NO853694L - VINYLTETRAZOLYLPHENYL DERIVATIVES, PREPARATION AND USE THEREOF. - Google Patents

Description

The present invention relates to the production of new vinyl-tetrazolephenyl derivatives.

From German OS 28 54 354 and 32 02 118 there is e.g. known that vinylbenzoic acid derivatives have pharmacological effects in topical and systemic therapy of neoplasias, acne, psoriasis and other dermatological disorders. However, these vinylbenzoic acid derivatives are not always satisfactory. Above all, their pronounced toxic (side) effect is unfortunate, which makes these compounds unsuitable as agents in topical and systemic therapy of neoplasias, acne, psoriasis and other dermatological disorders. The unfortunate aspect of the connections from German OS 28 54 354 is described, for example. by A. Kistler in Calcified Tissue International 33, 249-254 (1981) and is shown by repeated application to rodents according to the methodology described by R. C. Moon et al in Cancer Research 39, 1339-1346 (1979).

The task of the present invention is to provide compounds with comparable effectiveness and less toxic side effects.

It has now been found that vinyltetrazolylphenyl derivatives with

formula (I)

wherein R 1 and R 2 are hydrogen or a methyl group,

3 4

R and R hydrogen, halogen, a C^_^-alkyl or C-^_^-alkyl group,

R 1 is hydrogen, a C 1-6 alkyl group or a C 1-6 cycloalkyl group and

A likewise with C, .-alkyl group substituted methylene- or

1 2

ethylene residue or - when R and R form methyl groups - also means

the residues -CH2-C0- or -Cr^-CH-, and their physiologically tolerable salts are well suited for the treatment of diseases.

As the wavy C-H bond shown in formula I indicates,

can the compounds prepared according to the invention be present in

the cis-(Z) or trans-(E) form. The Trans-E forms are preferred. The methyl group must be mentioned as the preferred alkyl group on A. For

3 4 5

R and R are preferably hydrogen, methyl and methoxy. R is preferably hydrogen or methyl.

Typical examples of compounds according to the invention are, in addition to the substances mentioned in the examples: 2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-£4- (1H-tetrazol-5-yl)phenylj -ethene

2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenylj-ethene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1- U~

(1H-tetrazol-5-yl)phenyl}-1-butene

2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-butene

2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-butene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-T4-(1H-tetrazol-5-yl)phenyl]-1-octene

2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-f4-(1H-tetrazol-5-yl)phenyl}-1-octene

2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenylj-1-octene

2-(1,1,4,4,7-Pentamethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-propene

2-(1,1,3,3,6-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-T4-(1H-tetrazol-5-yl)phenyl}-1-propene

2-(1,1,2,3,3,6-Hexamethyl-2,3-dihydro-5(1H)-indenyl)-1^4-(1H-tetrazol-5-yl)phenylj -1-propene

2-(7-Ethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)

-1-[4-(1H-tetrazol-5-yl)phenyl}-1-propene

2-(6-Ethyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl-1-propene

2-(6-Ethyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)

-1-£4-(1H-tetrazol-5-yl)phenyl]-1-propene

2-[7-(2)-Methylethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl]-1-C4-(1H-tetrazol-5-yl )phenyl}-1-propene

2-T6-(2-Methylethyl)-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-C4-(1H-tetrazol-5-yl)phenyl3 -1-propene 2-[6-(2-Methylethyl)-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-

indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-propene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-X3-1H-tetrazol-5-yl)phenyl}-1-propene

2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[3-(1H-tetrazol-5-yl)phenyl]-1-propene

2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-T3-(1H-tetrazol-5-yl)phenyl]-1-propene

2-(7-butyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenylj-1- propene

2-(6-Butyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl}-1- propene

2-(6-Butyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-£4-(1H-tetrazol-5-yl)phenyl]- 1-propene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-cyclopropyl-1-[4-(1H-tetrazol-5-yl)phenyl} the food

2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclopropyl-1~C4-(1H-tetrazol-5-yl)phenyl]-ethene

2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclo-propyl-1-t 4-tetrazol-5-yl)phenyl]-ethene

2-(1,1,2,3,3,6-Hexamethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclopropyl-1-t4-(1H-tetrazol-5-yl)phenyl] - the ethene

2-(1,1,3,3,6-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclopropyl-1-[4-(1H-tetrazol-5-yl)phenyl ] -1-[4-(1H-tetrazol-5-yl)-phenyl}-ethene

2- r (1,1,3,3,7-Pentamethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-cyclopropyl-1-[4-(1H-tetrazol-5- yl)phenyl}-1-1a-(1H-tetrazol-5-yl)-phenyl]-ethene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-T4-(1H-tetrazol-5-yl)phenyl]-(3-methyl)- butene-1

2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl}-(3-methyl)- butene-1

2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-T4-(1H-tetrazol-5-yl)phenyl]-(3-methyl) -butene-1

2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclohexyl-1-f4-(1H-tetrazol-5-yl)phenyl}-ethene

2-(1,1,2,,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclohexyl-1-C4-(1H-tetrazol-5-yl)phenyl ] -ethene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-cyclohexyl-1-[4-(1H-tetrazol-5-yl)phenyl] - the ethene

