JPH0512336B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to phenylethylene derivatives, processes for their preparation and therapeutic agents containing the compounds and the use of the compounds for the treatment of diseases. It is known from DE 28 54 354 A1 that stilbene derivatives have a pharmacological action in the topical and systematic treatment of isomerogenesis, acne, psoriasis and other dermatological diseases. However, the pronounced toxic (side) effects of this compound are a particular drawback, which makes it suitable as a topical and systematic treatment for heterogeneous histogenesis, acne, psoriasis and other dermatological diseases. is not considered. The disadvantages of the stilbene derivatives described in German Pat.
~254 (1981) and reported in particular by R.C. Moon et al. in Cancer Research vol. 39, pp. 1339-1346 (1979). This is clear after several applications to similar animals.The object of the present invention was to provide a compound which exhibits similar effects, but with fewer toxic side effects.The present invention provides compounds of the formula: [In the formula, A represents a methylene or ethylene group optionally substituted with a _C1 - _C4 -alkyl group, ^R1 represents a hydrogen atom or a methyl group, and ^R2 represents a hydrogen atom or a methyl group. R ³ represents a hydrogen atom or a C _1-8 -alkyl group, R ⁴ represents a C _1-4 -alkyl group, and R ⁵ represents a p-hydroxyphenyleneaminocarbonyl group, tetrazol-5-ylaminocarbonyl or, when R ³ represents a C _1-8 -alkyl group, also represents a carboxyl group or ^a C _2-4 -carbalkoxy group] and optionally its physiologically acceptable derivatives _. Regarding salts with bases. A is preferably a methylene group or an ethylene group, optionally substituted by a methyl group. Of particular interest are compounds in which the phenyl rings are in trans position with respect to each other. The c-c bond shown in wavy form can extend to the front or back side of the drawing, thus forming a cis-(Z-)-
or trans-(E)-compounds. Typical examples of compounds of the invention are: 4-[2-methyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,6-trimethyl-1,2,3,4-tetrahydro) Naphtho-7-
yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,6-trimethyl-1,2,3,4-tetrahydronaphtho-7-
yl)-vinyl]-benzoic acid ethyl ester 4-[2-ethyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester 4-[2-ethyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1, 2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1,2, 3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-
Tetrahydronaphth-7-yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-
Tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphtho) -7-yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl) )-vinyl]-benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)- Vinyl]-benzoic acid methyl ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl] -Benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid Acid 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methyl-6-(2-methylpropyl)-1,2,3,4-tetrahydronaphtho-7) -yl)-vinyl]-benzoic acid ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methyl-propyl)-1,
2,3,4-tetrahydronaphth-7-yl)-
Vinyl]-benzoic acid 4-[2-methyl-2-(1,1,3,4,4,
6-hexamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester 4-[2-methyl-2-(1,1,3,4,4,
6-hexamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,2,3,3,
5-hexamethyl-indan-6-yl)-vinyl]-benzoic acid ethyl ester 4-[2-methyl-2-(1,1,2,3,3,
5-hexamethyl-indan-6-yl)-vinyl]-benzoic acid propyl ester 4-[2-methyl-2-(1,1,2,3,3,
5-hexamethyl-indan-6-yl)-vinyl]-benzoic acid isopropyl ester 4-[2-methyl-2-(1,1,2,3,3,
5-hexamethyl-indan-6-yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,3,3,5-
Pentamethyl-indan-6-yl)-vinyl]-
Benzoic acid 4-[2-methyl-2-(1,1,3,3,5-
Pentamethyl-indan-6-yl)-vinyl]-
Benzoic acid methyl ester 4-[2-methyl-2-(1,1,3,3,5-
Pentamethyl-indan-6-yl)-vinyl]-
Benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid methyl ester 4-[2-methyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid propyl ester 4-[2-ethyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester 4-[2-ethyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid 4-[2-ethyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid methyl ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-n- Butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-n-octyl- 1, 2, 3, 4-
Tetrahydronaphth-7-yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,6-trimethyl-1,2,3,4-tetrahydronaphtho-7-
yl)-vinyl]-benzoic acid 4-[2-methyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N- (Tetrazole-5
-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-tetrazole-
5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl ]-N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-
Tetrahydronaphth-7-yl)-vinyl]-N-
(Tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,2,3,3-
Pentamethyl-indan-6-yl)-vinyl]-
N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,3,3-tetramethyl-indan-6-yl)-vinyl]-N-
(Tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl )-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methyl-propyl)-1 ，
2,3,4-tetrahydronaphth-7-yl)-
vinyl]-N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydro Naphth-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide 4-[2-ethyl-2-(1,1,4,4-tetramethyl-1,2,3, 4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazole-5
-yl)-benzoic acid amide 4-[2-ethyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1-dimethyl-
1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl)-
Benzoic acid amide 4-[2-methyl-1,1,6-trimethyl-
1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5-yl)-
Benzoic acid amide 4-[2-methyl-2-(1,1,3,3,5-
Pentamethyl-indan-6-yl)-vinyl]-
N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,2,3,3,
5-hexamethyl-indan-6-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-1, 2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1,1,4,4-tetramethyl) -6-ethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-
(4-hydroxyanilide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-isopropyl-1,2,3,4-
Tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1,1,2,3,3-
Pentamethyl-indan-6-yl)-vinyl]-
Benzoic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1,1,3,3-tetramethyl-indan-6-yl)-vinyl]-benzoic acid-(4-hydroxyanilide) 4 -[2-Methyl-2-(1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxy anilide) 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methyl-propyl)-1,
2,3,4-tetrahydronaphth-7-yl-)
Vinyl]-benzoic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphtho-7- vinyl)-vinyl]-benzoic acid-
(4-hydroxyanilide) 4-[2-ethyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-( 4-hydroxyanilide) 4-[2-ethyl-2-(1,1,4,4,6-
Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1,1-dimethyl-
1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1,1,6-trimethyl-1,2, 3,4-tetrahydronaphtho-7-
yl)-vinyl]-benzoic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1,1,3,3,5-
Pentamethyl-indan-6-yl)-vinyl]-
Benzoic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1,1,2,3,3,
5-Hexamethyl-indan-6-yl)-vinyl]-benzoic acid-(4-hydroxyanilide) Insofar as the compound of the present invention is a derivative of free benzoic acid, it has an acidic hydrogen atom and can therefore be prepared in a conventional manner. It can be converted into physiologically acceptable, well water-soluble salts with bases. Suitable salts are, for example, ammonium salts, alkali metal salts, especially sodium,
Salts of potassium and lithium, alkaline earth metal salts, especially calcium or magnesium salts, and suitable organic bases such as lower alkyl amines such as methylamine or ethylamine, substituted lower alkyl amines, especially hydroxy-substituted alkylamines such as diethanolamine. , triethanolamine or tris-(hydroxymethyl)
- salts with aminomethane, piperidine or morpholine. When the novel compound has a tetrazole group, its alkali metal salts and alkaline earth metal salts can be produced. The novel compounds of the present invention have a formula: [In the formula, A and R ¹ to ^{R 4} represent the above]
The compound represented by the formula: [In the formula, R ⁶ represents the one listed for R ⁵ or represents a cyano group and R ⁷ represents the one mentioned above] with a phosphorus compound based on the Witschichhorner reaction, or b formula: ^A phosphonium salt ^represented by ^the _formula : [In the formula, R ⁶ represents the above-mentioned compound] is reacted with a benzaldehyde derivative represented by the above-mentioned compound by Witzig reaction, and subsequently, when R ⁶ does not represent a carboxyl group, the compound thus obtained is optionally quenched. and the free acid thus obtained or directly obtained is subsequently optionally reacted with a C _1-3 -alcohol, p-hydroxyaniline or 5-aminotetrazole and the compound thus obtained is optionally reacted with It can be obtained by converting it into a salt with a physiologically acceptable base. Reactions a) and b) proceed at temperatures below 100°C, preferably between 20 and 50°C. These reactions are
It can be carried out under atmospheric pressure or under pressure in a closed container, optionally heated to the abovementioned temperature range. These reactions are carried out using diluents or solvents such as lower saturated dialkyl ethers, dialkyl glycol ethers or cyclic ethers such as diethyl ether, ethyl-tert-butyl ether, 1,2
- dimethoxyethane, tetrahydrofuran or dioxane, aromatic hydrocarbons such as benzene, or alkylbenzenes such as toluene or xylene,
