LU84703A1 - PHENYLETHYLENE DERIVATIVES, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS - Google Patents

Description

! / / • - i «BASF Aktien Gesellschaft O.Z. 0050/35710 / 35711/35712 1 phenylethylene derivatives, their preparation and use n as medicaments 4 The invention relates to phenylethylene derivatives, process 5 for their preparation and therapeu-containing them; means and their use in combating! Diseases.

: t; From DE-OS 28 54 354 it is known that stilbene derivatives I ioo pharmacological effects in the topical and systemic therapy of neoplasia, acne, psoriasis and; have other dermatological affections. The main disadvantage, however, is the pronounced toxic I (side) effect of these compounds, which they use as agents in I 15 of topical and systemic therapy of neoplasia, i I acne, psoriasis and other dermatological affections i.

! make it seem unsuitable. The disadvantage of the J stilbene derivatives of DE-OS 28 54 354 is described, for example, by A. Kistler in Calcified Tissue International _33, 20 '249-254 (1981) and is particularly evident! repeated application on rodents according to the von! R.C. Moon et al [Cancer Research 39, 1339-1346 (1979) 3ίI published method.

j "" 25 The present invention is based on the object of providing t 'compounds with comparable potency but less toxic side effects.

The invention relates to phenylethylene derivatives of the formula 30 H-C CH. 4! 35 Bl / K2

J

. u i 5A5F stock corporation - 2 - 0.2. 0050/35710 / 35711/35712 «« * · where n A is an alkylene radical which may be substituted by a ^ -alkyl group, c R ^ is a hydrogen atom or a methyl group, 5 R2 is a hydrogen atom or a methyl group, o RJ is a hydrogen atom or a C R- Alkyl group, ii -1 “0 R a ^ -alkyl group and R ^ an n-hydroxyphenyleneaminocarbonyl-, tetrazol-5-yl-aminocarbonyl group or - if R represents a C ^ _g-alkyl • JO group - also a carboxyl or s represent alkoxy group, and optionally their salts with physiologically compatible bases.

* -g A is preferably a methylene or ethylene group optionally substituted by a methyl i: group.

y The connections in which the j | Phenyl rings are trans-constant to one another.

1 20 'J ---------------- - i; The W-shaped C-C bond can be placed before or v.

! run behind the drawing level and therefore belong to a jl cis (Z -) or a trans (E -) connection.

I: - M - il * !! 2 * Typical examples of. Compounds according to the invention are: h:

I.

I 4- [2-methyl-2- (1,1,4,4, β-pentàmethyl-l, 2,3,4-tetrahydro-I n aphth-7-yl) -viny1] -b enzoic acid, ethyl ester l I 30 4- [2-methyl-2- (1,1,4,4,6-pentamethyl-l, 2,3,4-tetrahydro-i naphth-7-yl) vinyl] benzoic acid

4- [2-Methyl-2- (1,1,6-trimethyl-l, 2,3,4-tetrahydro-naphth-7-yl) vinyl] benzoic acid 3S

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; »BASF share community - 3 - c2 * 0050/35710 / 35711/35712 j '4-E 2-methyl-2- (1,1,6-trimethyl-1,2,3,4-tetrahydro- - naphth- 7 ~ yl) -vinyl] -benzoic acid ethyl ester! - 4-C2-Ethyl-2- (l, 1,4,4,6-pentamethyl-l, 2,3,4-tetrahydro-5 naphth-7-yl) -vinyl] -benzoic acid ethyl ester i; 4-E2-ethyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-yl) -vinyl] -b enzoic acid 1 V * '10 4 -C2-methyl-2- (l, l, 4,4-tetramethyl-6-ethyl-l, 2,3,4-tetra-hydronaphth-7-yl) -vinyl] -benzoate ethyl 4-C2-methyl- 2- (1,1,4,4-tetramethyl-6-ethyl-l, 2,3,4-tetra-hydronaphth-r7-yl) -vinyl] -benzoic acid 15 i 4-E2-methyl-2- (1 , 1,4,4-tetramethyl-6-isopropyl-1,2,3,4- -t etrahydr onaphth-7-yl) -vinyl] -benzoic acid 4-E 2-methyl-2- (1, 1,4,4-tetramethyl-6-isopropyl-l, 2,3,4-20 · -tetrahydronaphth-7-yl) -vinyl] -benzoic acid ethyl ester 4-C2-methyl-2- (1,1,4,4 -tetramethyl-6-propyl-l, 2,3,4-tetra-hydronaphth-7-yl) vinyl] -benzoic acid 25 4-C2-methyl-2- (1,1,4,4-tetramethyl-6 -propyl-1,2,3,4-tetra-j'hydronaphth-7-yl) -vinyl] -benzoic acid ethyl ester 4-C 2-methyl-2- (1,1,4,4-tetramethyl-6-butyl- l, 2,3,4-tetra-hydronaphth-7-yl) vinyl] benzoic acid methyl ester 30 4- [2-methyl-2- (1,1,4,4-tetramethyl-6-butyl-l, 2, 3,4-tetra-hydronaphth-7-yl) vinyl] benzoic acid ethyl ester i 4-E 2-methyl-2- (1,1,4,4-tetrame thyl-6-butyl-l, 2, 3,4-tetra! 35 hydronaphth-7-yl) vinyl] benzoic acid / ^ i BASF Aktiengesellschaft "4- 0, Z * 357 ^ / 357¾ r 4- [2-methyl-2- (l, l, 4,4-tetramethyl-6 - (2-Inethyl-6- (2-ethyl-"! -Propyl) -1,2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid - ethyl ester 4- [2-methyl-2 - (1,1,4,4-tetramethyl-6- (2-methyl-propyl) - w! -R, 2,3,4-tetrahydronaphth-7-yl) -vinyl] -benzoic acid ijj 4- [2- Methyl ethyl 2- (1,1,3,4,4,6-hexamethyl-l, 2,3,4-tetrahydronaphth-7-yl) vinyl] benzoate '10 '4- [2-methyl -2- (l, 1,3,4,4,6-hexamethyl-l, 2,3,4-tetrahydro- £ napbth-7-yl) -vinyl] -benzoic acid 4- [2-methyl-2- ( l, l, 2,3,3,5-bexamethyl-indan-6-yl) vinyl] -! ^ -benzoic acid ethyl ester I 4- [2-methyl-2- (1,1,2,3,3,5 -hexamethyl-indan-6-yl) vinyl] - -benzoic acid propyl ester [i I 20 '4- [2-methyl-2- (l, l, 2,3,3,5-hexamethyl-indan-6-yl) -vinyi] - J -benzoic acid isopropyl it ϊ î 4- [2-methyl-2- (1,1,2,3 3 3 3 5-hexamethyl-indan-6-yl) -vinyl] -} j - '-benzoic acid i - j 25 \ * "4- [2-methyl-2- (l, 1,3,3,5-pentamethyl-indan-6-yl) vinyl] - ij -benzoic acid I- I 4 - [2-methyl-2- (l, l, 3,3,5-pentamethyl-indan-6-yl) vinyl] -! 30 -benzoic acid methyl ester! }! ! 4, - [2-methyl-2- (1,1,3,3,5-pentamethyl-indan-6-yl) vinyl] - ethyl benzoate 35

