DE3202118A1 - Substituted vinylbenzoic acid derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Vinylbenzoic acid derivatives of the formula (I) <IMAGE> in which R<1> and R<2> denote hydrogen or a methyl group, R<3> denotes an alkyl group having 1 to 4 carbon atoms, R<4> denotes a short-chain alkyl group, such as the methyl or ethyl group, R<5> denotes a carboxyl or a carbalkoxy group having up to three carbon atoms in the alkyl moiety and A denotes a methylene or ethylene radical which is optionally further substituted by alkyl groups, preferably the methyl group, and their physiologically tolerable salts, processes for their preparation and pharmaceutical compositions containing them, in particular for the treatment of neoplasms, acne, psoriasis, dermatological complaints and in rheumatic disorders.

Description

BASF Aktiengesellschaft 0.2.

"Substituted vinylbenzoic acid derivatives, their preparation and pharmaceutical preparations containing them

It is known, for example, from DE-OS 28 54 354 that stilbene derivatives have pharmacological effects in the topical and systemic therapy of neoplasms, acne, psoriasis and other dermatological conditions.

It is known to the person skilled in the art that the abovementioned stilbene - Derivatives are not always satisfactory. The main disadvantage is their pronounced toxic (side) effect, using these compounds as agents in the topical and systemic therapy of neoplasms, acne, and psoriasis make other dermatological affections seem unsuitable. The power of the stilbene derivatives DE-OS 28 54 354 is for example by A. Kistler in Calcified Tissue International 3J5, 249-254 (1981) and is revealed after repeated application to rodents, according to that of R. C. Moon et al in Cancer Research _3, 1339-1346 (1979).

The present invention is therefore based on the object of providing compounds with a comparable potency and less to provide toxic side effects.

The invention relates to vinylbenzoic acid derivatives of the formula (I)

Copy

"XT ^ X.

(D ₉

BASF Aktiengesellschaft - ^ - 3- OZ 0050/35712

1 2
In which R and R are hydrogen or a methyl group,

R ^ is an alkyl group with one to four carbon atoms,

Ii
R is a short-chain alkyl group, such as the methyl or

Ethyl group, R a carboxyl or a carbalkoxy group 5 with up to 3 carbon atoms in the alkyl part and A one methylene or ethylene radical optionally further substituted by alkyl groups, preferably the methyl group means, and their physiologically acceptable salts, processes for their preparation and containing them IQ pharmaceutical preparations, particularly useful in the treatment of neoplasms, acne, psoriasis, dermatological Affections and rheumatic diseases can be used.

5. The wavy C-C-3 bond can be before or run behind the plane of the drawing and therefore belong to a cis (Z -) - or a trans (E -) connection that both are according to the invention ..

Q Typical examples of compounds according to the invention are

Ethyl 4- [2-methyl-2- (1,1,4,4,6-pentamethy1-1,2,3,4-tetrahydronaphth-7-yl) vinyl] -benzoate

4- [2-Methyl-2- (1,4,4,6-pentamethy1-1,2,3,4-tetrahydronaphth-7-yl) vinyl] benzoic acid

4- [2-methyl-2- (l, l, 6-trimethyl-l, 2,3,4-tetrahydronaphth-7-yl) vinyl] benzoic acid

Ethyl 4- [2-methyl-2- (l, l, 6-trimethyl-l, 2,3,4-tetrahydronaphth-7-yl) vinyl] benzoate

Ethyl 4- [2-Sthy1-2- (1,1,4,6-pentamethy1-1,2,3,4-tetrahydronaphth-7-yl) vinyl] -benzoate

3 2 O 2Ί 1

8ASF Aktiengesellschaft - y- Lf OZ 00 ^ 0 / ^ 5712

^r 4- [2-Ethyl-2- ( _{1,1 J} 4 _i 4,6-pentamethy1-1,2,3,4-tetrahydronaphth-7-yl) vinyl] benzoic acid

