Baromedicine compounds and pharmaceutical and cosmetic compositions based on them

 

(57) Abstract:

The invention relates to new compounds of the formula (I)

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where AG represents a radical selected from formulas (a) and (b) below:

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R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, R8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H or X represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I). These compounds can be used, in particular, for the treatment of dermatological disorders associated with disorders of keratinization, and to fight skin aging. 3 S. and 8 C.p. f-crystals, 3 tables.

The invention relates to new and industrially applicable products, namely, bi-aromatic compounds, whose aromatic rings are linked through a divalent generativity radical. The present invention relates also to the use of these new compounds in pharmaceutical compositions intended for the implementation according to the invention have a pronounced activity in the field of cell differentiation and proliferation and apply specifically, for local or systemic treatment of dermatological disorders associated with disorders of keratinization, dermatological (or other) problems with inflammatory and/or immunoallergic component, and proliferation of dermal or epidermal cells, both benign and malignant character. These compounds can also be used to treat degenerative diseases of the connective tissue, to fight against skin aging caused by light irradiation or age, for the treatment of disorders of scarring. Moreover, these compounds find application in the field of ophthalmology, in particular in the treatment of diseases of the cornea.

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

Bi-aromatic compounds in which the aromatic ring is attached via a bivalent propylen, already described in the patent EP-661 258, as active substances in pharmaceutical or cosmetic compositions.

Compounds according to the patent EP-661 258 correspond to the following General formula:

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where Ar is a divalent aromatic radical, possibly substituted by the radical R5, R>
R1represents H, -CH3CH2OR6, -OR6, -COR7or-S(O)tR9and t is 0, 1 or 2.

R2and R3represent H, C1-C20alkyl, -OR6or SR6,

or R2and R3together form a 5 - or 6-membered ring, possibly substituted by methyl groups and/or possibly separated by an oxygen atom or sulfur.

R4and R5represent H, halogen, lower alkyl or-OR6,

R6represents H, lower alkyl or-R9,

R7represents H, lower alkyl, or-OR8,

R8represents H, linear or branched C1-C20alkyl, alkenyl, mono - or polyhydroxylated, possibly substituted aryl or aralkyl, or a sugar residue, or a residue of an amino acid or peptide,

R9represents lower alkyl,

R and R' represent H, lower alkyl, mono - or polyhydroxylated, possibly substituted aryl or sugar residue, or an amino acid or peptide residue, or R and R' together form a heterocycle, and

X represents a divalent radical, which is from right to left or Vice versa has the formula:

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or R10and R11together form oxo (=O) radical,

and salts of these compounds of the above formula, when1represents a functional group of carboxylic acid, as well as optical and geometrical isomers of these compounds.

Compounds of the present invention differ from the compounds according to the patent EP-661 258, essentially, the fact that the radical X or divalent propylenebis radical substituted divalent heterogenenous radical.

The explanation for such a substitution is that it has been unexpectedly discovered that such structural change can significantly enhance the cosmetic and pharmaceutical properties of the compounds and also to reduce some of its side effects.

The object of the present invention, therefore, are new compounds, which can be expressed the following General formula:

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where Ar represents a moiety selected from formulas (a) to (C) below: formula on page 3, the bottom

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< / BR>
< / BR>
Z represents O or S or N-R6,

R1represents a halogen atom, -CH3CH2-OR7, -OR7, -COR8or a polyether radical,

R2and R31-C20, alkyl, C3-C12cycloalkyl, -OR7or SR7and at least one of R12and R3represent a linear or branched C1-C20alkyl or C3-C10cycloalkyl

or R2and R3together form a 5 - or 6-membered ring, possibly substituted by at least one methyl group and/or may suspend the heteroatom selected from O or S.

R4and R5represent H, halogen atom, linear or branched C1-C20alkyl, -OR7or a polyether radical,

R6represents H, linear or branched C1-C10, alkyl or-OCOR9,

R7represents H, linear or branched C1-C10, alkyl or-COR9,

R8represents H, linear or branched C1-C10, alkyl, -OR10or

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R9represents a linear or branched C1-C10, alkyl,

R10represents H, linear or branched C1-C20, alkyl, mono - or polyhydroxylated, allyl, possibly substituted aryl or aralkyl, or a sugar residue,

r' and r", which movicel, possibly substituted aryl, an amino acid or peptide residue, or taken together with the nitrogen atom, form a heterocycle,

X represents a divalent radical, which is from right to left and Vice versa has the formula:

< / BR>
where Y represents O, S(O)nor Se(O)n',

n and n' is 0, 1 or 2,

provided that Ar is a radical of formula (a) above, where R1= -CH3, a halogen atom or or7and R5=H, then at least one of the radicals R2or R3is not-CH3,

and salts of compounds of formula (I), when R1represents a functional group of carboxylic acid and the optical isomers of the above compounds of formula (I).

If the compounds according to the invention have the form of salts, preferably, it should be a salt of an alkali metal or alkaline earth metal, or, alternatively, zinc salts or organic amine.

In accordance with the present invention, the term "C1-C10, alkyl", preferably, includes such radicals as methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, 2-ethylhexyl and octyl.

The term "linear or branched C1-C20alkyl" refers, in h is cilnim radicals. The term "C3-C12cycloalkenyl radical" refers to mono - and polycyclic radicals, in particular to cyclopropyl, cyclopentyl, tsiklogeksilnogo, 1-methylcyclohexyl and 1-adamantly radicals. The term "radical simple ester" refers to radicals containing from 2 to 5 carbon atoms in the chain which is broken by at least two atoms of oxygen, such as methoxyethoxide, methoxyethoxide and methoxyethoxymethyl radicals.

The term "monohydroxyethyl" refers to the radical, preferably containing 2 or 3 carbon atoms, in particular 2-hydroxyethylene, 2-hydroxypropionate or 3-hydroxypropionate the radical.

The term "polyhydroxyethyl" refers to the radical, preferably containing from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutane and 2,3,4,5-tetrahydroxyphenyl or pentaerythritol residue.

The term "aryl" preferably refers to phenyl radical, possibly substituted by at least one halogen atom, hydroxyl or functional nitrogroup.

The term "aralkyl" preferably refers to a benzyl or penicilina what Ruppel.

The term "sugar residue" refers to the residue obtained, in particular from glucose, galactose or mannose, or, alternatively, from glucuronic acid.

The term "amino acid residue" refers, in particular, residues derived from lysine, glycine or aspartic acid, and the term "peptide residue" relates, more specifically, to a dipeptide or Tripeptide residues derived from combinations of amino acids.

The term "heterocycle", preferably, relates to piperidine, morpholino-, pyrrolidine or piperazine derivatives - radicals, possibly substituted in the 4 position of the lower C1-C6the alkyl or mono - or polyhydroxyalkane, as indicated above.

When R1, R4and/or R5represent a halogen atom, this atom preferably is a fluorine atom, chlorine or bromine.

In accordance with the first preferred embodiment of the invention compounds according to the invention correspond to the following General formula:

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where Ar' is a radical of the formula:

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< / BR>
R1, R4, R5and X have the meanings indicated above for formula (I),

R11, R12, R13and R14

In accordance with a second preferred embodiment of the invention compounds according to the invention correspond to the following formula:

< / BR>
where W represents O or S,

R4, R11, R12, Ar' and X have the meanings indicated above for formula (I) and (II).

Finally, in accordance with a third preferred embodiment of the invention compounds according to the invention correspond to the following formula:

< / BR>
where R4, Ar' and X have the meanings indicated above for formula (I) to(III), at least one of the radicals R'2and/or R'3represents a mono - or polycyclic C5-C10cycloalkenyl radical, and the other has one of the meanings given for R2or R3.

Among the compounds of formulas (I) to(IV) above, in accordance with the invention, it should specifically be mentioned the following:

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

- 4-(5,5,8,8, -Tetramethyl-5,6,7,8-tetrahydro-2-afteraltynsarin)benzoic acid,

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

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

- 4-(5,5,8,8,-Tetramethylpiperidine)benzoate,

- 4-(5,5,8,8, -Tetramethyl-5,6,7,8-tetrahydro-2-afteraltynsarin)benzoic acid,

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

- 4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-afterallthistime)benzoic acid,

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

- 4-(5,5,8,8, -Tetramethyl-5,6,7,8-tetrahydro-2-afteraltynsarin)benzoic acid,

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

- 4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoic acid,

- Methyl 2-hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

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

- 6-(4-Methoxyethoxymethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalen,

- Ethyl 6-(5,5,8,8, -tetramethyl-5,6,7,8,-tetrahydro-2-aftersensations)nicotinate,

- 6-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinic acid,

- N-(4-Hydroxyphenyl)-4-(5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzamid,

- Methyl 5-(5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)-2-pyridinecarboxylic,

- 2-(4-chlorine is-2-aftersensations)benzoate

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

- Methyl 2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

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

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

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

- N-(4-Hydroxyphenyl)-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinamide,

- N-butyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl-silanisation)nicotinamide,

- Morpholine-4-yl-[6-(3,5,5,8,8, -pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)-3-pyridyl]metano,

- Methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)pyridine-2-carboxylate,

- 5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)-pyridine-2-carboxylic acid,

- [4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)-phenyl]methanol,

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

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

- Methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylamine-sulfinil)bimetal-5,6,7,8-tetrahydro-2-naphthylethylene)benzoic acid,

- 4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethylene)benzoic acid,

- 4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)phenol,

- Ethyl 4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

- Ethyl 4-(4-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

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

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

- Ethyl 4-(3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

- Ethyl 4-(3-methoxyethoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

- 4-(3-Methoxyethoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoic acid,

- 4-(3-Methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoic acid,

- Ethyl 4-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

- 4-(3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoic acid,

- [4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)phenyl] carbaldehyde,

- Medicate,

- Methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-8-aftersensations)benzoate,

- 4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-8-aftersensations)benzoic acid,

- Methyl 4-[3-(1-substituted)-4-methoxyphenyl)-1-Islamisation] benzoate,

- 4-[3-(1-Substituted)-4-methoxyphenyl)-1-Islamisation] benzoic acid,

- Methyl 4-[4-(1-substituted)-4-methoxyphenyl)-1-Islamisation] benzoate,

- 4-[4-(1-Substituted)-4-methoxyphenyl)-1-Islamisation] benzoic acid.

