DE1801312C - 2 (4 biphenylyloxy) -heptanoic acid, its alkali and alkaline earth salts and these compounds fertilize the medicinal products they contain - Google Patents

Description

The invention relates to 2- (4-biphenylyloxy) -he pt anic acid and its alkali and alkaline earth salts with valuable pharmacological properties, as well as drugs containing this acid or its salts.

The 2- (4-biphenylyloxy) -heptanoic acid of the formula I,

CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₃

CH - CO - OH (I)

and their alkali and alkaline earth salts have not yet been described. As has now been found to own this acid and its salts have valuable pharmacological properties. They particularly show hypolipemic Effectiveness in the broad sense, which z. B. in lowering cholesterol and triglyceride levels can be detected in the blood and liver after repeated oral administration to male rats. the The serum and liver lipids are extracted according to F o 1 c h, J. Biol. Chem., 226, p. 497 (1957). The triglycerides are according to Kessler and L e d e r e r, Technicon Symposia, Vol. I (1965), and the cholesterol according to Block et al., Technicon Symposia, Vol. I. (1965), determined with an automatic analyzer.

2- (4-Biphenylyloxy) -heptanoic acid and its alkali and alkaline earth salts. ', are further calibrated long residence time in plasma and low toxicity. They are suitable for oral and rectal administration in mammals for the treatment of hyperlipemic conditions such. B. Hypercholesterolemia.

Hydrolyzed to produce 2- (4-BiphenyIyIoxy) -heptanoic acid and its alkali and alkaline earth salts if a functional derivative thereof is used, the acid is obtained from a salt obtained, if desired free and / or leads an acid obtained or, by double conversion, directly the initially obtained Salt into one or another alkali or alkaline earth salt. As functional derivatives of 2- (4-biphenylyloxy) heptanoic acid are, for example, their esters of the general formula H,

so

CH _a -CK ₂ -CH ₂ -CH ₂ -CH ₃

CH-CO-OR ₁ (II)

in which R _{1 is} a hydrocarbon radical, in particular a lower alkyl radical, denotes the cyclohexyl, phenyl or benzyl radical

Furthermore come z. B. also the nitriles, amides and lower imido alkyl esters into consideration. The hydrolysis takes place, for example, by heating in alkanolic liquids or aqueous-alkanolic alkali hydroxide solutions. From the initially obtained alkali salt solution in the 2- (4-biphenylyloxy) -heptanoic acid can be

neither by concentration or evaporation and recrystallization directly win the corresponding pure alkali salt or first release the acid, then z. B. purify by recrystallization and, if desired, convert it into another alkali or alkaline earth salt. Functional derivatives of 2- (4-biphenylyloxy) -heptanoic acid can also be used in an acidic medium ζ. B. by heating in a mixture of 60 to 70 ° / _O iger sulfuric acid or in alkanolic aqueous hydrochloric acid, converted into the free acid.

The esters of the general formula II as well as the corresponding nitriles, amides and lower imidoalkyl esters are themselves new connections. To prepare the esters of the general formula II, one uses

»5 an alkali salt of p-phenylphenol with a reactive one Derivative of a 2-hydroxy-heptanoic acid ester of the general formula III,

CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₃
HO - CH - CO - O - R ₁ (III)

in which R _{1 has} the meaning given under formula I. in a suitable solvent, such as. B.

in ethanol at its boiling point or in dimethylformamide at 40 to 130 ^° C., preferably 60 to 90 ^° C., to. The required alkali salt of p-phenylphenol can be used as such: or before the reaction in situ, in ethanol z. B. by means of the corresponding alkali ethylate or in dimethylformamide with the aid of a suitable alkali hydride, especially sodium or lithium hydride.

