DE2003122A1 - Phenyloxy aliphatic acids - Google Patents

Description

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND)

Case SU 396 / 1-4 / DIV. / E
Germany

Ph ₁ A ₁ -Ph ₂ -OA ₂ -O-OH (D.

wherein Ph ₁ is an optionally substituted 1,2-phenylene group, Ph ₂ is an optionally substituted phenylene radical, a mono- or dihydroxy A. niederalky- LEN or Niederalkanoylenrest which together

009831/1877

Phenyloxy-aliphatic acids

The present invention relates to phenyloxy-aliphatic drugs Acids of the formula

forms a 5- to 7-valent ring with the group Ph, one of the ring carbon atoms of A ₁ containing the group Ph, and A being a divalent lower aliphatic hydrocarbon radical, and their functional derivatives, as well as processes for the preparation of these compounds.

The term '-'lower', when used in connection with organic groups and compounds, means that these groups and compounds contain up to 8, preferably up to 5 carbon atoms.

The phenylene radicals Ph, and Ph_, where the latter can represent a 1,2-, 1,3- or 1,4-phenylene group, are further unsubstituted or can contain one, two or more, identical or different substituents which any of those for substitution can take suitable positions. Such substituents are, for example, lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, η-butyl or isobutyl, 3- to 8-membered cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, etherified or esterified hydroxy, such as lower alkoxy, for example methoxy , Ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy, halogen, for example > fluorine, chlorine or bromine, or trifluoromethyl.

The rest of Ph stands primarily for 1,2-phenylene, (Lower alkyl) -l, 2-phenylene, (5- to 7-membered cycloalkyl) -l, 2-phen'ylene, (lower alkoxy) -l, 2-phenylene, (halogen) -1,2-phenylene or (trifluoromethyl) -l, 2-phenylene, while Php

009831/1977

1,2-, 1,3- or in particular 1,4-phenylene, ( lower alkyl) -1,2-phenylene, -1,3-phenylene or -1,4-phenylene, (lower alkoxy) -1,2-phenylene , -1,3-phenylene or -1,4-phenylene, (halogen) - 1,2-phenylene, -1,3-phenylene or -1,4-phenylene, or (trifluoromethyl) -l, 2-phenylene, -1,3-phenylene or -1,4-phenylene · represents.

The trivalent radical A-, which is connected to the two adjacent positions of the 1,2-phenylene radical Ph, * represents an unbranched or branched lower alkylene chain with preferably 3 to 8, in particular 3 to 5 carbon atoms, in which ring carbon atoms have one or two hydroxyl groups or one Oxo group and the phenylene radical Ph ₂ carry, represents. A. stands for example for a group of the formula -C _n H _2n-1 -CHOH, - ^c _n H _2n - <r0H,

-C Η _Λ , -C = O, -CH ₀ , -CHOH-CHOH. Or -CH ₀ -CHOH-COH, η 2n-lm 2m-lm 2m |

where η is an integer from 2-8, in particular 2-5, and · m = represent n-1. Particularly preferred radicals A ₁ are those

ι .ι it %

Groups of the following formulas -CR- (CH.) -CHOH, - (CH ₀ ) -CR-CHOH,

II It I ^d PI * P

-CR- (CH ₂ ) -CO, - (CH ₂ ) -CR-CO or -CR- (CH ₂ ) -CHOH-CHOH, where ρ is an integer from 1-3 * in particular 2, and q = p- 1 mean and R is hydrogen or lower alkyl , especially methyl .

A lower aliphatic radical A _? represents, for example, lower alkylene, lower alkenylene or lower alkynylene, preferably having up to 5 carbon atoms, such as methylene, 1,1- or 1,2-ethylene, 1,1-, 1,2-, 2,2- or 1,3-propylene , 1.1-, 1.2-,

009831/1977

2,3- or 1,4-butylene, or 1,1-, 2,2-, 3,3- or 2,4-pentylene; Ethenylene, 1,2-, 2,3- or 1,3-propenylene, 1,4-butenylene, 1,4- or 2,3-but-2-enylene or 2,3-pent-2-enylene; Ethynylene, 1,3-propynylene, 1,3-butynylene, 1,4-but-2-ynylene or 1,4-pent-2-ynylene. The remainder A _g can also be used for 1,1-cycloalkyls with 3- 8 * in particular 5-7 ring carbon atoms, for example 1,1-cyclopentylidene, 1,1-cyclohexylidene or 1,1-cycloheptylidene, and 1,1-cyclopropylidene, 1,1-cyclobutylidene or 1,1-cyclooctylidene.

Functional derivatives of acids of formula I are preferably their esters, e.g. lower alkyl, such as methyl, Ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butyl esters, or substituted lower alkyl esters, such as lower alkoxy lower alkyl or aryl lower alkyl esters / wherein aryl is an aromatic or heterocyclic radical of aromatic character, e.g. benzyl or 3-pyridyl methyl ester, in particular tert-amino-lower alkyl esters, in which the tert-amino group primarily di-lower alkyl-amino,., e.g. dimethylamine or diethylamino, or lower alkylenamino, e.g. pyrrolidino or piperidino, or monoaza- or wonooxa-lower alkylene-amino, such as piperazino or 4-lower alkylpiperazino, e.g. 4-methyl- or 4-ethyl-piperazino, or morpholino, means.

Further functional derivatives are optionally substituted amides, such as mono- or di-lower alkylamides, mono-

009831/1977

or bicyclic lower alkyleneamides, e.g. N, N-dimethyl- or N, N-diethyl8! Tiid, Ν, Ν-butylene- or Ν, Ν-pentylenamide, or 2,5-ethano-1,6-hexylenamide, or amides with amino acids, e.g.

Glycine, glycylglycine, taurine, methionine or aspartic acid, as well as nitrile or hydroxamic acids. In the above-mentioned ester and amide groups are 2 heteroatoms separated from each other by at least 2, preferably 2 or 3 carbon atoms,

and a tertiary amino group can be linked to the lower alkyl chain and a monoaza-cycloalkyl or monoaza-cycloalkyl-lower alkyl group, for example 2- or 3-pyrrolidyl, 1- (methyl- or ethyl) -3-pyrrolidyl, 3- or 4-pyrrolidyl, 3- or 4-piperidylmethyl, 1- (methyl- or ethyl) -3-piperidyl or -4-piperidyl, 1- (methyl- or ethyl) -3-piperidylmethyl or -4-piperidylmethyl .

Functional derivatives of the above compounds are also those of the hydroxy or oxo functions in radical A., for example esters with lower alkanecarboxylic acids, or lower alkylene or lower alkylidene ketals, for example mono- or diacetates, acetone ide or 1,2-ethylene ketals.

Further functional derivatives of compounds of the present invention are salts, such as ammonium or metal salts, and acid addition salts of compounds with a basic character, in particular pharmaceutically acceptable, non- toxic salts, such as the ammonium salts with ammonia or amines, or in particular metal salts, such as alkali - or earth

009831/1977

20Q3122

alkali metal, for example sodium, potassium, magnesium or calcium salts. Compounds with a basic character are, for example, tert-amino-lower alkyl esters, such compounds can form acid addition salts, such as those with inorganic or organic acids, e.g. hydrochloric, hydrogen bromide, sulfur, phosphorus, ant, vinegar, propylene, pivaline , Glycol, milk, malonic, amber, maleic, hydroxymalein, apple, wine, lemon, benzoin, salicylic, 4-amino-salicyl-, 2-phenoxy-benzoin, 2- Acetyloxybenzoic, nicotinic, isonicotinic, methanesulphonic, ethanesulphonic, ethane-1,2-disulphonic, 2-hydroxyethanesulphonic, p-toluenesulphonic or naphthalenesulphonic acid. Salts can also be used as intermediates, for example in the preparation of pharmaceutically acceptable salts, in the purification of the free compounds or for identification and characterization purposes. With regard to the close relationships between the new compounds in free form and in the form of their salts, the free compounds or salts are to be understood as meaning, appropriately and appropriately, the corresponding salts or free compounds above and below. _f

The compounds of the present invention have valuable pharmacological properties. So do they work E.g. lowering the cholesterol and triglyceride levels in the Blood; this effect can be demonstrated by means of in vivo and in vitro tests

009831/1977

can be detected, with the latter preferably using mammals such as rats, dogs or monkeys as test animals. The compounds of the present invention will be administered orally, for example, λ to male rats in the form of aqueous or Polyäthylenglykollösungen or suspensions by means of a gastric probe, or to male dogs in the form of gelatin capsules, for example, in daily doses from about 0.0001 to about 0.1 g / kg, in particular from about 0.0001 to about 0.05 g / kg and primarily from about 0.001 to about 0.025 g / kg. The test animals, for example rats, are given either a standard feed or a high-cholesterol feed; the total serum content of cholesterol is determined in the orbital blood before and after treatment with the test substances. In addition, free or esterified serum glycerine and liver substances such as glyceride glycerine, fatty phosphorus, glycogen and protein can be determined. Ä

At high daily doses, e.g., from about 0.05 to about 0.1 g / kg, the compounds of the present invention are effective in male rats also an enlargement of the liver, which indicates an enlargement of the cells as such, as well as their number. This hepatomegalic effect is reversible upon discontinuation of the test compounds.

The compounds of the present invention also exhibit anti-inflammatory properties, particularly in the turpentine pleuritis test in rats, as well as in the kaolin and

009831/1977

Carigeenin edema test in rat paws by the Winter method et al., Proc.Soc.Exptl.Biol.Med., Vol. Ill, p. 544 (1962) detectable are. In the latter, the test substances are in the form of aqueous solutions or suspensions by means of a gastric tube to adult male and female rats in daily doses of from about 0.001 to about 0.1 g / kg, preferably from about 0.01 to about 0.075 g / kg, in particular from about 0.04 to about 0.06 g / kg. About an hour later it becomes 0.06 ml a liquid aqueous suspension of carigeenin is injected into the left hind paw of the test animal; 3 hours later becomes the difference in volume and / or weight between the edemaic left hind paw and the right hind paw found and with the same difference in untreated. Control animals compared. With this comparison, the anti-inflammatory Effect of the test substances can be expressed.

The compounds of the present invention can therefore be used as hypolipidemic (hypocholesterolemic) agents for the treatment of tangles, such as the syndromes caused by arteriosclerosis, e.g. atherosclerosis, as liver protection or - remedies, e.g. in the treatment of liver injuries, " Poisoning or illness, as in the case of chemical poisoning such as carbon tetrachloride or cirrhosis of the liver, and / or as anti-inflammatory agents in the treatment of arthritic or dermatopathological conditions be used. They can also be used as intermediates in the

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Manufacture of other valuable products, in particular von pharmaV: logically active compounds can be used.

