CS208158B2 - Method of making the new stilbenes derivatives - Google Patents

Abstract

Compounds of the general formula <IMAGE> wherein n is 1 or 2 and, when n is 1, R<1> and R<2> are hydrogen, alkoxy or halogen, or, when n is 2, R<1> is hydrogen, alkoxy or halogen and R<2> is hydrogen; R<3>, R<4>, R<5> and R<6> are hydrogen or alkyl; R<7> is hydrogen, methyl or ethyl; R<8> and R<9> are hydrogen, alkyl or halogen, and R10 is -(CH=CR<19>)m<R11>, in which m is zero or 1 and R<11> is <IMAGE> or 2-oxazolinyl, or, when m is 1, also is hydrogen; R<12> is hydrogen or alkyl; R<13> is hydrogen, alkyl or -N(R<17>, R<18>) or -OR<14>; R<14> is hydrogen, alkyl or alkanoyl; R<15> is hydrogen, alkyl or -OR<16> or -(CH2)pN(R<17>, R<18>); R<16> is hydrogen, alkyl, hydroxy alkyl or optionally, substituted aryl, or aralkyl; R<17> and R<18> are hydrogen or alkyl or R<17> and R<18> together with the nitrogen atom form a heterocyclic group; R<19> is hydrogen or alkyl and p is zero, 1, 2 or 3; ketals and salts thereof are useful for the treatment of neoplasms, dermatological conditions and rheumatic illnesses.

Description

The invention relates to a process for the preparation of novel stilbene derivatives of the general formula I,

wherein (n is the number 1 or 2, and if n is the number 1 then

R @ ¹ and R @ ² are hydrogen, lower alkoxy having 1 to 6 carbon atoms or halogen or, in the case where n is 2,

R ¹ is hydrogen, C 1 -C 6 lower alkoxy or halogen;

R ² represents hydrogen,

R 3, r 4, r 5 and R 6 represent hydrogen or a lower alkyl group having 1 to 6 carbon atoms,

R ⁷ is hydrogen, methyl or ethyl;

R 8 and R ⁹ are hydrogen, lower alkyl of 1 to 6 carbon atoms or halogen, and

R 10 is a radical of the formula - (CH = CR 19) _m R H, where im is 0 or -1 and

R ¹¹ represents a radical of formula

R12 |

- CH - R ¹³ or

O

II -C-R ¹⁵ radical or a 2-oxazolinyl or if im = 1, R represents ⁿ itaiké hydrogen,

R12 is hydrogen or lower alkyl having 1 to 6 carbon atoms; R 13 is hydrogen, C 1 -C 6 alkyl or the radical of the formula -N (R ¹⁷ , R ¹⁸ ) or -OR 14,

R14 is hydrogen, (C1-C6) alkyl or -alkanoyl,

R15 is hydrogen, (C1-C6) -alkyl or -OR16,

R16 is hydrogen, alkyl having 1 to 6 carbon atoms, a hydroxyalkyl sku208 158 piin is 1 to 6 carbon atoms, aralkyl or with an alkyl, the aryl portion substituted with Ar alikylovou group or vzdr-ce - [CH 2) 2 N (R ^17, R ¹⁰ ),

R ¹⁷ and R ¹⁸ are hydrogen, alkyl of 1 to 6 carbon atoms or, together with the nitrogen atom to which they are bonded, are a heterocyclic radical,

R ( ¹⁹⁾ is hydrogen or (C1-C6) -alkyl, as well as iketals of compounds of formula (I) in which R ( ¹¹ ) is -C (O) R ( ¹⁵⁾ and R ( ^{15) is} hydrogen or (C1-C6) alkyl; and salts of the compounds of formula I.

The compounds produced by the process according to the invention (possess valuable pharmacological properties and can be used as active ingredients in pharmaceutical preparations.

The invention therefore also relates to pharmaceutical preparations based on the compounds of the formula I or salts thereof, as well as to a process for the preparation of the compounds of the formula I and intermediates which occur in this process.

As used herein, the term "lower" refers to groups of up to 6 carbon atoms.

The alkyl and alkoxy groups may have a branched or non-branched chain, such as methyl, ethyl, isopropyl or 2-methylpropyl, optionally methoxy, elthoxy or isopropyl.

Alicamoylic acids (groups are derived, for example, from acetic, propionic or ipivalic acid or also from higher carboxylic acids having up to 20 carbon atoms, for example from palmitic or istearic acid.

A preferred aryl group is phenyl. Examples of substituted acrylic groups include hydroxy, niitiro or halophenyl. A preferred aralkyloxy group is a benzyl group.

Examples of the heiterocyclic-N (R ¹⁷ , R ¹⁸ ) radicals are 5- or 6-membered nitrogen-containing heterocyclic radicals which may contain an additional oxygen, nitrogen or sulfur atom, such as ipiperidinoisyl, piperaziocino, morpholimoslkuipin, thiamorpholino, and pyrrolidinoethoxy. mention di (lower J alkyl ketals and lower alkylene ketals).

The oxaisolinyl moiety may be substituted with one or two lower alkyl groups.

Of the halogen atoms, -chlorine and bromine are preferred.

A preferred group of compounds of formula I are those wherein, when n is 1,

R ¹ and R ² are hydrogen, lower alkoxyslkupiinu or halogen, and if n = 2,

R ¹ represents hydrogen, lower alkoxy or halogen,

R ² represents hydrogen,

R ^3, R ^4, R ⁵ and R ⁶ are hydrogen or lower alkyl,

R ⁷ is hydrogen, methyl or ethyl,

R ⁸ and R ⁹ zinaimeinate hydrogen, lower alkyl sulfide or halogen, and

R ¹⁰ is a hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carbonyl, and cyclocarbonyl, foirimyl, alkylenedioxymethyl, alkanoyl, ikairbamoyl, mono (lower) alkylcarbamoyl, di (lower) alkylcarbamoyl, N-lower alkylcarbamoyl, N-lower alkylcarbamoyl, N-oxycarbamoyl -ny hunts.

Further preferred are compounds with n = 2, as well as those in which R ¹ , R ² , R ⁵ , R ⁶ , R ⁸ , R ⁹ are hydrogen and R ³ , R ⁴ , R ^{7 are} methyl.

Another preferred group of compounds of formula I, j _(SOU compounds in which ^R10 represents a radical - (CH = CH) _m R ^11, especially those wherein m = 0, and compounds in which R ¹¹ represents a lower alkoxycarbonyl group, lower alkylcarbamoyl a lower alkoxymethyl group and a lower alcain о у 1 ο χ yim eth у lov ous к up in u.

According to the invention, the compounds of the formula (I) are produced by reacting a compound of the formula (II) in the reaction

with a compound of formula III,

in which

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , n are as defined above, and either

A zin-am e a tri ar у 1 f o with a small у 1 o vo u group of formula!

| © Θ r-ch-r [ajj y, where

R is hydrogen, methyl or ethyl,

Q is aryl and

Y anioint of an organic or inorganic acid a

V represents a formyl group;

or

A is a formyl, acetyl or propionyl group;

V represents a dialkoxyphosphinylalkyl group in the formula

R-CH-P [zT0O] wherein

Z is a lower C 1 -C 6 alkoxy group according to known methods under Wittigoiv conditions (reaction in the presence of an acid binding agent or a Horner reaction with a base to give a compound of formula I, whereupon the residue R 10 is optionally functionalized.

Aryl skiupins marked with Q in said triarylphosphonium groups include all known aryl groups, in particular monovalent groups such as phenyl or phenyl substituted by lower alkyl, optionally lower alkoxy such as tolyl, xylyl, mesityl or p-melhoxyphenyl. •• W!

Of the inorganic anions of acid Y, the bromide or hydrosulfate ion is preferred, while the organic anion of the acid is the tosyloxy group.

The alkoxy groups designated by Z in the dialkoxyphosphinylalkyl group of the formula ^r-Ch-p mlo are in particular represented by lower alkoxy groups of 1 to 6 carbon atoms, such as methoxy or ethoxyisyl.

