DE1801312B - 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 the 2- (4-biphenylyloxy) -heptanoic acid and their alkali and alkaline earth having valuable pharmacological properties, as well as pharmaceutical compositions containing this acid or i ire 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)

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

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

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

ao acid transfer.

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

and their alkali and alkaline earth salts have not yet been described. As has now been found to own the 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 Extraction of the serum and liver lipids is carried out according to F o I c h, J. Biol. Chem., 226, p. 497 (1957). The triglycerides are according to Kessler and L e d c 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.

The 2- (4-Biphcnylyloxy) -heptanoic acid and its alkali and alkaline earth salts are further characterized by a long residence time in the plasma and low toxicity. They are suitable for oral and rectal administration to mammals for the treatment of hyperlipemic conditions such as 7 .. B. hypercholestcrinemia. ₅ "

Hydrolyzed to produce 2- (4-Biphcnylyloxy) -heptanoic acid and its alkali and alkaline earth salts If a functional derivative of the same is used, the acid obtained from the salt obtained is converted, 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 II,

CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₃

CH-CO-OR ₁ (FI)

CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₃

HO-CH-CO-OR ₁ (III)

in which R _{1 has} the meaning given under formula I, in a suitable solvent, such as ζ. Β in ethanol at its boiling point or in dimethylformamide at 40 to 130 ° C, preferably 60 to 9O ⁰ C, to. The required alkali salt of p-Phenvl phenol can be used as such or in situ before the reaction, in ethanol z. B. by means of the correspond to the alkali ethylate or in dimethylformamide with the help of a suitable alkali hydride, especially sodium or lithium hydride.

As reactive derivatives of 2-hydroxyheptane acid esters of the general formula III come for example halides, ie esters of 2-halo heptanoic acid, and arenesulfonic acid and alkanesulfonic acid derivatives, such as 2- (4-toluenesulfonyloxy) - and 2-methanesulionyloxy-heptanoic acid esters, in Consideration. A few such compounds, e.g. B. ethyl 2-bromoheptane are known; others can be prepared analogously to the known compounds and / or corresponding derivatives of lower alkanoic acids. Analogous to the reactive esters of compounds of the general formula III, reactive esters of 2-hydroxyheptanoic acid nitride, ζ. Β the well-known 2-bromo-heptanoic acid nitrile, react with alkali salts of p-phenylphenol. The nitrile of 2- (4-biphenylyloxy) -heptanoic acid obtained 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, ie into further ones for the hydrolysis to the 2nd - (4-Biphenylyloxy) -heptane acids or their salts converted into suitable starting materials.

Dns nitrile and the amide of 2- (4-biphenylyloxy) Heptanoic acid can also be started from lower (4-BiphcnyIyloxy) -n-pentyl-cyanoacetic acid acid-alkyl esters, the preparation of which is

is purified, to produce. By partial hydrolysis with an approximately equimolar amount of an aqueous or alkanolic alkali hydroxide solution, acidification and Decarboxylation gives the desired nitrile. When heating said substituted alkyl cyanoacetate with excess alkanolic Al potassium hydroxide solution and acidification, the monoamide der is formed substituted malonic acid, optionally in a mixture with the free, substituted malonic acid and the als End product of the desired 2- (4-biphenylyloxy) heptanoic acid of the formula I. Decarboxylation gives the amide of 2- (4-BiphenyIyloxy) -heptanoic acid or a mixture thereof with the free acid, the same how the pure amide can be converted into the uniform end product.

According to a second process, the 2- (4-biphenylyloxy) heptanoic acid and its alkali and Alkaline earth metal by making a functional derivative of (4-biplienylyloxy) -n-pentyl-malonic acid, in particular a lower dialkyl ester, also a lower nitrile alkyl ester or the dinitrile, with a heated inorganic or organic base until the equimolar amount of carbon dioxide is split off and, if desired, liberating the acid from the salt of 2- (4-biphenyiyloxy) heptanoic acid obtained and the latter or the salt obtained first is converted into an alkali metal or alkaline earth metal salt. For example (4-Biph3nyIyloxy) -n-pentylmalonic acid dialkyl ester is heated with excess alkanolic alkali, z. B. with methanolic potassium hydroxide solution, under reflux for a few hours. The Uri: act of the nitrile alkyl esters and the dinitrile is analogous, but under more energetic conditions, e.g. B. i.iit longer response times and / or carried out at a higher temperature in a closed vessel.

