JPS58128340A - Phenylethylene derivative, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to phenylethylene derivatives, processes for their preparation, and therapeutic agents containing said compounds and the use of said compounds for the treatment of diseases.

It is known from DE 28 54 354 A1 that stilbene vj conductors have a pharmacological action in the topical and systemic treatment of heterogeneous tissue neoplasia, spasm, scars 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 heteroneosis, spasticity, psoriasis and other dermatological diseases. is not considered. The drawbacks of the stilbene derivatives described in German Patent No. 2854354 are, for example, those of Kiatler A.
“Calcified Ti5sue International” by J.
ational) Volume 33, pp. 249-254 (19
1981) and especially Moon (R, C, Moon).
) et al. 16 Cancer Research (Cancer Research)
r Research) Volume 39, 1339-134
Ass f based on the method reported on page 6 (1979)
This is obvious after applying it several times to class i1 animals.

The objective of the present invention was to provide compounds that exhibit similar effects, but with fewer toxic side effects.

The present invention is based on the formula: [wherein A represents an alkylene group optionally substituted with an alkyl group, Ftl represents a hydrogen atom or a methyl group, R2 represents a hydrogen atom or a methyl group, and R3 is a water atom or self ~8-
represents an alkyl group, R4 represents a C1-4-alkyl group, and R5 represents a p-hydroxyphenyleneaminocarbonyl group, a tetrazol-5-ylaminocarbonyl group,
or, where Ba is a CI~8-alkyl group, the S group also represents a carboxyl group or a 02-4-carbalkoxy group], and optionally with its physiologically 4-substituted base. Regarding salt.

A is preferably a methylene group optionally substituted by a methyl group or an ethylene 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- or trans-
(E) - belongs to the compound.