or in the presence of saturated fatty acid hydrocarbons such as hexane, heptane or isooctane, lower fatty acid ketones such as acetone, methyl ethyl ketone or ethyl isobutyl ketone, dialkyl formamides such as dimethyl or diethyl formamide or in mixtures of the abovementioned solvents. It is advantageous to use cyclic ethers such as dioxane or tetrahydrofuran and especially dimethylformamide or mixtures thereof, in which case the reaction generally proceeds at temperatures below 30.degree. The reaction is carried out in the presence of a deprotonating agent () for the phosphorus compound (). Suitable deprotonating agents are alkali metal hydrides and amides, especially sodium and potassium salts, sodium and potassium salts of dimethylsulfoxide, alkyllithium compounds such as n-butyllithium or alkali metal alcoholates, preferably sodium methanolate and sodium It is ethanolate. When using fatty acid epoxy compounds, preferably butylene oxide, the reaction proceeds without addition of further reagents. Therefore, the fatty acid epoxy compound functions simultaneously as a solvent and a deprotonating agent. When using butylene oxide as fatty acid epoxy compound, the reaction can be carried out under pressure in a closed vessel at the boiling temperature of the reaction mixture or at a temperature of 100°C. Acid (R ⁵ = COOH) and C _1-3 -alcohol, p
The reaction with -hydroxyaniline or 5-aminotetrazole is accomplished by converting the acid into an activated derivative of the formula in which B represents a group COX and X represents a leaving group. In the above formula, X represents an acid group such as a halogen atom, especially a chlorine or bromine atom, or an N-oxysuccinimide group. The reaction proceeds at temperatures below 50° C. under atmospheric pressure or in a closed container under pressure. The reaction is carried out using diluents or solvents such as lower saturated dialkyl ethers, dialkyl glycol ethers or cycloaliphatic ethers such as diethyl ether, ethyl-tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, aromatic hydrocarbons such as benzene or alkylbenzenes such as toluene or xylene, or saturated aliphatic hydrocarbons such as hexane, heftane or isooctane, lower fatty ketones such as acetone,
It can be carried out in the presence of methyl ethyl ketone or methyl butyl ketone, dialkyl formamides such as dimethyl or diethyl formamide or in mixtures of the aforementioned solvents. In this case, preference is given to using linear or cyclic ethers such as diethyl ether or tetrahydrofuran and especially dimethylformamide, the reaction generally proceeding at temperatures below 30.degree. This reaction is usually carried out in the presence of a base as an acid binding agent. Suitable bases are alkali metal carbonates, especially sodium and potassium carbonates, hydrogen carbonates, organic tertiary bases such as pyridine or lower trialkylamines such as trimethyl or triethylamine. In this case, the base used is used in a stoichiometric amount or in slight excess relative to the benzoic acid halide used. Another method for preparing the acid derivatives of the invention starts from the corresponding free acid (R ⁵ =COOH); the acid is converted to C _{1 3} in a solvent in the presence of a substance that activates the carboxyl group and separates the water. - by reaction with alcohols, p-aminophenols or tetrazolamines. As the activation reagent for separating water, the reagents customary in peptide synthesis can be used ["The Peptides", Vol.
Academic Press, New York, 1965
, pp. 77-128]. The general principle of this reaction is
For example, treatment with carbodiimides, e.g. esters) or heterocyclic amides (eg imidazolides) by activating the carboxyl groups. The acid derivative of the present invention can then be obtained by treating the carboxyl group-activated compound with a C _1-3 -alcohol, p-aminophenol or tetrazolamine. The activation and coupling reactions are carried out in a solvent, preferably in N,N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane, acetonitrile, dimethylsulfoxide, N,N-dimethylacetamide and hexamethylphosphoric triamide. be able to. Suitable temperatures for both of the above steps, namely the reaction of the acid with the coupling agent and the reaction of the activated intermediate with p-aminophenol, are between 20 DEG and 100 DEG C. In this case, step by step:
This can be carried out either by isolating the activated intermediate product before addition of the p-aminophenol or, advantageously, by reacting the reaction components with each other without isolating them from intermediate stages. A preferred coupling method uses N,N-carbonyldiimidazole and operates in dimethylformamide, the reaction temperature for both steps being 20
~60℃. The compounds of the formula can have a cis- or trans-configuration as a single substance or are mixtures of cis-trans isomers. The mixture is
