DE2355115A1 - SUBSTITUTED PHENOXYALCANCARBON ACIDS, FUNCTIONAL DERIVATIVES AND SALT THEREOF, AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Applicant: CARLO ERBA S.p.A., Via Carlo Imbonati 24, 1-20159 Milan, Italy

Substituted phenoxyalkanecarboxylic acids, functional derivatives and salts thereof and processes for their preparation

The invention relates to new substituted phenoxyalkanecarboric acids, functional derivatives and salts thereof and processes for their production and pharmaceutical preparations containing them. ■

In recent years, the search ¹ for substances with hypolipidemic activity has led to the preparation of compounds with good pharmacological activity, but which have not significantly broadened the range of drugs indicated for the prevention or treatment of hyperlipidemia. Even today nicotinic acid, D-tyroxine, cholesteramine and clofibrate are the compounds of the Xiahl for this type of disorders, although there are also not negligible negative aspects related to the administration of these substances, such as the high levels required. Doses and the low gastrointestinal tolerance cannot be avoided. In addition, the hypocholesterolemic effect is often given more attention than

409819/1172: - '

ORIGINAL INSPECTED

the hypotriglyceridemi see effect, however, this preference is not justified for scientific reasons.

It has now been found that certain new compounds represent a real advance in the therapy of hyperlipid

anticancer insofar as it is a good hypolipidemic marriage Activity, especially good hypotriglyceridemic activity without any of the disadvantages mentioned above occurring "

The invention relates to new compounds of the general formula

where mean:

_{R 1} and R 2, which can be the same or different from one another, each represent a hydrogen atom, a lower alkyl radical or an unsulfited or halogen, lower alkyl or trifluoromethyl substituted phenyl group;

R ~ _f R, _s Rc, Rg and R ₇₅ which can be the same or different from one another, each a hydrogen atom or a halogen atom, a hydroxy, lower alkyl, lower alkoxy, cyano, nitro, unsubstituted or mono- or di- lower alkyl »substituted amino, acylamino, trifluoromethyl or penta

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- ■ 3 -

fluoroethyl group; .

η is the number 0.1 or 2 _S.

as well as the functional derivatives or salts thereof »

It should be noted ₉ that the above definition of the invention s according to s compounds also include all possible Sterecisomeren and their mixtures "The terms" alkyl group "used herein and" alkoxy "represent branched» chain or straight chain alkyl = and alkoxy groups _a The here in Compound with organic radicals ₉ groups or compounds used expression "low" stands for those organic radicals, groups or compounds _s which contain up to I _9, preferably up to 4 carbon atoms «

Examples of suitable medrigalkyl radicals are methyl, ethyl, n-propyl, isopropyl, n ° butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl-j n -Hexyl =, isohexyl, n-heptyl and isoheptyl radicals _o -

Examples of suitable Medrigaikoxyreste are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy _s, 'sec-butoxy, tert-butoxy radicals.

If R 1, R 1, R ^, Rg and / or R _{7 are} an acylamino group, the acyl radical is preferably an aliphatic Cj-CL-acyl radical.

• 409819/1172 -

Functional derivatives of the compounds given above are for example the esters of the acids of the formula I, e.g. the C, -C »-alkyl or -alkenyl esters, the cycloalkyl, cycloalkenyl , Cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl or azacycloalkyl, e.g. N-lower alkyl-substituted azacycloalkyl esters, in which the cycloaliphatic radical contains 3 to 7 ring members, the aryl or aryl lower alkyl esters, in which the aromatic radical is preferably an optionally substituted (e.g. by one or more alkyl or alkoxy groups substituted) phenyl group, the free or etherified hydroxy-lower alkyl esters, e.g. the lower alkoxy-lower alkyl or cycloalkoxy-lower alkyl esters or the tert-Amino-lower alkyl esters in which the tert «-amino group for example a di-lower alkylamino group, e.g. a dimethylamino or diethylamino group, a cyclic alkyleneamino group, e.g. a pyrrolidino or piperidino group, a cyclic monoaza, monooxa or monothiaalkyleneamino group, e.g. a piperazino or 4-lower alkyl piperazinogru.ppe, e.g. a 4-methyl-piperazino or 4-ethyl-piperazino group, is a moropholino or a thiomorpholino group.

Further preferred functional derivatives of the acids according to the invention of the formula I given above are, for example, the optionally substituted amides, such as the mono- or di-lower alkylamides, the free or etherified hydroxy mono- or di-lower alkylamides, the cyclic alkylenamides or the cyclic monooxa-, monoaza- or monothiaalkylenamides, the arylamides or aryl-lower alkylamides, in which the aromatic radical

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^ ^2x N-CH

preferably a phenyl group, which is optionally substituted by, for example, one or more lower alkyl or lower alkoxy groups. If it is in the functional derivative of an acid of Eormel I a Azacycloalkylester, so ¹ is preferably an ester of the type

where χ + y = 3, 4 or 5.

If the functional derivative of an acid is the " Formula I is its cyclic alkylene amide or a cyclic one Monooxa-, Monoaza- or Monothiaalkylenamid acts, so acts it is preferably one of the type

Wed

-b-C-N

where A is an oxygen, nitrogen or sulfur atom or a -CH ₂ radical and χ + y = 3, 4 or 5.

