CA1123839A - Stilbene derivatives - Google Patents

Abstract

ABSTRACT
This invention is concerned with compounds of the general formula (I) wherein n stands for 1 or 2 and, when n stands for 1, R1 and R2 represent hydrogen, lower alkoxy or halogen, or, when n stands for 2, R1 represents hydrogen, lower alkoxy or halogen and R2 represents hydrogen; R3, R4, R5 and R6 represent hydrogen or lower alkyl; R7 represents hydrogen, methyl or ethyl; R8 and R9 represent hydrogen, lower alkyl or halogen; and R10 represents a group of the formula -(CH=CR19)mR11, in which m stands for zero or 1 and R11 represents a group of the formula or or the 2-oxazolinyl group, or, when m stands for 1, also represents hydrogen; R12 represents hydrogen or lower alkyl; R13 represents hydrogen, lower alkyl of a group of the formula -N(R17,R18) or -OR14; R14 represents hydrogen, lower alkyl or alkanoyl;
R15 represents hydrogen, lower alkyl or a group of the formula -OR16 or -(CH2)pN(R17, R18) R16 represents hydrogen, lower alkyl, hydroxy-(lower alkyl), aryl, substituted aryl, aralkyl or aralkyl substituted in the aryl portion; R17 and R18 represent hydrogen or lower alkyl or R17 and R18 together with the nitxogen atom to which they are attached represent a heterocyclic group; R19 represents hydroqen or lower alkyl and p stands for zero, 1, 2 or 3; as well as ketals of compounds of formula I in which R11 represents a group of the formula -C(O)R15 and R15 represents hydroqen or lower alkyl, and salts of c????unds of formula I. The invention is also concerned w??? process for the manufacture of these com-pounds and salts and with pharmaceutical preparations con-taining them. Tha compounds of formula I and their salts are useful for the treatment of neoplasms, dermatological conditions and rheumatic diseases.

Description

RAN 4~60/91 The present invention relates to stilbene derivatives.
More particularly, the invention is concerned with stilbe~ne derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same. The invention is also concerned with intermediates occurring in said process.

The ~tilbene derivatives provided by the pr~sent invention arP compounds of the general formula , wherein n st&nds for 1 or 2 and, when n stands for 1, Rl and R2 represent hydrogen, lower alkoxy or halogen, or, when n stands for 2, Rl represents hydrogen, lower alkoxy or halogen and R2 represents hydrogen~ R3, lS R4, RS &nd R6 represent hydrogen or lower alkyl; R7 represents hydrogen, me~hyl or ethyl; R8 and R9 represent hydrogen, lower alkyl or halogen; and R10 represents a Grn/27.11.78 ~.~.Z383g -- 2 ~
group of the foxmula -(CH~CRl9) Rll i h m stands for zero or 1 and Rll represents a group of the formula R12 o - ~ -R or - I - R15 or the 2-oxazolinyl group, or, when m stands for l,also represents hydrogen; R12 represents hydrogen or lower alkyl; R13 represents hydrogen, low~r alkyl or a group of the formula N(R17 R18) or -oR14; R14 represents hydrogen, lower alkyl or alkanoyl;
RlS represents hydrogen, lower alkyl or a group of the formula -OR or -(CH2)pN(R17, R18); R16 represents hydrogen, lower alkyl, hydroxy-(lower alkyl), aryl, substituted aryl, aralkyl or aralkyl substituted in the aryl portion; R17 and R18 represent hydrogen or lower alkyl or R17 and R
tGgether with the nitrogen atom to which they are attached represent a heterocyclic gr_up; Rl9 represents hydrogen or lower alkyl and p stands for zero, 1, 2 or 3; as well as ketals of compounds of formula I in which Rll represents a group of the formula -C(O)R and R represents hydrogen or lower alXyl, and salts of compounds or formula I.

As used in this Specificatlon, the ter~ "lower" means that the groups qualified thereby contain up to 6 carbon atoms.

Alkyl and alkoxy groups can be straight-chain or branched-chain, examples of alXyl gro~ps being the methyl, ethyl, isopropyl and 2-methylpropyl groups and examples of alkoxy groups being the methoxy, ethoxy and isopropoxy groups. Alkanoyl groups are derived, for example, from acetic acid, propionic acid or pivalic acid, or also from a higher carboxylic acid containing up to 20 ca~bon atoms (e.g. from palmitic acid or stearic acid). me ~henyl group is a preferred aryl group. Examples of substituted aryl groups are hydroxy-, nitro- and halo-phenyl groups.
The benzyl group is a preferred aralkyl group. Examples of heterocyclic groups denoted by -N(Rl7,R18) are 5-membered or 6-membered nitrogen-containing hetarocyclic rings which may contain an oxygen or sulphur atom or a further nitrogen atom (e.g. the piperidino, piperazino, morpholino, thia-morpholino and pyrrolidino groups). Examples of ketals are di(lower alkyl) ketals and lower alkylene ketals. The oxazolinyl group can be substituted by one or two lower alkyl groups. Of the halogen atoms, chlorine and bromine are preferred.

A preferred class of compounds of formula I herein-before comprises those in which, when n stanas or l, Rl andR2 represent hydrogen, lower alkoxy or halogen, or, when n ~.2383~

stands for 2, R represents hydrogen, lower alkaxy or halogen and R2 represents hydrogen; R3, R4, R5 and R6 represent hydrogen or lower alkyl; R7 represents hydrogen, methyl or ethyl; R8 and R9 represent hydrogen, lower alk~l or halogen; and R10 represents hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carboxyl, alXoxycarbonyl, formyl, alkylenedio~ymethy-l, alkanoyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl, N-heterocyclylcarbonyl or 2-oxazolinyl. Furthermore, compounds of formula I in which n stands for 2 are preferred, as are compounds of formula I in which Rl, R , R5, R , R8 and R9 represent hydrogen and R3, R and R7 represent methyl. A furthex preferred class of compounds of formula I comprises those in which R10 represents a group of the formula -(CH=C~)mRll, especially when m stands for zero and, moreover, when R
represents lower alkoxycarbonyl, lower alkylcarbamoyl, lower alkoxymethyl or lower alkanoyloxymethyl.

According to the process provided by the present invention, the stilbene derivatives aforesaid (i.e. the compounds of formula I and their salts) are manufactured by reacting a compound of the general formula A

~R5,R ~ Rl (II) with a compound of the general formula ~L~.2383~

,X~Rl o -^
a~9 (III) rein Rl, R2, R3, R4 R5 R6 R8 R9 lo and n have the signi~icance given earlier, and either ~ represents a triarylphosphonium-alkyl group of the formula ~-CH-P[Q]3 ~ Y ~ , in which R represents a hydrogen atom or the methyl or ethyl group, Q represents an aryl group a~d Y represents the anion o~ an organic or inorganic acid, and B represents the formyl group; or A represents the formyl, acetyl or propionyl group and B
represents a dialkoxyphosphinylalkyl group of the formula R-CH-P[Z]2, in which R has the significance given earlier and Z
represents a lower alkoxy group;
to give a compound of formula I and, if desired, functlonally modifying the group R10.

The aryl groups denoted by Q in the aforementioned triarylphosphoniumalkyl groups include all generally known aryl groups, but especially mononuclear aryl groups such as phenyl, lower alkyl-substituted phenyl or lower alkoxy -substituted phenyl (e.g. tolyl, xylyl, mesityl and p -methoxyphenyl). Of the inorganic acid anions denoted by Y

~.23~39 the chloride, bromide and hydrosulphate ions are preferred and of the organic acid anions the tosyloxy ion is preferred.

The alkoxy groups denoted by Z in the aforementioned dialkylphosphinylalkyl groups are preferably lower alkoxy s groups (i.e. alkoxy groups containing 1-6 carbon atoms such as the methoxy and ethoxy groups).

The starting materials of formula II, insofar as their preparation is not known or described hereinafter, can be prepared according tc known methods or in an analogous manner to the methods described hereinafter.

