DE2604560A1 - Aryl-alkanoic acids substd. by acylamido gps - with hypoglycaemic and hypolipaemic activity - Google Patents

Abstract

Arylalknoic acids of formula (I), and their esters, amides and salts, are new: (where A is an aryl, aralkyl, arylvinyl, aryloxyalkyl or arylthioalkyl gp. opt. substd. by halogen, OH, CF3, alkyl, alkylthio, alkoxy, alkenyloxy, alkoxyalkoxy, alkylamino, aryloxy or alkoxyaryloxy or a heterocyclic system opt. substd. by halogen, alkyl or alokoxy; Y is a direct bond or a 1-3C alkylene gp.; X is an opt. unsatd. 2-8C alkylene gp. such that the benzene ring and the COOH gp. are sepd. by >2C atoms; R is H or lower alkyl). Cpds. (I) have hypoglycaemic and/or hypolipaemic activity.

Description

Phenylalkanecarboxylic acid derivatives and processes for their preparation

The present invention relates to phenylalkanecarboxylic acid derivatives of the general formula 1 in which A is an aryl, aralkyl or aryloxy group optionally substituted by hydroxy, halogen, trifluoromethyl, alkyl, alkylmercapto, alkoxy, alkenyloxy, alkoxyalkoxy, alkyl-substituted amino, aryloxy or alkoxy-substituted aryloxy groups Arylvinyl radical, aryloxyalkyl or arylthioalkyl radical or a heterocyclic ring system optionally substituted by halogen, alkyl or alkoxy groups, Y a valence stroke or an optionally branched lower alkylene group with 1-3 carbon atoms, X a straight-chain or branched, saturated or unsaturated alkylene chain with 2- 8 carbon atoms, with at least 2 carbon atoms between the benzene ring and the carboxyl group and R being hydrogen or lower alkyl, their physiologically harmless salts, esters and amides, processes for producing the same, and their use for producing drugs with hypoglycemic and / or hypoiipidaemic Effect.

Under 11-alkyl- "and" alkoxy- "are straight-chain or in all cases to understand branched radicals with 1-5 carbon atoms.

The straight-chain alkyl radical preferably has the methyl group in the branched alkyl radical, the tert. Butyl group and the alkyl mercapto group the methyl mercapto grouping use. Alkyl-substituted amino is said to be in particular Be dimethylamino. The alkenyloxy radical is a radical with 2-5 carbon atoms, especially the allyloxy group, preferably the phenoxy group and aryloxy group under alkoxy-alkoxy radical a radical with 2-5 carbon atoms, in particular the methoxyethoxy group. Aryl radical is understood to mean aromatics with 6-10 carbon atoms, in particular the Naphthyl and phenyl radical.

Aralkyl is said to be primarily the a-phenylethyl, the tert-butyl and / or hydroxy groups substituted B-phenylethyl and the fluorenyl- (9) -methyl radical, Arylvinyl is a styryl group which is optionally substituted by halogen and / or alkoxy mean. The aryloxyalkyl or arylthioalkyl radical is preferably the phenoxy or phenylthio-methyl radical use.

The optionally substituted heterocyclic ring system should be preferred the thienyl, pyrazolyl, isoxazolyl, pyridyl, pyrazinyl, chromanyl, quinolyl, Indolyl, benzoxazolyl or the optionally partially hydrogenated benzofuranyl radical represent.

Halogen is understood to mean fluorine, chlorine and bromine.

The new compounds of general formula I and their physiological Safe salts, esters and amides have surprisingly pronounced hypoglycemic properties and / or hypolipidemic activity.

The compounds of the general formula I can be prepared by processes known per se, preferably by a) an amine of the general formula II in which Y, X and R have the meanings given above, or their acid derivatives are reacted with a reactive acid derivative - the acid A-COOH, where A has one of the meanings given above, or b) a compound of the general formula III in which A, Y, R and X have the meanings given above and B oxidizes a radical represented by a radical in the carboxyl group, or c) a compound of the general formula IV in which A, R and Y have the meanings given above, Z is a straight-chain or branched, saturated or unsaturated alkylene chain with 1-7 carbon atoms, Z 'is Z or a valence stroke, R' is hydrogen or an alkyl group and G is the -C group or the -CH group, 0 L where L represents the hydroxyl group or halogen, reduced, or d) a compound of the general formula V in which A, R and Y have the meanings given above, M represents hydrogen or lower alkyl with 1-6 carbon atoms, and K represents a valence stroke or a straight-chain or branched, saturated or unsaturated alkylene chain with 1-6 carbon atoms, with a reactive methylene component of general formula VI in which P is hydrogen, alkali metal, lower alkyl or an acyl group and Q is hydrogen, the nitrile group, lower alkyl with 1- «carbon atoms, or the radical -COOP, in which P has the meaning given above, where the obtained unsaturated compound is then saponified, decarboxylated or hydrogenated, or e) in the event that X in the general formula I represents a straight-chain or branched, saturated alkylene chain with 2-4 carbon atoms, a compound of the general formula VII in which A, R and Y have the meanings given above, and M 'denotes hydrogen or lower alkyl having 1-2 carbon atoms, with a compound of the general formula VIII H2C = CHal2 (VIII), in which Hal denotes halogen, or f ) in the event that X in the general formula I represents a straight-chain, saturated alkylene chain with 2-4 carbon atoms, a ketone of the general formula IX in which A, R and Y have the meanings given above and U represents an alkyl group with 2-4 carbon atoms, under the conditions of the "Willgerodt-Kindler synthesis", or g) a halogen compound of the general formula X in which A, R, Y, K and Hal have the meanings given above and T can be hydrogen or lower alkyl of 1-6 carbon atoms with a reactive methylene component of the general formula XI where R2 is lower alkyl, R1 is hydrogen or lower alkyl with 1-6 carbon atoms, Me is alkali or alkaline earth metals and W is the radical OR2 or the methyl group, converts, saponifies and optionally decarboxylates and then optionally converts the acid derivatives of the general formula I obtained into the free Acid or, if desired, the free acid of the general formula I obtained is esterified, converted into an amide or into physiologically acceptable acid addition salts.

In process a), the reactive acid derivatives of the acid A-COOH are used especially acid chlorides use, which in the usual way by conversion of the carboxylic acid can be obtained with thionyl chloride. But their esters can just as well, Azides, anhydrides or mixed anhydrides can be used. The reaction with the Intermediate of the general formula II can be made according to "Schotten-Baumann" will. If you want to work under anhydrous conditions, it is preferable to use absolute conditions Pyridine or methylene chloride with an addition to a tert. Amine (such as triethylamine) used. Instead of the free amino compound, its salts can also be used.

As acid derivatives of the compounds of the general formula II come the esters, especially the methyl and ethyl esters, nitriles, acid amides or acid anhydrides in question, which are then optionally converted into the desired according to methods known per se free carboxyl group, the ester or amide group, can be converted.