Ethyl 4- [2-methyl-2- (1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphth-7-yl) vinyl] -benzoate

4-C2-Methy1-2- (1,1,4,4-tetramethyl-6-ethy1-1,2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid

4- [2-methyl-2- (l, l, 4,4-tetramethyl-6-isopropyl-l, 2,3,4- -tetrahydronaphth-7-yI) -vinyl! -benzoic acid

4- [2-methyl-2- (l, l, 4,4-tetranethyl-6-isopropyl-l, 2,3,4- -tetrahydronaphth-7-yI) -vinyl] -benzoic acid ethyl ester

4- [2-Methy1-2- (1,1,4,4-tetramethyl-6-propy1-1,2,3,4-tetra-

hydronaphth-7-yl) vinyl] benzoic acid

4- [2-Methy1-2- (1,1,4,4-tetramethyl-6-propyl-1,2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid ethyl ester

4- [2-Methy1-2- (1,1,4,4-tetramethy1-6-butyl-1,2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid methyl ester

4- [2-Methy1-2- (1,1,4,4-tetramethyl-D-butyl-1,2,3,4-tetrahydronaphth-7-yI) -vinyl] -benzoic acid ethyl ester

4- [2-Methy1-2- (1,1,4,4-tetramethyl-6-butyl-1,2,3,4-tetrahydronaphth-7-yl) vinyl] benzoic acid 30th

4- [2-Methy1-2- (1,1,4,4-tetrabethy1-6- (2-methyl-o- (2-methy1- propyl) -l, 2j3,4-tetrahydronaphth-7-yI) -vinyl] -benzoic acid ethyl ester COPY

BASF Aktiengesellschaft - JX- £ ^% ° · ^ζ -

'4-E2-Methy1-2- (1,1,4,4-tetramethy1-6- (2-methyl-propyI) - ""

-1,2,3,4-tetrahydronaphth-7-yI) vinyl] benzoic acid

Ethyl 4-C 2 -methy1-2- (1,1,3,4 , 'k , β-hexamethy1-1,2,3,4-tetrahydronaphth-7-yl) vinyl] benzoate

4-C2-Methy1-2- (1,1,3,4,4, β-hexamethy1-1,2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid

4- [2-Methy1-2- (1,1,2,3,3,5-hexamethyl-indan-6-yI) -vinyI] - ethyl benzoate

4- [2-methyl-2- (l, l, 2,3,3,5-hexaraethyl-indan-6-yl) vinyl] - propyl benzoate

4- [2-Methy1-2- (1,1,2,3,3,5-hexamethyl-indan-6-yl) -vinyI] - -benzoic acid isopropyl ester

4-C 2-Methy1-2- (1,1,2,3,3,5-hexamethyl-indan-6-y1) vinyl] - -benzoic acid

4- [2-Methy1-2- (1,1,3,3,5-pentamethyl-indan-6-yl) vinyl] - -benzoic acid

4- [2-methyl-2- (l, l, 3,3,5-pentamethyl-indan-6-yl) vinyl] - -benzoic acid ethyl ester

Ethyl 4- [2-Methy1-2- (1,1,3,3,5-pentamethyl-indan-6-yl) -vinyI] - -benzoate
30th

4- [2-Methy1-2- (1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid methyl ester

u - ¹

BASF Aktiengesellschaft - y ^ - £. 0.2. OO5C / 25712

Propyl 4- [2-methyl-2- (l, l _J 4,4,6-pentamethyl-l, 2 _J 3 _J ^l t-tetrahydro naphth-7-yl) vinyl] benzoate

Ethyl 4- [2-ethyl-2- (l _i l _J 4,4,6-pentamethyl-1,2,3 _J ⁱ i-tetrahydronaphth-7-yl) vinyl] benzoate

4- [2-Sthyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yD-vinyl] -benzoic acid

4- [2-Sthy1-2- (1,1,4,4,6-pent ame thy 1-1, '2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid methyl ester

as well as those particularly mentioned in the following examples but not included in the above list Links.