As reactive derivatives of 2-hydroxyheptanoic acid esters of the general formula III are, for example, halides, d. H. Esters of 2-haloheptanoic acid, as well as arenesulfonic acid and alkanesulfonic acid derivatives, such as 2- (4-toluenesulfonyloxy) and 2-methanesulfonyloxy-heptanoic acid esters, into consideration. Individual such compounds, e.g. B. the 2-bromoheptanoic acid ethyl ester, are known; others are analogous to the known compounds and / or corresponding Derivatives of lower alkanoic acids can be prepared. Analogous to the reactive esters of compounds of the general formula III can also be reactive esters of 2-Hydroxyheptansäurenitrils, z. B. the well-known 2-bromo-heptanoic acid nitrile, react with alkali salts of p-phenylphenol. The received Nitrile of 2- (4-biphenylyloxy) -heptanoic acid is either hydrolyzed directly to the acid or if desired in a manner known per se into the corresponding amide or a lower imidoalkyl ester or its Hydrohalide, d. H. in others for the hydrolysis to 2- (4-biphenylyloxy) -heptanoic acid or its salts converted into suitable starting materials.

The nitrile and the amide of 2- (4-biphenylyloxy) -heptanoic acidc can also be started from lower (4-biphenylyloxy) -n-pentyl-cyanoacetic acid alkyl esters, whose production is described below

is purified, to produce. By partial hydrolysis with aqueous-aicanolic potassium hydroxide solution or sodium hydroxide solution

the approximately equimolar amount of an aqueous or moderately elevated temperature and subsequent

Alkanolic alkali hydroxide solution, acidification and acidification obtained. It is preferable to heat a radio

Decarboxylation gives the desired nitrile derivative of the dicarboxylic acid mentioned.

When heating the substituted cyanoacetic acid mentioned, for example, one of the lower di-

acid alkyl esters with excess alkanolic alkyl alkyl esters or nitrile alkyl esters as well as z. B. also that

Potassium hydroxide solution and acidification creates the monoamide of dinitrile, with a water-containing mineral acid, whereby

substituted malonic acid, optionally mixed with the dicarboxylic acid formed by hydrolysis

with the free, substituted malonic acid and as the reaction conditions directly to the 2- (4-Bi-

End product desired 2- (4-biphenylyloxy) -heptan-xo phenylyloxy) -heptanoic acid is decarboxylated. When

acid of the formula I. By decarboxylation, water-containing mineral acids are obtained, for example

the amide of the 2- (4-biphenylyloxy) -heptanoic acid or example 60 to 70 ° / _o by weight sulfuric acid or in the overall

a mixture of these with the free acid, the vessel closed at the same time also concentrated hydrochloric acid, the

like the pure amide into the uniform end product via an organic, water-soluble or with water

can be performed. 15 miscible solvent with a suitable boiling point,

According to a second method, the z. B. acetic acid, may be added.
2- (4-BiphenylyIoxy) -heptanoic acid and its alkali and alkaline earth salts -Biphenylyloxy) -n-pentyl-malonic acid, ins- alkali salts consists in the fact that an alkali salt of the particular lower dialkyl ester, furthermore a 20 p-phenylphenol with a salt of a reactive lower nitrile alkyl ester or the dinitrile, with a derivative of 2-hydroxyheptanoic acid converts, inorganic or organic base up to the splitting if desired from the obtained salt of 2- (4-biting of the equimolar amount of carbon dioxide heated phenylyloxy) -heptanoic acid liberates the acid and / or and, if desired, from the obtained salt of the latter or, if desired, by double um-2- (4-biphenylyloxy) -heptanoic acid releases the acid, directly convert the salt initially obtained into an Al and the latter or the salt initially obtained into a potassium od he transferred alkaline earth salt. The conversion to alkali or alkaline earth salt. For example, (4-biphenylyloxy) -n-pentylmalonic acid thinning agent, e.g. B. in a lower, optionally alkyl ester with excess alkanolic alkali water-containing alcohol, such as ethanol or butanol, lye, z. B. with methanolic potassium hydroxide solution, some 30 or in dimethylformamide at a temperature of hours under reflux. The conversion of the nitrile about 8O ⁰ C to the boiling point of the reaction medium alkyl ester and the dinitrile is carried out analogously, but below. The formation of the more immediate reenergic conditions, e.g. For example, salts from the free tion times required with longer reaction components and / or at a higher temperature in the p-phenylphenol or the free acid are carried out in a preferably closed vessel. 35 wise in situ, e.g. B. by adding an alkali alcoholate,