The object of the present invention are also methods for obtaining compounds of formula (I) in accordance with the scheme of the reactions listed in tables a and B.

In accordance with table A, the compounds of formula (I), where X represents a divalent radical

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i.e. the compounds of formula (Ia) can be obtained by two methods of synthesis, depending, Y=oxygen or Kislorod.

When X= oxygen, the starting material is a compound of formula (1), which, in the presence of a base such as potassium hydride or sodium hydride, connect with trichloroethylene. Received dichlorethylene product of the formula (2) is then exposed to lithium base such as utility, in a solvent such as Theydon or heteroarylboronic, preferably iodirovannoi derivative, in the presence of a palladium catalyst, to obtain compounds of the formula (IIA), where Y=oxygen.

When Kislorod, first get acetylide lithium of the formula (5) of the aromatic or heteroaromatic acetylene compound (4) in the presence of lithium derivative, such as utility, in a solvent such as THF. Using as starting compound acetylide lithium (5), which was not selected, carry out the reaction of interaction with the compound of the formula (6) in a solvent such as THF, to obtain compounds of formula (Ia), where Kislorod.

Using as a starting material, these compounds of formula (Ia), where Y= S or Se, you can successfully get oxidized derivatives by oxidation with an oxidant such as meta-chlormadinone acid or periodate sodium.

Now, as shown in the table, the compounds of formula (I) in which X represents a divalent radical

< / BR>
i.e. the compounds of formula (Ic) can also be obtained by two methods of synthesis depending, Y=oxygen or Kislorod.

When Y= oxygen, the starting material is an aromatic or heteroaromatic saidinakar as THF, then attach to trichloroethylene. Received dichlorethylene product (8) is then exposed to lithium base such as utility in THF, to obtain oxoazetidin the compounds of formula (9). This acetylene connection then connect with arylhalides (10), preferably, iodirovannoi derivative, in the presence of a palladium catalyst, to obtain compounds of formula (Ic), where Y=oxygen.

When Kislorod, the source material is an aromatic acetylene compound of formula (11), which is converted into lithium derivative in the presence of utility, for example, in a solvent such as THF. Lithium acetylene derivative (12) is not isolated and is associated with romaticism or heteroaromatic compound of the formula (13), and the reaction of the interaction is carried out in a solvent such as THF. Thus, get the compounds of formula (Ic), where Kislorod.

Using as a starting material, these compounds of formula (Ic), where Y= S or Se, you can get oxidized derivatives by oxidation with an oxidant such as meta-chlormadinone acid (mCPBA) or periodate sodium.

When in the compounds according to the invention radicality protective alkyl group type.

By saponification of the ester functional group in the presence of a base such as sodium hydroxide or lithium hydroxide in an alcohol solvent or in THF, obtain the corresponding free acid.

When R1is a HE, the compounds can be obtained from the corresponding acid by recovery in the presence of a hydride, such as boron hydride.

When R1represents-CH=O, the compounds can be obtained by oxidation of the corresponding alcohols using magnesium oxide or pyridinium dichromate.

When R1represents a

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compounds can be obtained by transformation of the appropriate acid to the acid chloride, for example thionyl chloride, followed by contact with an aqueous ammonia or a suitable amine.

The object of the present invention are also the compounds of formula (I) above, as health products.

Compounds of General formula (I) have the effect of agonist or antagonist in relation to the expression of one or more biological markers in the test for differentiation Taratorkin cells (F9) embryos of mice (see Skin Pharmacol. 3, R. 256-267, 1990) and/or differeot compounds in differentiation and proliferation. The activity of compounds can be measured using tests on cellular transactivation using recombinant receptors RAR in accordance with the method described in B. A. Bernard et al., Biochemical and Biophysical Research Communication, vol.186, 977-983, 1992.

Compounds according to the invention is best suited for the following areas of treatment:

1) for treating dermatological disorders associated with keratinization-induced differentiation and proliferation, in particular for the treatment of common acne, black acne, polymorphonuclear leukocytes, pink acne, nodules racemose acne, nodular acne, senile acne and secondary acnes such as acne, appearing under the sun exposure, medications, and acne-related professional activities;

2) for treating other types of keratinization, in particular ichthyosis, conditions such as ichthyosis, disease Daria, keratodermia hands and feet, leukoplakia and similar disorders, skin Stripping or Stripping of the mucosa (cheeks);

3) for treating other dermatological disorders associated with keratinization with inflammatory and/or inflammatory-allergic component, and in particular all forms of psoriasis - skin, psoriasis mucous membrane, or nails and, or, alternatively, hypertrophy of the gums; the compounds according to the invention can also be used to treat certain inflammatory diseases that are not associated with a keratinization;

4) for treating all dermal and epidermal proliferate malignant and benign nature, regardless of whether they are viral or other origin, such as simple warts, flat warts and borodalopatoy epidermodysplasia, you can use them for the treatment of oral or red papillomatosis and proliferate caused by ultraviolet radiation, in particular in the case of basal cell carcinoma and epithelium cells of the spine,

5) for treating other dermatological disorders such as bullet and collagenosis,

6) for the treatment of certain eye disorders, particularly diseases of the cornea;

7) to restore or prevent aging of the skin, which is caused by exposure to light or age-related processes, or to weaken senile keratoses and pigmentations, or any pathologies associated with age or actinic aging;

8) to prevent or treat stigma epidermal and/or dermal atrophy induced by local or systemic application of covonia and to prevent or treat stretch marks;

10) for fighting Hyperborea acne or simple seborrhoea;

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

12) for the treatment of inflammation, such as arthritis;

13) for the treatment of any General or skin diseases of viral origin;

14) to prevent or treat alopecia;

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 atherosclerosis.

For the above therapeutic purposes, the compounds according to the invention is preferably used in combination with other compounds, the activity of the retinoid type, with vitamin D or its derivatives, corticosteroids, agents for destroying free radicals, alpha-hydroxy or alpha-keto acid or their derivatives, or, alternatively, with blockers of ion channels. The expression "vitamins D and their derivatives includes, for example, derivatives of vitamin D2or D3and in particular 1,25-dihydroxyvitamin D3. The expression "agents for destroying free radicals" includes, for example, alpha-tocopherol, peroxide-dismutase or SOD, original or certain metal is full-time, malic, citric, glycolic, almond, wine glycerin or ascorbic acid or their salts, amides or esters. Finally, the term "blockers of ion channels" means, for example, Minoxidil (2,4-diamino-6-piperidinedione-3-oxide) and its derivatives.

The object of the present invention are also pharmaceutical compositions containing at least one compound of formula (I) above, one of the optical or geometrical isomers of this compound or one of its salts.

Pharmaceutical compositions intended in particular for the treatment of the above diseases and are characterized in that they contain a pharmaceutically acceptable carrier, which is compatible with the selected method of introducing at least one compound of formula (I), one of the optical or geometrical isomers of this compound or one of its salts.

Compounds according to the invention can be assigned for oral, parenteral, local or intraocular injection.

For oral administration the compositions may be in the form of tablets, gelatin capsules, pills, sugar pills, syrups, suspensions, solutions, powders, granules, emulsions, beads or n the AI for parenteral administration can be in the form of solutions or suspensions for infusion or for injection.

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

Pharmaceutical compositions based on compounds according to the invention and intended for local use, are intended, in particular, for the treatment of skin and mucous membranes and may be in the form of ointments, creams, milk, balms, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be in the form of beads or nanospheres, or polymeric or lipid vesicles or polymer plates or hydrogels, which provide controlled release of the active ingredient. Moreover, these compositions for topical application can be either in anhydrous form or in aqueous form, depending on the clinical indications.

For intraocular destinations such compositions can be in the form of eye drops.

These compositions for local or intraocular application contain at least one compound of formula (I) above, or one of the optical or geometrical isomers of this compound or, alternatively, one of its salts, at a concentration of preferably from 0.001 to 5 wt.% the region of cosmetics, in particular, for the hygiene of the body and hair, and especially for the treatment of such skin types that have a tendency to acne, for hair growth, for combating hair loss, for combating oiling your hair and skin, to prevent harmful effects of the sun or for the treatment of physiologically dry skin, as well as to prevent and/or fight against aging caused by light irradiation or age.

In the field of cosmetic compounds according to the invention can be used (and preferably used in combination with other compounds having retinoid activity type, with b group vitamins or their derivatives, with corticosteroids, with agents that destroy free radicals, alpha-hydroxy or alpha-keto acid or their derivatives, or, alternatively, with blockers of ion channels; all these compounds described above.

