GB2024814A

GB2024814A - Acyl (bicyclic aryl) - aminoalkanoic acids

Info

Publication number: GB2024814A
Application number: GB7920410A
Authority: GB
Original assignee: Byk Gulden Lomberg Chemische Fabrik GmbH
Current assignee: Takeda GmbH
Priority date: 1978-06-14
Filing date: 1979-06-12
Publication date: 1980-01-16
Also published as: PL216291A1; PT69763A; DK245079A; GR65664B; IL57553A0; FR2432502A1; DE2923698A1; NZ190723A; AU525311B2; ATE797T1; AU4797779A; HU180209B; BE876934A; ZA792944B; JPS554375A; ES481493A1; DE2962385D1; EP0006217A1; EP0006217B1

Abstract

Acyl (bicyclic aryl) - aminoalkanoic 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 bicyclic aryl radical and n signifies 3, 4 or 5, as well as their salts of inorganic or organic bases exert in warm-blooded animals a protective action on the stomach and an increase in the pancreatic secretion, and in addition they exert an action on the liver and bile. Furthermore, they bring about 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 a@ attributed to disorders of the stomach or intestine or to reduced performances of the pancreas, bile and/or liver, or the treatment of diabetes. Processes for the production of the compounds and suitable pharmaceutical products are given.

Description

SPECIFICATION Substituted aminoalkanoic acids, their use and production and pharmaceutical products containing same The invention relates to substituted aminoalkanoic acids, their use and production and pharmaceutical products containing same. The compounds according to the invention are used in the pharmaceutical industry for the preparation of medicaments. Naphthylaminoalkanoic acids and their esters are ascribed a central depressive and strongly sedative action (DE-OS 1.543.802). When N - benzoyl anilinoalkanoic acids were investigated (D. Evans et al., J. Med. Chem. 12 (1969) 1006-10) the corresponding butyric acids showed no action of inhibiting inflammation, whereas in German published unexamined Patent Application DE-OS 1.917.036 N-acylanilinoalkanoic acids are described with a choleretic action, to which also further actions are attributed

aminoalkanecarboxylic acids and their derivatives are said to be used in agents with an anti-epileptic effect (DE-OS 2.634.288).In further German published unexamined Patent Applications (DE-OS 2.131.626, 2.131.674, 2.131.675, 2.131.679 and 2.131.680) trialkoxy- benzoyl - aminoalkanecarboxylic acids are described which may be used for the prophylaxis and treatment of the cardiac infarction. A new class of acyl - (bicyclic aryl) - aminoalkanoic acids has now been synthesised which is not mentioned in the publications cited nor is rendered obvious by them. Furthermore it has been found that these acyl(bicyclic aryl) - aminoalkanoic acids display interesting and particularly advantageous pharmacological properties. The invention relates to acyl (bicyclic aryl) aminoalkanoic 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 bicyclic aryl radical with 8 to 12 carbon atoms, n signifies 3, 4 or 5, and their salts of inorganic or organic bases. As aliphatic hydrocarbon radicals which may be saturated or unsaturated one may use straight or 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, especially with 1 to 3, carbon atoms are preferred. Branched alkyl radicals with 3 to 7 carbon 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 example the ethenyl, the ethinyl, the 1 - propenyl, 1, 3 butadienyl, 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

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, especially those with 1 carbon atoms, are preferred. As acyloxy groups one may use inter alia - 0 - CO - R groups, in which R' has the meaning given above, of which the alkanoyloxy groups with 1 to 7, especially with 2 to 5, carbon atoms, particularly the acetoxy group, are preferred.Besides the unsubstituted amino group one may use as substituents R , R and R4 also substituted amino groups, of which one may mention by way of example alkylamino and dialkylamino groups with 1 to 4, preferably with 1 or 2, carbon atoms in the alkyl radical, and also acylamino groups with the usual acyl groups used for protecting amino groups, such as alkanoyl groups with 2 to 5 carbon atoms. As bicyclic aryl radicals with 8 to 12 carbon atoms one may use, for example, those which are derived from pentalene, indene, naphthalene, azulene, heptalene, biphenylene. Hydrogenated bicyclic aryl radicals are derived from dihydro, tetrahydro or hexahydro derivatives, as representatives of which we may mention 1, 4- dihydronaphthalene, 1,2,3,4tetrahydronaphthalene, indane, 6, 7, 8, 9-tetrahydro - 5H - benzocycloheptene, 4, 5, 6, 7, 8, 9 - hexahydro 1 H - cyclopentacyclooctene. The bicyclic aryl radicals can also have single or multiple substitution, in which case the substituents may be halogen atoms, for example fluorine or chlorine, alkyl or alkoxy groups with 1 to 4 carbon atoms, optionally substituted amino groups, hydroxy or nitro groups. When calculating the number of carbon atoms of the aryl radical no account is taken of the carbon atoms of the substituents. 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 formation of salts one uses particularly 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 methylpropanol, 2 - amino - 2 - methyl -1, 3- propandiol, glucamine, N - methylglucamine, glucosamine, N - methylglucosamine, lysine, ornithine, arginine, quinoline. One embodiment of the invention consists of acyl (bicyclic aryl) - aminoalkanoic acids of the general formula I

