DE2163056A1 - CARBONIC ACID DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Merck patent limited liability company Darmstadt

December 14, 1971

Carboxylic acid derivatives and processes for their preparation

The invention relates to carboxylic acid derivatives of the general formula I.

wherein

Z and Z ² each 0 or S, R ¹ H or alkyl with 1-10 C atoms,

CR-COOR R ³ and R ⁴

H or COOR ⁷ ,

R ⁸ , R ⁸ -CH ₂ -, pR ³ -C ₆ H ₄ -,

3-hydroxypyrrolidino, 3-hy-

droxypiperidino, morpholino,

Isoindolino, 1,2,3,4-tetra

hydro-quinolino, 1-R -1,2,3,4-

tetrahydro-4-quinolyl,

1-R -4-piperidyl or

1-pyrryl,

each H

Carbon atoms or shark,

R ⁵ and R ^{6 are} each H, alkyl with 1-4

R ⁷ , R ⁹ and R ¹⁰ each have H or alkyl

1-10 carbon atoms,

Pyrrolidino, piperidino or

Homopiperidino and

Hal F, Cl, Br or J

mean,

and their physiologically harmless salts with acids or bases. (Hereinafter, Z ¹ , Z ² , R to R ° and Hai have the meaning given for formula I, unless something is expressly stated.

other is noticed).

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It has been found that these substances are well tolerated and have excellent cholesterol-lowering and triglyceride-lowering properties and have enzyme-inducing properties. They have an anti-arteriosclerotic effect. "

The compounds of the formula I and their physiologically harmless ones Salts can therefore be used as pharmaceuticals and also as intermediates for the production of other pharmaceuticals.

The subject of the invention are compounds of the formula I and their physiologically harmless salts,

The invention also relates to the preferred compounds

. fertilize the formula I, wherein the radicals Z and Z, R and R 'and

w 5 6

R and R are each the same (Formula Ia)

-COOR

Yes

and the preferred compounds of the formulas Ib to II below

-COOR

Ib

wherein

ο X a bond,

or p-C,> H. ~ means: 6 4

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HO.

(CH ₎

wherein

η is 1 or 2;

1 9 ι

~ "~ Z) ₂ = CR -CQOR ^X Ie

O ^ CR ^ COOR ¹ if

Ct

\ LV

Z ¹ ) -CR ² -COOR ¹ Ig

R "
\\ _{/ r} « ¹ ) ₂ -CB ² -C00R ¹

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R ^v

Il

and in particular compounds of the formulas I and Ia to II

wherein Z wherein R wherein R

O, and / or.

H, CH ₃ or C ₂ H ₅ , and / or

H, COOH, COOCH ₃ or COOC ₂ H_, and / or

5 wherein R is H, and / or

3 8 wherein R or R is piperidino

means.

The invention also relates to a process for the preparation of compounds of the general formula Γ and their physiologically harmless salts with acids or bases, the ι characterized in that a phenol or thiophenol of the formula II

R *

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with a compound of the formula III

wherein

III

X optionally esterified OH,

Cl, Br or J
means

converts or that a compound of the formula IV .5

- COOR

worxn Y tetramethylene, pentamethylene, hexamethylene, 2-hydroxy-tetrarethylene, 2-hydroxy-pentamethylene, 3-0xapentamethylene or o-xylylene,

X Cl, Br, _{I, NH 2} or an optionally esterified or etherified OH group and

X- a bond, -CH ₀ - or pC _c H -

mean

treated with cyclizing agents

or that in a compound of the formula V

where W

means an optionally functionally modified COOH group

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the remainder W by treatment with solvolysing, thermolysing or converting ester-forming agents to the residue COOR

or that a compound of the formula VI

wherein

X ³

H, Cl, Br, I, NH ₂ or SO ₃ M and one equivalent of a metal atom

VI

with a compound of the formula VII

B ³ -X ⁴

VII

wherein

X ⁴ H, M or X

means

3 4 with the proviso that the radicals X and X are not the same and one of these radicals is H or optionally M

and that optionally in a compound obtained the

2 2

Formula I converts the radical R into another radical R and / or a compound of the formula I obtained by treatment with acids or bases in their physiologically acceptable acid addition or metal or ammonium salts and / or a compound of the formula I from one of its salts Treating with a base or acid sets free.

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1 7 Q OK

In the above formulas, R, R, R and R are preferably H or alkyl with 1-4 carbon atoms, in particular methyl or ethyl, furthermore n-propyl, isopropyl, η-butyl, isobtttyl, sec-butyl, or tert-butyl. These radicals can also mean alkyl with up to 10 carbon atoms, e.g. n-pentyl, Isopentyl, n-hexyl, n-heptyl, n-octyl, isooetyl (2-ethyl-hexyl), n-nonyl or n-decyl.

5 6
R and R preferably denote H., also CHL or Cl; these radicals can also mean ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, fluorine, bromine or iodine.

X and X are preferably Cl or Br; In addition to free OH and J, these radicals can also include, for example, alkylsulfonyloxy with in particular 1-6 carbon atoms (for example methanesulfonyloxy), arylsulfonyloxy with in particular 6-10 carbon atoms (for example benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2-naphthalenesulfonyloxy) or Acyloxy with, in particular, 1-7 C atoms (eg acetoxy or benzoyloxy), X also _{denotes NH 2} or, for example, an etherified OH group with in particular 1-7 C atoms (eg methoxy, benzyloxy).

The compounds of the formula I are preferably prepared by reacting the compounds of the formula II with the compounds of the formula III obtain. Some of the phenols and thiophenols II are known. If they are new, they can be produced by known methods, e.g. by splitting their methyl ethers (corresponding to II, but Z CH "instead of Z H) with HBr. In the synthesis, the compounds III are expediently in situ by reaction a compound of the formula VIII

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VIII

2 1 obtained with a compound of the formula (X) ₂ CR-COOR (IX). To prepare compounds of the formula Ia, it is expedient to react 2 moles of II with 1 mole of IX, the intermediate product III

R ⁴ = * R ³ ; R ⁶ = R ⁵ ) is run through.

The reaction of II with III can be carried out by methods as described in the literature. For example, II can first be converted into a salt, in particular a metal salt, such as an alkali metal salt, for example a Li, Na or K salt. The salt formation can be achieved, for example, by reacting II with a metal salt-forming reagent, such as a Alkali metal (e.g. Na), an alkali metal hydride or amide (e.g. LiH or NaH, NaNH ₂ or KNHg), a lower alkali metal alcoholate (e.g. lithium, sodium or potassium methylate, ethylate or tert-butylate) _t one of a hydrocarbon derived organometallic compound (e.g. butyllithiura, phenyllithium or phenyl sodium), a metal hydroxide, carbonate or bicarbonate (e.g. LiOH, NaOH, KOH or Ca (OH) ₂ ; Li ₃ CO ₃ , Na ₃ CO ₃ or K ₂ CO ₃ ; NaHCO ₃ or KHCO ₃ ). The preparation of the salt of II is advantageously carried out in the presence of a solvent which is selected on the basis of its physicochemical properties, for example the solubility of the starting material or the reactivity of the metal compound. Suitable solvents are, for example, hydrocarbons (such as hexane, benzene, toluene or xylene), ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or diethylene glycol dimethyl ether), amides (e.g. dimethylformamide, dimethyl acetamide, diethyl acetamide, tetra-

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methylurea, hexamethylphosphoric acid triamide), alcohols (e.g. methanol or ethanol), ketones (e.g. acetone or butanone) or mixed solvents.

The phenol or thiophenol II or preferably a salt thereof is reacted with a compound of the formula III, preferably in the presence of a diluent, e.g. Solvent used for making the salt which, however, can be replaced by another solvent or diluted with such a solvent. The implementation will usually carried out at temperatures between -20 and 150 °, preferably between 20 and 120, particularly expedient at the boiling point of the solvent, it can be carried out under an inert gas such as nitrogen; However the presence of such is not required.

The formation of the metal salt of II can also be carried out in situ will; in this case, II and III are left together in the presence of a salt-forming reagent or another suitable base react.

A particularly preferred method consists in boiling the compounds II and III (X = Cl or Br, R = CH ₃ or C ₃ H ₅ ) together with an alcoholic (eg, ethanol) sodium alcoholate solution for several hours.

It is also possible to use a free phenol (or thiophenol II with a hydroxy acid derivative of the formula III (X = OH), preferably in the presence of a condensing agent to implement. Suitable condensing agents are, for example, acidic dehydration catalysts, e.g. mineral acids such as sulfuric acid or phosphoric acid, also p-toluenesulfonyl chloride, arsenic acid,

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Boric acid, NaHSO ₄ or KIISO ₄ , also disubstituted carbonic acid esters, such as diaryl carbonates (25, B ₀ diphenyl carbonate) or in particular dialkyl carbonates (e.g. dimethyl or diethyl carbonate) or carbodiimides (25.B. dicyclohexylcarbodiimide). If an acid is used as the condensing agent, the reaction is expediently carried out in an excess of this acid without the addition of a further solvent at temperatures between 0 and 100, preferably 50 and 60. However, it is also possible to add diluents, for example benzene, toluene or dioxane. A carbonate is preferably used at a higher temperature, expediently between 100 and about 210 °, in particular between 180 and 200 °, it being possible, if desired, to add a transesterification catalyst such as sodium or potassium carbonate or an alcoholate (eg sodium methylate).

Compounds of the formula IV can be described in the literature Methods to give compounds of formula I are cyclized, e.g. by heating in the presence or absence a solvent, optionally in the presence of an acidic or basic catalyst.