Particularly preferred compounds are those of the formula I in which R ^, R ,, R ^ and R ^ each represent a hydrogen atom or a methyl group, R _& , which is preferably in the 4-position, a hydrogen atom, a hydroxyl group or a halogen atom, preferably denotes a chlorine atom, η is the number 0 or 1, R, a hydrogen atom or a lower alkyl radical, preferably a methyl radical, and R "denotes a lower alkyl radical, preferably a methyl or ethyl radical, so-

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like the C-C alkyl esters, e.g. the hydroxy-lower alkyl esters, Lower alkoxy-lower alkyl ester, an amide, mono- or di-lower alkyl amide, hydroxymono- or di-lower alkyl amide or a pharmaceutically acceptable salt thereof. Particularly preferred esters are those with aliphatic C 1 -C 4 alcohols, in particular the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-octyl and n-dodecyl esters. When the amide is a mono- or di-lower alkyl amide or a hydroxymono- or di-lower alkyl amide. is the lower alkyl radical preferably a methyl or Ätiiylrest.

Examples of suitable salts of the compounds of the formula I. are the ammonium and metal salts, e.g. the sodium, potassium and calcium salts, as well as the salts with suitable amines and also the salts of a compound of the formula I which contain a basic group, e.g. an amino group, with a pharmaceutically, tolerated acid. Examples of specific compounds of the invention are as follows:

Ethyl α- [p- (4-hydroxyphenyl thio) phenoxy] α-methyl propionate; Ethyl α- [p- (4-hydroxyphenylthio) phenoxy] propionate; Ethyl cs- [p- (4-hydroxyphenyl thio) phenoxy] acetate; α- [ρ- (4-hydroxyphenyl thio) phenoxy T-ct -raethylpropionic acid; - [p- (4-Hydroxy-2-methylphenylthio) -m-methyl-phenoxy] -a-methyl-

propionic acid:, -

, -phenoxy]

Butyl α- [ρ- (4-hydroxyphenylthio) ^ α-methyl propionate; Ethyl α- [ρ- (4-hydroxy-2-methylphenyltMo) -m-methyl-phenoxy] -α-methyl-propionate;

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α- [ρ- (4 «chlorophenylthio) -m-methyl ° phenoxy] -propionic acid %. Ethyl-α- [ρ- (4 ~ hydroxyphenylthio) -phenoxy] «a-methyi-propionate · = sulfoxydj

Ethyl-α- [p- (4-hydro3iyphenylthio) = plienoxy] «a ° methyl = propioaat = '

S _? S ° dioxydf.

Ethyl ° a ° [p »(4-nitrophenylthio) -ra-methy! -Phenoxy} => a = methyl ° propionate

Ethyl = a- [ρ- (4-nitrophenylthio) = phenoxy -] "= a«> methyl propionate 5 ' Ethyl = a = - [p «- (2« nitrophenylthio) phenoxy] ° a ° methyl propionate 5 Ethyl = a ° [ρ- (4 »aminophenylthio) -m-methyl ^ phenoxy} ° a = methyl ° propionate

c ° [p- (phenyl thio) -phenoxy] -a-methyl- = propionic acid j Ethyl-α- [ρ- (phenylthio> -phenoxy] -α-methy1-propionate 5 ethyl-α- [p- (4- ChIOrPhGnJi-I ^ iO) -phenoxy] -a-methyl-propionate5 ethyl = a = [ρ- (4-chlorophenylthio) -phenoxy] -propionate ° ₉ ethyl-α- [p- (4-methoxyphenylthio) -phenoxy] Α-methylpropionate | - N-2 = hydroxyethyl-α- [p- (4-hydroxyphenyl thio) -phenoxy-] - α-methylpropionamido

The compounds according to the invention can after a? Er ° drive are produced, which is characterized by -that one

(a) a compound of the general formula

II

4 0 9 8 19/1172

in which the hydroxyl group is free or has been converted into a salt and in which η, R_, R ,, R ₁ -, R, and R _{7 have} the meanings given above,

l ^

with a compound of the general formula _n _ ^ ΰ = Ο

^R 2

wherein R, and R_, which are the same or different from one another can mean lower alkyl radicals,

and a compound of the general formula CHX.-, in which X is a halogen atom, reacts to form a compound of the formula I given above, in which R ₁ and R- are lower alkyl radicals, and, if desired, a free acid of the formula I in which R. and R_ Mean lower alkyl radicals, or a sulfoxide or a sulfone thereof is converted into a functional derivative or a salt thereof;

(b) a compound of the general formula II given above, wherein the hydroxyl group is free or converted into a salt, with a compound of the general formula

X-C-COOH III

E ₂

wherein X has the meanings given above and R, and R ", the may be the same or different from one another, in each case a hydrogen atom or a lower alkyl radical or an optionally such as

A 0 9 8 1 9/1 1 7 2

mean substituted phenyl radical given above,

or reacted with a functional derivative or a salt thereof with formation of a compound of the formula Γ given above or a functional derivative or a salt thereof, and, if desired, the compound of formula I or one functional derivative or a salt thereof into another Compound of the formula I or a functional derivative or a salt thereof is converted in a manner known per se and, if desired, a mixture of isomers is separated into the individual isomers.

The reaction - the compound of formula II with the compound

1 ^.
of the formula _ J ^ C = O and the compound of the formula CHX- becomes

5 ^

preferably in the presence of an alkaline agent, for example ein.Alkalimetall- or alkaline earth metal hydroxide, and while slowly adding the halo form, preferably from Chloroform or bromoform, at the reflux temperature to that Dissolving the compound of formula II in the aliphatic ketone and then maintaining the mixture at the reflux temperature for a period of time, which is preferably between 3 and 8 hours. is carried out. The reaction of the compound of the formula II with the free hydroxyl group with a compound of the formula III or a functional derivative thereof, for example an ester or an amide or a salt thereof, is preferably carried out in the presence of such agents - which are able to remove the hydrohalic acid such as an alkali metal hydroxide or carbonate.

