HU183178B - Process for preparing new carboxylic acid derivatives - Google Patents

Abstract

PROCEDURE FOR OBTAINING AMIDAS FROM CARBOXILIC ACIDS. IS TO HYDROLYTE FROM GENERAL FORMULA (I), IN THE PRESENCE OF AN ACID OR A BASE TO THE EBULLITION TEMPERATURE OF THE REACTION MIXTURE. THE COMPOUND OF GENERAL FORMULA (II) IS OBTAINED, WHICH IS OPTIONALLY TRANSFORMED BY REDUCTION, PASSED THROUGH A DIAZONIUM SALT, ALCOHILATION, ACILATION, HYDROLYSIS, DEBENCILATION, DEHALOGENATION OR IS TRANSFORMED IN THEIR PHYOLOGICALLY TOLERABLE SALTS.

Description

The present invention relates to novel carboxylic acid derivatives of the formula (I), to their physiologically acceptable salts with inorganic or organic acids and to bases where Z is a carboxyl group or to a base thereof, and to pharmaceutical compositions containing them.

The novel compounds of the formula I have valuable pharmacological properties, have an effect on metabolism and are predominantly antihyperglycaemic and / or lipid-lowering.

In the general formula 1, the substituents have the following meanings:

R is hydrogen, 4-chloro or a cyclic alkyleneimino group containing from 4 to 7 carbon atoms in the ring,

R, hydrogen, fluorine, chlorine or bromine,

C 1 -C 4 alkyl or C 1 -C 6 alkoxy, phenyl-substituted C 1 -C 3 alkoxy, hydroxy, nitro, amino, cyano or carboxyl, or alkanoylamino, alkoxycarbonyl containing 1 to 3 carbon atoms in the alkyl moiety - or dialkylaminosulfone swept,

R ₂ and R 1 are each independently C 1-7 alkyl, C 3-5 alkenyl, C 4-7 cycloalkyl, phenyl substituted C 1-3 alkyl, phenyl or adamanyl, or

R ₂ and R 1 represent a non-branched alkyleneimino group containing from 4 to 6 carbon atoms together with the nitrogen atom to which they are attached which has one or two C 1 -C 4 alkyl groups, a C 1 -C 3 alkoxy group, hydroxy, phenyl, optionally substituted by a carboxyl group or an alkoxycarbonyl group having 2 to 4 carbon atoms in total, and / or a methylene group of the aforementioned alkyleneiminogyur is an imino group optionally substituted by a C 1 -C 3 alkyl group. alkoxycarbonyl group having 2 to 4 carbon atoms in total, phenyl, halophenyl, benzyl, pyridyl or furoyl group; substituted, oxygen, or sulfur, carbonyl, sulfoxide, or sulfonyl group, and a C7-C10 saturated or partially unsaturated azabicycloalkyl group, the 3- and 5-position being substituted by three or four C1-C3 alkyl piperidino groups 1,4-dioxa-8-azaspiroalkyl having 6 to 9 carbon atoms, pyrrolyl, tetrahydropyridyl, heptamethyleneimino, octamethyleneimino, nonamethyleneimino, decamethyleneimino, undecamethyleneimino, or dodecamethylene imino group,

R _{4 is} hydrogen or C 1-3 alkyl,

X is nitrogen or -CH;

Y is oxygen, imino. or a methylene group optionally substituted with one or more C 1-3 alkyl groups,

Z is hydrogen, halogen, nitro, amino, cyano, formyl, hydroxymethyl or carboxyethylene, optionally having 1 to 7 carbon atoms. a carboxyl group esterified with an aliphatic alkanol, a C5-C7 cycloalkanol21 or a phenyl (C1-C4) alkanol optionally substituted with two or three alkoxy groups, egcarboxyl or ethylenedioxy groups, wherein the alkoxy groups contain from 1 to 3 carbon atoms; Acetylsubstituted with 4 carbon atoms substituted by alkoxycarbonyl, ethyl substituted by one or two alkoxycarbonyl groups having 2 to 4 carbon atoms, optionally

Carbamoyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, or N-alkylpiperazinyl, mono- or disubstituted with C 1-6 alkyl, C 5-7 cycloalkyl and / or C 3-5 alkenyl; the. alkyl having 1 to 3 carbon atoms; and Z may also be substituted with a carboxyl group when R 1 and R ₃ together with the nitrogen atom between them represent a cyclic alkyleneimino group as mentioned in the introduction.

The groups R, R 1 - R ₄ , Y and Z, within the definitions above, have the following meanings:

R is hydrogen, 4-chloro, pyrrolidinyl, piperidino or hexamethyleneimino,

R, hydrogen, fluorine, chlorine or bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert -butoxy, pentyloxy, isopentyloxy, neopenyloxy, tert-pentylOX1, hexyloxy, benzyloxy, Ι-phenylethoxy, 2-phenylethoxy, 1- phenylpropoxy, 2-hydroxy-1-carboxylic acid, 3-phenylpropoxy, nitro, cyano, amino, formylamino, acetylamino, propionylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl -. pro-carbonyl, isopropoxycarbonyl, dimethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, ethylmethylaminosulfonyl, methylpropylaminosulfonyl or ethylpropylamino sulfonyl,

R ₂ and R ₃ together with the nitrogen atom to which they are attached: dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, diphenylamino, dihcxylamino; , Diheprylamino, Ν-methyl-elylaniline, N-methylpropylamino, N-isopropylpropylamino, Nisobutylpropylamino, N-methylisopropylamino, Ν-methyl bulyl -amino, N-ethylbutylamino, N-ethylisopropylamino, N-ethylpentylamino, N-propylbutylamino, N-propylheptylamino, dicyclohexylamino, N- methylcyclohexylamino, N-elylcyclohexylamino, N-propylcyclohexylamino, N-isobutylcyclohexylamino, dibenzylamino, N-melylbenzylamino, N-ethylbenzyl- amino, N-propylbenzylamino, N-isopropylbenzylamino. N-Butyl-benzyl-amino. N-Hepryl-benzylamino, N-methyl- (phenylethyl) -amino, N-methyl-phenyl-propyl-amino, N-ethyl- (phenyl-ethyl) -amino, N-propyl (phenylethyl) - amino, N-bulyl- (phenylpropylamino, dialylamino, dibutenylamino, dipentenylamino, N-methyl-adamantylamino, N-ethyl-adamantylamino, N- propyl-adamantylamino-pyrrolidine, piperidino, hexamethyl-2183-178-imino-imino, heptamethylene-imino, oclamelylene-imino, nonamethylene-imino, decamelylene-imino, undecamethylene-imino, dodecamethylene-imino, methyl-pyrrolidine; -, dimethylpyrrolidinyl, 1,2,3,6-tetrahydropyridyl, melylpiperidino, dimethylpiperidino, trimethylpiperidino, tetramethylpiperidino, ethylpiperidino, diethylpiperidino, methyl- ethyl piperidino, propyl piperidino, dipropyl piperidino, methylpropyl piperidino, isopropyl piperidino, elyl propyl piperidino, butyl piperidino, isobuoyl piperidino, tert-butyl piperidino, cis-3 , 5-dimethylpiperidino, trans-3,5-dimethylpiperidino, cis-3,5-diethylpiperidino, trans-3,5- dipropylpiperidino, hydroxypyrrolidinyl, hydroxypiperidino, methoxypyrrolidinyl, methoxypiperidino, ethoxypiperidino, propoxypiperidino, isopropoxypiperidino, phenylpiperidino, carboxypyrrolidino, carboxy- piperidino, methoxycarbonylpiperidino, anoxycarbonylpiperidino, propoxycarbonylpiperidino, isopropoxycarbonylpiperidino, 3,3,5,5-tetramethylpiperidino, 3,3,5,5 -tetraetil-piperidino,

3,3,5,5-Tetrapropyl-piperidino, pyrrolidon-11-yl, piperidin-4-yl, hexahydroazepinone-1-yl, morpholino, methylmorpholino, dimethylniorfolino, propylmorphono, thiomorpholino, methylthiomorpholino, dimethylthiomorpholino, 1-oxidothiomorpholino, dimethyl 1-oxido-thiomorpholino,

1,8-Dioxidothiomorpholino, dimethyl-1dioxidothiomorpholino, piperazinyl, N-methylpiperazinyl, Ν-ethylpiperazinyl, N-propylpiperazinyl, Ν-isopropylpiperazinyl, N -phenyl-piperazinyl, N- (chlorophenyl) -piperazinyl, N- (bromophenyl) -piperazinyl, Ν-pyridyl-piperazinyl, N-methoxycarbonyl-piperazinyl, N-ethoxycarbonyl-piperazinyl, N -propoxycarbonyl-piperazinyl, N-fluoroyl-piperazinyl, tetrahydro-isoquinolin-2-yl, octahydro-isoquinolin-2-yl, decahydro-isoquinolin-2-yl, tetrahydro-3-benzazepin-3-yl- , decahydro-3-benzazepin-3-yl, octahydroisoindol-2-yl, 3-azabicyclo-nonan-3-yl, 1,4-dioxa-8-aza-spiro [4,5] decan- 8-yl or 1,4-dioxa-8-azaspiro [4,6] undecan-8-yl,

R _{4 is} hydrogen, methyl, ethyl, propyl or isopropyl,

Y is oxygen, imino, methylene, methylmethylene, ethylmelylene, propylmethylene, dimethylmethylene, diethylmethylene or methylpropylmethylene,

Z is hydrogen, chlorine or bromine, nitro, amino, cyano, formyl, hydroxymethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl; . isobuloxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, heptoxycarbonyl, benzyloxycarbonyl, phenylethoxycarbonyl, cyclopenloxycarbonyl, eiclohexyloxycarbonyl, cyclohexylcyclo -carbonyl, methyl, dimeloxymelyl, dyloxymethyl, triethoxymethyl, dipropoxymethyl, tripropoxymethyl, carboxymelyl, 1,3-dioxolan-2-yl, acetyl, methoxy -carbonylacetyl, ethoxycarbonylacetyl, isopropoxycarbonylacetyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-isopropoxycarbonylethyl, 2,2-bis - (ethoxycarbonyl) -ctil-. carbamoyl, melylcarbamoyl, ethylcarbamoyl. isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, allylcarbamoyl, diallylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, dihexylcarbamoyl, , N-methylethylcarbamoyl. cyclopentylcarbamoyl, cyclohexylcarbamoyl, cycloheptylcarbamoyl, dicyclohexylcarbamoyl, Ν-methylcyclohexylcarbamoyl, N-ethylcyclohexylcarbamoyl, N-propylcyclohexylcarbamoyl, N pentylcyclohexylcarbamoyl, piperidino-carbonyl, morpholino-carbonyl, liomorolinolcarbonyl, N-methyl-piperazinyl-carbonyl, N-ethyl-piperazinyl-carbonyl or N-propyl-piperazinyl-carbonyl- group.

Preferred compounds of formula I above are those wherein R is hydrogen,

R, hydrogen, fluorine, chlorine or bromine,

C 1 -C 6 alkoxy, C 1 -C 4 alkyl, C 2 -C 4 alkoxycarbonyl, hydroxy, cyano, carboxyl, nitro, amino, acetylamino, dimethylaminosulfonyl or benzyl -oxicsoport,

R _{2 is C} 1-6 alkyl, cyclohexyl, phenyl, benzyl, adamantyl or allyl,

R _{3 is C} 1-6 alkyl or allyl, or

R 1 and R ₃ are a non-branched alkylene minino group containing from 4 to 12 carbon atoms, together with the nitrogen atom to which they are attached, substituted with C 1-4 alkyl, phenyl, hydroxy, methoxy, carboxyl or alkoxycarbonyl having 2 to 4 carbon atoms in total. piperidino, at the 3- and 5-positions

A piperidino group disubstituted with C 1-3 alkyl, two and three at the 3- and 5-positions

Piperidino substituted with C 1 -C 3 alkyl, optionally substituted with one or two methyl groups, morpholino, thiomorpholino, 1-oxothiomorpholino or 1,1-dioxothiomorpholino, optionally in the 4-position methyl, benzyl, phenyl, chloro piperazinyl substituted with -phenyl, pyridyl, furoyl or alkoxycarbonyl having 2 to 4 carbon atoms in total, pyrrolyl, piperidin-2-yl (1) -1,2,3,6-tetrahydropyridyl, , 4-diazo-8-azaspiro [4,5] decan-8-yl,

1,4-dioxa-8-aza-spiro [4,6] undecan-8-yl, octahydro-isoindol-2-yl, 1,2,3,4-tetrahydro-isoquinolin-2-yl, , 2,3,4,5,6,7,8-octahydroisoquinolin-2-yl, decahydroisoquinolin-2-yl, 1,2,4,5-tetrahydro-3-benzazepin-3-yl -, decahydro-3-benzazepin-3-yl or 3-azabicyclo-nonan-3-yl,

R _{4 is} hydrogen or methyl.

X is CH or N,

Y is methylene, methylmethylene, dimethyl methylene, NH or oxygen, and Z is carboxyl, cyano, formyl or hydroxymethyl, alkoxycarbonyl having 2 to 4 carbon atoms in all, cyclohexyloxycarbonyl-; , benzyloxycarbonyl, diethoxymethyl, carboxymethyl, bis (2,2-ethoxycarbonyl) -yl, 2-3I

183,178 carboxyethylene or 2-oxycarbonylethyl, optionally substituted by an ethoxycarbonyl group, and 2-carboxyethyl, when R ₂ and R ₃ together with the nylogen moiety between them are one of the cyclic imino groups mentioned in the introduction. and salts of the above compounds, especially those compounds wherein R 1 is in the 5-16 position of the benzene ring.

Most preferred of the compounds of formula I are those wherein:

R is hydrogen,

R5 is hydrogen at the 5-position, fluorine, chlorine or bromine, C1-C3 alkyl or alkoxy, carboxyl, cyano or nitro,

R ₂ and R _{3 taken} together with the nitrogen atom to which they are attached form a Ν, Ν-dialkylamino or N-alkylcyclohexylamino group containing 1 to 3 carbon atoms in the alkyl moiety, pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino, oclamethylene, imino or nonamelylene imino group,

Piperidino substituted with C 1-4 alkyl, methoxy or phenyl, piperidino substituted at the 3- and 5-positions with one or two methyl or ethyl groups, optionally substituted with one or two methyl at the 2- and 6-positions, 1,4 - dioxa - 8 - ara - spiro [4,5] decan - 8 - yl 1,4 - dioxa - 8 - aza - spiro [4,6] undecan - yl - octahydro isoindo! - 2 - ii -, 1,2,3,4, - tetrahydroisoquinolin-2-yl, 1,2,3,4,5,6,7,8-octahydroisoquinolin-2-yl decahydroisoquinoline - 2 - il -,

1,2,4,5-Tetrahydro-3H-3-benzazepin-3-yl decahydro-3H-3-benzazepin-3-yl 3-aza-bicyclo [3,2,2'] nonan-3-yl - or N - adamantyl - (-) - amino,

R _{4 is} hydrogen or methyl,

X CH group,

Y is a methylene, diethyl methylene, dimethylmelylene or NH group or an oxygen atom,

Z is an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, a carboxylic, formyl or hydroxymethyl group and the acid addition salts thereof with inorganic or organic acids and, if Z is a carboxyl group, also with base.

The novel compounds of the present invention are prepared as follows:

a) An aminobenzoic acid of formula IV

wherein R, R 1, R ₂ , R ₃ and X are as defined in the introduction, or optionally the reactive derivative thereof prepared in the reaction mixture is reacted with an amine of the formula V wherein R ₄ , Y and Z are as defined in the introduction. or optionally reacting with an N-activated derivative of an amine of general formula (I) in the reaction mixture when an aminobenzoic acid of general formula IV is used and when Z does not contain a carboxyl or amino group in the N-activated derivative of an amine of formula (V).

The present invention thus relates to the acylation of an amine of formula V with an aminobenzoic acid of formula IV, in the presence of an acid activator or dehydrating agent, or with functional derivatives of such an acid, or with an amine of formula IV does not represent a carboxyl or amino group - reaction in the presence of an amino group activating agent or a reactive derivative of an amine.

Optionally, the functional derivatives of the aminobenzoic acids of formula IV in the reaction mixture, e.g. alkyl, aryl or aralkyl esters or thioesters thereof, such as methyl, ethyl, phenyl or benzyl esters or copper complexes, thmidazolides, acid halides such as acid chlorides or acid bromides, anhydrides, mixed anhydrides, aliphatic or aromatic carbonic, sulfonic acids or carboxylic acid esters, e.g. acetic acid, propionic acid, p-toluenesulfonic acid or 0-ethylcarbonic acid; and O-triphenylphosphonium complexes, N-acyloxyimides, azides, nitriles or corresponding aminothiobenzoic acid derivatives. Optionally, reactive derivatives of amines of formula V in the reaction mixture, when Z does not contain a carboxyl or amino group, e.g. their phosphazo derivatives.

Acid activating and / or dehydrating agents e.g. a chloroformic acid ester such as ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, N, N'-thionyldiimidazole, boron trifluoride -phosphine-carbon tetrachloride mixture.

The reaction is conveniently in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene or dimethylformamide, optionally in the form of a solution of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine. and in the presence of an acid activator, at a temperature of from -25 ° C to 250 ° C, preferably from -10 'to the reflux temperature of the solvent used. The process does not require isolation of the functional derivatives of the compounds of formula IV or V formed in the reaction mixture, and the reaction can be carried out in the absence of a solvent. The water formed during the reaction can be removed by azeotropic distillation, e.g. the mixture is heated in a water separator with toluene or the water is removed by the addition of a drying agent such as magnesium sulfate or molecular sieve.

b) For the preparation of compounds of the formula I in which R 1, with the exception of hydroxy and amino, is mentioned in the introduction, X is CH and Y * is optionally substituted with one or two C 1 -C 3 alkyl groups:

a compound of Formula VI, wherein R, R ₄ and Z are as defined in the introduction, R and Y are as defined above and E is a halogen atom, with an amine of Formula VII, wherein R ₂ and R _{3 are as defined in} the introduction, with.

-4183 178

The term "halogen" in the exchangeable group E is primarily defined as chlorine or bromine, or fluorine if R is nitro.

The reaction is conveniently carried out in a solvent such as water, water-methanol, water-ethanol, water-isopropanol, dimethylformamide or an excess of the amine of formula VII used, optionally in the presence of an inorganic or tertiary organic base. in the presence of copper and optionally in a pressure vessel at a temperature of 20-150 ° C, preferably at the reflux temperature of the reaction mixture, e.g. 100 ° C. The reaction may be carried out without solvent.

c) For the preparation of compounds of formula I in which Z is carboxy and Y is other than NH:

a compound of Formula VIII wherein R, R 1, R ₄ and X are as defined in the introduction, Y is the group other than NH mentioned in the introduction, and can be converted to a carboxyl group by oxidation A.

The above oxidizable group is e.g. formyl and its acetals, hydroxymethyl and its ethers, an optionally substituted acyl group such as acetyl, chloroacetyl, propionyl or malonic acid (I) yl or a malonester (I) yl group.

The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, pyridine or carbon tetrachloride at a temperature of 0-100 ° C, preferably 20-50 ° C. The reaction is preferably carried out with silver oxide in caustic soda, manganese dioxide in acetone or methylene chloride, hydrogen peroxide in caustic soda, bromine or chlorine in caustic soda or potassium caustic, or chromium trioxide in pyridine.

d) For the preparation of compounds of the formula I in which Z is a carboxyl group:

a compound of Formula IX wherein R, R 1, R ₄ , X and Y are as defined in the introduction and are hydrolyzed by B hydrolysis to a carboxyl group.

The above hydrolysable groups are e.g. the nitrile group, the functional derivatives of the carboxyl group, such as optionally substituted amides, esters, thioesters, orthoesters, iminoethers, amidine or anhydride, malonic (1) -yl, tetrazolyl, optionally substituted 1,3-oxazole (2) -yl or dihydro-1,3-oxazol- (2) -yl.

The hydrolysis is preferably in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol, water-ethanol, water-isopropanol or water dioxane. temperature, e.g. at room temperature to the reflux temperature of the reaction mixture.

When B is cyano in the compound of Formula IX, the reaction is conveniently carried out in a mixture of ethanol-hydrochloric acid, so that the appropriate imino and ortho ester or water is added to the reaction mixture, which can be hydrolyzed with water.

e) For the preparation of compounds of formula I wherein R _{2 is C} 1-7 alkyl, C 4-7 cycloalkyl, phenyl substituted C 1-3 alkyl or C 3-5 alkenyl, R 1-7 alkyl, 4- C 7 -cycloalkyl, C 3 -C 5 -alkenyl, C 1 -C 3 -alkyl or adamantyl substituted with phenyl, or R ₂ and R 5 together with the nitrogen atom containing 5-7 membered alkylimino-ring, C 1-4 -alkyl substituted piperidino or and at the 5-position are piperidino substituted with one C 1-3 alkyl group and Y is a methylene group optionally substituted with one or two C 1-3 alkyl groups:

optionally formed in the reaction mixture

A compound of Formula X wherein R, R 1, R ₄ , X and Z are as defined in the introduction, R 1 'is hydrogen, or the same as R, and Y is as defined above.

A compound of Formula XI, wherein R ₂ 'has the same meaning as defined in the introduction to R ₂ , or R 4' is a C 4-6 non-branched alkylene group, a N-pentylene group substituted with C 1-4 alkyl or - and in each case 4 is a n-pentylene group substituted with 1 to 3 carbon atoms and G is a nuccophilic leaving group such as halogen or sulfonyloxy, e.g. with chlorine, bromine or iodine, methanesulfonyloxy, or p-toluenesulfonyloxy, or formaldehyde in the presence of a reducing agent.

The alkylating agent of formula XI is e.g. a suitable halide or sulfate such as methyl iodide, elyl iodide, propyl bromide, benzyl chloride, benzyl bromide, dimethyl sulfate or diethyl sulfate.

The reaction is conveniently carried out in a solvent. such as acetone, tetrahydrofuran, dimethylformamide, dinethylsulfoxide or hexamelylphosphoric acid triamide, optionally in the presence of an inorganic base such as sodium carbonate, potassium carbonate or potassium tert-butylate or a tertiary organic base such as pyridine, ° C, preferably 2 () ~ 75 ° C. When a carboxylic acid of formula X is used, it may be used, depending on the reaction conditions, e.g. at room temperature and in the presence of an alcohol as the base at the same time.

The methylation may also be carried out by reducing a compound of formula X, e.g. in the presence of formic acid, or hydrogen and a hydrogenation catalyst, e.g. in the presence of palladium or platinum, optionally in a solvent such as formic acid or glacial acetic acid, at up to the boiling point of the reaction mixture with formaldehyde.

Compounds of formula (X) may also be prepared by reacting a meufelel-substituted isatoic anhydride with a corresponding amine of formula (V) in the reaction mixture.

(f) For the preparation of compounds of formula I in which Y is NH or O:

a compound of Formula XII wherein R, R, R and X are as defined in the introduction and Y is as defined above, or an alkali salt5

183178 X111 fenilszármazékkal adjusted to a formula in which R ₄ and Z jelcntésííek mentioned in the introduction, and L is a nucleophilic leaving group such as halo or sulfonyloxy group, for example. chlorine, bromine or iodine, methylsulfonyloxy, p-toluenesulfonyloxy or methoxysulfonyloxy.

The reaction is conveniently carried out in a solvent such as water ethanol, water isopropanol, tetrahydrofuran, dioxane, acetone, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide, preferably a base such as sodium carbonate, sodium hydroxide, potassium hydroxide, potassium hydroxide, potassium hydroxide, potassium hydroxide, in the presence of butylate at 0 to 150 ° C, preferably at the reflux temperature of the reaction mixture, e.g. 50-100 ° C. If an ester is used, this may be dependent upon the reaction conditions, e.g. at a higher temperature and in the presence of an excess of the base used, it can be simultaneously converted to the corresponding carboxylic acid.

g) For the preparation of compounds of the formula I in which R 1, other than hydroxy, carboxylamino and alkanoylamino, is mentioned in the introduction. X is CH. and Y is one or two C 1 -C 3 substituted methylene groups.

an amide of formula XIV, wherein R, R ₂ and R _{3 are as defined in} the introduction, and R is as defined above, or an alkali salt thereof with a compound of formula XV, wherein R ₄ and Z are as defined in the introduction, Y is above, and M is a nucleophilic leaving group such as halogen or sulfonyloxy.

The reaction is conveniently carried out in a solvent such as letrahydrofuran, dioxane, toluene, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide, optionally in the presence of a base such as sodium hydride or potassium tert-butylate, preferably at 20 ° C to 180 ° C. At -15 ° C.

h) For the preparation of compounds of the formula I in which R, hydrogen, fluorine, chlorine or bromine, C1-C4 alkyl or C1-C6 alkoxy, phenyl-substituted C1-C3 alkoxy, hydroxy, nitro, carboxyl or alkanoylamino; X is CH. Y is optionally one or two

Methylene esoporl substituted with C 1-3 alkyl and carboxyl Z:

acylating a compound of formula XVi, wherein R and R 1 to R _{4 have} the meanings given in the introduction, R and Y have the meanings indicated above, with an oxalyl halide or phosgene.

The Friedel-Crafts elution is conveniently carried out in a solvent such as nitrobenzene or carbon sulfide in the presence of a Lewis acid such as aluminum chloride at a temperature of 0 to 80'C, preferably 20 to 10'C.

i) Preparation of compounds of formula I wherein R, hydrogen, fluoro, chloro or bromo, C 1-4 alkyl or C 1-6 alkoxy, phenyl substituted C 1-3 alkoxy, nitro, carboxyl - or an alkanoylamino or alkoxycarbonyl group containing from 1 to 3 carbon atoms, X is CH, Y is optionally one or two

Methylene substituted with C 1-3 alkyl, and carboxyl Z:

reacting a compound of Formula XVII, wherein R, R ₂ , R, and R _{4 are as defined in} the introduction, and R and Y are as defined above, optionally with hypohalogenate prepared in the reaction mixture.

The reaction is conveniently carried out in a solvent such as a water-tetrahydrofuran or water-dioxane mixture at a temperature of 0 ° C to 80 ° C, preferably 25 ° C to 50 ° C.

When the process of the present invention provides a carboxylic acid amide of formula I wherein Z is a carboxyl group, this compound can be optionally converted by esterification or amidation to a corresponding compound of formula I wherein Z is an esterified carboxyl group or optionally has 1 to 6 carbon atoms. mono- or disubstituted carbamoyl with alkyl, C 5-7 cycloalkyl and / or C 3-5 alkenyl. piperidinocarbonyl, morpholinocarbonyl. thiomorpholinocarbonyl or N-alkylpiperazinylcarbonyl and / or a carboxylic acid amide of formula I wherein R and / or Z is a nitro group; this compound can be reduced by reduction to a corresponding compound of formula I wherein R , and / or Z is an amino group, and / or a carboxylic acid amide of formula I wherein R 1 and / or Z is amino can be converted to the corresponding compound of formula 1 via a suitable diazonium salt R, hydroxy or cyano, fluoro, chloro or bromo, and / or Z, chloro or bromo, or nitrile; and a compound of formula 1, wherein R, is hydroxy, optionally so prepared, followed by alkylation with a corresponding can be converted to a compound of formula k in his life R,

C 1 -C 6 alkoxy or C 1 -C 3 alkoxy substituted with phenyl and / or a carboxylic acid antide of formula I wherein R 1 is amino. then this compound can be acylated to give the corresponding compound of formula 1 wherein R is an alkanoylamino group having 1 to 3 carbon atoms in the alkyl moiety and / or a carboxylic acid amide of formula 1 wherein R, alkoxycarbonyl and / or R ₂ and R together with the nitrogen atom to which they are attached to form a C 4 -C 6 alkyleneimino ring substituted with an alkoxycarbonyl group, the alkoxy moiety having from 1 to 3 carbon atoms, can be hydrolyzed to give the corresponding compound of formula 1 wherein R, carboxyl and / or R ₃ forms, together with the nitrogen atom between them, a alkyleneimino ring substituted with a carboxyl group.