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 an indenyl, indanyl, naphthyl, dihydronaphthyl ortetrahydronaphthyl radical substituted

a hydrogen atom, a halogen atom, 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, a hydroxy group or a trifluoromethyl group,

hydrogen atom, a halogen atom, a methyl group, an alkoxy group with 1 to 4 carbon atoms, a nitro group or a trifluoromethyl group, and their salts of inorganic or organic bases.Preferred A radicals substituted with R5* and R"

ronaphthyl - (1) radicals. A further embodiment of the invention consists of acyl - (bicyclic aryl) - aminoalkanoic acids of the general formula 1**

in which

A** signifies a group of the formula

n** signifies 3, 4 or 5,

nify a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a nitro group, a hydroxy group or a trifluoromethyl group,

hydrogen atom, a chlorine atom, an ethoxy group, a methoxy group or a nitro group, and their salts of inorganic or organic bases. A further embodiment of the invention consists of acyl - (bicyclic aryl) - aminoalkanoic acids of the general formula I ***

in which

A*** signifies a group of the formula

n*** signifies 3, 4 or 5,

signify a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a nitro group, a hydroxy group or a trifluoromethyl group,

sent a hydrogen atom, a chlorine atom, a methoxy group or a nitro group, and their salts of inorganic or organic bases. A further embodiment of the invention consists of acyl - (bicyclic aryl) - aminoalkanoic acids of the general formula I ****

in which

A **** signifies a group of the formula

n**** signifies 3, 4 or 5,

and represent a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a nitro group, a hydroxy group or a trifluoromethyl group,

resent a hydrogen atom, a chlorine atom, a methoxy group or a nitro group, and their salts of inorganic or organic bases. Preferred representatives of the embodiments I**,

resent a hydrogen atom, a chlorine atom, a methoxy group, a hydroxy group or a trifluoromethyl group;

their pharmacologically compatible salts with inorganic or organic bases. Particularly preferred representatives of the emb-

n "** have the meanings given above, and their pharmacologically compatible salts with inorganic or organic bases. Further especially preferred representatives are

chlorine atom or a hydroxy group; R4** orR4*** sig-

and their pharmacologically compatible salts with inorganic or organic bases. Compounds according to the invention are, for example: 4 - [4 - methoxy - N - (4 - chloro - 1 - naphthyl) benzamido] - butyric acid; 4 - [3 - trifluoromethyl - N - (2 - methyl - 1 - naphthyl) benzamido] - butyric acid; 4 - [3, 5 - dichloro - N - (2 - methoxy - 1 - naphthyl) benzamido] - butyric acid; 4 - [2 - fluoro - N - (4 - methyl - 1 - naphthyl) benzamido] - butyric acid;

butyric acid; 4 - [3 - methoxy-4- methyl - N - (1 - naphthyl) benzamido] - butyric acid; 4 - [N - (4 - hydroxy - 1 - naphthyl) - 4 - methylbenzamido] - butyric acid; 4 - [3 - fluoro - 4 - methyl - N - (4 - nitro -1 - naphthyl) benzamido] - butyric acid;

butyric acid; 4 - [4 - methyl - 3 - nitro - N - (7 - methoxy -1naphthyl) - benzamido] - butyric acid; 4 - [N - (4 - bromo -1 - naphthyl) - hexanamido] butyric acid; 4 - [N - (3, 4 - dinitro - 1 - naphthyl) - acetamido] butyric acid;4 - [N - (3 - bromo - 4 - methyl - 1 - naphthyl) isovalerylamido] - butyric acid; 4 - [4 - chloro - 3 - nitro - N - (4 - ethoxy - 1 - naphthyl) - benzamido] - valeric acid; 4 - [2,4 - dichloro - N - (4 - chloro - 1 - naphthyl) benzamido] - valeric acid; 5 - [N - (4 - methoxy - 1 - naphthyl) - 3 - methylbenzamido] -valeric acid; 5 - [N - (5 - nitro - 1 - naphthyl) - propionamido] valeric acid; 6 - [3,4 - dichloro - N - (1 - naphthyl) - benzamido] caproic acid; 6 - [4 - methyl - 3 - nitro - N - (4 - ethoxy - 1 - naphthyl) - benzamido] - caproic acid; 6-[N-(1 - naphthyl) - methacryloylamido] - caproic acid; 6 - [N - (5 - methoxy - 2 - naphthyl) - crotonoylamido] - caproic acid;

naphthyl) - hexanamido] - butyric acid; 4 - [N - (7 - methoxy -1,2,3,4 - tetra hydro - 2 naphthyl) - propionamido] - butyric acid;

naphthyl) - acetamido] - caproic acid;4 - [3,4 - dichloro - N - (5, 6, 7, 8 - tetrahydro - 1 naphthyl) - benzamido] - butyric acid; 4 - [N - (1 - indanyl) - acetamido] - butyric acid; 4 - [4 - chloro - N - (2 - indanyl) - benzamido] - butyric acid; 6 - [3,4 - dichloro - N - (2 - indanyl) - benzamido] caproic acid; 4 - [3,4 - dimethoxy - N - (4 - indanyl) - benzamido] butyric acid; 6 - [3 - fluoro - 4 - methyl - N - (4 - indanyl) - benzamido] - caproic acid; 6 - [N - (5 - indanyl) - isovalerylamido] - caproic acid. Particularly interesting representatives of the compounds according to the invention are: 4 - [N - (1 - naphthyl) - acetamido] - butyric acid; 4 - [3 - trifluoromethyl - N - (1 - naphthyl) - benzamido] - butyric acid; 4 - [5 - chloro - 2 - methoxy - N - (1 - naphthyl) benzamido] - butyric acid; 5 - [4 - chloro - N - (1 - naphthyl) - benzamido] valeric acid; 5-[N-(1 - naphthyl) - isobutyramido] - valeric acid;