Compounds of the formula IV can be obtained, for example, by reacting a compound of the formula X.

wherein
Y and X ¹

the two groups X

have the meanings given above, but are identical or different and together can also mean 0 or NH,

with a compound of the formula XI

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CR ² -COOR ¹

XI

Compounds of the formula X are preferably those with the same groups X, for example, 1,4-dichloro _r, 1,4-dibromo- and 1,4-diiodobutane, 1,5-dichloro-, 1,5-dibromo- and 1, 5-diiodopentane, 1,6-dichloro-, 1,6-dibromo- and 1,6-diiodohexane, 1,4-dichloro-, 1,4-dibromo- and 1,4-diiodo-2-butanol, 1, 5-dichloro-, 1,5-dibromo- and l, 5-diiodo-2-pentanol, 2,2'-dichloro-, 2,2'-dibromo and 2,2 * -di3Oddiethylether, o-xylylene chloride, o -Xylylene bromide, o-xylylene iodide, phthalyl alcohol (o-hydroxymethylbenzyl alcohol) and its reactive esters, for example its bis-methanesulphonate or bis-p-toluenesulphonate, o-xylylenediamine, phthalane (isocumaran). Isoindoline, pyrrolidine, piperidine, homopiperidine, 2-hydroxypyrrolidine, 2-hydroxypiperidine, morpholine or 1,2,3,4-tetrahydroiso-

chxnolin.

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 ethers, tetrahydrofuran, Dioxane), aliphatic (such as petroleum ether, hexane) or aromatic (such as benzene, toluene, xylene) hydrocarbons, halogenated Hydrocarbons (such as chloroform, chlorobenzene), nitriles (such as acetonitrile), amides (such as dimethylformamide, dimethyl acetamide,

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Hexamethylphosphorsäuretriamid), sulfoxides (such as dimethyl sulfoxide) or mixtures of these solvents, one cyclizes usually at temperatures between 0 and 300, preferably between room and boiling temperature of the solvent used, which can be increased by applying pressure (up to 200 at) if desired can. The selection of the catalyst depends on the type of compound HX to be split off. In the case of X »halogen, basic catalysts are preferred, for example inorganic (alkali metal or alkaline earth metal hydroxides, carbonates or alcoholates such as NaOH, KOH, LiOH, Ba (OH) ₂ , Ca (OH) ₂ , Na ₂ CO ₃ , K ₃ CO ₃ , Li ₂ CO _3. , NaCO ₃ , KOCH ₃ , NaOC ₃ H ₅ , KOC ₂ H ₅ , K-tert, -butylate) or organic (e.g. tertiary bases such as triethylamine, pyridine, picolines, quinoline) bases. For X = OH, alkoxy, acyloxy, alkyl or arylsulfonyloxy, on the other hand, acidic catalysts are recommended, e.g. inorganic acids (such as sulfuric acid, polyphosphoric acid, hydrobromic acid, hydrochloric acid) and / or organic acids (such as formic, acetic, propionic or p- Toluenesulfonic acid), which in excess can also serve as a solvent at the same time; as a rule, stronger conditions are required for the cyclization of these substances. Compounds of the formula IV (X = »NH ₃ ) split off ammonia on heating, for example on melting, giving the desired compounds of the formula I.

A preferred mode of operation is not to isolate the compounds of the formula IV and XI, but rather to isolate them in statu nascendi in the presence or absence of an additional solvent (e.g. from X and XI) and directly to cyclize to compounds of formula I. To prepare compounds of the formula Ia, it is advantageous to add 2 moles of X as well 1 mole of a compound of the formula XII

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Z ¹ ) ₂ = CR ² -COOR ¹

XII

um, whereby the intermediate product XI (Z ^ = Z; R-R) is passed through, The use of a catalyst, e.g. a base such as NaOH, KOH, sodium or potassium carbonate, is possible, but not essential necessary. It is also possible to use an excess of the amino compound XI instead of the base.

The reaction of compounds of the formula X (both radicals X ^β Br) with XII in a boiling alcohol in the presence of potassium carbonate is particularly advantageous, the intermediate products being compounds of the formula IV (X ~ Br) which are cyclized in situ. Under these conditions the reaction is complete after about 1-12 hours.

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

Compounds of the formula I are furthermore by solvolysis (preferably hydrolysis), thermolysis, esterification or transesterification from compounds of the formula V available.

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In these, W denotes in particular one of the following radicals (in which R * and R "each denote, for example, alkyl having 1-4 carbon atoms, preferably methyl or ethyl, and these radicals, identically or differently and together, also tetramethylene or pentainethylene, optionally interrupted by O , can be): COOH; CHaI ₃ ; COOR ¹ ; C (OR ') _o ; COOAcyl (in which acyl is the radical of a carboxylic acid with up to 25 carbon atoms, preferably the radical

CR ² - CO-

means); CN; CONH ₃ ; CONHR '; CONR ¹ R ";CONIIOH; C (OH) = NOH; CONHNH ₂ ; CON ₃ ; C (OR ') = NH; C (N ^) - NNE ^; C (NHNH ₂ ) = NH; CSOH; COSH; CSOR ¹ ; CSNH ₂ ; CSNHR ¹ or CSNR ¹ R ". Compounds of the formula V are obtained, for example, by reacting phenols or thiophenols of the formula II with carboxylic acid derivatives of the formula

-CXR-W

available.

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Sine hydrolysis of compounds of the formula V (W «= functional modified COOH group) can be in acidic or optionally alkaline medium at temperatures between -20 and 300, preferably at the boiling point of the selected solvent, be performed. Suitable acidic catalysts are for example hydrochloric, sulfuric, phosphoric or hydrobromic acid; the basic catalysts are expediently used 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 water-containing mixtures. But you can "die Acid derivatives e.g., also in ether or benzene with added from strong bases such as potassium carbonate or without solvents saponify by fusing with alkalis such as KOH and / or NaOH or alkaline earths to form carboxylic acids of the formula I (R = H).

"One embodiment of the invention is the saponification of this> amides (V, W - CSNR ¹ R"), for example the corresponding thiomorphs, -piperidides, -pyrrolidides, -diraethylamides or -diethylamides. The amides (V, W «CONH ₂ ) can also be used as starting materials. The thioamides or amides are preferably hydrolyzed by heating with aqueous hydrochloric acid. The thioaraids or amides do not necessarily need to be isolated; the reaction mixture in which they are formed can also be subjected directly to hydrolysis.

By dry heating of, in particular, tertiary alkyl esters of the formula V (W «= COO-tert-alkyl) to temperatures between 50 and 350 °, acids of the formula I (R ¹ « H) are obtained. The thermolysis can also be carried out in inert solvents, such as benzene, water, dimethylformamide, ethylene glycol, glycerol, dimethyl sulfoxide, cyclohexanol, preferably with the addition of catalytic amounts of acids, such as p-toluenesulfonic acid.

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■ - 16 -

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Another embodiment of the invention is the hydrolysis of nitriles (V., W "" CN), which can be carried out in an acidic (eg with acetic acid / HCl) or alkaline (eg with KOH in cyclohexanol) medium. . .

. Esters of the formula I (R = alkyl with up to 10 carbon atoms) can be prepared by methods described in the literature. For example, an acid of the formula I (R «h) _m ± t

■ the beti'effenden alcohol of the formula R OH (where R is alkyl with up to 10 carbon atoms) in the presence of an inorganic or organic acid, such as HCl, HBr, HJ, H ₃ SO ₄ , ^H 3 ^P0 4> Trifluor- ^ acetic acid, benzenesulfonic acid or p-toluenesulfonic acid, or an acidic ion exchanger, optionally in the presence of an inert solvent, such as benzene, toluene or xylene, at temperatures between 0 ° and preferably boiling point. The alcohol is preferably used in excess. Furthermore, you can work in the presence of water-binding agents.

• th, for example of anhydrous heavy metal sulfates (such as CuSO ₄ , Fe ₂ (S0 ₄ ) ₃ , NiSO ₄ , CoSO ₄ , ZnSO ₄ ) or of molecular sieves. Man. can also remove the water of reaction azeotropically, using * advantageously hydrocarbons (e.g. benzene or toluene) or chlorinated hydrocarbons (e.g. chloroform or 1,2-dichloro

, ethane) adds. The esterification proceeds under mild conditions if the reaction water is chemically bound by adding preferably equimolar amounts of carbodiimides (eg N, N ^f -D.icyclohexylcarbodiiinid), using inert solvents such as ether, dioxane, benzene or 1,2-dimethoxyethane and bases such as pyridine can be added. The methyl esters (or ethyl esters) can also be prepared by reacting the free acids according to methods described in the literature with diazomethane (or diazoethane) in an inert solvent such as ether, benzene or methanol. Esters of the formula I (R = alkyl with up to 10 carbon atoms) can also be obtained by adding the carboxylic acids I (R = H) to olefins (for example isobutylene). According to methods described in the literature, this addition is preferably achieved in

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Presence of catalysts (e.g. ZnCl ₂ , BF_, II ^ SO., Arylsulfonic acids, pyrophosphoric acid, boric acid, oxalic acid) at temperatures between 0 and 200 °, pressures between 1 and 300 at and in inert solvents such as ether, tetrahydrofuran, dioxane, benzene, Toluene or xylene. ·. . '· ....

Furthermore, one can esters of the formula I (R = alkyl with up to 10 carbon atoms) by reacting metal salts of the Acids I (R = H), preferably the alkali metal, lead or Silver salts, alkyl halides corresponding to the alcohol in question, e.g. those of the formula R Hai (where R is alkyl rait means up to 10 carbon atoms), optionally in an inert Solvents, e.g. ether, benzene or petroleum ether, or with alkyl chlorosulfites, e.g. those of the formula R OSOCl (where R Means alkyl with up to 10 carbon atoms) and thermolysis of the adducts obtained. /. '·' ·

You can also the acid halides, anhydrides or nitriles of the formula V (W = COHaI, COOAcyl or CN) by reaction with an alcohol of the formula ROH (R = alkyl with up to 10 carbon atoms) '* optionally in the presence of an acidic catalyst or a base such as NaOH, KOH, Na ₃ CO ₃ , K ₃ CO ₃ , pyridine or an alkali metal alcoholate corresponding to the alcohol used, according to the methods described in the literature * in ester of the formula I (R = alkyl with 1-10 C Atoms). Preference is given to using an excess of the alcohol in question and working at temperatures between 0 and the boiling point,

Finally, you can esters of the formula I (R = alkyl with up to IQ_C atoms) by reacting other esters of the formula V OT = »COOR ¹ "

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B = any organic radical, preferably with alkyl .1-4 carbon atoms) with an excess of the alcohol in question or by reacting the carboxylic acids I (R = H) with any other esters of the alcohol in question (preferably alkanoates in which the alkanoyl radical has up to 4 carbon atoms), which are preferably are used in excess, produce. One works e.g. according to the transesterification methods described in the literature, especially in the presence of basic or acidic catalysts, e.g. sodium ethylate or sulfuric acid, and at temperatures between 0 and preferably boiling temperature.