The starting materials of the formula II can, if their preparation is not known or not further described, be prepared analogously according to known or described methods.

Compounds of formula (II) in which A is a formyl group, an acetyl group or a propionyl group and R @ 1 and R @ ² are hydrogen (oxo compounds of formula II) can be obtained, for example, by the addition of an i in the cyclopentene ring, it is substituted in accordance with the desired compound of formula I, or tetrahydroinaphthalein, which is appropriately substituted in the cyclohexene ring, undergoes an acylation reaction. This aicylation reaction can be carried out, for example, by acylating the indane derivative, optionally the indane derivative or the tetrahydrone aftalene derivative in the presence of a Lewis acid.

Suitable acylating agents are a mixture of formylbenzyl and hydrochloric acid, acetyl and propynyl halides, for example acetyl and propionyl chloride. Of the Lewis acids, aluminum halides such as aluminum chloride are preferred. The reaction is conveniently carried out in a solvent, such as nitiroibenzein, or a chlorinated hydrocarbon, such as methylene bromide. The reaction temperature is preferably Ό to about + 5 ° C.

The oxo compound of formula II in which R1 and R2 are hydrogen is obtained according to the invention with a phosphonate of formula III in which B is a dialkoxyphosainylmethyl group to form a compound of formula I in which R1 and R2 are hydrogen.

The fossonium salts of the formula II in which A is the 1- (triaryphthasonium) methyl [ethyl or propyl] group required by the condensation with the aldehyde of the formula III in which B is the cocoupin can be prepared, for example, as follows:

The oxo-compounds of formula II in which R1 and R2 are hydrogen are reduced at a temperature of 0 to about +5 ° C by a complex metal hydride, for example sodium borohydride in alkanol or by lithium maluminium hydride in elilheir, tetirahydrofuran or dioxane , to the corresponding alcohol. The alcohol obtained is then halogenated in the presence of an amine base, such as pyridine, using conventional halogenating agents, for example, phosphorus oxychloride or phosphorus tribromide. The halide obtained is then reacted with β-β-β-β-611 in a solvent, in particular β-β-β-β, in toluene or xylene to give the desired ammonium salt of formula II.

The oxo compounds and the phosphonium salts of the formula II in which R @ 1 and R @ 2 are alkoxy or halogen can be prepared, for example, by converting the corresponding phenol in a manner known per se by treatment with an alkylating agent, for example by reaction with a lower alkyl halide; ¹ · with lower alkanol in ρ ^ ίο ™ ^! of an acidic reagent, to the corresponding alikoxy derivative of formula II.

The phenols mentioned above are available, for example, as follows:

The non-substituted oxo compound of formula (II) in the aromatic part of the ring is nitrated by the action of a mixture of concentrated sulfuric acid and concentrated sulfuric acid. The nitro group, preferably entering the β-radical of the arythyimyl group, the acetyl group or the propyl group, is reduced in a manner known per se catalytically, for example using Raney nickel, to an amino group which is converted into the hydroxyl group via a diastere salt.

If the diazonium salt produced from the amine is treated with copper (I) halide, the corresponding halo-gelatin compound (II) is obtained.

By reacting the nitrous acid with the nitrating acid obtained again, the nitro group is introduced into the m-position to the aromatic group, the acetyl group or the pionopionyl group, which may also be By converting the hydroxy group to an alkoxy group, a derivative of the starting ketone of formula (II), which is substituted with the same or different thiothiothietylenes, is obtained, if desired.

The halogen atom in the aromatic core can optionally be removed again by reduction in a manner known per se.

Compounds of formula III wherein B is a formyl group can be prepared from phenylderivatives substituted at the 1-position by nitroisyl groups as described in Chem. Take Hten 102 (1969), pp. 2502-2507. These groups are also available by reduction of the corresponding p-carbonyl substituted phenyl derivatives. The reduction of the carboxyl group to the formyl group can be carried out, for example, with diisobutylaluminum hydride.

Compounds of formula - III in which B is a dialkoxyphosphiniylmethyl group used for condensation can be prepared from the above compounds of formula III in which B is a formyl group by converting the form 1 group by treatment with a metal hydride, e.g. sodium borohydride, to the hydroxymethylmethyl group, is halogenated using a conventional halogenating agent, e.g. ^IDUs phosphorous, and the obtained halogen derivative is reacted -s trialkyl, especially with triethyl phosphite to give the desired formula III · folsfoinátu.

The condensation components of formula III, in which B is a formyl group or a dialkoxypholytin-4-yl group, can be obtained further by halogenating the corresponding methyl substituted 1-position and the obtained halomethyl derivative is either indicated in The reaction with a trialkylphosphite, or hydrolyzed to a hydroxymethyl derivative, is oxidized by treatment with an oxidizing agent such as manganese dioxide.

The reaction of the compounds of the formulas II and III can be carried out according to known methods by the Whhgg or Hooner reaction. Preferably, the starting materials used are those compounds of formula III in which RH is not a phosphono group reactive group, in particular a formyl group.

Like- functional modification of R ⁱ⁰ of compound I are, for example conversion of carboxyl groups to u ^ IUS Elter, amide, or oxazolinderrvát éydroxymetéylovou group which may again elterifIkovat EIITE ^ ^{<^,} rififl ^ <^ f ^ 4 ^ 't; as well as the winter-saponification of the carboxylic acid ester or its reduction to the hydroxymethyl group.

The hydroxyethyl group can also be oxidized to the formyl group. Compounds of formula I which contain a foinmylo group can be converted, for example, by a Wititiig reaction, to a compound of formula I in which R 10 is a radical - (CH = CR 19). RH _m, wherein m = 1, R * is hydrogen or ^9-represents -alikylolvou -carbonyl and R ⁿ example, a group alk ^ T ^ y ^ i ^ t ^^^ lhylovou, alkanoyloxymethyloivou group, a carboxyl group, an alkoxycarbonyl group, an alkynyl group, or alkenyl.

All these conversions can be carried out according to methods known per se.

In the Wittig reaction, the components react in the presence of an acid binding agent, for example in the presence of a strong base such as butyl lithium, sodium hydride or sodium dimethyl sulfoxide, but particularly in the presence of an optionally lower alkyl-substituted ethylene oxide. as 1,2-butylene oxide, optionally in a solvent, for example in an ether such as diethyl ether or tetrahydrofuran, or in an aromatic hydrocarbon, such as benzene in tetrahydrofuran may freeze at room temperature and boiling point of the reaction mixture.

In the Hormer reaction, the components are condensed with a base and preferably in the presence of an inert organic solvent, for example sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, -dioxane or 12-dimethoxyalkane, or also sodium alkoxide in -alkanol, for example, sodium methoxide in methanol, at temperatures between 0 ° C and the boiling point of the reaction mixture.

In certain cases, it has proven expedient to carry out the above-mentioned in situ reactions, i.e. to condense the condensation components with one another, without having to isolate the respective phosphorous salt or the phosphomate.

The carboxylic acid of the formula I can be converted into the acid chloride, which can be converted into an ester by reaction with alcohols, or by reaction with amines, in a manner known per se, for example by treatment with thionyl chloride, preferably in the pyridine, or by phosphorus trichloride in toluene. the corresponding amide. The amides can be converted into amines in a manner known per se, for example by reduction with complex metal hydrides, such as lithium aluminum, in the form of amides.

The carboxylic acid ester of formula (I) may be hydrolyzed in a manner known per se, for example by treatment with alkali, in particular by treatment with an aqueous-alcoholic sodium hydroxide or potassium hydroxide in a temperature range between m.p. and m.p. The acid halide, or as described below, directly targets.

The carboxylic acid ester of the formula I can be converted, for example by treatment with lithium amide, directly into the corresponding amide. The lithium amide is reacted with the corresponding ester, preferably at room temperature.

Further, the carboxylic acid of formula I can be converted via an alkaloid by reaction with -s-2-amino-1-thiololimide or -s-2-amino-3-methylpropanal, followed by cyclization to the oxaiso-derivative of formula I.