Thus, the present invention also includes a cosmetic composition, which differs in that it contains cosmetically acceptable medium at least one compound of formula (I) above, or one of the optical or geometrical isomers of this compound or one of its salts, with the specified cosmetic composition can be applied in the different bubbles, soap or shampoo.

The concentration of the compounds of formula (I) in the cosmetic composition according to the invention preferably ranges from 0.001 to 3 wt.% from the total mass of the composition.

Pharmaceutical and cosmetic compositions according to the invention can also contain inert additives or pharmacodynamically or cosmetically active additives or combinations of these additives, and in particular: humidifiers; depigmenting agents, such as hydroquinone, azelaic acid, caffeic acid or kojic acid; softening means, moisturizing agents such as glycerol, PEG-400, thiomorpholine and their derivatives, or urea; agents with activity against acne or seborrhea, such as S-carboxymethylcysteine, S-benzylcyanide, their salts or derivatives, or benzoyl peroxide; antibiotics, such as erythromycin and its esters, neomycin, clindamycin and esters, and tetracyclines; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolinones; agents that promote the re-growth of hair, such as Minoxidil (2,4-diamino-6-piperidinedione-3-oxide) and derivatives thereof, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and Phenytoin (5,4-diphenyl-imidazolidin-2,4-dione); nastacia as anthralin and derivatives thereof, and finally, eicosa-5,8,11,14-terrainia acid and eicosa-5,8,11-tarinoita acid, esters and amides of these compounds.

The composition of the invention may also contain flavoring agents, preservatives such as esters of para-oksibenzoynoy acid, stabilizers, humidity regulators, pH regulators, osmotic pressure modifiers, emulsifiers, agents that protect against UV-a and UV-b, and antioxidants, such as alpha-tocopherol, bottled hydroxyanisol or bottled hydroxytrol.

Some examples of active compounds of the formula (I) according to the invention, as well as various cosmetic and pharmaceutical compositions based on these compounds below to illustrate the invention and are not restrictive.

EXAMPLES

Example 1.

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

(a) Methyl 4-trimethylsilylethynyl of 21.5 g (0.1 mol) of methyl 4-bromobenzoate, 300 ml of triethylamine and the mixture of 200 mg of palladium acetate and 400 mg of triphenylphosphine are placed in a three-neck flask. Then add 20 g (0,204 mol) of trimethylsilylacetamide, after which the mixture is heated gradually to 90oC for 1 hour, the al is evaporated. The residue is dissolved in 200 ml of hydrochloric acid (5%) and 400 ml of ethyl ether. Ethanol phase is separated after it has passed the deposition, washed with water, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel, elwira dichloromethane. After evaporation of the solvents will be collected 23 g (100%) of the desired derivative in the form of a colorless oil.

(b) Methyl 4-ethynylbenzoate.

38,33 g (226 mmol) of the product obtained above, 300 ml of methanol is introduced into the three-neck flask. Then add 125 g of potassium carbonate and the medium is stirred for 48 hours at room temperature. The solvent is evaporated and the resulting residue purified via chromatography on a column with silica gel, elwira dichloromethane. After evaporation of the solvents the residue is dissolved in heptane and, after filtering, collecting 32 g (100%) of the desired derivative in the form of a straw-yellow solid.

(C) Methyl 4-(5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-2-afteraltynsarin)benzoate

a 2.5 M solution of utility in hexane (20 mmol, 8.1 ml) was added to a solution of methyl 4-ethynylbenzoate (3 g, to 18.7 mmol) in THF (300 ml) at -78oC. the Temperature was maintained for 45 minutes and then looking up the al) in THF (60 ml) was then added at the same temperature. After this reaction medium was stirred for 1 hour at 0oWith, then it was poured into a mixture of ethyl ether and a saturated solution of ammonium chloride. The organic phase is twice washed with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40oC. After chromatography on a column of silica gel using a mixture of heptane/methylene chloride (60/40) and after evaporation was obtained 1.9 g of a white solid (27%).

1H (CDCl3): 1.28 (6N, s), 1.30 (6N, s), 1.69 (4H, s), 3.92 (3H, s), 7.25 - 7.31 (2H Ar, m), 7.42 (1H Ar, d, J=2Hz), 7.50 (1H, Ar, d, J=7.5 Hz), 8.00 (1H, Ar, d, J=7.5 Hz).

13C (CDCl3): 32.25 (CH3), 34,60 (C), AT 35.02 (C) 35.36 (CH2), 52.68 (OCH3), 81.26 (C) 96.96 (C), 124.82 (CH Ar), 125.56 (CH Ar), 128.29 (Ar), 128.37 (CH Ar), At 128.85 (Ar), 129.88 (Ar), 130.04 (2 CH Ar), 131,29 (2 CH Ar), 144.66 (S, Ar), 146.88 (Ar), 166.95 (COO).

Example 2.

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

A solution of methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-afteraltynsarin)benzoate (590 mg, 1.6 mmol) and lithium hydroxide (383 mg, 9.3 mmol) in THF was distilled within 24 hours. The reaction mixture was poured into a mixture of Et2/O, acidified to pH 1 using concentrated solution chlorotoluron the tub over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40oC. the resulting solid residue was vykristallizovyvalas heptane 440 mg (77%) with a white (colorless solid, melting point =of 193.5oC.

NMR (nuclear magnetic resonance) memorial plaques:

1H (CDCl3): 1.28 (6N, s), 1.30 (6N, s), 1.69 (4H, s), 7.29 - 7.32 (2H Ar, m), 7.42 (1H Ar, d, J=2Hz), 7.53 (1H Ar, d, J=8,5 Hz), 8.08 (1H Ar, d, J= 8.5 Hz).

13C (CDCl3): 31.44 (CH3), 33.80 (C) 34.22 (C), 34.54 (CH2), 81.30 (C), 100.01 (C), 124.06 (CH Ar), 124.81 (CH Ar), 127.59 (CH Ar), 127.94 (Ar), 128.46 (AG), 129.87 (2 CH Ar), 130.49 (2 CH Ar), 143.93 (Ar), 146.12 (CAr), 171.06 (soo).

Example 3.

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

A solution of meta-adventurou acid (700 ml) in CHCl3(12 ml) was added dropwise at 0oTo a solution of the product obtained in example 1 (500 mg, 1.3 mmol) in 6 ml of CHCl3. After stirring for 1 h, the mixture was concentrated in a rotary evaporator under vacuum. After chromatography on silikagelevye column using a mixture of heptane/methylene chloride (30/70) to obtain 280 mg of a white (colorless) solid product (52%).

1H (CDCl3): 1.32 (6N, s), 1.34 (6N, s) of 1.73 (4H, s), 3.93 (3H, s), 7.51 (2H Ar, d, J=8.3 Hz), 7.60 (2H Ar, d, J=8.5 Hz), 7.78 (1H Ar, dd, J1=8.5 Hz, J2=2Hz), 7.98-8.05 (3H Ar, m).

13C (CDCl3): 31.63 (CH3), 31.73 (04 C. (CH Ar), 129.68 (CH Ar), 132.44 (Ar), 132.69 (CH Ar), 138.37 (Ar), 152.50 (CAr), 165.83 (COO).

Example 4

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

(a) 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenesulfonic

1.7 M solution of tert-utility in pentane (or 37.4 mmol, 22 ml) is added to a solution of 2-bromo-5,6,7,8-tetrahydro-5,5,8,8, -tetramethyl-naphthalene (4,22 g, 15.8 mmol) in THF (100 ml) at -78oWith, an additive is produced within 30 minutes. Then in two steps add selenium (1,33 g, a 16.8 mmol). The mixture was stirred at 0oC for 15 minutes, then at room temperature for another 30 minutes After that add 1H hydrochloric acid (40 ml) and the reaction mixture is treated with ethyl ether. The organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40oC. To the resulting oil is added 10 ml of ethanol and 50 mg of sodium hydroxide. The mixture is vigorously stirred in a rotary evaporator under vacuum at 40oC. the Obtained solid is filtered through silica gel (elwira heptane), and then crystallized from a mixture of ethanol/ether. After filtering obtain 2.9 g (69%) of orange solid.

1H (CDCl3): 1.21 (6N, s), 17,8-tetrahydro-2-aftersensations) benzoate

Bromine (0.15 ml, 2.9 mmol) is added to a solution of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenedisulfonate (1.5 g, 2.8 mmol) in THF (3 ml). The mixture is stirred at room temperature for 2 hours and then remove the solvent. Added copper iodide (2.15 g; 11.3 mmol), methyl 4-ethynylbenzoate (810 mg, 5 mmol) obtained in example 1 (b) and DMF (15 ml). The reaction mixture was stirred at room temperature for 3 hours, then treated with ethyl ether and aqueous solution of ammonia. The organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40oC. the Residue is recrystallized from heptane and, after filtration, to obtain 1.8 g (75%) of a white powder, melting point =90-1oC.

1H (CDCl3): 1.28 (6N, s), 1.30 (6N, s), 1.69 (4H, s), 3.92 (3H, s), 7.29 (1H Ar, d, J=8.3 Hz), 7.36 (1H Ar, dd, J=1.9 Hz, J=8.3 Hz), 7.48-7.53 (neg, m), 7.98 (2H Ar, d, J=8.5 Hz).

Example 5

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

The lithium hydroxide (440 mg) is added to a solution of methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate (740 mg, of 1.74 mmol) obtained in example 4 in 15 ml of THF and 2 ml of a mixture water/methanol (1/1). The reaction mixture is distilled the spent hydrochloric acid and extracted with ethyl ether. After separation of the phases by settling the organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40oC. the Residue is recrystallized from heptane. After filtering receive 615 mg (86%) of a white powder, melting point =182oC.

