JPH0217539B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula In the formula, n represents 1 or 2; Z represents mercapto or a group -S(O) _n R; m represents 0.1 or 2; R is lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, lower alkanoyl - lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower carbalkoxy-lower alkyl or, if m represents 1 or 2, also represents lower alkoxy, hydroxy or mono-lower alkylamino. The present invention relates to tetrahydronaphthalene and indane compounds and pharmaceutically compatible salts of sulfonic and sulfinic acids of the formula. Furthermore, the present invention relates to a process for the preparation of compounds of formula, intermediates in said process and pharmaceutical preparations based on compounds of formula. The term "lower" as used herein preferably refers to groups containing 1 to 4 C atoms. Alkyl groups can be straight or branched. Preferred lower alkyl groups are methyl, ethyl and isopropyl. Examples of lower alkenyl groups are vinyl, allyl and methallyl. Examples of lower alkanoyl groups are acetyl, propionyl and butyryl. The term "halogen" includes fluorine, chlorine, bromine and iodine, with chlorine being preferred. Examples of lower carbalkoxy-lower alkyl groups are carbomethoxy- and carboethoxy-methyl and -ethyl. Examples of lower alkoxy groups are methoxy and ethoxy. Examples of alkylamino groups are methylamino, ethylamino, isoproramino, dimethylamino and diethylamino. The pharmaceutically compatible salts provided herein can be, for example, alkali metal and alkaline earth metal salts and ammonium salts. In the compound of formula, R is lower alkyl, lower alkenyl, hydroxy-lower alkyl, halo-
When lower alkyl, lower carbalkoxy-lower alkyl or m represents 1 or 2,
Also lower alkoxy, hydroxy or mono-
Compounds representing lower alkylamino are preferred. Furthermore, preferred compounds of the formula are those in which n represents 2. Further preferred are compounds of the formula in which m represents 2 and compounds in which R represents lower alkyl, hydroxy, lower alkoxy, lower alkylamino, hydroxy-lower alkyl or lower carbalkoxy-lower alkyl. The following compounds are of particular interest: Ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfonate; [2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfone; ethyl p-[2-(5,6,7,8- Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl sulfoxide; Ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl) -2-naphthyl)propenyl]phenyl sulfide; isopropyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
naphthyl) propenyl] phenyl sulfone. According to the invention, compounds of formula (a) are of formula The compound with the formula In the formula, n has the above meaning, and Z' is -SO ₃ ^-
M ⁺ , -SO ₂ ^- M ⁺ represents lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, A is a formula

represents a triarylphosphonium methyl group of the formula and B represents formyl; A represents acetyl and B represents the formula

represents a dialkoxyphosphonylmethyl group of the formula; where Q represents aryl, T represents lower alkoxy, Y ^- represents an anion of an organic or inorganic acid, and M ⁺ represents a cation; React with a compound or (b) formula in which n has the meaning given above and X represents halogen, is reacted with sulfur dioxide in the presence of a strong base, or (c) The compound in which n has the abovementioned meaning and X' represents di-lower alkylcarbamoylthio is treated with a base or reduced with a complex metal hydride and, if necessary, It can be produced by functionally changing the group represented by Z in the compound of the formula obtained according to (a), (b) or (c). The reaction in process (a) can be carried out under conditions known per se for Wittig and Horner reactions. The reaction of a compound of the formula in which A represents a triarylphosphonium methyl group with a compound of the formula (Bitzteig reaction) is carried out using a strong base such as butyllithium, sodium hydride or the sodium salt of dimethyl sulfoxide in the presence of an acid binder. optionally a solvent such as an ether such as diethyl ether or tetrahydrofuran or an aromatic hydrocarbon such as benzene. ) at a temperature between room temperature and the boiling point of the reaction mixture. Q in the above triarylphosphonium group
The aryl group represented by includes all generally known aryl groups, but especially mononuclear aryl groups,
For example, phenyl, lower alkyl-substituted phenyl or lower alkoxy-substituted phenyl (e.g. tolyl, xylyl, mesityl or p-
methoxyphenyl). Among the inorganic acid anions Y, chloride ions,
Bromide ions and hydrosulfate ions are preferred, and among organic acid anions, tosyloxy ions are preferred. formula

The alkoxy group represented by T in the dialkoxyphosphonylmethyl group of formula is preferably a lower alkoxy group containing 1 to 6 carbon atoms (eg methoxy or ethoxy). The reaction between a compound of the formula in which A represents acetyl and a compound in which B represents a dialkoxyphosphonylmethyl group (Horner reaction) is carried out using a base, preferably in the presence of an inert organic solvent, such as benzene, toluene, with sodium hydride in dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyalkanes,
Alternatively, it is carried out using sodium alcoholate in an alkanol, such as sodium methylate in methanol, at a temperature between 0° and the boiling point of the reaction mixture. Following process (a), compounds of the formula are obtained in which Z represents one of the groups represented by Z'. According to process (b), a compound of the formula in which X represents halogen, preferably bromine, is treated with a strong base such as butyllithium and reacted with sulfur dioxide. The reaction may be carried out in an inert organic solvent, for example an ether such as diethyl ether, or a hydrocarbon such as hexane, or a mixture thereof, advantageously at a temperature below room temperature (for example about 0°C).
