DE2202715A1 - Substituted indenyl acetic acids - Google Patents

Description

Patent attorneys
Dr. Ing.Walter Abitz Dr. Dietician F. Morf Dr. Ham-A. Browns

8 Munich 86,

2 U.

14259

MERCK & CC, INC. Rahway, New Jersey, VISt.A.

Substituted indenylessic acids

The invention relates to new, substituted indenyl acetic acid compounds and methods of making them. In particular, the invention relates to compounds of the following general formula:

(D

wherein

Ar) an aryl or heteroaryl radical;

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R. a hydrogen atom, an alkyl or haloalkyl radical;

E _{2 is} a hydrogen atom, an alkyl, haloalkyl, alkenyl or alkynyl radical;

R_, R ^, Rc and Rg each hydrogen atoms, halogen, acyl, Cyano, alkynyl, allyloxy, alkylsulfinyl or alkylsulfonyl, Alkenyl radicals

Rrp is an alkyl sulfinyl or alkyl sulfonyl radical;

Rg is a hydrogen atom, a halogen, hydroxy, alkoxy, haloalkoxy, hydroxyalkoxy, alkylsulfinyl or alkylsulfonyl radical and : J

M is a hydroxy, lower alkoxy, substituted lower alkoxy, Amino, alkylamino, dialkylamino, N-morpholino, Hydroxyalkylamino, polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino or the Grouping OMe, in which Me is a cation, mean

with the proviso that at least one of the radicals R ₃ , R 1, R ₁ - and R 1 - is not a hydrogen atom or a halogen atom when Ro is a hydrogen atom, a halogen radical, a hydroxy or haloalkyl radical.

The indenominational core can be in the 1-position by an aryl ring system, z. B. benzene, naphthalene or biphenyl, or a heteroaryl ring system, e.g. B. a pyrrole, furan, thiophene, Pyridine, imidazole, pyrazine, thiazole and the like which have an alkylsulfinyl or alkylsulfonyl substituent Contains and can also with a halogen radical (chlorine, fluorine or bromine), hydroxy radical, alkoxy radical (Methoxy, ethoxy, propoxy and the like) or a haloalkyl group (Fluoromethyl, chloroethyl, trifluoromethyl radical and the like.) Be substituted.

Typical examples of compounds of the invention are as follows:

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5-fluoro-2-methyl-1- (3 ', 4-' -bismethylsulfynylbenzylidene) -3-indenylacetic acid, 5-fluoro-2-methyl-1- (3 ^I , ^ -'-bismethylsulfonylbenzylidene) -3-indenylacetic acid , 5-Ethyny 1- 2-methyl-1- (4'-methyl-sulfynylbenzylidene) 3-indenyl acetic acid, 5-acetyl-2-methyl-1- (V-methylsulfynylbenzylidene) -3 -indenylacetic acid, 5-ethynyl-2-methyl-1- (3-hydroxy-4'-methylsulfinylbenzylidene) -3-indenylacetic acid, 5-ethynyl-2-methy1-1 - (3'-β-hydroxyethoxy-4 '-methyl -Bulfinylbenzylidene) -3-indenylacetic acid, 5-ethynyl-2-methyl-1- (3'-β-chloroethoxy-4- ¹ -methylsulfynylbenzylidene) -3-indenylacetic acid, 5-ithinyl-2-methyl-1- (3 '-ethoxy-4'-methylsulfynylbenzylidene) -3-indenyl-8-acetic acid, 5-allyloxy-2-methyl-1- (4'-methylsulfynylbenzylidene) -indenyl-3-acetic acid

and their corresponding amides, esters and pharmaceutically acceptable salts.

It should be noted that the compounds of the invention isomerized to their cis and trans isomers by known methods can be. It should also be noted that the cis isomer of the compounds of the invention is essential is more effective than the trans isomer. Accordingly, reference in the specification and claims to the Compounds of the invention not only the compounds per se, but also their geometric isomers (cis, trans) lock in.

Those skilled in the art will also find that the alkylsulfinyl derivatives of the invention are racemic mixtures of optically active enentiomorphic forms, which in their (+) - and (-) - forms can be separated by known methods. Furthermore, if R,. is a lower alkyl radical, another, asymmetric atom that leads to two more enantiomorphs

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Leads forms that are also encompassed by the scope of the invention.

Those skilled in the art will also note that some of the Compounds are polymorphic and have different crystalline structures, melting points, and solubility properties exhibit.

The invention also relates to a method of treating pain, fever or inflammation in patients under Use of a compound of formula I, especially a particularly preferred compound, as an active ingredient.

The compounds of the invention can be used to treat inflammation while reducing inflammation and providing relief used by pain in such diseases as rheumatoid arthritis, osteoarthritis, Rheumatoid arthritis, infectious arthritis, and rheumatic fever.

The compounds of formula I also have anti-pyretic and analgesic activity and are used in the same way and administered and used in the same dosage ranges as they are for treating inflammation, such as explained in more detail below, can be used.

Treatment of inflammation according to the method of the invention is topical, oral, rectal or parenteral Administration of an agent of a compound of the formula I, in particular the particularly preferred compounds, in a non-toxic, pharmaceutically-acceptable Carrier to patient.

The non-toxic pharmaceutical carrier can, for example be either a solid or a liquid. Examples of solid carriers are lactose, corn starch, gelatin

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tine, talc, sterotix, stearic acid, magnesium stearate, kaolin, sucrose, agar, pectin, cab-o-sil and acacia gum. Examples of liquid carriers are peanut oil, olive oil, seam oil, and water. Similarly, the carrier or diluent may include a delay material such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.

Various pharmaceutical forms of the therapeutically active agents can be used. For example, when a solid carrier is used, the compositions may take the form of tablets, capsules, powders, troches, or pills made by standard pharmaceutical methods. When a liquid carrier is used, the preparation may take the form of a soft gelatin capsule, a syrup, an aqueous solution or a liquid suspension. Suppositories can be prepared in the usual way by mixing the compounds according to the invention with. a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature. Such materials are cocoa butter and polyethylene glycol. Gels and lotions for topical applications can be prepared in a conventional manner .

The active compounds of the formula I and the agents according to the invention are used in a sufficient amount to treat inflammation, d. H. to reduce inflammation. Advantageously included the agents contain the active ingredient, namely the compounds of formula I, in an amount of about 0.1 mg to 50 mg each kg body weight per day (5 mg to 3.5 g per patient per day), preferably from about 1 mg to 15 mg / kg body weight per day (50 mg to 1 g per patient per day).

