GB2024813A - Acylbiphenylylaminoalkanoic acids - Google Patents

Abstract

Acylbiphenylylaminoalkanoic acids of the general formula I <IMAGE> in which R<1> signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical and n signifies a positive whole number from 3 to 5, as well as their salts of inorganic or organic barn exert on warm-blooded animals a protective action on the stomach and liver, and in addition they bring about an increase in the secretion of the pancreas and liver. In addition, they cause an inhibition of the formation of glucose from lactate and pyruvate in the liver. They are suitable for the treatment and prophylaxis of diseases which are due to disorders of the stomach or intestine or to reduced performances by the pancras, bile and/or liver. Processes for the production of the compounds and corresponding pharamaceutical products are given.

Description

SPECIFICATION Substituted amino acids, their use and production and pharmaceutical products containing same The Invention relates to substituted amino acids, their use and production and pharmaceutical products containing them. The compounds according to the invention are used in the pharmaceutical industry for the preparation of medicaments. In the investigation of N - benzoyl - anilinoalkanecarboxylic acids (D. Evans et al., J. Med. Chem. 12 (1969) 1006-10) the corresponding butyric acids showed no action of inhibiting inflammation, whilst in German published unexamined Patent Application DE-OS 19 17 036 N - acyl - anilinoalkanoic acids with a choleretic action are described, to which there are also ascribed further effects (DE-OS 2 450 680). a

and their derivatives are said to be used in agents with an anti-epileptic action (DE-OS 2 634288). In further German published unexamined Patent

2 131 679 and 2131 680) trialkoxy - benzoyl aminoalkanecarboxylic acids are described which may be used for the prophylaxis and treatment of the cardiac infarction. Now a new class of acylbiphenylylaminoalkanoic acids has been synthesised which are not mentioned in the publications cited nor are they rendered obvious by them.Furthermore it has been found that these acylbiphenylylaminoalkanoic acids possess interesting and particularly advantageous pharmacological properties. The Invention relates to acylbiphenylylaminoalkanoic acids of the general formula I

in which R signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hyd-

n signifies a positive whole number from 3 to 5, and their salts of inorganic or organic bases. As aliphatic hydrocarbon radicals which may be saturated or unsaturated, one may use straight or I branched alkyl radicals with 1 to 7 carbon atoms. Straight alkyl radicals are the methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl radical, of which those with 1 to 5, particularly 1 to 3, carbon atoms are preferred. Branched alkyl radicals with 3 to 7 carbon i atoms are, for example, the isopropyl, isobutyl, sec.-butyl or tert.-butyl radical, of which those with 3 to 5, particularly with 3 carbon atoms are preferred. Unsaturated hydrocarbon radicals are alkenyl and alkinyl radicals with 2 to 7 carbon atoms, for exanple ) the ethenyl, the ethinyl, the 1-propenyl, 1,3butadienyl, 2-butinyl radical, of which the 1-propenyl radical is preferred. As alicyclic hydrocarbon radicals one may use cycloalkyl radicals with 3 to 10 carbon atoms, for example the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radical, of which those with 5 to 7 carbon atoms are preferred. As optionally substituted phenyl groups one may

use those of the formula

signify a hydrogen atom, a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, an acyloxy group, an optionally substituted amino group, a nitro group or a trifluoromethyl group. As halogen atoms R , R and R4 one may use fluorine, chlorine or bromine, preferably fluorine and chlorine, especially

R4 one may mention inter alia those with 1 to 4 carbon atoms, of which those with 1 to 3, particularly those with 1 carbon atom are preferred. As acyloxy groups one may consider inter alia -O-CO-R groups, in which R has the meaning given above, of which the alkanoyloxy group with 1 to 7, especially 2 to 5 carbon atoms, particularly the acetoxy group, are preferred.Besides the unsubstituted amino

preponderantly substituted amino groups, of which for example one may mention alkylamino and dialkylamino groups with 1 to 4, preferably 1 or 2, carbon atoms in the alkyl radical, as well as acylamino groups with the usual acyl groups used for protecting amino groups, such as alkanoyl groups with 2 to 5 carbon atoms. As biphenylyl radicals one may use the 2-, 3- or 4-biphenylyl radical. Partially hydrogenated biphenylyl radicals are for example the 4 - cyclohexyl - phenyl radical, the 4-phenylcyclohexyl radical, the 2-cyclohexylphenyl radical. As substituents one may use halogen atoms, for example fluorine, chlorine or bromine, preferably chlorine, alkyl or alkoxy groups with 1 to 4, preferably 1, carbon atoms, optionally substituted amino groups, hydroxy or nitro groups. As salts one may use salts of inorganic and organic bases. Pharmacologically incompatible salts are converted by known methods into pharmacologically, that is to say biologically, compatible salts, which are preferred among the salts according to the Invention. As cations for the salt formation one uses mainly the cations of the alkali metals, alkaline earth metals or earth metals, but it is also possible to use the corresponding cations of organic nitrogen bases, such as amines, aminoalkanols, amino sugars or basic amino acids. For example one may mention the salts of lithium, sodium, potassium, magnesium, calcium, aluminium, ethylenediamine, dimethylamine, diethylamine, morpholine, piperidine, piperazine, methylcyclohexylamine, benzylamine, ethanolamine, diethanolamine, triethanolamine, tris - (hydroxymethyl) - amino - methane, 2 - amino - 2 -

propandiol, glucamine, N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine, arginine, quinoline. A modification of the Invention consists of acylbiphenylylaminoalkanoic acids of the general formuall*

in which R * signifies an aliphatic hydrocarbon radical with 1 to 7 carbon atoms, an alicyclic hydrocarbon radical with 3 to 10 carbon atoms or a phenyl radical

A* signifies a group of the formula

n* signifies a positive whole number from 3 to 5,

hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoromethyl group,

hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, and their salts of inorganic or organic bases.Another modification of the Invention consists of acylbiphenylylaminoalkanoic acids of the general formula 1**

in which R *signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radical

A** signifies a group of the formula

n* signifies a positive whole number from 3 to 5,

hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, a methyl group, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoromethyl group,

rogen atom and the other signifies a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, and their salts of inorganic or organic bases. A further modification of the Invention consists of acylbiphenylylaminoalkanoic acids of the general formula)***

in which

with 1 to 3 carbon atoms or a phenyl radical

A*** signifies a group of theformula

n*** signifies a positive whole number from 3 to 5,

signify a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl group,

hydrogen atom and the other signifies a hydrogen atom or a methoxy group, and their salts of inorganic or organic bases. A preferred form of embodiment of the Invention consists of acylbiphenylylaminoalkanoic acids of the genera) formula)**** -

in which

atoms, an alkenyl group with 2 or 3 carbon atoms or a phenyl group

A**** signifies a group of the formula

n**** signifies a positive whole number from 3 to 5, R2**** signifies a hydrogen atom, R3**** signifies a hydrogen atom, a fluorine atom, a 10 chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl group,

hydrogen atom, and the other signifies a hydrogen 15 atom or a methoxy group, and their pharmacologically compatible salts of inorganic or organic bases. Particularly preferred representatives of the forms of embodiment 1**** are those in which R3**** sig20 nifies a fluorine atom, a chlorine atom, a hvdroxy

pharmacologically compatible salts of inorganic or 25 organic bases. Further especially preferred representatives of the forms of embodiment 1* * or)**** are those in which A*** orA**** have the meaning of a 2-biphenylyl radical, and their pharmacologically 30 compatible salts of inorganic or organic bases. As compounds comprised by the general formula I one may mention by way of example