Compounds of formula II in which A represents a formyl, acetyl or propionyl group and Rl and R represent hydrogen ~oxo compounds of formula II] can ~e prepared, for example, by subjecting an indane derivative, which is substituted in the cyclopentene ring corresponding to the desired compound of formula I, or a tetrahydronaphthalene derivative, which substi~uted in the cyclohexene ring cor-responding to the desired compound of formula I, to an acylation. This acylation can be carried out, for example, in the presence of a Lewis acid.

Suitable acylating agents are formaldehyde/hydro-chloric acid, acetyl halides (e.g. acetyl chloride) and propionyl halides (e.g. propionyl chloride). me preferred Lewis acids are the aluminium halides such as aluminium 7 ~3.~3~339 ~richloride. The acylation is conveniently carried out in a solvent, such as nitrobenzene or a chlorinated hydrocarbon such as methylene chlorlde. The acylation is preferably carried out at a temperature of from 0C to about ~5C.

i A resulting oxo compound of formula II in which Rl and R2 each represent a hydrogen atom is reacted in accordance with the present invention with a phosphonate of formula III
in -~hich B represents a dialkoxyphosphinylalkyl group to give a compound of formula I in which Rl and R2 each represent a hydrogen atom.

The phosphonium salts of formula II in which A rep-resents a l-(triarylphosphonium)-(methyl or ethyl or propyl) group required for the reaction with an aldehyde of formula III in which B represents an oxo group can be prepared, for example, as follows:

A~ aforementioned oxo compound of formula II in which Rl and R2 represent hydrogen is reduced to give a cor-responding alcohol at about 0C to about +5C using a complex metal hydride (e.g. sodium borohydride in an alkanol or lithium aluminium hydride in an ether, tetrahydrofuran or dioxan). The resulting alcohol is subsequently halogenated in the presence of an amine base (e.g. pyridine) using a customary halogenating agent (e.g. phosphorus oxychloride or phosphorus tribromide~. The halide obtained is then reacted with a triarylphosphine in a solvent, preferably i~ Z3839 triphenylphosphine in toluene or xylene, to give a deslred phosphon~um salt of formula II.

Oxo compounds and phosphonium salts of formula II in which Rl and R2 represent alkoxy or halogen can be prepared, for example, by converting a corresponding phenol in a manner known per se into a corresponding alkoxy-substituted derivative of formula II by treatment with an alkylating agent (e.g. a lower alkyl halide or a lower alkanol in the presence of an acid agent).

The aforementioned phenols can be obtained, for example, as follows:

An oxo compound of formula II in which Rl and R2 represent hydrogen is nitrated by treatment with a mixture of concentrated nitric acid and concentrated sulphuric acid.
The nitro group which is preferentially introduced in the ortho-position to the formyl, acetyl or propionyl group is catalytically reduced in a manner known per se (e.g. with the aid of Raney-nickel) to the amino group which is replaced by the hydroxy group via the diazonium salt in a known manner.

If the diazonium salt prepared from the amine is .reated in the warm with a copper (I) halide, then there i~
obtained the corresponding halo derivative of the oxo com-pound of formula II. By treating said halo derivative with ~.Z38~39 g nitric acid it is possible to introduce, in the meta--position to the formyl, acetyl or propionyl group, a nitro group which likewise can be replaced in the manner previously described by the hydroxy group or a halogen atom~
By converting the hydroxy group into an alkoxy gxoup there can be obtained, if desired, ketones of formula II which carry similar or mixed substitution.

A halogen atom present on the aromatic nucleus can be removed, i desired, by reduction in a manner known per se.

The compounds of formula III in which B represents the formyl group can be prepared from phenyl derivatives which are nitro-substituted in the l-position in the manner des-cribed in Chem. Berichten 102 (1969), pages 2502-2507.
They can also be prepared by reducing a corresponding p--carboxy substituted phenyl derivative. The reduction of the carboxyl group to the formyl group can be carried out, for example, with dlisobutylaluminium hydride.

The compounds of formula III in which B represents a dialkoxyphosphinylmethyl group can ke prepared from the aforementioned compounds of ormula III in which B rep-resents the formyl group by converting the formyl group using a metal hydride (e.g. sodium borohydride) into the hydroxymethyl group, halogenating the hydroxymethyl group using a customary halogenating agent (e.g. phosphorus tri-chloride) and reacting the resulting halomethyl group with a 38~!3 trialkylphosphite, especially triethylphosphite, to give adesired phosphonate of formula III.

A compound of formula III in whlch B represents the formyl group or a dialkoxyphosphinylmethyl group can be prepared by halogenating a corresponding phenyl derivati~e which is methyl-substituted in the l-position and either reacting the resulting halomethyl derivative with a tri-alkylphosphite or hydrolysing said halomethyl derivative to the hydroxymethyl derivative and oxidising the latter by treatment with an oxidising agent (e.g. manganese dioxide).

The reaction of a compound of formula II with a com-pound of formula III in accordance with the process provided by the present invention can be carried out according to the known methods of the Wittig reaction or the Horner reaction.
There are preferably used as the starting ma~erials those compounds of formula III in which R10 represents a group which is not reactive towards phosphoranes such as, in particular, the formyl group.

The functional modification of a group R10, also in accordance with the process provided by the present inven-tion, can comprise, for example, the conversion of the carboxyl group into a salt, an ester, an amide, an oxaline derivative or into the hydroxymethyl group which can sub-sequently be etherified or esterified. Another functional C 25 modification comprises the saponification of a carboxylic 383~

acid ester or the reduction thereof to the hydroxymethyl group. The hydrox~methyl group can also be oxidised to the formyl group. Compounds of formula I which contain a formyl group can be converted, e.g. by means of a Wittig reaction, into compounds of formula I in which R10 rep-resents a group of the formula -(CH=CR19)mRl1 in which m stands for 1, R19 represents hydrogen or alkyl and R
reDresents alkoxymethyl, alkanoyloxymethyl, carboxyl, alkoxycarbonyl, or alkyl. All of ~hese functional modifications can be carried out according to methods known pex se.

In the case of the Wittig reaction, the starting materials are reacted with one another in the presence of an acid binding agent, for example, in the presence of a strong base such as butyl lithium, sodium hydride or the sodium salt of dimethyl sulphoxide, but preferably in the presence of an ethylene oxide which is optionally substituted by lower alkyl such as 1,2-butylene oxide, if desired in a solvent (e.g. an ether, such as diethyl ether or tetra-hydrofuran or an aromatic hydrocarbon such as ben~ene) at atemperature between room temperature and the boiling point of the reaction mixture.

In the case of the Horner reaction, the starting materials are reacted with one another in the presence of a base and, preferably, in the presence of an inert organic ~, solvent; for example, in the presence of sodium hydride in ~, ~L~.Z3839 benzene, toluene, dimethylformamide, tetrahydro~uran, dloxan or 1,2-dimethoxyalkane or in the presence of a sodium alcoholate in an alkanol le.g. sodium methylate in methanol) at a temperature between 0C and the boiling point of the S reaction mixture.

It has been found to be convenient in certain cases to carry out the aforementioned reactions in situ, i.e. to react ~he starting materials with one anothel~ without isolating the phosphonium salt or phosphonate in question from the medium in which it is prepared.

A carboxylic acid of formula I can be converted in a manner known per se (e.g. by treatment with thionyl chloride, prefera~ly in pyridine, or phosphorus trichloride in toluene) into an acid chloride which can be converted by l; reaction with an alcohol into an ester or by reaction with an amine into a corresponding amide. Amides can be con-verted into amines in a manner known per se; for example, by reduction with complex metal hydrides such as lithium aluminium hydride.

A carboxylic acid ester of formula I can be hydrolysed in a manner known per se (e.g. by treatment with alkali, especially by treatment with aqueous-alcoholic sodium hydroxide or potassium hydroxide) at a temperature between room temperature and the boiling point of the mixture and the resulting carboxylic acid can then be amidated via an - 13 - ~.Z 383g acid halide as described eaxlier. Alternatively, a carboxylic acid ester of formula I can be directly amidated as described hereinafter.