The lower dialkyl esters, the nitrile alky'e iters and an alkali hydroxide or alkali hydride, depending on whether the dinitrile of (4-biphenylyloxy) -n-pentyl-malonic acid is an anhydrous alkanol as the reaction medium, like this acid itself, new connections. They rely on water-containing alkanol or dimethylformamide, for example, analogously to the esters that are commonly used. As reactive esters of the 2-hydroxy common formula III by reaction of bromine 40 heptanoic acid come z. B. halides, arenesulfonic or chloro-n-pentyl-malonic acid dialkyl esters or -cycyl esters and alkanesulfonic acid esters in question; Examples of known anacetic acid alkyl esters or bromo-n-pentyl-ma are 2-bromoheptanoic acid and ionic acid nitrile with alkali metal salts of p-phenylphenol, 2-chloro-heptanoic acid,
z. B. in boiling absolute ethanol. The salts, if desired, of the bromine or chlorine compounds required for this purpose, 2- (4-biphenylyIoxy) -heptanoic acid, can be used, for example, by halogenation, analogously to use as therapeutic agents, generally those corresponding, known compounds with low, whose cations are in the eligible lower alkyl group, e.g. B. the bromo-n-butyl-malonic acid dosages no or a desired biolodiethyl ester (J. Am. Chem. Soc, 44, pp. 1578 to 1581 gische own effect and their solubility in [1922]), produced. 50 gastric and intestinal contents sufficient absorption

A third process for the preparation of the 2- (4-Bi- guarantees. Salts that do not meet this requirement

phenylyloxy) -heptanoic acid and its alkali and earth correspond, but z. B. crystallize well, can

Alkali salts consists in that the (4-biphenylyl- if necessary in the course of the pure preparation of the

oxy) -n-pental-malonic acid or an acidic salt of the acid or other salts may be useful. As salts

same with an inorganic or organic base, 55 of the 2- (4-biphenylyl-

in particular a monoalkali metal salt thereof, up to oxy) -heptanoic acid, the alkali metal salts, like that, are suitable

Elimination of the equimolar amount of carbon dioxide, the potassium salt, the lithium salt and, above all, the sodium

heated and when using the free dicarbon trium salt, also alkaline earth salts, such as the calcium salt,

Acid obtained acid, if desired, into an alkali metal salt. The salts are produced

or alkaline earth salt transferred. For example, 60 is generally heated by adding acid and

one said dicarboxylic acid at temperatures base in suitable solvents, such as methane!

between 130 and 200 ⁰ C, until the carbon dioxide. If necessary, filtering off the precipitated salts or

winding is finished. The 2- (4-biphenylyloxy) -malon- Evaporation of the salt solutions. Instead of free

acid is produced, for example, by hydrolysis of its never-bases can also correspond to soluble carbonates,

their dialkyl esters or of the corresponding nitrile 65 z. B. sodium or potassium carbonate or bicarbonate,

alkyl esters, d. H. (4-biphenylyloxy) -n-pentyl-malon- can be used. Furthermore, salts that are

acid dialkyl esters or (4-biphenylyloxy) -n-pentyl- used solvents are relatively sparingly soluble,

cyanoacetic acid alkyl esters, with alkanolic or by double conversion of another salt

5 6

the acid with a suitable salt of the base layer chromatogram apart from the acid only

put. Traces of acid amide can be seen.) The reaction solution

The 2- (4-BiphenyIyloxy) -heptansä.tre and its Al- is acidified with 2N hydrochloric acid, the ethanol in

Potash and alkaline earth salts are evaporated in vacuo, as above, and the aqueous phase is extracted with ether

thinks it is administered orally or rectally. The daily 5 and the ether washed twice with water. To

Doses range between 50 and 500 mg for drying with MgSO ₄ is obtained from the ether

grown patients. Suitable can unit forms, phase the crude 2- (4-biphenyl> loxy) -heptanoic acid, the

such as dragees, tablets, suppositories contain as recrystallized from a benzene / gasoline mixture

Are you? preferably 10 to 250 mg, e.g. B. 50 or will, m.p. 115 to 116 ° C.