^ Esters of the formula I (R = alkyl with 1-10 carbon atoms) can also be obtained by using compounds of the formula V, 'wherein W is a thioester, imino ether, oximino ether, hydrazone ether, thioamide ,. Amidine, amidoxime or amidhydrazone groups mean with dilute aqueous bases or acids, for example ammonia, KaOH, KOH, Ka ₃ CO ₃ , K ₂ ⁰⁰ O, HCl, H ₂ SO ^, with the addition of the relevant alcohol of the formula R ¹ OH (R " ¹ = alkyl with up to .10 carbon atoms) and elimination of hydrogen sulfide, ammonia, amines, hydrazine derivatives or hydroxylamine Solvolysis of other derivatives, such as some amidoximes or thioamides, only takes place at temperatures of up to 100 °.

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Compounds of formula I are still by reaction obtainable from compounds of the formula VI with compounds of the formula VII. The former are largely unknown.

During the synthesis, they are expediently in situ by

4 4

Setting a compound of the formula R -X with a compound of the formula XIII
.5

XIII

obtain. To prepare compounds of the formula Ia, it is expedient to use 2 moles of VII with 1 mole of a compound of the formula XIV

- COOR ¹

XIV

um, whereby the intermediate VI (Z ² = Z ¹ ; R ⁴ = R ³ ; R ⁶ = R ⁵ ) is passed through.

In detail, for example, N-haloamines of the formula VII

(X ⁴ · = Cl or Br) such as N-chloropyrrolidine, N-chloropiperidine, N-chlorhomopiperidine, N-chloroisoindoline, N-chloro-1,2,3,4-tetrahydroquinoline or the corresponding N-bromine compounds or also corresponding reactive derivatives of N-hydroxy compounds, for example N-hydroxypiperidine-O-sulfonic acid

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with carboxylic acid derivatives of the formulas VI, XIII or XIV (X = H) such as (4-piperidinophenoxy) phenoxyacetic acid, bis-phenoxy-acetic acid or bis-phenoxy-malonic acid or the esters of these acids, preferably in the presence of catalysts, for example metal salts such as iron (II) sulfate, AlCl ₃ , BF ₃ or ZnClg, in inert solvents such as CS ₂ , nitrobenzene, 1,2-dichloroethane or, if FeSO _{4 is used} , in concentrated or hydrous sulfuric acid. The reaction temperatures are expedient for this procedure between -20 and + 60 °, preferably between 0 and 40 °,

► ₄

Furthermore, free amines of the formula VII (X = H) such as pyrrolidine, piperidine, homopiperidine, 3-hydroxypyrrolidine, 3-hydroxypiperidine, morpholine, isoindoline or 1,2,3,4-tetrahydroisoquinoline with amino compounds of the formulas VI, XIII or XIV ( X ³ ^ NH ₂ ) such as (4-piperidinophenoxy) ~ (4-aminophenoxy) acetic acid, bis (4-aminophenoxy) acetic acid, bis (4-aminophenoxy) malonic acid or their esters are reacted, preferably under pressure Use of an excess of the base VII as a solvent and / or in the presence of an additional inert solvent and an acidic catalyst such as HCl or p-toluenesulfonic acid or Friedel-Crafts catalyst

»Sators such as AlCl ₀ at temperatures between about 50 and about 300, ο
preferably between 150 and 250. · '

Furthermore, you can, for example, metal derivatives, in particular the Na derivatives of the aforementioned amines of the formula VII (XH), but also, for example, pyrrole potassium, with halogen or sulfonic acid derivatives of the formulas VI, XIII or XIV (X-Cl, Br, J or SO ₃ M), e.g. (4-bromophenoxy) -4- <piperidinophenoxy) acetic acid, bis- (4-bromophenoxy) malonic acid, bis- (4-sulfophenoxy) -

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acetic acid and its salts or esters, preferably in the presence of an excess of base VII as solvent and / or an additional inert solvent or suspending agent such as benzene, dioxane, dimethylformamide or hexamethylphosphoric triamide at temperatures between 50 and 200 °, optionally under pressure / or an inert gas atmosphere. The metal derivatives of the amines VII can also be prepared _{in situ, for example with NaH or NaNH 2.}

If desired, a radical R can be used in a compound obtained

ο
can be converted into another radical R. For example, using the methods described above, an ester group can be saponified to give a COOH group or, conversely, a COOH group can be esterified to form a COOalkyl group. It is also possible to remove a COOH group by decarboxylation, for example by dry heating or by heating in solvents such as water, mineral acids such as hydrochloric acid or sulfuric acid, lower alcohols such as ethanol, dioxane, lower fatty acids such as acetic acid or hydrocarbons such as xylene Temperatures between about 20 and about 250 °. It is advisable to heat until the end of the COo development.

A compound of the formula I which has a basic nitrogen atom can be converted into the associated acid addition salt using an acid will. For this reaction, those acids come into question, which provide physiologically harmless salts, so are suitable organic and inorganic acids, such as aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic or sulfonic acids, such as formic acid

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Acetic acid, propionic acid, pivalic acid, Diäthylessigsäuro, oxalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid, phenyl-propionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, _s isonicotinic acid, methanesulfonic acid , Ethanedisulphonic acid,

"! 2-Hydroxyethanesulfonic acid, p-toluenesulfonic acid, naphthalene mono- 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 the formula I (R ^rf H) can be converted into one of their physiologically harmless metal or ammonium salts by reaction with a base. Particularly suitable salts are the sodium, potassium, magnesium, calcium and ammonium salts, and also substituted ammonium salts, such as, for example, the dimethyl and diethylammoniura, honoethanol, diethanolammonium and triethanolammonium, cyclohexylammonium. nium, dicyclohexylamraonium and dibenzylethylenediammonium salts.

Conversely, compounds of the formula I can be obtained from their acid additive salts by treatment with strong bases, such as sodium or potassium hydroxide, sodium or potassium carbonate, or a basic ion exchanger, or from their metal and ammonium salts by treatment with acids, in particular Mineral acids such as hydrochloric or sulfuric acid, set free.

If the compounds of formula I ent- a center of asymmetry. hold, they are usually in racemic form. "

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The racerates can be separated into their optical antipodes with the aid of known methods, as indicated in the literature, preferably with the aid of chemical methods. Thereafter, for example, diastereomers are formed from the racemic mixture by reaction with an optically active auxiliary. Thus, if appropriate, an optically active base can be reacted with the carboxyl group or an optically active acid can be reacted with the amino group of a compound of the formula I. For example, diastereomeric salts of the compounds of the formula I (R «= H) with optically active amines, such as quinine, cinchonidine, brucine, cinchonine, hydroxyhydrindarain, morphine, 1-phenylethylamine, 1-naphthylethylamine, phenybxynaphthylmethylamine, quinidine, strychnine, can be basic Amino acids such as lysine, arginine, amino acid esters, diastereomeric salts of the compounds of the formula. I with a basic nitrogen atom with optically active acids, such as (+) - and (_) _ tartaric acid, dibenzoyl - (+) - and - (-) - tartaric acid, diacetyl - (- i -) - and - (-) -tartaric acid, camphoric acid, ß-camphorsulphonic acid,. · (+) - and (-) - mandelic acid, (+) - and (-) - malic acid, (+) - and ■ (-) - 2-phenylbutyric acid, (+) - and (-) - dinitrodiphenic acid or] ( +) - and (-) - form lactic acid. In a similar way, ester diastereomers can be prepared by esterifying compounds of the formula I (R ■ »H) with optically active alcohols, such as borneol, menthol, 2-octanol. The difference in solubility of the ^'f resulting diastereomeric salts or esters allows for the selective crystallization of one form and the regeneration of the respective optically active compounds from the mixture,

The racemates can also be separated with the aid of chromatographic methods. You can optically active support materials such as e.g. tartaric acid, starch, cane sugar, cellulose or acetylated cellulose, and optically inactive and / or optically active solvents to use for separation into the pure enantiomers or a optically inactive carrier material, v / ie e.g. silica gel or

309825 / 1Ϊ64

Aluminum oxide in combination with an optically active solvent. The optical antipodes can also be separated biochemically using selective enzymatic reactions. For example, the racemic acids of the formula I (R = E) can be exposed to an asymmetric oxidase or, if appropriate, decarboxylase, which destroys one form by oxidation or decarboxylation, while the other form remains unchanged. The use is possible of a further Tlydrolase with a functional acid derivative of the racemic mixtures to the preferred formation of an optically active form, So.kann one ester of formula I (R = alkyl having 1-10 carbon atoms) to the action of a hydrolase "suspend which selectively saponifies one enantiomer and leaves the other unchanged.

Furthermore, it is of course possible to use optically active compounds obtained by the methods described by using starting materials that are already optically active.

The compounds of the formula I and / or, if appropriate, their physiologically acceptable salts can be mixed with - "* solid, liquid and / or semi-liquid drug carriers be used as medicinal products in human or veterinary medicine. Such organic substances are used as carrier substances * or inorganic substances in question that are used for parenteral, enteral or topical application are suitable and which do not react with the new compounds, as with- ■ " "For example, water, vegetable oils, benzy! alcohols, polyethylene · glycols, gelatine, lactose, starch, magnesium stearate, talc, Petroleum jelly, cholesterol. Solutions, preferably oily or aqueous solutions, are used in particular for parenteral administration, as well as suspensions, emulsions or implants. Tablets, coated tablets, capsules, syrups and juices are suitable for enteral application

309 8 2 5/1 16A

or suppositories, for topical application ointments, Creams or powder. The specified preparations can optionally be sterilized or auxiliaries, such as Lubricants, preservatives, stabilizers or wetting agents, emulsifiers, salts to influence the osmotic pressure, Contain buffer substances, coloring, flavoring and / or flavoring substances.