Process (b) gives rise to salts of sulfinic acids of the formula, ie compounds of the formula in which Z represents the group -SO ₂ ^- M ⁺ . According to method (c), a compound of formula is treated with a base or reduced with a complex metal hydride. Suitable bases are, for example, alkali metal hydroxides such as potassium hydroxide. This treatment is preferably carried out in an inert solvent with an alcoholic alkali hydroxide solution at a temperature up to the reflux temperature of the mixture, yielding compounds of the formula in which Z represents mercapto. Suitable complex metal hydrides are those known for reducing esters to alcohols, especially lithium aluminum hydride. This reaction is carried out under conditions known for such ester reductions, for example in a solvent such as diethyl ether or tetrahydrofuran.
It can be carried out at a temperature of 0° to the reflux temperature of the mixture. Conversion of a sulfonate or sulfinate to the corresponding free acid or ester as a fuuctional modification of the group represented by Z in compounds of formula; mono-lower alkyl amides of sulfonic or sulfinic acids. or conversion to di-lower alkyl amides; conversion of sulfinates to sulfones; oxidation of sulfides to sulfoxides and oxidation of sulfoxides to sulfones; conversion of hydroxy lower alkyl groups to halo-lower alkyl groups and lower Substitution of moieties into alkenyl groups; as well as alkylation of mercaptans to alkyl sulfides or Michael additions with suitable Michael acceptors such as methyl acrylate or methyl vinyl ketone are conceivable. A sulfonate or sulfinate, i.e. a compound of the formula in which Z represents -SO ₃ ^- M ⁺ or -SO ₂ ^- M ⁺ , is treated with an acid (e.g. an inorganic acid such as hydrochloric acid) to form the corresponding sulfonic or sulfinic acid,
That is, it can be converted into a compound of the formula in which Z represents SO ₃ H or SO ₂ H. Amides of sulfonic or sulfinic acids, i.e. Z is mono- or di-
The conversion into compounds of the formula lower alkyl-sulfonyl or -sulfinyl can be carried out in a manner known per se, for example by converting the acid into an acid halide (e.g. with thionyl chloride) and converting the acid halide into a mono-lower alkylamide or di- - It can be carried out by reacting with a lower alkylamine. Esters, ie compounds of the formula in which Z represents lower alkoxy-sulfonyl or sulfinyl, may be prepared using an alkylating agent such as triethoxonium tetrafluoroborate or a dialkyl sulfate (e.g. dimethyl sulfate or diethyl sulfate).
sulfonates or sulfinates, ie compounds of the formula in which Z represents -SO ₃ ^- M ⁺ or -SO ₂ ^- M ⁺ . Oxidation of sulfides, ie compounds of the formula in which Z represents lower alkylthio, to form the corresponding sulfoxides (Z=lower alkylsulfinyl) and the oxidation of the sulfoxides to the corresponding sulfones (Z=lower alkylsulfonyl) can be carried out using an oxidizing agent such as This can be done by treatment with a peracid (for example m-chloroperbenzoic acid). Sulfides can also be oxidized to sulfoxides by periodides (eg sodium periodate). Lower alkyl thioether or lower alkyl sulfoxide or -sulfone [Z=-S
(O) _nR , R=lower alkyl] is, for example, a lower alkyl compound (e.g. lower alkyl-sulfone)
is treated with a strong base (e.g. butyllithium) and the metal-organic compound is reacted with a lower carbalkoxy-lower alkyl halide (e.g. ethyl chloroacetate) or with an alkanoylating agent such as an alkanecarboxylic acid ester or an alkanoyl halide to produce the corresponding reaction. lower carbalkoxy
It can be converted into lower alkyl derivatives, ie compounds of the formula in which Z represents -S(O) _n R and R represents lower carbalkoxy-lower alkyl. Hydroxy-lower alkyl thioethers, -sulfoxides or -sulfones can be prepared by replacing the hydroxy group with a halogen atom (e.g. using a halogenating agent such as thionyl chloride) to form the corresponding halo-lower alkyl derivative [Z=-S(O) _n R, R=halo-lower alkyl], from which, upon treatment with a base (e.g. an amine such as triethylamine), a lower alkenyl thioether or lower alkenyl sulfoxide or -sulfone [Z=-S(O ) _n R, R = lower alkenyl]
can be obtained. Starting materials of the formulas, , and can be prepared in analogy to known methods or methods described below, even if the method for their preparation is unknown or not described below. and its pharmaceutically compatible and pharmacologically valuable compounds. The compounds can be used for the local and systemic treatment of benign and malignant neoplasms and pre-malignant lesions and for the systemic and local prevention of these conditions. The compounds are also suitable for the local and systemic treatment of acne, psoriasis and other dermatoses associated with enhanced or pathologically altered keratinization, as well as inflammatory and allergic dermatological conditions. ing. The compounds of formula and their pharmaceutically compatible salts can also be used for the inhibition of mucosal disorders associated with inflammation or degenerative or dysplastic changes. Compounds of the formula belonging to the retinoid class are distinctive in contrast to known retinoids, for example in experimental animals, where administration of retinoids results in a small amount of weight loss, which often occurs as a side effect (A-hypervitaminosis). The tumor-suppressing activity of this compound is significant. In a papilloma test in mice [Europ.J.
