NO155770B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE SUBSTITUTED OXOCARBOXYLIC ACIDS. - Google Patents

Description

The present invention relates to an analogous method for the production of therapeutically active substituted oxocarboxylic acids.

German Offenlegungsschrift 2 365 755 describes the α-keto acid ester which can serve as intermediate products for the production of amino acids or heterocyclic compounds. From Belgian patent 779 821, a method for the production of α-keto acids is known, the keto acids being mentioned as intermediate products in metabolism or as advantages for amino acids. 5-(4-Methoxy-phenyl)-2-oxovaleric acid was prepared by L.F. Fieser and H.L. Holmes [J.Amer.Chem.Soc. 58(1936)2319]. Certain substituted oxocarboxylic acids were now found as pharmaceutical active substances with a specific action.

The object of the present invention is the method for the production of substituted oxocarboxylic acids with the general formula I

in which

R means a hydrogen atom, a halogen atom, a hydroxy group,

a lower alkyl group, a lower alkoxy group or a

trifluoromethyl group,

R 2 a hydrogen atom or a halogen atom and

n an integer from 3 to 8, provided that R<1> does not mean a hydrogen atom, a fluorine atom, a methyl group or a methoxy group, and R 2 not a hydrogen atom when n has the meaning 3, and salts thereof.

As lower alkyl groups, straight-chain or branched alkyl radicals with 1 to 4 carbon atoms come into consideration. Straight-chain alkyl residues are e.g. methyl, ethyl, n-propyl and n-butyl residues, of which those with 1 and 2 carbon atoms are preferred. Branched alkyl residues are e.g. the isopropyl, isobutyl and sec.-butyl residue, of which those with 3 carbon atoms are preferred. Both straight-chain and branched lower alkyl groups come into consideration as alkyl residues of lower alkoxy groups. The methoxy group is preferred as a lower alkoxy group.

Halogen atoms are fluorine, chlorine and bromine atoms, of which fluorine, especially chlorine is preferred.

12 The substituents R and R are preferably in the meta or para position to the ketocarboxylic acid residue.

As salts, salts with inorganic and organic bases come

considering. Pharmacologically intolerable salts are transferred according to methods known per se to pharmacologically, i.e. biologically tolerable, salts, among which the salts according to the invention are preferred. As cations for the salt formation, above all the cations of the alkali metals, alkaline earth metals or earth metals are used, but also the corresponding cations of inorganic nitrogen bases such as amines, aminoalkanols, amino sugars, basic amino acids etc. are used.

Examples include the salts of ethylenediamine, dimethylamine, diethylamine, morpholine, piperidine, piperazine, N-lower alkyl piperazine (e.g. N-methylpiperazine), methylcyclohexylamine, benzylamine, ethanolamine, diethanolamine, triethanolamine, tris-(hydroxymethyl)aminomethane, 2-amino-2-methylpropanol, 2-amino-2-methyl-1,3-propanediol, glucamine, N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine, arginine and quinoline, preferably of lithium, sodium, potassium, magnesium, calcium and aluminium.

Preferred compounds produced according to the present invention are substituted oxocarboxylic acids of the general formula I

in which

R<1*>means a hydrogen atom, a chlorine atom, a methyl group, a

2*methoxy group or a trifluoromethyl group,

R a hydrogen atom or a chlorine atom and

n<*> an integer from 3 to 6, provided that R 1 does not mean a hydrogen atom or a methoxy group and R 2 is not a hydrogen

a

atom when n has the meaning 3,

and salts thereof.

Other particularly preferred compounds which are prepared according to the invention are substituted oxocarboxylic acids with the general formula I

in which R and R are in the meta or para position to the ketocarboxylic acid residue and R means a hydrogen atom or a chlorine atom, R a chlorine atom and n 3 to 5, and their pharmacologically acceptable salts with inorganic or organic bases.