The substances according to the invention can be used topically and systematic therapy of benign and malignant neoplasms, of premalignant lesions as well as systemic and topical prophylaxis of the affections mentioned will. They are also used for topical and systemic therapy for acne, psoriasis and others an increased or pathologically changed keratinization associated derraatoses, as well as inflammatory and allergic dermatological affections or diseases, as for example in G. Plewig and A. M. Kligman in "Acne riorphogenesis and Treatment", Springer-Verlagj Heidelberg 1975, are described, suitable. Furthermore, the compounds according to the invention can also in the fight against mucous membrane diseases with inflammatory or degenerative, metaplastic changes or rheumatic diseases in 3 consideration come.

BASF Aktiengesellschaft -X-? O. Z. 0050 / ^ 5712

'"The connections according to the invention can be applied to different Manufacture ways that are known in principle. E.g. you can use a carbony compound of the formula (II)

w ^{(II) i}

in which R, R _9, R ⁵ , R and A have the meanings given above, with a phosphorus compound of the general formula (III)

yn, r * JI r ~ \ \ _T! H - K r VLL-Wi

in the B? has the meaning given above and R denotes an alkyl group with, for example, up to three carbon atoms in the alkyl part, according to the so-called Wittig-Horner reaction. It is expedient to work in a solvent in the presence of the basic compounds customary for Wittig-Horner reactions. The compound obtained can advantageously be converted into a physiologically acceptable salt in a solvent and, if appropriate, in the presence of an acid-binding agent, if appropriate with a basic substance.

° OPY

32Ö2T18 "

BASF Aktiengesellschaft - y-%. 0.2. 0050/35712

"" One can also first establish a connection in an analogous manner in which R means the Nitri! group and this then saponify. The preparation of the corresponding benzoic acid nitriles is filed in the at the same time Patent application P described.

The reaction according to Wittig-Horner proceeds at a temperature of up to 10O ⁰ C, preferably at 20 to 50 ⁰ C. The reaction may be at atmospheric pressure or in a closed vessel at elevated pressure, optionally with heating to the specified temperature range performed.

This reaction can be carried out in the presence of a “diluent or solvent, for example a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ether, such as diethyl ether, ethyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon such as benzene or an alkylbenzene such as toluene or xylene, or a saturated aliphatic hydrocarbon such as hexane, heptane or isooctane, a lower aliphatic ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkyl formamide such as dimethyl or diethyl formamide, or in mixtures of the solvents mentioned . preferable to use cyclic ethers such as dioxane or tetrahydrofuran, and in particular, dimethylformamide or mixtures thereof, wherein the reaction is generally carried out at a temperature up to 30 ⁰ C expires.

The reactions are carried out in the presence of a deprotonating agent made for the phosphate (III). Alkali metal hydrides and alkali metal amides are particularly suitable of sodium and potassium, the sodium and potassium salts of

35

"- copy

IAS? Aktiengesellschaft - j / - *). 0.2. 0050/35712

^r Dimethyl sulfoxide, alkyllithium compounds such as n-butyllithium or alkali metal alcoholates, preferably sodium methoxide and sodium ethoxide. -

The vinyl benzoic acid esters of the general formula (I), in which thus R ^ means a Carbοalkoxygruppe, are, if desired, into the free carboxylic acids and their physiologically tolerable salts, by ester saponification convicted. Conversely, the free acid can of course be esterified in a known manner.

The hydrolysis takes place in the customary manner at generally up to 120 ^° C. and is preferably carried out at the boiling point of the reaction mixture. 5

It can be carried out at atmospheric pressure or in a closed vessel under increased pressure.

i The saponification / esterification is expediently carried out in

0 was a diluent or solvent, for example a dialkyl glycol ether or cyclic ether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, one lower aliphatic ketones, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, the esterification especially in

! 5 the intended lower aliphatic alcohol, such as

Methanol, ethanol, propanol or isopropanol, if appropriate in the presence of water or in mixtures of the above Solvent carried out with water.

