CS235549B2 - Method of tetrahydronaphthalene and indane new derivatives production - Google Patents

Description

(54) A process for the production of new tetrahydronaphthalene and indane derivatives

The present invention relates to the general formula (I) for the preparation of novel tetrahydronaphthalene and indane derivatives

(AND),

1-4 carbon atoms.

wherein n is 1 or 2, m is 1 or 2,

R represents an alkyl group

C 1 -C 4 alkyl groups can be straight-chain or branched. Preferred alkyl groups are methyl, ethyl and isopropyl.

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

Particularly preferred compounds are:

ethyl-p- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylsulfone, ethyl-p- [2- (5,6,7, 8-Tetrehydro-5,5,8,8-tetramethyl-2- (8-phenyl) propenyl] phenylsulfoxide, isopropyl-p- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthyl) propenyl phenyl sulfone.

According to the invention, the compounds of formula (1) are prepared by reacting 2- (5,6,7,8-tetrehydro-5,5,8,8-tetremethyl-2-nephtyl) propenyl optionally, (1,3,3-tetramethyl-5-indonyl) propenyl-4-phenyl-sulfides, -sulfoxides or -sulfones of formula 11

H ₃ C CH ₃ CH ₃ (CH ₂ ), H ₃ C CH ₃ (II), in which R is as defined above, act with oxidizing agents.

Oxidation of the compound of formula II to the corresponding sulfoxide (compound of formula I, m = 1 as well as oxidation of the sulfoxide to the corresponding sulfone (compound of formula I, m> 2)) can be carried out by treatment with oxidizing agents such as peracids such as m-chloroperbenzoic acid. also periodates, such as sodium periodate, to the sulfoxide.

The starting materials of the 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 fermacodynamically valuable compounds. These compounds can be used for the topical and sythetic therapy of benign and malignant lesions, as well as for the systemic and topical prophylaxis of said affection.

The compounds are further suitable for the topical and systemic treatment of acne, psories and other dermetoses, which are common to 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 further be used to combat mucosal diseases with inflammatory or degenerative or metaplestic 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 (hypervitaminosis A).

The effect of the reaction products manifested by tumor suppression is significant. Thus, in a papilloma test in mice (Europ. J. Cencer 10, 732 (1974)), diminution of tumors induced by dimethylbenzanthracene and croton oil is observed. For example, papilloma diameter decreases within 2 weeks with intraperitoneal administration of ethyl β- [2- (5,6,7,8-tetr8hydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylsulfone at 12.5 mg / kg / week by 56% at 6.25 mg / kg / week by 36% at 3 mg / kg / week by 12%

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. A possible overdose may be manifested by hypervitaminosis for vitamin A and is easily detected by their symptoms (peeling, hair loss).

This dose may be replicated 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 that is miscible with water. The capsules may contain, in addition to the active ingredient, fillers or thickeners. In addition, these preparations may contain flavor-improving additives as well as conventional substances used as preservatives, stabilizers, moisture-retaining agents and emulsifiers, and also salts for varying the osmotic pressure, buffers and other additives.

The above-mentioned carriers and diluents may consist of organic or inorganic substances, for example, water, gelatin, lectose, 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 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 can optionally be treated with admixtures of antioxidants such as tocopherol, N-methyl-γ-tocopheramine and butylated hydroxytoluene.

The following example illustrates the invention.

Example

6.4 g of ethyl β-2- (5,6,7,8-tetrrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl-phenylsulfide are dissolved in 150 ml of methylene chloride and at 0 3 g of m-chloroperbenzoic acid are added over a period of 6 hours. The reaction mixture was stirred at 0 ° C for 2 h, diluted with methylene chloride, extracted twice with ice-cold potassium carbonate solution and water, dried over sodium sulfate and evaporated. Chromatography on silica gel (eluent: hexane / ethyl acetate = 4: 1) followed by crystallization from hexane / ethyl acetate gave 3.1 g of ethyl-β-2- (5,6,7,8-tetrahydro-). 5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylsulfoxide, m.p. 148-150 ° C.