ICO mg of the acid or an alkali or alkaline earth metal used as starting material 2- (4-biphenylyl ·

salt. oxy) -heptanoic acid nitrile is produced as follows:

Iη Doseneinhehsformen for oral use b) In one with stirrer, reflux condenser, drip fly the content of active ingredient preferably between funnel and potassium hydroxide-containing dry 10 and 90%. tube-fitted round-bottom flasks are 57.0 g (0.5 mol)

The following examples explain the ethyl cyanoacetate in 200 ml of absolute ethanol

position of 2- (4-biphenylyloxy) -heptanoic acid and its dissolved. In order to increase the temperature to over 6O ⁰ C

Alkali and alkaline earth salts. to avoid, 11.5 g (0.3 mol) are metallic

. I _{only add 1} sodium to the solution in small portions.

Example 1 given. After about 2 hours, when the

10 g (0.031 mol) 2- (4-biphenylyloxy) -heptanoic acid- 20 given metallic sodium has completely dissolved, ethyl acetate with 2.1 g (0.038 mol) potassium will be 75.5 g (0.5 mol) n- Pentyl bromide is added dropwise with a hydroxide in 50 ml of methanol for 1 hour under reflux temperature of 40 to 50 ° C, and heated. The solution is then evaporated until the syrupy mixture is obtained, which is then concentrated to a similar consistency for 2 hours, and water is added to it. Heated to reflux.
File should result in a clear solution, otherwise it is 25 After cooling to room temperature, the undissolved material is removed by washing with ether. the reaction mixture is poured onto a mixture of ice and water, the alkaline solution is then poured with 2-η hydrochloric acid, and the oil which separates out is acidified in ether. The 2- (4-biphenylyloxy) -heptane acid is absorbed and initially precipitated as an oil with water until it becomes neutral. that washed slowly, especially during the action. The ether solution obtained is ridden with a little methanol, crystallized. Dryed by circulating over sodium sulfate, filtered and crystallized from methanol / water, then evaporated from acetone / water in a rotary evaporator. The ser CDER of hexane is cleaned and then it has residue in vacuo at a Olbadtemperaden mp. 115-116 "C. Door distilled of 140 to 150 ⁰ C. The n-pentyl-cyano-

29.84 g (0.1 mol) of 2- (4-biphenylyloxy) -heptanoic acid-ethyl ester boils at 117 to 119 ° C / 12 Torr,

are dissolved in 200 ml of methanol. To the obtained solution 35 c) In a with stirrer, reflux condenser and drop

solution is added 3.8 g (0.095 mol) of carbonate-free sodium funnel provided flask, 36.6 g (0.2 mol)

trium hydroxide and evaporated to dryness. The reverse n-pentyl cyanoacetic acid ethyl ester, 160 ml H ₂ O, 20.5 g

stand is obtained by extraction with ether from the starting (0.25 mol) sodium acetate and a spatula tip of phthalic

freed of substance, whereupon the pure sodium salt was added back-monoperic acid and added to this mixture

remains that does not melt up to 35O ° C. 40 with thorough stirring 32 g (0.2 mol) of bromine at room

The ester required as starting material is added dropwise at temperature as follows. The reaction mixture will

produced: then heated to 60 ° C _{for 2V 2 hours and after}

a) In one with a stirrer, reflux condenser and cauldron cooling taken with ether. The received

lium hydroxide-containing ether solution provided is then successively with a

Round-bottomed flask dissolve 3.68 g (0.16 mol) of sodium in 45 dilute sodium bisulfite solution, dilute sodium

150 ml of absolute ethanol. The sodium carbonate solution produced in this way and water until neutral

trium ethylate solution, 27.2 g (0.16 mol) of powder action are washed, dried over sodium sulfate,

Sated p-phenylphenol is added and nitrated in the resulting product and then in a rotary evaporator

NEN solution of the sodium salt of p-phenylphenol evaporated. The residue is in vacuo

then 35 g (0.1475 mol) of 2-bromo-heptanoic acid 50 distilled.