The compounds of the general formula II are new and can, for example, by hydrolysis of a compound of the general formula XII in which Y, R and X have the meanings given above and R "is supposed to mean hydrogen or lower alkyl, preferably methyl or ethyl and V is an aryl, lower alkyl or alkoxy radical, can be prepared in an acidic or alkaline medium.

The compounds of the general formula XII with V lower alkyl and Alkoxy are new and, like the compounds of general formula I, are hypoglycemic and / or hypolipidemic effects.

As an oxidizable group B in substances of the general formula III hydroxymethyl, aminomethyl and formyl groups or their functional groups are preferred Derivatives in question with the usual oxidizing agents, such as permanganates or dichromates, in the case of the formyl group also with atmospheric oxygen, easily to Carboxyl group can be oxidized.

The compounds of the general formula III, which are used as starting compounds are used in process b) are new and have as precursors of the compounds of the general formula I likewise hypoglycemic and / or hypolipidaemic activity. They are produced by processes known per se, in particular analogous to processes a), where instead of the acid of the general formula II the corresponding compound with the oxidizable group B is used. Of course you can but also vice versa compounds of the general formula I or

their acid derivatives such as esters, acid halides and acid amides in compounds of the general formula. III can be converted by reduction.

The ketocarboxylic acid derivatives of the general formula IV used as starting material in process c) can, in the event that Zu denotes a valence stroke, by reacting a compound of the general formula XIII in which A, R and Y have the meanings given above, with an acid ester chloride of the general formula XIV where Hal is chlorine or bromine, Z is a straight-chain or branched, saturated or unsaturated alkylene chain with 1-7 carbon atoms and R "'is lower alkyl, preferably methyl or ethyl, represent, according to Friede, l-Cra fts conditions in a manner known per se. The esters obtained in this way can then be hydrolyzed to form the acid.Instead of an acid ester chloride, an acid anhydride of the general formula XV in which D should be a straight-chain or branched, saturated or unsaturated alkylene chain with 2-7 carbon atoms.

In the event that Z 'is not the same as the valence stroke, the can be used as Starting material used in process c) ketocarboxylic acid derivatives of the general Formula (IV) according to methods known per se, such as Claisen's ester condensation represent.

The compounds of the general formula IV, which are used as starting compounds used in method c) are new and also have hypoglycemic and / or hypolipidemic activity.

The reduction of the compounds of the general formula IV with G = keto group can e.g. with the help of zinc / hydrochloric acid in the sense of a "Clemmensen reduction" or according to "Wolff-Kishner" with hydrazine / alkali. Preferably she will but catalytically in the presence of precious metals such as e.g.

Palladium or platinum carried out. The preferred solvent is in this case a lower alcohol. It can also be used in glacial acetic acid, which has a trace of sulfur or perchloric acid or molar amounts of hydrochloric acid was added. The reaction temperature is 20-600C, the pressure between 1 and 10 at. Hydrogen.

Compounds of the general formula IV with can be prepared, for example, by reducing the corresponding keto derivatives.

The reduction can be catalytic in the presence of noble metals such as e.g. palladium or platinum. Also found as a reducing agent complex metal hydrides use. Sodium borohydride is preferably used. In this case, the reaction in an alcohol, especially methanol, or can also be carried out in an aqueous alkaline medium. From the hydroxy compounds the halogen derivatives can be prepared by generally known methods. the Reduction to compounds of the general formula I can be carried out under those given above Perform conditions (G P keto group).

The reactions according to process d) are among those generally known Reaction conditions of the "Perkin reaction" or the wKnoevenagel reaction "carried out. The acid derivatives shown according to the "Cope" variant are then saponified to acid with decarboxylation. Under lower alkyl of the substituent P is understood to mean alkyl groups with 1-5 carbon atoms, especially methyl and Ethyl groups. The cinnamic acid derivatives produced in this way can then, for example, catalytically hydrogenated with palladium or platinum to give the saturated compounds.

The compounds of the general formula used in process e) VII can be prepared by reducing the corresponding oxo derivatives. As a reducing agent are complex metal hydrides' preferably sodium borohydride, lithium borohydride or Hydrogen used in the presence of palladium or platinum. Implementation with Compounds of the general formula VIII are in a strongly acidic medium, such as 90 % but sulfuric acid. Hal is understood to mean, in particular, chlorine.

The ketones of the general formula IX used in process f) can easily be prepared by acylation according to "Friedel-Crafts". That at the "Willgerodt-Kindler synthesis" obtained thiomorpholide is preferably in alkaline Medium saponified.

The reaction according to process g) is carried out according to the method known per se carried out the alkylation of ß-dicarbonyl compounds. Under the lower alkyl group of the substituent R2 is understood to mean alkyl groups with 1-5 carbon atoms, in particular Methyl and ethyl.

Those occurring as intermediates in the processes listed above Esters can be isolated or, if appropriate, directly to the corresponding carboxylic acids to be saponified. Conversely, the carboxylic acids obtained can again per se known methods are implemented to the desired esters.

Saponifications of the esters, nitriles, amides, etc. are preferably carried out in alkaline medium.

In principle, they are suitable for any esterification of the carboxyl group all alcohols. The lower monohydric alcohols such as methanol and ethanol are preferred or propanol as well as polyhydric alcohols, e.g. glycol, or alcohols with others functional groups such as ethanolamine or glycol ether.

The amides of the general formula I according to the invention can according to an known methods from the carboxylic acids or their reactive derivatives Implementation can be made with amines. The amine components include, for example, ammonia, Alkylamines, dialkylamines, etc. in question; however, amino acids such as p-aminobenzoic acid are preferred Anthranilic acid, phenylalanine and ß-alanine.

As physiologically harmless salts come in particular alkali, Alkaline earth and ammonium salts, as well as salts with basic blood sugar lowering effective Compounds, especially biguanides, are in question.

These salts are produced in a manner known per se, for example by reaction with the corresponding free bases or carbonates.

As anti-hypoglycemic and / or antihyperlipidaemic according to the invention Preparations are all common oral and parenteral forms of application in question, for example tablets, capsules, coated tablets, syrups, solutions, suspensions, drops, Suppositories, etc. For this purpose, the active ingredient is mixed with solid or liquid Carrier materials and then brings them into the desired shape.

Solid carriers are e.g. starch, lactose, mannitol, methyl cellulose, Talc, highly dispersed silicic acid, higher molecular fatty acids (such as stearic acid), Gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable Fat, solid, high molecular weight polymers (such as polyethylene glycols). For oral application If desired, suitable preparations can contain flavorings and sweeteners. The preferred injection medium is water, .which the usual additives for injection solutions such as stabilizers and solubilizers and / or buffer included. Such targets are e.g. acetate or tartrate buffers, Ethanol, complexing agents (such as ethylenedinminetetraacetic acid and their non-toxic Salts), high molecular weight polymers (such as liquid polyethylene oxide) to regulate viscosity.