As examples of the acids produced according to the invention, e.g. 6-(2,4-dichlorophenyl)-2-oxokaproic acid, 2-oxo-6-(3-trifluoromethylphenyl)-caproic acid, 5-(3,4-dichlorophenyl)-2-oxovaleric acid, 7-(3-chlorophenyl) )-2-oxoheptanoic acid, 7-(4-methoxyphenyl)-2-oxoheptanoic acid, 7-(4-bromophenyl)-2-oxoheptanoic acid, 8-(4-n-butoxyphenyl)-2-oxo-octanoic acid, 8-(3 -fluorophenyl)-2-oxooctanoic acid, 2-oxo-8-(3-trifluoromethylphenyl)octanoic acid, 7-(4-methyl-phenyl)-2-oxo-heptanoic acid, 8-(4-hydroxyphenyl)-2- oxo-octanoic acid, 9-(4-chlorophenyl)-2-oxo-nonanoic acid, 9-(3-trifluoromethyl-phenyl)-2-oxo-nonanoic acid, 10-(2,4-dichlorophenyl)-2-oxo- decanoic acid, 10-(4-methylphenyl)-2-oxo-decanoic acid.

Preferred representatives are

2-oxo-6-phenylcaproic acid,

6-(4-methoxyphenyl)-2-oxo-caproic acid,

5-(4-chlorophenyl)-2-oxo-valeric acid,

and their pharmacologically tolerable salts.

The compounds according to the invention have valuable pharmacological properties which make them industrially usable. They have a hypoglycemic effect.

Due to their beneficial effect, the substituted oxocarboxylic acids according to the invention with the general formula I or I<1> and the embodiments thereof I and I as well as their salts suitable for the treatment of prophylaxis of diseases which are due to disturbances in the glucose metabolism. E.g. treat prediabetic conditions to prevent the manifestation of diabetes, e.g. diabetes in adults, labile diabetes in young people.

As medicine, the new compounds can be used as such or possibly in combination with suitable pharmaceutical carriers. If, in addition to the active ingredients, the new pharmaceutical preparations also contain pharmaceutical carriers, the active ingredient content of these mixtures is 1 to 95, preferably 15 to 85% by weight of the total mixture.

in

The active substances in the human medicine area are used in all forms, e.g. systemic, on the condition that the design or the maintenance of an adequate blood or tissue level of active substances is satisfied. It can e.g. achieved through oral or parenteral delivery in suitable doses. Advantageously, the pharmaceutical preparation and the active ingredient are available in the form of unit doses, which can be adapted to the desired administration. A unit dose can e.g. be a tablet, a dragee, a capsule, a suppository or a measured volume amount of a powder, a granule, a solution, an emulsion or a suspension.

Under "unit dose" in the meaning of the present invention is understood a physically determined unit, which contains an individual amount of active ingredient therein in combination with a pharmaceutical carrier, whose active substance content corresponds to a fraction or multiple of a single therapeutic dose. A single dose preferably contains the amount of active substance that is given in one application and which normally corresponds to a full, half, one-third or one-quarter daily dose. When only a fraction such as half or a quarter of the unit dose is needed for a simple therapeutic delivery, the unit dose is advantageously divisible, e.g. in the form of a tablet with fracture marks.

The pharmaceutical preparations according to the invention contain when they are present in unit doses and e.g. is intended for use on humans, approx. 2 to 200 mg, preferably 10 to 100 mg and especially 20 to 60 mg of active ingredient.

In general, it has proven beneficial in human medicine to give the active substance or substances orally in a daily dose of approx. 0.1 to 30, preferably 0.3 to 15, especially 0.6 to 3 mg/kg body weight, optionally in the form of several, preferably 1 to 3 single doses to achieve the desired results. A single dose contains the active substance or substances in amounts from approx. 0.05 to 10, preferably 0.1 to 5, especially 0.3 to 1 mg/kg body weight.

In a parenteral treatment, e.g. an intravenous or an intramuscular application similar doses may be used. In this therapy, approx. 0.3 to 1 mg of active ingredient per kg body weight.

The therapeutic administration of the pharmaceutical preparation takes place by long-term treatment, generally at fixed times such as 1 to 4 times per week. day, e.g. always after meals and/or in the evening. In acute conditions, medication is administered at varying times. Under special circumstances, it may be necessary to deviate from the dosages mentioned, and then depending on the species, body weight and age of the individual being treated, the nature and degree of the disease, the nature of preparation and application of the medicine as well as the period or the interval within which no administration takes place. Thus, in some cases it may be sufficient to use less than the above-mentioned amount of active substance, while in other cases the above-mentioned amount of active substance must be exceeded. The determination of the individual necessary optimal dosage and application of the active substance is carried out by the expert on the basis of his professional knowledge.

