DE2202729A1 - Substituted indensic acids - Google Patents

Description

^ur

'Patent Attorney'"ο- Walter Dreter F.

20 JAN. 1972 14258

MERCK & CO., INC. Rahway, New Jersey, V.St.A.

Substituted indeno acids

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

(D

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R ^. the grouping - (CHp) COM, in which η is 2 to 4, -CH (OH) CH ₂ CH ₂ COM,
-CH ₂ CH (OH) CH ₂ COM,
-CH ₂ CH ₂ CH (OH) COM,

O
-CCH ₂ CH ₂ COM,

O
-CH ₂ CCH ₂ COM,

O
-CH ₂ CH ₂ CCOM or

B ¹

- (CH ₂ ) _m -C- (CH ₂ ) _n COM, wherein
E.

R and R ¹ each represent a hydrogen atom, alkyl, aryl or halogen radicals,

m is 1 or 0 and η is 1 or 0, with the proviso that, when m is 0, η cannot be 0 and when η is 0, m cannot be 0 and

an aryl or heteroaryl radical;

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

R ,, R ^, Rc and R ^ each hydrogen atoms, alkyl, acyloxy, Alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino, dialkylaminoalkyl, sulfamyl, Alkylthio, mercapto, hydroxy, hydroxyalkyl, alkyl-bulfonyl, Halogen, cyano, carboxyl, carboalkoxy, carbamido, haloalkyl, cycloalkyl, cacloalkoxy, Alkenyloxy, acyl, alkenyl or alkynyl radicals;

Rn is an alkylsulfinyl or alkylsulfonyl radical;

Rg is a hydrogen atom, a halogen, hydroxy, alkoxy or haloalkoxy radical and

M is a hydroxy, lower alkoxy, substituted lower alkoxy, Amino, alkylamino, dialkylamino, N-morpho

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lino, 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 H ,, E ^ ,, Et and R _{a is} not a hydrogen atom.

The indenominational core can be in the 1-position by an aryl ring system, z. B. benzene, naphthalene oder.Biphenyl or a heteroaryl ring system, e.g. B. a pyrrole, furan, thiophene, Pyridine, imidazole, pyrazine, thiazole, and the like, may be substituted with an alkylsulfinyl or alkylsulfonyl substituent contains and can also be replaced by a halogen radical (chlorine, fluorine or bromine), hydroxy radical, alkoxy radical (methoxy, Ethoxy, propoxy and the like) or haloalkyl (fluoromethyl, chloroethyl, trifluoromethyl and the like) be substituted.

Typical compounds of the invention are as follows:

5 ~ Fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid

5-fluoro-1- (4'-methylsulfinylbenzylidene) -3-indenyl-ybutyric acid

5-chloro-2-methyl-1- (4 ^l -methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid

6-Allyloxy-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid

6-fluoro-5-methoxy-2-methyl-'1- (4- '-methylsulfynylbenzylidene) -indenyl-γ-butyric acid

5-cyano-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid

5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-γ- (ß-hydroxybutyric acid)

5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-γ- (ß-ketobutyric acid)

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5-Pluoro-2-methyl-1- (4 ^l ~ methylsulfinyl'benzylidene) -3-indenyl-γ- (ß-chlorobutyric acid)

5-Fluoro-2-methyl-1 - (^ ^l -methylsulfinylbenzylidene) -butyric acid

5-fluoro-2-methyl-1- (4 -'- m'ethylsulfinylbenzylidene) -a- (ethoxyacetic acid)

5-fluoro-2-methyl-1- (4'-methylsulfinyrbenzylidene) -y- (ß-butynoic acid)

5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -Y- (γ-ketobutyric acid )

5-fluoro-2-fluoromethyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-β-propionic acid

5-fluoro-1- (4'-methylsulfinylbenzylidene) -2-vinyl-3-indenyl-β-propionic acid

and their corresponding amides, esters and pharmaceutically acceptable salts.

Ee it should be noted that the connections of the inventor dung into their cis and trans isomers according to known processes can be isomerized. It should also be noted that the cis isomer of the compounds according to the invention is much more effective than the trans isomer. Accordingly, reference in the specification and claims is intended to be on the compounds according to the invention not only the compounds per se, but also their geometric isomers Include (ice, trans).

It is also clear to the person skilled in the art that the alkylsulfinyl derivatives of the invention are racemic mixtures of optically active enantiomorphic forms which can be separated into their (+) and (-) forms by known methods. Furthermore, if R and E ^{1 are} different, an additional asymmetric atom results, which leads to two further enantiomorphic forms, which are likewise to be regarded as lying within the scope of the invention.

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• J

Furthermore, the person skilled in the art recognizes 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 by reducing inflammation and relieving it the pain in such diseases as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever.

The compounds of the formula I also have anti-pyretic properties and analgesic efficacy and are administered in the same manner and in the same dosage ranges and as used to treat inflammation as discussed above.

The treatment of inflammations according to the method according to the invention is carried out topically, orally, rectally or parenterally Administration of a medicament 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, 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,

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Sesame oil and water. Likewise, the carrier or diluent can include a time delay material, such as glyceryl monostearate or glyceryl distearate alone or together with a wax.

Various pharmaceutical forms of the therapeutically active agents can be used. For example, if If a solid carrier is used, the agents can take the form of tablets, capsules, powders, troches or lozenges Accept pills made using standard pharmaceutical methods. If a liquid carrier is used, the preparation can be in 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, which is solid at skin temperature, but at cectal temperature is liquid. Such materials are cocoa butter and polyethylene glycol. Gels and lotions for topical applications can be prepared in the usual way.

The active compounds of the formula I according to the invention Agents are used in an amount sufficient to treat inflammation; H. to reduce inflammation, administered. Advantageously, the agents contain the active ingredient, namely the compounds of formula I, in an "amount of about 0.1 mg to 50 mg per kg body weight - per day (5 mg to 3.5 g de 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).

The method of treatment according to the invention comprises administration a compound of the formula I, in particular a particularly preferred compound in a mixture with a ^ em non-

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toxic pharmaceutical carrier as exemplified above cited to a patient. The compounds of the formula I and in particular the particularly preferred compounds are used in an amount of 0.1 mg to 50 mg / kg of body weight 3§ ^ a-Si preferably from about 1 mg to about 15 mg de kg body weight administered per day. The fastest and most effective anti-inflammatory effect is when administered orally at a daily dose of about 1 to 15 mg / kg received per day. It should be noted, however, that although preferred dosage ranges are given, the dosage level for any particular patient on the effectiveness depends on the specific compound used. Also, those skilled in the art in therapeutic Use of medicinal agents, especially those of formula I, many other factors that contribute to the effects modify the drug, taking into account such as age, body weight, gender, diet, Time of administration, route of administration, rate of elimination, drug combination, reaction sensitivities and severity of the specific disease.

In the preparation of the compounds according to the invention, the starting material is a β-arylpropionic acid. This connection is produced according to the method shown in flow diagram I, which explains various alternative routes. So it can be a substituted benzaldehyde with a substituted ethyl acetate in a Claisen reaction or with an α-halogenated propionic acid ester in a reformate sky reaction to be condensed. The resulting unsaturated ester is obtained as the benzylpropionic acid starting material reduced and hydrolyzed. On the other hand, a substituted malonic ester gives in a typical Malonic ester synthesis and acid hydrolysis of the substituted ester obtained, the benzy! Propionic acid directly, or the Benzaldehyde can be combined with propionic anhydride in a redu-

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decorative medium reacted with the formation of benzylpropionic acid will.

Designations:

X is a halogen radical, usually Cl or Br;

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

R ₂ is an alkyl, alkenyl, alkynyl or haloalkyl radical and

R ,, R ^, Rc and Rg can each be hydrogen atoms, alkyl, Acyloxy, alkoxy, nitro, amino, acylamino, alkylamino, Dialkylamino, dialkylaminoalkyl, sulfamyl, Alkylthio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, Halogen, cyano, carboxy, carbalkoxy, carboxamido, haloalkyl, cycloalkyl, cycloalkoxy, Represent alkenyloxy, acyl, alkenyl or alkynyl radicals.

Reagents:

1. Zn dust in an anhydrous, inert solvent, such as for example 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 100o.

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 the β-arylpropionic acid starting material

aterials.

CHO

X-CH-COOE

ZH-CH-COOE

OH

H-i "CH-

COOH

R,

H = C-COOE

i ²

"CH ₂ -CH-COOE

CH (COOE)

-CH ₂ -C (COOE) ₂

¹ -CH ₂ X

P.

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In the preparation of the compounds of the invention, a number of routes are again possible, as shown in flow diagram II is shown. The first stage consists in the ring closure of the ß-ary! Propionic acid with the formation of an indanone, which by a Friedel-Crafts reaction using a Lewis acid catalyst or by heating with polyphosphoric acid can be carried out. The indanone can with an α-halo ester by Reformatsky reaction with introduction the aliphatic acid side chain with replacement of the carbonyl group be condensed. This introduction can also be done 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 stored instantly to India. If the way about the Reformatsky reaction is used, the intermediate 3-hydroxy-3-aliphatic acid derivative must be used dehydrated to the indene. The introduction of the 1-substituent occurs in one of two ways. The first is the direct reaction of the indene with the aldehyde the specified structural properties using a strong base a ^ -ls catalyst and optionally Warming with the formation of the carbanion. The reaction can be carried out in a number of solvents, e.g. B. polar solvents, such as dimethoxyethane, aqueous methanol, pyridine, liquid ammonia, dimethylformamide and the like. Or even be carried out in non-polar solvents such as benzene and the like. It can also be brominated and an indanon then dehydrobrominated to an indenone, and the indenone carbonyl can be substituted by using the a-triphenylphosphinyl compounds of the desired Structure to be replaced. It should be noted that there is a lower alkyl ester of the desired compound in the third Level forms. This ester can then be hydrolyzed to obtain the free acids and to obtain the

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Sulphoxides and sulphones are oxidized from which salts, other esters and the amides can be formed. the Keto- and halogen-substituted acid side chains can be produced by oxidation or halogenation of the hydroxy acid side chain getting produced.

Designations:

X, E, R ₂ , IU, R ^, En and Rg are the same as in flow diagram I;

Ar is an aryl or heteroaryl radical; R- is the grouping - (CH ₂ ) _n COM, in which η equals 2 to

is, .