A typical example of a compound of the present invention is: 4-[2-methyl-2-(1,1,4,4,6-bentamethyl-1,2,3,4-tetrahydronaphtho- 7-ylhubinyl]-benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4,6-bentamethyl-1.2,3.4-tetrahydronaphth-7-ylarpinyl]-benzoic acid 4- [2-methyl-2-(1
,1,6-1rimether-1,2,3,4-tetrahydronaphth-7-yl)-vinyltobenzoic acid 4-[2-methyl-2-(1,1,6-drimethyl-1
．． 2,3.4-Tetrahydronaphth-7-yl]-hinyl]-benzoate ester 4-[2-ethyl-2-
(1,1,4,4,6-bentamethyl-1,2,3.4
-tetrahydronaphth-7-yl)-vinyl benzoic acid, methyl ester 4-[2-ethyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphtho-7- yl)-vinyltwobenzoic acid 4-[2-methyl-2-(1
,1,4,4-tetramethyl-6-ethyl-1,2,3
,4-tetrahydronaphth-7-yl]-vinyl]-benzo-f acid ethyl ester 4-[2-methyl-2-(1,1,4j4-tetramethyl-6-ethyl-1,2,3,4 -Tetrahydronaphth-7-yl]-vinyltobenzoic acid 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ithugrobyl-1,2-,3,,4-tetrahydrona7) -'/-yl)-vinylcoubenzyl-4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ituprobyl-1.2.3.4-tetrahydronaphth-7-ylhubinyl] -benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-broby-1.2.3.4-tetrahydronaphth-7-yl)-vinylcoubenzoic acid 4- [2-Methyl-2-(1,1,4,4-tetramethyl-6-broby-1,2,3j4-tetrahydronaphth-7-yl)-vinyl]-benzoyl ethyl ester 4-[2-methyl- 2-(1,1,4,4-tetramethyl-6-butyl-1z 2-3-4-tetrahydronaphth-7-ylnovinyltobenzoic acid methyl ester 4-[2-methyl-2-(1, 1,4,4-tetramethyl-6-butyl-1,2,3.4-tetrahydronaphth-7-ylun-vinyl]-benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4- Tetramethyl-6-butyl-1,2.3.4-tetrahydronaphth-7-yl]-vinyl)-benfate 4-[2-methyl-2-(1,1,4j4-tetramethyl-6-( 2-Methyl-6-(2-methylprobyl J-
1,2,3,4-tetrahydronaphth-7-yln-vinyl]-benzoic acid ethyl ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-(2-methyl-propyl)) -1゜2j3,4-
Tetrahydronaphth-7-ylhubinyl]-benzoic acid 4-[2-methyl-2-(1,1,3,4,4゜6-hexamethyl-1,2,3,4-tetrahydronaphtho-7)
-yl)-vinyl]-an,l&samp;
-yltubinyl”-benzoic acid 4-[2-methyl-2-
<1.1,2,3,3゜5-he'Ft)-j-ruindan-6-yl)-vinyk]-anM, ethyl fragrant ester 4-[2-methyl-2-(1, 1,2,3,3゜5-hexamethyl-indan-6-yltubinyl"-benzoic acid probyl ester 4-[2-methyl-2-(1, l, 2, 3, 3
゜5-hexamethyl-indan-6-yl)-vinylcoubenzoic acid isoglobyl ester 4-[2-methyl-2-(1,1j2,3,3゜5-hexamethyl-indan-6-yl)-vinylcou Benzoic acid 4-[2-methyl-2-(1,1,3,3,5-bentamethyl-indan-6-ylnovinyl)benzoic acid 4-[2-methyl-2-(1,1, 3,3,5-Pentamethyl-indan-6-ylnovinyl]-benzoic acid methyl ester 4-[2-methyl-2-(1,1,3,3,5-pentamethyl-indan-6-yl)-vinyl] -Anne S, dioxylic acid ether ester 4-[2-methyl-2-(1,1,4,4,6-bentamether-1,2,3.4-tetrahydronaphth-7-yl)-vinylcoubenzoic acid methyl ester 4-[2-Methyl-2-(1,1,4,4,6-bentamether-1,2,3.4-tetrahydronaphth-7-yl]-vinylcoubenzoic acid probyl ester [2-ethyl-2 -(1,1,4,4,6-bentamethyl-1.2,3.4-tetrahydronaph)-7-yl)-hinyl]-aminoacid 1j1,4,4,6-bentamethyl-1.2,3.4-tetrahydronaphth-7-ylun-vinyl]-benzoic acid 4-[2-ether-2-(1
, 1,4,4j6-bentamethyl-1,2,3.4-tetrahydronaphth-7-yl]-vinyl)-benthIFf
f Methyl ester 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-n-butyl-1,2,3,4-tetrahydronaphth-7-yl)-vinylcoubenzoic acid 4 -[2-Methyl-2-(1,1,4,4-tetramethyl-6-n-octyl-1,2,3,4-titrahydronaphth-7-ylun-vinyl]-benzoic acid 4-[2- Methyl-2-(1,1,6-)dimethyl-1
,2,3,4-tetrahydronaphth-7-yl)-vinylcoubenzoate 4-[2-methyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphtho- 7-il]
-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4,6-bentamethyl-1j2,3.4-tetrahydro+])-7 -yl]-vinyl]-N-tetrazol-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-tetrahydronacto-7-ylun-vinyl]-
N-(tetrazol-5-yl-benzoic acid amide 4-[2-methyl-2-(1,1,2,3j3-pentamethyl-indan-6-yl)-vinyl]-N-(tetrazol-5-yl) -benzoic acid amide 4-[2-methyl-2-(1,1,3,3-tetramethyl-intan-6-yl)-vinyl]-N-(tetrazol-5-yl)-benzoic acid amide 4- [2-Methyl-2-(1,1,4,4-tetramethyl-6-zorobyl-1j2,3,4-tetrahydronaphth-7-ylnovinyl J-N-(tetrazole-5-
yl)-benzoic acid amide 4-[2-methyl-2-(1,
1j4,4-tetramethyl-6-(2-methyl-propyl)-1゜2.3.4-tetrahydronaphth-7-yl)-vinyl)-N-(tetrazol-5-yl-tobenzoic acid amide 4-[ 2-Methyl-2-(1,1,4,4-tetramethyl-6-butyl-1,2.3.4-tetrahydronaphth-7-yl]-vinyl]-N-(tetrazol-5-yltubenzoic acid Amide 4-[2-ethyl-2-(1,1
,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yln-vinyl]-NCtetrazol-5-yl)-benzoic acid amide 4-[2-ethyl-2-(1,1 ,4,4,6-bentamethyl-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-(nat2zol-5-yl)-benzoic acid amide 4-[2-methyl-1,1,6-1-dimethyl-1,2
, 3,4-tetrahydronaphth-7-yln-vinyl)
-N-(tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,3,3,5=pentamethyl~indan-6-ylnovinyl]-N-(tetrazol-5- yl)-benzoic acid amide 4-[2-methyl-2-(1, 1, 2, 3, 3゜5-hexamethyl-indan-6-yl]-vinyl J-N-(
Tetrazol-5-yl)-benzoic acid amide 4-[2-methyl-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-ylhubinyl]-benzoic acid mono (4-Hydroxyanilide) 4-[2-Methyl-2-(1,1,4,4,6-bentamethyl-1,2,3.4-tetrahydronaphth-7-ylnovinyl)-benzoic acid-(4-hydroxy Anilidono 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid mono( 4-Hydroxyanilide 4-[2-methyl-2-(1,1,4,4-tetramethyl-6-improvil-1,2,3,4-tetrahydronand-7-yllavinyl]-benzoic acid mono( 4- and droxyanilidora 4-[2-methyl-2-(1j1.2
,3,3-pentamethyl-indan-6-ylnohynyl]-benzoic acid mono(4-hydroxyanilideno4-[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]-aminocarboxylic acid-(4-hydroxyanilide) 4-[2-methyl-2-(1 , 1,4,4-tetramethyl-6-(2-methyl-propyl).