Cancer 10, 732 (1974)] Regression of tumors induced by dimethylbenzanthracene and perilla oil is observed. For example, ethyl p-[2-(5,6,7,8-
Tetrahydro-5,5,8,8-tetramethyl-
When 2-naphthyl)propenyl phenyl sulfone was administered intraperitoneally, the diameter of papillomas decreased by 56% and 6.25 mg/kg over 2 weeks at a dosage of 12.5 mg/Kg/week.
It was reduced by 36% at a dosage of Kg/week and by 12% at a dosage of 3mg/Kg/week. In treating the above-mentioned diseases, the compounds provided by the present invention are advantageously administered orally in dosages of about 5 to 200 mg/day, preferably 10 to 50 mg/day for adults. be able to. Possible overdosage itself represents a condition of vitamin-A hypervitaminosis, which is easily recognized by its symptoms (scaling, hair loss). The results of the papilloma test and the determination of tamine A excess for some of the compounds of the formula of the invention are shown in the table below. The compounds used in the test are as follows. A: Ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
naphthyl)propenyl] phenyl sulfone, B: ethyl p-[2-(1,1,3,3-tetramethyl-5-indanyl)propenyl] phenyl sulfone, C: ethyl p-[2-(5,6 ,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
naphthyl)propenyl]phenyl sulfide, D: ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
naphthyl)propenyl]benzenesulfinate.

【table】

[Table] Additionally, the toxicity of the compounds of the present invention is extremely low;
For example, the acute toxicity of Compound A above is >8000 mg/Kg po and >4000 mg/Kg ip in mice. The method for measuring this acute toxicity is as follows. [Toxicity test method] Animals used: Fu¨ (Füllinsdorf), supplied from the animal breeding farm of the applicant company (Füllinsdorf/B1, CH-4414, facility of the Biologics-Medicine-Fürschung Aktiengesellschaft). ) Strain-specific pathogen-free (SPF) male white mice were used for these experiments. These mice weighed 18-20 g on the day of administration. The animals were kept in an air-conditioned animal room for 24 hours. The room temperature is 21±1℃, and the relative humidity is
It was 65±6%. There are 12 light/dark cycles in a day:
It was hot for 12 hours. All animals were fed a standard diet of pellets (NAFAG Gossau SG, Switzerland, No. 850)
and tap water provided ad libitum. Animals were allowed a minimum of 1 day to acclimate to the test facility prior to treatment. During the observation period, animals were housed in groups of four in type 2 Macrolone cages. Four animals were used per dose level. Animals were fasted overnight before administration. Drug Administration Test compounds substantially insoluble in water were suspended in rapeseed oil. Administration was by intraperitoneal (ip) injection and orally (po). A constant dosing volume of 50ml/Kg was used. Maximum dosage is 4000mg/Kgi.p. and 8000
mg/Kgp.o. Observations: Dosed animals were observed for clinical signs and mortality for 30 days following dosing. The dosage can be administered in a single dose or in divided doses. Accordingly, the compounds of the formula and their pharmaceutically compatible salts can be used as medicaments, eg in the form of pharmaceutical preparations. Pharmaceutical preparations for systemic use are prepared, for example, by incorporating as the active ingredient a compound of formula, or a pharmaceutically compatible salt thereof, into a non-toxic, inert solid or liquid carrier normally employed in such preparations. be able to. Pharmaceutical preparations can be administered enterally, parenterally or topically. For enteral administration, pharmaceutical preparations in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories are suitable, for example. For parenteral administration, pharmaceutical preparations in the form of infusion or injection solutions are suitable. The dosage at which the compounds are administered can vary depending on the method and route of administration and according to the needs of the patient. Compounds provided by the invention can be administered in one or more dosages. Preferred dosage forms consist of capsules containing about 5, 20 or 50 mg of active substance. Pharmaceutical preparations can contain inert as well as pharmacologically active additives. Tablets or granules can contain, for example, a series of binders, filler substances, carrier substances or diluents. Liquid preparations can take the form of sterile solutions that are miscible with water, for example. In addition to the active substance, capsules contain a filler or thickening agent.