-CH (OH) CH ₂ CH ₂ COM ₁

-CCH ₂ CH ₂ COM,

0
-CHpCCHpCOM,

-CH ₂ CH ₂ CCOM or.

R ¹

- (CH ₂ ) _m -C- (CH ₂ ) _n COM, wherein
E.

R and R ¹ each represent an alkyl, aryl or halogen radical,

m'1 or 0 and η 1 or 0, with the proviso that, when m is 0, η cannot be 0, and when η is 0, m cannot be 0 and M is a hydroxy, lower alkoxy, substituted lower alkoxy, Amino, alkylamino, dialkylamino, N-morpholino, Hydroxyalkyl amino, polyhydroxyalkylamino, Di alkyl amino, alkyl amino, aminoalkylamino radical. or represents the grouping OMe, in which Me is a cation;

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nt

Hg is a hydrogen atom, a halogen, hydroxy, alkoxy or haloalkoxy radical and
denote a hydrogen atom or a lower-alkyl radical.

Reagents: <'■'

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

2. Warming together with polyphosphoric acid.

3. Reformatsky reaction: Zn in an inert solvent, heat. 4-. p-Toluenesulfonic acid and CaClp or J ^ at 200 °.

5. Reaction with aldehyde or ketone using a strong base as a catalyst (K-tert-butoxide or any alkoxide, NaOH, KOH, NaNH ₂ and the like.) If necessary, heating with formation of the carbanion in a solvent, such as 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.

COOH

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Although the syntheses described are esters of acids According to the invention, some desired esters are obtained more easily by adding a simple ester to the final Acid is formed, to which the free acid is hydrolyzed and transesterified. The simple lower alkyl or benzyl esters are commonly used in the synthesis of the compounds. Other esters are from the standpoint of therapeutic usability of the compounds more favorable, such as the methoxymethyl, diethylaminoäthy1-, Dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, N-pyrrollidinylethyl, N-piperidinylethyl, N-morpholinylethyl, N-ethyl-2-piperidinylethyl, N-pyrolli ~ dinylmethyl, N-methyl-2-pyrollidinylmethyl, 4-methyl-1-piperazinylethyl, Methoxyethyl, Ä'thoxyäthylester and the like. These are most often made from the corresponding alcohol and 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 beneficial therapeutically and the like

Similarly, salts are made by neutralizing the indenyl acids with bases or by reacting others twice Get salts. The metal salts, such as, for example, alkali metal or alkaline earth metal salts, are particularly favorable the amine and quaternary ammonium salts which are water soluble are, however, the heavy metal salts are also suitable for some purposes, e.g. B. the iron, aluminum salts and the like.

The following examples serve to further illustrate the invention:

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example 1

A. Ethyl 5-fluoro-2-methyl- ^: 5-inde rj yl-Y-butyrate

To 1.70 g (0.025 mol) of sodium ethoxide in 25 ml of dimethylformamide (DMF) 9.14 g (0.020 mol) of γ-ethoxycarbonylp ropyl tripheny lpho sphoni umbromi d in 25 ml DMF was added over 10 minutes under nitrogen. The mixture will Stirred for 90 minutes at room temperature. 3.28 g (0.020 mol) of 6-fluoro-2-methylindan-1-one in 25 ml of DMF are added and the mixture is stirred at room temperature for 1 hour. After this period ends, will the temperature slowly increased to 130 for 9 minutes. The mixture is cooled to room temperature (25 °) and in vacuo concentrated to remove most of the DMF. The residue is extracted with ether, then warmed with ether, separated and the essential extract dried over MgSO ^ and concentrated in vacuo to obtain the crude product. The crude product is chromatographed over silica gel and eluted with benzene, ethyl 5-fluoro-2-methyl-3-indanylidene-4-butyrate is obtained.

The ester from the previous step is treated with 0.050 g of p-toluenesulfonic acid monohydrate in 50 ml of benzene for 10 hours held under reflux. The mixture is cooled, sequentially with water, saturated sodium bicarbonate solution and water extracted. The benzene extract is dried over MgSO ^, and concentrated in vacuo, with ethyl 5-fluoro-2-methyl-3-indenyl-y-butyrate is obtained.

B. cis and trans-5-fluoro-2-methyl-1- (4'-methylthiobenzylidene) -3-indenyl-Y ~ butyric acids

, The ester (0.393 g, 0.0015 mol) from Example 1A in 15 ml Methanol is mixed with 0.162 g (0.003 mol) of sodium methoxide and 0.342 g (0.00225 moles) of p-methylthiobenzaldehyde

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? y π

14258 ZZU

and the mixture is refluxed for 5 hours. 10 ml of water are added and the new mixture is refluxed for an additional hour. The mixture is cooled to 25 °, extracted with methylene chloride, the aqueous layer acidified to pH 2 and extracted with ether. The essential extract is dried over MgSO ^ and concentrated in vacuo to an oil. The oil is chromatographed on silica gel and eluted with methanolic chloroform to give cis- and trans-5-i'luoro-2-methyl-1- (4 ^l -methylthiobenzylidene) -3-indenyl-y-butyric acids.

C. cis-5-Fluoi> 2-methyl-1- (V-methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid

To a solution of 0.600 g (0.00168 mol) of the cis-thio compound from Example 1-B in 50 ml of methanol, 15 ml of water and 50 ml of acetone are 2 g of sodium periodate in 2 ml of water admitted. The mixture is left to stand. Every day for three consecutive days 2 g of sodium periodate are taken added in 2 ml of water. On the fourth day, saturated sodium chloride solution is added and the mixture is with Extracted methylene chloride, the organic phase over

MgSO ^ dried and concentrated to a glass in vacuo. To the residue in 100 ml of methanol is added 1 ml of concentrated sulfuric acid, and the mixture is left under for 1 hour Held at reflux. The mixture is concentrated in vacuo at room temperature, the residue in benzene and water added, the benzene solution with water, 5% sodium bicarbonate and washed with saturated saline. The benzene extract is over MgSO. dried and put on silica gel chromatographed. That with 1%, methanolic chloroform The eluate obtained is concentrated to dryness in vacuo. The residue is saponified with sodium methoxide in methanol. The mixture is concentrated to dryness, taken up in ethyl acetate-water, the aqueous layers adjusted to pH 2.

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acidifies and separates the layers. The aqueous layer becomes extracted with ethyl acetate, and the combined, organic extracts are dried over MgS (X and in vacuo to Concentrated dry. The residue is crystallized from acetone / n-hexane, cis-5 "-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y-butyric acid is obtained.

Using the same reaction conditions and measures the following indenylbutyric acids are obtained from the corresponding indanone.

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/ P

Starting material product

4,5 or 6-chloro-1-methyl-cis-4,5 or 6-chloro-2-methylindanone i - ^ '- methylsulfinylbenzylidene) -

3-indenyl-y-butyric acid

4, 5 or 6-fluoro-2-, ·. · Cis -4, 5 or 6-fluoro-2-methylmethylindanone 1- (4'-methylsulfinylbenzylidene) -

3-indenyl-y-butyric acid

^ öDifluor ^ methylin cis-5,6-difluoro-2-methyl-1-danone (4'-methylsulfinylbenzylidene) -

3-indenyl-y-butyric acid

5-fluoro-6-metb.oxy-2-cis-6-fluoro-5-πletlloxy-2-meth.ylmethylindanone 1- (4'-methylsulfinylbenzylideii)

J-indenyl-y-butyric acid

4 ₁ 6-Difluoro-2-methyl- cis-5 _l 7-Difluoro-2-methyl-1- (4'-indanone methylsulfinylbenzylidene) -3-

indenyl-y-butyric acid

5 or 6-cyano-2-methyl- cis-5 or 6-cyano-2-methyl-1-indanone (4 ¹ -methylsulfinylbenzylidene) -

idl ^ ta

6-Allyloxy-2-methyl> '. Indanone cis ~ 5-Allyloxy-2-methyl-1- (prepared by cycli- (4'-methylsulfinylbenzylidene) sation of p-allyloxy-3-indenyl-y-butyric acid benzaldehyde)

Example 2

A. 6-fluoroindanone

200 g (1.61 moles) p-fluorobenzaldehyde, 242 g (2.42 moles) acetic anhydride and 132.0 g (1.61 ml) of anhydrous sodium acetate are mixed and refluxed for 20 hours held. The contents are then cooled and poured into 8 liters of water. The precipitate is by adding 302 g Potassium hydroxide dissolved in 2 liters of water. The aqueous solution is extracted with ether and the ethereal extracts with Washed 2.5 η sodium hydroxide solution. The combined, aqueous layers are heated to boiling for 5 minutes, cooled to 0 ° with concentrated hydrochloric acid acidified and filtered. The solution is heated with water, dried and used as received.

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B. Ethyl 3-fluorine-3-indenyl-y-butyrate

To 1.70 g (0.025 mol) of sodium ethoxide in 25 ml of dimethylformamide (DMF) are 9.14 g (0.2 mol) of γ-ethoxycarbonylpropyltriphenylphosphonium bromide in 25 ml DMF added over 10 minutes under nitrogen. The mixture is 90 minutes stirred at room temperature. 0.020 mol of 6-fluoroindanone in 25 ml of DKF 'are added to this mixture and that Mixture stirred at room temperature for 1 hour. At the end of this period, the temperature is adjusted using a heated oil bath slowly increased to 130 ° and held at 130 ° for 9 minutes. The mixture is brought to room temperature (25 °) cooled and concentrated in vacuo to remove most of the DMF. The residue is extracted with ether, then warmed with ether, separated and the ethereal extracts dried over MgSO ^, and in vacuo with receipt of the crude product concentrated. The crude product is chromatographed over silica gel and eluted with benzene, whereby Ethyl 5-fluoro-3-indanylidene-V-butyrate is obtained.

The ester from the previous stage is refluxed for 10 hours with 0.050 g of p-toluenesulfonic acid monohydrate in 50 ml of benzene. The mixture is cooled, extracted successively with water, saturated sodium bicarbonate solution and water. The benzene extract is dried over MgSO ^ and concentrated in vacuo to give ethyl 5 ^: -fluoro-3-indenyl-y-butyrate.