- naphthyl) - propionamido] - butyrate;

butyric acid; 5 - [4 - chloro - N - (indan - 5 - yl) - benzamido] valeric acid; 4 - [2 - hydroxy - N - (1 - naphthyl) - benzamido] butyric acid

caproic acid; and their pharmacologically compatible salts. The compounds according to the invention display valuable pharmacological properties which make them commercially utilisable. In warm-blooded animals they develop in the main a stomach protective action and an increase in the pancreatic secretion, and in addition they exert an effect on the liver and gall (antihepatotoxic effect and choleresis). 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 acyl (bicyclic aryl) - aminoalkanoic 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 complaints, hepatobiliar functional disorders, acute and chronic hepatitis, intoxications of the liver, fatty degenerations 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,

tered 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 according to the invention for the preparation of medicaments which are employed for combating the illnesses listed. The invention further relates to pharmaceutical preparations which contain one or more of the acyl (bicyclic aryl) - aminoalkanoic 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 bicyclic aryl radical with 8 to 12 carbon atoms, n signifies 3, 4 or 5, and/ortheir pharmacologically compatible salts of inorganic or organic bases. Forms of embodiment of the pharmaceutical preparations are those which contain acyl (bicyclic aryl)

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 mainte- . nance of adequate blood ortissue 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 advantageouslythe 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, ora 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 order to 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 intramuscular or intravenous application, it is possible to use, similar dosages. With this therapy one applies 50 to 100 mg of active principles. 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, forthetherapeutically 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 possible to use, for example, tablets, pills, hard and soft capsules, for example or 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 pa raffi n. 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 suspension agents, 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 solutions 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 acyl (bicyclic aryl) - aminoalkanoic acids according to the invention or their 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; tranquilisers, 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 acyl (bicyclic aryl) - aminoalkanoic acids and/ortheir 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 or sulphonyl ureas), for example carbutamide, tolbutamide, chlorpropamide, glibenclamide, glibornuride, glisoxepide, gliquidone, glymidine, or hypolipidaemics, such as benzafibrat and nicotinic acid as well as their derivatives and salts. A further object of the invention is a process for the production of the acyl (bicyclic aryl) - aminoalkanoic 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 bicyclic aryl radical with 8 to 12 carbon atoms, n signifies 3, 4 or 5, and their salt of inorganic or organic bases, which is characterised by the fact that a) a (bicyclic aryl) - aminoalkanoic acid of the general formula II

in which A and n have the meanings given above, optionally with protection of the carboxyl group, is acylated with an acyl derivative of the general formula III

-group, and R has the meaning given above, and if desired is then converted into a salt or b) a (bicyclic aryl)- aminoalkenoic acid of the general formula IV

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

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

given above, are reacted. If the (bicyclic aryl) - aminoalkanoic acids of the formula II are made to react whilst protecting the carboxyl group, those representatives are used the protective groups of which do not react with the acyl derivative 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 ester, possibly also solutions with inorganic or organic bases, such as alkali or alkaline earth metal oxides, 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 mesyloxy or p - tolyl - sulphonyloxy group, an alkoxy group, preferably a methoxy or ethoxy group, an alkylmercapto group, such as a methylmercapto or ethylmercapto group. The reaction of the (bicyclic aryl) - aminoalkanoic 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

yethane or ketones, for example methylethylketone, or amides, for example dimethylformamide, or sulphoxides, for example dimethylsulphoxide. Expediently, if R7 signifies a leaving group, the acylation is carried out in the presence of an acid-binding agent (proton acceptor). Suitable as such, for example, are 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 anhydrides, that is to say if R7 signifies a R'-CO-O-group, it is also sufficient to heat the compounds II and II 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 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 II are produced by various processes which are in themselves known. Thus, they are obtained by reacting halogen-alkanoic acids of the formula VI, preferably with the protection of the carboxyl group as an ester group, with a (bicyclic aryl) - amine 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 for this 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 react- ing an alkenoic acid ester VIII

in which n has the meaning given above and R 9 signifies an alkyl group with 1 to 5 carbon atoms or a benzyl group, with a (bicyclic aryl) - amine 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 R 9 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 II are also obtained by the solvolysis of functional (bicyclic aryl) - aminoalkanoic acid derivatives of the general formula IX A-NH-CnH2n-G (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 (bicyclic aryl) - amines VII with lactones of the general 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 into the corresponding esters, for example by heating in the corresponding alkanols in the presence of a mineral acid, such as hydrochloric acid or sulphuric acid. The intermediate products II are alternatively obtained in a known manner by the hydrogenation of (bicyclic aryl) - iminoalkanoic acids XI

