Bicyclic aromatic compounds and containing pharmaceutical and cosmetic compositions

 

(57) Abstract:

Describes new bicyclic aromatic compounds of General formula I, where R1group CO-O-R8; R8is hydrogen, alkyl, linear or branched radical with 1 to 20 carbon atoms or R; R is lower alkyl; And a is a radical selected from groups (a), (b), (d); X - represents-O -, - S(O)tor-NR9-; R2is hydrogen, halogen, lower alkyl group OR9; t is an integer of 0, 1 or 2; R9is hydrogen, halogen, lower alkyl group OR9; t is an integer of 0, 1 or 2; R9is hydrogen or lower alkyl; R11and R12is hydrogen or lower alkyl, or their salts. The compounds exhibit activity in relation to differentiation and cell proliferation. Also describes pharmaceutical and cosmetic compositions based on the compounds of formula I. 3 C. and 11 C.p. f-crystals, 1 Il.

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The present invention relates to bicyclic aromatic compounds as new and biologically active products. It also relates to the use of these new compounds in pharmaceutical compositions intended for use in human medicine or veterinary medicine, or in cosmetic compositions.

Compounds according to the invention can also be used in cosmetic compositions for the care of the body, and hair care products.

Compounds according to the invention can be represented by the following General formula (I):

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where:

R1denotes a hydrogen atom, happy is-O-(CH2)m-(CO)n- R6; a radical - CO-R7the radical-CO-O-R8or more radical - S(O)p- R9and the value of "m", "n" and "p", as well as various radicals R3+ R9have the following value;

R9denotes a hydrogen atom or a halogen atom, a lower alkyl radical, a radical - NO2a radical - O - COR4the radical OR9or the radical:

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moreover, the radicals R4, R9and R10have the following value:

Ar represents a radical chosen among the radicals of the following formulae (a) to (e):

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in which R2have the above significance and R9has the following value:

X denotes-O-, -S(O)t- or a radical-NR9-, and the value "t" and the radical R9have the following value:

Y and Z denote-O - S(O)t- or radical - CR11R12and the value of "t" and the radicals R11and R12have the following value:

having in mind that in the above:

- "m" denotes an integer equal to 1, 2, or 3;

"n" denotes an integer of 0 or 1;

"p" denotes an integer of 0, 1, 2 or 3, and

"t" represents an integer of 0, 1 or 2;

- R3denotes the hydrogen atom or the bottom of toroda or a lower alkyl radical,

- R6denotes a lower alkyl radical or a heterocycle,

- R7denotes a hydrogen atom, a lower alkyl radical or a radical

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in which R' and R", identical or different, denote a hydrogen atom, a lower alkyl radical, a mono - or polyhydroxyalkane radical, if necessary substituted aryl radical or a residue of an amino acid or peptide or sugar; or taken together, form a heterocycle;

- R8denotes a hydrogen atom, a linear or branched alkyl radical with 1-20 C-atoms, alkanniny radical, mono - or polyhydroxyalkane radical, aryl or Uralkaliy radical, if necessary substituted, or a sugar residue or an amino acid residue or peptide ;

- R9denotes a hydrogen atom or a lower alkyl radical;

- R10denotes a hydrogen atom or a lower alkyl radical;

- R11denotes a hydrogen atom or a lower alkyl radical;

- R12denotes a hydrogen atom or a lower alkyl radical;

- Y and Z cannot simultaneously denote an oxygen atom or a radical-S(O)t.

The invention also relates to salts of compounds of the above formula (I), in which radika is whether the radical R2indicates the amine function, as well as chiral analogues of the above compounds. When the compounds according to the invention are in the form of salts, it is preferably of the salts with alkali or alkaline earth metal, or of salts of zinc or of an organic amine.

According to the present invention, by "lower alkyl radical" is understood radical with 1-6 C-atoms, preferably metal, ethyl, ISO-propyl, boutigny, tert.-botilony and sexily radicals.

Under linear or branched alkyl radical with 1-20 C-atoms see especially methyl, ethyl, sawn, 2-ethylhexyl, octillery, dodecylphenyl, hexadecimally and octadecenyl radicals.

Under monohydroxyethyl radical see radical containing preferably 2 or 3 carbon atoms, especially 2-hydroxyethylene, 2-hydroxypropyl or 3-hydroxypropyl radical.

Under polyhydroxyalkane radical see radical, preferably containing 3 to 6 carbon atoms and 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutane, 2,3,4,5-tetrahydroxyphenyl radicals or the rest of pentaerythritol.

Under and the least one halogen atom, the hydroxyl or nitro group.

Under Uralkali radical preferably understand benzyl or finitely radical, if necessary substituted by at least one halogen atom, hydroxyl or nitro group.

Under alkenyl radical see radical containing preferably 2-5 C atoms and having one or more double bonds (ethylene nancysinatra), such as mainly allyl radical.

Under the sugar residue understand the remainder originating in particular from glucose, galactose or mannose, or glucuronic acid.

Under amino acid residue understand especially the residue derived from lysine, glycine or aspartic acid, and residue peptide understand mainly dipeptide or Tripeptide the residue, the resulting combination of amino acids.

Finally, under the heterocycle preferably understand piperidino, morpholino-, pyrrolidine or piperazine derivatives radical, if necessary substituted in position 4 alkyl radical with 1-6 C atoms or a mono - or polyhydroxyalkane radical such as defined above.