benzamido] - butyric acid, 4 - [2,4 - dichloro - N - (6 - methyl - biphenyl - 2 - yl) benzamido] - butyric acid, 4 - [N - (2' - ethyl - biphenyl - 2 - yl) - n - butyramido] butyric acid, 4 - [3 - fluoro - 4 - methyl - N - (3, 2' - dimethyl biphenyl - 2 - yl) - benzamido] - butyric acid, 4 - [3,5 - dimethoxy - N - (4 - chloro - biphenyl - 3 - yl) - benzamido] - butyric acid, 4 -[N - (4, 4'- dimethyl - biphenyl - 3 - yl) hexanoylamido] - butyric acid, 4 - [3 - trifluoromethyl - N - (6 - ethoxy - biphenyl - 3 yl) - benzamido] - butyric acid, 4 - [2 - bromo - N - (2' - methoxy - biphenyl - 4 - yl) benzamido] - butyric acid, 4 - [3- methoxy - 4 - methyl - N - (4' - methoxy biphenyl - 4 - yl) - benzamido] - butyric acid, 5 - [4 - methyl - 3 - nitro - N - (biphenyl - 2 - yl)benzamido] valeric acid, 5 - [3 - chloro - N - (4' - methoxy - biphenyl - 4 - yl) benzamido] valeric acid, 5 - [4 - fluoro - N - (6 - ethoxy - biphenyl - 3 - yl) benzamido] -valeric acid, 5 - [4 - methoxy - N - (2' - fluoro - biphenyl - 2 - yl) benzamido] valeric acid, 5 - [N - (4' - chloro - biphenyl - 4- yl) methacryloylamido] - valeric acid, 6 - [2 - methoxy - N - (6 - methyl - biphenyl - 2 - yl) benzamido] - caproic acid, 6 - [3,5 - dichloro - N - (4, 4' - dimethyl - biphenyl - 3 yl) - benzamido] - caproic acid, 6 - [2,4 - dimethyl - N - (4' - chloro - biphenyl - 4 - yl) benzamido] - caproic acid, 6 - [3 - methoxy - 4 - methyl - N - (2' - fluoro - biphenyl - 2 - yl) - benzamido] - caproic acid, 6 - [4 - nitro - N - (biphenyl - 2 - yl) - benzamido] caproic acid, 6 - [N - (4' - ethoxy - biphenyl - 4 - yi) isovaleroylamido] - caproic acid. Preferred representatives of the compounds according to the Invention are 4 - [4 - chloro - N - (biphenyl - 2 - yl) - benzamido] butyric acid, 4 - [N - (biphenyl - 2 - yl) - acetamido] - butyric acid, 4 - [4 - fluoro - N - (biphenyl - 2 - yl) - benzamido] butyric acid, 4 - [N - (biphenyl - 2 - yi) - crotonoylamido] - butyric acid, 6 - [4 - chloro - N - (biphenyl - 2 - yl) - benzamido] caproic acid, 6 - [2,4 - dichloro - N - (biphenyl - 2 - yl) - benzamido] - caproic acid, 6 - [5 - chloro - 2 - methoxy - N - (biphenyl - 2 - yi) benzamido] - caproic acid, 5 - [2 - hydroxy - N - (biphenyl - 2 - yl) - benzamido] valeric acid and their salts. The compounds according to the Invention display valuable pharmacological properties which make them commercially utilisable. In warm-blooded animals they develop a protective action for stomach and liver, and in addition they bring about an increase in the secretion of the pancreas and liver (bile). In addition they bring about an inhibition of the formation of glucose from lactate and pyruvate in the liver. Because of their advantageous activity, the acylbiphenylylaminoalkanoic acids are suitable for the treatment and prophylaxis of diseases which are attributable to disorders of the stomach or intestine or to reduced performances of the pancreas, bile and/or liver. For example one treats gastric or intestinal ulcers, Billroth II, pancreatic insufficiency, sprue, indigestions and malabsorptions of different aetiology, acute and chronic pancreatitis, indirect disorders of the pancreatic function (supporting of the production of secretin and pancreozymin), as well as gall bladder and bile duct inflammations, disorders of the bile flow, motility disorders of the bile ducts, a feeling of repletion, flatulence, constipation, upper abdominal complaint, hepato-biliarfunctional disorders, acute and chronic hepatitis, intoxications of the liver, fatty degeneration of the liver,diabetes (maturity onset diabetes), insulin deficiency diabetes in the form of "brittle diabetes", late diabetic damage. The Invention thus furthermore relates to a process for the treatment of mammals suffering from one or more of the above-mentioned diseases. The process is characterised in that a therapeutically active and pharmacologically tolerated amount of one or more compounds of the general formulae I, I*,

to the sick mammal. The Invention also relates to the use of the compounds according to the Invention in combating the illnesses indicated above. The Invention likewise comprises the use of the compounds i according to the Invention for the preparation of medicaments which are employed for combating the illnesses listed. The Invention further relates to pharmaceutical products which contain one or more of the acylbiphenylylaminoalkanoic acids of the general formula I

in which RI signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical, n signifies a positive whole number from 3 to 5, and/ortheir pharmacologically compatible salts of inorganic or organic bases. Forms of embodiment of the pharmaceutical products are those which contain acylbiphenylylaminoalkanoic acids of the formulae I*,

and/ortheir pharmacologically compatible salts of inorganic or organic bases. The pharmaceutical products are produced according to known processes. As pharmaceutical products the new compounds can be used as such or if desired in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations in addition to the active principles contain pharmaceutical carriers, the active principle content of these mixtures is 1 to 95, preferably 15 to 85 per cent by weight of the total mixture. In accordance with the Invention it is possible in the field of human and veterinary medicine to use the active principles in any desired form, for example systemic, provided that the formation or maintenance of adequate blood or tissue levels or local concentrations of active principle is ensured. This can either be carried out by oral, rectal or parenteral administration in suitable doses. More advantageously the pharmaceutical preparation of the active principle occurs in the form of unit doses which are designed forthe particular form of administration desired. A unit dose can be, for example, a tablet, a pill, a capsule, a suppository, or a measured volume of a powder, a granulate, a solution, an emulsion, a suspension, a sol or a gel. "Unit dose" in the sense of the present Invention is to be understood to mean a physically determined unit which contains an individual quantity of the active component in combination with a pharmaceutical carrier, the active principle content of which corresponds to a fraction or multiple of the therapeutical individual dose. An individual dose preferably contains the quantity of active principle which is dispensed in a single application and which corresponds usually to a whole, a half or a third or a quarter of the daily dose. If for an individual therapeutical administration only a fraction, such as a half or a quarter of the unit dose is required, the unit dose is advantageously divisible, for example in the form of a tablet with a notch for breaking. The pharmaceutical preparations according to the Invention, if they occur in unit doses and are intended for application, for example to human beings, may contain 0.5 to 1000 mg, advantageously 1 to 750 mg and especially 5 to 500 mg of active principle. Generally speaking, it has been found advantageous both in human medicine and in veterinary medicine, to administer the active principle or principles in oral administration in a daily dose of 0.01 to 40, preferably 0.1 to 30, especially 0.2 to 20 mg/kg body weight, possibly in the form of several, preferably 2 to 3 individual administrations, in orderto achieve the desired results. An individual administration contains the active principle or principles in quantities of 0.01 to 20, preferably 0.1 to 15, especially 0.2 to 10 mg/kg body weight. In a parenteral treatment, for example intromuscularor intravenous application, it is possible to use similar dosages. With this therapy one applies 50 to 1000 mg of active principle. The therapeutical administration of the pharmaceutical preparation is carried out in the case of long-term medication generally at fixed points of time, such as 1 to 4 times a day, for example before or after meals and/or in the evening. In the case of acute attacks the medication is carried out at varying points of time. Under certain circumstances it may be necessary to differ from the said dosages, namely according to the nature, the body weight and the age of the patient to be treated, the nature and severity of the disease, the nature of the preparation and the application of the drug as well as the period of time or interval within which the administration takes place. Thus in some cases it may be sufficient to manage with less than the above-mentioned quantity of active principle, whereas in other cases the quantity of active principle mentioned above must be exceeded.The determination of the optimum dosage and type of application of the active principles necessary in each case can at anytime be carried out by the expert on the basis of his technical knowledge. The pharmaceutical preparations consist as a rule of the active principles according to the Invention and non-toxic pharmaceutically compatible drug excipients which are used as an admixture or diluent in the solid, semi-solid or liquid form or as an encapsulating agent, for example in the form of a capsule, a tablet coating, a bag or another container, for the therapeutically active component. An excipient can, for example, serve as a vehicle for the uptake of the medicament by the body, as a formulation aid, as a sweetening agent, as a flavour corrector, as a colouring material or as a preservative. The carriers are in each instance adapted by the specialist to the diseases which are to be treated with the pharmaceutical preparations. For oral use it is possibleto use, for example, tablets, pills, hard and soft capsules, for example of gelatine, dispersible powders, granulates, aqueous and oily suspensions, emulsions, solutions or syrups. Tablets can contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or lactose; granulating and distributing agents, for example maize starch or alginates; binders such as for example starch, gelatine or gum acacia; and lubricants, such as for example aluminium or magnesium stearate, talcum or silicone oil. They can also be provided with a coating which can also be designed in such a way that it gives a delayed dissolution and resorption of the drug in the gastrointestinal tract and therefore ensures, for example, a better compatibility, protraction or retarding. Gelatine capsules can contain the pharmaceutical product mixed with a solid diluent, for example calcium carbonate or kaolin, or an oily diluent, for example olive oil, groundnut oil or liquid paraffin. Aqueous suspensions can contain suspension agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, gum dragon or gum acacia; dispersants and wetting agents, for example polyoxyethylene stearate, heptadecaethylene oxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; preservatives, such as for example methyl or propyl hydroxybenzoates; flavouring materials; sweetening agents, for example sodium cyclamate, saccharin. Oily suspensions can contain for example groundnut oil, olive oil, sesame oil, coconut oil or liquid paraffin and thickeners such as for example beeswax, paraffin wax or cetyl alcohol; also they may contain sweeteners, flavouring materials and anti-oxidants. Powders and granulates which are dispersible in water can contain the pharmaceutical products in admixture with dispersants, wetting agents and suspending agents, for example those mentioned above, as well as sweeteners, flavouring materials and colouring materials. Emulsions can contain, for example, olive oil, groundnut oil or liquid paraffin as well as emulsifiers, such as for example gum acacia, gum dragon, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavouring materials. For rectal use of the pharmaceutical products one uses suppositories, which are produced with the help of binders which melt at rectal temperature, for example cocoa butter or polyethyleneglycols. For parenteral use of the pharmaceutical products one uses sterile injectable aqueous suspensions, isotonic saline solution or other solutions which can contain dispersants or wetting agents and/or pharmacologically compatible diluents, for example propyleneglycol or butyleneglycol. The active principle or principles can if desired be formulated with one or more of the said carrier materials or additives also in a microencapsulated form. If the acylbiphenylylaminoalkanoic acids according to the Invention and/ortheir salts are to be used for the treatment of diseases which are based on disorders of the stomach or intestine or on reduced performances of the pancreas, bile and/or liver, the pharmaceutical preparations can also contain one or more other pharmacologically active components of other groups of pharmaceutical products, such as antacids, for example aluminium hydroxide, magnesium aluminate; tranquilizers, such as benzodiazepines, for example Diazepam; spasmolytics, such as for example Bietamiverin, Camylofin; anticholinergics, such as for example oxyphencyclimine, phencarbamide; despumation agents, for example dimethylpolysiloxane; laxatives, for example Bisacodyl; swelling agents; if desired also ferments, bile acids, antibiotics, vitamins, amino acids or fatty acid mixtures. If the acylbiphenylylaminoalkanoic acids and/or their salts are formulated as antidiabetic products, the pharmaceutical preparations can also contain one or more pharmacologically active components belonging to different groups of pharmaceutical products, such as additional antidiabetics (sulphonamides, sulphonyl ureas), for example carbutamide, tolbutamide, chlorpropamide, glibenclamide, glibornuride, glisoxepide, gliquidone, glymidine, or hypolipidaemics, such as benzafibrat or nicotinic acid as well as their derivatives and salts.Afurther object of the Invention is a process for the production of acylbiphenylylaminoalkanoic acids of the general formula I