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The method of treatment of the invention comprises the administration of a compound of the formula I, in particular a particularly preferred compound in admixture with a non-toxic, pharmaceutical carrier, for example of the type mentioned above, to a patient (animal or human). The compounds of the formula I and in particular the particularly preferred compounds are administered in an amount of 0.1 mg to 50 mg / kg of body weight per day, preferably from about 1 mg to about 15 mg per kg of body weight per day. The fastest and most effective anti-inflammatory effect is obtained by oral administration of a daily dose of about 1 to 15 mg / kg per day. It should be noted, however, that while preferred dosage ranges are indicated, the dosage level for any particular patient will depend on the effectiveness of the specific compound used. The person skilled in the art of the therapeutic use of medicinal agents, in particular those of the formula I _{1, will also recognize} many other factors which modify the effects of the drugs, such as age, body weight, gender, diet, time of administration, route of administration, rate of excretion, drug combination, Reaction sensitivities and the severity of the specific disease are taken into account.

In making the compounds of the invention the starting material is a β-aryl propionic acid. This connection is established according to the _{method described in flow diagram I 1,} which explains the various alternative routes. A substituted benzaldehyde can thus be condensed with a substituted ethyl acetate in a Claisen reaction or with an α-halogenated propylene acid ester in a Reformatsky reaction. The resulting unsaturated ester is reduced and hydrolyzed to obtain the benzylpropionic acid starting material. On the other hand, a substituted malonic ester in a typical malonic

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ester synthesis and acid hydrolysis of the substituted one obtained Esters directly the benzy! Propionic acid, or the Benzaldehyde can be reacted with propionic anhydride in a reducing medium to form benzyl propionic acid will.

Designations:

X is a halogen radical, usually Gl or Br;

E is an esterification group, usually methyl, ethyl or benzyl group;

Ep is a hydrogen atom, an alkyl, haloalkyl, . Alkenyl or alkynyl radical;

R ₇ ,, R ^, R _n - and R, - are each hydrogen atoms, halogen, acyl, cyano, alkenyl, alkynyl, allyloxy, alkylsulfinyl or alkylsulfonyl radicals.

Reagents:

1. Zn dust in an anhydrous, inert solvent, ζ. Β. Benzene and ether.

2. KHSO ^ or p-toluenesulfonic acid.

3 · NaOC ₂ H, - in anhydrous ethanol at room temperature.

4. H ₂ , palladium on carbon, 2.8 kg / cm ² (40 psi), room temperature.

5. NaOH in aqueous alcohol at 20 to 100 ° -r

6. NaOC ₂ Hc or any other strong base such as NaOH or K-tert-butoxide.

7. Acid.

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(I) Preparation of β-arylpropionic acid starting material

HO

I ²

t-CH-

X-CH-COOE

R R

H-CH-COOE H

COOE

R.

, -CH-COO «

H ₂ -CH-COOE

/CM

^U 2

H ₂ -C (COOE) ₂

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In preparing the compounds of the invention, again a number of routes as shown in Flow Scheme II possible. The first stage consists in the ring closure of the ß-arylpropionic acid to form an indanone, which is produced by a Friedel-Crafts reaction using a Lewis acid catalyst or by heating with polyphosphoric acid. The indanone can with an α-haloester in the Reformatsky reaction with the introduction of the aliphatic acid side chain with replacement of the Carbonyl group are condensed. It can also be introduced using a Wittig reaction in which the Reagent is an α-triphenylphosphinyl ester, a reagent which replaces the carbonyl group with a double bond on a carbon atom. This is instantly reflected in the Indene rearranged. If the Reformatsky reaction route is used, the intermediate product must be 3-Hydroxy-3-aliphatic acid derivative dehydrated to indene will. The introduction of the 1-substituent occurs in one of two ways; the first is the direct one Implementation of the indene with the aldehyde of the specified structural properties using a strong base as Catalyst and, if necessary, heating to form the carbanion. The reaction can take place in a number of solvents, for example polar solvents such as dimethoxyethane, aqueous methanol, pyridine, liquid ammonia, Dimethylformamid'und the like, or even in non-polar Solvents such as benzene and the like. Can be carried out. The indanon can also be brominated and then turned into an indenone are dehydrobrominated and the indenone carbonyl group by the substituent using the oc-triphenylphosphinyl compounds the desired structure can be replaced. It should be noted that E in the third stage and in the fifth stage represents a lower alkyl group and thus forms a lower alkyl ester of the desired compound. This ester can then be hydro-

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be lysed and with preservation of the sulfoxides and sulfones are oxidized, from which the salts, other esters and the amides can be made. Level 6 can also be performed when E is a hydrogen atom.

Designations:

X, E, 1 * 2 »R *, R ^, Rn and Rg are the same as in the flow diagram I;

Ar is an aryl or heteroaryl radical; Ry. is a hydrogen atom, an alkyl or haloalkyl radical; R is a hydrogen atom, or a lower alkyl radical and

Rg is a hydrogen atom, a halogen, hydroxy, alkoxy, Haloalkoxy, alkylsulphinyl, hydroxyalkoxy or alkylsulphonyl radical.

Reagents:

1. Friedel-Crafts reaction using a Lewis acid catalyst.

2. Heating together with polyphosphoric acid.

J. Reformatsky reaction: Zn in inert solvent, heating.

4. p-Toluenesulfonic acid and CaCl ₂ or _{I 2} at 200 °.

5 · Wittig reaction using (C ^ H ₁ -), P = CHCOOE "at 20 to 120 ° in ether, benzene, toluene, xylene and the like.

6. Reaction with aldehyde or ketone using a strong base as a catalyst (K-tert-butoxide or any - an alkoxide, NaOH, KOH, NaNH ₀ and the like.), Optionally heating with formation of the carbanion in solvents, such as, for example liquid ammonia, dimethylformamide, 1,2-dimethoxyethane, pyridine, aqueous alcohol and the like.

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(II) Preparation of α- (1-substituted methylenyl-3-indenyl) aliphatic Acids.

COOE

14259 l

Although the syntheses described give esters of the acids of the invention, some desired esters become simpler by forming a simple ester of the final acid, hydrolyzing to the free acid, and re-esterifying obtain. The simple lower alkyl or benzyl esters are commonly used in the synthesis of the compounds. Other esters are more beneficial from the standpoint of the compounds' therapeutic utility, such as the methoxymethyl, diethylaminoethyl, dimethylaminoethyl, Dimethylaminopropyl, diethylaminopropyl, N-pyrollidinyl - ethyl, N-piperidinylethyl, N-morpholinylethyl, N-ethyl-2-piperidinylethyl, N-pyrollidinylmethyl-, N-methyl-2-pyrollidinylmethyl-, 4-methyl-i-piperazinylethyl, ethoxyethyl, Ethoxyethyl ester and the like. These become the most common made from the corresponding alcohol / indenylic acid.