The following examples show some of the numerous process variants, which can be used for the synthesis of the compounds according to the invention. she however, are not intended to represent a limitation of the subject matter of the invention.

Example 1 β- # 4- [2- (6-chloro-chroman-2-carboxamido) -ethyl] -phenyl # -propionic acid To a solution of 3.1 g of ß- [4- (2-aminoethyl) phenyl] propionic acid ethyl ester hydrochlorid.in A solution of 2.8 g of 6-chloro-chroman-2-carboxylic acid chloride is added at OOC to 24 ml of sodium hydroxide solution in 20 ml of methylene chloride. The mixture is left to stir for 3 hours at 200 ° C., acidified with 2N Hydrochloric acid and shakes the separated organic phase with sodium bicarbonate solution the end. The methylene chloride solution is concentrated and the residue with 20 ml of ethanol / Heat 20 ml of sodium hydroxide solution on a water bath for 1 hour. After the Ethanol is extracted with ether and the aqueous phase is acidified. The precipitation is recrystallized from isopropanol.

Yield: 2.4 g 52%. M.p .: 128-130 ° C.

The ß- / 4- (2-aminoethyl) phenyl 7-propionic acid ethyl ester hydrochloride used as the starting product is prepared as follows: Variant I: 4- (2-Acetamidoethyl) benzoic acid is over a mixed anhydride with sodium borohydride to form 4- (2-acetamidoethyl) benzyl alcohol (Mp. 72-73 ° C) and then reduced with activated manganese dioxide to 4- (2-acetamidoethyl) benzaldehyde (Mp: 81-83 ° C) oxidized. Subsequent reaction with malonic acid gives 4- (2-acetamidoethyl) cinnamic acid (Mp: 206-208 ° C), the ß- [4- (2-Acetamidoethyl) phenyl] propionic acid (melting point 132-1330C) is hydrogenated.

It is then saponified under acidic conditions and directly with ethanol to give ß- / 4- (2-aminoethyl) phenyl] propionic acid ethyl ester hydrochloride (Mp: 165-167 ° C) implemented.

Variant II: N-acetyl-phenethylamine is added with ethyl malonate.

to ß-oxo-ß- / 4- (2-acetamido-ethyl) -phenyl-7-propionic acid ethyl ester (Fp: 89-92 ° C), reduced to ß- [4- (2-Acetamidoethyl) phenyl] propionic acid ethyl ester (Mp: 96-98 ° C), saponified alkaline to ß- [4- (2-aminoethyl) phenyl] propionic acid (mp: 270-2720C) and then esterified to the desired ethyl ester hydrochloride.

In an analogous manner, 1. by reacting the ß- [4- (2-aminoethyl) phenyl] propionic acid ethyl ester hydrochloride with the corresponding carboxylic acid chlorides the following compounds: a) β- # 4- [2- (4-chloro-benzamido) -aethyl] -phenyl # -propionic acid Mp: 171-1730C after reprecipitation b) β- # 4- [2- (3-trifluoromethyl-benzamido) -aethyl] -phenyl # -propionic acid Mp: 113-115 ° C from toluene c) β- # 4- [2- (2-butoxy-benzamido) -aethyl] -phenyl # -propionic acid Mp: 6-880C from ethyl acetate d) β- # 4- [2- (2-methylmercapto-benzamido) -aethyl] -phenyl # -propionic acid Mp: 135-136 ° C. from methanol e) β- # 4- [2- (2-methoxy-5-methyl-benzamido) -aethyl] -phenyl # -propionic acid Mp: 97-990C from toluene f) β- # 4- [2- (5-chloro-2-methoxy-benzamido) -aethyl] -phenyl # -propionic acid Mp: 118-120 ° C from ethyl acetate g) - <4- 2- (2-amyloxy-5-chlorobenzamido) ethyl] -phenyl # -propionic acid Mp: 91-93 ° C. from ethyl acetate h) β- # 4- [2- (2-allyloxy-5-chlorobenzamido) -aethyl] -phenyl-propionic acid Mp: 118-120 ° C. from toluene i) β- # 4- [2- (5-fluoro-2-methoxy-benzamido) -aethyl] -phenyl-propionic acid Mp: 126-128 ° C. from isopropanol j) β- # 4- [2- (5-chloro-2-phenoxy-benzamido) -aethyl] -phenyl # -propionic acid Melting point: 102-1050C from isopropanol The compound contains 1.5 mol of water of crystallization k) β- # 4- [2- (2,5-dichloro-benzamido) -aethyl] -phenyl # -propionic acid, mp: 189-191 ° C Methanol l) β- # 4- [2- (2,5-dimethoxy-benzamido) -aethyl] -phenyl # -propionic acid, mp: 77-79 ° C from isopropanol / toluene m) β- # 4- [2- (3,5-dichloro-2-mwthoxy-benzamido) -aethyl] -phenyl # -propion acidic melting point: 108-110 ° C. from isopropanol / water n) β- # 4- [2- (2-phenylpropionamido) -aethyl] -phenyl # -propionic acid Mp: 124-1-60C from isopropanol o) β- # 4- [2- (5-chloro-2-methoxy-cinnamoyl) -aethyl] -phenyl-propionic acid Mp: 144-145 ° C from isopropanol / water p) ß- # 4- [2- (5-chloro-3-methoxy-thenoyl- (2) -amino) -ethyl] -phenyl # propionic acid, melting point: 123-124 ° C. from isopropanol q) β- [4- (2-nicotinoylaminoethyl) phenyl] propionic acid Melting point: 180 ° C. from isopropanol / water r) β- # 4- [2- (5-chloro-2-methyl-2,3-dihydrogenzo [b] furoyl- (7) -amino) ethyl] phenyl # propionic acid, mp: 1450C from isopropanol s) β- # 4- [2- (4-methylindole-2-carboxamido) ethyl] phenyl # propionic acid Mp: 168-1700C from methanol 2. by reaction of # [4- (2-amino-ethyl) -phenyl-2-butyric acid ethyl ester hydrochloride with 5-chloro-2-methoxy-benzoyl chloride: a) γ- # 4- [2- (5-chloro-2-methoxy-benzamido) -aethyl] -phenyl # -butyric acid Mp: 107-109 ° C from benzene b) γ- # 4 - [(5-chloro-2-methoxy-benzamido) -methyl] -phenyl # -butyric acid (Na salt) mp: 127-130 ° C. The acid was isolated in the form of its Na salt. That about this γ - [(4-aminomethyl) phenyl] butyric acid ethyl ester hydrochloride used as the starting product is shown as follows: E-phenylbutyrate becomes γ- (4-chloromethyl-phenyl) -butyreaethylester (Boiling point 0.01: 123-125 ° C) chloromethylated and from this with the help of the Gabriel synthesis the γ - [(4-aminomethyl) phenyl] butyric acid ethyl ester hydrochloride (melting point: 152-155 ° C) won.