When the radical R2denotes the atom of halogenase (I), included in the scope of the present invention particularly include the following:

4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy) benzoic acid,

4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid,

4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl) benzoic acid,

4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl) benzoic acid,

4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine) benzoic acid,

5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-2 - thiencarbazone acid,

4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyloxy) benzoic acid,

4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid,

4-(3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy) benzoic acid,

4-(3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy) benzoic acid,

4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)acetophenone,

4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetamide,

4-(3-bromo-5,5,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy) benzoic acid,

3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid,

3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid,

the 3rd is ahydro-2-naphthylthio) nicotinic acid,

2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid,

2-chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid,

4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid,

4-(3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid,

4-(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid,

4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)Benalmadena,

4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzaldehyde,

N-ethyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamid,

N-4-hydroxyphenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide.

According to the present invention, particularly preferred compounds of formula (I) are such that adhere to at least one, and preferably all, of the following conditions:

- R1refers to the radical - CO - R7,

- R2denotes a lower alkyl radical and the radical OR9,

Ar represents a radical of formula (a),

and X denotes-O-, -S - or-NR9-.

The object of the present invention are methods for producing compounds of formula (I), carried out the may be obtained (see the drawing) through a combination of sodium salt of phenol derivative (3) with a halogenated derivative (7), preferably brominated or iodirovannoi derivative, in the presence of a complex of copper bromide with dimethyl sulfide in a solvent such as pyridine. As for the phenol derivative (3), they can be obtained by reaction type Friedel-from phenol (2) and dehalogenating derivative (I) in the presence of a Lewis acid such as floridaonline.

The compounds of formula (Ib) can be obtained (see the drawing) through a combination of sodium salt Colnago derivative (6) with the halogenated derivative (7), preferably brominated or iodirovannoi derivative, in the presence of a catalyst, such as certain transition metal complexes, in an alcohol solvent, such as ethyl or butyl alcohol. As suitable catalysts in particular, one can specify such on the basis of Nickel or palladium, for example, as the complexes of Ni(II) with various phosphines or tetrakis (triphenylphosphine)palladium (0). Tirinya derivative (6) can be obtained from the phenol derivative (3) through dialkyldithiocarbamate derivatives (4) and (5) under the General conditions described by M. Newman and H. Carpiodes formula (Ib), for example, using meta-chlormadinone acid.

When in the General formula (I), X represents the radical - NR9then the compound can be obtained according to reaction type Ullman by direct nucleophilic substitution halogenated derivative (7), preferably iodirovannoi derivative, an aniline derivative (8), in the presence of a base such as potassium carbonate or N-methylmorpholine, and copper:

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In the above formulas and reactions R1and R2have the meanings mentioned above for the General formula (I), or they mean their protected derivatives, so that they were compatible with the reaction conditions of the combination. In particular, when they represent a hydroxyl radical, it is preferably protected in the form of tert.-butyldimethylsilyloxy or methoxyethoxyethoxy group. Removing the protective groups are carried out either in the presence of tetrabutylammonium or trimethylsilane, or in an acidic environment (e.g., hydrochloric acid).

Compounds according to the invention are active in relation to the expression of some markers of differentiation in human keratinocytes in vitro ( Anal. Biochemen 192, 232 - 236 (1991) and/or they have a good comedolytic activity in t the following areas:

1). for the treatment of dermatological diseases associated with disorders of keratinization, which leads to differentiation and proliferation, especially for treating common, polymorphic black, red acne; usercookie acne, conglobata, senile acne, secondary acne such as those caused by solar radiation, drug or occupational acne;

2). for the treatment of other types of disorders of keratinization, especially for the treatment of ichthyosis, idiotphone States, disease Darrier, plantar keratoderma, leukoplakia and makoplasty States, herpes on the skin or on mucous membranes (mouth);

3). for treating other dermatological diseases associated with disorders of keratinization with inflammatory and/or immunoallergic component and especially all forms of psoriasis, skin, mucous ungual psoriasis, and even psoriatic rheumatism, or cutaneous atopy, such as eczema, or respiratory atopy or hypertrophy of the gums; the connection can also be used in certain inflammatory diseases, does not constitute violations of keratinization;

4). to ensure all termicheskih or epidermal of proliteracy, benign or locatetv and and borodavkindima epidermodysplasia, oral or Floridia papillomatosis, and proliferate, which can be caused by ultraviolet radiation, especially in the case of basic - and spinocellular of epithelium;

5). for treating other dermatological disorders such as bullous dermatoses and collagen;

6). to treat certain eye disorders, such as diseases of the cornea;

7). to restore or fight against aging skin, which is the age or polonizirovannaya or for reductions pigmentations and actinic keratoses, or to deal with any pathologies associated with age or actinic aging;

8). to prevent or feleciana stigmata of epidermal and/or termicheskoi atrophy caused by local or systemic corticosteroids, or any other form of cutaneous atrophy;

9). for prevention or treatment of impaired wound healing or for the prevention or recovery of scars on the skin when it is stretched;

10) for combating disorders of adipose function, such as hyperseborrhea acne or seborrhea;

11) for the treatment or prevention of cancerous or precancerous lesions;

12) for the treatment of inflammatory diseases, such as Arktiki or treatment of hair loss;

15) for the treatment of dermatological or General diseases with an immunological component;

16) for the treatment of diseases of the cardiovascular system such as arteriosclerosis.