The amides, both the simple amide and the substituted amides, are prepared from the indenic acids in a similar manner and the corresponding amines. Morpholide and bis (hydroxyethyl) amide are particularly suitable therapeutically and the like

Similarly, salts are made by neutralizing the Indenyl acids obtained with bases or by double reaction of other salts. The metal salts are particularly suitable ζ. Alkali or alkaline earth salts, and the amine and quaternary ammonium salts which are water soluble, however are for some purposes also the heavy metal salts, e.g. B. iron, aluminum salts and the like., Suitable.

The following examples serve to further illustrate the invention:

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example 1

A. (5 _< 4-dimethylthio) -benzaldehyde; yd

To a mixture of 168 g (1.1 mol) phosphorus oxychloride and 158 8 (1 »07 mol) N-methyl-N-phenyl form amide are added dropwise 182.3 g (1.0 mol) of 1,2-bis-methylmercaptobenzene with stirring added at 50 °. The mixture is heated to 50 ° and held there for 2 hours, cooled to 25 ° and quenched in a mixture of ice and saturated sodium acetate. The solid is filtered off, dried and extracted from ethyl acetate / n-hexane recrystallized, and (3,4-dimethyl thio) benzaldehyde.

B. cis and trans-5-fluoro-2-methyl-1- (3 ^l , 4 -'-dimethylthiobenzylidene) -3-indenylacetic acids

22 g (0.40 mol) of powdered sodium methoxide become a suspension of 44.05 g (0.2 mol) of methyl 5-fluoro-2-methylindenyl-3-acetate and 46.2 g (0.22 mol) of (3,4-dimethylthio) benzaldehyde added in 400 ml of methanol under dry nitrogen. A clear solution is obtained, and this one The mixture is refluxed for 1 hour. An equal volume of water is added and the reflux treatment another 30 minutes to complete the saponification continued. The solution is cooled to room temperature and diluted with several volumes of water. nitrogen is blown through to remove any remaining ether. By adding 400 ml of 50% aqueous acetic acid the product is precipitated. The precipitate is filtered off, washed well with water and first in a Desiccator over potassium hydroxide beads, then at 100 ° in dried in an oven. The crude product is taken up in methylene chloride solution and over silica gel H to separate the cis and trans isomers chromatographed by integration of the 2-CH, signal in the NiIR spectrum at 7 »83

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for the cis form and 8.20 ppm for the trans form.

C. cis -5-fluoro-2-methyl-1- (3 ', V-bismethylsulfinylbenzylidene) -3-indenylacetic acid

1113 g (0.0422 mol) of sodium metaperiodate trihydrate in 85 ml of water become 3 * 62 g (0.01 mol) of cis-5-fluoro-2-methyl-1- (3 ', 4 ^l -dimethylthiobenzylidene) -3 -indenylacetic acid in 240 ml of methanol and 10 ml of acetone was added at room temperature. The mixture is stirred overnight, after which only a trace of starting material remains and only a trace of sulfone has formed. The mixture is concentrated to a small volume, diluted with water and filtered. The precipitate is washed well with water, dried in the air and then in vacuo at 50 ° and recrystallized from ethyl acetate / η-hexane and cis-5-fluoro-2-methyl-1- (3 *, 4 ^l -bismethylsulfinyl) is obtained ) -3-indenylacetic acid.

Example 2

cis -5-fluoro-2-methyl-1- (3 ', 4'-bismethylsulfonylbenzylidene) -3-indenylacetic acid

To 1.97 g (0.005 mol) of cis -5-fluoro-2-methyl-1- (3 ', 4'-bismethylsulfinyl) -benzylidene-3-indenylacetic acid in 20 ΐαΐ acetone are slowly 0.011 mol of m-chloroperbenzoic acid with stirring admitted. The mixture is heated with stirring and evaporated to about dryness at 40 °. The residue is taken up in a minimum amount of 50% ethanol, filtered and the filtrate is cooled. The raw product will filtered off and recrystallized from methanol / water, wherein cis -5-fluoro-2-methyl-1- (3 ', 4'-bismethylsulfonylbenzylidene) -3-indenylacetic acid is obtained.

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Example 3

A. p-Acetyl-α-methylcinnamic acid

A mixture of 148.16 g (1 mol) of p-acetylbenzaldehyde, 162.5 g (1.25 mol) of propionic anhydride and 96.1 g (1 mol) of sodium propionate is heated to 135 ° with stirring for 20 hours under nitrogen. The reaction mixture is cooled to 50 ° and poured into 2500 ml of water. A solid precipitates, de? dissolves after adding 2500 ml of saturated potassium carbonate solution. The mixture is extracted twice with 3 liter portions of ether. Concentrated hydrochloric acid and ice are added to the aqueous phase until pH 2 is reached. The precipitate is filtered off, washed and dried, and p-acetyl-α-methylcinnamic acid is obtained.

B. p-acetyl-q-methylhydrocinnamic acid

153 g (0.72 mol) of p-acetyl-oc-methylcinnamic acid and 5 units of platinum- ^ oxide in 1500 ml of methanol are at 25 ° and 3 »2 kg / cm (45 p.s.i.) hydrogenated until theoretical uptake is complete. The catalyst is filtered off and the Ultrat narrowed to about a third of the volume. 22.5 ml 155 & Lge potassium hydroxide solution are added and the mixture is refluxed for 30 minutes, after which it is poured into water and extracted with 2 κ 300 ml of ether. The aqueous layer is acidified with concentrated hydrochloric acid at 10 °. The separated oil is extracted with 3 x 300 ml of ether, dried over MgSO ^ and concentrated. The residue is recrystallized from acetone / n-hexane, and p-acetyl-2-methylhydrocinnamic acid is obtained.

C. p- (of, q'-dichloroethyl-α-methylcinnamic acid

To 154.5 g (0.75 mol) of p-acetyl-a-methylhydrocinnamic acid

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the previous stage in 500 ml of "isooctane-free unsaturated constituents" are slowly added over 2 hours at 0 "to 5 ° with stirring. The mixture is allowed to come to room temperature (25 °) and is set stirring continued at 25 ° for 18 hours. With continuous stirring, the mixture is heated under reflux and kept there for 2 hours. The mixture is cooled to 50 ° and poured, with stirring, onto 500 g of ice and water. The mixture is kept at room temperature for 2 more hours The layers are separated and the aqueous phase is extracted with 2 × 100 ml of benzene. The combined organic phase is washed with water and saturated brine, dried over MgSO ^ and concentrated to dryness in vacuo, p- (ct ', a' -Dichloroethyl) -a-methylcinnamic acid is obtained.