The pharmaceutical preparations usually consist of the active substances produced according to the invention and non-toxic, pharmaceutically acceptable drug carriers, which are used as additives or diluents in solid, semi-solid or liquid form or as encapsulating agents, e.g. in the form of a capsule, a tablet coating, a bag or another container for the therapeutically active ingredient. A carrier can e.g. serve as a mediator for the absorption of the medicine in the body, as a formulation aid, as a sweetener, as a flavor corrector, as a coloring agent or as a preservative.

For oral use, e.g. tablets, dragées, hard and soft capsules, e.g. of gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions or solutions come into question.

Tablets may contain inert diluents, e.g. calcium carbonate, calcium phosphate, sodium phosphate or xylitol, granulating and dispersing agents, e.g. calcium phosphate or alginates, binders, e.g. starch, gelatins or acacia gums, and glidants, e.g. aluminum or magnesium stearate, talc or silicone oil. They can also be equipped with a cover, which is also such that you get a delayed dissolution and resorption of the medicine in the digestive tract and thus e.g. a better tolerability, pro-traction or retardation. Gelatin capsules may contain the medicinal substance mixed with a solid diluent, e.g. calcium carbonate or kaolin, or an oily diluent, e.g. paraffin oil.

Aqueous suspensions may contain suspending agents, e.g. sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth or gum acacia, dispersing and wetting agents, e.g. polyoxyethylene stearate, heptadecaethylene oxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin, preservatives, e.g. methyl-

or propyl hydroxybenzoate, flavoring agents, sweeteners, e.g. saccharin, sodium cyclamate.

Oily suspensions can e.g. contain paraffin oil and thickeners, such as beeswax, hard paraffin or cetyl alcohol, further sweeteners, flavoring agents and antioxidants.

Water-dispersible powders and granules can contain the medicinal substances in admixture with dispersing, wetting and suspending agents, e.g. the above, as well as with sweeteners, flavoring agents and coloring agents.

Emulsions can e.g. contain paraffin oil in addition to emulsifiers such as azakie gum, tragacanth gum, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents.

For parenteral application of the medicinal substances, sterile injectable aqueous solutions, isotonic salt solutions or other solutions which may contain dispersing or wetting agents bg/or pharmacologically tolerable diluents, e.g. propylene or butylene glycol.

The active ingredient or active ingredients can optionally be formulated

with one or more of the specified carriers or additives also in microencapsulated form.

In addition to the substituted oxocarboxylic acids produced according to the invention, in which the substituents have the meaning indicated above, and/or their salts, the pharmaceutical preparations may also contain one or more pharmacologically active ingredients from other drug groups such as antidiabetics (sulfonamides, sulfonylureas, and others) , e.g. carbutamide, tolbutamide, chlorpropamide, glibenclamide, glibornurid, gliso-xepid, gliquidone, glymidine or hypolipidemic agents such as nicotinic acid and their derivatives and salts.

8

In the analog method according to the present invention

a) solvolyze an oxocarboxylic acid ester with the general formula II

12 3 where R , R and n have the meaning stated above and R means a lower alkyl residue, and optionally transfer the subsequently obtained acids to the salts or obtained salts to the acids or b) solvolyse and decarboxylate a diester with the general formula III

12 3'

where R , R , R and n have the above meaning,

and possibly then transfers obtained acids into the salts or obtained salts into the acids.

in

The compounds with the general formula I are prepared according to methods known per se. The production of the compounds I can, in addition to the indicated process variants, also take place analogously to other methods described in the literature, e.g. mentioned: the methods specified in Belgian patent 779 821, the methods of H. Poisel [Ber. 111 (1978)3136], R. Fischer and T. Wieland [Ber. 93 (1960) 1387], J. Anatol

and A. Medete [Synthesis 1971, 538], E.E. Eliel and A.A. Hartmann [J.org.Chem. 37 (1972) 505], K. Tanaka et al.