in which R signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenyl radical, n signifies a positive whole number from 3 to 5, and their salts of inorganic and organic bases, which is characterised by the fact that a) a biphenylylaminoalkanoic acid of the general formula II A-NH-CnH2n-COOH (II), in which A and n habe the meanings given above, if desired with protection of the carboxyl group, is acylated with an acyl derivative of the general formula III

group, and RI has the meaning given above, and if desired is then converted into a salt or else b)a biphenylylaminoalkenoicacid of the general formula IV

in which R , A and n have the meanings given above, is hydrogenated, if desired with protection of the carboxyl group, and if desired is then converted into a salt or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V

in which R', A and n have the meanings given above and G signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a salt. For the production of the compounds of modifications I*, I**, I*** * or 1* *** corresponding initial

**** in which the substituents have the corresponding meaning, are reacted. If the biphenylylaminoalkanoic acids of the formula II are reacted with the protection of the carboxyl group, those representatives are used the protective groups of which do not react with the acyl derivatives III. Suitable representatives are for example esters of alkanols, including those with 1 to 5 carbon atoms, or phenalkanols, such as methyl, propyl, butyl, benzyl or phenethyl esters, possibly also solutions with inorganic or organic bases, such as alkali or alkaline earth metal hydroxides, ammonia, tertiary nitrogen bases (for example triethylamine, pyridine). In the acyl derivatives III a leaving group R7 is for example a hydroxy group, a halogen atom, preferably a chlorine or bromine atom, an alkylsulphonyloxy or benzenesulphonyloxy group, such as a mesyloxy or p-tolylsulphonyloxy group, an alkoxy group, preferably a methoxy or ethoxy group, an alkylmercapto group, such as a methylmercapto or ethylmercapto group. The reaction of the biphenylylaminoalkanoic acids II with the acyl derivatives III is carried out by known processes. The reaction is carried out in suitable solvents, such as water or hydrocarbons, for example benzene, toluene, xylene, or ethers, for example tetrahydrofuran, dioxan, 1,2-dimethoxyethane, or ketones, for example methylethylketone, or amides, for example dimethylformamide, or sulphoxides, for example dimethylsulphoxide. Expediently the acylation, if R7 signifies a leaving group, is carried out in the presence of an acidbinding agent (proton acceptor). Suitable as such one may mention by way of example alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or alkali metal carbonates such as sodium carbonate, potassium carbonate, or tertiary amines such as pyridine, triethylamine, ethyldiisopropylamine. If the acyl derivatives III are acid anhyd-

group, it is also sufficientto heat the compounds II and III in an inert solvent. The reaction can be varied within wide limits, for example-20 to +100[deg]C, temperatures around room temperature (10 to 30[deg]C) being preferred. If the compounds II are acylated with the protection of the carboxyl group, then after the acylation the protective group is split off again in the usual manner. If salts are used as protective group, the liberation of the acids I obtained is effected by reaction with a suitable mineral acid, such as hydrochloric acid, or sulphuric acid. If esters are used as protective groups, the acylation is followed by the saponification of the reaction product to give compounds of the formula I. The saponification is preferably carried out with an alcoholic (for example ethanolic) alkali metal hydroxide (for example potassium hydroxide) solution at room temperature, optionally with the addition of an inert diluent such as dioxan or benzene. The initial compounds of the formula are produced by various processes which are in themselves known. Thus, they are obtained by reacting halogenalkanoic acids of the formula VI, preferably with the protection of the carboxyl group as an ester group, with a biphenylylamine of the formula VII

in which n and A have the meanings given above and R8 signifies a halogen atom, preferably a chlorine or bromine atom. The reaction is expediently carried out in the presence of an inert solvent, for example benzene, cyclohexane, diethyl ether, with the addition of a proton acceptor. One may use forthis purpose, for example, an excess of the amine VII used for the reaction. If desired, however, it is also possible to add a different proton acceptor. The starting products II are also obtained by reacting an alkanoic acid ester VIII

in which n has the meaning given above and R9 signifies an alkyl group with 1 to 5 carbon atoms or a benzyl group, with a biphenylylamine VII. The reaction is expediently carried out in the presence of an inert solvent, such as hydrocarbons, for example benzene, toluene, xylene or ethers, for example tetrahydrofuran, dioxan, 1,2-dimethoxyethane, or ketones, for example methylethylketone, or amides, for example dimethylformamide, or sulphoxides, for example dimethylsulphoxide, or nitriles, for example acetonitrile. Expediently the reactants are heated in the solvent, for example by boiling under reflux. The protective group R9 is expediently split off only afterthe reaction of the resultant intermediate products II with the acyl derivatives III so as to obtain the end products I. The initial compounds If are also obtained by the solvolysis of functional biphenylylaminoalkanoic acid derivatives of the general formula IX