2.3.4-Tetrahydronaphth-7-yl)-vinylcoubenzoic acid-(4-hydroxyanilide) 4-[2-
Methyl-2-(1,I,4,4-tetramethyl-6-
Butyl-1,2,3.4-tetrahydronaphth-7-yl)-vinylcoubenzoic acid mono(4-hydroxyanilide) 4-[2-Ether-2-(1,1j4,4-tetramethyl-1,2, 3,4-tetrahydronaphth-7-yl)
-Vinylcoubenzoic acid-(4-hydroxyanilide) 4-[2-ethyl-2-(1,1,4j4j6-bentamethyl-1,2,3.4-tetrahydronaphth-7-yl]-vinylcoubenzoic acid-(4 -hydroxyanilide) 4-[2-methyl-2-(1,1-dimethyl-1,2,
3j4-tetrahydronaphtho-7-ilbu beer]
-&breath-f acid-(4-hydroxyanilide) 4-[2-methyl-2-(il J t6-)dimethyl-1,2,3,4-tetrahydronaphth-7-yl]-
Vinylcoubenzoic acid mono(4-hydroxyanilide) 4-[2-Methyl-2-(1,1,3,3,5-pentamethyl-indan-6-yl)-vinylcoubenzoic acid mono(4-hydroxyanilide)] 4 -[2-methyl-2-(
1,1,2,3,3゜5-hexamethyl-indan-6
-yl)-vinylcoubenzoic acid-(4-hydroxyanilide) The adducts of the invention, insofar as they are derivatives of free benzoic acid, have acidic ice atoms and are therefore physiologically acceptable as bases in the usual manner. can be converted into good water-soluble salts.Suitable salts include, for example, ammonium salts, alkali metal salts, especially sodium, potassium and lithium salts,
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 jetanolamine, triethanolamine or Salts with tris-(hydroxymethyl)-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 compound of the present invention is a) a compound of the formula (III): [wherein A and R1-R4 represent the above-mentioned compounds]; or represents a cyan group, and R7 represents the above-mentioned phosphorus compound based on the Witschichhorner reaction, or υ Formula ■: [In the formula, A, R1, R", R" and R4 represents the above-described one, and X represents a chlorine atom or a bromine atom. If R6 does not represent a carboxyl group, the compound so obtained is optionally saponified and the free acid thus obtained or directly obtained is subsequently converted to C
1-3-alcohol, p-hydroxyaniline or 5-
It is obtained by reaction with aminotetrazole and optionally converting the compound thus obtained into its salt with a physiologically compatible base.

Said reactions a) and 1 are carried out at temperatures below 100°C, advantageously between 20°C and
Proceed at a temperature of 50°C. These reactions can be carried out at atmospheric pressure or under pressure in a closed vessel, optionally heated to the temperature range mentioned above.

These reactions are carried out in the presence of diluents or solvents such as lower saturated dialkyl ethers, dialkyl glycol ethers or cyclic ethers such as diethyl ether, ethyl-te
rt-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, heptane or isooctane, lower aliphatic ketones such as acetone , methyl ethyl ketone or methyl isobutyl ketone,
It can be carried out in the presence of a dialkylformamide such as dimethyl or diethylformamide or in a mixture of the bath agents mentioned above. 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 (1) for the phosphorus compound (Ill). Suitable deprotonating agents are alkali metal hydrides and amides, especially sodium and potassium salts, sodium and potassium salts of dimethyl sulfoxide, alkyllithium compounds such as n-butyllithium or alkali metal alcoholates, preferably sodium metal oxides and Sodium etalate.

When using an aliphatic epoxidation adduct, preferably butylene oxide, the reaction proceeds without addition of further reagents. Therefore, the aliphatic epoxy compound simultaneously functions as a solvent and a deprotonating agent. When using butylene oxide as the aliphatic epoxy compound, the reaction mixture is heated under pressure in a closed container at the boiling temperature of the reaction mixture or at 100°C.
The reaction can be carried out at a temperature of 1-.