A carboxylic acid ester of formula I can be converted directly into a corresponding amide, for example by treat-ment with lithium amide. The ester is advantageously treated with lithium amide at room temperature.

A carboxylic acid of formula I can be converted into an oxa~oline derivative of formula I via a halide by reaction with 2-aminoethanol or 2-amino-2-methyl-1-propanol and subsequent cyclisation.

A carboxylic acid or carboxylic acid ester of formula - I can be reduced in a manner known per se to give a cor-responding alcohol of formula I. The reduction is advan-tageously carried out using a metal hydride or alkyl metalhydride in an inert solvent. Especially suitable hydrides are the mixed metal hydrides such as lithium aluminium hydride or bls~methoxy-ethylenoxy]-sodium aluminium hydride.
Suitable solvents are, inter alia, ether, tetrahydrofuran or dioxan when lithium aluminium hydride is used and ether, hexane, benzene or taluene when diisobutylaluminium hydride or bis~methoxy-ethylenoxy]-sodium aluminium hydride is used.

An alcohol of formula I can be etherified with an alkyl halide (e.g. methyl iodide), for example, in the :, - 14 ~ 3~ 39 presence of a base, preferably sodium hydride, in an organic solvent such as dioxan, tetrahydrofuran, 1,2-dimethoxyethane or dimethylformamide, or in the presence of an alkali metal alcoholate in an alkanol, at a temperature between 0C and room temperature.

An alcohol of formula I can be esterified by treatment with an alkanoyl halide or anhydride, conveniently ln the presence of a base ~e.g. pyridine or triethylamine) at a t mperature range between room temperature and the boiling point of the mixture.

A carboxylic acid of formula I forms salts with bases, especially with alkali metal hydroxides and preferably with sodium hydroxide or potassium hydroxide.

The compounds of formula I occur predominantly in the trans form. Cis isomers which may be obtained can be separated or isomerised to the trans isomers in a mannex known per se where desired.

The stilbene derivatives provided by the present invention are pharmacodynamically valuable. They can be used for the topical and systemic therapy of benign and malignant neoplasms and of premalignant lesions as well as for the systemic and topical prophylaxis of the said conditions.

~ . -- 15 _ 1~.23l 33~

The present stilbene derivatlves are also suitable ror the topical and systematic therapy of acne, psoriasis and other dermatoses accompanied by an intensified or patho-logically altered cornification, as well as of in~lammatory and allergic dermatological conditions. They can moraover be used for the control of mucous membrane diseases associated with inflammatory or degenerative or metaplastic changes.

Compared with known retinoids, the stilbene deriv-atives provided by this invention are characterised in thatthey are active in extraordinarily slight amounts.

The tumour-inhibiting activity of the present stilbene derivatives is significant. In the papilloma test in mic~, tumours induced with dimethylbenzanthracene and croton oil regress. In the case of the intraperitoneal administration of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)propenyl]-benzoic acid ethyl ester, the diameter of the papilloma decreases in the course of 2 weeks by 75 at a dosage of 0.2 mg/kg/week, by 56~ at a dosage of 0.1 mg/kg/week and by 48~ at a dosage of O.OS mg/kg/week. In the case of oral administration of p-~(E)-2-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid ethyl ester to mice, the diameter of the induced tumours decreases in the course of 2 weeks (5 individual doses/week) ~y 63~ at a dosase of 0.4 mg(S x 0.08 mg)/Xg/week, by 48% at a dosage of 0.2 mg (5 x 0.04 mg)/kg/week and by 37% at a dosage of 0.05 mg (5 x 0.01 mg)/kg/week.

- 16 - ~ 383~
The stilbene derivatives provided by this invention can also be used for the oral treatment of rheumatic ill-nesses, especially those of an in1ammatory or degenerative kind whlch attac~ the joints, muscles, tendons and other parts of the motor apparatus. Examples of such illnesses are rheumatic arthritis, Bechterew's spondyl-arthritis ankylopcetica and psoriatic arthropathy.

For the treatment of these illnesses, the presPnt stiIbene derivatives are administered orally, the dosage in the case of adults conveniently being about 0.01-1 mg/kg body weight per day, preferably 0.05-0.5 mg/~g/day. A
possible over-dosage can manifest itself in the form of a vit-A hypervitaminosis which can readily be recognised from its symptoms (scaling of the skin, hair loss).

The dosage can be administered as a single dosage or in several sub-divided dosages.

The stilbene derivatives provided by the present invention can therefore be used as medicaments, or example in the form of pharmaceutical preparations which contain them in association with a carrier material.

The pharmaceutical preparations suitable for systemic .administration can be produced, for example, by adding a compound of formula I or a salt thereof as the active ingredient to non-toxic, inert, solid or liquid carriers which are conventionally-used in such preparations.

- 17 - ~ Z 3~ 3g The pharmaceutical preparations can be administered enterally, parenterally or topically. Suitable preparations for enteral ad~inistration are, for example, tablets, capsules, dragées, syrups, suspensions, solutions and sup-positories. Sultable preparations for parenteral admln-istration are infusion or injection solutions.

~ he dosages in which the present stilbene derivatives are administered can vary according to the particular dosage form and mode of administration as well as according to the requirements of the patient, The stilbene derivatives of this invention can be administered in amounts of ca 0.01 mg to ca 5 mg daily in one or more dosages. ~ preferred form of administratlon comprises capsules containing ca 0~1 mg to ca l.0 mg of active ingredient.

The pharmaceutical preparations can contain inert as well as pharmacodynamically active addltives. Tablets or granulates, for example, can contain binding agents, filling agents, carrier substances or diluents. Liquid preparations can take the form of, for example, sterile solutions which are miscible with water. Capsules can contain, in addition to the active ingredient, a filling agent or thic.~ening agent. Furthermore, flavour-improving additives, substances normally used as preservatives, stabilisers, wetting agents and emulsifying agents as well ~.Z3~39 as salts for varying the osmotic pressure, buffers and other additives may also be present in the pharmaceutical preparations.

The aforementioned carrier substances and diluents can be organic or inorganic in natuxe; for example, water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkyleneglycols and the like. A prerequisite is that all adjuvants used in the production of the pharma-ceutical preparations are non-toxic.

For topical administration, the pharmaceutical preparations are conveniently provided in the orm of oint-ments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Ointments, creams and solutions are preferred. These pharmaceutical preparations for topical administration can be produced by mixing the present stilbene derivatives with non-toxic! inert, solid or liquid carriers which are customary per se in such preparations and which are suitable for topical administration.

For topical administration there ara suitably used ca 0.001~ to ca 0.3~, preferably 0.02% to 0.1%, solutions, as well as ca 0.002% to ca 0.5%, preferably ca 0. 02~, to ca 0.1~, ointments or creams.

The pharmaceutical preparations may contain an anti-oxidant (e.g. tocopherol, N-methyl-~-tocopheramine, butylated hydroxyanisole or butylated hydroxyto-luene).

383~

The following Examples illustrate the process provided by the present invention:

Example 1 300 ml of butylene oxide are added to 30.5 g of ~1-~(1,1,3,3-tetramethyl-5-indanyl)ethyl]-triphenylphosphonium bromide and 8 g of 4~ethoxycarbonylbenzaldehyde and the mixture is ~hen stirred at 65C for 12 hours in an inert gas atmosphere. The resulting clear solution is cooled, introduced into ca 500 ml of ice/water and extracted twice with hexane. The organic extract is extracted three tim~s with methanol/water, dried over sodium sulphate and concen-treated under reduced pressure. m e residue is puri~ied by adsorption on silica gel using hexane/ether (19:1) or the elution. The p-[(E)-2-(1,1,3,3-tetramethyl-5-indanyl)-lS -propenyl]-benzoic acid ethyl ester obtained from the eluate melts at 70-71C after recrystallisation from ether/hexane.