-6Ι83 178 wherein the alkylene iminogyíírü 4-6 szénaíomos, and / or I karbonsavamidol formula is prepared, wherein R ₂ and R together with the nitrogen atom between them form a ₃ N-piperazinyl, this compound removal of the benzyl can be converted to the corresponding compound of formula 1 wherein R ₂ and R ₃ together with the nitrogen atom between them are piperazinyl and / or a carboxylic acid amide of formula I wherein R 1 is chloro or bromo is then dehalogenated to give can be converted to the corresponding compound of formula I wherein R is hydrogen and / or a carboxylic acid amide of formula I wherein Z is an optionally esterified carboxylic acid, then reduced to a suitable compound of formula I can be prepared by oxidation to a corresponding compound of formula I wherein Z is a hydroxymethyl group and / or a carboxylic acid amide of formula I wherein Z is a hydroxymethyl group, and / or to prepare a carboxylic acid amide of formula I wherein Z is a hydroxymethyl group, this compound can be converted by halogenation followed by reaction with a malonic acid ester to a corresponding compound of formula I wherein Z is substituted by two alkoxycarbonyl groups and / or To prepare the carboxylic acid amide of formula I wherein Z is formyl, the compound can be acetally converted to the corresponding compound of formula I wherein Z is a dialkoxymethyl group and / or a carboxylic acid of formula I n-acid amide having a Z formyl group can be converted by condensation and optionally subsequent hydrolysis to a corresponding compound of formula I wherein Z is ethylene substituted with carboxyl or alkoxycarbonyl and / or a carboxylic acid of formula I amide wherein Z is hydrogen, this compound can be converted by Friedel-Crafts acylation to the corresponding compound of formula 1 wherein Z is optionally substituted by an alkoxycarbonyl group and / or a carboxylic acid amide of formula I, wherein Z is a nitrile group, this compound may be converted by alcoholysis to a corresponding compound of formula I wherein Z is a trialkoxymethyl group and / or a compound of formula I via an appropriate iminoester to prepare the arbonic acid amide wherein R 1 is a cyano group, this compound can be hydrolyzed to give the corresponding compound of formula I wherein R 1 is an alkoxycarbonyl group and / or a carboxylic acid amide of formula 1 wherein Z acetyl group, this compound can be converted, by heating with an amine and sulfur and then an inorganic base, to a corresponding compound of formula I wherein Z is 2-carboxymethyl and / or a carboxylic acid amide of formula I wherein Z is carboxyl converting this compound into the sulfonic acid hydrazide and then disproportionately converting it into the corresponding compound of formula 1 wherein Z is formyl and / or a carboxylic acid amide of formula I wherein R, hydrogen, fluorine, chlorine or br m, C 1-4 alkyl such as C 1-6 alkoxy or phenyl substituted C 1-3 alkoxy, X is CH, Y is optionally substituted with one or two C 1-3 alkyl groups, and Z is chloro or bromo, then c / t can be converted to the organic compound and then treated with carbon dioxide to give the corresponding compound of formula I wherein Z is carboxyl.

The subsequent esterification or amidation is suitably carried out in a suitable solvent, for example, a suitable a ^: alcohol or amine, pyridine. in toluene or dioxane, in the presence of an acid activator and / or dehydrating agent such as thionyl chloride, ethyl chloroformate, Ν, Ν'-dicyclohexylcarbodiimide or carbonyl dimethyl idazole; with a suitable carbonic acid ester at 0-50 ° C, preferably by transesterification at room temperature.

The subsequent reduction of the nitro compound is preferably carried out in a solvent such as water, water-ethanol mixture, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, preferably with hydrogen, in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium carbon, metals such as iron, tin or with zinc in the presence of an acid, with salts such as ferrous sulfate, stannous chloride or sodium indithionite, or hydrazine in the presence of Raney nickel at 0 to 50 ° C, preferably at room temperature.

For a diazonium salt, e.g. reaction of fluoroborate, hydrosulphate in sulfuric acid or hydrochloride in the presence of copper or a suitable copper (I) salt such as rcz (I-chloride and hydrochloric acid, copper (I) -bromide and bromobromic acid or trisodium copper (I) tetracyanide 7 at a slightly elevated temperature, such as 15-100 [deg.] C. The diazonium salt required for the reaction is conveniently prepared in a suitable solvent, such as a mixture of water, hydrochloric acid, methanolic hydrochloric acid or dioxane, so that a suitable amino compound is formed. nitrite, such as sodium nitrite or an ester of nitric acid, is diazotized at low temperatures, e.g., -10 to + 5 ° C.

The subsequent acylation is conveniently carried out in a solvent such as methylene chloride, ether, tetrahydrofuran or excess acylating agent, e.g. formic acid, acetic acid or propionic acid or their anhydrides, acid chlorides or esters, optionally with an inorganic or tertiary organic base, which may also serve as a solvent7

-7 '

183,178 and, in particular, in the presence of an acid activator or dehydrating agent, at a temperature of -25 to 150 ° C, preferably -10 ° C to the reflux temperature of the reaction mixture.

The subsequent hydrolysis is suitably in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or triflic acetic acid or a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol, water ethanol, water isopropanol or water dioxane. temperature, e.g. at the reflux temperature of the reaction mixture.

The subsequent removal of the benzyl group or the subsequent dehalogenation is conveniently carried out in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid with catalytically activated hydrogen, e.g. hydrogen in the presence of platinum or palladium-carbon at 0 ~ 75 ° C, preferably at room temperature,

Hydrogen pressure.

The subsequent O-alkylation is preferably carried out with a suitable halide or sulfuric acid ester, e.g. nielyl iodide, dimethyl sulfate, ethyl bromide, p-toluenesulfonic acid benzyl ester or methanesulfonic acid isopropyl ester, optionally in the presence of a base such as sodium hydride, potassium hydroxide or potassium tert-butylate and preferably in a solvent such as diethane, in dimethylformamide at O-75 ° C, preferably at room temperature.

The subsequent reduction with the metal hydride is conveniently carried out with a complex metal hydride such as lithium aluminum hydride in a solvent such as diethyl ether, tetrahydrofuran or dioxane at 0-100 ° C, preferably at the reflux temperature of the reaction mixture.

The subsequent oxidation of a hydroxymethyl group is conveniently carried out with a metal oxide such as manganese dioxide in a solvent such as aetone or dichloromethane at a temperature of from Q to 50 ° C, preferably at room temperature.

Subsequent conversion of a hydroxymethyl group to a halomethyl group with a halogenating agent such as lionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in solvents such as methylene chloride, carbon tetrachloride, benzene and nitrobenzene. followed by reaction with a malonic acid ester, e.g. with an alkali salt of the malonic acid dielyl ester at a temperature of 0-100 ° C, preferably 20-50 ° C.

The subsequent acetal formation is conveniently carried out in the appropriate alcohol, e.g. methanol or ethanol, in the presence of an acid such as hydrochloric acid or sulfuric acid, or with a suitable orloester, e.g. with ortho-formic acid triethyl ester at 0-100 ° C, preferably 30-60 ° C, by recrystallization.

The subsequent condensation of a formyl compound is conveniently carried out in a solvent such as pyridine-Ajagy tetrahydrofuran with malonic acid, a malonic acid ester or a trialkylphosphonic acetic acid ester, optionally in the form of a base such as a condensing agent. piperidine, potassium tert-butylate or sodium hydride at 0-100 ° C, followed by acidification with hydrochloric acid or sulfuric acid to give the desired acid.

Subsequent Freedel - Crafts acylation with a suitable acid halide or acid anhydride in a suitable solvent such as carbon disulfide, methylene chloride, dichloroethane or nitrobenzene. The reaction is carried out in the presence of a Fredel-Crafts catalyst such as aluminum chloride at 0-50 ° C, preferably at room temperature.

The subsequent alcoholysis is preferably a solvent in a suitable anhydrous alcohol, e.g. in anhydrous methanol, ethanol or propanol, in the presence of an acid such as hydrochloric acid or sulfuric acid, at a higher temperature, preferably at the reflux temperature of the reaction mixture.

The subsequent Willgerodt reaction is conveniently carried out in an alcoholic solvent such as methanol, ethanol or isopropanol, and the acetyl compound with an amine, e.g. with morpholine in the presence of sulfur. The corresponding thioamide thus obtained is then heated to the corresponding acetic acid derivative in the presence of an inorganic base such as sodium hydroxide, and very preferably at the reflux temperature of the reaction mixture.

Subsequent disproportionation of a sulfonic acid hydrazide prepared by reaction of a suitable hydrazine with a suitable reactive carboxylic acid derivative is carried out in the presence of a base such as sodium carbonate in a solvent such as ethylene glycol at 100-200 ° C, preferably 160-170 ° C.

Conversion of a suitable compound of formula I into a suitable organic metal compound is conveniently carried out in an inert solvent such as diethyl ether, tetrahydrofuran, dioxane or a mixture of tetrahydrofuran-hexane, optionally in the presence of a protective gas, e.g. in the presence of nitrogen, preferably with a suitable lithium compound, e.g. butyl lithium in n-hexane at -60 + 50 ° C. Subsequently, the resulting solution of a suitable organic metal compound is optionally poured into solid carbonic acid under an inert gas atmosphere.

The compounds of formulas I and Ia may also be converted into their physiologically acceptable salts with inorganic or organic acids or, when Z is a carboxyl group or a carboxyl group, with bases. For example, such hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid, and bases, e.g. sodium hydroxide, potassium hydroxide or cyclohexylamine.

The compounds of formula IV-XVII used as starting materials are known in the literature or may be prepared by methods known per se. so e.g. a compound of Formula 11 or IV is prepared by reacting with a 2-chloro group

Reaction of 2-bromo-nitrocarboxylic acid or a derivative thereof with a suitable amine, followed by reduction of the nitroesoporl of the prepared 2-amino-compound with catalytically activated hydrogen, nascent hydrogen, metals or fc salts, and the corresponding amino compound via a suitable diazonium salt . The starting compounds of formula IV wherein R, alkoxy or phenylalkyloxy are prepared by alkylation of the resulting hydroxycarboxylic acid and subsequent hydrolysis if necessary.

-8183 178

Compounds of general formula V in which Y is other than NH or oxygen, e.g. is prepared by reacting a suitable 4- (α-bromoalkyl) -benzene derivative with sodium cyanide, and then the resulting cyano compound is catalytically hydrogenated.

Compounds of formula V wherein Y is NH or oxygen, e.g. is made to be a proper one

The 4- (α-bromoalkyl) -benzoyl derivative is reacted with a hydroxamic acid or its ester or acylhydrazine, and the resulting product is subsequently hydrolyzed if necessary.

Compounds of general formula V wherein Y is NH can be prepared by reacting a 4-formyl or 4-acylbenzene derivative with an N-acylhydrazine, followed by hydrolysis of the resulting hydrazone. by catalytic hydrogenation and the acyl group is cleaved by hydrolysis. An ester of formula V thus prepared can, if desired, be converted to the corresponding carboxylic acid by hydrolysis.

The starting compounds of formulas VI, VIII-X, XIV, XVI and XVII are prepared by reacting a suitable benzoic acid in the presence of an acid activator or a water-attractant or a reactive derivative of a suitable benzoic acid with ammonia or appropriate benzylamine.

XII used as starting materials. Compounds of formula (I) are prepared by reacting a suitable carboxylic acid ester with hydrazine or hydroxylamine.

Compounds of formula XIII or XV used as starting materials are prepared by halogenation of a suitable alcohol or by reaction of a sulfonic acid halide with a suitable alcohol in the presence of a base.

As mentioned in the introduction, the novel compounds of formulas I and Ia have valuable pharmacological properties and have an effect on metabolism. The compounds of the formula I are predominantly glucose-lowering and / or lipid-lowering. Compounds of formula I wherein Z is hydrogen, halogen, nitro, amino or cyano are valuable intermediates for the preparation of new compounds of formula I.

By way of example, the following compounds were tested:

A = 4- [2- (5-chloro-2-dimethylamino-benzoylamino) -ethyl] -benzoic acid,

B = 4- [2- (5-bromo-2-dimethylamino-benzoylamino) -ethyl] -benzoic acid,

C = methyl 4- [2- (5-chloro-2-piperidinobenzoylamino) ethyl] benzoic acid,

D = 4- [2- (5-chloro-2-piperidinobenzoylamino) ethyl] benzoic acid,

E = 4- [2- (5-chloro-2- (2-methylpiperidino)

- benzoyl amino) ethyl] benzoic acid,

F = 4 - [2- (5-chloro-2- (3-methylpiperidino))

- benzoyl-amino) -yl] benzoic acid,

G = 4- (2- (5-chloro-2- (4-methylpiperidino))

- benzoyl amino) ethyl] benzoic acid,

I I = methyl ester of 4- [2- (5-chloro-2- (3,5-dimethylpiperidino) benzoylamino) ethyl] benzoic acid, = 4. [2- (5-chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl] -benzoic acid,

K = 4 - [2- (5-chloro-2- (4-methoxy-piperidino)

- benzoyl amino) ethyl] benzoic acid,

L = 4- [2- (5-methoxy-2-piperidinobenzoyl)

- amino) ethyl] benzoic acid hydrochloride,

M = 4- [2- (5-chloro-2-heptamethylenylamino)

- benzoyl amino) ethyl] benzoic acid,

N = 4 - [2- (5-chloro-2- (1,4-dioxa-8-aza)

- spiro [4,5] decan-8-yl) -benzoylamino) ethyl]

- benzoic acid,

O-4- [2- (5-chloro-2-hexamethylene-imino-benzoylamino) -ethyl] -benzoic acid,

P = 4- [2- (5-chloro-2-thiomorpholino-benzoyl)

- amino) ethyl] benzoic acid,

Q = 4- [2- (5-bromo-2-piperidinobenzoyl)

- amino) ethyl] benzoic acid,

R = 4 - [2- (5-chloro-2-piperidinobenzoyl amino) -! - methyl ethyl] benzoic acid,

S = 4- (2- (5-bromo-2- (2-methylpiperidino))

- benzoyl amino) ethyl] benzoic acid,

T-4- (2- (5-chloro-2- (2,6-dimethylmorpholino) benzoylamino) ethyl] benzoic acid,

U = 4- (2- (5-chloro-2- (2,6-dimethylthiomorpholino) benzoylamino) ethyl] benzoic acid,

V - 4- [2- (5-bromo-2-heptamethylene imino)

- benzylamino) ethyl] benzoic acid clilester,

W = 4- [2- (5-bromo-2-heptamethylene imino)

- benzoyl amino) ethyl] benzoic acid,

X = 4- [2- (5-chloro-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid,

Y = 4- (2- (5-chloro-2- (decahydroisoquinoline)

- 2-yl) benzoylamino) ethyl] benzoic acid hydrochloride

7, - 4- [2- (5-bromo-2-octamethylene imino)

- benzoyl amino) ethyl] benzoic acid hydrochloride,

AA = 4- [2- (5-ethyl-2-piperidinobenzoyl)

- amino) ethyl] benzoic acid,

BB = 4 - [2- (5-methyl-2-piperidinobenzoyl)

- amino) ethyl] benzoic acid,

CC = 4 - {2 - [2 - (N - adamantyl - (1) - N - methyl)

- amino) - 5 - chloro - benzoylamino] - ethyl} benzoic acid,

DD = 4- (2- (2-piperidino-nicotino-amino)

- ethyl] benzoic acid,

EE = 4 - (2 - (5 - chloro - 2 - octamethylene imino

- benzoyl amino) ethyl] benzoic acid ethyl ester,

FF = 4- [2- (5-chloro-2-octamethylene imino)

- benzoyl amino) ethyl] benzyl alcohol,

GG - N ¹ - [! - (1-carboxyphenyl) ethyl] -N ²

- (5-chloro-2-piperidinobenzoyl) hydrazine,

HH = 4- [1- (5-chloro-2-octamethylene imino)

- benzoyl-amino-oxy) -ethyl] -benzoic acid, ₍ a II = 4- [2- (2-ethyl-amino-5-chloro-benzoyl)

- amino) ethyl] benzoic acid (cf. Belgian Patent No. 837 311, Example 5), for blood glucose lowering effect.

/. Blood glucose lowering effect

The blood glucose-lowering effect of test substances on self-bred female dogs weighing 180-220 g 9

183,178 rats were fasted 24 hours prior to the start of the experiment. Test substances immediately before the start of the experiment

They were suspended in 1.5% methylcellulose and administered to the animals by gavage.

Blood was collected immediately after and 1, 2, 3, and 4 hours after administration of the test substance, each time from the rheoorbital vein. In each case, 50 μΐ of blood was bleached with 0.5 ml of 0.33 N perchloric acid and centrifuged. In the supernatant, glucose was determined by analytical photometry using the hexokinase method. The statistical evaluation was performed with the Sludcnt t-test, p = 0.05, the limit of significance.

The table below gives the values found as a percentage of the control.

Tabulate in mg / kg '~ I (j mg / kg ................ 5 mg / kg

Experimental material 1 2 34 1 234 1234 hours clock hour

THE -31 -21 - 10 -10 -32 ---—---------— · --------.... .. ".", N. S. N. S. N. S. - 18 N. S. N. S. -12 B -33 -23 N. S. N. S. - 14th -9 N. S. N. S. N. S. N. S. N. S. N. S. C -44 -37 -23 -24 -41 -26 -23 - 14th -31 -2! - 18 - 15 D -44 -43 -41 -38 -33 -37 -36 -26 -37 - 34 -28 -30 E -42 -43 -38 -31 -34 -24 - 14th N. S. -31 - 18 N. S. N. S. F -51 -48 -41 -40 -41 -40 -44 -39 -44 -42 -38 -35 G -30 -24 -27 -25 - 24 -26 N. S. N. S. - 24 -20 -21 -13 H -35 -41 -44 -38 -39 -46 -33 -20 -42 -47 -42 - 43 l -41 - 37 -38 -40 -39 -38 -30 -40 -47 -46 -49 -50 K -43 -44 -39 -34 -40 -34 -16 N. S. -40 -32 -20 N. S. L -47 -39 -29 -27 -34 N. S. - 15 - 16th -37 -29 N. S. N. S. M -38 -40 -38 -36 -38 -37 -38 -36 -42 -41 -40 -34 N -43 -41 -36 -25 - 35 -34 -24 - 19th - 36 - 17th - 10 N. S. SHE -41 -37 -33 -24 -42 -39 -25 -22 -33 -26 -23 - 15 P -37 -41 -32 -30 -37 -30 -26 -21 -29 - 19th N. S. N. S. Q -38 -39 -34 -37 -40 -42 -43 -44 -32 -40 -32 -23 R -52 -37 -37 -30 -25 -28 -21 -21 -27 -25 N. S. N. S. s -42 -44 -38 -32 - 39 - 34 -24 - 12 T -48 -29 -25 -33 u -41 -43 -41 -40 V -34 -43 -39 -40 - 19th -19 -24 -26 w -44 -49 -41 - 46th -34 -36 -38 -38 X -51 -44 -39 -41 -45 -43 -45 -46 -37 -43 -37 49 Y -40 -45 -45 -49 -46 -79 -38 -46 z -45 -43 -42 -35 AA - 40 -44 -29 -39 -41 -40 -32 - 32 BB -40 -31 - 14th N. S. CC -39 -42 -41 -38 DD -39 -26 -22 -25 -37 - 18 N. S. N. S. -28 - 17th N. S. N. S. EE -42 -41 -43 -41 -42 -41 -40 -43 -42 -41 -40 -43 FF -35 -36 -28 -23 GG N. S. -31 -33 -22 - 15 -25 - 13 N. S. HH -41 -21 N. S. N. S. 11 N. S. N. S. N. S. N. S.

N. S. not statistically significant

-10183 178

2. Acute loxicity

Toxic effects of the test substances were investigated in self-bred female and male mice weighing 20-26 g by oral administration in a single dose in a 1% methylcellulose suspension. The observation period was then at least 7 days.

The values found are shown in the following table:

Informative toxicity> 2000 mg / kg p.o.

(None of the 6 animals died)> 1000 mg / kg p.o.

(None of the 5 animals died)> 2000 mg / kg p.o.

(None of the 6 animals died)> 1000 mg / kg p.o.

(None of the 6 animals died)> 1000 mg / kg p.o.

(None of 10 animals died)> 1000 mg / kg p.o.

(None of 10 animals died)> 1000 mg / kg p.o.

(None of 10 animals died)> 1000 mg / kg p.o.

(None of the 6 animals died)> 1000 mg / kg p.o.

(None of the 6 animals died)

The compounds of the formula I and their physiologically tolerated salts according to the invention are useful in the treatment of Diabetes Mellitus by their pharmacological properties. For this purpose, the compounds, if appropriate in combination with other active compounds, may be prepared in the form of conventional galenical formulations such as tablets, dragees, capsules, powders or suspensions. In adults, a single dose is 1 to 50 mg, preferably 2.5 to 20 mg, once or twice daily.

An embodiment of the process of the invention is illustrated by the following examples.

The starting materials were prepared as follows:

The example

- (Decahydro-isoquinolin-2-yl) -5-nitro-benzoic acid g (0.136 mol) decahydro-isoquinoline, 27.3 g (0.136 mol) 2-chloro-5-nitrobenzoic acid and 38.6 g potassium carbonate It is heated under reflux in 500 ml of ethanol for 18 hours with stirring. The ethanol is distilled off, the residue is dissolved in 800 ml of water and the pH is adjusted by the addition of 2N hydrochloric acid.

Set to 4, then the product crystallizes. Yield: 38 g (92%)

Melting point crystallized from isopropanol:

132-134'C.

Example B

- (1,4 - Dioxa - 8 - aza - spiro [4,5] decane - 8

- d) - 5 - nitro - benzoic acid

2-Chloro-5-nitrobenzoic acid (20.1 g, 0.1 mol) in 200 N ethanol with 42.9 g (0.3 mol) of 1,4-dioxo-8-azaspiro [4,5] decane for 8 hours heating at reflux. The solvent was distilled off. the residue was taken up in water, quenched with 2N hydrochloric acid to pH 5.2, and the product precipitated. The product was extracted with chloroform, the chloroform extract was dried over sodium sulfate, and the solvent was distilled off, whereupon the compound crystallized.

Yield: 12 g (39%).

Melting point crystallized from ethanol: 155 'C.

Similarly as described in Examples A and B, the following compounds were prepared:

- (2-methylpiperidino) -5-nitrobenzoic acid, 99%, m.p. 164 'C;

(3-methylpiperidino) -5-nitrobenzoic acid, 85%, m.p. 161C;

- (4-methylpiperidino) -5-nitrobenzoic acid, yield: 85%, m.p. 155'C;

(3-ethyl-6-methyl-piperidino) -5-nitro-benzoic acid, yield: 76%, m.p.

- (3,5-dimethylpiperidino) -5-nitrobenzoic acid, yield: 65%, m.p. 72 ° C;

(4-methoxy-piperidino) -5-nitro-benzoic acid, yield: 68%, m.p. 140 ° C;

Nitro-2- (4-phenylpiperidino) benzoic acid, 88%, m.p. 196 'C;

- (4-Ethoxycarbonyl-piperidino) -5-nitro

- benzoic acid, 82%, m.p. 160 'C;

Nitro-2-thiomorpholino-benzoic acid, 80%, mp 2.35 'C;

Nitro-2- (1,2,4,5-tetrahydro-3-benzazepino) -benzoic acid, 68%, mp 222 ° C;

- nitro-2- (1,2,3,4-tetrahydro- (I) -isoquinoline) -benzoic acid, 70%, m.p. 195'C;

Nitro-2- (4-phenylpiperazinyl) benzoic acid, 88%, m.p. 196 'C;

- nitro-2- (4-pyridyl - (2) -piperazinyl) -benzoic acid, 66%, mp 192 ° C;

(trans - 3,5 - dimethylpiperidino) - 5 - nitro

benzoic acid, yield 63%, mp 132 'C;

- (3,3,5,5-letramethyl-piperidino) -5-nitro-benzoic acid, 98%, mp 138 ° C;

- (3,5-dimethylmorpholino) -5-nitrobenzoic acid, 75%, m.p. 164'C;

- (3,5-dimethylthiomorpholino) -5-nitro-benzoic acid, yield 70%, mp 118 ° C;

- (3-aza-bicyclo [3,2,2] nonan-3-yl) -5-nitro

- benzoic acid, yield: 72%, m.p.

- nitro-2-nonamelylene imino-benzoic acid, yield: 80%, m.p. 127'C;

Nitro-2-decamethyl-iminobenzoic acid, 92%, mp 128 ° C;

- nitro-2-undecamethylene-imino-benzoic acid, yield: 91%, melting point: 120'C;

- nitro-2-dodecamelylene-imino-benzoic acid, 95% yield, mp 115 'C;

-111

183,178

- (Ν-Methyl-Ν-ferrylamino) -5-nylro-benzoic acid. yield: 10%, m.p. 115'C;

- (N - ethyl - N - cyclohexylamino) - 5 - nitro

- benzoic acid, 78%, mp 74 'C;

- (N-butyl-N-cyclohexylamino) -5-nitro

- benzoic acid, yield 84%, m.p. 56 'C;

- (N - cyclohexyl - N - isobutylamino) - 5 - nitro

- benzoic acid, yield 63%, mp 20 ° C;

- (decahydro-3-benzazeptn-3-yl) -5-nitro

benzoic acid, 98%, mp 20 ° C;

(octahydro-isoindol-2-yl) -5-nitro-benzoic acid, yield: 80%, mp 128 'C;

(4-isopropyl-piperidino) -5-nitrobenzoic acid, 79%, mp 142 'C;

(4-tert-butyl-piperidino) -5-nitro-benzoic acid, yield 57%, mp 136 ° C;

2- (1,4-dioxa-8-aza-spiro [4,6] undecane-8)

- yl) - 5 - nitrobenzoic acid, 75%, m.p. 135 'C; '

2,4-dipiperidino-5-nitrobenzoic acid, 31%, m.p. 152 'C;

- chloro-2-piperidino-5-nilobenzoic acid, yield: 18%, m.p. 133'C;

- nitro-2- (1,2,3,6-tetrahydro-1-pyridyl) benzoic acid, yield 58%, mp 215 ° C;

(N - methyl - N - benzylamino) - 5 - nitro benzoic acid, yield; 93%, mp 123-126 ° C;

- [4- (4-Chloro-phenyl) -piperazinyl] -5-nylro

benzoic acid hydrochloride, yield: 71.5%, m.p. 225-227'C (dec.);

- (4-Ethoxycarbonyl-piperazine!) - 5-Nilro

- benzoic acid, yield: 23.1%, melting point 155-156'C;

- [4- (2-drill!) - piperazinyl] - 5 - nitro benzoic acid, yield 64.8%, m.p.

200-205'C;

- (4-Benzyl-piperazinyl) -5-nitrobenzoic acid

hydrochloride, yield: 86.6%, m.p. 142-145'C.

Example C

Hexamethyleneimino - 5 - nitrobenzoic acid nitrile

18.4 g (0.11 mol) of 2-chloro-5-nitrobenzoic acid nitrile in 250 ml of ethanol are heated at reflux for 4 hours with 22.4 g (0.21 mol) of hexamethyleneimine. The mixture was cooled and water (500 mL) was added to precipitate the product as an oil. The precipitated product is taken up in chloroform, dried over sodium sulfate, the chloroform is distilled off and the distillation residue is recrystallized from ethanol. Yield: 19.7 g (73%). Melting point: 70 'C.

Example D

- Amino-2- (decahydro-isoquinolin-2-yl) -benzoic acid g (0.118 mol) 2- (decahydro-isoquinolin-2)

- yl) -5-nitrobenzoic acid is dissolved in 250 ml of dimethylforminide and hydrogenated at 5 bar of hydrogen in the presence of 10% palladium on carbon at room temperature. After hydrogen uptake ceased, the catalyst was filtered off, the solvent was evaporated in vacuo and the residue was recrystallized from ethanol. Yield: 31.2 g (96%). Melting point: 252 'C.

This is an example

- Amino-2- (1,4-dioxa-8-aza-spiro [4.5] decan-8-yl) -benzoic acid g (0.039 mol) 2- (1,4-dioxa-8-aza-spiro {4 , 5] decane-8-ii) -5-nitrobenzoic acid was hydrogenated in 100 ml of dimethylformamide at 5 bar of hydrogen pressure at room temperature in the presence of 10% palladium-on-carbon catalyst. After hydrogen uptake ceased, the catalyst was filtered off, the solvent was distilled off and the residue was recrystallized from ethanol. Yield: 9 g (83%). Melting point: 209 'C.

Similarly to Examples D and E, the following compounds were prepared:

- amino-2- (1-pyrrolidinyl) -benzoic acid, 79%, mp 208 ° C;

- amino -2- (2-methylpiperidino) benzoic acid, yield 84%, m.p. 240'C;

- amino -2- (3-methylpiperidino) benzoic acid, 75%, m.p. 192'C;

- amino -2- (4-methylpiperidino) benzoic acid, yield: 88%, m.p. 215'C:

- amino -2- (3-ethyl-6-methylpiperidino) benzoic acid, yield: 59%, m.p. 219'C;

- amino-2- (cis-3,5-dimethyl-piperidino)

benzoic acid, 87%, mp 234 'C;

- amino-2- (4-methoxy-piperidino) -benzoic acid, yield: 80%, m.p. 228 'C;

- amino - 2 - heptamethylene - irnino · benzoic acid, yield 64%, mp 214'C;

amino -2- (4-phenylpiperidino) benzoic acid, 76%, mp 275 ° C;

- amino -2- (4-ethoxycarbonyl-piperidino)

- benzoic acid, yield: 85%, m.p. 203 'C;

- amino-2-thiomorpholino-benzoic acid, yield: 76%, m.p.