The reaction of acid 1 (R5=C00H) with cl-+3-alcohol, p-hydroxyaniline, and 5-aminotetrazole produces an activated product of formula I in which R represents a group COX and X represents a leaving group. This is accomplished by converting the acid into a derivative. In the above formula, X represents an acid group such as a halogen atom, especially a chlorine atom or an odor X 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 can be carried out using diluents or solvents such as lower saturated dialkyl ethers, dialkyl glycol ethers or cycloaliphatic ethers such as diethyl ether, ethyl-ter
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, heptane or isooctane, lower fatty ketones such as acetone,
It can be carried out in the presence of methyl ethyl ketone or methyl isobutyl ketone, dialkyl formamides such as dimethyl or diethyl formamide or in a mixture of the bath agents mentioned. In this case, preference is given to using in particular dimethylformamide to convey linear or cyclic ethers such as diethyl ether or tetrahydrofuran;
In this case, the reaction generally proceeds at a temperature below 30°C.

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.

#j of the present invention! Another method for preparing vj conductors starts from the corresponding free acid 1 (R'=C0OH); the nucleic acid is converted into a C10-alcohol, p - consists of reacting with an amine phenol or a tetrazole amine.

As the activating reagent for separating water, the reagents customary in peptide synthesis can be used [It The Peptides], Volume 1, Academic Press, New York, 1965, 7.
See pages 7-128]. The general principle of this reaction is that, for example, treatment with a carbodiimide, e.g. The method consists in activating the carboxyl groups by intermediate formation of esters (for example p-nitrophenyl esters) or complex amides (for example imidazolides).

Next, the carboxyl group-activated compound is converted into C1~
The acid derivatives of the invention are obtained by treatment with S-alcohols, p-aminephenols or tetrazolamines. Said activation and binding reaction is carried out in a bath agent, preferably with N,N-dimethylformamide, tetrahydrofuran,
It can be carried out in dioxane, methylene chloride, nitromethane, acetonitrile, dimethylsulfoxide, N,N-dimethylacetamide and hexamethylphosphorus hatriamide. 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 the p-amine phenol, are between 20 and 100°C. In this stepwise reaction, the activated intermediate product is isolated before the addition of the p-amine phenol, or the reaction components are advantageously reacted with each other without being isolated from the intermediate step. It can be implemented by

In a preferred coupling method, using N,N-carbonyldiimidazole and operating in dimethylformamide, the reaction temperature for both IjiS attachment steps is from 20 DEG to 60 DEG C.

The compounds of formula I can have a cis- or trans-configuration as a single substance or are mixtures of cis-trans isomers. The mixture was analyzed by HPLC or “C-
Qualitative analysis can be carried out by NMR spectroscopy, and the desired isomer in each case can be isolated as a pure isomer, optionally by fractional crystallization or by chromatography, for example using a silica gel column, or by preparative HPL chromatography. Colander.

The compound of the present invention and its physiologically acceptable salts are useful for the local and systematic treatment and pre-disease of benign and malignant heterogeneous tissue neoplasia and pre-malignant disorders, such as skin, mucous membranes and internal organs, and for the prevention of convulsions. In the local and systematic treatment of psoriasis, psoriasis and other dermatological diseases with pathologically altered keratinization, and in the treatment of inflammatory or degenerative diseases involving joints, muscles, bulges and other musculoskeletal parts. It is possible to treat equine diseases. 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 determined, for example, by the following standard tests.

■ Inhibition of keratinization in tracheal tissue culture to confirm anticancer activity A standard test investigates the endogenous properties of the compounds of the invention to increase differentiation of epithelial cells. It is generally known that this preliminary testing method is extremely important in predicting the efficacy of Klk-based retinoids for preventing tumors within epithelial tissues.

In this case, it is also known that all in vitro test systems have shortcomings when predicting in vivo wettability. Apart from this fundamental limitation, the tracheal alveolar culture system is one of the most versatile methods for investigating the biological activity of new retinoids.

To investigate the ability of a test substance to suppress stratification within a specified in vitro system. The tracheas of hamsters in the very early stages of vitamin A deficiency were cultured. At the time of tracheectomy, the experimental animals were 29 to 30 days old (21 days after weaning) and were still showing weight gain. Average body l is 47-5
It was 2F. The tracheal epithelium was generally a weak columnar or cobblestone epithelium with only discrete locations of bilateral shoulder 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-10660 supplemented with crystalline bovine insulin, 1μ?/
ld halodrotarotezone - semi-succinic yio, iμf/
m/, glutamine 2mM, penicillin 100 units/- and sterobtomycin 100μ? /ml). A mixture consisting of 50% oxygen, 45% nitrogen and 5% carbon dioxide was introduced into the culture. The culture dish was gently shaken to bring the tracheal tissues into contact with the gas and culture medium. All tracheal tissues were initially kept in the culture medium without the addition of retinoid for 3 days. After 3 days, several tracheal tissues were removed. These almost all showed obvious bilateral shoulder metaplasia.The remaining tracheal tissue was divided into groups and the groups were then treated with the following additives: 1. The final concentration of dimethyl sulfoxide in the culture medium was not more than 0.1%.

b) White violet dimethyl sulfoxide culture medium without other additives was grown three times a week.