The lower dialkyl esters, the nitrile alkyls and the dinitrile of (4-biphenylyloxy) -n-pentyl-malonic acid are, like this acid itself, new compounds. They can, for example, analogously to the esters of the general formula III by reacting bromine or chloro-n-pentyl-malonic acid dialkyl esters or -cyanoacetic acid alkyl esters or bromo-n-pentyl-malononitrile with alkali salts of p-phenyl-phenol, e.g. B. in boiling absolute ethanol. The bromine or chlorine compounds required for this purpose are, for example, analogous to corresponding, known compounds with a lower AiKylgruppc, z. B. the bromo-n-butyl-malonic acid diethyl ester (J. Am. Chem. Soc, 44, pp. 1578 to 1581 [1922]).

A third process for the preparation of 2- (4-biphenylyloxy) -heptanoic acid and its alkali and Erdnlkalisalze consists in that one the (4-biphenylyloxy) -n-pen (al-malonsuurc or an acidic salt dcriclben with an inorganic or org mix base, in particular a mono alkali metal salt thereof, heated to Ahspalliing the äquimolarcn amount of carbon dioxide and the acid obtained by the use of the free dicarboxylic acid, if desired, converted into an alkali metal or alkaline earth metal salt. for example, by heating said dicarboxylic acid to temperatures of 130-200 ⁰ C until The 2- (4-biphenylyloxy) -malonic acid is obtained, for example, by hydrolysis of its lower dialkyl esters or of corresponding nitrile-alkyl esters, ie (4-biphenylyloxy) -n-pentyl-malonic acid dialkyl esters or (4-biphenylyloxy) -n-pentylcyanoacetic acid alkyl esters, with alkanolic or aqueous-alkanolic potassium hydroxide solution or sodium hydroxide solution at idle elevated temperatures and succession obtained from acidification. A functional derivative of the dicarboxylic acid mentioned, for example one of the lower dialkyl esters or nitrile alkyl esters already mentioned, and z. B. also the dinitrile, with a water-containing mineral acid, the dicarboxylic acid formed by hydrolysis is decarboxylated under the reaction conditions directly to 2- (4-biphenylyloxy) -heptanoic acid. The water-containing mineral acid used is, for example, 60 to 70% sulfuric acid or, in a closed vessel, concentrated hydrochloric acid, which is an organic, water-soluble or water-miscible solvent with a suitable boiling point, e.g. B. acetic acid, may be added.

Another process for the preparation of 2- (4-biphenylyloxy) -heptanoic acid and its alkali and alkaline earth metal salts consists in reacting an alkali metal salt of p-phenylphenol with a salt of a reactive derivative of 2-hydroxyheptanoic acid, if desired from the salt obtained 2- (4-biphenylyloxy) -heptanoic acid releases the acid and / or, if desired, converts the latter or, by double conversion, directly as the salt initially obtained is converted into an alkali metal or alkaline earth metal salt. The reaction is preferably carried out in a solution b / .w. Thinners, e.g. B. carried out in a lower, optionally water-containing alcohol such as ethanol or butanol, or in dimethylformamide, at a temperature of about 8O ⁰ C to the boiling point of the Reaktionsrnediums. The formation of the salts required as immediate reaction components from the free p-phenylphenol or the free acid is preferably carried out in situ, e.g. B. by adding an alkali metal alcoholate, an alkali metal hydroxide or alkali metal hydride, depending on whether an anhydrous alkanol, a water-containing alkanol or dimethylformamide is used as the reaction medium. As reactive esters of 2-hydroxyheptanoic acid come z. B. halides, arenesulfonic acid esters and alkanesulfonic acid esters in question; known examples are 2-bromoheptanoic acid and 2-chloro-heptanoic acid.