In the above areas of therapy, the compounds according to the invention can preferably be used in combination with other compounds displaying the activity of the retinoid type of vitamins or their derivatives, with corticosteroids, with anti-free radicals-hydroxy - or-keto acid or their derivatives, or blocking ion channels means. Under vitamin D or derivatives of them understand, for example derivatives of vitamin D2or D3for example, 1,25 - dihydroxyvitamin D3. Under tools against free radicals understand, for example-tocopherol, superoxide Dismutase, Original or some agents education chelate compounds with metals. Under-hydroxy or a-keto acid or their derivatives see, for example, lactic, malic, citric, glycolic, almond, wine, glycerol or ascorbic acid or their salts, amides or esters. Finally, under the blocking ion channels means understand, such as Minoxidil(2,4-diamino-6-Pipa is asepticheskie composition, containing at least one compound of formula (I) above, one of its chiral analogues or one of its salts.

A pharmaceutical composition characterized in that it includes pharmaceutically acceptable and compatible with the method of administration provided for in this last medium at least one compound of formula (I), one of the chiral analogues or one of its salts in an effective amount.

Introduction compounds according to the invention can be implemented enteric (intestinal), parenteral, topical or ocular (main) way.

For enteral introduction of the composition may be in the form of tablets, gelatin capsules with the medicine, pills, syrups, suppositories, solutions, powders, granules, emulsions, microspheres or nanospheres or vesicles, lipid or polymer, allowing controlled release of active beginning. For administration by parenteral compositions may be in the form of solutions or suspensions for perfusion or for injection.

Compounds according to the invention is usually administered in a daily dose of about 0.01 - 100 mg/kg of body weight and this in 1-3 reception.

For topical application by pharmaceutical is made, powders, impregnated swabs, solutions, gels, pulverizing drugs, lotions or suspensions. They can also be in the form of microspheres or nanospheres or lipid or polymeric visicol or polymer pieces of patches and hydrogels allowing controlled release of the current beginning. These compositions for topical application, in addition, can be either in anhydrous form or in aqueous form.

For insertion through the eye they are eye drops.

Compositions for topical introduction or insertion through the eyes contain at least one compound of the above formula (I) or one of its optical or geometric isomers or one of its salts, at a concentration of preferably 0.001 to 5 wt.%, calculated on the total weight of the composition.

The compounds of formula (I) according to the invention also find application in the cosmetic field, in particular for hygiene and hair care products, and especially for treatment of the skin with tendency to acne for new hair growth against hair loss, for combating the greasy appearance of the skin or hair, for protection against the harmful effects of the sun or for the treatment of physiologically dry skin, for Prekrasnaya according to the invention can preferably be used in combination with other compounds, with retinoid activity type, with vitamin D or its derivatives, with corticosteroids, with anti-free radicals-hydroxy - or-keto acid or their derivatives, or blockers of ion channels, and all of these different products are listed above.

The present invention therefore relates to cosmetic compositions, which is characterized in that it comprises, in a cosmetically acceptable and suitable for topical administration carrier, at least one compound of the above formula (I) or one of its chiral analogues or one of its salts, with this cosmetic composition may be in the form of a cream, milk, lotion, gel, lipid or polymeric microspheres or nanospheres or vesicles, a soap or shampoo.

The concentration of the compounds of formula (I) in the cosmetic compositions according to the invention is preferably 0.001 to 3 wt.%, in the calculation of the totality of the composition.

The medicinal and cosmetic compositions according to the invention, can also contain inert or pharmacodynamically or cosmetically effective additives or their mixture, in particular: wetting, depigmentary, hydrating agents like glycerin, PEG-400, thiomorpholine and its derivatives or urea, antisubmarine or protivoluchevye agents, such as S-carboxymethylcysteine, S-benzyl group probably facilitates their salts or their derivatives, or benzoyl peroxide, antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines, antifungal agents such as ketoconazole or polymethylene-4,5-isothiazolin-3-ones, the agents that foster new hair growth, such as Minoxidil(2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and phenytoin(5,4-diphenyl-imidazolidin-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and especially carton; antipsoriasis agents, such as anthralin and its derivatives, and finally, eicosa-5,8,11,14-Terranova acid and eicosa-5,8,11-TRINOVA acid, their esters and amides.

Compositions according to the invention can also contain improves the taste of agents, preservatives such as esters of para-hydroxybenzoic acid, stabilizers, regulating humidity agents; regulating pH agents, encoders osmotic pressure; emulsifiers, UV-a and UV-b filters, the Xia, as an illustration and without limiting their scope of protection of the invention, several examples of active compounds of the formula (I) according to the invention, as well as various specific formulations based on such compounds.

Example 1

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2 - naphthyloxy) benzoic acid.

(a) Methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoate

In a three-neck flask under nitrogen atmosphere injected with 5.3 g (15 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol and 70 ml of pyridine and small portions add 430 mg (15 mmol) of sodium hydride (80% in oil). Stirred for 30 minutes, add sequentially to 3.9 g (15 mmol) of methyl-4-iodobenzoate and 4.6 g (to 22.5 mmol) of copper bromide with dimethyl sulfide and refluxed for 16 hours. The reaction medium is evaporated to dryness, treated the residue with water and diethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira dichloromethane hexane (50-50). After evaporation of the solvents to obtain 3.4 g (67%) of the target complex methyl ester.