Particularly valuable, primarily with regard to the pharmacological effects, are compounds of the formula I in which Ph, 1,2-phenylene, (lower alkyl) -1,2-phenylene, (5-to-7-ring-membered cycloalkyl) -1, 2-phenylene, (lower alkoxy) -1,2-phenylene, (halogen) -1,2-phenylene or (trifluoromethyl) -1,2-phenylene, Ph ₂ for 1,2-, 1,3- or 1, ² I-phenylene, - "(lower alkyl) -1,2-phenylene, -1,3-phenylene or -1,4-phenylene, (lower alkoxy) -1,2-phenylene, -1,3-phenylene or -1 , 4-phenylene, (halogen) -1,2-phenylene, -1,3-phenylene or -1,4-phenylene or (trifluoromethyl) -1,2-phenylene, -1,3-phenylene or -1,4 -phenylene, Ap is Nledalkylen and A, one of the groups of the formula -C (R) - (CH ₂ ) -CHOH, - (CH ₂ ) -C (R) -CHOH, -C (R) - (CH ₂ ) -C = O,

t I I

- (CHg) -C (R) -C = O or -C (R) - (CH ₂ ) -CH (OH) -CHOH, in which p, q and R have the meanings given above, as well as lower alkyl or Nlederalkoxy-lower alkyl esters, aryl-lower alkyl esters, in which aryl is a phenyl radical which may optionally contain the substituents indicated for the radical Ph ", pyridyl lower alkyl esters, Am-lower alkyl esters, in which Am is di-lower alkylamino, lower alkylenamino or monoaza- or mono oxa- lower alkyleneamino, Monoaza-cycloalkyl or monoazaöycloalkyl-lower alkyl esters of the above acids, heteroatoms of the esterifying part being separated from the oxygen atom of the carboxy group by at least 2 carbon atoms, furthermore

009831/1977

Amides, mono- or di-lower alkyl amides, mono- or bicyclic Lower alkylene amides, hydroxamic acids or nitriles, as well as salts such as pharmaceutically acceptable, non-toxic salts, e.g. Ammonium, alkali metal or alkaline earth metal salts thereof or pharmaceutically acceptable, non-toxic acid addition salts of basic esters.

Compounds of the formula are particularly valuable with regard to their pharmacological effects

CH, 0

I ³ H
R_ 1— j! 0-0 C-OR ₂

CH,

wherein one of the radicals X and Y is a direct bond and the other is hydroxymethylene or carbonyl, r is 0, 1 or 2, R is hydrogen or lower alkyl, Rp is hydrogen, lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl, pyri- ι dyl- represents lower-alkyl, di-lower-alkyl-amino-lower-alkyl, lower-alkyleneamino-lower-alkyl, N-lower-alkyl-piperidyl or N-lower-alkyl-piperidyl-lower-alkyl, with hetero, such as nitrogen atoms, from the oxygen atom of the carboxy group in these groups

009831/1977

at least two carbon atoms are separated, each of the radicals R, and Rj, is hydrogen, lower alkyl or halogen and R ₁ - is hydrogen or, if Y is hydroxymethylene, also hydroxy, salts, such as pharmaceutically acceptable, non-toxic salts, e.g. the ammonium, alkali metal or alkaline earth metal salts of the compounds in which Rp is hydrogen, as well as pharmaceutically acceptable acid addition salts of compounds in which R «contains a basic nitrogen ™ atom.

Primarily valuable, in terms of its pharmacological Effects, are compounds of the formula

CH, 0
I \ t

o — c— ^ c-or · ¹ I ²

(Ib)

wherein R ^ is hydrogen, an alkali metal ion, or lower alkyl and R 'is hydrogen or hydroxy, which in daily oral doses of about 0.0001 to about 0.05 g / kg, especially from about 0.001 to about 0.025 g / kg in rats fed normal chow or a high cholesterol diet, administered have excellent hypocholesterolemic effects. 009831/1977

The compounds of the present invention are prepared by methods known per se, for example by adding a) to a compound of the formula

-Ph ₂ -Z ₁ (ii)

in which Z. is a group which can be converted into the free or functionally modified group of the formula -O-Ap-C (= 0) -OH , the radical Z is converted into the latter, or b) in a compound of

Formula 0

Ph ₁ Α ..- Ph ₀ -OA ₀ -C-OH <III)

\ 2 ^ y 322

or a functional derivative thereof, in which A represents a lower alkylene or lower alkenylene radical which forms a 5- to 7-membered ring with the group Ph. in which one of the ring carbon atoms bears the group Php, converts the group A- into the group A, and if desired, converting a compound obtained into another compound of the invention.

In a starting material of the formula II, the group Z. can be converted in one or more steps into the optionally functionally modified group of the formula -0-A ₀ -C (* = 0) -OH . A particularly suitable group Z is a free hydroxyl group, modified into a salt form or esterified. In a hydroxyl group that has been converted into the salt form, the cation part is in particular a metal, such as alkali metal, for example sodium or potassium, cation. One esterified

009831/1977

"'Phenolic hydroxyl group Z is e.g. one by carbonic acid -hai best or a carbonic acid halide esterified

»Hydroxy group, i.e. a group of the formula -O-C (= O) -R, in which R is an etherified or esterified hydroxy group, e.g. Halogen, such as chlorine or bromine, or a lower alkoxy, such as methoxy or ethoxy, as well as phenyloxy groups. Such a starting material is made with an acid

of the formula Zp-Ap-C (= 0) -OH (ila) or a functional Deri- | vat converted thereof, where one of the radicals Z ₁ and Zp represents a reactive esterified hydroxyl group and the other represents a free hydroxyl group or hydroxyl group present in salt form. Those starting materials are preferably selected in which Z .. is a hydroxyl group present in salt form and Z _p is a strong acid, such as a strong mineral, in particular hydrogen halide, for example hydrogen chloride or hydrogen bromide, and sulfur, or a strong organic sulfone - As a Niederalkansulfon- or Benzolsulfon-, ™ eg methanesulfonic, ethanesulfonic or p-toluenesulfonic acid, represents esterified hydroxyl group. Preferred reactants are acids of the formula IIa and the corresponding esters or nitriles, wherein Zp is halogen, preferably and primarily chlorine or bromine, with an atomic weight over 19 *.

The starting material of the formula II, in which Z _{1 represents} a hydroxyl group present in salt form, can also contain

009831/1977

a lower aliphatic aldehyde or ketone corresponding to the radical -Ap- in the presence of a tri- or tetrahalogenated one Methane derivative, such as chloroform, 1,1,1-trichloroacetone, Bromoform, 1,1,1-tribromoacetone, iodoform, chloral, chloral hydrate, Bromal, bromal hydrate, carbon tetrachloride or carbon tetrabromide, implemented. The reaction is preferably carried out using an excess of the non-phenolic Reactants and in the presence of a strong base such as an alkali metal, e.g. sodium or potassium hydroxide, also a diluent, which can also be provided by the excess of the aldehyde or ketone, carried out.

If Z. is the above esterified hydroxyl group, the corresponding starting material with the acid of the formula Ha or a derivative thereof, in which Zp is a hydroxyl group represents, being at temperatures of about 100 ° C. to about 210 ° C., if desired, in the presence of a suitable Transesterification catalyst, such as sodium or potassium carbonate, and operates in the absence or presence of a diluent.

The starting materials of the formula III can preferably by treatment with oxidizing agents with which a Methylene into a hydroxymethylene or a carbonyl group or an ethenylene into a mono- or dihydroxymethylene group can be converted into the compounds of the present invention. Such means are e.g. heavy metal oxides, which preferably contain more than two oxygen atoms per metal atom, furthermore corresponding acid

009831/1977

'ren or salts thereof, such as chromium trioxide, chromic acid or sodium dichromate, Vanad lump pentoxide, potassium permanganate or osmium or Ruthenium tetroxide. Further oxidizing agents are hydrogen peroxide or peracids, especially percarboxylic acids, such as lower alkane percarboxylic or perbenzoic acids, e.g. peracetic, Perbenzoic, 3-chloroperbenzoic or monoperphthalic acid. Peroxides are primarily used in the oxidation of starting materials of the formula III, in which the group A is a lower alkenylene radical I. represents, used; in this way epoxides are formed, which hydrolytically, e.g. by treatment with aqueous mineral acids, whereby the corresponding dihydroxy compounds are obtained, or then reductively, e.g. by treatment with hydride reducing agents, such as complex light metal hydrides, e.g. lithium aluminum hydride, whereby the corresponding monohydroxy compounds receives, can be split.

A starting material of the formula III, in which the group A is a lower alkenylene radical, can also be substituted with halo- " genes, e.g. bromine, or with a hydrogen halide, e.g. bromine

hydrogen, to be reacted, mono- or dihalogen, in particular mono- or dibromo adducts being obtained. These can be converted into the compounds of the formula I in which A _{1 is} a free or esterified mono- or dihydroxy-lower alkylene group.

is converted by hydrolysis or under acylating conditions, preferably an aqueous alkali

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metal or alkaline earth metal hydroxide, a heavy metal oxide, e.g. lead (II) oxide, or a carboxylic acid metal salt, e.g. Alkali metal or silver lower alkanoate, such as sodium, potassium baits Silver acetate / propionate or pivalate is used. in the The course of this reaction can be oxidation or partial hydrolysis with the formation of compounds of the formula I in which A. a lower alkanoylene or a dihydroxy-lower alkylene radical, in which only one hydroxyl group is esterified, occur.

Compounds obtainable according to the process can be converted into one another in a manner known per se. So e.g. compounds with free carboxyl groups can be converted into functionally modified derivatives, e.g. in esters by treating with an alcohol such as a lower alkanol in the presence of an esterifying agent such as an acid such as hydrochloric or sulfuric acid, or a carbodiimide such as dicyclohexylcarbodiimide, or with a suitable diazo compound. A carboxylic acid obtainable according to the process can also be converted into an acid halide, e.g. chloride, converted and the latter with the formation of a corresponding ester or amide with an alcoholate, such as an alkali metal, e.g. sodium or potassium alcoholate, such as lower alkoxide, or treated with ammonia or a primary or secondary amine "A carboxylic acid or a salt thereof may also be with a reactive ester of an alcohol, such as an ali

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. - 17 -

phatic halide or a tert-amino-lower alkyl halide, be reacted in the presence of a base, e.g. potassium carbonate, to form an ester.

An ammonium salt of a process obtainable

Before acid can be used, e.g. by treatment with phosphorus pentoxide or oxychloride, can be dehydrated to form the amide; the latter gives the corresponding on further dehydration Nitrile. . .

In a compound obtained with a functionally modified carboxyl group, the latter can be converted into a free or converted into another functionally modified carboxyl group; for example, an ester obtained may preferably be hydrolyzed by treatment with a basic agent such as sodium or potassium hydroxide. A received Nitrile or amide can be hydrolytically converted into the free by treatment with a strong base or acid, e.g. sulfuric acid Acid to be transferred.