C. cis and trans-5-fluoro-1- (V-methylthiobenzylidene) -3-indenyl-y-butyric acids

0.0015 mol of the ester from Example 2-A in 15 ml of methanol are mixed with 0.162 g (0.003 mol) of sodium methoxide and 0.342 g ■ (0.00225 mol) p-methylthiobenzaldehyde treated, and that The mixture is refluxed for 5 hours. 10 ml of water

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are added and the new mixture becomes another Refluxed for hour. The mixture is cooled to 25 °, extracted with methylene chloride, the aqueous layer acidified to pH 2 and extracted with ether. The essential extract is dried over MgSO ^ and in a vacuum to a concentrated oil. The oil is chromatographed over silica gel and eluted with methanolic chloroform, with cis- and trans-5-fluoro-1- (4 -'-methylthiobenzylidene) -3-indenyl-ybutyric acids can be obtained.

D. cis-5-i ^l luor-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y-butyric acid

2 g of sodium periodate in 2 ml of water are added to a solution of the cis-thio compound (0.00168 mol) from Example 2-B in 50 ml of methanol, 15 ml of water and 50 ml of acetone. The mixture is left to stand. Every day, on three consecutive days, 2 g of sodium periodate in 2 ml of water are added. On the fourth day, saturated sodium chloride solution is added and the mixture is extracted with methylene chloride, the organic phase over MgSO ^ ^; dried and concentrated in vacuo to a glass. 1 ml of concentrated sulfuric acid is added to the residue in 100 ml of methanol and the mixture is refluxed for 1 hour. The mixture is concentrated in vacuo at room temperature, taken up in benzene and water, and the benzene solution is washed with water, 5% sodium bicarbonate and saturated salt solution. The benzene extract is dried over MgSO ^ and chromatographed on silica gel. The eluate obtained with 1% methanolic chloroform is concentrated to dryness in vacuo. The residue is saponified with sodium methoxide in methanol. The mixture is concentrated to dryness, taken up in ethyl acetate-water, the aqueous layers acidified to pH 2 and the layers separated. The aqueous layer is treated with ethyl

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acetate extracted, and the combined organic extracts are dried over MgSCL and in vacuo to dryness concentrated. The residue is crystallized from acetone / n-hexane, yielding ice-5-fluoro-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y-butyric acid.

Using the same reaction conditions and measures, the following indenyl-γ-butyric acids are selected get the corresponding benzaldehydes:

Respondents

o-, m- or p-fluorobenzaldehyde

o-, m- or p-chlorobenzaldehyde

3,4-difluorobenzaldehyde

enz-

aldehyde 2,4-difluorobenzaldehyde

m- or p-cyanobenzaldehyde

Pr-allyloxybenzaldehyde

product

cis-4, 5- or 6-fluoro-1- (4'-

methylsulfinylbenzylidene) ~ 3-indenyl-y-butyric acid cis-4, 5- or 6-chloro-1- (4'-

methylsulfinylbenzylidene) -3-indenyl-y-butyric acid cis-5,6-difluoro-1- (4'-methyl-

sulfinylbenzylidene) -3-indenyl-γ-butyric acid

cis-6-Pluoro-5-iiiethoxy-1- (4 ^l methylsulfinylbenzylidene) -3-indenyl-y-butyric acid cis-5,7-Difluoro-1- (4'-methyl-

sulfinylbenzylidene) -3-indenyl-γ-butyric acid

cis-5 or 6-cyano-1- (4'-methyl-

sulfinylbenzylidene) -3-indenyl-γ-butyric acid

ciss-6-allyloxy-1- (4 ^l -methyl-

sulfinylbenzylidene) -3-indenyl-γ-butyric acid

example

A. 5-fluoro-2-methylindenyl-3- (ß-ethanol)

9.8 g of methyl 5-fluoro-2-methylindenyl-3-acetate in 75 ml of ether are stirred to a suspension of 1.0 g of lithium aluminum hydride in 50 ml of ether for a period of

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Added 30 minutes. The reaction mixture is then refluxed for 3 hours, cooled, and 50 ml Methanol was slowly added and then 50 ml of water admitted. The entire solution is filtered through Celite and dried with anhydrous magnesium sulfate. The solution it is filtered and concentrated to give an oil which solidifies, pp 64 to 66 °.

B. 5-Fluoro-2-methylindenyl-5-acetaldehyde

1> 92 g of the above alcohol in 50 ml of a solution of 20 g Chromium trioxide bis-pyridyl complex in 3OO ml of methylene chloride is stirred at room temperature for 45 minutes. The solution is then filtered and the residue is washed with ethyl acetate. The combined organic layers are poured into 200 ml of water and more ethyl acetate is added added until the organic layers are lighter than water. The organic layer is poured over anhydrous magnesium sulfate dried, filtered and evaporated to dryness to give a dark red oil.

The oil is chromatographyerb on 100 g of silica gel and the Aldehyde eluted with benzene. The oil obtained has the following NMR spectrum (in dimethyl sulfoxide):

Triplet 0.37 (J. »1» 5 c.p.s.) multiplet 2.5 to 3.3

two wide

Singlets 6.30 and 6.65

Singlet 8.95

C methyl 5-fluoro-2-methyl-5-indenyl-y- (ß-hydro3cybutyrate

A mixture of 28.5 g (0.15 mol) of 5-fluoro-2-methyl-3-indenylacetaldehyde, 13.1 g (0.20 mol) of activated zinc dust, 23.0 g (0.15 mol) of methyl bromoacetate and an iodine

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crystal in 750 ml of dry benzene is refluxed for 5 hours. The mixture γ ', poured into 750 ml of 5% sulfuric acid, extracted with ether, the ether extract dried over MgSO ^ and the ethereal solution concentrated. The crude ester is crystallized from methanol / n-hexane, and methyl 5-fluoro-2-methyl-3-indenyl-γ- (ß-hydroxybutyrate) is obtained.

D. cis and trans-5-fluoro-2-methyl-1- (4'-methyl thiobenzylidene) -3-indenyl-y- (ß-hydroxybutyric acids)

11 g (0.20 mol) of powdered sodium ethoxide become a suspension of 27> 8 g (0.1 mol) of esters according to the example 3-C and 16.7 g (0.11 mol) of methylthiobenzaldehyde in 200 ml of methanol were added under dry nitrogen. A clear solution is obtained and this mixture is refluxed for 1 hour. The same volume Water is added and the reflux treatment is JO minutes continued to finish the saponification. The solution is cooled to room temperature (25 °) and with several Volume V / water diluted. The product is precipitated by adding 200 ml of 50% strength acetic acid. The precipitation will filtered off, washed well with water and dried in vacuo over potassium hydroxide pellets. The raw product is in Taken up methylene chloride and chromatographed on silica gel to separate the cis and trans isomers, the identifiable by integrating the 2-CEL signal in the NMR spectrum are.

E. cis-5-i'luor-2-methyl-1- (4 ^l -methylsulfinylbenzylidene) -3-indenyl-y- (ß-hydroxybutyric acid)

, To a solution of the thio compound (3.84 g, 0.01 mol) from Example 3-D in 100 ml of methanol, '100' ml of acetone and 20 ml of water are 11.3 g of sodium periodate in 20 ml of water admitted. The mixture is stored for 24 hours at 25 ° under nitrogen

- 23 2 09832/1229

ßoff stirred, after which the mixture is concentrated to a small volume in vacuo. The concentrate is diluted with water, filtered, the precipitate washed and dried in air and then in vacuo at 50 °. The residue will recrystallized from methanol / n-hexane and cis-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y- (β-hydroxybutyric acid) is obtained.

Using the same reaction conditions and measures the following indenyl-y- (ß-hydroxybutyric acids) made from the indenyl ester.

Source material. product

Methyl 5,6-difluoro-2-methyl-ice-5,6-difluoro-2-methyl-i- (4'-indenyl-3-acetate methylsulfinylbenzylidene) -3-

indenyl-y- (ß-hydroxybutter-

acid)

Methyl-5-fluoro-6-methoxy- cis-5-I ¹ luoro-6-methoxy-2-methyl-2-methylindenyl-J-acetate i- (V-methylsulfinylbenzylidene) -

J-indenyl-y- (ß-hydroxybutter-

acid)

Methyl 5,7-difluoro-2-methyl-cis-5,7-difluoro-2-methyl-1- (4'-indenyl-3-acetate methylsulfinylbenzylidene) -3-

indenyl-γ- (ß-hydroxybutyric acid)

Methyl-5-cyano-2-methyl-cis-5-cyano-2-methyl-1- (4'-methylindenyl-3-acetate . sulfinylbenzylidene; -3-indenyl-

y- (ß-hydroxybutyric acid)

Methyl-5-niethoxy-2-methyl-cis-5 ~ ^M ethoxy-2-methyl-1- (4 'indenyl-3-acetate methylsulfinylbenzylidene) -3-

indenyl-y- (ß-hydroxybutyric acid)

Methyl 5-allyloxy-2-methyl-cis-5-allyloxy-2-methyl-1- (4 'indenyl-3-acetate methylsulfinylbenzylidene) -3-

indenyl-y- (ß-hydroxybutyric acid)

Methyl 5,6-difluoroindenyl-cis-5,6-difluoro-1- (4'-methyl-3-acetate sulfinylbenzylidene) -3-indenyl-

y- (ß-hydroxybutyric acid)

Methyl-5- fluoro-6-methoxy-cis-5-I'luoro-6-methoxy-1- (4 ^l indenyl-3-acetate methylsulfinylbenzylidene) -3-

indenyl-y- (ß-hydroxybutyric acid)

- 24 -

2 09832/1229

ft "

Starting material product

Methyl 5,7-difluoroindenyl-cis-5,7-difluoro-1- (4'-methyl-3-acetate sulfinylbenzylidene) -3-indenyl-

γ- (ß-hydroxybutyric acid)

Methyl ^ -cyanoindenyl ^ - cis-5-cyano-1- (V-methyl-

acetate - sulfinyIbenzylidene) -3-indenyl-

γ- (ß-hydroxybutyric acid)

Methyl 5-nietkoxyindenyl-3-cis-5-methoxy-1- (4'-methyl acetate sulfinylbenzylidene) -3-indenyl-

γ- (ß-hydroxybutyric acid)

Methyl ^ -allyloxyindenyl ^ - cis -5-allyloxy-1- (4'-methyl acetate sulfinylbenzylidene) -3-indenyl-

3-γ- (ß-hydroxybutyric acid)

Example 4

cis-5-i'luoro-2-methyl-1- (4 ^l -methylsulfinylbenzylidene) 3-indenyl-y- (ß-ketobutyric acid)

To a solution of the thio compound (3.84 g, 0.01 mol) from Example 3-D in 150 ml of 80% acetic acid are at 60 ° with stirring over 10 minutes, 1.3 g of chromium trioxide were added. The mixture is kept at 60 to 65 °, with stirring for a further 20 minutes. i) the mixture is in 200 g Poured ice and water, filtered, washed with water and the precipitate air dried. The residue is recrystallized from methanol / n-hexane, and ci £ -5-fluoro-2-methyl-1- (V ~ methylsulfinylbenzylidene) -3-ihdenyl-y- (ß-ketobutyric acid) is obtained.

