Baromedicine compounds and pharmaceutical and cosmetic compositions comprising them

 

(57) Abstract:

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, coat N, and salts of compounds of formula (I), when R1represents a carboxylic acid, and optical and geometrical isomers of the above compounds of formula (I). Pharmaceutical composition having antagonistic activity against receptors of the retinoic acid containing compound of the formula I and a pharmaceutically acceptable carrier. Cosmetic composition having antagonistic activity against receptors of the retinoic acid containing compound of the formula I and a cosmetically acceptable carrier. 3 C. and 10 C. p. F.-ly.

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The invention relates to new and useful industrial products, to Bermatingen compounds in which the aromatic nuclei are joined using propylenebis or alltimemovie divalent radical. The invention also relates to the use of these new compounds in pharmaceutical compositions intended for use in medicine for human or veterinary medicine, or alternatively in cosmetic compositions.

Compounds according to the invention have significant activity in the fields of cell differentiation and proliferation, and they are used more specific, dermatologically States (and similar) with an inflammatory component and/or immunoallergic component, and dermal or epidermal proliferation, either benign or malignant development. These compounds can also be used in the treatment of degenerative diseases of the connective tissue to combat skin aging or photo-induced or chronological (occurring over time), and in the treatment of disorders associated with scarring. They also find application in the field of ophthalmology, in particular, in the treatment of corporate.

Possible is also the use of compounds according to the invention in cosmetic compositions for the care of the body and hair.

In the application EP-661258 already disclosed baromedicine compounds, aromatic nuclei which are connected using propylenebis divalent radical, as substances that are active in the pharmaceutical or cosmetic compositions.

Compounds according to the application EP-661258 correspond to the following General formula:

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in which Ar represents a divalent aromatic radical, optionally substituted by the radical R5or getesa nitrogen,

R1represents H, -CH3, -CH2OR6, -OR6, -COR7or-S(O)tR9in which t is 0, 1 or 2,

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

or R2and R3taken together form a 5 - or 6-membered ring, optionally substituted by methyl groups and/or optionally separated by an oxygen atom or sulfur,

R4and R6represent H, halogen, or lower alkyl, or-OR6,

R6represents H, lower alkyl or-COR9,

R7represents H, lower alkyl-N(R)R1or8,

R8represent H, C1-C20alkyl which may be linear or branched, alkenyl, mono - or polyhydroxylated, optionally substituted aryl or aralkyl, or sugar, or amino acid or peptide residue,

R9represents lower alkyl,

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

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

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in which R11taken together, form an oxo (= O) radical,

and salts of these compounds of the above formula where R1represents a functional group of a carboxylic acid, and optical and geometrical isomers of these compounds.

Compounds according to the present invention in comparison with the compounds of application EP-661258 differ mainly in the fact that-X-Ar-R1the Deputy is in the ortho-position with respect to R2the radical, or a 5 - or 6-membered ring when R2and R3taken together, whereas in the application EP-661258, -X-Ar-R1the Deputy is in the meta position.

This is so because, surprisingly and unexpectedly been found that this modification in the structure allows it is possible to greatly increase its pharmaceutical and cosmetic properties and, in addition, to reduce some side effects.

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

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in which Ar represents a radical selected from the following formulas (a) to (C):

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in which Z is an oxygen atom or sulfur,

R1represents-CH4represents a linear or branched C1-C20alkyl and is in the ortho - or meta-position relative to X-Ar connection,

R3represents lower alkyl, or

R2and R3taken together form a 5 - or 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur,

R4represent H, halogen, linear or branched C1-C20alkyl, -OR8polyester radical, or aryl,

R5represent H, halogen, linear or branched C1-C20alkyl or-OR8radical,

R6represents H, lower alkyl or-COR9radical,

R7represents H, lower alkyl-N(r')r ' or-or SIG10,

R8represent H, lower alkyl or-COR9,

R9represents lower alkyl,

R10represent H, C1-C20alkyl which may be linear or branched, alkenyl, mono - or polyhydroxylated, optionally substituted aryl or aralkyl or a sugar residue,

r' and r" represent H, lower alkyl, mono - or polyhydroxylated, optionally substituted aryl, or an amino acid, or OTL, which is right to left or Vice versa has the formula:

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in which R11represents H or-OR6, R6having the same meaning as above,

R12represents H or lower alkyl, or

R11and R12taken together, form an oxo (= O) radical,

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

If the compounds according to the invention is provided in a salt form, it preferably is a salt of alkali or alkaline earth metal or alternative zinc or organic amine.

According to the present invention, the lower alkyl is to be understood as C1-C6radical, preferably methyl, ethyl, ISO-propyl, boutigny, tert-botilony and sexily radicals.