[Tetrahedron Letters 1978, 4809], K. Ogura et. eel. [Tetrahedron Letters 1978, 375].

The solvolysis of the oxocarboxylic acid esters II and diesters III takes place e.g. with an aqueous or alcoholic (e.g. ethanolic) alkali metal hydroxide (e.g. potassium hydroxide) solution at room temperature, optionally with the addition of an inert diluent such as dioxane or toluene. The solvolysis preferably takes place with aqueous solutions of mineral acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, possibly with the addition of an organic solvent, such as dioxane or diglyme, at temperatures between 0°C and the solvent's boiling temperature, preferably between 20 and 70° C. The decarboxylation of the diester III takes place by heating the individual solutions, possibly at the same time as the solvolysis.

The transfer of the oxocarboxylic acids with the general formula I or the embodiments I and I to the salts can occur through direct alkaline solvolysis, e.g. hydrolysis, of the ester II (R 3 = lower alkyl). The inorganic or organic bases are used as alkaline reaction partners if salt is desired. However, the salts are also obtained when the acids I are reacted with the stoichiometric equivalent of the corresponding base, e.g. sodium hydroxide or sodium ethanolate, or transfer readily soluble salts through double conversion into sparingly soluble salts, or transfer any salts into pharmacologically tolerable salts. The production of the free oxoacids I is preferred to that of the salts.

For the production of the substituted oxocarboxylic acids in embodiments I and I, oxocarboxylic acid esters of the general formula II and II are used, respectively. diesters III and <.>■■<+>+■

III.

in which R , R and n respectively R , R and n have the meaning given above, R means a lower alkyl radical and R a methyl or ethyl radical. The preparation of oxocarboxylic acid esters with the general formula II, II and II1 takes place according to methods known per se, e.g. according to DOS 23 65 755. However, it can also be carried out by ozonolysis of α-methylene carboxylic acid esters with the general formula IV 12 3 in which R , R , R and n: have the meaning indicated above. The α-methylene carboxylic acid ester IV (respectively the corresponding embodiments IV and IV -*■+ ) is prepared analogously to those by H. Stetter and H. Kuhlmann [Synthesis 1978, 29], Ph.E. Pfeffer et al. [J.Org.Chem. 37 (1972) 1256] and W.S. Wads- worth, jun. and W.D. Emmons [J.Amer.Chem.Soc. 83 (1961) 1733] described methods. The production of the diester III takes place according to methods which are common to those skilled in the art, e.g. by reacting the carboxylic acid ester V with dialkyl oxalate VI

12 3

wherein R , R , R and n have the meaning indicated above, in the presence of a strong base, e.g. sodium ethanolate or potassium tert-butylate. The carboxylic acid esters V are available through known methods, e.g. according to R. Huisgen et al. Liebig's Annals 586(1954)52.

The following examples serve to illustrate the invention without limiting it. Temperature indications are in °C.

EXAMPLES

EXAMPLE 1

2-oxo-6-phenylcaproic acid

a) 10.0 g of the diester obtained according to b) is heated together with 100 ml of 6 N hydrochloric acid and 100 ml of dioxane for 4 hours at approx. 100°C. After cooling, dilute with 1.2 1 water and extract several times with methylene chloride. The organic phase is washed with water and saturated sodium chloride solution, then dried and evaporated. The oily residue is purified by high vacuum distillation [boiling point 130-135° at 0.1 torr (13.3 Pa)] and column chromatography (eluent: chloroform). Back is 2.9 g of 2-oxo-6-phenylcaproic acid as a non-crystallizing oil, yield 43% (of theory). b) 47.9 g of 5-phenylvaleric acid ethyl ester is added to a sodium ethylate suspension prepared from 6.4 g of sodium and 100 ml of ethanol with subsequent evaporation of excess ethanol and addition of 100 ml of toluene. While stirring, 44.1 g of diethyl oxalate is added dropwise and heated for 2.5 hours at reflux. After cooling, the solution is stirred with 500 ml of ice water, acidified with 2 N sulfuric acid to pH 2. Several extractions with methylene chloride give, after drying, filtration through a short column of silica gel and evaporation, 62.1 g of 3-ethoxycarbonyl-2-oxo-6- phenylhexanoic acid ethyl ester, which is reacted without further purification according to a).