in which A and n have the meanings given above, optionally with the protection of the carboxyl group. 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 (bicyclic aryl) - amines 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 (bicyclic aryl) aminoalkenoic 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 10, 109-114, 541-555; 14, 630-649. The splitting off of 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 R 9 and n have the meanings given above and R10 signifies a halogen atom, preferably a bromine atom, by amination with a (bicyclic aryl) amine 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 (bicyclic aryl) amines VII are known compounds or are produced by analogy processes; for example the halogenalkanoic acids VI are accessible by solvolysis, such as hydrolysis or alcoholysis, of the corresponding lactones and subsequent halogenation. (Bicyclic aryl) - amines VII are obtained by the reduction of corresponding nitro compounds which are accessible by the nitration of suitable bicyclic aryls. 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 in which G signifies a-CN group or a

group, in which 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 alkylamino, 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 group, in which 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 derivatives 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 repre-

O-R 9 or-CN group and R 9 has the meaning given above. They constitute valuable intermediate products for the production of the compounds I and their salts. Forthe 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, possibly with concentration of their solutions. In order to purify them, 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 (bicyclic aryl) - amines 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

acid R' = p - chlorophenyl, A = - naphthyl, n = 3 4.0 g of a- naphthylamine, 3.6 g of ethyldiisopropylamine, 5.5 g of ethyl 4 - bromobutyrate and 20 ml of cyclohexane are heated to boiling together for 3 hours under reflux. After cooling, the formed precipitate is filtered off, and the filtrate is concentrated by evaporation in vacuo. The residue (after evaporation) is dissolved in 30 ml of benzene. After the addition of 3.5 g of ethyldiisopropylamine thereto, a mixture of 4.7 g ofp - chlorobenzoyl chloride and 10 ml of benzene is added (accompanied by agitation) drop by drop at room temperature over a period of 30 minutes. The agitation is then continued for a further hour, the precipitate is filtered off, and the filtrate concentrated by evaporation.The evaporation residue is dissolved in 50 ml of benzene and is mixed with a solution of 2.0 g of potassium hydroxide in 20 ml of ethanol. After allowing the resulting solution to stand at room temperature for 12 hours, it is extracted twice with 50 ml of water on each occasion. The combined aqueous phases are washed once with diethyl ether and then acidified with dilute hydrochloric acid. The precipitate is filtered off and recrystallized from a 1:1 mixture of isopropyl alcohol and water to obtain 6.3 g (61.3% of

EXAMPLE 2

zamido}butyric acid R = 2, 4 - dichlorophenyl, A = a - naphthyl, n = 3 This compound is obtained by the process

zoyl chloride. The title compound, MP 134[deg] to 136[deg], is crystallized from (1:1) isopropyl alcohol/water. EXAMPLE 3

zamido}butyric acid R = m - trifluoromethylphenyl, A = a - naphthyl, n = 3 This compound is obtained according to the process of Example 1, but using m - trifluoromethylben- zoyl chloride. The title compound, MP 128[deg] to 129[deg], is crystallized from (1:1) isopropyl alcohol/water. EXAMPLE 4 4 - {o - hydroxy - [N - (a - naphthyl)]benzamido}butyric acid R' = o - hydroxyphenyl, A = a - naphthyl, n = 3 This compound is obtained by the process of Example 1, but using o - acetoxybenzoyl chloride. The title compound, MP 126[deg] to 128[deg], is crystallized from (1:1) ethanol/water. EXAMPLE 5

zamido}butyric acid R' = 5 - chloro - 2 - methoxyphenyl, A = a - naphthyl, n=3 This compound is obtained by the process of Example 1, but using 5 - chloro - 2 - methoxybenzoyl chloride. The title compound, MP 170[deg] to 171[deg], is crystallized from isopropyl alcohol. EXAMPLE 6

zamido}butyric acid R = 3, 4, 5 - trimethoxyphenyl, A = a - naphthyl, n = 3 This compound is obtained by the process of Example 1, but using 3, 4, 5-trimethoxybenzoyl chloride. The title compound, MP 143[deg]to 145[deg], is crystallized from (2:1) isopropyl alcohol/diethyl ether. EXAMPLE 7 4 - [N - (a - naphthyl) acetamido]butyric acid

This compound is produced by the process of Example 1, but using acetyl chloride. The title compound, MP 117[deg] to 119[deg] is crystallized from cyclohexane. EXAMPLE 8

acid R =p - chlorophenyl, A = a - naphthyl, n = 4

zamido}valerate 7.2 g of a - naphthylamine, 6.5 g of ethyldiisopropylamine, 10.5 g of ethyl 5- bromovalerate and 40 ml of cyclohexane are heated to boiling under reflux for 20 hours. After cooling, the resulting precipitate is filtered off, and the filtrate is concentrated in vacuo. The evaporation residue is taken up in 80 ml of benzene. After the addition of 6.8 g of ethyldiisopropylamine, a mixture of 9.2 g ofp - chlorobenzoyl chloride and 20 ml of benzene is added drop by drop over a period of 1 hour and accompanied by agitation at room temperature. After 24 hours the reaction mixture is diluted with diethyl ether, and the precipitate is filtered off.The filtrate is washed successively with water, dilute hydrochloric acid and sodium bicarbonate solution; it is then dried and concentrated by evaporation. The evaporation residue is purified by chromatography over a silica gel column (eluting agent: dichloromethane) and is then recrystallized from a (1:1) mixture of cyclohexane and petrol ether (BP 50[deg] to 70[deg]C) to obtain 13.2 g (64% of theory)