WITH1-C20alkyl which may be linear or branched, understood as representing, in particular, methyl, ethyl, sawn, ISO-propyl, sexily, Gately, 2-ethylhexyl, octillery, monilinia, dodecylphenyl, hexadecimally and octadecenyl radicals.

Monohydroxylation, 2-hydroxypropyl or 3-hydroxypropyl radical.

Polyhydroxyethyl understood as representing a 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 or 2,3,4,5-tetrahydroxyphenyl radicals or interfraternity the rest.

Polyether radical is understood as representing a radical containing from 1 to 6 carbon atoms and from 1 to 3 atoms of oxygen or sulfur, such as radicals methoxymethyl ether, methoxyethoxymethyl ether or methylthiomethyl ether.

Aryl is understood as representing peredelnyj radical, tofinally radical or phenyl radical, optionally substituted by at least one halogen atom, one hydroxyl, one microfunctional group, a single lower alkyl, one CF3radical, one aminosalicylate not necessarily protected acetyl functional group or optionally substituted by one or two lower alkyl(Lamy), one alkoxyalkyl or one polyether radical. Aryl is preferably understood as representing a phenyl radical, optionally substituted by at him, CF3radical, one aminosalicylate not necessarily protected acetyl functional group or optionally substituted by one or two lower alkyl(Lamy), one alkoxylation one or polyester radical, where the latter has the meaning as defined above.

If the Deputy is alkoxyalkyl, the latter preferably is C1-C12alkoxyalkyl, such as, in particular, methoxy, ethoxy, propyloxy, isopropoxy, hexyloxy, heptyloxy, octyloxy and nonelectronically.

Aralkyl preferably understood as representing a benzyl radical or finitely radical, optionally substituted by at least one halogen atom, one hydroxyl or one nitro functional group.

Alkenyl understood as preferably represents a radical containing from 2 to 5 carbon atoms and containing one or more ethylene unsaturated bonds, such as, more specifically, allyl radical.

The sugar residue is understood as representing the residue formed, in particular from glucose, galactose, mannose or glucuronic acid.

The balance of amino acids ponimaenie the remainder is understood as representing more specifically dipeptide or Tripeptide residue, formed from combinations of amino acids.

The heterocycle is preferably understood as representing piperidinyl radical, morpholinyl radical, pyrolidine radical or pieperazinove radical, optionally substituted in the 4-position of the lower C1-C6the alkyl or mono - or polyhydroxyalkane, as defined above.

If R4and R5represents halogen, the latter is preferably a fluorine atom, chlorine or bromine.

According to a preferred variant, the compounds according to the invention correspond to the following General formula:

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in which Ar represents a radical of the following formula (a) or (b)

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R1is-COR7,

R5and R7have the meanings as defined above for formula (I),

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

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R11and R12represent H,

R13and R14that are the same or different, represent N or CH3,

Y represents oxygen atom or sulfur, or a methylene, ethylene or isopropylidene divalent radical, and

n is 1 or 2.

In particular, omanut the following connections:

-Methyl 2-hydroxy-4-[3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoate,

-2-Hydroxy-4-[3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoic acid,

- Methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoate,

-2-Hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoic acid,

Methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoate,

-2-Hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoic acid,

Ethyl 4-[3-hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoate,

-4-[3-Hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid,

-4-[3-(5,5,8,8-Tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid,

-Ethyl 4-[3-(4,4-dimethylthiochroman-5-yl)-3-hydroxyprop-1-inyl] benzoate,

-4-[3-(4,4-Dimethylthiochroman-5-yl)-3-hydroxyprop-1-inyl] benzoic acid,

-4-[3-(4,4-Dimethylthiochroman-5-yl)prop-1-inyl] benzoic acid,

Ethyl 4-[3-(3,5-di-tert-butyl-2-(methoxyethoxy)-phenyl)-3-hydroxyprop-1-inyl] benzoate,

-4-[3-(3,5-Di-tert-butyl-2-(methoxyethoxy)phenyl)-3-hydroxyprop-1-inyl] benzoic acid,

-Ethyl 4-[3-(3,5-di-tert-butyl-2-hydroxyphenyl)-3-hydroxyprop-1-inyl] benzoate,

-Ethyl 4-[3-(3,5-di-tre] benzoate,

-4-[3-(3,5-Di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-inyl] benzoic acid,

-4-[3-(3,5-Di-tert-butyl-2-methoxyphenyl)prop-1-inyl] benzoic acid,

- Ethyl 4-[3-(5-tert-butyl-4-(methoxyethoxy)biphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate,

-4-[3-(5-tert-Butyl-4-(methoxyethoxy)biphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoic acid,

- Ethyl 4-[3-(5-tert-butyl-4-(methoxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate,

-4-[3-(5-tert-Butyl-4-methoxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoic acid,

- Ethyl 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-methoxypropan-1-inyl] benzoate,