3. by reacting # - [4- (2-aminoethyl) phenyl] valeric acid ethyl ester hydrochloride (Mp: 148-1520C) with 5-chloro-2-methoxy-benzoyl chloride: # - # 4- [2- (5-chloro-2-methoxy-benzymido) -aethyl] -phenyl # -valeric acid Melting point: 95-970C from benzene / isopropanol 4, by reaction of α-methyl-β- [4- (2-aminoethyl) phenyl] propic acid ethyl ester hydrochloride (Oil) with 5-chloro-2-methoxy-benzoyl chloride: α-methyl-ß- # 4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl # -propionic acid Melting point: 109-113 ° C. from dilute acetic acid. Production of the hydrochloride:% α-methyl-4- (2-acetamido-ethyl) -cinnamic acid (Mp: 145-149 ° C) becomes α-methyl-ß- [4- (2-acetamido-ethyl) -phenyl] -propionic acid Hydrogenated (oil), then to the hydrochloride of α-methyl-ß- [4- (2-aminoethyl) phenyl] propionic acid saponified and then converted to the desired ethyl ester hydrochloride.

5. by reaction of ß- (4-aminophenyl) propionic acid ethyl ester hydrochloride with 5-chloro-2-methoxy-benzoyl chloride the ß- [4- (5-chloro-2-methoxy-benzamido) -phenyl] -propionic acid Mp: 188-1900C from ethanol 6. by reaction of ß- [4- (2-aminopropyl) phenyl] propionic acid ethyl ester hydrochloride (Mp: IIS-1170C) with 5-chloro-2-methoxy-benzoyl chloride β- # 4- [2- (5-chloro-2-methoxy-benzamido) -propyl] -phenylpropionic acid Mp: 125-1260C from isopropanol / water. Preparation of the hydrochloride: N-acetyl-4-acetyl-amphetamine (Melting point: 99-100 ° C) is oxidized to 4- (2-acetamido-propyl) benzoic acid (melting point: 207-208 ° C), obtained therefrom by reducing the 4- (2-acetamido-propyl) -benzyl alcohol (oil), the is then oxidized to 4- (2-acetamido-propyl) -benzaldehyde (mp: 84-86 ° C). By condensate with malonic acid, 4- (2-acetamido-propyl) -cinnamic acid is obtained (melting point: 207-2080C), which is then hydrogenated to β-g4- (2-acetamido-propyl) -phenyl 7-propionic acid (melting point 93-960C) will. Subsequent acid hydrolysis gives the ß-g4- (2-aminopropyl) -phenyl hydrochloride 7-propionic acid, which is esterified to the above-mentioned ethyl ester hydrochloride.

7. by reacting α-methyl-4- (2-aminoethyl) ethyl cinnamon ester hydrochloride (Mp: 2700C) with 5-chloro-2-metho.y: benzoyl chloride α-methyl-4- [2-methoxy-benzamido) -ethyl] -cinnamic acid Mp: 188-1910C from ethanol.

8. by reaction of ß- # 4- [2- (N-methyl-amino) -ethyl] -phenyl # -propionic acid ethyl ester hydrochloride (Mp: 162-164 ° C.) with 5-chloro-2-methoxy-benzoyl chloride β- # 4- [2- (N-methyl-5-chloro-2-methoxy-benzamido) -ethyl] -phenyl # -propionic acid Mp. 152-153 ° C. from toluene. Preparation of the hydrochloride: 4- [2- (N-methyl-acetamido) -ethyl] -acetophenone is converted to 4- [2- (N-methyl-acetamido) -ethyl] -benzoic acid (melting point 149-151 ° C), reduced to 4- [2- (N-methyl-acetamido) -ethyl] -benzyl alcohol (oil) and then to 4- [2- (N-methyl-acetamido) -ethyl] -benzaldehyde (M.p .: 54-590C) oxidized. After condensation with malonic acid, 4- [2- (N-methyl-acetamido) -ethyl] -cinnamic acid is obtained (Melting point: 157-158 ° C), the ß- # 4- [2- (N-methyl-acetamido) -ätlyl ~ / -phenylz-propionic acid (Mp: 133-134 ° C. Is hydrogenated. After hydrolysis, the hydrochloride of B-94- [2- (N-methyl-amino) -ethyl] -phenyl-propionic acid is obtained (Mp: 211-212 ° C) and from it by esterification das.oben specified ethyl ester hydrochloride.

9. by reaction of ß- [4- (aminomethyl) phenyl] propionic acid ethyl ester hydrochloride (Mp: 192-193 ° C) with 5-chloro-2-methoxybenzoyl chloride β- [4- (5-chloro-2-methoxy-benzamido-methyl) -phenyl] -propionic acid Mp: 152-153 C from isopropanol. Production of the hydrochloride: 4-cyano-cinnamic acid becomes reduced to β- [4- (aminomethyl) phenyl] propionic acid hydrochloride (melting point: 210-212 ° C.) and then esterified to the ethyl ester hydrochloride given above.

10. by reaction of γ- [4- (2-amino-ethyl) -phenyl] -but-2-enoic acid ethyl ester hydrochloride with 5-chloro-2-methoxy-benzoyl chloride a) γ- (4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl # -but-2-eng acid m.p. 180-1830C cum precipitated) 11. by reaction of α, α-dimethyl-β- [4- (2-amino-ethyl) -phenyl] -propionic acid ethyl ester hydrochloride with 5-chloro-2-methoxy-benzoyl chloride a) α, α-dimethyl-β- # 4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl> Propionic acid, melting point 138-1410C from ethyl acetate The starting material used for this purpose a, a-Dimethyl-β- [4- (2-amino-ethyl) -phenyl] -propionic acid ethyl ester hydrochloride (mp. 113-117 ° C) is shown as follows: N-acetyl-phenaethylamine is added with dimethylmalonic acid methyl ester chloride according to Friedal-Crafts for α, α-dimethyl-ß-oxo-ß- [4- (2-acetamidoethyl) phenyl] propionic acid methyl ester (Bp 0.1: 215 - 220 ° C), reduced via the stage of a, a-dimethyl-hydroxy-P- [4- (2-acetamido-ethyl] -phenyl] -propionic acid methyl ester (Mp: 120-123 ° C.) for the methyl α, α-dimethyl-β- [4- (2-acetamido-ethyl) -phenyl] -propionate (Boiling point 0.1: 180-190 ° C, saponified to give α, α-dimethyl-β- [4- (2-aminoethyl) phenyl] propionic acid hydrochloride (Mp: 230-235 ° C) and then esterified to the desired ethyl ester hydrochloride.

