CS235550B2 - Method of tetrahydronaphthalene and indane new derivatives production - Google Patents

Description

in this case, they have the meanings given above, they are converted to a monoalkylamide or a dialkyl amide having 1 to 4 carbon atoms in the alkyl radicals.

The conversion of the sulfonic acid or sulfinic acid of the formula II to the compound of the formula I can be carried out in a known manner, for example by converting the acid into an acid halide (e.g. by thionyl chloride) and reacting the acid halide with the corresponding monoalkylamine or dielkylamine.

The starting materials of the general formula (II) can be prepared analogously to known processes or analogously to the processes described below, if they are not known or are not further described.

The reaction products of formula I are pharmacodynamically valuable compounds. These compounds can be used for the topical and systemic therapy of benign and malignant neoplasms, premalignant lesions as well as for the systemic and topical prophylaxis of said affection. *

These compounds are further suitable for the topical and systemic treatment of acne, psoriasis and other dermatoses, which are common by enhanced or pathologically altered corneal corners, as well as inflammatory and allergic dermatological affections. The reaction products of formula I and their pharmaceutically usable salts can furthermore also be used to combat diseases of the mucosa with inflammatory or degenerative or metaplastic changes.

The novel compounds belonging to the group of retinoids are distinguished from the known retinoids by, for example, causing a slight weight loss in the experimental animals as a side effect of retinoids (hypervitamihose A).

The effect of the reaction products resulting in tumor suppression is significant. Thus, in the papilloma test in mice (Europ. J. Cancer 10, 732 (1974)), diminution of tumors induced by dimethylbenzanthracene and step tone oil can be observed.

For the treatment of these diseases, the compounds of the invention are administered orally, suitably at a dose of from about 5 to 200 mg per day, preferably from 10 to 200 mg. 50 mg / day for adult patients. Possible overdose can manifest itself as hypervitaminosis to vitamin A and can be easily detected by their symptoms (peeled skin, hair loss).

This dose may be administered as a single dose or may be divided into several sub-doses.

The compounds of formula I and their pharmaceutically usable salts can therefore be used as medicaments, for example in the form of pharmaceutical preparations.

Formulations for systemic administration may be prepared, for example, by adding to the compound of formula I or a pharmaceutically acceptable salt thereof as the active ingredient the nontoxic, inert solid or liquid carriers which are customary in such preparations.

Said preparations may be administered enterally, parenterally or topically. For enteral administration, for example, tablets, capsules, dragees, syrups, suspensions, solutions and suppositories are suitable. Formulations in the form of infusion solutions or injectable solutions are suitable for parenteral administration.

The dosages at which the compounds of the invention are administered may vary according to the mode of administration and the type of formulation as well as the requirements of the patient.

The compounds of the invention may be administered in single or multiple doses. A preferred dosage form is a capsule containing about 5, 20 or 50 mg of active ingredient.

These preparations may contain inert but also pharmacodynamically active ingredients. Tablets or granules contain, for example, binders, fillers, carriers or diluents.

Liquid preparations may be present, for example, in the form of a sterile solution which is miscible with water. The capsules may contain, in addition to the active ingredient, fillers or thickeners. In addition, these preparations may contain flavor enhancers, as well as conventional substances used as preservatives, stabilizers, humectants and emulsifiers, as well as salts for varying the osmotic pressure, buffers and other additives.

The aforementioned carriers and diluents may consist of organic or inorganic substances, for example water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols, and the like. poisonous.

For topical use, the compounds according to the invention are conveniently used in the form of ointments, elixirs, creams, solutions, ions, sprays, suspensions and the like. Ointments and creams as well as solutions are preferred. These topical preparations can be prepared by mixing the compounds of the invention as an active ingredient with inert solid or liquid carriers customary in such formulations which are suitable for topical treatment.

About 0.05 to 5%, preferably 0.1 to 1% solutions, ointments or creams are suitable for topical use.

These preparations may optionally be treated with admixtures of antioxidants, for example tocopherol, K-methyl-γ-tocopheramine, as well as butylated hydroxyanisole or butylated hydroxytoluene.

The following example illustrates the invention:

Example

(a) 4.05 g of sodium hydride (50% suspension in mineral oil) are washed with absolute water, dried under a water pump vacuum and suspended in 100 ml of dimethylformamide. At 0 ° C, a suspension of 43 g of [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. Low: 14 ° C. At the same temperature, a suspension of 16 g of p-formylbenzenesulfonic acid sodium salt in 200 ml of dimethylformamide is added dropwise to the deep red solution thus obtained. After stirring at room temperature for 3 hours, the brown-red solution is poured onto ice and the mixture is evaporated to dryness in a water-jet vacuum. The crystalline, gray residue was suspended in ethyl acetate, the mixture was filtered, and the residue on the filter was washed several times with ethyl acetate. Recrystallizing the residue twice from boiling water yielded 10 g of sodium-β-β2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenybenzenesulfonate having a higher decomposition temperature. 300 ° C.

2355ÍÍÓ 4 ^!

(b) 4.8 g of sodium sulfonate obtained in (a) are suspended in 50 ml of ditaethylformamide and 2.0 g of thionyl chloride are added. After stirring for half an hour at room temperature, 15 ml of ethyl amine was added to the yellow suspension, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture is then poured onto ice, extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. A brown oil is obtained, which, together with a 1: 1 mixture of hexane and ether, is filtered through a short column of silica gel and then recrystallized from a mixture of hexane and ether. 1.6 g of N-ethyl-β- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetromethyl-2-n-phenyl) propenyl ^] benzsulfonamide (colorless crystals), m.p. Mp 137-138 ° C.

Claims (3)

A process for the preparation of novel tetrahydronaphthalene and indene derivatives of the general formula I in which n is 1 or 2, ψ is 1 or 2, R represents a monoalkylamino group or a (C 1 -C 4) dialkylamino group, characterized in that C 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl is optionally 2- (1,1,3,3-tetramethyl-5-indonyl) propenyl-3-phenylsulfinic acid or sulfonic acid of formula II SPUOH in which mn is as defined above, will convert to C 1-4 alkyl or monoalkylamide or dialkylamide. 2. The process of claim 1 wherein the starting compound is a compound of formula (II) wherein n is 2 and m is as defined in 1. 3. A process according to claim 1 or 2, wherein the starting material is a compound of formula (II) wherein m is 2 and n is as defined in (1) or (2).