- amino-2- (1,2,4,5-tetrahydro-3-benzazepino) -benzoic acid, yield: 86%, m.p. 258 'C;

- amino-2- (1,2,3,4-tetrahydro-1-isoquinolinyl) -benzoic acid, yield: 66 m.p. 220'C;

- amino -2- (4-phenylpiperazinyl) benzoic acid, 83%, m.p. 255 'C:

- amino -2- (4-pyridyl - (2) piperazinyl) benzoic acid, 80%, mp 248 ° C;

- amino-2- (trans -3,5-dimethylpiperidino)

- benzoic acid, yield: 89 m.p. 156 'C;

- amino-2- (3,3,5,5-tetramelyl-piperidino)

benzoic acid, 98% yield. melting point: below 20 'C;

- amino-2- (3,5-dimethylmorpholino) benzoic acid, yield 83%, mp 255 ° C;

-12183 178

- amino-2- (3,5-dimethylthiomorpholino) benzoic acid, yield: 50%, m.p. 233 'C;

- amino -2 .- (3-aza-bicyclo [3,2,2] nor> an - 3

- il) - benzoic acid, yield: 8%, m.p. 288 ° C;

- amino-2-octamethylene-iminobenzoic acid, 88%, m.p. 191 C;

amino-2-nonamethylene-iminobenzoic acid, 80%, mp 212 'C;

- amino - 2 - decamethylene - iminobenzoic acid, yield: 52%, m.p. 202 ° C;

- amino - 2 - undecamethylene - iminobenzoic acid, yield 93%. mp: 242 'C;

amino-2-dodecamethylene-iminobenzoic acid, 59%, mp 224 'C;

Amino - 2- (N-methyl-N-phenylamino) benzoic acid, 47%, mp 184 ° C;

- amino - 2 - (N - ethyl - N - cyclohexylamino)

benzoic acid, 66%, m.p. 160 'C;

- amino - 2 - (N - butyl - N - cyclohexylamino)

benzoic acid, yield 48%, mp 140 ° C;

amino-2- (N-cyclohexyl-N-isobutyl-amino) -benzoic acid, 62%, mp 20 ° C;

- arnino-2- (decahydro-3-benzazepin-3-yl) -benzoic acid, yield: 54%, m.p. 204'C;

- amino-2- (octahydro-isoindol-2-yl) -benzoic acid, yield 43%, mp 228 ° C;

- amino -2- (4-isopropyl-piperidino) benzoic acid, 50%, mp 231 C;

- amino -2- (4-tert-butyl-piperidino) benzoic acid, yield: 8! %, m.p. 276 'C;

- amino -2- (1,4-dioxa-8-aza-spiro [4,6] undecan-8-yl) -benzoic acid, 49%, mp 235 ° C;

- amino-2- (1,2,3,6-tetrahydro-1-pyridyl)

- benzoic acid, yield: 51%, m.p. 232 ° C;

- amino -2- (4-methylpiperazinyl) benzoic acid

hydrochloride, yield: 90%, melting point: below 20 ° C;

- amino - 2 - (N - methyl - N - benzylamino)

- benzoic acid, 95% yield, mp 20 ° C;

- amino -2- (4- (4-chlorophenyl) piperazinyl)

benzoic acid hydrochloride, yield: 80.5%, m.p. 305 C (dec);

- amino -2- (4-ethoxycarbonyl-piperazinyl)

- benzoic acid, yield: 87.5%, m.p. 195-197'C;

- amino -2- (4- (2-furod) piperazinyl] benzoic acid, 97% yield, mp 20 ° C;

- amino -2- (4-benzyl-piperazinyl) -benzoic acid hydrochloride, yield: 80%, mp 200-210'C.

Example F

- Chloro-2- (decahydro-isoquinolin-2-yl) -benzoic acid g (0.0365 moles) of 5-amino-2- (decahydro-isoquinolin-2-yl) -benzoic acid was dissolved in 55 ml of half-concentrated hydrochloric acid and heated to 0 ° C. Dissolved in 10 ml of water

Diazotate with 2.7 g (0.039 mol) of sodium nitrite. After the addition was complete, the reaction mixture was stirred for an additional 15 minutes and then the diazonium salt solution was added dropwise to a suspension of 4 g of copper powder in 40 ml of concentrated hydrochloric acid. The reaction mixture was stirred overnight to form a dark green homogeneous solution which was diluted with 100 ml of water and extracted thoroughly with chloroform. The extract was dried over sodium sulfate, the chloroform was distilled off and the residue was purified by column chromatography on silica gel with ethyl acetate-methanol (9.5: 0.5). Yield: 4.8 g (45%). Melting point: 138 'C.

Example G

- Chloro-2- (1,4-dioxa-8-aza-spiro [4,5] decan-8-yl) benzoic acid

8.5 g (0.031 mol) of 5-amino-2- (1,4-dioxa-8)

aza-spiro (4,5] -decane-8-yl) benzoic acid was dissolved in 28 ml of half-concentrated hydrochloric acid and diazotized at 0 ° C with a solution of 2.4 g (0.034 mol) of sodium nitrite in 10 ml of water. The diazonium salt solution was added dropwise with stirring to a suspension of 3 g of copper powder in 3 ml of concentrated hydrochloric acid. After the evolution of nitrogen had ceased, the mixture was stirred for a further 2 hours, diluted with water and extracted with chloroform. The chloroform product was dried over sodium sulfate and the solvent was distilled off. Trituration of the residue with petroleum ether gave 6.1 g (66%) of product. Melting point: 180'C.

Similarly as described in Examples F and G, the following compounds were prepared:

- chloro-2-pyrrolidinylbenzoic acid, 30%, m.p. 164 'C;

Chloro-2 · (2-methylpiperidino) benzoic acid, 74%, mp 124 124C;

- chloro-2- (3-methylpiperidino) benzoic acid, yield 47%, m.p. 165 ° C;

- chloro-2- (4-methylpiperidino) benzoic acid, 52%, mp 107 ° C;

(3-ethyl-6-methyl-piperidino) -5-chloro-benzoic acid, yield 73%, mp 20 ° C;

- chloro-2- (cis-3,5-dimethylpiperidino) benzoic acid, yield 46%, m.p. 167'C;

- chloro-2- (trans-3,5-dimethylpiperidino)

benzoic acid, yield 63%, mp 132 'C;

- chloro-2- (4-methoxy-piperidino) -benzoic acid, yield 63%, mp 136 ° C;

- chloro-2-heptamethylene-iminobenzoic acid, yield 58%, mp 20 ° C;

- chloro-2- (4-phenylpiperidino) benzoic acid, elution: 51%, m.p. 217'C;

- chloro-2- (4-ethoxycarbonylpiperidino) benzoic acid, 97% yield, mp 20 ° C;

- chloro-2-hexamethylene-iminobenzoic acid, 34%, m.p. 113 'C;

- chloro-2-thiomorpholino-benzoic acid, 16%, m.p. 160'C;

- chloro-2- (1,2,4,5-tetrahydro-3-benzazepino) -benzoic acid, 59%, m.p. 174 ° C;

-131

183,178

- chloro-2- (1,2,3,4-tetrahydro-1-isoquinolinyl)

- benzoic acid, yield: 50%, m.p. 182 'C;

- chloro-2-pl-phenyl-piperazinyl) -benzoic acid, yield 42%, mp 154 ° C;

- chloro-2- (4-pyridyl - (2) -piperazinyl) benzoic acid, yield 45%, m.p. 168 'C;

bromine -2- (2-methylpiperidino) benzoic acid, 31%, m.p. 168 ° C;

- chloro-2- (3,3,5,5-tetramethylpiperidino) benzoic acid, 62%, mp 20 ° C;

- bromo-2- (4-methoxy-piperidino) -benzoic acid, yield 48%, mp 138 ° C;

- chloro-2- (3,5-dimethylmorpholino) benzoic acid, yield: 50%, m.p. 174'C;

- chloro-2- (3,5-dimethylthiomorpholino) benzoic acid, yield 18%, mp 134 ° C;

- bromo-2-heptamethylene-imino-benzoic acid, 15%, m.p. 104'C;

- chloro -2- (3-aza-bicyclo [3,2,2] nonan-3 (ii)) - benzoic acid. yield: 16%, m.p. 199 'C;

Chloro-2-octamethylene-iminobenzoic acid, 70%, m.p. 84 'C;

- chloro-2-nonamenylene imino-benzoic acid, 30%, m.p. 78 'C;

- chloro-2-decamethylene-iminobenzoic acid, 65%, mp 70 'C;

- chloro-2-undecamethylene-iminobenzoic acid, yield: 41%, m.p. 41 'C;

- chloro-2-dodecamethylene-iminobenzoic acid, yield 36%, m.p. 40'C;

- chloro-2- (N-phenyl-n-methylamino) benzoic acid, yield: 27%, m.p.

(N-ethyl-N-cyclohexylamino) -5-chloro-benzoic acid, yield: 24%, m.p. 152 ° C;

- (N-Butyl-N-cyclohexylamino) -5-chloro

- benzoic acid, yield: 16%, m.p. 145 'C;

- chloro - 2 - (N - cyclohexyl - N - isobutylamino)

- benzoic acid, yield 22%, mp 131 ° C;

- chloro-2- (decahydro-3-benzazepin-3-yl)

- benzoic acid, yield 70%, mp 153 ° C;

- bromo-2- (decahydro-3-benzazepin-3-yl) -benzoic acid, yield 54%, m.p. 154'C;

- chloro-2- (octahydro-isoindol-2-yl) -benzoic acid, 33%, m.p. 164'C;

- bromo-2-octamethylene-iminobenzoic acid, yield 48%, mp 94 'C;

- chloro-2- (4-isopropyl-piperidino) -benzoic acid, yield 43%, m.p. 172'C;

- chloro-2- (4-tert-butyl-piperidino) benzoic acid, yield: 35 m.p. 161 ° C;

- chloro-2- (1,4-dioxa-8-aza-spiro [4,6] undecan-8-yl) -benzoic acid, yield: 42%, m.p.

- chlorine * 2 - (1,2,3,6-tetrahydro-1-pyridinyl)

- benzoic acid, yield 73%, m.p. 173 'C;

- chloro-2- (4-methylpiperazinyl) benzoic acid

hydrochloride, yield: 75%, m.p. 132 DEG C.;

- chloro-2- (N-methyl-N-benzylamino) benzoic acid, yield: 18.2%, m.p. 156-157 ° C;

- chloro-2- [4- (4-chloro-phenyl) -piperazinyl] - 14 benzoic acid, yield: 30.5%, m.p. 228-230 ° C;

(4-ethoxycarbonyl-piperazinyl) -5-chloro-benzoic acid, 52%, mp 129-130'C;

- chloro -2- (4- (2-fluorophenyl) piperazinyl] benzoic acid, 33.1%, m.p. 200-202C;

(4-Benzyl-piperazinyl) -5-chloro-benzoic acid hydrochloride, yield: 42.8%, melting point (decomposition): 230-232 ° C.

Example II

- Amino - 2 - hexamethylene - imino - benzoic acid nitrile

21.4 g (0.087 mol) of 2-hexamethylene-imino-5-nitrobenzoic acid nitrile are dissolved in 200 ml of dioxane and 500 ml of methanol and hydrogenated at room temperature under 5 bar of hydrogen in the presence of 10% palladium on carbon. The catalyst was filtered off and the solvent was evaporated to give 20 g (100%) of product. Melting point: below 20 'C.

Example J

- Chloro-2-hexamethylene-imino-benzoic acid nitrile g (0.092 mol) 5-amino-2-hexamethylene-imino-benzoic acid nitrile was dissolved in 90 ml of half-concentrated hydrochloric acid and 6.5 g (0.094 mol) of sodium nitrite at 30 ° C. A solution of 1 ml of water in water is diazolized dropwise. After the addition was complete, the reaction mixture was stirred for an additional 15 minutes. The diazonium salt solution was added with stirring to a side of copper (I) chloride in concentrated hydrochloric acid, which was heated to 70'C. After the elimination of the nitrogen evolution, the product was extracted with chloroform, the extract was dried over sodium sulfate, the chloroform was distilled off and the residue was purified by silica gel column chromatography. Eluent is toluene.

Yield: 5 g (2.3%). Melting point: below 20 'C.

Example K

- Chloro-2-hexamethylene-intino-benzoic acid 5 g (0.021 mol) of 5-chloro-2-hexamethylene-imino

- Benzoic acid nitrile was heated with 170 g of potassium hydroxide solution (32 g) and water (20 ml) for 8 hours. The resulting melt was dissolved in water to give a pH value

Set to 5 so that the amide is quantitatively precipitated; followed by hydrolysis with half concentrated hydrochloric acid.

Yield: 3.6 g (67.4%), m.p. 113 ° C. Similarly as described in Examples 11 to K, the following compounds were prepared:

- amino - 2 - morpholino - benzoic acid nitrile. yield: 68%, m.p. 142 'C;

- chloro-2-morpholino-benzoic acid nitrile, yield: 20%, m.p. 57 'C;

-14 «83 178

- chloro-2-morpholino-benzamide, 98%, mp 280 'C;

- chloro-2-morpholino-benzoic acid, yield: 60%, m.p.

Example L

- Cyano - 2 - octamethylene - imino - benzoic acid

Dissolve 26.2 g (0.1 mol) of 5-amino-2-octamethylene iminobenzoic acid in 38 ml of concentrated hydrochloric acid, dilute with 280 ml of water and at 0 ° C.

A solution of sodium nitrite (7.6 g, 0.11 mol) in water (30 mL) was diazotized dropwise. The reaction mixture was stirred for 0.5 hour and then adjusted to pH 7 with sodium carbonate. A solution of trisodium tetracyano-copper (I) complex is then added dropwise to the diazonium salt solution at 0'C.

The above copper (I) complex solution is prepared as follows:

g (0.128 mol) of CuSO ₄ -5H ₂ O and 8.7 g nátríuin chloride in 100 ml of water, 6.6 g (0.0635 mole) of sodium - hydrogen - szülőiből, 4.4 g of sodium hydroxide in 50 ml of water The precipitated copper (I) chloride was filtered off with suction, suspended in 50 ml of water and dissolved in a solution of 17 g (0.346 mol) of sodium cyanide in 30 ml of water.

After the evolution of nitrogen ceased, the reaction mixture was heated at 70 DEG C. for one hour. The mixture was cooled, adjusted to pH 5.5 with 2N hydrochloric acid, and extracted with chloroform. The chloroform extract was dried over sodium sulfate, the chloroform was distilled off, and the crude product was purified by silica gel column chromatography with ethyl acetate as eluent.

Yield: 9 g (30%). Melting point: below 20 'C.

Example M

Heptamethylene Imino - 5 - hydroxybenzoic acid

26.7 g (0.107 mol) of 5-amino-2-heplamelylene

Iminobenzoic acid is dissolved in 190 ml of 3N sulfuric acid and diazotized at 0'C with 8.3 g (0.12 mol) of sodium nitrite in 30 ml of water. After stirring for half an hour, 2 g of finely powdered urea are added. The diazonium salt solution was added dropwise to 320 ml of 50% sulfuric acid heated to 90 ° C with vigorous stirring. After the evolution of nitrogen ceased, the solution was adjusted to pH 4 with ammonia at room temperature and the product was extracted with chloroform. The extract was dried over sodium sulfate, the chloroform was distilled off and the dry residue was purified by chromatography on a silica gel column with chloroform as eluent. The product was crystallized from isopropanol to yield 8 g (30%). Melting point: 199 'C.

The following compounds were prepared according to Example M:

- hexamethyleneimino-5-hydroxybenzoic acid, yield 24%, m.p. 214 'C;

- hydroxy-2-octamethylene-iminobenzoic acid, 27%, m.p. 208 'C;

- hydroxy -2- (4-tert-butyl-piperidino) benzoic acid, 33% yield. mp 240 ° C;

Hydroxy-2- (cis-3,5-dimethylpiperidino) benzoic acid, 67.4%, mp 248-250 ° C.

Example N

Methoxy - 2 - octamethylene - imino benzoic acid

3.2 g (12.2 mol) of 5-hydroxy-2-octamethylene iminobenzoic acid in 20 ml of absolute dimethylformamide are mixed with 0.6 g (25 mmol) of sodium hydroxide and the mixture is heated to 50 ° C the sodium salt is partially precipitated. Methyl iodide (5.2 g, 36.6 mmol) in absolute dimethylformamide (3 mL) was added and the mixture was stirred at room temperature for 5 hours. The dimethylformamide is distilled off and the crude 5-methoxy-2-octamethylene

The methyl iminobenzoic acid is purified by chromatography on a silica gel column with chloroform as the eluent.

Yield: 90%. Melting point: below 20 'C.

The above ester is hydrolyzed with caustic soda at 80 ° C. The hydrolyzate was acidified to pH 5.2 and extracted with chloroform. The extract was dried over sodium sulfate, the solvent was distilled off and the residue was triturated with petroleum ether.

Yield: 85%. Melting point: 84 'C.

Similarly to Example N, the following compounds were prepared:

hexamethyleneimino-5-methoxybenzoic acid, 88%, m.p. 141 'C;

- heptamethylene imino-5-methoxybenzoic acid, yield: 30%, melting point: 120 ° C;

- heptamethylene-imino-5-isopropoxy-benzoic acid, 78%, m.p. 120'C;

- ethoxy-2-octamethylene-iminobenzoic acid, 87%, mp 20 ° C;

isopropyloxy-2-octamethylene-iminobenzoic acid, 60%, m.p. 78'C;

butyl (2) oxy - 2 - octamethylene imino benzoic acid, yield: 48%, m.p.

methoxy-2- (4-tert-butyl-piperidino) benzoic acid, 22%, m.p. 156 ° C;

- methoxy-2- (3,5-cis-dimethyl-piperidino)

- benzoic acid, yield: 90%, m.p. 124 'C;

- hexyloxy-2-piperidino-benzoic acid, yield 73%, mp 72 'C;

- benzyloxy-2-piperidino-benzoic acid, yield: 41%, m.p.

The final products of formula 1 are prepared as follows:

/. example

- [2- (5-Chloro-2-dimethylaminobenzoyl)

(amino) ethyl] benzoic acid methyl ester

1.06 g (5.3 mmol) of 5-chloro-2-dimethylamino

Benzoic acid was dissolved in 5 ml of absolute tetrahydrofuran and 1.03 g (6.3 mmol) of Ν, Ν'-carbonyldiimidazole was added at room temperature. The mixture is reacted for 1-2 hours and then formed

-151

A solution of 1.13 g (6.3 mmol) of 4- (2-amino-ethyl) -benzoic acid methyl ester in 2 mL of tetrahydrofuran was added to imidazolid 183 178. The reaction mixture was allowed to stand at room temperature for 16 hours and then tetrahydrofuran was distilled off in a rotary evaporator. The crude ester was passed through a silica gel column with toluene · ethyl acetate 9; Purify by chromatography on a 1: 1 mixture. The combined fractions were evaporated and the dry ester containing the purified ester was treated with petroleum ether.

Yield: 0.9 g (47.5%). Melting point: 94 ° C.

Example 2

4- / 2- (5-Chloro-2-dimethylaminobenzoyl)

(amino) ethyl] benzoic acid

0.55 g (1.56 mmol) of 4- (2- (5-chloro-2-dimethyl)

Dissolve the methyl ester of amino-benzoyl-amino) -ethyl] -benzoic acid in 40 ml of a 2: 1 mixture of methanol and dioxane. To the solution was added 0.29 g (4.8 mmol) of potassium hydroxide in 3 mL of water and 30 mL of water was added dropwise at room temperature so that the ester did not precipitate. After a few hours, the organic solvent was distilled off in a rotary evaporator, the aqueous phase was extracted with chloroform and the pH of the aqueous phase was adjusted to 5.5 with 2N hydrochloric acid, whereupon the acid precipitated.

Yield: 0.38 g (70%). Melting point: 165 ° C.

Example 3

4- / 2- (5-Chloro-2-dimethylamino-benzoylamino) -ethyl-benzoic acid

0.32 g (1 mmol) of 4- (2- (2-amino-5-chloro-benzoylamino) -ethyl] -benzoic acid (m.p. 196 ° C, prepared from 2-amino-5-chloro-benzoic acid and 4 - ( From 2-aminoethyl) benzoic acid methyl ester as in Example i and then acidified as in Example 2) in 10 ml of formalin and 30 ml of glacial acetic acid, followed by addition of 500 mg of 10% palladium on carbon in an autoclave at 5 bar with hydrogen The catalyst is filtered off and the solvent is distilled off, then the acid is dissolved in caustic soda and precipitated with 2N hydrochloric acid.

Yield: 0.11 g (30%). Melting point: 165 ° C.

Example 4

- [2- (5-Chloro-2-dimethylamino-benzoyl-amino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2-methylamino-benzoylamino) -ethyl] -benzoic acid (m.p. 205 ° C) according to Example 3.

Yield: 30%. Melting point: 165 ° C.

Example 5

4- / 2- (5-Chloro-2-dimethylamino-benzoylamino) -ethyl] -benzoic acid methyl ester

1.06 g (5.3 mmol) of 5-chloro-2-dimethylamino

- Benzoic acid is converted to acid chloride with 7 ml of lionyl chloride at 40-50'C. Thionyl chloride is distilled off and the crude acid chloride is treated with 0.95 g (5.3 mmol) of 4- (2-aminoethyl) -benzoic acid methyl ester in 10 ml of absolute pyridine. The reaction mixture is stirred at room temperature for 2 hours and then stirred for about 2 hours. After heating for 20 minutes at 50-70 ° C, the pyridine is removed by rotary evaporation. The dry residue was dissolved in ice water, made basic with caustic soda, and this solution was extracted with chloroform. The extract was dried over sodium sulfate, the chloroform was distilled off, and the dry residue was purified by chromatography on a silica gel column (toluene / ethyl acetate 9: 1).

Yield: 1.4 g (73%). Melting point: 94 ° C.

Example 6

- [2- (5-Bromo-2-dimethylamino-benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-bromo-2-dimethylaminobenzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 93.5%. Melting point: 99 ° C.

Example 7

4- / 2- (5-Bromo-2-dimethylaminobenzoyl)

(amino) ethyl ethyl benzoic acid

Prepared 4- (2- (5-bromo-2-dimethylamino)

benzoylamino) ethyl] benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 77%. Melting point. 187 ° C.

Example 8

4- / 2- (5-Fluoro-2-dimethylaminobenzoyl)

(amino) ethyl] benzoic acid methyl ester

Prepared from 5-fluoro-2-dimethylaminobenzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 44%. Melting point: 56 ° C.

Example 9

4- / 2- (5-Fluoro-2-dimethylaminobenzoyl)

(amino) ethyl] benzoic acid

Prepared 4- (2- (5-fluoro-2-dimethylamino)

benzoylamino) ethyl] benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 73%. Mp 108 ° C.

Example 10

4- / 2- (2-Dimethylamino-benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 2 - dimethylaminobenzoic acid and 4- (2 - aminoethyl) benzoic acid methyl ester.

Example 1. The reaction is carried out at 60-70 ° C.

Yield: 98%. Melting point: 74 ° C.

-16-benzoyl-amino) -ethyl] -benzoic acid; By alkaline hydrolysis according to Example 2.

Yield: 36.5%. Melting point: below 20 'C.

183 178 //. example

4- (2- (2-Dimethylamino-benzoylamino)

- ethyl] benzoic acid

4- (2- (2-Dimethylaminobenzoyl) is prepared

by hydrolysis from the methyl ester of (amino) ethyl] benzoic acid according to Example 2.

Yield: 84%. Melting point: 107 'C.

Example 12

4- (2- (5-Chloro-2-diethylamino-benzoyl-amino) -ethyl] -benzoic acid - Melyl ester

Prepared from 5 - chloro - 2 - diethylamino - benzoic acid! and 4- (2-aminoethyl) benzoic acid methyl ester as in Example 1.

Yield: 51%. Melting point: 93 'C.

Example 13

- [2- (5-Chloro-2-diethylamino-benzoyl-amino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2-diethylamino-benzoylamino) -ethyl] -benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 80%. Melting point: 95 'C.

Example 14

4- (2- (5-Chloro-2-diisobutylamino-benzoic acid ethyl ester)

Prepared from 5-chloro-2-diisobutylamino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 1.

Yield: 20%. Melting point: below 20 'C.

Example 15

4- (2- (5-Chloro-2-diisobutyl-aminobenzoyl)

(amino) ethyl] benzoic acid

Prepared 4- (2- (5-chloro-2-diisobutylamino)

by hydrolysis from the ethyl ester of benzoylamino) ethyl] benzoic acid according to Example 2.

Yield: 90%. Melting point: 113 ° C.

Example 16

- [2- (5-Chloro-2-dipentylamino-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5 - chloro - 2 - dipentylamino - benzoic acid! and 4- (2-aminoethyl) benzoic acid ethyl ester as in Example 1.

Yield: 83%. Melting point: 118-120 ° C.

Example 17

- / 2- (5-Chloro-2-dipentylamino-benzoyl-antino) -ethyl] -benzoic acid

Prepared 4- (2- (5-chloro-2-dipentylamino)

Example 18

4- (2- (5-Chloro-2- (1-pyrrolyl) -benzoylamino) ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (1-pyrrolyl) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 64%. Melting point: 120-121 ° C.

/ Example 9

4- (2- (5-Chloro-2- (1-pyrrolyl) benzoyl amino) ethyl] benzoic acid

Prepared from 4- (2- (5-chloro-2- (1-pyrrolyl) benzoylamino) ethyl] benzoic acid methyl ester by alkali hydrolysis according to Example 2.

Yield: 26%. Melting point: 250-255 ° C.

Example 20

4- (2- (5-Chloro-2- (N-cyclohexyl-methylamino) -benzoylamino) -ethyl] -benzoic acid, ethyl ester

Prepared from 2- (N-cyclohexylmethylamino) -5-chlorobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 1.

Yield: 45%. Melting point: 98 'C.

Example 21

4- (2- (5-Chloro-2- (N-cyclohexylmethylamino) benzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-chloro-2- (N-cyclohexylmethylamino) benzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 2.

Yield: 58%. Melting point: 166 ° C.

Example 22

- (2- (5-Bromo-2-piperidinobenzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-bromo-2-piperidino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example I.

Yield: 87%. Melting point: 76'C.

Example 23

- (2- (5-Bromo-2-piperidinobenzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-bromo-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 2.

Yield: 99. Melting point: 201 'C.

-171

18? 178

Example 24

- [2- (5-Chloro-2-pyrrolidinyl-benzoyl-amino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2-pyrrolidinylbenzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 43%. Melting point: 164'C.

Example 25

4-) 2- (5-Chloro-2-pyrrolidinyl-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2-pyrrolidinyl-benzoylamino) -ethyl] -benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 68%. Melting point: 184'C.

Example 26

- [2- (5-Chloro-2-piperidino-benzoylamino)

ethyl] benzoic acid methyl ester

Prepared from 5-chloro-2-piperidinobenzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 72%. Melting point: 98 'C.

Example 27

4-) 2- (5-Chloro-2-piperidinobenzoylamino)

- ethyl] benzoic acid

4- (2- (5-chloro-2-piperidinobenzoyl) is obtained

by hydrolysis from the methyl ester of (amino) ethyl] benzoic acid according to Example 2.

Yield: 82%. Melting point: 200 'C.

Example 30

- [2- (5-Chloro-2- (3-methyl-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (3-methylpiperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example I.

Yield: 51%. Melting point: 93 'C.

3). example

- [2- (5-Chloro-2- (3-methylpiperidino) benzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-chloro-2- (3-methylpiperidino) benzoylamino) ethyl] benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 83%. Melting point: 194 'C.

Example 32

- [2- (5-Chloro-2- (4-methyl-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (4-methylpiperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 48%. Melting point: 55 'C.

Example 33

- [2- (5-Chloro-2- (4-methylpiperidino) benzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-chloro-2- (4-methylpiperidino) benzoylamino) ethyl] benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 83%. Melting point: 211 'C.

Example 28

- [2- (5-Chloro-2- (2-methyl-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (2-methylpiperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 23%. M.p. 82'C.

Example 29

- [2- (5-Chloro-2- (2-methylpiperidino) benzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-chloro-2- (2-methylpiperidino) benzoylamino) ethyl] benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 57%. Melting point: 178'C.

Example 34

4-) 2- (5-Chloro-2- (5-ethyl-2-methyl-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (5-ethyl-2-methylpiperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example I.

Yield: 10%. Melting point: below 20 'C.

Example 35

4-) 2- (5-Chloro-2- (5-ethyl-2-methylpiperidino) benzoylamino) ethyl] benzoic acid

4- (2- (5-chloro-2- (5-ethyl-2-methyl) methyl) is obtained

(piperidino) benzoylamino) ethyl] benzoic acid

- methyl ester by alkaline hydrolysis according to Example 2.