The following compounds are obtained in an analogous manner: methyl-β- [2- (5,6,7,8-tetrahydro-5,6,6-tetramethyl-2-naphthyl) propenyl] phenylsulfide and m-chloroperbenzoic acid are obtained from methyl- p- (2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl) diphenylsulfoxide, m.p. 155-156 ° C; from methyl p- {2- (5,6,7,8-tetrahydro-5,8,8,8-tetramethyl-2-naphthyl) propenyl] phenylsulfoxide and m-chloroperbenzoic acid, methyl p-2- (5) is obtained. (6,7,8-tetrahydro-5,5,8,8-tetramethyl) propenyl] phenylsulfone, m.p. 176-178 ° C.

The starting flight can be produced as follows: S- (p-formylphenyl) dimethylthiocarbamate (melting point / 8 to 80 ° C) can be prepared from p-hydroxybenzaldehyde via O- (p-formylphenyl) dimethylthiocarbamate (melting point 94 to 96 ° C) by the procedure , described by MS Newmann and HA Karnes in J. Org. Chem., 31, 3980 (1966).

g of 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide are heated together with 25.2 g of S- (p-formyiphenyl) dimethylthiocarbamate in 1 liter of butylene oxide at reflux for 40 hours. The reaction mixture was cooled, poured onto 1 L of methanol / water (6: 4), extracted three times with hexane, the organic phase was washed with water, dried over sodium sulfate and evaporated. The crude product was filtered through silica gel (4: 1 hexane: ethyl acetate) and then recrystallized from ethyl acetate / hexane. 39 g of S- p -p- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl-1-phenyl dimethylthiocarbamate are obtained in the form of colorless crystals, m.p. 107 to 109 ° C.

500 mg of lithium aluminum hydride are suspended in 10 ml of tetrahydrofuran, and a solution of 5 g of S- [beta] - [5,6,7,8-tetrahydro-5,5,8,8-tetramethyl] -ethanol is added dropwise under ice-cooling. After 2 hours of stirring at room temperature, excess lithium aluminum hydride is decomposed by dropwise addition of water under ice-cooling, and after acidification of the solution with 1 N hydrochloric acid solution, extraction with ether is carried out. NaOH and evaporated to give 3.5 g of p- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] thiophenol as a colorless oil which is very Oxidation sensitive material, which is recrystallized from hexane / ether, m.p. 97-98 ° C.

500 mg of sodium hydride (50% suspension in mineral oil) was washed with absolute pentane, dried in a water pump vacuum and suspended in 10 ml of dimethylformamide. Under cooling with a solution, a solution of 3.3 g of N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl} thiophenol in 5 ml of dimethylformamide is added dropwise. After stirring for 1 hour at 0 ° C, ethyl iodide was added dropwise, the temperature was allowed to rise to room temperature and the reaction mixture was stirred for a further 3 hours. The reaction solution is poured onto ice, extracted with ether, the organic phase is washed with 2 N hydrochloric acid solution and water, dried over sodium sulfate and evaporated. The crude product was filtered through silica gel (eluent: hexane / ethyl acetate 9: 1) and recrystallized from hexane. 2.7 g of ethyl p-f [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylsulfide, m.p. 88 DEG-89 DEG C., are obtained.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of novel tetrahydronaphthalene and indane derivatives of the general formula I 232549 where n is 1 or 2, m is 1 or 2, R is C 1 -C 4 alkyl, characterized in that 2-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl optionally 2- ( 1,1,3,3-tetramethyl, in which R is as defined above, is treated with an oxidizing agent. ÍT · 2. The process of claim 1, wherein n is 2 and R 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 R is as defined in (1) or (2) to form compounds of formula (I) wherein m is 2 and the remaining symbols have the meanings given in point 1 or 2. 4. A process according to any one of claims 1 to 3, wherein the starting materials are compounds of formula (II) wherein R is ethyl and n is as defined in 1, 2 or 3.