The carboxylic acid or carboxylic acid ester of formula I can be reduced in a manner known per se to the corresponding alcohol of formula I. This reduction is preferably carried out by treatment with a metal hydride or a metal alkyl hydride in an inert solvent. Preferred hydrides are mixed metal hydrides such as lithium aluminum hydride or bis (methoxymethyleinoxy) sodium malimide hydride. Suitable solvents include, but are not limited to, ethers, tetrahydrofuran or diooane, when lithium aluminumimide hydride is used, and ethers, hexane, benzene or toluene, when diisobutylaluminium hydride or bis- (methooyethyleneaoyluminium aluminum hydride) is used.

The alcohol of formula I can be etherified in the presence of a base, preferably in the presence of sodium hydride, in an organic solvent such as diooane, tetrahydrofuran, 1,2-dimethooyethane, dimethylforimamide, or also in the presence of an alkali metal alkooid in alkanol at temperatures between 0 ° C and the site temperature by treatment with an alkyl halide such as methyl iodide.

The alcohol of the formula I can also be esterified by treatment with an alkanoyl halide or anhydride, suitably in the presence of a base, for example in the presence of pyridine or tri-. ethylaimide, in the temperature range between room temperature and the boiling point of the reaction mixture.

The carbooylic acids of the formula I form salts with bases, in particular with alkali hydroxides (preferably hydroxides of sodium or potassium).

The compounds of the formula I are present mostly in the form of trans. The c-isomers which are formed can optionally be separated in a manner known per se or can be isolated to the trans-isomers.

The reaction products of formula I are pharmacodynamically valuable compounds. They can also be used for topical and systemic therapy of benign and malignant neoplasms, pre-mahgic conditions, as well as for systemic and local profilazion of said affections.

Further, these compounds are useful for the local and · Íssreteimiclkou. ^ (^^ RAPI acne pwscrr ^ ii ^ íÍsy and other dei ^ i ^ u ^ dtóíz associated with enhanced NEB pathologically altered · c ¹ · rohovatěním and also inflammatory and allergic Furthermore, the reaction products of formula I can also be used to combat mucosal diseases with inflammatory or metaplastic changes.

The novel compounds are distinguished from the known retinoids in that they are effective in extremely low amounts.

The effect of the compounds of the invention on tumor suppression is significant. It was observed in the papillon test in mice by the disappearance of the tumors induced by dimethylbenzanthracene and proton oil. Papillon diameter decreased over two weeks with p - [(EJ-2- (5,6, -)

7,8-tetrahydro-5,5,8-Biletramethyl-2-naphthylpropenyl of benzoic acid at 0.2 mg / kg / week by 75 ·%, at 0.1 img / lkg / week by · 56% and at 0.05 mg / kg / week by · 48%.

Oral administration of mouse p - [(E) -2- (5? 6,7,8-tetrahydryl-5,5,8,8-e-trimethyl-2-naphthyl) propenyl] benzoate phthylmethyl ester decreases the average of the induced tumors over the course of two weeks (5 single doses / week) at 0.4 mg (5 x 0.08 mgj / kg / week o-63%, at 0.2 mg (5 x 00 ⁴ ·> mgj / kg / week by ⁴⁸ ° at 0.05 mg (5 x 0.01 mgj / kg / week o · 37 ° / o).

The compounds of the formula I and their salts can further be used, for oral administration, for the treatment of irreumatic diseases, in particular those of the inflammatory and degenerative type, such as the joints, muscles, tendons and other parts of the locomotor system. such diseases include, but are not limited to, chronic polyarthritis, spoindylarthritis ankylopoetics, and Bechterew and arthropathea psoriatica.

For the treatment of such diseases, the active compounds according to the invention are administered orally, suitably in a dose in adults of about 0.01 to 1 mig / day, preferably 0.05 to 0.5 mg. Possible overdose can manifest in the form of hypervitaimnosis A and can be easily recognized by its symptoms (peeling of skin, hair loss j.

The dose may be administered as a single dose or may be divided into several sub-doses.

The compounds of the formula I can therefore be used as medicaments, for example in the form of pharmaceutical preparations.

Formulations which are also systemically administrable may be prepared, for example, by adding to the compound of formula (I), as active ingredient, a non-toxic inert solid or liquid carrier customary in such preparations.

The formulations may be administered enterally, pareinterally, or topically. For example, tablets, capsules, dragees, syrups, suspensions, solutions, and suppositories are suitable for administration. Formulations in the form of infusion or injection solutions are suitable for parenteral administration.

The dosage in which the compounds of the invention are administered may vary depending on the type of use and the mode of administration as well as the requirements of the patients.

The compounds of the invention may be administered in an amount of about 0.01 to about 5 µg per day in single or multiple doses. Preferred dosage forms are capsules containing about 0.1 mg to 1.0 mg of active ingredient.

These preparations may contain inert or pharmacodynamically active ingredients. Tablets or granules may contain, for example, a variety of binders, fillers, carriers or diluents. The liquid preparations may be present, for example, in the form of a sterile solution which is miscible with water.

Capsules may contain, in addition to the active ingredient, a filler or thickener. In addition, flavor enhancers as well as conventional preservatives, stabilizers, moisture-retaining agents and emulsifiers, as well as salts for varying the osimotic pressure, buffers and dialectic additives may be included in such formulations.

The abovementioned carriers and diluents may consist of organic or inorganic substances, for example water, gelatin, lactose, starch, magnesium salt of siteairic acid, talc, gum arabic, polyalkyleinglylkoil ár od, provided that no ipomycin substances used in the manufacture of these preparations were not toxic.

The compounds of the invention are conveniently used in the form of ointments, elixirs, creams, lotions, baths, spirals, a-poid suspensions. Ointments and creams as well as solutions are preferred. These toast preparations can be prepared by admixing the compounds of the invention as active ingredient with nontoxic, inert, topical application of a solid or liquid carrier which is customary in such preparations.

Suitably, at least 0.001 to about 0.3%, preferably 0.002 to 0.1% (solutions as well as about 0.002 to about 0.5%, preferably about 0.002 to aisi 0.1% ointment or cream) are suitable for toasting application.

If desired, an antioxidant, for example tolcoferol, N-meth-1-hexanol and min, as well as butylated hydroxyanisole or butylated hydroxytoluene, may be added to these preparations.

Example 1

30.5 g of [1- (1,1,3,3-tetramethyl-5-indanyl) ethyl] triphenylphenylphosphonium bromide and 8 g of 4-methoxycarbonylbenzaldehyde are stirred for 1.2 hours in an inert gas at 65 ° C after the addition of 300 ml of butylene oxide. The resulting clear solution was cooled, then poured into about 500 mL of ice / water and extracted twice with hexane. The organic extract was shaken three times with a mixture of methanol and water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel absorption (eluent: hexane / ether 19: 1). P - [(E) -2- (1,1,3,3-tetraimethyl-5-indanyl [propenyl] benzoate ethyl ester) of the acid obtained from the eluate melts at 70-71% after recrystallization from an ether / hexane mixture.

[1- (1,1,3,3-tetramethyl-5-indanyl) ethyl] triphenylphosphonium bromide, which is used as starting material, can be produced, for example, by the following zippers:

87.8 g of acetyl chloride are dissolved in 240 ml of nitirobeinzen. 149.2 g of aluminum chloride are added in portions to this solution. The mixture is cooled to 0-5 ° C and then 195.0 g of solution is added dropwise with vigorous cooling

1.1.3.3- tetramethylindane in 360 ml of niltrobenzene. The temperature should not exceed 5 ° C. The reaction mixture was stirred 15 hours at 0 ^Oi C then poured into 3 liters of ice-water and extracted with ether. The ether extract was washed twice with 2N sodium hydroxide solution and saturated sodium chloride solution, dried over sodium sulfate and then concentrated first under vacuum of a water pump and then potoim, in order to remove low-benzene, under high vacuum. The residual oily (1,1,3,3-tetramiethyl-5-indanyl) methyl ketone boils at 100-103 ° C / 1 mm Hg.