The desired isomer can be analyzed qualitatively by HPLC analysis or by ¹³ C-NMR spectroscopy and in each case the desired isomer can be isolated by fractional crystallization or by chromatography, e.g. using a silica gel column or by preparative HPL chromatography. It can be isolated as a pure isomer. The compounds of the invention and their physiologically acceptable salts are useful for the local and systematic treatment and prophylaxis of benign and malignant heterogeneous tissue neoplasia and premalignant disorders, such as the skin, mucous membranes and internal organs, as well as acne, psoriasis. and other pathologically altered keratinization, and in the local and systematic treatment of dermatological diseases involving joints, muscles, tendons and other parts of the musculoskeletal organs, such as inflammatory or degenerative types of rheumatic diseases. Can be treated. Preferred fields of application are the treatment of dermatological diseases as well as the prevention and treatment of precancers and tumors. In this case, low toxicity is advantageous. Pharmacological effects can be established, for example, by the following standard tests. 1. Inhibition of Keratinization in Tracheal Tissue Cultures to Confirm Anticancer Effect A standard test investigates the endogenous properties of the compounds of the invention to increase the differentiation of epithelial cells. It is generally known that this pre-testing method is extremely important in predicting the efficacy of new retinoids to prevent tumors within epithelial tissues. In this case, it is also known that all in vitro test systems are associated with drawbacks when predicting in vivo activity. Apart from this fundamental limitation, the tracheal cell culture system is one of the most important methods for investigating the biological activity of new retinoids. The ability of a test substance to inhibit cancer formation in a defined in vitro system is investigated. The tracheas of hamsters in the very early stages of vitamin A deficiency were cultured. At the time of tracheectomy, experimental animals were 29 to 30 days old (after weaning).
21 days later) and still showed weight gain. The average weight was 47-52g. The tracheal epithelium was generally a weak columnar or cobblestone epithelium with only discrete locations of scaly metaplasia. The husband's trachea was incised along the membranous dorsal wall from the larynx to the carina and cultured in serum-free culture medium (CMRL-1066 supplemented with crystalline bovine insulin, 0.1 μg/ml halodrocrotisone-hemisuccinate). 0.1μg/ml,
Curtamine 2mM, penicillin 100 units/ml and steroptomycin 100 μg/ml).
A mixture consisting of 50% oxygen, 45% nitrogen and 5% carbon dioxide was introduced into the culture. The culture shear was gently shaken to bring the tracheal tissue into contact with the gas and culture medium. All tracheal tissues were initially kept in culture medium without the addition of retinoids for 3 days. After 3 days, several tracheal tissues were removed. Almost all of them showed obvious scale-like metaplasia. The remaining tracheal tissue was divided into groups and the groups were then treated with the following additives: a test substance dissolved in spectrally pure dimethyl sulfoxide; the final concentration of dimethyl sulfoxide in the culture medium was less than 0.1%; It wasn't expensive. b Equivalent amounts of dimethyl sulfoxide culture medium without other additives were changed three times a week. All remaining tracheal tissues were post-processed after 10 days of culture. Tracheal tissue was fixed in 10% buffered formaldehyde solution and mounted in paraffin. A 5 μm section through the center was stained with hexatoxylin and eosin and examined under a microscope for the presence of keratin and keratohyalin. Both were observed in approximately 90% of all control cultures maintained in the absence of test substance. A dose-response curve for the compound of the invention was constructed. Table 1 below shows the extrapolated molar doses that inhibit keratinization (ED50%) in 1/2 of the treatment. Table 1 Example number of test substance ED ₅₀ (mol/) 2 1・10 ^-11 7 1・10 ^-11 18 3・10 ^-12 19 1・10 ^-12 26 1・10 ^-12 Vitamin A acid 1・10 ^-11 Furthermore, the compounds of the invention (particularly the compound of Example 2) induce significant cell differentiation into granulocytes in leukemic cells of patients suffering from promeolozytisch leukemia. 2. The anti-arthrogonitis effect of the compound of the present invention has been demonstrated in animal experiments using conventional methods.
This can be confirmed using the model (Adjuvans-Arthritis-Modell). 3 The dermatological action, for example for the treatment of acne, can be confirmed in particular by the acne-therapeutic action. Polyan (ester of lanolin alcohol and linoleic acid, Herst-
Amerchol Corp, USA] 5% tar in 1
Acne was induced by topical application (0.5 ml/day) for 5 consecutive days per week for 2 weeks. Subsequently, the test substance in ethanol/propylene glycol (70:30 v/v, 0.5 ml) was applied to the inner epidermis of one ear of each rabbit once per day for 5 consecutive days per week for 2 weeks. Local treatment was performed by applying over a period of time. The other ear of each experimental animal served as an untreated control. After a further 72 hours of treatment with the test substance, the rabbits were sacrificed. Approximately 6 points from each ear wing just outside the ear canal
A cm ² skin sample was removed and the sample was subdivided into pieces approximately 1 cm ³ in size. Heat these skin areas to 60℃
immersed in warm water for 2 minutes. The epidermis was carefully peeled off using the flat end of a spatula and small tweezers and then placed on the sample plate with the peeled side facing upwards.