Preferred solvents are aqueous mixtures of ethanol and methanol, the reaction taking place at the boiling point of the reaction mixture is carried out.

BASF Aktiengesellschaft -o / ^ · / [QOZ OO5C / 35712

^r The saponification is particularly preferred to sodium 'and potassium, organic tertiary bases such as pyridine or lower trialkylamines, such as trimethylamine or triethylamine is done in the presence of alkali such as alkali metal hydroxides, alkali metal carbonates and bicarbonates, in mixtures with water. The base used is used in a stoichiometric amount or in a slight excess relative to the ester. Sodium or potassium hydroxide is preferably used.

The esterification is advantageously carried out by introducing hydrogen chloride gas into the reaction mixture. The methyl esters can also be obtained by the action of diazomethane on the free acid.

You can also use the compounds according to the invention Wittig reaction of a phosphonium salt of the general formula (IV) ...

P ^

(IV),

12 3 4
in which R, R, R, R 'and A mean the above

have and X is a suitable anion, preferably chlorine or bromine, with a p-carbalkoxy-bensaldehyde of formula (V)

COPY

BASF Aktiengesellschaft - \ ό / - ηη . OZ 0050,05712

_r he T

where Fr has the meaning given above. If appropriate, the esters obtained are converted into the free acid or a physiologically acceptable salt.

The starting compounds of the formula (II) can be uniform have the cis or trans structure or represent mixtures of the two E / Z isomers. An isomerization at In addition, the aforementioned implementations cannot be ruled out. The resulting mixture in such cases, for example of the compounds of the formula (I) according to the invention can by HPLC analysis or by a ^ C-NMR spectrum determined quantitatively and the isomer desired in each case, optionally by fractional crystallization or Chromatography with, for example, silica gel columns or isolated isomerically pure by preparative HPL chromatography will.

The compounds according to the invention have, insofar as they are derivatives represent the free benzoic acid, an acidic hydrogen atom and can therefore with bases in the usual way in a physiologically compatible, readily water-soluble Salt to be transferred. Suitable salts are, for example, ammonium, alkali metal, especially sodium, Potassium and lithium, alkaline earth metal salts, in particular calcium or magnesium, and salts with suitable ones organic bases, such as with lower alkyl amines, e.g. Methylamine or ethylamine, with substituted lower alkylamines, in particular ~~ hy ~ drö "xysubstituted alkylamines, such as diethanolamine, triethanolamine or tris (hydroxymethyl) aminomethane, Piperidine or morpholine.

The compounds according to the invention and their physiological ' ■ Compatible salts can be used in topical and systemic therapy due to their pharmacological properties "COPY

SASF Public Company -1 ^ - /) £. 0.2. C05SO571

^p and also prophylaxis of precancerous diseases and carcinomas of the skin, the mucous membranes and internal organs as well as in the topical and systemic therapy of acne, psoriasis and other dermatological diseases associated with pathologically altered cornification and for the treatment of rheumatic diseases, especially those of an inflammatory or degenerative nature, affecting joints, muscles, tendons and other parts of the musculoskeletal system. In addition to the therapy of dermatological diseases, a preferred area of indication is the prophylactic and therapeutic treatment of pre-cancerous diseases and tumors.

The pharmacological effects can for example in the following test models are shown: The compounds according to the invention raise hamster rancheal · tissue in vitro that occurs after vitamin A deficiency Keratinization. This keratinization belongs to the early phase of carcinogenesis, which is carried out in a similar technique in vivo after initiation by chemical compounds, by energetic radiation or after viral cell transformation by the compounds according to the invention of the formula. (I) is inhibited. This methodology can be taken from Cancer Res. _3_6, 964-972 (197ο) or from Nature _25O, 64-66 (1974) and Nature 25-3, 47-50 (1975).