D. 6- (a, q-Dichloroethyl) -2-methyl-1-indanone .

52.5 g (0.20 mol) of the acid from Example 3-C are added to 500 g of polyphosphoric acid. The mixture takes effect stirred and heated on a steam bath for 2 hours. The mixture is cooled slightly and poured onto 600 g of ice and water poured. The precipitate is extracted with 3 × 200 ml of ether and the essential extract washed with saturated potassium carbonate, water and saturated saline and concentrated in vacuo. The residue from 6- (oc, a-dichloroethyl) -2-methyl-1-indanone is used without further purification.

E. Methyl 5- (aia-dichloroethyl) -2-methylindenyl-3-acetate

A mixture of 36 * 5 g (0.15 mol) indenone from Example 3-D, 9.11 g (0.20 mol) of activated zinc dust, 19.1 g (0.15 mol) of methyl bromoacetate and a crystal of iodine in 750 ml of dry Benzene is refluxed for 5 hours. After this time, a

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get at least 95% conversion to product. The mixture is poured onto 750 ml of 5% sulfuric acid, extracted with ether, the ether extract over HgSO. dried and the essential solution concentrated. The crude ester is redissolved in 265 ml of benzene and 55 g of phosphorus pentoxide are added and the resulting mixture is refluxed for 30 minutes. The mixture is decanted, the residue washed with benzene and the benzene layers combined, washed with water and dried _{over MgSO 7.} After concentrating the dry, organic phase, the product methyl 5- (a, a-dichloroethyl) -2-methylindenyl-3-acetate is obtained as a residue.

F. cis- and trans-5-ethynyl-2-methyl-1- (4'-methylthiobenzylidene) -3-indenylacetic acids

22 g (0.40 mol) of powdered sodium methoxide are added to ground a suspension of 29 »9 E (0.1 Hol) methyl 5- (a, a-dichloroethyl) -2-methylindenyl-3-acetate and 15.2 g (0.1 mol) of 4-methylthiobenzaldehyde in 400 ml of methanol, and the mixture is refluxed for 2 hours. The mixture is stirred when sodium chloride precipitates to reduce the thrust. An equal volume of water is added and the reflux treatment is continued for 1 hour. The mixture is cooled to room temperature and as in example 1-B worked up, with cis- and trans-5-ethynyl-2-methyl-1- (4'-methylthiobenzylidene) -J-indenyl acetic acids can be obtained.

G. cis -5-Ethynyl ~ 2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenylacetic acid

According to the method according to Example 1-C, 3.46 g (0.01 mol) of the cis product from Example 3-i ^{1 are dissolved} in crude cis-5-ethynyl-2-methyl-1- (4'-methylsulfinylbenzylidene) - 3-indenylacetic acid transferred. The raw material is in methylene chloride

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recorded and chromatographed on silica gel. The product is eluted with methanolic chloroform solution and the pure material is recrystallized from acetone / n-hexane.

Example 4

cis -5-acetyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl acetic acid

1 »81 S (0.005 mol) of the product from Example 3-G in 150 ml Ethyl acetate is stirred with 3.18 g (0.01 mol) of mercury (II) acetate for 24 hours at 25 °. Hydrogen sulfide will introduced into the mixture to precipitate mercury as a sulfide. The mixture is filtered through diatomaceous earth, the residue was washed with ethyl acetate and the filtrate was concentrated to dryness in vacuo. The residue will be off Recrystallized methanol / n-hexane, and cis-5-acetyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenylacetic acid is obtained.

Example 5

A. cis -5-Acetyl-2-methyl-1- (4'-methylthiobenzylidene) -3-indenyl acetic acid

3.46 g (0.01 mol) of ice-5-ethynyl-2-methyl-1- (V-methylbhiobenzylidene) -3-indenylacetic acid, prepared according to the method according to Example 3 ~ ^F , are prepared according to the method according to Example 3- G converted into cis -5-acetyl-2-methyl-1- (4'-methylthiobenzylidene) -3-indenylacetic acid.

B. cis -5-Acetyl-2-methyl-1- (V-methylsulfinylbenzylidene) -3-indenylacetic acid

1.82 g (0.005 mol) of the product according to Example 5-A are converted into cis-5-acetyl-2- according to the method according to Example 1-C

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methyl-1- (4 ^l -meth.ylsulfinylbenzylidene) -3-indenyl acetic acid transferred.

Example 6

A. trans - ^ - Acetyl - ^ - methyl-i- (4 ¹ -methyl thiobenzylidene) -3-indenylacetic acid

1 "73 g (0.005 mol) of trans-product of example by the method of Example 3-G i ⁿ trans-5-acetyl-2-methyl-1 - (4" -methyl thiobenzyliden) -3-indeny 1- acetic acid transferred.

B. trans -5-acetyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl acetic acid

0.364 g (0.001 mol) of the trans product from Example 6-A are converted into trans-5-acetyl-2-methyl-i- (4 ¹ -methylsulfinylbeiizylidene) -3-indenylacetic acid by the method according to Example 1-C.

Example 7

A. trans -5-ethynyl-2-methyl-1- (4'-methylsulfinyl-. benzylidene) -3-indenylacetic acid

1> 73 g (0.005 mol) of the trans product from Example 3-Ϊ ¹ are obtained by the method according to Example 3-G · to obtain "trans-5-ethynyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenylacetic acid transferred.

B. trans -5-ethynyl-5-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenylacetic acid

0.362 g (0.001 mol) of the trans product from Example 7-A are converted into trans-5-

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Acetyl-2-methyl-1- (4'-diethylsulfinylbenzylidene) -3-indenylacetic acid convicted.

Example 8

A. 3-Hydroxy-4-methylthiobenzaldehyde

0.35 mol of o-hydroxythioanisole in 200 ml of methylene chloride are added 66.67 6 (0.5 mole) anhydrous aluminum chloride was added. The mixture is stirred and cooled while adding dichloromethyl methyl ether is added dropwise. After complete dissolution, the mixture is at room temperature for 15 minutes touched. The liquid phase is poured into 300 g of ice and water and the unreacted aluminum chloride washed with methylene chloride until the wash solutions are colorless. The washing solutions and the decanted material are united. The layers are separated and the organic layer washed with saturated potassium carbonate, about MgSO. dried and distilled, with J-hydroxy-4-methylthiobenzaldehyde is obtained.