12. by reaction of 6- [4- (2-aminoethyl) phenyl] hexanoic acid ethyl ester hydrochloride (Mp: 182-185 ° C.) with 5-chloro-2-methoxybenzoyl chloride 6- # 4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl-hexanoic acid ? p: 360C from toluene Production of the hydrochloride: N-acetylphenethylamine is with adipic acid methyl ester chloride (Kpl7: 113-1160C) according to Friedel-Crafts for 6-Oxo-6- [4- (2-Acetamido-ethyl) -phenyl] -hexanoic acid methyl ester (oil) reacted and then reduced to 6- [4- (2-acetamido-ethyl) -phenyl] -hexanoic acid methyl ester (oil). After alkaline hydrolysis (melting point of the amino acid: 200-205 ° C.) and subsequent esterification the ethyl ester hydrochloride given above is obtained with ethanol.

13. by reaction of 6- [4- (2-aminoethyl) phenyl] hexanoic acid ethyl ester hydrochloride with 4-chloro-benzoyl chloride 6- <4- [2- (4-chloro-benzamido) -ethyl] -phenyl> -hexanoic acid Melting point: 140-143 ° C. from ethanol / diethyl ether 14. by reaction of 7- [4- (2-amioethyl) phenyl] heptanoic acid ethyl ester hydrochloride (Mp: 137-1390C) with 5-chloro-2-methoxybenzoyl chloride 7- <4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl> -heptanoic acid Mp: 103-1060C from diethyl ether production of the hydrochloride: N-acetylphenethylamine is followed by the hyptanedioic acid monomethyl ester (bp17: 125-128 ° C) with the acid chloride Friedel-Crafts on 7-Oxo-7- [4- (2-Acetamidosethyyl) -phenyl] -heptanoic acid methyl ester (01) reacted, saponified to the corresponding carboxylic acid (mp: 97-10o0c) and then reduced to 7- [4- (2-acetamido-ethyl) phenyl] -heptanoic acid (melting point: 108-110 ° C.). To alkaline hydrolysis and subsequent esterification with ethanol you get that ethyl ester hydrochloride given above.

15. by reaction of 7- [4- (2-aminoethyl) phenyl] heptanoic acid ethyl ester hydrochloride with 4-chloro-benzoyl chloride 7- <4- [2- (4-chloro-benzamido) -aethyl] -phenyl> -heptanoic acid Melting point: 145-148 ° C. from diethyl ether 16. by reaction of 9- [4- (2-aminoethyl) phenyl] nonanoic acid ethyl ester hydrochloride (Mp: 135-1380C) with 5-chloro-2-methoxybenzoyl chloride 9- <4- [2- (5-chloro-2-methoxy-benzamido) ethyl] phenyl> -nonic acid Melting point: 97-100 ° C. from ethyl acetate. Production of the hydrochloride: N-acetylphenethylamine is with the acid chloride of the nonanedioic acid monomethyl ester (Kpj2: l48-1506C) after Friedel-Crafts on 9-0xo-9- [4- (2-Acetamido-ethyl) -phenyl] -nonasäuremethylester (oil) to set, saponified to the corresponding carboxylic acid (mp: 106-1080C) and then to 9- [4- (2-Acetamido-ethyl) -phenyl] -nonic acid (mp: 115-1180C) reduced. After more alkaline Hydrolysis and subsequent esterification with ethanol give the above Ethyl ester hydrochloride.

Example 2 4- [2- (4-chloro-benzamido) -ethyl] -cinnamic acid To a solution of 4.9 g of 4- [2-aminoethyl] cinnamic acid hydrochloride (melting point <300 ° C.) in 22 ml in sodium hydroxide solution 30 ml of acetone are added and then a solution of 3.75 g of 4-chloro-benzoyl chloride is added dropwise in 15 ml of acetone and a further 2 ml in sodium hydroxide solution. The mixture is left to stir for a further 2 hours at 20 ° C, acidifies, sucks off the precipitate and recrystallizes it from ethanol.

Yield: 4.32 g - 61%. Mp: 253-255 ° C.

Example 3 β- [4- (2-Phenylmercapto-acetamido-ethyl) -phenyl] -propionic acid To a solution of 3.5 g of ß- [4- (2-aminoethyl) phenyl] propionic acid ethyl ester and 1.6 g of triethylamine in 30 ml of absolute methylene chloride are added dropwise at 0 ° C a solution of 2.9 g of phenyl mercaptoacetyl chloride in 40 ml of absolute methylene chloride. After 50 minutes at OOC and 2 hours at 290C, extraction is carried out with water, the organic Phase dried and concentrated. The residue (6.0 g) is boiled in a solution bath of 1.3 g of sodium hydroxide in 50 ml of ethanol for 1 hour on the water. The unusual one Sodium salt is suctioned off, it is dissolved in water and the acid is precipitated by adding Hydrochloric acid.

The crude product is recrystallized from isopropanol.

Yield: 2.3 g = 67%. Mp: 119-122 ° C.

In an analogous manner, the reaction of ß- / 4- (2-aminoethyl) phenyl] propionic acid ethyl ester is obtained with the corresponding acid chlorides a) ß- [4- (2-phenoxy-acetamido-ethyl) -phenyl] -propionic acid Mp: 140-141 ° C. from isopropanol b) β- 4- [2- (6-chloro-quinoline-8-carboxamido) -ethyl 7-phenyl-propionic acid mp: 210-2120C after reprecipitation B e i s p i e l 4 ß- <4- [2- (5-bromo-2-methoxy-benzamido) -ethyl] -phenyl> -propionic acid To 7.84 g of 3- {4- [2- (5-bromo-2-methoxy-benzamido) -ethyl] -phenyl} 0 propanol (mp: 48-50 C) a solution of 2.0 g of sodium dichromate is added to 100 ml of methylene chloride 1.5 ml of sulfuric acid in 20 ml of water. The mixture is stirred for 6 hours at room temperature, separates the phases, deacidifies the organic layer and concentrates it after drying. The residue is recrystallized from isopropanol.

Yield: 5.44 g # 67%. Mp: 120-121 ° C.

For example 5 γ- <4- [2- (4-methyl-indole-2-carboxamido) -ethy] -phenyl> -butyric acid 7.56 g of γ-oxo-γ- (4- [2- (4-methyl-indole-2-carboxamido) -ethyl? -Phenyl) -butyric acid (Mp: 210-2120C) are dissolved in 50 ml of glacial acetic acid with the addition of 0.5 g of palladium / carbon and 0.5 ml of perchloric acid hydrogenated at 1 atm hydrogen and 400C. After completion the hydrogen uptake is filtered, the solution concentrated to half and under Cooling mixed with water. One extracts several times with ether, concentrates the organic Phase one and the residue recrystallizes from toluene.