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

Above and below, the temperatures are given in degrees Celsius. In the examples below, "customary work-up" means: the mixture is cooled, evaporated, water is added, extracted with ether, the ethereal solution is washed with sodium bicarbonate solution and with water, dried over Na ₃ SO ₄ , the ether is distilled off and the crude product is purified by distillation or crystallization, optionally by crystallization of an acid addition salt.

example 1

a) 9.2 g of sodium are dissolved in 500 ml of absolute ethanol. 70.8 g of 4-piperidinophenol are added with stirring (1-p-hydroxyphenyl-piperidine) and then with 31.4 g Dichloroacetic acid ethyl ester and the mixture boiled for 20 hours. Intermediate there is 2- (4-piperidinophenoxy) -2-chloroacetic acid ethyl ester, that is not isolated. It is worked up as usual and bis (4-piperidinophenoxy) ethyl acetate is obtained. Dihydrochloride, decomposition point 208 ° (from ethanol / acetone),

309825/1 164

Instead of dichloroacetic acid ethyl ester one can also use Use ethyl dibromoacetate.

Analogously one obtains from

4-pyrrolidinophenol (obtainable by reacting p-anisidine with 1,4-dibromobutane and subsequent treatment of the 4-pyrrolidinoanisole obtained with HBr)

2 ~ methyl-4-piperidino-phenol (F _e 231-233 °; obtainable by catalytic hydrogenation of 2-chloromethyl-4-nitroanisole to give 2-methyl-4 ~ amino ~ anisole, ether cleavage

with 48% HBr and conversion with 1.5 dibromopentane)

2 ~ chloro-4-piperidino-phenol (mp 90-92 °; available

by reaction of 2-chloro-4-amino-anisoi with 1,5-dibromopentane to 2-chloro-4-p:
and ether splitting with HBr)

Dibromopentane to 2-chloro-4-piperidino-anisole (m.p. 68-69 °)

3 ~ chloro-4-piperidino-phenol (m.p. 89 °; available from Conversion of 3-nitro-4-bromo-anisole with piperidine to 3-nitro-4-piperidino-anisole, hydrogenation to 3-amino-4-piperidino-anisole, Diazotization and Sandmeyer reaction to 3-chloro-4-piperidino-anisole and ether cleavage with HBr)

4-homopiperidino-phenol (available from p-anisidine and 1,6-dibrorahexane via 4-homopiperidino-anisole)

4-pyrrolidinomethyl-phenol (obtainable by reaction of p-methoxybenzyl chloride with pyrrolidine too 4-pyrrolidinomethyl-anisole and ether cleavage with HBr)

4-piperidinomethyl-phenol (obtainable by reaction of p-Methoxy'benzyl chloride with piperidine to form 4-piperidinomethyl-anisole and ether splitting with HBr)

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4-homopiperidinoraethyl-phenol (obtainable by reaction from p-methoxybenzyl chloride with homopiperidine to 4-honiopiperidinomethyl anisole and ether splitting rait HBr)

4- (4-pyrrolidinophenyl) phenol (obtainable by reaction, of 4 ~ amino-4'-methoxy-diphenyl with 1,4-dibromobutane to 4-pyrrolidino-4'-methoxy-diphenyl and ether cleavage with HBr)

4- (4-piperidinophenyl) -phenol (F. 193-195 °; obtainable by reaction of 4-amino-4-methoxy ^t-biphenyl with 1,5-dibromopentane to give 4-piperidino-4'-methoxy-biphenyl (F . 190 192) and ether splitting with HBr)

4- (4-Homopiperidinophenyl) -phenol (obtainable by reaction of 4-amino-4'-methoxy-diphenyl with 1,6-dibromohexane to ^{4-homopiperidino-4-methoxy-t} diphenyl and ether cleavage with HBr)

4- (3-Hydroxy-pyrrolidino) -phenol (F, 163 - 164 °; obtainable by reacting p-anisidine with 1,4-dibromo-2-butanol to 4- (3-hydroxy-pyrrolidino) -anisole (m.p. 73-74 °) and ether cleavage with HBr)

4- (3-Hydroxy-piperidino) -phenol (M.p. 140-143 °; available by hydrogenation of 3-chloro-4- (3-hydroxypiperidino) anisole on 5% Pd / MgO to 4- (3-hydroxy-piperidino) -anisole (mp 170-172 °) and ether cleavage with HBr)

3-chloro-4- (3-hydroxypiperidino) phenol (obtainable by reacting 3-nitro-4-bromo-anisole with 3-hydroxypiperidine to 3-nitro-4- (3-hydroxypiperidino) -anisole, hydrogenation on 5% Pd / C to 3-amino-4- (3-hydroxypiperidino) -anisole (M.p. 122 - 123 °), diazotization and Sandmeyer reaction to 3-chloro-4- (3-hydroxy-piperidino) -anisole (F. 70 - 72 °) and ether splitting with HBr).

309825/1 164

4 ~ morpholino-pheriol (obtainable by reacting p-aminophenyl-benzyl ether with 2,2'-dibromodiethyl ether to form 4-morpholinophenyl-benzyl ether and hydrogenolysis) 4-isoindolino-phenol (mp 215 °; obtainable by reacting p-anisidine with o-Xylylene dibromide to 2-p-methoxyphenylisoindoline and ether cleavage with HBr) 4- (1,2,3,4-tetrahydroquinolino) phenol (mp 106-108 °; obtainable by reacting Np-methoxyphenyl anthranilic acid with acetic anhydride and subsequent saponification to lp-methoxyphenyl - ^ - hydroxy - ^ - quinolone, reaction with POCl ₃ to lp-methoxyphenyl - ^ - chloro - ^ - quinolone (mp 192-194 °) , hydrogenation to 1-p-methoxyphenyl-3 , 4-dihydro-2-quinolone, (mp 161-162 °), LiAlH ₄ -reduction to 1-p-methoxyphenyl-l, 2,3,4-tetrahydroquinoline and ether cleavage with HBr)

4- (l, 2,3,4-tetrahydro-4-quinolyl) phenol (melting point 123 - 125 °; hydrochloride, melting point 217 - 220 °; obtainable by cyclization of p-methoxycinnamic acid anilide with polyphosphoric acid to give 4- (p-Methoxyphenyl) -1, 2,3,4-tetrahydro-2-quinolone, reduction with LiAlH ₄ to 4- (p-methoxyphenyl-1,2,3,4-tetrahydroquinoline (mp 83-85 °). and ether splitting with HBr)

4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) phenol (F. 220-222 °; obtainable by methylation of 4- (p-methoxyphenyl) -1, 2,3,4-tetrahydroquinoline with formaldehyde / H «5% Pd / C to 1-methyl-4-p-methoxyphenyl-1,2,3,4-tetrahydroquinoline (Bp. 164 - 172 ° / 0.01 mm) and ether splitting. with HBr)

4- (l-methyl-4-piperidyl) -phenol (obtainable by treating l-methyl-4-piperidinol with phenol / AlClg in benzene or of l-methyl-4-piperidone with p-anisylmagnesium bromide with subsequent dehydration, hydrogenation and ether cleavage)

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4- (1-pyrryl) -phenol (m.p. 118-119 °; available from Conversion of p-aminophenol with 2,5-diethoxytetrahydro- • furan)

by reaction with ethyl dichloroacetate or with ethyl dibromoacetate:

Bis- (4-pyrrolidino-phenoxy) -acetic acid ethyl ester Bis- (2-methyl-4-piperidino-phenoxy) -acetic acid ethyl ester Bis- (2-chloro-4-piperidino-phenoxy) -acetic acid ethyl ester Bis- (3-chloro-4 ~ piperidino-phenoxy) -acetic acid ethyl ester Bis- (4-homopiperidino-phenoxy) -acetic acid ethyl ester Bis- (4-pyrrolidinomethyl-phenoxy) -acetic acid ethyl ester Bis- (4-piperidinomethyl-phenoxy) -acetic acid ethyl ester Bis- (4-homopiperidinomethyl-phenoxy) -acetic acid ethyl ester Bis- / 4- (4-pyrrolidinophenyl) -phenoxy-7-acetic acid ethyl ester Bis- / 4 "- (4-piperidinophenyl) -phenoxy-7-acetic acid ethyl ester Bis- / 4- (4-homopiperidinophenyl) -phenoxy7-acetic acid ethyl

ester
Bis- / 4 "- (3-hydroxy-pyrrolidino) -phenoxy7-acetic acid ethyl-

ester
Bis - /? - (3-hydroxy-piperidino) -phenoxy7-acetic acid ethyl-

ester
Bis- / 3-chloro-4- (3-hydroxypiperidino) -phenoxy-7-acetic acid ethyl ester

Bis- (4-morpholino-phenoxy) -acetic acid ethyl ester Bis- (4-isoindolino-phenoxy) -acetic acid ethyl ester,

164-167 ° F.
Bis- / i- (1,2,3,4-tetrahydro-quinolino) -phenoxy7-vinegar-

acid ethyl ester
Bis- / ¥ - (1,2,3,4-1etrahydro-4-quinoly1) -phenoxy / -acetic-

acid ethyl ester
Bis - /? - (l-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy7-

ethyl acetate
Bis- / 4 "- (1-methyl-4-piperidyl) -phenoxy-7-acetic acid ethyl ester

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Bis- / 4- (I-pyrryl) -phenoxy / -acetic acid ethyl ester.

b) 4.38 g of bis (4-piperidiiio-phenoxy) -acetic acid ethyl ester are boiled with 1 g of KOH in 25 nil ethanol for 2 1/2 hours. It is evaporated, water is added, the mixture is extracted with ether and hydrochloric acid is added to pH 5. The bis (4-piperidino-phenoxy) acetic acid obtained is filtered off with suction and converted into the cyclohexylamine salt (mp 182-184 °).