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§> i », BASF shares society -5- cz- 0050/35710 / 35711/35712 r 4- [2-methyl-2- (1,1,4,4,6-pentamethyl-l, 2,3,4- tetrahydro- η naphth-7-yl) vinyl] -b enzoic acid methyl ester 3 4- [2-methyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro- 5 naphth-7-yl) vinyl] benzoic acid propyl ester 4 "[2-ethyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-th trahydr o-naphth-7- yl) -vinyl] -benzoic acid ethyl ester 10 4- [2-ethyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydr o- 55 naphth-7-yl) -vinyl ] -benzoic acid 4-C2-ethyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-yl) -vinyl] -benzoic acid methyl ester 15 4- [2 -Methyl-2- (1,1,4,4-tetramethyl-6-n-butyl-l, 2,3,4-tetra-hydronaphth-7-yl) vinyl] -b enzoic acid - 4-l2-methyl -2- (1,1,4,4-tetramethyl-6-n-octyl-l, 2,3,4-tetra-.

20 hydronaphth-7-yl) vinyl] benzoic acid 4- [2-methyl-2- (1,1,6-trimethyl-l, 2,3,4-tetrahydro-naphth-7-yl) vinyl] - benzoic acid 25 4- [2-methyl-2- (1,1,4,4-tetramethyl-l, 2,3,4-tetrahydrotent naphth-7-yl) vinyl] -N- (tetrazol-5- yl) -benzoate amide 4- [2-methyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydr0-naphth-7-yl) -vinyl] -N-tet razole -5-yl) benzoic acid amide 30 '4- [2-methyl-2- (1,1,4,4-tetramethyl-6-ethyl-l, 2,3,4-tetra-hydronaphth-7- yl) -vinyl] -N- (tetrazol-5-yl) benzoic acid amide 35 ii BASF Akiieneeseüschsft - 6 - 0.2. 0050/35710 / | '35711/35712! : * | r 4- [2-methyl-2- (l, l, 4,4-tetramethyl-6-isopropyl-l, 2,3,4- ^ -tetrahydronaphth-7-yl) -vinyl] -N- (tetrazol-5-yl) benzoic acid amide '5 4- [2-methyl-2- (1,1,2,3,3-pentamethyl-indan-6-yl) vinyl] - -N- (tetrazole -5-yl) ~ benzoic acid amide 4_ [2-methyl-2- (1,1,3,3-tetrahedral ethyl-indan-6-yl) vinyl] --N- (tetrazol-5-yl) - benzoic acid amide 10 * T 4- [2-methyl-2- (l, l, 4,4-tetramethyl-6-propyl-l, 2,3,4-tetra-hydronaphth-7-yl) vinyl] -N- (tetrazol-5-yl) benzoic acid amide 4- [2-methyl-2- (1,1,4,4-tetramethyl-6- (2-methyl-propyl) -15 -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-l, 2, 3,4-tetra-hydronaphth-7-yl) vinyl] -N- (tetrazol-5-yl) benzoic acid amide 20 4- [2-ethyl-2- (1,4,4,4-tetramethyl-1, 2,3,4-tetrahydro-naphth-7-yl) vinyl] -N- (tetrazol-5-yl) benzoic acid amide; 4- [2-Ethyl-2- (1,1,4,4,6-penta / methyl-l, 2,3,4-tetrahydro-2 5 naphthyl-7-yl) vinyl] -N- (tetrazole -5-yl) -benzoic acid amide 4- [2-methyl-2- (1,1-dimethyl-l, 2,3,4-tetrahydronpahth-7-yl) - vinyl] -N- (tetrazol-5- yl) -benzoic acid amide 30 4- [2-methyl-l, 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 35 [<u / / 5ASF Akiiencessüschsfi - 7 - OZ 0050/35710 / 35711/35712. jf! ! '. * 'ί' 'r 4- [2-methyl-2- (1,1,2,3,3,5-hexamethyl-indan-6-yl) vinyl] -1-N- (tetrazol-5-yl ) -benzoesâureamid! 5 4- [2-Methyl-2- (1,1,4,4-tetramethyl-l, 2,3,4-tetrahydro-5 naphth-7-yl) vinyl] benzoic acid- (4-hydroxyanilide) 4 - [2-Methyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-tetra-hydronaphth-7-yl) vinyl] benzoic acid- (4-hydroxyanilide) * 0 4- [2-Methyl-2- (l, l, 4,4-tetramethyl-6-ethyl-l, 2,3,4-tetra-!. * Hydronaphth-7-yl) -vinyl] -benzoic acid- ( 4-hydroxyanilide) 4- [2-methyl-2- (1,1,4,4-tetramethyl-6-isopropyl-l, 2,3,4 - tetrahydronaphth-7-yl) -vinyl] -benzoic acid- ( 4-hydroxy-5 anilide) 4-Γ2-methyl-2- (1,1,2,3,3-pentame ethyl indan-β-yl) vinyl] - benzoic acid- (4-hydroxyanilide) 20 · 4 -12-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-l, 2,3,4-tetra-hydronaphth-7-yl) vinyl] benzoic acid (4-hydroxyanilide) 25; '4- [2-methyl-2- (l, l, 4,4-tetramethyl-6- (2-methyl-propyl) -1,2,3,4-tetrahydronaphth-7-yl) vinyl] - benzoic acid - (4-hydroxyanilide) 30 4-C2-methyl-2- (1,1,4,4-tetramethyl-6-butyl-l, 2,3,4-tetrahydronaphth-7-yl) vinyl ] -benzoic acid- (4-hydroxyanilide) 4- [2-ethyl-2- (1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphth-7-yl) vinyl] benzoic acid - (4-hydroxyanilide)! 35 ^ i - 1 BASF AJciier.cesellschaft - 8 - 0. Z. 0050/35710 / 35711/35712 • / · i · p 4- [2-ethyl-2- (l, l, 4,4,6-pentamethyl -l, 2,3,4-tetrahydro-1-naphth-7-yl) -vinyl] -benzoic acid- (4-hydroxyanilide) s 4- [2-methyl-2- (1,1-dimethyl-l, 2, 3,4-tetrahydros, nai> hth-7-yl) vinyl] benzoic acid- (4-hydroxyanilide) 4- [2-methyl-2- (1,1,6-trimethyl-l, 2,3 * 4-tetrahydro-naphth-7-yl) vinyl] -benzoic acid- (4-hydroxyanilide) * q 4- [2-methyl-2- (1,1,3 * 3,5-pentamethyl-indan-6- yl) -vinyl] - -benzoic acid- (4-hydroxyanilide) · i | 4- [2-Methyl-2- (1,1,2,3,3,5-hexamethyl-indan-6-yl) vinyl] - -benzoic acid- (4-hydroxyanilide).