ethyl ester dissolved. The resulting reaction solution is heated under reflux for 7 hours, the resulting ethyl bromine-n-pentyl-cyanoacetic acid, the potassium ester boiling at 122 to 124 ° C./10 Torr,
bromide separates. The ethanol is evaporated, the d) dissolved in ether with a stirrer, dropping funnel and potassium residue and the solution is shaken out with a hydroxide-containing drying tube until an acidified 55 flask 17.0 g (0.1 mol) 4-hydroxybiphenyl sample of the alkaline extract is no longer turbid in 350 ml of dimethylformamide at room temperature. Then you shake the ethereal solution three more times. 4.8 g (0.1 mol) of Namit 0.5 η sodium hydroxide solution are added to this solution and then with water. triumhydrid-dispersion (50 ° / ₀ by weight dispersion in mineral dried over sodium sulfate and evaporated. oil) was added under stirring. After complete conversion of the 2 - (4 - biphenylyloxy) - heptanoic acid- 60 set to the sodium salt, 26.2 g (0.1 mol) of ethyl ester are chromatographically pure. Rf = 0.9, Kie- bromo-n-pentyl-cyanoacetic acid-ethyl ester with space acid gel neutral, benzene-ethanol = 100:15 at temperature added dropwise and the mixture then _R. . . Heated for 1 hour with stirring on the water bath to an example 1 temperature of 60 ^° C. After cooling down

a) Ig 2 - (4 - uiphenylyloxy) - heptanoic acid nitrile 65, the reaction mixture obtained is converted to a mixture

(0.00358 mol) are poured into a solution of 1 g of KOH from ice and water, the oil which separates out

in 35 ml of ethanol and 8 ml of water for 42 hours under calcined and with 1 N sodium hydroxide and water up to

Reflux heated to boiling. (Afterwards are washed in the thin to neutral reaction. The obtained

Ether solution is dried over sodium sulfate, fil- 5 η-sulfuric acid and 100 ml of glacial acetic acid is triturated for 24 hours and then evaporated in vacuo. The heated to boiling under reflux. The reaction residue is poured by column chromatography (after cooling, the silica mixture is poured onto 800 ml of ice acid gel [0.05 to 0.2 mm - Merck)], benzene as solvent, the 2- (4-biphenylyloxy) - solvent) cleaned. After evaporation of the ben- 5 heptanoic acid precipitates in crystals. After Umzols and drying of the remaining residue of the obtained 2- (4-biphenylyloxy) -n-pen- zin melts crystallized from a mixture of benzene and Benkristallisiert the purified acid at 114-115 ⁰ C. tyl-cyanessigsäüre ethyl ester of m.p. 56 to 59 ° C.

e) In a round-bottom flask equipped with a magnetic stirrer, 17.6 g (0.05 mol) of 2- (4-biphenylyloxy) - io B is ρ ie I 5
ethyl n-pentyl cyanoacetate and 55 ml of 1 n-HaOH

Stirred for 2 hours while warming to 80 to 90 ° C (an a) 1.5 g (0.00285 mol) 2- (4-biphenylyloxy) -n-pentyl-

Instead of aqueous 1N NaOH, alcoholic ethyl cyanoacetate can also be used in a solution of 1 n-NaOH can be used). After cooling, 0.8 g of KOH in 20 ml of ethanol and 2 ml of water for 21 hours the reaction mixture diluted with water is heated to boiling under reflux. After the ethereal the remaining aqueous phase with hydrochloric acid evaporate the ethanol in vacuo and acidify with acidified and the now separated oil in ether 2 η-hydrochloric acid, ethers out, washes the ether phase with it taken up and then washed with water. Water and dry over magnesium sulfate. After The 2- (4-biphenylyloxy) -n-pentyl-cyanoacetic evaporation obtained gives a mixture of 2- (4-bisacid is further processed as a raw product. 20 phenylyloxy) -2-carboxy-heptanoic acid amide, 2- (4-biphe-