B. cis and trans-5-ethynyl-2-methyl-1- (3'-hydroxy-4'-methylthiobenzylidene) -3-indenylacetic acids

22g (0.40 mol) of powdered sodium methoxide becomes a suspension of 29.9 g (0.1 mol) of methyl 5- (cc, oc-dichloroethyl) -2-methylindenyl-3-acetate and 15.2 g (0.1 mol) of 3-hydroxy-4-methylthiobenzaldehyde in 400 ml of methanol were added, the mixture is refluxed for 2 hours. If sodium chloride precipitates, the mixture is stirred, to reduce the thrust. An equal volume of water is added and the reflux treatment is continued for 1 hour. The mixture is cooled to room temperature and worked up as in Example 1-B, using cis- and trans-5-a'thynyl-2-methyl-1- (3'-hydroxy-4'-methylthiobenzylidene) -3-indenyl acetic acids can be obtained.

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C. cis -5-Ethynyl-2-methyl-1- (3 ^l -hydroxy-4'-diethylsulfinylbenzylidene) -3-indenylacetic acid

11 »3 g (0.0422 mol) of sodium metaperiodate trihydrate in 85 ml of water become 3.62 g (0.0i mol) of cis-5-ethynyl-2-methyl-1- (3'-hydroxy-4'- methylthiobenzylidene) -3-indenylacetic acid in 240 ml of methanol and 10 ml of acetone were added at room temperature. The mixture is stirred overnight, after which only a trace of starting material remains and only a trace of sulfon has formed. The mixture is concentrated to a small volume, diluted with water and filtered. The precipitate is washed well with water, dried in air and then in vacuo at 50 ° and recrystallized from ethyl acetate / η-hexane, cis-5-ethynyl-2-methyl-1- (3 ^l -hydroxy-4'- methylsulfinyl) -3-indenylacetic acid is obtained.

Using the same reaction conditions and measures, if o-chlorothioanisole, o-bromothioanisole and o-cyanothioanisole are reacted according to stages A, B and G, cis-5-ethynyl-2-methyl-1- (3 ^l -chlor -4'-methylsulfinylbenzylidene) -3-indenyl acetic acid, cis - ^ - ethynyl-2-methyl-1- (3 '- "bromo-4 ^l -methylsulfinylbenzylidene) -3-indenyl acetic acid and cis-5-a'thynyl- 2-methyl-1- (3'-cyano-V-methylsulfinylbenzylidene) -3-indenylacetic acid was obtained.

Example 9

A. o- (β-Hydroxyäthoyy) -thio anisole

1 g (0.1 mol) of o-hydroxythioanisole in 6.8 g (0.1 Mol) sodium ethoxide dissolved in 100 ml of absolute ethanol and stirred with the addition of 8.1 g (0.1 mol) of ß-hydroxyethyl chloride. The mixture is refluxed for 2 hours and cooled. The o- (ß-hydroxyethoxy) thioanisole is extracted.

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Using the same reaction conditions and measures if o-hydroxythioanisole with ß-hydroxymethyl chloride, ß-hydroxypropyl chloride or ß-hydroxybutyl chloride is implemented, o- (ß-hydroxymethoxy) -thioanisole, o- (ß-hydroxypropoxy) -thioanisole or o- (ß-hydroxybutoxy) -thioanisole obtain.

B. cis -5-ethynyl-2-methyl- ^/ 1- (3'-β-hydroxyethoxy-4 ^l methylsulfinylbenzylidene) -3-indenylacetic acid

The product from Example 9 - A- is according to the methods of Examples 8-A, 8-B and 8-C to give cis -5-a'thynyl-2-methyl-1- (3'-β-hydroxyethoxy: -V-methylsulfinylbenzylidene) -3-indenylacetic acid implemented.

In this way, the other thioanisols according to Example 9-A. with the formation of the corresponding indenylacetic acid.

Example 10

A. o- (ß-Chlorätho3cy) -thioanisol

0.1 mol of o- (ß-hydroxyethoxy) thioanisole are refluxed in excess thionyl chloride and allowed to dry evaporated to give o- (ß-chloroethoxy) thioanisole.

Other o- (β-hydroxyalkoxy) thioanisoles can be used in the same way with other thionyl halides to obtain the corresponding o- (ß-haloalkoxy) thioanisole, such as, for example o- (ß-bromomethoxy) -thioanisole, o- (ß-chloropropoxy) -thioanisole or o- (ß-bromobutoxy) -thioanisole, under reflux be treated.

- 22 -

209831/1180

B. cis-5-ethynyl-2-methyl-1- (3'-ß-chloroethoxy-4 · - methylsulfinylbenzylidene) -3-indenyl acetic acid

The product from Example 10-A is according to the methods of Examples 8-A, 8-B and 8-C to give cis-5-ethynyl-2-methyl-1- (3'-β-chloroethoxy-V-methylsulfinylbenzylidene) -3-indenylacetic acid implemented.

In this way, the other thioanisoles from Example 10-A can be implemented to form the corresponding indenyl acetic acid.

Example, 11
A. o ~ ethoxythioanisole

S (° »1 mol) o-chlorothioanisole are in Mitrobenzol, the copper powder (100 mg) and 6.8 g (0.1 mol) of sodium ethoxide contains, stirred under reflux for 2 hours. The product is steam distilled and the distillate is dried and fractionally distilled under reduced pressure, whereby o-Äthoxythiοanisol is obtained.

Using the same reaction conditions and measures if o-chlorothioanisole is reacted with sodium methoxide, sodium propoxide and sodium tert-butoxide, o-methoxythioanisole, o-propoxythioanisole or o-tert.-butoxythioanisole obtain.

B. cis-5-lthynyl-2-methyl-1- (3 ^t -ethoxy-4 ^! -Methylsulfine; / l -benzylidene) -3-indenylacetic acid

The product from Example 11-A is according to the methods of Examples 8-A, 8-B and 8-C to give cis -5-ithynyl-2-methyl-1- (3'-ethoxy-4'-methylsulfinylbenaylidene) -5-indenylacetic acid implemented.

- 23 209831/1180

In this way, the other thioanisoles from Example 11-A can be reacted to form the corresponding indenylacetic acid.

Example 12

A. cis -5-Hydroxy-2-methyl-1- (4 -'-methylthiobenzylidene) indenyl-3-acetic acid

10, Og cis ^ -Methoxy ^ -methyl-i- (4'-methylthiobenzylidene) -indenyl-3-acetic acid are in 10.0 g of pyridine hydrochloride heated to 190 ° for 15 minutes.

The melt is poured into ice and the solid is filtered, dried and recrystallized from benzene, whereby cis -5-Hydroxy-2-methyl-1- (4'-methylthiobenzylidene) indenyl-3-acetic acid is obtained.