Analogously, by saponification of the corresponding ethyl esters (acidification up to the specified pH values):

Bis- (4-pyrrolidino-phenoxy) -acetic acid (pH 5) Bis- (2-methyl-4-piperidino-phenoxy) -acetic acid (pH 5) Bis- (2-chloro-4-piperidino-phenoxy) ~ acetic acid (pH 5) Bis- (3-chloro-4-piperidino-phenoxy) acetic acid (pH 5) Bis- (4-homopiperidino-phenoxy) -acetic acid (pH 5) bis- (4-pyrrolidinomethyl-phenoxy) -acetic acid (pH 5) Bis- (4 ~ piperidinomethyl-phenoxy) -acetic acid (pH 5) Bis- (4-homopiperidinomethyl-phenoxy) -acetic acid (pH 5) Bis- / 4- (4-pyrrolidinophenyl) -phenoxy / -acetic acid (pH 5) bis- / 4- (4-piperidinophenyl) -phenoxy7-acetic acid (pH 5) Bis- / 4 "- (4-homopiperidinophenyl) -phenoxy7-acetic acid (pH 5) ^ Bis - /? - (3-hydroxy-pyrrolidino) -phenoxyT-acetic acid (pH 4.5

Bis- / 4 "- (3-hydroxy-piperidino) -phenoxy / -acetic acid (pH 4.5) Bis ~ / 3 ~ -chloro-4- (3-hydiioxy-piperidino) -phenoxy / acetic acid

(pH 4)

Bis- (4-morpholinophenoxy ^ acetic acid (pH 5) Bis- (4-isoindolino-phenoxy) -acetic acid (pH 4) bis- / 4 ~ - (1,2,3,4-tetrahydro-quinolino) -phenoxy / acetic acid

(pH 4)
Bis- / 4- (1,2,3,4-tetrahydro-4-quinoly1) -phenoxyZ-acetic acid

(pH 5.5)
Bis- / 4 "- (l-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxy / -

acetic acid (pH 4)
Bis- / 4 "- (l-methyl-4-piperidyl) -phenoxy / -acetic acid (pH 5)

Bis- / 4 "- (l-pyrryl) -phenoxy / -acetic acid (pH 4)

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Example 2

10.5 g of 4-isoindolino-phenol are added to a suspension of 1.2 g of NaH in 100 ml of diethyl acetamide. The mixture is stirred for one hour at room temperature, heated to 100 °, after adding 3.9 g of ethyl uiehloroacetate, it is maintained at 160 for 48 hours, worked up as usual and, after purification by chromatography, ethyl bis (4-isoindolino-phenoxy) -acetate, F. 164-167 ° _E

Example 3

A mixture of 3.54 g of 4-piperidinophenol and 0.46 g of sodium in 100 ml of xylene is boiled for 3 hours. The mixture is allowed to cool to 20 °, and 1.57 g of ethyl dichloroacetate are added to 10 ml of xylene added, the suspension is stirred for 6 hours at the boiling point, cooled and treated with 2 ml of ethanol The inorganic Precipitate is filtered off, the filtrate is evaporated, the residue is taken up in ether, the solution with NaHCOo solution and saturated NaCl solution, washed over MgSO. dried and evaporated. One receives bis - * (4 «piperidino-'phenoxy) - ethyl acetate; Dihydrochloride, decomposes at 2o8 »

Analogously, the phenols mentioned in Example 1 are obtained by reaction with

Methyl dichloroacetate

N-propyl dichloroacetate Isopropyl dichloroacetate, n-Butyl dichloroacetate

Isobutyl dichloroacetate Dichloroacetic acid sec, ~ butyl ester

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Tert-butyl dichloroacetate Dichloroacetic acid isoamyl ester Dichloroacetic acid n-hexyl ester N-octyl dichloroacetate Dichloroacetic acid ~ (2 ~ ethylhexyl) ~ ester Dichloroacetic acid n ~ decyl ester

the corresponding esters given in Example Ib) Acids, e.g. bis ~ (4 -! - piperidinophenoxy) ~ acetic acid ~ - methyl ester «N-propyl ester -isopropyl ester - n-butyl ester «Isobutyl ester -sec.-butyl ester -terto-butyl ester -Isoajiiyl ester —N — hexy ester -n-octyl ester - (2-ethyl-hexyl) ester —N-decyl ester "

Example 4

A solution of 15.7 g of ethyl dichloroacetate in 30 ml of acetone is slowly added to a stirred mixture of 35.4 g of 4-piperidinophenol, 13.8 g of K ₃ CO ₃ and 80 ml of acetone. The mixture is boiled for 12 hours with stirring, filtered, works as usual and receives bis «(4 ~ piperidinophenoxy) -acetic acid- ethyl ester, dihydrochloride, decomposition at 208 °,

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Example 5

2Tu a mixture of 17.7 g of 4-piperidinophenol and 27.9 g 4-piperidinophenoxy-glycolic acid ethyl ester (obtainable by selective hydrolysis of 4-piperidinophenoxy-broniacetic acid- ethyl ester with water) 15 g of sulfuric acid are added and the reaction mixture is stirred at 50-60 for 2 hours. To water is added to the cooling, dilute NaOH is added to pH 8 and the aqueous phase is extracted with ether. It is dried, evaporated and obtained bis ~ (4 ~ piperidinophenoxy) -acetic acid ethyl ester, Dihydrochloride, decomposes at 208 °,

Example 6

a) 35.4 g of 4-piperidinophenol are dissolved in 200 ml of acetone. 8 g of NaOH are added with stirring and then 21.8 g of dibroraacetic acid (or 12.9 g Dichloroacetic acid) in 60 ml of acetone, 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 1 of water, the solution is washed several times with ether and with HCl bis pH 5 acidified. The precipitated bis ~ (4 ~ piperidinophenoxy) ~ acetic acid is converted into the cyelohexylamine salt (F, 182-184 °) convicted.

The acids given in Example Ib) are obtained analogously from the phenols mentioned in Example la),

b) 1 g of bis (4-piperidinophenoxy) -acetic acid is dissolved in 20 ml of ether and ethereal CH ₂ H ₂ solution is added dropwise until it remains yellow. After evaporation, bis (4-piperidinophenoxy) -acetic acid methyl ester is obtained.

The others given in Example Ib) are obtained analogously Acids the corresponding methyl esters.

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c) 5 g of bis (4-piperidinophenoxy) acetic acid are dissolved in 200 ml of saturated ethanolic hydrochloric acid, left to stand for 12 hours at room temperature, boiled for 2 hours and evaporated. The residue is dissolved in water, the aqueous solution is adjusted to pH 8 with 1 η NaOH and with ethyl acetate extracted. It is dried, evaporated and dis ~ (4-piperidinophenoxy) ~ acetic acid ethyl ester is obtained, Dihydrochloride, decomposes at 208 °.

Analog obtained from the Example Ib) stated acids with hydrochloric acid äthanbliseher the appropriate ethyl ester described in Example la) · If instead of ethanol Ψ other alcohols, we obtain the corresponding ester,

with n-octanols
Bis (4-piperidinophenoxy) «acetic acid n-octyl ester _e

Example 7

a) Dissolve 24.2 g of sodium in 630 ml of methanol and then add 186 g of 4-piperidinophenol with stirring. A solution of 152 g of dimethyl dibromomalonate in 840 ml of benzene is then added dropwise and the reaction mixture is boiled for 18 hours while stirring. In situ arises 4 — Piperi « dimethyl dinophenoxy-bromo-malonate, which is not isolated will. Then it is evaporated, mixed with Y / ater, extracted with ether and the ethereal phase is washed with sodium hydroxide solution. After drying and evaporation, bis- (4'-piperi · - dinophenoxj ^ -malonsäurediinethylesterj dihydrochloride, 197-199 ° F.

The phenols given in Example 1 are obtained analogously:

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Dimethyl bis (4-pyrrolidino-phenoxy) -inalonate Dimethyl bis (2-mothyl-4-piperidino-pIienoxy) malonic acid Bis (2-chloro-4-piperidino-phenoxy) -raalonic acid di-ethyl ester Bis - »(3-chloro-4-piperidino ~ phenoxy) ~ raalonic acid dimethyl ester,

F «90 - 92 °

Bis- (4-hoiaopiperidino ~ phenoxy) -inalonic acid dimethyl ester Bis- (4-pyrrolidinomethyl-phenoxy) -malonic acid dimethyl ester Bis- (4-piperidinomethyl-phenoxy) -malonic acid dimethyl ester Bis- (4-homopiperidinomethyl-phenoxy) -nialonic acid dimethyl ester Bis- / i "- (4-pyrrolidinophenyl) -plienoxyy ^r -nialonsäui * ediinethylester

211-213 ° F.

Bis- ^ j4 - (4-homopiperidinophenyl) ~ phenox27-malonic acid dimethyl ester Bis - ^ - (3 ~ hydroxypyrrolidino) ~ plienoxyy-malonic acid dimethyl ester Bis- / 4- (3-hydroxypiperidino) phenoxyJ7-malonic acid dimethyl ester

dimetl ^ lester

Bis - »(4-morpholino-phenoxy) -malonic acid dimethyl ester Bis- (4-isoindolino-phenoxy) -malonic acid di-ethyl ester Bis - ^ - (1,2,3, ^ '- tetrahydrochinoXxnoJ-'phenoxyy — malonic acid— dimethyl ester

Bis - ^ / 4- (1,2,3,4-tetrahydr o ^ 4-quinolyl) -phenoxyy ^ malonic acid dimethyl ester

Bis- ^ r ~ (l-methyl ~ 1,2,3,4-tetrahydro-4-quinolyl) -phenoxyy ^ - dimethyl malonate

Bis- / JL- (1-methyl 1-4-piperidyl) -phenoxyj ^ -malonic acid dimethyl ester - ^ 4- (1-pyrryl) -phenoxyJT-ina ionic acid dimethyl ester.

The corresponding diethyl esters, Z ₀ B ₈ bis (4-piperidinophynoxy) malonic acid diethyl ester (P. 115-117 °) are obtained analogously with dibromomalonic acid diethyl ester.