To 2.66 g of lithium aluminum hydride, 40 ml of absolute ether are added. Upon cooling to 0 to 5 ^C over 30 C was added dropwise 26 g minuit

1.1.3.3-Tetamethyl-5-indinylmethylmethyl ketone. After an additional 30 minutes, 25 ml of saturated sodium sulfate solution was carefully added dropwise to the mixture. The reaction solution was filtered. The filtrate was washed once with 1 N sodium hydroxide solution and twice with saturated sodium chloride solution, dried over sodium sulfate and evaporated to give a yellow solid. removing the solvents under reduced pressure. The remaining oily α-1,1,3,3-pentamethyl-5-indanethanol, which is a uniform compound according to thin layer chromatography (solvent system: hexane / etheir 80:20), is immediately further processed as follows:

24.4 g of α-1,1,3,3-pentylmethyl-5-indanethanol are dissolved in 20 ml of absolute ether and 100 ml of absolute hexane. To this solution, after addition of 2 drops of pyridine, 16.2 g of phosphorus tribromide, dissolved in 80 ml of absolute hexane, are added dropwise at 0-5 ° C over 30 minutes. After stirring for an additional hour at 0-5 ° C, the reaction product is poured into ice / water and thoroughly extracted with ether. The ethereal extract was washed twice with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residual oily 5- (1-bromo-methyl) -1,1,3,3-tetramethylindian, which is a uniform compound according to thin-layer chromatography (solvent system: hexane / ether 95: 5), is immediately further processed. as follows:

(26.3 g of triphenylphosphine is dissolved in 120 ml of xylene. To this solution is added 30.9 g of 5- (1-chloromethyl) -1,1,3,3-tetrajmethylindane, which is dissolved in 60 ml of xylene. The mixture is heated to 100% with stirring and the potoim is left at this temperature for 12 hours, and the resulting thick, oily inoculation crystallizing 1- (1,1,3,3-tetramethyl-5-iindanyl) ethyltriphenylphosphonium bromide melts after recrystallization from the mixture. methylene chloride and toluene at 151-156 [deg.] C. (The crystals contain 0.3 equivalents of toluene).

Example 2

2.4 g of 1,1,3,3-methyl-5-methyl-ethyl ketone and 3,4 g of ethyl 4 - [(diethoxyphosphininyl) methyl (benzoic acid) are dissolved in 7 ml of dimethylformamide. A solution of sodium ethoxide, which was made from 0.33 g of sodium and 7 ml of ethanol, was added dropwise at room temperature under argon atmosphere, and the mixture was stirred at 70 ° C for 18 hours. The mixture was extracted with ether and extracted with ether, washed with saturated sodium chloride ¹ solution, dried over sodium sulfate, and evaporated under reduced pressure to give the remaining ethyl ester p- [(E) -2- (1,1,3, 3-Tetra-ethyl-S-andanyl-propenyl] -benzoic acid is a brown oil which is purified by silica gel chromatography (eluting with hexane / ether 9: 1), which ester is recrystallized from hexane / ether at 70-71 ° C.

Example 3

In an analogous manner to that described in Example 1, [1- (5,6,7,8-ethoxyhydroxy-5,5,8,8-tetrafluoromethyl-2-naphthyl)] can be used. ethyl] triphenylphosphonium omide and z.

4-ethoxyikarboinylbenzaldehydu obtain ethyl p- [(E) -2- (tetrahydro-5Д7Д 5,5,8,8-tetroΐm · ethyli2i] yofty ^l (propenyl (benzoic acid, mp 90-91 ° C.

[1- (5,6,7,8,8-tetrahydro-1,2,3-tetrahydro-1,2,3,4-tetrahydro-2-naphthyl) ethyl (triphenylphosphine iumbiromide) used as the starting material, it can be produced in an analogous manner to that described in Example 1

5.6.7.8itetrΌhydгo _5-1-5Д8 tetromethsli noftolenu through (5,6,7,84ΘtrahydгOi5,5Д8 tertraιmethyl-2-naphthyl) methyl ketone, 5Д7ДtetιrahydIO - ciД5Д8-PE; -o ntameιthsli2i inoftalenmethoyol

2- (bromoethyl) -5,6,7,8 -1-trichloro-o-5,5,8,8-

-tetr aimeth у in na f talen.

[1- (3-Imethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetromethyl-2-naphthyl) -ethyl] triphenyl-4-carboxylic acid which is used as starting material can be produced in an analogous manner to that described in Example 1, from

3tmhthox5-5,6,7Дtetrohydr е-ЬДЗД

-the tram! hyl to phthalene over 3-methoxyethoxy] -5,8,8-tetrohydrot5,5Д8t

-te tromet · hyli2inaftsl] me thylket on,

3-methoxs-5Д7,8-tetrahydrogOi5,5Д8-

tetrene-1-Z-naphthalene ethanol a

2- (1'-Bromoethane) -3-methoxy-5,6,7,8-tetrahydro-5 H -tetra-trimethyl-phthalene.

Example 5

In an analogous manner to that described in Example 1, it may be obtained from [1- (5,6,7,8-tetrahydro-5,5,8-tetraetramethyl) -2-trifluoromethyl (ethyl) triphenylphosphonium. bromide a, z

3-Methyl-4-methoxycarbonylbutyl aldehyde to obtain p - [(E) -2- (5,6,7,3,3-tetrahydro-5-,8,8,8-tetramethylmethyl) -2-naphthyl] propenyl] -2-methylsulfonic acid ethyl ester as a colorless oil thin-layer chromatography (Rf = -0.6; hexane / 15% ether):

3-Ethylmethoxycarbonyloyl (l-octadehyde, which is used as a condensation component) can be prepared from 4-nitro-3-methylbenzoic acid in an analogous manner, as described for the preparation of 2-methyl-4-methoxybutylbentonylbentoldehyde [cf. Huneclk] et al., Chem. Beir. 102, 2502-2507 (19659)).

Example 1 a d 6

In an analogous operating procedure to that described in Example 1, [1- (1,1,2-D-3-polyethylenomethyl-5-indyl) ethyl] triphenylphosphorium bromide may be formed from -

4-ethoxycarbenylbenzaldehyde to obtain p- [(R) -2- (1,1,2-trimethyl-5-indolinyl) -piperenyl] -benzoic acid ethyl ester, m.p. 79-80 ° C.

Example 4

By an analogous working procedure to that described in Example 1, [1- (3-methoxycarbonyl) -5,5,8,8-tetramethyl-2-naphthyl] ethyl (triphenylphosphonium bromide) may be

4-ethoxycarbonyl-11benzene aldehyde to obtain p - [(E) -2- (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-etramethyl-2-) ethyl ester naphthyl) propylphenyl] thiazole isomers having a melting point of 97-98 ° C. ,

In a manner analogous -popsán as in example 1, - from [1] ^7-methoxy-l lДЗ Leeroy-methyl-5H-Indanylamino) ethyl] triphenylphosphine and pnrumbromidu

4-ethoxycarepnyleentaldehyde to obtain p- [(E) -2- (7-methyl-1,1-ethoxy-1,1,3,3-ether-ethyl-5-piperazin-5-yl) -propenyl (benzoic acid ethyl ester, m.p. 72-73 ° C).

[1- (7-Imethoxy-1,1,3,3-tetramethyl-5-indanyl) ethyl] trienphosphonium fluoride which is used as the starting material can be prepared, for example, as follows;

84.3 g of (1,1,3,3-tetramethyl-5-indainyl) methyiliketoin (Example 1) are dissolved in 160 ml of concentrated sulfuric acid and the solution is cooled to -20 ° C. At this temperature, a nitric acid made of 40 ml of concentrated nitric acid and 80 ml of concentrated sulfuric acid was added over 10 minutes. Upon completion of the addition, the thick slurry is immediately poured onto. ice and extracted twice with ether. The ethereal extract was washed with sodium bicarbonate solution and brine, dried over sodium sulfate and freed from solvent under reduced pressure. The resulting (64-nitro-1,1,3,3-tetiramethyl-5-indanylmethyl ketone) was recrystallized from ether / hexane at 111-1-12 ° C.