in which A, n and G have the meanings given above, by means of processes which are known to the technician. Expedient forms of execution are described under process variant c). The starting products II are further obtained by reacting biphenylylamines VII with lactones of the aeneral formula X

in which n has the meaning given above, in a known manner. The reaction is carried out for example by heating the reactants VII and X (e.g. to the boiling point of the solvent) in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or nitriles, for example acetonitrile.The acid obtained can then be converted if desired into the corresponding esters, for example by heating in the corresponding alcohols in the presence of a mineral acid, such as hydrochloric acid or sulphuric acid. The intermediate products are alternatively obtained in a known manner by the hydrogenation of biphenylyliminoalkanoic acids XI

in which A and n have the meaning given above, optionally with the protection of the carboxyl group in a known manner. The hydrogenation is carried out for example with Raney nickel under hydrogen pressures of 1 to 250 atmospheres at room temperature in absolute ethanol. The acids XI are accessible by reacting the biphenylylamines VII with oxo-acid esters XII

in which n and R9 have the meanings given above. The hydrogenation according to process variant b) is carried out according to methods such as are known to the technician. Thus the biphenylylaminoalkenoic acids IV are hydrogenated with hydrogen in the presence of a transition metal or noble metal catalyst or the corresponding oxides or complexes in inert solvents. Suitable metals, for example, are platinum, palladium, iridium, rhodium. A summary of the hydrogenation process is to be found inter alia in Kirk-Othmer 11,418-462; Ullmann

any protective group which may be present is carried out in the usual manner. The alkenoic acids IV are obtained for example from the halogenalkenoic acid esters XIII

in which R9 and n have the meanings given above and R10 signifies a halogen atom, preferably a bromine atom, by amination with a biphenylylamine VII, acylation with an acyl derivative III and if desired subsequent saponification. The production is carried out by known methods, halogenation (production of XIII) and.amination, for example analogous to J. Heterocycl. Chem. 8 (1971) 21; acylation and saponification are carried out analogously to the description of the present Application. The halogenalkanoic acids VI and biphenylylamines VII are known compounds or are produced by analogy processes; for example the halogenalkanoic acids VI are accessible by sovolysis, such as hydrolysis or alcoholysis, of the corresponding lactones and subsequent halogenation. The biphenylylamines VII are obtained by the reduction of corresponding nitro compounds which are accessible by the nitration of corresponding biphenyls. The solvolysis according to process variant c) is carried out by processes known to the technician. A functional acid derivative in this case is understood to mean a derivative whose functional group G can be converted by solvolysis into the free carboxyl group. Typical representatives are for example those

which Y X signifies an oxygen or a sulphur atom or a substituted nitrogen atom, especially an imino, alkylimino or hydroxyimino group and Y signifies a hydroxy group or a monovalent eliminable electrophilic radical, especially a free or substituted amino group, preferably a monoalkyl or dialkyl or aryl amino group, a hydroxyamino or hydrazino group, a hydrazobenzene group, a 2-hydroxyethylamino group, a free or substituted mercapto group, preferably an alkylthio group, a substituted hydroxy group, preferably an alkoxy group, an azido, a chloro or bromo radical,a morpholino group or a piperidino group, in which Y is not a hydroxy group if X represents an oxygen atom. An alkyl radical of an alkylimino, a monoalkylamino, a dialkylamino, an alkylthio and an alkoxy group is to be understood to mean an alkyl radical with up to 5 carbon atoms, whilst an aryl radical of an arylamino group is to be understood to mean an aryl radical with up to 10 carbon atoms. Preferred representatives of the acid derivative V are those in which G signifies a-CN group or a

X signifies an oxygen atom, a sulphur atom or an imino group and Y signifies an amino, monoalkylamino, dialkylamino, phenylamino, alkoxy, alkylthio, chloro or bromo radical. Particularly preferred representatives of the acid derivative V are the corresponding acid amides, alkyl esters of the acid and nitriles, that is to say those compounds of the formula V in which G represents a -CO-NH2, -CO-NH-R9, -CO-NR92, -CO-O-R9 or-CN group and R9 has the meaning given above. They constitute valuable intermediate products for the production of the compounds I and their salts. For the solvolysis of the functional carboxylic acid derivatives V one uses a medium which gives off water, which consists wholly or partly of water or of agents which split off water under hydrolysis conditions. The reaction can be carried out as a homogeneous reaction, in which case one usually operates in the presence of a polar organic solvent or a solutizer. Advantageously one uses as solvent, for example, low-molecular alcohols, dioxan, acetone, low-molecular carboxylic acids, N-methylpyrrolidone, sulpholan or dimethylsulphoxide. However, it is also possible to carry out the hydrolysis as a heterogeneous reaction. The pH of the medium which splits off water depends upon the chemical nature of the acid derivative used, but also on the nature of the compound of the general formula I which is desired and it can therefore be neutral, acid or basic.It is adjusted to the desired value with acids, bases or buffers. The hydrolysis temperatures are between 0[deg]C and the boiling point of the medium which splits off water, generally between 0[deg] and 150[deg]C, and especially between 20 and 120[deg]C. The hydrolysis temperatures depend individually also on whether one operates under pressure or without pressure. The reaction times are between 10 minutes and 20 hours according to the charge, the reaction temperatures and other reaction parameters. After the hydrolysis has ended, the acids I are isolated by using the usual methods, for example by recrystallisation or by the acidification of their solutions, if desired with the concentration of their solutions. In order to purify it, their alkaline solution can be extracted with an organic solvent which is not miscible with the alkaline solution, for example diethyl ether, benzene, chlorobenzene, chloroform or methylene chloride. The carboxylic acid derivatives V are obtained by methods which are current to the technician. For example they are obtained by the reaction of functional halogenalkanoic acid derivatives XIV

in which R8, n and G have the meanings given above, with biphenylylamines VII followed by acylation with acyl derivatives III. The conversion of the acids of the general formula

salts can be carried out by direct alkaline hydrolysis of the acid derivatives of the formula V. As alkaline reactant one uses the particular inorganic or organic base whose salt is desired. However, one also obtains the salts if one reacts the acids of the general formula I with the stoichiometrical equivalent of corresponding base, for example sodium hydroxide or sodium alcoholate, or else readily soluble salts are converted by double decomposition into sparingly soluble salts, or else any salts are converted into pharmacologically compatible salts. The following Examples illustrate the Invention in greater detail, but without restricting it. The abbreviations MP and BP signify melting point and boiling point respectively. EXAMPLE 1

butyric acid RI =p-chlorophenyl, A = biphenyl-2-yl, n = 3 a) Ethyl 4-(biphenyl-2-yl) aminobutyrate 30.0 g of 2-aminobiphenyl, 23.4 g of ethyl diisopropylamine and 35.4 g of ethyl 4-bromobutyrate are heated togetherto 150[deg] for 3 hours while stirring. After cooling, the reaction product is stirred with diethyl ether, the precipitated salt is filtered off, and the residue (remaining after evaporating off the ether) is recrystallized from isopropyl alcohol to obtain 32.0 g (63.7% of theory) of ethyl 4- (biphenyl - 2 yl) amino butyrate, MP 60[deg] to 62[deg].

zamido] butyrate 9.8 g ofp-chlorobenzoyl chloride is added drop by drop at room temperature (while stirring and within 30 minutes) to a solution of 16.0 g of ethyl 4 (biphenyl - 2 - yl) - aminobutyrate and 7.3 g of ethyl diisopropylamine in 70 ml of benzene.After a further hour, the precipitate is filtered off, the filtrate is evaporated, and the evaporation residue is recrystallized from cyclohexane to obtain 18.0 g (75.6% of theory) of ethyl 4 - [(p - chloro - N - (biphenyl - 2 - yl) benzamido] butyrate, MP 100[deg] to 102[deg]. c) 4-[p-chloro-N-(biphenyl-2-yl)benzamido] butyric acid 15.0 g of ethyl 4 - [p - chloro - N - (biphenyl - 2 - yl) benzamido] - butyrate is dissolved in 100 ml of benzene and, after the addition thereto of a solution of 2.8 g of potassium hydroxide in 20 ml of ethanol, is then stirred at room temperature for 5 hours. The solvent is then distilled off in vacuo, and the obtained residue is dissolved in water. The resulting aqueous solution is acidified with dilute hydrochloric acid, and the precipitate, which separates out, is taken up in methylene chloride.The residue remaining, after drying and distilling off the methylene chloride, is recrystallized from an ethanol/water mixture (2:1 ) to obtain 10.1 g (72.1% of theory) of 4 - [p - chloro - N - (biphenyl - 2 - yl) benzamido] butyric acid, MP 135[deg] to 137[deg]. EXAMPLE 2

zamido] butyric acid R' = a, a, a - trifluoro - m - tolyl, A = biphenyl - 2 - yl, n =3

yl) benzamido] butyrate Analogously to Example 1 b, 11.8 g of ethyl 4 (biphenyl -2-yl) aminobutyrate and 5.4 g of ethyldiisopropylamine are reacted in 70 ml of benzene with 8.7 g of m - trifluoromethylbenzoyl chloride. The reaction product is recrystallized from a mixture of isopropyl alcohol and water (1:1) to obtain 16.0 g (84.4% of theory) of ethyl - 4- [m -trifluoromethyl - N