In addition, the compounds according to the invention inhibit the proliferation rates of certain malignant cells. This methodology can be found in J. Natl. Cancer Inst. JSO, 1035-1041 (1978), Experimental Cell Research JL17, 15-22 (1978) and Proc. Natl. Acad. May be. USA 77, 2935-2940 (198Ο) can be taken. Furthermore, reference is made to the determination of the antagonistic effect against phorbol esters, as described in Cancer Res. _3 £, 2196-2201 COPY

35 (1977).

ASF Aktiengesellschaft -Vl / - ή2. 0.2. 00 _p 0/3 p712

^r The anti-arthritic effect of the compounds of the invention can be determined in a conventional manner in the animal experiment in the adjuvant arthritis model. The dermatological activity, for example for the treatment of acne, can be demonstrated by the comedolytic activity and the ability to reduce the number of cysts in the rhino mouse model.

This method is described by L. H. Kligman et al in The Journal of Investigative Dermatology 73, 35-358 (1979).

Accordingly, the invention furthermore relates to therapeutic agents for topical and systemic use which contain a compound of the formula (I) as an active ingredient in addition to customary carriers or diluents, and the use of a compound of the formula (I) for the production of a medicament. _j

The production of the therapeutic agents or preparations takes place with the usual liquid or solid · Carriers or diluents and the pharmaceutical-technical auxiliaries used in the usual way, according to the desired type of application and with a dosage suitable for the application, in the usual way, for example by mixing the active ingredient with the solid or liquid normally used in such preparations Carriers and auxiliary materials.

The agents can accordingly be administered orally, parenterally or topically. Such preparations are for example tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions, infusion or Injection solutions as well as pastes, ointments, gels, creams, COPY Lotions, powders, solutions or emulsions and sprays.

BASF Aktiengesellschaft -13 / - Ak. ° ' ^Z ' °° 50/35712

therapeutic agents can be used according to the invention Compounds used when applied locally in a concentration from 0.001 to 1.0%, preferably from 0.001 to 0.1% concentration Concentration and preferably for systemic use contained in a single dose of 0.1 to 50 mg and daily in one or more doses depending on the type and Severity of the disease to be administered.

commonly used pharmaceutical technical auxiliaries are for example for local use alcohols such as isopropanol, ethoxylated castor oil or ethoxylated hydrogenated castor oil, polyacrylic acid, glycerol monostearate, Paraffin oil, petrolatum, wool grease, polyethylene glycol 400, polyethylene glycol 400 stearate and ethoxylated Fatty alcohol, for systemic use, milk sugar, propylene glycol and ethanol, starch, talc, polyvinylpyrrolidone. The preparations can optionally contain an antioxidant, for example tocopherol as well butylated hydroxyanisole or butylated hydroxyltoluene or flavor-enhancing additives, stabilizers, Emulsifiers, lubricants, etc. can be added. The prerequisite is that all are pharmaceutical in the manufacture The substances used in the preparation are toxicologically harmless and are compatible with: the active substances used.

Preparation of the compounds according to the invention

example 1

(Ξ) -4- [2-Methy1-2- (1,1,4,4, o-pentamethy1-1,2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid ethyl ester

To a suspension of 250 ml of dimethyl sulfoxide and 9 g SO ^ iges iNiatriumhydridj previously with petroleum ether from 20iigen Paraffin portion had been freed within a half an hour a solution of 90 g of p-carboxyethyl-benzyl-

Aktiengesellschaft - \ V <- / IS ' OZ- 0050/35712

^r phosphonic acid diethyl ester in 150 ml of DMSO was added dropwise at about 35 ° C. Subsequently, for about 2 hours at 4O ⁰ C is stirred and a solution of 36.6 g of 7-acetyl-1,1,4,4,6-pentamethyltetralin added dropwise within 10 minutes in 70 ml of dimethyl sulfoxide. ·

The next day, 100 ml of ethanol are added to the mixture, the mixture is poured onto 2 liters of ice-water and acidified with 2N hydrochloric acid. The resulting solid is filtered off and rinsed on the filter with 150 ml of ethanol and, for fine cleaning, washed with 75 ml of methanol. There remain 35 g of (E) -4- [2-Methyl-2- (l, 2,4,4,6-pentamethyl-l, 2,3, ⁱ i-tetrahydronaphth-7-yl) -vinyl] -benzoic acid ethyl ester from m.p. 108 to 109 ° C.