T5

The compounds according to the invention, insofar as they are derivatives of free benzoic acid, have an acidic water: atom and can therefore be converted with bases in a customary manner into a physiologically compatible, readily water-soluble salt. Suitable salts are, for example, ammonium salts, alkali metal salts, in particular sodium, potassium and lithium, alkaline earth metal salts, in particular calcium or magnesium, and salts with suitable organic bases, such as with lower alkyl 5 amines, e.g. Methylamine or ethylamine - with substituted “* ized lower alkylamines, especially hydroxy-substituted alkylamines - such as diethanolamine, triethanolamine or tris (hydroxymethyl) aminomethane -, piperidine or morpholine.

30th

If the new compounds have a tetrazole residue, their alkali and alkaline earth salts can be prepared.

35 / ^ BASF Aktiençeseüschaft - 9 - 0. 2. 00.50 / 35710 / 35711/35712 F The new compounds are made by

a) a compound of formula II

H-C CH-c J \ / 3 Λ-Η. ·

R R

1 4 10 wherein A and R -R have the meaning given in claim 1, with a phosphorus compound

Formula III

R5 - ^^ - CH2-P0 (0R7) 2 III, 6 5 where R has the meaning given for R or a 7

Cyano group and R 'represents a ^ -alkyl group, implemented according to Wittig-Horner or 20'

b) a phosphonium salt of the formula IV

f H3C \ / CH3 Θ 0

C-v '' '5sI''CH-P (C6H5) 3X

· - 25 <oSS3 · ιοί ä wherein A, R, R, RJ and R have the meaning given in claim 1 and X is chlorine or bromine, with a benzaldehyde derivative of the formula H-CO ^ g) - * 6 V, 35

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/ i - · SASr Àkiien Gesellschaft - 10 - 0.2. 0050/35710 / 35711/35712 '-t # • - <i * "in which R ^ has the meaning given above, is converted according to Wittig, and then - if R ^ is not a carboxyl group - the compound thus obtained is optionally saponified and if desired, the free acids obtained in this way or directly obtained are then reacted with a C 1-4 alcohol, p-hydroxyaniline or 5-aminotetrazole and the compounds thus obtained are converted into their salts 10 with physiologically compatible bases, if desired.

The reactions a) and b) take place at a temperature of up to 100 ° C., expediently at 20 to 50 ° C. The reactions can be carried out at atmospheric pressure or in a closed vessel under elevated pressure, if appropriate with heating to the specified temperature range.

These reactions 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 i aliphatic hydrocarbon, such as hexane, heptane or

Carry out 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 30 mixtures of the solvents mentioned. Cyclic ethers such as dioxane or tetrahydrofuran and, in particular, dimethylformamide or mixtures thereof are preferably used, the reaction generally taking place at a temperature of up to 30 ° C.

3S

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BASF AWienceseüschafi - 11 - O.Z. 0050/35710 / 35711/35712 i! f \\ \ 'r The reactions are carried out in the presence of a deprotonating agent for the phosphorus compound (III). Alkali metal hydrides and alkali metal amides, in particular sodium and potassium, the sodium and potassium salts of dimethyl sulfoxide, alkyl lithium compounds such as n-butyllithium or alkali metal alcoholates, preferably sodium methoxide and sodium ethanolate, are suitable.

When using an aliphatic epoxy compound, preferably butylene oxide, the reaction is successful without the addition of other agents. Aliphatic epoxy compounds are thus both a solvent and a deprotonating agent. If butylene oxide is used as the aliphatic epoxy compound, the reaction can be carried out at the boiling point of the reaction mixture or at a temperature around 100 ° C. in a closed vessel under elevated pressure.

c

The reaction of the acid I (R "= C00H) with a ^ -alcohol, p-hydroxyaniline or 5-aminotetrazole is achieved by converting the acid into an activated derivative of the

Formula I, wherein R represents the radical COX with X in the meaning of a leaving group.

X represents an acid residue, e.g. a halogen atom - in particular 25 chlorine or bromine - or the N-oxysuccinimide ^ residue dari ~

The reaction takes place at a temperature of up to 50 ° C. at atmospheric pressure or in a closed vessel under increased pressure.