1H (CDCl3): 1.28 (6N, s), 1.30 (6N, s), 1.69 (4H, s), 7.29 (1H Ar, d, J= 8.3 Hz), 7.36 (1H Ar, dd, J=1.9 Hz, J=8,3 Hz), 7.52-7.55 (3H Ar, m), 8.07 (2H Ar, d, J=8.5 Hz).

Example 6

Methyl 2-hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations) benzoate

(a) Methyl 4-trimethylsilylethynyl-2-hydroxybenzoate

The method described in example 1 (a), using as a starting material of 4.00 g (14.4 mmol) of methyl 4-iodo-2-hydroxybenzoate receive of 3.07 g (86%) of the desired compound in the form of oil, painted in orange color.

1H (CDCl3): 0.06 (s, 9H), 3.75 (s, 3H), 6.76 (dd, 1H, J =8.2/1.5 Hz), 6.87 (d, 1H, J=1.4 Hz); 7.56 (d, 1H, J=8.2 Hz), 10.53 (s, 1H).

(C) Methyl 4-ethinyl-2-hydroxybenzoate

of 3.07 g (12.4 mmol) of methyl 4-trimethylsilylethynyl-2-hydroxybenzoate mixed in a 500 ml three-neck flask with 50 ml of THF and add drop of 13.7 ml of tetrabutylammonium (1 M/THF). The reaction mixture is stirred for 1 hour at room tempeau phase is dried over anhydrous magnesium sulfate and concentrated. Get 2,48 g (100%) powder beige color, melting point =62oC.

1H NMR (CDCl3): 3.21 (s, 1H), 3.96 (s, 3H), 6.98 (dd, 1H, J =8.2/1.5 Hz), 7.10 (d, 1H, J=1.3 Hz), 7.78 (d, 1H, J=8.2 Hz), 10.76 (s, 1H).

(C) Methyl 2-hydroxy 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate

The method described in example 4 (b), after reaction of 1.5 g (2.8 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenedisulfonic in 2 ml THF with bromine (0.15 ml, 2.9 mol), added copper iodide (2.15 g; 11.3 mmol) and methyl 4-ethinyl-2-hydroxybenzoate (890 mg; 5 mmol) in 10 ml of DMF. After purification on a column with silica gel (dichloromethane 10/heptane 90), obtain 2.15 g (97%) of the desired derivative of ester in the form of a yellow solid, melting point =70oC.

1H NMR (CDCl3): 1.28(d,12H) 1.69(s,4H) 3.95(s,3H) 6.94(dd,1H) 7.04(d,1H) 7.26-7.37(m,2H) 7.51 (d, 1H) 7.77(d, 1H) 10,77(s,1H).

1With NMR (CDCl3): 31.8; 4CH3/34.2 Cq/34,6; Cq/34.9 2CH2/52.4; CH3/75.1; Cq/101.6; Cq/111.9; Cq/119.7; SN/121.9; SN/124.5; Cq/127.0; SN/127,8; SN/ 128.1; SN/129.9; SN/130,4 Cq/144.7;/146.7; Cq/161.2 Cq/170.1 Cq.

Example 7.

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

A solution of 2-hydroxy-4-(5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-2-aftersensations) benzoate (1.2 g, of 2.72 mmol), placenames poured into a mixture of ethyl acetate and water, acidified to pH 1 with concentrated hydrochloric acid and extracted once with ethyl acetate. After separation of the phases by settling, the organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40oC. Get 1 g (86%) of white solid, melting point =170oC.

1H NMR (DMSO): 1.28(m, 12H); 1.68(s,4H); 6.95 (d, 1H); 7.03 (s, 1H); 7.25-7.37 (m, 2H); 7.51 (s.1H); 7.83(d, 1H).

13WITH NMR (DMSO): 31.8; SN3/34.2; Cq/34.6; Cq/34.9; 2CH2/76.0; Cq/101.5; Cq/119.7; SN/122.1; SN/124.4 Cq/127.1; Cq/127.9; SN/128.2; SN/130.9; SN/131.4; Cq/144.7; Cq/146.7; Cq/161.6; Cq/174.2; Cq.

Example 8.

6-(4-methoxyethoxymethyl-selanik)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalen.

(a) 1-iodo-4-methoxyethoxymethyl

5 g (22.7 mmol) of 4-iodophenol added to a suspension of 75% sodium hydride (872 mg, 27,25 mmol) in 20 ml of dimethylformamide. The mixture is stirred for 30 minutes at room temperature and then add at 2.59 ml (34,1 mmol) methoxymethane. The solution is stirred for 2 hours and then the medium is poured into a mixture of ethyl acetate and water. After separation of the phases by settling, the organic phase is washed twice with water, dried with anhydrous magnesium sulfate, and concentrate the Mr (CDCl3): 3.45(s,3H); 5.13(s,2H); 6.80(d, 2H); 7.55(d,2H).

13C NMR (CDCl3): 56.0 CH3/84.3; Cq/94.3; CH2/118.4; 2CH/138.2; 2CH/ 157.0 Cq.

(C) 1-trimethylsilylethynyl-4-methoxyethoxymethyl

5,74 g (21,7 mmol) 1-iodo-4-methoxyethoxymethyl, 100 ml of triethylamine and the mixture of 1.53 g (2,18 mmol) of dichloro-bis(triphenylphosphine)palladium and 831 mg (4,37 mmol) of copper iodide were placed in a three-neck flask. Then added 6,14 ml (43,5 mmol) trimethylsilylacetamide and the mixture was stirred for 48 hours at room temperature. The mixture is then poured into a mixture of water and ethyl acetate. The organic phase is washed twice with water and, after separation of the phases by settling, the organic is dried over anhydrous magnesium sulfate and concentrate.

(C) 1-ethinyl-4-methoxyethoxymethyl

In a manner analogous to the method of example 1(b) by reacting the product obtained according to example 8(b) with 50 ml of methanol and potassium carbonate for 15 hours at room temperature, and after purification on a column of silica gel (dichloromethane 20/heptane 80) obtain 840 mg (24%) of the desired compound as a yellow oil.

1H NMR (CDCl3): 3.00(s,1H); 3.46 in(s,3H); 5.17(s,2H); 6-97(d, 2H); 7.42(d, 2H).

13C NMR (CDCl3): 56.1; CH3/76.1; Cq/83.5; SN/94.2; CH2/115. the Talin.

In a manner analogous to the method according to example 4(b), carry out the subsequent reaction of 1,3 g (2,44 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenedisulfonic in 2 ml THF with bromine (0,13 ml, 2.5 mmol), added copper iodide (1.86 g; 9.8 mmol) and 1-ethinyl-4-methoxyethoxymethyl (713 mg; 4.4 mmol) in 10 ml of DMF. After purification on a column with silica gel (dichloromethane 20/ heptane 80) to obtain 1.7 g (90%) of the desired derivative in the form of a yellow oil.

1H NMR (CDCl3): 1.27(m, 12H); 1.67(s, 4H); 3.47(s, 3H); 5.18(s,2H); 6.98(dd,2H); 7.01-7.51 (m, 5H).

13With NMR (CDCl3): 31.8; SN3/34.1; Cq/34.5; Cq 34.9; 2CH2/56.1; CH3/68.3; Cq/77.5; Cq/102.0; Cq/116,1; 2Ch/116.7; Cq/ 125.3; Cq/ 133.3; 2CH/ 144,2; Cq/ 146.5; Cq/ 157.4; Cq.

Example 9,

6-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-aftersensations) nicotinic acid,

(a) Ethyl-6-trimethylsilylethynyl-3-pyridinecarboxylic

In a manner analogous to the method of example 1(a), using as starting material 4 g (14.4 mmol) of methyl 6-iodo-3-pyridinecarboxylic, got 3,29 g (92%) of the desired compound in the form of painted beige powder, melting point =55oC.

1H NMR (CDCl3): 0.10 (s, N), 1.22 (t, 2H, J=7.1 Hz), 4.23 (q, 3H, J= 7,1 Hz), 7.33 (d, 1H, J=8.2 Hz), 8.06 (dd, 1H, J =8.1/2.1 Hz), 8.97 (d, 1H, J=2.1 Hz).

(C) Ethyl-6-ethnicnational

JV is ethyltrimethylammonium, received of 1.00 g (43%) of the desired compound in the form of flakes beige, temp. melting point =35oC.

1H NMR (CDCl3): 1.42 (t, 3H, J =7.1 Hz), 3.33 (s, 1H), 4.42 (q, 2H, J = 7.2 Hz), 7.56 (d, 1H, J =8.1 Hz), 8.28 (dd, 1H, J =8.1/2.1 Hz), 9,18 (d, 1H, J = 2.0 Hz).(c) Ethyl 6-(5,5,8,8,-tetramethyl-5,6,7,8,-tetrahydro-2-aftersensations)nicotinate

In a manner analogous to the method according to example 4(b), carry out the subsequent reaction of 1.84 g (3.4 mmol) of 5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenedisulfonic in 2 ml THF with bromine (of 0.18 ml, 3,49 mmol), added copper iodide (2.64 g; a 13.9 mmol) and ethyl-6-ethnicnational (1 g; 5.7 mmol) in 10 ml of DMF. Get 1,95 g (78%) of the desired compound as a brown oil.