75.8 g of (6-nitro-1,1,3,3-tetramethyl-5-indanyl) methylthyl ketone are dissolved in 1500 ml of imetihamol and this solution is hydrogenated under a nitrogen atmosphere using 20 g of Rainey nickel at 45 ° C for 48 hours. The reaction solution was then filtered (Speedex) and the solvent was removed under reduced pressure. The resulting (6-amino-1,1,3,3-tetraimethyl-5-indanyl) methylkeitone melts after recrystallization from ether / hexane mixtures at 161-162 ° C.

113.1 g of (6-amino-1,1,3,3-tetramethyl-5-iindanylimidyl ketone) are suspended in 2260 ml of 20% hydrochloric acid and the suspension is cooled to 0-5 ^° C. A solution of 33.9 g of sodium nitrite in 115 ml of water is added dropwise, the mixture is stirred for 30 minutes, and the cold reaction solution is then added dropwise to a solution of 243.2 g of copper (I) chloride in 2'50 ml of water and 250 ml. concentrated hydrochloric acid, heated to 40-45 ^C centigrade. the reaction mixture was then cooled, poured into ice water and extracted three times with methylene chloride. the organic extract was washed with brine, dried Sinan sulfate and in vacuo solvent The residue is purified by chromatography on silica gel (eluent: hexane / acetone 19: 1) (6-chloro-1,1,3,3-tetramethyl-5-indanyl) methyl ketoneine obtained from the eluate melts after recrystallization from silica gel; hexane / ether mixtures at 69 and 71 ° C.

Analogously to the above, the following compounds can be obtained:

(6-chloro-7-nitro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone, m.p. 119-120 ° C;

from (6-chloro-7-nitro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone to give (6-chloro-7-amino-1,1,3,3-tetramethyl16).

M.p. 116-117 ° C.

21.1 g of (6-chloro-7-amino-1,1,3,3-tetrafluoromethyl-5-indainyl jimethyliketome) is added to 48 ml of concentrated sulfuric acid and after heating to 50 DEG C. 140 g A solution of 5.5 g of sodium nitrite in 20 ml of water is added dropwise over 45 minutes to the mixture, cooled to 0 to 5 [deg.] C. The cold reaction mixture is added dropwise to a solution of 60 ml of water with stirring over 2 hours. and 60 ml of concentrated sulfuric acid, which is kept at 70 DEG C. The mixture is cooled, poured into ice water and extracted three times with ether, and the organic phase is washed with brine, dried over sodium sulphate and under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ether 19: 1) to give (6-chloro-7-hydroxy-1,1,3,3-teitramethyl 1-5-i). ndanyl) imethyl ketone obtained from the eluate melts after recrystallization from a mixture of hexane and ether at 78 to 80 ° C .

4.4 g of (6-chloro-7-hydroxy-1,1,3,3-tetraimethyl-1-5-indanyl) methyl ketone are dissolved in 10 ml of dimethylformamide, to which 1.1 g of hydroxide is added first. potassium iodide (dissolved in 1.2 mL of water), then 5.5 mL of methyl iodide, then stirred at room temperature for 3 hours, then poured into ice water and extracted twice with ether. Washed several times with brine, dried over sodium sulfate and freed from the solvent under reduced pressure (6-chloro-7-methoxy-1,1,3,3-tetramethyl-5-indainyl): methyl ketone melts after recrystallization 59 to 60 ^° C.

g (6-chloro-7-methoxy-1,1,3,3-teitramethyl-5-indanyl) methyl ketone is dissolved in about 200 ml of methanol and after addition of 10 g of triethylaimine and 2.5 g of 5% palladium; The catalyst is hydrogenated at room temperature. 1 molar equivalent of hydrogen is consumed over 5 hours. The reaction solution was filtered (Speedex). The filtrate was evaporated. The residue was dissolved in a mixture of water and ether and extracted several times with ether. The organic extract was washed with brine, dried over sodium sulfate and freed from solvent under reduced pressure. The resulting (7-methoxy-1,1,3,3-tetramethyl-5-indamyl) imethyl ketone melts after recrystallization from hexane at 76-77 ° C.

An analogous procedure to that described in Example 1 can be prepared from (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone via 7-methoxy-α-1,1,3, 3-Peintamethyl 1-5-indainmethanol, 5- (1-bromoethyl) -7-methoxy-1,1,3,3-tetramethylindane, [1- (7-methoxy-1,1,3,3-teitramethyl-5)] (Indanyl) ethyl] triphenylphosphonium bromide, m.p. 209-210 ° C.

8 15 8

Example 8

In an analogous manner to that described in Example 1, p - [(E) -2-ethyl ester can be prepared from [(1,1,3,3-l-etiramethyl-5-hndanylmethyl) triphenylphosphonium chloride and produced. (1,1,3,3-tetramethyl-5-indanyl) vinyl] benzoic acid, m.p. 151-152 ° C.

[(1,1'- ₍ 3,3-Tetimethyl-5-indanylmethyl) methyl] triphenylphosphonium chloride, which is used as starting material, can be prepared, for example, by the following process:

34.2 g of 1,1,1,1-tetramethylindrine, 150 ml of glacial acetic acid, 309 ml of concentrated hydrochloric acid and 77 ml of formaldehyde solution (35%) are heated at room temperature. with stirring for 2 hours at 75-78 ° C. Then; an additional 7.7 ml of 35% formaldehyde solution was added dropwise over 10 minutes. The reaction mixture is kept at the same temperature for 15 hours, then cooled, then stirred at room temperature for 15 hours ^. add to about 1 liter of ice-water and extract thoroughly with toluene. The organic phase is washed with a fault until neutral, dried over sodium sulphate and evaporated under reduced pressure. pressure. The crude product obtained, i.e., a reddish oil, is distilled through a Vigreux column. Pure 5-chloro-methyl-1,1,3,3-tetramethylindane is obtained at 143-146 ° C / 2533 Pa.

In an analogous manner to that described in Example 1, [1- (1,1,1-tetramethyl-5-indanyl) methyl] triphenylphosphine can be prepared from 5-chloromethyl-1,1,3,3-tetramethylindane and triphenylphosphine. cniumchlcrid.

Example 9

A logical process such as that described in Example 1 can be used to produce 4 '- (1- (1,1,3,3-tetramethyl-4-iudanyl) ethyl) triphenylphosphonium bromide and 4-acetylbenzatylhyde. (E) 2 - (1, 3, 3, 3, 3-methyl-1-methyl-propenyl) acetophenones, m.p. 130-131 ° C.

EXAMPLE 10 0 g of p - [(E) -2- (5,6,7,8-tetrahydro-4-methyl-tetramethyl-4-naphthyl) ethyl ester. The propenyl] benzoic acid (Example 3) was dissolved in 500 ml of ethanol at 45 ° C, and a solution of 20 g of potassium hydroxide in 50 ml of water was added dropwise with stirring, followed by stirring at 55 ° C for 18 hours. The mixture is acidified to pH 2 with 3N sulfuric acid solution and extracted twice with methylene chloride, and the methylene chloride extract is washed with saturated sodium chloride solution, dried with anhydrous sodium sulphate and concentrated in vacuo. The remaining p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid melts as recrystallization from a mixture of methylene chloride and hexane at 247. to 248 ° C.

Example 11

To a suspension of 7.0 g of p - [(E] -2- (5,6,7,8-tetrahydro-α, 1,8,8-tetrahydromethyl-12-naphthyl) propenyl] benzoic acid (Example 10) in 40 ml of absolute of ether, - 3.5 ml of thionyl chloride was added dropwise with stirring at 0-5 [deg.] C. The reaction solution was warmed to room temperature by addition of 5 drops of pyridine. A clear yellow solution of the acid chloride was added dropwise to a solution of 3 ml of ethylamine in 20 ml of absolute ether under stirring for 2 hours at room temperature and then added. with a saturated sodium-chloride solution and extracted twice -se - ether. - Etheoiciký extract - nasyceným- washed with NaCl-sodium, dried over anhydrous, magnesium sodným- and evaporated under reduced -tlaku ^1. monoethylamid remaining p- [(E (2-N, N-tetrahydro-S, N, N-telramethyl-2-naphthyl) propenyl] benzoic acid melts after recrystallization from of methylene chloride-hexane at 177-178.5 ° C.