The HPLC analysis (Si 60 5 / um, 150 bar, .n-heptane / ethyl acetate (93: 2), t _R = 3.1 min) shows an isomer purity greater than 93 % .

■ ^ C-NMR spectrum (CDCl ,, data in ppm)

(The method of counting the carbon atoms was made arbitrarily for the assignment of the NMR signals)

BASF Aktiengesellschaft

O. Z, OC5C / 35712

Ί4.4θ (C ₂₁ ); 19.74 (C _37); 20.35 (C _26); 31.96 (C ₃₅ , 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 _16, C _12); 128.55 (C _5); 129.00 (C 1 _{-C 18} ); 129.63 (C _15, C _17); 131.72 (Cg); L4L, 98 (C _13); 142.93 (C _11); 143.11 (C ₁₀ ); 143.83 (C ₉ ); 166.80 (C _19);

The signal at 19.74 (C ₂₇ ) confirms the Ξ (trans) geometry of the compound.

Example 2

25 30

4.7 g (E) -4- [2-methyl-2- (1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid ethyl ester are stirred with 1.7 g of 86 ^ potassium hydroxide in a mixture of 100 ml of ethanol and 5 ml of water for 6 hours at 8O ⁰ C. After the entire reaction mass has been transferred to 1 liter of water, it is acidified with 2N hydrochloric acid, the colorless precipitate obtained is filtered off and, after drying on the suction filter, washed with 100 ml of heptane. After drying, 4.0 g of (E) -4- [2-methyl-2- (l, l, 4,4,6-pentamethyl- -1,2,3,4-tetrahydronaphth-7-yI) - vinyl! -benzoic acid of m.p. 206 ⁰ C.

13,

i-NMR spectrum (dg-DMSO, data in ppm)

(The method of counting the carbon atoms was made arbitrarily for the assignment of the NMR signals).

COOH

35

COPY

BASF Aktiengesellschaft - iyC 4 ?. 0.2. 0050/35712

"19.36 (C ₂₅ ); 20.17 (C ₂₄ ); 31.60 (C ₃₀ , C ₂₁ , C ₃₃ , C ₃₃ ); 33.51 (C ₂ , C ₃ ); 3 ^, 71 ( C ₄ , C ₁ ); 125.40 (Cg); 128.00 (C ₅ , C ₁₃ ); 128.61 (C ₁₆ ); 128.95; 129.42 (C ₁₄ , C ₁₈ ); 129, 42 CC ₁₅ , C ₁₇ ); 131.12 (C ₆ ); 141.20 (C ₁₃ ); 141.70 (C ₇ ); 142.16 (C ₁₀ ); 142.52 (C ₁₁ ); 143, O8 (C _9); 1β7,26 (C _19).

The signal at 19.36 (C ₃ ^) demonstrates the E (trans) geometry of the compound.

Example 3

13.5 g (E) -4- [2-methyl-2- (l, l, 4,4,6-pentamethyl-l, 2,3,4- Tetrahydronaphth-7-yl) vinyl] benzonitrile are dissolved in a mixture of 200 ml of ethanol and 200 ml of 10 N sodium hydroxide Heated to boiling temperature for 3 hours. After cooling, it is poured into 1 liter of water, the colorless low- • chop off and after drying you get 14.9 g (E) -4- -C 2-methyl-2- (1,1,4,4,6-pentamethy1-1,2,3,4-tetrahydronaphth-7- yl) vinyl] benzoic acid from m.p. 204 to 206 ° C, which is identical to that prepared in Example 2 Material.

