloride, chromium (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.

The subsequent Sandmeyer reaction is expediently in one suitable solvents such as water, water / hydrochloric acid or acetic acid by transfer the amino compound obtained by means of nitrous acid or its ester at lower Temperatures, e.g. at 0 - 100C, in a corresponding diazonium salt and then Heating, e.g. to 50 - 1000C, optionally in the presence of a catalyst, e.g. in the presence of the corresponding copper (I) salt or of copper in the presence of hydrochloric acid.

The subsequent acylation is expediently carried out in a solvent such as methylene chloride, ether, tetrahydrofuran or in an excess of that used Acylating agents, e.g.

Formic acid, acetic acid or propionic acid or their anhydrides, Acid chlorides or esters, if appropriate in the presence of an inorganic base or a tertiary organic base, which also acts as a solvent can serve, and optionally in the presence of an acid activating or dehydrating agent at temperatures between -25 and 1500C, preferably but at temperatures between -10 ° C and the boiling point of the reaction mixture, carried out.

The subsequent alcoholysis is carried out in a corresponding alcohol as a solvent such as methanol, ethanol or isopropanol in the presence of an acid, e.g. hydrogen chloride, sulfuric acid or phosphoric acid, at temperatures up to Carried out boiling temperature of the reaction mixture.

The subsequent hydrolysis is expediently either in the presence an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable one Solvents such as ethanol, water / ethanol, water / isopropanol or water / dioxane at elevated temperatures, e.g. at the boiling point of the reaction mixture, carried out.

The aminobenzoic acid amides obtained can also be converted into their physiological compatible salts with inorganic or organic acids or bases, if R5 represents a hydrogen atom, convert. The acids here come, for example Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, Tartaric acid, succinic acid, maleic acid or fumaric acid and sodium hydroxide as bases, Potassium hydroxide or cyclohexylamine into consideration.

The compounds of the general formulas used as starting materials II to IX are obtained by processes known per se or are known from the literature. For example, a compound of the general formula II is obtained by reaction of 2- chloro- or 2-bromo-5-nitro-benzoic acid or the corresponding nitrile with a corresponding amine, subsequent reduction of the nitro group of the resultant 2-amino compound and conversion of the amino group in the 5-position according to Sandmeyer in the remainder R1. A nitrile obtained in this way is converted into a corresponding one by means of hydrolysis Benzoic acid converted.

A compound of the general formula III is obtained by bromination a corresponding p-alkyl benzoic acid ester, subsequent conversion of the so obtained p- (d-bromoalkyl) -benzoic acid into the corresponding cyano compound, which by means of catalytic hydrogenation into a compound of the general formula III is convicted. An ester obtained in this way can, if desired, by means of hydrolysis be converted into the corresponding: carboxylic acid of the general formula III.

A compound of the general formulas used as a starting material IV, VI, VII and VIII are obtained by reacting a corresponding benzoic acid with a corresponding phenylalkylamine in the presence of an acid activating or dehydrating agent.

As already mentioned at the beginning, the new aminobenzoic acid amides have of the general formula I and their physiologically acceptable acid addition salts with inorganic or organic acids or bases, if R5 is a hydrogen atom represents, valuable pharmacological properties, in particular a blood sugar lowering Effect.

For example, the substances A = 4-C2- (5-chloro-2-dimethylamino-benzoylamino) -äthyl7-benzoic acid, B = 4- [2- (5-bromo-2-dimethylamino-benzoylamino) -ethyl] -benzoic acid, C = 4- [2- (5-chloro-2-piperidino-benzoylamino) -ethyl] -benzoic acid methyl ester, D = 4- [2- (5-chloro-2-piperidino-benzoylamino) -ethyl] -benzoic acid.

E = 4- [2- (5-chloro-2- (2-methyl-piperidino) -benzoylamino) -ethyl] -benzoic acid, F = 4-C2- (5-chloro-2- (3-methyl-piperidino) -benzöylamino) -ethyl7-1 benzoic acid, G = 4- [2- (5-chloro-2- (4-methyl-piperidino) -benzoylamino) -ethyl] -benzoic acid, H = 4- [2- (5-chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl] benzoic acid methyl ester, I = 4- [2- (5-chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl] benzoic acid, K. = 4- [2- (5-chloro-2- (4-methoxy-piperidinoi) -benzoylamino) -ethyl7benzoic acid, L. r 4- / 2- (5-methoxy-2-piperidino-benzoylamino) -ethyl / -benzoic acid hydrochloride, M ~ 4-L2- (5-chloro-2-heptamethylçnimino-benzoylamino) -ethyl / benzoic acid, N = 4- [2- (5-chloro-2- (1,4-dioxa-8-aza-spiro [4, 5] decan-yl (8)) benzoylamino) ethyl] benzoic acid, 0 = 4- / 2- (5-chloro-2-hexamethyleneimino-benzoylamino) -ethy -benzoic acid, P = 4- [2- (5-chloro-2-thiomorpholino-benzoylamino) -ethyl] benzoic acid, = 4- [2- (5-Bromo-2-piperidino-benzoylamino) -ethyl] benzoic acid and R - 4-L2- (5-chloro-2-piperidino-benzoylamino) -1-methyl-ethyl-7-benzoic acid compared to S = 4- (2-ethylamino-5-chloro-benzoylamino) -ethyl] -benzoic acid (see Example 5 of BE-PS 837 311) examined for their biological properties as follows: 1. Blood sugar lowering effect: The blood sugar lowering effect of the examined Substances were self-bred on female rats weighing 180-220 g checked, which were given an empty stomach 24 hours before the start of the experiment. The too The substances to be examined were dissolved in 1.5% methyl cellulose immediately before the start of the experiment suspended and administered 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 were each deproteinized with 0.5 ml of 0.33 N perchloric acid, centrifuged and in the supernatant glucose by the hexokinase method using 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- punch 25 mg / kg 10 mg / kg # 5 mg / kg 1 2 3 4 1 2 3 4 1 2 3 4 Hours hours hours A -31 -21 -10 -10 -32 -18 (-6) (-8) -12 (-3) (-3) (1) B -33 -23 (-7) (2) -14 - 9 (-3) (3) (-2) (0) (+5) (2) c -44 -37 -23 -24 -41 -26 -23 -14 1-31 -21 -18 -15 D -44 -43 -41 -38 -33 -37 -36 -26 -37 -34 -28 -30 E -42 -43 -38 -31 -34 -24 -14 (-10) 31 -18 (-9) (-2) F -51 -48 -41 -40 -41 -40 -44 -39 -44 -42 -38 -35 G -30 -24 -27 -25 -24 -26 (-14) (-10 -24 -20 -21 -13 H -35 -41 -44 -38 -39 -46 -33 -20 -42 -47 -42 -43 J -41 37 -38 -40 -39 -38 -30 -40 -47 -46 -49 -50 K -43 -44 -39 -34 -40 -34 -16 (-6) -40 -32 -20 (-10) L -47 -39 -29 -27 -34 (-13) -15 -16 -37 -29 (-16) (- 6) M -38 -40 -38 -36 -38 -37 -38 -36 -42 -41 -40 -34 N -43 -41 -36 -25 -35 -34 -24 -19 -36 -17 -10 (-1) 0 -41 -37 -33 -24 -42 -39 -25 -22 -33 -26 -28 -15 P -37 -41 -32 -30 -37 -30 -26 -21 -29 -19 (-11) (- 6) Q -38 -39 -34 -37 -40 -42 -43 -44 -32 -40 -32 -23 R -52 -37 -37 -30 -25 -28 -21 -21 -27 -25 (-10) (-10) S (-5) (-1) (-4) (-2) 2. Orientation toxicity: The toxic effects of the substances after oral administration (suspension in 1% methyl cellulose) in a single dose with a follow-up period of at least 7 days were tested in female and male mice bred by our own bred 20-26 g. The following table contains the values found: Substance orientating toxicity A) 2,000 mg / kg po (0 of 6 animals died) B> 1,000 mg / kg po (0 out of 5 animals died) D) 2,000 mg / kg po (0 of 6 animals died) H> 1,000 mg / kg po (0 of 6 animals died) J> 1,000 mg / kg po (1 of 6 animals died) > 1,000 mg / kg po (O of 10 animals died) Because of their pharmacological properties, the aminobenzoic acid amides prepared according to the invention and their physiologically tolerable salts are suitable for the treatment of diabetes mellitus.