After air drying overnight, the specimens were examined under a stereomicroscope. The small part containing keratinous material remained completely. Pimples are discernible as scattered, uniformly shaped, cylindrical to circular cuticles, the size and number of which are proportional to the activity of the test substance. The acne treatment effect was confirmed as the percentage reduction in the number of acne compared to the control ear (see Table 2). Table 2 Test Substance Example Number Acne Treatment Activity % 1 75 2 78 5 54 6 68 7 59 8 62 Vitamin A Acid 67 4 As another measure of dermatological activity, the utricle in the rhino-mouse model The number of efficacy tests utilized is reduced. This method is described in “The journal of Investigative Dermatology” by LHKligman et al.
Dermatology), Vol. 73, pp. 354-358 (1979
year). In this case, the cysts, so-called cystic acne, present as hereditary lesions on the skin of reno mice are degenerated by administration of the active substance, and the reduction is expressed as a percentage. Table 3 Test Substance Example Number Reduction Rate % 1 65 2 68 5 69 6 59 7 62 8 52 Vitamin A Acid 60 5 Compatibility of the test substance based on topical application was determined using six male New Zealand rabbits. This was confirmed in an experiment. The dorsal region of each test animal was shaved approximately 6 cm ² . After dissolving the test substance in ethanol/propylene glycol (70:30v/v), 0.2
ml was applied by carefully rubbing into place twice a day at 6 hour intervals for 9 consecutive days using an automatic micropipette. All test surfaces were judged subjectively in the morning for erythema and epidermal exfoliation before each application. At this time, a numerical scale of 0 to 3 (0 =
No response, 1 = mild, 2 = moderate, 3 = strong response) were used. The mean values for erythema development and epidermal exfoliation represent the relative ability of the test substance compared to vitamin A acid.

[Table] Another subject of the invention is therefore therapeutic agents and pharmaceuticals for topical and systemic application which contain as active substance a compound of the formula () in addition to the customary carriers or diluents. The use of a compound of formula () for the preparation of The therapeutic agents or preparations are prepared in the customary manner, based on the desired form of application and in doses appropriate for the application, using the customary liquid or solid carrier substances or diluents and the normally used pharmaceutical technical auxiliaries. For example, the active substances can be prepared by mixing them with the solid or liquid carrier substances and auxiliaries customary in the formulations. The active substances according to the invention can therefore be processed for oral, parenteral or topical application. Examples of preparations of this type include tablets, coated tablets, dragees, capsules, pills, powders, solutions or suspensions, infusions or injection solutions as well as pastes, ointments, gels, creams, lotions, powders, solutions or emulsions and This applies to sprays. The therapeutic agent comprises the compound to be used according to the invention in a concentration of 0.001 to 1% for topical application, advantageously 0.001 to 0.1% and advantageously 0.1 to 0.1% for systematic application.
It can be contained in a single dose of 50 mg and can be processed into one or more dosage forms per day based on the type and severity of the disease. Commonly used pharmaceutical technical auxiliaries are, for example, for topical forms alcohols such as isopropanol, oxyethylated castor oil or oxyethylated hydrogenated castor oil, polyacrylic acid, glycerol monostearate, paraffin oil, petrolatum, lanolin. , polyethylene glycol 400, polyethylene glycol 400-stearate and ethoxylated fatty alcohols, for systematic application lactose, propylene glycol and ethanol, starch, talc, polyvinylpyrrolidone. The formulation optionally contains antioxidants such as tocopherols and butylated hydroxyanisole or butylated hydroxyltoluene or flavoring additives, stabilizers,
Emulsifiers, lubricants, etc. may also be added. In this case, it is a prerequisite that all the substances used in the production of the preparation are toxicologically safe and compatible with the active substance used. Next, compounds of the invention are prepared in Examples. Example 1 (E)-4-[2-methyl-2-(1,1,4,4,
6-Pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester 250 ml of dimethyl sulfoxide and 80% sodium hydride, from which 20% of the paraffin component was previously removed with petroleum ether. A solution of 90 g of p-carboxyethyl-benzyl-phosphoric acid diethyl ester in 150 ml of DMSO was added to a suspension of 9 g at 35° C. over a period of 0.5 h.