Furthermore, an ester obtained can be prepared, for example, by treating with an alcohol such as a lower alkanol in Presence of a suitable transesterification catalyst, such as a metal alcoholate, e.g. a sodium, potassium or aluminum lower alkoxide, an alkali metal cyanide or an ammonium base, e.g. Nr-benzyl-N, N, N-trimethylammonium hydroxide, transesterify. An ester obtained can also be converted into an amide, for example by treatment with ammonia or a primary or secondary Amine, if necessary, under increased pressure, or in the hydroxamic acid, e.g. by treatment with hydroxylamine

00983 1/1977

will.

A nitrile obtained can, for example, by treating with an alcohol such as a lower alkanol in the presence of a Mineral acid, e.g. sulfuric or hydrochloric acid, in the corresponding ester can be converted.

Furthermore, obtained compounds in which the group A _{1 represents} a lower alkanoylene radical can be reduced using ketone reducing agents. Such agents are, for example, catalytically activated hydrogen, e.g. hydrogen in the presence of platinum or nickel catalysts, or electrolytically generated hydrogen, or chemical reducing agents (nascent hydrogen), e.g. reducing metal compounds, preferably in the presence of hydrogen-generating agents, e.g. zinc in the presence of alkali metal hydroxides, alkali or alkaline earth metals or their A.-r.algarr.e, as well as aluminum amalgam in the presence of alcohols such as lower alkanols, preferably simple or complex light metal hydrides such as borohydrides or alkali metal hydrides or alkali metal borohydrides, e.g. lithium aluminum hydride or sodium borohydride; the reduction can also be carried out according to the Meerwein-Fonndorf-Verley reaction, ie by treatment with an aluminum lower alkoxide.

Correspondingly, compounds obtained in which the group A is a hydroxy-lower alkylene radical can be added the corresponding alkanoyl compounds are oxidized, e.g. according to the Oppenauer reaction, whereby aluminum-low-

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alkoxides in the presence of aliphatic or cycloaliphatic ketones, e.g. acetone or cyclohexanone, or by treatment with a known oxidizing agent suitable for alcohol dehydrogenation, such as heavy metal salts or oxides, e.g. alkali metal chromates or permanganates, or chromium III, iron III, copper II or lead IV salts, such as halides, Sulfates or acetates thereof.

In the compounds obtained, the oxygen function can be functionally modified in a hydroxy or oxo-lower alkylene radical A _1. So one can add a hydroxyl group, for example by treatment with an acid or a suitable functional derivative such as a halide or anhydride, as well

ι a reactive ester thereof, preferably in the presence of a suitable esterifying agent, such as a carbodiimide, for example dicyclohexylcarbodiimide, or a basic agent, for example pyridine. Two, preferably adjacent hydroxyl groups in a dihydroxy-lower alkylene group A may be acetallsiert g or ketalized, for example, propane-2,2-dimethoxy by treatment with an aldehyde or ketone, or a functional derivative thereof, such as benzaldehyde, acetone or, in

Presence of a suitable acidic agent, e.g., p-toluenesulfonic acid.

In a compound obtained in which group A.

For example, if represents a lower alkanoylene radical, the oxo group may be ketalized; the reaction can be modified, for example, by treatment with a lower alkanediol in the presence of a suitable one

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acidic reagent such as p-toluenesulfonic acid.

Functionally modified hydroxy or oxo groups, for example in the above-mentioned hydroxy- lower alkylene or lower alkylene groups A, are converted into the free hydroxy or oxo groups by methods known per se, for example by alkaline or acidic hydrolysis.

An acid obtained can be converted into its salts by methods known per se, for example by reaction with an approximately stoichiometric amount of a suitable salt-forming agent, such as ammonia or ammonium hydroxide, or an alkali metal hydroxide, amide or hydride. A salt of this type can be returned to the free acid , for example by treatment with an acid, such as hydrochloric, sulfuric or acetic acid.

A compound obtained having a basic group, such as an amino group, can be converted into an acid addition salt, for example by reaction with an acid such as one of the abovementioned, or with a suitable anion exchanger, and isolated as such. A salt can be converted into the free compound , for example, by treatment with a basic agent such as an alkali metal hydroxide, ammonia or hydroxy ion exchanger. In the above reactions with compounds of the formula I in which group A. is a hydroxy-lower alkylene radical , care must be taken that no dehydration takes place under strongly acidic conditions

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• · Conditions and with the formation of compounds of the formula III, wherein the group A ^. represents a lower alkenylene radical, can go on.

Mixtures of isomers obtained can be made using physical-chemical differences, e.g. solubility, Adsorption and boiling points, separated into the individual isomers. Racemates can be known per se Process, e.g. separation of diastereoisomeric salts or ^

Esters, such as salts of d-a-phenylethylamine, d-a- (l-naphthyl) ethylamine or ^ -Cinchonidin with d, ^ -acids of the formula I, or Salts of d- or ^ -tartaric acid with basic esters of such acids, or esters of optically active acids, e.g. d-camphor sulfonic acid, with phenolic starting materials in the optical isomers are separated.

The above reactions can be carried out according to standard methods, in the absence or presence of diluents, preferably those which are "inert" towards the reactants and / or are able to dissolve them, from catalysts or Condensing agents, if necessary, in an inert gas, e.g. nitrogen atmosphere, with cooling or heating and / or under increased pressure, 'be carried out.

The invention also relates to those modifications • of the process, according to which one at some stage as an intermediate The compound formed is used as the starting material and the remaining step (s) are carried out with this

009831/1977

is (are), or the proceedings are interrupted at any stage is, or according to which starting materials formed under the reaction conditions or in the form of salts or reactive Derivatives are used.

Is used according to the process preferably those starting materials which lead to those compounds of the invention which are particularly preferred as described above.

The starting materials are known or, if new, can be prepared by methods used for the known compounds. For example, you can create connections of the formula II from those of the formula

-Ph ₂ -X ₁ (IV)

using the oxidation methods as they are for the transformation of starting materials of the formula III are used.

The pharmacologically acceptable compounds of the present invention can be used, for example, in the manufacture of pharmaceutical Preparations are used which contain an effective amount of the active ingredient together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers that are suitable for enteral, parenteral or topical administration. Tablets or gelatin capsules are preferably used, which

009831/1977
t

the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets further also contain binders, for example magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, Natriumearboxymethylcellulo- ä se and / or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, Alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures and / or adsorbents, colorants, flavorings and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions, suppositories, primarily fat emulsions or suspensions. The pharmaceutical preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, for example by means of conventional mixing, granulating or coating processes, and contain from about 0.15 to about 75% in particular from about 1% to about 50 $ of the active.

009831/1977

t *

- 2k -

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius and, unless otherwise stated, optical rotations are determined in liquid methanolic solutions.

009831/1977

. - 25 Example 1

A mixture of 0.8 g of 4- (4-hydroxyphenyl) -1,2,3,4-tetrahydro-naphthalen-1-one, 0.16 g of a 56% suspension of sodium hydride in mineral oil and 35 ml Xylene is stirred on the steam bath until the evolution of hydrogen ceases and then 0.668 g of ethyl 2-bromo-isobutyrate is added. The mixture is λ boiled under reflux for 6 hours and subsequently filtered. The filtrate is evaporated under reduced pressure and the residue is distilled. The fraction boiling at 185-200 ° / 0.35 mm Hg is collected, taken up in ether, filtered and the filtrate is evaporated. The ethyl 2- [4- (4-0xo-l, 2,3,4-tetrahydro-l-naphthyl) phenyloxy] isobutyrate of the formula is obtained

CH, O

I ⁵ H

—G G-OC ₀ H _n

I 2 5

which has strong bands in the infrared absorption spectrum

* ■ -1 -1

1720 cm and 1670 cm shows.

The raw material can be produced as follows:

A mixture of 30.7 g of 4-phenyl-1,2,3,4-tetrahydronaphthalen-1-one and 32 ml of acetic anhydride is added with stirring and cooling in an ice bath with a solution of 6.4 g of smoke-

009831/1977

the nitric acid in 10 ml of acetic anhydride is added dropwise. The mixture is left for 16 hours at room temperature left to stand, poured onto ice and extracted with ether. The organic extract is mixed with an aqueous sodium hydrogen carbonate solution washed, dried and evaporated. A mixture of 27 g of the residue containing 4- (4-nitro-phenyl) -1,2,3,4-tetrahydro-naphthalen-l-one contains, 27 g of hydroxylamine hydrochloride and 250 ml of pyridine is taken for 18 hours Boiled to reflux and evaporated under reduced pressure. The residue is taken up in water and the mixture with Aether extracted. The organic extract is washed with water, dried, evaporated and the residue from ethanol recrystallized. The oxime of 4- (4-nitrophenyl) -l, 2,3,4-tetrahydro-naphthalen-l-one is obtained, which melts at 208-212 °.

A mixture of 5 * 8 g of the oxime des 4- (4-nitrophenyl) -l, 2,3,4-tetrahydro-naphthalen-1-one and 50 ml of 6 normal hydrochloric acid is refluxed for 3 hours boiled, then diluted with water and extracted with ethyl acetate. The organic extract is dried, evaporated and the residue is recrystallized from aqueous ethanol. The 4- (4-nitro-phenyl) -l, 2,3,4-tetrahydro-naphthalen-1-one is obtained, which melts at I30 - I32.

A solution of 3.7 g of 4- (4-nitro-phenyl) -l, 2,3,4-tetrahydro-naphthalen-1-one in 100 ml of 95 # aqueous

009831/1977

. - 27 -

Ethanol is hydrogenated in the presence of 0.4 g of a 10 # palladium-carbon catalyst at room temperature under a pressure of 3 atmospheres. The mixture is filtered, the filtrate is concentrated and the precipitate obtained from the cold concentrate is filtered off. To yield the 4- (4-Amino-phenyl) -1,2,3,4-tetrahydro-naphthalen-l-one, which in I30 - I36 ⁰ melts.

A solution of 2.8 g of 4- (4-aminophenyl) -1,2,3,4-

tetrahydro-naphthalen-1-one in 3 ml of dioxane, 3 »5 ml of water and" 2.6 ml of concentrated sulfuric acid is treated at 0 with 0.825 g of sodium nitrite in 2 ml of water. The resulting solution of the diazonium salt is added dropwise over the course of 30 minutes , to a boiled Geraisch of 8 ml of concentrated sulfuric acid and 6 ml of water :. ^: oM "^ etzt, pour ice mixture on F, 1.s and extracted with chloroform. The organic extract is dried and evaporated, the residue is recrystallized from a mixture of diethyl ether and hexane and sublimed at a pressure of 0.3 mm Hg. To yield the 4- (4 "hydroxy-phenyl) -1,2,3 * 4-tetrahydro-naphthalen-1-one, which at 148 - I51 ⁰ melts.