All remaining tracheal tissues were explanted after 10 days of culture. 10% buffered formaldehyde'#! Fixed in solution and mounted in paraffin. Centrally removed 5 μm sections were colored with hexatoxylin and eosin and examined under a microscope for the presence of keratin and keratobialin. Both were observed in approximately 90% of all control cultures maintained in the absence of test substance. The violet action curve of the invention-8' product was plotted.

Table 1 below shows that v2 of one culture suppresses keratinization (FD
50%), indicating the molar dose obtained by extrapolation.

Table 1 Test substance ED56 Example number (Moni/t)21.1
o -11 71-10-" 183.10-12 191.10-42 261.10-1 Vitamin A acid 1-io-""Furthermore, the compound of the present invention (particularly the compound of Example 2) promeolozytlach
It induces significant cell differentiation into granulocytes in leukemic cells of patients with leukemia.

2) The anti-intersegmental inflammation effect of the compound of the present invention has been demonstrated in the adjuvant altorrhizal model (Adj
uvana-arthritis-model).

3) The dermatological action, for example for treating spasticity, can be confirmed in particular by the acne-therapeutic action.

In both ears of the white rabbit polyan (an ester of lanolin alcohol trinolic acid, Herat.

Made by Amerchol Corp, USA] Medium 5%
Acne was induced by applying tar once locally (0.5 tILt/day) for 5 consecutive days per week for 2 weeks. Subsequently, ethanol/propylene glycol (70: 30 v/v, 0.5 at)
Topical treatment was performed using the test substance in each rabbit by applying it to the inner epidermis of one ear once per day for 5 consecutive days per week for 2 weeks. 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-sized skin samples were removed from each ear just outside the ear canal and the samples were subdivided into approximately 1-sized sample pieces. These skin areas were immersed in warm water at 60°C for 2 minutes. After carefully peeling off the epidermis using the flat end of a spatula and a small bottle set, place the peeled side up on a specimen plate and, after air drying overnight, examine the specimen under a stereomicroscope. Ta. The follicle portion 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 reduction rate of the number of acne compared to the control ear (see Table 2).

M2 Table Acne treatment activity examples of test substances November
75 2 78 54 6 68 59 8 62 Vitamin A&, 674) As a measure of dermatological activity, testing of efficacy in reducing the number of utricle in the rhino mouse model was used. This method is based on Kligman (L, H, K11gm1n
) Others, 'The Journal of Investigatip Dermatology'
Investigatlve DermIItolog
y), Vol. 73, pp. 354-358 (1979). In this case, cysts present as hereditary skin lesions in rhino mice, so-called cystic spasticity, are degenerated by administration of the active substance, and their reduction is expressed as an axe.

Table 3 Reduction rate of test substance Example number 饅1 652
6869 6 5962 52 Vitamin A Acid 60 5) The compatibility of the test substance on a topical basis was confirmed in an experiment using 6 male white New Zealand rabbits. Approximately 6 cII of hair was shaved on the back of each test animal. The test substance was mixed with ethanol/propylene glycol (70:30
v/v) and then applied by carefully rubbing 0.2 d into the designated locations using an automatic micropipette twice a day at 6 hour intervals for 9 consecutive days.

All test m1 were judged subjectively in the morning for erythema and epidermal excoriation before each application. At this time, a numerically graded scale of O to 3 (0 - no reaction, l - mild, 2;
Moderate, 3-strong response) was utilized. The mean values for erythema development and epidermal exfoliation represent the relative ability of the test substance compared to vitamin A acid.

Example number of m4 table test substance Erythema Epidermal peeling 2
2.8 2.75
2.0 1.77
3.0 3. Os
1.4 1.0
Vitamin A acid 3.0 3.0 Therefore, another subject of the invention is a compound for topical and systemic application which contains, in addition to the usual carriers or diluents, a compound of formula (1) as active substance. The use of the compound of formula (1) for the manufacture of therapeutic agents and medicaments.

