DE2312344A1 - Alpha-phenoxy-propionic and -(chloro)phenylacetic acids - with pharmacological (e.g. hypocholesterolaemic and hypoglycaemic) activity - Google Patents

Abstract

New cpds. of formula (I): (where R1 is H or 1-4C alkyl, R2 is Me, phenyl or chlorophenyl, R3 is piperidino, isoindolino, 1,2,3,4-tetrahydroquinolino, 1-R4-1,2,3,4-tetrahydro-4-quinolyl, 4-piperidinophenyl, 4-piperidinophenoxy or 1-pyrrolyl, R4 is H or 1-4C alkyl) and their salts reduce cholesterol, triglyceride and uric acid levels and have liver enzyme inducing activity. They can be prepd. e.g. by reacting the corresp. R3-substd. phenol with X-CHR2-COOR1 (where X is free or esterified OH, Cl, Br or I).

Description

Phenoxyacetic acid derivatives and process for their preparation The invention relates to new phenoxyacetic acid derivatives of the general formula I wherein R¹ is H or alkyl having 1-4 carbon atoms, R² is methyl, phenyl or chlorophenyl, R³ is piperidino, isoindolino, 1,2,3,4-tetrahydroquinolino, 1-R4-1,2,3,4-tetrahydro-4 -quinolyl, 4-piperidinophenyl, 4-piperidinophenoxy or 1-pyrryl and lt4 mean H or alkyl with 1-4 carbon atoms and their physiologically acceptable salts with acids or bases.

It has been found that these substances are excellent and are well tolerated cholesterol lowering, triglyceride level lowering, uric acid level lowering and have liver enzyme-reducing properties.

The compounds of formula I and their physiologically harmless clear Salts can therefore be used as medicinal products and also as intermediate products for manufacture other medicines are used.

The invention relates to compounds of the formula I and their physiologically acceptable salt. The compounds of the formula I include compounds of the following formulas Ia to Ie, in which Ri and R have the meanings given above: wherein A is p-C6H4- or p-C6H4-O- and n is 0 or 1; and in particular compounds of the formulas I and Ia to le in which R¹ is H, CH3 or C2H5 and / or in which R² is CH3, C6H5, m-chlorophenyl or p-chlorophenyl, preferably C6H5 or p-chlorophenyl. Compounds of the formulas Ic and Id are particularly valuable pharmaceutically.

The invention also relates to a process for the preparation of compounds of the formula I and their physiologically acceptable salts with acids or bases, which is characterized in that a phenol of the general formula II wherein R³ has the meaning given for formula 1 with a compound of the general formula III X-CHR²-COOR¹ where III X is free or esterified OII, C1, Br or J and R¹ and 112 have the meaning given for formula I, or that a compound of the general formula IV wherein Y is pentamethylene or o-xylylene and Z is C1, Dr, J, NH2 or an optionally esterified or etherified OH group and 2 R¹, R², A and n are as defined, treated with cyclizing agents or in a compound of the general formula V where W is an optionally functionally modified COOH group and R² and R³ have the angogplane hedeuting, the radical W is converted into the radical G00111 by treatment with salvolysing, thermolysis or ester-forming agents and that, if appropriate, a compound of the formula I obtained by treating with Acids or bases in their physiologically harmless acid addition or metal bzm. Ammonium salts are converted and / or a compound of the formula I is liberated from one of its salts by treatment with a base or acid.

In the above remarks, R1 and R4 preferably denote H, methyl or ethyl, also n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

X and Z are preferably Cl or Br; these leftovers can besides free OH and J but also e.g. alkysulfonyloxy with in particular 1 - 6 carbon atoms (e.g. Methanesulfonyloxy), arylsulfonyloxy with in particular 6-10 carbon atoms (z * Bo benzolaufonyloxy, p-toluenesulfonyloxy, 1- or 2-naphtha linsulfonyloxy) or acyloxy with in particular 1 - 7 carbon atoms (e.g. acetoxy or benzoyloxy), Z also denotes NH2 or e.g. an etherified OH group with in particular 1 - 7 carbon atoms (e.g.

Methoxy, benzyloxy).

The compounds of formula I can according to known in the Methods described in the literature are produced. Preferably they are through Reaction of the phenols 11 obtained with the acetic acid derivatives of the formula III. the Some phenols II are known. As far as they are new, they can be used after familiar ones Methods are produced, e.g. by splitting their Methyl ether (corresponding to II, but OCH3 instead of OH) with HBr. the compounds III are largely known. The implementation of II with III can still be carried out using methods as described in Literature are described0 For example, the phenol II can first be converted into a salt transferred, in particular a metal salt such as an alkali metal salt, e.g. a Li-, Na- or Salts Salt formation can be achieved, for example, by using the Reacts phenol with a metal salt-forming agent, such as an alkali metal (e.g. Na)> an alkali metal hydride or anide (e.g. LiH or NaH, NaNH2 or KNH3), a lower alkali metal alcohol (e.g. lithium, sodium or potassium methylate, ethylate or tert-hutylate), an organometallic compound derived from a hydrocarbon (e.g. butyllithium, phenyllithium or phenylsodium), a metal hydroxide, carbouate or bicarbonate (e.g. of Li, Na, K or Ca). The production of the salt of II is advantageously carried out in the presence of a solvent that has the basis of its physicochemical properties, e.g. the solubility the starting material or the reactivity of the metal compound is selected. Suitable solvents are, for example, hydrocarbons (such as hexane, benzene, toluene or xylene), ether (e.g.

Diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or diethylene glycol dimethyl ether), Amides (e.g. dimethylformamide), alcohols (e.g. methanol or ethanol), ketones (e.g. Acetone or butanone) or solvent mixtures.

The phenol II or preferably a salt thereof is with a Compound of formula III preferably reacted in the presence of a diluent, e.g. the solvent used for the production of the salt, but replaced by another solvent or diluted with one can be. The implementation is usually at temperatures between -20 and 1500 carried out, preferably between 20 and 1200, particularly useful at the boiling point of the solvent. You can under an inert gas, zD. nitrogen be performed; however, it is not necessary to have one.

The formation of the metal salt of phenol II can also be carried out in situ will; in this case the phenol and the compound III are allowed to mix with one another In the presence of a salt-forming reagent or another suitable base, react.

A particularly preferred method is that the compounds 11 and III (X = Ol or Dr, R¹ = CH3 or C2H5) together with an alcoholic (e.g. ethanolic) sodium alcoholate solution boils for several hours.

It is also possible to use a free phenol II with a hydroxy acid derivative of the formula III (X = OH), preferably in the presence of a condensing agent. Suitable condensing agents are, for example, acidic dehydration ketalysers, e.g. Mineral acids such as sulfuric acid or phosphoric acid, also p-toluenesulfonyl chloride, Arsenic acid, boric acid, NaHSO4 or KHSO4, also disubstituted carbonic acid esters, such as diaryl carbonates (e.g. diphenyl carbonate) or, in particular, dialkyl carbonates (e.g. dimethyl or diethyl carbonate) or carbodiimides (e.g. dicyclohexylcarbodiimide). When an acid serves as a condensing agent, the reaction becomes convenient in one Excess of this acid without the addition of a further solvent at temperatures between 0 and 1000, preferably 50 and 600 carried out. However, it can also Diluents, e.g.

Benzene, toluene or dioxane can be added. Works with a carbonate one preferably at a higher temperature, expediently between 100 to about 2100, in particular between 180 and 2000, with a transesterification catalyst if desired such as sodium or potassium carbanate or an alcoholate (e.g. sodium methylate) can.

Compounds of the formula IV can be described in the literature Methods for compounds of the formula I can be euelized, e.g. by heating in Opposite or absence of a solvent, possibly in the presence of a acidic or basic catalysts.

Compounds of the formula IV are zOB. obtainable by reacting a compound of the formula VI ZyZ in which VI Y and Z have the meaning given above, but the two groups Z can be the same or different and together can also mean O or NH, with a compound of the formula VII in which R¹, R², A and n have the meaning given above. Preferred compounds of the formula VI are those with the same groups Z, for example 1-, 5-dichloro-, 1,5-dibromo- and 1,5-diiodopentane, o -Xylylene chloride, o-xylylene brozide, o-xylylene iodide, phthalyl alcohol (o-hydroxymethylbenzyl alcohol) and its reactive esters, for example its bis-methanesulphonate or bis-ptoluenesulphonate, o-xylylenediamine, phthalane (isocoumaran), isoindolein.

Suitable solvents for the cyclization of IV are e.g. water, lower aliphatic alcohols (such as methanol, ethanol, isopropanol, n-butanol), Glycols (such as ethylene glycol), ethers (such as diethyl or diisopropyl ether, tetrahydrofuran, Dioxane), aliphatic (such as petroleum ether, llexane) or aromatic (such as benzene, toluene, Xylene) hydrocarbons, halogenated hydrocarbons (such as Chloroferm, chlorobenzene), Nitriles (such as acetonitrile), amides (such as dimethylformamide, dimethylacetamide), sulfoxides (such as dimethyl sulfoxide) or mixtures of these solvents. One cyclizes in the Usually at temperatures between 0 and 300 °, preferably between room and boiling temperature of the solvent used, which can be obtained by applying pressure (up to 200 a :) if desired, can increase. The selection of the catalyst depends on the Type of connection to be split off HZ. In the case of Z = halogen, basic catalysts are used preferred, e.g. inorganic (alkali metal or alkaline earth metal hydroxides, carbonates or alcoholates) or organic (e.g. tertiary bases such as triethylamine, pyridine, Picoline, quinoline) bases. For Z = OH, alkoxy, acyloxy, alkyl or arylsulfonyloxy In contrast, acidic catalysts, e.g. inorganic acids (such as sulfuric acid, Polyphosphoric acid, hydrofluoric acid, hydrochloric acid) and / or organic Acids (such as formic, acetic, propionic or p-toluenesulfonic acid), which are in excess can also serve as a solvent at the same time; in the flail are for cyclization these substances require more vigorous conditions. Compounds of formula IV (e.g. = NH2) split off ammonia when heated, e.g. when melting, whereby the desired Compounds of the formula I arise.

A preferred procedure is to use the compounds of the formula IV not to isolate them, but to put them in statu nascendi in presence or absence an additional solvent (e.g. from VI and VII) and to cyclize directly to compounds of formula I. Using a Catalyst, e.g. a base such as 01l, KOll, sodium or potassium carbonate is possible, but not absolutely necessary.

It is also possible to use an excess of the amino compound VII instead to use the base.

The implementation of compounds of the formula is particularly advantageous VI (both radicals Z = Br) with VII in a boiling alcohol in the presence of potassium carbonate, where compounds of the formula IV (X = Br) are formed as intermediates, which in cyclized in situ. Under these conditions the reaction is about 1 - Finished £ 2 hours.