3 0 9 H 2 5/1 1 θ 4

b) Analogously to Example Ib), dimethyl bis (4 ~ piperidinophenoxy) malonate is obtained by boiling rait KOH in ethanol bis- (4-piperidinophenoxy) -malonic acid

Analogously, by saponification of the corresponding dimethyl or, diethyl ester:

Bis- (4-pyrrolidino-phenoxy) -malonic acid bis- (2-methy1-4-piperidino-phenoxy) -malonic acid bis- (2-chloro-4-piperidino-phenoxy) -malonic acid bis- (3-chloro-4— piperidino-phenoxy) -malonic acid, bis- (4-homopiperidino-phenoxy) -malonic acid, bis- (4-pyrrolidinomethyl-phenoxy) -malonic acid, bis- (4-piperidinomethyl-phenoxy) -malonic acid, bis- (4-homopiperidinomethyl-phenoxy) -malonic acid Bis- _i / 4- (4-pyrrolidinophenyl) -phenoxyy ^r -malonic acid BiS- ^ ^- - (4-piperidinophenyl) -phenox27-raalonic acid Bis- ^ 4- (4-homopiperidinophenyl) -phenoxyJ7-malonic acid Bis- ^ / 4- (3-hydr oxy pyrrolidino) -phenoxyy "-ma ion acid bis- ^ T- (3-hydroxypiperidino) -phenoxy7-malonic acid bis - ^ - chloro ^ -iS-hydroxypiperidinoJ-phenoxyJ ^ -raalonic acid bis- (4-morpholine- phenoxy) -malonic acid bis (4-isoindolino-phenoxy) -malonic acid - ^ T- (1,2,3,4-tetrahydroquinolino) -phenoxy ^ -malonic acid - ^ - (1,2,3,4-tetrahydro -4-quinolyl) -phenoxyJ ⁷ -malonic acid - ^ j4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxyj ⁷ -.

malonic acid

Bis- ^ X-il-methyl ^ -piperidylJ-phenoxjT'-malonic acid Bis- ^ 4- (l-pyrryl) -phenoxyy ^r -malonic acid.

309825/1 16A

2163055

c) A solution of 5 g of the disodium salt of the bis- (4-piperidino " phenoxy) malonic acid in 50 ml of water is acidified with concentrated hydrochloric acid and heated to 100 ° for 30 minutes. Afterward sodium hydroxide solution is added to pH 5, extracted with chloroform / tetrahydrofuran, dried, evaporated and receives bis (4-piperidinophenoxy) acetic acid. Cyclohexylamine salt, F. 182 "184 ° (from methanol)"

Example 8

a) A solution of 3.86 g of 4-piperidino thiophenol (available by reducing 4-piperidinobenzene sulfochloride with Sn / HCl) in 35 ml of dimethylformamide, 0.48 g of NaH offset. The mixture is stirred for 1 hour at 20 °, then a solution of 1.57 g of ethyl dichloroacetate in 10 ml is added dropwise Dimethylformamide is added and the mixture is stirred at 80 ° for 2 hours. The reaction mixture is mixed with water and as usual worked up. Ethyl bis (4-piperidino-phenylmercapto) -acetic acid esters are obtained

Analogously with the corresponding thiophenols one obtains:

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Bis - ^ - pyrrolidino-phenyliaercaptq ^ acetic acid ethyl ester bis (2-ynethyl-4-piperidino-phenylmercapt ^ -acetic acid ethyl ester bis- (2-chloro-4-piperidino-phenylmeroapto) -ethyl acetate bis- (3-chloro-4-piperidino- phenylmercapto) ethyl acetate bis (4-homopiperidino-phenylmercapto) -acetic acid ethyl ester Bis- (4-pyrrolidinomethyl-phenylmercapto) -esoetic acid ethyl ester Bis «(4-piperidinomethyl-phenylmercapto) -acetic acid ethyl ester bis- (4-homopiperidinomethyl-bis (4-homopiperidinomethylester) bis- (4-homopiperidinomethylester) ^ - (4-pyrrolidinophenyl) -phenylmercapto7-acetic acid ethyl ester bis - ^ - (4-piperidinophenyl) -phenylmercapto7-acetic acid ethyl ester bis- /% - (4-homopiperidinophenyl) - phenylmercaptoT-acetic acid ethyl ester bis- / i "- (3-hydroxy pyrrolidino) -phenyliaereaptoj-ethyl acetate bis- ^ ~ (3-hydroxypiperidino) -phenylmercapto7-acetic acid ethyl ester Bis- ^ "- ehlor-4- (3-hydroxypiperidino) -phenylmercapto7-acetic acid ethyl ester

Bis- (4-morpholino-pheny-mercapto) -acetic acid ethyl ester Bis- (4-isoindolino-phenylmercapto) -acetic acid ethyl ester Bis— ^ j4— (1,2,3,4 — tetrahydro-quinolino) —phenyl mercapt cjT — acetic acid— ethyl ester

BiS - ^ - (1,2,3,4-tetrahydro-4-quinolyl) -pheny Imercapto7-ethyl acetate

Bis- / 4- (l-methyl-l, 2,3,4-tetrahydro-4-quinolyl) -pheny liuereaptoT- · ethyl acetate

Bis- / 4- (l-methyl-4-piperidyl) - phenylmercaptoZ-acetic acid ethyl ester .Bis- ^ r- (l-pyrryl) -phenylmercapto7-acetic acid ethyl ester,

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b) Analogously to Example Ib), bis (4-piperidino-phenylineroapto) acetic acid ethyl ester is obtained by saponification with KOII in ethanol bis ~ (4-piperidino-phenylinereapto) -acetic acid.

The corresponding esters are obtained analogously by saponification

Bis (4-pyrrolidino-phenylmercapto) -acetic acid bis- (2-methyl-4-piperidino-phenylmercapto) -acetic acid bis- (2-chloro-4-piperidino-phenylinereapt o) -acetic acid bis- {3-chloro-4 ~ piperidino-pheny! mercapto) -acetic acid bis- (4-homopiperidino-phenylmercapto) -acetic acid bis- (4-pyrrolidinomethyl-phenylmercapto) -acetic acid bis- (4-piperidinomethyl-phenylmercapto) -acetic acid bis- (4-homopiperidinomethyl-phenylmercapto ) -acetic acid bis- ^ T- (4-pyrrolidinophenyl) -phenylmercaptoJ ^{; r} -acetic acid bis- / ά- (4-piperidinophenyl) -phenylmercapto / -acetic acid bis- / £ - (4-homopiperidinophenyl) -phenylmercapto7-acetic acid bis- ^ 4- (3-hydroxypyrrolidino) -phenylmercapto7-acetic acid bis- ^ T-CS-hydroxypiperidinoJ-phenylmercaptoT-acetic acid bis- ^ - chloro-4- (3-hydroxypiperidino) -phenylmercapto / ^r -acetic acid bis- (4-morpholino- phenylmercaptο) acetic acid bis (4-isoindolino-phenylmercapto) acetic acid

Bis- / ά- (1,2,3,4-tetrahydro-quinolinoj-phenylmereapto ^ -acetic acid - ^ T- (1,2,3,4-tetrahydro-4-quinolyl) -phenylmereaptjo / ^r -ess: igsäure

acetic acid
Bis- _i / 4- (l-methyl-4-piperidyl) -phenylmercapto7-acetic acid

309 ^r i25 / 116A

Example 9

a) To a mixture of 3.86 g of 4-piperidino-thiophenol, 2g A solution is added dropwise with stirring to KoCOo and 20 ml of acetone of 2.74 g of dibromomalonic acid diethyl ester in 10 ml of acetone and then cooks for 14 hours. Customary work-up gives I3is- (4 "piperidinophenylmercapto) -malonic acid" diethyl ester.

Analogously with the corresponding thiophenols one obtains:

™ Bis- (4-pyrrolidino ~ phenylmercapto) ~ malonic acid diethyl ester Bis- (2-methyl-4-piperidino-phenylmercapto) ~ malonic acid diethyl'-ester Bis- (2-chloro-4-'Piperidino-phenylmercapto) ~ malonic acid diethyl ester Bis - (3-chloro-4-piperidino-phenylmercapto) -malonsäurediäth3 ^r lester bis (4 "homopiperidino-phenylmex'capto) -malonsäurediäthylester bis (4 ~ pyrrolidinomethyl-phenylmercapto)" malonsäurediätliylester bis (4-piperidinomethyl-phenylmercapto) - diethyl malonate bis (4- »homopiperidinomethyl-phenylmercapto) -ma.lonsäurediethyl—

ester I 'bis ₍₍ / 4- (4-pyrrolidinophenyl) -phenylmercapto7'-malonic acid diethyl-

Ester Bis- ^ f- (4-piperidinophenyl) -phenylmercapto7-malonic acid diethyl ester Bis- / 4- (4-homopiperidinophenyl) -phenylmercapto7'-malonic acid diethyl ester Bis-> ^ / 4-i (3-hydroxypyrrolidino) -phenylmercapto7-malonic acid diethyl ester 4 - '(3-hydroxypiperidino) -phenylmercapt _i o7-malonic acid diethyl ester

309ft25 / 116A

Bis - ^ '- chloro-4- (3-hyilroxypiperidino) ~ phenylmercapto7-malon'-acid diethyl ester

Bis (4 ~ Diorpliolino-plienylinercapto) «diethyl malonate bis (4-isoindolino-phenyliaercapto) -inalonsäurediäthylester Up - * / i ~ (i» j ² 314-tetrahydro-quinolino) -phenylmercapto7'- raalonsäurediäthylester

Bis - ^ / 4- (1,2,3,4 ~ tetrahydro-4-ehinolyl) ~ phenylniereapto7 ^r ~ malonic acid diethyl ester

Bis - ^ / 4- (1-methyl-1,2,3,4-tetrahydro-4-ehinolyl) «phenylmercaptoT-malonic acid diethyl ester

Bis - ^ - (l-methyl-4-piperidyl) -phenylmercapto7 ^r "-malonsäurediäthylester

Bis " _/ ^" (l-pyrryl) -phenylniercapto7 ~ malonic acid diethyl ester _e

With dimethyl dibromomalonate, the corresponding dimethyl esters _{e are obtained analogously}

b) The ester obtained according to a) is analogous to Example Ib) with KOH saponified in ethanol to bis ~ (4 ~ piperidinophenylmereapto) ~ malonic acid

The corresponding malonic acids are obtained analogously by saponification of the esters given under a).

c) Decarboxylation of the disodium salt obtained according to b) Acid analogous to Example Ic) gives bis <- (4 ~ piperldinophenylmercapto) acetic acid »

3 0 9 8 2 5/1 164

2183056

Example 10

a) 17.7 g of 4 «piperidinophenol and are added to a solution of 2.4 g of sodium in 100 ml of absolute ethanol with stirring then a solution of 29.75 g of 2- (4-piperidinophenoxy) -2-chloroacetic acid ethyl ester dropwise (obtainable by reaction of the sodium salt of 4-piperidinophenol with chloroacetic acid ethyl acid ester and subsequent chlorination of the resulting 4-piperidinophenoxy-acetic acid ethyl ester) in 100 ml of absolute Ethanol · It is boiled for 20 hours, worked up as usual and obtained bis ^ (4-piperidinophenoxy) '- ethyl acetate; Dihydrochloride, decomposes at 208 °

Analogously, with the phenols given in Example 1, the corresponding phenols that differ in the two p-positions are obtained substituted bis-phenoxy-acetic acid ethyl ester, e.g.