Example 12

11.3 g of ethyl p - [[E) -2- (5,6,7,8,4-Hydro-5,5,8,8-tetramethyl-2-naphthyl) propylene] benzoic acid foam ( Example 3) was dissolved in 20 ml of absolute ether and 20 ml of absolute tetrahydrofuran and this solution was added dropwise at 0-5 ° C to a suspension of 1.33 g of lithium aluminum hydride in 20 ml of absolute ether. The reagent was stirred for 12 hours under an inert gas atmosphere at room temperature, then; is added dropwise at 0-5 cc of saturated sodium sulfate solution and the mixture is filtered (Speedex). The filtrate is diluted with ether and washed. . once with a saturated solution of acidic sodium carbonate and twice with a saturated solution of sodium chloride, dried with sodium sulphate and concentrated under reduced pressure. The resulting p - [(E) -2- (5,6,7,8-tetrrhydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzyl alcohol melts after recrystallization from a mixture of methanol and ether at 123 DEG C. 124 ° €.

Example 13

To a suspension of 6.6 g of p- [(E) -2- (5,6,7,8-tetrahydro ^o-5,5,8,8 - tetramethyl-2-naftylJpr · ^o ^ i ^ peinyljl m The reaction mixture (Example 12) in ether (19 ml) and pyridine (10 ml) was added dropwise with stirring at about 5 DEG C. with acetyl chloride (5.8 ml) and stirred at room temperature for 3 hours. The mixture is then added to about 100 ml of ice-water and extracted three times with ether, washed once with 1N hydrochloric acid, then three times with saturated sodium chloride solution, dried with sodium sulphate and concentrated. - p - [(E) -2- (5., 6, -

7,8-aetrdh.ydg 51 (8,8,8,8tretramethalfyaftyl) 208158 propenynbenzyl acetate melts after recrystallization from ether at 100 to 101 ^° C.

Example 14

5.0 g p - [. (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetraethyl-2-naphthyl) propynyl] -benzyl alcohol (Example 12), which is dissolved in 25 ml dimethyl dimethyl fluoride, is added to a solution of 0.4 g of sodium hydride in 10 ml of diimethylformaimide. After stirring at room temperature for 1 hour, 4.3 g of methyl iodide was added and the mixture was stirred for a further 2 hours. The reaction mixture was then added to about 200 ml of ice water and extracted three times with ether. The ethereal extract was washed three times with a saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting p - [(E) -2- (5.6, -)

7.8- (tetrahydro-5,5,8,8-tetraimethyl-2-naphthyl) propenylbenzyme melts after recrystallization from ether at 55 to 56 ° C.

Example 15

3.48 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylpropyl) benzoic acid [Example 10] was suspended in 12 ml toluene. After the addition of 3.57 g of thionyl chloride, the suspension is stirred for 12 hours at 50 and then evaporated to dryness under reduced pressure. The residue was dissolved in G ml of methylene chloride. This solution was added dropwise to a solution of 2.3 g of 2-amino-2-imethyl-1-propanol in 6 ml of methylene chloride at 0 ° C. The white suspension was stirred for 2 1/2 hours at room temperature, diluted with ethyl acetate, washed three times with water, dried over sodium sulfate, and concentrated under reduced pressure. The white crystalline residue is suspended in 20 ml of ether and 6 g of thionyl chloride are added dropwise thereto at 0 ° C. The white suspension was stirred at room temperature for 30 minutes and then saturated sodium carbonate solution was carefully added until the pH was approximately 9. Now the clear solution was diluted with ether. The ether phase is washed three times with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Remaining 2- [p- / (E) -2- (5,6, -

7.8- ttιtгahydl _l ro-5,5,8,8 - t t'Γamethyl-2-naphthyl) prioppnnV / phenyl ^^ - dimethyl-Z-oxazoline melt JPO recrystallizing from ether at 115-116 ° C.

Example 16

Ainalogick ým. By a process such as that described in Example 1, it is possible to prepare from [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propyl] triphenylphosphoniumhrimide and from 4-methoxycarbonylbenzeneadehyde from p - [(E)] -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-butenyl [benzoic acid ethyl ester, m.p. 82 ° C.

[· 1- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylpropyl) trenylphosphonium broinide, which is used as the starting material, can be produced by: in an analogous manner to that described in Example 1, from 5,6,7,8-etrahydro-5,58A-etramethylnaphthalene and propionic acid chloride.

Example 17

By an analogous procedure to that described in Example 1, p- [(E) -2- (5.6, -)

7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-propenylbenzoic acid and from diethylanene to obtain p- [(E) -2- (5,6,7,8-tetrahyld 0-5,5,8) diethylamide, 8-tetramethyl-2-naphthyl) propenyl] benzoic acid, m.p. 111-112 ° C.

Example 18

By an analogous procedure to that described in Example 1, p- [[e) -2- (5.6, -)

7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl (benzoic acid) from morpholine to give morpholine p- [(E) -2- (5,6,7,8-theory) Hydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid, m.p. 143-144 ° C.

Example 1 9

Using an analogous procedure to that described in Example 11, ρ - [(E) -2- (5, -

6.7.8-Tetrahydro-5,5 ₍ 8-tertamethyl-2-naphthyl-propenyl) -benzoic acid and from isopropanol • obtain the isopropyl ester of p - [(E) -2- (5,6, -)

7.8-tetrahydro-C, 5,8,8-teteamethyl-2-n-yl] propenyl] benzoic acid, m.p. 119-120 ° C.

Example 20

Using an analogous procedure to that described in Example 11, it is possible to from p- [^] - (5,6, -

7.8-tetrahydoo-5, 5, 8, 8-thetaamethyl-2-naphthylphenylphenylbenzoic acid and from 2-diethylamino-ethanate to give 2-diethylaminoethyl ester p- [(E) -2- (5,6,7, 8-tetrahydro-5,5,8,8-tetrauriethyl-2-naphthyl-propenyl (benzoic acid, m.p. 65-66 ° C).

Example 2 1

6.7 g of p - [(E) -2- (5,6,7,8-tetrahydro-4,5,5,8,8-tetraimethyl-2-naphthyl) propylene]] benisyl alcohol (Example 12 J is dissolved in 100 ml of absolute ether and this solution is added dropwise over 10 minutes to a stirred suspension of manganese dioxide in 100 ml of absolute ether, cooled to 0-5 [deg.] C. The mixture is stirred overnight at room temperature and then filtered through Celite. Yellowish oil crystallizes · Recrystallization from ether gives p- [[E) - [5,6,7,8-tetrahydro-5,5,8,8-] - as colorless crystals tetram ^, ethyl-2-naphthyl [propenyl] benzaldehyde as colorless crystals, m.p. 140-141 ° C.

Example 22

In a manner analogous · as described in Example 1, from [l- (5,67,8-te ^ i • i ^] ^^ - d: řor5,! ^, D ^ _i I ^ ^ I -TC N-dimethyl-24-naphthyl) ethyl] triphenylphosphonium bromide a. from 4-acetylbenzaldehyde to produce 4 '- [(E) -2- (5,6,7,8-tetrahydro-5,8,8-teteamethyl-2-methylpropenyl) acetophenone, m.p. Mp 149 ° C.