If desired, unreacted primary (formula VI) or secondary (formula IV) amino compounds before further work-up by acylation, e.g. by treatment with acetic anhydride, converted into non-basic compounds will.

Compounds of the formula I are furthermore described in the literature Methods by solvolysis (preferably hydrolysis), thermolysis, esterification or Transesterification of compounds of formula V available. In these, W means in particular one of the following radicals (in which 1t5 and R6 e.g. each alkyl with 1 - 4 carbon atoms, preferably methyl or ethyl, and these radicals are identical or different and together also tetramethylene or pentamethylene, optionally interrupted through 0, can be): COOH; CHal3 (where Hal is C1, Dr or J); COHal; COOR5; C (OR5) 3; COOAcyl. (- where acyl is the residue of a carbonic acid with up to 25 carbon atoms, preferably denotes the radical R³- (p-C6H4) -OCHH2-CO-); CN; CONH2; CONHR5; CONR5R6 CONHOH; C (OH) = NOH; CONHNH2; CON3; C (OR5) = NH; C (NH2) = NNH2; C (NHNH2) = NH; CSOH; COSH; CSOR5; CSNH2; CSNHR5 or CSNR5R6.

Compounds of the formula V are, for example, by reacting Pheuelen Formula II with acetic acid derivatives of the formula X-CHR² -W available.

A llydrolysis of compounds of the formula v (w = functionally modified COOH group), in particular of esters, amides, thioamides or nitriles, can be used in acidic or alkaline medium at temperatures between 20 and 300 °, preferably at the boiling point of the chosen solvent acidic catalysts see, for example, salt, sulfur, phosphorus or Hydrobromic acid; the basic catalysts used are appropriately sodium, Potassium or calcium hydroxide, sodium or potassium carbonate.

The preferred solvent is water; lower alcohols such as methanol, ethanol; Ethers such as tetrahydrofuran, dioxane; Amides such as dimethylformamide; Nitriles such as acetonitrile; Sulfones such as tetramethylene sulfone; or their mixtures, especially the mixtures containing water. However, the acid derivatives can also be used, for example, in Ether or benzene with the addition of strong bases such as potassium carbonate or without solvents by fusing with alkalis such as KOH and / or NaO11 or alkaline earths to form carboxylic acids of formula I (R¹ = 11) saponify.

By dry heating of, in particular, tertiary alkyl esters of Formula V (W = COO-tert-alkyl) at temperatures between 50 and 350 ° is obtained Acids of formula I (R¹ = H). Thermolysis can also be carried out in inert solvents carry out.

Esters of the formula I (R¹ = alkyl with 1 - 4 carbon atoms) can according to in methods described in the literature.

So you can, for example, an acid of the formula I (R¹ = H) with to the relevant alcohol of the formula R¹ OH (where R¹ is alkyl with 1 - 4 carbon atoms) in the presence of an inorganic or organic acid such as HCl, HBr, HJ, H2SO4, H3PO4, trifluoroacetic acid, benzenesulfonic acid or p-toluenesulfonic acid, or one acidic ion exchanger, optionally in the presence of an inert solvent, such as benzene, toluene or xylene, at temperatures between 0 and preferably Convert boiling temperature. The alcohol is preferably used in excess It can tor of the formula 1 @@ 1 = alkyl with i - 4 carbon atoms) also by addition of the Carbene acids I (R¹ = H) to olefins (e.g. isobtitylene) can also be used you can prepare esters of the formula I (111 = alkyl with 1 - 4 carbon atoms) by per se known conversion of metal acids of acids I (R¹ = H), preferably the alkali metal, Lead or silver salts, with alkyl halides of the formula R¹Hal (where R¹ is alkyl with 1 - 4 carbon atoms), or with alkyl chlorosulfites, e.g. those of the formula R¹ OSOCl (in which R¹ is alkyl having 1-4 carbon atoms) and thermolysis of the obtained Adducts.

Acid halides, anhydrides or nitriles of the formula V can also be used (1Y = OOHal, OOOAcyl or CN) by a reaction known per se with an alcohol of the formula R¹OH (R¹ = alkyl with 1-4 carbon atoms), optionally in the presence of one acidic catalyst or a base in ester of the formula I (R¹ = alkyl with i - 4 C atoms). Preferably one uses an excess of the relevant Alcohol and works at temperatures between 0 and boiling point.

Finally, one can use ester of the formula I (R = alkyl X carbon atoms) obtained transesterification methods described in the literature, in particular by reaction all of these esters of the formula V (W = COOR7; R7 = any organic radical, preferably Alkyl with 1 - d C-htones) with an excess of the alcohol in question or through Conversion of the Carbousäaren I (it '= 11) with any other esters of the relevant Alcohols (preferably alkanoates in which the alkanoyl radical has up to 4 carbon atoms), especially in the presence of basic or acidic catalysts, e.g. sodium ethylate or sulfuric acid, and at temperatures between 0 ° and preferably boiling point rature.

Furthermore, you can use esters of the formula I (R = alkyl with 1 - 4 carbon atoms) obtained by adding compounds of the formula V, wherein W is a thioester, imino ether, Oximinoether, bydrazone 2ether, thioamide, amidine, amidoxime or amidhydrazone group means with dilute aqueous bases or acids with the addition of the relevant Alcohol of the formula lLiOlI (R = alkyl with 1 - 4 carbon atoms) and elimination of sulfuric water, Ammonia, amines, hydrazine derivatives or hydroxylamine solvolyzed according to the usual mathodes.