can be included. Furthermore, flavor-improving additives, substances commonly used as preservatives, stabilizers, moisture retainers and emulsifiers, as well as salts, buffers and other additives for modifying osmotic pressure may be present. The carrier materials and diluents mentioned above may be organic or inorganic in nature, such as water, gelatin, lactose, solids, magnesium stearate, talc,
It can be gum arabic, polyalkylene glycol, etc. It is firstly necessary that all adjuvants used in the manufacture of pharmaceutical preparations be non-toxic. For topical administration, the pharmaceutical preparations are advantageously used in the form of ointments, tinctures, creams, solutions, lotions, syrups, suspensions, and the like. Ointments, creams and solutions are preferred. These pharmaceutical preparations for topical administration mix the compound provided by this invention as the active ingredient with a non-toxic, inert solid or liquid carrier commonly used in such preparations and suitable for topical administration. It can be manufactured using For topical administration, it is advantageous to use about 0.05 to about 5%, preferably 0.1% to 1% solutions, ointments or creams. If desired, antioxidants can be included in the drug preparation, such as tocopherol, N-methyl-gamma-tocopheramine, butylated hydroxyanisole or butylated hydroxytoluene. The following examples further illustrate the invention. Example 1 Sodium hydride (50% suspension in mineral oil) 4.05
g was washed with anhydrous pentane, dried under water pump vacuum and suspended in 100 ml of dimethylformamide. This was added to [1-(5,6,7,8
A suspension of 43 g of -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide was added dropwise, and the mixture was stirred at 0°C for 1 hour. At the same temperature, a suspension of 16 g of the sodium salt of p-formyl-benzenesulfonic acid in 200 ml of dimethylformamide was added dropwise to the deep red solution thus obtained. After stirring for 3 hours at room temperature, the brown-red solution was poured onto ice and
Evaporate to dryness under water pump vacuum. The crystalline gray residue was suspended in ethyl acetate, suctioned off and washed several times with ethyl acetate. The residue was recrystallized twice from boiling water to obtain sodium p-[2-(5,6,7,8-tetrahydro-5,
10 g of 5,8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfonate was obtained. Example 2 2.0 g of sodium sulfonate obtained according to Example 1 were suspended in 70 ml of half-strength hydrochloric acid, warmed briefly and cooled in an ice bath. The precipitate was suctioned off, washed with half-concentration hydrochloric acid and water, and placed under high vacuum.
Dry at 50°C. p- with melting point 103-110℃ (decomposition)
[2-(5,6,7,8-tetrahydro-5,5,
1.9 g of 8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfonic acid was obtained. Example 3 4.8 g of sodium sulfonate obtained according to Example 1 was suspended in 50 ml of dimethylformamide,
Treated with 2.0 g of thionyl chloride. After stirring for 0.5 hour at room temperature, 15 ml of ethylamine were added to the yellow suspension and the mixture was stirred for a further 1 hour at room temperature.
The mixture was poured into water and extracted with ethyl acetate.
The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. A brown oil was obtained which was passed over a short column containing silica gel with a mixture of hexane and ether (1:) and then recrystallized from hexane/ether. N-ethyl-p-[2] with a melting point of 137-138°C
-(5,6,7,8-tetrahydro-5,5,8,
8-tetramethyl-2-naphthyl)propenyl]
1.6 g of benzenesulfonamide [colorless crystals] was obtained. Example 4 1.5 g of sodium sulfonate obtained according to Example 1 were suspended in 120 ml of methylene chloride and treated with a solution of 760 mg of triethyloxonium tetrafluoroborate in 15 ml of methylene chloride. The mixture was stirred at room temperature for 45 minutes, the precipitate was suctioned off, washed with ether and the liquid was evaporated. After recrystallization from isopropyl ether, melting point 155 ~
Ethyl p-[2-
(5,6,7,8-tetrahydro-5,5,8,
8-tetramethyl-2-naphthyl)propenyl]
1.3 g of benzene sulfonate was obtained. Example 5 6-(p-bromo-α-methylstyryl)-1,
13.0 g of 2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene was dissolved in 300 g of anhydrous ether.
Dissolved in ml. To this was added dropwise 20 ml of a 2N solution of butyllithium in hexane while cooling with ice.