They can be used for this purpose, possibly in combination with others Active substances in the usual pharmaceutical preparation forms such as tablets, dragees Incorporate capsules, powders 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 4- [2- (5-chloro-2-dimethylamino-benzoylamino) -ethyl] benzoic acid methyl ester To one Solution of 1.6 g (5.3 mmol) of 5-chloro-2-dimethylaminobenzoic acid in 5 ml of absolute Tetrahydrofuran is 1.03 g (6.3 mmol) of N, N'-CarFonyl-diimidazole at room temperature added.

After 1-2 hours, the imidazolide formed becomes a solution of 1.13 g (6.3 mlol) 4- (2-amino-ethyl) -benzoic acid methyl ester in 2 ml of tetrahydrofuran added. After 16 hours of standing at room temperature, the tetrahydrofuran becomes distilled off on a rotary evaporator. The crude ester is poured over a silica gel column Purified chromatographically with toluene / ethyl acetate (9: 1) as the mobile phase. The dry residue of the combined fractions containing the purified ester, is treated with petroleum ether.

Yield: 0.9 g (47.5% of theory), melting point: 94 ° C. Calc .: C 62.7 H 5.88 N 7.57 Found: 63.3 5.86 7.75 Example 2 4-L2- (5-chloro-2-dimethvlamino-benzoylami 0.55 g (1.56 mmol) of methyl 4- [2- (5-chloro-2-dimethylamino-benzoylamino) -ethylubenzoate are dissolved in 40 ml of a mixture of methanol / dioxane (2: 1). After adding 0.29 y (4.8 mmol) of potassium hydroxide, dissolved in 3 ml of water, are at room temperature 30 ml of water were added dropwise so slowly that there was no precipitation of the ester. After a few hours, the organic solvent is distilled off on a rotary evaporator, the aqueous phase extracted with chloroform and the aqueous phase with 2N hydrochloric acid set to prl 5.5, the acid precipitates out.

Yield: 0.38 g (70% of theory), melting point: 1650 ° C. Calc .: C 62.45 H 5.52 N 8.06 Found 62.30 5.62 7.87 Example 3 4- [2- (5-Chloro-2-dimethylamino-benzoylamino) -ethyl] benzoic acid 0.32 g (1 mmol) 4-L2- (2-amino-5-chloro-benzoylamino) -ethyl / benzoic acid (melting point: 1960C, prepared from 2-amino-5-chlorobenzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1 and subsequent alkaline saponification analogous to example 2) in 10 ml of formalin and 30 ml of glacial acetic acid after adding 500 mg of 10% palladium carbon treated with hydrogen at room temperature in an autoclave at 5 bar. After filtration and distilling off the solvent, the acid is dissolved in sodium hydroxide solution and with 2N hydrochloric acid precipitated.

Yield: 0.11 g (30% of theory), melting point: 1650 ° C. Calc .: C 62.45 H 5.52 N 8.06 Found: 62.38 5.68 7.90 Example 4 4- [2- (5-Chloro-2-dimethylamino-benzoylamino) -ethyl] benzoic acid Manufactured from 4-t2- (5-chloro-2-methylamino-benzoylamino) -ethyl2benzoic acid (melting point: 2050C) analogous to example 3.

Yield: 30% of theory, melting point: 1650C example 5 4-12-5-chloro-2-dimethylamino-benzoylamino) -ethyl / benzoic acid methyl ester, 06 g (5.3 mmol) of 5-chloro-2-dimethylaminobenzoic acid are added to 7 ml of thionyl chloride converted into the acid chloride at 40-50 ° C. After distilling off the thionyl chloride the crude acid chloride is dissolved in 10 ml of absolute pyridine with 0.95 g of 5.3 mmol) of methyl 4- (2-aminoethyl) benzoate reacted After stirring for 2 hours at room temperature, about 20 minutes at 50-70 ° C heated and then the pyridine is distilled off on a rotary evaporator. The dry residue is dissolved in ice water, made alkaline with sodium hydroxide solution and this solution with Chloroform extracted. their dry residue is that of the dried over sodium sulphate Chloroform extracts are over a silica gel table with toluene: ethyl acetate = 9.1 as Eluent purified by chromatography.

Yield: 1.4 g (73% of theory), melting point: 940 ° C. Calc .: C 62.7 H 5.98 N 7.57 Found: 62.9 5.73 7.63 Example 6 4- [2- (5-Bromo-2-dimethylamino-benzoylamino) -ethyl] -benzoic acid ethyl ester Manufactured from 5-bromo-2-dimethylamino-benzoic acid and 4- (2-aminomethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 93.5% of theory, melting point: 99 ° C. Calc .: C 56.35 H 5.21 N 6.90 Found: 56.10 5.31 7.01 Example 7 4- [2- (5-Bromo-2-dimethylamino-benzoylamino) -ethyl] benzoic acid Prepared from methyl 4- [2- (5-bromo-2-dimethylamino-benzoylamino) -ethyl-benzoate by alkaline hydrolysis as in Example 2.

Yield: 77% of theory, melting point: 1870 ° C. Calc .: C 55.4 H 4.89 N 7.16 Found: 55.2 4.97 7.01 Example 8 4- [2- (5-Fluoro-2-dimethylamino-benzoylamino) -ethyl] -benzoic acid methyl ester Manufactured from 5-fluoro-2-dimethylamino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 44% of theory, melting point: 560 ° C. Calc .: C 66.30 H 6.14 N 8.13 Found: 66.28 6.22 8.13 Example 9 4- [2- (5-Fluoro-2-dimethylamino-benzoylamino) -ethyl] benzoic acid Prepared from methyl 4- [2- (5-fluoro-2-dimethylamino-benzoylamino) -äthylgbenzoate by alkaline hydrolysis as in Example 2.

Yield: 73% of theory, melting point: 1080C, calc .: C 65.55 H 5.80 N 8.47 Found: 64.98 5.68 8.38 Example 10 4-L2- (2-dimethylamino-benzoylaino) Methyl ethyl benzoate Manufactured from 2-dimethylamino-benzoic acid and methyl 4- (2-amino-ethyl) benzoate analogous to Example 1. The reaction was carried out at 60-70 ° C.

Yield: 98% of theory, melting point: 740 ° C. Calc .: C 70.0 H 6.78 N 8.56 Found: 69.8 6.92 8.54 Example 11 4-2) - (2-DimethYlamino-benzoylamino) -ethYl7benzoic acid Manufactured from methyl 4- [2- (2-dimethylamino-benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 84% of theory, melting point: 1070 ° C. Calc .: C 69.25 H 6.45 N 8.96 Found: 69.50 6.62 9.00 Example 12 4- [2-5-Chloro-2-diethylamino-benzoylamino) -ethyl] -benzoic acid methyl ester Manufactured from 5-chloro-2-diethylamino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 51% of theory, Melting point: 93 ° C Calc .: C 64.86 H 6.48 N 9 12 65.01 6.54 3.98 Example 13 4- [2- (5-chloro-2-diethylamino-benzoylamino) ethyl] benzoic acid Prepared from methyl 4- [2- (5-chloro-2-diethylamino-benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 80% of theory, melting point: 950 ° C. Calc .: C 64.1 H 6.17 N 7.46 Found: 64.2 6.09 7.32 Example 14 Ethyl 4- [2- (5-chloro-2-diisobutylamino-benzoylamino) ethyl] benzoate Manufactured from 5-chloro-2-diisobutylamino-benzoic acid and ethyl 4- (2-amino-ethyl) -benzoate analogous to example 1.

Yield: 20% of theory, melting point <20 ° C. Calc .: C 68.03 H. 7.69 N 6.10 Cl 7.72 Found: 68.59 7.68 5.93 7.51 Example 15 4- [2- (5-chloro-2-diisobutylamino-benzoylamino-ethyl] benzoic acid Prepared from ethyl 4- [2- (5-chloro-2-diisobutylamino-benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 90% of theory, melting point: 113 ° C. Calc .: C 66.88 H 7.24 N 6.49 Cl 8.22 Found: 66.50 7.28 6.32 8.40 Example 16 4-t2- (5-chloro-2-dipentylamino-benzoylamino) -äthylJbenzoic acid methyl ester Manufactured from 5-chloro-2-dipentylamino-benzoic acid and ethyl 4- (2-amino-ethyl) -benzoate analogous to Example 1.

Yield: 83% of theory, melting point; 117-120 ° C calc .: C 69.05 H 8.07 N 5.75 Cl 7.28 Found: 68.84 7.99 6.05 7.54 Example 17 4- [2- (5-Chloro-2-dipentylamino-benzoylamino) -ethyl] benzoic acid Manufactured from 4-t2- (5-chloro-2-dipentylamino-benzoylaminoethylbenzoic acid ethyl ester by alkaline hydrolysis as in Example 2.