-4-[3-(3,5-Di-tert-butyl-2-methoxyphenyl)-3-methoxypropan-1-inyl] benzoic acid,

-Methyl 4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] -benzoate,

-Ethyl 6-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] -nicotinate,

-4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-inyl] benzaldehyde,

-4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-inyl] phenol,

- Ethyl 4-[3-(5-tert-butyl-4-hydroxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate,

-4-[3-(5-tert-Butyl-4-methoxybiphenyl-3-yl)prop-1-inyl] benzoic acid,

-4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-inyl] -benzoic acid,

-4-[3-{ 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-1-naphthyl)prop-1-inyl] benzoic acid,

-2-Hydroxy-4-[3-(5-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoate,

-2-Hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoic acid,

-2-Hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoic acid,

-4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-inyl] benzamid,

N-Ethyl-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzamid,

-N-(4-Hydroxyphenyl)-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzamid,

-Morpholin-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoic acid

-4-[3-(4,4-Dimethylthiochroman-8-yl)prop-2-inyl] benzoic acid,

-4-[3-(5,5,8,8-Tetramethyl-5, b, 7,8-tetrahedronal-1-yl)prop-2-inyl] benzoic acid,

-4-[3-(4,4-Dimethyl-6-panitikan-8-yl)prop-1-inyl] benzoic acid,

-4-[3-(4,4-Dimethyl-6-phenylpropan-8-yl)prop-1-inyl] benzoic acid,

-4-[3-(4,4-Dimethyl-6-panitikan-8-yl)prop-2-inyl] benzoic acid,

-4-[3-(4,4-Dimethyl-6-(p-tolyl)thiochroman-8-yl)prop-1-inyl] benzoic acid,

-4-[3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahedronal-1-yl)prop-2-inyl] benzoic acid,

-4-[3-(5,5,8,8-Tetramethyl-3-(p-tolyl)-5,6,7,8-tetrahedronal-1-yl)prop-2-inyl] benzoic acid,

-4-(3-[3-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid,

-2-Hydroxy-4-[3-(5,5,8,8-tetramethyl-3-(p-tolyl)-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] beclate.

Another object of the present invention are methods of preparing compounds of formula (I), the above, according to the reaction scheme 1 (see the end of the description).

The compounds of formula (I) can be prepared from Alojamientos derivative (1), preferably brominated or iodirovannoi derived by conversion of the magnesium derivative, followed by reaction with methoxyethanol in the presence of CuBr and receiving propargilovyh derivative (2). The latter subsequently combined with galoidzamyescyennykh derivative (3), preferably iodirovannoi or brominated derivative, in the presence of a palladium catalyst, for example bis(triphenylphosphine)palladium (II) chloride, in a solvent such as triethylamine.

The compounds of formula (I) can also be prepared by the sequence of reactions, including the reaction of lithium trimethylsilylacetamide with the aldehyde compound (4), and removing the protection tetrabutylammonium in THF with getting propargilovyh alcohol (6). The combination of the latter with galoidzamyescyennykh derivative (3), preferably iodirovannoi or brominated derivative, in the presence of a palladium catalyst, for example bis(triphenylphosphine)balladlike invention. The last connection through recovery of the functional alcohol groups in the carbide in the presence of trimethylsilylmethyl in a solvent such as hexane, or by hydride transfer from a silane, such as triethylsilane, in the presence of BF3. Et2O in a chlorinated solvent such as methylene chloride gives the compound of formula (I).

The compounds of formula (I) can also be prepared by the sequence of reactions involving the reaction of a benzoyl chloride of formula (8) with an acetylene derivative of the formula (9) in the presence of a Lewis acid (for example, AlCl3) in a chlorinated solvent such as dichloromethane. Acetylene ketone (10), thus obtained, is restored in gidrauxilirovanne compound (I') according to the invention by the action of alkali metal hydride such as sodium borohydride in an alcohol solvent (e.g. methanol). Restoration of functional alcohol group of compound (I') in the carbide is carried out, as described above, and gives compound of formula (I).

Allene compounds of formula (I) can be prepared by heating compounds of formula (I) in the presence of a base (NaOH, Et3N, DBU) in a solvent such as heptane or THF.

the major schemes of the reaction depending on the values of the radical y

If Y represents a sulfur atom, R13and R14represent-CH3and n= 2, that is, 4,4-dimethylthiochroman derivative, the latter can be obtained from 2-bromothiophene at the expense of combination reaction with 4-bromo-2-methyl-2-butene in the presence of potassium carbonate or sodium hydride in DMF and then subjected to cyclization or in the presence of p-toluensulfonate acid or in the presence of aluminum chloride or polyphosphoric acid according to the reaction scheme 2 (see the end of the description).