67.. b) 4-[m-trifluoromethyl-N-(biphenyl-2-yl) benzamido] butyric acid 16.0 g of ethyl - 4 - [m - trifluoromethyl - N -

benzene are mixed with a solution of 3.4 g of potassium hydroxide in 25 ml of ethanol and stirred at roon temperature for 8 hours.When further processed analogously to Example 1 c, 13.7 g (91.3% of theory) of 4 - [m - trifluoromethyl - N - (biphenyl - 2 - yl) benzamido] butyric acid, MP 156[deg] to 157[deg], are obtained. EXAMPLE 3

butyric acid RI = p - fluorophenyl, A = biphenyl - 2 - yl, n = 3

zamido] butyrate Analogously to Example 1 b, 10.0 g of ethyl 4 (biphenyl - 2 - yl) aminobutyrate and 4.6 g of ethyldiisopropylamine in 50 ml of benzene are reacted with 5.6 g ofp-fluorobenzoyl chloride. The reaction product is recrystallized from cyclohexane to obtain 12.1 g (84.6% of theory) of ethyl 4 - [p - fluoro - N (biphenyl - 2 - yl) - benzamido butyrate, MP 83[deg] to 84.. b) 4-[p-fluoro-N-(biphenyl-2-yl)benzamido] butyric acid 11.2 g of ethyl 4 - [p - fluoro - N - (biphenyl - 2 - yl) benzamido] - butyrate in 50 ml of benzene is mixed with a solution of 2.2 g of potassium hydroxide in 20 ml of ethanol and stirred at room temperature for 8 hours. When processed analogously to Example 1 c, 7.1 g (71.7% of theory) of 4 - [p - fluoro - N - (biphenyl -2-yl) benzamido] butyric acid, MP 120[deg] to 122[deg], are obtained. EXAMPLE 4

RI = 5-chloro-2-methoxyphenyl, A = biphenyl - 2 - yl, n=3 Analogously to Example 1,10.0 g of ethyl 4 (biphenyl - 2 - yl) aminobutyrate and 4.6 g of ethyldiisopropylamine in 50 ml of benzene are reacted with a solution of 7.3 g of 5 - chloro - 2 - methoxybenzoyl chloride in 20 ml of benzene to obtain, as reaction product, 15.0 g (94.1% of theory) of ethyl 4 -

benzamido] butyrate as a viscous non-distillable oil. The saponification of this ester yields 12.4 g (88% of theory) of 4 - [5 - chloro - 2 - methoxy - N - (biphenyl 2 - yl) benzamido] butyric acid, MP 160[deg] to 162[deg]. EXAMPLE 5

Analogously to Example 1,16.0 g of ethyl 4(biphenyl - 2- yl) aminobutyrate and 7.3 g of ethyldiisopropylamine in 70 ml of benzene are reacted with 4.4 g of acetyl chloride to obtain, as reaction product, 14.0 g (76.2% of theory) of ethyl 4 - [N (biphenyl - 2 - yl) acetamido] butyrate as a viscous non-distillable oil. The saponification of this ester and recrystallization of the crude product obtained from isopropyl alcohol yields 10.1 g (79.0% of theory) of 4 - [N - (biphenyl - 2 - yl) acetamido] butyric acid, MP 124[deg] to 125[deg]. EXAMPLE 6

RI = CH3-CH=CH-, A = biphenyl - 2 - yl, n = Analogously to Example 1, 10.0 g of ethyl 4 -

diisopropylamine in 70 ml of benzene are reacted with 3.8 g of crotonyl chloride to obtain, as reaction product, 10.1 g (81.5% of theory) of ethyl 4 - [N (biphenyl 2 - yl) crotonoylamido] butyrate as a viscous non-distillable oil. The saponification of this ester and recrystallization of the crude product obtained from isopropyl alcohol yields 5.1 g (55% of theory) of 4 - [N - (biphenyl - 2 - yl) crotonoylamido] butyric acid, MP 127[deg] to 128[deg]. EXAMPLE 7

valeric acid RI =p - chlorophenyl, A = biphenyl - 2 - yl, n = 4 50.0 g of 2-aminobiphenyl, 38.2 g of ethyldiisopropyamine and 61.9 g of ethyl 5-bromovalerate are reacted analogously to Example 1 a to obtain 80.0 g of ethyl 5 - (biphenyl - 2 - yl) aminovalerate as a non-crystallizing oil. 30.0 g of this ester is reacted, analogously to Example 1 b, with 13.1 g of ethyldiisopropylamine and 17.1 g ofp - chorobenzoyl chloride in 70 ml of benzene; the ethyl 5 -[p - chloro - N - (biphenyl - 2 yl) benzamido] valerate obtained as an oily intermediate product is then saponified analogously to Example 1 cto obtain 22.1 g (53.7% of theory) of 5 [p chloro - N - (biphenyl - 2 - yl) benzamidoJ valeric acid, MP 170[deg] to 173[deg]. EXAMPLE 8

valeric acid RI = o - hydroxyphenyl, A = biphenyl - 2 - yl, n = 4 15.0 g of ethyl 5 - (biphenyl - 2 - yl) ami novalerate is reacted, analogously to Example 1 b, with 6.6 g of ethyldiisopropylamine and 10.0 g of o - acetoxybenzoylchloride in 70 ml of benzene to obtain, as reaction product, 17.0 g (73.4% of theory) of ethyl 5 -[o acetoxy - N - (biphenyl 2 - yl) - benzamido] valerate as a viscous non-distillable oil. The saponification of

hydroxy- N - (biphenyl - 2 - yl) benzamido] valeric acid, MP 138[deg] to 139[deg]. EXAMPLE 9

caproic acid RI =p - chlorophenyl, A = biphenyl - 2 - yl, n = 5 20.0 g of 2-aminobiphenyl, 15.3 g of ethyldiisopropylamine and 26.3 g of ethyl 6-bromocaproate are reacted, analogously to Example 1 a, to obtain 36.0 g

non-crystallizing oil. 18.0 g of this ester are reacted, analogously to Example 1 b, with 7.5 g of ethyldiisopropylamine and 10.1 g ofp-chlorobenzoyl chloride in 70 ml of benzene. The resulting reaction product is purified chromatographically over a silica gel column (eluent: methylene chloride) to obtain

(biphenyl - 2 - yl) benzamido] caproate as a viscous non-distillable oil. Saponification of this ester yields 8.1 g (75.1% of theory) of 6 - [p - chloro - N - (biphenyl - 2 - yl) benzamido] caproic acid, MP 93[deg] to 95[deg]. EXAMPLE 10

benzamido] caproic acid RI = 5 - chloro - 2 - methoxyphenyl, A = biphenyl - 2 -

8.0 g of ethyl 6 - (biphenyl - 2 - yl) aminocaproate and 3.3 g of ethyldiisopropylamine in 50 ml of benzene are reacted with a solution of 5.3 g of 5 - chloro 2 - methoxy - benzoyl chloride in 20 ml of benzene, analogously to Example 1 a, to obtain, as reaction product, 11.1 g (90% of theory) of ethyl 6 - [5 - chloro - 2 - methoxy - N - (biphenyl - 2 - yl) benzamido] caproate as a viscous non-distillable oil. The saponification of this ester yields 7.0 g (67% of theory) of 6 - [5 - chloro - 2 - methoxy - N - (biphenyl - 2 - yl) benzamido] - caproic acid, MP 164[deg] to 165[deg]. EXAMPLE 11