Yield: 36.5% of theory, melting point: <200C.

Calc .: C 68.03 H 7.68 N 6.10 Cl 7.72 Found: 67.93 7.64 6.02 7.86 Example 18 methyl 4- [2- (5-chloro-2- (1-pyrrolyl) benzoylamino) ethyl] benzoate Manufactured from 5-chloro-2- (1-pyrrolyl) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 64% of theory, melting point: 120-121 ° C. Calc .: C 65.88 H 5.00 N 7.32 Cl 9.26 Found: 65.86 4.85 7.47 9.38 Example 19 4-L2- (5-chloro-2- (1-pyrrolyl) -benzoylamino) -ethyl / benzoic acid Manufactured from 4- [2- (5-chloro-2- (1-pyrrolyl) -benzoylamino) -ethyl / benzoic acid methyl ester by alkaline hydrolysis as in Example 2.

Yield: 26% of theory, melting point: 250-2550C, calc .: C 65.13 H 4.65 N 7.59 Cl 9.61 Found: 65.07 4.74 7.34 9.07 Example 20 4-L2- (5-chloro-2- (N-cyclohexyl-methylamino) -benzoylaminoJ Ethybenzoic acid ethyl ester Manufactured from 2- (N-Cyclohexyl-methylamino) -5-chloro-benzoic acid and ethyl 4- (2-amino-ethyl) -benzoate analogous to Example 1.

Yield: 45% of theory, melting point: 980 ° C. Calc .: C 67.78 H 7.05 N 6.33 Found: 67.60 6.81 6.28 Example 21 4-E2- (5-chloro-2- / N-cyclohexyl-methylamino7benzoylamino) Ethyl-benzoic acid Prepared from ethyl 4- [2- (5-chloro-2- [N-cyclohexylmethylamino] benzoylamino) ethyl] benzoate) by alkaline hydrolysis as in Example 2.

Yield: 58% of theory, melting point: 166 ° C. Calc .: C 66.58 H 6.56 N 6.75 Found: 66.63 6.79 6.66 Example 22 4-C2- (5-Bromo-2-piperidino-benzoylamino) äthyljbenzoic acid ethyl ester Manufactured from 5-bromo-2-piperidino-benzoic acid and Ethyl 4- (2-aminoethyl) benzoate analogous to Example 1.

Yield: 87% of theory, melting point: 760 ° C. Calc .: C 60.13 H 5.92 N 6.09 Found: 60.35 5.97 6.19 Example 23 4- S- (5-Bromo-2-piperidino-benzoslamino) -ethylbenzoic acid Manufactured from ethyl 4- [2- (5-bromo-2-piperidino-benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2, yield: 99 4 of theory, melting point: 201 0C calc. T C 58.47 H 5.37 N 6.49 found: 58.56 5.40 6.55 example 24 4-t2- (5-chloro-2-pyrrolidino-benzoylamino) -ethylj% enzoic acid methyl ester from 5-chloro-2-pyrrolidino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 43% of theory, melting point: 16,400, calc .: C 65.19 H 5.99 N 7.24 Found: 65.35 6.00 7.23 Example 25 4-t2- (5-chloro-2-pyrrolidino-benzovlamino) -äthyl7-benzoic acid Prepared from 4- [2- (5-chloro-2-pyrrolidino-benzoylamino) -thyl / benzoic acid methyl ester by alkaline hydrolysis as in Example 2.

Yield: 688 of theory, melting point: 184 ° C. Calc .: C 64.42 H 5.68 N 7.52 cl 9.51 Found: 64.46 5.96 7.47 9.38 Example 26 4- [2- (5-Chloro-2-piperidino-benzoylamino) -ethyl] -benzoic acid methyl ester Manufactured from 5-chloro-2-piperidino-benzoic acid and methyl 4- (2-aminoethyl) benzoate analogous to example 1.

Yield: 72% of theory, melting point: 9800.

Calc .: C 66.00 H 6.29 N 7.00 Found: 66.00 6.37 6.81 example 27 4- [2- (5-Chloro-2-piperidino-benzoylamino) -ethyl] -benzoic acid Prepared from 4- [2- (5-chloro-2-piperidino-benzoylamino) -ethyl] -benzoic acid methyl ester by alkaline hydrolysis as in Example 2.

Yield: 82% of theory, melting point: 2000 ° C. Calc .: C 65.20 H 5.98 N 7.24 Found: 65.10 6.00 7.30 Example 28 4- [2- (5-Chloro-2- (2-methyl-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester Manufactured from 5-chloro-2- (2-methyl-piperidino) -benzoic acid and 4- (2-aminoethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 23% of theory, melting point: 820 ° C. Calc .: C 66.57 H 6.56 N 6.75 Found: 66.82 6.42 6.78 Example 29 4- [2- (5-Chloro-2- (2-methyl-piperidino) -benzoylamino) -ethyl] -. Benzoic acid Prepared from methyl 4- [2- (5-chloro-2- (2-methyl-piperidino) -benzoylamino) -ethyl] benzoate by alkaline saponification as in Example 2.

Yield: 57% of theory, melting point: 1780 ° C 65.91 H 6.29 N 6.99 65.73 6.28 7.13 Example 30 4- [2- (5-chloro-2- (3-methyl-piperidino) -benzoylamino) -ethyl] -benzoene methyl acid ester Manufactured from 5-chloro-2- (3-methyl-piperidino) -benzoic acid and 4- (2-Amino-ethyl) -benzoic acid methyl ester analogous to Example 1.

Yield: 51% of theory, melting point: 93 ° C. Calc .: C 66.57 H 6.56 N 6.75 Found: 66.52 6.38 6.81 Example 31 4-b2- (5-Chloro-2- (3-methyl-piperidino) -benzoylamino) -ethylbenzoic acid Prepared from methyl 4- [2- (5-chloro-2- (3-methyl-piperidino) -benzoylamino) -ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 83% of theory, melting point: 1940 ° C. Calc .: C 65.91 H 6.29 N 6.99 Found: 66.20 6.25 6.95 Example 32 4- [2- (5-Chloro-2- (4-methyl-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester Manufactured from 5-chloro-2- (4-methyl-piperidino) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 48% of theory, melting point: 550C, calc .: C C 6 &, 57 H 6.56 N 6.75 66.38 6.36 6.82 Example 33 4- [2- (5-Chloro-2- (4-methyl-piperidino) -benzoylamino) -ethyl] -benzoic acid Prepared from methyl 4- [2- (5-chloro-2- (4-methyl-piperidino) -benzoylamino) -ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 83% of theory, melting point: 2110 ° C. Calc .: C 65.91 11 6.29 N 6.99 Found: 66.07 6.25 7.02 Example 34 4-L2- (5-Chloro-2- (5-ethyl-2-methyl-piperidino) -benzoylamino) -ethyl-benzoic acid, methyl ester Manufactured from 5-chloro-2- (5-ethyl-2-methyl-piperidino) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 10% of theory, melting point: <200c, calc .: C 67.78 H. 7.05 N 6.33 Found: 68.00 7.10 6.50 Example 35 4- [2- (5-Chloro-2- (5-ethyl-2-methyl-piperidino) -benzoylamino) -ethyl / benzoic acid Prepared from methyl 4- [2- (5-chloro-2- (5-ethyl-2-methyl-piperidino) -benzoylamino) -ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 60% of theory, melting point: 40.degree Ber .: C 67.19 H 6.81 N 6R53 Found: 67.30 6.98 6.42 Example 36 4- [2- (5-Chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl ] methyl benzoate Prepared from 5-chloro-2- (3,5-dimethyl-piperidino) -benzoic acid and methyl 4- (2-aminoethyl) benzoate analogous to Example 1.

Yield: 85% of theory, melting point; 95 ° C calc .: C 67.20 H 6.81 N 6.53 Found: 67.14 6.62 6.68 Example 37 4- [2- (5-Chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester 2.7 g (0.01 mol) of 5-chloro-2- (3,5-dimethyl-piperidfno) -benzoes, acid with 3.57 g (0.03 mol) of thionyl chloride in 20 ml of chloroform was refluxed for 4.5 hours. The reaction milk is then concentrated in vacuo. The residue is in 10 ml Dissolved chloroform and with stirring at room temperature in a solution of 2.16 g (0.01 mol) 4- (2-amino-ethyl) -benzoic acid methyl ester hydrochloride and 3.03 g (0.03 Mol) triethylamine, dissolved in 15 ml of chloroform, added dropwise. After 15 minutes it is Addition finished.