zamido}valeric acid 12.8 g of ethyl 5 -{p - chloro - [N - (a - naphthyl)] benzamido} - valerate in 100 ml of benzene are mixed with a solution of 2.6 g of potassium hydroxide in 20 ml of ethanol. After 2 days the solvent is distilled off, the residue is then dissolved in water, and the resulting aqueous solution is washed with diethyl ether and then acidified with dilute hydrochloric acid.The reaction product is extracted with diethyl ether, and the residue (remaining after drying and distilling off the solvent) is recrystallized from ethyl acetate/petrol ether (1:1 ) to obtain 10.6 g (88.9% of theory) of 5 -{p - chloro [N - (a - naphthyl)] benzamido}valeric acid, MP 169[deg] to 170[deg]. EXAMPLE 9

acid R =p - chlorophenyl, A = a - naphthyl, n = 5 Following the process of Example 8a (but replacing ethyl 5 - bromovalerate with ethyl 6 - bromocaproate) ethyl -{p - chloro - [N - (a- naphthyl)] benzamido}caproate, MP 76.5[deg]to 77.5[deg] is obtained from cyclohexane/petrol ether (1:1). By saponification of this ester according to Example 8b 6 -{p - chloro - [N - (a- naphthyl)] benzamido}caproic acid, MP 131[deg] to 132. is obtained from ethyl acetate/petrol ether (1:1). EXAMPLE 10

acid R = p - chlorophenyl, A = - naphthyl, n = 4 Following the process of Example 1, but replacing ethyl 4 - bromobutyrate by ethyl 4 - bromovalerate, 4

acid, MP 119[deg] to 120[deg] is obtained from ethyl acetate/petrol ether (1:1). EXAMPLE 11 4 - {p - chloro - [N - (7 - methoxy - 1- naphthyl)]benzamido}butyric acid R =p - chlorophenyl, A = 7 - methoxy - 1 - naphthyl, n=3 10.4 g of 1 - amino - 7 - methoxynaphthalene, 7.8 g of ethyldiisopropylamine, 11.8 g of ethyl 4 bromobutyrate and 50 ml of cyclohexane are heated to boiling under reflux for 5 hours. After cooling, the precipitate is filtered off, the filtrate is concentrated by evaporation and the evaporation residue is taken up in 70 ml of benzene. After the addition of 7.8 g of ethyl diisopropylamine and 10.5 g ofp - chlorobenzoyl chloride thereto, the mixture is agitated at room temperature for 2 hours.The residue (which remains after filtering off the precipitate and concentrating the filtrate by evaporation) is purified chromatographically (aluminium oxide column; eluating agent: dichloromethane) to obtain 12.3 g (48.1% of theory) of ethyl - 4 -{p - chloro - [N - (7 - methoxy - 1 naphthyl)] benzamido}butyrate, MP 92[deg] to 94[deg], from isopropyl alcohol. By the saponification of 9.0 g of this ester according to the process of Example 8b, 7.4 g (88% of

naphthyl)] benzamido}butyric acid, MP 148[deg] to 150[deg], is obtained from isopropyl alcohol. EXAMPLE 12

zamido}butyric acid R' = p - chlorophenyl, A = 4 - ethoxy - 1 - naphthyl, n =3 Following the process of Example 1, but replacing a - naphthylamine by 1 - amino - 4 - naphthol - ethyl

obtained from ethyl acetate/petrol ether (1:1). EXAMPLE 13 4 - [N - (1, 2, 3, 4- tetrahydro - 1- naph-

=3 14.7 g of 1 - amino -1,2,3,4 - tetrahydronaphthalene and 9.7 g of ethyl 4 - bromobutyrate are stirred together for 48 hours at room temperature. After addition of 200 ml of diethyl ether thereto the resulting precipitate is filtered off, and the filtrate is shaken with dilute hydrochloric acid. The hydrochloric acid extract is neutralized (pH approx. 7) with dilute ammonia solution. The separated oil is taken up in diethyl ether, and the residue (10.9 g), which remains after drying and distilling off the solvent, is taken up in 100 ml of benzene. Afterthe addition of 5.9 g of ethyldiisopropylamine thereto, 3.6 g of acetyl chloride are added slowly and dropwise while stirring.After 3 hours the resulting reaction mixture is mixed with 200 ml of diethyl ether and shaken successively with water, dilute hydrochloric acid and sodium bicarbonate solution. The residue (12.4 g), remaining after drying and distilling off the solvent, is taken up in 100 ml of benzene and mixed with a solution of 3.0 g of potassium hydroxide in 20 ml of ethanol. After 24 hours the mixture is shaken out with water, and the aqueous phase is acidified. The initial oily precipitate is taken up in dichloromethane. After distilling off the solvent, the product crystallizes out after several days. It is recrystallized from a mixture (2:1) of isopropyl alcohol and petrol etherto

tetrahydro - 1 - naphthyl) acetamido] butyric acid, MP 141[deg]to 142[deg]. EXAMPLE 14 4 - [N - (1, 2, 3, 4 - tetrahydro - 1- naph-

R' = - CH(CH3)2, A = 1,2,3,4 - tetrahydro - 1 naphthyl, n = 3 Following the process of Example 13, but using isobutyryl chloride instead of acetyl chloride, 4 - [N -

isobutyramido] butyric acid, MP 92.5[deg] to 93.5[deg], is obtained.