EXAMPLE 2

6-(4-Methoxyphenyl)-2-Oxocaproic acid

a) Analogously to example la), the diester produced according to b) is hydrolyzed and decarboxylated with 6 N hydrochloric acid. The

combined methylene chloride extracts are evaporated, the residue is dissolved in diethyl ester and extracted several times with 1 N caustic soda. The aqueous phases are acidified with 6 N hydrochloric acid to pH 5.5 and washed three times with diethyl ether. The aqueous phase is then brought to pH 1-2 and extracted with methylene chloride. After drying and evaporation, a tough oil remains, which is crystallized from petroleum ether (50-70°C) cold. Yield 6.2 g (51% of theory), m.p. 22-25°C.

b) Analogous to example lb), 17.2 g of 3-ethoxycarbonyl-6-(4-methoxyphenyl)-2-oxocaproic acid ethyl ester is prepared from 14.7 g

5-(4-Methoxyphenyl)-valeric acid ethyl ester and 11.8 g of diethyl oxalate with sodium ethylate as base.

EXAMPLE 3

5-(4-chlorophenyl)-2-oxovaleric acid

a) 5-(4-chlorophenyl)-2-oxovaleric acid ethyl ester (residue from

b).take up in 100 ml of 6 N hydrochloric acid and 100 ml of dioxane and

o

heated for 3 hours at 100 . After cooling, dilute with 1 1 water and extract several times with methylene chloride. The organic phase is washed several times with water, dried over magnesium sulphate and evaporated. The residue is high-vacuum distilled in a ball tube furnace and recrystallized from petroleum ether. 5.7 g of the title compound with m.p. 82-84°.

b) Dissolve 14 g of 5-(4-chlorophenyl)-2-methylenevaleric acid ethyl ester in 350 ml of ethanol and treat with the equivalent

amount of ozone. After flushing the equipment with nitrogen, add approx. lg palladium-on-carbon (10% Pd) and reduces the formed ozonide in a circulation process with hydrogen. The catalyst is then filtered off and the solution evaporated in a vacuum. c) Analogously to the method described by H. Stetter and H. Kuhlmann [Synthesis 1979, 29], one obtains from 71 g 3-(4-chloro-phenyl)-propylmalonic acid monoethyl ester, 10.42 g paraformaldehyde, 47 ml pyridine and 3.1 ml piperidine 53.3 g 5-(4-chloro-phenyl)-2-methylenevaleric acid ethyl ester with boiling point 120-123° at 0.05 torr (6.65 Pa). d) A solution of 16.8 g of potassium hydroxide in 400 ml of ethanol is added dropwise at room temperature to 92 g of 3-(4-chlorophenyl)-propylmalonic acid diethyl ester in 200 ml of ethanol. Stir for 24 hours, evaporate strongly in a vacuum, take up the residue in 500

ml of water and extract twice with 100 ml of diethyl ether. The aqueous phase is acidified under ice-cooling with concentrated hydrochloric acid and extracted 3 times with 200 ml di-

ethyl ether, the organic phase is evaporated after drying over sodium sulfate. 71.8 g of 3-(4-chloro-phenyl)-propylmalonic acid ethyl ester is obtained as a viscous oil.

e) At 50° drip<p>e<r>, add 108.5 g of malonic acid diethyl ester to a sodium ethylate solution recently prepared from 15.6 g of sodium

and 750 ml of ethanol. The solution is held for 2.5 hours at this temperature and then 220 g of p-toluenesulfonic acid-(3-(4-chlorophenyl)-propyl]-ester is added dropwise. After the addition is complete, the mixture is stirred for 6 hours at 50°, then mixed with 800 ml of water and extract 3 times with a total of 1 1 of diethyl ether. The combined organic phases are distilled after drying over sodium sulfate and evaporation of the solvent. 105.6 g of 3-(4-chlorophenyl)-propylmalonic acid diethyl ester with a boiling point of 145-155 ° at 0.01 torr (1.33 Pa).

f) At 0°, 135 ml of pyridine is added dropwise to 150 g of 3-(4-chloro-phenyl)-propanol-1 and 206.6 g of p-toluenesulfonic acid chloride in

300 ml of chloroform. After the addition is complete, stir for 3 hours at room temperature and pour the solution into a mixture of 400 ml of water and 120 ml of concentrated hydrochloric acid. The organic phase is separated, washed 3 times with water, dried over sodium sulfate and evaporated in vacuo to a yellowish viscous oil, yielding 285 g of p-toluenesulfonic acid [3-(4-chlorophenyl)-ipropyl] ester.