The mixture is then refluxed for a further 30 minutes. After cooling down the reaction mixture is twice with water and once with dilute acetic acid washed. The chloroform phase is dried over sodium sulfate and concentrated. For further purification, the residue obtained is passed through a silica gel column (Chloroform / acetone w 9: 1). The pure fractions are after evaporation of the solvent recrystallized again from methylene chloride / petroleum ether (20: 1).

Yield: 3.3 g (77 t of theory), melting point: 94-95 ° C. Calc .: C 67.20 H 6.81 N 6.53 cl 8.27 Found: 67.11 6.78 6.70 8.39 Example 38 4- [2- (5-chloro-2- (3,5-dimethyl piperidino) benzoylamino) ethyl] benzoic acid 2.15 g (0.005 mol) of methyl 4- [2- (5-chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl] -benzoate are heated under reflux for 30 minutes in 50 ml of ethanol and 10 Kl IN sodium hydroxide solution.

After cooling, most of the alcohol is removed in vacuo and mixed with 60 ml of water. When weakly acidifying with acetic acid to about pH 6 a precipitate separates out, which is filtered off with suction after standing for a while and is made from isopropanol is recrystallized.

Yield: 1.82 g (87.5% of theory), melting point: 204-206 ° C Calc .: C 66.58 H 6.56 N 6.75 Cl 8.55 Found: 66.59 6.48 6.71 8.45 Example 39 4- [2- (5-chloro-2- (4-methoxy- piperidino) benzoylamino) ethyl] benzoic acid ethyl ester Manufactured from 5-chloro-2- (4-methoxy-piperidino) -benzoic acid and 4- (2-aminoethyl) -benzoic acid ethyl ester analogous to example 1.

Yield: 60% of theory, melting point: <20 ° C, calc .: C 64.78 H. 6.57 N 6.30 Found: 64.95 6.62 6.15 Example 40 4- [2- (5-chloro-2- (4-methoxy-piperidino) -benzoylamino) -ethyl] -benzoic acid Prepared from ethyl 4- [2- (5-chloro-2- (4-methoxy-piperidino) -benzoylamino) -ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 85% of theory, melting point: 188 ° C. Calc .: C 63.38 H 6.04 N 6.72 Found: 63.46 5.95 6.72 Example 41 Ethyl 4- [2- (5-methoxy-2-piperidino-benzoylamino) ethyl] benzoate Manufactured from 5-methoxy-2-piperidino-benzoic acid and 4- (2-aminoethyl) -benzoic acid ethyl ester analogous to example 1.

Yield: 66% of theory, melting point: 118 ° C. Calc .: C 70.22 H 7.36 N 6.82 Found: 70.76 7.42 7.36 Example 42 4-j2- (5-Methoxy-2-piperidino-benzoylamino) EthyF / benzoic acid hydrochloride Prepared from ethyl 4- [2- (5-methoxy-2-piperidino-benzoylamino) ethyl benzoate by alkaline hydrolysis as in Example 2. The compound obtained was in Acetone converted into the hydrochloride with isopropanolic hydrochloric acid. Yield: 91 % of theory, melting point: 1580C Calc .: C 63.07 H 6.49 N 6.68 Found: 63.00 6.31 6.61 Example 43 4- / 2- (5-chloro-2-heptamethyleneimino-benzoylamino) -ethyl-benzoic acid-ethyl ester Manufactured from 5-chloro-2-heptamethyleneimino-benzoic acid and ethyl 4- (2-aminoethyl) benzoate analogous to example 1.

Yield: 24% of theory Melting point: <20 ° C Calc .: C 67.78 H. 7.05 N 6.33 Found: 67.95 7.16 6.33 Example 44 4- (5-Chloro-2-heptamethyleneimino-benzoylamino) -äthyl7-benzoic acid Prepared from ethyl 4- [2- (5-chloro-2-heptamethyleneimino-benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 47% of theory, melting point: 186 ° C. Calc .: C 66.57 H 6.56 N 6.75 Found: 66.45 6.43 6.70 Example 45-4-fl2- (5-Nitro-2-piperidino-benzoylamino) -äthylJbenzoic acid methyl ester Manufactured from 5-nitro-2-piperidino-benzoic acid and Ethyl 4- (2-aminoethyl) benzoate analogous to Example 1.

Yield: 70% of theory, melting point: 1040 ° C. Calc .: C 64.92 H 6.40 N 9.87 Found: 65.17 6.38 9.67 Example 46 4- [2- (5-Nitro-2-piperidino-benzoylamino) ethyl] benzoic acid Manufactured from ethyl 4- [2- (5-nitro-2-piperidino-benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 69 t of theory, melting point: 194-1950C, calc .: C 63.46 H 5.83 N 10.57 Found: 63.20 5.79 10.38 Example 47 4- [2- (5-Chloro-2- (4-phenyl-piperidino) -benzoylamino) -ethyl] -benzoic acid- methyl ester Manufactured from 5-chloro-2- (4-phenyl-piperidino) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 62% of theory, melting point: 1240 ° C. Der .: C 70.50 H 6.13 N 5.87 Found: 70.60 6.26 5.84 Example 48 4- [2- (5-chloro-2- (4-phenyl-piperidino) -benzoylamino) -ethyl] -benzoic acid Prepared from methyl 4- [2- (5-chloro-2- (4-phenyl-piperidino) -benzoylamino) -ethyl7benzoate by alkaline hydrolysis as in Example 2.

Yield: 92.8 of theory, melting point: 1880C, calc .: C 70.04 H 5.88 N 6.05 Found: 70.12 6.08 6.05 Example 49 4- [2- (5-chloro-2- (1,4-dioxa-8-aza-spiro [4.5] decan-yl - (8)) Benzoylamino-ethyl] benzoic acid methyl ester Made from 5-chloro-2- (1,4-dioxa-8-azaBspiro / 4,57decan-yl- (8)) - benzoic acid and 4- (2-Amino-ethyl) -benzoic acid methyl ester analogous to Example 1.

Yield: 45.8 of theory, melting point: 1670C, calc .: C 62.81 H 5.93 N 6.1t Found: 62.80 5.89 5.93 Example 50 4- [2- (5-chloro-2- (1,4-dioxa-8-aza-spiro [4.5] decan.yl - (8)) - benzoylamino) Ethyl benzoic acid Prepared from methyl 4- [2- (5-chloro-2- (1,4-dioxa-8-aza-spiro [4,5] decanyl- (8)) benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 82% of theory, melting point: 1900 ° C. Calc .: C 61.95 H 5.88 N 6.28 Found: 61.74 6.03 6.52 Example 51 4- [2- (5-Chloro-2- (4-ethoxycarbonyl-piperidino) -benzoylamino) -ethy1 / benzoic acid, methyl ester Manufactured from 5-chloro-2- (4-ethoxycarbonyl-piperidino) -benzoic acid and 4- (2-aminoethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 17% of theory, melting point; 70 ° C calc .: C 63.48 H 6.18 N 5.92 Found: 63.30 6.08 5.91 Example 52 4-t2- (5-chloro-2- (4-hydroxycarbonyl-piperidino) Benzoylamino) ethyl2benzoic acid Prepared from methyl 4- [2- (5-chloro-2- (4-ethoxycarbonyl-piperidino) benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 71% of theory, melting point: 238 ° C. Calc .: C 61.32 H 5.38 N 6.50 Found: 61.32 5.33 6.71 Example 53 4- / 2- (5-Chloro-2-hexamethyleneimino-benzoylamino) -ethyi / benzoic acid methyl ester Manufactured from 5-chloro-2-hexamethyleneimino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 72% of theory, melting point: 81 ° C. Calc .: C 66.60 H 6.56 N 6.75 Found: 66.28 6.30 6.67 Example 54 4- [2- (5-Chloro-2-hexamethyleneimino-benzoylamino) -ethyl] benzoic acid Manufactured from 5- [2- (5-chloro-2-hexamethyleneimino-benzoylamino) ethyl] benzoic acid methyl ester by alkaline hydrolysis as in Example 2.

Yield: 89% of theory, melting point: 1820C, calc .: C 66.00 H 6.29 N 6.99 Found: 66.20 6.40 7.15 Example 55 4-t2- (5-chloro-2-morpholino-benzoylamino) -äthyl7benoesäuremethylester Manufactured from 5-chloro-2-morpholino-benzoic acid and Methyl 4- (2-aminotethyl) benzoate analogous to Example 1.

Yield: 80 t of theory, melting point: 111 ° C. Calc .: C 62.55 H 5.75 N 6.95 Found: 62.48 5.74 6.94 Example 56 4- [2- (5-chloro-2-morpholino-benzoylamino) ethyl] benzoic acid Prepared from methyl 4- [2- (5-chloro-2-morpholino-benzoylamino) -ethyl] -benzoate by alkaline hydrolysis as in Example 2.