Therapeutic agents or preparations can be prepared in the customary manner, based on the desired application form and in doses appropriate for the application, using the customary liquid or solid carrier substances or diluents and the normally used pharmaceutical technical auxiliaries. The active substances can be prepared, for example, by mixing the active substances 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 this type of preparation include tablets, coated tablets, dragees, cassettes, pills,
Powders, solutions or suspensions, infusion or injection solutions as well as pastes, gels, creams, lotions, powders,
This includes bath solutions or emulsions and sprays.

The therapeutic agent comprises the compound to be used according to the invention in a concentration of o, ooi to 1 h in topical form, advantageously o, ooi to 0.1 h, and advantageously in case of systematic application. 0.1~50
It can be contained in a single dose of 1 g and can be processed into one or more dosage forms per day depending on the type and severity of the disease.

Commonly used pharmaceutical technical auxiliaries are, for example, for topical forms alcohols such as inpropanol, oxyethylated castor oil or oxyethylated castor oil, polyacrylic acid, glycerin mo/stearate, paraffin oil, petrolatum , lanolin, polyethylene glycol 400, polyethylene glycol 400-stearate and ethoxylated fatty alcohols, lactose, propylene glycol and ethanol, starch, talc, polyvinylpyrrolidone for systematic common forms. Optionally, antioxidants such as tocopherols and butylated hydroxyanine or butylated hydroxyltoluene or low-taste additives, stabilizers, emulsifiers, lubricants, etc. can also be added to the formulation. In this case, it is a prerequisite that all the substances used in the production of the formulation 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-bentamethyl-1,2,3.4-tetrahydronaphth-7-yl]-vinylcoubenzoic acid ethyl ester 20% paraffin component was removed with petroleum ether in advance.
In a suspension of dimethyl sulfoxide 25 (Jrnl) and 80% sodium hydride (9y) for 0.5 h,
The number of baths of p-carboquinethyl-benzyl-diethylnisder phosphate 90y in MS0 150 me was increased at 35°C. Subsequently, stir at 40°C for 2 hours and
Dimethyl sulfoxide 7〇-A 7-acetyl-1,1,4,4,6-bentamenaltetralin 3 within 0 minutes
6.61 of the bath liquid was added dropwise, and after standing overnight, the batch was charged with ethanol/lz 100, poured with ice water 2 and acidified with 2N hydrochloric acid. The precipitate formed was separated and the filter was purified with 150 g of ethanol and washed with 75 g of methanol. (EJ-4-[2-methyl-
2-(1゜2.4,4,6-bentamethyl-1.2,3
．． 4-Tetrahydronaphth-7-yl)-vinylcoubenzoic acid ethyl ester (melting point 108-109°C) 35V
remained.

HPLC analysis [Si 605 firn, 150 bar, n-hebuta 7/h (Il, ethyl ester (98:2
), tR=3.1 min] showed that more than 98% of the compound consisted of one isomer.

'3C-NMR spectrum (CDCl3, pprn
)=(The numbering of C atoms was done as follows to correspond to the NMR signal.) 14.40 (Cat) p 19.74 (Cgy
J; 20.35 (CuJ z31.96 (Cz
s*Cz<+C23jCzz ) ; 34.02 (
CI-C<J; 35.32 (C2, C3);
60.94 (C20); 126.11
(C8), +128.41 (C16, Cl2)
; 128.55 (Cs); 129.00
(C14°C18n,' 129.68 (C
ts 1c17]; 131.72 (Ca)
; 141.98CC1m): 142.93
(CIIJ t 143.11 (CtoJ t
143.83(Cg)y 166-80
(C1s) p19.74 (Signal at CyJ indicates IC-()synth)-geometric isomerism of the compound.

Example 2 (E)-4-[2-Menaloo 2-(1,1,4°4.6
-Pentamethyl-1,2,3,4-tetrahydronaphtho-7-ylnovinylcoubenzoic acid ethyl ester4.
7 tons with 86% potassium hydroxide '1.71, 100% of ethanol and 5% of water! The mixture was stirred at 80°C for 6 hours. After transferring the entire reaction mixture to 1 t of water, 2N
After acidification with hydrochloric acid, the colorless precipitate obtained was separated off and, after drying on a suction filter, washed with 100 ml of hebutane. After drying, ■)-4-[2-methyl-2-(1,1,
4,4,6-bentamethyl-1.2,3.4-tetrahydronaphth-7-yl]-vinyl”-Female breath (melting point 2
06℃) 4. Of remained.