(b) 4-(5,6,7,8-Tetrahydro-5,5,8,8-Tetera, 40 ml THF and 40 ml of 2 N. methanolic sodium hydroxide solution and the whole mixture was stirred at room temperature for 8 hours. The reaction medium is evaporated to dryness, the residue is treated with water, acidified to pH 1, extracted with diethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira a mixture of dichloromethane with diethyl ether (97-3). After evaporation of the solvents to obtain 2.3 g (71%) of the target acid so pl. 234-235oC.

Example 2

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid

(a) Ethyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate

In the flask was injected 30 ml of ethanol, then in small portions add 500 mg (23 mmol) of sodium and stirred the whole mixture for 30 minutes. Then add successively 2 g (9.1 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naftiliaki, 2.4 g (9.1 mmol) of methyl-4-iodobenzoate and 100 mg (0.09 mmol) of tetrakis(triphenyl-phosphine)palladium(0), then refluxed for 4 hours. The reaction medium is evaporated, the residue is treated with water and ethyl acetate, the organic phase is decanted, washed with water what led silicon, elwira dichloromethane. After evaporation of the solvent to obtain 2.1 g (63%) of a compound of ethyl ether.

(b) 4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid

Similar to the above example 1(b), of the 1.9 g (5.2 mmol) obtained in the previous paragraph. (a) a complex of ethyl ether to obtain 1.6 g (90%) of the target acid so pl. 187-188oC.

Example 3

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl) benzoic acid

(a) Ethyl-4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl)benzoate

Into the flask impose 1.1 g (3.1 mmol) of ethyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate and 30 ml of dichloromethane and then add 970 mg ( 3.1 mmol) metacompetencies acid.

The whole mixture was stirred at room temperature for two hours, the reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica, elwira dichloromethane. After evaporation of the solvent receive 1 g (84%) target of ester.

(b) 4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl) benzoic acid

Similar wireapi the t 890 mg (99%) of the target acid so pl. 214 - 216oC.

Example 4

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl) benzoic acid

(a) Ethyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl)benzoate

Into the flask enter 1,05 g (2.8 mmol) of ethyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate and 30 ml of dichloromethane and then add a 2.45 g (7,12 mmol) metacompetencies acid. The whole mixture was stirred at room temperature for two hours, the reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of silica, elwira dichloromethane. After evaporation of the solvent receive 1,09 g (95%) target of ester.

(b) 4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl) benzoic acid

Similar to the above example 1(b), it follows from the 1,09 g (2.7 mmol) obtained in the previous p. (a) complex ethyl ester, get 1 g (99%) of the target acid so pl. 216-220oC.

Example 5

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine) benzoic acid

Into the flask is administered sequentially of 1.02 g (5 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtylamine, 1.24 g (5 m is ü refluxed for 24 hours, reaction medium was poured into 15 ml of 5 n hydrochloric acid, the precipitate filtered off, washed with this last water. Solid proscout in ethanol, filtered, dried. Then receive 200 mg (12%) of the target acid so pl. 262 to 264oC.

Example 6

5-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-2-thiencarbazone acid

In the flask was introduced 40 ml of n-butyl alcohol, then add small portions 300 mg (13 mol) of sodium, and the whole mixture is stirred for 30 minutes. Then add successively 1.1 g (5 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naftiliaki, 1.1 g (5 mmol) of methyl 5-bromo-2-thiophenecarboxylate and 230 mg (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0), then the whole mixture is refluxed for 4 hours. The reaction medium is evaporated, treated the residue with water and ethyl acetate, the organic phase is decanted, washed with water, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira a mixture of ethyl acetate with hexane (60 - 40). After evaporation of the solvents to obtain 180 mg (10%) 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-2-thiophencarboxylic acid so pl. 141-142oC.

Petralito-2-naphthol

In a three-neck flask enter 50,8 g (0.27 mol) of 2,5-dichloro-2,5-dimethyl-hexane, 30 g (0.27 mol) of 2-methyl-phenol and 500 ml of dichloromethane. At 0oC add small portions of 14.8 g (0.11 mol) of aluminum chloride, and the whole mixture was stirred at room temperature for 12 hours. Reaction medium was poured into ice water, extracted with dichloromethane, the organic phase is decanted, washed containing bicarbonate and water, dried over magnesium sulfate and evaporated. The obtained residue proscout in hexane, filtered and then obtain, after drying, of 54.4 g (90%) of the target phenol with so pl. 125-126oC.

(b) Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoate

Similar to the above example 1(a), by reacting 1.1 g (5 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthol with 0,89 g (4.1 mmol) of methyl-4-bromobenzoate, get a 670 mg (46%) of the target complex methyl ester with so pl. 133 - 135oC.

(b) 4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyloxy) benzoic acid

Similar to the above example 1(b) follows from 670 mg (1.9 mmol) obtained in the previous p. (b) complex methyl ester, obtain 620 mg (96%) of the target acid so pl. 208-210oC.