The salts of 2- (4-biphenylyloxy) -heptanoic acid to be prepared, if desired, are used as therapeutic active ingredients generally those in question whose cations are in the relevant Dosages have no or a desired biological intrinsic effect and their solubility in the Gastric and intestinal contents ensure adequate absorption. Salts that do not meet these requirements correspond, but z. B. crystallize well, can optionally in the course of the purification of the Acid or other salts useful scm. As salts of the invention; g: 2- (4-biphenylyloxy) heptanoic acid which can be prepared in accordance with the alkali salts are suitable, such as the potassium salt, the lithium salt and, above all, the sodium salt, also alkaline earth salts, such as the calcium salt, the magnesium salt. The production of df.f salts takes place

generally by combining acid and base in suitable solvents such as methanol, optionally filtering off the precipitated salts or evaporating the salt solutions. Instead of free Bases can also correspond to soluble carbonates,

z. B. sodium or potassium carbonate or bicarbonate can be used. Furthermore, salts that are used in Solvents are relatively sparingly soluble, also due to the double conversion of another salt

the acid with a suitable salt of the base.

The 2- (4-biphenylyloxy) -heptanoic acid and its alkali and alkaline earth salts are, as mentioned above, administered orally or rectally. The daily doses range between 50 and 500 mg for adults Patient. Suitable unit dosage forms such as dragees, tablets, suppositories contain as Active ingredient preferably 10 to 250 mg, e.g. B. 50 or ICO mg of the acid or an alkali or alkaline earth metal salt.

In unit dose forms for peroral use the content of active ingredient is preferably between 10und90 ° / _0th

The following examples explain the preparation of 2- (4-biphenylyloxy) heptanoic acid and its Alkali and alkaline earth salts.

example 1

10 g (0.031 mol) of ethyl 2- (4-biphenylyloxy) heptanoate are refluxed with 2.1 g (0.038 is'ol) of potassium hydroxide in 50 ml of methanol for 1 hour. Then the solution is evaporated to a syrupy consistency and mixed with water. This should result in a clear solution, otherwise the undissolved has to be removed by washing with ether. The alkaline solution is then acidified with 2N hydrochloric acid. The 2- (4-biphenylyloxy) -heptanoic acid initially precipitates as an oil, which slowly crystallizes, especially when rubbed with a little methanol. Recrystallization from methanol / water, from acetone / water CDER of hexane it is cleaned and then has denSchmp. 115 to 116 ^C C.

29.84 g (0.1 mol) of 2- (4-biphenylyloxy) heptanoic acid are dissolved in 200 ml of methanol. To the solution obtained 3.8 g (0.095 mol) of carbonate-free sodium hydroxide are added and the mixture is evaporated to dryness. The residue weather! freed from the starting material by extraction with ether, whereupon the pure sodium salt remains, that does not melt up to 350 C.

The ester required as a starting material is produced as follows:

a) In a round-bottom flask equipped with a stirrer, reflux condenser and potassium hydroxide-containing drying tube, 3.68 g (0.16 mol) of sodium are dissolved in 150 ml of absolute ethanol. 27.2 g (0.16 mol) of powdered p-phenylphenol are added to the sodium ethyl solution thus prepared and 35 g (0.1475 mol) of ethyl 2-bromo-heptanoate are dissolved in the resulting solution of the sodium salt of p-phenylphenol. The reaction solution obtained is refluxed for 7 hours, during which potassium bromide separates out. The ethanol is evaporated off, the residue is dissolved in ether and the solution is extracted with 0.5 η sodium hydroxide solution until an acidified sample of the alkaline extra gravel is no longer cloudy. The ether solution is then shaken out three times with 0.5 η sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated. The ethyl 2- (4-biphenylyloxy) heptanoate obtained is chromatographically pure. Rf = 0.9, silica gel neutral, benzene-ethanol = 100:15.