009831/1977

. - 28 Example 2

A mixture of 0.8 g of ethyl 2- [4- (4-oxo-1,2,3,4-tetrahydro-1-naphthy1) phenyloxy] isobutyric acid, 0.25 g of potassium hydroxide and 8 ml of methanol wild at room temperature Left to stand for 16 hours and then evaporated under reduced pressure. The residue is taken up in water, the aqueous solution washed with hexane, acidified with hydrochloric acid and extracted with ether. The organic one Extract is made with aqueous sodium hydrocarbonate solution shaken the aqueous solution with hydrochloric acid acidified again, extracted with ether and the extract evaporated. 2- [4- (4-Oxo-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid is obtained the formula

C-OH

which melts at 124 - 126 °.

00983 1/1977

- 29 Example 3

A mixture of 0.5 g of 2- [4- (4-0xo-l, 2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid, 5 ml of 95% ethanol and 0.1 g of sodium borohydride is stirred at room temperature for 5 hours. After adding a few drops
Acetic acid, the mixture is evaporated under reduced pressure, the residue is taken up in water and the aqueous mixture is extracted with chloroform. The organic extract
is dried, filtered and evaporated. The 2- [4- (4-hydroxy-1,2,3 * ^ - tetrahydro-1-naphthyl) phenyloxy] isobutyric acid of the formula is obtained

C-OH

which in the UV absorption spectrum have maxima at 224 ιημ (£
15 ^! 790) and 274 πιμ (£ = ΐ'48θ).

»009831/1977

Example 4

A solution of 0.4 g of 2- [4- (3,4-epoxy-1,2,3,4-tetrahydro-1-naphthy1) -phenyloxy] -isobutyric acid -n-butyl ester in a minimal amount of 0, 1N solution of hydrogen chloride in 95% aqueous ethanol is left to stand at room temperature for 16 hours and then evaporated under reduced pressure. The residue is taken up in 10 ml of ethanol, 5 ml of a 2 normal aqueous potassium hydroxide solution are added to the solution, the mixture is left to stand at room temperature for 16 hours and then slowly concentrated. The concentrate is diluted with 5 ml of water, the aqueous phase is washed with ether, acidified with hydrochloric acid and extracted with ether. The organic extract is washed with concentrated aqueous sodium chloride solution, dried and evaporated. The 2- [4- (trans-3,4-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid of the formula is obtained

CH 0

which in the UV absorption spectrum has maxima at 267 πιμ (£ = I ¹ 310) and 283 ηιμ (£ = 910). The corresponding 2- [4- (cis-3,4-dihydroxy-1,2,3,4-tetrahydro-1-naphthy1) phenyloxy] isobutyric acid of the formula

009831/1977

-0-C C-OH

HOHO *

is obtained directly by oxidation of 2- [4- (l, 2-dihydro-l-naphthyl) -phenyloxy3-isobutyric acid or their n-butyl esters obtained with osmium tetroxide.

The starting material is obtained as follows!

A mixture of 0.5 g of 2- [4- (4-hydroxy-1,2,3,4-tetrahydro-l-naphthyl) -phenyloxy-3-isobutyric acid and 10 ml of aqueous formic acid (90 %) is refluxed for 2 hours and slowly evaporated * The residue is taken up in water, the Gemisw? ■ ».: fc ether extracted", the organic extract with water gowaselior., Getroc'cnv '■■ and evaporated. The 2- [4- (1,2-dihydro-l ~ naphthyl) «phenyloxy3-3 xo ~ butyric acid, which melts at 105-106, is obtained.

A mixture of 0.5 ε 2- [4- (l, 2-dihydro-l-naphthyl) - ^ phenyloxy3-isobutyric acid, 0.5 ml thionyl chloride and ^l 3 ml benzene is k. Boiled under reflux for hours and evaporated under reduced pressure. The residue is taken up twice in 5 ml of benzene and evaporated each time. The residue wi: u in 5 ml dry: ;; n-butanol was added, the solution was slowly evaporated and the residue was taken up in 10 ml of chloroform. The organic solution is washed with aqueous sodium carbonate solution, dried and

009831/1977 BAO ORiGiNAL

• ■ * ·

• · · It

- 32 -

evaporated to a volume of approximately 2 ml. The ice-cold concentrate, which contains the 2- [4- (1,2-dihydro-l-naphthyl) phenyloxy] isobutyric acid n-butyl ester contains, is mixed with a cold solution of 0.5 g of 3-chloro-perbenzoic acid in 2 ml of chloroform offset. The mixture is in an ice bath for one hour stirred, left to stand at about 4 for 24 hours, diluted with 16 ml of chloroform, then with a cold aqueous Sodium hydrocarbonate solution and a concentrated aqueous sodium chloride solution, dried and evaporated. The 2- [4- (3,4-epoxy-1,2,3,4-tetrahydro-inaphthy1) phenyloxy] -i is obtained sobut tertiary acid n-butyl ester.

Example 5

A solution of 60 g of methyl 2- [4- (1,2,3,4-tetrahydro-lnaphthyl) phenyloxy] isobutyric acid in 250 ml of carbon tetrachloride is mixed with a solution of 60 g of chromium trioxide in 250 ml of acetic anhydride, which is added dropwise, within 1.5 hours, with stirring and cooling to 0 ° to 10, is added treated. The reaction mixture is stirred for a further hour at 0 and then on ice-water poured. The organic phase is separated off and the aqueous solution extracted with carbon tetrachloride. The combined organic solutions are made with water

009831/1977

■ - 33 -

washed and saturated aqueous sodium hydrocarbonate solution, dried, filtered and evaporated. The residue will Chromatographed on 1110 g of aluminum oxide (neutral, activity III). Elute with a mixture of hexane and benzene (400 ml 1: 1, 800 ml 3: 5 and 400 ml 1: 3). The ones with 3: 5- and The fractions obtained in 1: 3 mixtures are combined and evaporated. The residue is recrystallized from a mixture of hexane and diethyl ether. The 2- [4- (4-0xo-1,2,3 * 4-tetrahydro-l-naphthyl) phenyloxy] isobutyric acid is obtained methyl ester of the formula

C G-OCH

which melts at 83 - 85 ^0.

Example 6

A mixture of 14 g of 2- [4- (4-0xo-l, 2,3,4-tetrahydro-l-naphthyl) phenyloxy] isobutyric acid methyl ester, 4 g of potassium hydroxide and 100 ml of methanol is left to stand for 16 hours at room temperature and under reduced pressure Evaporated pressure. The residue is taken up in water, the aqueous solution with concentrated hydrochloric acid acidified and extracted with ether. The organic extract

809831/1977

is dried, filtered, evaporated and the residue recrystallized from diethyl ether. The 2- [4- (4-oxo-1,2,3 ^ -tetrahydro-l-naphthyl) -phenyloxy] -isobutyric acid, which melts at 124-126 °.

Example 7

A mixture of 2.8 g of 4- (4-hydroxyphenyl) -1,2,3,4-tetrahydro-naphthalen-1-one, 25 ml of acetone and 4 g of sodium hydroxide are added dropwise, with stirring, with 2.8 g of chloroform in 10 ml of acetone. The mixture is an hour boiled under reflux and filtered after cooling. The filter residue is dissolved in water, the solution with 2-n. Hydrogen chloride acidified and extracted with ether. The organic extract becomes more aqueous with water and saturated water Washed sodium chloride solution, dried, evaporated and the residue from a mixture of hexane and benzene recrystallized. The 2- [4- (4-oxo-l, 2,3,4-tetrahydro-l-naphthyl) phenyloxy] isobutyric acid is obtained, which melts at 124 126. /

The starting material is prepared as follows: To a solution of 30 g of 1- (4-hydroxyphenyl) -1,2,3,4-tetrahydro-naphthalene in a minimal amount of acetone is first the solution of 6 g of sodium hydroxide in 60 ml of water

009831/1977

. - 35 -

and then, with stirring, in portions, 21 g of benzoyl chloride in 15 ml of acetone are added. The suspension obtained is diluted with water and filtered, and the residue is recrystallized from isopropanol. One obtains the 1 - (4-benzoyloxy-phenyl) - 1 * 2,3,4-tetrahydro naphthalene, which at 106 - 108 ° melts. A solution of 5 g of l- (4-Benzoyloxyphenyl) -1,2,3,4-

tetrahydro-naphthalene in 50 ml carbon tetrachloride is

ter stirring and cooling to 0-10 ° dropwise within an hour, mixed with a mixture of 5 g of chromium oxide and 25 ml of acetic anhydride. The mixture is stirred at 0 for a further 2 hours , poured onto ice-water and extracted with ether. The organic extract is washed with sodium hydrocarbonate solution and water, dried, filtered and evaporated, and the residue is recrystallized from methanol. To yield the 4- (4-benzoyloxy-phenyl) -l, 2,3,4-tetrahydro-naphthalen-1-one, which at 175 - 176 ° melts.

A mixture of 5.4 g of 4- (4-benzoyloxyphenyl) -l »2,3» 4-tetrahydro-naphthalen-l-one, 5 »4 g of potassium hydroxide and 200 ml of methanol is refluxed for 5 minutes and evaporated . The residue is taken up in water and the solution is extracted with ether. The organic extract is mixed with aqueous sodium hydrocarbonate solution, water and saturated aqueous sodium chloride solution.

dries, evaporated and the residue from ethyl acetate um-. crystallized. 4- (4-Hydroxyphenyl) -l, 2,3,4-tetrahydro-naphthalen-1-one, which melts at 15-153 °, is obtained.

009831/1977

Example 8

A solution of 2.3 g of 2- [4- (4-oxo-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid in 100 ml of 95 # aqueous ethanol is added in portions with 0.92 g Sodium borohydride, while stirring and cooling with ice, are added. The reaction mixture is left at room temperature for 16 hours left to stand, then acidified with dilute acetic acid and evaporated under reduced pressure. The residue is taken up in water, extracted with ether, the organic extract dried, filtered and evaporated. Of the The residue is first recrystallized from a mixture of petroleum ether and diethyl ether and then from benzene. You get trans-2- [4- (4-hydroxy-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid the formula

which melts at 148 - 150 °.

The combined mother liquors are evaporated and the residue is taken up in a minimal amount of ether. The solution will remain until a precipitate has formed Cyclohexylamine is added dropwise. The residue is filtered off and recrystallized from acetone. The cyclohexylammonium salt of the eis-2- [4- (4-

009831/1977

Hydroxy-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid the formula

Λ> - < Ή CH 0
I ι ·
> —0 — C — C — OH HO _x OH, H*'

which melts at 211-214 °. The salt is taken up in diethyl ether and the solution is shaken with 2N sulfuric acid. The organic layer is separated,. \ evaporated and the residue dried in a high vacuum. The amorphous free acid is obtained.