The ~1-(1,1,3,3-tetramethyl-5-indanyl)ethyl]-~ri-phenylphosphonium bromide used as the starting material can be prepared, for example, as follows:

87.8 g of acetyl chloride are dissolved in 240 ml of nitrobenzene. 149.2 g of aluminium chloride are introduced portionwise into the solution. The mixture is cooled down to 0-5C and then treated dropwise while cooling well with a solution of 195.0 g of 1,1,3,3-tetramethyl-indane in 360 ~J.23839 ml of nitrobenzene. The temperature should no~ rise above 5C. The mixture is stirred at 0C for 15 hours, then introduced into 3 litres of ice/water and extracted with ether. The ether extract is washed twice with a 2-N sodlum hydroxide solution and twice with a saturated sodium chloride solution, dried over sodium sulphate and concen-trated, firstly in a water-jet vacuum and then in a high vacuum to remove the nitrobenzene. The residual oily ~1,1,3,3-tetramethyl-5-indanyl)-methyl ketone boils at lQ0--103C/0.5 Torr.

2.6~ g of lithium aluminium hydride are treated with 40 ml of absolute ether. While cooling to 0-5C there are added dropwise within 30 min~tes 26 g of lrl,3,3-tetra-methyl-5-indanyl methyl ketone. After a further 30 minutes, the mixture is cautiously treated dropwise with 25 ml of a saturated sodium sulphate solution. The solution is filtered. The filtrate is washed once with a l-N sodium hydroxide solution and twice with a saturated sodium chloride solution, dried over sodium sulphate and concen-trated under reduced pressure to remove the solvent. Theresidual oily a-1,1,3,3-pentamethyl-5-indane-methanol, which is uniform according to thin-layer chromatography [flow agent: hexane/ether (80:20)], is immediately processed as follows:

24.0 g of ~-l,1,3,3-pentamethyl-5-indane-methanol are dissolved in 20 ml of absolute ether and 100 ml of absolute hexane. After the addition of 2 drops of pyridine, the l~.Z3839 solution is treated dropwise over a period of 30 minutes with 16.2 g of phosphorus tribromide dis501ved in 80 ml of absolute hexane. After stirring at 0-5C for a further hour, the product is introduced into ice/water and exhaustively extracted wlth ether~ The ether extract is washed twice with a saturated sodium bicarbonate solution and twice with a sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure to remove the solvent. The residual ~ily 5~ bromoethyl)-1,1,3,3--tetramethyl-indane, which is uniform according to thin-layer chromatography ~flow agent: hexane/ether (95:5)~, is immediately processed as follows:

26.3 g of triphenylphosphine are dissolved in 120 ml of xylene. The solution is treated with 30.9 g of 5~
-bromoethyl)-1,1,3,3-tetramethyl-indane dissolved in 60 ml of xylene. The mixture is warmed to 100C while stirring and left at this temperature for 12 hours. The thick-oily 1-(1,1,3,3-tetramethyl-5-indanyl)ethyl-triphenylphosphonium bromide which thereby separates out and which crystallises after seeding melts a~ 151-156C after recryst~llisation ~rom methylene chloride/toluene (crystals contain 0.3 equivalents of toluene).

Example 2 2.4 g of 1,1,3,3-tetramethyl-5-indanyl methyl ketone and 3.4 g of 4-[(diethoxyphosphinyl)methyl]-benzoic acid - 2~ 3~39 ethyl ester are dissolved in 7 ml of dimethylformamide, The solution is treated dropwlse under ~rgon at room tem-perature ~hile stirring with a sodium ethanolate solutlon (prepared from 0.33 g of sodium and 7 ml of ethanol) and ; subsequently stirred at 70C for 18 hours. The mixture is subsequently introduced into ice/water and extracted with ether. The ether extract is washed with a saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residual p- L (E)-2-~l,1,3,3-tetramethyl-5-indanyl)propenyl]-benzoic acid ethyl ester, a brown oil, is puriried by adsorption on silica gel using hexane/ether (9:1) for the elution. Tne ester melts at 70-71C after recrystallisation from hexane/ether~

Example 3 In a manner analogous to that described in Example l, from ~1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide and 4-ethoxycarbonyl--benzaldehyde there can be obtained p~c~E)-2-~s~6~7~8--tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid ethyl ester or melting point 90-91C.

The [l-~5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)ethyl]-triphenYlphosphonium bromide used as the starting material can be prepared in a manner analogous to that des~ribed in Example l, rrom 5,6,7,8-tetrahyd~o-5,5,8, 8-tetramethyl-naphthalene via (i,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-naph-thyl)methyl Xetone, 5,6,7,8-tetrahydra- ~ -- 23 _ ~.2383~
-a-5,5,8,8-pentamethyl-2-naphthalene-methanol and 2-(bromo-ethyl3-5,6,7,8~tetrahydro-5,5,8,8-tetramethyl-naphthalene.

Example 4 In a manner analogous to that described in Example 1, from tl-(3-methoxy-5~6~7~8-tetrahydro-s/5~8~8-tetrameth -2-naphthyl)ethyll~triphenylphosphonium bromide and 4--ethoxycarbsnyl-benzaldehyde there can be obtained p`~(E)--2-~3-methoxy-5,6,7 r 8-tetrahydro-5,5,8,8-tetramethyl-2--~aphthyl)propenyl]-ben~oic acid ethyl ester of melting point 97-98C.

The ~1-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)ethyl]-triphenylphosphonium bromide used as the starting material can be prepared in a manner analogous to that described in Example 1, rrom 3-methoxy--5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene via (3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)methyl ketone, 3-methoxy-5,6,7,8-tetrahydro-S,S, 8,8-tetramethyl-2-naphthalene-methanol and 2-(1-bromoethyl~-

-3-methoxy-5,6,7,8-tetrahydro-S,5,8,8-tetramethyl-naphtha-lene~

Example S

In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,i,8,8-tetramethyl-2-naphthyl)-.

~3.Z3~339 ethyl]-triphenylphosphonium bromide and 3-methyl-4-ethoxy-carbonyl-benzaldehyde there can be obtained p-~(E)-2-(5,6,7, 8-tetrahydro-5,5,8,8~tetramethyl-2-naphthyl)propenyl]-2--methyl-benzoic acid ethyl ester as a colourless oil which is S uniform according to thin-layer chromatography, (Rf = 0.6;
hexane/15~ ether).

The aforementioned 3-methyl-4-ethoxycarbonyl-benz-aldehyde can be prepared from 4-nitro-3-methyl-benzoic acid in a manner analogous to that described for the preparation of 2-methyl-4-ethoxycar~onyl-benzaldehyde by Huneck et al in Chem. Ber. 102, 2502-2507 (1969).

Example 6 In a manner analogous to that described in Example l r from [l-(1,1,2,3,3-pentamethyl-5-indanyl)ethyl]-triphenyl-phosphonium bromlde and 4-ethoxycarbonyl~benzaldehyde there can be obtained p-~(E)-2-(1,1,2,3,3-pentamethyl-5-indanyl)-propenyl]-benzoic acid ethyl ester of melting point 79--80C.

Example 7 In a manner analogous to that described in Example l~
from [1-(7-methoxy-1,1,3,3-tetramethyl-5-indanyl)ethyl]--triphenylphosphonium bromide and 4-ethoxycarbonyl-benz-aldehyde there can be obtained p-[(E)-2-(7-methoxy-1,1,3,3-~.Z383~

-tetramethyl-5-indanyl)-propenyl]-ben~oic acid ethyl ester of melting point 72-73C.

The [1-~7-methoxy-1,1,3,3-tetramethyl-5-indanyl)-ethyl]-triphenylphosphonium bromlde used as the starting material can be prepared, for example, as follows:

84.3 g of (1,1,3,3-tetramethyl-5-indanyl) methyl ketone (prepared as descri~ed in Example 1) are dissolved in 160 ml of concentrated sulphuric acid and the solution is cooled down to -20C. At this temperature there is added during 10 minutes the nitrating acid prepared from 40 ml of concentrate,d nitric acid and 80 ml of concentrated sulphuric acid. After completion of the addition, the thick paste is immediately poured on to ice and extracted twice with ether~
The ether extract is washed with a sodium bicarbonate solution and a sodium chloride solution, dried over sodium sulphate and freed from solvent under reduced pressuxe.
The separated (6-nitro-1,1,3,3-~etramethyl-5-indanyl) methyl ketone melts at 111-112C after recrystallisation from ether/hexane.