1H NMR (CDCl3): 1.28-1.30(m,12H); 1.40(t,3H); 1.69(s,4H); 4.41(q.2H); 7.12-7.59(m,4H); 8.24(dd,1H); 9.16(d, 1H).

(d) 6-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinic acid

In a manner analogous to the method in example 7, reaction of 600 mg (1,36 mmol) of ethyl 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinate in 30 ml of THF and 1 g of sodium hydroxide, and after grinding the powder from heptane receive 200 mg (36%) of the desired compound as a yellow solid, melting point =128oC.

1H NMR (CDCl3): 1.27-1.30(m,12H); 1.68(s, 4H); 7.26-7.52(m,5H); 8.32 (d, 1H); 9.26(s,1H).

Example 9

N-(4-Hydroxyphenyl)-4-(5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)Besame

A solution of 250 mg (0,63 mmol) of 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoic acid obtained in example 5, 169 mg (1.25 mmol) of 1-hydroxybenzotriazole, 240 mg (1.25 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DK) and 82 mg (0.75 mmol) of 4-aminophenol in 20 ml of THF was stirred at room temperature for 15 hours. Then added water and ethyl acetate. After stirring and separation of the phases by settling the aqueous phase is extracted with ethyl acetate. The organic phases are then combined and washed with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40oC. the resulting product was then purified on a column with silica gel (ethyl acetate 20/ heptane 80). Receive 200 mg (65%) of the desired compound as a white solid, melting point =202oC.

1H NMR (DMSO): 1.23 (s, 6H); 1.25 (s, 6H); 1.64 (s, 4H); 6.72-6.76 (d, 2H); 7.39 (s, 1H); 7.51-7.55 (d, 2H); 7.59-7.61 (d, 2H); 7.64-7.67 (d, 2H); 7.95-7.98 (d, 2H); 9.28 (s, 1H); 10.10 (s, 1H).

Example 11

Methyl 5-(5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)-2-pyridinecarboxylic

Odo-2-pyridinecarboxylic, get 4.25 g (68%) of the desired compound in the form of a powder orange color, melting point =45oC.

1H NMR (CDCl3): 0.28 (s, 9H), 4.01 (s, 3H), 7,87 (dd, 1H, J =8.1/2.0 Hz), 8.08 (d, 1H, J=8.1 Hz), 8.77 (d, 1H, J=1.3 Hz).

(C) Methyl-5-ethinyl-1-pyridinecarboxylic

In a manner analogous to the method according to example 6 (b), using as source material 2.25 g (9.6 mmol) of methyl 5-trimethylsilylethynyl-2-pyridinecarboxylic, got 380 mg (24%) of the desired compound as a yellow powder. Melting point =40-5oWITH,

1H NMR (CDCl3): 3,40 (s, 1H), 4.02 (s, 3H), 7.93 (dd, 1H, J=8.1/2.0 Hz), 8.12 (d, 1H, J=8.1 Hz), 8.83 (d, 1H, J=1.9 Hz).

(C) Methyl 5-(5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)-2-pyridinecarboxylic

In a manner analogous to the method according to example 4(b), after reaction 918 mg (1.73 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2 - diselenide

2 ml of THF, with bromine (0.092 ml, 1.78 mmol), was added copper iodide (1.62 g; 8.5 mmol) and methyl 5-ethinyl-2-pyridinecarboxylic (500 mg, 3.1 mmol) in 10 ml of DMF. After grinding to a powder of heptane obtain 420 mg (32%) of the desired compound as a yellow solid. Melting point =75oC.

1H NMR (CDCl3): 1.28-of 1.29 (d,12H); 1.69 (s, 4H); 4.02 (s,3H); 7.27-7.37 (m,2H); 7.54 (d, 1H); 7.84(dd, 1H); 8.11 (d,1H); 8.77(s,1H).

N/ 128.2; CH/ 128.3; SN/ 138.7; SN/ 145.1; SN/ 145.8; Cq/ 146.9; Cq/ 151.6; SN/ 165.2; Cq.

Example 12

2-(4-Chlorophenylsulfonyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen

In a manner analogous to the method according to example 4(b), after reaction of 2 g (5.25 mmol) of bis (4-chlorophenyl) diselenide in 5 ml of THF with bromine (0.266 ml, 5.15 mmol), added copper iodide (4.11 g; 21.6 mmol) and 6-ethinyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalen (2.18 g, 10 mmol) (as described in patent application EP 0,661,258 A1) in 20 ml of DMF and, after purification on a column of silica gel (gipton), obtain 1.85 g (45%) of the desired compound as a colourless oil.

1H NMR (CDCl3): 1.28(s,12H); 1.68(s,4H); 7.26-7.30(m,4H); 7.46-7.52(m, 3H).

Example 13

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

(a) 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenesulfonic

In a manner analogous to the method according to example 4(a), by reaction of 4.4 g (15.8 mmol) of 2-bromo-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylheptane) with 22 ml tributyrate and selenium (1.33 g, 16.8 mmol) in 100 ml THF, get 3.26 g (74%) of the desired derivative of selenium in the form of a yellow solid (melting point =126oC).

1H NMR (CDCl3): 1.14 (6N, s), 1.23 (6N, s), 1.61 (4H, s), to 2.35 (3H, s), 7.05 (1H Ar, s), 7.55 (1HAr, s).

(C) Methyl 4-(3,5,5,8,8-pentamethyl-and 1.5 g (2.75 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenedisulfonic in 5 ml of THF with bromine (0.15 ml, 2.9 mmol), added copper iodide (2.1 g, 11.05 mmol) and 4-ethynylbenzoate (790 mg, 4.94 mmol) in 20 ml of DMF, and after grinding the powder from heptane obtain 1.57 g (70%) of the desired compound in the form of a solid white color. Melting point =104oC.

1H NMR (CDCl3): 1.27-1.29 (m,12H); 1.68(s,4H); 2.36 (s,3H); 3.91 (s.3H); 7.12(s,1H); 7.50(d,2H); 7.73 (s, 1H); 8.00 (d,2H).

13C NMR (CDCl3): 21.4 CH3/ 32.3; 2CH3/ 32.4; 2CH3/ 34.5; Cq/ 34.8; Cq/ 35.5; 2CH2/ 52.7; CH3/75,0; Cq/ 102.2; Cq/ 125.9; Cq/ 128.5; Cq/ 129.1; 2CH/ 129.8; Cq/ 130.1; 2CH/ 131.5; 2CH/ 134.9; Cq/ 144.7; Cq/ 145.3; Cq/167.0; Cq.

Example 14

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

In a manner analogous to the method according to the example 7 by reaction 1.35 g (3.07 mmol) of methyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate in 20 ml of THF and 3 g of sodium hydroxide, and after grinding the powder from heptane gain of 1.05 g (80%) of the desired compound as a white solid, melting point =240oC.

1H NMR (CDCl3): 1.27-1.30(m,12H); 1.68(s,4H); 2.35 (s,3H); 7.13 (s,1H); 7.50 (d,2H); 7.71(s,1H); 8.00(d, 2H).

13C NMR (CDCl3): 20.5; CH3/ 31,5; 4CH3/ 33.6; Cq/ 33.9; Cq/ 34.6; 2CH2/ 73.6; Cq/ 101.6; Cq/ 125.0; Cq/ 127.1; Cq/ 127.9; SN/ 128.3; SN/ 129.4; 2CH/ 130.5; 2CH/ 133.8; Cq/ 143.9; 2Cq/ 144.5; Cq/167.5; Cq.

In a manner analogous to the method according to example 4 (b), after reaction of 1 g (1.78 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenedisulfonic in 5 ml of THF with bromine (0.092 ml, 1.78 mmol), added copper iodide (1.36 g, 7.15 mmol) and methyl 4 - ethinyl-2-hydroxybenzoate (566 mg; 3.2 mmol) obtained in Example 6 (b), in 10 ml of DMF 20, and after grinding the powder from heptane, receive 715 mg (49%) the desired compound as a brown solid, melting point =102oC.

1H NMR (CDCl3): 1.20(s,6H); 1.23(s,6H); 1.60(s,4H); 2.28(s,3H); 3.87(s, 3H); 6.87(dd,1H); 6.97(d,1H); 7.04(s,1H); 7.64(s,1H); 7.71 (d.1H); 10.70(s, 1H).

13C NMR (CDCl3): 20.7; CH3/ 31.7; 4CH3/ 33.8; Cq/ 34.1; Cq/ 34.8; 2CH2/ 74.9; Cq/ 101.4; Cq/ 111.7; Cq/ 119.4; Cq/ 121.6; SN/ 125,1; Cq/128.4; 2CH/ 129.7; SN/ 130.3; Cq/ 134.2; Cq/144.1; Cq/ 144.7; Cq/ Owed 161.1; Cq/ 169.9; Cq.

Example 16

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

In a manner analogous to the method according to the example 7 by reaction of 500 mg (1.1 mmol) of methyl 2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate in 20 ml of THF with 500 mg of sodium hydroxide, receive 464 mg (99%) of the desired compound as a brown solid, melting point =248oC.

1H NMR (CDCl3+DMSO): 0.89 (s,6H); 0.92 (s,6H); 1.30(s,4H); 1.96(s,3H); 6.55 (ddq/ 34.7; 2CH2/74.1; Cq/ 101,6; Cq/ 112.5; Cq/ 118.9; SN/ 121.3; SN/ 125.0; Cq/ 128.0; SN/ 128.3; SN/ 129.6; Cq/ 130.4; SN/ 133.9; Cq/ 144.0; Cq/ 144.0; Cq/ 144.5; Cq/161.4; Cq/171.9; Cq.