Yield: 60%. Melting point: 40 'C.

-18183 178

Example 36

- [2- (5-Chloro-2- (3,5-dimethyl-piperidino))

- benzoylamino) ethyl] benzoic acid methyl ester Prepared from 5-chloro-2- (3,5-dimethylpiperidino)

benzoic acid and 4- (2 - aminoethyl) benzoic acid

methyl ester as in Example 1.

Yield: 85%. Melting point: 95 'C.

Example 37

- [2- (5-Chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester

5-Chloro-2- (3,5-dimethylpiperidino) benzoic acid (2.7 g, 0.01 mol) was heated under reflux for 3.5 hours (3.57 g, 0.03 mol) in thionyl chloride (20 ml). The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform (10 mL) and stirred at room temperature with methyl 4- (2-aminoethyl) benzoate hydrochloride (2.16 g, 0.01 mol) and 3.03 g (0 03 mol) of a solution of triethylamine in 15 ml of chloroform was added dropwise. Addition was complete in 15 minutes, then the mixture was heated under reflux for an additional 30 minutes. The reaction mixture was cooled, washed twice with water and once with dilute acetic acid, and the chloroform layer was dried over sodium sulfate and concentrated. For further purification, the resulting residue was subjected to silica gel column chromatography with chloroform-acetone (9: 1). purified. The pure fractions were combined, the solvent was evaporated and the product was recrystallized from methylene chloride / petroleum ether (20: 1).

Yield: 3.3 g (77%). M.p. 94-95'C.

Example 38

- [2- (5-Chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl] -benzoic acid

Methyl 4- (2- (5-chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl) -benzoic acid, 2.15 g (0.005 mol) in 50 ml of ethanol and 10 ml of 1 N sodium hydroxide and refluxed for 30 minutes. After cooling the reaction mixture, most of the alcohol was removed in vacuo and the residue was stirred with water (60 mL). The mixture was mixed with acetic acid for approx. After slightly acidifying to pH 6, a precipitate formed which was filtered off with suction and recrystallized from isopropanol.

Yield: 1.82 g (87.5%). Mp 204-206'C.

Example 39

- [2- (5-Chloro-2- (4-methoxy-piperidino))

- benzoyl amino) ethyl) benzoic acid elyl ester Prepared from 5-chloro-2- (4-methoxy-piperidino)

benzoic acid and 4- (2 - aminoethyl) benzoic acid

ethyl ester according to Example 1.

Yield: 60%. Melting point: below 20 'C.

Example 40

4- (2- (5-Chloro-2- (4-methoxy-piperidino) -benzoylamino) -ethyl] -benzoic acid

Prepared from the ethyl ester of 4- (2- (5-chloro-2- (4-methoxy-piperidino) -benzoylamino) -ethyl] -benzoic acid by the basic hydrolysis according to Example 2.

Yield: 85%. Mp 188 ° C.

Example 41

- [2- (5-Methoxy-2-piperidinobenzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-methoxy-2-piperidino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 1.

Yield: 66%. Melting point: 118 'C.

Example 42

4- (2- (5-Methoxy-2-piperidinobenzoylamino) ethyl] benzoic acid hydrochloride

Prepared from 4- [2- (5-methoxy-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl cleaver by basic hydrolysis according to Example 2. The resulting compound was converted to the hydrochloride with isopropanolic hydrochloric acid in acetone.

Yield: 91%. Melting point: 158'C.

Example 43

- [2- (5-Chloro-2-heptamethylene-imino-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2-heptamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 1.

Yield: 24%. Melting point: below 20'C.

Example 44

- [2- (5-Chloro-2-heptamethylene-imino-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2-heptamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 2.

Yield: 47%. Melting point86 'C.

Example 45

- [2- (5-Nitro-2-piperidinobenzoyl amino) ethyl] benzoic acid ethyl ester

Prepared from 5-nitro-2-piperidino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 1.

Yield: 70%. Melting point: 104'C.

-191

183,178

Example 46

4- (2- (5-Nitro-2-piperidinobenzoylamino) ethyl] benzoic acid

Prepared from 4- [2- (5-nitro-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester

By alkaline hydrolysis according to Example 2.

Yield: 69%. Melting point: 194-195 ° C.

Example 47

- [2- (5-Chloro-2- [4-phenyl-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (4-phenylpiperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 62%. Melting point: 124'C.

Example 48

4- (2- (5-Chloro-2- (4-fend-piperidino] benzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-chloro-2- [4-phenyl-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 92%, m.p. 188 ° C.

Example 49

4- (2- (5-Chloro-2- [1,4-dioxa-8-aza-spiro (4,5) decan-yl - (8) J-benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (1,4-dioxa-8-aza-spiro (4,5] decanyl - (8)) - benzoic acid and 4- (2-aminoethyl) -benzoic acid methyl ester Example 1 according to.

Yield: 45%. Melting point: 167 ° C.

Example 52

- [2- (5-Chloro-2- (4-carboxypiperidino)]

benzoyl amino) ethyl ethyl benzoic acid

4- (2- (5-chloro-2- [4-ethoxycarbonyl) 4- (2- (5-chloro-2-chloro) ethyl) is prepared)

- piperidino] benzoylamino) ethyl] benzoic acid

- methyl ester by alkaline hydrolysis according to Example 2.

Yield: 71%. Melting point; 238 ° C.

Example 53

4- (2- (5-Chloro-2-hexamethylene-imino-benzoylamino) -ethyl) -benzoic acid methyl ester

Prepared from 5-chloro-2-hexamethylene-imino-benzoic acid and 4- [2-amino-ethyl] -benzoic acid methyl ester according to Example 1.

mining; 72%. Melting point: 81 'C.

Example 54

4- (2- (5-Chloro-2-hexamethylene-imino-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2-hexamethylene iminobenzoylamino) ethyl] benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 89%. Melting point: 182'C.

Example 55

4- (2- (5-Chloro-2-morpholino-benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2-morpholinobenzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 80%. Melting point: 111 'C.

Example 50

- [2- (5-Chloro-2- (1,4-dioxa-8-aza-spiro [4,5] decan-yl - (8)) - benzoylamino] ethyl]

- benzoic acid

Prepared from 4- (2- (5-chloro-2- (1,4-dioxa-8-aza-spiro [4,5] decan-yl - (8)) - benzoylamino)

by the hydrolysis of ethyl ethyl benzoic acid methyl ester according to Example 2.

Yield: 82%. Melting point: 190'C.

Example 51

4- (2- (5-Chloro-2- (4-ethoxycarbonyl-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (4-ethoxycarbonylpiperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 17%. Melting point: 70 'C,

Example 56

4- (2- (5-Chloro-2-morpholino-benzoylamino)

- ethyl] benzoic acid

Prepared from 4- [2- (5-chloro-2-morpholino-benzoyl)

by hydrolysis from the methyl ester of (amino) ethyl] benzoic acid according to Example 2.

Yield: 78%. Melting point: 186 'C.

Example 57

4- (2- (5-Chloro-2-thiomorpholino-benzoyl (inino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2-thiomorpholinobenzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 45%. Melting point: 160'C.

-20183 178

5 <S '. example

- [2- (5-Chloro-2-thiomorpholino-benzoyl-amino) -ethyl} -benzoic acid

Prepared from 4- [2- (5-chloro-2-thiomorpholino-benzoylamino) -ethyl] -benzoic acid methyl ester

By alkaline hydrolysis according to Example 2.

Yield: 57%. Mp 210 ^e C.

Example 59

- [2- (5-Chloro-2-thiomorpholino-benzoyl-amino) -ethyl] -benzoic acid methyl ester - S-oxide

Prepared from 5-chloro-2-thiomorpholinobenzoic acid S-oxide and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 63%. Mp 152 ° C.

Example 60

- [2- (5-Chloro-2-thiomorpholino-benzoyl-amino) -ethyl] -benzoic acid S-oxide

Prepared from 4- (2- (5-chloro-2-thiomorpholino-benzoylamino) -ethyl] -benzoic acid methyl ester S-oxide by the basic hydrolysis according to Example 2.

Yield: 82%. Mp 202 ° C.

Example 61

4- [2- (5-Chloro-2- [1,2,4,5-tetrahydro-3H)

- 3 - benzazepinyl (3)] - benzoylamino) ethyl]

benzoic acid methyl ester

Prepared from 5-chloro-2- [1,2,4,5-tetrahydro-3H

From 3 - benzazepinyl - (3) - benzoic acid and 4- (2 - aminoethyl) -benzoic acid methyl ester according to Example 1.

Yield: 69%. Melting point: 126 ° C.

Example 62

- [2- (5-Chloro-2- [1,2,4,5-tetrahydro-3H)

- 3 - benzazepinyl (3)] - benzoylamino) ethyl]

- benzoic acid

Prepared from 4 - [2- (5-chloro-2- [1,2,4,5-tetrahydro)

- 3H - 3 - benzazepinyl (3)] - benzoylamino) ethyl]

by hydrolysis from benzoic acid methyl ester according to Example 2.

Yield: 89%. Mp 148 ° C.

Example 63

- [2- (5-Chloro-2- [1,2,3,4-tetrahydro-isoquinolinyl (2)] - benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- [1,2,3,4-tetrahydroisoquinolinyl (2)] benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 43%. Melting point: 94 ° C.

Example 64

- [2- (5-Chloro-2- [1,2,3,4-tetrahydro-isoquinolin-yl (2)] - benzoylamino) -ethyl] -benzoic acid

Prepared from the methyl 4- (2- (5-chloro-2- [1,2,3,4-tetrahydroisoquinolinyl (2)] benzoylamino) ethyl] benzoate as described in Example 2. by alkaline hydrolysis.

Yield: 86%. Melting point: 173 ° C.

Example 65

- [2- (5-Chloro-2- [4-phenyl-piperazinyl] -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (4-phenylpiperazinyl) benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 1.

Yield: 40%. 132'C.

Example 66

- [2- (5-Chloro-2- [4-phenyl-piperazinyl] -benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2- [4-phenyl-piperazinyl] -benzoylamino) -ethyl] -benzoic acid methyl ester by basic hydrolysis according to Example 2.

Yield: 82%. Melting point: 166 ° C.

Example 67

- [2- (5-Chloro-2- [4-pyridyl (2) piperazinyl] -benzoylamino) ethyl) -benzoic acid methyl ester

Prepared from 5-chloro-2- (4- (2-pyridyl) piperazine 1] -benzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester hydrochloride-bithionyl chloride and triethylamine according to.

Yield: 44.6%. 153-154 ° C (hydrochloride).

Example 68

- [2- (5-Chloro-2- [4-pyridyl (2) piperazinyl] -benzoylamino) ethyl] -benzoic acid

Prepared 4- (2- (5-chloro-2- [4-pyridyl - (2))

piperazinyl] benzoylamino) ethyl] benzoic acid

- methyl ester by alkaline hydrolysis according to Example 2.

Melting point: 120 ° C. Yield: 27%.

-21I

183 ί 78

Example 69

4- (2- (5-Chloro-2-piperidino-benzoylamino) -1-methyl-ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2-piperidino-benzoic acid and 4- (2-amino-1-methylethyl) -benzoic acid methyl ester according to Example 1.

Yield: 42.7%. Melting point: 93-94 ° C.

Example 70

4- (2- (5-Chloro-2-piperidino-benzoylamino)

- 1 - methylethyl] benzoic acid

Prepared from 4- [2- (5-chloro-2-piperidinobenzoyl)

by hydrolysis from the methyl ester of amino) -1 - methylethyl] benzoate according to Example 2.

Yield: 76%. Melting point: 192-194 ° C.

Example 71

4- (2- (5-Chloro-2-dimethylaminobenzoyl)

(amino) -1-methyl-ethyl] -benzoic acid

Prepared 4- (2- (5-chloro-2-dimethylamino)

(benzoylamino) -1-methyl-ethyl] -benzoic acid by alkaline hydrolysis according to Example 2.

Yield: 86%. Melting point: 159-161 ° C.

Example 72

4- (2- (5-Chloro-2-dimethylaminobenzoyl)

(amino) -1-methyl-ethyl] -benzoic acid methyl ester

Prepared from 5 - chloro - 2 - dimethylaminobenzoic acid! and 4- (2-amino-1-methylethyl) benzoic acid

methyl ester as in Example 1.

Yield: 61.5%. Melting point: 79-80 ° C.

Example 73

- [2- (5-Amino-2-piperidinobenzoylamino) ethyl] benzoic acid ethyl ester g (70.5 mmol) 4- (2- (5-nitro-2-piperidinobenzoylamino) ethyl) The benzylic acid ethyl ester was hydrogenated in 500 ml of methanol: ethanol (1: 1) in the presence of a palladium on carbon catalyst at room temperature under a hydrogen pressure of 5 bar.

Yield: 93%. Melting point: below 20 'C.

Example 74

4- (2- (5-Amino-2-piperidinobenzoylamino) ethyl] benzoic acid dihydrochloride

Prepared from 4- (2-5-amino-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester. the

By alkaline hydrolysis according to Example 2. The product is then converted to the dihydrochloride with isopropanolic hydrochloric acid in acetone.

Yield: 87%. Melting point: 70 'C.

Example 75

4- (2- (5-Acetylamino-2-piperidinobenzoyl)

- amino) ethyl] benzoic acid ethyl ester Prepared from 2.5 g (6.3 mmol) of 4- (2- (5-amino-2-piperidinobenzoylamino) ethyl] benzoic acid

ethyl ester and 25 ml acetic anhydride at room temperature. The reaction product precipitates and is washed with ether.

Yield: 1.9 g (69%). Melting point: 165'C.

Example 76

4- (2- (5-Acetylamino-2-piperidino-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-acetylamino-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 2.

Yield: 98%. Melting point: 212 ° C.

77. pé'Ida

4- (2- (5-Dimethylamino-silicon fond-2-piperidino-benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-dimethylaminosulfonyl-2-piperidinobenzoic acid and 4- (2-ethylamino) -benzoic acid methyl ester according to Example 1.

Yield: 77%. Melting point: 138-140 ° C.

Example 78

4- (2- (5-Dimethylaminosulfonyl-2-piperidinobenzoylamino) ethyl] benzoic acid

4- (2- (5-Dimethylaminosulfonyl) 4- (2- (5-dimethylamino) sulfonyl) is prepared

- 2 - piperidinobenzoylamino) ethyl] benzoic acid

- methyl ester by alkaline hydrolysis according to Example 2.

Yield: 91%. Melting point: 220 'C.

Example 79

4- (2- (5-Cyano-2-piperidinobenzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-cyano-2-piperidino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 1.

Yield: 76%. Melting point: 97 'C.

Example 80

4- (2- (5-Cyano-2-piperidinobenzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-cyano-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester from

By alkaline hydrolysis according to Example 2.

Yield: 40%. Melting point: 190 'C.

-22183 178

Example 81

- [2- (5-Ethoxycarbonyl-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester hydrochloride

Ethyl ester of 4- [2- (5-cyano-2-piperidinobenzoylamino) ethyl] benzoic acid (2.5 g, 6.2 mmol) was dissolved in ethanol (80 mL) and saturated with hydrochloric acid. After allowing the mixture to stand at room temperature for 6 days, the solvent was distilled off, the residue was dissolved in ice-water, adjusted to pH 9 with sodium hydroxide solution and extracted with chloroform. The extract was dried over sodium sulfate, the solvent was distilled off and the residue was converted to ethereal hydrochloric acid in ether.

Yield: 2.5 g (89.1%). M.p. 86-88'C.

Example 82

- [2- (5-Carboxy-2-piperidinobenzoyl amino) ethyl] benzoic acid

Prepared from 4- (2- (5-ethoxycarbonyl-2-piperidinobenzoylamino) ethyl] -benzoic acid ethyl ester hydrochloride by the basic hydrolysis according to Example 2.

Yield: 92%. Melting point: 242'C.

Example 84

- / 2- (5-Antino-2- [4-hydroxy-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester

5.3 g (12.4 mmol) of 4- (2- (2- (4-hydroxy-piperidino) -5-nitro-benzoylamino) -ethyl] -benzoic acid methyl ester in 100 mL of methanol in the presence of 10% palladium on carbon hydrogenated at room temperature under a hydrogen pressure of 1 bar.

Yield: 91%. Melting point: 78 'C.

Example 85

4- (2- (5-Chloro-2- (4-hydroxy-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester

Dissolve 20.5 g (52 mmol) of methyl 4- (2- (5-amino-2- [4-hydroxy-piperidino] -benzoylamino) -ethyl] -benzoic acid in 80 ml of semi-concentrated ice-cold hydrochloric acid and 25 ml of ice-cold water. The solution was added dropwise to a suspension of 10 ml of HCl and 6 g of copper powder. Purify by elution with a mixture of I ratio.

Yield: 30%. Melting point: below 20 'C.

Example 83

- [2- (2- [4-Hydroxy-piperidino] - 5-nitro)

benzoylamino) ethyl] benzoic acid methyl ester

a) 4- [2- (2-Chloro-5-nitro-benzoylamino)

Methyl 2 - chloro - 5 - nitrobenzoic acid, ethyl ethyl benzoate, is converted to imidazolide (6.8 g, 44 mmol) in N, N '- carbonyldiimidazole (40 mL) in absolute tetrahydrofuran. The mixture was reacted for 2 hours and then at room temperature 7.9 g (44 mmol) of 4- (2-amino)

ethyl ethyl benzoic acid methyl ester was added and the reaction mixture was stirred for about 1 hour. Stir for 16 hours. The solvent is then distilled off and the crude product is purified by chromatography on a silica gel column, eluting with a 1: 1 mixture of toluene and ethyl acetate.

Yield: 12 g (83%). Melting point: 163 'C.

b) 4- [2- (2- [4-Hydroxy-piperidino] -5-nitro-benzoylamino) -ethyl] -benzoic acid methyl ester g (14 mmol) 4- (2- (2-chloro-5-nitro) - benzoyl

Dissolve the methyl ester of (amino) ethyl] benzoic acid in ethanol (100 mL) with 4 - hydroxypiperidine (2.83 g, 28 mmol) at reflux for 14 hours. The solvent was then distilled off in a rotary evaporator, the dry residue was dissolved in ice water, adjusted to pH 5 with dilute hydrochloric acid and extracted with chloroform. The extract was dried over sodium sulfate, the chloroform was distilled off, and the residue was crystallized from isopropanol.

Yield: 5.5 g (92%). Melting point: 147 'C.

Example 86

4- (2- (5-Chloro-2- (4-hydroxy-piperidino] -benzoylamino) -ethyl] -benzoic acid

4.5 g (11.3 mmol) of 4- (2- (5-amino-2- [4-hydroxy-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester are dissolved in 20 ml of semi-concentrated hydrochloric acid and 0 ° C. Diazotize with 0.87 g (12.4 mmol) of sodium nitrite in 6 mL of water and add dropwise to a suspension of 1.2 g of copper powder in 3 mL of concentrated hydrochloric acid and stir for 2 h and then for 75 min. The cooled solution is extracted with chloroform, the chloroform solution is dried over sodium sulfate, the solvent is distilled off and the residue is purified on a silica gel column, eluting with a 9: 1 mixture of chloroform and methanol.

Yield: 2.4 g (52%). Melting point: 190'C.

Example 87

4- (2- (5-Chloro-2- [3-hydroxy-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 4- (2- (5-amino-2- (3-hydroxy-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester according to Example 85.

Yield: 30%. Melting point: 20 'C.

Example 88

- [2- (5-Chloro-2- [3-hydroxy-piperidino] -benzoylamino) -ethyl] -benzoic acid hydrate

-23183 178

Prepared from 4- (2- (5-amino-2- (3-hydroxy-piperidino) -benzoylamino) -ethyl] -benzoic acid methyl ester according to Example 86.

Yield: 40%. Melting point: 100-110'C.

Example 89

- [2- (2- [3-Hydroxy-piperidino] -5-nitro-benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 4- (2- (2-chloro-5-nitro-benzoylamino) -ethyl] -benzoic acid methyl ester and 3-hydroxypiperidine according to Example 83.

Yield: 43.5%. Melting point: 78-80 ° C.

Example 90

- [2- (5-Amino-2- [3-hydroxy-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 4- (2- (2- (3-hydroxy-piperidino) -5-nitro-benzoylamino) -ethyl] -benzoic acid methyl ester by catalytic hydrogenation according to Example 84.

Yield: 90%. Melting point: 82 'C.

Example 91

- [2- (2-Piperidino-5-propoxy-benzoyl-amino) -ethyl] -benzoic acid - Ethyl ester (7.6 mmol) 2-piperidino-5-propoxy-benzoic acid was dissolved in 60 ml of absolute tetrahydrofuran. g (8 mmol) of N, N'-carbonyldiimidazole was added and the mixture was dried at ca. Heat at reflux for 10-14 hours. When the imidazolide was almost quantitatively formed, 1.5 (8 mmol) of 4- (2-aminoethyl) -benzoic acid ethyl ester was added and refluxed for a further 4-6 hours. The tetrahydrofuran is then distilled off in a rotary evaporator and the crude ester is purified by silica gel column chromatography (eluent: toluene / ethyl acetate 9: 1). The fractions containing the purified ester were combined and the solvent was distilled off.

Yield: 2.4 g (72%). Melting point: below 20 ° C.

Example 92

- [2- (2-Piperidino-5-propoxy-benzoyl-amino) -ethyl] -benzoic acid hydrochloride

Dissolve 1.8 g (4.1 mmol) of ethyl 4- (2- (2-piperidino-5-propoxy-benzoylamino) -ethyl] -benzoic acid in a mixture of 15 ml of methanol and 15 ml of dioxane. 1 ml of 30% sodium hydroxide diluted with water was added dropwise so that the ester did not precipitate, and the addition was complete over a period of about 2 hours, after which the reaction mixture was stirred for a few hours, the organic solvents The aqueous phase is extracted with chloroform and the aqueous phase is brought to pH 24 with 2N hydrochloric acid, the product is extracted with chloroform, the chloroform phase is dried and the chloroform is distilled off.

Yield: 1.65 g (90%). Melting point: 236 'C.

Example 93

- [2- (5-Isopropoxy-2-piperidinobenzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-isopropoxy-2-piperidinobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 91.

Yield: 58%. Melting point: 70-72 ° C.

Example 94

-] 2 - (5 - Isopropoxy - 2 - piperidinobenzoyl

- amino) ethyl] benzoic acid hydrochloride Prepared from 4- (2- (5-isopropoxy-2-piperidino)

by hydrolysis from the ethyl ester of benzoylamino) ethyl] benzoic acid according to Example 92.

Yield: 82%. Mp 225-226 ° C,

Example 95

- [2- (5-Hexyloxy-2-piperidinobenzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-hexyloxy-2-piperidino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 92.

Yield: 61%. Melting point: 66 'C.

Example 96

- [2- (5-Hexyloxy-2-piperidinobenzoyl)

(amino) ethyl] benzoic acid hydrochloride

4- (2- (5-hexyloxy-2-piperidino) was prepared

benzoylamino) ethyl] benzoic acid by ethyl hydrolysis according to Example 92.

Yield: 87%. Melting point: 152-154 ° C.

Example 97

- [2- (5-Benzyloxy-2-piperidinobenzoyl)

Prepared from 5 - benzyloxy - 2 - piperidino - benzoic acid and 4- (2 - amino - ethyl) -benzoic acid ethyl ester according to Example 91.

Yield: 55%. Melting point: 120'C.

Example 98

- [2- (5-Benzyloxy-2-piperidinobenzoyl)

(amino) ethyl] benzoic acid

4- (2- (5-Benzyloxy-2-piperidino) was prepared

benzoylamino) ethyl] benzoic acid by ethyl hydrolysis according to Example 92.

Yield: 86%. Melting point: 176'C.

-241.33 178

Example 99

- [2- (5-Chloro-2-piperidino-benzoylamino) -2-melyl-ethyl] -benzoic acid methyl ester

Prepared from 5 - chloro - 2 - piperidino - benzoic acid! and 4- (2-aminopropyl) benzoic acid methyl ester according to Example 91.

Yield: 54%. Melting point: below 20 'C.

Example 100

4- (2- (5-Chloro-2-piperidinobenzoylamino)

- 2 - Methyl - ethyl] -benzoic acid

4- (2- (5-chloro-2-piperidinobenzoyl) is obtained

by hydrolysis from the methyl ester of 2 - amino) -2 - methylethyl] benzoic acid according to Example 92.

Yield: 49%. Melting point: 142-145 ° C.

Example 101

- [2- (3-Chloro-2-piperidino-benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 3-chloro-2-piperidinobenzoic acid and 4- (-2-aminoethyl) benzoic acid methyl ester according to Example 91.

Yield: 63%. M.p. 92-94 ° C.

Example 102

- [2- (3-Chloro-2-piperidino-benzoylamino)

- ethyl] benzoic acid

4- (2- (3-Chloro-2-piperidinobenzoyl) is obtained

by hydrolysis from the methyl ester of (amino) ethyl] benzoic acid according to Example 92.

Yield: 57%. Mp 155-158 ° C.

Example 103

4- (2- (4-Chloro-2-piperidinobenzoylamino) ethyl] benzoic acid, ethyl ester

Prepared from 4-chloro-2-piperidino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 91.

Yield: 71%. Melting point: below 20 ° C.

Example 104

- [2- (4-Chloro-2-piperidino-benzoylamino)

- ethyl] benzoic acid

4- (2- (4-Chloro-2-piperidinobenzoyl) is obtained

(amino) ethyl] benzoic acid by ethyl hydrolysis according to Example 92.

Yield: 66.7%. Melting point: 164-166 ° C.

Prepared from 5-bromo-2- (2-methylpiperidino)

benzoic acid and 4- (2 - aminoethyl) benzoic acid

ethyl ester according to Example 91.

Yield: 74%. Melting point: 98 'C.

Example 106

4- (2- (5-Bromo-2- (2-methyl-piperidino] -benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-bromo-2- (2-methylpiperidino) -benzoylamino) ethyl] -benzoic acid by ethyl hydrolysis according to Example 92.

Yield: 73%. Melting point: Γ83'C.

Example 107

- [2- (5-Chloro-2- (3,5-trans-dimethyl-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (3.5-trans-dimethylpiperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 91.

Yield: 75%. 105-107'C.

Example 108

-] 2- (5-Chloro-2- (3,5-trans-dimethylpiperidino] -benzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-chloro-2- [3,5-trans-dimethyl-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester by basic hydrolysis according to Example 92.

Yield: 86%. Melting point: 164-167 ° C.

Example 109

4- (2- (5-Bromo-2- (3,5-cis-dimethyl-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-bromo-2- (3.5-cis-dimethyl-piperidino) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester according to Example 91.

Yield: 82%. M.p. 142-144'C.

Example 110

- [2- (5-Bromo-2- (3,5-cis-dimethyl-piperidino] -benzoylamino) -ethyl] -benzoic acid

4- (2- (5-bromo-2- (3,5-cis-dimethyl) -4-) is prepared

- piperidino] - benzoylamino] - ethyl] - benzoic acid

methyl ester by alkaline hydrolysis according to Example 92.

Yield: 88%. Melting point: 184-185 ° C.

Example 105

- (2- (5-Bromo-2- (2-methylpiperidino] benzoylamino) ethyl] benzoic acid ethyl ester

-25i

183,178 / 77. example

- [2- (5 - 'Fetoxy-2- [2,3-cis-dimethyl-piperidino] -benzoylamino) - ethylbenzoic acid ethyl ester

Prepared from 5-methoxy-2- (3,5-cis-dimethyl-piperidino) -benzoic acid and 2- (aminoethyl) -benzoic acid ethyl ester according to Example 91.

Yield: 14%. Melting point: 97-99 ° C.

Example 772

- [2- (5-Methoxy-2- [3,5-cis-dimethyl-piperidino] -benzoylamino) -ethyl] -benzoic acid

Prepared from 4- [2- (5-methoxy-2- [3,5-cis-dimethyl-piperidino] -benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 53%. Melting point: 200-203 ° C.

Example 713

- [2- (5-Chloro-2- [3,3,5,5-tetramethyl-piperidino] -benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2- (3,3,5,5-tetramethylpiperidino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 91.

Yield: 34%. Mp 108 ° C.

Example 114

- [2- (5-Chloro-2- [3,3,5,5-tetramethyl-piperidino] -benzoylamino) -ethyl] -benzoic acid

Prepared from 4 - [2- (5-chloro-2- [3,3,5,5-tetramethyl)

- piperidino] benzoylamino) ethyl] benzoic acid

ethyl ester by alkaline hydrolysis according to Example 92.

Yield: 99%, m.p. 170-172 ° C.