A compound of the formula I which has a basic nitrogen atom can be converted with an acid into the associated acid addition salt. For this Acids that provide physiologically harmless salts are suitable for implementation. Organic and inorganic acids such as aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carbon or Sulfonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, Oxalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, Maleic acid, Lactic acid, tartaric acid, malic acid, amine carboxylic acids, sulfamic acid, benzoic acid, Salieylic acid, phenylpropionic acid, citric acid, glycenic acid, aseorbic acid, nicotinic acid, Isonicotinic acid, methane sulfonic acid, ethanedisulfonic acid, ß-hydroxyethanesulfeaic acid, p-Tolnolsulfenic acid, naphthalenemone and disulfonic acids, sulfuric acid, nitric acid, Hydrohalic acids such as hydrochloric acid or hydrobromic acid, or Phosphoric acids such as orthophosphoric acid.

On the other hand, the compounds of formula I (R¹ = H) by reaction with a base in one of their physiologically harmless metal or ammonium salts be transferred. Sodium in particular come as salts. Potassium, magnesium, Cakleiam and ammenium salts into consideration, further substituted ammonium salts, such as e.g. the dimethyl, diethyl and diisopropylammonium, monoethanol, diethanol and triethanolammonium cyclohexylammonium, dicyclahexylammonium and dibenzylethylenediammonium salts.

Conversely, compounds of formula 1 can be added from their acid salts by treatment with strong bases or from their metal and ammonium aces Treatment with acids set free, The compounds of formula I contain at least one center of asymmetry and are usually racemic Shape before.

The racemates can be made using known methods such as those in the literature are to be separated into their optical antipodes.

Furthermore, it is of course possible to use optically active connections to obtain the described method by using the starting materials that are already optically active.

The compounds of the formula I and / or, if appropriate, their physiological Incredible salts can be mixed with solid, liquid and / or semi-liquid Drug carriers used as drugs in human or veterinary medicine will. Organoscopic or inorganic substances are used as carrier substances in prage, which are suitable for parenteral, enteral or topical application and which do not react with the new compounds, such as Water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, lactose, Starch, magnesium stearate, Telk, Vaseline, cholesterol, for parcntera len application In particular, solutions, preferably liquid or aqueous solutions, serve as well Suspensions, emulsions or implants. Suitable for neteral application Tablets, dragees, capsules, sirape, juices or suppositerion, for the 'topical' Use ointments, creams or powders The specified preparations can optionally be sterilized or auxiliary substances, such as lubricants, preservatives, stabilizers or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, Contain color, flavor and / or aroma substances.

The substances are preferably used in dosages between 10 and 1000 mg administered per dosage unit.

Example 1 a) 2.3 g of sodium are dissolved in 100 ml of absolute ethanol, adds 17.7 g of 4-piperidinophenol (1-p-hydroxyphenyl-piperidine), adds 24.3 g in drops Add α-bromo-phenylacetic acid ethyl ester and boil the mixture for 10 hours. The reaction mixture is evaporated, the residue with water added and the aqueous solution extracted with ethyl acetate. The ethyl acetate solution is washed twice with dilute KOH and twice with water. One dries, the solvent evaporates and inherits α-phenyl-α-4-piperidinophenyoxy-acetic acid ethyl ester. Hydrochloride, m.p. 149-151 °.

Instead of the α-bromo-phenylacetic acid-ethyloster one can also ethyl α-chloro-phenylacetate or ethyl α-iodo-phenylacetate use.

4- (1,2,3,4-tetrahydroquinolino) pheaol is obtained analogously from 4-isoindolinophenol 4- (1,2,3,4-Tetrahydro-2-quinolyl) phenal 4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) phenol 4- (4-piperidinophenyl) phenol 4- (4-piperidinophenoxy) phenol 4- (1-pyrryl) phenol with ethyl α-bromophenyl acetate: α-phenyl-α-4-isoindolinophenoxy-acetic acid monster F. 712 ° α-Phenyl-α4- (1,2,3,4-tetrahydroquinolino) -phenoxyacetic acid ethyl ester, . 96-980 α-Phenyl-α-1- (1,2,3,4-tetrahydro-4-quinolyl) -phenoxyacetic acid ethyl ester α-Phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid ethyl ester Oil # # 1.5950 α-Phenyl-α-4- (4-piperidinophenyl) -phenoxy-acetic acid ethyl ester, F. 126-1280 α-Phenyl-α-4- (4-piperidinophenoxy) -phenoxy-acetic acid ethyl ester a-Phenyl-a-4- (i-pyrryl) -phenoxy-acetic acid ethyl ester.