EXAMPLE 4

2-oxo-7-(3-trifluoromethylphenyl)-heptanoic acid

a) Analogous to example la) the diestes obtained according to b) are hydrolyzed and decarboxylated with 6 N hydrochloric acid in dioxane at

100°. After extractive work-up and purification by ball-tube distillation, 5.6 g of the title compound is obtained as a tough, colorless oil, which does not crystallize.

b) Analogous to example lb), 3-ethoxycarbonyl-2-oxo-7-(3-trifluoromethylphenyl)-heptanoic acid ethyl ester is prepared from

10.9 g of 6-(3-trifluoromethylphenyl)-caproic acid ethyl ester and 6 g of diethyl oxalate with sodium ethylate as base, yield 11.7 g (80% of theoretical yield).

c) 11.4 g of 6-(3-trifluoromethylphenyl)-caproic acid are dissolved in 200 ml of ethanol and heated after the addition of 2 ml of concentrated sulfuric acid for 6 hours at reflux. After distilling off the main amount of solvent, mix with water and extract with methylene chloride. Treatment with sodium bicarbonate solution, drying and evaporation yields 12.6 g of the corresponding ethyl ester as an oil, which is used without further purification in b). d) 24.9 g of 4-(3-trifluoromethylphenyl)-butylmalonic acid diethyl ester are heated with 4.5 g of potassium hydroxide in 200 ml of toluene:methanol (2:1) for 36 hours at reflux and then extracted with acid. The residue that remains after drying and evaporation is heated for 2 hours in a vacuum at approx. 17 0°, whereby carbon dioxide is released and the corresponding caproic acid used in c) is formed. e) In a Grignard solution of 28.5 g of 2-(3-trifluoromethylphenyl)-ethyl bromide and 2.9 g of magnesium prepared in 200 ml of diethyl ether, 5.5 g of oxirane is dripped into 20 ml of diethyl ether at approx. 0 C. After stirring for 1 hour and mixing with 100 ml of 10% sulfuric acid, extract with diethyl ether and distill the residue. You get approx. 18.5 g of 4-(3-trifluoromethylphenyl)-butan-1-ol which is dissolved in 70 ml of toluene and mixed and stirred with 16 g of p-toluenesulfonic acid chloride and 25 ml of pyridine. After 2 days, the precipitate is filtered off and worked up extractively. After evaporation of the organic phase, 25.7 g of tosylate of the substituted butanol remains, which is taken up in 250 ml of ethanol and dripped into a solution prepared from 11.5 g of diethyl malonate and 1.6 g of sodium in 220 ml of absolute ethanol. The mixture is heated for 24 hours at reflux, then evaporated and distributed between water and methylene chloride. After several extractions, the combined organic phases are dried and evaporated. The residue is purified chromatographically over a 500 g silica gel column and yields 24.9 g of 4-(3-trifluoromethylphenyl)-butylmalonic acid diethyl ester which is used in d).

EXAMPLE 5

10-(4-chlorophenyl)-2-oxodecanoic acid

a) 5.7 g of the diester obtained according to b) is hydrolyzed and decarboxylated according to example la) with 6N hydrochloric acid in dioxane. After work-up and purification by column chromatography, 3.8 g of the title compound remains as a colorless oil. b) 5.3 g of the compound obtained according to c) is reacted according to example lb) with diethyl oxalate and sodium ethylate.