Yield: 78% of theory, melting point: 1860C, calc .: C 61.75 H 5.44 N 7.20 Found: 61.60 5.41 7.10 Example 57 4- [2- (5-Chloro-2-thiomorpholino-benzoylamino) -ethyl] benzoic acid methyl ester Manufactured from 5-chloro-2-thiomorpholino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to Example 1 Yield: 45% of theory, melting point: 160 ° C., calc .: C 60.20 H 5.53 N 6.69 Found: 60.62 5.76 6.96 Example 58 4- [2- (5-Chloro-2-thiomorpholino-benzoylamino) ethyl] benzoic acid Prepared from methyl 4- [2- (5-chloro-2-thiomorpholino-benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 57% of theory, melting point: 210 ° C. Calc .: C 59.32 H 5.23 N 6.92 Found: 59.25 5.19 6.80 Example 59 4- [2- (5-chloro-2-thiomorpholino-benzoylamino) ethyl] benzoic acid methyl ester-S-oxide Manufactured from 5-chloro-2-thiomorpholino-benzoic acid-S-oxide and 4- (2-Amino-ethyl) -benzoic acid methyl ester analogous to Example 1.

Yield: 63% of theory, melting point: 1520 ° C. Calc .: C 57.99 H 5.33 N 6.44 Found: 58.30 5.22 6.52 Example 60 4- [2- (5-Chloro-2-thiomorpholino-benzoylamino) -ethyl] -benzoic acid-S-oxide Prepared from 4- [2- (5-chloro-2-thiomorpholino-benzoylamino) -ethyl] -benzoic acid methyl ester S-oxide by alkaline hydrolysis as in Example 2.

Yield: 82% of theory, melting point: 2020C, calc .: C 57.07 H 5.03 N 6.66 57.46 5.07 6.30 Example 61 4- [2- (5-chloro-2- [1,2,4,5-tetrahydro-3H-3benzazepin-yl- (3)] - benzoylamino ) ethyl] benzoic acid methyl ester Prepared from 5-chloro-2- / 1,2,4,5-tetrahydro-3H-3benzazepinyl- (3)] benzoic acid and methyl 4- (2-aminoethyl) benzoate analogous to Example 1.

Yield: 69% of theory, melting point: 1260C Ber .: C 70.04 H 5.88 N 6.05 70.20 5.81 5.94 Example 62 4- [2- (5-chloro-2- [1,2,4,5-tetrahydro-3H-3benzazepine- yl (3)] benzoylamino) ethyl] benzoic acid Prepared from methyl 4- [2- (5-chloro-2- (1,2,4,5-tetrahydro-3H-3-benzazepin-yl- (3)] benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 89% of theory, melting point: 148 ° C. 3er .: C 69.55 H 5.61 N 6.24 Found: 69.87 5.90 6.10 Example 63 4- [2- (5-Chloro-2- [1,2,3,4-tetrahydro-isoquinolin-yl- (2)] benzoylamino ) ethyl] benzoic acid methyl ester Prepared from 5-chloro-2- [1,2,3,4-tetrahydro-isoquinolyl- (2)] -benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester analogous to example 1.

Yield: 43% of theory, melting point: 940 ° C. Calc .: C 69.55 H 5.61 N 6.24 Found: 69.65 5.65 6.14 Example 64 04 5-Chloro-2-E1,2,3,4-tetrahydro-isoquinolin-yl- (2-7benzoylamino) -ethyl] benzoic acid Prepared from 4- [2- (5-chloro-2- (1,2,3,4-tetrahydro-isoquinolinyl - (2)] benzoylamino) ethyl] benzoic acid methyl ester by alkaline hydrolysis as in Example 2.

Yield: 86% of theory, melting point: 1730c, calc .: C 69.04 H 5.33 N 6.44 Cl 8.15 Gef,: 68.45 5.56 6.21 8.57 Example 65 4- [2- (5-chloro-2- (4-phenyl-piperazino) -benzoylamino-ethyl] - methyl benzoate Manufactured from 5-chloro-2- (4-phenyl-piperazino) -benzoic acid and 4- (2-amino-ethyl) benzoic acid methyl ester analogous to example 1.

Yield: 40% of theory, melting point: 132 ° C., calc .: C 67.84 H 5.90 N 8.79 Gef 67.72 5.92 Example 66 4- [2- (5-Chloro-2- (4-phenyl-piperazino) -benzoylamino) -ethyl] benzene acid Prepared from methyl 4- [2- (5-chloro-2- (4-phenyl-piperazino) -benzoylamino) -ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 82% of theory, melting point: 1660 ° C. Calc .: C 67, Q7 H 5.65 N 9.06 Found: 67.30: 5.96 8.99 Example 67 4 (5-chloro-2- (4-pyridyl- (2) -piperazino) -benzoylamino) -ethyl] -benzoic acid methyl ester Prepared from 5-chloro-2- [4- (2-pyridyl) -piperazino] benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester hydrochloride in the presence of thionyl chloride and triethylamine analogous to Example 37.

Yield: 44.6 t of theory, melting point of the hydrochloride: 153-154 C Calc .: C 60.58 I1 5.48 N 10.87 Cl 13.76 Found: 60.31 5.52 10.68 13.93 Example 68 4- [2- (5-Chloro-2- (4-pyridyl- (2) -piperazino) -benzoylamino-ethyl] -benzoic acid from 4- [2- (5-chloro-2- (4-pyridyl- (2) -piperazino) -benzoylamino-ethyl] -benzoic acid methyl ester by alkaline hydrolysis as in Example 2.

s Expansion: 27% of theory, melting point: 1200C (decomp.).

Calc .: C 64.58 H 5.42 N 12.05 Cl 7.63 Found: 64.36 5.49 11.87 7.48 example 69 4- / 2- (5-chloro-2-piperidino-benzoylamino) -1 -methyl-ethyl? -Benzoic acid methyl ester Made from 5-chloro-2-piperidino-benzoic acid and 4- (2-amino-1-methyl-ethyl) methyl benzoate analogous to Example 1.

Yield: 42.7% of theory, melting point: 93-94 ° C. Calc .: C 66.57 H 6.56 Cl 3.54- N 6.75 Found: 66.82 6.57 8.47 6.58 Example 70 4- [2- (5-Chloro-2-piperidino-benzoylamino) -1-methyl ethyl] benzoic acid Prepared from methyl 4- [2- (5-chloro-2-piperidino-benzoylamino) -1-methyl-ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 76% of theory, melting point: 192-1940C, calc .: C 65.91 H 6.28 Cl 8.84 N 6.99 Found: 66.00 6.30 8f77 6.87 Example 71 4- [2- (5-chloro-2-dimethylamino-benzoylamino) -1-methyl-ethyl] -benzoic acid Prepared from methyl 4- [2- (5-chloro-2-dimethylamino-benzoylamino) -1-methyl-ethyl] benzoate by alkaline hydrolysis as in Example 2.

Yield: 86% of theory, melting point: 159-161 ° C. Calc .: C 63.23 H. 5.87 Cl 9.83 N 7.76 Found 63.42 6.07 9.56 7.67 Example 72 4- [2- (5-chloro-2-dimethylamino-benzoylamino) -1-methyl-ethyl ] -ben zoe säure-methyl es ter Manufactured from 5-chloro-2-dimethylamino-benzoic acid and 4- (2-Amino-1-methyl-ethyl) -benzoic acid methyl ester analogous to example, game 1.

Yield: 61.5% of theory, melting point: 79-80 ° C. Calc .: C 64.07 H 6.18 Cl 9.46 N 7.47 Found: 64.40 6.52 9.14 7.20 Example 73 4- [2- (5-Amino-2-piperidino-benzoylamino) ethyl] benzoic acid ethyl ester 30 g (70.5 mmol) of ethyl 4- [2- (5-nitro-2-piperidino-benzoylamino) ethyl] benzoate are in 500 ml of methanol: ethanol (1: 1) and palladium-carbon as a catalyst Hydrogenated room temperature and a hydrogen pressure of 5 bar. After removing the Catalyst and distilling off the solvent is the compound by filtration Purified on silica gel with ethyl acetate as the mobile phase.