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The compound of the formula II can also be used in the reaction in the form of a salt, for example in the form of an alkali metal salt, which can be produced, for example, by reaction with an alkali metal hydride or alkali metal alcoholate. When the ftmktionelle derivative of the compound of formula III a nitrile is _r can be obtained by hydrolyzing the reaction product, for example by treatment with concentrated aqueous acids or with alkaline agents, such as Alkal ime tallhydr oxy to a compound of formula I having a free carboxyl group can be obtained . Other functional derivatives of the compound of the formula III can be, for example, the acid anhydrides or halides. In this case too, the reaction product can easily be converted into the compounds of the formula I or a functional derivative thereof using methods customary in organic chemistry, for example by treatment with alcohols and with ammonia or amines or hydrolysis. The compounds of the formula I can be converted into another compound in a manner known per se.

For example, a compound of the formula I in which η denotes the number 0 or a functional derivative or a salt thereof can be converted into a sulfoxide, preferably by treatment with H ₇ O ₇ or with peracids, which can be prepared in situ. Peracids used with preference are peracetic acid, m- * chloroperbenzoic acid and permaleic acid.

A compound of the formula I in which η is the number O or 1 or a functional derivative or a salt thereof can be used in

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a sulfon (η = 2) can be converted, for example by treatment with excess H ₉ O ₀ O

Free acids can be esterified using alcohols in the presence of esterifying agents, for example strong acids such as hydrochloric acid, sulfuric acid, benzene sulfonic acid or p-toluenesulfonic acid, and also dicyclohexylcarbodiimide or diazo compounds. The esters may _s be hydrolyzed to free acids, for example, by treatment with suitable basic agents, such as aqueous alkali metal ■ hydroxides, or they may be with alcohols to give other esters in the presence of acids or alkaline Agenzieny such as mineral acids or complex heavy metal Saur en as well as alkali metal carbonates or " alcoholates, are transesterified. The esters can be converted to amides by treatment with ammonia or suitable amines. The amides may be hydrolyzed under acidic _s or alkaline conditions, for example by treatment with aqueous mineral acids and / or Garbonsäuren or alkali metal hydroxides, and they may be alcohol or transaminated.

Phenolic hydroxyl groups may be etherified _s for example, using the corresponding metal, such as alkali metal phenolates, by treatment with reactive ~ Low. alkyl esters of strong acids, for example halides or Niedrigalky Diniedrigalkylsulfaten and diazo compounds ₉ - z _a B. Niedrigdiazoalkanen. Phenol ethers can be split, for example by treatment with strong. Acids or acid salts, e.g.

40 9 8 19/1172

Hydrobromic acid and acetic acid and pyridine hydrochloride. In a nitro compound, the nitro group can become the amino group be reduced, for example by treatment with catalytically activated hydrogen or with a chemical reducing agent (nascent hydrogen).

Compounds with a primary amino group can be mixed with reactive esters of alcohols as well as with reactive functional derivatives, such as halides, e.g. chlorides or anhydrides of acids, converted and thus in compounds with secondary or tertiary and acylated amino groups.

By treatment with nitrous acid, compounds with a free amino group can be converted into diazonium salts, after the Sandmeyer reaction, for example by hydro. lysis at elevated temperatures by treatment with copper (II) halides or cyanides and with a lower alkanol, preferably below neutral or weakly / acidic or alkaline Conditions in which the corresponding hydroxyl, halogen, cyano or lower alkoxy compounds can be converted.

A free acid can in a manner known per se, for example by reaction with a stoichiometric amount of a suitable Salt-forming agent, e.g. ammonia, an amine or an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate, can be converted into a salt. The ammonium or metal salts of this type can be obtained by treatment with an acid, such as hydrochloric acid, sulfuric acid or acetic acid, into the

40981 9/1172

ORIGINAL INSfECTED

free acid can be converted until the required "pH value is reached." ^r ■ "=

A basic compound can be converted into an acid addition salt are, for example, by reaction with an inorganic or organic, pharmaceutically acceptable acid, such as Hydrochloric acid, hydrobromic acid and sulfuric acid or succinic acid, citric acid, tartaric acid, ascorbic acid. The acid addition salt obtained in this way can be converted into the free by treatment with a base, for example an alkali metal hydroxide Compound to be converted.

• ■ "■" -

Mixtures of isomers can be divided into the individual isomers in a manner known per se, e.g. by fractional distillation or crystallization and / or by chromatography. Racemic Products can be split into the optical antipodes, e.g. through splitting, such as through fractional crystallization, of mixtures of diastereoisomeric salts, e.g. with d-oc-phenylethylamine, d-a- (l-naphthyl) ethylamine or 1-cin-chonidine, and, if desired, by releasing the free antipodes the salts.

The starting materials are known or, if they are new, they can be prepared in a manner known per se. For example, the compounds of the formula II are either commercially available or they can, for example, according to the method described in "J. Am. Chem. Soc", 5_3, 3466 (1931), or according to the method described ^{in 11 J. Am. Chem.} Soc. "56, 1978 (1934), or according to that in" Croat. Chem. Acta ", 29, 277 (1957), or according to the method described in" J.Am.Chem.Soc. ¹¹ , 51, 1526 (1929),

0 9 8 19/1172 'ORIGINAL INSPECTED

235 5 ' ¹ p

The intermediates and starting materials obtainable by the processes described above can also be converted into one another using the methods described for the final substances.