EXAMPLE 15

tetrahydro - 1 - naphthyl, n = 3 Following the process of Example 13 and replac-

thyl)propionamido] butyric acid is obtained as a viscous oil which does not crystallize even after several weeks. Asolution of 8.9 g of this acid in 90 ml of isopropanol is mixed with a sodium isopropylate solution, which is produced by dissolving 0.60 g of sodium in 50 ml of isopropanol. The solvent is distilled off, and the residue is mixed with anhydrous diethyl ether. After a certain time it solidifies to form a solid crystal mass. This is ground down and washed several times with anhydrous diethyl ether to obtain 8.3 g (87.3% of theory) of the sodium salt of 4 - [N - (6 - methoxy-1, 2, 3,4-tetrahydro-1 naphthyl)propionamido] butyric acid as colorless hygroscopic crystals which melt without a sharp mefting point at 75[deg] to 85[deg]. EXAMPLE 16 Sodium salt of 4 - [N - (6 - methoxy - 1, 2,3,4 -

rahydro.-1 - naphthyl, n = 3 The title compound is produced as in Example 15, but using isobutyryl chloride instead of propionyl chloride. It forms strongly hydroscopic crystals which melt without a sharp melting point at from 90[deg] to 95[deg]. EXAMPLE 17

This compound [MP = 93[deg] to 94[deg] from diethyl ether/petrol ether (1:1)] is produced by the process of Example 1, but using ethyl 5 - bromovalerate instead of ethyl 4 - bromobutyrate and using isobutyryl chloride instead ofp - chloro - benzoyl chloride. EXAMPLE 18

acid R =p - chlorophenyl, A = indan - 5 - yl, n = 4 a) Ethyl 5- (indan - 5- ylaminoJvalerate 13.3 g of 5 - aminoindane, 23.0 g of ethyl 5 bromovalerate and 14.2 g of ethyl diisopropylamine are stirred together for 12 hours at 50.. After addition of diethyl ether thereto, the resulting precipitate is filtered off, the solvent is removed, and all volatile components are distilled off from the residue at 50[deg] under a pressure of 10-2 mm Hg. The residue (which is left) is recrystallized from petrol etherto obtain 8.3 g (55.7% of theory) of ethyl 5 - (indan - 5 ylamino)valerate, MP 61[deg] to 63[deg].

valeric acid 6.3 g of ethyl 5- (indan - 5-ylamino)valerate and 3.1 g of ethyl diisopropylamine are reacted in 50 ml of benzene with 4.2 g ofp - chlorobenzoyl chloride.The resulting residue (left after filtering off the precipitate and concentrating the filtrate by evaporation) is saponified as described in Example 8b. Recrystallization of the crude product from ethyl acetate/petrol ether (1:2) yields

to 134[deg]. EXAMPLE 19

zamido}butyric acid

Following the process of Example 18, but using ethyl 4 - bromobutyrate instead of ethyl 5 bromovalerate and using 3,4 - dichlorobenzoyl chloride instead ofp - chlorobenzoyl chloride, yields

butyric acid, MP 58[deg] to 59[deg], from ethyl acetate/petrol ether (1:2).

EXAMPLE 20 Ampoules containing 600 mg of 4 - [N - (a - naphthyl) - acetamido] 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. 15.0 kg of 4 - [N - (a - naphthyl)acetamido] butyric acid are added thereto before adding slowly, while stirring, caustic soda solution (10 per cent by weight NaOH). When a solution is obtained, the pH is adjusted to from 7.5 to 8.0. Sodium pyrosulfite' ) is added and the mixture is stirred until everything has dissolved. The resulting solution is made up to 250 kg with double-distilled water. The solution is charged into 10-ml amopules and sterilized in an autoclave for 30 minutes at 120[deg].

EXAMPLE 21 Ampoules containing 600 mg of 4 -15 - chloro - 2 -

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 to which 15 kg of 4 -15 - chloro - 2 - methoxy - [N - (anaphthyl)] benzamido} - butyric acid are then added while stirring. Then caustic soda solution (10 percent by weight NaOH) is added, and the resulting mixture is adjusted to a pH of 8.0. It is made up to 250 kg with double-distilled water. The obtained solution is charged into 10-ml ampoules and sterilized in an autoclave for 30 minutes at 120[deg].