Using the same reaction conditions and measures the following indenyl-γ- (ß-ketobutyric acids) are obtained:

209832/1229

14258

Source material

product

cis-5,6-difluoro-2-methyl-1- (4'-methylthiobenzylidene) -3-indenyl-y- (β-hydroxybutyric acid;

cis-5-fluoro-6-methoxy-2-methyl-1- (4'-methylthiobenzylidene) -3-indenyl-y- (ß-hydroxybutyric acid)

cis-5,7-Difluoro-2-methyl-1- (4'-methylthiobenzylidene) -3-ind.enyl-y- (ß-hydroxybutyric acid)

cis -5-cyano-2-methyl-1- (4'-methylthiobenzylidene) -3-indenyl-γ- (β-hydroxybutyric acid

cis-5-methoxy-2-methyl-1- (4'-methylthiobenzylidene) -3-indenyl-y- (ß-h ^ hydroxybutyric acid)

cis-5-allyloxy-2-methyl-1- (4'-methylthiobenzylidene) -3-indenyl-y- (ß-hydroxybutyric acid)

cis -5-acetyl-2-methyl-1 - (^ '- methylthiobenzylidene) -3-indenyl-γ- (β-hy droxybutyric acid)

cis-5,6-pifluoro-1- (4'-

methylthiobenzylidene) -3-indenyl-v- (ß-hydroxybutyric acid)

eis- 5-I1 \ iot- 6-methoxy-1- (4'-methylthiobenzylidene) -3-indenyl-y- (ß-hydroxybutyric acid)

cis-5,7-pifluoro-1- (4'-methyl thiobenzylidene) -3- indenyl-γ- (ß-hydroxy butyric acid)

cis-5-cyano-1- (4'-methyl-

thiobenzylidene) -3-indenyl-

y- (ß-hydroxybutyric acid) cis-5 »6-difluoro-2-methyl-1- (4 * -methylsulfinylbenzylidene) -3-indenyl-y- (ß-ketobutyric acid)

cis-5-fluoro-6-methoxy-2-methyl- (4'-methylsulfinylbenzylidene) -3-indenyl-y- (ß-ketobutyric acid)

cis-5,7-Difluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y- (ß-ketobutyric acid)

cis-5-cyano-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-γ- (ß-ketobutyric acid)

cis-5-methoxy-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-γ- (ß-ketobutyric acid)

cis -5-Allyloxy-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y- (β-ketobutyric acid ure)

cis -5-acetyl-2-methyl-1- (4'-methylsulfiny Ib EnzyIi den) -3-indenyl-y- (ß-ketobutyric acid)

cis-5,6-difluoro-1- (4'-methylsulfinylbenzylidene) -3-indenyly- (ß-ketobutyric acid)

cis-5-fluoro-6-methoxy- (4'-

methylsulfinylbenzylidene) -3-

indenyl-y- (ß-ketobutyric acid)

s5,7 (y sulfinylbenzylidene) -3-indenyly- (ß-ketobutyric acid)

ciss-5-cyano-1- (4 ^l -methylsulfi-

nylbenzylidene) -3-indenyl-y-

(ß-ketobutyric acid)

- 26 -

209032/1229

Starting material product

cis-5-methoxy-i- (4 '-methyl- cis-5-methoxy-i- (4' -methylsulfi-

thiobenzylidene) -3-indenyI- nylbenzylidene) -3-indenyl-y- (B-

γ- (ß-hydroxybutyric acid; ketobutyric acid)

cis-5-allyloxy-i- (4'-methyl- cis-5-allyloxy-1- (4'-methyl-

thiobenzylidene) -3-indenylsulfinylbeneylidene) -3-indenyl-

y- (β-hydroxybutyric acid,) y- (β-ketobutyric acid;

cis- 5-acetyl-1- (4'-methyl- cis-5-acetyl-1- (4'-methylsulfinyl-

thiobenzylidene) -3-indenylbenzylidene) -3-iB-den-rl-y- (ß-

γ- (ß-hydroxybutyric acid; ketobutyric acid)

Example 5

A. cis-5-fluoro-2-methyl-1- (V -methyl thiobenzylideii) -3-indenyl-γ- (ß-chlorobutyric acid)

To a solution of the thio compound according to Example 3-D g, 0.01 mol) in 100 ml of pyridine are 2.72 g (0.024 mol)

Thionyl chloride is added and the mixture is heated to 60 °. The temperature is slowly increased to 90 ° over 2 hours and held at 90 to 95 ° for a further hour. The mixture is cooled to 20 °, poured into 300 g of ice and water and stirred at 15 ° to 20 ° for 2 hours. The mixture is filtered, the precipitate is washed with water and dried in vacuo over calcium chloride at 25 °. The residue is recrystallized from ethyl acetate / n-hexane, and luor-2-methyl-1 is obtained cis-5-i ^l (4'-methylthiobenzyIiden) -3-indenyl-y- (ß-chloro-butyric acid).

B. cis-5-I'luoro-2-methyl-1- (4 ^l -methvlsulfinylbenzylidene) -3-indenyl-y- (ß-chlorobutyric acid)

0.403 6 (0.001 mol) of the chloric acid from Example 5-k are converted into cis-5-3-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-yr (ßchlorobutyric acid) according to the method according to Example 3-E convicted.

- 27 -209832/1229

J?

Example 6

trans-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y- (ß-chlorobutyric acid)

3.84 g (0.01 mol) of trans-5-fluoro-2-methyl-1- (4 ^l -methylthiobenzylidene) -3-indenyl-y- (ß-hydroxybutyric acid) are prepared according to the method of Examples 5-A and 5-B converted into trans-5-I ^% luoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-γ- (β-hydroxybutyric acid).

Example 7

A. Ethyl 5iCc-difluoro-2-methyl-3-indenyl-Y-btityrate

A mixture of 24.6 6, (0.15 mol) 6-fluoro-2-methyl-1-indanone, 12.76 (0.20 moles) activated zinc dust, 0.15 moles ethyl bromofluorobutyrate and an iodine crystal in 750 ml dry Benzene is refluxed for 5 hours. The mixture is poured into 750 ml of 5% sulfuric acid, with ether extracted, the ether extract over MgSO ^. dried and the essential solution concentrated. The crude ester is used in 220 ml of benzene redissolved, 44 g of phosphorus pentoxide are added, and the resulting mixture is taken for 30 minutes Held at reflux. The mixture is decanted, the residue washed with benzene, combined the benzoil layers, washed with water, then with saturated saline solution and dried over .MgSO ^. After concentrating the dry, organic phase gives ethyl 5, oc-difluoro-2-methyl-3-indenyl-y-butyrate as a residue.

B. cis and trans-5ja-difluoro-2-methyl-1- (4'-methylthiebenzylidene) -3-indenyl-y-butyric acids

0.10 mol of the ester from Example 7-A are according to the method according to Example 1-B in cis and trans-5 »α-di fluoro-2-methyl-

20 9 8 3 "f9 f 2 2 9

1- (4'-methylthiobenzylidene) -3-ii ^{1 <} 3-enyl-y-butyric acids transferred.

C. cis -5> α-Difluoro-2-methyl-1- (V-methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid

0.358 g (0.001 mol) of cis-5, a-difluoro-2-methyl-1- (V-methylthiobenzylidene) -3-indenylbutyric acid are converted into cis-5 _, cc-difluoro-2-methyl by the method according to Example 1-C -1- (4'-methylsulfinylbenzylidene) -3-indenyl-y-butyric acid transferred.

Using the same reaction conditions and measures as in Example 7, the corresponding acids obtain: ,

Starting material product

5,6-difluoro-2-methyl-1-cis-5,6-a-trifluoro-2-methyl-1-indanone (V-methylsulfinylbenzylidene) -

3-indenyl-y-butyric acid

6-i ¹ luor-5 ~ methoxy-2-methyl- cis-5 »oc-difluor-6-methoxy-1-indanone 2-methyl- ^/ l- (4 ^I -m ethyl sulfiny l-

benzylidene) -3-iπdenyl-γ-butyric acid

4,6-difluoro-2-methyl-1- cis-5,7ia-trifluoro-2-methyl-1-indanone (4 ¹ -methylsulfinylbenzylidene) -3-

indenyl-y-butyric acid

& -Cyano-2-methyl-1-indanone cis-5- "Cyano-2-methyl-1- (4'-

methylsulfinylbenzylidene) -3-indenyl-y-butyric acid

6-methoxy-2-methyl-1-indanone cis-5-methoxy-2-methyl-1- (4'-

methy1sulfinyIbenzyliden) -3-indenyl-y-butyric acid

6-allyloxy-2-methyl-1-cis-5-allyloxy-2-methyl-1-indanone (4'-methylsulfinylbenzylidene) -

3-indenyi-y-butyric acid

5, G-Difluor-I-indanone cis- ^ e-Trifluor-i-CA -'- methyl-

Bulfinylbenzylidene) -3-indenylybutyric acid

- 29 -209832/1229

Starting material product

6-fluoro-5-methoxy-1-indanone cis-5 »oc-difluoro-6-methoxy-1-

(4'-methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid

4,6-difluoro-1-indanone 'cis-5,7, a-trifluoro-1- (4 · -

methylsulfinylbenzylidene) -3-indenyl-y-butyric acid

6-cyano-i-indanone cis-5-cyano-1- (4'-methylsul-

finylbenzylidene) -3-indenyl-ybutyric acid

6-methoxy-1-indanone ciss-5-methoxy-1- (4 '-methylsulfi-

nylbenzylidene) -3-indenyl-ybutyric acid

6-allyloxy-i-indanone cis-5-allyloxy-1- (4'-methyl-

sulfinylbenzylidene) -3-indenyl-γ-butyric acid

Example 8

A. Atb-yl-3-fluoro-2-methyl-3-indenyl-β-butyrate

According to the method according to Example 7-A, 24.6 g (0.15 mol) 6-fluoro-2-methyl-1-indanone with 29.3 g (0.15 mol) of ethyl β-bromobutyrate to obtain ethyl 5-fluoro-2-methyl-3-indenyl-ß-butyrate condensed.