With ethyl 2-chloropropionate, α-bromo-α- (o-chlorophenyl) -acetic acid ethyl ester is obtained analogously, α-Bromo-α- (m-chlorophenyl) -acetic acid ethyl ester or α-bromo-α- (p-chlorophenyl) -acetic acid ethyl ester: α-4-Piperidinophenoxy-propionic acid ethyl ester α-4-Isoindolinophenoxy-propionic acid ethyl ester α-4- (1,2,3,4-Tetrahydroquinolino) -phenoxy-propionic acid ethyl ester α-4- (1,2,3,4-Tetrahydro-4-quinolyl) -phenoxy-propionic acid ethyl ester α-4- (1,2,3,4-Tetrahydro-4-quinolyl) -phenoxypropionic acid ethyl ester α-4- (4-piperidinophenyl) -phenoxy-propionic acid ethyl ester α-4- (4-piperidinophenoxy) -phenoxy-propionic acid ethyl ester α-4- (1-pyrryl) -phenoxy-propionic acid ethyl ester α-o-Chlorophenyl-α-4-piperidinophenoxy-acetic acid ethyl ester α-o-chlorophenyl-α-4-isoindolinophenoxy-acetic acid ethyl ester ethyl alpha-o-chlorophenyl-alpha-4- (1,2,3,4-tetrahydroquinolino) phenoxyacetate Ethyl α-o-chlorophenyl-α-4- (1,2,3,4-tetrahydro-4-quinolyl) phenoxyacetate α-o-Chlorophenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid ethyl ester α-o-Chlorophenyl-α-4- (4-piperidinophenyl) -phenoxy-acetic acid ethyl ester α-o-Chlorophenyl-α-4- (4-piperidinophenoxy) -phenoxy-acetic acid ethyl ester α-o-Chlorophenyl-α-4- (1-pyrryl) -phenoxy-acetic acid ethyl ester α-m-chlorophenyl-α-4-piperidinophenoxy-acetic acid ethyl ester, Hydrochloride, m.p. 149-151 ° α-m-Chlorophenyl-α-4-isoindolinophenoxy-acetic acid ethyl ester α-m-Chloromphenyl-α-4- (1,2,3,4-tetrahydroquinoline) -phenoxyacetic acid ethyl ester α-m-Chloromphenyl-α-4- (1,2,3,4-tetrahydroquinoline) -phenoxyacetic acid ethyl ester α-m-Chlorophenyl-α-4- (1-methyl-1,2,3,4-tetrahydro4-quinolyl) phenoxy-acetic acid ethyl ester α-m-chlorophenyl-α-4- (4-piperidinophenyl) -phenoxy-acetic acid ethyl ester, F. 96-97 ° α-m-Chlorophenyl-α-4- (4-piperidinophenyl) -phenoxy-acetic acid ethyl ester α-m-Chlorpenyl-α-4- (1-pyrryl) -phenoxy-acetic acid ethyl ester α-p-chlorophenyl-α-4-piperdinophenoxy-acetic acid ethyl ester α-p-Chlorophenyl-α-4-iseindolinophenoxy-acetic acid ethyl ester α-p-Chlorophenyl-α-4- (1,2,3,4-tetrahydroquinolino) -phenoxyacetic acid ethyl ester Oil # 1.6129 α-p-Chlorophenyl-α-4- (1,2,3,4-tetrahydro-4-quinolyl) -phenoxyacetic acid ethyl ester α-p-Chlorophenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid ethyl ester α-p-Chlorophenyl-α-4- (4-piperdinophenyl) -phenoxy-acetic acid ethyl ester, M.p. 122 ° α-p-Chlorophenyl-α-4- (4-piperdinophenoxy-phenoxy-acetic acid ethyl ester α-p-Chlorophenyl-α-4- (1-pyrryl) -phenoxy) -acetic acid ethyl ester, m.p. 1090.

b) 3.39 g of α-phenyl-α-4-pieoeridinophenoxy-acetic acid ethyl ester are boiled with 3 g of KOH in 30 ml of ethanol for 2 hours. It is evaporated, added with water, extracted with Acther and hydrochloric acid to pH 4 is added. The received α-Phenyl-α-4-piperidinophenoxy-acetic acid is filtered off with suction.

Analogously, saponification of the corresponding ethyl esters gives: α-phenyl-α-4-isoindolinophenoxy-acetic acid α-Phenyl-α-4- (1,2,3,4-tetrahydroquinolino) -phenoxy-acetic acid α-Phenyl-α-4- (1,2,3,4-tetrahydro-4-quinolyl) -phenoxyacetic acid.

α-Phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid, diisopropylamine salt, m.p. 165-168 ° α-phenyl-α-4- (4 -piperidinophenyl) -phenoxy-acetic acid α-phenyl-α-4- (4-piperidinophenoxy) -phenoxy-acetic acid α-phenyl-α-4- (1-pyrryl) -phenoxy-acetic acid α-4-piperidinophenoxy-propionic acid α- 4-Isoindolinophenoxy-propionic acid α-4- (1,2,3,4-tetrahydroquinolino) -phenoxy-propionic acid.

α-4- (1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-propionic acid.