The compounds according to the invention have a high hypolipid

hemic activity, especially high hypotriglyceridemic Activity on. This activity has been demonstrated under the following experimental conditions:

The compounds were administered orally for 7 days in the form of suspensions or solutions in various doses, with the animals used for this, young male Sprague Dawley rats, who were treated with it, were killed on the eighth day »· the. The lipid level in the serum was determined, and the weight of the liver was also determined both in absolute terms and as a percentage certainly.

The data obtained were statistically evaluated and the specific activity of the various compounds, which expresses the hypolipidemic activity, and the hepatomegalia-inducing effect is determined in the form of the ED,, - values. The results obtained were compared with those seen using known hypolipidemic Agents such as clofibrate were obtained under the same experimental conditions and it was found that the compounds according to the invention are much more pronounced hypolipidemic than, for example, clofibrate

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ORIGINAL IHSPECTED

Activi ts as well.

The Hepatomegal'ia was particularly hypotriglyceridean with respect to it Effect considered, taking the therapeutic index as the ratio of hypotriglyceridemic Effect to hepatomegalia-inducing effect was calculated; In this respect, too, those according to the invention have proven themselves Connections as better than the known comparison connections. ·

The compounds according to the invention can advantageously be pharmaceutical Carriers or diluents, such as gelatin capsules, microcrystalline cellulose, lactose, natural gums, starches, such as Corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose? Ethyl cellulose, methyl cellulose, cellulose acetate phthalate, gelatin, talc, stearic acid, magnesium stearate as well as other non-toxic, compatible substances, such as those used in pharmaceutical preparations to be incorporated. The preparations of the invention are preferably those suitable for oral administration Form., For example in the form of tablets and capsules.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto. Some of the in oily compounds given in the following examples not by their boiling point (at which they are when heated decompose) and they were therefore determined by their retention ". time characterizes. It became the retention time of the following

409819/1172

? Ί RR 1 1 "

- 16 - Z O O - ^! .

Links:

Ethyl-α- [ρ- (4-hydroxyphenylthio) -phenoxy] -α-methyl-propionate, Butyl-α- [ρ- (4-hydroxyphenylthio) -phenoxy] -a-methyl-propionate, Ethyl a- [p- (2-nitrophenylthio) -phenoxy] -a-methy1-propionate, Ethyl-α- [p- (phenylthio) -phenoxy] -a-methyl-propionate, Ethyl a- [p- (4-methoxypheny1thio) -phenoxy] -a-ynethyl-propionate, Ethyl α- [ρ- (4-chlorophenylthio) -phenoxy] -a-methyl-propionate and Ethyl α- [ρ- (4-chlorophenylthio) phenoxy] propionate

using a Fractovap ^ gas chromatograph, model GI, under Using the following experimental gas-liquid chromatography conditions certainly:

Glass column (length 2 m, inner diameter

3 mm)

stationary phase OV-7 1% on acid washed

silanized gas-chromium-P (0.15 to 0.12 mm (100 to 120 mesh))

Temperatures column: range between 220 and

260 C (see the respective example

Injection opening and detector (FID): 300 ⁰ C

^ -Flow rate 60 ml / min.

Before the compounds ethyl-α- [p- (4-hydroxyphenylthio) -phenoxy] α-methyl-propionate and butyl-α- [p- (4-hydroxyphenylthio) -phenoxy] · α-methyl propionate the experimental conditions given above

4 0 9 8 19/1172 OHiGlHAL INSPECTED

■ 2355H 5

have been subjected to gas chromatiographic analysis, they were treated with N-O-bis (trimethylsilyl) acetamide for 30 minutes converted into their trimethylsilyl esters at 50 C and subsequent dilution in chloroform.

The retention time of the compound ethyl-α- [p- (4 ~ aminophenylthio) m-methyl-phenoxy] -a-methyl-propionate was by means of a Fractovap ^ Gas Chromatograph, Model GBj using the following experimental gas chromatographic conditions certainly: "

pillar

stationary phase

Temperatures

Glass (length 2 m, inner diameter 3 mm)

XE 60 1% on acid-washed, silanized gas-chromium-P (0.15 to 0.1-2 mm (100 to 120 mesh))

Column: 230 ⁰ C

Injection port: 300 C Detector (F.I.D.): 320 ° C

^ -Flow rate 50 ml / min.

The structure of the oily compounds given in the examples was confirmed by its infrared spectra.

example 1

20 g of thiobisphenol were dissolved in 200 ml of anhydrous dimethyl

4 0 9 8 19/1 172

ORIGINAL SNSPEpTED

2 3 5 5 ¹ ~ ^] 5

formamide (DMF) dissolved and in.small portions were taken Stirring 4.4 g of 50% NaH added. After stirring for 30 minutes 17.9 g of ethyl a-brbmisobutyrate were added dropwise at room temperature. After stirring at 155 ° C. for 2 hours, the mixture was cooled, filtered, then the solvent was removed in vacuo evaporated. The product that remained was taken up with acidified water and extracted with benzene, which was then washed with NaCl saturated water and dried over sodium sulfate. The one left behind during evaporation The product was ethyl-α- [p- (4-hydroxyphenylthio) phenoxy] -a-methy 1-propionate (7.1 g) (column temperature: 250 G, retention time 4 minutes 48 seconds); IR (capillary film):

\ 7 OH 3400 cm " ¹ , VC = O 1730 cm" ¹ , V COC 1270, 1230, 1170, 1140 cm " ¹ .