Work-up and purification through silica gel filtration gives, after evaporation of the solvent, 5.7 g of 10-(2,4-dimethyl-phenyl)-3-ethoxycarbonyl-2-oxodecanoic acid ethyl ester. c) 8.3 g of 9-(4-chlorophenyl)-9-oxonanoic acid ethyl ester [obtained according to d)] is reduced analogously to example 5c) with hydrazine hydrate and worked up. 5.3 g of 9-(4-chlorophenyl)-nonanoic acid ethyl ester is obtained as an oil. d) According to the method described by Papa et al. [J. Amer. Chem.Soc. 69 (1947)3018] 12.3 g of azelaic acid ethyl ester chloride in 20 ml of chlorobenzene are mixed with 9.5 g of aluminum trichloride cold and then heated overnight at 150°. After mixing the complex with dilute hydrochloric acid, the organic phase is washed and evaporated and the residue is extracted with diethyl ether. After column chromatography and evaporation of the solution, 8.3 g of 9-(4-chlorophenyl)-9-oxonanoic acid ethyl ester are obtained as a viscous oil;

in

EXAMPLE 6

6-(4-Methoxyphenyl)-2-oxocaproic acid sodium salt 4.5 g of 6-(4-methoxyphenyl)-2-oxocaproic acid are stirred in 19.0

ml 1 N caustic soda for 15 minutes at room temperature. The mixture is filtered, washed once with diethyl ether and evaporated to dryness. The residue dried at 3 0 in'1 vacuum consists of pure sodium salt.

EXAMPLE 7

5-(4-Chlorophenyl)-2-oxovaleric acid calcium salt 5.3 g of 5-(4-chlorophenyl)-2-oxovaleric acid are dissolved in 25 ml of 1 N caustic soda and adjusted to pH 8.5 with a little semi-concentrated hydrochloric acid. After adding 2.0 g of calcium chloride dihydrate in 6 ml of water with stirring, the calcium salt is precipitated, which after filtration is dried in a vacuum at 40°C.

EXAMPLE 8

10,000 capsules with an active substance content of 25 mg are prepared as follows: 250 g of 5-(4-chlorophenyl)-2-oxovaleric acid are dissolved in 3,000 ml of methylene chloride. The solution is mixed well with 750 g of micronized silicic acid. The mixture is evaporated to dryness and then filled into size 4 hard gelatin capsules.

EXAMPLE 9

10,000 tablets with an active substance content of 30 mg are produced as follows:

300 g 5-(4-chlorophenyl)-2-oxovaleric acid, 800 g xylitol, 500

g of calcium phosphate, 30 mg of amorphous silicic acid and 40 g of sodium lauryl sulfate are mixed and sieved. This mixture is moistened with a solution of 50 g of polyvinylpyrrolidone (average molecular weight 25,000) in 320 ml of ethanol and granulated through a sieve with a mesh size of 1.25 mm. The granulate is dried at 40° and mixed with 160 g of pectin, 100 g of talc and 20 g of magnesium stearate. This mixture is pressed into tablets of 200 mg and 8 mm cross section.

PHARMACOLOGY

The compounds according to the invention, as a result of their insulinotropic effect, lower the blood glucose level, during which it differs in principle in its chemical structure from pancreatic beta-cytotropic substances (e.g. sulphonylureas). Particularly advantageously, it has been shown that the insulinotropic action of the compounds, in contrast to commercial sulphonylureas, is dependent on the glucose concentration of the surrounding medium. The compounds according to the invention thus show prerequisites for a so-called "thinking antidiabetic", which only stimulates insulin release in hyperglycemia, while in euglycemic conditions it does not induce any further insulin release. Under such conditions, the risk of hypoglycaemia is ruled out.

In the following table, the compounds that are examined are denoted by a consecutive number which is assigned as follows:

Table I shows investigations of the insulin secretion from isolated perfused rat pancreas during 60 min. by only supplying glucose and by supplying representatives from the present compounds to the perfusate.

To table I:

I<+> = Insulin release upon addition of the test compound

and glucose

I = Insulin release without the addition of the test compound, but with the addition of glucose

From table I it can be seen that the insulin release by simply adding glucose at a concentration of 8.3 mmol/1 compared to that for 4 mmol/1 is increased by a factor of 2.3. Simultaneous tolbutamide addition increases insulin secretion at this glucose concentration by factors of 10.4 and 8.5. Compound 2 according to the invention, on the other hand, at a glucose concentration of 4 mmol/1 has no influence on insulin secretion, while at a glucose concentration of 8.3 mmol/1 it causes a clear increase in insulin secretion (by 4.7 times).