α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxypropionic acid, cyclohexylamine salt, m.p. 203-205 ° α-4- (4-piperidinophenyl) -phenox-propionic acid, m.p. 215 ° α-4- (4-piperidinophenoxy) -phenoxy-propionic acid, m.p. 160-162 ° α-4- (1-pyrryl) -phenoxy-propionic acid α-o-chlorophenyl-α-4-piperidinophenoxy-acetic acid α- o-Chlorophenyl-α-4-isoindolinophenoxy-acetic acid α-o-chlorophenyl-α-4- (1,2,3,4-tetrahydroquinolino) -phenoxyacetic acid α-o-chlorophenyl-α-4- (1,2,3 , 4-tetrahydro-4-quinolyl) -phenoxyacetic acid α-o-chlorophenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid α-o-chlorophenyl α-4- (4-piperidinophenyl) -phenoxy-acetic acid α-o-chlorophenyl-α-4- (4-piperidinophenoxy) -phenoxy-acetic acid α-o-chlorophenyl-α-4- (1-pyrryl) -phenoxy- acetic acid α-m-chlorophenyl-α-4-piperidinophenoxy-acetic acid, 1. 185-190 ° α-m-chlorophenyl-α-4-isoindolinophenoxy-acetic acid, α-m-chlorophenyl-α-4- (1,2,3 , 4-tetrahydroquinolino) -phenoxyacetic acid α-m -chlorophenyl-α-4- (1,2,3,4-tetrahydro-4-quinolyl) -phenoxyacetic acid α-m -chlorophenyl-α-4- (1-methyl-1 , 2,3,4-tetrahydro-4-quinolyl) -phenexy-acetic acid α-m-chlorophenyl-α-4- (4-piperidinophenyl) -phenoxy-acetic acid α-m-chlorophenyl-α-4- (4-diperidinophenoxy ) -phenoxy-acetic acid α-m-chlorophenyl-α-4- (1-pyrryl) -phenoxy-acetic acid α-p-chlorophonyl-α-4-piperidinophenoxy-acetic acid, mp 173-175 ° α-p-chlorophonyl- α-4-isoindolinopheuoxy-acetic acid α-p-chlorophonyl-α-4- (1,2,3,4-tetrahydroquinolino) -phonoxyacetic acid, diisopropylamine salt, mp 155-158 ° α-p-chlorophonyl-α-4- ( 1,2,3,4-tetrahydro-4-quinolyl) -phenoxyacetic acid α-p-chlorophonyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid, Diisopropylamine salt, m.p. 174-181 ° α-p -chlorophonyl-α-4- (4-piperidinophenyl) -phenoxy-acetic acid α-p-Chlorphonyl-α-4- (4-piperidinophenoxy) -phenoxy-acetic acid ap-Clilorphenyl-α-4- (1 -pyrry 1) -phenoxy-esetic acid.

Example 2 22.5 g of 4- (1,2,3,4-tetrahydroquinolino) phenol are ground added to a suspension of 2.4 g of Moll in 200 ml of dimethylacetamide.

The mixture is stirred for one hour at room temperature, and after adding 27, 75 g of α-bromo-α-p-chlorophenylacetic acid ethyl ester for 20 hours at 90 °, cools, mixed with water and extracted with Acther.

The ether solution is washed twice with 2N NaOH and evaporated after drying. Α-p-Chlorophenyl-α-4- (1,2,3,4-tetrahydroquinolino) -phenoxy-acetic acid ethyll ester is obtained. Free acid, diisopropylamine salt, mp 155-158 °.

Example 3 A mixture of 2.25 g. 4- (1,2,3,4-tetrahydroquinolino) phenol and 0.23 g of sodium in 50 itil xylene is cooked for 3 hours. } .n lets cool down to 20 °, add 2.78 g of α-bromo-α-chlorophenyl acetic acid ethyl ester i 10 ml of xylel, the suspension is stirred for 6 hours at the boiling point, cooled and treated with nit 2 ml of ethanol. The inorganic precipitate is filtered off, the filtrate is evaporated, the residue taken up in Acther, the solution with NaHCO3 solution and saturated Washed NaCl solution, dried over MgSO4 and evaporated. Α-p-Chlorophenyl-α-1- (1,2,3,4-tetrahydroquinolino) -phenoxy-acetic acid ethyl ester is obtained.

Analogously, the plienols mentioned in Example 1 are obtained by Reaction with a-bromophenyl acetic acid, a-bromopropionic acid, α-bromo-α-o-chlorophenyl-acetic acid, α-bromo-α-m-chlorophenylacetic acid and α-bromo-α-chlorophenylacetic acid-methyl-, -pro pyl-, -isopropyl-, -n-butyl-, -isobutyl-, -sec.-butyl- or -tert. butyl ester the corresponding esters of the acids given in Example ib), for example α-phenyl-α-4- (1,2,3,4-tetrahydroquinolino) phenoxy Acetic acid methyl ester, n-propyl ester, -isepropyl ester, -n-butyl ester, -isobutyl ester, -sck, -butyloster and -tert.-butyl ester.

Example 4 A solution of 27.75 g of α-bromo-α-p-chlorophenyl-acetic acid ethyl ester in 50 ml of acetone is slowly added to a stirred mixture of 25.3 g of 4- (4-piperidinophenyl) phenol, 13.8 g of K2CO3 and 80 ml of acetone were added. Cook for 12 hours while stirring, filter, evaporates, and receives α-p-chlorophenyl-α-4- (4-piperidinophenyl) phebnoxy-acetic acid ethyl ester, 122 ° F.

Example 5 To a mixture of 2ã, 3 g of z 4-piperidinophenyl) -phesol and 21.45 g of ethyl α-m-chlorophenyl glycolate become 16 g of sulfuric acid added and the reactin mixture stirred at 50-600 for 2 hours. After cooling water is added to dilute NaOLI up to pH 8 and the aqueous phase extracted with ether. It is dried, dumped and obtained α-m-chlorophenyl-α-4- (piperidinophenyl) -phenoxyacetic acid ethyl ester, F. 06 - 97 °.

Example 6 a) 23.9 g of 4- (1-methyl-1,2,3,4-tetrhydro-4-quinolyl) phenol are dissolved in 200 μl of acetone. 4 g of NaCH are added with stirring and then with stirring and boiling dropwise 21.5 g of α-bromo-phenylacetic acid (or 17.05 g of a-ohior-phenylacetic acid) in 60 ml of acetone are added, the mixture is stirred for a further hour at 56 ° and left to stand for 24 hours. The acetone is distilled off, the residue is dissolved in 1 liter of water and the solution is repeated several times washed with ether and acidified to pH 4 with HCl.

Α-Phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid is obtained. Diisopropylamine salt, m.p. 165-168 °.