Using the same procedure, the following compounds were made:

Ethyl α- [p- (4-hydroxyphenylthio) phenoxy] acetate, m.p. 112 bis 114 C, after crystallization from benzene; Ethyl α- [p- (4-hydroxyphenylthio) phenoxy] acetate, m.p. 121 bis 122 C, after crystallization from benzene; Ethyl α- [p- (4-hydroxy-2-methyl-phenylthio) -m-methyl-phenoxy] -a-methyl-propionate, F. 70 to 72 C, after crystallization from ligroin.

Example 2

A mixture of 1 mole of thiobisphenol and 6.5 moles of sodium

409819/1172

hydroxyd in 24.MoI acetone mrde heated under reflux, then 1 mol of chloroform was added dropwise, the exothermic reaction being monitored. After this addition, the mixture became Maintained at the boil for 5 hours, filtered and that Acetone was distilled off. "The product that remained was dissolved in water and, after acidification, with chlorine was added the α- [ρ- (4-Hydroxypheny1 thio) -phenoxy] was α-methyl-propionic acid separated off (yield 27%), F. 96 bis 98 C (after crystallization from toluene).

Following the same procedure, the following compounds were made

manufactured: - '

α-] p- (4-Hydroxy- 2-methylphenylthio) -m-methyl 1-phenoxy] -α-methyl 1-propionic acid, F. 140 C for crystallization from benzene)> α- [ρ- (4-Hydroxyphenyithio) -phenoxy] -a-ethyl-propionic acid.

Example 3

4.7 g of a- [p- (4-Hydroxyphenylthio) -phenoxy] -a-methyl-propionic acid chloride were heated in 47 ml of octanol for a few hours, the excess octanol was evaporated under vacuum and the remaining product was purified to give 2.1 g of octyl α- [p- (4-hydroxyphenylthio) phenoxy] α-methyl propionate.

Following the same procedure, the following compound was made manufactured?

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Dodecyl α- [ρ- (4-hydroxyphenylthio) phenoxy] α-methyl propionate. Example 4

2 g of the α- [ρ- (4-hydroxyphenylthio) phenoxy] -a-methylpropionic acid prepared in Example 2 or by saponifying the ethyl ester prepared in Example 1 were dissolved in 20 ml of butanol and concentrated in the presence of 0.2 ml Hydrochloric acid was heated to boiling for 30 minutes, then the reaction mixture was evaporated to dryness, the remaining oil was taken up in ethyl ether, washed with an aqueous 5% NaHCO 2 solution and finally with water. The organic phase was _{dried over Na 3} SO and bleached with animal charcoal. The product remaining on evaporation was 1.4 g of butyl α- [p- (4-hydroxyphenylthio) phenoxy] -oc-methyl propionate (column temperature: 260 ° C., retention time 6 minutes 3 seconds); IR (CHCl-): V OH 3400 cm " ¹ , y C = O 1720 cm", γ COC 1270, 1230, 1170, 1140 cm.

Using the same procedure, the following compounds were made:

Propyl a- [p- (4-hydroxyphenylthio) phenoxy] propionate; Ethyl α- [p- (4-hydroxy-2-methylphenylthlo) -m-methyl-phenoxy] -a-methyl-propionate, F. 70 to 72 ° C (after crystallization from ligroin). - - ■ -

409819/1172 ^^ _msPEC tEff

Example 5

A solution of 0.045 mol of 2.2 ^l -di-tert-butyl-6.6 ^l -dimethyl-4,4'-thiobisphenol in 400 ml of acetone was after the addition of 0.045 mol of K “CO, for 18 hours under strong Stirring kept at boiling. After cooling, 0.045 mol of ethyl a-bromopropionate was added dropwise, the mixture was then stirred again and refluxed again for 60 hours. After cooling and filtering, the reaction mixture was evaporated to dryness and taken up in ethyl ether, which was then washed with water _{, dried over Na 2} SO, and removed by evaporation under vacuum. 4.6 g of product were isolated from the remaining oil, which after saponification with KOH in ethanol was α- [p- (5-itert-butyl-4-hydroxy-3-methyl-phenylthio) -o-tert-butyl -o'-methy! phenoxy "! propionic acid (m.p. 54 to 56 ° C)."

Example 6 . ~~. - -

To a solution of 4 g of ethyl a- [p- (4-hydroxyphenylthio) phenoxy] -a-methylpropionate in 100 ml of glacial acetic acid, a stoichiometric amount of H ₃ O ₇ (36 ml) was added with stirring, then the mixture was added stirred at room temperature for 24 hours and then poured into ice water. The solid thereby gradually forming product was filtered off, washed with water and dried to give 2.3 g of ethyl ^a-i [p- (4-hydroxypheny1thio) -phenoxy] -a-methylpropionate sulfoxide, F. 99 to 101 of C (after crystallization from benzene / ligroin).

4098 19/1172

7 r _3ö £ ο

Example 7

A stoichiometric amount of 50% NaH (7.2 g) was added in portions with stirring to a solution of 37.6 g of 4,4 ^I- dihydroxydiphenylsulphone in 400 ml of DMF. After stirring for 1 hour at room temperature, 24.6 g were added Ethyl α-bromoisobutyrate was added dropwise, the mixture was then stirred for 24 hours at room temperature. The reaction mixture was filtered and the solvent was removed by evaporation in vacuo. The remaining product was taken up in ethyl ether and washed with water. The ethyl ether was then dried over NaSO, and evaporated. The remaining product was isolated and 5.4 g of ethyl a ~ [p- (4-hydroxyphenylthio) phenoxy] -a-methylpropionate S, S-dioxide, mp 153 to 155 ° C. (after crystallization from ethanol ). The ethyl α- [p- (4-hydroxyphenylthio) phenoxy] -a-methyl-propionate-S, S-dioxide was also obtained by oxidizing the corresponding sulfide with _{excess H 7} O _{9 in boiling acetone, F. 152} up to 154 C (after crystallization from ethanol).