B. cis -5-Hydroxy-2-raethyl-1- (4'-methylsulfinylbenzylidene) indenyl-3-acetic acid

11 »3 g (0.0422 mol) of sodium metaperiodate trihydrate in 85 ml of water are converted into 13.52 g (0.042 mol) of cis-5-hydroxy-2-methyl-1- (4'-methylthiobenzylidene) -ijidenyl-3- acetic acid in 240 ml of methanol and 50 ml of acetone at room temperature. The mixture is stirred overnight, concentrated to a small volume, diluted with water and filtered. The precipitate is washed, dried at 70 ° and crystallized from ethyl acetate, cis-5-hydroxy-2-methyl-1- (4'-methylsulfinylbenzylidene) indenyl-3-acetic acid being obtained.

C. Methyl-cis -5-hydroxy-2-methyl-1- (4'-methylsulfinyl benzylidene) indenyl-3-acetate

12.2 g of the product from Example 12-B v / earth in 50 ml

- 24 -

209831/1 180

Dissolve methanol, and there is 0.1 ml of concentrated sulfuric acid admitted. The solution is refluxed for 1 hour, cooled and dissolved in 200 ml of saturated sodium bicarbonate solution poured. The solution is extracted with 2 × 100 ml of methylene chloride and the methylene chloride solution with 2 × 50 ml Water washed. The organic phase is dried, filtered and evaporated, whereby crystalline methyl-cis-5-hydroxy-2-methyl-1- (4'-methylsulfinylbenzylidene) indenyl-3-acetate remains behind.

D. cis -5-allyloxy-2-methyl-1- (4'-methylsulfinyrbenzylidene) indenyl-3-es sigic acid

11.4 g (0.031 mol) of the product from Example 12-C, 4.14 g (0.031 mol) potassium carbonate, 100 ml acetone and 6.05 g (0.05 mol) allyl bromide are together 2 layers with stirring heated to reflux. 10 ml of water are added to the solution and this is heated to 50 ° for 10 minutes. To Cooling and evaporation to half a volume are followed by extraction with 2 × 20 ml of methylene chloride. The watery Phase is acidified and cis-5-allyloxy ~ 2-methyl-1- (4'-methylsulfinylbenzylidene) indenyl-3-acetic acid is collected and dried.

Example 15

(~) -5-Acetyl-2-methyl-1- (4'-methylsulfinylbenzylidene) indenyl-3-acetic acid

To 3.80 g (0.01 mol) of D, L-5-acetyl-2-methyl-1- (4'-methylsulfinylbenzylidene) indenyl-3-acetic acid 3 »14 g (0.0107 mol) of cinchonidine are added in 160 ml of methanol at 25 °. The mixture, which forms a solution, is concentrated to dryness in vacuo. Multiple, fractional crystallization from ethyl acetate gives a salt with constant rotation and Melting point. 0.194 g (0.00029 moles) of the salt are in

- 25 - ■

209831/1 180

Dissolve 10 ml of methanol and add 0.58 ml of dilute 0.5N hydrochloric acid to the mixture. The precipitation is filtered, washed well with water and dried at 70 ° in a desiccator, (-) - 5-Acetyl-2-methyl-1- (4'-methylsulfinylbenzylidene) indenyl-3-acetic acid is obtained.

Example 14

(+) - 5-Acetyl-2-methy1-1- (4'-methylsulfinylbenzylidene) indenyl-3-acetic acid

(+) - Enriched material from Example 4 is collected and obtained (+) - enriched acid (2.43 g, 0.0065 mol) as described in Example 13 for the (-) - isomer, decomposed. The salt is mixed with 2.11 g (0.0065 mol) of dihydroquinidine in 50 nil of methanol and repeated recrystallization Manufactured to constant rotation and constant melting point. 0.134 g (0.0002 moles) of the salt will be decomposed as in Example 13 to give the desired compound.

Example 15

Methyl cis -5-fluoro-2-methyl-1- (3 ', 4'-bismethylsulfinylbenzylidene) -3-indenyl acetate

11 · _ν 4 g (0.03 mol) of cis-5-fluoro-2-methyl-1- (3 ', 4'-bismethylsulfinylbenzylidene) -3-indenylacetic acid are dissolved in 50 ml of methanol, 1.0 ml of concentrated sulfuric acid is added added, and the mixture is refluxed for 3 hours. The mixture is cooled, poured into ethyl acetate and extracted sequentially with saturated sodium bicarbonate, water and saturated brine. The ethyl acetate extract is dried over MgSO ^, concentrated to dryness and the residue is recrystallized from ethyl acetate / n-hexane.

- 26 209831/1180

Example 16

cis -5-acetyl-2-methyl-1- (3'-fluoro-4'-nietliylsulfilylbenzyli den; -3-indenylac et amide

3.98 g (0.01 mol) of cis -5-acetyl-2-methyl-1- (3'-fluoro-4'-methylsulfinylbenzylidene) -3-indenyl acetic acid are heated with ml of thionyl chloride for 25 minutes. The mixture will cooled to 25 ° and poured into ice-cold, concentrated ammonia solution while stirring. The precipitated amide is with Washed water, dried and recrystallized from methanol / water, cis -5-acetyl-3-methyl-1- (3'-fluoro- (V-methylsulfinylbenzylidene) -3-indenylacetamide is obtained.

Similarly, when ammonia is replaced with an equivalent amount of the following amines, the corresponding ones become Amides obtained.

Morpholine

Dimethylamine

Ethanolamine

Benzylamine

N, N-diethylethylenediamine

Benzyl glycinate

Piperidine

Pyrrolidine

N-methylpiperazine

N-phenylpiperazine

N-hydroxyethylpiperazine

Piperazine

Diethylamine

Diethanoiamine

aniline

p-ethoxyaniline

p-chloroaniline

- 2? -209831/1180

14259 4?

ρ-fluoroaniline

p-trifluoromethylaniline

Butylamine

Cyclohexylamine

Methylamine

D-Gl uc ο s ami n

Tetra-o-acetyl-d-glucosamine

D-galactosylamine

D-mannosylamine

Ν, Ν-dimethylglycine amide

Ν, Ν-dibutylglycine amide

N-methyl-2-aminomethylpiperidine N-methyl-2-aminomethylpyrrolidine

ß-ethoxyethylamine

Di- (ß-ethoxyethyl) amine

ß-phenethylamine.