Example 8

4-(pildimaterjaliga

In a flask, under nitrogen atmosphere, introducing 4.1 g (was 0.138 mol) of sodium hydride (30% in oil) and 200 ml of DMF. Cooled to 0oC and added dropwise a solution of 25.2 g (0,115 mol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthol in 100 ml of DMF and the whole mixture is stirred until cessation of gas evolution. Then add a solution 18,55 g (0.15 mol) of dimethylthiocarbamate in 200 ml of DMF and again the whole mixture is stirred for 8 hours at room temperature. After this, the reaction medium is poured into water, extracted with ethyl acetate, the organic phase is decanted, washed with water, dried over magnesium sulfate, and finally evaporated. The resulting residue is purified by chromatography on a column of silica, elwira a mixture of ethyl acetate with hexane (30-70). After evaporation of the solvents receive a 20 g (68%) of the desired product with so pl. 110 - 111oC.

(b) - 3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-afterdelconfirm

In a flask under nitrogen atmosphere enter 20,1 g (65,8 mmol) obtained in the previous p. (a) product and within 6 hours heated at 240oC. the Reaction medium is extracted with dichloromethane, washed with water, the organic phase is decanted, dried over magnesium sulfate and evaporated. Get to 18.1 g (90%) of the desired product with so square 138 - 139o< the previous p. (b) product and 300 ml of methyl alcohol. Add 30 g (75 mmol) of sodium hydroxide, and the whole mixture is refluxed for three hours. The reaction medium is evaporated, treated the residue with water, acidified with concentrated hydrochloric acid and finally filtered. The obtained solid is washed with water, dried and then obtain 18 g (99%) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naftalie with so pl. 97 - 98oC.

(d) Ethyl-4-(3,5,5,8,8-pentamethyl-5,5,7,8-tetrahydro-2-naphthylthio)benzoate

Similar to example 2(a), by reacting 2 g (8.5 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naftalie with 2.24 g (8.5 mmol) of methyl-4-iodobenzoate, after recrystallization from ethanol, will receive 2 g (63%) of a compound ethyl ester with so pl. 109 - 110oC.

(d) 4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid

Similar to example 1(b), from 2 g (5.2 mmol) obtained in the previous paragraph. (g) complex ethyl ester, get 1,58 g (85%) of the target acid so pl. 253 - 254oC.

Example 9

4-(3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy) benzoic acid

(a) 3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol

The analogue of the ENT-2,5-dimethylhexane, after chromatography on a column of silica with elution with dichloromethane, obtain 25.4 g (89%) of the target phenol with so pl. 88-89oC.

(b) Methyl-4-(3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoate

Similar to example 1(a), by reacting 2 g (8.6 mmol) of 3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol with 1.52 g (7 mmol) of methyl-4-bromobenzoate receive 1.5 g (56%) of the target complex methyl ester in the form of a yellow oil.

(b) 4-(3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy) benzoic acid

Similar to example 1(b) from 1.5 g (4 mmol) obtained in the previous p. (b) complex methyl ester, obtain 1.24 g (86%) of the target acid so pl. 195 - 196oC.

Example 10

4-(3-Isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy) benzoic acid

(a) 3-Isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol

Similar to example 7(a), by reacting 30 g (0.22 mol) of 2-isopropylphenol from 40.3 g (0.22 mol) of 2,5-dichloro-2,5-dimethylhexane and after chromatography on a column of silica with elution with a mixture of dichloromethane hexane (40-60), get 48,9 g (90%) of the target phenol with so pl. 79 - 80ooC.

(b) 4-(3-Isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy) benzoic acid

Similar to example 1(b), 800 mg (2.1 mmol) obtained in the previous p. (b) complex methyl ester, obtain 690 mg (90%) of the target acid so pl. 205-206oC.

Example 11

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)acetophenone

Similar to example 1(a) follows by interaction of 6.6 g (32 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol from 5.4 g (27 mmol) of 4-bromoacetophenone, obtain 6.3 g (72%) of the target ketone in the form of a slightly yellowish oil.

Example 12

4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzaldehyde

Similar to example 1(a), by the interaction of 5.3 g (15 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 3.1 g (16.5 mmol) of 4-bromobenzaldehyde, after purification by chromatography on a column of silica with elution with a mixture of dichloromethane hexane (50-50) obtain 2.4 g of the target aldehyde with so pl. 75-76(a) Methyl-4-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoate

Analogous to example 1(a), by reacting 1 g (3.5 mmol) of 3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 770 mg (2,94 mmol) of methyl-4-iodobenzoate get 700 mg (58%) of the target complex methyl ester with so pl. 135-136oC.

(b) 4-(3-Bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 - naphthyloxy) benzoic acid

Analogous to example 1(b) follows from 700 mg (1.6 mmol previous complicated methyl ester, get 650 mg (95%) of 4-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy) benzoic acid with so pl. 229 - 230oC.

Example 14

3-Methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid

(a) 3-Methyl-4-identia acid.

In a three-neck flask enter 20 g (0,132 mol) 3-methyl-4-amino-benzoic acid and 175 ml of 20% sulfuric acid. If -10oC was added dropwise a solution of 11.9 g ( 0,172 mol) of sodium nitrite in 50 ml of water and stirred for two hours. This solution through cooled to -5oC addition funnel was added dropwise to a solution of 35 g (0,211 mol) of potassium iodide, 35.2 g (0.185 mol) of copper iodide and 175 ml of 20% sulfuric acid. Stirred for 8 hours, the reaction medium is filtered, the obtained solid substance was dissolved in ethyl acetate, the resulting solution was washed with contineu acid so pl. 205-210oC.