Yield: 93% of theory, melting point: <20 ° Ber .: C 69.84 IS 7.39 N 10.62 Found: 70.10 7.20 10.43 Example 74 4- / 2- (5-Amino-2-piperidino-benzoylamino.) -äthylJbenzoic acid dihydrochloride Prepared from 4-L2- (5-amino-2-piperidino-benzoylamino) -ethyl / -benzoic acid ethyl ester by alkaline hydrolysis as in Example 2. The product is then dissolved in acetone converted into the dihydrochloride with isopropanolic hydrochloric acid.

Yield: 87% of theory, melting point: 700 ° C. Calc .: C 57.26 H 6.18 N 9.54 Found: 57.40 6.30 9.52 Example 75 4-t2- (5-Acetamino-2-piperidino-benzoylamino) ethyl benzoic acid ethyl ester Prepared from 2.5 g (6.3 mmol) 4- / 2- (5-amino-2-piperidinobenzoylamino) ethyl / benzoic acid ethyl ester and 25 ml of acetic anhydride at room temperature. The reaction product precipitates and is washed with ether.

Yield: 1.9 g (69% of theory), melting point: 1650 ° C. Calc .: C 68.62 H 7.14 N 9.6G Found: 68.92 7.09 9.50 Example 76 4- [2- (5-Acetamino-2-piperidino-benzoylamino) ethyl] benzoic acid Manufactured from ethyl 4- [2- (5-acetamino-2-piperidino-benzoylamino) -äthylJbenzoic acid by alkaline hydrolysis as in Example 2.

Yield: 98% of theory, melting point: 212 ° C. Calc .: C 67.46 H 6.64 N 10.26 Found: 67.00 6.67 10.04 Example 77 4 5-Dimethylaminosulfonyl-2-piperidino-benzoylaml-nt7-ethylbenzoic acid methyl ester Manufactured from 5-dimethylaminosulfonyl-2-piperidino-benzoic acid and 4- (2-ethylamino) -benzoic acid methyl ester analogous to example 1.

Yield: 77% of theory, melting point calc .: C 60.87 H 6.60 N 8.87 S 6.77 Found: 61.08 6.67 8.86 6.80 Example 78 4-J2- (5-DLmethylaminosulEonyl-2-piperidino-benzoylamine ethyl] benzoic acid Prepared from methyl 4- [2- (5-dimethylaminosulfonyl-2-piperidinobenzoylamino) ethyl] benzoate by alkaline saponification as in Example 2.

Yield 91% of theory, melting point 220 ° C. Calc .: C 60.11 H 6.36 N 9.14 S 6.98 Gef * 60.30 6.42 8.96 6.98 Example 79 4- [2- (5-Cyano-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester Manufactured from 5-cyano-2-piperidino-benzoic acid and 4- (2-aminoethyl) -benzoic acid ethyl ester analogous to Example 7 Yield: 76 * of theory, melting point: 97 ° C. Calc .: C 71.08 H 6.71 N 10.36 Found: 71.37 6.74 10.33 Example SO 4- [2- (5-Cyano-2-piperidino-benzoylamino) -ethyl] -benzoic acid Prepared from ethyl 4- [2- (5-cyano-2-piperidino-benzoylamino) ethyl] benzoate by alkaline hydrolysis as in Example 2 Yield: 40% of theory, melting point: 19Q ° C Calc .: C 70.00 H 6.14 N 11.13 Found: 69.81 6.03 10.98 example 81 4- / 2- (5-Xthoxycarbonyl-2-piperidino-benzoylamino) -ethyl / -benzoic acid ethyl ester hydrochloride 2.5 g (6.2 mmol) of ethyl 4- / 2- (5-cyano-2-piperidino-benzoylamino) -ethyl-benzoate are dissolved in 80 ml of ethanol and saturated with hydrogen chloride. After six days Standing at room temperature, the solvent is evaporated, the residue in ice water dissolved, adjusted to pH 9 with sodium hydroxide solution and extracted with chloroform. After drying The evaporation residue becomes over sodium sulfate and distilling off the solvent converted into the hydrochloride in ether with hydrochloric acid.

Yield: 2.5 g (89.1% of theory), melting point: 86-880C Calc .: C 63.85 H 6.80 N 5.72 Cl 7.24 Found: 63.71 6.69 5.74 7.11 Example 82 4-C2- (5-Hydroxycarbonyl-2-piperidino-benzoylamino) -äthyl-7-benzoic acid Prepared by alkaline hydrolysis of 4-L2- (5-ethoxycarbonyl-2-piperidino-benzoylamino) -äthyl7benzoic acid ethyl ester hydrochloride analogous to example 2.

Yield: 92% of theory, melting point: 2420C, calc .: C, 66.65 H. 6.10 br 7.06 Found: 65.96 6.18 7.23 Example 83 4-L2- (2- (4-Hydroxypiperidino) -5-nitro-benzoylamino) -ethyl / -benzoic acid methyl ester a) 4-2- (2-chloro-5-nitro-benzoylamino) -ethyl / benzoic acid methyl ester 8 g (40 mmol) 2-chloro-5-nitro-benzoic acid are dissolved in 40 ml of absolute tetrahydrofuran with 6.8 g (44 mmol) N, N'-carbonyldiimidazole converted into the imidazolide. After a reaction time 7.9 g (44 mmol) of 4- (2-aminoethyl) benzoic acid methyl ester are added over 2 hours Room temperature added and still-approx. Stirred for 16 hours. After distilling off the The crude product is solvent over a silica gel column with toluene: ethyl acetate (1: 1) purified by chromatography as eluent.

Yield: 12 g (83% of theory), melting point: 163 ° C. Calc .: C 56.28 H 4.17 N 7.72 Found: 56.58 4.41 7.82 b) 4-t2- (4-Hydroxypiperidino) -5-nitro-benzoylamino) -ethyl-ben zoe acid methyl ester A solution of 5 g (14 mmol) 4- / 2- (2-chloro-5-nitro-benzoylamino) -ethy Methyl ubenzoate in 100 ml of ethanol is mixed with 2.83 g (28 mmol) of 4-hydroxypiperidine Heated to reflux temperature for 14 hours. After distilling off the solvent in a rotary evaporator, the dry residue is dissolved in ice water, with diluted Hydrochloric acid adjusted to pH 5 and extracted with chloroform. After drying over sodium sulfate, Distilling off the chloroform, the residue is crystallized from isopropanol.

Yield 5.5 g (92% of theory), melting point: 142 ° C. Example 84 4- [2- (5-Amino-2- (4-hydroxy-pipeirdino) -benzoylamino) -ethyl] -benzoic acid methyl ester 5.3 g (12.4 mmol) of methyl 4- [2- (2- (4-Hydroxypiperidino) -5-nitrobenzoylamino) ethyl] benzoate are in 100 ml of methanol with 10% palladium-carbon at room temperature and a Hydrogen pressure VwL 1 bar hydrogenated.

Yield: 91% of theory, melting point: 78 ° C. Example 85 4- [2- (5-Chloro-2- (4-hydroxypiperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester 20.5 g (52 mmol) of methyl 4- [2- (5-amino-2 (4-hydroxypiperidino) benzoylamino) ethyl] benzoate are dissolved in 80 ml of half-centered ice-cold hydrochloric acid and with a solution diazotized from 4 g of sodium nitrite in 25 ml of ice-cold water; This solution is going to a suspension of 6 g of copper powder and 0 ml of HCl was added dropwise. After the evolution of nitrogen has ended a toothy oil falls out. This oil is extracted with chloroform and after drying over sodium sulate over a silica gel column with the mobile phase ethyl acetate: methanol (9: 1) cleaned.

Yield. 30% of theory, melting point: <20 ° C, calc .: e 63.38 H 6.04 N 6.72 63.62 6.21 6.55 Example 86 4- / 2- (5-chloro-2- (4-hydroxy-piperidino) -benzoylamino) -ethyl / -benzoic acid 4.5 g (11.3 mmol> 4-L2- (5-amino-2- (4-hydrqxy-piperidino) -benzoylamino) -ethyl] benzoic acid methyl ester are dissolved in 20 ml of half-concentrated hydrochloric acid and at 0 ° C with 0.87 g (12.4 mmol) of sodium nitrite, dissolved in 6 ml of water, diazotized.

This solution becomes a suspension of 1.2 g of copper powder in 3 ml of concentrated hydrochloric acid was added dropwise. After stirring for 2 hours, it is stirred for approx. 20 Heated to 75 ° C. for minutes. The cooled solution is extracted with chloroform, the chloroform solution dried with sodium sulfate and the evaporation residue over a silica gel column was purified with chloroform: methanol (9: 1) as the eluent.