Analogously to Example 1010.0 g of ethyl 6-

diisopropylamine and 3.4 isobutyryl chloride in 70 ml of benzene yields 8.9 g (72.6% of theory) of ethyl 6

viscous non-distillable oil. The saponification of this ester yields 6.1 g (74% of theory) of 6 - [N - (biphenyl 2-yl) isobutyramido] caproic acid, MP 120[deg]to 121[deg]. EXAMPLE 12

zamido]butyric acid RI =p - chlorophenyl, A = biphenyl - 4 - yl, n = 3

24.0 g (57.3% of theory) of ethyl'4 - (biphenyl - 4 - yl) aminobutyrate, MP 82[deg] to 84[deg], are obtained analogously to Example 1 b, from 25.0 g of 4-aminobiphenyl, 19.2 g of ethyldiisopropylamine and 28.9 g of ethyl 4-bromobutyrate.

butyric acid Analogously to Example 1 b, 10.0 g of ethyl 4 (biphenyl -4-yl) aminobutyrate and 4.6 g of ethyldiisopropylamine in 70 ml of benzene are reacted with 6.2 g ofp-chlorobenzoyl chloride to obtain 9.4 g (62.9% of theory) of ethyl 4 - [p - chloro - N - (biphenyl -4-yl) benzamido] butyrate as a viscous nondistillable oil. Saponification of this ester, analogously to Example 1 a, yields 7.0 g (79.7% of theory) of

butyric acid, MP 192[deg] to 194[deg]. EXAMPLE 13

benzamido] butyric acid RI =p - chlorophenyl, A = 6 - methoxybiphenyl - 3 -

aminobutyrate 29.5 g of 5 - amino - 2 - methoxybiphenyl, 19.2 g of ethyldiisopropylamine and 28.9 g of ethyl 4-bromobutyrate are heated together (while stirring) for 4 hours at 125[deg]. After cooling, the resulting reaction product is stirred with diethyl ether and filtered from the precipitated salt.The residue (remaining after evaporating off the ether) is recrystallized from isopropyl alcohol to obtain 22.5 g (48.5% of theory) of ethyl 4 - (6 - methoxybiphenyl - 3 - yl) aminobutyrate, MP 71 [deg] to 72[deg]. b) 4-[p-chloro-N-(6-methoxybiphenyl-3-yl) benzamido] butyric acid 8.0 g of ethyl 4 - (6 - methoxybiphenyl - 3 - yl) aminobutyrate and, 3.3 g of ethyldiisopropylamine in 50 ml of benzene are reacted, analogously to Example 1 b, with 4.6 g ofp-chlorobenzoyl chloride. The reaction product is dissolved in 50 ml of benzene and, after the addition thereto of a solution of 2.3 g of potassium hydroxide in 20 ml of ethanol, is then stirred for 8 hours at room temperature. After distilling off the solvent, the residue is dissolved in water; the resulting solution is acidified with dilute hydrochloric acid and extracted with diethyl ether.The residue (remaining after evaporating off the ether) is

obtain 8.1 g (73.5% of theory) of 4 - [p - chloro - N - (6 - methoxybiphenyl - 3 - yl) - benzamidol butyric acid, MP 114[deg] to 116[deg]. EXAMPLE 14 4 - [5 - chloro - 2 - methoxy - N - (6 - methoxybiphenyl

RI = 5 - chloro- 2 - methoxyphenyl, A = 6 - methoxybiphenyl - 3 - -yl, n = 3 Analogously to Example 13, reacting 7.0 g of ethyl 4 - (6 - methoxybiphenyl - 3 - yl) aminobutyrate with 4.6 g of 5 - chloro - 2 - methoxybenzoyl chloride, followed by saponification of the intermediate product, yields 7.1 g (70.1% of theory) of 4-[5 - chloro - 2 - methoxy - N - (6 - methoxybiphenyl - 3 - yl) benzamido] - butyric acid, MP 155[deg] to 156[deg]. EXAMPLE 15

caproic acid R = 2, 4 - dichlorophenyl, A = biphenyl - 2 - yl, n = 5 Following the procedure of Example 9, but substituting 2, 4- dichlorobenzoyl chloride for p-chlorobenzoyl chloride, yields 6 [2,4 - dichloro - N

112. to 113[deg], from ethyl acetate/petrol ether (1:1). EXAMPLE 16

R = p - chlorophenyl, A = 1', 2', 3', 4', 5', 6' - hexahydrobiphenyl - 4 - yl, n = 3 Following the procedure of Example 1 a-c, but substitutingp - cyclohexylaniline for 2 - amino -

hexahydrobiphenyl - 4 - yi) - benzamido] butyric acid, MP 75[deg] to 77[deg], is obtained from isopropyl alcohol/water (1:1). EXAMPLE 17 5 - [p - chloro - N - (biphenyl - 2 - yl) benzamido] valeric acid

A solution of 8.0 g of ethyl 5 - (biphenyl - 2 - yl) aminovalerate (see Example 7) in 60 ml of benzene is mixed with a solution of 2.2 g of potassium hydroxide in 20 ml of ethanol. After allowing the resulting admixture to stand for 24 hours at room temperature, the solvent mixture is distilled off in vacuo. The residue is then dissolved in water; the obtained aqueous solution is washed with diethyl ether and then acidified with dilute hydrochloric acid. The formed precipitate, which is oily at first, is taken up in dichloromethane. The solvent is then distilled off and the residue recrystallized from ethyl acetate/pet- . rol ether (1:1) to obtain 5.6 g (77.3% of theory) of 5 [N - (biphenyl - 2 - yi) amino] valeric acid, MP 73[deg] to 75..

valeric acid

is dissolved in 40 ml of 0.2 N caustic soda solution. Into the resulting clear solution (while vigorously stirring and constantly controlling the pH) 3.5 g of p-chlorobenzoyl chloride is added, drop by drop, while concurrently adding dilute caustic soda solution in orderto maintain the pH at between 7 and 8. After the addition of acid chloride is complete, the solution is stirred for a further 30 minutes at pH 8 and then acidified to pH 3 with dilute hydrochloric acid. The precipitate, which is oily at first crystallizes after a time. It is filtered off and recrystallized from isopropyl alcohol to obtain 7.6 g (93% of theory) of 5 - [p chloro - N - (biphenyl - 2 - yl) benzamido] valeric acid, MP 170[deg] to 173[deg], which is identical with the compound obtained by the procedure of Example 7.

EXAMPLE 18 Ampoules containing 600 mg of 4 - [p - chloro - N (biphenyl - 2 - yi) benzamido] butyric acid; size of batch: 250 kg. 25.0 kg of 1, 2 - propyleneglycol and 150.0 kg of double-distilled water are placed in a vessel to which 15.0 kg of 4 - [p - chloro - N - (biphenyl - 2 - yl) benzamido] butyric acid are added. Then, while stirring, caustic soda solution (10 percent by weight NaOH) is slowly added. When a solution is obtained, the pH is adjusted to from 7.5 to 8.0. Sodium pyrosulfite*) is added, and the resulting mixture is stirred until all components have dissolved. Using double-distilled water, the solution is made up to 250 kg. The solution is then charged into 10-ml ampoules and sterilized in an autoclave for 30 minutes at 120[deg].

EXAMPLE 19 Ampoules containing 600 mg of 4-[N - (biphenyl 2 - yl) - crotonoylamido] butyric acid; size of batch: 250 kg. 50.0 kg of 1, 2- propyleneglycol and 150.0 kg of double-distilled water are placed in a vessel. While

crotonoylamido] butyric acid are added thereto. Then caustic soda solution (10 per cent by weight NaOH) is added, and the resulting mixture is adjusted to a pH of 8.0. Using double-distilled water, . it is made up to 250 kg. The solution is charged into 10-ml ampoules and sterilized in an autoclave at 120[deg] for 30 minutes.