Example 17

Ethyl 6-(3,5,5,8,8-pentamethyl - 5,6,7,8-tetrahydro-2-aftersensations) -nicotinate. In a manner analogous to the method according to example 4 (b), after reaction of 1 g (1.78 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenedisulfonic in 5 ml of THF with bromine (0.092 ml, 1.78 mmol), added copper iodide (1.36 g, 7.15 mmol) and ethyl 6-ethnicnational (463 mg of 2.64 mmol) in 10 ml of DMF, and obtain 1.06 g (88%) of the desired compound as brown solids, melting point =95oC.

1H NMR (CDCl3): 1.20(s,6H); 1.24(s,6H); 1.34(t,3H); 1.61(s,3H); 4.33(q, 2H); 7.07(s,1H); 7.38(d,1H); 7.67(s,1H); 8.17(dd,1H); 9.08(d,1H).

13C NMR (CDCl3): 13.9; CH3/ 20.9; CH3/ 31.5; SN3/ 33.7; Cq/ 34.0; Cq/ 34.6; 2CH2/ 61.2; CH2/ 77.2; Cq/ 101,2; Cq/ 124.2; Cq/ 124,3; Cq/ 125.2; Cq/ 128.4; SN/ 129.4; SN/ 134.8; Cq/ 136.8; Cq/ 144.0; Cq/ 145.1; Cq/ 146,3; Cq/150.8; Cq/164,5; Cq.

Example 18

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

In a manner analogous to the method according to example 7, by interacting 800 mg (1.73 mmol) of ethyl 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinate in 20 ml of THF with 800 mg of sodium hydroxide and after purification on a column of silica compound is P>oC.

1H NMR (CDCl3): 1.27(s, 6H); 1,31 (s, 6N); 1.68(s,4H); 2.40(s,3H); 7.15(s, 1H); 7,26 (s, 1H); 7,49 (d, 1H); 7,74 (s, 1H); 8,32 (d, 1H); a 9.25 (s, 1H).

13With NMR (CDCl3): 21.7; CH3/32.2; Cq/34.7; Cq/35.3; 2CH2/78,9; Cq/ 101.7; Cq/ 124.0; Cq/ 124.9; Cq/ 126.1; SN/ 129.1; SN/ 130.2; SN/ 135.6; Cq/ 1382; SN/ 144.8; Cq/ 145.9; Cq/ 147,6; Cq/152.0; CH/169.5; Cq.

Example 19

N-(4-Hydroxyphenyl)-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinamide

In a manner analogous to the method in example 10, by reacting 300 mg (0.72 mmol) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinic acid with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-DICYCLOHEXYL-carbodiimide and 95 mg (0.87 mmol) of 4-aminophenol in 20 ml of THF, after purification on a column of silica gel (ethyl acetate 20/heptane 80), receive 20 mg (6%) yellow solid, temp. melting point =172oC.

1H NMR (DMSO): 1.17-1.19(m, 12H); 1.56(s,4H); 2.27(s,3H); 6.68(d,2H); 7.21(s, 1H; ) 7.46(d,2H); 7.58 (d, 1H); 7.64 (s, 1H;) 8.22 (dd, 1H); 8.99(s, 1H); 9.30(s, 1H); 10.2(s,1H).

13C NMR (DMSO): 31.6; 4CH3/ 33.5; CH2/ 33.8; CH2/ 34.0; Cq/ 34.5, Cq/47,6; CH3/74.9; Cq/ 102.0; Cq/ 115.2; 2CH/ 122.3; 2CH/ 124.4; Cq/ 125.9; SN/ 128.7; SN/ 128.9; SN/ 130.4; Cq/ 134.8; Cq/ 136.1; SN/ 144.0; Cq/ 144.1; Cq/145.1; Cq/ 149.3; Cq/ 154.1; Cq/ 156.8; Cq.

Example 20

N-butyl-6- (3,5,5,8,8-pentamethyl-5,6,7,8 - Tetra the mol) 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinic acid with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 63.5 mg (0.87 mmol) of butylamine in 20 ml of THF. After purification on a column with silica gel (ethyl acetate 20/heptane 80), receive 60 mg (17%) yellow solid, melting point =172oC.

1H NMR (CDCl3): 0.97(t,3H); 1.27-1.37(m,12H); 1.37-1.46(m,4H); 1.68(s, 4H); 2.39(s,3H); 3.47(q,2H); 6.13(m,1H); 7.14(s,1H); 7.46(d,1H); 7.74(s,1H); 8.07(dd,1H); 8.87(s, 1H).

13C NMR (CDCl3): 31.8; CH3/ 20.2; CH2/ 21.2; CH3/ 31,7; SN3/ 34.0; Cq/ 34.3; Cq/ 35.0; 2CH2/ 40.0; CH2/ 76.2; Cq/ 101.2; Cq/ 124.7; Cq/ 126.0; SN/ 128.7; SN/ 129.7; CN/ CN/ 35.1; Cq/ 135.3; SN/ 144.3; Cq/ 145.4; Cq/ 145.5; Cq/; Cq.

Example 21

Morpholine-4-yl-[6-(3,5,5,8,8, -pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)-3-pyridyl]metano

In a manner analogous to the method in example 10, 300 mg (0,72 mmol) 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinic acid react with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and to 75.7 mg (0.87 mmol) of the research in 20 ml of THF. After purification on a column with silica gel (ethyl acetate 20/heptane 80), receive 60 mg (17%) of colorless oil.

1H NMR (CDCl3): 1.27-1.32 to(m, 12H); 1.68(s, 4H); 2.39(s,3H); 3.81(sbr, 8H); 7,13(s,1H); 7.45(d,1H); 7.71-7.75(m,2H); 8.61(d,1H).

13C NMR (CDCl3): 21,2; CH3/31.8; 4CH3/ 3448.3; CH/ 167.4; Cq,

Example 22

Methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)pyridine-2-carboxylate

In a manner analogous to the method according to example 4 (b), after reaction 945 mg (1.68 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenedisulfonic in 5 ml of THF with bromine (0.092 ml, 1.78 mmol), added copper iodide (1.32 g, 6.95 mmol) and methyl 5-ethinyl-2-pyridinecarboxylic (500 mg, 3.1 mmol) in 10 ml of DMF, and after grinding the powder from heptane, get 1 g (73%) of the desired derivative in the form of solids, melting point =52oC.

1H NMR (CDCl3): 1.27-1.29(m, 12H); 1.68(s,4H); 2.37(s,3H); 4.02(s,3H); 7.14(s,1H); 7.71(s,1H); 7.85(dd, 1H); 8,02 (s,1H); 8.11 (d, 1H).

13C NMR (CDCl3): 20.7; CH3/ 31.5; 2CH3/ 31.6; 2CH3/ 33.7; Cq/ 34.0; Cq/ 34.6; 2CH2/ 52.7; CH3/ 78.9; Cq/ 98,1; Cq/ 123.7; Cq/ 124.2; CH/ 124.5; Cq/ 128.4; CH/ 128.5; CH/ 134.3; Cq/ 138.3; CH/ 144.0; Cq/ 144.9; Cq/ 145.5; Cq/ 151.2; CH/ 162,2; Cq.

Example 23

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)-2-piridinkarbonovaya acid

In a manner analogous to the method according to the example 7 by reaction of 800 mg (1.73 mmol) of methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)-2-pyridinecarboxylic in 20 ml of THF with 2 g of sodium hydroxide, and after grinding the powder from heptane, to obtain 580 mg (65%) of the desired connected is,6H); 1.69(s,4H); 2.39(s,3H); 7.16(s, 1H); 7.69(s,1H); 7.93(d,1H); 8.17(dbr,1H); 8.66(sbr,1H).

13C NMR (CDCl3): 21.2; CH3/ 31.8; 2CH3/ 3.9; 2CH3/ 34.1; Cq/ 34.3; Cq/ 34.9; 2CH2/ 124.6; Cq/ 128.8; SN/ 129.3; SN/ 134.9; Cq/ 139.8; SN/ 144.4; 2Cq/ 145.5; 2Cq.

Example 24

[4-(5,5,8,8-Tetramethyl - 5,6,7,8-tetrahydro-2-aftersensations) phenyl] methanol

A solution of 1M diisobutylaluminum in toluene (4 ml, 4 mmol) drop by drop add at a temperature of 0oWith a solution of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate obtained in example 4 (750 mg, 1.8 mmol) in toluene (20 ml). The solution is stirred for 4 hours at 0oC and then treated with a solution of the double tartrate salt potassium sodium, filtered and dissolved in a mixture of ethyl ether and water. The organic phase is washed with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40oC. Receive 418 mg (60%) of colorless oil.

1H NMR (CDCl3): 1.26(s, 6H); 1.28(s, 6H); 1.76(s, 4H), 4.67(s, 2H), 7.24-7.37(m, 4H), 7.46(d, 2H, J =8.2 Hz), 7.52(d, 1H, J =1.9 Hz).

Example 25

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

In a manner analogous to the method of example 1 (C), by reaction of 234 mg (1.1 mmol) of 6-ethinyl-1,1,4,4-tetramethyl-1,2,3,4-tetr purification on a column with silica gel (dichloromethane 30 /heptane 70), get the desired derivative in the form of a solid substance.

1H NMR (CDCl3): 1.28(6N, s), 1.29(6N, s), 1.69 (4H, s), 3.91 (3H, s), 7.30(2H Ar, s), 7.49-7.54(3H Ar, m), 8.0(2HAr, d, J=6.9 Hz).