Example 2

a) Ig 2 - (4 - biphenylyloxy) heptanoic acid nitrile (0.CU358 mol) are refluxed for 42 hours in a solution of 1 g of KOH in 35 ml of ethanol and 8 ml of water. (Thereafter, only traces of acid amide can be seen in the thin-layer chromatogram apart from the acid.) The reaction solution is acidified with 2η hydrochloric acid, the ethanol is evaporated in vacuo and the aqueous phase is extracted with ether and the ether is washed twice with water. After drying with MgSO ₄ , crude 2- (4-biphenylyloxy) heptanoic acid is obtained from the ether phase, which is recrystallized from a benzene / gasoline mixture, melting point 115 ° to 116 ° C.

ίο The 2- (4-biphenylyloxy) heptanoic acid nitrile used as the starting material is made as follows:

b) In a drying tube containing a stirrer, reflux condenser, dropping funnel and potassium hydroxide provided round-bottom flasks will be 57.0 g (0.5 mol)

Ethyl cyanoacetate dissolved in 200 ml of absolute ethanol. To increase the temperature above 60 ^; To avoid C, 11.5 g (0.3 mol) of metallic sodium are only added to the solution in small portions. After about 2 hours, when the

so given metallic sodium. has completely dissolved, 75.5 g (0.5 mol) of n-pent _y l bromide hinzugitropft at a temperature of 40 to 50 ⁰ C, and the obtained mixture is heated then for 2 hours at the boil under reflux.

After cooling to room temperature, the reaction mixture is poured onto a mixture of ice and water, the oil which separates out is taken up in ether and washed with water until it reacts neutral. The ether solution obtained is dried over sodium sulfate, filtered and then evaporated in a rotary evaporator. The residue is distilled under vacuum at an oil bath temperature of 140 to 150 ⁰ C. The ethyl n-pentyl cyanoacetate boils at 117 to 119C / 12 Torr.

c) In a flask equipped with a stirrer, reflux condenser and dropping funnel, 36.6 g (0.2 mol) of ethyl n-pentylcyanoacetate, 160 m ^× H ₂ O, 20.5 g (0.25 mol) of sodium acetate and A spatula tip of phthalic monoperic acid was added and 32 g (0.2 mol) of bromine were added dropwise to this mixture at room temperature with thorough stirring. The reaction mixture is then heated 2 ¹ I ₂ hours OE0 ° C and added with ether after cooling. The ether solution obtained is then washed successively with a dilute sodium bisulfite solution, dilute sodium bicarbonate solution and water until the reaction is neutral, dried over sodium sulfate, nitrated and then evaporated in a rotary evaporator. The residue is distilled in vacuo.

The ethyl bromo-n-pentyl-cyanoacetate obtained boils at 122 to 124 ° C / 10 torr.

d) In a round-bottomed flask equipped with a stirrer, a dropping valve and potassium hydroxide, 17.0 g (0.1 mol) of 4-hydroxybiphenyl are dissolved in 350 ml of dimethylformamide at room temperature. 4.8 g (0.1 mol) of sodium hydride dispersion (M) are added _^0/0 by weight dispersion in mineral oil) with stirring to this solution. After complete implemen tation to the sodium salt 26.2 g (0.1 mol) of bromo-n-pentyl-cyanoacetate äthylcster at room temperature was added dropwise and the mixture then heated for 1 hour under stirring on a water bath to a temperature of 6O ⁰ C. After cooling, the resulting reaction mixture is poured onto a mixture of ice and water, the oil which separates out is extracted with ether and washed with 1N sodium hydroxide solution and water until it reacts neutral. The received

Ether solution is dried over sodium sulfate, filtered and then evaporated in vacuo. the The residue is chromatographed on a column (silica gel [0.05 to 0.2 mm - Merck)], benzene as the solvent) cleaned. After evaporating the benzene and drying the remaining residue the obtained 2- (4-biphenylyloxy) -n-pentyl-cyanoacetic acid-ethyl ester crystallizes off, 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) -n-pentyl-cyanoacetic acid ethyl ester and 55 ml I n-l IaC) H stirred for 2 hours while warming to SO to W C (an Instead of aqueous I n-NaOII can also be alcoholic In-NaOH can be used). After cooling down the reaction mixture diluted with water is extracted with ether, the remaining aqueous phase with hydrochloric acid acidified and the oil which has now separated out is taken up in ether and then washed with water. The 2- (4-biphenylyloxy) -n-pentyl-cyanoacetic acid obtained is processed further as a crude product.