The mixture was stirred for an additional 1.5 hours at 0°C. A strong stream of sulfur dioxide was then introduced into the mixture for 30 minutes and then poured into a mixture of water and saturated sodium carbonate solution. The aqueous suspension thus obtained was extracted twice with ether, the aqueous solution was filtered,
The colorless precipitate was dried at 80°C under high vacuum. After recrystallization from boiling water, melting point 312-320℃ (decomposed)
Sodium p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfinate
7.1g was obtained. 6-(p-bromo-α-
methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene could be prepared as follows: [1-(5,6,7,8- Tetrahydro-5,
5,8,8-tetramethyl-2-naphthyl)ethyl triphenylphosphonium bromide 50g
was heated under reducing reflux for 3 hours with 13.9 g of p-bromobenzaldehyde in 400 ml of butylene oxide. The mixture was cooled, poured into 500 ml of methanol/water (6:4) and extracted three times with hexane. The organic phase was washed twice with water, dried over sodium sulphate and evaporated. The yellow-orange oil thus obtained was recrystallized from ethyl acetate and had a melting point of 133.
6-(p-bromo-α-
14.5 g of methylstyryl-1,2,3,4-tetramethylnaphthalene was obtained. Example 6 8.5 g of sodium sulfinate obtained according to Example 5 was suspended in 350 ml of anhydrous methylene chloride,
It was treated with a solution of 4.6 g of triethyloxonium tetrafluoroborate in 20 ml of methylene chloride while cooling on ice. The mixture was stirred for 2 hours at +5°C, the precipitate was suctioned off, backwashed with methylene chloride and the liquid was evaporated. After filtration of the colorless oil over silica gel using hexane/ether 4:1 as eluent and crystallization from hexane/ether, ethyl p.
-[2-(5,6,7,8-tetrahydro-5,
4.8 g of 5,8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfinyl was obtained. Example 7 2.5 g of sodium sulfinate obtained according to Example 5 were suspended in 60 ml of anhydrous dimethylformamide and treated with 1.0 g of ethyl iodide. The mixture was stirred for about 6 hours until a clear yellowish solution was obtained. This solution was diluted with plenty of water and extracted with ethyl acetate. The organic phase was washed several times with water, dried over sodium sulphate and evaporated. Melting point 158-161 after recrystallization from hexane/ethyl acetate
Ethyl p-[2-(5,
1.9 g of 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfone was obtained. In a similar manner as above, from sodium p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfinate and methyl iodide , methyl p with a melting point of 176-178℃
-[2-(5,6,7,8-tetrahydro-5,
5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfone was obtained; sodium p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- From 2-naphthyl)propenyl]benzenesulfinate and allyl bromide, allyl p-[2-(5,6,7,8-tetrahydro-
5,5,8,8-tetramethyl-2-naphthyl)
Sodium p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfinate and 2, From 2,2-trifluoroethyl iodide, 2,2,2-trifluoroethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8- Tetramethyl-2-naphthyl)propenyl]phenylsulfone was obtained. Example 8 [1-(5,6,7,8-tetrahydro-5,
18.1 g of 5,8,8-tetramethyl-2-naphthyl)ethyl triphenylphosphonium bromide
under reflux with 5.0 g of p-ethylsulfonyl-benzaldehyde in 250 ml of butylene oxide.
heated for an hour. The mixture was cooled, poured into 500 ml of methanol/water (6:4) and extracted three times with hexane. The organic phase was washed with water, dried over sodium sulphate and evaporated. the crude product,
It was filtered over silica gel using hexane/ethyl acetate (1:1) as eluent and recrystallized from hexane/ethyl acetate. Ethyl p-[2-(5,6,7,8-
Tetrahydro-5,5,8,8-tetramethyl-
2-naphthyl)propenyl phenyl sulfone
9.2g was obtained. p-ethylsulfonyl used as starting material
Benzaldehyde was prepared as follows: Sodium hydride (50% suspension in mineral oil) 7.8
g was washed with anhydrous pentane, dried under water pump vacuum and suspended in 100 ml of dimethylformamide. To this was added dropwise 11.3 g of ethyl mercaptan while cooling with ice, the mixture was stirred at room temperature for 1 hour, and then 100 ml of dimethylformamide was added to the mixture.
4-bromobenzaldehyde in the solution was added dropwise. Ten
After minutes, the mixture was poured onto ice and extracted with ethyl acetate. The organic phase was washed with 2N hydrochloric acid and water, dried over sodium sulphate and evaporated. The oily residue was filtered over silica gel using hexane/ether (4:1) as eluent.
17.5 g of 4-thioethylbenzaldehyde was obtained as a pale light yellow oil. 10 g of 4-thioethylbenzaldehyde was dissolved in 150 ml of methylene chloride and treated in portions with 22 g of m-chloroperbenzoic acid while cooling on ice. The mixture was diluted with methylene chloride, extracted twice with ice-cold potassium carbonate solution and water, dried over sodium sulphate and evaporated. 4-Ethylsulfonyl-benzaldehyde 9.1 as colorless crystals with a melting point of 107-109 °C after recrystallization from hexane/ether.