Example 8

To a solution of 13 g of 4-hydroxy-2-methyl-4 ^l -nitro-diphenyl sulfide in 150 ml of anhydrous dimethylformamide was added in small portions with stirring at room temperature 2.65 g of 50% strength NaH. After 1/2 hour, 11.7 g of ethyl a-brora-amethyl propionate were added dropwise and the mixture was 2 hours

409819/1172

ORIGINAL INSPECTED

kept boiling for a long time. After cooling and filtering, the solution was evaporated to dryness _3, the back while "remaining product was aufgenonmen in benzene and water _s

washed with water then saturated with 8% NaOH and finally isit / NaCl. After drying over sodium sulfate and filtering, the solvent was completely evaporated. The thereby remaining product subsequently crystallized from iso propyl ether morde ~ to give 2.8 g of ethyl-α- [p- (4-nitrophenylthio) -m-methylphenoxy] -a ° F. meth.ylpropionat _s 80 to 82 ° C.

Following the same procedure, the following compounds were made manufactured; . "" ■■ "..-.

Ethyl-α- [p- (4-nitrophenylthio) -phenGxy3-a-methylpropionät, F. 52 to 53 ° C (after crystallization from isopropyl ether); Ethyl α- [p- (2-nitrophenylthio) -phenoxy] -oc-methylpropionate (Column temperature: 260 C; retention time: 6 min. 13 sec.);

IR (CHCl): VC = O 1740 cm " ¹ , V" NO 1515, 1340 cm " ¹ , VC-OC

-1
1300, 1240, 1180, 1140 cm.

Example 9

A solution of 1.0 g of ethyl α- [p- (4-nitrophenylthio) -m-methylphenoxy] -a-methylpropionate in 20 ml of ethanol was in the presence of a catalyst (10% palladium on activated carbon) in a Parr apparatus hydrogenated. After stirring for about 2 hours, the Reaction ended; the reaction mixture was filtered twice

ORiGINALINSPECTED 40 9-8 19/1172

2355 Π 5

and the solvent was evaporated. The remaining product yielded 0.5 g of ethyl α- [p- (4-aminophenylthio) -m-methylphenoxy] -a-methylpropionate (retention time: 16 min. 30 sec.), IR (CHCl): V NH ₂ 3420, 3380 cm " ¹ , VC = O 1725 cm" ¹ , VC-OC 1280, 1240, 1170, 1140 cm " ¹ .

Example 10

6 g of the ethyl α- [p- (4-aminop ^x henylthio) -m-methylphenoxyj-a-methyl propionate obtained in Example 9 was dissolved in 25 ml of acetic anhydride and kept in a water bath for 1 hour. Evaporation of the reaction mixture to dryness gave a thick oily residue which was then purified to give 4.1 g of ethyl-α- [p- (4-acetylaminophenyl-

thio) -in.-me thy lphenoxy] -a-me thy lpropionate. Example 11

To a mixture of 1 mol of p-phenylthiophenol and 6.5 mol Sodium hydroxide in 24 moles of acetone, which was heated to reflux, was taken under. Control the exothermic reaction slowly 1 mol of chloroform was added dropwise. After this addition, the mixture was boiled for 5 hours, then filtered and the acetone was distilled off. The remaining product was dissolved in water and after acidification with hydrogen chloride acid became the α- [ρ- (phenylthio) -phenoxyj-a-methylpropionic acid obtained (yield 37%), mp 98 to 100 ° C. (after crystallization from cyclohexane).

4 0 9 8 19/1172 ORIGINAL INSPECTED

The α- [ρ- (phenylthio) phenoxy ■ i-a-me.thylpr.opionic acid yielded after boiling for 2 hours in absolute ethanol in the presence of concentrated HCl the corresponding ethyl ester (yield

given method 76%), which is also obtained according to the example / in the following

could be. (Column temperature: 220 C, retention time: 5, min. 30 sec.), IR (CHCl ₃ ) -: VC = O 1730 cm " ¹ , ν COC 1280, 1230, 1180, 1140 cm" ¹ .

Example 12

The stoichiometric amount of 50% NaH (2.0 g) was added in small portions with stirring at a temperature of 25 to 35 ° C. to a solution of 9.8 g of 4-chloro-4 ^{l -hydroxydiphenyl sulfide in 100 ml of anhydrous DMF} . After stirring for 2 hours, a stoichiometric amount of ethyl α-bromoisobutyrate was added dropwise, then the reaction was continued for 20 hours at room temperature. After filtering, the solvent was completely removed in vacuo, the remaining product was taken up in ethyl ether, which was then washed with water saturated with NaCl, dried over Na ~ SO, and also evaporated. The remaining oil gave 3 g of ethyl-α - [p- (4-chlorophenylthio) - phenoxy] -a-methylpropionate (column temperature: 240 C, retention time; 4 min. 57 sec.), IR (capillary film): VC = O 1740 cm " ¹ , V COC 1280, 1230, 1180, 1140 cm " ¹ .