Example 775

- [2 - (5 - Chloro - 2 - [piperidone - (2) - i! (1)])

benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5 - chloro - 2 - [piperidone - (2) - yl - (1)]

benzoic acid and 4- (2 - aminoethyl) benzoic acid

ethyl ester according to Example 91.

Yield: 42%. Mp 118 ° C.

Example 776

- [2 - (5 - Chloro - 2 - [piperidone - (2) - yl - (7)]

benzoylamino] ethyl] benzoic acid hydrate

Prepared from 4 - [2 - (5 - chloro - 2 - [piperidone - (2))

ethyl (1)] benzoylamino) ethyl] benzoic acid by alkaline hydrolysis according to Example 92.

Yield: 64%. Melting point: 190-193 ° C.

Example 117

- [2- (5-Bromo-2- [4-methoxy-piperidino])

benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-bromo-2- (4-methoxy-piperidino)

benzoic acid and 4- (2 - aminoethyl) benzoic acid

ethyl ester according to Example 91.

Yield: 82%. Melting point: below 20 ° C.

Example 118

- [2- (5-Bromo-2- [4-methoxy-piperidino] -benzoylamino) -ethyl] -benzoic acid

Prepared from the ethyl ester of 4- [2- (5-bromo-2- [4-methoxy-piperidino] -benzoylamino) -ethyl] -benzoic acid by basic hydrolysis according to Example 92.

Yield: 65%. Melting point: 186 ° C.

Example 119

- [2- (5-Chloro-2- [2,6-dimethylmorpholino]

benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-chloro-2- (2,6-dimethylmorpholino)

benzoic acid and 4- (2 - aminoethyl) benzoic acid

ethyl ester according to Example 91.

Yield: 52%. Melting point: 111-112 ° C.

Example 120

- [2- (5-Chloro-2- [2,6-dimethyl-morpholino] -benzoylamino) -ethyl] -benzoic acid

Prepared from the ethyl ester of 4- [2- (5-chloro-2- [2,6-dimethylmorpholino] -benzoylamino) ethyl] -benzoic acid by alkaline hydrolysis according to Example 92.

Yield: 86%. Melting point: 232 ° C.

/ 27th Example 2 [2- (5-Chloro-2- [2,6-dimethyl-thiomifolino] -benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2- (2,6-dimethylthiomorpholino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 91.

Yield: 71%. Melting point: below 20 ° C.

Example 722

- [2- (5-Chloro-2- [2,6-dimethyl-thiomorpholino] -benzoylamino) -ethyl] -benzoic acid

Prepared from 4- [2- (5-chloro-2- [2,6-dimethyl-thiomorpholino] -benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 51%. Melting point: 183-185 ° C.

-26183 178

Example 123

- [2- (5-Chloro-2- [thiomorpholino-1,1-dioxide] benzoylamino) ethyl} benzoic acid ethyl ester

Prepared from 5-chloro-2- (thiomorpholino-1.1-dioxide) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 91.

Yield: 40%. Melting point: 158 ° C.

Example 124

- [2- (2-Hexamethylene-imino-5-methoxy-benzoylamino) -ethyl} -benzoic acid ethyl ester

Prepared from 2-hexamethylene-imino-5-methoxy-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 91.

Yield: 46%. Melting point: 92 ° C.

Example 125

- [2- (2-Hexamethylene-imino-5-methoxy-benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- [2- (2-hexamethylene-imino-5-methoxy-benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 92%. Melting point: 126 ° C.

Example 126

- [2- (2-Heptamethylene-imino-5-methoxy-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 2-heptamethylene-imino-5-methoxy

benzoic acid and 4- (2 - aminoethyl) benzoic acid

ethyl ester according to Example 91.

Yield: 30%. Melting point: below 20 ° C.

Example 127

- [2- (2-Heptamethylene-imino-5-methoxy-benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- [2- (2-heptamethylene-imino-5-methoxy-benzoylamino) -ethyl] -benzoic acid ethyl ester by alkaline saponification according to Example 92.

Yield: 97%. Melting point: 110-112 ° C.

Example 128

- [2- (2-Heptamethylene-imino-5-isopropyloxy)

benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 2-heptamethylene-imino-5-isopropoxy-benzoic acid and 4- (2-amino-ethyl) -benzoic acid

ethyl ester according to Example 92.

Yield: 62 Melting point: below 20 ° C.

Example 129

- [2- (2-Heptamethylene-imino-5-isopropoxy)

- (bis-benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- (2- (2-heptamethylene-imino-5-isopropoxy-benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 91%. Mp 202 ° C.

Example 130

- [2- (5-Bromo-2-heptamethylene-imino-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-bromo-2-heptamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 91.

Yield: 42.5%. Melting point: 81 ° C.

Example 131

- [2- (5-Bromo-2-heptamethylene-imino-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-bromo-2-heptamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 94%. Melting point: 189 C.

Example 132

- [2- (2- (3-aza-bicyclo [3,2,2]) nonan-3)

- ii] - 5 - chlorobenzoylamino) ethyl] benzoic acid

- ethyl ester

Prepared from 2- (3-aza-bicyclo [3.2.2] nonan-3-yl) -5-chloro-benzoic acid and 4- (2-amino-ethyl)

benzoic acid ethyl ester according to Example 91.

Yield: 82%. Melting point: I14 ° C.

Example 133

- [2- (2 - [3-Aza-bicyclo [3,2,2] nonan-3)

- yl] - 5 - chloro - (benzoylamino) ethyl] benzoic acid

- hydrochloride

4- (2- (2- (3-azabicyclo (3,2,2)) nonane was prepared)

- 3 - yl] - 5 - chlorobenzoylamino) ethyl] benzoic acid

ethyl ester by alkaline hydrolysis according to Example 92.

Yield: 98%. Melting point: 158 ° C.

Example 134

- [2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid ethyl ester

Prepared from 5-chloro-2-octamethylene-imino-benzoic acid and 4- (2-benzoyl-ethyl) -benzoic acid

ethyl ester according to Example 91.

Yield: 41%. Melting point: below 20 ° C.

-27183 178

Example 135

4- [2- (5-Chloro-2-octamethylene-imino-benzoylamino) -ethyl] -255-benzoic acid

Prepared from 4- [2- (5-chloro-2-octamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 94%. Melting point: 172 'C.

Example 136 ~ [2- (5-Chloro-2-nonamethylene-iminobenzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2-nonamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 91.

Yield: 24%. Melting point: below 20 ° C.

Example 137

- [2- (5-Chloro-2-nonamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid

Prepared from 4- (2- (5-chloro-2-nonamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 82%. Melting point: 173-174 ° C.

Example 138

- [2- (5-Chloro-2-decamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid ethyl ester

Prepared from 5-chloro-2-decamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 91.

Yield: 65%. Melting point: below 20 'C.

Example 139

- [2- (5-Chloro-2-decamethylene-imino-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2-decamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 58%. Melting point: 177'C.

Example 140

- [2- (5-Chloro-2-undecamethylene-imino-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2-undecamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 91.

Yield: 71%. Melting point: 80'C.

Example 141

- [2- (5-Chloro-2-undecamethylene-imino-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2-undecamethylene 28 iminobenzoylamino) ethyl] benzoic acid ethyl ester by alkaline hydrolysis according to Example 92, 77%, mp 218-220 ° C. .

Example 142

- [2- (5-Chloro-2-dodecamethylene-imino-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2-dodecamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 92.

Yield: 53%. Melting point: below 20 'C.

Example 143

4- (2- (5-Chloro-2-dodecamethylene-imino-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2-dodecamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester by alkaline saponification according to Example 92.

Yield: 33%. Melting point: 185-187 ° C.

Example 144

- [2- (5-Chloro-2- [N-methylanilino] benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-chloro-2- (N-methylanilino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 91.

Yield: 70%. Melting point: below 20'C.

Example 145

- [2- (5-Chloro-2- [N-methylanilino-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2- [N-methylanilino] benzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 65%. Melting point: 186-188 ° C.

Example 146

- [2- (2 -] N-Ethyl-cyclohexylamino] -5-chloro-benzoylamino) -ethylbenzoic acid - ethyl ester

Prepared from 2- (N-ethylcyclohexylamino) -5-chlorobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 91.

Yield: 41%. Melting point: 94 'C.

Example 147

- [2- (2- [N-Ethyl-cyclohexylamino] -5)

- chlorobenzoylamino) ethyl] benzoic acid

Prepared 4 - (2- (2- [N-ethyl-cyclohexylamino])

5-chloro-benzoylamino) -ethyl] -benzoic acid by ethyl acetate hydrolysis according to Example 92.

Yield: 63%. Melting point: 163'C.

-28183 178

Example 148

- [2- (2- (2-butylcyclohexylamino) -5-chlorobenzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 2- (N-butyl-cyclohexylamino) -5-chlorobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 91.

Yield: 46%. Melting point: 77'C.

/ 49th example

- [2- (2- (N-Butyl-cyclohexylamino) -5-chloro-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- [2- (2- (N-butylcyclohexylamino] -5-chlorobenzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 92.

Yield: 79%. Melting point: 85 'C.

Example 150

4- / 2- (5-Chloro-2- [N-isobutyl-cyclohexyl]

ethylamino - benzoyl - amino) - ethyl] - benzoic acid

Prepared from 5 - chloro - 2- (N - isobutyl - cyclohexyl)

- amino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 91.

Yield: 46%. Melting point: 83 'C.

Example 151

4- / 2- (5-Chloro-2- [N-isobutyl-cyclohexylamino] -benzoylamino) -ethyl] -benzoic acid

Prepared from 4- [2- (5-chloro-2- (N-isobutyl-cyclohexylamino] -benzoylamino) -ethyl] -benzoic acid ethyl ester by basic alkaline saponification according to Example 92.

Yield: 62%. Melting point: 129'C.

Example 152

4- / 2- (5-Chloro-2-dimethylamino-benzoylamino) -2-methyl-ethyl] -benzoic acid methyl ester

Prepared from 5 - chloro - 2 - dimethylaminobenzoic acid! and 4- (2-aminopropyl) benzoic acid methyl ester according to Example 91.

Yield: 34%. Melting point: below 20 'C.

Example 153

- [2- (5-Chloro-2-dimethylaminobenzoyl)

(amino) -2-methyl-ethyl] -benzoic acid

Prepared 4- (2- (5-chloro-2-dimethylamino)

(benzoylamino) -2-methylethyl] benzoic acid by basic hydrolysis according to Example 92.

Yield: 49%. Melting point: 142-145 ° C.

Example 154

4- / 2- (3-Chloro-2-dimethylaminobenzoyl)

(amino) ethyl] benzoic acid methyl ester

Prepared from 3-chloro-2-dimethylaminobenzoic acid and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 91.

Yield: 76%. Melting point: below 20 'C.

Example 155

4- / 2- (3-Chloro-2-dimethylaminobenzoyl)

(amino) ethyl] benzoic acid

Prepared from 4- (2- (3-chloro-2-dimethylamino)

by hydrolysis from the methyl ester of benzoylamino) ethyl] benzoic acid according to Example 92.

Yield: 76%. Melting point: 175-178'C.

Example 756

4- / 2- (2-Dimethylamino-5-methoxybenzoyl)

(amino) ethyl] benzoic acid methyl ester

Prepared from 2-dimethylamino-5-methoxy-benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester according to Example 91.

Yield: 81%. Melting point: below 20 'C.

Example 157

4- / 2- (2-Dimethylamino-5-methoxybenzoyl)

(amino) ethyl] benzoic acid

4- (2- (2-Dimethylamino-5-methoxy) is prepared

by hydrolysis from the methyl ester of benzoylamino) ethyl] benzoic acid according to Example 92.

Yield: 71%. 147-150'C.

Example 158

- [2- (4-Chloro-2-dimethylaminobenzoyl)

(amino) ethyl] benzoic acid ethyl ester

3.55 g (10 mmol) of 4- (2- (4-amino-2-dimethyl)

- Amino-benzoyl-amino) -ethyl] -benzoic acid ethyl ester, m.p. 135-136 ° C, prepared from 4- (2- (2-dimethylamino-4-nitrobenzoyl-amino) * ethyl-benzoic acid ethyl ester. hydrogen chloride in the presence of palladium on carbon) was diazotized by dropwise addition of 820 mg (11.6 mmol) of sodium nitrite in 4 ml of concentrated hydrochloric acid and 5 g of ice in 5 ml of water. The mixture was allowed to stand overnight, diluted with water and extracted with chloroform, the chloroform extract was evaporated and the residue was purified by silica gel column chromatography (EtOAc, EtOAc, 1: 1). 75th

Yield: 27%. Melting point: 97-99 ° C.

-29I

183,178

Example 759

4- (2- (4-Chloro-2-dimethylaminobenzoyl)

(amino) ethyl] benzoic acid

Prepared 4- (2- (4-chloro-2-dimethylamino)

from benzoylamino) ethyl] benzoic acid ethyl ester by alkaline saponification according to Example 92.

Yield: 95%. Melting point: 163-165 ° C.

Example 160

4- (2- (2-Dimethylamino-4-nylbenzoyl)

(amino) ethyl] benzoic acid ester

Prepared according to Example 91 for 2-dimethylamino

Of 4 - nitrobenzoic acid and 4 - (2 - aminoethyl) benzoic acid ethyl ester.

Yield: 95%. Melting point: 145 'C.

Example 165

4- (2- (5-Chloro-2- (decahydro-isoquinolin-2-yl] -benzoylamino) -ethyl] -benzoic acid ethyl ester

2.5 g (8.5 mmol) of 5-chloro-2- (decahydro-isoquinolin-2-yl) -benzoic acid are heated at reflux for 8 hours with 1.4 g (8.6 mmol) of carbonyldiimidazole in 30 ml of absolute tetrahydrofuran. . To the resulting imidazole was added ethyl ethyl 4- (2-aminoethyl) benzoate (1.64 g, 8.6 mmol) and the reaction mixture was heated at reflux for an additional 12 hours. The solvent was distilled off and the ester was purified by silica gel column chromatography (toluene / ethyl acetate 9: 1).

Yield: 2.7 g (68%). Melting point: below 20 'C.

Example 161

4- (2- (6-Chloro-2-dimethylamino-benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 6 - chloro - 2 - dimethylaminobenzoic acid and 4 - (2 - aminoethyl) benzoic acid methyl ester as in Example 91.

Yield: 25%. Melting point: 115-117 ° C.

Example 162

4- (2- (6-Chloro-2-dimethylaminobenzoyl)

(amino) ethyl ethyl benzoic acid

Prepared 4- (2- (6-chloro-2-dimethylamino)

by hydrolysis from the methyl ester of benzoylamino) ethyl] benzoic acid according to Example 92.

Yield: 35%. Mp 155-158 ° C.

J63. example

4- (2 - (- 2- (4-Benzyl-piperazinyl) -5-chloro)

- benzoylamino) ethyl] benzoic acid ethyl ester Prepared from 2- (4-benzylpiperazinyl) -5-chloro

benzoic acid and 4- (2 - aminoethyl) benzoic acid

ethyl ester according to Example 91.

Yield: 39%. Melting point: below 20'C.

Example 164

4- (2- (2-Piperazyl-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 4- (2- (2- (4-benzyl-piperazinyl) -5-chloro-benzoylamino) -ethyl] -benzoic acid ethyl ester by catalytic hydrogenation at room temperature under hydrogen pressure in the presence of palladium on carbon.

Yield: 60%. Melting point: below 20 ° C.

Example 166

-] 2- (5-Chloro-2- [decahydro-isoquinolin-2-yl] -benzoylamino) -ethyl] -benzoic acid hydrochloride

1.9 g (4.1 mmol) of ethyl 4- (2- (5-chloro-2- [decahydro-isoquinolin-2-yl] -benzoylamino) -ethyl] -benzoic acid in a 1: 1 mixture of dioxane and methanol. Dissolve in 40 ml, add 5 ml of 30% sodium hydroxide solution diluted with 20 ml of water and hydrolyze at room temperature After a few hours the organic solvents are distilled off, the mixture is extracted with chloroform and the pH of the aqueous phase is 4 to 5N and the acid which precipitates at this pH is extracted with chloroform, the extract is dried, the chloroform is distilled off, and the product is precipitated in acetone with isopropanolic hydrochloric acid.

Yield: 1.5 g (77%). Melting point: 226'C.

Example 167

4- (2- (5-Chloro-2- [decahydro-3-benzazepine)

- 3 - yl] - benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-chloro-2- (decahydro-3-benzazepin-3-yl) benzoic acid and 4- (2-aminoethyl)

benzoic acid ethyl ester according to Example 165.

Yield: 97%. Melting point: below 20 ° C.

Example 168

- [2- (5-Chloro-2- (decahydro-3-benzazepin-3-yl] -benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- (2- (5-chloro-2- (decahydro-3-benzazepin-3-yl) -benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 166.

Yield: 84%. Melting point: 216'C.

-30183 178

Example 175

4- / 2- (5-Cyano-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-cyano-2-octamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 30%. Melting point: 94 ° C.

Example 769

4- / 2- (5-Bromo-2-decahydro-3-benzazepine

- 3 - yl] - benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-bromo-2- (decahydro-3-benzazepin-3-yl) -benzoic acid and 4- (2-aminoethyl)

benzoic acid ethyl ester according to Example 165. Yield: 98%. Melting point: below 20 ° C.

Example 170

- (2- (5-Bromo-2- [decahydro-3-benzazepine

- 3 - yl] - benzoylamino) ethyl] benzoic acid hydrochloride

Prepared 4- (2- (5-bromo-2 - [decahydro-3)

from benzoazepin-3-yl] -benzoylamino) -ethyl] -benzoic acid ethyl ester according to Example 166.

Yield: 84%. Melting point: 216'C.

Example 171

4-) 2- (5-Chloro-2- [octahydro-isoindol-2-yl] -benzoylamino) -ethyl] -benzoic acid ethyl ester

- Chloro-2- (octahydro-isoindol-2-yl) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester prepared according to Example 165.

Yield: 72%. Melting point: below 20 ° C.

Example 172

- [2 - (5 - Chloro - 2 - / octahydro - isoindole - 2

- yl] - benzoyl - amino) - ethyl - benzoic acid hydrochloride

4- (2- (5-Chloro-2- [octahydro-isoindol-2-yl] -benzoylamino) -ethyl] -benzoic acid was prepared.

ethyl ester by alkaline hydrolysis according to Example 166.

Yield: 83%. Melting point: 214 ° C.

Example 173

- [2- (5-Bromo-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-bromo-2-octamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 84%. Melting point: below 20 ° C.

Example 174

- [2- (5-Bromo-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- (2- (5-bromo-2-octamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester by the basic hydrolysis according to Example 166.

Yield: 90%. Melting point: 164 ° C.

Example 176

4- / 2- (5-Cyano-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-cyano-2-octamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 166.

Yield: 87%. Melting point: 186'C.

Example 177

4- / 2- (2-Octamethyleneimino-5-nitro-benzoylamino) -ethyl] -benzoic acid, ethyl ester

Prepared from 2-octamethylene-imino-5-nitro-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 50%. Melting point: 6 ° C.

Example 178

4- / 2- (2-Octamethyleneimino-5-nitro-benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- (2- (2-octamethylene-imino-5-nitrobenzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 166.

Yield: 93%. Mp 148 ° C.

Example 179

4- / 2- (5-Amino-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid ethyl ester dihydrochloride

Prepared from 4- (2- (2-octamethylenimino-5-nitrobenzoylamino) ethyl] -benzoic acid ethyl ester in methanol solution in the presence of 10% palladium-on-carbon catalyst at room temperature under 5 bar hydrogen pressure.

Yield: 79%. Mp 162 ° C.

Example 180

4- / 2- (5-Amino-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- (2- (5-amino-2-octamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester hydrochloride by the basic hydrolysis according to Example 166.

Yield: 50%. Melting point: 130 'C.

-31183 178

Example 181

- [2- (2-Oklamelylene imino-5-methoxy benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 2-oclamethylenimino-5-methoxy-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 80%. Melting point: below 20 ° C.

Example 182

- [2- (2-Octamethyleneimino-5-methoxy-benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- [2- (2-octamethylene-imino-5-methoxy-benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 166.

Yield: 83%. Melting point: 216 'C.

Example 183

4- (2- (5-Ethoxy-2-octamethylene-imino-benzylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-ethoxy-2-octamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 66%. Melting point: below 20 'C.

Example 184

4- (2- (5-Ethoxy-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- (2- (5-ethoxy-2-octamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester by basic hydrolysis according to Example 166.

Yield: 98%. Melting point: 172 ° C.

Example 185

4- (2- (5-Isopropoxy-2-octamethylene-imino)

benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-isopropoxy-2-octamethylene-imino

benzoic acid and 4- (2 - aminoethyl) benzoic acid

ethyl ester according to Example 165.

Yield: 87%. Melting point: below 20 ° C.

Example 186

4- (2- (5-Isopropoxy-2-octamethylene-imino)

benzoyl - amino - diethyl} - benzoic acid hydrochloride

Prepared from 4- [2- (5-isopropoxy-2-octamethylene)

- iminobenzoylamino) ethyl] benzoic acid by ethyl hydrolysis according to Example 166.

Yield: 93%. Mp 152'C.

Example 187

4- (2- (5-Butyl (2) -oxy-2-octamethylene-iminobenzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-butyl (2) oxy-2-octamethylene iminobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 165.

Yield: 64%. Melting point: below 20 'C.

Example 188

- [2- (5-Butyl (2) -oxy-2-octamethylene-iminobenzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- (2- (5-butyl (2) -oxy-2-octamethylene-iminobenzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 166.

Yield: 88%. Melting point: 142 'C.

Example 189

4- (2- (5-Clem -2- (4-isopropyl-piperidino))

benzoylamino) ethyl] benzoic acid

Prepared from 5-chloro-2- (4-isopropyl-piperidino)

benzoic acid and 4- (2 - aminoethyl) benzoic acid

ethyl ester according to Example 165.

Yield: 72%. Melting point: below 20 'C.

Example 190

4- (2- (5-Chloro-2- [4-isopropyl-piperidino] -benzoylamino) -ethyl} -benzoic acid

Prepared from the ethyl ester of 4- (2- (5-chloro-2- (4-isopropyl-piperidino) -benzoylamino) -ethyl] -benzoic acid by the basic hydrolysis according to Example 166.

Yield: 75%. Melting point: 164'C.

Example 191

4- (2- (5-Chloro-2- [4-tert-butyl-piperidino] -benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2- (4-tert-butyl-piperidino) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 63%. Melting point: 103 'C.

Example 192

4- (2- (5-Chloro-2- [4-tert-butyl-piperidino] -benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2- [4-tert-butyl-piperidino] -benzoylamino) -ethyl] -benzoic acid ethyl ester according to Example 166.

Yield: 87%. Melting point: 160'C.

-32183 178

Example 193

- [2- (5-Chloro-2- [1,4-dioxa-8-aza-spiro [4,6-jundecan-8-yl] benzoylamino) ethyl]

benzoic acid dietary supplement

Prepared from 5-chloro-2- (1,4-dioxa-8-aza-spiro [4,6] undecan-8-yl) -benzoic acid and 4 - (2)

ethyl amino benzoate as in Example 165.

Yield: 43%. Melting point: below 20 'C.

Example 194

- [2- (5-Chloro-2- [1,4-dioxa-8-aza-spiro [4,6] undecan-8-yl] benzoylamino) ethyl]

- benzoic acid

Prepared from 4 - [2- (5-chloro-2- [1,4-dioxa-8-aza-spiro [4,6] undecan-8-yl] -benzoylamino)

ethyl ethyl benzoic acid by alkaline hydrolysis according to Example 166.

Yield: 71%. Melting point: 185 'C.

Example 199

- [2- (5-Amino-2,4-dipiperidino-benzoyl)

(amino) ethyl] benzoic acid ethyl ester

1.4 g (2.8 mmol) of 4- [2- (5-nitro-2,4-dipiperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester are dissolved in 100 mL of ethanol and treated with 10% palladium hydrogenation in the presence of carbon catalyst at a hydrogen pressure of 5 bar. The catalyst was filtered off and the solvent was evaporated. The product was crystallized from acetone to give 0.8 g (60%) of product. Melting point: 172 'C.

Example 200

- [2- (5-Amino-2,4-dipiperidino-benzoyl)

(amino) ethyl] benzoic acid hydrochloride

Prepared from 4- [2- (5-amino-2,4-dipiperidino)

from benzoylamino) ethyl] benzoic acid ethyl ester according to Example 166.

Yield: 95%. Melting point: 271 'C.

Example 195

- [2- (2-Diallylamino-5-chlorobenzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 2-diallylamino-5-chlorobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 165.

Yield: 48%. Melting point: below 20 ° C.

Example 196

- [2- (2-Diaryl-amino-5-chloro-benzoyl-amino) -ethyl] -benzoic acid

Prepared from 4- [2- (2-diallyl-amino-5-chloro-benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 166.

Yield: 75%. Melting point: 130 ° C.

Example 197

- [2- (5-Nitro-2,4-dipiperidino-benzoyl-amino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-nitro-2,4-dipiperidino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 40%. Melting point: below 20 'C.

Example 198

- [2- (5-Nitro-2,4-dipiperidino-benzoyl-amino) -ethyl] -benzoic acid.

Prepared from 4- [2- (5-nitro-2,4-dipiperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester by basic hydrolysis according to Example 166.

Yield: 95%. Mp 208 ° C.

Example 201

- [2 - (N - Adamantyl - (1) - N - methylamino)

Ethyl ester of 5 - chlorobenzoylamino) ethyl benzoic acid

Prepared from 2- (N-adamantyl (!) - N-methylamino) -5-chlorobenzoic acid and 4- (2-amino)

ethyl ethyl benzoate as in Example 165.

Yield: 0.85 g (34%). Melting point: 20 ° C, m.p.

Example 202

- [2- (2- [N-Adamantyl (1) -N-methylamino] -5-chlorobenzoylamino) ethyl] benzoic acid

Prepared from the ethyl 4- (2 -) - 2- (N-adamantyl (1) -N-methylamino) -5-chlorobenzoylamino] ethyl] benzoate by the basic hydrolysis according to Example 166.

Yield: 0.33 g (64%). Melting point: 207 'C.

Example 203

- [2- (5-Chloro-2- [1,2,3,6-tetrahydro-pyridyl] -benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2- (1,2,3,6-tetrahydro-pyridyl) -benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 4.7 g (88%). Melting point: below 20 'C.

-331

183,178

Example 204

4- (2- (5-Chloro-2- (1,2,3,6-tetrahydro-pyridyl] -benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2- [1,2,3,6-tetrahydro-pyridyl] -benzoylamino) -ethyl] -benzoic acid by ethyl hydrolysis according to Example 166.

Yield: 2.27 g (73.7%). Melting point:

181-182'C.

Example 205

4- (2- (5-Chloro-2- (N-isobutyl-N-propyl)

ethylamino - benzoyl - amino) - ethyl] - benzoic acid

Prepared from 5 - chloro - 2- (N - isobutyl - N - propyl)

- amino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 165.

Yield: 5.8 g (86.8%). Melting point: below 20 ° C.

Example 206

- (2 - (5 - Chloro - 2 - [N - isobutyl - N - propyl

- amino] - benzoyl - amino) - ethyl] - benzoic acid

4- (2- (5-Chloro-2- [N-isobutyl-N-propylamino] -benzoylamino) -ethyl] -benzoic acid was prepared.

- Of ethyl ester, in .66. For example, by alkaline hydrolysis as described in Example 3a.

Yield: 2.7 g (79%). Melting point: 128 'C.

Example 207

- (2- (2-N, N-Diethylamino-3-methyl-benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 2-N, N-diethylamino-3-methyl-benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester according to Example 165.

Yield: 57%. Melting point: below 20 ° C.

Example 208

- [2- (2-N, N-Diethylamino-3-methyl-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (2-N, N-diethylamino-3-methyl-benzoylamino) -ethyl] -benzoic acid methyl ester by alkaline saponification according to Example 166.

Yield: 63.1%. Melting point: 150-152 'C.

Example 209

4- (2- (5-Chloro-2- [4- (2-furoyl) piperazinyl] -benzoylamino) ethyl] benzoic acid ethyl ester

Prepared according to Example 165 from 5-chloro-2- (4- [2-furoyl] piperazine) 1) -benzoic acid and 4- (2-aminoethyl) -benzoic acid methyl ester.

Yield: 88.4%. Melting point: 93-95 ° C.

Example 210

- [2- (5-Chloro-2- (4- (2-furoyl) piperazinyl] benzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-chloro-2- (4- (2-furoyl) piperazinyl) -benzoylamino) ethyl] -benzoic acid methyl ester by alkaline saponification according to Example 166.

Yield: 26.4%. Melting point: 187-188 ° C.

Example 211

- [2- (5-Chloro-2- (N-methyl-N-benzylamino] -benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2- (N-methyl-N-benzylamino) benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 165.