EXAMPLE 20 Tablets containing 50 mg of 4 - [p - fluoro - N (biphenyl-2-yl) benzamido] butyric acid. 25.0 kg of 4 - p - fluoro - N - (biphenyl - 2 - yl) benzamido] - butyric acid, 35.0 kg of lactose and 26.0 kg of maize starch are granulated with 21.5 kg of polyvinylpyrrolidone (molecular weight: approx. 25,000) in about 6 liters of water. The granulate is passed through a sieve with a mesh width of 1.25 mm and, after drying, is admixed with 8.0 kg of carboxymethylcellulose, 2.5 kg of talcum and 1.0 kg of magnesium stearate. The dry granulate is pressed into tablets with a diameter of 8 mm, a weight of 250 mg and a hardness of from 5 to 6 kg. In a similar manner tablets containing 4 - [p chloro - N - (biphenyl - 2 - yl) benzamidoj butyric acid or 4 - [N - (biphenyl - 2 - yi) crotonoylamido] butyric acid are prepared.

EXAMPLE 21

butyric acid, 24.0 kg of lactose and 16.0 kg of maize starch are granulated with 4.0 kg of polyvinylpyrrolidone (molecular weight: approx. 25,000) in about 5.5 liters of water and then pressed through a sieve with a mesh width of 1.25 mm. After drying, 10.0 kg ofcarboxymethylcellulose, 4.0 kg of talcum and 2.0 kg of magnesium stearate are admixed therewith. On an eccentric machine the resulting granulate is pressed into tablets with a diameter of 9 mm, a weight of 250 mg and a hardness of from 4 to 5 kg.

EXAMPLE 22 Tablets containing 300 mg of4-[p - chloro - N biphenyl - 2 - yl) benzamido] butyric acid. 60.0 kg of 4 - [p - chloro - N - (biphenyl - 2 - yl) benzamido] - butyric acid, 12.0 kg of lactose and 8.0 kg of maize starch are granulated with 4.0 kg of polyvinylpyrrolidone (molecular weight: approx. 25,000) in about 6 liters of water and then pressed through a sieve with a mesh width of 1.25 mm. After drying, 10.0 kg of carboxymethylcellulose, 4.0 kg of talcum and 2.0 kg of magnesium stearate are admixed therewith. On a rotary pelleting machine the resulting granulate is pressed into tablets with a diameter of 11 mm, a weight of 500 mg and a hardness of from 6 to 7 kg. Analogously, tablets are produced which contain 300 mg of 4 - [p - chloro - N - (biphenyl - 2 - yl) benzamido] caproic acid. EXAMPLE 23 10,000 capsules with an active-principle content of 50 mg are produced from the following components: 500 g of 4 - [N - (biphenyl - 2 - yl) crotonoylamido] butyric acid, 495 g of microcrystalline cellulose and 5 g of amorphous silica. The active principle in finely-powdered form, the cellulose and the silica are thoroughly mixed and packed into hard gelatin (size 4) capsules.

PHARMACOLOGY The acylbiphenylylamino acids exert a marked protective action on the stomach and liver of rats, and in addition increase the pancreatic and bile secretion of rats, in which they are found to be superior to the known commercial preparations, for example Piprozoline, Carbenoxolone. In addition they bring about an inhibition of the formation of glucose from lactate and pyruvate in the liver of rats, in which they are superior to known commercial preparations, for example Buformin, Phenformin. In the tables which follow, the compounds investigated are characterised by a serial number which has been allocated as follows: Serial No. Name of compound 1 Piprozoline 2 Carbenoxolone 3 Buformin 4 Phenformin 5 4 - [N - (biphenyl - 2 - yi) - acetamido] butyric acid

benzamido] - butyric acid 7 6 - [p - chloro - N - (biphenyl- 2 - yl) benzamido] - caproic acid 8 4 - [m - trifluoromethyl - N - (biphenyl - 2 - yl) - benzamido] - butyric acid

crotonoylamido] - butyric acid 11 5 -[p - chloro - N - (biphenyl - 2 - yl)benzamido] -valeric acid 12 6 - [2,4 - dichloro - N - (biphenyl - 2 yl) - benzamido] - caproic acid 13 6-[5-chloro-2-methoxy-N(biphenyl - 2 - yi) - benzamido] - caproic acid 14 4 - [p - chloro - N - (biphenyl - 2 - yl)benzamido] - butyric acid 15 5 - [o - hydroxy - N - (biphenyl - 2 - Yl)benzamido] - valeric acid

(biphenyl - 2 - yl) - benzamido] butyric acid

biphenyl - 3 - yl)- benzamido] butyric acid

methoxy - biphenyl - 3 - yl) - benzamido] - butyric acid 20 4 - [p - chloro - N - (1', 2', 3', 4', 5', 6', hexahydro - biphenyl - 4 - yi) - benzamido] - butyric acid. Table I shows the stomach protective action (reversal of the stomach ulcer caused by the ligature of the pylorus and administering 100 mg/kg of acetylsalicylic acid per os) after intraduodenal application in the rat, the lethal action after intraperitoneal administration in the mouse and also the therapeuti-

the compounds according to the Invention. Table Stomach protection action

* ) Dose which reduces the mean ulcer index by 50%

Table II shows investigations regarding the antihepatotoxic action (ED25;50) of the compounds according to the Invention after oral application to waking rats and the lethal action after intraperitoneal 5 application on the mouse (LDso) as well as the therapeutical quotients (TQ = LD5o/ED25 and

Table II Antihepatotoxic effect, toxicity and therapeutical quotient

Explanations to Table II: *) ED25 or EDso = dose which shortens the hexobarbital narcosis by 25 and 50% respectively of rats suffering from liver damage from CCl4. **) LDso (per os) cited from Herrmann et al. Arzneim. - Forsch. 27 (1977) 467 ***) peros,i.p.notapplicable Table III shows for representatives of the compounds according to the Invention the influence on the bile secretion (choleresis) of narcosed rats afterthe . intraduodenal application (ED50) and the lethal action on the mouse (LDso) after intraperitoneal application

Table III Bile secretion, toxicity and therapeutical quotient

the bile secretion (liquid volume; 30-min. fraction) by a maximum of 50% * * ) LDso (p.o.) cited from Herrmann et al.Arzneim.Forsch. 27 (1977) 467 Table IV shows, for representatives of the compounds according to the Invention, the influence of the pancreatic secretion of narcotized rats after the intraduodenal application (EDso) and the lethal action on the mouse (LDso) after intraperitoneal application, as well as the therapeutical quotient (TQ =

Table IV Pancreatic secretion, toxicity and therapeutical quotient

* ED50 = dose which brings about an increase in the pancreatic secretion (liquid volume; 30-min, fraction) of a maximum of 50% ** ) LDso (per os) cited from Herrmann et al. Arzneim.-Forsch. 27 (1977) 467. ***) peros, i.p. not applicable Table V shows the results of the investigation of the influence of representatives of the compounds according to the Invention on the formation of glucose from lactate and pyruvate in the isolated perfused liver of fasting rats, the inhibition of the glucose formation being shown for a substance concentration of 0.2 mmole/litre in the perfusate and the ED50- determined from 4 concentrations the range from 0.02 to 1.00 mmol/litre-and the lethal action on the mouse (LDso) after intraperitoneal application. Table V Inhibition of the formation of glucose from lactate and pyruvate in the isolated perfused rat liver and toxicity on the mouse