75.8 g of (6-nitro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone are dissolved in 1500 ml of methanol and the solution is hydrogenated at 45C for 48 hours under nitrogen with the aid of 20 g of Raney-nickel. 15 litres of hydrogen are taken up. The solution is then filtered through Speedex and the solvent is removed under reduced 3~3~

pressure. The separated (6-amino-1,1,3,3-tetramethyl-5--indanyl) methyl ketone melts at 161-162C after recrystal-lisation from ether/hexane.

113.1 g of (6-amino-1,1,3,3-tetramethyl-5-indany~
S methyl ketone are suspended in 2260 ml of 20% hydrochloric acid and the suspension is cooled down to 0-5C. The cold mixture is treated dropwise within 10 minutes with a solution of 33.9 g of sodium nitrite in 115 ml of water and the resulting solution is stirred for 30 minutes. The cold solution is subsequently introduced dropwise over a period of 2 hours while stirring into a solution of 243.2 g of copper (I) chloride in 250 ml of water and 250 ml of concen-trated hydrochloric acid, which is warmed to 40-45C. The mixture is then cooled down, introduced into ice-water and lS extracted three times with methylene chloride. The organic extract is washed with a sodium chloride solution, dried over sodium sulphate and freed from solvent under reduced pressure. The residue is purified by adsorption on silica gel using hexane/acetone (19:1) for the elution. The (6--chloro-1,1,3,3-tetramethyl-S-indanyl) methyl ketone obtained from the eluate melts at 69-71C after recrystal-lisation from hexane/ether.

In an analogous manner, from (6-chloro-1,1,3,3-tetra-methyl-5-indanyl) methyl ketone there can be obtained (6--chloro-7-nitro-1,1,3,3-tetramethyl-S-indanyl) methyl ketone of melting point 119-120C, and from (6-chloro-7-nitro-~ ~`.23~33~

-1,1,3,3-tetramethyl-5-indanyl) methyl ketone there can be obtalned (6-chloro-7-amino-1,1,3,3-tetramethyl-5-indanyl) methyl ketone of melting point 116-117C.

21.1 g of (6-chloro-7-amino-1,1,3,3-tetramethyl-5--indanyl) methyl ketone are introduced into 48 ml o concen-trated sulphuric acid and, after the warming to S0C, the mixture is treated slowly with 140 ml of distilled water, After cooling down to 0-5C, there is introduced dropwise into the mixture over a period of 45 minutes a solution of 5.5 g of sodium nitrite in 20 ml of water. The resulting cold mixture is lntroduced dropwise while stirring over a period of 2 hours into a solution, held at 70C, of 60 ml of water and 60 ml of concentrated sulphuric acid. The mixture is cooled, then introduced into ice-water and extracted three times with ether. The organic phase is washed with a sodium chloride solution, dried over sodium sulphate and freed from solvent under reduced pressure.
The residue is purified by adsorption on silica gel using hexane/ether (19:1) ror the elution. The t6-chloro-7--hydroxy-l,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained from the eLuate melts at 78-80C ater recrystal-lisation from hexane/ether~

4.4 g of (6-chloro-7-hydroxy-1,1,3,3-tetramethyl-5--indanyl) methyl ketone are dissolved in 10 ml of dimethyl-formamide. The solution is treated first with 1.1 g ofpotassium hydroxide (dissolved in 1.2 ml of water) and then ~.Z3l33g with 5.5 ml of methyl iodide and the resulting mixture is subsequently stirred at room temperature for 3 hours. The mixture is introduced into ice-water and extracted twice with ether. The organic extract is washed several times with a sodium chloride solutlon, dried over sodium sulphate and freed from solvent under reduced pressure. The separated (6-chloro-7-methoxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone meLts at 59-60C after recrystallisation.

25 g of (6-chloro-7-methoxy-1,1,3,3~te~ramethyl-5--indanyl) methyl ketone are dissolved in ca 200 ml of methanol and, after the addition of 10 g of triethylamine and 2.5 g o~ 5~ palladium/carbon catalyst, the mixture is - hydrogenated at room temperature. 1 mol equivalent of hydrogen is taken up over a period of 5 hours. The solution is filtered over Speedex. The filtrate is evaporated. The residue is dissolved in water/ether and extracted several times with ether. The organic extract is washed with sodium chloride solution, dried over sodium sulphate and freed from solvent under reduced pressure.
The separated (7-methoxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone melts at 76-77C a~ter recrystallisation from hexane.

In a manner analogous to that described in Example 1, .rom (7-methoxy-1,1,3,3-tetramethyl-5-1ndanyl) methyl ketone via 7-methoxy-~-1,1,3,3-pentamethyl-5-ir.dane-methanol and

5-(1-bromoethyl)-7-methoxy-1,1,3,3-tetramethyl-indane there ~.Z3839 can be obtained [1-(7-methoxy-1,1,3,3-tetramethyl-S-indanyl)-ethyl]-triphenylphosphonium bromide of melting point 209--210C.

Example 8 In a manner analogous to that described in Example 1, from [(1,1,3,3-tetramethyl-5-indanyl)methyl]-triphenyl-phosphonium chloride and 4-ethoxycarbonyl-benzaldehyde there can be obtained p-[(E)-2-(1,1,3,3-tetramethyl-5-indanyl)-vinyl]-bengoic acid ethyl ester of melting point 151-152C.

The ~(1,1,3,3-tetramethyl-5-indanyl)methyl~-triphenyl-phosphonium chloride used as the starting material can be prepared, for example, as follows:

34.2 g of 1,1,3,3-tetramethyl-indane, lS0 ml of glacial acetic acid, 300 ml of concentrated hydrochloric acid and 77 ml of formaldehyde solution (35~) are warmèd to 75-78C while stirring for 2 hours. A further 7.7 ml o~
35~ formaldehyde solution are then àdded dropwise within 10 minutes. The mixture is held at the same temperature for lS hours, then cooled down, introduced into ca 1 litre of ice-water and exhaustively extracted with toluene. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated under reduced pressure. The resulting crude product, a reddish cil, is distilled over a Vigreux column The pure 5-chloromethyl-1,1,3,3-tetra-methyl-indane boils at 1~3-146C/l9 mmHs.

1~.23~39 In a manner analogous to that described in Example 1, from 5-chloromethyl 1,1,3,3-tetram~thyl-lndane and trl-phenylphosphine t~ere can be obtained ~1-(1,1,3,3-tetra-methyl-5-indanyl)m~thyl]-trlphenylphosphonium chlorlde.

S Example ~

In a manner analogous to that described in Example 1, from ~1-(1,1,3,3-tetramethyl-S-indanyl)ethyl~-triphenyl-phosphonium bromide and 4-acetyl-benzaldehyde there can be obtained 4'-E(E)-2-(1,1,3,3-tetramethyl-5-indanyl)propenyl~--acetophenone of meltinq point 130-131C.

Example 10 49 g of p-~(E)-2-(5,6,7,8-tetrahydro-S,5,8~8-tetra-methyl-2-naphthyl)propenyl]-benzoic acid ethyl ester (prepared as descri~ed in Example 3) are dissolved in 500 ml of ethanol at 45C and the resulting solution is treated dropwise while stirring with a solution of 20 g of potassium hydroxide in S0 ml of water. The mixture is stirred at 55C for 18 hours, then cooled, introduced into ice/water, acidified to pH 2 with 3-N sulphuric acid and extracted twice with methylene chloride. The methylene chloride extract is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. me residual p-~(E)-2-(5,6,7,8~tetra-hydro-5,5,8,$-tetramethyl-2-naphthyl)propenyl]-benzoic acid ~-~.Z~839 melts at 247-248C after recrystallisation from methylene chloride/hexane.