Yield: 47%. M.p. 93-95'C.

Example 212

4- (2- (5-Chloro-2- (N-methyl-N-benzylamino] -benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (5-chloro-2- [N-methyl-N-benzylamino] -benzoylamino) -ethyl] -benzoic acid ethyl ester by alkaline saponification according to Example 166.

Yield: 64.2%. Melting point: 127-128 'C.

Example 213

4- (2- (2- (4-Ethoxycarbonyl-piperazinyl))

Ethyl ester of 5 - chloro - benzoylamino) ethyl] benzoic acid

Prepared from 2- (4-ethoxycarbonyl-piperazinyl)

From 5-chlorobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 165.

Yield: 71.2%. Melting point: below 20 'C.

Example 214

- [2- (2- [4-Ethoxycarbonyl-piperazinyl] -5-chloro-benzoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (2- (4-ethoxycarbonylpiperazinyl) -5-chlorobenzoylamino) ethyl] benzoic acid ethyl ester by alkaline saponification according to Example 166.

Yield: 93%. Melting point: 168-170 ° C.

Example 215

4- (2- (5-Ethyl-2-piperidinobenzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 6-ethyl-1- (5-bromo-pentyl) -4H-3,1-benzoxazine-2,4- (1H) -dione and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 217.

mining; 55.6%. Melting point: below 20 ° C.

-34 221. example

4- (2- (2-Piperidino-nicotinodamino) ethyl]

- benzoic acid

Prepared from 4- (2- (2-piperidino-nicotinoylamino) -ethyl] -benzoic acid ethyl ester by basic saponification according to Example 166.

Yield: 54.2%. Melting point: 153-155 'C.

183,178

Example 216

- [2- (5-Ethyl-2-piperidino-benzoyl-amino)

- ethyl] benzoic acid

4- (2- (5-Ethyl-2-piperidinobenzoyl) is obtained

by hydrolysis from ethyl ester of (amino) ethyl] benzoic acid according to Example 166.

Yield: 84.5%. Melting point: 177 ° C.

Example 217

- [2- (5-Methyl-2-piperidinobenzoylamino) ethyl] benzoic acid ethyl ester

10.6 g (32.5 mmol) of 1- (5-bromo-pentyl) -6-methyl-4H-3,1-benzoxazine-2,4- (1H) -dione (prepared from 1,5-dibromo-pentane and 6-methyl-4H

Of 3,1-benzoxazine-2,4 - (1H) -dione) in 100 ml of absolute dioxane 19.3 g (0.1 mol) of 4- (2-amino)

Ethyl benzoic acid ethyl ester and 13 g N - ethyl diisopropylamine are stirred at room temperature for 4 days. The reaction mixture was evaporated, water was added and the mixture was extracted with chloroform. The chloroform extract was dried and evaporated, and the residue was chromatographed on silica gel, eluting with 10: 1 toluene / ethyl acetate.

Yield: 6.85 g (53.5%). Melting point: below 20 'C.

Example 222

- [2- (2-Octamethylene-iminone-nicotinoylamino) -ethyl] -benzoic acid ethyl ester

Prepared according to Example 165 from 2-octamethylene iminonicotinic acid and 4- (2-aminoethyl) benzoic acid methyl ester.

Yield: 41%. Melting point: below 20'C.

Example 223

- [2- (2-Octamethylene-imino-nicotinoylamino) -ethyl] -benzoic acid

Prepared from 4- (2- (2-octamethylene-imino-nicotinoylamino) -ethyl] -benzoic acid methyl ester by alkaline saponification according to Example 166.

Yield: 63%. Melting point: 179-181 ° C.

Example 218

- [2- (5-Methyl-2-piperidinobenzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-methyl-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester by alkaline saponification according to Example 166.

Yield: 80%. Melting point: 199-200 ° C.

Example 224

- [2- (5-Chloro-2- [4-methyl-piperazinyl] -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (4-methylpiperazinyl) benzoic acid hydrochloride and 4- (2-aminoethyl) benzoic acid methyl ester according to Example 165.

Yield: 52%. Melting point: below 20'C.

Example 219

- [2- (5-Chloro-2- (4-p-chloro-phenyl-piperazinyl] -benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2- [4- (p-chlorophenyl) piperazinyl] benzoic acid and ethyl 4- (2-aminoethyl) benzoate as in Example 165.

Yield: 64.1%. Melting point: 153-155 'C.

Example 225

- [2- (5-Chloro-2-piperidino-benzoylamino) -2-methyl-propyl] -benzoic acid ethyl ester

Prepared from 5-chloro-2-piperidino-benzoic acid and 4- (2-amino-2-methyl-propyl) -benzoic acid ethyl ester hydrochloride (m.p. 199 'C) according to Example 165.

Yield: 51%. Melting point: below 20'C.

Example 220

- [2- (2-Piperidino-nicotinodamino) ethyl] benzoic acid ethyl ester

Prepared from 2-piperidino-nicotinic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 70.3%. Melting point: 56-58 ° C.

Example 226

- [2- (5-Chloro-2-piperidino-benzoylamino)

- 2 - methylpropyl] benzoic acid

4- (2- (5-chloro-2-piperidinobenzoyl) is obtained

ethylamino) -2 - methylpropyl] benzoic acid ethyl ester according to Example 166.

Yield: 62%. Melting point: 208 'C.

-351

183,178

Example 227

4- (2- (5-Chloro-2- [1,2,3,4,5,6,7,7,8-octahydro)

- isoquinolin-2-yl] -benzoylamino) ethyl] benzoic acid ethyl ester

Prepared from 5-chloro-2- (1,2,3,4,5,6,7,8-octahydro

- isoquinolin - 2 - yl) - benzoic acid and 4- (2 - amino

ethyl ethyl benzoate as in Example 165.

Yield: 58%. Melting point: below 20 ° C.

Example 228

4- [2- (5-Chloro-2 - [[2,3,4,5,6,7,8] octahydro)

- isoquinolin - 2 - yl] - benzoylamino) - ethyl] benzoic acid hydrochloride

Prepared from 4- (2- (5-chloro-2- (1,2,3,4,5,6,7,8-octahydro-isoquinolin-2-yl] -benzoylamino) -ethyl] -benzoic acid ethyl ester from by alkaline hydrolysis according to example.

Yield: 82%. Melting point: 220 ° C.

Example 229

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid methyl ester

Prepared from 5-chloro-2-octamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid methyl ester according to Example 165.

Yield: 83%. Melting point: below 20 ° C.

Example 230

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid, ethyl ester

Prepared from 4- (2- (5-chloro-2-octamethylene iminobenzoylamino) ethyl] benzoic acid and absolute ethanol with a stoichiometric amount of thionyl chloride.

mining; 86%. Melting point: below 20 ° C.

23). example

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid - eiclohexyl ester g (7 mmol) 4- (2- (5-chloro-2-octamethylene)

- iminobenzoylamino) ethyl] benzoic acid in 30 ml of absolute pyridine was converted to 1.2 g (7.4 mmol) of carbonyldiimidazole to imidazolide at room temperature. To the reaction mixture was added cyclohexanol (1.48 g, 14.8 mmol) and heated at reflux for 2-3 hours. The solvents are then distilled off and the crude product is purified by chromatography on a silica gel column with toluene / ethyl acetate as eluent.

Yield: 2.7 g (75%). Melting point: 88 'C.

Example 232

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

- (amino) - ethyl] - benzoic acid - terbutyl ester

4.3 g (0.01 mol) of 4- [2- (5-chloro-2-octamethylene)

Iminobenzoylamino) ethyl] benzoic acid was suspended in 150 ml of a mixture of acetic acid tert-butyl ester, 1.43 g (0.01 mol) of 70% perchloric acid and the mixture was stirred for 24 hours at room temperature. The reaction mixture was dissolved in chloroform (500 ml) and the chloroform solution was carefully extracted with water. The chloroform layer was dried over sodium sulfate and the chloroform was distilled off. The crude product is purified by chromatography on a silica gel column, eluting with a mixture of toluene and ethyl acetate.

Yield: 3 g (62%). Melting point: below 20 'C. Similarly as described in Examples 229-231, the following compounds were prepared:

4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid propyl ester;

Yield: 70%, m.p. 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid isopropyl ester;

Yield: 84%, m.p. 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid butyl ester;

yield: 90%, melting point: below 20 ° C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid isobutyl ester;

Yield: 74%, m.p .: 20 ° C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid hexyl ester;

yield: 63%, melting point: below 20 ° C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

- (amino) - ethyl] - benzoic acid - benzyl ester:

Yield: 83%, m.p .: 20 ° C.

Example 233

4- (2- (5-Chloro-2-s) would be lylene iminobenzoyl

(amino) ethyl] benzyl alcohol

4.57 g (0.01 mol) of 4- (2- (5-chloro-2-octamethylene)

- Iminobenzoylamino) ethyl] benzoic acid ethyl ester is dissolved in 100 ml of absolute ether, added to a suspension of 0.72 g (0.011 mol) of lithium aluminum hydride in 30 ml of absolute ether and the mixture is refluxed for 1 hour. heated. The reaction mixture was cooled and water (15 mL) was carefully added. The mixture is filtered, the ether phase is dried over sodium sulfate and the crude product is purified by chromatography on a silica gel column, eluting with a 1: 1 mixture of toluene and ethyl acetate.

Yield: 3.5 g (84%). Melting point: below 20 ”C.

Example 234

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

Amino - ethyl) - benzylmalonic acid - diethyl ester

2.58 g (5.5 mmol) of 4- [2- (5-chloro-2-octamethylene)

- iminobenzoylamino) ethyl] benzyl chloride hydrochloride (prepared as 2.3 g (5.5 mmol) 4- (2- (5

- chloro - 2 - octamethylene - imino - benzoyl - amino)

- ethyl] - benzyl alcohol! and thionyl chloride in chloroform) are dissolved in 25 ml of absolute ethanol and the

After evaporation, water is added and the mixture is extracted with ether. The aqueous phase is acidified. the precipitate formed is filtered off with suction and recrystallized from acetonitrile.

Yield: 0.96 g (24%). Melting point: 151 'C.

Solution 183 178 is added dropwise to a solution of 3.2 g (20 mmol) of diethyl malonic acid and 20 mmol of sodium ethylate in absolute ethanol. Reaction mixture A was heated at reflux for 4 hours, then concentrated, acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform extract was evaporated and the residue was purified by chromatography on a silica gel column, eluting with a 10: 1 mixture of toluene and ethyl acetate.

Yield: 1.7 g (60.7%). Melting point: 80-82'C.

Example 235 [2- (5-Chloro-2-octamethylene-iminobenzoylamino) -ethyl) -benzene

Prepared from 5-chloro-2-octamethylene-imino-benzoic acid and 2-phenylethylamine according to Example 165.

Yield: 69%. Melting point: 66 'C.

Example 236

- (2- (5-Chloro-2-piperidinobenzoylamino)

- ethyl) - acetophenone Aluminum chloride (15 mmol) in dichloroethane (10 mL) was stirred with acetyl chloride (0.6 g, 7.6 mmol) under cooling. After the addition was complete, 1 g (2.92 mmol) of 2- (5-chloro-2-piperidinobenzoylamino)

ethyl ethyl benzene was added and the mixture was stirred at 40-45 ° C for 3 hours. The mixture was evaporated and ice-cold dilute hydrochloric acid was added to the residue. The product was extracted with chloroform, the extract was dried over sodium sulfate, evaporated and the residue chromatographed on a silica gel column, eluting with 10: 1 chloroform: ethyl acetate.

Yield: 0.42 g (37.4%). M.p. 61-63'C.

Example 237 *

4- (2- (5-Chloro-2-octamethylene imino-benzoylamino) ethyl) -acetofchon hydrochloride

Prepared according to Example 236 from [2- (5-chloro-2-octamethylene-iminobenzoylamino) -ethyl] -benzene with acetyl chloride in the presence of aluminum chloride.

mining; 41%. Melting point: 160 ° C.

Example 238

4-) 2- (5-Chloro-2-piperidino-benzoylamino)

ethylphenylacetic acid

4.86 g (10 mmol) of 4- (2- (5-chloro-2-piperidino)

- benzoyl-amino) -ethyl] -enitol-lio-acetic acid -morlolide (m.p. 20 ° C, prepared 4- (2- (5)

- chloro-2-piperidino-benzoylamino) -ethyl] -acetophenone by Willgerodt's reaction with sulfur and morpholine) in 50 ml of ethanol, 2 g (50 mmol) of sodium hydroxide! Cook for 2 days. Then the mixture

Example 239

4-) 2- (5-Chloro-2-octamethylene-imino-benzoylamino) -ethyl] -benzaldehyde

0.35 g of finely powdered anhydrous sodium carbonate is suspended in 3.5 ml of ethylene glycol, and 0.35 g (0.59 mmol) of N ¹ -4- (2- (5-chloro) - is added under stirring in a 160-170 ° C bath. 2-Octamethylene-imino-benzoylamino) -ethyl] -benzoyl-N ² -tosyl-hydrazine (m.p. 153-158 ° C, prepared 4- (2- (5-chloro-2-octamethylene-imino-benzoyl)) (amino) ethyl] benzoic acid and tosylhydrazine (carbonyldiimidazole in tetrahydrofuran) After 1.5 minutes, when the gas evolution ceased, the bath was removed and a large amount of ice was added a few minutes later, and the mixture was extracted twice with ether, The combined extracts were dried, filtered and concentrated in vacuo to give a pale yellow resin oil which was purified by column chromatography on silica gel eluting with chloroform-acetone (20: 1).

Yield: 66%. Melting point: below 20 'C.

Mass Spec: Calculated:

m / e = 412/414 (1 Cl) Found: m / e = 412/414 (1 Cl).

The hydrochloride x 0.5 H ₂ O had a melting point of 156 ° C.

Example 240

4-) 2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl ethyl benzaldehyde

0.50 g (1.2 mmol) of 4- [2- (5-chloro-2-octamethylene)

Iminobenzoyl-amino) -ethyl] -benzyl alcohol (75 L in absolute acetone) was shaken with 7.5 g of active manganese dioxide for 2 hours at room temperature, then filtered through a plug of G4 glass and the filtrate was concentrated in vacuo. The brownish viscous oil thus obtained was purified by column chromatography (silica gel, 20: 1 chloroform: acetone).

Yield: 5%. Melting point: below 20 'C. Mass Spec: Calculated:

m / e = 412/414 (1 Cl) Found: m / e = 412/414 (1 Cl).

Example 241

4- (2- (5-Chloro-2-octamethylene-imino-benzoylamino) -ethyl] -benzaldehyde-diethyl acetate

0.23 g (0.56 mmol) of 4- (2- (5-chloro-2-octamethylene-iminobenzoylamino) -ethyl] -benzaldehyde, 0.20 mL (1.2 mmol) of triethyl ortho-acetic acid, A mixture of 0.02 g of ammonium chloride and 0.2 ml of anhydrous ethanol is heated for 30 minutes at 90 [deg.] C. The mixture is cooled and poured into 2N ammonium hydroxide.

-37'83,178 and extracted with ether. The ether extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on a silica gel column, eluting with a 10: 1 mixture of toluene-acetone.

Yield: 23%. Melting point: below 20'C. Mass spectrum: Calculated: m / e = 486/488 Found: m / e = 486/488.

Example 242

- [2- (5-Chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] cinnamic acid (2.4 mmol) 4- (2- (5-chloro-2-octamethylene)

- iminobenzoylamino) ethyl] benzaldchide and 1 g (10 mmol) of malonic acid in 10 ml of absolute pyridine were added 0.5 ml of piperidine and the reaction mixture was heated at 100 ° C for 1 hour. The mixture is then poured into a mixture of ice and dilute hydrochloric acid and the precipitate formed is suctioned off. The product is purified by chromatography on silica gel, eluting with a 1: 1 mixture of toluene and ethyl acetate.

Yield: 21%. Melting point: 90 'C.

Example 243

4- (2- (5-Chloro-2-piperidino-benzoylamino)

ethyl ethyl benzoyl acetic acid ethyl ester

Prepared by Friedel - Crafts glycation (2 - (5 - chloro

- 2 - piperidino - benzoylamino) - ethyl] -benzene with ethyl malonic acid as in Example 236.

Yield: 21%. Melting point: below 20 'C. Mass spectrum: Calculated:

m / e = 456/458 (Cl), found m / e = 456/458 (Cl).

Example 244

4- (2- (5-Chloro-2-octamethylene-imino-benzoylamino) -ethyl] -nylrobenzene

Prepared from 5-chloro-2-octamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -nitrobeuzole according to Example 165.

Yield: 85%. Melting point: 102 'C.

Example 245

4- (2- (5-Chloro-2-octamethylene-imino-benzoylamino) -ethyl] -aniline

Prepared from 4- (2- (5-chloro-2-octamethylene iminobenzoylamino) ethyl] nitrobenzene reduced in tin (II) chloride hydrochloride.

Yield: 74%. Melting point: 87'C.

Example 246

4- (2- (5-Chloro-2-octamethylene-imino-benzoylamino) -ethyl-toluene-hydrochloride

Prepared from 5-chloro-2-octamethylenimine imino 38 benzoic acid and 4- (2-aminoethyl) toluene according to Example 165.

Yield: 69%. Melting point: 167-171 ° C.

Example 247

4- (2- (5-Chloro-2-octamethylene-imino-benzoylamino) -ethyl] -chlorobenzene

Prepared from 5-chloro-2-octamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -chlorobenzene according to Example 165.

Yield: 66%. Melting point: 58 'C.

Example 248

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid nitrile

4.36 g (0.01 mol) of 4- (2- (5-chloro-2-octamethylene)

- iminobenzoylamino) ethyl] aniline is dissolved in 3.8 ml of concentrated hydrochloric acid, diluted with 28 ml of water and 0.76 g (0.011 mol) of sodium nitrite dissolved in 3 ml of water is added dropwise at 0 ° C. . The reaction mixture was stirred for a further 1/2 hour and then adjusted to pH 6 with sodium carbonate. This diazonium salt solution is added dropwise at 0'C to a freshly prepared solution of trisodium tetracyano-copper (I) complex. (This complex solution was prepared from 3.2 g (0.0128 mol) of copper sulfate pentahydral and 0.87 g of sodium chloride in 10 mL of water. The copper salt was dissolved in 0.66 g of sodium hydrogen sulfate dissolved in 5 mL of water. , Reduced with 44 g of sodium hydroxide to copper (1), washed with rcz (I) chloride and added to a solution of 1.7 g of sodium cyanide in 30 ml of water). After the evolution of nitrogen has ceased, the reaction mixture is heated at 70 ° C for 1 hour. The mixture was then cooled and extracted with chloroform at pH 8. The crude product from the chloroform extraction needle was purified by column chromatography on silica gel eluting with 8: 2 toluene / ethyl acetate.

Yield: 38%. Melting point: 102'C.

Example 249

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] - ortho - benzoic acid - ethyl ester 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

Equimolar amounts of nitrile and absolute ethanol in aminoethyl ethyl benzoate are saturated with hydrogen chloride in ether. The reaction mixture is allowed to stand at 4'C for 4 days, during which time the iminoether hydrochloride precipitates in partially oily, partly crystalline form. The solvent is decanted off, the product is washed with ether and excess ethanol is added at 4 'C and the reaction mixture is allowed to stand at this temperature for 2 days. The solvent was distilled off and the crude product was purified by silica gel column chromatography with toluene as eluent.

Yield: 30%. Melting point: below 20'C.

-381X3 178

Example 250

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid - morpholide g (4.7 mmol) 4- (2- (5-chloro-2-oclamclylene)

Iminobenzoylamino) ethyl] benzoic acid was dissolved in absolute pyridine (20 mL) and converted to quantitative imidazolide by adding 0.83 g (5.1 mmol) of carbonyldiimidazole at room temperature. To the reaction mixture was added morpholine (0.41 g) and the mixture was heated at reflux for 6 hours. The pyridine is then distilled off and the residue is purified by chromatography on a silica gel column, eluting with a 6: 4 mixture of toluene / ethyl acetate.

Yield: 1.8 g (76.5%). Melting point: below 20'C.

251. pE'DAY

4- (2- (5-Chloro-2-octane-ethylene-iminobenzoyl)

- amino) ethyl] benzoic acid piperidide g (4.7 mmol) 4- (2- (5-chloro-2-octamethylene)

Iminobenzoylamino) ethyl] benzoic acid is suspended in 30 ml of absolute toluene and converted to a salt with 0.65 ml of triethylamine. After cooling to -10 ° C, 0.5 g (4.7 mmol) of ethyl chloroformate is added and the mixture is stirred for another 30 minutes. For mixed anhydride. 0.4 g (4.7 mmol) of piperidine was added. After standing for 2 hours, the solvents were distilled off and the crude product was purified by silica gel column chromatography (ethyl acetate).

Yield: 2 g (86%). Melting point: below 20 'C. Similarly as described in Examples 250 and 251, the following compounds were prepared:

4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid amide;

Yield: 75%. Mp 122'C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid dipropylamide;

Yield: 75%, m.p .: 20 ° C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid diallylamide;

yield: 70%, melting point: below 20 'C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid thiomorpholides;

yield: 70%, melting point: below 20 'C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid - N - methyl piperazide;

Yield: 75%, m.p .: 20 ° C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid - N - ethyl - N - cyclohexyl

- amides;

yield: 58%, melting point: below 20'C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid isopropylamide;

yield: 54%, m.p. 171 'C; 4- (2- (5-chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid butylamide;

Yield: 53%, m.p. 163 ° C.

Example 252

A '- [1- (4-Ethoxycarbonyl-phenyl) -ethyl] - A ²

(5 - chloro - 2 - piperidinobenzoyl) hydrazine

2.4 g (10 mmol) of 5-chloro-2-piperidinobenzoic acid. In dry THF (15 mL), N, N-carbonyldiimidazole (1.62 g, 1 mmol) was added and the reaction mixture was stirred for 5 min at 20 ° C and 45 min at reflux. The solution is cooled and 2.08 g (10 mmol) of ethyl 4- (1-hydrazinoethyl) benzoic acid (prepared in the appropriate amount of 4- (1-hydrazino) are added at 20 ° C.

- ethyl) benzoic acid ethyl ester hydrochloride, m.p. 98-100 ° C and stoichiometric amounts of aqueous sodium hydroxide under ice-cooling, the product was extracted with chloroform, the chloroform extract dried and concentrated in vacuo to 9 ml. anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and partitioned between water and chloroform. The combined chloroform extracts were dried, filtered and concentrated in vacuo. The red-brown oily residue was purified by chromatography on a silica gel column (toluene / acetone 8: 1).

Yield: 41.9%. Melting point: below 20'C (pale yellow oil).

Mass spectrum: Calculated:

m / e = 429/431 (Cl) found m / e = 429/431 (Cl).

253. for example

The ¹ - (1- (4-ethoxy - carbonyl - phenyl) - ethyl] - ²

- (5-Chloro-2-dimethylaminobenzoyl) hydrazine Prepared from 5-chloro-2-dimethylaminobenzoic acid, carbonyldiimidazole and 4- (1-hydrazino)

ethyl ethyl benzoic acid in anhydrous telrahydrofuran according to Example 252.

Yield: 18%. Melting point: below 20'C. Mass spectrum: Calculated:

m / e = 389/391 (Cl) found: m / e = 389/391 (Cl).

Example 254

A ¹ - [l - (4 - Carboxyphenyl) ethyl] - A ² - (5

- chloro - 2 - piperidinobenzoyl) - hydrazine

1.8 g (4.2 mmol) of N ¹ - [1- (4-ethoxycarbonylphenyl) ethyl] - N ² - (5-chloro-2-piperidinobenzoyl)

Hydrazine and 0.20 g (5 mmol) of sodium hydroxide in a mixture of 8 ml of ethanol and 8 ml of water were stirred at 60 ° C for 5 hours. The ethanol is then distilled off in vacuo, the residue is adjusted to pH 6 with 2 π hydrochloric acid and extracted several times with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The solid evaporation residue was recrystallized from methanol.

Yield: 45.8%. Melting point: 212-215 ° C.

-39183 178. 1

Example 255; V '- (1- (4- Carboxy - phenyl) - ethyl] - Λ' ² - (5

- chloro - 2 - dimethylaminobenzoyl) hydrazine

Prepared from Ν '- [1- (4-ethoxycarbonylphenyl) ethyl] - N ² - (5-chloro-2-dimethylaminobenzoyl)

from hydrazine by saponification with sodium hydroxide according to Example 254.

Yield: 34.4%. Melting point: 210-212 ° C.

Example 256

4- (1- (5-Chloro-2-octamethylene-iminobenzoyl)

- amino oxy) ethyl] benzoic acid methyl ester g (7.1 mmol) 5 - chloro - 2 - octamethylene imino

Benzoic acid and 1.2 g (7.4 mmol) of carbonyldiimidazole in 10 ml of anhydrous pyridine are stirred at 20 ° C for 40 minutes. Then 1.4 g (7.2 mmol) of 4 was added to the mixture

- (1-Amino-oxy-ethyl) -benzoic acid methyl ester (freshly prepared according to Example 252, 4- (1-amino)

oxyethyl) benzoic acid methyl ester hydrochloride, m.p. 158-160 ° C), and the reaction mixture is stirred at 100 ° C overnight. The reaction mixture is then evaporated to dryness in vacuo and the residue is purified by chromatography on a silica gel column (toluene / ethyl acetate 9: 1).

Yield: 41%. Melting point: below 20 'C.

Example 257

- (5 - Chloro - 2 - octamethylene - iminobenzoyl

Amino - oxy - methyl) - benzoic acid methyl ester

Prepared from 5-chloro-2-octamethylene-imino benzoic acid, carbonyldiimidazole and 4- (amino)

- oxy - methyl) - benzoic acid - methyl ester! (freshly prepared from its hydrochloride, m.p. 252-255 ° C) in anhydrous pyridine according to Example 256.

Yield: 38%. Melting point: below 20 'C. Mass spectrum: Calculated:

m / e 444/446 (Cl) found m / e = 444/446 (Cl).

. Example 258

3- (1- (5-Chloro-2-dimethylamino-benzoylamino-oxy) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2-dimethylaminobenzoic acid, carbonyldiimidazole and 4- (1-aminooxyethyl) benzoic acid methyl ester according to Example 256, but the reaction was carried out in anhydrous tetrahydrofuran at 16 ° C. reaction time.

Yield: 59%. Melting point: below 20'C.

Example 259

4- (1- (5-Chloro-2- [cis-3,5-dimethyl-piperidino] -benzoylamino) -ethyl] -benzoic acid methyl ester

Prepared from 5-chloro-2- (cis-3,5-dimethyl-40-piperidino) -benzoic acid, carbonyldiimidazole and 4- (1-amino-oxy-ethyl) -benzoic acid methyl ester according to Example 256.

Yield: 85%. Melting point: below 20'C.

Example 260

4- (1- (5-Chloro-2-piperidino-benzoylamino-oxy) -ethyl] -benzoic acid methyl ester

Potassium salt of 5-chloro-2-piperidino benzhydroxamic acid (7.55 g, 25.8 mmol) (m.p. 153 DEG C.) and 6.30 g of 4- (1-bromoethyl) benzoesax 'methyl ester in 20 mL of dimethyl. -formamide was stirred at 20 ° C for 18 hours, then three times water was added and ether! extracted. The ether extract was dried, filtered and concentrated in vacuo. The evaporation residue was purified by column chromatography on silica gel, eluting with cyclohexane-ethyl acetate (1: 1).

Yield: 69.2%. Melting point: below 20 ° C.

Example 261

- (5 - Chloro - 2 - dimethylamino - benzoylamino

oxy - methyl) benzoic acid

To 4.8 g (19 mmol) of potassium salt of 5-chloro-2-dimethylamino benzhydroxamic acid (melting point 140 DEG C.) and 1.06 g (19 mmol) of potassium hydroxide in 50 ml of a 1: 1 mixture of ethanol-water. 4.2 g (19 mmol) of 4-bromomethylbenzoic acid are added and the mixture is refluxed for 6 hours. The reaction mixture is then concentrated in vacuo and the residue is dissolved in water by addition of potassium hydroxide solution. The mixture was extracted with ethyl acetate, the pH of the aqueous phase was adjusted to 7, and ethyl acetate was added. extract again. This ethyl acetate extract was dried, filtered and concentrated in vacuo. The residue was purified on a silica gel column, eluting twice with chloroform-methanol 9: 1 and 4: 1. The unitary fractions were combined, evaporated and the residue was partitioned between water and ethyl acetate. The ethyl acetate extract was concentrated in vacuo to give an almost colorless oil, which crystallized by trituration with ether.

Yield: 1.5%. Melting point · 160-16! 'C.