It was added dropwise. Subsequently, the mixture was stirred for a further 2 hours at 40°C and dissolved in 70 ml of dimethyl sulfoxide within 10 minutes.
A solution of 36.6 g of -acetyl-1,1,4,4,6-pentamethyltetralin was added dropwise. After leaving it overnight, add 100% ethanol to this batch.
ml, poured into ice water 2 and acidified with 2N hydrochloric acid. The precipitate formed was separated and the filter vessel was purified with 150 ml of ethanol and washed with 75 ml of methanol. (E)-4-[2-methyl-2-(1,2,
35 g of 4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester (melting point 108 DEG -109 DEG C.) remained. HPLC analysis [Si 60 5 μm, 150 bar, n-heptane/acetic acid ethyl ester (98:2), t _R = 3.1
minutes) showed that more than 98% of the compound consisted of one isomer. ¹³ C-NMR spectrum (CDCl ₃ , expressed in ppm): (The numbering of C atoms was done as follows to correspond to the NMR signal.) 14.40 (C ₂₁ ); 19.74 (C ₂₇ ); 20.35 (C ₂₆ ); 31.96
(C ₂₅ , C ₂₄ , C ₂₃ , C ₂₂ ); 34.02 (C ₁ , C ₄ ); 35.32
(C ₂ , C ₃ ); 60.94 (C ₂₀ ); 126.11 (C ₈ ); 128.41 (C _1
6 ,
C ₁₂ ); 128.55 (C ₅ ); 129.00 (C ₁₄ , C ₁₈ ); 129.68
(C ₁₅ , C ₁₇ ); 131.72 (C ₆ ); 141.98 (C ₁₃ ); 142.93
(C ₁₁ ); 143.11 (C ₁₀ ); 143.83 (C ₉ ); 166.80 (C ₁₉
); The signal at 19.74 ( _C27 ) indicates the E-(trans)-geometric isomerism of the compound. Example 2 (E)-4-[2-methyl-2-(1,1,4,4,
4.7 g of 6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid ethyl ester together with 1.7 g of 86% potassium hydroxide in a mixture of 100 ml of ethanol and 5 ml of water. 80 at
Stirred at ℃ for 6 hours. The entire reaction mixture was transferred to 1 ml of water and then acidified with 2N hydrochloric acid, and the colorless precipitate obtained was separated off and, after drying on a vacuum filter, washed with 100 ml of heptane. After drying, (E)-4-[2-
Methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphtho-7-
4.0 g of vinyl)-vinyl]-benzoic acid (melting point 206°C) remained. ¹³ C-NMR spectrum (d ₆ -DMSO, expressed in ppm) (The numbering of C atoms was done as follows to correspond to the NMR signal.) 19.36 (C ₂₅ ); 20.17 (C ₂₄ ); 31.60 (C ₂₀ , C ₂₁ , C ₂₂
，
C ₂₃ ); 33.51 (C ₂ , C ₃ ); 34.71 (C ₄ , C ₁ ); 125.40
(C ₈ ); 128.00 (C ₅ , C ₁₂ ); 128.61 (C ₁₆ ); 128.95
129.42 (C ₁₄ , C ₁₈ ); 129.42 (C ₁₅ , C ₁₇ ); 131.12
(C ₆ ); 141.20 (C ₁₃ ); 141.70 (C ₇ ); 142.16 (C ₁₀ )
;
152.52 (C ₁₁ ); 143.08 (C ₉ ); 167.26 (C ₁₉ ). The signal at 19.36 ( _C25 ) indicates the E-(trans)-geometric isomerism of the compound. Example 3 A Preparation of Starting Materials A suspension in 100 ml of dimethyl sulfoxide is first prepared from 9 g of 80% sodium hydride, freed of 20% paraffinic content with petroleum ether and 0.5
p- in 150 ml of dimethyl sulfoxide within hours.
Cyanobenzylphosphonic acid diethyl ester 75.9
g of solution was added dropwise at about 35°C. Stir for further 2 hours at 40°C and add 50% dimethyl sulfoxide within 10 minutes.