I got g. Example 9 Analogously to the method described in Example 8, 1-(1,1,3,3-tetramethyl-5-indaniel)ethyl-triphenylphosphonium bromide and 4-ethylsulfonylbenzaldehyde, melting point 125 Ethyl p-[2-
(1,1,3,3-tetramethyl-5-indanyl)propenyl]phenylsulfone was obtained; [1-(5,6,7,8-tetrahydro-5,
5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide and 4
-n-propylsulfonyl-benzaldehyde to propyl p-[2-(5,
6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfone was obtained;
5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide and 4
- from isopropylsulfonylbenzaldehyde to isopropyl p-[2-
(5,6,7,8-tetrahydro-5,5,8,
8-tetramethyl-2-naphthyl)propenyl]
Phenyl sulfone was obtained; [1-(5,6,7,8-tetrahydro-5,
5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide and 4
- from isobutylsulfonylbenzaldehyde,
1-Methylpropyl p-[2-
(5,6,7,8-tetrahydro-5,5,8,
8-tetramethyl-2-naphthyl)propenyl]
Phenyl sulfone was obtained; [1-(5,6,7,8-tetrahydro-5,
2-[[p-
[2-(5,6,7,8-tetrahydro-5,5,
[1-(5,6,7,8-tetrahydro-5,
5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide and 4
- From ethylthio-benzaldehyde, melting point 88 ~
[1-(5 ,6,7,8-tetrahydro-5,
From 5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 4-methylthiobenzaldehyde, melting point 119
Methyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2
-naphthyl)propenyl]phenyl sulfide was obtained. The benzaldehyde derivative is prepared by reacting p-bromobenzaldehyde with the corresponding mercaptan as described in Example 8, and then converting the reaction product into m
- It could be produced by oxidation with chloroperbenzoic acid. Example 10 Ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl sulfide was dissolved in 150 ml of methylene chloride, and 0 m- within 6 hours at °C
Treated with 3 g of chloroperbenzoic acid. The mixture was stirred for a further 2 hours at 0° C., diluted with methylene chloride, washed twice with ice-cold potassium carbonate solution and water, dried over sodium sulfate and evaporated. Hexane/ethyl acetate (4:
After chromatography on silica gel using 1) and recrystallization from hexane/ethyl acetate, ethyl p-[2-(5,6,
3.1 g of 7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl phenyl sulfoxide was obtained. In the same manner as above, methyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl sulfide and m-
From chloroperbenzoic acid, methyl p-[2-(5,6,7,8-tetrahydro-5,
5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl sulfoxide is obtained; and methyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthyl)propenyl] phenyl sulfoxide and m-
From chloroperbenzoic acid, methyl p-[2-(5,6,7,8-tetrahydro-5,
5,8,8-tetramethyl-2-naphthyl)propenyl phenyl sulfone was obtained. Example 11 6.0 g of 2-[[p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]sulfonyl]ethanol and 150 ml of tetrahydrofuran dissolved in
After addition of 1 ml of pyridine, the mixture was treated slowly with 1.7 g of phosphorus tribromide while cooling on ice. After 15 minutes, the mixture was poured into ice/water and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulphate and evaporated. The brownish oil thus obtained was dissolved in 200 ml of tetrahydrofuran and, after addition of 70 ml of triethylamine, the mixture was heated to 60° C. for 6 hours. The mixture was poured into ice/water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated. After filtration over silica gel using hexane/ethyl acetate (4:1) as eluent and crystallization from hexane/ethyl acetate, the melting point was 130.
~132°C vinyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2
−naphthyl)propenyl] phenyl sulfone 2.5
I got g. Example 12 2-[[p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]sulfonyl]ethanol 4.5g to 50ml acetonitrile Dissolve and treat with 4 g of triphenylphosphine and 10 ml of carbon tetrachloride. After boiling under reflux for 4 hours, add 2 g of triphenylphosphine and 2 ml of carbon tetrachloride.
was added and the mixture was heated under reflux for a further 3 hours.
The mixture was cooled, poured into water, extracted with ethyl acetate, dried and evaporated. After chromatography on silica gel using hexane/ethyl acetate (4:1) as eluent and crystallization from pentane/ether, the 2-
2.2 g of chloroethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfone was obtained. Example 13 5.3 g of methyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfone was dissolved in 100 ml of anhydrous tetrahydrofuran, Treated with 9 ml of a 2M solution of butyllithium in hexane at -75°C. After stirring at −75° C. for 30 minutes, 1.8 ml of ethyl chloroacetate was added thereto and the mixture was stirred for a further 2 hours at room temperature. The mixture was poured into ice/water, extracted with ethyl acetate, dried and evaporated. After filtration over silica gel using hexane/ethyl acetate (4:1) as eluent and crystallization from hexane/ethyl acetate, ethyl [[p-[2-(5,6 ,7,8-tetrahydro-
5,5,8,8-tetramethyl-2-naphthyl)
propenyl phenyl sulfonyl acetate
2.5g was obtained. Example 14 [1-(5,6,7,8-tetrahydro-5,
5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide 99g
was heated under reflux with 25.2 g of S-(p-formylphenyl)dimethylthiocarbamate in 1 part of butylene oxide for 40 hours. The mixture was cooled, poured into 1 methanol/water (6:4) and extracted three times with hexane. The organic phase was washed with water, dried over sodium sulphate and evaporated. The crude product was filtered over silica gel using hexane/ethyl acetate (4:1) as eluent and recrystallized from ethyl acetate/hexane. Melting point 107~109
S-[p-[2-(5,6,
7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]
39 g of dimethylthiocarbamate was obtained. S-(p-formylphenyl)dimethylthiocarbamate used as starting material (melting point 78-80
℃) MS Newmann and HA Karnes in J.