Example 23

3.0 g of 4 '- [(Et-2- [5,6,7,8-tetrahydro ^, η 5,5,8,8t-tetramethylth-2-naphthyl) propyl] acetophenone (Example 22), dissolved in 40 ml of benzene is heated with a catalytic amount of p-toluenesulphonic acid and 0.6 g of ethylethylene glycol in a Dean-Stark apparatus, the resulting water being continuously separated. After heating under reflux for 2 days, the reaction mixture was cooled, poured into a mixture of ice and saturated sodium bicarbonate solution and thoroughly extracted with ether. The ether extract is washed twice with saturated sodium chloride solution, sprout over sodium sulfate and evaporated to withdrawing the solvent under reduced pressure, ^1. The oily residue was purified by silica gel chromatography using hexane / ether (9: 1) as eluent. 2-Methyl-2 - N - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl) -2-naphthyl] propenyl] phenynyl] -1,3 -to the ¹ xolane obtained from the eluate melts after recrystallization from ether at 122 to 123 ° C,

Example 24

K 10.4 g 4 ^< - [(E) -2- (5,6,7,8-tetralelydro-5,5)

8.8-triethyl-1-naphthyl-1-pentyropeinyl lacetophenone (Example 22), which is dissolved in 100 milliliters of absolute methanol, is added cautiously at 0 to -5 ° C in portions. 0 g of sodium. The reaction solution was stirred at 0 ^° C for 1 hour and at room temperature for 2 hours, then poured into ice-water and thoroughly extracted with ether. The ether solution was washed twice with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The resulting alpha-methyl-p- [(E) -2- ⁽¹ 5,6,7,8ttetraeydr 0t5,5i8,8ttetτaιm · ethyl-2-naphthyl Jpropenyl] benzylalkobol melts after přeieiryytaloyání of ether at 121-123 ° C.

Example 25

By an analogous procedure (as described in Example 14), -z-methyl-β- [(E) -2- (5,67,8-tetrahydro-5, 5,8,8-tetrafluoroethyl) -z-may be -propyl phenylbenzyl alcohol to produce 1,2 _x 3,4-tetrahydro-6 - [(E) -p- (1-methoxyethyl) -a-rithithylstyryl] -1,1,4,4-β-β-β Mp 88-89 ° C.

Example 26

In an analogous manner to that described in Example 13, α-meteyl-p - [(Et-2- (5,6,7,8-tetrahydro-5,5,8,8-tetrahydro-ethyl) -2-aaphthyl] can be: ) Propenyl] benzyl alcohol to produce α-methyl-p - [(E) -2- (5,6,7,8-tetrahydro-3,5,5,8,8-tetrahydro-β-2-naphthyl-propenyl) -benzyl acetate, temperature mp 85-86 ° C.

Example 1 -a -d - 27

Using an analogous procedure to that described in Example 1, [1- (5,6,7,8-tetrahydro-5,5,8,8-etramethyl-2-naphthyl) ethyl] -tiphenyl-thiostoate bromide and 4-methylbenzaldehyde can be prepared from 6- [(El-pa-diimetlhylstyryl] t1,2,3,4-tetraeydro'-l 1,4,4ttetr'a! ^methyl-N: naphthalene, melting point 84 to 85 - ° C.

Example 28

In an analogous manner to that of Example 1, [1- (5,6,7,8-tetrahydro-5,5,8,8-trimethyl-2-naphthyl) ethyl] triphenyl may be used. · Phosphonium bromide and from 4-isopropylbenzaldehyde to produce 6 - [(E) -p-t-propyl · α-methyl · styryl] 1,2,3,4-tetrahydro-1,2,4,4-tetrameteyl · aaftatene, m.p. to 87 ° C.

Example 29

In an analogous manner to that described in Example 1, [1- (5,6,7,8-tetrahydro-5,5,8,8-tetraethylaminomethyl-2-carboxylic acid)] can be used. -naphthyl) ethyl] triphenylphosphonium bromide and from 2,4-dimethylbenzaldehyde-tert -butyl-6- [[E) -at-2,4-trimethylstyryl] -1,2,3,4-tetrahydro mp 54-56 ° C.

Example - 30

An analogous procedure to that described in Example 1, but preferably with a longer reaction time, can be made from meteyltriphenylphosphonium bromide and from p - [[E - 2- (5,67,8-tetraeydeo-5,5,8,8-tetramethyl)]. · 2-naaty1)! pr · opeιnyl] benzaldehyde t - (example 21) prepared 1,2,3,4ttetcahydгo-l, l, 4,4-EET ramethyl _l · 6- [(E) -atnltthyí-ptvьna1styry1]. m.p. 94-95 cc.

Example d 31

In an analogous manner to that described in Example 1, but preferably with an extended reaction time, ethyltrifeaylphosphonium bromide and β - [(E) -2- (5,6,7,8-tetrahydro-5,5), 8,8-teterιmethyl · 2-natfy1) propenyl]] benzaldehyde (example 21) to produce 1,2,3,4-tetraeydro-l ^ι 1,4,4ttaethme ΐhyl · 6- [(E) - and-methyltp · -allylstyryllaafealene, m.p. 64-63 ° C.

EXAMPLE 32 g of p - [(E) -2t (5,6,7,8-t ¢ el. E e e ^ ir ir ir ir ir · · · ,55,5,8,8t)

tetramethyl-2-naphthyl] -propenyl] -benzaldehyde [Example 21) and 1.4 g of diethyl ethylsulfonic acid ethyl ester are dissolved. in 5 ml of dimethyl ethylformamide. To this solution was added sodium aoxide solution with stirring at room temperature. (made from 6.16 g of sodium in 3 ml of absolute alcohol). After 18 hours. After stirring at room temperature, the reaction mixture was poured into an ice-cooled 1 N hydrochloric acid solution and thorough extraction with ether was performed. The ethereal phases are washed with a saturated sodium bicarbonate solution and with a sodium chloride solution and, after drying, concentrated under reduced pressure. · Drying is carried out with anhydrous sodium sulphate. The residue is purified by adsorption. Silica gel using hexane / ether (19: 1) as the eluent. (E) -p - [(E) -2- [5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl] -piropenyl] cinnamic acid ethyl ester obtained from the eluate melts after recrystallization from the mixture hexane and ether at 126. to 127 ° C.

Example 33

Analogous. By working procedures as described in Example 1, p- [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoate can be used acid benzyl ester prepared from benzylchlcridu p- [(E) -2- (5,6,7,8-tttrahydro 5,5,8,8-tetгamethy'l-2-on ftyl ^ι) Pirc ^ j ^ j ^ R m.p. 113-114 ° C.

Example 34

Analogous. workflow, such as. is described in Example 11, starting from p - [(E) -2- (5,6,7,8-teteahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid and 4 -1т1гоЬеп2aldehyde. produce 4-nitroibenzyl-p - [(E) -2-

- (5,6,7,8-tetrahydro'-5,5, B, 88etraanethyl-2-naphthyl Jprcpenyl jbenzoát, mp. 183 DEG C. 184 ^g

Example 35

By an analogous procedure to that described in Example 11, p - [(E] -2-

- ((N, N -tetrahydro) - (tetramethyl) -

-naphthyl] propenyl-benzylic acid and from 2-hydroxyethyl-p-

- [(E) -2- {5,6,7,8-tetrahydro-5,5,8,8-tetraimethyl-2-naphthyl] propenyl] benzoate, m.p. 138 to 139 ° C.

Example .. 36

To a solution of 14.1 g of p - [(E) -2- (5,6,7,8-tetrahydro-o-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] - (E) -cinnamic acid ethyl ester (example 32) 60 ml of a 20% solution of dibutylaluminum hydride (Di-bah) in hexane was added dropwise with stirring in 70 ml of absolute hexane at room temperature under an inert gas atmosphere with stirring, and the mixture was further stirred overnight. pe. at 0-5 ° ^{C. For} 50 ml of methanol and the mixture zfiltιrujt over Speedex. .Filtrát. diluted. ether, washed once with pr · sat. solution. sour. sodium ^carbonate: twice with saturated - sodium chloride dried over sodium sulphate and concentrated under reduced pressure to give 3 [beta] - {{(E) ^ 2 - ([alpha] 5,6,7,8-tetrahydro-5,5,8,8- &lt; / RTI &gt; tetramethyl-2-naphthyl-propenyl-phenyl) - (N-propan-1-ol) melts after recrystallization from hexane at 109-110 ° C.