Example 9

A mixture of 10 g of 2- (4-hydroxyphenyl) -l, 2,3,4-

tetrahydro-naphthalen-1-one, 75 ml of acetone and 14.3 g of sodium hydroxide ^ is added under stirring and refluxing with 10 g of chloroform in 30 ml of acetone dropwise. Stirring is made easier by adding acetone. The mixture is refluxed for one hour and then evaporated under reduced pressure. The residue is taken up in water, the solution is acidified with 2N hydrochloric acid and extracted with ether. The organic extract is shaken with an aqueous sodium hydrocarbonate solution, the aqueous layer with 2 normal chlorine water

009831/1977

acidified and extracted with ether. The organic one The extract is washed with water, dried, filtered and evaporated. The oily 2- [4- (l-oxo-1,2,3,4-tetrahydro-2-naphthyl) phenyloxy] isobutyric acid is obtained the formula

which are characteristic bands in the I.R. at I73I cm "and I678 cm".

The starting material is prepared as follows: A mixture of 103 g of 4-methoxyphenyl-acetonitrile and 500 ml of dimethylformamide is added in portions with stirring with 33> 5 g of a 53 ^ suspension of sodium hydride in Mineral oil was added and the mixture was stirred until the evolution of hydrogen ceased. The reaction mixture is then covered with ice cooled and with stirring dropwise with 130 g of 2-phenylethyl bromide added in 500 ml of toluene. The mixture is left to stand at room temperature for 16 hours and then filtered. The filtrate is evaporated under reduced pressure and the residue is taken up in water. The watery one The mixture is extracted with ether and the organic extract is dried, filtered and evaporated. You get that α - (4-methoxyphenyl) -7-phenylbutyronitrile.

009831/1977

A mixture of I37 g of α - (Jf-Methoxypheny I) - ^ v -

phenylbutyronitr11, 36Ο ml of a 50 # aqueous sodium hydroxide solution and 5 ^ 5 ml of ethylene glycol is refluxed for 5 hours, left to stand at room temperature for 16 hours and then poured into 2000 ml of water. The aqueous mixture is washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with ether. The organic extract is dried, filtered and evaporated under reduced pressure and the residue is distilled. The fraction boiling at 185-200 ° / b, 25 mm Hg is recrystallized from hexane. The α- (4-methoxyphenyl) -7-phenyl butyric acid, which melts at 9 ^ -96 ⁰ , is obtained.

A mixture of 59 * 5 g of phosphorus pentachloride and 100 ml of benzene is treated in portions with 72 g of α - {h -Methoxyphenyl ) -7-phenyl butyric acid, refluxed for 15 minutes and then evaporated under reduced pressure. The residue is taken up twice in benzene, evaporated each time under reduced pressure, then taken up in ml of benzene and added dropwise with stirring and ice-cooling to a solution of 59 * 5 g of aluminum chloride in 500 ml of benzene. The mixture is stirred for two hours at room temperature, refluxed for 2 hours,

Left to stand at room temperature for 16 hours, then poured onto a mixture of ice and concentrated hydrochloric acid. The mixture is extracted with benzene, the

009831/1977

organic extract dried, filtered, evaporated and the residue recrystallized from isopropanol. The 2- (4-methoxyphenyl) -l, 2,3> 4-tetrahydro-naphthalen-1-one, which ^{melts at 107 - HO 0} , is obtained.

A mixture of 20 g of 2- (4-methoxyphenyl) -1, 2,3,4-tetrahydro-naphthalen-1-one, 350 ml of acetic acid and 350 ml of 48 # aqueous hydrobromic acid is refluxed for 6 hours , left to stand at room temperature for 16 hours, then diluted with water and extracted with diethyl ether. The organic extract is washed with water and a saturated aqueous sodium hydrocarbonate solution and shaken with a 10 ^ aqueous sodium hydroxide solution. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with diethyl ether. The organic extract is washed with water, dried, filtered, evaporated and the residue is recrystallized from ethanol. The 2- (4-hydroxyphenyl) -1,2, J>, 4-tetrahydro-naphthalen-1-one, which melts at 137-138 °, is obtained.

009831/1977

- ² U example 10

A mixture of 10.5 g of 2- [4- (l-oxo-l, 2,3,4-tetrahydro-2-naphthyl) phenyloxy] isobutyric acid and 200 ml of a saturated solution of hydrogen chloride in methanol is added for 16 hours Boiled to reflux, and evaporated under reduced pressure. The residue is taken up in water, the aqueous mixture is extracted with ether, the organic extract is washed with aqueous sodium hydrocarbonate solution, dried, filtered and evaporated. The residue is distilled. The fraction boiling at 190-210 ° / 25 _mm Hg is methyl 2- [4- (1- 0xo-1,2,3,4-tetrahydro-2-naphthyl] phenyloxy] isobutyric acid methyl ester.

Example 11

A mixture of 4.4 g of 2-Methy1-2- (4-hydroxyphenyl) -1,2,3,4-tetrahydro-naphthalen-l-one, 50 ml of acetone and 5.95 g of sodium hydroxide are refluxed with stirring and boiling mixed with 4.15 B chloroform in 15 ml acetone. The mixture is refluxed for 1 hour and diluted in portions with a total of 200 ml of acetone. The reaction. mixture is evaporated under reduced pressure, the Ruckle was taken up in water, the aqueous solution with 2-nor-

009831/1977

acidified hydrochloric acid and extracted with ether. The organic extract is mixed with aqueous sodium hydrocarbonate solution shaken, the aqueous phase acidified with 2-normal hydrochloric acid and again with ether extracted. The organic extract is washed with water, dried and evaporated under reduced pressure. You get the oily 2- [4- (l-oxo-2-methyl-1,2,3,4-tetraliydro-2-naphthyl) phenyloxy] isobutyric acid the formula

CH, 0 I ³ H

—C C — OH

The starting material is prepared as follows: A mixture of 15 g of 2- (4-methoxyphenyl) -1,2,3,4-tetrahydro-naphthalen-1-one, 50 ml of dimethylformamide and ml of toluene is mixed with 2.86 g of a 53 ^ suspension of Sodium hydride in mineral oil, while stirring and cooling with ice, added. The reaction mixture is, after 2 hours, under Stirring and cooling with ice, a mixture of 8.5 g of methyl iodide and 25 ml of toluene is added dropwise. That The mixture is left to stand for 16 hours, then diluted with ether and filtered, and the residue is washed with ether. The piltrate is evaporated under reduced pressure and the residue is taken up in water. That aqueous mixture is extracted with ether, the organic

009831/1977

The extract was washed with water, dried, evaporated and the residue was recrystallized from isopropanol. You get 2-methyl-2- (4-methoxyphenyl) -1,2,3,4-tetrahydro-naphthalen-l-one, which melts at 62-63.

A mixture of 8.5 g of 2-methyl- (4-methoxyphenyl) -1,2,3,4-tetrahydro-naphthalen-l-one, 140 ml of acetic acid and 140 ml of 48 # aqueous hydrobromic acid Boiled under reflux for 6 hours, left to stand for 16 hours at room temperature and then poured onto ice-water. f The mixture is extracted with ether, the organic extract is washed with aqueous sodium bicarbonate solution, dried and filtered and evaporated. The residue is distilled and that boiling at 180-200 ° / 0.25 mm Hg Fraction recrystallized from a mixture of hexane and benzene. The 2-methyl-2- (4-hydroxyphenyI) -1,2,3,4-tetrahydro-naphthalen-1-one is obtained, which melts at 126 - 128 °.

Example 12

A mixture of 6.4 g of 2- [4- (1-oxo-2-methyl-1,2,3,4-tetrahydro-2-naphthyl) phenyloxy] isobutyric acid and 100 ml of a methanolic hydrogen chloride solution is 24 hours boiled under reflux and then evaporated under reduced pressure •. The residue is taken up in water that

009831/1977

1 ·

1 ·

ti- ii

- 44 -

aqueous mixture extracted with ether, the organic extract washed with an aqueous sodium hydrocarbonate solution, dried, filtered, evaporated and the residue recrystallized from isopropanol. The methyl 2- [4- (l-oxo-2-methyl-1,2,3,4-tetrahydro-2-naphthyl) phenyloxy] isobutyric acid is obtained the formula

which melts at 99-100.

Example I3

A mixture of 4.8 g of 2- (4-hydroxy-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ol, 50 ml of acetone and 7.8 g of sodium hydroxide is _y, with stirring and refluxing drop by drop; treated with 4.2 g of chloroform in 30 ml of acetone. Stirring is facilitated by diluting with acetone. The reaction mixture is refluxed for one hour and then evaporated under reduced pressure. The residue is taken up in water, the solution is acidified with 2N hydrochloric acid and extracted with ether. Of the

009831/1977

organic extract is mixed with an aqueous sodium hydrocarbonate solution extracted, the aqueous layer acidified with a 2 · 'normal hydrochloric acid and again with Aether extracted. The organic extract is made with water washed, dried, filtered and evaporated. The residue is made from a mixture of ethyl acetate and petroleum ether and recrystallized from a mixture of hexane and diethyl ether. 2- [4- (1-Hydroxy-1,2,3,4-tetrahydro-2-naphthyl) phenyloxy] isobutyric acid is obtained the formula

OH

G-C-OH

which melts at I38 - 140 °.

The starting material is prepared as follows: A solution of 11.9 g of 2- (4-hydroxy-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-one in 200 ml of 95 $ -iS ^em ethanol is added portionwise , with stirring and cooling, mixed with 3 * 7 S sodium borohydride. The mixture is left to stand for 16 hours at room temperature, acidified with dilute acetic acid and evaporated under reduced pressure. The residue is taken up in water, the mixture is extracted with ether, the organic extract with aqueous sodium hydroxide solution, water and a saturated solution aqueous sodium chloride solution • washed, dried and evaporated.

009831/1977

- 46 - The residue is recrystallized from aqueous ethanol.

The 2- (4-hydroxyphenyl) -l, 2,3,4-tetrahydronaphthalen-1-ol is obtained, which melts at 164 - 166 °.

Example 14

A solution of 3.2 g of methyl 2- [4- (1,2-dihydro-1-naphthyl) phenyloxy] isobutyric acid 2.7 g of osmium tetroxide are added to 60 ml of pyridine and the mixture is kept at room temperature Stirred for 2 hours. A mixture of 4.7 g of sodium hydrosulfite, 78 ml of water and 52 ml of pyridine is then added and the reaction mixture was stirred for 30 minutes and afterwards extracted with chloroform. The organic extract is washed with 2N hydrochloric acid and water, dried, evaporated and the residue recrystallized from a mixture of hexane and diethyl ether. You get the 2- [4- (cis-3,4-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl) -phenyloxyj-isobutyric acid methyl ester the formula

CH 0 I ^ Il

Η0 ··· <></ ^x > —0 — CC — OCH

I. : ch_

OR ^

which melts at 104 - IO5. After saponification with a "Necessarily, solution of potassium hydroxide and acidification with

009831/1977

Hydrochloric acid, the 2- [4 - (. Eis-3,4-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid is obtained, which melts at 172 - 173 °. ■ and with the one in the example 4 available product is identical. λ The raw material is produced as follows: A solution of 8.1 g of methyl 2- [4- (4-oxo-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy} isobutyric acid in 250 ml of anhydrous methanol is added in portions, under i Cooling, mixed with 1.8 g of sodium borohydride. The mixture is stirred for 5 hours, then acidified with acetic acid and evaporated under reduced pressure. The residue is taken up in water and extracted with ether. The organic one The extract is washed with aqueous sodium hydrocarbonate solution and evaporated. The oily 2 ~ [4- (4- Hydroxy-1,2,3,4-tetrahydro-1-naphthyl) -phenyloxy-isobutyric acid methyl ester.