f)! 2.9 g (0.04 mol) of 2- (4-biphenylylo \ v) -n-pentylcyanoacetic acid and a trace of metallic copper powder are mixed well and carefully heated in a round-bottomed flask with the free flame. Carbon dioxide begins to develop at a temperature of 120 ° C. the temperature rising rapidly to 190 ^{3 C.} For complete decarboxylation, the temperature is briefly increased (about 1 minute) to 200.degree. C. After cooling, the residue is recrystallized from ethyl alcohol in the presence of animal charcoal .

Example 3

a) 16 g (0.04 mol) of crude 4-biphenylvIoxy-n-pentylmalonic acid diethyl ester is refluxed for _{18 hours in a solution of 5.4 g of KOH (85 "0} ) in 30 ml of methanol. After the methanol has been evaporated off in vacuo the residue is dissolved in about 500 ml of ice water and the resulting solution is acidified with 10 ml of concentrated hydrochloric acid. The precipitated colorless crystals are washed with water and dissolved in 200 ml of methanol. After filtration, the 2- (4- Biphenylyloxy) heptanoic acid precipitated. Mp. 114 to 115 C.

The 4-biphenylyloxy-n-pentyl-malonic acid diethyl ester is made as follows:

b) To a solution of 1.15 g (0.05 mol) of sodium in 60 ml of absolute ethanol is added with CO., - exclusion 8.5 g (0.05 mol) of 4-hydroxy-biphenyl were added. 15.45 g of bromine-pentyl-malonic acid diethyl ester are added to the solution obtained added and heated to boiling under reflux for 7 hours. The alcohol is then evaporated off in vacuo and the The residue was taken up in ether and washed three times with 0.5 η sodium hydroxide solution and then until neutral Reaction shaken out with water.

After drying. Evaporation and chromatographic purification (silica gel Merck. 0.05 to 0.2 mm. Eluent: benzene) gives a yellow oil. n ² i = L5334.

Example 4

8 g of 4 - biphenylyloxy - η - pentyl - malonic acid diethyl ester are in a mixture of 20 ml of 5 η-sulfuric acid and 100 ml of glacial acetic acid for 24 hours heated to boiling under reflux. After cooling, the reaction mixture is poured into 800 ml of ice water poured, whereby the 2- (4-biphenylyloxy) -heptanoic acid separates out in crystals. After recrystallization from a mixture of benzene and gasoline, the purified acid melts at 114 to 115 ° C.

ίο example

a) 1.5 g (0.00285 mol) ethyl 2- (4-Biphcnylyloxy) -n-pentylcyanoacetate are in a solution of 0.8 g KOI! in 20 ml of ethanol and 2 ml of water for 21 hours heated to boiling under reflux. After the ethanol has evaporated off in vacuo, it is acidified with 2 η-hydrochloric acid. ether out, wash the ether phase with water and dry over magnesium sulfate. After Evaporation gives a mixture of 2- (4-biphenylyloxy) -2-carboxy-heptanoic acid amide. 2- (4-biphenylyloxy) -heptanoic acid and 2- (4-biphenylyloxy) -heptanoic acid amide. This mixture is 20 minutes in Xylene heated to boiling. After evaporation, a mixture of 2- (4-biphenylyloxy) heptanoic acid amide is obtained and the corresponding acid.

b) This mixture is in a solution of 1 g of KOH in 40 ml of ethanol and 5 ml of water for 40 hours heated to boiling under reflux and then, as described for the saponification of the nitrus (Example 2, a), worked up. After recrystallization from benzene / petroleum ether, the 2- (4-biphenylyloxy) heptanoic acid obtained melts at 115 to 116 C.

c) The mixture of 2 - (4 - biphenylyloxy) - 2 - carboxy - heptanoic acid amide obtained under Example 3. a), 2- (4-Biphenylyloxy) -heptanoic acid amide and 2- (4-Bi-phenylyloxy) -heptanoic acid can also be saponified acidic: 0.6 g of the mixture obtained under 5. a) become in a mixture of 34 ml of 70 ° sulfuric acid (V / V) and 17 ml of glacial acetic acid under reflux for 6 hours heated to a temperature of 90 C. After the acetic acid has evaporated in vacuo. Dilute with water and ether, after drying of the ether, 2- (4-biphenylyloxy) -heptanoic acid is obtained. After two recrystallizations from benzene gasoline, the acid melts at 114 to 116 "C.