Example ll Into a suspension of 7.0 g of p-[(E)-2-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid (prepared as described in Example lO) in 40 ml of absolute ether are introduced dropwise, a~ter addition of 1.8 ml of pyridine, while stirring at 0-5C 3.5 ml of thionyl chloride. ALter the addition of 5 drops of N,N-dimethyl-formamide, the solution is warmed to room temperature,stirred for 18 hours and then decanted off. The clear yellow solution of the acid chloride is introduced dropwise u~der argon into a solution of 3 ml of ethylamine in 20 ml of absolute ether. The mixture is stirred at room temperature for Z hours, then introduced into a saturated sodium chloride solution and extracted twice with ether.
The ether extract is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate and evapor-ated under reduced pressure. The residual p ~(E)-2-(5,6,7, 8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]--benzoic acid monoethylamide melts at 177-178.5C after recrystallisation from methylene chloride/hexane.

Exam~le 12 :

11.3 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-benzoic acid ethyl es-ter - 32 - ~ 3839 (prepared as described in Example 3) dissolved in 20 ml of absolute ether and 20 ml of absolute tetrahydrofuran are introduced dropwise at 0-5C into a suspension of 1.33 g of lithium aluminium hydride in 20 ml of absolute ether. The solution is stirred at room temperature for 12 hours under an inert gas, then treate,d dropwise at 0-5C ~ith 5 ml of a saturated sodium sulphate solution and filtered over Speedex.
The filtrate i5 diluted with ether and washed once with a saturated sodium bicarbonate solution and twice with a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The separated p-[(E~-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--2-naphthyl)propenyl]-benzyl alcohol melts at 123-124C
after recrystallisation from methanol/ether.

Example 13 5.8 ml of acetyl chloride are introduced dropwise at ca 5C while stirring into a suspension o~ 6.6 g of p-~(E)--2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzyl alcohol (prepared as described in Example 12) in 10 ml of ether and 10 ml of pyridineO The mixture is stirred at room temperature for 3 hours, then introduced into ca 100 ml of ice/water and extracted three times with ether. The ether extract is washed once with l-N hydro-chloric acid and three times with a saturated sodium chloride solution, dried over sodium sulphate and concen-trated under reduced pressure. The separated p-[(E)-2-31~39 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)pro-penyl]-benzyl acetate melts at 100-101C after recrystal-lisation from ether.

Example 14 s S.0 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-benzyl alcohol (prepared as described in Example 12) dissolved in 25 ml of dimethyl-formamide are introduced into a solution of 0.4 g of sodium hydride in 10 ml of dimethylformamide. After stirring at room temperature for 1 hour, the mixture is treated with 4.8 g of methyl iodide and the resulting mixture is stirred for a further 2 hours. The solution is then introduced into ca 200 ml of ice/water and extracted three times with ether.
The ether extract is washed three times with a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The separated p-[(E)--2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzyl methyl ether melts at 55-56C after recrystaLlisation from ether.

Example 15 3.48 g of p-~(E)-2-(5,6,7,8-tetrahydro~5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-benzoic acid (prepared as described in Example 10) are suspended in 12 ml of toluene.
After the addition of 3.57 g of thionyl chloride, the 3~33~

suspension is stirred at 50C for 12 hours and then evaporated to dryness under reduced pressure. The residue is dissolved in 6 ml of methylene chloride. The solution is introduced dropwise at 0C into a solution o~ 2.3 g of 2-amino-2-methyl-1-propanol in 6 ml of methylene chlorlde.
The white suspension is stirred at room temperature for 2.5 hours, diluted with ethyl acetate, washed three times with water, dried over sodium sulphate and concentrated under reduced pressure. The white crystalline residue is sus-pended in 20 ml of ether and treated dropwise at 0C with6 g of t~ionyl chloride. The white suspension is stirred at room temperature for 30 minutes and then treated cautiously with a saturated sodium carbonate solution until the pH value amounts to ca 9. The now clear solution is diluted with ether. The ether phase is washed three times with a saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residual 2-_ p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-phenyl 7-4,~-dimethyl-2--oxazoline melts at 115-116C after recrystallisation from ether.

Example 16 In a manner analogous to that described in Example 1, from [l-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propyl]-triphenylphosphonium bromide and 4-ethoxycarbonyl--benzaldehyde there can be obtained p-[(E)-2-(5,6,7,8-tetra-~3.23~339 hydro-5,5,8,8-tetramethyl-2-naphthyl)-1-butenyl]-benzoic acid ethyl ester of melting point 82-83C.

The ~1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)propyl]-triphenylphosphonium bromlde used as the starting material can be obtained in a manner analogous to that described in Example 1 from 5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-naphthalene and propionic acid chloride.

Exam~le 17 In a manner analogous to that described in Example 11, from p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)propenyl]~benzoic acid and diethylamine there can be obtained p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-benzoic acid diethylamide of melting point 111-112C.

Example 18 In a manner analogous to that described in Example 11, from p-~(E)-2-~5,6,7,8-tetrahydro-5,5,8,8-te~ramethyl-2--naphthyl)propenyl]-benzoic acid and morpholine there can be obtained p-~(E)-2-~5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)propenyl]-benzoic acid morpholide of melting point 143-144C.

~.Z3~3~

Example 19 In a manner analogous to that described in Exampl~ 11, from p-~(E)-2-~5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-~--naphthyl)propenyl]-benzoic acid and isopropanol there can S be obtained ~-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra~
methyl-2-naphthy})propenyl]-benzoic acid isopropyl ester of melting poin. 119-120C.

. Example ~Q

6.7 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-benzyl alcohol (prepared as described in Example 12) dissolved in 100 ml of absolute ether are added dropwise within 10 minutes to a stirred suspension, cooled to 0-SC, of manganese dioxide in 100 ml of absolute ether. The mixture is stirred at room tem-perature overnight and then filtered ~hrough*Celite. mefiltrate is concentrated to dryness on a rotary evaporator.
*trade mark ~L~.23~39 The yellowish oil crystallises. Recrystallisation from ether yields p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-benzaldehyde in the form o~
colourless crystals of melting point 140-141C.

Examole 21 In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium ~romide and 4 acetyl-benz-aldehyde there can be obtained ~ (E)-2-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-acetophenone of melting point 148-149C.

Example 22 3.0 g of 4'-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-acetophenone (prepared as des-cribed in Example 22) dissolved in 40 ml of ben~ene are treated with a catalytic amount of p-toluenesulphonic acid and 0.6 g of ethyleneglycol and warmed in a Dean-Stark apparatus, the water formed being concurrently separated off. After heating under reflux for 2 days, the mixture is cooled down, introduced into ice/saturated sodium bicar bonate solution and exhaustively extracted with ether. The ether extract is washed twice with a saturated sodium chloride solution, dried over sodium sulphate and evaporated _ under reduced pressure to remove the solvent. The oily ~.2~3~

residue ls purified by adsorption on silica gel using hexane/ether (9:1) for the elution. The 2-methyl-2-L p--[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tet_amethyl-2-naphthyl)-propenyl]-phenyl 7-1, 3-dioxolane obtained from the eluate melts at 122-123C after recrystallisation from ether.

Example 23 1.0 g of sodium borohydride is cautiously added portionwise at 0-5C to 10.4 g of 4'-~(E~-2-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyl)~ropenyl]-acetophenone (prepared as described in Example 21) dissolved in 100 ml of absolute methanol. The solution is stirred at 0C for 1 hour and at room temperature for 2 hours, then introduced into ice/water and exhaustively extracted with ether. The ether solution is washed twice with a saturated sodium chloride solution, dried over sodium sulphate and concen-trated under reduced pressure. The separated a-methyl-p--~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl~-benzyl alcohol melts at 121-123C after crystal-lisatlon from ethe~, Example 24 In a manner analogous to that described in Example 14, from -methyl-p-[~E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-benzyl alcohol there can be obtained 1,2,3,4-tetrahydro-6-[(E)-p~ methoxyethyl)-a~

~.Z3~39 - 3g --methyl-styryl]-1,1,4,4-tetramethylnaphthalene of meltlng point 88-89C

Example 25 In a manner analogous to that described ln Example 13, ; from a-methyl-p-[~E)~2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-b~nzyl alcohol there can be obtained -methyl-p-t(E)-2-(5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-naphthyl)propenyl]-benzyl acetate of melting point 85-86C.