Example 26

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)phenol

(a) 4-trimethylsilyltriflate

In a manner analogous to the method of example 1 (a), using as source material 4.63 g (17.7 mmol), 4-iodobenzylamine receive 3.72 g (90%) of the desired compound as a yellow powder, melting point =45oC.

1H NMR (CDCl3): 0.05(s; 9H); 2,10 (s, 3H); 6.84(dt,2H); 7.28(dt,2H).

13C NMR (CDCl3): 0.00; 2CH3/ 21.2; CH3/ 94.4; Cq/ 104.3; Cq/ 120.9; Cq/ 121.2; 2CH/ 133.2; 2CH/ 150.7; Cq/ 169.1; Cq.

(b) 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethylene)phenyl acetate

In a manner analogous to the method according to example 4 (b), after reaction 1.39 g (2.4 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenide in THF with bromine (0.22 ml, 4.3 mmol), was added copper iodide (1.82 g, 9.6 mmol) and ester 4-trimethylsilyl-ethynylbenzoate (1 g, 4.3 mmol) in DMF at a temperature of 80oWith, an additive made for 15 hours, and after purification on a column with silica gel (dichloromethane 20 /heptane 80), obtain 220 mg (16%) of the desired compounds which,1H).

13C NMR (CDCl3): 19.2; CH3/ 19.5; CH3/ 30.3; SN3/ 32.4; Cq/ 32.7; Cq/ 33.4; CH2/ 33.5; CH2/ 68.7; Cq/ 99.9; Cq/ 119.5; Cq/ 120.1; 2CH/ 124.2; Cq/ 126.7; SN/ 126.9; SN/131.0; 2CH/ 133.0; Cq/ 142.5; Cq/ 143.5; Cq/ 138.0; Cq/ 167.5; Cq.

(C) 4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)phenol

A mixture of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)phenylacetate (500 mg, 1.1 mmol) and potassium carbonate (160 mg, 1.1 mmol) in methanol (20 ml) is stirred for 24 hours at room temperature, and then treated with ethyl acetate and water.

The organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at a temperature of 40oC. the Product was then purified on a column of silica gel (ethyl acetate 20 /heptane 80). Receive 300 mg (66%) of a clear oil.

1H NMR (CDCl3): 1.25-11.27 (m, 12H); 1.66 (s, 4H); 2.35(s,3H); 6.77 (d, 2H); 7.09(s,1H); 7.38(dd,2H); 7.73(s,1H).

13C NMR (CDCl3): 20.3; CH3/ 31.4; SN3/ 33.6; 2Cq/ 34.6; 2CH2/ 67.2; Cq/103.7; Cq/ 115.3; Cq/ 115.6; 2CH/ 127.7; Cq/ 128.5; 2CH/ 133.0; 2CH/ 133.6; Cq/ 143.6; Cq/ 143.9; Cq/ 156.0; Cq.

Example 27

Ethyl 4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate

In a manner analogous to the method according to example 4 (b), raagi mmol), add copper iodide and ethyl 4-trimethylsilylethynyl (644 mg; 2.8 mmol) in DMF at a temperature of 80oC; produce additive for 15 hours. After purification on a column with silica gel (dichloromethane 20 /heptane 80), obtain 220 mg (16%) of the desired compound as a yellow oil.

1H NMR (CDCl3): 1.29(s, 6H); 1.37-1.43(m,9H); 1.65(q,4H); 4.39(q,2H); 5.72(s,1H); 7.26(s,1H); 7.43(s,1H); 7.55(d,2H); 8.03(d,2H).

Example 28

Ethyl 4-(4-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate

In a manner analogous to the method according to example 4 (b) reacting 1 g (1.5 mmol) 4-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenide in THF with bromine (0.092 ml, 1.78 mmol), added copper iodide and ethyl 4-trimethylsilylethynyl (644 mg; 2.8 mmol) in DMF; the additive is carried out at 80oC for 15 hours. After purification on a column with silica gel (dichloromethane 20 /heptane 80) obtain 420 mg (31%) of the desired compound as a yellow oil.

1H NMR (CDCl3): 1.17(q,6H); 1.31 (m, 9H); 1.49-1.57(m,4H); 3.38(s,3H); 4.25(q,2H); 5.10(s,2H); 7.08(d,1H); 7.14(d,1H); 7.41(d,2H); 7.88(d,2H).

Example 29

4-(4-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naftiliaki-ethinyl)benzoic acid

In a manner analogous to the method according to example 7, by the reactions is THF, reacts with 500 mg of sodium hydroxide, and after grinding the powder from heptane, to obtain the desired compound in the form of solids.

1H NMR (CDCl3): 1.28 (s, 6N;) 1.39 (s, 6N); 1.66 (m, 2H); 3.51 (s, 3H); 5.23 (s, 2H); 7.19 (d, 1H, J=1.8 Hz); 7.25 (d, 1H, J=1.8 Hz); 7.56 (d, 2H, J=8.5 Hz); 8.06 (d.2H, J=8.5 Hz).

Example 30

[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)phenyl] carbaldehyde

A mixture of [4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)phenyl]methanol obtained in example 24 (280 mg, 0.7 mmol) and pyridine dichromate (526 mg, 1.4 mmol) in dichloromethane (10 ml) was stirred at room temperature for 4 hours. After filtration through silica gel and concentration in a rotary evaporator under vacuum at 40oTo receive 173 mg (63%) of the desired product as a yellow oil.

1H NMR (CDCl3): of 1.28 (s, 6N), 1.30 (s, 6N), 1.70 (s, 4H), 4.67 (s, 2H), 7.23 (1H Ar, d, J=8.3 Hz), 7.29 (1H Ar, dd, J=1.9 Hz, J =8.3 Hz), 7.52 - 7.59 (3H Ar, m), 7.84 (1H Ar, d, J=6.7 Hz); 9.99 (H, S).

Example 31

Methyl 4-(4,4-dimethylthiochroman-8-Islamisation benzoate

(a) 2-bromo-1-(3-methylbut-2-ethylthio)benzene

19.30 g (102.0 mmol) of 2-bromothiophene, 160 ml of DMF and 15.50 g (112.0 mmol) of potassium carbonate are placed in a three-neck flask. Then drop by drop add 13 ml (112.0 mmol) 1-bromo-3-methyl-2-butanetriol with ethyl acetate, after separation of the phases by settling the organic phase is separated, washed with water, dried over anhydrous magnesium sulfate and evaporated. Collect 26.00 g (99%) of the desired compound as an orange oil.

1H NMR (CDCl3): d 1.65 (s, 3H), 1.73 (s, 3H), 3.56 (d, 2H, J =7,7 Hz), 5.32 (td, 1H, J=7.7/1.4 Hz), 6.96-7.06 (m, 1H), 7.22-7,26 (m, 2H), 7.52 (d, 1H, J=7.7 Hz).

(b) 4,4-Dimethyl-8-promotionen

26,00 g (102.0 mmol) 2-bromo-1-(3-methylbut-2-initio)benzene, 180 ml of toluene and 23.20 g (122.0 mmol) of para-toluensulfonate acid are placed in a three-neck flask. The reaction mixture is distilled for four hours and evaporated to dryness. The residue is dissolved in aqueous sodium bicarbonate solution and extracted with ethyl acetate, and the organic phase is separated after settling, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column with silica gel, elwira heptane. Collect of 20.00 g (76%) of the desired compound as orange oil.

1H NMR (CDCl3): d 1.33 (s, 6H), 1.94 (t, 2H, J=6.0 Hz), 3.04 (t, 2H, J = 6.1 Hz), 6.89 (t, 1H, J=7.9 Hz), 7,34 (d, 2H, J=7,9 Hz).

(C) 4,4-Dimethyl-8-mikromaiseman

One crystal of iodine, magnesium (208 mg, 8.56 mmol) and several drops of a solution of 4,4-dimethyl-8-bromothiophene (2 g, 7.78 mmol) in ethyl Clonney the mixture is heated for 2 hours and then add selenium (615 mg, 7.78 mmol) at room temperature. Stirring is continued for 30 minutes and then add 1N hydrochloric acid solution. The reaction mixture was treated with ethyl ether. The organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40oC. To the resulting oil is added ethanol. The mixture is vigorously stirred for several minutes and then concentrated in a rotary evaporator under vacuum at 40oC.

The resulting product was then purified on a column with silica gel (dichloromethane 20/heptane 80). Receive 300 mg (15%) of a white solid.

1H NMR (CDCl3): 1.33 (6N, s), 1.96 (2H, m), 3.09 (2H, m), 6.93 (1H Ar, t, J= 7.8 Hz), 7.26 (1H Ar, dd, J=7.8 Hz, J=1.3 Hz), 7.47 (1H Ar, dd, J=7.8 Hz, J=1.3 Hz).

(C) Methyl 4-(4,4-dimethylthiochroman-8-Islamisation)benzoate

In a manner analogous to the method according to example 4 (b), carry out the reaction of 300 mg (1.9 mmol) of 4,4-dimethyl-8-mikrokontinenta, in 2 ml of THF, with bromine (0.117 ml, 2.2 mmol), added copper iodide (780 mg) and methyl 4-ethynylbenzoate (562 mg; 3.5 mmol) in 20 ml of DMF and after purification on a column with silica gel (dichloromethane 20 /heptane 80), receive the desired derivative in the form of a yellow solid.