Example 6

To a solution of 2.3 g (0.1 mol) sodium in

120 ml of absolute ethanol are given 8.5 g (0.05Mo!) Of 4-hydroxy-biphenyl. After the added substance has completely dissolved, the mixture is cooled to 0 to 5 ° C. and 10.45 g (0.05 mol) of 2-bromo-heptanoic acid are added at this temperature. The reaction mixture is heated to boiling, the alcohol is evaporated, the residue is dissolved in water and the solution is acidified with 2η hydrochloric acid. The obtained 2- (4-BiphenylyIoxy) -heptanoic acid (colorless crystals) melts ^r after recrystallization from 250 ml of 65 ° / ,, aqueous ethanol at 113 to 115 C.

MaTi dissolves 1 g (0.00335 mol) 2- (4-biphenylyioxy) -heptanoic acid in 20 ml methanol and rubs it into a solution of 0.168 g (0.00254 mol) KOH (86 ° ₀ ) in 10 ml methanol. The clear solution is dried to

evaporates and the residue washed well with ether. The crystals are dissolved in hot ethyl acetate and filtered. After evaporation of the filtrate, the crystalline potassium salt of 2- (4-BiphenyIyIoxy) -heptan

109 585/413

1999

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 COj. 6.5 g (0.0218 mol) of 2- (4-biprienylyloxy) -heptanoic acid in 150 ml of methanol are added to the suspension of Ca (OH) _{2 and the mixture is heated for 10 minutes.} After evaporation to dryness, it is triturated with ether and washed well. The residue obtained is extracted with hot methanol. Colorless crystals are obtained which decompose slowly from 290 ° C. without melting. They easily dissolve in chloroform.

Test report
The following compounds were examined:

I 4 - chlorophenoxy - isobutyric acid ethyl ester (cf. British patent 860 303 or USA patent 3,262,850).

10

II 2 - (4 - biphenylyloxy) - 5 - methyl - hexanoic acid (cf. Farma'.o [Pavia] Ediz. sei. Vol. 20, 1965, pp. 456 to 462, reported in Chemical Abstracts, Vol. 63, 1965, column 8248 a to d).

III 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 I c h. .1. Biol. Chem. 226, p. 497 (1957). The triglycerides are according to Kessler and Lederer, Technicon Symposia, Vol. I (1965), and 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. Chol. serum
Triglyc. Lipid. P. Chol. liver
j triglyc. Lipid. P. substance dose
mg'kg po 37
-48
-56 -4I
-53
-56 -38
-42
-54 -H
- 22
-18 -55
-71
-71 -> - 7
- 11
-S I.
4-chloro-henoxy-isobutyric acid ethyl ester ..
Il
2- (4-Biphenylyloxy) -5-rr.ethyl-! Iexanoic acid
III
2- (4-biphenylvloxy) heptanoic acid 2 50
2 50
2 50

Table II substance J dose inhibition I.
4-chlorophenoxy isobutter
acid ether ester .. J 200 -8th II
2- (4-biphenylyloxy) -5-methyl-
hexanoic acid 1
J
I. 100
200 -6
--24 III
2- (4-BiphenyIyloxy) -heptane
acid 100
200
100 -19
-50 -30

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

From Tables I 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 and was surprising not to be expected.

1999

Claims (2)

Patent claims: 1. 2- (4-Biphenylyloxy) -heptanoic acid and its alkali and alkaline earth salts. 2. Medicinal products, characterized by a content of 2- (4-biphenylyloxy) -heptansäiTe or theirs Alkali or alkaline earth salts in addition to the usual inert carriers and additives.