The compounds listed in the table below are either by Wittig-Horner reaction or by Saponification of the corresponding esters or nitriles produced.

BASF Aktiengesellschaft

0.2. 0050/35712

= r U «a) ι

N ^- VUI 7

'' ^Η I '' I

ι ι ι

3- O V

5 (M I. I. ! ■ «<" \
O ι I. ι I. ι ι

ORIGINAL

O
ι I. 1 ORfGINAL ^; ! Κ> - - ¹ T
I. no- - ^? -
T -;
γ ι -CIl -ClI ι = 5ΡΡΓΤΓΡΠ BATH

Stereo value of chemistry formerly shift

( ¹³ C-NMH) of H * ¹ [ppmj

rtaine

CH ₃ -CH ₁ J-CIl- -CH _:

-ClI. -COOC ₂ II ₅ 10Ü

(E) -1- [2-methyl-2-

(1,1,3, 'Mo-hexamet nyll "2,3, ¹ l-tetrahydronaphth-7-

y 1 J-vinyl / benzoic acid ethyl ester

-CH ₂ -CUy- -

CIl ₃ -CH, -CIl,

-couii

276-277 e.g.

10.48 (Z) -1- [2-methyl-2-,

(1,1,1, t, 6-pentamethyll >> 2,3 > 't-ttilruiiydronaphth-7-yl ) vinyl / benzoic acid

-Cl! ..- CH, .- -Cl-, -Cll. -CII ₀ -CII ₀ -CII. -CII., -COUIl iy8-l <) 9

) y ,,, tet diamonds hy 1-6-propyl-1,2,3 j'l-tetrahydronaphth-7-y1) -vinylJ-benzoic acid

-CII ₂ -CII-

-CII -CIi ₃ -CIl ₃

-CH. -CÖÜH

2ί> 1 Ε

(E) -l | - [2-Hetiiyl-2- (1,1,3, Ί, Ί, 6-hexamethyi- ^^ At

^ ,, yp yi) -vinylJ-benzoic acid

-CII ₂ -CH ₂

-CH., -CH-, -CIl-,

-CH ₀ -CII. -COOH 2'j2 Z 32.79 (-CIl ₀ -) (E) -4- [2-ethyl-2- (1,1, 'I,' I * ^^ eetramethyll itetra

y ^^. hydronaphth-7-yl) vinyl / benzoic acid ti

Oil

ρ co St. hO O ö O O VoT \ VJI —J l · - ' Iv)

BASF Aktiengesellschaft - 1 ^ - JlV- ° ²

^ Example 14

In a solution of 4.0 g of (E) -4- [2-methyl ~ 2- (1,1,4,4,6-pentamethy1-1,2,3,4-tetrahydronaphth-7-yl) vinyl ! -benzoic acid in 300 ml of ethanol is passed in gaseous hydrogen chloride at the boiling point of the reaction mixture until it is saturated. It is then kept at the boiling temperature for a further 4 hours and, after cooling, flushed with nitrogen. After evaporation of the reaction mass, it is digested with 30 ml of methanol and the remaining solid is filtered off and dried. There remain 3, δ g of (E) -4- [2-methyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl) vinyl] - ethyl benzoate of melting point 109 to HO ⁰ C. The material is identical to that

15 esters prepared according to Example 1.

COPY

Claims (1)

Claim Viny! Benzoic acid derivatives of the formula (I) (D, 1 2
in which R and R are hydrogen or a methyl group, R ^ is an alkyl group with one to four carbon atoms, R is a short-chain alkyl group such as the methyl or ethyl group, R- ^{3 is} a carboxyl or a carbalkoxy group with up to 3 carbon atoms in the alkyl part and A denotes a methylene or ethylene radical optionally further substituted by alkyl groups, preferably the methyl group, and their physiologically acceptable salts, processes for their production and pharmaceutical preparations containing them. ' copy 743/81 Mu / IG 22.01.I9S2