EXAMPLE 22 Tablets containing 50 mg of 6 -{p - chloro - [N - (a-

zamido} - caproic 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 resulting granulate is sieved 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. Thus-produced 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 mannertablets containing sodium 4-

pared. EXAMPLE 23

- naphthyl)] benzamido}valeric acid. 40.0 kg of 4 -{p - chloro - [N - (a - naphthyl)] benzamido} - valeric acid, 24.0 kg of lactose and 16.0 kg of maize starch are granulated with 4.0 kg of *) 0.0625kg polyvinylpyrrolidone (molecular weight: approx. 25,000) in about 5.5 liters of water and pressed through a sieve of 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. Using 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 24 Tablets containing 300 mg of 5 - [N - (a - naphthyl) - isobutyramidowaleric acid. 60.0 kg of 5 - [N - (a- naphthyl)isobutyramido]valeric 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 about6liters of water and are 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. EXAMPLE 25 10,000 capsules with an active principle content of 50 mg are produced from the following components: 500 g of 6-{p - chloro - [N - (a - naphthyl)] benzamido}caproic 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 acyl - (bicyclic aryl) - aminoalkanoic acids exert a marked protective action on the stomach and cause an increase in the pancreatic secretion in rats, and also they exert an action on the liver and bile (liver protection and choleresis) in rats, and are shown to be superior to known commercial preparations, for example Piprozoline, Carbenoxolone; in addition, they exert an inhibitive effect on the formation of glucose from lactate and pyruvate in the liver of rats, in which they have been found to be superior to known commercial preparations, for example Buformin, Phenformin. In the tables which follow, the compounds investigated are marked by a serial number which has been allocated to them as follows:

Table I SerialNo. Name of compound 1 Piprozoline 2 Carbenoxolone 3 Buformin 4 Phenformin

thyl) - benzamido] - butyric acid 8 4 - [2; 4 - dichloro - N - (a - naphthyl) benzamido] - butyric acid 9 4 - [m - trifluoromethyl - N - (a - naphthyl) - benzamido] - butyric acid

naphthyl) - benzamido] - butyric acid 11 4 - [5 - chloro - 2 - methoxy - N - (a naphthyl) - benzamido] - butyric acid 12 4 - [p - chloro - N - (a - naphthyl) benzamido] - valeric acid 13 4 - [p - chloro - N - (7 - methoxy - 1 naphthyl) - benzamido] - butyric acid 14 5 - [p - chloro - N - (a - naphthyl) benzamido] - valeric acid

benzamido] - caproic acid 16 4-[N-(1,2,3,4-tetrahydro-1naphthyl) - acetamido] - butyric acid

naphthyl) - isobutyramido] - butyric acid

- valeric acid Stomach protection action 19 Sodium4-[N-(6-methoxy-1,2,3,4 - tetrahydro - 1 - naphthyl) - propionamido] - butyrate 20 4 - [3,4- dichforo - N - (indan - 5 - yl) benzamido] - butyric acid

benzamido] - valeric acid 22 4 - [2 - hydroxy - N - (1 - naphthyl) benzamido] - butyric acid Table I shows the stomach protective action (reversal of the stomach ulcer caused by the ligture of the pylorus and administering 100 mg/kg of

application in the rat, the lethal action afterthe intraperitoneal administration in the mouse and also

resentatives of the compounds according to the invention.

Table I (continuation)

* ED50 = dose which reduces the mean ulcer index by 50 %. Table II shows the influence on the pancreatic secretion of narcosed rats after the intraduodenal application (EDso) and the lethal action on the mouse (LDso) afterthe intraperitoneal application of representatives of the compounds according to the invention and also the therapeutical quotient (TQ =

Table II Pancreatic secretion, toxicity and therapeutical quotient

+) ED50 = dose which brings about an increase in the pancreatic secretion (liquid volume; 30-minute fraction) by a maximum of 50 %. ++) LD.50 (p.o.) cited from Herrmann et al.Arzneim.Forsch. 27 (1977)467 Table III shows investigations in the antihepatotoxic action (ED25;50) of the compounds according to the invention after oral application to waking rats and the lethal action after intraperitoneal application on the mouse (LD50) as well as the therapeutical quotient (TQ = LD50/ED25 or LDso/EDso). Table III

+) ED25 and ED50 = the dose which shortens the hexobarbital narcosis by 25% and 50% respectively of rats suffering from liver damage from CCI4. ++) LD50 (p.o.), cited from Herrmann et al. Arzneim. Forsch.27 (1977) 467 Table IV shows the influence on the bile secretion (choleresis) of narcotized rats afterthe intraduodenal application (EDso) and the lethal action on the mouse (LDso) afterthe intraperitoneal application of representatives of the compounds according to the invention and also the therapeutical quotient (TQ =

Table IV Bile secretion, toxicity and therapeutical quotient

+++) ED50 = dose which brings about an increase in the bile secretion (liquid volume; 30-minute fraction) by a maximum of 50%. ++) LDso (p.o.) cited from Herrmann et al. Arzneim. Forsch.27, (1977)467 Table V shows the results of the investigation of the influence of representatives of the compounds according to the invention on the glucose formation 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 mmol/litre in the perfusate and the ED50determined from 4 concentrations in the range from 0.02-1.00 mmol/litre-and the lethal action on the mouse (LDso) after intraperitoneal application. Table V Inhibition of the glucose formation from lactate and pyruvate in the isolated perfused rat liver and toxicity on the mouse

*) substance concentration of 0.2 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