Following the same procedure, the following compounds were made manufactured:

Ethyl α- [p- (4-chlorophenylthio) phenoxy] propionate (column temperature

temperature: 240 ° C: retention time: 5 min. 17 sec. V: IR (CHC1 ">:

409 81 9/1172

235511

N / C = O 1750 CnT ¹ ^ COC 1280, 1240, 1195, 1130, 1090 cm "¹; ethyl α- [ρ- (4-chlorophenylthio) -m-methylene! Phenoxy] -ceynethyl propionate;
Ethyl-α- [ρ- (4-chlorophenylthio) -m ~ methylphenoxy] -propionate · ·

The last-mentioned compound was saponified by KOH in ethanol and crystallization from benzene the α- [ρ- (4- chlorophenylthio) -m-nie thy! phenoxy] -propionic acid, Mp 99 ° C.

Example 13

An aqueous solution of 4.5 g of the potassium salt of ethyl α- [p- (4-hydroxyphehylthio) phenoxy] α-methylpropionate was prepared and cooled to 2 ° C., then this temperature became 2.0 during the dropwise addition g of dimethyl sulfate maintained. The resulting white suspension was stirred at 2 ° C. for 1 hour and at room temperature for 2 hours, after which water and ice were added. After extraction with chloroform, which was then washed with 8% NaOH and then with water saturated with NaCl, dried with CaCl ^ and finally evaporated to dryness, the oily residue gave 1.5 g of ethyl-α- [p- (4- methoxyphenylthio) phenoxy] amethylpropionate (column temperature: 240 C, retention time: 6 min. 27 sec.), IR (CHCl ₃ ): VC = O 1730 cm " ¹ , V COC 1280, 1230, 1180, 1140 cm" ¹ , γ> -OCH 1030 cm " ¹ .

Ethyl α- [p- (4-methoxyphenylthio) -phenoxy] -a-methylpropionate was also made by methylating the "corresponding 4-hydroxy derivative manufactured.

^409819/1172

Example 14

3.3 g of the ethyl ester of a- [p- (4-Hydroxyphenylaiio) -phenoxy] -α-methyl propionic acid were-for 5 hours in 3 ml of ethanolamine heated to 95 to 100 C. 'The excess amine was taking Distilled off in vacuo, the mixture was then dissolved in ethyl ether taken up, then washed and evaporated and that remaining product yielded 2.5 g of N-2-hydroxyethyl-a- [p- (4-hydroxyphenylthio) phenoxy] - «- methylpropionamide, F, 97 to 99 ° C.

■ * ■ ■■■ ·. "According to the same procedure, the following compounds

manufactured: .

N-2-hydroxyethyl-ir- [p- (4-hydr oxy-3-methyl-phenyl thio) -m-methyl-

phenoxy T-a-methyl propionamide ;; '

N-2-hydroxyethyl- [p- (4-chloro-phenylthio) -m-methyl 1-phenoxy] -propionamide; .- ·· ". ■

N, M-Pentamethylen-α- [p- (4-hydr oxy-phenyl thio) -phenoxy] -α-methyl propionamide.

4098 19/1172

ORIGINAL INSPECTED

Claims (1)