Yield: 2.4 g (52% of theory), melting point: 1900C, calc .: C 62.6 H 5.75 N 6.93 Found: 62.14 5.84 6.83 Example 87 4- [2- (5-Chloro-2- (3-hydroxy-piperidino) -benzoylamino) -ethyl] -ben zoe acid-methyl es ter Manufactured from 4- [2- (5-Amino-2- (3-hydroxy-piperidino) -benzoylamino) methyl ethyl 7benzoate analogous to Example 85, yield: 30% of theory, melting point: 200C Calc .: C 63.38 H 6.04 N 6.72 Found: 63.48 6.21 6.65 example 88 4- [2- (5-chloro-2- (3-hydroxypiperidino) benzoylamino) ethyl] benzoic acid hydrate Prepared from methyl 4- [2- (5-amino-2- (3-hydroxypiperidino) benzoylamino) ethyl] benzoate analogous to example 86.

Yield: 40 g of theory, melting point: 100-1 100C, calc .: C 59.93 H 5.98 N 6.65 Found: 60.19 6.08 6.62 Example 89 4- [2- (2- (3-Hydroxypiperidino) -5-nitro-benzoylamino) -ethyl] -ben methyl zoate Prepared from methyl 4- [2- (2-chloro-5-nitro-benzoylamino) ethyl] benzoate and 3-hydroxy-piperidine analogous to Example 83.

Yield: 43.5% of theory, melting point: 78-800 ° C. Example 90 4-L2- ~ t5-amino-2- (3-hydroxypiperidino) benzoylamino) ethyne methyl benzoate Prepared from methyl 4- [2- (3-Hydroxypiperidino) -5nitro-benzoylamino) ethyl] benzoate by catalytic hydrogenation analogous to Example 84.

Yield: 90 * of theory, melting point: 820C example A tablets with 5 mg 4- [2- (5-chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl / benzoic acid Composition:. 1 tablet contains: Active ingredient (1) 5.0 mg corn starch (1) 62.0 mg lactose (3) 48.0 mg polyvinylpyrrolidone (4) 4.0 mg magnesium stearate (5) 1.0 mg 120.0 mg Preparation method: 1, 2, 3 and 4 are mixed and added with water moisturizes. The moist mixture is pressed through a sieve with a mesh size of 1.5 mm and dried at approx. 450C. The dry granules are passed through a sieve with a mesh size of 1.0 mm beaten and mixed with 5. The finished mixture is pressed on a tablet press with punches of 7 mm diameter, which are provided with a dividing notch, into tablets.

Tablet weight: 120 mg Example B coated tablets with 2.5 mg 4- [2- (5-chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -äthyl / benzoic acid 1 tablet core contains: Active ingredient (1) 2.5 mg potato starch (2) 44.0 mg milk: sugar (3J 30.0 mg Polyvinyl pyrrolidone (4) 3.0 Magnesium stearate (5) mg 0.5 mg 80.0 mg Manufacturing process: 1, 2, 3 and 4 are used mixed well and moistened with water.

The moist mass is pressed through a sieve with 1 mm mesh size, dries at approx. 450C and then beats 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 dragee 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.

Drage weight: 120 mg Example C tablets with 10 mg 4- [2- (5-chloro-2-hexamethyleneimino-benzoylamino) -ethyl] benzoic acid Composition: 1 tablet contains: Active substance 10.0 mg lactose powder 70.0 mg corn starch 31.0 mg polyvinylpyrrolidone 8.0 mg magnesium stearate 1.0 mg 120.0 mg Production method: The mixture of the active ingredient, lactose 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 ° C. 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 4-t2- (5-chloro-2-hexamethyleneimino-benzoyl-- amino) i 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 mixed with a 15% solution of polyvinylpyrrolidone, moistened in water. The moist mass is through a Sieve with 1 mm mesh size, dried at 450C and then through rubbed the same sieve. After mixing with the specified amount of magnesium stearate are pressed from this tablet cores.

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

Dragéegewicht: 180 mg Example E tablets with 10 mg 4- [2- (5-chloro-2-piperidino-benzoylamino) -ethyl7ben zoic acid Composition: 1 tablet contains: Active ingredient 10.0 mg milk sugar powder. 70.0 mg.

Corn starch 31.0 mg polyvinylpyrrolidone 8.0 mg magnesium stearate 1.0 mq 120.0 mg Manufacturing process: see analogous to example C.

Example F Dragees containing 5 mg of 4-L2- (5-chloro-2-piperidino-benzoylamino) äthyl7benzoic acid 1 tablet core contains: Active substance 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: see example D.

Claims (1)