The phenols mentioned in Example 1a) are obtained analogously acids specified in Example 1b).

b) I g of α-phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -pheno = xy-acetic acid are dissolved in 20 ml of ether and added dropwise with ethereal diazomethane solution up to for permanent yellowing. After evaporation, methyl α-phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) phenoxyacetate is obtained.

c) 5 g of α-phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid are dissolved in 200ml of saturated ethanolic hydrochloric acid, left for 12 hours at room temperature etchen, boil for 2 hours and evaporate. The residue is dissolved in the water aqueous solution adjusted to pH 8 with n NaO and extracted with ethyl acetate. It is dried, evaporated and obtained α-phenyl-α-1- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenexy-acetic acid-ethyl ester.

The acids given in Example 1b) are obtained analogously ethanolic hydrochloric acid, the corresponding ethyl ester mentioned in Belspiel 1a).

Example 7 30si g of ethyl α-4- (4-aminophenexy) phenoxy-propionate (obtainable by reacting 4- (4-nitrophenoxy) phenol with ethyl 2-chloropropionate to α-4- (4-nitrophenoxy) phenoxyprepionic acid ethyl ester and subsequent reduction of the nitro group), 34.5 g of 1,5-dibromopentate and 27 g of I (2C03 are dissolved in 100 ml of n-butanol Cooked for 24 hours while stirring. Then it is suctioned off, the solvent is distilled off, the residue is mixed with water and extracted with chloroform. The extract will dried and evaporated. Ethyl α-4- (piperidinophenoxy) phenoxypropionate is obtained. Free acid, m.p. 160 - 1620.

Analogously, from α-phenyl-α-4-aminophenoxy-acetic acid, α-4-aminophenoxy-propionic acid, a-0-, a-m- or a-p-chlorophenyl-α-4-aminophenoxy-acetic acid, α-Phenyl-α-4- (4-aminophenyl) -phenoxy-acetic acid, α-4- (4-aminophenyl) -pyenoxy-propionic acid, α-o-, α-m- or α-p-chlorophenyl-α-4- (4-aminophenyl) -phenoxyacetic acid, W-phenyl-a-4- (4-aminophenoxy) -phenoxy-acetic acid, α-4 - (- 4-aminophenoxy) -phenoxy-propionic acid, α-o-, α-m- or α-p-chlorophenyl-α-4- (4-aminophenoxy) -phenoxy-acetic acid respectively.

from the methyl, ethyl, α-propyl, isoprupyl, α-butyl, Isebutyl, sec-butyl or tert-butyl esters of these acids by reaction with 1,5-dibromopeatane or o-xylych bromide, the corresponding piperidino or isoindolino compounds.

Example 8 A mixture of 23.7 g of 2- (1-aminophenoxy) propionic acid isobutyl ester, 23 g of 1,5-dibromopeniane, 14 g of Na2CO3 and 100 ml of aectenitrile are stirred for 48 hours cooked. It is filtered and evaporated, and the residue is taken up in dilute hydrochloric acid on, washed with ether, made alkaline with dilute sodium hydroxide solution, extracted with ether, dry, evaporate and obtain 2- (4-piperidinophenoxy) propionic acid isobutyl ester.

Example 4 34.7 g of α-phenyl-α-4- (4-aminophenyl) -phenoxy-acetic ethyl esters are powdered in 350 ml of n-butanol together with 23 g of 1,5-dibromopentane and 15 g K2C03 cooked for i5 hours. It is cooled, filtered, the butanol is distilled off and dissolved the residue in 150 ml of benzene and boiled for 2 hours with 10 ml of acetic anhydride.

The reaction mixture is cooled, washed with 1N NaOll and washed with 20% HC1 extracted. The aqueous hydrochloric acid solution is made alkaline with Ether extracted, the ether phase washed neutral with water, dried and evaporated. A-phenyl-a-4- (4-piperidinophenyl) -phenoxy-acetic acid ethyl ester, mp 126, is obtained - 1280.

Example 10 2 g of α-phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetentrile (obtainable from 4- (methyl-1,2,3,4-tetrahydroe-4-quinolyl) -phenol and α-bromo-α-phenyl-acetonitrile) are boiled with 2 g of KOH in 20 ml of ethanol and 2 ml of water for 40 hours. One steams a, mixed with water, extracted with ether, added hydrochloric acid to pH 5 and receives a-phenyl - 4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid, Diisopropylamine salt. 165-168 ° F.

Alkaline hydrolysis of the nitrogenous nitriles is obtained in an analogous manner the carboxylic acids listed in Example 1b).

Example 11 10 g of α-chlorophenyl-α-4- (1,2,3,4-tetrahydroquinolino) phenoxyacetonitrile are treated with 60 ml of acetic acid and 60 ml of Ron-centered hydrochloric acid for 2 hours under nitrogen cooked. It is evaporated, dissolved in dilute NaOH, extracted with ether, and hydrochloric acid is added to pll 5 and receives α-p-chlorophenyl-α-4- (1,2,3,4-tetrahydroquinoline) -phenyoxyacetic acid, Diisopropylmain Salt, m.p. 155-158.

In an analogous manner, the corresponding nitriles are obtained by acid hydrolysis in Example 1b) mentioned carboxylic acids.

Example 12 3 g of α-phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) phenoxy-acetamide (obtainable from 4- (1-methyl-1,2,3,4-totrahydro-4-quinolyl) -phenol and a-bromo-phenylacetamide) and 5 g of KOH are in 100 ml of ethanol boiled under nitrogen for 3 hours.