***) cited from Bertarelli, P., Boll.chim.farm. 97(1958)396. The compounds according to the invention are characterized as compared with the comparative 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 one can obtain inhibition effects of up to 86%. The determination of the pharmacological properties was carried out by the following methods: Influence on the pancreatic and bile secretion of the narcotized rat Execution of experiment: Male Sprague-Dawley rats (body weight 250-300g) are narcosed 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 near to the hepatic duct, and both sections are catheterised 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 obtained 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 prior to 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 forantihepatotoxic effect Influence on the hexobarbital sleeping period of the rat after liver damage by CC/4. Execution of test: On the basis of VOGEL et. al. (Arzneim. - Forsch. 25 (1975) 82) liver cell damage is produced in fasting female Sprague-Dawley rats (190 10 g body weight, 10 animals/dose per test batch by the oral administration of carbon tetrachloride (0.15 ml/kg CCl4 in 2.5 ml/kg olive oil), and the extent of this damage is determined by the prolonging of the sleeping period induced by hexobarbital sodium (50 mg/ml/kg i.v.; caudal vein, duration of injection 45-60 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 sleep-

the groups treated as compared with the prolongation of the sleeping periode of the CCl4 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/10 ml/kg acetylsalicyclic 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 and 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 perfused rat liver Forthis 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 Krebs-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 liver via 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 mmo1/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 occurring before and 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 NHRI 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 LDso, i.e. the dose at which 50% of the animals die, is determined graphically from the dose/effect curve.

Claims

1. Acyl (bicyclic aryl) - aminoalkanoic 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 bicyclic aryl radical with 8 to 12 car- bon atoms, n signifies 3, 4 or 5, and their salts of inorganic or organic bases.

2. Acyl (bicyclic aryl) - aminoalkanoic acids of the general formula I

in which R1 * 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 an indenyl, indanyl, naphthyl, dihydronaphthyl ortetrahydronaphthyl radical substituted with R5 * and R6* , n* signifies 3, 4 or 5,

a hydrogen atom, a halogen atom, 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, a hydroxy group or a trifluoromethyl group, R5* and R6 * are the same or different and signify a hydrogen atom, a halogen atom, a methyl group, an alkoxy group with 1 to 4 carbon atoms, a nitro group or a trifluoromethyl group, and their salts of inorganic or organic bases.

3. Compounds in accordance with Claim 2, in which A represents a 5 - indanyl, 1 - naphthyl or 1, 2, 3, 4-tetrahydronaphthyl- (1) radical substituted

4. Acyl (bicyclic aryl) - aminoalkanoic acids of the general formula 1"

in which R ** signifies an aliphatic hydrocarbon radical with 1 to

5 carbon atoms or a phenyl radical substituted

A" signifies a group of the formula

n" signifies 3, 4 or 5,

hydrogen atom, a chlorine atom, an ethoxy group, a methoxy group or a nitro group, and their salts of inorganic or organic bases. 5. Acyl (bicyclic aryl) - aminoalkanoic acids of the general formula I ***

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

A*** signifies a group of the formula

n*** signifies 3, 4 or 5,

sent a hydrogen atom a chlorine atom, a methoxy group or a nitro group, and their salts of inorganic or organic bases.

6. Acyl (bicyclic aryl) - aminoalkanoic acids of the general formula I ****

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

A**** signifies a group of the formula

**** signifies 3, 4 or 5,

resent a hydrogen atom, a chlorine atom, a methoxy group or a nitro group, and their salts of inorganic or organic bases.

7. Compounds in accordance with Claims 4 or 5

rogen atom, a chlorine atom, a methoxy group, a hydroxy group or a trifluoromethyl group; R 4**,

n **** have the meanings given above, and their pharmacologically compatible salts of inorganic or organic bases.

8. Compounds in accordance with Claim 4 or 5 or

group with 1 to 3 carbon atoms or a substituted

nify a hydrogen atom or a chlorine atome; R5**,

ings given above, and their pharmacologically compatible salts of inorganic or organic bases.

9. Compounds in accordance with Claim 4 or 5, in which R' ** or R *** signify an alkyl group with 1 to 3 carbon atoms or a substituted phenyl radical; R **

nify a chlorine atom or a hydroxy group; R4** or

a hydrogen atom or a methoxy group; R6 ** or R6 *** signify a hydrogen atom and n** or n *** signify 3 or 4, and their pharmacologically compatible salts of inorganic or organic bases.

10. Pharmaceutical products containing as active ingredient one or more compounds according to Claim 1 to 9.

11. Process for the production of the acyl (bicyclic aryl) - aminoalkanoic 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 bicyclic aryl radical with 8 to 12 carbon atoms, n signifies 3, 4 or 5, and their salts of inorganic or organic bases, characterised by the fact that a) a (bicyclic aryl) - aminoalkanoic acid of the general formula II A-NH-CnH2n-COOH (II), in which A and n have the meanings given above, optionally with protection of the carboxyl group, is acylated with an acyl derivative of the general formula III R'-CO-R7 (III), in which R7 signifies a leaving group or a R - CO - 0 group and R has the meaning given above, and if desired is then converted into a salt or b) a (bicyclic aryl) - aminoalkenoic acid of the general formula IV

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.

12. Pharmaceutical compositions containing from 1% to 95% by weight of the total mixture of at least one compound according to Claims 1 to 9 in admixture with one or more solid or liquid pharmaceutically acceptable inert carriers.

13. A process for the preparation of the acyl (bicyclic aryl) - aminoalkanoic acids of the general formula I according to Claim 1 substantially as described with reference to the specific examples hereinbefore set forth.