This reaction can be seen in the presence of a diluent or solvent, for example a lower saturated dialkyl ether, dialkyl glycol ether or cycli-35 ether, such as diethyl ether, ethyl tert-butyl ether, / - 'j BASr AWienceseüsdisft - 12 - CZ 0050/35710 / t " 35711/35712 · "1,2-dimethoxyethane, tetrahydrofuran or dioxane, a ** 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 aliohatic Ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone, one! Dialkylformamids, such as dimethyl or diethylformamide, or in mixtures of the solvents mentioned. Be-i - preference is given to using linear or cyclic ethers, such as diethyl ether or tetrahydrofuran, and in particular; _ Dimethylformamide, the reaction generally taking place at a temperature of up to 30 ° C.

The reaction is usually carried out in the presence of a base as an acid-binding agent. Suitable bases are alkali metal carbonates, bicarbonates, especially of sodium and potassium, organic tertiary bases such as pyridine or lower trialkylamines, such as trimethyl or triethylamine. The base used in a ratio of 20 to the benzoic acid halide used is used in a stoichiometric amount or in a slight excess.

Another possibility for producing the acid derivatives according to the invention is based on the corresponding free 25 acids I (R ^ = COOH); you put them in the present. one which activates the carboxyl group and releases water

Using a solvent with a C - alcohol, i p-aminophenol or tetrazolamine.

30 The reagents customary in peptide synthesis can be used as water-releasing activating reagents (cf. "The Peptides", Volume I, Academie Press, N.Y., 1965, pages 77 to 128). The general principle of the reaction is the activation of the carboxyl group, 35 for example by treatment with a carbodiimide, such as

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/ u. * · · S BASF share company - 13 - O.Z. 0050/35710 / j '35711/35712 * NjN'-dicyclohexylcarbodiimide, or by intermediate formation of the acid azide, a mixed anhydride (for example with carbonic acid monoesters), an activated ester (for example the p-nitrophenyl ester) or a 5 heterocyclic amide (for example an inidazolide) of the corresponding benzoic acid.

The treatment of a compound activated on the carboxyl group with a p-aminophenol or -jQ tetrazolamine then leads to the acid derivative according to the invention. The activation and linking reactions can be carried out in solvents, preferably in N, N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane, acetonitrile, dimethyl sulfoxide, N, N-dimethylacet - *, 5 amide and hexamethylphosphoric acid triamide. A suitable temperature for both stages, i.e. the reaction of the acid with the coupling agent and the reaction of the activated intermediate with p-amino-phenol is between 20 and 100 ° C. One cannot do this step by step by activating the

Intermediate isolated or advantageous before the addition of the p-aminophenol by bringing the reactants to the reaction one after the other without isolation of intermediates.

25: 'In a preferred linking method, Ν, Ν-carbonyldiimidazole is used and the reaction is carried out in dimethylformamide, the reaction temperature being 20 to 60 ° C for both stages.

30th

The compounds of the formula I can have the cis-trans structure or can be mixtures of the cis-trans isomers. A mixture can be determined by HPLC analysis 1λ or by an -x NMR spectrum and 35 / ^ IBA Sr Aktiengesellschaft - 14 - CZ 0050/35710 / 35711/35712 r the desired isomer, if appropriate by fractional "* ionizing crystallization or chromatography using, for example, silica gel columns or isomerically pure by preparative HPL chromatography.

The compounds according to the invention and their physiologically tolerated salts can be used for topical and systemic therapy and prophylaxis of benign and malignant neoplasms and pre-malignant lesions - e.g. Precancerous 10 and carcinoma of the skin, 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, as well as for the treatment of rheumatic diseases, especially those of an inflammatory or degenerative nature, the joints, muscles, tendons and other parts of the musculoskeletal system infested, used.

A preferred area of indication is next to therapy !!! of dermatological diseases the prophylactic and therapeutic treatment of precancerous and tumors.

Their low toxicity is an advantage.

The pharmacological effects can be demonstrated, for example, in the following test models: 25 1. Abolition of keratinization in tracheal cultures to demonstrate the anti-tumor effect:

The intrinsic property of the 30 compounds according to the invention to increase the differentiation of epithelial cells is determined in the test model. The high significance of this screening method in predicting the potential use of a new retinoid for the prevention of tumors in epithelial tissue is generally recognized. It is known that each in vitro .il · BASF Akiiencesellschsft - 15 - C.2. 0050/35710 / fl '35711/35712 a β · * 1 test system has disadvantages when it comes to the "* fl prediction of in vivo activity. Apart from | fl these fundamental restrictions, the system | fl of traeheal cell cultures is one of the most valuable fl 5 methods to determine the biological activity of new retinoids fl.

fl The ability of the test substances to cancel the ICeratinization in a defined in-vitro system 10 is determined. Tracheae from hamsters in a very early state of vitamin A deficiency were taken into culture. At the time of Traehea withdrawal, the animals were 29-30 days old (after weaning after 21 days) and 15 still showed weight gain. Their average weight was 47 to 52 g. The tracheal epithelium was generally a weak columnar or plaster epithelium with only a few spots of saucy metaplasia. Each trachea was from the larynx to the 2Q. Carina opened along the membrane-like dorsal wall and in serum-free medium (CMRL-1066 supplemented by crystalline bovine insulin, 1.0 µg / ml, hydrocortisone hemisuceinate, 0, lyug / ml; glutamine'2 mM; penicillin,. 100 units / ml, and streptomycin, 100 ^ ug / ml) taken in 25 culture. The cultures were gassed with a mixture of 50% oxygen, 45% nitrogen and 5% carbon dioxide. The culture dishes were swiveled slightly to bring the tracheae into contact with gas and culture medium. All tracheae were initially kept in the culture medium for 30 days without the addition of retinoids. After 3 days, some tracheae were removed.

Almost all of them showed clear squamous metaplasias.

The remaining tracheae were divided into groups which were then treated with the following additives: BASF Aktiengesellschaft - 16 - C.2- 0050/35710 / 35711/35712 P a) test substance dissolved in spectroscopically pure dimethyl-1 sulfoxide; the final concentration of t

Dimethyl sulfoxide in the culture medium was never greater than 0.1%.

ir s w b) The equivalent amount of dimethyl sulfoxide without further addition.