2-(4,4,7-Trimethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-propene

2-(4,4-Dimethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetra-zol-5-yl)phenyl]-1-propene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-2-oxo-naphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenyl] -1-propene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-2,3-dioxo-naphth-6-yl)-1-[4-(1H-tetrazol-5-yl) phenyl]-1-propene

2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-2-oxo-indenyl)-1--£4-(1H-tetrazol-5-yl)phenyl]-1 -propene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-3-oxo-naphth-6-yl)--1-[4-(1H-tetrazol-5-yl)phenyl ]-1-propene

2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-2-hydroxy-indenyl)--1-[4-(1H-tetrazol-5-yl)phenyl]-1 -propene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-2-hydroxy-naphth--6yl)-1-t 4-(1H-tetrazol-5-yl)phenyl]-1- propene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-3-hydroxy-naphth--6-yl)-1-["4-(1H-tetrazol-5-yl) phenyl]-1-propene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-2-oxo-naphth-6-yl)--1-[4-(1H-tetrazol-5-yl)phenyl }-ethene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-3-oxo-naphth-6-yl)--1-[4-(1H-tetrazol-5-yl)phenyl ]-ethene

2-(1,1,4,4-Tetraethyl-1,2,3,4-tetrahydro-2-oxo-naphth-6-yl)--1-T4-(1H-tetrazol-5-yl)phenyl] -1-butene

2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-3-oxo-naphth-6-yl)--1-[4-(1H-tetrazol-5-yl)phenyl ]-1-butene

The compounds are prepared according to the invention by reacting an azide with a nitrile of formula (II)

1 2 3 4 5

wherein R , R , R , R , R and A have the meanings given above.

The reaction with the azide during tetrazole formation proceeds at a temperature from approx. room temperature to approx. 200°C, preferably at 60 to 100°C. The reaction can take place at normal pressure or in a closed apparatus under elevated pressure, suitably during heating to the indicated temperature range.

Appropriately, the turnover is carried out in the presence of a diluent or solvent, e.g. one of the lower saturated dialkyl ethers, dialkyl glycol ethers or cyclic ethers, 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, an alkyl formamide, such as dimethyl or diethylformamide, in protic solvents such as alcohols or in mixtures of the aforementioned solvents. Cyclic ethers, such as dioxane or tetrahydrofuran and especially dimethylformamide or mixtures thereof, are preferably used, during which the reaction generally proceeds at a temperature from 60 to 100°C.

It is recommended to carry out the reaction in the presence of an inorganic halide. As inorganic halides, ammonium chloride, lithium chloride, aluminum (III) chloride are particularly relevant.

As azides, alkali azides, such as lithium azide, sodium azide or potassium azide, preferably sodium azide or 1,1,3,3-tetramethylguanidinium azide, come into consideration.

The starting compounds of formula (II) can uniformly have a cis- or trans-structure or be mixtures of the two E-/Z-isomers. An isomerization during the production of the new compounds in sterically uniform form cannot be ruled out. The isomer mixture formed in such cases by the compounds of formula (I) produced according to the invention can be determined quantitatively by HPLC-13

analysis or with a C-NMR spectrum, and the desired isomer is optionally isolated by fractional crystallization or chromatography with e.g. silica gel columns or with preparative HPLC chromatography in pure form.

The preparation of the starting nitriles with formula (II) is described in German OS 32 02 125 or can be prepared according to the work regulations specified therein. For example, a carbonyl compound of formula (III) in which R"1", R^, R^, R4, R5 and A have the above meanings can be reacted with a para- or meta-substituted phosphorus compound of formula (IV)

in a Horner-Emmons reaction.

The compound produced according to the invention has an acidic hydrogen atom on the tetrazole ring and can therefore be transferred with a base in the usual way in a physiologically tolerable, water-soluble salt. Suitable salts are e.g. ammonium-y alkali metal (especially sodium, potassium and lithium) and alkaline earth metal salts, especially of calcium or magnesium as well as salts with suitable organic bases such as with lower alkylamines, e.g. methylamine or ethylamine, with substituted lower alkylamines, especially hydroxy-substituted alkylamines such as diethanolamine, triethanolamine or tris-hydroxymethylaminomethane, piperidine or morpholine.

The compound produced according to the invention and their physiologically tolerable salts can, due to their pharmacological properties, be used in topical and systemic therapy and also in the prophylaxis of precancers and carcinomas in the skin, mucous membranes and internal organs as well as in topical and systemic therapy of acne, psoriasis and other dermatological diseases that have a connection with pathologically changed horn formation as well as in the treatment of rheumatic diseases, especially those of an inflammatory or degenerative type that attack joints, muscles, tendons and other parts of the locomotor system. Preferred indication areas are, in addition to the therapy of dermatological diseases, the prophylactic and therapeutic treatment of precancers and tumors, as well as the treatment of arthritic diseases. The dermatological activity, e.g. for the treatment of acne, can be demonstrated, among other things, by determining the comedolytic activity and the ability to reduce the number of utriculi in the Rhino mouse model. This method is described by L.H. Kligman et al. in The Journal of Investigative Dermatology 73, 354 to 38 (1979) and by J.A. Mezick et al. in "Models of Dermatology (Ed. Maibach, Lowe) Vol. 2, pp. 59-63, Karger, Basch 1985. The antiarthritic effect of the compound prepared according to the invention can be determined in the usual way in animal experiments in the Adjuvant arthritis model. The preventive effect on the formation and development of premalignant lesions can, for example, be demonstrated in the following experimental models. The compound produced according to the invention cancels in vitro the keratinization that begins with vitamin A deficiency in hamster treacal tissue. This keratinization belongs to a early phase of carcinogenesis which in a similar technique in vivo after initiation with chemical compounds is inhibited by high-energy radiation or after viral cell transformations with the compound of formula (I) prepared according to the present invention. This methodology can be read in Cancer Res. 36, 96 4 to 972