1. Substituted phenoxyalkanecarboxylic acids, characterized by the general formula (D - 28 - Claims where mean: R ₁ and R ₉ , which can be identical or different from one another, each represent a hydrogen atom, a lower alkyl radical or an unsubstituted or halogen, lower alkyl or trifluoromethyl substituted phenyl group, R, R ,, R ₁ -, R ^ and R ₇ , which can be the same or different from one another, each represent a hydrogen atom or a halogen atom, a hydroxy, lower alkyl, lower alkoxy, cyano, nitro, unsubstituted or mono - Or di-lower alkyl-substituted amino, acylamino, trifluoromethyl or pentafluoroethylene group and η the number 0, 1 or 2, as well as functional derivatives or salts thereof. 2. A compound according to claim 1, characterized in that the functional derivative is an ester or a 0 9 8 19/1172 _omasMA i_ INSPECTED ng Amid acts. 3. A compound according to claim 1, characterized in that the functional derivative is a C _{1 -C o} -alkyl or alkenyl ester, a cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl or azacycloalkyl ester in which the cycloaliphatic radical contains 3 to 7 ring members, an aryl or aryl lower alkyl ester, a free or etherified hydroxy lower alkyl ester, a tert-amino lower alkyl ester, an amide, a mono- or di-lower alkyl amide, a free or etherified hydroxy mono- or di-lower alkyl amide, a cyclic alkylene amide cyclic monooxa-, monoaza-, monothiaalkyleneamide, an arylamide or an aryl lower alkylamide, 4. A compound according to claim 1, characterized in that it the functional derivative is a C, -C, "- alkyl ester a hydroxy lower alkyl ester, a lower alkoxy lower alkyl ester, an amide, a mono- or di-lower alkyl amide, a hydroxymono- or di-lower alkyl amide. 5. A compound according to claim 1, characterized in that in the general formula IR _n , R ,, Rt- and R _{7 are} each a hydrogen atom or a methyl group, R ^ is a hydrogen atom, a hydroxyl group or a halogen atom, η the number 0 or 1 , R, a hydrogen atom or a lower alkyl radical and R "denotes a lower alkyl radical, as well as a CJC ₁ , - alkyl ester, a hydroxy lower alkyl ester, a lower 409 8 1 9/1 1 72 ( ORIGINAL INSPECTED alkoxy lower alkyl ester, an amide, a mono- or di-lower alkylamide, a hydroxymono- or di-lower alkylamide or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 5, characterized in that the alkyl ester is a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,
n-Qctyl or n-Dodecylester acts. 7. A compound according to claim 5, characterized in that the amide is a mono- or di-lower alkyl amide
or a hydroxy mono- or di-lower alkyl amide. 8. A compound according to claim 5, characterized in that it the amide is a mono- or dimethylamide or is a mono- or diethylamide. 9. Ethyl α- [p- (4-hydroxyphenylthio) phenoxy] α-methyl propionate. 10. Ethyl α- [p- (4-hydroxyphenylthio) phenoxy] propionate. 11. Ethyl α- [p- (4-hydroxyphenylthio) phenoxy] acetate. 12. α- [ρ- (4-Hydroxyphenylthio) phenoxy] -a-methy! -Propionic acid. 13. α- [ρ- (4-Hydroxy-2-methylphenylthio) -ni-methyl-phenoxy] -α-methy! -Propionic acid. 409819/1172 14. α- [ρ- (4-Hydroxyphenylthio) phenoxy} -a-! Ethyl propionic acid. 15. Octyl α "[ρ- (4-rhydroxyphenylthio) phenoxy ■] -α-methyl propionate 16. Dodecyl α- [ρ- (4-hydroxyphenylthio) phenoxy] - α-methyl propionate. 17. Butyl α- [ρ- (4-hydroxyphenylthio) phenoxy] α-methyl propionate. "■■" »■ 18 * Propyl α- [ρ- (4-hydroxyphenylthio) phenoxy] propionate. 19. Ethyl α- [ρ- (4-hydroxy-2-methylphenylthio) -m-methyl-phenoxy] -α-methyl propionate. 2Q. α- [ρ- (5-tert-butyl-4-hydroxy '»3-methyl-phenylthio) -o-tert-butyl-o'-methylphenoxy ^ -propionic acid. 21. α- [ρ- (4-Hydroxypheny 1 thio) -phenoxyI-α-methyl-propionate sulfoxide. 22. Ethyl a- [p- (4-hydroxyphenylthiO) -phenoxy] -a-methylpropionate-S, S-dioxide. 23. Ethyl α- [p- (4-nitrophenylthio) -m-methyl-phenoxy] -α-methylpropionate. ■ Λ098 1Β / 1172 ORIGINAL INSPECTED 24. Ethyl α- [ρ- (4-nitrophenylthio) phenoxy] -α-methylpropionate. 25. Ethyl-a- [p- (2-nitrophenylthio) -phenoxy] -a-raethy 1-propionate, 26. Ethyl α- [p- (4-aminophenylthio) -m-methyl-phenoxy] -a-methyl propionate. 27. Ethyl α- [p- (4-acetylaminophenylthio) -m-methyl-phenoxy] -amethyl-propionate. 28 »α- [p- (phenylthio) phenoxy] -a-methy1-propionic acid. 29. Ethyl α- [ρ- (phenylthio) phenoxy] α-methyl propionate. 30. Ethyl a- [p- (4-chlorophenylthio) phenoxy] -a-methyl propionate. 31. Ethyl α- [p- (4-chlorophenylthio) phenoxy] propionate. 32. Ethyl a- [p- (4-chlorophenylthio) -m-methyl-phenoxy] -a-methylpropionate. 33. Ethyl α- [p- (4-methoxyphenylthio) phenoxy] -a-methylpropionate. 34. & thyl a- [p- (4-hydroxy-2-methyl-phenylthio) -m-methylphenoxy] -a-raethyl propionate. 35. a- [p- (4-Chloro-phenylthio) -m-methyl-phenoxy] -propionic acid. A09819 / 1 36. N-2-hydroxyethyl-a- [ρ- (4-hydroxyphenylthio) -phenoxy} -α-methyl-propionamide. · 37. N-2-hydroxyethyl-a- [ρ- (4-hydroxy-3-methyl-phenylthio) -mmethyl-phenoxy] -a-methyl-propionamide. . - 38. N-2-Hydroxyethyl-a- [p- (4-chloro-phenylthio) -m -raethylphenoxyj-propionamide. 39. N, N-Pentamethylene-a- [p- (4-hydroxyphenylthio) -phenoxy] -a-methyl-propionamide. . ' 40. A method for producing a compound according to any one of preceding claims, characterized · that one (a) a compound of the general formula ^ ₇ 4 wherein the hydroxyl group is free or converted into a salt and n, R_, R,, R -, "- R" and R _{7 have} the meanings given in the preceding claims, «· R ₁ with a compound of the general formula ^Vs "C = O wherein R. and R-, which are the same or different from one another can be, mean lower alkyl radicals, with a 40 9 81 9/1 172`` · ' binding the general formula CHX ₃ wherein X is a halogen atom, reacts to form a compound of the formula I given in claim 1, wherein R, and R ~ mean lower alkyl radicals, and desired if a free acid of the formula I, in which R, and R "Niedri mean alkyl radicals, or a sulfoxide or a sulfone thereof is converted into a functional derivative or a salt thereof, * (b) a compound of the formula II, in which the hydroxyl group is free or converted into a salt, with a compound the general formula X-C-COOH (HI) R ₂ wherein X has the meaning given above and R, and R, which can be the same or different from one another, each represents a hydrogen atom or a lower alkyl radical or an optionally substituted phenyl group as indicated in the preceding claims, or with a functional derivative or a salt thereof is reacted to form a compound of the specified in claim 1 409819/1172 Formula I or a functional derivative or a salt thereof, and, if desired, a compound of Formula I or a functional derivative or a salt thereof in a manner known per se into another compound of the formula I or a functional derivative or a salt thereof and, if desired, a Isomeregeiiiiseh separates into the individual isomers. 41V ^ compound, characterized by the general formula II given in claim 40, as it can be obtained by the method according to claim 40 . 42. Pharmaceutical preparation, characterized in that that they a compound according to any one of claims 1 to 39 and 41 in conjunction with a pharmaceutically acceptable one Contains carrier or diluent. 4,998,971 172