Yield: 3.42 g e 47%. M.p .: 132-134 ° C.

Example 6 4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -cinnamic acid 11.5 g of malonic acid in 100 ml of absolute pyridine are added to 31.75 g of 4-g2- (5-chloro-2-methoxy-benzamido) -ethyl 7-benzaldehyde (melting point: 115-116 ° C. and 1 ml of piperidine. The reaction mixture is heated so long on the water bath until the carbon dioxide development has ended, after To cool, it is poured onto ice / concentrated hydrochloric acid and the precipitate is filtered off with suction.

It is then recrystallized from ethanol.

Yield: 23.4 g of A 65%. Mp: 197-198 ° C.

Example 7 4- [2- (5-chloro-2-methoxybenzamido) -ethy] -α-methyl-cinnamic acid 3.175 g of 4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzaldehyde (mp: 115-116 ° C), 1.3 g propionic anhydride and 0.96 g sodium propionate are left at 130-135 ° C. for 30 hours. react with each other.

Then it is mixed with 2N sodium hydroxide solution, extracted several times with methylene chloride, treats the aqueous phase with activated charcoal and acidifies. The precipitation will recrystallized from ethanol.

Yield: 1.61 g # 45%. Mp: 188-191 ° C.

Example 8 3- <4- [2- (5-chloro-2-methoxybenzamido) ethyl] phenyl> butyric acid A mixture of 1G, 1 g of 1- {4- [2- (5-chloro-2-methoxybenzamido) ethyl] phenyl} ethanol (oily Product made by reduction of 4- [2- (5-chloro-2-methoxybenzamido) ethyl] acetophenone (Mp: 99-1000C)) and 14.1 g of l, l-dichloroethylene is at 50C within 2 hours added dropwise to 9.7 ml of 90% sulfuric acid. Then it is poured onto ice, etherified, extracted the organic phase with 2N sodium hydroxide solution and acidify the aqueous phase with concentrated Hydrochloric acid. The oily product is reprecipitated from soda / hydrochloric acid and then in ethyl acetate recorded.

The filtered solution is concentrated and the residue with ether and Water. brought to crystallization.

Yield: 3.08 g # 17%. Mp: 125-127 ° C.

Example. 9 β- [4- (2-Benzamidoaethy) -phenyl] -propionic acid 2.8 g of 4- (2-Benzamidoaethy) -propionphenone (Mp: 127-128 ° C.) are mixed with 0.5 g of sulfur and 3.5 g of morpholine within 1 hour heated to 100 ° C and then refluxed for 3 hours. You laept something cool down, mixed with ethanol, filtered, the filtrate cools well and sucks off. You get 3.2 g of the Thionopholis of ß- [4- (2-Benzamidoaethyl) phenyl] propionic acid (melting point: 165-168 ° C. 2 g of this thiomorpholide are heated with a solution of 0.6 g of potassium hydroxide in 10 ml of ethanol under reflux for 3 hours. After concentrating, dilute with water, treated with activated charcoal, filtered and acidified with concentrated hydrochloric acid. The end product which is sucked off and recrystallized from isopropanol has a melting point from 164-1650C.

For example, 10 β- <4- [2- (5-chloro-2-methoxy-benzamido) ethyl] phenyl> propionic acid 7.19 g of 4- [2- (5- (5-chloro-2-methoxy-benzamido) -ethyl] -cinnamic acid are dissolved in methanol hydrogenated using 1 g of palladium / barium sulfate at room temperature. After the uptake of 1 mol of hydrogen / mol of substance used, the hydrogenation is carried out interrupted, the solution filtered, concentrated and the residue from isopropanol / water recrystallized.

Yield: 6.14 g # 85%. M.p .: 118-120 ° C.

B e i s i e l 11 Salt of β- <4- [2- (5-chloro-2-methoxy-benzamido) -aethyl] -phenyl> -propionic acid with phenaethyl biguanide 1.8 g of β- <4- [2- (5-chloro-2-methoxy-benzamido) -aethyl] -phenyl> -propionic acid if it is dissolved in 30 ml of methanol, there is a solution of 0.12 g of sodium in 5 ml of methanol and constricts in a vacuum. The residue is dissolved in 30 ml of ethanol, added with 1.15 g of phenmethylbiguanide hydrochloride, refluxed for 5 hours, testifies hot and the filtrate is concentrated. The residue is taken up in isopropanol and precipitated again with ether. Repeat this process four times. Then lies the desired salt in solid fern with a melting point of 160-162 ° C B. e i 5 p i e 1 12 β- <4- [2- (5-methoxy-quinoline-8-carboxamido) -aethyl] -phenyl> -propionic acid hydrochloride To 4.2 g of 5-methoxy-quinoline-8-carboxylic acid and 5.35 g of β- [4- (2-aminoethyl) phenyl] propionic acid ethyl ester hydrochloride 2.1 ml of phosphorus oxychloride are added to methylene chloride at -150C with stirring 8.9 ml of triaethylamine. Let it stir for 30 minutes at -15 ° C and 2 hours at + 200C, mixed with water, the organic phase shakes with dilute sodium hydroxide solution and the methylene chloride phase is completely concentrated after neutralization. The so incurred oily ethyl ester is mixed with 50 ml of ethanol / 50 ml of 2N sodium hydroxide solution for 1 hour saponified at 800C. The alcohol is removed using a Rotavapor and the aqueous extract is extracted Solution with methylene chloride and acidify it. The precipitated crude product is recrystallized from isopropanol.

Yield: 2.9 g = 34% melting point: 222-2250 ° C. In an analogous manner, one obtains by reaction of the p- [4- (2-Aninoaethyl) phenyl] propionic acid ethyl ester hydrochloride with the corresponding carboxylic acids the following compounds: a) β- <4- [2- (2-N, N-dimethylamino-benzamido) -aethyl] -phenyl> -propionic acid hydrochloride Mp: 206-2080C from ethanol b) p- <4-E2- (5-methyl-pyrazine-2-carboxamido) -aethyl] -phenyl> -propionic acid Mp: 164-165 ° C from isopropanol c) B- <4- / 2- (fluorenyl- (9) -acetamido) -ethyl 7-phenyl> -propionic acid M.p .: 218-2190C from ethyl acetate.

d) β- <4- [2- (6-Bromo-quinoline-8-carboxamido) -aethyl] -phenyl> -propionic acid Mp: 212-2140C from ethanol / ethylene chloride e) β- <4- [2- (2-methyl-quinoline-8-carboxamido) -aethyl] -phenyl> -propionic acid Mp: 140-1410C from isopropanol f) β- <4- [2- (quinoline-8-carboxamido) ethyl] phenyl> propionic acid hydrochloride mp: 204-2060C from isopropanol (the compound contains 1 mol of water of crystallization).

g) B- <4- / 2- (5-bromo-2-methoxy-nicotinoylamino) -ethyl 7-phenyl-4-propionic acid Mp: 124-125 ° C. from isopropanol h) β- <4- [2- (5-chloro-2-methyl-benzoxazole-7-carboxamido) -ethyl] -phenyl> -propionic acid i) ß-44- / 2- (indole-7-carboxamido) -ethyl ~ 7-phenyl> -propionic acid Fp: 107-109 ° C from toluene.

j) β- <4- [2- (3,5-di-tert-butyl-4-hydroxy-benzamido) -ethyl] -phenyl> -propionic acid Fp .: 187-1910C from ethyl acetate.

k) β- <4- <2- [3- (3,5-di-tert-butyl-4-hydroxyphenyl) -propionamido t ethyl> -phenyl # -propionic acid (sodium salt) m.p .: 265-268 ° C.