Example 262

4- (2- (5-Chloro-2-piperidinobenzoylamino)

(oxy) ethyl] benzoic acid

6.0 g (14.4 mmol) of 4- [2- (5-chloro-2-piperidino)

Benzoyl-amino-oxy) -ethyl] -benzoic acid methyl ester and 1.15 g (28.8 mmol) of sodium hydroxide in 100 ml of ethanol are heated at 50-60 ° C for 6 hours. The mixture was concentrated in vacuo and the residue partitioned between dilute hydrochloric acid and chloroform. The chloroform extract was dried, filtered and concentrated in vacuo. The residue was crystallized from chloroform-methanol by addition of petroleum ether.

Yield 44.8%. Melting point: 201-203 ° C.

-40i 83 178

Example 263

4- (1- (5-Chloro-2-dimethylaminobenzoyl)

Amino - oxy) ethyl] benzoic acid

Prepared 4- (1- (5-chloro-2-dimethylamino)

Benzoyl-amino-oxy) -ethyl] -benzoic acid, methylated with sodium hydroxide in ethanol-water mixture as in Example 252. The product was extracted with ethyl acetate and recrystallized from ethanol.

Yield: 65.7%. M.p. 202-205 ° C.

Example 264

- [1- (5-Chloro-2- (cis-3,5-dimethyl-piperidino) -benzoylamino-oxy) -ethyl] -benzoic acid

Prepared from 4 - [1- (5-chloro-2- (cis-3.5-dimethyl)

(piperidino) benzoylaminooxyloxyethyl] benzoic acid methyl ester with sodium hydroxide in ethanol-water mixture by saponification according to Example 252.

Yield: 63.8%. Mp 205-208 ° C.

Example 265

- (5 - Chloro - 2 - oclamethylene - iminobenzoyl

- aminooxymethyl) benzoic acid

Prepared from 4- (5-chloro-2-oclamethyleneimino)

by saponification from methyl benzoyl-amino-oxy-methyl) -benzoic acid with sodium hydroxide according to Example 252 in a mixture of ethanol and water.

Yield: 43.1%. Melting point: crystallized from ether: 135-138 ° C.

Example 266

4- (1- (5-Chloro-2-octamethylene) -mino-benzoyl

Amino - oxy) ethyl] benzoic acid

Prepared from 4- (1- (5-chloro-2-octamethylene imino-benzoylamino-oxy) -ethyl] -benzoic acid methyl ester by saponification with sodium hydroxide in ethanol-water mixture according to Example 252.

Yield: 69%. Melting point: 187-190 ° C.

Example 267

- (4- (2- [5-Chloro-2-piperidinobenzoyl)

- amino] - ethyl) - phenyl] - propionic acid ethyl ester

1.2 g (5 mmol) of 5-chloro-2-piperidinobenzoic acid, 1.5 g (5.8 mmol) of 3- [4- (2-aminoethyl) phenyl]

propionic acid, ethyl ester hydrochloride and triphenylphosphine (1.84 g, 7 mmol) in absolute acetonitrile (30 mL) and carbon tetrachloride (0.5 mL, 5 mmol) and triethyl (2.45 mL, 17.5 mmol) were added successively. once. The reaction mixture is stirred for 20 hours at room temperature, the precipitate is filtered off and the filtrate is evaporated. The residue was purified by chromatography on a silica gel column with 5: 1 loluene-ethyl acetate.

Yield: 1.2 g (54.5%). Melting point: below 20 ° C.

Example 268

- (4- (2- (5-Chloro-2-piperidinobenzoyl)

- amino] - ethyl) - fend] - propionic acid

Prepared from 3- (4- (2- (5-chloro-2-piperidino-benzoylamino) -ethyl) -phenyl] -propionic acid ethyl ester by the alkaline saponification according to Example 166.

Yield: 80%. Melting point: 139 'C.

Example 269/4 (2/5-Chloro-2-octylmethylene-imino

Benzoyl - amino] - ethyl) - fend] - Propionic acid

Prepared from 5-chloro-2-octamethylene-imino-benzoic acid and 3- [4- (2-amino-ethyl) -phenyl] -propionic acid ethyl ester hydrochloride according to Example 267.

Yield: 76%. Melting point: below 20 ° C.

Example 270

3- {4- (2- (5-Chloro-2-octamethylene-imino)

- benzoyl-amino] -ethyl) -phenyl] -propionic acid

Prepared from 3- (4- (2- [5-chloro-2-octamethylene)

- iminobenzoylamino] ethyl) phenyl] propionic acid

ethyl ester by alkaline saponification according to Example 166.

Yield: 79%. M.p. 92-94'C.

Example 271

- (2- (2-Piperidino-5-propyl-benzoyl (imino) -ethyl] -benzoic acid - ethyl ester

Prepared from 1- (5-bromo-pentyl) -6-propyl-4H-3,1-benzoxazine-2,4- (1H) -dione and 4- (2-aminoethyl) -benzoic acid ethyl ester, m.p. as in the example.

Yield: 41%. Melting point: below 20 ° C.

Example 272

4- (2- (5-Butyl-2-piperidino-benzoyl-amino) -ethyl] -benzoic acid ethyl ester

Made 6 - buty! From -1- (5-bromo-pentyl) -4H -3,1-benzoxazine-2,4- (1H) -dione and 4- (2-aminoethyl) -benzoic acid ethyl ester according to Example 217.

Yield: 59%. Melting point: below 20 ° C.

Example 273

4- (2- (4-Chloro-5-nitro-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 4-chloro-5-nitro-2-piperidino benzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester according to Example 165.

Yield: 20%. Melting point: below 20 ° C.

-41183 178

Example 274

4- (2- (5-Chloro-2-Okiamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid

0.45 g (1 mmol) of 4- (2- (5-chloro-2-octamethylene)

A mixture of iminobenzoylamino) ethyl] benzaldehyde hydrochloride, 5 ml of 0.5 N sodium hydroxide and 0.30 g (1.3 mmol) of silver oxide was heated on a steam bath for 45 minutes with vigorous stirring. The reaction mixture was cooled, acidified with 2N sulfuric acid and extracted with ether. The organic phase is dried, filtered and concentrated in vacuo. The residue was purified by chromatography on a silica gel column with chloroform-methanol (10: 1).

Yield: 34%. Melting point: 172 ° C.

Example 275

4- [2- (5-Chloro-2-octamethylene-iminobenzoyl)

- (amino) ethyl] benzoic acid, sodium salt g (11.7 mmol) 4- (2- (5-chloro-2-octamethylene)

iminobenzoylamino) ethyl] benzoic acid is dissolved in 20 ml of absolute tetrahydrofuran and 0.27 g (11.7 mmol) of sodium and 10 ml of ethanol are added; then the sodium salt of the product precipitates. To the mixture was added ether (80 ml), stirred for 1 hour, aspirated at 80 ° C and the product dried in an air circulation oven.

Yield: 4.5 g (85%). Melting point: 290 'C.

Example 276

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

- amino) ethyl] benzoic acid hydrochloride g (11.7 mmol) 4- (2- (5-chloro-2-octamethylene)

Iminobenzoylamino) ethyl] benzoic acid is dissolved in 150 ml of hot acetone and filtered. The hydrochloride of the product is selected with hydrochloric acid in isopropanol.

Yield: 5 g (92%). Melting point: 205 'C.

Example 279

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid ethyl ester

5.6 g (0.02 mol) of 5-chloro-2-octamethylene imino

2 g (0.02 mol) of triethylamine in 50 ml of absolute toluene are added to the benzoic acid and the mixture is converted to a mixed anhydride at -5 DEG C. with 2.2 g (0.02 mol) of ethyl chloro-formic acid. The reaction mixture was stirred for 0.5 h and then prepared from 4.59 g (0.02 mole) of ethyl 4- (2-aminoethyl) benzoic acid hydrochloride and an equivalent amount of 2 g (0.02 mole) of triethylamine. A solution of ethyl 4- (2-aminoethyl) -benzoic acid in 30 ml of chloroform is added. After stirring for 3 hours at room temperature, dilute hydrochloric acid was added, the organic layers were separated and dried over sodium sulfate. The solvents were distilled off and the residue was eluted on a silica gel column with toluene-ethyl acetate 1: 1 (9: 1) to afford the 4- (2-ethoxycarbonylamino-ethyl) benzoic acid ethyl ester as a by-product.

Yield: 1.6 g (18%). Melting point: below 20'C.

Example 280

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid

5.6 g (0.02 mol of 5-chloro-2-octamethylene imino)

2 g (0.02 mol) of triethylamine in 50 ml of absolute toluene are added to the benzoic acid and the mixture is converted to a mixed anhydride with 2.2 g (0.02 mol) of ethyl chloroformate at -5 ° C. After stirring for 0.5 hour, a solution of 3.3 g (0.02 mol) of 4- (2-aminoethyl) benzoic acid in 20 ml of 1N sodium hydroxide was added and the reaction mixture was stirred at room temperature for 4 hours. After adding 20 ml of water, the organic phase is separated off and extracted with chloroform, the aqueous phase is acidified to pH 5.5 with 1N hydrochloric acid, and the acid is precipitated and recrystallized from ethyl acetate.

Yield: 1.2 g (14%). Melting point: 172'C.

Example 277

4- (2- (5-Ethyl-2-octamethylene-imino-benzoyl)

(amino) ethyl] benzoic acid ethyl ester

Prepared from 5-ethyl-2-octamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester according to Example 165.

Yield: 78%. Melting point: below 20 'C.

Example 278

4- (2- (5-Ethyl-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid

4- (2- (5-ethyl-2-octamethylenimine imino) is prepared

from benzoylamino) ethyl] benzoic acid ethyl ester by alkaline saponification according to Example 166.

Yield: 85%. Melting point: 145'C.

Example 281

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid

8.87 g (12.6 mmol) of copper (II) - bis (5-chloro-2-octamethylene-iminobenzoate) -dihydrochloride complex (prepared from 5-amino-2-octamethylene-benzoic acid via the diazonium salt with rcz (!) Chloride, 177 DEG-178 DEG C.) Dissolve 25 ml of absolute pyridine and add 3 g (25.3 mmol) of thionyl chloride under ice-cooling dropwise, maintaining the temperature at 20-30. the mixture was stirred for 0.5 h and then 4.9 g (25.3 mmol) of 4 - (2

- aminoethyl) benzoic acid ethyl ester was added and the mixture was heated at 70'C for 3 hours. The pyridine is then distilled off and the residue is dissolved in a mixture of 50 ml of methanol and 50 ml of dioxane.

-42183 178

4.6 g of potassium hydroxide dissolved in 90 ml of water were added and the mixture was stirred at room temperature for 16 hours. The solvents were then distilled off, the residue was dissolved in water (140 mL), the pH of the solution was adjusted to 5.5, and the product precipitated, which was recrystallized from ethyl acetate.

Yield: 4.1 g (38%). Melting point: 172 'C.

Example 282

- [2- (5-Chloro-2-octyl-tamelylene-imino-benzoylamino) -ethyl] -benzoic acid - ethyl ester

10.5 g (15 mmol) of copper (II) - bis (5-chloro-2-octamethylene-iminobenzoate) -dihydrochloride complex (prepared from 5-amino-2-octamethylene-iminobenzoic acid via the diazonium salt with copper (I) chloride 177-178 ° C) Dissolve in 25 ml of absolute pyridine and add to the solution. 5.4 g (33 mmol) of carbonyldiimidazole are added and carbon dioxide is formed. After stirring for 0.5 h at room temperature, ethyl 4- (2-aminoethyl) benzoate (6.8 g, 35 mmol) in absolute pyridine (5 mL) was added and the mixture heated at 70 ° C for 3 h. The pyridine is then distilled off, the residue is dissolved in water, extracted with chloroform at pH 4 and the chloroform extract is dried over sodium sulfate. The extract was evaporated and the residue was purified by silica gel column chromatography (toluene / ethyl acetate).

Yield: 10 g (66%). Melting point: below 20'C.

Example 283

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid

8.4 g (0.02 mol) of 4- (2- (5-chloro-2-octamethylene)

- imino-benzoyl-amino) -ethyl] -chlorobenzene (m.p. 58 ° C) was dissolved in tetrahydrofuran (ml), cooled to -60 ° C and pre-cooled in nitrogen (18 ml, 0.04 mole) to 2.3 ml. a solution of n-butyllithium in hexane (molar) was added. After 15 minutes, the reaction mixture was maintained under nitrogen for about 15 minutes. Pour into 10 g of finely powdered carbon dioxide. The mixture was allowed to warm to room temperature, evaporated and the residue was dissolved in water. The pH was adjusted to 5.5 and the product was precipitated, recrystallized from ethyl acetate and then purified by chromatography.

Yield: 1 g (12%). Melting point: 172'C.

Example 284

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid

11.5 g (0.03 mol) of 2- (5-chloro-2-octamethylene)

- solution of imino-benzoyl-amino) -ethylbenzene in 50 ml of carbon disulphide at 0-5'C

Oxalyl chloride (7.6 g, 0.06 mol) was added dropwise followed by addition of aluminum chloride (8 g, 0.06 mol). The reaction mixture is stirred for 1 hour and then the same amounts of oxalyl chloride and aluminum chloride are added again. The reaction mixture was heated for 2 to 3 hours at 50 ° C, then cooled, ice-water and hydrochloric acid were added, and extracted with vascular chloroform. The chloroform extract was dried and evaporated, and the residue was recrystallized twice from ethyl acetate by addition of activated carbon.

Yield: 2.4 g (19%). Melting point: 172 'C.

Example 285

4- (2- (5-Chloro-2-piperidino-benzoylamino)

- ethyl] benzoic acid

To a solution of sodium hypobromyl (prepared from 4.5 ml of water in 0.92 g (23 mmol) of sodium hydroxide and 0.36 ml (7 mmol) of bromine under ice-cooling) with stirring for 15 minutes at 35-40 ° C 6 0.60 g (1.56 mmol) of 4- (2- (5

- chloro - 2 - piperidinobenzoylamino) ethyl] acetophenone is added dropwise. After allowing the reaction mixture to stand at 35-40 ° C for 40 minutes, aqueous sodium hydrogen sulfite solution and water were added and the mixture was concentrated in vacuo. The residue is dissolved in water, the solution is acidified with 2N hydrochloric acid under cooling and the precipitate precipitated is taken up in ether / ethyl steel. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to a nearly colorless solid residue (0.45 g) was recrystallized from hot acetone, filtered and dried at 110 "C / 3.4 · 10 ³ torr.

Yield: 0.06 g (10%). Melting point: 201-203 ° C.

Example 286

4- (2- (5-Chloro-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid

Prepared according to Example 285 using 4- (2- (5-chloro-2-octamethylene-iminobenzoylamino) -ethyl] -acetophenone bromide with sodium hypobromite.

Yield: 11%. Melting point: 171-172'C.

Example 287

4- (2- (5-Chloro-2-piperidinobenzoylamino)

ethyl] benzoic acid ethyl ester

0.82 g (0.002 mole) of 4- (2- (2-bromo-5-chloro-benzoylamino) -ethyl] -benzoic acid ethyl ester (m.p. 116-118 'C, prepared from 2-bromo-5).

of chlorobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester) with piperidine (0.85 g, 0.01 mol) and a latex copper powder was heated at 100 ° C for 1 hour with stirring. The reaction mixture was cooled, acidified with acetic acid and extracted three times with chloroform. The combined chloroform phases are dried over sodium sulfate, the solvent is distilled off and the residue is chromatographed on silica gel.

-43183 178 column with chloroform-ethyl steel (19: 1).

Yield: 0-19 g (48%).

Mass spectrum: Calculated:

m / e = 414/416 (Cl) found: m / e = 414/416 (Cl).

Example 288

- [2- (5-Chloro-2-piperidino-benzoylamino)

ethyl] benzoic acid ethyl ester

0.48 g (0.002 mol) of 5-chloro-2-piperidino-benzoic acid amide (m.p. 140-142 ° C, prepared from 5-chloro-2-piperidino-benzoic acid by reaction with carbonyldiimidazole and ammonia) 0.09 g (0.002) mole) in 55% sodium hydride in 5 ml of absolute toluene with stirring for 10 min. Heat at 60 ° C. After the evolution of hydrogen had ceased, the mixture was cooled to room temperature and added dropwise with 0.51 g (0.002 mol) of ethyl 4- (2-bromoethyl) -benzoic acid (M ⁺ = 256/258 m / e, 1 Br) to give 4 - (2) hydroxyethylbenzoic acid

ethyl ester (thionyl bromide) in 2 ml absolute toluene. The reaction mixture was heated at reflux for 6 hours, cooled, aqueous ethanol was added and the mixture was extracted several times with chloroform. The combined chloroform extracts were dried over sodium sulfate, the solvent was distilled off and the residue was purified on a silica gel column with chloroform / ethyl acetate (19: 1).

Yield: 0.2 g (25%).

Mass spectrum: Calculated:

m / e = 414/416 (Cl) found m / e = 414/416 (Cl).

Example 289

4- (2- (5-Chloro-2-octamethylene-iminobenzoyl)

(amino) ethyl] benzoic acid ethyl ester

8.2 g (0.02 mol) of 4- [2- (5-chloro-2-octamethylene)

- iminobenzoylamino) ethyl] benzoic acid nitrile (m.p. 102'C) was dissolved in ethanol (80 ml) and saturated with hydrogen chloride gas. After 24 hours, the reaction mixture was heated to 50 ° C for 1 hour and the solvents were distilled off. The residue was dissolved in ice-water, adjusted to pH 9, and extracted with chloroform. The organic phase is evaporated and the residue is purified by silica gel column chromatography.

Yield: 6.4 g (70%). Melting point: below 20 ° C.

Example 290

- [2- (5-Hydroxy-2-piperidinobenzoylamino) ethyl] benzoic acid ethyl ester

Prepared in analogy to Example 1 from 5-hydroxy-2-piperidinobenzoic acid and 4- (2-aminoethyl) benzoic acid ethyl ester. Yield 17%. 193 'C.

29 /. example

4 - (- (5-Hydroxy-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid ethyl ester

Prepared from 5-hydroxy-2-octamethylene-imino-benzoic acid and 4- (2-amino-ethyl) -benzoic acid ethyl ester in analogy to Example 1. Yield: 39%. 128 ° C.

Example 292

4- (2- (5-Hydroxy-2-piperidinobenzoylamino) ethyl] benzoic acid

Prepared from 4- (2- (5-hydroxy-2-piperidino-benzoylamino) -ethyl] -benzoic acid ethyl ester

In an analogous manner to Example 2. Yield: 72%. Mp 222-224 'C.

Example 293

- [2- (5-Hydroxy-2-octamethylene-imino-benzoylamino) -ethyl] -benzoic acid hydrochloride

Prepared from 4- (2- (5-hydroxy-2-octamethylene iminobenzoylamino) ethyl] benzoic acid ethyl ester in analogy to Example 2. Yield: 29%, m.p. 208-210 ° C.

The following examples illustrate the preparation of some pharmaceutical compositions.

Example 294

Tablets with 4 mg of 4- [2- (5-chloro-2- (3,5-dimethyl-piperidino) -benzoylamino) -ethyl] -benzoic acid

The composition contains:

active ingredient 5.0 mg corn starch 62.0 mg lactose 48.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearal 1.0 mg

120.0 mg

Production procedure:

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed and moistened with water. The wet mixture was passed through a 1.5 mm mesh sieve and ca. Dry at 45 ° C. The dry granulate is sieved through a 1.0 mm mesh sieve and mixed with magnesium stearate. The finished mixture is compressed into tablets using a tablet press with a diameter of 7 mm with a notch on the score. Each tablet weighs 120 mg.

-44 297. example

Dragees 5 mg of 4- / 2- (5-chloro-2-hexamethylene)

- iminobenzoylamino) ethyl] benzoic acid

composition

183,178

Example 295

Dragees containing 2.5 mg of 4- / 2- (5-chloro-2-octamethylene-iminobenzoylamino) -ethyl] -benzoic acid

Contents of dragee seed composition:

agent 2.5 mg potato starch 44.0 mg milk sugar 30.0 mg polyvinylpyrrolidone 3.0 mg magnesium stearate <3.5 ⁿⁱ S 80, Ö mg

Production procedure

The active ingredient, potato starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The wet mass is passed through a 1 mm mesh sieve, approx. Dried at 45 ⁰ C, and the granules were sieved through the mesh sieve. Magnesium stearate is mixed with the granulate and the mixture is pressed into a tablet machine with 6 mm diameter convex dragee cores. The dragee cores thus obtained are coated with a layer consisting essentially of sugar and talc in a known manner. The finished dragees are polished with wax. The weight of one dragee is 120 mg.

Example 296

Tablets containing 10 mg of 4- / 2- (5-chloro-2-hexamethylene-iminobenzoylamino) -ethyl] -benzoic acid

Composition tablet contents:

agent 10.9 mg milk sugar, powdered 70.0 mg cornstarch 31.0 mg polyvinylpyrrolidone 8.0 mg magnesium stearate 1.0 mg 120.0 mg

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

Production process

The mixture of the active ingredient, calcium phosphate and corn starch was moistened with a 15% aqueous solution of polyvinylpyrrolidone. The wet mass is passed through a 1 mm mesh sieve, dried at 45 ° C and then sieved through a sieve of the above size. To my granule is mixed with a certain amount of magnesium stearate and the dragee seeds are pressed out of the mixture. The weight of one dragee is 130 mg and the print head is 7 mm in diameter.

A sugar and talcum coat is applied to the dragee cores thus prepared in a known manner. The finished dragees are polished with wax. One d ^; azse weight 180 mg.

Example 298

Tablets containing 10 mg of 4- / 2- (5-chloro-2-piperidinobenzoylamino) ethyl] benzoic acid

composition

tablet contents: agent 10.0 milk sugar, powdered 70.0 cornstarch 31.0 polyvinylpyrrolidone 8.0 magnesium stearate 1.0 120.0

The preparation is the same as described in Example 294.

Production process

The mixture of active ingredient, lactose and corn starch is moistened with 20% aqueous polyvinylpyrrolidone solution. The wet mass

It is granulated through a 1.5 mm mesh sieve and dried at 45 ° C. The dried granulate was sieved through a 1 mm mesh sieve and homogenized by mixing with magnesium stearate. Each tablet weighs 120 mg. The nozzle is 7nm in diameter and is provided with a column groove.

-45183 178

Example 299

Dragees containing 5 mg of 4- (2- (5-chloro-2-piperidinobenzoylamino) ethyl] benzoic acid

Contents of dragee seed composition:

active ingredient 5.0 mg calcium phosphate, secondary 70.0 mg ¹ corn starch 50.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 1.0 mg

130.0 mg

The preparation procedure is the same as in Example 295.

Claims (27)