(4 ~ pyrrolidinophenoxy) - (4-piperidinophenoxy) acetic acid- ethyl ester

j [] L ~ (1,2,3,4-tetrahydroquinolino) -phenoxyj ⁷ "- ^ -piperidinophenoxy) -acetic acid ethyl ester

/ 4- (1-methyl-1,2,3,4-tetrahydro-4-quinolyl) -phenoxv7 ~ (4- ' piperidinophenoxy) ethyl acetate ^ T- (l ~ methyl-4-piperidyl) phenoxy ^ - (4-piperidinophenoxy) ethyl acetate

If 4-piperidino-thiophenol is used, one obtains

(4-Piperidino-phenylmercapto) - (4-piperidinophenoxy) -acetic acid ethyl ester.

309825 / 116Ü

Ij) Analogously to Example Ib), by saponification of the according to a.) obtained ester rait KOH in ethanol the corresponding acids, e.g.

(4-Pyrrolidinophenoxy) - <(4-piperidinophenoxy) acetic acid ^ T (1,2,3,4-tetrahydroquinolino) -phenoxyJ ⁷ - (4-piperidinophenoxy) acetic acid

/ 4- (1-methyl-1, 2,3,4-tetrahydro-4 "-quinolyl) -phenoxyj7- (4-piperidinophenoxy) -acetic acid

/ 4- (1-Methyl-4-piperidyl) -phenoxyy ^r - (4-piperidinophenoxy) -acetic acid

(4-Piperidino-phenylmercapto) - (4-piperidinophenoxy) ~ acetic acid.

Example 11

2.4 g of sodium are dissolved in 60 ml of methanol and then 17.7 g of 4-piperidinophenol _{e are added with stirring} Mole of 4 ~ piperidinophenol with 1 mole of dimethyl dibroinmalonate) in 200 ml of benzene and the reaction mixture is boiled for 16 hours while stirring. After the usual work-up, bis- (4-piperidino-phenoxy) -malonic acid dimethyl ester is obtained; Dihydrochloride, m.p. 197-199 °.

Analogously, with the phenols given in Example 1, the corresponding substitutes with different substitutions in the two p-positions are obtained th bis-phenoxymalonic acid dimethyl ester, e.g.

(4-Pyrrolidinophenoxy) - (4-piperidinophenoxy) malonic acid dimethyl ester

/ 4 "- (1-pyrryl) -phenoxyy ^r -. (4-.piperidinophenoxy) -malonic acid dimethyl ester.

0 ^c i:.: ^J B / 1 1 64

Example 12

23 g 1,4-dibromo ~ 2 ~ butano'l, 15.1 g bis (p-aminophenoxy) ~ acetic acid ethyl ester (obtainable by reaction of Na-4-nitrophenolate converts dichloroacetic acid ethyl ester to bis ~ (4-nitrophenoxy) - ethyl acetate and subsequent hydrogenation) and 27 g of K ₃ CO ₃ are boiled in 400 ml of n-butanol for 12 hours. Intermediate there is a mixture consisting of ^ - (3-hydroxypyrrolidino) -phenoxyy ^iP - ^ - (3-hydroxy-4-Tjroml) utylamino) -phenoxyy ^r ~ acetic acid ethyl ester and ^ / j? - (3-hydroxy-pyrrolidino) -phenoxyj ^^ / p- (2-hydroxy «4 ~ bromobutylamino) -« phenoxyj ⁷ -acetic acid ethyl ester.

Analogously one obtains from

Bis- (4-amino-phenoxy) -acetic acid methyl ester Bis- (2-methyl-4-amino-phenoxy) -acetic acid methyl ester Bis- (2-chloro-4-aminophenoxy) -acetic acid methyl ester Bis- (3-chloro-4-aminophenoxy) -acetic acid methyl ester

by reaction with 1,4-dibromobutane, 1,5-dibromopentane, 1.6 · dibromohexane, 1.4% dibromo-2-butanol, 15S-dibromo-pentanol, 2.2 ^! -üibrom diethyl ether or o-xylylene bromide:

Bis- (4-pyrrolidino-phenoxy) -acetic acid methyl ester Bis- (4-piperidino-phenoxy) -acetic acid methyl ester Bis- (2-methy1-4-piperidino-phenoxy) -acetic acid methyl ester Bis- (2-chloro-4-piperidino-phenoxy) -acetic acid methyl ester Bis- (3-chloro-4-piperidino-phenoxy) -acetic acid methyl ester Bis- (4-homopiperidino-phenoxy) -acetic acid-methyl ester Bis- (4-pyrrolidinomethyl-phenoxy) -acetic acid methyl ester

3 0 9 8 2 B / 1 1 6

Bis (4-piperidinomethyl ~ phenoxy) methyl acetate bis (4 ~ hojaopiperidinomethyl-phenoxy) -ess igsäuremethylest he bis _/ ^ 4- (4-pyrrolidinophenyl) -phenoxyy ^r ~ essigsäuremetliylester _bis! ^ - (4 "piperidinophenyl) -pheiioxyy ^r ~ acetic acid methyl ester Bis - ^^ - (4-homopiperidinophenyl) -phenoxy ^ - ethyl acetate Bis-ZI-iS-hydroxypyrrolidinoJ-phenoxyy ^ acetic acid ethyl ester Bis- / 4- ^> (3« -hydroxy-p ± peridino) -phenoxyy ^r -acetic acid methyl ester Bis - ^ '- chloro ^ -iS-'hydroxy-piperidinoJ-phenoxyy-acetic acid methyl · ·

Bis (4-morpholino-phenoxy) -acetic acid methyl ester Bis- (4-isoindolino-pherioxy) -acetic acid methyl ester.

Example 13

A mixture of 16.5 g of bis (4-amino-phenoxy) -essigsäureisobutylester, 23 g of 1, ö-Dibrömpentan, 14 g Na _o C0 _Q and 100 ml of acetonitrile is boiled for 48 hours under stirring. Intermediate forms (4-piperidinophenoxy) - _i / 4- (5-l3rompentylamino) -phenoxyJTL-isobutyl acetate, is filtered, evaporated, the residue is taken up in dilute hydrochloric acid, washed with ether, do with dilute sodium hydroxide solution alkaline, extracted with ether , dried, evaporated and obtained bis- (4-piperidinophenoxy) -acetic acid isobutyl ester.

309825/1164

- 4G -

2183056

Example 14

16.5 g of bis (4-aminophenoxy) -acetic acid ethyl ester are boiled in 170 inX n-butanol together with 23 g of 1,5-dibromopentane and 14 g of powdered K ₀ CO _{0 for} 15 hours. the butanol distills off, - dissolves the residue in 150 ml of benzene and boils with 10 ml of acetic anhydride for 2 hours. The reaction mixture is cooled, washed with 1N NaOH and extracted with 20% HCl. The aqueous hydrochloric acid solution is made alkaline, extracted with ether, the ether phase washed neutral with water, dried and evaporated. Bis- (4-piperidino-phenoxy) -acetic acid ethyl ester, dihydrochloride, decomposition at 208 is obtained.

Example 15

2 g bis- (4-pyrrolidino-phenoxy) -acetonitrile (available from 4 * -Pyrrolidino-phenol and Diohloracetonitril) are with 2 g of KOH in 20 ml of ethanol and 2 ml of water boiled for 40 hours, It is evaporated, mixed with water, extracted with ether, hydrochloric acid is added to pH 5 and bis - ^ - pyrrolidinophenoxy) acetic acid is obtained.

In an analogous manner, alkaline hydrolysis of

309825/11

2183058

Bis ~ (4-piperidino-phenoxy) -acetonitrile bis ~ (2-methyl-4-piperidino-phenoxy) ~ acetonitrile bis- (2 ~ chloro-4-piperidino-phenoxy) ~ acetonitrile bis- (3-chloro-4- piperidino ~ phenoxy) -acetonitrile bis- (4-homopiperidino-phenoxy) -acetonitrile bis- (4-pyrrolidinoiae thy 1-phenoxy) -acetonitrile bis- (4-piperidinomethyl-phenoxy) -acetonitrile bis- (4-homopiperidinomethyl-phenoxy) -acetonitrile bis- _< / 4- (4'pyrrolidiiioplienyl) -phenoxyy ^r -acetonitrile bis- / Τ- (4-piperidinophenyl) -phenoxyJ7-acetonitrile bis- ^ 4- (4-homopiperidinophenyl) -phenoxyy «acetonitrile bis- ^ 4- (3-hydroxy-pyrrolidino) -phenoxy-4-acetonitrile bis- / 4- (3-hydroxy-piperidino) -phenoxy-7-acetonitrile

Bis- (4-morpholino-phenoxy) -acetonitrile bis- (4-isoindolino-phenoxy) -acetonitrile bis - /? - (1,2,3,4-te trahydro-quinolino) -phenoxyj ^ -aceonitril bis- ^ / T- (1,2,3,4-te trahydr 0-4-quinolylj-phenoxyy ^ -acetonitrile bis- ^ l- (1-methyl-1,2,3,4 ~ tetrahydro-4-quinolyl) -phenoxyy ⁷ -acetonitrile

Bis / 4- (l-ineth; .l-4-piperidyl) -phenoxyy ^r ~ acetonitrile

the corresponding carboxylic acids

3 0 Q '''? 5/1 1 6

, Example 16

14 g of bis "(4 = -pyrroliiixno piienoxy ~}« acetoaitril be nit 6NC nil acetic acid and 60 ml concentrated hydrochloric acid 2 StuMsE mrfcsr Stickstof cooked "It is evaporated eiöj dissolved in dilute KeOH ₂ extracted with ether, hydrochloric acid is to pE 5 hiiiEi!: ϊΐπ, ΰ. er «* hold up> - (4« pyrrolitTino ~ phenoxy} - »es-3igasurs _e