The nutrient medium was changed three times a week.

10 All remaining tracheae were removed after 10 days

Culture worked up. The tracheae were fixed in 10% buffered formaldehyde solution and embedded in paraffin. Sections of 5yUm through the center were stained with hexatoxylin and eosin and checked under the 15 microscope for the presence of keratin and

Examined keratohyalin; both were observed in approximately $ 0% of all control cultures kept without test substance. Dose curve of the compounds of the invention were recorded. In the following 20 · Table 1 the extrapolated molar doses are given which prevent keratinization in the half of the cultures (ED 50 '?).

. 1 Table 1: 25 • * Substance of the example ED_n [mol / l] 2 1.10 "11 7 '1.10" 11 L 30 18 3.10 “12 19 1.10“ 12 26 1.10 “12

Vitamin A acid l.lO “1 ^ 35 / ('i I BASF shares eeseüschafi - 17 - 0.2- 0050/35710 / |' 35711/35712

II

In addition, the compounds according to the invention (in particular the compound of example 2) induce cell differentiation to mature! Granulocytes in leukemia cells from patients with promeolocytic leukemia.

2. The antiarthritic activity of the compounds according to the invention can be determined in a conventional manner in animal experiments using the adjuvant arthritis model.

10 3The dermatological activity, e.g. for the treatment of acne, can include can be demonstrated by the comedolytic activity.

Î5 The formation of comedos was achieved by applying one topical application (0.5 ml per day) to 5% tar in polyan J (ester of lanolin alcohol and linolenic acid, manufacturer Amerchol Corp., USA) to both ears of albino rabbits on 5 consecutive days each Week, 20 times over two weeks. Then the topical treatment is carried out - with the test substances in ethanol: propylene glycol (70: 30; v / v; 0.5 ml), which is applied to the inner skin surface of one ear of each rabbit a * once a day for 5 consecutive days per 25 weeks over two Have been applied for weeks. The * - second ear of each animal served as untreated

Control.

After the subsequent treatment 30 (72 hours) with the test substance, the rabbits became i 2. killed. A skin sample of approximately 6 cm from each -. Ear cup just outside the ear canal was removed? removed and cut them into slices about 1 cm in size.

3S

a ‘! * 1 · ’I3ASF Akiieneeseüschafi - 18 - 0. Z. 0050/35710 / 35711/35712 r These areas of the skin were Λ at 60 ° C for 2 minutes

Water submerged. After carefully peeling off the epidermis with the flat end of a spatula and small tweezers, these were placed on the slide with the dermal side up. After air drying overnight, the test strips were assessed under the stereomicroscope. Follicular parts with horny material remain intact. The comedones are recognizable as discrete, cohesive, cylindrical JO to round horn parts, the size and number of which is proportional to the activity of the tested substance. The comedolytic effect was determined as the decrease in the comedo number in% compared to the control ear, cf.

Table 2.

15

Table 2 ^ Substance of the example comedolytic activity in% 1 75 20 2 78 5 54 6 68 ’7 59 8 52 25 Vitamin A acid. 67 14. Another measure of dermatological activity was the ability to reduce the number of utriculi in the Rhino mouse model. This method is from L.H. KLigman et al in The Journal of

Investigative Dermatology, 73, 354-358 (1979). Cysts present in Ehino mice, which are present as genetic lesions of the skin, so-called acne cysts, are re-formed by the administration of active substance-35 and the decrease is expressed in%.

OAc? Shares company - 19 - 0.2. 0050/35710 / BA ~ 35711/35712

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r Table 3 "*

Substance of the example decrease in% '1 65 2 68 5 5 69 6 59 7 62 8 52

Vitamin A acid 60 10 5. The tolerance of the test substances according to topical

Application was determined in experiments with 6 white male New Zealand rabbits *. With each ο

Test animals were each shaved about 6 cm large back-15 areas. After dissolving the test substances in

Ethanol: propylene glycol (70: 30, v / v), 0.2 ml of it was applied with an automatic micropipette for 9 consecutive days by careful rubbing in. At a certain point twice a day at 20 6-second intervals.

! All test areas were checked before each application

Tomorrow subjectively assessed for erythema and desquamation. A numerically graded scale 25 from 0 to 3 was used (0 - no reaction, 1 = mild, 2 = medium, I 3 = severe). The mean of erythema formation and

Desquamation shows the relative irritability of the test substances compared to vitamin A acid.

30th

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| v .; SASr Aktienceseüschafi -20- O.Z. 0050/35710 / 35711/35712 * "Table 4 Ί

Substance of the example erythema desquamation '· 2 2.8 2.7 5 2.0 1.7' 5 7 3.0 3.0 8 1.4 1.0

Vitamin A acid 3.0 3.0

Accordingly, the invention further relates to IQ therapeutic agents for topical and systemic use which comprise a compound of the formula (I) in addition to conventional carriers or diluents as an active ingredient, and the use of a compound of the formula (I) for the preparation of a medicament.

15

The therapeutic agents or preparations are produced using the customary liquid or solid carriers or diluents and the pharmaceutical-technical auxiliaries used in the customary manner, in accordance with the desired type of application and with a dosage suitable for use, in the customary manner, for example by mixing the active ingredient mil: the solid or liquid carriers and auxiliaries which are conventional in such preparations.

25th

Accordingly, the agents can be administered orally, parenterally or topically. Such preparations are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions, infusion or injection solutions, and pastes, ointments, gels, creams, lotions, powders, solutions or emulsions and sprays.

When used locally, the therapeutic agents can use the compounds to be used according to the invention in 0.001 to 35% concentration, preferably in 0.001 to 0.1% / μJ

SA Sr Aktiengesellschaft - 21 - C. 2. 0050/35710 / 35711/35712 ί I β '' concentration and in systemic use preferably n 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 are administered, c commonly used pharmaceutical technical auxiliary substances are, for example, alcohol for local use, such as isopropanol, oxyethylated castor oil or oxyethylated hydrogenated castor oil, polyacrylic acid, glycerol 10 monostearate, paraffin oil, petroleum jelly, wool fat , Polyethylene "= glycol 400, polyethylene glycol 400 stearate and ethoxylated fatty alcohol, for systemic use milk sugar, propylene glycol and ethanol, starch, talc, poly-vinyl pyrrolidone. If necessary, a g of antioxidant, for example tocopherol and butylated hydroxyanisole or butylated hydroxyltoluene or flavor-improving additives, stabilizers, bulking agents, lubricants etc. can be added to the preparations. The prerequisite is that all substances used in the manufacture of pharmaceutical preparations are toxicologically harmless and are not compatible with the active substances used.