Example 26 In a manner analogous to that described in Example 1, from tl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide and 4-methyl-benz-aldehyde there can be obtained 6-~(E)-p,a-dimethylstyryl]--1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of melting point 84-85C.

Example 27 In a manner analogous to that described in Example 1, from tl-(5,6,7,8~tetrahydro-5,5,8,8~tetramethyl-2-naphthyl)~
ethyl]-triphenylphosphonium bromide and 4-isopropyl-benz-aldehyde there can be obtained 6-[(E)-p- sopropyl-a-methyl-styryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of melting point 86-87C.

~.Z3B39 Example 28 In a manner analogous to that described in Example 1, from tl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-~aphthyl)-ethyl]-triphenylphosphonium bromide and 2,4-dimethyl-benz-aldehyde there can be obtained 6-[(E)-a,2,4-trimethylstyryl]--1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of melting point 54-56C.

Example 29 In a manner analogous to that described in Example 1, but preerably with a longer reaction time, from methyl~
-triphenylphosphonium bromide and p-~(E)-2-(5,6,~,8-tetra-hydro-5,5,8,8-tetramethyl 2-naphthyl)propenyl~-benzaldehyde (prepared as described in Example 20) there can be obtained 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-~(E)--methyl-p--vinylstyryl]naphthalene of melting point 94-95C.

Example 30 In a manner analogous to that described in Example 1, but preferably with a longer reaction time, from ethyl--triphenylphosphonium bromide and p-[(E)-2-~5,6,7,8-tetxa-hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzaldehvde (prepaxed as described in ~xample 20~ there can be obtained 1,2,3,4-tetrahydro-1,1,4,4 tetramethyl-6-~(E)- methyl-p--allylstyryl]naphthalene of melting point 64-66C.
S ~.

~.~.23839 Example 31 2 g of p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-benzaldehyde (prepared as des-cribed in Example 20) and 1.4 g of diethylphosphonoacetic acid ethyl ester are dissolved in 5 ml of dimethylformamide.
A sodium alcoholate solution (prepared using 6.16 g of sodium in 3 ml of absolute alcohol~ is added thereto at room temperature while stirring.` After stirring at room temperature for 18 hours, the mixture is poured into ice--cold l-N hydrochloric acid and exhaustively extracted with ether. The ether phases are washed with saturated sodium bicarbonate solution and sodium chloride solutlon and, after drying over anhydrous sodium sulphate, are concentrated under reduced pressure. The residue is purified by adsorption on silica gel using hexane~ether (19:1) for the elution. The (E)-p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-naphthyl)propenyl]-cinnamic acid ethyl ester obtained from the eluate melts at 126-127C after recrystallisation from hexane/ether.

Example 32 In a manner analogous to that described in Example 11, from p-~(E)-2 (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)propenyl]-benzoic acid and benzyl alcohol there can be obtained p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-~t ~_. methyl-2-naphthyl)propenyl]-benzoic a~id benzyl ester of melting point-113-114C.
-3~33~3 In a manner analogous to that described in Example 11, from p-~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)propenyl]-ben20ic acid and 4-nitro-benzyl alcohol there can be obtained 4-nitrobenzyl p-~(E)-2-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyl~propenyl]-benzoate of meltlng point 183-184C.

Example 34 In a manner analogous to that described in Example 11, from p-~tE)-2-(s~6~7~8-tetrahydro-5~5~8~8-tetramethyl-2--naphthyl)propenyl]-benzoic acid and ethyleneglycol there can be obtained 2-hydroxyethyl p-~(E)-2-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-ben~oate of meltin~ point 138-139C.

Example 35 60 ml of a 20% solution of dibutylaluminium h.ydride in hexane are added dropwise at room temperature under an inert gas atmosphere and while stirring to a solution of 14.1 g of p-~(E)-2-(5~6/7~8-tetrahydro-s~5~8~8-tetramethyl-2-naphthyl!
propenyl]-(E)-cinnamic acid ethyl ester (prepared as des-cribed in Ex~mple 31) in 70 ml of absolute hexane and the mixture is stirred overnight. The solution is then treated dropwise at 0-5C with iO ml of methanol and filtered over ~, ....

l~.Z~
- ~3 -Speedex. The filtrate is diluted with ether, washed once with a saturated sodium bicarbonate solution and twlce with a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The separated 3~P- r ~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]phenyl 7- ~E)-2-propen-1-ol melts at 109-110C after recry~tallisation from hexane.

Example 36 In a manner analogous to that described in Example 13, from 3~P~ r [(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--2-naphthyl)propenyl~phenyl 7- (E)~2-propen-1-ol there can be obtained 3-P-L [(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]phenyl 7 2-propen-1-yl acetate of melting point 109-110C.

Example 37 In a manner analogous to that described in Example 14, from 3-p / ~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--2-naphthyl)propenyl]phenyl 7- (E)-2-propen-1-ol there can be obtained 3-p-/ ~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl~propenyl]phenyl 7 2-propen-l-yl methyl ether of melting point 88-90C.

The following Examples illustrate pharmaceutical preparations pro~ided by the invention:

- 44 _ 1~.2 ~83g Exam~le A

Capsules for oral administration can contain the fol-lowing ingredlents:
Per capsule p-~(E)-2-(5,6,7,8~Tetrahydro--5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoic acid ethyl ester 0.1 mg - Wax mixture 50.5 mg Vegetable oil 98.9 mg Trisodium salt of ethylenediamine-tetraacetic acid 0~5 mg Example B

An ointment can have the fol~owing composition:
p-[(E)-2-(5,6,7,8-Tetrahydro--5,5,8,8-tetramethyl-2-naphthy7)-propenyl]-benzoic acid ethyl ester 0.01 g Cetyl alcohol 2.t g Lanolin 6.0 g Vaseline 15.0 g Distilled water q.s. ad 100.0 g

Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
CLAIMS: EV RAN 4060/91 1) A process for the manufacture of compounds of the general formula (I) , wherein n stands for 1 or 2 and, when n stands for 1, R1 and R2 represent hydrogen, lower alkoxy or halogen, or, when n stands for 2, R1 represents hydrogen, lower alkoxy or halogen and R2 represents hydrogen; R3.
R4, R5 and R6 represent hydrogen or lower alkyl; R7 represents hydrogen, methyl or ethyl; R8 and R9 represent hydrogen, lower alkyl or halogen; and R10 represents a group of the formula -(CH=CR19)mR11, in which m stands for zero or 1 and R11 represents a group of.the formula or or the 2-oxazolinyl group, or, when m stands for 1, also represents hydrogen; R12 represents hydrogen or lower alkyl; R13 represents hydrogen, lower alkyl or a group of the formula N(R17,R18) or -OR14; R14 represents hydrogen, lower alkyl or alkanoyl;
R15 represents hydrogen, lower alkyl or a group of the formula -OR16 or -(CH2)pN(R17, R18); R16 represents hydrogen, lower alkyl, hydroxy-(lower alkyl), aryl, substituted aryl, aralkyl or aralkyl substituted in the aryl portion; R17 and R18 represent hydrogen or lower alkyl or R17 and R18 together with the nitrogen atom to which they are attached represent a piperidino, piperazino, morpholino, thia-morpholino or pyrrolidino group; R19 represents hydrogen or lower alkyl and p stands for zero, 1, 2 or 3; as well as ketals of compounds or formula I in which R11 represents a group or the formula -C(O)R15 and R15 represents hydrogen or lower alkyl, and salts of compounds or formula I, which process comprises reacting a compound of the general formula (II) with a compound of the general formula (III) , wherein R1, R2, R3, R4, R5, R6, R8, R9, R10 and n have the significance given in
1. claim 1, and either A represents a tri-arylphosphoniumalkyl group of the formula , in which R represents a hydrogen atom or the methyl of ethyl group, Q represents an aryl group and Y represents a chloride, bromide, hydrosulphate or tosyloxy ion and B represents the formyl group; or A
   represents the formyl, acetyl or propionyl group and B represents a dialkoxyphospninyl-alkyl group of the formula , in which R has the signilicance giver. earlier in this claim and Z represents a lower alkoxy group;
   to give a compound of formula I and, if desired, saponifying a carboxylic acid ester obtained to yield a carboxylic acid and, if further desired, converting a so-obtained carboxylic acid into a salt or a carboxylic acid ester, or into an amide or into an oxazoline derivative; or converting a carboxylic acid or a carboxylic acid ester into the hydroxy-methyl group and, if further desired, esterifying or etherifying said hydroxy-methyl group or oxidizing said hydroxymethyl group to yield a formyl group and submitting the latter to a Wittig reaction to yield a compound of formula I in which R10 is a group -(CH=CR19)R11 wherein R19 is as above and R11 is lower alkoxymethyl, lower alkanoyloxymethyl, carboxyl, lower alkoxycarbonyl, alkyl or alkenyl.
2. 2. A process as in Claim 1 wherein in the compounds of formulae II and III n stands for 1 and R1 and R2 represent hydrogen, lower alkoxy or halogen, or n stands for 2 and R1 represents hydrogen, lower alkoxy or halogen and R2 represents hydrogen; and in either case R3, R4, R5 and R6 represent hydrogen or lower alkyl; R7 represents hydrogen, metnyl or ethyl; R8 and R9 represent hydrogen, lower alkyl or halogen; and R10 represents hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carboxyl, alkoxycarbonyl, formyl, alkylenedioxymethyl, alkanoyl, carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, piperidinocarbonyl, piperazinocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl, pyrrolidinocarbonyl or 2-oxazolinyl.
3. 3) A process as in claim 1 for the manufacture of compounds of formula I, wherein n stands for 2.
4. 4) A process as in claim 3 for the manufacture of compounds of formula I, wherein R1, R2, R5, R6, R8 and R9 represent hydrogen and R3, R4 and R7 represent methyl.
5. 5) A process as in claim 4 for the manufacture of compounds of formula I, wherein R10 represents a group of the formula -(CH=CH)mR11.
6. 6) A process as in claim 5 for the manufacture of compounds of formula I, wherein m stands for zero.
7. 7) A process as in claim 6 for the manufacture of compounds of formula I, wherein R11 represents lower alkoxycarbonyl, lower alkylcarbamoyl, lower alkoxymethyl or lower alkanoyloxymethyl.
8. 8. A process as in Claim 1 for the manufacture of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid ethyl ester, wherein [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphoniumbromide is reacted with 4-ethoxycarbonyl-benzaldehyde.
9. 9. A process as in Claim 8 for the manufacture of p-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzyl acetate, wherein the p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]benzoic acid ethyl ester obtained is treated with lithium aluminium hydride to yield the corresponding benzyl alcohol which is reacted with acetyl chloride in pyridine.
10. 10. A process as in Claim 8 for the manufacture of p-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzyl methyl ether, wherein the p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]benzoic acid ethyl ester obtained is treated with lithium aluminium hydride to yield the corresponding benzyl alcohol which is reacted with methyl iodide in the presence of sodium hydride.
11. 11. A process as in Claim 8 for the manufacture of p-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid monoethylamide , wherein the p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]benzoic acid ethyl ester obtained is treated with aqueous-methanolic potassium hydroxide to yield the corresponding benzoic acid which is reacted with thionyl chloride and subsequently with ethylamine.
12. 12) compounds of the general formula (I) , wherein n stands for 1 or 2 and, when n stands for 1, R1 and R2 represent hydrogen, lower alkoxy or halogen, or, when n stands for 2, R1 represents hydrogen, lower alkoxy or halogen and R2 represents hydrogen; R3.
    R4, R5 and R6 represent hydrogen or lower alkyl; R7 represents hydrogen, methyl or ethyl; R8 and R9 represent hydrogen, lower alkyl or halogen; and R10 represents a group of the formula , in which m stands for zero or 1 and R11 represents a group of the formula or or the 2-oxazolinyl group, or, when m stands for 1, also represents hydrogen; R12 represents hydrogen or lower alkyl; R13 represents hydrogen, lower alkyl or a group of the formula ?N(R17, R18) or ?OR14; R14 represents hydrogen, lower alkyl or alkanoyl;
    R15 represents hydrogen, lower alkyl or a group of the formula ?OR16 or ?(CH2)pN(R17, R18); R16 represents hydrogen, lower alkyl, hydroxy-(lower alkyl), aryl, substituted aryl, aralkyl or aralkyl substituted in the aryl portion; R17 and R18 represent hydrogen or lower alkyl or R17 and R18 together with the nitrogen atom to which they are attached represent a piperidino, piperazino, morpholino, thia-morpholino or pyrrolidino group; R19 represents hydrogen or lower alkyl and p stands for zero, 1, 2 or 3; as well as ketals of compounds of formula I in which R11 represents a group of the formula ?C(O)R15 and R15 represents hydrogen or lower alkyl, and salts of compounds of formula I, whenever prepared according to the process of claim 1 or by an obvious chemical equivalent thereof.
13. 13) Compounds according to claim 12, wherein in a compound of formula II and III n stands for 1 and R1 and R2 represent hydrogen, lower alkoxy or halogen, or n stands for 2 and R1 represents hydrogen, lower alkoxy or halogen and R2 represents hydrogen;and in either case R3, R4, R5 and R6 represent hydrogen or lower alkyl;R7 represents hydrogen, methyl or ethyl;R8 and R9 represent hydrogen, lower alkyl or halogen;and R10 represents hydroxymethyl, alkoxymethyl, alkanoy-loxymethyl, carboxyl, alkoxycarbonyl, formyl, alkylenedioxy-methyl, alkanoyl, carbamoyl, mono(lower alkyl) carbamoyl, di(lower alkyl) carbamoyl, piperidinocarbonyl, piperazinocarbonyl, mor-pholinocarbonyl, thiamorpholinocarbonyl, pyrrolidinocarbonyl or 2-oxazolinyl, and salts thereof, whenever prepared according to the process claimed in claim 2 or by an obvious chemical equivalent thereof.
14. 14) Compounds according to claim 12, wherein n stands for 2, whenever prepared according to the process claimed in claim 3 or by an obvious chemical equivalent thereof.
15. 15) Compounds according to claim 12, wherein n stands for 2, and wherein R1, R2, R5, R6, R8, and R9 represent hydrogen and R3, R4, and R7 represent methyl, whenever prepared according to the process claimed in claim 4 or by an obvious chemical equivalent thereof.
16. 16) Compounds according to claim 15 wherein R10 represents a group of the formula -(CH=CH)mR11, whenever prepared according to the process claimed in claim 5 or by an obvious chemical equivalent thereof.
17. 17) Compounds according to claim 16, wherein m stands for zero, whenever prepared according to the process claimed in claim 6 or by an obvious chemical equivalent thereof.
18. 18) Compounds according to claim 17 wherein R11 repre-sents lower alkoxycarbonyl, lower alkylcarbamoyl, lower alkoxymethyl or lower alkanoyloxymethyl, whenever prepared according to the process claimed in claim 7 or by an obvious chemical equivalent thereof.
19. 19) p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl]-benzoic acid ethyl ester, whenever prepared according to the process claimed in claim 8 or by an obvious chemical equivalent thereof.
20. 20) p-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzyl acetate, whenever prepared according to the process claimed in claim 9 or by an obvious chemical equivalent thereof.
21. 21) p-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzyl methyl ether, whenever prepared according to the process claimed in claim 10 or by an obvious chemical equivalent thereof.
22. 22) p-[(E)-2-(5,6,6,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid monoethylamide, whenever prepared according to the process claimed in claim 11 or by an obvious chemical equivalent thereof.