(1976) or in Nature 250, 64 to 66 (1974) and Nature 253, 47 to 50 (1975).

In addition, the rate of reproduction of certain malignantly altered cells is inhibited by the compound produced according to the invention. This methodology appears from J. Nati. Cancer Inst. 60, 1035 to 1041 (1978), Experimental Cell Research 117, 15 to 22 (1978) and Proe. Nati.Acad.Sei.USA 77, 2936 to 2940 (1980). Reference is also made to the determination of the antagonistic effects against phorbol esters described in Cancer Res. 37, 2196 to 2201 (1977).

As therapeutic agents for topical and systemic use, a compound of formula (I) is mixed with usual carriers or diluents and can be used in combating diseases.

The production of the therapeutic agents or preparations takes place with the usual liquid or solid carriers or diluents and the normally used pharmaceutical technical aids depending on the desired type of application and with a suitable dosage for the use in the usual way, e.g. by mixing the active substance with the usual solid or liquid carriers and auxiliary substances in such preparations.

The agents can therefore be administered orally, parenterally or topically. Such preparations are e.g. tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions, infusion or injection solutions as well as pastes, ointments, gels, creams, lotions, powders, solutions or emulsions and sprays.

The therapeutic agents can contain the compounds prepared according to the present invention for local applications in 0.001 to 1% concentrations, preferably in 0.001 to 0.1%

ig concentration and for systemic applications preferably in a single dose of 0.1 to 50 mg, and given daily in one or more doses depending on the nature and degree of the disease.

Commonly used pharmaceutical technical aids are e.g. for local applications. alcohols, such as isopropanol, oxytylated castor oil or oxytylated hydrogenated castor oil, polyacrylic acid, glycerol monostearate, paraffin oil, petroleum jelly, wool fat, polyethylene glycol 400, polyethylene glycol 400 stearate and ethoxylated fatty alcohol, for systemic applications milk sugar, propylene glycol and ethanol, starch, talc, polyvinyl pyrrolidone. The preparations can optionally have an antioxidant added, e.g. tocopherol as well as butylated hydroxyanisole or butylated hydroxytoluene or taste-improving additives, stabilizers, emulsifiers, lubricants, etc. A prerequisite is that all substances used in the manufacture of the pharmaceutical preparations are toxicologically harmless and compatible with the active substances used.

The following examples illustrate the invention.

Example 1

(E)-2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1 -propene

To a suspension of 65 g of sodium azide in 500 ml of tetrahydrofuran, 33.5 g of anhydrous aluminum chloride were introduced at 0° C. in small portions. Then heated approx. 4 5 minutes at reflux, mixed with 16.5 g of (E)-4-£2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 -propenyl]-benzonitrile and then stirred again for 24 hours at reflux temperature. After cooling, the reaction mixture was poured into 2.5 l of ice water, mixed with 250 ml of ethanol and acidified with 2 N hydrochloric acid. The solid formed was filtered off and washed on the filter with 100 ml of cold methanol. After drying in a stream of nitrogen, 12.2 g (66% d.Th.) (E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1 - [4-(1H-tetrazol-5-yl)phenyl]-1-propene, m.p. 227 to 230°C back.<13>C-NMR spectrum shows that it is the isomerically pure title compound in trans configuration.

Analogously, the substances in the following table were prepared.

Claims (2)

1. Process for the production of vinyltetrazolylphenyl derivatives of formula (I) 1 2 where R and R are hydrogen or a methyl group, R 3 and R 4 are hydrogen, halogen, a C 1 -alkyl or C 1 -alkoxy group, R 5 hydrogen, a C 1 -g alkyl group or a C 1 -g cycloalkyl group and A a methylene or ethylene residue optionally substituted with a C 1 -4 alkyl group, or - when R 1 09q§ 2 is a methyl group - also means the residues -Cr ^-CO- or -Cr^ -CH-, and their physiologically tolerable salts, characterized by reacting an azide with a nitrile of formula (II) 1 2 3 4 5 wherein R, R, R, R, R and A have the meanings given above. 2. Process according to claim 1, in the preparation of a compound of formula (I) which exists in E-form and in which R 1 and R 2 have 3 4 the unintended meanings and R and R mean hydrogen, methyl and/or methoxy and R hydrogen or methyl, characterized by using correspondingly substituted starting compounds.