B. cis and trans-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -β-butyric acids

26.2 g (0.10 mol) of ethyl 5-fluoro-2-methyl-3-indenyl-ß-butyrate according to the method of Example 1-B in cis- and trans-5-i ^l luor-2- methyl-1- (4'-methyl thiobenzylidene) -3-indenyl-ß-butyric acids, and these are in turn converted individually into cis and trans-5-i ^> lüor-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-ß-butyric acids transferred.

- 30 -

209832/1229.

Example 9

A. Ethyl-3-fluoro-2- methyl-3-indenyl-a-ethoxyacetate

According to the method according to Example 7-A, 24.6 g (0.15 Mol) 6-fluoro-2-methyl-1-indanone with 31 »7 B (0 * 15 mol) Ethyl-a-bromo-a-ethoxyacetate to obtain ethyl-5-fluoro-2-methyl-3-indenyl-a-ethoxyacetate condensed.

B. cis and trans-5-fluoro-2-methyl-1- (4'-iaethylsulfinylbenzylidene) -oc-ethoxy acetic acids

27.8 g (0.10 mol) of ithy1-5-fluoro-2-methyl-3-indenyl-ethoxyacetate are according to the method according to Example 1-B in cis- and trans-5-fluoro-2-methyl-1- (4'-methoxythiobenzylidene) -3 ~ indenyl-a-ethoxyacetic acids transferred, and these are in turn individually by the method according to Example 1-C in cis- and trans-5-fluoro-2-methyl-1- (4'-methylsulfiny1-benzylidene) -oc-ethoxy acetic acids transferred.

Example 10

A. Methyl 5-fluoro-2-methyl-5-indenyl-Y- (ß-butinoate) "

According to the method according to Example 7-A, 24.6 g (0.15 Moles) 6-fluoro-2-methyl-1-indanone with 26.6 g (0.15 moles) of methyl 4-bromo-3-butinoate condensed to give methyl 5-fluoro-2-methyl-3-indenyl-y- (ß-butinoate).

B. cis and trans-5-5 ^l luoro-2-methyl-1- (4'-methyl-sulfinylbenzylidene) -y- (ß-butynoic acids)

. 29.3 g (0.12 mol) of methyl 5-fluoro-2-methyl-3-indenyl-y- (ß-butinoate) are according to the method according to Example 1-B in cis- and trans-5-fluoro-2-methyl-1- (4 · -methylthiobenzylidene) -3-indenyl-y- (ß-butynoic acids) convicted and these are

- 31 - ■
209832/1229

again individually according to the method according to Example 1-C in cis- and trans-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -y- (ß-butynoic acids) convicted.

Example 11

CISS-5-i ^l luor-2-methyl-1- (4'-methylsulfinylbenzylidene) -y (y-ketobutanoic acid)

0.761 g (0.002 mol) of the acid from Example 10 in 60 ml of ethyl acetate are mixed with 1.27 g (0.004 mol) of mercury (II) acetate stirred for 24 hours at 25 °. Hydrogen sulfide is introduced into the mixture to precipitate mercury as sulfide. The mixture is made by diatomaceous earth filtered, the residue washed with ethyl acetate and the filtrate evaporated to dryness in vacuo. The residue is recrystallized from ethyl acetate / n-hexane, and cis-5- (i \ Luor-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y- (y-ketobutyric acid) is obtained.

Using the same reaction conditions and measures as in Example 11, the following y- (y-ketobutyric acids) obtain.

Starting material product

cis-5-fluoro-2-methyl-1- (4'-cis-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -methylsulfinylbenzylidene) -yy- (ß-butynoic acid) (y-ketobutyric acid)

cis -5 »6-difluoro-2-methyl-cis-5> 6-difluoro-2-methyl-1-1- (4'-methylsulfinylbenzyl- (4'-methylsulfinylbenzylidene) -idene) -y- (β-butyric acid ) y- (y-ketobutyric acid) cis-5-methoxy-6-fluoro-2- cis-5-methoxy-6-fluoro-2-methylmethyl-1- (4'-methylsulfinyl-1- (4'-methylsulfinylbenzylidene) - benzylidene) -y- (ß-butynoic acid) y- (y-ketobutyric acid) cis - ^^ - difluoro - ^ - methyl- cis-5,7-difluoro-2-methyl-1- : i- (4'-methylsulfinylbenzyl- (4'-methylsulfinylbenzylidene) -idene) -y- (ß-butynoic acid) y- ^ ketobutyric acid)

- 32 -209832/1229

14258

Starting material

^ yy ^ methylsulfinylbenzylidene) -y- (ß-butynoic acid)

^ y ^ y (4 ¹ -methylsulfinylbenzylidene) -y- (ß-butynoic acid)

ice-5-allyoxy-2-methyl-1- (4 ' -methyl sulfinylbenzylidene) -y- (ß-butynoic acid) product

s51- (4'-methylsulfinylbenzylidene) -y- (B-butynoic acid)

cis-5,6-Mfluoro-1- (4'-

methylsulfinylbenzylidene) -

y- (ß-butynoic acid)

cis-5-methoxy-6-fluoro-1- (4'-methylsulfinylbenzylidene) -y- (ß-butynoic acid)

cis-5,7-difluoro-1- (4'-methylsulfinylbenzylidene) -γ- (ß-butynoic acid)

cis-5-cyano-1-C4'-methylsulf ynylbenzylidene) -γ- (ßbutinic acid)

cis-5-cyano-2-methyl-1- (4'-

methylsulfinylbenzylidene) -y-

(γ-ketobutyric acid)

cis -5-methoxy-2-methyl-1- (4'-

methylsulfinylbenzylidene) -y-

(γ-ketobutyric acid; cis-5-allyloxy-2-methyi-1- (4 ¹ -methylsulfinylbenzylidene) -y- (γ-ketobutyric acid)

cis-5-i'lu.or-1-C4 ^l -methylsulfinyl-

benzylidene) -y- (y-ketobutyric acid

cis-5,6-difluoro-1- (4'-methyl-

sulfinylbenzylidene) -y- (y-keto-

butyric acid)

cis -5-methoxy-6-fluoro-1- (4'-methylsulfinylbenzylidene) -y- (γ-ketobutyric acid;

cis-5 ₎ 7-difluoro-1- (4'-methylsulfinylbenzylidene; -y- (y-ketobutyric acid)

-cis -5-cyano-1-C4'-methylsulfinylbenzylidene) -y- (γ-ketobutyric acid )

cis - ^ - Methoxy-i- (4'-methyl- cis-5-methoxy-1- (4'-methylsulfinylbenzylidene) -ysulfinylbenzylidene) -y- (y-keto- (ß-butynoic acid) . butyric acid)

ciss-5-allyloxy-i- (4'-methyl- cis-5-allyloxy-1- (4 "-methyl-BUlfinylbenzylidene) -y- (ßsulfinylbenzylidene) -y- (ybutic acid) ketobutyric acid

Example 12

A. 4-Fluoro-α-fluoromethylcinnamic acid

0 g (0.5 mol) of ß-fluoropropionic acid in 460 ml of water are neutralized with 20 g (0.5 mol) of sodium hydroxide and the solution is concentrated to dryness in vacuo and further dried over phosphorus pentoxide to give sodium ß-fluoropropionate .

- 33 -209832/1229

To 115 »1 g (1» 25 mol) ß-fluoropropionic acid in 1 liter of absolute Ethanol are added with stirring at 15 to 20 ° 311.8 g (1.25 mol) of thallium ethoxide, and the mixture is Stirred for 1 hour at 25 ° and concentrated to dryness in vacuo. Be consecutive to the residue 500 ml of ether and 148.8 g (1.25 mol) of thionyl chloride in 400 ml of ether were added with stirring at 25 °. The mixture will kept with stirring for 30 minutes at 25 ° and then in vacuo concentrated to a syrup, taking ß-fluoropropionic anhydride is obtained.

A mixture of 61.2 g (0.5 mol) p-fluorobenzaldehyde, 103 g (0.62 mol) ß-fluoropropionic anhydride and 57.0 g (0.5 mol) Sodium ß-fluoropropionate, which was previously prepared, is heated to 135 ° under nitrogen with stirring for 20 hours. The reaction mixture is cooled to 50 and in Poured 1.25 l of water. The mixture is extracted twice with 1.5 1 portions of ether. Become the aqueous phase 500 g ELs and concentrated hydrochloric acid except for Add pH 2. The precipitate is filtered off, washed and dried, and 4-fluoro-α-fluoromethylcinnamic acid is obtained.

B. D _t L-4-fluoro-q-fluoromethylhydrocinnamic acid

59.5 g (0.3 mol) of the acid from Example 12-A and 1.8 g of platinum oxide in 600 ml of methanol are hydrogenated at 3 »2 kg / cm (45 p.b.i.) and at 25 °, until the theoretical recording is finished. The catalyst is filtered off and. the filtrate concentrated to about 1/3 volume. 112 ml of 15% potassium hydroxide solution is added and the mixture is refluxed for 30 minutes , after which it is poured into water and extracted with 2 × 150 ml of ether. The aqueous layer is acidified with concentrated hydrochloric acid at 10 °. The separated oil is extracted with 3 × 150 ml of ether, dried over MgSO ^ and

209832 ³ Π ~ 229

concentrated. The residue is recrystallized from acetone / n-hexane, and 4-fluoro-α-fluoromethyl-

hydrocinnamic acid. .

C. D. L-6-fluoro-2-fluoromethyl-i-indanone

50.0 g (0.25 moles) of the acid from the previous step are added to 625 ^ l of polyphosphoric acid. The mixture is effectively stirred and heated on a steam bath for 2 hours. The mixture is then cooled and added to 1 kg of ELs and Poured water. The precipitate is washed with ether (3 χ JOO ml) extracted and the essential extract washed with saturated potassium carbonate, water and saturated brine and concentrated in vacuo. The residue from 6-IPluoro-2-fluoromethyl-1-indanone is used without further purification.