It is evaporated, water is added, the mixture is extracted with ether and hydrochloric acid is added up to pH 4 and receives α-phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid, Diisopropyl amine salt, m.p. 165-168 °.

The corresponding amides are obtained analogously by alkaline hydrolysis the carboxylic acids mentioned in Example 1 b).

Example 13 10 g of α-p-Chlorophenyl-α-4- (1,2,3,4-tetrahydro-quinolino) -phenoxy Acetyl chloride (obtainable from the acid and SOCl2) are mixed with 100 ml of absolute n-propanol 3 hours heated to 95 °. It is evaporated, the residue is mixed with dilute Sodium hydroxide solution and extracted the aqueous solution with ether. The ethereal will Washed twice with dilute NaOlI and twice with water, dry and evaporate the ether off and receives α-p-chlorophenyl-α-4- (1,2,3,4-tetrahydroquinolino) -phenoxy-acetic acid-n-propyl ester.

Analogously, alcoholysis of the acid chlorides of the formula V is obtained (W = COCl) the corresponding ester.

Example 15 9 g of a-p-Chlorophellyl-a-4 ^ (i, 2,3,4-tetrahydro-quinolino) -pherloxyacetyl chloride are dissolved in 100 ml of absolute tetrahydrofuran and mixed with 3 g of potassium tert-butoxide offset. The mixture is stirred for 30 minutes at room temperature, filtered off with suction and the "Filtra.t" is evaporated a, works up as described in Example 14 and uric acid-tert-butyl 4- (1,2,3,4-tetrahydroquinolino) -phenoxy-acetic acid-tert-butyl ester.

Claims (1)

P a t e n t a n s p r ü c h e 1. Phenoxyacetic acid derivatives of the general formula I. wherein R¹ II or alkyl having 1-4 carbon atoms, R 2 is methyl, phenyl or chlorophenyl, R 3 is piperidino, isoindolino, 1,2,3,4-tetrahydroquinolino, 1-R4-1,2,3,4-tetrahydro-4 -quinolyl, 4-piperidinophenyl, 4-piperidinophenoxy or i-pyrryl and R4 denote H or alkyl with 1-4 carbon atoms and their physiologically acceptable salts. 2. Compounds of the general form Ia to Ie (in which R¹, R² and R4 have the meaning given in claim 1) @ 3. α-Phenyl-α-4-piperidinophenoxy-acetic acid ethyl ester. 4. α-Phenyl-α-4- (1,2,3,4-tetrahydroquinolino) -phenoxy-acetic acid. 5. α-Phenyl-α-4- (1,2,3,4-tetrahydroquinolino) -phenoxy-acetic acid ethyl ester. 6. α-Phenyl-α-4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy-acetic acid. 7. α-Phenyl-α-4- (4-piperidinophenyl) -phenoxy-acetic acid ethyl ester. 8. α-4- (4-Methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxypropionic acid. 9. α-4- (4-piperidinophenyl) phenoxy propionic acid. 10. α-4- (4-piperidinophenoxy) phenoxy propionic acid. 11. α-m-Chlorophenyl-α-4-piperidinophenoxy-acetic acid. 12. α-m-Chlorophenyl-α-4-piperidinophenoxy-acetic acid ethyl ester. 13. α-m-Chlorophenyl-α- (4-piperidinophenyl) -phenoxy-acetic acid ethyl ester. 14. α-p-Chlorophenyl-α-4-piperidinophenoxy-acetic acid. 15. α-p-Chlorophenyl-α-4- (1,2,3,4-tetrahydroquinolino) -phenoxy-acetic acid. 16. α-p-Chlorophenyl-α-4- (1-methyl-1,2,3-4-tetrahydro-4-quinolyl) -phenoxy-acetic acid. 17. α-p-Chlorophenyl-α-4- (4-piperidinophenyl) -phenoxy-acetic acid ethyl ester. 18. α-p-Chlorophenyl-α-4- (4-piperidinophenoxy) -phenoxy-acetic acid. 19. α-p-Chlorophenyl-α-4- (1-pyrryl) -phenoxy-acetic acid ethyl ester. 20. A process for the preparation of preliminary compounds of the general formula I and their physiologically acceptable salts 1, characterized in that a phenol of the general formula II wherein R3 has the meaning given in claim 1, with a compound of the general formula III X-CHR²-COOR¹ in which III X is free or esterified OH, C1, Br or J and R¹ and lt2 have the meaning given in claim 1, reacts or that a compound of the general formula IV ntamethylene or o-xylylene, Z is Cl, Br, I, NH2 or an optionally esterified or etherified OH group, A is p-C6H4- or p-C6H4-O- and n is O or 1 and R¹ and R² have the meanings given cyclizing agents or that one in a compound of the general formula V in which W denotes an optionally functionally modified COOH group and R2 and R3 have the specified meaning, the REst W is dealing with solvolyzing, thermolysis. converting or ester-forming agents into the radical COOR¹ and that one optionally obtained a compound of the formula I by treatment with Acids or bases in their physiologically harmless acid addition or metal or. Ammoniumsazo converted and / or a compound of the formula I from one of its salts sets free by treatment with a base or acid. 21. Process for the production of pharmaceutical preparations, thereby characterized in that at least one compound of the general formula I, optionally together with at least one solid, liquid or semi-liquid auxiliary or carrier and optionally together with at least one other active ingredient into a suitable one Brings dosage form. 22. A pharmaceutical preparation containing an effective dose of a Compound of the formula I in addition to at least one solid liquid or semi-liquid Carrier or additive.