f) 12.9 g (0.04 mol) of 2- (4-biphenylyloxy) -n-pentyl-nyly! oxy) -heptanoic acid and 2- (4-biphenylyloxy) -hepcyanoacetic acid and a trace of metallic copper-tanoic acid amide. This mixture is mixed well in powder for 20 minutes and heated to boiling xylene in a round bottom flask. After evaporation it gets carefully warmed with a free flame. With a mixture of 2- (4-biphenylyloxy) -heptane-Temperiiur of 120 ° C begins the carbon dioxide 25 acid amide and the corresponding acid.
winding, the temperature to 19O ⁰ C b) this mixture is rapidly rises g in a solution of Figure 1. For complete decarboxylation of the KOH in 40 ml of ethanol and 5 ml of water is 40 hours Temperature short time (about 1 minute) to 200 ⁰ C ER- heated to boiling and then höht under reflux. After cooling, the residue is worked up as described for the saponification of the nitrile (ethyl alcohol recrystallized in the presence of animal charcoal, game 2, a). Siert after recrystallization. The resulting 2- (4-biphenylyloxy) -heptansäure- from benzene / petroleum ether melts the obtained 2- (4-Binitril melts at 68 to 70 ⁰ C. phenylyloxy) -heptanoic acid at 115 to 116 ° C.

c) The mixture obtained from Example 3, a)

Example 3 2- (4- biphenylyloxy) -2-carboxy-heptanoic acid amide,

35 2- (4-biphenylyloxy) -heptanoic acid amide and 2- (4-bi-phe-

a) 16 g (0.04 mol; crude 4-biphenylyloxy-n-pentyl-nylyloxy) -heptanoic acid can also be saponified acidic: malonic acid diethyl ester is in a solution of 0.6 g of the mixture obtained under 5, a) 5.4 g of KOH (85 ° / ₀ ) in 30 ml of methanol were heated under reflux for 18 hours in a mixture of 34 ml of 70 ° / _{0 iger sulfuric acid.} After evaporation of the (V / V) and 17 ml glacial acetic acid for 6 hours under reflux the methanol in vacuo, the residue is warmed in approximately 40 to a temperature of 9O ⁰ C. After the 500 ml of ice water is dissolved and the resulting solution is acidified by evaporating the acetic acid in vacuo, diluting 10 ml of concentrated hydrochloric acid. The extracted with water and extracted with ether are obtained after the fallen colorless crystals are dried with water, the 2- (4-biphenylyloxy) -heptane-washed and dissolved in 200 ml of methanol. After the acid. After two recrystallization from Ben filtration, the acid melts at 114 to 116 "C by adding dropwise water 45 zol / gasoline.

the 2- (4-biphenylyloxy) heptanoic acid precipitated, m.p.

114 to 11'5 ° C. Example 6

The 4-biphenylyloxy-n-pentyl-malonic acid diethyl

ester is prepared as follows: To a solution of 2.3 g (0.1 mol) of sodium in

b) 8.5 g (0.05 mol) in 60 ml of absolute ethanol are added to a solution of 1.15 g (0.05 mol) of sodium 50 120 ml of absolute ethanol under CO ₂ -AuS-4-hydroxy-biphenyl . After the dissolution is complete, 8.5 g (0.05 mol) of 4-hydroxy-biphenyl are added to the added substance at 0 to 5 ° C. 15.45 g of bromine are cooled to the resulting solution and at this temperature 10, 45 g (0.05 mol) of n-pentyl-malonic acid diethyl ester are added and 2-bromo-heptanoic acid is added. The reaction is heated to boiling under reflux for 7 hours. The mixture is then heated to the boil, the alcohol is evaporated off and the alcohol is evaporated in vacuo the evaporated, the residue dissolved in water and the residue taken up in ether and acidified three times with solution with 2η-hydrochloric acid ) Reaction shaken out with water.Melts after recrystallization from about 250 ml

After drying, evaporation and chromatographic 60 65 ° / _o aqueous ethanol at 113 to 115 ° C.
graphic purification (silica gel Merck, 0.05 to 1 g (0.00335 mol) of 2- (4-biphenylyioJty) -hep-

0.2 mm, eluent: benzene) a tanic acid is obtained in 20 ml of methanol and added to a Lögelbe oil, n ' _B ^s = 1.5334. Dissolution of 0.168 g (0.00254 mol) KOH (86 ° / ₀ ) in 10 ml

Methanol. The clear solution is dried to

B eis ρ ic 1 4 ⁶ S evaporates and the residue washed well with ether.