For example, 13 β- <4- [2- (5-methyl-pyrazole-3-carboxamido) -aethyl] -phenyl> -propionic acid To a Loesang of 1.12 g of 5-methyl-pyrazole-3-carboxylic acid in 25 ml of abs. Tetrahydrofuran 1.27 ml of triethylamine and 0.85 ml of ethyl chloroformate are added at -100C. After 15 minutes you still give once 1.27 ml of triaethylamine and then 2.57 g of ß- [4- (2-Aminoaethyl) phenyl] propionic acid ethyl ester hydrochloride to Let stir for 1 hour at + 200C, suction off, concentrate the filtrate and take off the residue in methylene chloride. After extraction with 2N hydrochloric acid, 2N sodium hydroxide solution and neutralizing one dries and concentrates. The resulting crude ester is with 0.6 g of caustic soda in 30 ml of ethanol heated under reflux for 1 hour. After cooling off The precipitated sodium salt is suctioned off, dissolved in water and carefully acidified at. The deposited precipitate is recrystallized from 20% ethanol.

Yield: 22%, m.p. 202-205 ° C.

B e i 5 p i e 1 14 N- <ß- <4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl> -propionyl> -paminobenzoic acid To 7.22 g of β- <4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl> -propionic acid 2.2 g of triethylamine and 2.6 g of triethyl chloroformate are added to 100 ml of methylene chloride at -100C. After 30 minutes, a solution of 3.7 g of ethyl p-aminobenzoate is added dropwise at this temperature in 40 ml of methylene chloride, heated to 40 ° C. for 5 hours, then extracted with 2 n Hydrochloric acid, 2N sodium hydroxide solution and water, the organic phase dries and concentrates. The so precipitated ethyl ester (mp: 158-1620C) is with 50 ml of ethanol / 50 ml 1 n Sodium hydroxide solution heated on a water bath for 30 minutes, the ethanol removed and the aqueous solution acidified after extraction with methylene chloride. The precipitation it is suctioned off and recrystallized from isopropanol.

Yield: 3.5 g (40% of theory)? P: 216-2200C in an analogous manner is obtained by reacting β- <4- [2- (5-chloro-2-methoxy-benzamido) ethyl] phenyl> propionic acid with ethyl anthranilic acid a) N- <ß- <4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl> -propionic acid anthranils acid m.p .: 163-1650C from isopropanol with phenylalanine ethyl ester the b) ß- <4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl> -propionyl> phenylalanine ~ mp: 152-1540C to isopropanol with B-alanine ethyl ester N- <ß- <4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl> -propionyl> -ß alanine m.p .: 127-1300C from isopropanol be i s p i e l 15 N- <4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -cinnamoyl> -p-am benzoic acid 4.5 g of 4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -cinnamic acid and 2 g of p-aminobenzoic acid ethyl ester is dissolved in 100 ml of absolute tetrahydrofuran. At 20 ° C., 1 ml of phosphorus oxychloride is added first and then add 3 ml of triethylamine. After 4 hours one sucks off, the filtrate is concentrated completely one, the residue is treated with 2N sodium hydroxide solution and extracted with chloroform. the organic phase is shaken with 2N hydrochloric acid, dried and concentrated. The ethyl ester thus obtained (mp: 118-120 ° C.) is saponified at room temperature with 30 ml of ethanol / 10 ml of 2N sodium hydroxide solution. After 24 hours you vacuum the precipitated Remove the sodium salt, wash it well with ethanol and dissolve it in a little water. After this Acidification precipitates the desired compound and is recrystallized from ethanol.

Yield: 1.1 g (18% of theory) mp: 258-260 ° C. The substance contains 1 mole of crystal water Example In the same way as in the example 1 is obtained by reacting the ß- / 4- (2-aminoethyl) phenyl7-propionic acid ethyl ester hydrochloride with the corresponding carboxylic acid chlorides the following compounds: a) ß- <4- [2- (5-chloro-2- (ß-methoxyaethoxy) -benzamido) -aethyl] -phenyl> -propionic acid Melting point: 99-101 ° C. from isopropanol b) β- <4- [2- (2-methoxy-naphthanlin-1-carboxamido) -aethyl] -phenyl> -propionic acid Mp: 124-125 ° C. from isopropanol c) β- <4- [2- (5-chloroindole-2-carboxamido) -aethyl] -phenyl> -propionic acid Mp: 257-258 ° C. from ethanol d) β- <4- [2- (naphthalene-1-carboxamido) -aethyl] -phenyl> -propionic acid Mp: 143-1440C from isopropanol e) β- <4-r2- (naphthalene-2-carboxamido) -aethyl] -phenyl> -propionic acid Mp: 187-188 ° C from ethanol / water f) β- <4- [2- (3-methoxy-naphthalene-2-carboxamido) -aethyl] -phenyl> -propionic acid Epr 156-1570C from isopropanol g) I ~ <4-r2- (2-phenoxy-benzamido) -aethyl] -phenyl> -propionic acid Mp: 124-1250C from isopropanol h) β- <4- [2- (2-allyloxy-5-methyl-benzamido) -aethyl] -phenyl] -phenyl-propionic acid Mp: 67-690C from toluene i) β- <4- [2- (3-chloro-5-methyl-benzamido) -aethyl] -phenyl> -propionic acid Mp: 158-1600C from isopropanol / water j) β- <4- [2- (2-methoxy-5-trifluoromethyl-benzamido) -aethyl] -phenyl-propionic acid Mp: 118-121 ° C from ethyl acetate k) β- <4- [2- (4-bromo-2-methoxy-benzamido) -aethyl] -phenyly-propionic acid Mp: 108-111 ° C from ethyl acetate 1) ß- <4- [2- (5-chloro-2-methyl-benzo [b] furoyl- (7) -amino) -aethyl] -phenyl) propionic acid m.p .: 143-1450C from toluene m) β- <4- [2- (quinoline-2-carboxamido) -aethyl] -phenyl) -propionic acid Mp: 135-137 ° C (precipitated) n) β- <4- [2- (5-chloro-2- (4-methoxyphenoxy) benzamido) ethyl] phenyl> propionic acid Ip: 199-2010C-from ethanol o) β- <4- [2- (5-methylisoxazole-3-carboxamido) -aethyl] -phenyl> -propion acidic melting point: 164-167 ° C. from ethanol p) β- <4- [2- (2-ethoxy-5-methyl-benzamido) -ethyl] -phenyl-propionic acid Mp: 82-830C from xylene B e i s i e l 17 ß- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -phenyl} -propionic acid methyl ester 3.62 g of B-44-g2- (5-chloro-2-methoxy-benzamido) -ethyl 7-phenyl> -propionic acid (Preparation cf. Example 1f) is dissolved in 30 ml of methanol and hydrochloric acid is passed in and reflux for 10 hours. It is then concentrated, the residue with 2N sodium hydroxide solution added, extracted with ether and the ethereal phase after Concentrated drying.