.- ■■■■ · '. ■■ -: ■■■. . . . j

A mixture of 6 g of 2- [4- (4-hydroxy-1,2,3,4-tetra- ™ hydro-1-naphthyl) -phenyloxy] -isobutyric acid hiiethy! ester and 6O ml of 90 # formic acid is refluxed for 15 minutes boiled and poured into water. The mixture is with ether . extracted. The organic extract becomes more aqueous with water and Washed sodium hydrocarbonate solution, dried, filtered

and evaporated. The residue is distilled and the at Fraction boiling at 180 - 200 ° / 0.3 mm Hg on aluminum oxide (neutral, activity III) chromatographed. The pillar will

0098317 1977

If

ι <t

al t

- 48 -

■ · ■. ■ ■ '· ■ / J.

with 250 ml of a l: l mixture of benzene and hexane and with / 250 ml of benzene and the combined eluted fractions einge- · _t evaporated. The methyl 2- [4- (1,2-dihydro-l-naphthyl) phenyloxy] isobutyric acid is obtained.

A mixture of 0.7 g of methyl 2- [4- (l, 2-dihydro-l-naphthyl) phenyloxy] isobutyric acid, 25 ml of methanol and 1 g of potassium hydroxide will stand at room temperature for 16 hours left and evaporated under reduced pressure. The back | ™ stand is taken up in 5 ml of water. The received lower J

Impact is filtered off, dissolved in 25 ml of water, the solution is acidified with 2N hydrochloric acid and with Aether extracted. The organic extract is dried and evaporated. Der.Rückstand is made from a mixture of Recrystallized hexane and aqueous ethanol. The 2- [4- (l, 2-dihydro-l-naphthyl) phenyloxy] isobutyric acid is obtained, which melts at I05 - 106 °.

Example 15

A mixture of 0.1 g of methyl 2- [4- (cis-3,4-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyrate, 2 ml of 2,2-dimethoxypropane and 3 p-toluenesulfonic acid crystals is left to stand on the steam bath for 30 minutes, then diluted with 20 ml of chloroform, with 5 #

009831/1977

20O3T22

'.- · - ■ - ^k9: -. ~ ■: ■■■■■ -

aqueous potassium carbonate solution and water, dried and evaporated. The residue is taken up in a minimal amount of pentane, the organic solution is cooled in a dry ice-acetone bath, the resulting precipitate is filtered off and recrystallized from pentane and hexane. The aeetonide of 2- [4- (cis-3,4-dihydroxy-1 i 2,3> 4-th tr ahydr ο -1-naphthyl) phenyloxy] -is obut ters acid methyl ester of the formula is obtained

0 — OGH

which melts at 75- "76 °.

Example 16 ...

A mixture of 1 g of 2- [4 - (ice r-3,4-dihydroxy-1,2,3,4 · tetrahydro -1-naphthyl) -phenyloxy] -is © butyric acid -methyle, 75 ml pyridine and 10 ml of acetic anhydride is one hour on the steam bath allowed to stand, and poured onto .Eiswasser _»s the mixture is extracted with ether, the organic ex- tract with ...; 2N Ghlorwasserstoffsäure and water ge--.

009831/1977

. - 50 -

wash, dry and evaporate. The residue is taken up in a minimal amount of hexane and the solution is dissolved Aluminum oxide (neutral, activity III) chromatographed. The column is eluted with benzene and diethyl ether. the combined fractions are evaporated and the residue is recrystallized from hexane. The methyl 2- [4- (cis-3,4-diacetyloxy-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid is obtained the formula

σ - och

which melts at 123 - 126 °.

Example 17

If in Example 5 the racemic methyl 2- [4- (l, 2,3 * 4-tetrahydro-1-naphthyl) phenyloxy] isobutyrate by the methyl ester of the optically active β- or d-2- [4- (l, 2,3,4-tetrahydro-1-naphthyl) -phenyloxy] -isobutyric acid replaced ([a] _Q = -27 ° or + 27 °), one obtains the € - or d-2- [ 4- (4-Oxo-1,2,3,4-tetrahydro-1-naphthyl) -phenyloxy] -iso-butyric acid methyl ester, [a] _D = -62 ° or + 62 °.

009831/1977

tiff f t f

- 200312?

- ■ ν .ν '■ —- si - ■ ■

By reducing the optically active esters mentioned above or the corresponding free acids according to Example 8 or 14, the trans -t - or d -2- [4- (4-hydroxy-1,2,3,4-tetrahydro ~ l) are obtained -naphthyl) -phenyioxy] -isobutyric acid, mp. 150 153 ° * [«] q - -22 ^Q or + 22.3 °, or the corresponding methyl ester

The last-mentioned compounds are dehydrated according to Example V \ , whereby the d- or ^ -2- [4- (1,2-dihydro-inaphthyl) -phenyloxy] -isobutyric acid methyl ester is obtained with inversion of the rotation (ah of the line) which in dilute methanolic solution have the values [α] _β = +31.5 or -22.2. (Determinations of the optical rotation are carried out in very high dilutions, because in the range of shorter wavelengths of 200 - 400 πιμ, due to strong specific rotation, high rotation values are obtained) ■■ «. ^: The above d- or ^ -dihydro compounds are oxidized according to Example 14, reversing the optical direction of rotation, the B- or d-2- [4- (cis-3,4-dihydroxy-Ii2 * 3 * ^ -tetrahydro-1-naphthyl) -phenyloxy] -isobutyric acid, F, 158-160 °, [α] ξ ⁵ = -65.8 ° or + 65.8 °. The diacetate of the d-compound, which is prepared according to Example 16, melts at 142-143 °, [a] ^ ⁵ = + 111.7 °. ■ '■ - ■ "^;". ::. "■'". "-. ■ '-" / ■ ...:,'. . '-;

0ü983i / t9T7

I t

- 52 Example l8

A solution of 1.2 g of methyl 2- [4- (1,2-dihydro-1-naphthyl) phenyloxy] isobutyric acid in 10 ml of chloroform is treated with a mixture of 1 ml of bromine and 10 ml of chloroform. The bromine is added dropwise with stirring and cooling of the mixture in an ice bath. As soon as the bromine color remains stable, you stop adding more bromine and steam the reaction mixture under reduced pressure. The methyl 2- [4-trans-3,4-dibromo-1-naphthyl) phenyloxy] isobutyric acid is obtained.

A mixture of 5.3 g of 2- [4- (trans-3,4-dlbromo-lnaphthyl) -phenyloxy] -isobutyric acid methyl ester, 5.5 S potassium acetate and 7.5 ml acetic acid is on the steam bath for one hour heated and refluxed for 12 hours with stirring, then cooled and diluted with 100 ml of ether. The above- j de solution is separated from the residue by decanting, washed with water, dried, filtered and evaporated. The residue is chromatographed on 110 g of neutral aluminum oxide (activity III). The column is first co-eluted

a 6: 1 mixture of benzene and hexane, using the 2- [4— " (3-Bromo-1,2-dihydro-1-naphthyl) -phenyloxy] -isobutyric acid methyl ester, P. 8l - 83 °. With a 9: 1 mixture of benzene and hexane, methyl 2- [4- (4-0xo-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid is obtained, · Which melts at 83 - 84 °.

009831/1977

. This "product is identical to that of Example 5. _ ■

With 9: 1 mixtures of benzene and acetone and benzene and diethyl ether, 2- [4-trans-3,4-diacetyloxy-1,2 ^: i 3,4-tetrahydr ο -1 -naphthy 1) -pheny is obtained loxy] -i sobut t er acid e methyl ester of the formula

HJ-C-O-

HO-C-O

^y w

which melts at II7-119 and with ethyl acetate and then methanol the 2- [4- (trans-3-acetyloxyT4-hydroxy-1 _J 2 _J 3 _J ⁱ * · ^ tetrahydro-1-naphthyl) -pheny lox-yl-isobutyric acid -methyl ester of the formula '. - ^:

HO

C: C-OCH,

which melts at 140 - 144 °,

, 009831/1977

- 54 Example 19

A mixture of 0.5 g of 2- [4- (trans-3,4-diacetyloxy-l, 2,3,4-tetrahydro-l-naphthyl) -phenyloxy] -isobuttersäure-methylester, 10 ml of methanol and 0.2 g of potassium hydroxide is left to stand at room temperature for 20 hours and evaporated under reduced pressure. The residue is taken up in water, the solution acidified with hydrochloric acid and extracted with ethyl ester. The organic extract is dried and evaporated. The 2- [4- (trans-3,4-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid, which melts at 215-216, is obtained. The product is identical to that of the
Example 4 identical '.

Example 20

Tablets with a content of 0.05 S of the active substance are made as follows:
Ingredients (for 1000 tablets):

trans-2- [4- (4-hydroxy-1,2,3,4-tetrahydro-

1-naphthyl) phenyloxy] isobutyric acid 50.0 g

Milk sugar 84.7 g

Corn starch ■ 13 * 0 p

Stearic acid x 1.0 g

Magnesium stearate 1.0 g

Silica gel 009831/1977 0.3 g

purified water . q.s.

f β. It

All powdery substances are individually ^{sifted through a 0.3:} Roman mesh size sieve and thoroughly mixed. A paste for the granulation of trans- 2- [k - (4-hydroxy-1,2,3,4-tetrahydrο-1-naphthy1) -phenyloxy] -isobutyric acid is made from a third of the starch and a suitable amount of water Milk sugar and a third of the starch, if necessary with the addition of a further amount of water. The granulate is dried for 16 hours at 35 °, driven through a sieve with 1.2 mm mesh size and, with the rest of the starch, mixed with stearic acid, magnesium stearate and silica gel and made into tablets of 0.15 g (7.1 ram diameter), which have a breaking groove, pressed.

