CS235547B2 - Process for the preparation of new tetrahydronaphthalene and indane derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of novel tetrahydronaphthalene and indane derivatives of the general formula I in which n is 1 or 2, and pharmaceutically acceptable salts of these compounds. Suitable pharmaceutically acceptable salts are, for example, alkali metal salts or alkaline earth metal salts and ammonium salts. Preferred compounds of the formula I are those in which n is 2. The process according to the invention consists in reacting [2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]- or [2-(1,1,3,3-tetramethyl-5-indonyl)-propenyl]-halobenzenes of the general formula II

Description

The present invention relates to a process for the preparation of novel tetrahydronaphthalene and indane derivatives of the formula I

wherein n is 1 or 2, and pharmaceutically acceptable salts thereof.

Suitable pharmaceutically acceptable salts are, for example, alkali metal or alkaline earth metal salts as well as ammonium salts.

Preferred compounds of formula I are those wherein n is 2.

The process according to the invention consists in the conversion of 2- [5,6,7,8-tetrahydro-5,5,8,87-tetramethyl-2-naphthyl] -propenyl] - [2- (1,1,3, 3-tetramethyl-5-indonyl) propenyl halobenzenes of formula II

wherein n is the same as in formula I

X is halogen, acts in the presence of a strong base with sulfur dioxide, and optionally the obtained aulfinic acid salt is converted to the free acid.

According to the invention, a compound of formula II in which X is halogen, preferably bromine, is treated with a strong base such as butyllithium and sulfur dioxide. This reaction ae can be carried out in an inert organic solvent, for example an ether, such as diethyl ether, or a hydrocarbon, such as hexane, or mixtures thereof, conveniently at temperatures below room temperature, for example at about 0 ° C. The sulfinic acid salts of the formula I obtained can be converted by treatment with an acid, for example a mineral acid such as hydrochloric acid, into the corresponding eulfinic acid, i.e. the compound of the formula I.

The starting materials of the formulas (II) and (e) can be prepared analogously to known processes or analogously to the processes described below if their preparation is not known or is not further described.

The reaction products of formula I and their pharmaceutically usable salts are pharmacodynamically valuable compounds. These compounds can be used for the topical and symatic therapy of benign and malignant neoplasms, premalignant lesions, as well as for the ayatemic and topical prophylaxis of said affection.

These compounds have long been useful for the topical and systemic therapy of acne, psoriasis, and other dermatoses, which are common to enhanced or pathologically altered corneal corners, as well as inflammatory and allergic dermatological affections. The reaction products of the formula I and their pharmaceutically usable salts aa can furthermore also be used for combating mucosal diseases and for inflammatory or degenerative or metaplastic changes.

The novel compounds belonging to the group of retinoids and e, as opposed to the known retinoids, are distinguished, for example, by causing slight loss of weight in experimental animals, which is a side effect of retinoids (hypervitaminoaa A).

For the treatment of these diseases, the compounds of the invention are administered orally, conveniently at a dose of about 5 to 200 mg per day, preferably 10 to 50 mg / day for adult patients. Eventual overdose of ee can manifest hypervitaminosis for vitamin A and can be easily detected by its symptoms (scaling 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 ayetemic application may be prepared, for example, by adding to the compound of formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient the non-toxic, inert solid or liquid carriers customary in such formulations.

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

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. Preferred dosage forms are β capsules containing 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 formulations may be presented, for example, in the form of a sterile solution that is miscible with water. The capsules may contain fillers or thickeners, depending on the active ingredient. 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 altering the atmospheric pressure, buffers and other additives.

The above-mentioned 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 of the invention are conveniently used in the form of ointments, elixirs, creams, solutions, lotions, sprays, suspensions and the like. Ointments and creams as well as solutions are preferred. These topical formulations 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% of solutions, are suitable for topical use,

Ointments or creams.

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

The following example illustrates the invention:

Example> 3.0 g of 6- (p-bromo-06-methylstyryl) -1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene are dissolved in 300 ml of absolute ether. While cooling with ice, 20 ml of a 2N solution of butyllithium in hexane is added dropwise and the mixture is stirred for a further 1.5 hours at 0 [deg.] C. Then an intense stream of sulfur dioxide is introduced into the reaction mixture for 30 minutes. sodium carbonate, the resulting aqueous suspension is extracted twice with ether, the aqueous solution is filtered and the colorless precipitate is dried at 80 ° C under high vacuum.

After recrystallized! from boiling water 7.1 g of sodium p- [2- (5,6,7,8-tetrahydro-5,5,8,8-tertamethyl-2-naphthyl) propenyl] benzenesulfinate are obtained, m.p. 312-320 ° C. (decomposition).

The 6- (p-bromo-5S-methylstyryl) -1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthene used as starting material can be prepared as follows:

g [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide was heated with boiling 13.9 g of p-bromobenzaldehyde in 400 ml of butylene oxide for 3 hours to boiling under reflux. The reaction mixture is cooled, poured onto 500 ml of methanol / water (6: 4), extracted three times with hexane for three times, the organic phase is washed twice with water, dried over sodium sulphate and evaporated. A yellow-orange oil is obtained which is recrystallized from ethyl acetate. 14.5 g of 6- (p-bromo-1-methylstyryl) -1,2,3,4-tetramethylnaphthalene are obtained in the form of colorless crystals, m.p. 133-136 ° C.

Claims (2)

SUBJECT OF THE INVENTION 1. A process for the preparation of the novel tetrahydronaphthalene and indane derivatives of the general formula I with ₂ h in which n is 1 or 2, and their pharmaceutically usable salts, characterized in that: -5,5,8,8-tetramethyl-2-naphthyl) propenyl] - optionally [2- (1,1,3,3-tetramethyl-5-indonyl) propenyl] halobenzenes of formula II H, CH, CH X ICH,), H ₃ C CH ₃ ♦ wherein n is as defined above X is halogen, acts in the presence of a strong base with sulfur dioxide, and then the optionally obtained sulfinic acid salt is converted to the free acid. 2. A process according to claim 1, wherein the starting material is a compound of formula (II) in which n is 2, X being as defined in point 1.