A solution of 53.5 g of 7-acetyl-1,1,4,4,6-pentamethyltetralin in ml was added dropwise. The next day, the reaction mixture was poured into ice water 3 and
Acidified with 2N hydrochloric acid. The resulting solid material was separated off and washed on the strainer with 75 ml of methanol. After drying, (E)-4-[2-methyl-2-(1,1,4,
30.2 g of 4,6-pentaethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzonitrile (melting point 140 DEG -140 DEG C.) were obtained. HPLC analysis [Si 60.5 μm, 150 bar, 25 cm column, n-heptane/ethyl acetate (97:
3), t _R =3.2 minutes], it showed isomer homogeneity of 95% or more. B Manufacture of target substance (E)-4-[2-methyl-2-(1,1,4,4,
6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzonitrile
13.5 g were heated to boiling temperature for 3 hours in a mixture of 200 ml of ethanol and 200 ml of 10N caustic soda solution. After cooling, it is poured into water 1, the colorless precipitate is filtered off and, after drying, (E)-4-[2-methyl-
2-(1,1,4,4,6-pentamethyl-1,
2,3,4-tetrahydronaphth-7-yl)-
14.9 g of vinyl]-benzoic acid (melting point 204 DEG -206 DEG C.) were obtained (see Example 2). The compounds listed in the table below were obtained by the Witschichhorner reaction or by saponification of the corresponding esters or nitriles.

【table】

acid ethyl ester

Claims (1)

[Claims] 1 Formula: [In the formula, A represents a methylene or ethylene group which may be substituted with a _C1 - _C4 -alkyl group, ^R1 represents a hydrogen atom or a methyl group, and ^R2 represents a hydrogen atom or a methyl group. , R ³ represents a hydrogen atom or a C ₁ -C ₈ -alkyl group, R ⁴ represents a C ₁ -C ₄ -alkyl group, and R ⁵ represents a p-hydroxyphenyleneaminocarbonyl group or a tetrazole-5- yl-aminocarbonyl group or, if R ³ is a C ₁ -C ₈ -alkyl group, a carboxyl group or a C ₂
~ _C4 -carbalkoxy group] and its salts with physiologically acceptable bases. 2 In the formula, A represents an ethylene group,
R ¹ and R ² represent a methyl group, R ³ represents a C ₁ -C ₈ -alkyl group, R ⁴ represents a methyl group, and
Phenylethylene derivatives and their salts with physiologically acceptable bases according to claim 1, wherein R ⁵ represents a carboxyl group or a C ₂ -C ₄ -carbalkoxy group. 3. The phenylethylene derivative according to claim 1 or 2, wherein the phenyl rings are in trans position with respect to each other. 4 (E)-4-[2-methyl-2-(1,1,4,4
-tetramethyl-6-isobutyl-(2-methylpropyl)-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid, the phenyl according to claim 1 Ethylene derivative. 5 Formula: [In the formula, A represents a methylene or ethylene group which may be substituted with a _C1 - _C4 -alkyl group, ^R1 represents a hydrogen atom or a methyl group, and ^R2 represents a hydrogen atom or a methyl group. , R ³ represents a hydrogen atom or a C ₁ -C ₈ -alkyl group, R ⁴ represents a C ₁ -C ₄ -alkyl group, and R ⁵ represents a p-hydroxyphenyleneaminocarbonyl group or a tetrazole-5- yl-aminocarbonyl group or, if R ³ is a C ₁ -C ₈ -alkyl group, a carboxyl group or a C ₂
~ _C4 -carbalkoxy group] and its salts with physiologically acceptable bases, comprising: a) the formula: [In the formula, A and R ¹ to ^{R 4} represent the above]
The compound represented by the formula: Based on the Witschie-Horner reaction with a phosphorus compound of the formula [wherein R ⁶ represents the same as mentioned for R ⁵ or represents a cyano group and R ⁷ represents a C ₁ -C ₄ -alkyl group] or b) Formula: A phosphonium salt ^{represented by the formula} : [In the formula, R ⁶ represents the above-mentioned compound] is reacted with ^a benzaldehyde derivative represented by Saponification and the free acid thus obtained or directly obtained are then optionally converted to C ₁ -C ₃ -alcohols, p-
1. A process for the preparation of phenylethylene derivatives, characterized in that they are reacted with hydroxyaniline or 5-aminotetrazole and the compounds thus obtained are optionally converted into their salts with physiologically acceptable bases.