(b) Methyl-3-methyl-4-iodobenzoate

Into the flask is injected, 24,4 (0,093 mol) 3-methyl-4-iodobenzoyl acid, 250 ml of methanol and added dropwise 2.5 ml of concentrated sulfuric acid. Refluxed for 12 hours, the reaction medium is evaporated, the residue treated with ethyl acetate and water, the organic phase is decanted, dried over magnesium sulfate and evaporated. The remainder proscout in methanol, filtered and gain of 21.9 g (85%) of the target complex methyl ester with so pl. 58-59oC.

(b) 3-Methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 - naphthylthio) benzoic acid

Similar to example 2(a), by reacting 2.4 g (11 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naftalie with 3 g (11 mmol) of methyl 3-methyl-4-iodobenzoate, just get a 1.96 g (51%) of 3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid with so pl. 195-196oC.

Example 15

3-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid

(a) Ethyl-3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoate

Similar to example 2(a), by the interaction of 2.55 g (11 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naftalie with 3 g (11 mmol) of methyl 3-methyl-4-iodobenzoate oil.

(b) 3-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid

Analogous to example 1(b) follows from 1.86 g (47 mmol) videolounge complex ethyl ester, obtain 1.5 g (97%) of 3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid with so pl. 217-218oC.

Example 16

3-Methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy) benzoic acid

(a) Methyl-3-methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8 - tetramethyl-2-naphthyloxy)benzoate

Analogous to example 1(a) follows by interaction of 2.1 g (8,7 mmol) of 3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 2 g (7.2 mmol) of methyl 3-methyl-4-iodobenzoate get to 2.18 g (79%) of the target complex methyl ester as a pale yellow oil.

(b) 3-Methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 - naphthyloxy) benzoic acid

Analogous to example 1(b) follows from 2,18 g (5.7 mmol videolooking difficult methyl ester, gain of 1.9 g (90%) of 3-methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy) benzoic acid with so pl. 210-211oC.

Example 17

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) nicotinic acid

(a) Ethyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)nicotinate

Similar to (3.4 mmol) of methyl-6-etniciteit, obtain 620 mg (47%) of the target product in a complex of ethyl ether.

(b) 6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) nicotinic acid

Analogous to example 1(b), 620 mg (1.6 mmol) videolounge complex ethyl ester, obtain 520 mg (90%) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) nicotinic acid so pl. 257 - 260oC.

Example 18

2-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2 - naphthylthio) benzoic acid

(a) Ethyl-2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoate

Similar to example 2(a), by reacting 2 g (8,53 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naftalie with 2.37 g (8,53 mmol) of methyl 2-hydroxy-4-iodobenzoate get 2,42 g (71%) of the desired product in the form of a complex of ethyl ether with so pl. 74-75oC.

(b) 2-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2 - naphthylthio) benzoic acid

Analogous to example 1(b), it follows from 2.4 g (6.1 mmol) videolounge complex ethyl ester, gain of 2.06 g (92%) of 2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid with so pl. 197-200oC.

Example 19

2-Chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid

(a) 2-Chloro-4-iodine is given 14,26 g (80%) of 2-chloro-4-iodobenzoyl acid.

(b) Methyl 2-chloro-4-iodobenzoate

Similar to example 14(b) follows from a 13.9 g (up 49.2 mmol) of 2-chloro-4-iodobenzoyl acid, get to 11.52 g (79%) of the target complex methyl ester in the form of butter.

(C) Ethyl-2-chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2 - naphthylthio)benzoate

Similar to example 2(a), by reacting 2 g (8.5 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naftalie with 2,41 g (8.5 mmol) of methyl 2-chloro-4-iodobenzoate, earn 1.25 g (35%) of the desired product in the form of a complex of ethyl ether.

(g) 2-Chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid

Analogous to example 1(b) by way of a 1.25 g (3 mmol) videolounge complex ethyl ester, get 1 g (96%) of 2-chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid with so pl. 202-205 areoC.

Example 20

(3-Ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid

(a) O-3-Ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-afterdelconfirm

Analogous to example 8(a), by reacting 5 g (21 mmol) of 3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 3.5 g (2.8 mmol) of dimethylthiocarbamate, obtain 4.9 g (72%) of the desired product with so pl. 82 - 83oC.

(b) S-3-Ethyl-5,6,7,8-tetroxane product, obtain 4.5 g (99%) - 3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-afterdeserialize in the form of a brown-colored oil.

(b) 3-Ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio

Analogous to example 8(b), it follows from 4.5 g (14 mmol) videolounge obtain 2.9 g (84%) of the target thiol in the form of an orange oil.

(d) Ethyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 - naphthylthio)benzoate

Similar to example 2(a), by reacting 2 g (8.5 mmol) of 3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naftalie with 2.1 g (8 mmol) of methyl-4-iodobenzoate get 1,9 g (64%) of the desired product in the form of a complex of ethyl ether.

(d) 4-(3-Ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid

Analogous to example 1(b), of the 1.9 g (5.1 mmol) videolounge complex ethyl ester, obtain 1.7 g (89% of 4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) benzoic acid with so pl. 232-235oC.