009831/1977

Claims (1)

. - 56 claims: 1. Process for the preparation of phenyloxy-aliphatic acids of the formula Ph ₁ A, —Ph _o —0 — A ₅ —0—0H (I), where Ph _{1 is} an optionally substituted 1,2-phenylene radical, Ph _{2 is} an optionally substituted phenylene radical, A is a mono- or dihydroxy-lower alkylene or a lower alkanoylene radical which, together with the group Ph, is a 5- to 7-membered Ring forms, where one of the ring carbon _{atoms of A 1 contains} the group Php, and Ap stands for a divalent lower aliphatic hydrocarbon radical, and functional derivatives thereof or salts of such compounds, characterized in that a) in a compound of the formula (II) wherein Z _{1 is} a free or functionally modified · * · ι Represents a group of the formula -0-A ₂ -C (= 0) -OH convertible group, the radical Z _{1 is converted} into the latter, or b) in a compound of the formula It Ph ₃ A ₅ -Ph ₂ -OA ₂ -C-OH (III) 0 0 9831/1977 or a functional derivative thereof, in which A is a lower alkylene or lower alkenylene radical which forms a 5- to 7-membered king _{with the group Ph 1 , in which one of the ring carbon ens to fatome bears the group Ph 2} , the group A., in the group a converted, and, if desired, a resulting compound in · transferred to another compound of the ¹ invention and / or, if desired, a resulting free compound into a salt or a resulting salt into the free compound or 'in a other salt transferred; and / or, if desired, separating a mixture of isomers obtained into the individual isomers. 2. The method according to claim 1, characterized in that Z ₁ in the starting material of the formula II represents a free hydroxyl group modified into a salt form or esterified. 3 * method according to claim 2, characterized in that that the cation part of a hydroxyl group that has been converted into the salt form represents an alkali metal cation. 4. The method according to claim 2, characterized in that an esterified phenolic hydroxyl group Z-. a group of the formula -O-C (-O) -R, where R is a etherified or esterified Hydroxy group means is. . 0.983 1/1 97 7 5. The method according to any one of claims 1-3 *, characterized in that that a starting material of the formula II with an acid of the formula Zp-Ap-C (= 0) -OH (ila) or a functional Reacts derivative thereof, one of the radicals Z- and Zp is a reactive esterified hydroxyl group and the other represents a hydroxyl group present in salt form. 6. The method according to claim 5 *, characterized in that starting materials are used in which Z is a hydroxyl group present in salt form and Z _{p is} a hydroxyl group esterified by a strong acid. 7. The method according to claim 5 * characterized in that that one uses starting materials, wherein Z, one in salt form Hydroxyl group present and Z “one through a strong mineral acid or represents a strong organic sulfonic acid esterified hydroxy group. 8. The method according to claim 5 *, characterized in that acids of the formula Ha or corresponding esters or nitriles, wherein Z _? stands for halogen, used as starting materials. 009831/1977 * 9 · method according to one of claims 1-3 * thereby characterized in that a starting material of the formula II, in which Z represents a hydroxyl group in salt form, with a lower aliphatic corresponding to the radical -Ap- Aldehyde or ketone converts in the presence of a tri- or tetrahalogenated methane derivative. 10. The method according to claim 9 *, characterized in that f that the tri- or tetrahalogenated methane derivative is chloroform, 1,1,1-trichloroacetone, bromoform, 1,1,1-tribromoacetone, iodoform, chloral, chloral hydrate, bromal, bromal hydrate, carbon tetrachloride or carbon tetrabromide is used. 11. The method according to claim 9 or 10, characterized in that there is an excess of the aldehyde or ketone and the tri- or tetrahalogenated methane derivative are used and works in the presence of a strong base. " 12. The method according to any one of claims 1, 2 and 4, characterized in that a starting material of the formula II, wherein Z _{1 is} an esterified hydroxyl group, with an acid of the formula Zp-Ap-C (= 0) -OH or one functional derivative thereof, wherein Zp represents a hydroxyl group. 009831/1977 ■ · - - 60 - 13. The method according to claim 12, characterized in that that one works at temperatures of about 100 C to about 210 ° C. 14. The method according to claim 1, characterized in that that starting materials of the formula III are converted into compounds of the formula I by treatment with oxidizing agents. 15. The method according to claim l4, characterized in that that heavy metal oxides or corresponding acids or salts thereof, hydrogen peroxide or peracids are used as oxidizing agents used. j 16. The method according to claim l4 or 15, characterized in that that in the oxidation of starting materials of the formula III, in which the group A is a lower alkenylene radical P represents, cleaves epoxides obtained hydrolytically or hydrogenolytically. 17. The method according to claim 1, characterized in that starting materials of the formula III, in which the group A_ represents a lower alkenylene radical, treated with halogen or hydrogen halide and resulting mono- or dihalogen adducts by hydrolysis or under acylating conditions. 009831/1977 18. The method according to any one of claims 1-5 » 7-10 and ,. IS-ίο, characterized in that one obtained connections with free carboxyl group converts to ester. 19. The method according to any one of claims 1-17, characterized characterized in that one obtained compounds with free Converts carboxyl group to ester. ■ ■: ■. ■■■■ '' ■■ · ■ ■ / ■ 'i 20. Method according to one of claims 1-5. » 7-10 and 12-16, characterized in that the compounds obtained with free carboxyl groups are converted into acid halides and these are converted into esters or converts to amides. 21. The method according to any one of claims 1-17 * characterized in that one obtained compounds with free carboxyl groups in acid halides and these in esters or Amide converts. - (j .22. Process according to one of Claims 1-5 * 7 ^ 10 and 12-16, characterized in that ammonium salts are yon
acids obtained with the formation of amides or nitriles
dehydrated. . 0098 3 1/1977 23 · method according to one of claims 1-17 * thereby characterized in that ammonium salts of acids obtained are dehydrated to form amides or nitriles. 2h. Process according to one of Claims 1-5 * 7-10 and 12-16, characterized in that the esters, amides or nitriles obtained are hydrolyzed to free acids. 25 · The method according to any one of claims 1-17, characterized in that that one obtained esters, amides or nitriles: hydrolyzed to free acids. 26. The method according to any one of claims 1-5 * 7-10, 12-16, l8 and 20, characterized in that one obtained ester transesterified or converted into amides or hydroxamic acids. P> 27 ·. Method according to one of claims 1-21, characterized in that the esters obtained are transesterified or converted into amides or hydroxamic acids. 28. The method according to any one of claims 1-5, 7-10, 12-16 and 22, characterized in that the nitriles obtained converts to ester. 009831/1977 29 · Method according to one of claims 1-17 * 22 and 23, characterized in that the nitriles obtained in Ester converts. 30. The method according to any one of claims 1-5 * 7-10 * 12-16, 18, 20, 22, 2%, 26 and 28, characterized in that in compounds obtained in which the group A _{1 is} a lower alkanoylene radical represents, the keto group is reduced. fj 31 · "Method according to one of claims 1-29, characterized characterized in that in compounds obtained in which the group A. is a N'iederalkanoylenrest, the keto group is reduced. 32. The method according to any one of claims 1-5, 7-10, 12-16, 18, 20, 22, 2 $, 26 and 28, characterized in that the compounds obtained in which the group A is a hydroxy-lower alkylene radical represents, the hydroxyl group is oxidized to the oxo group. 33 »The method according to any one of claims 1-29, characterized in that in the compounds obtained in which the group A _{1 represents} a hydroxy-leatheralkylene radical, the hydroxy group is oxidized to the oxo group. _t,. . 0 09831/197 7 34. The method according to any one of claims 1 ~ 33> characterized in that in the compounds obtained the oxygen function in a hydroxy or oxo-lower alkylene radical ■ A _{1 is} functionally modified. 35. The method according to claim 34, characterized in that hydroxyl groups in hydroxy- _{lower alkylene radicals A 1} of compounds obtained are esterified. 36. The method according to claim 34, characterized in that that two adjacent hydroxyl groups in hydroxy-lower alkylene residues A. of compounds obtained acetalized or ketalized will. 37 · The method according to claim 34, characterized in that oxo groups in lower alkanoylene residues A. From ₀ compounds obtained are ketalized. ■ 38 · Method according to one of claims 1-37 * thereby characterized in that the compounds obtained are radio-controlled modified hydroxyl or oxo groups converted into free hydroxyl or oxo groups by alkaline or acidic hydrolysis will. 009831/1977 39i method according to one of claims 1H5> 7 "XQ * - 12-0: 6, 18, 20, 22, 2 ^> 26 ", 28, 30 and 32, characterized., that one formed at some stage as an intermediate Compound ^ is used as the starting material and the rest " liche level (s) wit this JdurßJigefiüirtΊνίίΓΰ (become), or the 1 / experience is interrupted at some level. # 0, 1 / experience iiaph one of the claims XrJ> 8 _t dadureli - gekennzeielanet ^ that one at some level as intermediate pro « dufct formed compound is used as starting material and the rest of the stage (n | init of this is dura-led (knows - j, © who interrupts the failure on some of your sticks, one of the claims | ie \ "&> _t . T 1% '-UQ ₉ 22 _? 