α-phenethylamine

Dibenzylamine

D-mannosamine

Example 17

tert -Butyl-cis -5-methylsuirinyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -> - indenyl acetate

5.98 g (0.01 mol) of cis -5-methylsulfinyl-2-methyl-1- (V-methylsulfinylbenzylidene) -3-indenylacetic acid become 30 ml of isobutylene and 0.1 ml of concentrated sulfuric acid admitted. The mixture is tightly closed and shaken for 18 hours at 25 °, quenched to 0 ° and the whole thing into a separatory funnel, containing 50 ml of ether, 25 ml of water, Contains 25 ml of ice and 1.0 g of sodium hydroxide, poured. The layers are separated, the aqueous layer extracted with 2 × 40 ml ether, the ethereal extracts with Water and saturated brine and washed over

- 28 209831/1180

dried. The ethereal extract is concentrated to dryness and the residue is recrystallized from ethyl acetate / n-hexane, whereby the desired compound is obtained.

Example 18

AmEoniuni-cis-5-allyloxy-2-niethyl-1- (4 ^l -methylsulfinylbenzylidene) -3-indenyl acetate

1 ml of methanolic 1N-ammonia is added to 0.394 g (0.001 hol) of cis-5-allyloxy-2-methyl-1- (4 ^l -methylsulfinylbenzylidene) -3-indenylacetic acid in 10 ml of methanol. The mixture is evaporated to dryness to give the desired compound.

Example 19

Calcium cis-5-ethinyl-2-methyl-1- (4 ^l -methylsulfinylbenzylidene) -> 3-indenyl acetate

To a slurry of 0.72? g (0.002 mol) of cis -5-ethynyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenylacetic acid in 10 ml of water, 0.076 g (0.001 mol) of hydrated calcium oxide is added and the mixture becomes Minutes stirred. The mixture is concentrated to dryness in vacuo, slurried with 10 ml of methanol and again to the Dry "concentrated, v / whether the desired compound is obtained.

Example 20

Aluminum cis -5-acetyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl acetate

To a solution of 0.246 g (0.001 times) Aluniiniuni tert-butoxide in ^ O ml of ether 1.131 {5 (0.003 mol) ice-5-

~ 2 \) 2 0 9 8 Π> ■ 'ι Ϊ J Ci

Acetyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenylacetic acid added in 50 ml of pyridine with stirring at 10 °. The mixture is concentrated to dryness in vacuo, whereby the desired connection is obtained.

Example 21

Sodium cis-5-ethinyl-2-methyl-1- (4 ^l -methylsulfinylbenzylidene) -3-indenyl acetate

To 0.362 g (0.001 mol) of cis -5-ethynyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenylacetic acid 10 ml of methanolic 0.1 N sodium methoxide are added in methanol. That Concentrate mixture to dryness in vacuo to give the desired compound.

Example 22

Methoxymethyl-cis -5-allyloxy-2-methyl-1 ~ (p-methylsulfinylbenzylidene) -3-indenyl acetate

0.055 mol of chloromethyl methyl ether are added to a suspension of 0.05 mol of cis-5-allyloxy-2-methyl-1- (p-methylsulfinylbenzylidene) -3-indenylacetic acid and 0.15 mol of anhydrous potassium carbonate in 250 ml of anhydrous acetone. The mixture is stirred overnight at room temperature. About 200 ml of diethyl ether are added and the mixture is filtered. The filtrate is washed once with 100 ml of water and dried over anhydrous sodium sulfate. It is then filtered and the solvent removed in vacuo. The residue is chromatographed on 200 g of acid-washed aluminum oxide using ether / petroleum ether (varying from 10 to 60 % ether, based on volume) as the eluent, methoxymethyl-cis-5-allyloxy-2-methyl-1- (p-methylsulfinylbenzylidene) -3-indenyl acetate is obtained.

- 30 -

2 0 9 B 3 1/1 1 8 0

Example 23

β-Dimethylaniinoethyl-cis-3-allyloxy-2-met] iyl - 1- (p-methyl-sulfinyrbenzylidene) -3-indenyl acetate

A solution of 0.0054 moles of NjN'-dicyclohexylcarbodiimide in 6 ml of anhydrous tetrahydrofuran becomes a solution of 0.005 mol of cis-5-allyloxy-2-methyl-1- (p-methylsulfinylbenzylidene) -3-indenylacetic acid and 0.0054 mol of 2-diethylaminoethanol in 17 ml of anhydrous tetrahydrofuran. The mixture is stirred overnight at ambient temperature. The dicyclohexylurea is filtered off and it is grounded 2 ml of glacial acetic acid was added to the filtrate. After the mixture 1 hour, it is filtered and 200 ml of ether are added to the filtrate. The solution will then extracted three times with 100 ml of 2.5N HCl, and the extracts are combined, washed twice * with 100 ml of Ither, ice cold, Made slightly alkaline with concentrated NH ^ OH and extracted three times with 100 ml of ether. The ether extracts are combined, washed ten times with 100 ml of water to remove traces of starting amine, over anhydrous potassium carbonate dried, filtered and evaporated in vacuo. The oily residue consists of ß-diethylaminoethyl-cis-5-allyloxy-2-methyl-1- (p-methylsulfinylbenzylidene) -5-indenyl acetate.

If 2-dimethylaminoethanol, 3-dimethylamino-i-propanol, 5-diethylamino-1-propanol, N-ß-hydroxyethylpiperidine, N-ß-hydroxyethylpyrrolidine, N-hydroxymethylpyrrolidine, N-methyl-2-hydroxymethylpyrrolidine, N-ethyl-2-hydroxymethylpiperidine, 1-ß-hydroxyethyl-4'-methylpiperazine or N-ß-hydroxyethylmorpholine is used in place of 2-diethylaminoethanol in the above procedure, the corresponding ß-dimethylaminoethyl-, y-dimethylaminoprop7 / l-, γ-diethylaminopropyl, ß-N-piperidiirylethyl, ß-H-pyrroli-

- 31 209831/1180

dinylethyl, N-pyrrolidinylmdthyl _} α '- (1'-methylpyrrolidinylmethyl) -, 4-methyl-i-piperazinylethyl, N-ethyl-2-piperidinylethyl and N-morpholinylethyl esters.