Yield: 2.2 g = 58% mp: 58-610C.

B e i 5 p i e 1 18 In a manner analogous to that described in Example 2 is obtained by reacting a) ß- (4-aminophenyl) propionic acid with 2-ethoxy-5-chlorobenzoyl chloride β- / 4- (2-ethoxy-S-chloro-benamido) -phenyl-7-propionic acid mp: 1820C from ethanol.

b) ß- ß- (4-aminophenyl) propionic acid with 2-methoxy-5-methylbenzoyl chloride β- [4- (2-Methoxy-5-methyl-benzamido) -phenyl] -propionic acid m.p. 1640C from ethanol.

c) 4-Amino-cinnamic acid with 5-chloro-2-methoxy-benzoyl chloride 4- (5-chloro-2-methoxy-benzamido) -cinnamic acid Mp 285 ° C from ethanol / dimethylformamide d) 4-amino-cinnamic acid with 2-methoxy-5-methyl-benzoyl chloride 4- (2-Methoxa-5-methyl-benzamido) -cinnamic acid m.p. 2270C from ethanol / dimethylformamide e) 4-Amino-cinnamic acid with 2-ethoxy-5-chloro-benzoyl chloride 4- (2-ethoxy-5-chloro-benzamido) cinnamic acid Mp. 278-280 ° C from ethanol / dimethylformamide

Claims (4)

Claims 1. Phenylalkanecarboxylic acid derivatives of the general formula I in which A is an aryl, aralkyl which is optionally substituted by hydroxy, halogen, trifluoromethyl, alkyl, alkylmercapto, alkoxy, alkenyloxy, alkoxyalkoxy, alkyl-substituted amino, arylot or alkoxy-substituted aryloxy groups or arylvinyl radical, aryloxyalkyl or arylthioalkyl radical or a heterocyclic ring system optionally substituted by halogen, alkyl or alkoxy groups, Y a valence stroke or an optionally branched lower alkylene group with 1-3 carbon atoms, X a straight-chain or branched, saturated or unsaturated alkylene chain with 2 -8 carbon atoms, with at least 2 carbon atoms between the benzene ring and the carboxyl group and R being hydrogen or lower alkyl, as well as their physiologically acceptable salts, esters and amides. 2. Process for the preparation of phenylalkanecarboxylic acid derivatives of the general formula I. in which A is an aryl, aralkyl or aryloxy groups optionally substituted by hydroxyl, halogen, trifluoromethyl, alkyl, alkylmercapto, alkoxy, alkenyloxy, alkoxyalkoxy, alkyl-substituted amino, aryloxy or alkoxy-substituted aryloxy groups Arylvinyl radical, aryloxyalkyl or arylthioalkyl radical or a heterocyclic ring system optionally substituted by halogen, alkyl or alkoxy groups, Y a valence line or an optionally branched lower alkylene group with 1-3 carbon atoms, X a straight-chain or branched1 saturated or unsaturated alkylene chain with 2-8 Carbon atoms, where there must be at least 2 carbon atoms between the benzene ring and the carboxyl group and - denote hydrogen or lower alkyl, as well as their physiologically acceptable salts, esters and amides, characterized in that either a) an amine of the general formula II in which Y, X and R have the meanings given above, or their acid derivatives are reacted with a reactive acid derivative of the acid A-COOH, where A has one of the meanings given above, or b) a compound of the general formula III in which A, Y, R and X have the meanings given above and B represents a radical which is free into the carboxyl group, oxidizes, or £) a compound of the general formula IV in which A, R and Y have the values listed above, Z is a straight or branched, saturated or unsaturated alkylene chain with 1-7 carbon atoms, Z 'is Z or a valence stroke, R' is hydrogen or an alkyl group and G is the -Group or the Group, where L represents the hydroxyl group or halogen, reduced, or d) a compound of the general formula V in which A, R and Y have the meanings given above, M represents hydrogen or lower alkyl with 1-6 carbon atoms, and K represents a valence stroke or a straight or branched, saturated or unsaturated alkylene chain with 1-6 carbon atoms, with a reactive methylene component of general formula VI in which P is hydrogen, alkali metal, lower alkyl or an acyl group and Q is hydrogen, the nitrile group, lower alkyl having 1- <carbon atoms, or the radical -COOP, in which P has the meaning given above, where the obtained unsaturated compound is subsequently saponified, decarboxylated or hydrogenated, or in the event that X in general formula I represents a straight-chain or branched, saturated alkylene chain with 2-4 carbon atoms, a compound of general formula VII in which A, R and Y have the meanings given above, and M1 is hydrogen or lower alkyl with 1-2 carbon atoms, with a compound of the general formula VIII H2C = CHal2 <VIII), in which Hal is halogen, reacts or f) in the event that X in the general formula I represents a straight-chain, saturated alkylene chain having 2-4 carbon atoms, a ketone of the general formula IX in which A, R and Y have the meanings given above and U represents an alkyl group with 2-4 carbon atoms, reacts under the conditions of the "Willgerodt-Kindler synthesis", or g) a halogen compound of the general formula X in which A, R, Y, K and Hal have the meanings given above and T can be hydrogen or lower alkyl of 1-6 carbon atoms with a reactive methylene component of the general formula XI where lower alkyl, R1 is hydrogen or lower alkyl with 1-6 carbon atoms, Me is alkali or alkaline earth metals and W is the radical OR2 or the methyl group, reacted, saponified and optionally decarboxylated and then optionally the acid derivatives of the general formula I obtained into the free acid or, if desired, the free acid of the general formula I obtained is esterified, converted into an amide or into physiologically acceptable acid addition salts. 3. Use of phenylalkanecarboxylic acid derivatives of the general Formula I for the production of drugs with hypoglycemic and / or hypolipidemic Effect. 4. Pharmaceutical preparations, characterized by a content on phenylalkanecarboxylic acid derivatives of the general formula I.