It could be produced from p-hydroxybenzaldehyde via O-(p-formylphenyl)dimethylthiocarbamate (melting point 94-96°C) according to the method described in Org.Chem.31, 3980 (1966). Example 15 500 mg of lithium aluminum hydride was suspended in 10 ml of tetrahydrofuran, and S-[p-[2-(5,6,
7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]
A solution of 5 g of dimethylthiocarbamate was added dropwise. After stirring for 2 hours at room temperature, the excess lithium aluminum hydride was decomposed by addition of water with ice cooling, the solution was acidified with 1N hydrochloric acid and the mixture was extracted with ether. The ether phase was washed neutral with water, dried over sodium sulphate and evaporated. p-[2 as colorless oil
-(5,6,7,8-tetrahydro-5,5,8,
8-tetramethyl-2-naphthyl)propenyl]
3.5 g of thiophenol was obtained, which is extremely sensitive to oxidation and could be crystallized from hexane/ether, melting point 97-98°C. Example 16 Sodium hydride (50% suspension in mineral oil) 500
mg was washed with anhydrous pentane, dried under water pump vacuum and suspended in 10 ml dimethylformamide. To this was added 3.3 g of p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]thiophenol in 5 ml of dimethylformamide while cooling on ice. The solution was added dropwise. After stirring at 0° C. for 1 hour, 3 g of ethyl iodide was added dropwise thereto, and the mixture was allowed to reach room temperature and stirred for a further 3 hours. The solution was poured onto ice and extracted with ether. The organic phase was washed with 2N hydrochloric acid and water, dried over sodium sulphate and evaporated. The crude product was filtered over silica gel using hexane/ethyl acetate as eluent and recrystallized from hexane. 2.7 g of ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl sulfide having a melting point of 88-89 DEG C. was obtained. Example 17 p-[2-(5,6,7,8-tetrahydro-
5,5,8,8-tetramethyl-2-naphthyl)
Propenyl] Dissolve 3.5 g of thiophenol in 20 ml of dimethylformamide, and dissolve methyl acrylate 4
It was treated with g. After adding a few drops of triethylamine,
This mixture was stirred at 60°C for 2 hours. After cooling, the mixture was poured into ice/water, extracted with ether, washed with water, dried and evaporated. The crude product was filtered over silica gel using hexane/2% ethyl acetate as eluent and crystallized from hexane/ether. Methyl 3- with melting point 90-92℃
[[p-[2-(5,6,7,8-tetrahydro-
5,5,8,8-tetramethyl-2-naphthyl)
Propenyl phenyl thio propionate
3.1g was obtained. The product obtained according to the above section was oxidized with m-chloroperbenzoic acid and methyl 3-
[[p-[2-(5,6,7,8-tetrahydro-
5,5,8,8-tetramethyl-2-naphthyl)
Propenyl]phenyl]sulfonyl]propionate was obtained. Example 18 3.9 g of ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfone was dissolved in 20 ml of tetrahydrofuran, and - Treated with 5.5 ml of a 2M solution of butyllithium in hexane at 78°C.
After 15 minutes, 370 mg of methyl acetate was added to this. After stirring for 30 minutes at −78°C, add 2.75 ml of butyllithium.
After 15 minutes, add 185 mg of methyl acetate to this mixture.