Patent claims A process for the preparation of a novel carboxylic acid amide of formula 1, wherein R is a hydrogen atom, a 4-position chlorine atom or a cyclic alkyleneimino group containing 4 to 7 carbon atoms in the ring, R, hydrogen, fluorine, chlorine or bromine, C 1-4 alkyl or C 1-6 alkoxy, phenyl; substituted C 1-3 alkoxy, hydroxy, nitro, amino, cyano or carboxyl, or alkanoylamino, alkoxycarbonyl or dialkylaminosulfonyl containing 1 to 3 carbon atoms in the alkyl moiety, R ₂ and R ₃ are each independently C 1 -C 7 alkyl, C 3 -C 5 alkenyl, C 4 -C 7 cycloalkyl, C 1 -C 3 alkyl substituted by phenyl, phenyl or adamanyl, or R ₂ and R 1 represent a non-branched alkyleneimino group containing from 4 to 6 carbon atoms in the ring form together with the nitrogen atom between them and having one or two C 1 -C 4 alkyl groups, a C 1 -C 3 alkoxy group, hydroxy, phenyl, carboxy; Is optionally substituted with an alkoxycarbonyl group containing from 2 to 4 carbon atoms and / or a methylene group of the aforementioned alkyleneimino ring is imino, optionally substituted with 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 4 carbon atoms in all, , substituted with halogenphenyl, benzyl, pyridyl or furoyl, substituted with oxygen or sulfur, substituted with carbonyl, sulfoxide, or sulfonyl, and saturated or partially unsaturated azabicycloalkyl having 7 to 10 carbon atoms in the 3- and 5-positions piperidino group substituted with three or four C 1-3 alkyl groups, containing 1,4-dioxa-S-aza containing 6 to 9 carbon atoms -spiroalkyl, pyrrolyl, tetrahydropyridyl, heptamethyleneimino, octamethylenimino, nonamethyleneimino, decamelylenimino, undecamethyleneimino or dodecamethyleneimino, R ^{4 is} hydrogen or C 1-3 alkyl, X is nilogen or -CH-, Y is oxygen, imino, or methylene optionally substituted with one or two C 1-3 alkyl groups, Z is hydrogen, halogen, nitro. amino, cyano, formyl, hydroxymethyl or carboxyethylene, optionally carboxyl esterified with C 1 -C 7 aliphatic alkanol, C 5 -C 7 cycloalkaryl or phenyl (C 1 -C 4) alkanol optionally with two or three alkoxy groups, a carboxyl or ethylenedioxy-substituted methyl group wherein the alkoxy groups are C 1 -C 3, optionally substituted by an alkoxycarbonyl group containing from 2 to 4 carbon atoms in total, an ethyl group substituted by one or two alkoxycarbonyl groups having from 2 to 4 carbon atoms, optionally 1- Carbamoyl mono- or disubstituted with C 6 alkyl, C 5-7 cycloalkyl and / or C 3-5 alkenyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkylpiperazinylcarbonyl, wherein the alkyl is 1-3 carbon atoms. carbon atoms, substituted and Z karboxilcsoportíal ethyl group, if R ₂ and R ₃ k combine with the nitrogen ztük Next is a cyclic alkylene-imino group, the above-described - as well as the above-mentioned compounds with inorganic or organic acids and - where Z comprises a carboxyl group or such a group - bearable formed with bases also physiologically salts thereof wherein a) an reactive derivative of an aminobenzoic acid of formula IV, wherein R, R 1, R ₂ , R-, and X are as defined herein, or, optionally, an amine of formula V, wherein R ₄ , Y and Z are as defined herein, or an aminobenzoic acid of formula IV is optionally reacted with an N-activated derivative of an amine of formula V when Z does not contain a carboxyl or amino group in the N-activated derivative of an amine of formula V, obsession b) for the preparation of compounds of formula I wherein R 1, except hydroxyl and amino, is X, -CH- and Y is optionally substituted with one or two C 1 -C 3 alkyl groups, R ₂ , R ₃ , and R _{4 are} compounds of formula VI, wherein R, R ₄ and Z are as defined above, R and Y are as defined above, and E is halogen, with an amine of formula VII wherein R ₂ and R ₃ are as defined herein, or (c) for the preparation of compounds of formula I wherein Z is carboxyl and Y is other than NH, X, R; R 1, R ₃ , R ₃ and R _{4 are} as defined in the disclosure. -46183 178 a compound of the general formula Vil - in which R, R 1, R ₂ , R ₃ , R ₄ and X are as defined above, Y is excepted for NH and can be converted to carboxyl by oxidation oxidized, or d) compounds of formula, wherein Z is carboxy, R, R _s, R _2, R _3, R _4, a compound IX of the formula stated above, X and Y - in which R, R "R ₂ , R ₃ , R ₄₁ X and Y are as defined herein and are hydrolyzed to B to form a carboxyl group, or e) for the preparation of compounds of formula I wherein R _{2 is C} 1 -C 7 alkyl, C 4 -C 7 cycloalkyl, phenyl-substituted C 1 -C 3 alkyl or C 3 -C 5 alkenyl, R _{3 is C} 1 -C 7 alkyl, C 1 -C 5 cycloalkyl, C 3 -C 5 alkenyl, C 1 -C 3 alkyl or adamantyl substituted with phenyl, or R ₂ and R _{3 taken} together with the nitrogen atom to which they are attached are C 4 -C 6 alkylenedimino ring, C 1 -C 4 alkyl-substituted piperidino; a piperidino group substituted with one C 1-3 alkyl group, and Y is a methylene group optionally substituted with one or two C 1-3 alkyl groups, R, R 1, R ₄ , X, Y and Z being as defined above, optionally in the reaction mixture; A compound of Formula X wherein R, R _t , R ₄ , X and Z are as defined herein R _{3 is} hydrogen or the same as R ₃ and Y is as defined above for a compound of formula XI in which R _{2 is the} same as R ₂ or R ₃ of the compound of formula 4 A -C 6 unsubstituted alkylene group, a C 1 -C 4 alkyl substituted n-pentylene group or a C 2 -C 4 alkyl substituted n-pentylene group, and G is a nucleophilic leaving group, preferably halogen or formaldehyde or in the presence of a reducing agent, or f) for the preparation of compounds of the formula I in which Y is NH or O, R, R 1, R ₂ , R ₃ , R ₄ , X and Za are compounds of the general formula XII - in which R, R, , R ₂ , R, and X are as defined above, and Y is as defined above - or an alkali metal salt thereof - or a phenyl derivative of formula XIII in which R ₄ and Z are as defined and L is a nucleophilic leaving group, preferably halogen. , obsession g) for the preparation of compounds of general formula I in which R 1, with the exception of hydroxy, carboxyl, amino or alkanoylamino, is represented by X, CH and Y is optionally substituted with one or two C 1 -C 3 alkyl groups. methylene, R, R ₂ , R ₄ and Z are salts of an amidyl of general formula XIV in which R, R ₂ and R ₃ are as defined herein and R is as defined above or an alkali metal salt of a compound of formula XV in which R ₄ and Z is as defined above, Y is as defined above, and M is a nucleophilic leaving group, preferably a halogen atom, or h) for the preparation of compounds of the formula I in which 1% hydrogen, fluorine, chlorine or bromine, C 1-4 alkyl or C 1-6 alkoxy, phenyl-substituted C 1-3 alkoxy, hydroxy, nitro- , carboxyl or alkanoylamino, X is CH, Y is optionally substituted with one or more C 1-3 alkyl, and Z is carboxyl, R ₂ , R ₃ and R _{4 are} compounds of formula XVI as hereinbefore defined. - where R, R ₂ , R ₃ and R ₄ are as defined herein and R and Y are as defined above - acylated with an oxalyl halide or phosgene in the presence of a Lewis acid, or i) for the preparation of compounds of the formula I in which R, hydrogen, fluorine, chlorine or bromine, C 1-4 -alkyl or C 1-6 -alkoxy, phenyl-substituted C 1-3 -alkoxy, nitro, carboxyl, or an alkanoylamino or alkoxycarbonyl group containing a C 1-3 alkyl moiety, X a CH group, Y optionally substituted by one or two C 1-3 alkyl groups, and Z a carboxyl group, R, R ₂ , R, and R ₄ a. reacting a compound of formula XVII, wherein R, R ₂ , R ₃ and R ₄ are as defined above, and R and Y are as defined above, optionally with hypohalite prepared in the reaction mixture, and optionally followed by the preparation of a compound of general formula I wherein Z is a carboxyl group by esterification or amidation of a corresponding compound of formula I to a carboxyl group esterified with C 1-7 aliphatic alkanol, C 5-7 cycloalkanol or phenyl (C 1 -C 4) alkanol, or optionally C 1-6 alkyl, C 5-7 cycloalkyl and / or 3- A carbamoyl group mono- or disubstituted with C 5 alkenyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N-alkylpiperazinylcarbonyl, and / or a compound of formula I wherein R, and / or Z is nitro, by reduction; to a corresponding compound of formula I wherein R and / or Z are amino groups and / or a prepared compound of formula I wherein R and / or Z is amino is converted to a corresponding compound of formula I via a suitable diazonium salt R, hydroxy or cyano, fluoro, a chlorine or bromine atom and / or a Z chlorine or bromine atom or a cyano group. in addition, optionally, a compound of formula I, wherein R, is a hydroxy group, is prepared by alkylation of a corresponding compound of formula I -471 183,178 to a needle compound wherein R 1 is C 1 -C 6 alkoxy or phenyl-substituted C 1 -C 3 alkoxy and / or a prepared compound of Formula 1 wherein R 1 is amino is acylated to form a compound of Formula 1 in the formula R; an alkanoylamino group containing 1 to 3 carbon atoms in the azalkanoyl moiety, and / or a prepared compound of formula I wherein R 1 is an alkoxycarbonyl group and / or R ₂ and R ₃ are C 4 -C 6 alkylene substituted with an alkoxycarbonyl group; -mino, where the alkoxy moiety contains 1 to 3 carbon atoms, is converted by hydrolysis to the corresponding compound of formula 1 wherein R, carboxyl and / or R ₂ and R ₃ together with the nitrogen atom between them represent a carboxyl substituted alkylene mino; the imino ring has 4 to 6 carbon atoms and / or a compound of formula I wherein R ₂ and R ₃ together with the nitrogen atom between them are N-benzylpiperazinyl is converted to the corresponding compound of formula I wherein R ₂ and R ₃ together with the nitrogen atom between them represent a piperazinyl group and / or a compound of formula I wherein R _{1 is a} chlorine or bromine atom can be dehalogenated to give the corresponding compound of formula I wherein R, hydrogen and / or a compound of Formula I wherein Z is an optionally esterified carboxy group, by reduction with a metal hydride to give the corresponding compound of Formula I wherein Z is a hydroxymethyl group, and / or a compound of Formula I, Z is a hydroxymethyl group, by oxidation to a corresponding compound of formula Ϊ in which Z is a formyl group and / or a compound of formula I in which Z is a hydroxymethyl group by halogenation followed by reaction with a malonic acid ester to give the corresponding compound of formula I wherein Z is substituted by two alkoxycarbonyl groups and / or a prepared compound of general formula 1 wherein Z is formyl is acylated to the corresponding compound of formula Z wherein Z is dialkoxymethyl and / or a prepared compound of formula 1, wherein Z is formyl, by condensation and optionally subsequent hydrolysis to the corresponding compound of formula 1 wherein Z is carboxy or alkoxy arylene substituted arylene; and / or a compound of formula I wherein Z is hydrogen. Friedel Crafts are used to acylate to give the corresponding compound of formula I wherein Z is an optionally substituted acetyl carbonyl group and / or a compound of formula I wherein Z is nitrile is converted to the corresponding compound of formula I via alcohol wherein Z is a trialkoxymethyl group and / or a compound of formula I wherein R 1 is cyano is converted by hydrolysis or alcoholysis to the corresponding compound of formula I wherein R 1 is alkoxycarbonyl and / or a prepared 1 Compounds of formula (II) wherein Z is acetyl are heated with an amine and sulfur and then in the presence of an inorganic base to give the corresponding compound of formula (I) wherein Z is a carboxy a methyl group and / or a compound of formula I where Z is a carboxyl group converted to a sulfonic acid hydrazide and then disproportionate to the corresponding compound of formula I wherein Z is formyl and / or a compound of formula I wherein R is _{t is} hydrogen, fluoro, chloro or bromo, C 1-4 alkyl or C 1-6 alkoxy, or phenyl substituted C 1-3 alkoxy, X CH, Y optionally substituted with one or two C 1-3 alkyl groups, and, via a suitable organic metal compound of a chlorine or bromine atom Z, is converted with carbon dioxide to a corresponding compound of formula I wherein Z is a carboxyl group and / or a base of a compound of formula I prepared with an inorganic or organic acid or isso is also converted to a physiologically tolerable salt. (Priority: July 11, 1980) 2. A process for the preparation of a new carboxylic acid amide of the formula R in which R _{4 is a} hydrogen atom or a C 1-3 alkyl group, R 1, hydrogen, fluorine, chlorine or bromine, nitro, amino, C 1 -C 3 alkanoylamino, C 1 -C 6 alkoxy, cyano, carboxyl, C 1 -C 3 alkoxycarbonyl or alkyl; dialkylamino-sulphonyl, R _a and R _a are independently C 1-7 alkyl or C 4-7 cycloalkyl, or R ₁ and R _3a , together with the nitrogen atom between them, represent a C 4 -C 6 alkyleneimino group optionally substituted with one or two C 1 -C 3 alkyl groups, a C 1 -C 3 alkoxy group, hydroxy, phenyl; , a carboxyl group or an alkoxycarbonyl group containing from 2 to 4 carbon atoms in total -48-183 178 is substituted or is substituted by a methylene group of the alkyleneimino ring with a total of 3 or 4 carbon atoms, a cyclic ketal group, an oxygen or sulfur atom, a sulfoxide group or an imino group substituted by a phenyl or pyridyl group, and pyrrolyl, means and For the preparation of their physiologically tolerable salts with carboxyl or alkoxycarbonyl groups having 2 to 5 carbon atoms in total, and also with inorganic or organic acids and, if Z, carboxyl groups, with bases, a) an aminobenzoic acid of formula IVa, wherein R _1a , R ₁ and R _{1a are} as defined herein, or optionally a reactive derivative of the reaction mixture with a phenylalkylamine of formula Va, wherein R ₄ and Z are _{as defined in} the scope - or, if an aminobenzoic acid of formula IVa is used and Z _is a alkoxycarbonyl group having 2 to 5 carbon atoms in total - optionally reacting with a reactive derivative in the reaction mixture, or b) a Γ compounds of formula wherein R _Ia, nitro, R _2a, R _a, R ₄ and Z _are as defined above, with a Via nitrobenzamide formula in which R ₄ and Z ₃ have the same meanings and halogen E, with an amine of formula VIIa, in which R ₁ and R _3a are as defined herein, or c) for the preparation of compounds of the formula, in which Z is _a carboxyl group - R 1, R _2i, R _3a and R a is a compound represented by the general formula V a - wherein R ₄ and A according to claim 1 defined and R _Ia, R ₂ ,, and _R3a is stated above - is oxidized, or d) for the preparation of compounds of formula Γ wherein Z, carboxyl, R _b "R _2a , and Z are compounds of formula IXa as defined herein, wherein R ₄ and B are as defined in claim 1, and R _Ia , R ₂₁ and R _a are as defined in the scope of this invention, or e) for the preparation of compounds of the formula, in which R, _a and Ar are independently C 1 -C 7 alkyl or C 4 -C 7 cycloalkyl, or R _2a and R _3n together with the nilogen atom between them are C 4 -C 6 alkyleneimino; A piperidino group substituted with C 3 alkyl; or a 3- and 5-positions is substituted with a C1-3 alkyl piperidino, R _Ia, R ₄ and Z are as defined above, with a Xa meant any pharmaceutically acceptable general formula: - wherein R ₄ I, is as defined Claim _Rla and Z _a has the same meaning as defined above and R _3a , hydrogen or R _{3a has} the same meaning as a compound of formula Xla, in which R _2a , has the same meaning as R _2a , or R _1a , is a C4-C6 non-branched alkylene group, a C1-C3 alkyl substituted n-pentylene group or a 2- and 4-position C1-C3 alkyl substituted n-pentyl group, and G is a nucleophilic leaving group, preferably halogen. and, if desired, subsequently producing a compound of formula Γ wherein Z is a carboxyl group. rt, by esterification to a corresponding compound of formula Γ in which Z _{B is} an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, and / or by reduction of a prepared compound of formula R in which R _{1a is} nitro to the corresponding compound of formula,, wherein R _{1a is} amino and / or a compound of formula Γ in which R _1a is prepared is converted, via a suitable diazonium salt, to the corresponding compound of formula 1 'wherein R _{1a is} cyano, fluoro, chloro or bromo; and / or a compound of the formula, in which R _{1a is} an amino group is converted to the corresponding compound of the formula R in which R _{1a is} an alkanoylamino group containing 1 to 3 carbon atoms in the alkoxyl moiety and / or therein, a compound of formula 1 'wherein R _{1a is a} cyano group, is converted by alcoholysis to a corresponding compound of formula R wherein R _{t1 is} an alkoxycarbonyl group containing from 1 to 3 carbon atoms in the alkoxy moiety and / or a compound of formula elő. wherein _Rla alkoxycarbonyl and / or R. and R, together _with the nitrogen atom between them substituted alkoxycarbonyl, alkylene containing 4-6 carbon atoms in the iminocsoportol nlkilén-iminogyürűben means, wherein the alkoxy part has from 1 to 3 carbon atoms, by hydrolysis to a corresponding compound of formula Γ in which R _{1a is a} carboxyl group and / or R _a and R a., together with the nitrogen atom between them, represents an alkyleneimino group substituted with a carboxyl group, wherein the imino ring has 4 to 6 carbon atoms; The compound of formula Γ is converted into a physiologically acceptable salt with an inorganic or organic acid or, if Z is _a carboxylic base. (Priority: July 13, 1979) 3. Procedure is. I new carboxylic acid amides of general formula: - wherein R _{| h} for hydrogen, chlorine or bromine, C 1-6 -alkoxy, benzyloxy, amino nilrovagy, R _b and R _b are independently C 1 -C 4 alkyl, C 4 -C 7 cycloalkyl or phenyl, or R _b and R _b together with the ring, C5-12 alkylene-imino group or the piperidino nitrogen in between them. in which one -491 183,178 methylene groups are replaced by methylmethylene, methoxyethylethylene, carbonyl, irnino or benzylimino groups, the piperidino group substituted at the 3- and 5-positions by a C1-C3 alkyl group, the 4-position melylene group being optionally oxygenated. or a sulfur atom, a sulfoxide or a sulfone group, a piperidino group substituted in the 3- and 5-positions with a total of three or four C 1-3 alkyl groups, a 1,1-dioxothiomorpholino or a C 7-9 azabicycloalkyl group, Y _{b is} methylene optionally substituted with C 1-3 alkyl, and Z _{b is a} carboxyl group or an alkoxycarbonyl group containing 2 to 5 carbon atoms in total - and with inorganic or organic acids or - if Z _{b is a} carboxyl group - for the preparation of their physiologically tolerable salts with bases, a) an aminobenzoic acid of formula IVb - in which R _b, R _2b and R _1b is as stated _- optionally a reactive derivative produced in the reaction mixture a Vb phenyl alkyl amine of the general formula: - wherein Z _b and Y _b are as defined in Claim - or, where a V _b phenyl alkylamine having the general formula optionally reacted formed in the reaction mixture of N-activated derivative thereof, if used as a IVb amino acid of formula, and when the N-aktivált'Vb phenyl alkyl amines of the formula Z _{b =} 2 Alkoxycarbonyl containing -5 carbon atoms, or b) for the preparation of compounds of formula I wherein R, _{h is a} nitro group at the 3- or 5-position, R, _b , R-, _b , Y _b and Z _h are nylobenzamides of formula VIb as defined herein. wherein Z _b and Y _b are as defined above and E is reacted with an amine of formula Vllb in which R _2b and R _{1b are} as defined herein, or c) for the preparation of a compound of formula I wherein Z _{b is a} carboxyl group, R, _b , R, _b , R, _b and Y _{b are} as defined in the general formula VIIb, wherein A is as defined in claim 1 , R, _b , R _2b , R, _b and Y _b are as defined herein, or d) for the preparation of compounds of formula 1 wherein Z _{b is a} carboxyl group, hydrolyzing a compound of formula IXb wherein B is as defined in claim 1, R _1b , R, _b , R _1b and Y _b are as defined in the scope of this invention. , obsession e) for the preparation of compounds of formula I wherein R _2b and R _b are independently C 1 -C 4 alkyl, C 4 -C 7 cycloalkyl or phenyl, or R _1b and R _b in the ring together with the nitrogen atom to which they are attached; A C 6 alkyleneimino group, a methylpiperidino group or a 3 and a 5-position represents two substituted three or four C 1-3 alkyl piperidino, R _b, Y _b and Z _b are as defined above, with a Xb compound of the general formula: - wherein R _b, Y _b and Z _b have the same meanings of circle, and R _1b, a hydrogen atom or identical R _Jb above reports - a XIb compound of the formula wherein R _b, identical _R2b fixed circular serine ti reports, or Xb is a compound of formula R _b, groups of 5-6 or a methyl-substituted n-pentylene group or two, three or four (1-3C) alkyl substituted n-pentylene groups at the 2- and 4-position and G is a nucleophilic leaving group, preferably a halogen substituent; followed by esterification of a compound of formula I wherein Z _{b is a} carboxyl group converting the corresponding compound of formula Γ wherein Z _{b is} an alkoxycarbonyl group having 2 to 5 carbon atoms in total, and / or reducing the compound of formula I wherein R _{ih is} nitro to a corresponding compound of formula I in which R _{lb is} an amino group, and / or a compound of formula I, wherein R ', amino is converted via an appropriate diazonium salt to a corresponding compound of formula I wherein R _{1b is} chloro, bromo or hydroxy, and optionally so prepared a compound of formula I, wherein R _lb hydroxyl radical, alkylation or benzylation converted to a corresponding compound of formula I, wherein R _Ib benziloxivagv l-4 carbon atoms, and / or I prepared á the compound of the general formula wherein R, _b and R, _b together with the nitrogen atom between them is N-benzylpiperazinyl is converted to the corresponding compound of formula I wherein R _2b and R, _b are pipcrazinyl together with the nitrogen atom thereof means and / or a compound of formula I is produced, wherein R _Ib is chlorine or bromine, dehalogenation converted to a corresponding compound of formula f, wherein R _b is hydrogen, and / or an obtained compound of the general formula with inorganic or organic acid, or, if Z _{b is a} carboxyl group, to a physiologically tolerable salt. (Priority: December 7, 1979) 4. A process for preparing the novel carboxylic acid amides of formula I 'wherein R ₄ , X, Y and Z are as defined in claim 1. R _{c is} hydrogen, 4-chloro or piperidino, R _{k is} hydrogen, halogen, C 1-4 alkyl or C 1-6 alkoxy, hydroxy, amino, niuro or cyano. -50183 178 R11 _; in each case C 1-3 -alkyl or C-3-5-alkenyl substituted with phenyl; R _{c is C} 1-7 alkyl, C 3-5 alkenyl or adamantyl, or R _jc and R _t together with the nitrogen atom to which they are attached form a C 4-12 alkyleneimino group, a C 1-4 alkyl substituted piperidino group, a 3- and 5-yl group each substituted with a C 1-3 alkyl group, a 4- piperazinyl substituted with C 1-3 alkyl, halophenyl, alkoxycarbonyl or furoyl having from 2 to 4 carbon atoms in general, tetrahydropyridyl, octahydroisoquinolyl, decahydroisoquinolyl, decahydroindole For the preparation of their physiologically tolerable salts with 10 carbon atoms, 4-dioxa-8-aza-spiro-alkyl and also with inorganic or organic acids and, if Z is carboxylic, bases, a) an aminobenzoic acid of formula IVc in which X is as defined in claim 1 and R _c , R _1c , R _2c and R _c are a reactive derivative thereof, or optionally prepared in the reaction mixture with an amine of formula Ve, wherein R ₄ , Y and Z are either reacted with an N-activated derivative of an amine of formula I - or an N-activated derivative of a reaction mixture of Ve, when an aminobenzoic acid of formula IVc is used and when the amine of formula Ve is N- in an activated derivative thereof, Z is free of carboxyl or amino, or c) for the preparation of compounds of formula 1 'wherein Z is a carboxyl group and Y is other than NH, X, R _c , R _1c , R _2c , R _3c and R _{4 are} as defined in the foregoing compounds of formula VIIIc In which R ₄ , A and X are as defined in claim 1, R _c , R 1 _c , R _2c , R _3c and Y are as defined in the scope, or d) for the preparation of compounds of formula I 'wherein Z is a carboxyl group, X, Y, RC R _2c , R _3c and R _{4 are} as defined above, a compound of formula IXc - wherein R ₄ , Β, X and Y are as defined in claim 1 and R _c , R _tc , R _2c and R _3c are as defined in the scope - hydrolyzed, or e) for the preparation of compounds of formula I 'in which R _{2c is C} 1 -C 3 alkyl or C 3 -C 5 alkenyl optionally substituted by phenyl, R 1, _C 1 -C 7 alkyl, C 3 -C 5 alkenyl or adamantyl, or R _c and R _k together with the nitrogen atom between them represent a C 4 -C 6 alkyleneimino ring, a C 1 -C 4 alkyl-substituted piperidino group, or a C 1 -C 3 alkyl substituted piperidino group at the 3 and 5-positions; Y is a methylene group optionally substituted with one or two C 1 -C 3 alkyl groups, a compound of formula Xc optionally formed in the reaction mixture, wherein R ₄ , X and Z are as defined in claim 1, R _c , R, _c , R _{2 <} . R _k and Y is as defined in the scope and R _{k is} hydrogen or the same as R _k - a compound of formula Xlc in which G is as defined in claim I and R, _{c are the} same as R, _c , or Xc is a non-branched alkylene group having from 4 to 6 carbon atoms, a n-pentylene chain substituted with C 1 -C 4 alkyl, or a n-pentylene group substituted with 2 to 4 carbon atoms at the 2- and 4-position; react, or f) for the preparation of compounds of the formula Γ 'in which Y is NH or O, R _c , R _Ic , R _2c , R _k ' P, ₄ , X and Z are compounds of formula XI 1c, wherein X is as defined in claim 1, R _c . R, _c , R _2c , R _3c and Y are as defined herein, or an alkali metal salt thereof, is reacted with a phenyl derivative of formula XIIIc, wherein R ₄ , L and Z are as defined in claim I, and optionally thereafter, A compound of formula I 'wherein Z is a carboxyl group is converted by esterification or amidation to a corresponding compound of formula I' wherein Z is C 1-7 aliphatic alkanol, C 5-7 cycloalkanol or I'enyl- (C 1-4) alkyl. alkanol-esterified carboxyl group or optionally mono- or disubstituted with C 1 -C 6 alkyl, C 5 -C 7 cycloalkyl and / or C 3 -C 5 alkenyl group. alkylpiperazinylcarbonyl, and / or a compound of formula 1 'having the following formula: R _k and / or Z is nitro, by reduction to a corresponding compound of formula 1 'having R _1c and / or Z and / or a prepared compound of formula 1' wherein R _1c and / or Z is amino, via a suitable diazonium salt to form a corresponding compound of formula I 'wherein R _{1c is} hydroxy or cyano, chlorine or bromine and / or Z is chloro or cyano, and optionally a compound of formula Γ' so prepared, wherein R _The hydroxyl group is alkylated to give the corresponding compound of formula Γ ', wherein R _{1c is a C} 1-6 alkoxy group, and / or a compound of formula I', wherein Z is a hydroxymethyl group, is oxidized to the corresponding compound of formula 1 ' with a k pletében Z is formyl, and / or a generated I 'compound of formula 51 -51 183 178 wherein Z is hydroxymethyl, haíogénezéssel and subsequently converted to a compound of formula in a reaction carried out malonsavészterrel ^'one sub appropriate I' wherein substituted Z two-alkoxycarbonyl-ethyl group, and / or a generated I 'compound wherein Z is a formyl group, by acetalization to a corresponding compound of formula I 'wherein Z is a dialkoxymethyl group and / or a compound of formula Γ' wherein Z is a formyl group, by condensation and optionally followed by hydrolysis to a corresponding I '. is converted into a compound of the formula wherein Z is a ethylene group substituted by a carboxy or alkoxycarbonyl group and / or a prepared compound of formula 1 'wherein Z is a hydrogen atom by FriedelCrafts acylation. to a corresponding compound of formula I 'wherein Z is an acetyl group optionally substituted by an alkoxycarbonyl group and / or a prepared compound of formula I' wherein Z is a nitrile group by alcoholysis to a corresponding compound of formula 1 ' Z is a trialkoxymethyl group and / or a compound of the formula Γ in which Z is a trialkoxymethyl group is hydrolyzed to the corresponding compound of formula I 'in which Z is an alkoxycarbonyl group and / or a compound of the formula amelynek Acetyl group Z, when heated with an amine and sulfur and then in the presence of an inorganic base, is converted to the corresponding compound of formula 1 'wherein Z is a carboxymethyl group and / or A compound of formula 1 'wherein Z is a carboxyl group converted to a sulfonic acid hydrazide and then disproportionate to a corresponding compound of formula I' wherein Z is a formyl group and / or a prepared compound of formula V with an inorganic or organic acid or carboxylic acid - converted to a physiologically tolerable salt with a base (Priority: April 30, 1980) 5. Process for process a) according to any one of claims 1 to 3, characterized in that the reaction is carried out in the presence of an acid activating agent or dehydrating agent, optionally in the presence of an inorganic or tertiary organic base and in a solvent. (Priority: July 1980) 6. A method of carrying out process a) according to any one of claims 1 to 5, characterized by. the reaction being carried out in the presence of an amine activating agent, optionally in the presence of an inorganic or tertiary organic base, and in a solvent. (Priority; July 11, 1980) 7. A process according to any one of claims 1 to 4, wherein the water formed during the reaction is removed by azeotropic distillation or by the addition of a desiccant. (Priority: July 11, 1980) 8. Figures 1-4. Process a) according to any one of claims 1 to 4 or 5 to 7 Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature of from -25 ° C to 25 ° C, preferably from -10 ° C to the boiling point of the solvent used. (Priority: July 11, 1980) 9. Process b) according to any one of claims 1 to 3, characterized in that the reaction is carried out in excess of the amine used. (Priority: July 11, 1980) 10. Process b) according to any one of claims 1 to 7 or process according to claim 9, characterized in that the reaction is carried out in the presence of an inorganic or tertiary organic base, in the presence of an accelerator such as copper and / or under pressure. (Priority: July 1980, N.) 11. Process b) according to any one of claims 1 to 8 or process according to claim 9 or 10, characterized in that the reaction is carried out at a temperature of 20 to 150 ° C, preferably at the reflux temperature of the reaction mixture, for example 100 ° C, and in a solvent. (Priority: July 11, 1980) 12. Process c) according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature of 0 to 100 ° C, preferably 20 to 50 ° C, and in a solvent. (Priority: July 11, 1980) 13. Process for process d) according to any one of claims 1-4, characterized in that the hydrolysis is carried out in the presence of an acid or a base. (Priority: July 11, 1980) 14. Process d) according to any one of claims 1 to 4 or process according to claim 13, characterized in that the reaction is carried out at reflux temperature of the reaction mixture in a solvent. (Priority: July 11, 1980) 15. Process c) according to any one of claims 1 to 3, characterized in that the reaction is carried out in the presence of an inorganic or tertiary organic base and in a solvent. (Priority: July 11, 1980) 16. Process (e) according to any one of claims 1 to 4 or process according to claim 15, characterized in that the reaction is carried out at a temperature of 0 to 150 'C, preferably 20 to 75' C. (Priority: July 11, 1980) The process of process f) according to claim 1 or 4, wherein the reaction is carried out in the presence of a base and in a solvent. (Priority: July 11, 1980) Process f) according to claim 1 or 4 or process according to claim 17, characterized in that the reaction is carried out at a temperature of 0 to 150'C, preferably 50 to 100'C. (Priority: July 11, 1980) 19. The process of claim 1, wherein the reaction is carried out in the presence of a base such as sodium hydride or potassium tert-butylate and in a solvent. (Priority: July 11, 1980) Process f) according to claim 1 or process according to claim 19, characterized in that the reaction is carried out at a temperature of 20 to 180 ° C, preferably 50 to 15 ° C. (Priority: July 11, 1980) 21. The process of claim 1, wherein the Lewis acid is aluminum chloride. (Priority: July 11, 1980) Process h) according to claim I or process according to claim 21, characterized in that the reaction is carried out at 0-80 ° C, preferably The reaction is carried out at a temperature of 20 to 60 'C and further in a solvent. (Priority: July 1980) 23. Process for carrying out process i) according to claim I, characterized in that the reaction is carried out at a temperature of 0 to 80 ° C, preferably 25 to 50 ° C, and in a solvent. (Priority: July 20, 1980) 24. A method of reducing blood sugar and / or containing a carboxylic acid amide of formula I or a physiologically tolerable salt thereof, as defined in claim 1, wherein R, R 1, R ₂ , R ₃ , R ₄ , X, Y and Z are present. or for the preparation of a lipid-lowering pharmaceutical composition, wherein the active ingredient of any one of claims 1 to 10 is formulated together with a carrier, diluent, excipient and / or other excipient in the pharmaceutical composition to form a pharmaceutical composition. (Priority: July 11, 1980) 25. A compound which Γ carboxylic acid amide or physiologically acceptable salt thereof - R _ls, R _{2 i,} R _{Ja, R4,} and Z, as defined in the preamble of the claim 2 - containing, glucose-lowering and / or pharmaceutical compositions lipidcsökkenlő acting preparation wherein characterized in that the active ingredient produced by any of the methods of claim 2 is formulated in a pharmaceutical composition in admixture with a carrier, diluent, excipient and / or other excipients customary in the pharmaceutical formulation. (Priority: July 13, 1979) 26. A method as active ingredient I carboxylic acid amide or physiologically tolerated acid addition salt of the formula - R _h, R _2h, R _1h, Y _h, and Z _{B are} as defined in the preamble of the claims 3 - pharmaceutical compositions containing, vcrcukorcsökkentő and / or lipid lowering preparation wherein characterized in that the active ingredient produced by any of the methods of claim 3 is formulated in a pharmaceutical composition in admixture with a carrier, diluent, excipient and / or other excipients customary in the pharmaceutical formulation. (Priority: December 7, 1979) 27. A process for the preparation of a carboxylic acid amide of the formula I 'or a physiologically tolerated salt thereof, as defined in claim 4, wherein R _c , R _lc , R, _t , R _k , R ₄ , X, Y and Z are as defined in claim 4. and / or for the preparation of a pharmaceutical composition having lipid-lowering activity, characterized in that the active ingredient obtained by any of the processes according to claim 4 is formulated in a pharmaceutical composition in admixture with a carrier, diluent, excipient and / or other excipient. (Priority: April 30, 1980) 8 pieces of figure