Example 21

Ethyl-4-(3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-naphthylthio)benzoate

(a) O-3-Isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-afterdelconfirm

Analogous to example 8(a), by reacting 5 g (20.3 mmol) of 3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8- - 00oC.

(b) S-3-Isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-afterdelconfirm

Analogous to example 8(b), it follows from 2.9 g (8,7 mmol) videolounge obtain 1.63 g (56%) S-3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-afterdeserialize with so pl. 103 - 104oC.

(in) 3-Isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio

Analogous to example 8(b), it follows from 4.5 g (14 mmol) videolounge obtain 2.9 g (84%) of the target thiol in the form of an orange oil.

(d) Ethyl-4-(3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate

Similar to example 2(a) follows by interaction of 1.35 g (5.1 mmol) of 3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naftalie with 1.1 g (5.1 mmol) of methyl-4-bromobenzoate get 1.3 g (66%) of the desired product in the form of a complex of ethyl ether.

Example 22

Ethyl-4-(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate

(a) 3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol

Analogous to example 7(a), by the interaction of 13.6 g (0.1 mol) of 2-n-propylene from 18.3 g (0.1 mol) of 2,5-dichloro-2,5-dimethylhexane, after chromatography on a column of silica with elution with dichloromethane, obtain 11.6 g (65%) pildimaterjaliga

Analogous to example 8(a), by reacting 15 g (61 mmol) of 3-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 9.8 g (79 mmol) of dimethylthiocarbamate receive 15.9 g (78%) O-3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-afterdeserialize.

(C) S-3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 - afterdelconfirm

Analogous to example 8(b) from 10 g (30 mmol) videolounge obtain 6.8 g (68%) of S-3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-afterdeserialize with so pl. 102-104oC.

(g) 3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio

Analogous to example 8(b) follows from 6.8 g (to 20.4 mmol) videolounge receive a 5 g (93%) of the target thiol in the form of a colorless oil.

(e) Ethyl-4-(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate

Similar to example 2(a), by reacting 2 g (7.6 mmol) of 3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naftalie 2 g (7.6 mmol) of methyl-4-iodobenzoate will receive 2 g (65%) of the desired product in the form of a complex of ethyl ether.

Example 23

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoimidazol

In a three-neck flask, under nitrogen atmosphere, introducing 144 mg (3.8 mmol) whether the 2-naphthylthio)benzoate in 25 ml of THF and refluxed for 8 hours. The excess hydride is decomposed with a solution of the double salt is the tartrate of sodium and potassium, the reaction medium is extracted with ethyl acetate. The organic phase is decanted, dried on magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira mixture of heptane with ethyl acetate (90-10). Obtain 660 mg (51%) of the target alcohol so pl. 81-82oC.

Example 24

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzaldehyde

In a three-neck flask, under nitrogen atmosphere, enter 60 μl (0.7 mmol) of oxalicacid and 5 ml dichloromethane. At -60oC add 100 μl (1.4 mmol) of DMSO and stirred for 10 minutes, then add a solution of 200 mg (0.6 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoimidazole in 5 ml of dichloromethane and 400 μl (3 mmol) of triethylamine. At room temperature for 1 hour and stirred, and then the reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira mixture of heptane with ethyl acetate (80-20). Get 145 mg (73%) of the target aldehyde with so pl. 98-99oC.

Example 25

N-Ethyl-4-(3,5,5,8 olklore

In the flask, introduce a solution of 1.4 g (4 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio) benzoic acid in 100 ml of anhydrous dichloromethane, add 900 ml (4.4 mmol) of dicyclohexylamine and stirred for one hour. Then add 320 μl (4.4 mmol) of thionyl chloride and stirred for one hour. Is evaporated to dryness, the residue is treated with anhydrous diethyl ether, filtered salt dicyclohexylamine and the filtrate is evaporated. Receive 1.5 g (100%) of a crude carboxylic acid which is used as is, in the continuation of the synthesis.

(b) N-Ethyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide

Into the flask enter 640 μl (8 mmol) of a 70% aqueous solution of ethylamine and 20 ml THF. Was added dropwise a solution of 735 mg (2 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)of benzoyl chloride in 30 ml of THF and stirred at room temperature for three hours. The reaction medium is poured into water, extracted with ethyl acetate, the organic phase is extracted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira mixture of heptane with ethyl acetate (90-10). After evaporation of the solvents, obtain 307 mg (41%) target ethylamide with so pl. p.223-224(a) N-4-Acetoxyphenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide

Similar to example 25(b) follows by interaction of 735 mg (2 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)of benzoyl chloride with 900 mg (6 mmol) of 4-aminobenzoylamino receive 250 mg (26%), the target amide with so pl. 186-187oC.

(b) N-4-Hydroxyphenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide

Similar to example 2(a) from 100 mg (0.2 mmol) of N-4-acetoxyphenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide, obtain 65 mg (71%) of the desired product with so pl. 236 - 237oC.

Example 27

In this example, illustrate various specific formulations based on the compounds according to the invention.