Processed with. After another 30 minutes, butyllithium solution
The same operation was repeated by adding 1.4 ml and 93 mg of methyl acetate. The mixture was allowed to reach room temperature, poured into ice/water and extracted with ether. After drying and evaporating the organic phase, the residue is crystallized from ethyl acetate/hexane to give a
-[[p-[2-(5,6,7,8-tetrahydro-
5,5,8,8-tetramethyl-2-naphthyl)
2.6 g of propenyl[phenyl]sulfonyl]-2-butanone was obtained. Methyl p-[2-
(5,6,7,8-tetrahydro-5,5,8,
8-tetramethyl-2-naphthyl)propenyl]
From phenyl sulfone and ethyl acetate, melting point 140
~141°C 1-[[p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2
-naphthyl)propenyl]phenyl]sulfonyl]-2-propanone is obtained. Example 19 Sodium p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfinate was suspended in 150 ml of benzene and chloro Treated with 1.3 g of methyl methyl ether. After heating to 85°C for 8 hours, the solvent was removed by evaporation and the oily residue was eluted with hexane/ethyl acetate (9:
1) on silica gel. After recrystallization from hexane/ethyl acetate, methyl [[p-[2-(5,
1.1 g of 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]sulfonyl]methyl ester was obtained. Example 20 Sodium p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfinate 4
g was suspended in a mixture of 80 ml of ethanol and 750 mg of acetic acid. Add this mixture to methyl vinyl ketone 750
mg and stirred at room temperature for 20 hours. The mixture was then washed with water, extracted with ether, dried and
and evaporated. After recrystallization from hexane/ethyl acetate, 4-[[p-[2
-(5,6,7,8-tetrahydro-5,5,8,
8-tetramethyl-2-naphthyl)propenyl]
3.5 g of phenyl]sulfonyl]-2-butanone was obtained. Reference Example A It was possible to prepare an ointment containing 1% of active substance from the following ingredients: Active substance, for example ethyl p-[2-(5,6,
7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl phenylsulfone 1.0g Vaseline, white 35.0g Wax, white 4.0g Paraffin oil, viscosity 18.0g DEHYMULS E* 7.0 g Benzoic acid 0.2 g Water, deionized water Added 100.0 g *High molecular weight aliphatic ester; provided by: Deutsche Hydrierwerke Reference example B It was possible to prepare an ointment containing 0.1% of active substance from the following ingredients: Active substance , for example ethyl p-[2-(5,6,
7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl phenylsulfone 0.1g Vaseline, white 35.0g Wax, white 10.0g Paraffin oil, viscous 18.0g Dehimalus 7.0g Benzoic acid 0.2 g water, deionized water added 100.0 g Reference example C A suspension ointment could be prepared from the following ingredients: Active substance, e.g. ethyl p-[2-(5,6,
7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl phenylsulfone 0.3g Paraffin oil, viscous 36.7g Vaseline, white 45.0g LUNACERA M* 15.0g Castor oil, Solid 3.0g *Hydrocarbon wax; Provided by: Luneburger Wachsbleiche

Claims (1)

[Claims] 1 formula In the formula, n represents 1 or 2; Z represents mercapto or a group -S(O)mR, and m represents 0,1
or 2; R represents lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, lower alkanoyl-lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower carboalkoxy-lower alkyl, or m represents 1 or 2; also represents lower alkoxy, hydroxy or mono-lower alkylamino, as well as compounds of the formula
= SO ₃ H) or sulfinic acid (Z = SO ₂ H). 2 R is lower alkyl, lower alkenyl, hydroxy-lower alkyl, halo-lower alkyl, lower carbalkoxy-lower alkyl, or m is 1
or 2, it also represents lower alkoxy, hydroxy or mono-lower alkyl. 3 Claim 1 or 2 in which n represents 2
Compounds described in Section. 4 Claim 1 in which Z represents a group -SO ₂ R
The compound according to any one of items 1 to 3. 5. Claims 1 to 4 in which Z represents the group -S(O)mR and R represents lower alkyl, hydroxy, lower alkoxy, lower alkylamino, hydroxy-lower alkyl or lower carbalkoxy-lower alkyl. A compound according to any one of. 6. The compound according to claim 1, which is ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzenesulfonate. 7. The compound according to claim 1, which is ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl sulfone. . 8 The compound according to claim 1 which is ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl sulfoxide . 9 Ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl sulfide according to claim 1 Compound. 10 Isopropyl p-[2-(5,6,7,8-
Tetrahydro-5,5,8,8-tetramethyl-
The compound according to claim 1, which is 2-naphthyl)propenyl] phenyl sulfone. 11 formula The compound with the formula In the formula, n represents 1 or 2, and Z' is -SO ₃ ^-
M ⁺ , -SO ₂ ^- M ⁺ represents lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl, A represents a triarylphosphonium methyl group of the formula [formula] and B represents formyl; A is acetyl and B represents a dialkoxyphosphonylmethyl group of the formula; where Q represents aryl, T represents lower alkoxy, Y ^- represents an anion of an organic or inorganic acid, and M ⁺ represents a cation, the formula is characterized in that it is reacted with a compound of In the formula, n and Z' have the above meanings. 12 formula wherein n represents 1 or 2 and X represents halogen, the compound of the formula is reacted with sulfur dioxide in the presence of a strong base. In the formula, Z'' represents a lower alkyl sulfinate, and n has the above meaning. A method for producing a compound of formula 13. wherein n represents 1 or 2 and X' represents di-lower alkylcarbamoylthio, the compound of the formula is treated with a base or reduced with a complex metal hydride. In the formula, Z represents mercapto and n has the above meaning.