D. Ethyl 5-fluoro-2-fluorometh-yl-3-indenyl-β-propionate

According to the procedure according to. Example 7 - A- will give 32.6 g (0.18 Mol) 6-IPluoro-2-fluoromethyl-1-indanone in ethyl 5-fluoro-2-fluoromethyl-3'-indenyl-ß-propionate convicted.

E. cis and trans-5-i ^l luor-2-fluoromethyl-1- (4 ^l methylthiobenzyliden) -3-indenyl-ß-propvdonsäuren

0.12 mol of the esters from Example 12-D are used according to the method according to Example 1-0 in cis- and trans-5-fluoro-2-fluoromethyl-1- (V-methylthiobenzylidene) -3-indenyl-β-propionic acids convicted.

P. cis and trans-5-fluoro-2-fluoromethyl-1- (V-methylsulfinylbenzylidene) -3-indenyl-β-propionic acids

0.717 g (0.002 mol) of the acids from Example 12-E are individually converted into eic- and trans-5-J? Luoromethyl-1- (4- ¹ -methylsulfynylbenzylidene) -3-indenyl- ßpropionäuren transferred.

209832 Π 229

14-258

Using the same reaction conditions and measures as in Example 12, the following compounds are obtained:

Starting material product

3,4-difluorobenzaldehyde

3-fluoro-4-methoxybenzaldehyde

2,4-Di f 1 urobenzaldehyde 4- Cy anob enz al deny d

4-allyloxybenzene aldehyde

4-methoxybenzaldehyde cis and trans-5 »6-difluoro-2-fluoromethyl-1- (A'-methylsulfinylbenzylidene) -3-indenyl-β-propionic acids

cis and trans-5-methoxy-6-fluoro-2-fluoromethyl-1- (4- ' -

methylsulfinylbenzylidene) -3-indenyl-ß-propionic acids

cis- and trans-5) 7-difluoro-2-fluoromethyl-1- (4'-methylsulfinylbenzylidene) -3-indenylß-propionic acids

cis and trans-5-cyano-2-fluoromethyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-β-propionic acids

cis and trans -5-allyloxy-2-fluoromethyl-1- (4'-methylsulfinylbenzylidene ) - 3-indenylß-propionic acids

cis- and trans-5-methoxy-2-fluoromethyl-1- (V-methylsulfinylbenzyli den) -3-indenylß-propionic acids

Example 1 ^

A q- (p-fluorobenzylidene) -ß _t Y-dichlorobutyric acid

According to the method according to Example 12-A, 62.1 g (0.5 mol) p-fluorobenzaldehyde and 275 g (1.75 mol) β, γ-dichlorobutyric acid as the sodium salt and anhydride to give α- (p-fluorobenzylidene) -β, γ-dichlorobutyric acid condensed.

- 36 -209832/1229

B. D _? Lg- (p-fluorobenzyl) -ß, γ-dichlorobutyric acid

78 »9 g (0.3 mol) of the acid from Example 13-A are after the method according to Example 12-B in D, L-a- (p-IFluorobenzyl) -ß, γ-dichlorobutyric acid convicted.

C. D, L-6-fluoro-2- (i ', 2 ^f -dichloroethyl) -1-indanone

66.3 S (0 * 25 mol) of the acid from Example 13-B are after the method according to Example 12-C in 6-fluoro-2- (i ', 2'-dichloroethyl) -1-indanone convicted.

D. D, L-6-I-fluoro-2-vinyl- ^/ 1-indanone

To a mixture of 14.4 g (0.22 mol) powdered zinc, 9.6 g (0.007 mol) of anhydrous zinc chloride in 75 ml of methanol at 60 ° a solution of 49.6 g (0.2 mol) of indanone from Example 13-0 in 100 ml of methanol is carried out at such a rate added that the mixture is kept under mild reflux. The mixture is stirred to agglomerate to prevent zinc dust. Stirring and reflux treatment are started 1 hour after the addition of the Indanons continued. The mixture is filtered through diatomaceous earth, the residue is washed and the combined The filtrate was concentrated to dryness in vacuo. The mixture is taken up in chloroform / water and the chloroform is washed and dried over MgSO ^ and concentrated in vacuo to an oil, which is used without further purification.

E. Ethyl 5-fluoro-2-vinyl-5-indenyl-ß-propionate

35 »2 g (0.2 mol) D, L-6-fluoro-3-vinyl-1-indanone from example 13-D are converted into ethyl 5-fluoro-2-vinyl-3-indenyl-ß-propionate according to the method according to Example 13-C transferred »

- 37 -209832/1229

F. cis and trans-5-fluoro-1- (V-methylthiobenzylidene) -2-vinyl-3-indenyl-ß-propionic acids

0.15 mol of the esters from Example 13-E are according to the Method according to Example 12-D in cis- and trans-5-i "luoro-1- (V-methylthiobenzylidene) -2-vinyl-3-indenyl-β-propionic acids convicted.

G. cis- and trans-5-fluoro-1- (V-methylsulfinylbenzylidene) -2-vinyl-3-indeny1-β-p ropionic acids

0.001 mol of cis- and trans-5-5 ¹ IuOr-I- (V-methylthiobenzylidene) -2-vinyl-3-indenyl-ß-propionic acids are converted into cis- and trans-5-fluoro-1 individually by the method according to Example ID - (4'-methylsulfinylbenzylidene) -2-vinyl-3-indenyl-ß-propionic acids transferred.

Using the same reaction conditions and measures, the following indenyl-ß-propionic acids are obtained:

Starting material product

3,4-difluorobenzaldehyde cis- and trans-5> 6-difluoro-1-

(V-methylsulfinylbenzylidene) -2-vinyl-3-indenyl-ß-propionic acids

4-fluoro-3- ⁿ iethoxybenz- cis- and trans-6-methoxy-5-

aldehyde fluoro-1- (V-methylsulfiny1-

benzylidene) -2-vinyl-3-indenyl-

ß-propionic acids

2,4-difluorobenzaldehyde cis and trans-5 »7-difluoro-1-

(4'-methylsulfinylbenzylidene) -2-vinyl-3-indenyl-β-propionic acids

4-cyanobenzaldehyde cis- and trans-5-cyano-1- (4'-

methylsulfinylbenzylidene) -2- vinyl- 3-indenyl-ß-propionic acids

4-methoxybenzaldehyde cis and trans-5-ethoxy-1- (V-

methylsulfinylbenzylidene) -2-viny1-3-indeny1 -ß-propionic acids

- 38 -209832/1229

Starting material product

4-allyloxybenzaldehyde cis and trans-5-allyloxy-1-

(4 ¹ -methylsulfinylbenzylidene) -2-vinyl-3-indenyl-β-propionic acids

4-chlorobenzaldehyde cis and trans-5-chloro-1 ~ (4'-

methylsulfinylbenzylidene) -2-vinyl-3-indenyl-ß-propionic acids ·

Example 14

A. 5-H; ydroxy-4-meth; v'rthiobenzaldeh; 7d

0.35 mol of o-hydroxythioanisole in 200 ml of methylene chloride are added to 66.67 g (0.5 mol) of anhydrous aluminum chloride. The mixture is stirred and cooled while Dichloromethyl methyl ether is added dropwise. After complete dissolution, the mixture is at room temperature for 15 minutes touched. The liquid phase is in 300 g of ice and water decanted and the unreacted aluminum chloride washed with methylene chloride until the wash solutions are colorless. The washing solutions and the decanted Material are combined. The layers are separated and the organic layer washed with saturated potassium carbonate washed over MgSO ^. dried and distilled, whereby 3-hydroxy-4-methylthiobenzaldehyde is obtained.

B. cis and trans-5-IIIior-2-methyl- ^/ l- (3 ^l -hydroxy- (V-methylthiobenzylidene) -3-indenyl-y-butyric acids

22 g (0.40 mol) of powdered sodium methoxide are added to a suspension of 0.1 mol of methyl 5-fluoro-2-methyl-3- ■ indenyl-y-butyrate and 15.2 g (0.1 mol) of 3- Hydroxy-4-methylthiobenzaldehyde in 400 ml of methanol was added _; and the mixture is refluxed for 2 hours. The mixture is stirred when sodium chloride precipitates to avoid puffing

- 39 -209832/1229

to belittle. 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-fluoro-2-methyl-1- (5'-hydroxy-4 ¹ -methylthiobenzylidene) -3-indenyl-y-butyric acid can be obtained.

C. cis - ^ - Ethynyl - ^ - methyl-i-Cj'-hydroxy - ^ '- methylsulfinylbenzylidene) -3-indenylacetic acid

11> 3 6 (0.0422 mol) sodium metaperiodate trihydrate in 85 ml Water become 3j6> 2 g (0.01 hol) of cis-5-ethynyl-2-methyl-1- (3'-hydroxy-4'-methylthiobenzylidene) -3-indenylacetic acid added in 240 ml of methanol and 10 ml of acetone 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 on a Concentrated small volume, diluted with water and filtered. The Mederschelg is washed well with water, in the air and then dried in vacuo at 50 and made from ethyl acetate / η-hexane recrystallized, whereby cis-5-ethynyl-2-methyl-1- (3′-hydroxy-4′-methylsulfinyl) -3-indenyl acetic acid is obtained.

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

209832/1229

Example 15

A. o- (ß-Hydroxyethoxy) thioanisole

14.1 g (0.1 mol) of o-hydroxythioanisole are 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 reaction mixture is refluxed for 2 hours kept and chilled. The o- (ß-hydroxyethoxy) thioanisole is extracted.

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 obtained.

B. cis -5-fluoro-2-methyl-1- (3'-β-hydroxyethoxy-4'-methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid

The product from Example 15-A is according to the methods of Examples 14-A, 14-B and 14-C to give cis-5-3? Luoro-2-methyl-1- (3'-β-hydroxyethoxy-4'-methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid implemented.

In this way, the other thioanisoles according to Example 15-A with formation of the corresponding 3-indenyl-ybutyric acid implemented.

Example 16

A. o- (ß-chloroethoxy) thioanisole

0.1 mol of o- (ß-hydroxyethoxy) thioanisole is in excess Thionyl chloride refluxed and preserved

- 41 -209832/1229

evaporated to dryness from o- (ß-chloroethoxy) thioanisole.