A. Introduce oral formulation

(a) Tablet weight 0.2 g:

the compound obtained in example 7 - 0.001 g

starch - 0,114 g

the dicalcium phosphate (secondary calcium phosphate) at 0.020 g

silicon dioxide - 0,020 g

lactose - 0,030 g

talc - 0,010 g

magnesium stearate 0.005 g

(b) Suspension for drinking in ampoules of 10 ml:

the compound of example 8 0.05 g

glycerin - 1,000 grams

70% sorbitol - 1,000 grams

the sodium saccharinate - 0,010 g

methyl-para-hydroxybenzoate - 0,080 g

flavouring funds - enough

purified water - Dr. ,020 g

isopropylmyristate - 81,700 g

liquid vaseline oil - 9,100 g

silicon dioxide (Aerosil 200, manufactured in the sale by the company DEGUSSA) - 9,180 g

(b) Ointment

the compound of example 9 - 0,300 g

medical vaselin - up to total amount 100 g

(C) non-ionic cream water-in-oil

the compound of example 7 - 0,100 g

the mixture forming the emulsion of lanolin alcohols, waxes and oils (bucerine anhydre, issued for the sale of the company BDF) - 39,900 g

methyl-para-hydroxybenzoate - 0.075 g

propyl-para-hydroxybenzoate - 0.075 g

sterile demineralized water to 100 g

(g) Lotion

the compound of example 8 - 0,100 g

polyethylene glycol (PEG-400) - 69,900 g

95% ethanol - 30,000 g

(e) Hydrophobic ointment

the compound of example 7 - 0,300 g

isopropylmyristate - 36,400 g

silicone oil ("Rhodarsil 47 V300, manufactured in the sale by the company RHÔNE-POULENC) - 36,400 g

beeswax - 13,600 g

silicone oil ("Abil 300 000 cst", issued for the sale by the company GOLDSCHMIDT) - up to 100 g

(a) non-ionic cream oil-in-water

the compound of example 7 - 0,500 g

cetyl alcohol - 4,000 grams

glycerylmonostearate - 2,500 grams

stearate PEG-50 - 2,500 grams

oil tallow tree - 9,200 g

propylene glycol - 2,000 g

methyl-p is to 100 g

1. Bicyclic aromatic compounds of General formula I

< / BR>
where R1group CO-O-R8where R8is hydrogen, alkyl, linear or branched radical with 1 to 20 carbon atoms or COR7where R7- lower alkyl; Ar is a radical selected from the following group:

< / BR>
< / BR>
X denotes-O -, - S(O)tor-NR9-;

R2is hydrogen, halogen, lower alkyl group OR9;

t is an integer equal to 0,1 or 2;

R9is hydrogen or lower alkyl;

R11and R12is hydrogen or lower alkyl;

or their salts.

2. Connection under item 1 in the form of alkali or alkaline earth metal or zinc salts, or organic amine.

3. Connection under item 1 or 2, in which the lower alkyl radicals are methyl, ethyl, ISO-propyl, boutigny, tert.-botilony and sexily radicals.

4. Compounds according to any one of paragraphs.1 to 3, in which the linear or branched alkyl radicals with 1 to 20 C-atoms are methyl, ethyl, sawn, 2-ethylhexyl, octillery, dodecylphenyl, hexadecimally and octadecenyl radicals.

5. Compounds according to any one of paragraphs.1 to 4, in which the aryl radical PR is a hydroxyl.

6. Compounds according to any one of paragraphs.1 to 5, in which the halogen atoms are chosen in the group comprising fluorine, chlorine and bromine.

7. Connection on p. 1, a 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoic acid, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoic acid, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl)benzoic acid, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethyl)benzoic acid, 5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-2-thiencarbazone acid, 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoic acid, 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoic acid, 4-(3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoic acid, 4-(3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy)benzoic acid, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine)benzoic acid, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)acetophenone, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzaldehyde, 4-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoic acid, 3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-benzoic acid, 3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoic acid, 3-methyl-4-(3-ethyl-5,6,7,8-Tenova acid, 2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)-benzoic acid, 2-chloro-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)-benzoic acid, 4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-benzoic acid, 4-(3-isopropyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoic acid, 4-(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)-benzoic acid, 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)Benalmadena, 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzaldehyde, N-ethyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)-benzamid, N-4-hydroxyphenyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzamide.

8. Connection on p. 1, which has at least one, and preferably all of the following characteristics R1refers to the radical-CO-R7; R2denotes a lower alkyl radical or a radical-OR9; Ar represents a radical of formula (a) p. 1; X represents-O-, -S - or-NR9-; R7and R9have the values listed in paragraph 1.

9. Compounds according to any one of paragraphs.1 - 8 active in relation to differentiation and cell proliferation.

10. The pharmaceutical composition active in the differentiation and proliferation of CL is d one compound according to any one of paragraphs.1 - 8, in an effective amount.

11. The composition according to p. 10, characterized in that the concentration of the compound according to any one of paragraphs.1 - 8 is 0.001 - 5 wt.% calculated on the whole composition.

12. Cosmetic composition, characterized in that it comprises in a cosmetically acceptable medium, at least one of the compounds according to any one of paragraphs.1 - 8.

13. The composition according to p. 12, characterized in that the concentration according to any one of paragraphs. 1 - 8 is 0.001 - 3 wt.% in the calculation of the totality of the composition.

14. The composition according to p. 12 and 13, characterized in that it is used for hygiene or skin care.

 

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