In an analogous manner, acid hydrolysis gives that in example named nitriles the corresponding carboxylic acids,

Example 17

3 g bis (4-pyrrolidino «phenoxy) acetamide (obtainable from 4 «pyrrolidinophenol and dichloroacetamide) and 5 g of KOH boiled in 100 ml of ethanol under nitrogen for 3 hours. It is evaporated, water is added and the mixture is extracted with ether Hydrochloric acid is added up to pH 4 and receives bis ~ (4-pyrrolidino-phenoxy) acetic acid"

In an analogous manner, alkaline hydrolysis of

Bis- (4-piperidino-phenoxy) -acetamide Bis (2-methyl-4-'piperidino-phenoxy) -acetamide Bis (2-chloro-4-piperidino) phenoxy) acetamide Bis «(3-chloro ~ 4 ~ piperidino) phenoxy) acetamide Bis- (4-homopiperidino-phenoxy) -acetamide Bis * - (4-pyrrolidinomethyl-phenoxy) -acetamide Bis (4-piperidinomethyl-phenoxy) -acetamide Bis- (4-homopiperidinomethyl-phenoxy) -acetamide Bis- ^ 4- (4-pyrrolidinophenyl) -phenox £ 7-acetamide Bis ~ / 4 ~ (4 ~ piperidinophenyl) -phenoxyy-acetamide

3.09 825/1184

21S3056

Bxs - ^ "(4-honiopiperidinophenyl) - phenoxyy ^r -acetäniid Bis ~ ^ - (3-hydroxy-pyrrolidino) -phenoxyJ7-aeeta: mid bis- / 4" - (3-hydroxypiperidino) «phenoxyJ7 ~ acetamide

Bis (4-inorpholino-phenoxy) -acetamide bis ~ (4-isoindolino-phenoxy) ~ Z4 -aeetamid bis (l, 2 _J 3,4-tetrahydro-quinolino) -ph8iioxyJ ⁷ '-acetaiaid bis / 4 " - (1,2,3,4-tetrahydro-4-ehinolyl) ~ phenoxyJ7-acetamide Bis - ^ / T- (l-methyl-1, .2,3,4-tetrahydro ~ 4 ~ ciiiiiolyl) - phenoxyj ⁷ -acetamide

Bis-Z4- (1-ynethyl-4-piperidyI) - «plienoxy _i 7 ~ .acetaiijid B is ~ £ ί ~> (1-pyrry 1) -phe η oxy / ^ ac et amide

the corresponding carbonic acids «.

Example 18

10 g bis ~ (4-piperidino ~ phenoxy) ~ aetyl chloride (obtainable from the acid and SOCl ₂ ). are heated for 3 hours at 95 ° ISIT 100 ml of absolute α-propanol. Do you pour in _? the residue is mixed with dilute sodium hydroxide solution and the aqueous solution is extracted with ether. The ether solution is washed twice with dilute NaOH and twice with water. It is dried, the ether is evaporated and bis «- (4« piperidino «phenoxy) - acetic acid n-propyl ester is obtained.

The corresponding esters are obtained analogously by alcoholysis of the acid chlorides of the formula V (WJ = COCl).

309825/1164

Example 19

9 g of ßis (4 ~ piperidino ~ pherioxy) ~ acetyl chloride are dissolved in 100 ml dissolved in absolute tetrahydrofuran and treated with 3 g of potassium tert-butoxide The mixture is stirred for 30 minutes at room temperature, filtered off with suction and the piltrate is evaporated, working as in the example and receives bis (4-piperidino-phenoxy ^ acetic acid-tert-butyl ester.

. Example 20

To a mixture of 24.4 g of bis-phenoxy-acetic acid, 14 g Iron (II) sulfate heptahydrate, 15 ml concentrated sulfuric acid and 6 ml of water, while stirring, a solution of 24 g of N-chloropiperidine in 30 ml is concentrated within 10 minutes Sulfuric acid was added dropwise. Intermediate arises (4-Piperidino phenoxy) -phenoxyacetic acid. The mixture is stirred for another 15 minutes at 20, Pour the mixture onto ice water, wash with ether, add sodium hydroxide solution to pH 5 and extract with chloroform. After evaporation, bis ~ (4-piperi ~ dino-phenoxy) acetic acid; Cyclohexylamine Salt, F. 182-184 ο

"In the same way, bis-phenoxymalonic acid gives Bis ™ (4« piperidinophenoxy) malonic acid, which is very easily decarboxylated to bis (4-piperidino «phenoxy) acetic acid.

309825/1164

Example 21

SS ml piperidine, unü. ? ₅ 3 g Ha-HH _? rjQrdee. under lülnrea saä Einloi'lirii vom StieEaitciL 3i?: i3 ötuucl ©, geköcfeto i-asolalisBeas adds

TJsitore 38 ral piperidine, boil and boil 12 sinuden iiat stirring. Intermediary creates the Trinatriums & lz OCE (4-Piperi * dino-pi eaoxy!) - (4 "sul £ ophenoxy)" fflaloiisäure. After cooling, water is added, the mixture is washed with ether and the aqueous phase, which contains bis- (4-piperidinophenoxy) malonic acid in the form of its disodium salt, is acidified with concentrated hydrochloric acid. The mixture is heated to 100 ° for 30 minutes, neutralized to pH 5, and bis (4- "piperidinuphenoxy) acetic acid · cyclohexylamine salt, mp 182-184 °, is obtained.

Example 22

A mixture of 34.5 g of bis (p-aminophenoxy) acetic acid * * dihydrochloride, 30 ml of piperidine and 1 g of AlCl ₀ is heated to 200 in an autoclave for 48 hours. Intermediate is formed (4-aminophenoxy) - (4-piperidinophenoxy )-acetic acid. After the usual work-up, bis (4-piperidinophenoxy) acetic acid is obtained. Cyclohexylamine salt, m.p. 182-184 °.

3 0 9 H 7 5/1164

Claims (1)

~ 52 - Γΐ / Compounds of the general formula I wherein 2
Z and Z each O or S, R ¹ H or alkyl with 1 - 10 C atoms, R ² H or COOR ⁷ R ³ and R ⁴ R ⁸ , R ⁸ -CH ₂ -, pR ⁸ -C ₆ H ₄ -, 3-hydroxypyrrolidino, 3-hydroxy piperidino, morpholino, Isoindolino, 1,2,3,4-tetra 9 λ hydro-chinoliiio, 1-R -1 ^, 3, -? tetrahydro-4-quinolyl, 1-R-4-piperidyl or 1-pyrryl,
R ⁵ and R ^{6 are} each H, alkyl with 1-4 C atoms or Hai each H or A
1-10 carbon atoms, Q IO Ii, R and R ^v each with H or alkyl R pyrrolidino, piperidino or homopiperidino and Hal F, Cl, Br or J
mean, as well as their physiologically harmless salts with acids or bases 309! * 75/1164 2o compounds of the general formulas Ia to II » 3. Bis (4-piperidinophenoxy) acetic acid. 4 · bis- (4-piperidinophenoxy) -acetic acid ethyl ester » 5β bis (4-isoindolinophenoxy) -acetic acid ethyl ester. 6, bis (4-piperidinophenoxy) malonic acid dimethyl ester. 7. Bis ~ (4-piperidinophenoxy) ~ malonic acid diethyl ester. 8β bis- (3-chloro-4-piperidinophenoxy) -malonic acid dimethyl ester. 9. Dimethyl bis- ^ 4- (4 ~ piperidinophenyl) -phenoxyJT'-malonic acid 10 · Process for the preparation of compounds of the general formula I and their physiologically acceptable salts with acids or bases, characterized in that a phenol or »thiophenol of the formula II "5 in which I 13 5 Z, R. And R have the meaning given in claim 1 or a reactive functional derivative of such a compound with a compound of formula III 309825/1 16 ~ 54 - Z ² -CXII ² -C00Ii ¹ wherein X is optionally esterified oil, Cl, Br or J and ρ "Ι p Λ Λ Z, R, It, R and R have the meaning given, converts or that a compound of the formula IV CR ² ^ COOR ¹ wherein Y tetramethylene, pentamethylene, hexamethylene, 2-hydroxytetramethylene, 2 — hydroxy— pentamethylene, 3 ~ 0xapenta- * methylene or o-xylylene, X Cl, Br, _{I, NH 2} or an optionally esterified or etherified OH group and X is a bond, -CH ₂ - "or PC _n H .- * and IPIP λ / nO * fc Z | Z-, R, R and R to R have the meaning given to have treated with eyecatching agents or that in a compound of the formula V 3 ü 9 8; Γ) / I 1 ß k wherein W denotes an optionally functionally modified COOL group and -ι ρ Q P. _v Z, Z and R to R have the meaning given, the remainder W by treatment with solvolysing, thermolysing or ester-forming agents into the residue GOOR or that a compound of the formula VI , in which X ³ H, Cl, Br, I, NH ₀ or SO _Q M and _{M is an} equivalent of a metal atom and Z, Z, R, R and R to R have the meaning given, with a compound of the formula VII _R 3 " _X 4 wherein VII X ⁴ denotes Π, M or X and 3
R, M and X have the meaning given, with the proviso that the radicals X and X are not the same and one of these radicals is H or optionally M, implements and that, if appropriate, in a compound of the formula I obtained, the radical R is converted into another radical R and / or a compound of .Formel I obtained by treating with Acids or bases are converted and / or into their physiologically harmless acid addition or metal or ammonium salts a compound of the formula I is set free from one of its salts by treatment with a base or acid. 11. Process for the production of pharmaceutical preparations, 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 brings substance and optionally together with at least one other active ingredient into a suitable dosage form, 12. Pharmaceutical preparation containing an effective dose a compound of the formula I in addition to at least one solid, liquid or semi-liquid carrier or additive. 13. Pharmaceutical preparations containing 10 to 1000 mg a compound of the formula I in addition to at least one solid, liquid or semi-liquid carrier or additive. 309825/1164