Similarly, other o- (β-hydroxyalkoxy) ~ thioanisoles can be mixed with other thionyl halides to give the corresponding o- (ß-haloalkoxy) -thioanisols, for example o- (ß-bromoethoxy) -thioanisole, o- (ß-chloropropoxy) -thio Bnisol or o- (ß-bromobutoxy) thioanisole, under reflux be treated.

B. cis -5-fluoro-2-methyl-1- (3 ^l -β-chloroethoxy-V-methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid

The product from Example 16-A is prepared by the methods of Examples 14-A, 14-B and 14-C to give cis-5-fluoro 2-methyl-1- (3'-ß-chloroethoxy-4 ^l -methylsulfinylbenzylidene ) -3-indenyl-y-butyric acid implemented.

In this way, the other thioanisols can according to Example 16A with formation of the corresponding indenyl-γ-butyric acids implemented.

Example 17
A. o-ethoxythioanisole

85 6 (O »1 mol) o-chlorothioanisole (prepared according to the Process according to Example 14-A) is carried out in nitrobenzene, the 100 mg copper powder and ^ 6 »8 g (0.1 mol) 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, o-lthoxythioanisole being obtained.

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

209832 / -V «2- <

7 9 14258 * * *

B. ei s-5-fluoro-2-methyl-1- (3'-ethoxy-4'-m ethyl ε ul fix: "* benzylidene) -3-indenyl-y-butyric acid

The product from Example 17A is according to the methods of Examples 14A, 14-B and "'14 -C to obtain cis ^{-5- 1} ^ nor- 2-methyl-1- (3 ^l -ethoxy-4 ^l -methylsulfinylbenzylidene) -3-indenyl-y-butyric acid implemented.

In this way the other thioanisoles of example 17-A with formation of the corresponding indenyl-y-butte-acids implemented.

Example 18

Methyl cis-5-fluoro-2-methyl-1- (3 ', 4'-bismethylsulfirg-1benzylidene) -3-indenyl-y-butyrate

0.03 moles of cis -5-fluoro-2-methyl-1- (3 ', 4'-bismethylsulfinylbenzylidene) -3-indenyl-γ-butyric acid are in 50 ml of methanol dissolved, 1.0 ml of concentrated sulfuric acid is added, and the mixture is refluxed for 3 hours. The mixture is cooled, poured into ethyl acetate and washed sequentially with saturated sodium bicarbonate, water and extracted from saturated saline. The ethyl acetate extract is over MgSO. dried, concentrated to dryness and the residue crystallized from ethyl acetate / n-hexane.

Example 19

cis ^ -Fluoro ^ -methyl-i-O'-fluoro ^ '- methylsulfinylbenzylidene) -3-indenyl-y-propionic acid amide

0.01 mol ei f! -5-I ^l luor-2-methyl-1- ^(3-fluoro-l 4 ^l -methylsulfinylbenzyliden) -3-indenyl-y-propionic acid is heated with 5 ml of thionyl chloride 25 minutes. The mixture is cooled to 25 ° and poured into ice-cold, concentrated ammonia while stirring

- 43 -209832/1229

■ 2292729

solution poured. The precipitated amide is washed with water, dried and recrystallized from methanol / water to give cis-5-i ^l luor-3-methyl-1- (3 ^{l -i>} liior- (4 ^l -methylsulfinylbenzyliden) -3-indenyl y-propionic acid amide 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

Ν, Ν-diethylethylenediamine

J benzyl glycinate

Piperidine

Pyrrolidine

N-methylpiperazine

N-phenylpiperazine

N-hydroxyethylpiperazine

Piperazine

Diethylamine

Diethanoiamine

aniline

p-Ä "thoxy anilin

p-chloroaniline

p-fluoroaniline

p-Tri f1uo rmethy1 an i1in

Butylamine

Cyclohexylamine

Methylamine

D-glucosamine

Tetra-o-acety1-d-glucosamine

D-G al ac to sy I amin

D-mannosylamine

209832/1229

N, N-dimethyl gly cinami d

Ν, Ν-dibutylglycine amide

N-methyl-2-aminomethylpiperidine

N-methyl-2-aminomethylpyrrolidine

ß-ethoxyethyl amine

M- (ß-ethoxyethyl) amine

ß-phenethylamine

oc-phenethylamine

Dibenzylainin

D-mannosamine

Example 20

tert-Butyl-cis-5-fluoro-2-methyl-1- (4 -'-iaethylsulfinylbenzylidene) -3-indenyl-y-butyrate

0.01 mol of cis-5-I ^l luor-2-methyl-1- (4 -'- methylsulfinylbenzylidene) -5-indenyl-y-butyric acid are added to 30 ml of isobutylene and 0.1 ml concentrated sulfuric acid. The mixture is tightly closed and shaken at 25 ° for 18 hours, quenched to 0 ° and the whole is poured into a separating funnel containing 50 ml of ether, 25 ml of water and 25 ml of ice and 1.0 g of sodium hydroxide. The layers are separated, the aqueous layer extracted with 2 × 40 ml ether, the ethereal extracts washed with water and saturated saline solution and dried _{over MgSO 2.} The ethereal extract is concentrated to dryness and the residue is crystallized from ethyl acetate / n-hexane to give the desired compound.

Example 21

Ammonium cis -5-allyloxy-2-methyl-1- (4'-methylsulfinylbenzylidene) -5-indenyl-β-propionate

To 0.001 mole of cio-5-allyloxy-2-methyl-1- (4'-methylsulfinyl-

- 45 -209832/1229

benzylidene) -3-indenyl-ß-propionic acid in 10 ml of methanol , 1 ml of methanolic 1N ammonia is added. The mixture is evaporated to dryness and the desired compound is obtained.

Example 22

Calcium cis -5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -5-indenyl-y-butyrate

To a slurry of 0.002 mole of cis -5-fluoro-2-methyl-1- (4 ^L -methylsulfinylbenzylidene) -3-indenyl-γ-butyric acid in 10 ml of water is added 0.076 g (0.001 mole) of hydrated calcium oxide and the mixture is stirred for 15 minutes. The mixture is concentrated to dryness in vacuo, slurried with 10 ml of methanol, and concentrated to dryness again to give the desired compound.

Example 23

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

To a solution of 0.246 g (0.001 mol) of aluminum tert-butoxide in 50 ml of ether, 0.003 mol of cis-5-acetyl-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-ß-

ml ο

propionic acid in 50V pyridine was added with stirring at 10. The mixture is concentrated to dryness in vacuo and the desired compound is obtained.

Example 24

Sodium cis-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) 3-indenyl-y-butyrate

To 0.001 mole of cis-5-fluoro-2-methyl-1- (4 ^l -methylsulfinyl-

- 46 -

209832/1229

benzylidene) -3-indenyi-y-butyric acid in methanol 10 ml of methanolic 0.1N sodium methoxide were added. That The mixture is concentrated to dryness in vacuo to give the desired compound.

Example 25

Methoxymethyl cis -5-allyloxy-2-methyl-1- (p-methylsulfinylbenzylidene) -5-indenyΙ-γ-butyrate

0.055 mol of chloromethyl methyl ether become a suspension from 0.05 hol cis -5-allyloxy-2-methyl-1- (p-methylsulfinylbenzylidene) -3-indenyl-γ-butyric 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 that 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 is removed in vacuo. The residue is increased to 200 g with Acid washed aluminum oxide using ether / petroleum ether (from 10 to 60% ether, based on the volume, varying) chromatographed as the eluent, and one receives methoxymethyl-cis-5-allyloxy-2-methyl-1- (p-methylsulfinylbenzylidene) -3-indenyl-y-butyrate.

Example 26

β-Diethylaminoethyl-cis-5-allyloxy-2-methyl-1- (p-methylsulfinylbenzylidene) -3-indenyl-γ-butyrate

A solution of 0.0054 mol ^, H'-dicyclohexylcarbodiimide in 6 ml of anhydrous tetrahydrofuran becomes a solution of 0.005 Hol cis-5-] ^? luoro-2-methyl-1- (p-methylsulfamylbenzylidene) -3-indenyl-y-butyric acid and 0.0054 mol of 2-diethylaminoethanol in 17 ml of anhydrous tetrahydrofuran to-

- 47 -209832/1229

given. The mixture is stirred overnight at ambient temperature. The dicyclohexylurea is filtered off and 2 ml of glacial acetic acid are added to the piltrate. After the mixture has stood for 1 hour, it is filtered and 200 ml of iither are added to the piltrate. The solution is then extracted three times with 100 ml of 2, n-III, and the extracts are combined, washed twice with 100 ml of ether, ice-cooled, made slightly alkaline with concentrated NIKOH and extracted three times with 100 ml of ether. The ether extracts are combined, washed ten times with 100 ml of water to remove Ts]) Ui ¹ Cn. Starting amine, dried over anhydrous potassium carbonate, filtered and evaporated in vacuo. The oily residue consists of ß-diethylaminoethyl-cis -> - all7 /] oxy-2-methyl-1- (pmethyl sulfinylbenzylidene) -3-indenyl-γ-butyrate.

If 2-dimethyl aminoethanol, 3-dimothylamino-i-propanol, 3-diet] jylamino-1-propanol, N-ß-hyd3'oxy; \ thylpiperidine, N-Ji-Hydroxyiithyüpyri'ol i din, N- Hydroxymethylpyrrolidine, N-methyl-2-hydroxymethylpyrrolidine, N-ethyl-2-hydroxymethylpiperidine, 1-ß-hydroxyethyl - ^ '- methylpiperazine or N-ß-hydroxyethylmorpholine is used in the above process instead of 2-diethylaminoethanol, the corresponding ß -Dimethylaminoethyl-, γ-dimethylarainopropyl-, y-diethylaiuinopropyl-, ß-N-piperidinylethyl-, ß-N-pyrrolidinylethyl-, N-pyrrolidinylmethyl-, n '- (i'-Hethylpyrrolidinylmethyl ) _Ί ^l \ - methyl-1- piperazinylethyl, N-ethyl-2-piperidinylethyl and N-horpholinyliithyl oster were obtained.