1H NMR (C=1.3 Hz), 8.00 (2H Ar, d, J= 8.5 Hz).

Example 32

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

In a manner analogous to the method according to example 2, carry out the reaction of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethylene)benzoate in THF, and after crystallization from heptane, to obtain the desired derivative in the form of a white solid.

1H NMR (CDCl3): 1,28 (6N, s), 1.29 (6N, s), 1.70 (4H. s), 7,30 (2H Ar, s), 7.43 to 7.50 (3H Ar, t), 7.99 (2HAr, d, J=7.5 Hz).

Example 33

The lithium salt of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-inculturating)benzoic acid

0.05 mmol of the acid obtained in example 2, and 0.55 mmol of lithium hydroxide in 10 ml of methanol are mixed at ambient temperature. The reaction mixture was concentrated under vacuum using a rotary evaporator.

The obtained solid was sequentially washed with ethyl acetate, heptane and ethyl ether. The lithium salt was obtained in the form of water-soluble beige solid (yield 73%).

According to the above process, the lithium salts of the acids prepared in examples 5, 14, 16, and 32, were synthesized and obtained with the same output.

Example 34

With the ASS="ptx2">

0.28 mmol of the acid obtained in example 7, and 0.28 mmol diethanolamine in 5 ml of methanol were mixed at ambient temperature. The reaction mixture was concentrated under vacuum using a rotary evaporator. The obtained solid was sequentially rinsed with heptane and ethyl ether. Salt diethanolamine was obtained in the form of water-soluble white powder (yield 77%).

According to the described process, the diethanolamine salt of the acid prepared in examples 2, 5, 16, and 32, were synthesized and obtained with the same output.

EXAMPLES OF COMPOSITIONS

Example 35

The following describes the various pharmaceutical and cosmetic compositions based on compounds according to the invention:

A. COMPOSITIONS FOR ORAL administration

(a) tablets 0,2 g

Connection example 1 - 10,001 g

Starch - 0,114 g

The dicalcium phosphate at 0.020 g

Silicon dioxide - 0,020 g

Lactose - 0,030 g

Talc - 0,010 g

Magnesium stearate 0.005 g

In this example, the compound of example 1 can be replaced by the same quantity of one of the compounds according to examples 4, 6, 11, 13 or 15.

(C) Suspension for a drink in 5 ml vials

Connection example 3 - 20,001 g

Glycerin - 0,500 g

70% Serbia water, qs 5 ml

(C) the Tablets of 0.8 g

Connection example 2 - 0,500 g

Pre gelatinising starch - 0,100 g

Microcrystalline cellulose - 0,115 g

Lactose - 0.075 g

Magnesium stearate - 0,010 g

In this example, the connection example 2 can be replaced by the same quantity of one of the compounds according to examples 6, 11, 14 or 28.

(d) Suspension for a drink in 10 ml vials

Connection example 3 - 0,200 g

Glycerin - 1,000 grams

70% sorbitol - 1,000 grams

The sodium saccharinate - 0,010 g

Methyl p-hydroxybenzoate - 0,080 g

Flavor qs

Purified water, qs to 10 ml

B. COMPOSITION FOR LOCAL APPLICATION

(a) Ointment

Connection example 2 - 20,020 g

Isopropylmyristate - 81,700 g

Liquid petrolatum - 9,100 g

Silica ("Aerosil-200" manufactured by Degussa) - 9,180 g

(b) Ointment

Connection example 1 - 0,300 g

White petrolatum 100 g

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

Connection example 1 - 0,100 g

A mixture of lanolin alcohols as emulsifiers, waxes and oils ("anhydrous eucerin" manufactured by BDF) - 39,900 g

Methyl p-hydroxybenzoate - 0.075 g

Propyl p-hydroxybenzoate - 0.075 g

Sterile distilled water qs to 100 g is emeram 4, 16, 22, 27 or 32.

(d) Lotion

Connection example 3 - 0,100 g

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

95% ethanol - 30,000 g

(e) Hydrophobic ointment

Connection example 1 - 0,300 g

Isopropylmyristate - 36,400 g

Silicone oil ("Rhodorsil 47V300", manufactured by Rhone-Poulenc) - 36,400 g

Beeswax - 13,600 g

Silicone oil ("Abil 300.000 cst.", manufactured by Goldschmidt) - 100 g

(f) non-ionic cream-type oil-in-water

Connection example 2 - 1,000 grams

Cetyl alcohol - 4,000 grams

Glycerylmonostearate - 2,500 grams

PEG-stearate - 502,500 g

Caritive oil - 9,200 g

Propylene glycol - 12,000 g

Methyl p-hydroxybenzoate - 0.075 g

Propyl p-hydroxybenzoate - 0.075 g

Sterile distilled water - 100 g

In this example, the connection example 2 can be replaced by the same quantity of one of the compounds according to examples 5, 9, 12, 19 or 32.

TEST ACTIVITY

The test results on the differentiation is carried out on the cells teratocarcinoma mouse embryos (F9) to identify molecules RAR agonist, as described in the paper Skin Pharmacol. 3, pp.256-267, 1990.

After treatment with the compounds according to the examples in the table.1, A, B, teratocarcinoma cells (F9) mouse embryolethality environment.

The activity of the product is expressed by the indicator AC50, which represents the concentration of the test product, which gives half of the maximum number of secreted plasminogen activator.

The results presented in table.1 show that the compounds of examples 1, 2, 4, 5, 16 and 18 are agonists of RAR.

1. Baromedicine connection related through generativity radical and having the following formula:

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where Ar is a radical selected from the group consisting of

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R1represents a halogen atom, -CH3-CH2OR7, -OR7, COR8or a polyether radical;

R2and R3taken together form a 5 - or 6-membered ring, possibly substituted by at least one methyl group and/or may suspend a sulfur atom;

R4and R5represent H, halogen atom, linear or branched C1-C10alkyl, -OR7or a polyether radical;

R7represents H;

R8represents N, OR10or

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R10represents H or a linear or branched C1-C10alkyl;

r' and r", Otie together with the nitrogen atom, form morpholino ring;

X represents a divalent radical, which is from right to left or Vice versa is a formula

-Y-CC

where Y represents S(O)nor Se, and n= 0, 1, or 2,

and salts of compounds of formula (I), when R1represents a carboxylic acid function.

2. Connection on p. 1, where they are in the form of a salt of an alkali metal or alkaline earth metal, or an alternative, in the form of zinc or of an organic amine.

3. Connection under item 1 or 2, in which the alkyl radical WITH1-C10choose from the group consisting of the radicals methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, 2-ethylhexyl and Attila.

4. Compounds according to any one of the preceding paragraphs, in which the polyether radical chosen from the group: methoxyethoxy, ethoxyethoxy and methoxyethoxyethoxy radicals.

5. Compounds according to any one of the preceding paragraphs, corresponding to the following General formula (II)

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where Ar' is a radical of the formula

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and R1, R4, R5and X have the meanings specified in paragraph 1;

R11, R12, R13and R14the same or different, predstavlyaemoi:

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in which R4, R11, R12, Ar' and X have the meanings specified in paragraph 5.

7. Compounds according to any one of the preceding paragraphs, taken from the group consisting of:

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

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

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

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

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

Methyl 4-(5,5,8,8-tetrahydro-2-afteraltynsarin) benzoate,

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

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

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

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

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

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

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

6-(4-Methoxyethoxymethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene,

Ethyl 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinate,

6-(5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinic acid,

N-(4-Hydroxyphenyl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzamide,

Methyl 5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)-2-pyridine of carboxylate,

2-(4-Chlorophenylsulfonyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene,

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

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

Methyl 2-hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

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

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

6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinic acid,

N-(4-Hydroxyphenyl)-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)nicotinamide,

N-Butyl-6-(3,5,5,8,8-PE is hydro-2-aftersensations)-3-pyridyl] methanone,

Methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)pyridine-2-carboxylate,

5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)pyridine-2-carboxylic acid,

[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)phenyl] methanol,

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

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

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

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

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

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

4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-aftersensations)phenol.

Ethyl 4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

Ethyl 4-(4-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

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

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

4-(3-methoxyethoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoic acid,

4-(3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoic acid,

Ethyl 4-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoate,

4-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)benzoic acid,

[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-aftersensations)phenyl] carbaldehyde,

Methyl 4-(4,4-dimethylthiochroman-8-Islamisation)benzoate,

4(4,4-dimethylthiochroman-8-Islamisation)benzoic acid,

Methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-8-aftersensations)benzoate,

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

Methyl 4-[3-(1-substituted)-4-methoxyphenyl)-1-Islamisation] benzoate,

4-[3-(1-substituted)-4-methoxyphenyl)-1-Islamisation] benzoic acid

Methyl 4-[4-(1-substituted)-3-methoxyphenyl)-1-Islamisation] benzoate, and

4-[4-(1-substituted)-3-methoxyphenyl)-1-Islamisation] benzoic acid.

8. Pharmaceutical composition, characterized in that it contains, in a pharmaceutically acceptable carrier, at least one connection, the definition is, the underwater connection according to any one of paragraphs. 1-7 is from 0.001 to 5% of the total weight of the composition.

10. Cosmetic composition, characterized in that it contains, in a cosmetically acceptable medium, at least one compound according to any one of paragraphs. 1-7.

11. The composition according to p. 10, characterized in that the concentration of at least one compound according to any one of paragraphs. 1-7 is from 0.001 to 3% of the total weight of the composition.

 

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-assisted replication of retrovirus" target="_blank">

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also known as nicorandil
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