P atent claims 1. New aminobenzoic acid amides of the general formula in which 1 is a hydrogen or halogen atom, a nitro, amino, alkanoylamino, alkoxy, cyano, carboxyl, alkoxycarbonyl or dialkylamidosulfonyl group, where the alkyl part can each contain 1 to 3 carbon atoms R2 and R3, which are the same or can be different, alkyl groups with 1 to 7 carbon atoms or cycloalkyl groups with 3 to 7 carbon atoms or R2 and R3 together with the intervening nitrogen atom an imino group with 3 to 7 carbon atoms Alkoxy group with 1 to 3 carbon atoms, a hydroxy, phenyl, carboxyl or alkoxycarbonyl group with a total of 2 to 4 carbon atoms, or in which a methylene group of the iminoringes by a cyclic ketal group with a total of 3 or 4 carbon atoms, by an acid. substance or sulfur atom, by a sulfoxide or by an imino group, by a phenyl or pyridyl group, pe is substituted can be a pyrrolyl-l getrahydro-isoquinolyl or tetrahydrobenzazepinyl group, R4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and R5 denote a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and their physiologically compatible salts with inorganic or organic acids or bases when R5 represents a hydrogen atom. 2. New compounds of general formula I according to claim 1, in the R1 is a hydrogen, fluorine, chlorine or bromine atom, a methoxy, nitro, amino, Acetamino, cyano, carboxyl, dimethylamidosulfonyl or an alkoxycarbonyl group with a total of 2 or 3 carbon atoms, R2 and R3, which are the same or different can be alkyl groups with 1 to 5 carbon atoms or cyclohexyl groups odor R2 and R3 together with the intermediate nitrogen atom a pyrrolyl, pyrrolidino, Hexamethyleneimino, LL'eptamethyleneimino, morpholino, thiomorpholino or thiomorpholno-S-oxide group, an optionally by a hydroxy, methoxy, carboxyl, methoxycarbonyl, Piperidino group substituted by ethoxycarbonyl or phenyl group, one by 1 or 2 alkyl groups each with 1 or 2 carbon atoms substituted piperidino group, one substituted in the 4-position by a phenyl, pyridyl (2) or pyridyl (4) group Piperazino group, a 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,4,5-tetrahydro , 3H-3benzpazepin-3-yl or 1,4-dioxa-8-aza-spiro [4,5] -decan-8-yl group, R4 represents a hydrogen atom or the methyl group and R5 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, and their physiologically acceptable salts with inorganic or organic acids or bases, if R5 is a hydrogen atom represents. 3. New compounds of general formula 1 according to Ans p. uch 1 in R1 is a fluorine, chlorine or bromine atom, the cyano or methoxy group, R2 and R3 together with the nitrogen atom, the dimethylamino, N-methyl-cyclohexylamino, diethylamino, Pyrrolidino-, piperidino-, hexamethyleneimino-, heptamethyleneimino-, 2-ethyl-piperidino-, 3-methyl-piperidino-, 4-ethylpiperidino-, 4-methoxy-piperidino-, 4-ethoxycarbonylpiperidino-, 3,5-dimethylpiperidino-, 2-methyl-5-ethylpiperidino-, morpholino-, 1,4-dioxa-8-aza-spiro [4,5-] decan-8-yl-, Thionorpholino or thiomorpholino-s-oxide group, R4 is a hydrogen atom or the Methyl group and R5 a hydrogen atom or an alkyl group having 1 to 3 carbon atoms mean, and their physiologically acceptable salts with inorganic or organic Acids or bases, if R5 represents a hydrogen atom 4. New compounds of the general formula I according to claim 1, in which R1 is the methoxy group, a chlorine or bromine atom, R2 and R3 together with the nitrogen atom one optionally through a methyl group-substituted piperidino group, the dimethylamino, 4-methoxy-piperidino, 3, 5-dimethylpiperidino -, hexamethyleneimino, heptamethyleneimino, Thiomorpholino or 1,4-dioxa-8-aza-spiro [4,5] decan-8-yl group, R4 is a hydrogen atom or the methyl group and R5 denote a hydrogen atom or the methyl group, and their phystologically acceptable salts with inorganic or organic acids or bases when R5 represents a hydrogen atom. 5. 4-L2- (5-chloro-2- (2-methyl-piperidino) -henzoylamino) -ato.yl / -benzoic acid and its salts with inorganic or organic acids or bases. 6. 4- [2- (5-Chloro-2- (4-methoxy-piperidino) -benzoylamino) -ethyl] -benzoic acid and its salts with inorganic or organic acids or bases 7. 4- [2- (5-chloro-2-piperidino-benzoylamino) ethyl] benzoic acid and its salts with inorganic or organic acids or bases. 8. 1- [2- (5-Bro, -2-piperidino-benzoylamino) ethyl] benzoic acid and its Salts with inorganic or organic acids or bases. 1- [2- (5-Methoxy-2-piperidino-benzoylamino) ethyl] benzoic acid and its Salts with inorganic or organic acids or bases. 10. 4- [2- (5-chloro-2-heptamethyleneimino-benzoylamino) -ethyl] -benzoic acid and its salts with inorganic or organic acids or bases. 11. 4- / 2- (5-chloro-2-hexamethyleneimino-benzoylamino) -ethyl / s benzoic acid and its salts with inorganic or organic acids or bases. 12. 4- / 2- (5-chloro-2- (N-cyclohexyl-N-methylamino) -benzoylamino) -äthvl / benzoic acid and its salts with inorganic or organic acids or Bases. 13. Use of the new compounds according to claim 1 zrekä = fung of diabetes mellitus. 14. Medicament containing a compound according to claim 1 in addition to one or more inert carriers and / or diluents. 15. Process for the preparation of new aminobenzoic acid amides of the general formula in which R1 is a hydrogen or halogen atom, a nitro, amino, alkanoylamino, alkoxy, cyano, carboxyl, alkoxycarbonyl or dialkylamidosulfonyl group, where the alkyl part can each contain 1 to 3 carbon atoms, R2 and R3, the same or can be different, alkyl groups with 1 to 7 carbon atoms or cycloalkyl groups with 3 to 7 carbon atoms or R2 and R3 together with the intermediate nitrogen atom an imino group with 3 to 7 carbon atoms in the imino ring, which is replaced by 1 or 2 alkyl groups each with 1 to 3 carbon atoms , an alkoxy group with 1 to 3 carbon atoms, a hydroxy, phenyl, carboxyl or alkoxycarbonyl group with a total of 2 to 4 carbon atoms, or in which a methylene group of the imino ring by a cyclic ketal group with a total of 3 or 4 carbon atoms, by a Oxygen or sulfur atom, by a sulfoxide or by an imino group, by a phenyl or pyridyl group uppe is substituted, can be replaced, a pyrrolyl, tetrahydro-isoquinolyl or tetrahydro-benzazepinyl group, R4 is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms and R5 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, and of their physiological Compatible salts with inorganic or organic acids or bases, if R5 represents a hydrogen atom, characterized in that a) an aminobenzoic acid of the general formula in which R1, R2 and R3 are as defined at the outset, or their reactive derivative, optionally prepared in the reaction mixture, with a phenylalkylamine of the general formula in which R4 and R5 are as defined at the outset, or with its reactive derivative which may be formed in the reaction mixture, if an aminobenzoic acid of the general formula II is used and R5 is an alkyl group having 1 to 4 carbon atoms, or b> to produce a compound of general formula 1, in which R1 represents the nitro group, a nitrobenzamide of the general formula in which R4 and R5 are as defined at the outset and X represents a halogen or pseudohalogen, with an amine of the general formula in which R2 and R3 are as defined at the outset, is reacted or c) for the preparation of a compound of the general formula I in which R5 represents a hydrogen atom, a compound of the general formula in which R1 to R4 are as defined at the outset and A represents a group which can be converted into a carboxyl group by oxidation, is oxidized, or t is a compound of the general formula to produce a compound of the general formula I in which R5 is hydrogen in which R1 to R4 are as defined at the outset and B represents a group which can be converted into a carboxyl group by hydrolysis, is hydrolyzed or e) for the preparation of a compound of the general formula I in which R2 and R3, which can be identical or different, contain alkyl groups 1 to 7 carbon atoms or cycloalkyl groups with 3 to 7 carbon atoms or R2 and R3 together with the intermediate nitrogen atom represents an imino ring with 3 to 7 carbon atoms optionally substituted by 1 or 2 alkyl groups each with 1 to 3 carbon atoms, a compound of the general formula in which R1, R4 and R5 are as defined at the outset and R3 'represents a hydrogen atom or has the meanings mentioned above for R3, with a compound of the general formula R2' - X, (Ix) in which R2 'has the meanings mentioned for R2 at the beginning or, together with the radical R3 'of the formula VIII, represents a straight-chain alkylene group having 3 to 7 carbon atoms, which can be substituted by 1 or 2 alkyl groups each having 1 to 3 carbon atoms, and X is a nucleophilic leaving group, is reacted and, if desired, then a 1 obtained compound of the general formula 1, in which R5 represents a hydrogen atom, is converted by esterification into a corresponding compound of the general formula I, in which R5 represents an alkyl group with 1 to 4 carbon atoms, and / or a compound of the general formula I obtained , 1 in which R1 represents the nitro group, by means of reduction into a corresponding compound of the general The formula I, in which R1 represents the amino group, is converted and / or a compound of the general formula I obtained in which R1 represents the amino group, by means of conversion into its corresponding diazonium salt and subsequent Sandmeyer reaction into a corresponding compound of the general formula I, in which R1 represents the cyano group, a fluorine, chlorine or bromine atom, is converted and / or a compound of the general formula I obtained in which R1 represents the amino group, by means of acylation, into a corresponding compound of the general formula I, in the R1 represents an alkanoylamino group with 1 to 3 carbon atoms in the alkanoyl part, is converted and / or a compound of the general formula I in which R1 represents the cyano group is converted by means of alcoholysis into a corresponding compound of the general formula I in which R1 has an alkoxycarbonyl group 1 to 3 carbon atoms in the alkoxy part, Eber leads and / or a obtained Ver Bond of the general formula T, in which R1 represents an alkoxycarbonyl group and / or R2 and, together with the nitrogen atom in between, represents an imino group with 3 to 7 carbon atoms in the Mminoring substituted by an alkoxycarbonyl group, the alkoxy part each containing 1 to 3 carbon atoms, by means of hydrolysis into a corresponding compound of the general formula I in which R1 is the carboxyl group and / or R2 and R3 together with the nitrogen in between; atom represents an imino group substituted by a carboxyl group with 3 to 7 carbon atoms in the imino ring, is converted andX or a compound of the general formula 1 obtained is converted into its physiologically acceptable salts with inorganic or organic acids or bases, if R5 represents a hydrogen atom. 16. The method according to claim 15, characterized in that the implementation is carried out in a solvent. 17. The method according to claims 15a and '6, characterized in that that the reaction is carried out in the presence of an inorganic or tertiary organic base is carried out. 18. The method according to claims 15a and 16, characterized in that that the water formed during the reaction by azeotropic distillation or is removed by adding a desiccant. 19. The method according to claims 15a and 16-18, characterized in that that the reaction at temperatures between 250 and 2500C, but preferably at Temperatures between -1O0C and the boiling point of the solvent used, is carried out. 20. The method according to claims 15b and 16, characterized in that that the reaction in the presence of an excess of the amine used of the general Formula V is carried out. 21. The method according to claims 15b and 16, characterized in that that the reaction in the presence of an inorganic or tertiary organic base is carried out. 22. The method according to claims 15b, 16, 20 and 21, characterized in that that the reaction at temperatures between 20 and 1500C, but preferably at the boiling temperature of the reaction mixture is carried out. 23. experience according to claims 15c and 16, characterized in that that the reaction at temperatures between 0 and icooc, but preferably at Temperatures between 20 and 50 ° C is carried out. 24. The method according to claims 15d and 16, characterized in that that the hydrolysis is carried out in the presence of an acid or base. 25. Approach according to claims 15d, 16 and 24, characterized in that that the reaction is carried out at the boiling point of the reaction mixture. 26. The method according to claims 15e and 16, characterized in that that the alkylation in the presence of an inorganic or tertiary organic Base is carried out. 27. The method according to claims 15e and 16, characterized in that that the methylation is carried out with formaldehyde in the presence of a reducing agent will. : 28. Method according to claims 15e, 26 and 27, characterized in that that the reaction is carried out at temperatures between 0 and 1500C. 29. The method according to claims 15e, 16 and 26, characterized in that that the alkylation is carried out at temperatures between 20 and 750C. i30. Method according to claim 27, characterized in that the Methylation is carried out at the boiling point of the reaction mixture.