Example 37

By analogous workflow, - as. is described in Example 13, can be from 3-p ^ - ^ phi (E) -2- (6,7,8-5 _J-5 tetaahydro \ 5; 8 \ 8-tetramethyl-2 t Jpropenyl naphthyl] phenyl 1 | - (E) -2-propan-1-ol produce 3-p - ([(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl) prop-1-yl- m.p. 109-110 cc.

Example 38

Analogous working. as described in Example 14, 3-p - {{(E) -2- (5,6-

7,8-tetralohydro-5 (8,8- (1-methyl-propenyl) phenyl) - (E) -Ziperopen-1 3-p - {[(E) -2- (5,6,7,8,4-dimethyl-5,6,7,8-tetramethyl-4-naphthyl) propenyl] phenyl] -2-prpen-1-ylmethyl ether; mp 88-90 ° C.

Example A

Capsules for oral. application can have. the following composition:

on. 1. capsule ethyl ester p - [(E) -2 - (- 5,6,7,8-

-tetrahydroc-5,5,8,8-tetramethylethyl -2-naphthyl] propenyl] benzoic acid 0.1 mg mixture of waxes 50,5- mg vegetable oil 98.9 mg trisodium salt ethylenediamine- tetraacetic acids 0.5 mg

Example B

The ointment may have the following composition:

• Μγ-ΐθ ^ ΐ ’ρ- [(E) -2- (5,6,7,8-

- teta ahydro-5,5,8,8-tetaaimethyl 1- -2-naphthyl] propenyl] benzoic acid 0.01 g cetylalikohol 2.7 G fat from .. sheep wool 6.0 G vaseline 15.0 G distilled water as needed > do 100.0 G

Claims (9)

A process for the production of novel stilbene derivatives of the general formula I, in which n is 1 or 2, and in case n is 1, R ¹ and R ² are hydrogen, lower alkoxyskuipinu having 1 to 6 carbon atoms or halogen, or even if n represents numbers a 2, R ¹ is hydrogen, C 1 -C 6 lower alkoxy or halogen and R ² represents hydrogen, R ³ , R ⁴ , R ⁵ and R ⁶ represent hydrogen or a lower alkyl group having 1 to 6 carbon atoms, R ⁷ denotes hydrogen, methyl or ethyl, R ⁸ and R ⁹ represent hydrogen, a lower alkyl group having 1 to 6 carbon atoms or halogen, and R ¹⁰ is - (CH = CR ¹⁹ ) _m R ¹¹ , with m being 0 or 1 a R ¹¹ represents a radical of formula R ¹² —CH — R ¹³ or O-C-R ¹⁵ radical or a 2-oxazolinyl, or if ni = 1, the symbol R ¹¹ represents also hydrogen, R ¹² denotes hydrogen or a lower alkyl group having 1 to 6 carbon atoms, R ¹³ is hydrogen, alkyl having 1 to 6 carbon atoms or a radical of the formula -N (R ^1? R ¹⁸⁾ -OR ^14, R ¹⁴ is hydrogen, (C 1 -C 6) alkyl or alkanoyl, R ¹⁵ is hydrogen, (C 1 -C 6) alkyl or OR ¹⁶ , R ¹⁶ represents hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, aralkyl, aralkyl substituted in the aryl moiety or - (CH 2) 2 N (R ¹⁷ , R ¹⁸ ), R ¹⁷ and R ¹⁸ are hydrogen, alkyl of 1 to 6 carbon atoms or together with the nitrogen atom to which they are attached represent a heterocyclic radical, R ¹⁹ represents hydrogen or an alkyl group having 1 to 6 carbon atoms and ketals of the compounds of formula I in which R ¹¹ represents a radical —C (O) R ¹⁵ and R ¹⁵ represents hydrogen or an alkyl group having 1 to 6 carbon atoms and salts of compounds of formula (I), characterized in that a compound of formula (P) is reacted with a compound of formula (III) in which: R ^X , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ and n are as defined above, and either A stands for three ar у 1 phospho i uma lik у left group of the formula I © Θ where means R is hydrogen, methyl or ethyl, Q is an aryl group a Y an anion of an organic or inorganic acid, and В means for a myth group, or A represents a formyl group, an acetyl group or a propionate group, and V represents a dialkoxyisophinylalkyl group of formula r-ch-p 1, wherein: Z stands for C 1 -C 6 carbon atoms, under Wittig reaction conditions in the presence of an acid binding agent, optionally Hoirlneircvy reaction with a base, to give compounds of the general formula I, whereafter, if desired, functionally modifying a radical R ¹⁹ 2. A process according to item 1 for the preparation of isoproteins of the general formula I, wherein in the case where n = 1, R ¹ and R ² represent hydrogen, alkoxysikupinu having 1 to 6 carbon atoms or halogen, and when n = - 2, R ¹ represents hydrogen, alkoxyskupiinu having 1 to 6 carbon atoms or • a halogen, R ² represents hydrogen, R ^3, R ^4, R ⁵ and R ⁶ represent hydrogen or alikylovou group having 1 to 6 carbon atoms, R ⁷ is hydrogen, methyl or ethyl, ₍ R 8 _and r 9 are hydrogen, C 1 -C 6 alkyl or halogen, and R ¹⁰ represents hydroxymethyl, alkoxyethyl, and anoyloxyethyl, icarboxil, and oxylcarbonyl, phenoxy, alkylenedioxymethyl, alkanoyl, kairbamoyl, monoalkylcarbaimoyl (C 1 -C 6) alkyl, (C 1 -C 6) dialkylcarbamoyl in alkyl radicals, N-heteroicyclylkairibonyl or 2-oxazoliinyl, characterized in that compounds of formulas II and III are used as starting materials in which n, R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ^7, R ⁸ and R ⁹ have the above meanings, а а а В have the meanings given in point 1. 3. The process of item 1 for producing compounds of formula I wherein n is 2 and the remaining symbols are as defined in item 1, characterized in that compounds of formulas II and III are used as starting materials, wherein n is the number 2 and the remaining symbols have the meaning given in point 1. 4. The method according to item 3 к preparing compounds of formula I wherein R @ ^1, R ^2, R ^5, R ⁶ and R ⁹ is hydrogen and R ^3, R ⁴ and R ⁷ is methyl and the remaining symbols are defined in significant section 3, characterized in that the starting materials used are compounds of the formulas II а III in which R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ and R ⁹ are as defined above, and the remaining symbols have the meaning given in point 3. 5. A method according to claim 4 к preparing compounds of formula I wherein ^R10 represents a radical - (CH ^ CHJmR ¹¹ and the remaining symbols have the meaning given under point 4, characterized in that the starting materials used are compounds of formulas II а III, in which the general symbols have the indications referred to in point 4. 6. A process according to claim 5 for the preparation of compounds of formula I in which me is zero and the remaining symbols have the meaning given in point 5, characterized in that compounds of formulas II and III are used as starting materials, the meaning referred to in point 5. 7. A method according to claim 6 к preparing compounds of formula I in něimž R ¹¹ represents an alkoxycarbonyl group having 1 to 6 carbon atoms in alkoxylo.vé portion alkyllkarbamcylojvou group having 1 to 6 carbon atoms in the alkyl alkoxyimethylovou group having 1 to 6 carbon and the remaining symbols have the meaning given in point 6, characterized in that compounds of formulas II and III in which R ^{11 is as} defined above are used as starting materials. that meaning and other symbols have the meaning given in point 6. 18. The process of clause 7 for producing p-[(E) -2- (3-methoxy-5,6,7) eithyl ester, 8-tetrahydro-5,5,8,8-tetraethylamino-2-naphthyl) piperidininyl] benzoic acid, characterized in that [1- (3-methoxy-5,6,7,8-tetrahydro-5, 5,8,8-Tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide is treated with 4-ethoxycarbonylbenzaldehyde. 9. The process of claim 7 for the preparation of p - [(E) -2- (5,6,7,8-tetraihydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] benzoic acid eithyl ester, characterized in that: to [1- (5,6, - 7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide is treated with 4-ethoxycarboinylbenzaldehyde.