An almost equally strong or a higher degree of increase in insulin release is achieved by adding the compounds 3 or 4 according to the invention.

The pharmacological properties were measured according to the following method:

A: Laboratory animals

Fasted male Sprague-Dawley rats (220-280 g) of the strain mus rattus served as experimental animals, under standard conditions (day-night rhythm 1'2h/12h, 23°C, 55% humidity, water and standard diet "Altromin" ad ad libitum). 18 to 20 hours before the start of the experiment, they were removed from the fSret.

B: Perfusion medium

The perfusion of the rat pancreas is carried out analogously to the method described by Lenzen [Amer.J.Physiol. 236(1979) E391-E400]. Krebs-Henseleit buffer is used as perfusion medium, which contains 1 mg/ml bovine serum albumin (Serva)

and glucose ...as indicated. The perf us ion medium is equilibrated in a gas washing bottle with carbogen (95%C>2/5%CC)2 constantly at 37.5°C and pH 7.4.

C. Perfusion and surgery

The rats are anesthetized with Nembutal (0.8 ml/kg). The pancreas is isolated with the stomach, the adjacent duodenal loop and the vascular system for supply and discharge. The cannulation takes place retro-grade through the aorta. All branching vessels are ligated so that the perfusion solution reaches the pancreas through the celiac artery, flows through it, collects in the vena lienalis and vena pancreatico-duodenalis and then opens into the portal vein. The portal vein is again cannulated retrograde and here the perfusate is collected fractionally. The isolated organ preparation is transferred to a thermostated glass shard with an opening at the bottom for receiving the drainage capillaries.' Pancreas is infused with a constant flow of 4 ml/min. When at least 3.7 ml is collected again, the preparation is used for the experiment. After a pre-perfusion of 10 min. during which the pancreas is flushed free of blood, perfused over 20 min. without substance at the stated glucose concentration and over 60 min. with constant test substance concentration and the specified glucose concentration. The perfusate is first collected over 10 min. for 2 min. distances and then in 5

in

my. distances.

D. Insulin determination

The insulin determination is carried out with the radioimmunoassay from the company Becton and Dickinson. This sample works with March-125

wine antibodies against porcine insulin and with I-labelled porcine insulin. The free antigen is separated in this experiment by adsorption on dextran-coated activated carbon and subsequent centrifugation. As a standard for the reference curve, very pure rat insulin from the company Novo is used.

From the insulin concentration of the individual perfusate fractions, the amount of insulin secreted during 60 min is calculated. With perfusion without substance, experiments show that insulin secretion becomes constant after 10 min. The outflow between 11 and 60 min. is then extrapolated from the outflow between 11 and 20 min. As a result, the preparation is subjected to stress for a shorter time, and at the same time a control is obtained for each trial in the same experiment.

Claims (3)

1. Analogous process for the preparation of therapeutically active substituted oxocarboxylic acids of the general formula I in in which R means a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, R 2 a hydrogen atom or a halogen atom and n an integer from 3 to 8, provided that R<1> does not mean a hydrogen atom, a fluorine atom, a methyl group or a methoxy group, and R 2 a hydrogen atom when n has meant the 3, and salts thereof, characterized in that one a) solvolyzes an oxocarboxylic acid ester with the general formula II 1 2 <1> 3 where R , R and n have the meanings given above and R means a lower alkyl residue and possibly transfers the resulting acids into the salts or the salts obtained into the acids, or b) solvolyze and decarboxylate a diester with that gene real formula III where R 1 , R 2 , R 3 and n have the above meaning, and optionally then transfer obtained acids into the salts or obtained salts into the acids. 2. Process according to claim 1, characterized by producing 6-(4-methoxyphenyl)-2-oxo-caproic acid from the correspondingly substituted starting compounds. 3. Process according to claim 1, characterized by producing 5-(4-chlorophenyl)-2-oxovaleric acid from the correspondingly substituted starting compounds.