209832/1229

Claims (24)

14258 f V at; n η t; η η s ρ r ü ch . Association cltir. * B'oiiutil L Π ¹ U ₀ ψι (A. WOl'LIl H. dit) (Kruppiefun ^ - (OfLJ 0011, ν / οιΊπ η 2 bu; '\ ι.; U , -CH (OIi) OH ₀ OiL ₁ OOH, -CiL ₁ CH (OH) OH ₀ OOM, -CH ₀ OH ₀ OH (OII) OOiI, -COH ₂ OH ₂ OOfI, C) O
-CH ₂ OH ₀ COOH odor R ¹
- (CILJ ₁ -C- (OiL,) COM, ν / οι, 'ίη c. UL ι ei ti R and R ¹ tjfiv / oi.Ι.ί! V / ai: fi £! L '£ it; of't "at; oiiie, alkyl · -, aryl or Haloyeririisüo may; beLLeu, m 1 odor O and Ί or 0 iuü, 111 Lb dor Hafjijßabo, dam ;, v / enn m is 0 ;, .. lye) 209032/1229 2 2 O 27 2 ¹⁴²⁵⁸ JO η nichb 0 isb and if η 0 isb, in not, 0 ujt ,; Rp is a water fco ITa tor, an alkyl, alkenyl, alkynyl or haloalkyl of t ;; To an aryl or heberoarylresb; Ii ₃ ,, R ^, K ₁ - and IL- Each water bofi'abotuo, alkyl. ·, Acyl oxy-, alkoxy-, liibro-, / uuLnu-, Ac.yl.anii no-, alkyl amino-, di alkyl ami no-, dialkyl.ami.non.Lk/L--, sulfaniyl- ·, Alkyl bh.io, Hercapbo--, Hydro;: /, Hydro xy ~ - alkyL-, Alky! .Sulfonyl-, üalo ^ en, Cyano, C! Fit. ⁱ l> oxy, Garbo alkoxy, carbamido, {[alo ^ fjn ..) 1 Iy 1 -, cycloalkyl, cycloalkoxy, All:;. ny 1 oxy -, Acy L--, alkenyl odoL 'Alkynylresbe; Rrp an Alkylr.uirinyl- or AlkyUui 1. fimylrt!, · -;! ;; Hn a V / assersbof faboui, einon Hal.ο ^ ιη-, ilydcoiiy- ·, Alkoxy- or Halogerialkox; / refib and M is hydroxy, lower alkoxy,, sub,; l; i. l, ui .orten lower alkoxy, amino, alkylnmino, dinlkylamino, N-Moipholino-, Hydx-oxyaLky Lnuii.no ■, b'o Ly-hydroxy alkyl amino-, Di alky Lym i.noa 1 ky I -uii.i no - ·, Amino alkyl ami nore st- or die (lruppi eiiinp; OHe, where Me is a cation, bedeubon; mib the · stipulation that at least one · dr> i. ' lioübe Ii ,, Ii _{1 t} Rc and Rr no V / assersboffatoui in Ii, 2. A compound according to claim 1, characterized in that j <; okorm /, oi chnet ;, dar> ii Ar is a phenyl radical darijbellb. 3 · Compound according to claim 2, (hdiirch gelecntu ', eic.linet; that H ,. the groupiHing - (CH ₀ ) COII, v / orin η ?. Bin 4 ir.b, CH ₀ CH (OH) CH ₀ COM, CH ₀ CH ₂ CH (OH) COM, 0 8AD ORIGINAL CCH ₂ CH ₂ COM, - 50 -2098 3 2/122 9 Si
O -GH ₂ CCH ₂ COIl, -CH ₂ CH ₂ CCOH or - (CH ₂ ) _m -C- (CH ₂ ) _n CO H, wherein
E. E and H ¹ each represent hydrogen atoms, alkyl, aryl or halogen radicals, m is Λ or 0 and η 1 or 0 int, with the hatred that when m is 0, η is not 0 and v; snn η is 0 , m is not 0; Hp a hydrogen atom or a lower alkylrect; E, a hydrogen atom: B ^ a halogen, lower g-Alhoxy- or Ally] oxyren; Ec and IL · hydrogen atom; He _{7 is} a lower alkyl sulfonyl or lower alkyl sulfonyl radical; Eg a hydrogen atom, a halogen, hydroxy, low-alkoxy- odej · halogone-low edrig-alkyl radical and M is a hydroxy, lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N-morpholino, hydroxya] kylainino, polyhydroxyalkylamino, Dialkylaminoalkylamino, aminoalkylamino radicals or the grouping Olle, in which Me is a cation. 4. A compound according to claim 3, characterized in that M represents a hydroxy radical. 5 · cis and trans isomers of a compound according to claim ^J \. - 51 209832/1229 6. A compound according to claim 4, characterized in that R. the grouping - (CILj) ₁₁ COOH, wherein η is 2 to 4; Rp is a methyl radical; R, a hydrogen atom; R ^ is a fluorine residue; Rc and Rg are hydrogen atoms; Rn denotes a methylsulfinyl radical and Rg denotes a hydrogen atom. 7. Compound according to claim 4, characterized in that R _{1 represents} the grouping -Ch (OH) CH ₂ CH ₂ COOH; Rp is a methyl radical; R _{2 is} a hydrogen atom; R ^ is a fluorine residue; Rc and R ^ are hydrogen atoms; fin is a methylsulfinyl radical and Rg is a hydrogen atom. 8. A compound according to claim 4, characterized in that R _{1 is} the grouping -CH ₂ CH (Oh) CH ₂ COOH; R _{2 is} a methyl radical; R, a hydrogen atom; R ^ is a fluorine residue; Rr and R, - hydrogen atoms; fin a methylsulfinyl radical and R _{D is} a hydrogen atom ö mean. 9. Compound according to claim 4, characterized in that R _{1 represents} the grouping -CH ₂ CH ₂ Ch (OH) COOH; R _{2 is} a methyl radical; R, a hydrogen atom; R ^ is a fluorine residue; - 52 - 209832/1229 H _c and Rc hydrogen atoms; a methylsulfinyl radical and R "represent a hydrogen atom. 10. A compound according to claim 4, characterized in that R _{1 is} the grouping -CCH ₂ CH ₂ COOH; Rp is a methyl radical; R ₅ . a hydrogen atom; R ^, a fluorine residue; Rc and Rc water to ff atoms; Rn denotes a methylsulfinyl radical and Rq denotes a hydrogen atom. 11. A compound according to claim 4, characterized in that Il R ₁ the grouping -CH ₂ CCH ₂ COOH; R _{2 is} a methyl radical; R, a hydrogen atom; R ^ is a fluorine residue; R _c and R _{c are} hydrogen atoms; Rn denotes a methylsulfinyl radical and Rq denotes a hydrogen atom. 12. A compound according to claim 4, characterized in that R _{1 is} the grouping -CH ₂ CH ₂ CCOOH; R _{2 is} a methyl radical; R, a hydrogen atom; R ^ is a fluorine residue; Rc and Rg are hydrogen atoms; Toffatom mean rn a Methylsulfinylrest and Rq one water. 209832/1229 13 · Process for the preparation of compounds of formula wherein the grouping - (CH ₂ ) _n COM, wherein η is 2 to 4-. -CH ₂ CH (OH) CH ₂ COM, -CH ₂ CH ₂ CH (OH) COM, -CCH ₂ CH ₂ COM, -CH ₂ CCH ₂ COM, 0
CH ₂ CH ₂ CCOM or B ' , in which B and B ¹ each represent hydrogen atoms, alkyl, aryl or halogen radicals, m is 1 or 0 and η is 1 or 0, with the proviso that when m is 0, η is not 0 and when η is 0, m is not 0; a hydrogen atom, an alkyl, alkenyl, alkynyl or haloalkyl radical; an aryl or heteroaryl radical; R-, R ^, Rc and Rg each hydrogen atoms, alkyl, Acyloxy, alkoxy, nitro, amino, acylamino,. Alkylamino, dialkylamino, dialkylaminoalkyl, SuIfamyl, alkylthio, mercapto, hydroxy, Hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carboalkoxy, carbamido, haloalkyl, Cycloalkyl, cycloalkoxy, alkenyloxy, acyl, alkenyl or alkynyl radicals; H _{n is} an alkylsulfonyl or alkylsulfinyl radical; Ro is a hydrogen atom, a halogen, hydroxy, Alkoxy or haloalkoxy radical and M is a hydroxy, lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N-Morphclino-, Hydroxyalkylamino-, Polyhydroxyalkylamino-, Dialkylaminoalkylamino, aminoalkylamino radical or the grouping OMe, in which Me is Cation is mean with the proviso that at least one of the radicals R ,, R ^, R ₁ - and Rc is not a hydrogen atom, characterized in that (A) an indenyl acid is reacted with an aldehyde and (b) the 1-alkylthiobenzylidene-3-indenylic acid obtained is oxidized. 14. Medicament, characterized by a content of a compound according to claim 1. 15. Medicament according to claim 14, characterized by a content of cis-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y-butyric acid. 16. Medicament according to claim 14, characterized by a content of cis-5-fluoro-1- (4'-methylsulfinyl- - 55 -209832/1229 benzylidene) -3-indenyl-y-butyric acid. 17 · Medicament according to claim 14, characterized by a content of cis-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y- (ß-hydroxybutyric acid), 18. Medicament according to claim 14, characterized by a content of cis-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-y- (ß-ketobutyric acid). 19 · Medicament according to claim 14, characterized by a content of cis-5-fluoro-2-methyl-1- (V-methylsulfinylbenzylidene ^^ - indenyl-y-Cß-chlorobutyric acid). 20. A pharmaceutical composition according to claim 14, characterized by a content of cis-5-i ^l luor-2-methyl-1- (4'-methylsulfinylbenzylidene) -ß-butyric acid. 21. Medicament according to claim 14, characterized by a content of cis-5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -a-ethoxyacetic acid. 22. Medicament according to claim 14, characterized by a content of eis-5-J ¹ IuOr-2-methyl-i- (4'-methylsulfinylbenzylidene) -y- (ß-butynoic acid). 23 · The composition of claim 14, characterized by a content of cis-5-I ^l luor-2-methyl-1- (4 ^l -methylsulfinylbenzyliden) -y (y-ketobutterßäure). 24. Medicament according to claim 14, characterized by a content of cis-5-fluoro-2-fluoromethyl-1- (4 ^l methylsulfinylbenzylidene) -3-indenyl-ß-propionic acid. - 56 -209832/1229 5 * 25- Medicament according to claim 14-, characterized by a content of cis-5-fluoro-1- (4'-methylsulfinylbenzylidene) -2-vinyl-3-indenyl-ß-propionic acid. 209832/1229