Explanations to Table V: * ) substance concentration of0.2 mmol/litre in the perfusate ** ED50 = dose which brings about an inhibition of the glucose formation of a maximum of 50% *** ) cited from Soling H. D., Creutzfeldt, W., Int Biguanid Symp., Aachen 1960, Stuttgart, Thieme Verlag ****) cited from Bertarelli, P., Boll.chim.farm. 97 (1958) 396 The compounds according to the Invention are characterised as compared with the comparison compounds 3 and 4 by a considerably stronger inhibition of the formation of glucose from lactate and pyruvate. Whereas 3 and 4 exert practically no inhibition at the concentrations used, with the compounds according to the Invention it is possible to achieve inhibition effects of up to 99%. The determination of the pharmacological properties was carried out by the folliwng methods: Influence on the pancreatic and bile secretion of the narcotized rat Execution of experiment Male Sprague-Dawley rats (body weight 250-300 g) are narcotized with 1.2 g/kg urethane i.m. Then the abdominal cavity is opened medially, the bile duct is ligatured shortly above the place where it leads into the duodenum and also nearto the hepatic duct, and both sections are catherised towards the liver. As in the rat all the pancreatic ducts lead out into the central section of the bile duct, it is possible in this way to discharge separately the pancreatic secretion from the distal (ligatured) section and the bile from the proximal section of the bile duct. The quantities of pancreatic juice and bile juice secreted are measured at intervals of 30 minutes over a period from 2 hours before to 3 hours after the intraduodenal administration of the compounds to be tested (quantity of liquid administered 5 ml/kg). The body temperature of the animals is maintained at 36 to 38[deg]C by means of electric blankets and radiation; the temperature is monitored rectally. Evaluation: The liquid volumes of the 30-minute fractions after the administration of the substance are related in each case to the quantity of bile or pancreatic juice secreted priorto the application of the substance (= 100%, mean of the last two measurements). The maximum percentage increase in the pancreatic or bile secretion is represented according to the dose and from this the EDso is determined by interpolation. Test for antihepatotoxic effect Influence on the hexobarbital sleeping period of the rate after liver damage by CCl4 Execution of test: On the basis of VOGEL et al. (Arzneim.-Forsch. 25 (1975) 82) liver cell damage is produced in fastening female Sprague-Dawley rats 190 10 g body weight, 10 animals/dose pertest batch) by the oral administration of carbon tetrachloride (0.15 ml/kg CCI4 in 2.5 ml/kg olive oil), and the extent of this damage is determined by the prolongation of the sleeping period induced by hexobarbital sodium (50 mg/ml/kg i.v.; caudal vein, duration of injection 5-60 seconds) 47 hours after the administration of the CCI4. The compounds to be tested are administered 1 hour prior to the administration of CCI4 orally in a liquid volume of 10 ml/kg. Evaluation: The antihepatotoxic effect of the compounds to be tested (sodium salts in aqueous solution) is determined by the reduction of the prolongation of the

in the groups treated as compared with the prolongation of the sleeping period of the CCI4 control group (= 100%). The EDso is determined by interpolation from the dose/effect curve. Testing the antiulcerogenic action The ulcer provocation is carried out on rats which have been made to fast for 24 hours (female, 180-200 g) by ligature of the pylorus (under ether narcosis) and the oral application of 100 mg/10ml/kg acetylsalicylic acid. The administration of the substances was carried out intraduodenally (2.5 ml/kg) immediately afterthe ligature of the pylorus. The closure of the wound was carried out by means of Michel clamps. 4 hours after this, the animals were destroyed whilst inebriated with ether by dislocation of the atlas and the stomach was resected. The stomach opened longitudinally is fixed on a cork board, and using a stereomicroscope with an enlargement of 10 X the number of size (= diameter) of any ulcers present were determined.The product of the degree of severity (according to the following scale of points) and the number of ulcers was used as the individual ulcer index. Scale of points:

As a measure of the antiulcerogenic effect one used the reduction in the mean ulcer index of each treated group as compared with that of the control group(= 100%). Determination of the inhibition of the formation of glucose in the isolated prefused rat liver For this purpose one uses young male SpragueDawley rats (160 to 200 g). The rats are kept in cages of up to 5 animals in a temperature-controlled room (23[deg]C) with a fixed day/night rhythm (12/12 hours). Food is withheld from the animals 20 to 22 hours prior to the operation. They are allowed to take water ad lib. The operation and the perfusion of the liver are carried out using the technique of R. Scholz et al. (Eur. J. Biochem. 38 (1973) 64-72). The perfusion liquid used is Kreb-Henseleit bicarbonate buffer (pH 7.4), which is saturated with an oxygen/carbon dioxide mixture (95/5) and contains 1.6 mmol/litre of L-lactate and 0.2 mmol/litre pyruvate. The perfusion liquid is pumped into the livervia a cannula inserted into the portal vein.The effluent perfusion liquid is collected via a cannula inserted into the Vena cava. The liver is perfused for approximately 2 hours. The test compounds are infused for 16 minutes each from the 32nd to the 80th minute after the perfusion in increasing concentrations (0.02 to 1.00 mmol/litre). Samples of the effluent perfusion liquid are collected at one-minute intervals and analysed for glucose, lactate and pyruvate using standard enzymatic methods. The percentages shown in Table V relate to the condition occuring before and after the after the administration of the compounds, the changes caused solely by lactate and pyruvate being set as being equal to 100%. Determination of toxicity The toxicity investigations are carried out on female NMRI mice (body weight 22-26 g). The animals (5 animals per dose) are given food and water ad lib. Different doses of the substances are administered intraperitoneally. The duration of observation is 14 days. The LD50, i.e. the dose at which 50% of the animals die, is determined graphically from the dose/effect curve.

Claims (12)

1. Acylbiphenylylaminoalkanoic acids of the general formula I

in which R signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenyl radical, N signifies a positive whole number from 3 to 5, and their salts of inorganic or organic bases.

2. Acylbiphenylylaminoalkanoic acids of the general formula I*

in which R * signifies an aliphatic hydrocarbon radical with 1 to 7 carbon atoms, an alicyclic hydrocarbon radical with

3 to 10 carbon atoms or a phenyl radical

A* signifies a group of the formula

n* signifies a positive whole number from 3 to 5, R1*, R3* and R4* are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to

4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to

5 carbon atoms, a nitro group or a trifluoromethyl group,

hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group,and their salts of inorganic or organic bases. 3. Acylbiphenylylaminoalkanoic acids of the general formula 1**

in which R signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radical

A** signifies a group of the formula

N* * signifies a positive whole number from 3 to 5, R ** signifies a hydrogen atom, R ** and R4" are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, a methyl group, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoromethyl group, one of the substituents R5** or R6** signifies a hydrogen atom and the other signifies a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, and their salts of inorganic or organic bases. 4. Acylbiphenylylaminoalkanoic acids of the general formula 1* *

in which R *** signifies an aliphatic hydrocarbon radical wit 1 to 3 carbon atoms or a phenyl radical

A*** signifies a group of the formula

N*** is a positive whole number from 3 to 5, R *** signifies a hydrogen atom, R3*** and R4*** are the same or different and signify a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl group,

hydrogen atom and the other signifies a hydrogen atom or a methoxy group, and their salts of inorganic or organic bases. 5. Acylbiphenylylaminoalkanoic acids of the general formula 1****

in which R **** signifies an alkyl group with 1 to 3 carbon atoms, an alkenyl radical with 2 or 3 carbon atoms, or a phenyl group

A**** signifies a group of the formula

n* *** signifies a positive whole number from 3 to 5, R **** signifies a hydrogen atom, R **** signifies a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl group, R4**** signifies a hydrogen atom or a chlorine atom,

hydrogen atom and the other signifies a hydrogen atom or a methoxy group, and their pharmacologically compatible salts of inorganic or organic bases.

6. Compounds in accordance with Claim 4 or 5, in which A*** orA**** hasthe meaning of a 2-biphenylyl radical, and their pharmacologically compatible salts or inorganic or organic bases.

7. Compounds in accordance with Claim 5, in which R **** signifies a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group and R5 and R6**** denote hydrogen atoms, and their pharmacologically compatible salts of inorganic or organic bases.

8. Compounds in accordance with Claim 5, in which A**** has the meaning of a 2-biphenylyl radical, R3**** signifies a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group and

pharmacologically compatible salts of inorganic or organic bases.

9. Pharmaceutical products containing as active ingredient one or more compounds in accordance with Claim 1 to 8.

10. Process for the production of acylbiphenylylaminoalkanoic acids of the general formula

in which R signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenyl radical, n signifies a positive whole number from 3 to 5, and their salts of inorganic bases, characterized by the fact that a) a biphenylylaminoalkanoic acid of the general formula II

in which A and n have the meanings given above, optionally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III R -CO-R7 (III), in which R7 is a leaving group or a R -CO-O- group and RI has the meaning given above, and if desired is then converted into a salt or

in which R , A and n have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then converted into a salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V

in which R , A and n have the meanings given above and G signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a salt.

11. A process for the production of acyl-

mula I according to to Claim 1, substantially as described with reference to the specific examples hereinbefore set forth.

12. Pharmaceutical compositions containing from 1% to 95% by weight of the total mixture of at least one compound according to Claim 1 to 8 in admixture with one or more solid or liquid pharmaceutically acceptable inert carriers.