13C-NMR spectrum (4-DMSO*Ppnl
) (The numbering of C atoms was done as follows to match the NMR signal.) 19.36 CCx5) p 20.17 (C24)
; 31.60 (C20sCz!rctxaCm)
p 33.51 (Cn, Cs); 34.71
(C4, CIJ; 125.40 (Cs+) p 1
28.00 CC5, C5x) p 128.61 (
Cts);128-95129.42 CCuhClm
); 129.42 (Cxi 1c17);
131.12CCa); 141.20 (Ct
, qL 141.70 (C7); 142.
16 (CtoJ; 142.52 (Cn)
; 143.08 (Co) ; 167.26
The signal at (019)·19.36 CCzs) indicates the E- (transler geometric isomerism) of the compound.

Example 3 A. Preparation of starting mobilization From 92% of 80% sodium hydride deparaffinized with petroleum ether, a suspension in 100% of dimethyl sulfoxide was prepared and within 0.5 hours. A bath solution of 75.92% p-cyanobenzylphosphonic acid diethyl ester in 150% dimethyl sulfoxide
Added dropwise at °C. Further stirring was carried out at 40°C for 2 hours and within 10 minutes the 7-acetyl-
1,1,4,4,6-bentamethyltetralin 53.5
# of F! On the day after adding Solution I dropwise, the reaction mixture was poured into 3 portions of ice water and made soluble with 2N acid. Separate the resulting solid material and add 75 tId of methanol on a F filter.
! Washed with. After drying, (ld-4-(2-methyl-
2-(1,1,4,4゜6-be/taethyl-1,2,3
,4-tetrahydronaphth-7-yl]-vinylcubenzonitrile (melting point 140-140'C) 30.2
flJ''-obtained y, -8 HPLC analysis [Sl 60
．． 5 μm, 150 bar, 25Q@column, n-hegetane/Chuang Dong ether ester (97:3), tR = 3.2
95% or more of isomer identity.

B. Production of target substance (E)-4-[2-methyl-2-(1,1,4゜4.6
-Ink methyl-1,2,3,4-tetrahytronaf)
-7-yl]-vinylcubenzonitrile 13.59 m ethanol and ION caustic soda solution 200 m
heated to boiling temperature for 3 hours in a mixture with mg. After cooling, it was poured into 1 t of water, the colorless precipitate was suction filtered, and after drying K, CE) -4-(2-methyl-2-(1,1,
4,4,6-bentamethyl-1.2,3.4-tetrahydronaphth-7-yl]-vinylcoubenzoic acid (melting point 2
(04-206°C) 14.99 was obtained (see Example 2).

The compounds listed in the table below were synthesized (E)-4-[2-methyl-2-<x, ,4. t,a-pentamethyl-1゜2
．． 3.4-tetrahydronaphth-7-yl)-vinyl"
Gaseous Mizuki chloride was introduced into the bath of benzo-tf acid 401 at the boiling temperature of the reaction mixture until saturation. Continuing,
The mixture was further maintained at boiling temperature for 4 hours, and after cooling was washed with nitrogen. After evaporation of the reactants, it was soaked with 30rnt of methanol, filtered and the residue was dried. (E) -4-[
2-Methyl~2-(1゜1j4.,4,6-bentamethyl-1,2,3.4-tetrahydronaphtho-7-
yl]-vinylcoubenzoic acid ethyl ester (melting point l(
] 99-110°C 93.6 was obtained (see Example 1)
.

Example 18 (E)-4- in 200 d of anhydrous tetrahydrofuran
[2-Methyl-2-(1,1,4,4-tetramethyl-
1,2,3,4-Tetrahydronaphth-7-yl)-vinylbenzoic acid (see Example 2) was rapidly added to a suspension of 20.9r of tetrahydronaphth-7-yl) and 5.8 parts of pyridine.
Anhydrous thionyl chloride in 0-5.37! bath solution was added. After stirring for 2 hours at room temperature, the precipitate formed was separated from the P and the filtrate was made up to a total volume of 240 cm with tetrahydrofuran.

100 tnt of this bath solution was gradually added within 10 minutes to 8.2 tnt of p-aminophenol in tetrahydro7ran 100-
1 suspension. Subsequently, the mixture was stirred at room temperature for a further 20 hours. The reaction mixture was stirred into 1 t of water and 2N
After acidification with hydrochloric acid, the precipitate formed was separated off and recrystallized from ethanol with addition of water.

After separation and drying, (E) -4-C2-methyl-2-(
1,1,4,4-tetramethyl-1,2,3゜4-tetrahydronaphth-7-yl)-vinylcoubenzoic acid mono(
4-Hydroxyanilide) (melting point 252-253℃J1
1.1r was obtained.

13C-CNR spectrum (ds-DMSO) The resonance signal appearing at 17.30 ppm for the methyl group bonded to carbon atom 2 of the olefinic ethylene group indicates that the adduct obtained is the E-(trans)-isomer. Show that.