- 32 209831/1180

Claims (22)

Godfather ta nsprüche ■ 8 R ₇ , R ^, R ₁ - and an aryl or heteroaryl radical; ,. a hydrogen atom, an alkyl or haloalkyl rest; ~ a hydrogen atom, an alkyl, haloalkyl, Alkenyl or alkynyl radical; ^, R ₁ - and R ^ in each case V / hydrogen atoms, halogen, acyl, cyano, alkynyl, allyloxy, alkylsulfinyl or alkylsulfonyl, alkenyl radicals; R ₁ -? an alkylsulfinyl or alkylsulfonyl radical; Rg is a hydrogen atom, a halogen, hydroxy, alkoxy, Haloalkoxy, hydroxyalkoxy, alkylsulfinyl or ■ alkylsulfonyl radical and
M is a hydroxy, lower-alkoxy, substituted lower-alkoxy, amino, alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino, polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino radical or the group OHe, in which He is a cation , mean,
with the provision that at least one of the radicals R ₇ , 209831/1180 14259 3 * R ^, Rn and R ^ are not a hydrogen atom or a halogen radical when Rg is a hydrogen atom, a halogen radical, a hydroxy radical or a haloalkyl radical. 2. Compound according to claim 1, characterized in that represents a phenyl radical. 3 · Connection according to claim 2, characterized in that R. a hydrogen atom or a lower alkyl radical; Rp is a hydrogen atom or a lower alkyl radical; R-, a hydrogen atom: 3
R ^ is an acyl, lower alkynyl or allyloxy radical; Rt and Rg hydrogen atoms; Rr _{7 is} a lower-alkylsulphonyl or lower-alkylsulphonyl radical; Rq is a hydrogen atom, a halogen, hydroxy, lower-alkoxy or halo-lower-alkyl radical and M is a hydroxy, lower-alkoxy, substituted lower-alkoxy, amino, alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino, polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino radical or the grouping OMe, in which Me is a cation , mean. · * 4. A compound according to claim 3 »characterized in that II is a hydroxy group. 5. cis and trans isomers of a compound according to claim 4. 6. A compound according to claim 4, characterized in that R. is a hydrogen atom; Rp is a methyl radical; R, a hydrogen atom; 3
R ^, an acetyl radical; R ₁ - and R ^ - hydrogen atoms;
5 b - 34 -209831 / 1180 $ 14259 Γ a methylsulfinyl radical; R _{0 is} a hydrogen atom and ο Yl mean a hydroxy radical. . 7. A compound according to claim 4, characterized in that R ,. a hydrogen atom; Rp is a methyl radical; R-, a hydrogen atom; R. an ethynyl radical; Rr and R _c hydrogen atoms; Rr _{7 is} a methylsulfinyl radical; Ro an atom of hydrogen and M represent a hydroxy group. 8. A compound according to claim 4, characterized in that R 1 is a hydrogen atom; ^λ Rp is a methyl radical; R, a hydrogen atom; R ₂ ^ is an allyloxy radical; Rr- and R ^ - hydrogen atoms: 5 b ' a methylsulfinyl radical; _t R _{D is} a hydrogen atom and N represent a hydroxy group. 9 · Compound according to claim 4, characterized in that R ^. a hydrogen atom; Rp is a methyl radical; R-, a hydrogen atom: R ^ a jithinyl radical; R ₁ - and R ^ - hydrogen atoms; Rr _{7 is} a methylsulfynyl radical; Rq denotes a hydroxyrest and Il denotes a hydroxy radical. 209831/1 14259 ^L 8 10. A compound according to claim 4, characterized in that R. is a hydrogen atom; a methyl radical; a hydrogen atom; i ^ an allyloxy radical; I ₁ and IL hydrogen atoms; a methylsulfinyl radical; denotes a hydroxy group and M denotes a hydroxy group. 11. A compound according to claim 4, characterized in that R. is a hydrogen atom; Hp is a methyl radical; R, a hydrogen atom; R ₁ . an allyloxy group; Br and IL hydrogen atoms; Bn is a methylsulfinyl radical; Rg denotes an ethoxy group and M denotes a hydroxyl group. 12. Process for the preparation of compounds of the formula -CHCO ₂ H - 36 209831/1180 wherein (Ij) an aryl or heteroaryl radical; E. a hydrogen atom, an alkyl or halogen alkyl radical;
Rp is a hydrogen atom, an alkyl, haloalkyl, Alkenyl or alkynyl radical;
R_, R ^, R ₁ - and R ^ - each hydrogen atoms, halogen, acyl, cyano, alkynyl, AlIyIoxy, alkylsulfiny1 or alkylsulfonyl, alkenyl radicals; Rr _{7 is} an alkylsulfinyl or alkylsulfonyl radical and Ro is a hydrogen atom, a halogen, hydroxy, alkoxy, haloalkoxy, hydroxyalkoxy, alkyl sulfinyl or alkylsulfonyl radical, with the hatred that at least one of the radicals R ^, R., Rj- and Eg no hydrogen atom or halogen radical is when Rg is a hydrogen atom, a halogen radical, Hydroxy radical or haloalkyl radical, characterized in that (A) an indenylacetic acid is reacted with an aldehyde and (b) the i-alkylthiobenzylidene-3-indenyl acetic acid obtained is oxidized. 13 · Medicines characterized by a content of one The compound of claim 1. 14-. Medicament according to claim 13, characterized by a content of cis-5-i ^1- luoro-2-methyl-1- (3 ^l , V-bismethylsulfinylbenzylidene ") -3-indenylacetic acid. 15 · Medicament according to claim 13 _5, characterized by a content of cis-5-fluoro-2-methyl-1- (3 ', V-bismethylsulfonyl) -benzylidene-3-indenylacetic acid. ■ - 37 209831/1180 16. Medicament according to claim 13, characterized by a content of cis-5-ethynyl-2-methyl-1- (4 ^l -methylsulfinylbenzylidene) -3-indenyl acetic acid. 17 · Medicament according to claim 13, characterized by a content of cis-5-acetyl-2-methyl-1- (4 ^l -methylsulfinylbenzylidene) -3-indenyl acetic acid. 18. Medicament according to claim 13 »characterized by a content of cis-5-ethynyl-2-methyl-1- (3'-hydroxy-4'-methylsulfinylbenzylidene) -3-indenylacetic acid. 19 · Medicament according to claim 13, characterized by a content of cis-5-ethynyl-2-methyl-1- (3'-ß-hydroxyethoxy-4 ¹ -methylsulfinylbenzylidene) -3-indenyl acetic acid. 20. Medicament according to claim 13, characterized by a content of cis-5-ethynyl-2-methyl-1- (3'-ß-chloroethoxy-4'-methylsulfinylbenzylidene) -3-indenyl acetic acid. 21. Medicament according to claim 13, characterized by a content of cis-5-ethynyl-2-methyl-1- (3'-ethoxy-4'-methylsulfinylbenzylidene) -3-indenyl acetic acid. 22. Medicament according to claim 13, characterized by a content of cis-5-allyloxy-2-methyl-1- (4'-methylsulfinylbenzylidene) indenyl-3-acetic acid. - 38 -209831/1180