The following examples illustrate the preparation of the compounds 25 according to the invention

Example 1 (E) -4- [2-Methyl-2- (1,1,4,4,6-pentamethyl-l, 2,3,4-tetra-hydronaphth-7-yl) vinyl] benzoic acid thylester

33 To a suspension of 250 ml of dimethyl sulfoxide and 9 S.

A solution of 90 g of diethyl p-carboxyethyl-benzylphosphonate in 150 ml of DMSO at 35 ° C. was added over a period of 0.5 h to 80% sodium hydride, which had previously been freed from the 20% paraffin portion with petroleum ether. i AL · - BASF Aktiengesellschaft - 22 - 0.Z. 0050/35710 / 35711/35712 i. · '»Drips. The mixture was then stirred for a further 2 h at 40 ° C. and a solution of 36.6 g of 7-acetyl-1,1,4,4,6-pentamethyltetralin in 70 ml of dimethyl sulfoxide was added dropwise within 10 min.

5

After standing overnight, 100 ml of ethanol were added, the mixture was poured onto 2 l of ice-water and acidified with 2N hydrochloric acid. The resulting precipitate was ab--. filtered and rinsed on the filter with 150 ml of ethanol *, q and washed with 75 ml of methanol. There remained 35 g of (E) -4- [2-methyl-2- (1,2,4,4,6-pentamethyl-l, 2,3,4-tetra-hydronaphth-7-yl) vinyl] - ethyl benzoate, Scbmp. 108 to 109 ° C.

15 HPLC analysis (Si 60 5yUm, 150 bar, n-heptane / ethyl acetate (98: 2), tR * 3.1 min) showed that the compound consisted of more than 98% of an isomer.

^ C-NMR spectrum (CDCl ^, data in ppm): 20 -, (The C atoms were counted arbitrarily to assign the NMR signals) «15 20 22 23 6

VsA7À lyj10, 6 24 25

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î; BASF Aktiengesellschaft - 23 - 0.2. 0050/35710 / 35711/35712 «3" 14.40 (C21); 19.74 (C27); 20.35 (C26); 31.96 (C ^, C2i}, C23 »c22); 34.02 ( C1, C4) 5 35.32 (Cg, Cj; 60.94 (C ^) x 126.11 (Cg); -128.41 (Clß, C ^); 128.55 (C ^); 129.00 (Cl4,

Cl8); 129.68 (C15, C17); 131.72 (Cg); 141.98 (C ^); 5 142.93 (Cu); 143.11 (C ^); 143.83 (Cg); 166.80 (C ^);

The signal at 19.74 (C ^) confirms the E (Trans) geometry of the connection.

10 Example 2 4.7 g (E) -4- [2-methyl-2- (1,1,4,4,6-pentarnethyl-1,2,3,4 -...-.....

-tetrahydronaphth-7-yl) -vinyl] -benzoic acid ethyl ester was stirred with 1.7 g of 86% potassium hydroxide in a mixture of 15 100 ml of ethanol and 5 ml of water at 80 ° C. for 6 h. After the entire reaction mass had been transferred into 1 liter of water, it was acidified with 2N hydrochloric acid, the colorless precipitate obtained was filtered off and, after drying, washed on a suction filter with T.00 ml of heptane. After drying "20- there remained 4.0 g of (E) -4- [2-methyl-2- (1,1,4,4,6-pentamethyl-1,2,3,4-t et rahyd ronaphth -7-yl) -vinyl] -b enz0e acid, mp. 206 ° C.

13 C-NMR spectrum (dß-DMS0, data in ppm) 25 (the C atoms were counted arbitrarily to assign the NMR signals).

25 1 «30 20 21 I I Oi R6 r T O if11 1215 18 ~ 22 22

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ISASF AkiiençeseUschsit - 24 - 0.2. 0050/35710 / 35711/35712 "19.36 (C25); 20.17 (C24) j 31.60 (C2Q, C21, C ^, C ^); 33.51 (C2, C3); 34.71 ( C ^, Cj; 125.40 (Cg); 128.00 (0 $, Cl2) * 128.6l (Cl6); 128.95; 129.42 (C ^, C ^) * 129.42 CCi5, C17 ); 131.12 (C6); 141.20 (C ^); 141.70 (C?); 5 142.16 (C10); 142.52 (Cu); 143.08 (C ^; 167.26 (¾).

The signal at 19.36 (C ^) confirms the E- (trans -) geometry of the connection.

10 Example 3 A. Preparation of the starting material

A suspension in 100 ml of dimethyl sulfoxide was prepared from 9 g of 80% sodium hydride, which had initially been freed from the 20% paraffin portion with petroleum ether 15 and a solution of 75.9 g of p-cyano was obtained within 0.5 h - Diethyl benzylphosphonate in 150 ml of dimethyl sulfoxide was added dropwise at about 35 ° C. The mixture was stirred for a further 2 hours at 20 ° C. and a solution of 53.5 g of 7-acetyl-1,1,4,4,6-pentamethyltetralin in 50 ml of dimethyl sulfoxide was added dropwise within 10 minutes.

; The following day, the reaction mixture was poured onto .3 1 ice-water and acidified with 2 N hydrochloric acid. The ent-; The solid was filtered off and washed on the filter with 75 ml of methanol. After drying, 30.2 g of (E) -4- [2-methyl-2- (l, 1,4,4,6-pentaethyl-l, 2,3,4 - tetrahydronaphth-7-yl) remained vinyl] -benzonitrile, mp. 140 to 30 141 ° C.