Examples 19-21 The compounds listed in the table below were obtained analogously to Example 18: Zeng 31 Example 24 (E)-4-C2-Methyl-2-(1, 1,4,4-tetramethyl-1°2.
3.4-tetrahydronaphth-7-yl)-vinyl"-
Benzoic acid (see Example 2) To the suspension of 1.8 S' and pyridine 0.5- was rapidly added a solution of thionyl chloride 0.5- in tetrahydro7ran 5-. After stirring for 2 hours at room temperature, the precipitate formed was filtered off and the solution f was added to a suspension consisting of 0.52 kg of anhydrous 5-aminotetrazole and 0.51 kg of pyridine in 20 kg of tetrahydrone and subsequently The mixture was further stirred at room temperature for 20 hours. The reactant was stirred into 400 ml of water, acidified with 2N hydrochloric acid, and the precipitate formed was separated from F and washed with methanol and petroleum ether. (E) -4-C2-methyl-2-(1,1
4.4-Tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-N-(tetrazol-5-ylcoubenzoic acid amide (melting point 289-290°C
) 1.7 F is obtained.

C-NMR spectrum (d6-DMSO) 1 for the methyl group bonded to carbon atom 2 of the olefinic ethylene group
The resonance signal appearing at 7.41 ppm indicates that the obtained compound is the E-(trans no isomer).

Examples 25-29

Claims (6)

[Claims] (1) Formula: [In the formula, A represents an alkylene group optionally substituted with a Cl-4-alkyl group, R1 represents a hydrogen atom or a methyl group, R2 represents a hydrogen atom, and R2 represents a methyl group, R3 is a hydrogen atom or C1-8-
represents an alkyl group, R4 represents a Cl-4-alkyl group and R' represents a P-hydroxyphenyleneaminocarbonyl group or a tetrazol-5-yl-aminocarbonyl group, or R3 represents a Cl-8-alkyl group; When represented, it can represent a carboxyl group or a 02-4-carbalkoxy group] and its salts with physiologically acceptable bases. (2) In formula f, A represents an ethylene group, R1 and R2 represent a methyl group, R3 represents a 01-8-alkyl group, R4 represents a methyl group, and R5 represents a carboxyl group or a C2-4- represents a carbalkoxy group,
A phenylethylene derivative according to claim 1 and its salt with a physiologically acceptable base. (3) The phenylethylene derivative according to claim 1 or 2, wherein the phenyl rings are in trans position with respect to each other. (4) (1) -4-(2-methyl-2-(1,1,
4゜4-Tetramethyl-6-ynbutyl-(2-methylglobil)-1,2,3,4-tetrahydronaphtho-7
The phenylethylene derivative according to claim 1, which is -yl)-vinylcoubenzoic acid. (5) Formula: RI H2 [In the formula, A represents an alkylene group which may be substituted with an 01-4-alkyl group, R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group. , R3 is a hydrogen atom or c1-8-
represents an alkyl group, R4 represents a C,~4-alkyl group, and R5 represents a l)-hydroxyphenyleneaminocarbonyl group or a tetrazol-5-yl-aminocarbonyl group, or R3 represents a 01-8-alkyl group. can represent a carboxyl group or a 02-4-carbalkoxy group] and its salt with a physiologically acceptable base. Il: H2OCM. [In the formula, A and R1□ R4 do not represent the above] A compound represented by the formula m = [In the formula, R6 represents the same as listed for RIIK or represents a cyano group, and R7 represents c1 -represents a 4-alkyl group] based on the Witsch-Horner reaction, or by reacting with a phosphorus compound represented by the formula (2): [wherein A, R', R2, RB and R4 are the above-mentioned ones] and X represents a chlorine atom or a bromine atom] is reacted with a benzaldehyde derivative of the formula v: [wherein R6 represents the above] based on a Witzig reaction, and subsequently R6 is If it does not represent a carboxyl group, the compound so obtained is optionally saponified and the free acid thus obtained or directly obtained is subsequently optionally converted to C! ~3-alcohol, p-hydroxyaniline is 5
- Process 0 for the preparation of phenylethylene derivatives, characterized in that they are reacted with aminotetrazole and the compound thus obtained is optionally converted into its salt with a physiologically acceptable base. (6) Formula: [In the formula, A represents an alkylene group optionally substituted with a cl-4-alkyl group, R1 represents a hydrogen atom or a methyl group, R2 represents a hydrogen atom or a methyl group, R3 is a hydrogen atom or 01-8-
Represents an alkyl group, RQ! When Cs~represents a 4-alkyl group, A medicament containing a phenylethylene derivative represented by the following formula (which may represent a carboxyl group or a 02-4-carbalkoxy group) and its salt with a physiologically acceptable base.