The crystals are dissolved in hot ethyl acetate and filtered.

8 g of 4 - biphenylyloxy - η - pentyl - malonic acid - di- After evaporation of the filtrate, this is obtained äthylcster are in a mixture of 20 ml of crystalline potassium salt of 2- (4-biphenylyloxy) -heptan-

acid. The crystals slowly decompose from 300 ^° C. without melting. They easily dissolve in chloroform. 0.4 g of Ca (0.01 mol) are decomposed in 40 ml of water with the exclusion of _{CO 2.} To the suspension of Ca (OH) _2, 6.5 g (0.0218 MoI) 2- (4-biphenylyloxy) -heptanoic acid in ¹¹⁵⁰ ml of methanol added and heated for 10 minutes to boil. After evaporation to dryness, it is triturated with ether and washed well. The residue obtained is extracted with hot methanol. There are colorless crystals that slowly decompose above 29o ⁰ C without melting. They easily dissolve in chloroform.

Test report The following compounds were examined:

I 4 - chlorophenoxy - isobutrsic acid ethyl ester (cf. British patent S60 303 or USA patent 3,262,850).

10

II 2 - (4 - biphenylyloxy) - 5 - methyl - hexanoic acid (cf. Farmaco [Pavia] Ediz. Sei. Vol. 20, 1965, Pp. 456 to 462, reported in Chemical Abstracts, Vol. 63, 1965, Column 8248 a to d).

111 2 - (4 - biphenylyloxy) - heptanoic acid (according to the invention Connection).

Hypolipemic effectiveness was increased by lowering cholesterol and triglyceride levels in

ίο blood and liver after repeated oral administration detected in male rats. The serum and liver lipids were extracted according to F ο 1 c h, J. Biol. Chem., 226, p. 497 (1957). The triglycerides are according to Kessler and Lederer, Technicon Symposia, Vol. I (1965), and the cholesterol according to B i ο c k et al., Technicon Symposia, Vol. I (1965), determined with an automatic analyzer. In the following Table I are those after the above Methods obtained values of hypolipemic activity are summarized.

Table I.

substance dose
mg / kg po serum
Choi. I triglyc. -41
-53
-56 Lipid. P. liver
Choi. I triglyc. I lipid. P. -55
-71
-71 + 7
+ 11 I.
4-chlorophenoxy-isobutyric acid ethyl ester ..
II
2- (4-biphenylyloxy) -5-methyl-hexanoic acid
III
2- (4-biphenylyloxy) heptanoic acid to to to
3 S3 3 -37
-48
-56 -38
-42
54 -11
-22
-18

Table 11

substance

I.
4-chlorophynoxy-isobutter- j

acid ethyl ester \

II ι

2- (4-biphenylyIoxy) -5-methyl-

hexanoic acid c

2- (4-biphenylyloxy) -heptanic acid I

dose

200 100

200 100

200 100

inhibition

-24 -19

-50 -30

In the adjacent table 11 is the anti-inflammatory Effect of the above substances in the bolus alba edema test on rats.

From Tables Γ and II it can be seen that the substance according to the invention with respect to the hypolipemic Activity is slightly to significantly superior to the comparison substances and with regard to on the anti-inflammatory effect is clearly superior to the substances mentioned. The extent of the The superiority of the sum of the effects of the substance according to the invention is surprising and wai not to be expected.

Claims (2)

Patent claims: 1. 2- (4-Biphenylyloxy) heptanoic acid and its Alkali and alkaline earth salts. 2. Medicines, characterized by a Ge. stop at 2- (4-biphenylyloxy) -heptanoic acid or its Alkali or alkaline earth salts in addition to the usual inert carriers and additives,