The HPLC analysis (Si 60 5 ^ um, 150 bar, 25 cm column, n-heptane / ethyl acetate (97: 3), tR = 3.2 min) shows an isomer purity of more than 95%.

iBASr Akiiencçseüschsit - 25 - C. 2- 0050/35710 / 35711/35712 rB. Preparation of the final product ** * 13.5 g of (E) -4- [2-methyl-2- (1,1,4,4,6-pentamethy1-1,2,3,4- -tetrahydronaphth-7-yl ) -Vinyl] -benzonitrile were heated in a mixture of 200 ml of ethanol and 200 ml of 10N sodium hydroxide solution at boiling temperature for 3 hours. After cooling, the mixture was poured into 1 liter of water, the colorless precipitate was filtered off with suction and, after drying, 14.9 ε (E) -4- [2-methyl-2 - (1,1,4,4,6-pentamethyl) was obtained -1,2,3,4-tetrahydronaphth-7-yl) -, * 10-vinyl] -benzoic acid, mp. 204 to 206 ° C, cf. Example 2.

The compounds listed in the table below were prepared either by Wittig-Horner reaction or by saponification of the corresponding esters or nitriles.

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In a solution of 4.0 g of (E) -4- [2-methyl-2- (l, l, 4,4,6-l '-pentamethyl-l, 2,3,4-tetrahydronaphth-7-yl ) -vinyl] -benzoic acid J 5 in 300 ml of ethanol was introduced at the boiling point of the reaction mixture gaseous hydrogen chloride to 1 saturation. Then was 4 hours

Boiling temperature maintained and flushed with nitrogen after cooling. After evaporation of the reaction mass 10, the mixture was digested with 30 ml of methanol, filtered off and the residue was dried. 3.6 g of (E) -4- [2-methyl-2- - (1,1,4,4,6-pentamethyl-l, 2,3 * 4-tetrahydronaphth-7-yl) vinyll were obtained -benzoic acid ethyl ester, mp. 109 to 110 ° C, see. Example 1. .

15

Example 18

To a suspension of 20.9 g of (E) -4- [2-methyl-2- (1,4,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl) vinyl ] -benzoic-20 · acid (see Example 2) and 5 * 8 ml of pyridine in 200 ml of anhydrous tetrahydrofuran, a solution of 5.3 ml of thionyl chloride in 10 ml of tetrahydrofuran was quickly added.

After stirring for two hours at room temperature, the precipitate formed was filtered off and the filtrate with = 25 tetrahydrofuran. Total volume of 240 ml filled up.

100 ml of this solution were gradually added to a suspension of 8.2 g of p-aminophenol in 100 ml of 30 tetrahydrofuran within 10 minutes. The mixture was then stirred at room temperature for a further 20 h. The reaction mixture was stirred into 1 * 1 water, acidified with 2N hydrochloric acid, the resulting precipitate was filtered off and extracted from ethanol

Addition of water recrystallized.

35

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5ASF Aktiengesellschaft - 30 - O.Z. 0050/35710 / 35711/35712 r * 1

After filtering off and drying, 11.1 g of (E) -4- [2-methyl-2- (1,1,4,4-tetramethyl-1,2,3,4-tetrahydro naphth-7-yl remained ) vinyl] -benzoic acid- (4-hydroxyanilide),

Mp 252 to 253 ° C.

5 ^ C NMR spectrum (dg - DMSO)

The resonance signal appearing at 17.30 ppm for the methyl group on the carbon atom 2 of the olefinic ethylene group 10 shows the compound obtained as the E- (trans -) -. & Isomers from.

Examples 19 to 21 15 The compounds listed in the table below were obtained analogously to Example 18:

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35 ij. 'il * BASF AktienceseUschsft - 32 - ° -z * 0050/35710 / 35711/35712 r Example 24 JT.

W

To a suspension of 1.8 g of (E) -4- [2-methyl-2- (1,4,4,4-5-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl) vinyl ] -benzoic acid (see Example 2) and 0.5 ml of pyridine in 15 ml of tetrahydrofuran, a solution of 0.5 ml of thionyl chloride in 5 ml of tetrahydrofuran was quickly added. After 2 h of stirring at room temperature, the precipitate formed was filtered off, the piltrate was added to a suspension of 0.5 g of anhydrous 5-aminotetrazole and 0.5 g of pyridine in 20 ml of tetrahydrofuran, and the mixture was then stirred for a further 20 h at room temperature . The reaction mass was stirred into 400 ml of water, acidified with 2N hydrochloric acid, the precipitate formed was filtered off and washed with methanol and

Washed petroleum ether. There remained 1.7 g of (E) -4- [2-methyl - 2- (1,1,4,4-tetramethyl-l, 2,3,4-tetrahydronaphth-7-yl) vinyl] -N - (tetrazol-5-yl) benzoamide, mp 289-290 ° C.

20C NMR spectrum (dg-DMS0)! The resonance signal appearing at 17.41 ppm for the

Methyl group on carbon atom 2 of the olefinic ethylene group indicates the compound obtained as the E- (trans -) - '25 isomer.

Examples 25 to 29

The compounds 30 listed in the table below were obtained analogously to Example 1: 35 »/» /; «SA5F Aktiengesellschaft - 33 - 0.2. 0050/35710 / '35711/35712 I1! r-! r ·> ο. ι! Ο tî _ 11 cï es i te te “e r— JJ s. Ο l 1 e £ - j 1 ra 1 · eœî. jj ic 2 ce I 'SI tua je a jj 1 »jj e >> 1-1 jj jj ai e jj _ c.jS'— ι« n t-jso ee jj ~ HI 2nl ΓΟΙ JJ Æ S JJ JJr- JJ | - «e>,« 2 C2

tf C I PO I JJ Jj JJ JT JS2 JJ I

I - O lf \ -r— -DI e Jj - - II 1 — i J JT - I vCU iJ ni JT Jj «cnn mr-1 Ι -T ni - E ·> I Jj« «ni -> j I h > iC «JCeJï-.srl'CJnitMî'i '^ mz

• 1 ^ M »« —ί Q) «·> 2 C ·» «H * C

Ψ- * G C5 ^ L · 1— * ΙΌ I E ι-ή —ι E «**>« ”4 W t- L · W 1 3 * -r- ^ C w 1> £ * 1 £