21, Μ) * SB, 3Oj J) B and 3ß ₄ characterized in that the starting material is formed under the legal conditions" or iii iNariji ¥ on salts or reactio.nsf; 4hig; ßn derivatives yer ^ are used, according to one of the claims "i ^ fe. ^ $ Q & WQ% \ Bß- MS f 11 / lit f 43 · Process according to one of claims 1-5, 7-10 / 12-16, 18, 20, 22, 24, 2.6, 28, 30, 32, 39 and 4l, characterized in that compounds of the formula I according to claim 1, wherein Ph 1,2-phenylene, (lower alkyl) -1,2-phenylene, (5- to 7-membered cycloalkyl) -1,2-phenylene, (lower alkoxy) -1,2-phenylene, (halogen) - is 1,2-phenylene or (trifluoromethyl) -1,2-phenylene, Php for 1,2-, 1,3- or 1,4-phenylene, fe (lower alkyl) -1,2-phenylene, -1,3-phenylene or -1,4-phenylene, (lower alkoxy) -1,2-phenylene, -1,3-phenylene or -1,4-phenylene, ( Halogen) -1,2-phenylene, -1,3-phenylene or -1,4-phenylene or (trifluoromethyl) -lj2-phenylene, -1,3-phenylene or -1,4-phenylene, Ap is lower alkylene and A, a group of 4 of the formula -C (R) - (CH ₀ ) -CHOH, - (CH ₀ ) -C (R) -CHOH, -C (R) - (CH ₀ ) -C = O, - ( CiC ₂ ) -C (B) -C = O or -C (H) - (CH ₂ ) -CH (OH) -CHOH represents, where * ρ for an integer from 1-3 * Q for p-1 and R represents hydrogen or lower alkyl, or lower alkyl or lower alkoxy ^ lower alkyl esters, aryl-lower alkyl esters, in which aryl eipen is phenyl 'radical, which may optionally _{contain the substituents specified for the radical Ph 2} , pyridyl-Ap-iiiederalkylester, in which Am is di-lower alkylamino, amino or monoaza- or monooxa-lower alkyleneamino, sLBa- oyeloalkyl- or Moncaza-cycloalkyl-niederailiylegfcer above acids, wherein the heteroatom is part of veresteriiden 3awerstoffatom the carboxy group getrenrit by NIIT, Awjide, mono- or Üiriiedera4teyl _"8wWe? mono bioyolische Uieueralkylenwmiue _Λ HydroxapsEiwen ού &ρ" or salts of such ¥ ertoipduügen eii3i / ifff 44. The method according to any one of claims 1-33 and 38-42, characterized in that the connections shown in claim 43 are established. ^; 45. The method according to any one of claims 1-5, 7-10, 12-16, 18, 20, 24, 26, 28, 30, 32, 39 and ¹ U, characterized in that one compounds of the formula CH, 0 If one of the radicals X and Y is a direct bond and the «Represents other hydroxymethylene or carbonyl, r 0, 1 or 2 is, R- hydrogen or lower alkyl means ^ R «hydrogen, Nlederalkyl, Niederalkoxy-Niederalkyi, Phenyl ^ nlederalkyl, Pyidyl-lower alkyl, di-lower-alkyl-amino-lower-alkyl, lower-alkyl-amino-lower-alkyl N-lower alkyl-piperidyl or N-lower alkyl-piperidyi-lower alkyl represents, Where in these groups heteroatoms from the oxygen atom of the carboxy. group are separated by at least two carbon atoms * Each of the radicals R4 and R ^ for hydrogen, lower alkyl or Halo- ; 009ΰ3 | / Ί977 gen and R ₁ . Hydrogen or, if Y is hydroxymethylene, also denotes hydroxy, or prepares salts thereof. 46. The method according to any one of claims 1-21, 24-33 and 38-42, characterized in that the in claim 45 connections shown. 47 · Method according to one of Claims 1-5 * 7-10> 2-l6, 18, 20, 24, 26, 28, 30, 32, 39 and 4l, characterized in that that you can get compounds of the formula (Ib) wherein R ^ is hydrogen, an alkali metal ion, or lower alkyl and R ^ is hydrogen or hydroxy. 009831/1977 i υ υ 3 1 2 1 iffl; te§pf Help f- Jl: tilt fki -e tiüi äif liilffll isi ili Uli ®m iiä- Äillä fsa ^^ e ^ i * ■ $ j fiüi feip -iiSiifViiff • i · i ι ι ti - 70 - Method haeh claim i for * production Viii S- [ i dädüreh marked> that the 2-f 4- (4-Oj ^ oI jöj Sin kst iahydro -1 -naphfchyl) -piienyloxy ] - iti converts the free acid * 54 * Method according to claim 53i dädtireB because the external material is to be treated lit Öigenwart. of methanol in the fföie Sättfö taiWäiidili Procedure according to ÄnsprliäÜ 1 Mtit ⁴ itoolelltifti Vö « 4-tetrahydrö-i -ha ^ hihf 1) * 0mf iöJtjf j kenn'Böieiiinet, däää filift if4 i * £ | 6 * Vefiähfötl Meh Äfisjirüeh ^ i dädür'öil i Mi ffläh dür'öh iehäidein inife §Iü iti deti fieispieiefi 1-J feöäötoiifeiöi Viffatüpen ι §Ää iti am Selapleliii 4 = if u% - 71 - 6 (K λ-...-. The after, the yerfahren, the claims 51-57 "rhält-, _ loan compounds: ._ ^-,, -,:...?.. / ^; ;: -: 61 . The according to: the method of, claims he 1-5 / 7-10, 12-16, 18, 20, 22, 24, 26, 28, 30, 32, 39, 41, ^ 3, ^ 5, Λ7 ^ Λ9 and. ·, 51- ^ 58 compounds available. 62., / The compounds obtainable according to the method,, the ^^ claims, _k .l-59. . · ;,, -. '., ..., .. 31 / 197.7; I.
t ι • * 63. Phenyloxy-aliphatic acids of the formula -Ph ₂ -0-A ₂ -C-0H (I),, where Ph is an optionally substituted 1,2-phenylene radical, Ph _{2 is} an optionally substituted phenylene radical> · A. represents a mono- or dihydroxy-lower alkylene or a lower alkanoylene radical which, together with the group Ph., forms a 5- to 7-membered ring, one of the ring carbon atoms of A containing the group Ph ₂ , and A _{3 being} a divalent one lower aliphatic hydrocarbon residue. . 64. Functional derivatives of the compounds according to proverb 63. 65. esters, amides, nitriles or hydroxamic acids of encryption W compounds according to claim 63., 66. Compounds of formula I according to claim 63 * in which Ph ₁ 1,2-phenylene, (lower alkyl) -l, 2-phenylene, (5- to 7-ringed cycloalkyl) -l, 2-phenylene, (lower alkoxy) - 1,2-phenylenji (halogen) -1,2-phenylene or (trifluoromethyl) -l, 2-phenylene represents, Ph _{2 represents} 1,2-, 1,3- or 1,4-phenylene, (lower alkyl ) -1,2-phenylene, -1,3-phenylene or -1,4-phenylene, (lower alkoxy) -1,2-phenylene, -1,3-phenylene or -1,4-phenylene, (halogen) - I ₄ 2- 009831/1977 122 • 'phenyXengi -X ^' - P ^ enyXen or to ^ deufeet; i «« 3 Ä, © ine α ^ Ρ groups of , »-Cafe) _n - in |> for a ^ gan ^ e gahl γρά. ^: X-Wj ,; q fte pX and R pr or , W0 |? In ^ aryl © inen Ph ^ n ^ lrgsfc the füp αρη remainder? 1 ^ ₂ im t> enen Swbslifcuenfcen en ^ hal1 <en can ,, Pyridyl - - or Mono ^ xanniedeFalkylenaroin «? eats / mono * - «Or Wonoaga-eyqXioalkyI-NiederaXfeyXesfcer der ^ Sfuren ^ wofeei heteroatoms; df5 verefte ^ n / Jen feiXs vom Oxygen atom, of the carfeoxy group by at least ^ monoxide ^ atoms jgetteeimt is>Amide> Mono- oder J3iniede ^ aXkyX * amide _A mono « jä & $ Gi $ pUt & \ # & * fa Hyfjrpxamicäuren or by V ^ Mndun ^ -7 * (Ia) wherein one of the radicals X and Y is a direct bond and the other is hydroxymethylene or carbonyl, r is 0, 1 or 2 , R _{1 is} hydrogen or lower alkyl, Rg is hydrogen, lower alkyl, .Nlederalkoxy-lower alkyl, phenyl-lower alkyl, pyridyl-lower alkyl , Di-lower alkyl-amino-lower alkyl, lower alkylenamino-lower alkyl, N-lower alkyl-piperidyl or N »Ni @ dira! Kyl ~ piperidyl-lower alkyl, where in these groups heteroatoms are separated from the oxygen atom of the carboxy group by at least two carbon atoms, each of the radicals R, and R ^ are hydrogen, lower alkyl or halogen and R ^ are hydrogen or, if Y is hydroxymethylene, also hydroxy. 69. Compounds of Formula GH- 0 1 J 'η. τ I " Ο— 0—0 — OEI OH 000831/1077 t? ■ (V ■ ύ κ - 75; -> wherein Rl is hydrogen, an alkali metal ion or lower alkyl .- · v
and R * is hydrogen or hydroxy. 70. 2 - [- 4- (4-Oxo-l., 2> 3> 4-tetrahydroÖ-l-naphthyl) -phenyloxy] isobutyric acid ethyl ester. 71 ". -phenyloxyί- ifebbüttersäuf e '*' "■ 2- [4- (li-% di« oxy-i ^ 2 ^^ - tetrahydro-1-naphthyl} -phenyl- oxyT-Isobutt er acid. 73. iiyfrrd-i-nWph- 74. ■■ *! ^ ^; 2 £ ^ cis ^ 5, ^ bihy ^ phenyloxy ·] isobutyric acid. ■ - """ ^E - '"^r;;""^;"'' ^PY ° · ■ '- ^■■ έ" ^t? "- '■■"' i -; ^ iyr) ^ phenyioxy] - 75. 2-B-Pi isobutyric acid methyl ester. ^'>:; · 76. trans-2-I4 - (% - _hydroxy-l;, ^ i3, 4-tetrahydro-l-naphthyl) -phenyloxy] -iäobüttersäure. , 0098314197.7 % t - 76 ■ - 77. cis-2- [4- (4-Hydroxy-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid: 78. 2- [4- (1- 0xo-1,2,3,4-tetrahydro-2-naphthyl) phenyloxy] isobutyric acid. 79. 2- [4- (l-Oxo-2-methyl-1,2,3,4-tetrahydro-2-naphthyl) - ^ phenyloxy] isobutyric acid. 80. 2- [4- (1- 0xo-2-methyl-1,2,3,4-tetrahydro-2-naphthyl) phenyloxy] isobutyric acid methyl ester. 81. 2- [4- (1-Hydroxy-1,2,3,4-tetrahydro-2-naphthyl) phenyloxy ] isobutyric acid. 82. 2- [4- (cis-3,4-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl) - Dk j phenyloxy] isobutyric acid methyl ester. ir _t ■ - 83. Acetonide of methyl 2- {4- (cis-3,4-dihydroxy * -l, 2,3 _/ 4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid. 84. 2- [4- (cis-3,4-diacetyloxy-1,2,3,4-tetrahydro-1-naph-, methyl) phenyloxy] isobutyric acid methyl ester. 009831/1977 85. / '- a- [4- (4 oxy] -i3obutyric acid, methyl ester 86. d "2-E4" (4-Oxo-1,2,3 * ^ - tetrahydro-1-naphthyl) phenyl oxy] isobutyric acid methyl ester " 87. trans - / - 2- [4- (4-hydroxy-1,2,3,4-tetrahydro-1-naphthyl) phenyloxy] isobutyric acid, * ethyl) phenyloxy] isobutyric acid. thyl) -phenyloxy] «isobutyric acid. 90.d ^ -C ^ naphthyl) -phenyloxy} -isobutyric acid. f 91. 2- [4-trans-3, * - I> acetyloxy-1,2,3,4 ~ tetrahydro-lnaphthyl) «phenyloxy] -isobutyric acid methyl ester. 92. 2-C4- (trans -3-acetyloxy-4-hydroxy-1,2,3,4-tetrahydrol-naphthyl) -phenyloxy] -isobutyric acid methyl ester. 009831/1977 - 78 93 · Salts of compounds of claims 71 and 72. 9 ^. Pharmaceutically acceptable salts of compounds of claims 71 and 72. 95. Salts of compounds of claims 63-68, 73, 74, 76-79, 81 and 87-90. 96. Pharmaceutically usable salts of compounds of claims 63-68, 73, 74, 76-79, 81 and 87-90. 97. Pharmaceutical preparations, characterized by a content of one of the compounds claimed in claims 70-72 and 92. 98. Pharmaceutical preparations, characterized by a content of one of the compounds claimed in claims 63-69, 73-90 and claimed. 99. Pharmaceutical preparations characterized by a content of one of the beanspruch- in claims 91 and 92 _(th compounds. 100. The new compounds described in the examples . 009831/1977