JJ ^ «ü î -». = 5 nCNIH. ® I «- <| O C

OJ ü (D W ι-i »-w»> 1 L CM »2. w i- <C5 f ^ 4J 1> i V I π Z 2! C-r-i 25 I >> -

r— <I v — j · * 3 r ·? I C ^ I · “! SCQ r-4 O ï £ 1— «'1 p

>> - = r I »« -:>, VJ2 K> * t-i> C >> L | C>) C = 3 e 0? - E, £ l C r û, t— Ö Æ 1 © . H iim 1 c «p 2 ü o * uo 1 c -5: c 1Π« O • f- '$ 0) 0.0 ü ^ HN 0> O ^ fr5 © 30 W 2 ΣΝΗ U ε * ΟΙ EÜÄCS-PI-AC Σ ^ Ν ι ·> ,: ι cn * iiie 112e ι ccs Wrt Ce CU ni ni CU \ C ï— 2 ru VD 2 Ä CU ni e i_j | mC3 i — 1 I> si: I! I i — ISI ι_ι I 2 I H> S I ni I I ni 2 n. | ni C η I ni '' JC >> I O - >> in ~ >> JJ H -> 5 O ni CT> jni I 2 n * K I 2 I I £ ή> 1 I £ S> | I i> 1 n »JJ H C n% JJ I-I nj β. | njjn | n. YY | î. ta o> >> a> 63 α> o taeemaejiin 63 a> ir \ e - ç | 2 wgii -n H C I w £ 2 | > - E 1 s YY e m

S. ft E l- UO ni VD JC

e> fi. & m t— cs ru vo B3: 3 Q. «« «« * I £> i_j O r- C - * t- u σ ru m eu ru m m cr m es ό e

1 22 O -H

2 ^ / s- E 63 63 63 ω 63

SI -SI

I CO C 0

CO ------- Vfi - ni (- O

co co eo c \ ru eu eu eu ru ι

i-n I II 1 HP

c «cp t * - m c vo t—

.¾ o CO CO. 0 OS CM

I_I ru CM CM CM

"m m" "as Ξ ο o ο o I...

- m en S _τη 5 2 “o ô jîS *" 2s. 1 2 ° 1 ^ = ^ = o o

I I

m m os ss o rn mm eu o 1 ss ss s: es 1 o 00 I I 1 _m m _m _m • j ^ 5 o SS Ö 3 a 1 10 11 30 1 I * cu 1 1

= K. _w _ <M

ü x / = = I ss o o

<CU O I II

s: 1 eu eu eu O O “2 2 1 m ü o - o 21 11 il in vo— co o \

• J Z CM CM OJ CM I CM

/ -

Claims (4)

5 H3C 'CH 4 J \ / 3 ΪΓ j * COi' 1 / X2 RR 10 where A is an alkylene radical which may be substituted by a ^ -alkyl group, R ^ is a hydrogen atom or a methyl group, p ^ 5 R is a hydrogen atom or a methyl group, R ^ a hydrogen atom or a C. "alkyl group, li i_0 R a C ^ alkyl group and R ^ a p-hydroxyphenylenaminocarbonyl or 3 tetrazol-5-ylaminocarbonyl group or - if R 20 - means a C ^ _g alkyl group - also one Represent carboxyl or C2 _ ^ - carbalkoxy group, and optionally their salts with physiologically compatible bases. - Sr: 25 2. Phenylethylene derivatives of the formula I according to claim 1, in which A is an ethylene radical 1 2 R and R is methyl groups 3 R is a C 1-4 alkyl group 1-30 ° a methyl group and 5 R is a carboxyl or C ^ ^ - carbalkoxy group, and their salts with physiologically acceptable acids. i ^ | jl 3ASF Akiienceseüscrisft - 35 - O.Z. 0050/35710 / §3 "35711/35712« Μ 9 · fl · 9 * "3 · phenylethylene derivatives of the formula I according to Claim 1 ** 9 or 2, characterized in that the phenyl rings 9 are in the trans position with respect to one another. H 5 4. (E) -4- [2-Methyl-2- (l, l, 4,4-tetramethyl-6-isobutyl-II '- (2-methylpropyl) -l, 2,3,4-tetrahydronaphth -7-yl) - | -vinyl] -benzoic acid. I- 5 · Process for the preparation of the compounds of I 10 formula I according to claim 1, characterized in that Η * man I a) a compound of the formula II I 15 I HC CH- 'I \ / 3 4 I ^ cwco's i w - * 9 20. RR fl fl fl i M [wherein A and R -R have the meaning given in claim 1, with a phosphorus compound fl r 25 of the formula III. * ^ 9 I K6 - / ^> - CH2-P0 (0R7) 2 III, fl 30 in which R ^ has the meaning given for R ** or fl 7 represents a cyano group and R represents a ^ -alkyl- fl * group, according to Wittig-Horner or ^ 9 I 35 I Λ - mr *. * »! . * i! BASF AkiienceseUschafi - 36 - 0.Z. 0050/35710 / j “35711/35712 b) a phosphonium salt of the formula IV 1 • · H-C CH-3 \ / 3 Θ .'C'Tl'VCH'PtC6H5,3 'X® 5 V ^ -Î ^ rS IV,. , / v; 12 3 4 “'in which A, R, R 3 RJ and H have the meaning given in claim 1 and X is chlorine or bromine, unit a benzaldehyde derivative of the formula V B. H-C0 "Q-K6 V 'in which R ^ has the meaning given above, converted according to Wittig · 20 and then - if R ^ does not represent a carboxyl group - the compound obtained in this way is optionally saponified and the free or 1 acids thus obtained are then, if desired with a 25 C1_2 "Aikoholi p-hyd-roxyaniline or 5-aminotetrazole and the compounds thus obtained - if desired - converted into their salts with physiologically compatible bases. 30 6.’ Medicament containing a compound of formula I A according to claim 1. 7. A compound of formula I according to claim 1 for use in combating diseases. 35 l "A \ 1 ΰ ft" / 7 Λ X