When Y represents an oxygen atom, R13and R14represent-CH3and n= 2, that is, 4,4-dimethylthiochroman derivative, the latter can be obtained from phenol by reaction with 3-methyl-3-butene-1-yl-diphenylphosphine in the presence of chloride of tin, then litrovaya in the presence disutility and tetramethylethylenediamine and reaction with diiodomethane (K. McWilliams, J. Org. Chem. , 1966, 61, 7408-14), according to the reaction scheme 3 (see end of description).

When Y represents isopropylidenebis radical, R13and R14represent-CH3and n= 2, i.e. tetrahydroaluminate derivative, the latter can be obtained from 3-bromophenol due to the reaction with 2,5-dichloro-2,5-dimethylhexane in the presence of chloride is m hydroformylation (H. Kotsuki, Synthesis, 1996, 470-2) according to the reaction scheme 4 (see end of description).

When Y represents a methylene radical, R13and R14represent-CH3and n= 2, i.e. tetrahydrobiopterine derivative, the latter can be obtained from 2-bromoanisole due to the reaction in combination with a zinc derivative of 1-bromo-4-methylpent-3-ene in the presence of a palladium catalyst, such as PdCl2/(dppf) (R. L. Danheiser, J. Org. Chem. , 1995, 60, 8341-8350), then cyclization in the presence of a Lewis acid such as aluminum chloride, then demetilirovania BBr3formation triflate and hydroformylation, as described above.

This sequence of reactions may be represented by reaction scheme 5 (see the end of the description).

When R1represents-COOH, the compounds are prepared when the group R1protected by a protecting group, alkyl, allyl or tert-Putilkovo type.

The transformation of the free form can be:

in the case of alkyl protecting group using sodium hydroxide or lithium hydroxide in an alcohol solvent such as methanol or THF;

in the case of allyl protecting group using a catalyst, such as certain her group, tert-Putilkovo type using trimethylsilylmethyl.

When R1is HE, the compounds can be obtained from the corresponding acid by recovery in the presence of lithium aluminum hydride.

When R1is-CON(r')r", the compound can be obtained by transformation of the appropriate acid to the acid chloride, for example thionyl chloride, and then by reaction with ammonia or the appropriate amine.

Another object of the present invention are compounds of formula (I) as defined above, as a medicinal product.

These compounds exhibit activity in the test for cellular differentiation of mouse embryonic teratocarcinoma (F9) (Cancer Research, 43, of 5,268 R., 1983) and/or in the test for inhibition of ornithine decarboxylase after induction TPA in mice (Cancer Research, 38. R, 793-801, 1978). These tests show the activity of the compounds in cell differentiation and proliferation, respectively.

In the test for the differentiation of cells (F9), it becomes possible to assess agonistic activity, such antagonistically activity on the receptors of retinoic acid. This is because antagonist is inactive, if there is one in this test, but partially or fully ingibiruet activator. Therefore, these compounds also inhibit the activity in the test, which is the identification RAR-antagonist molecules, as described in French patent application No. 95-07302 filed June 19, 1995, the applicant company. This test includes the following stages: (i) a sufficient number RAR-agonist molecule is applied locally to the portion of skin of a mammal, (ii) molecule capable of inhibiting RAR-antagonist activity, is introduced systematically, or locally the same mammal or in the same part of the skin of a mammal before, during or after steps (i) and (iii) evaluated the response of the skin thus treated mammal. Thus, the response to topical application to the ear of the mammal RAR-agonist molecule, which corresponds to the increase in the thickness of this ear, can be Engibarov due to systemic or local injection RAR-antagonist molecules.

Compounds according to the invention are particularly suitable for the following treatment areas:

1) for treating dermatological conditions associated with disorders of keratinization, including differentiation and proliferation, especially for treating common acne, comedones Il is gray, such as solar, drug or occupational acne,

2) for treating other types of disorders of keratinization, in particular ichthyosis, ichtiozoformnye States, disease Darier's, keratodermia Palmar-plantar, leukoplakia and leukoplakia States or skin sclerosus or lichen belonging to the mucous membrane (oral),

3) for treating other dermatological conditions associated with disorders of keratinization with inflammatory and/or immunoallergic component, and in particular all forms of psoriasis, or skin-related mucosal or ungual, and even psoriatic rheumatism, or alternatively cutaneous atopy, such as eczema, or respiratory atopy or alternatively gingival hypertrophy; the compounds may also be used for certain inflammatory conditions that do not show violations of keratinization,

4) for treating all dermal or epidermal proliferate whether they are benign or malignant and whether or not they have a viral nature, such as simple warts, flat warts and epidermodysplasia borodavchatyi education, flowering or oral papillomatosis, and cast new the and epithelioma spinous cells,

5) for treating other dermatological disorders such as bullous dermatoses and collagen diseases,

6) for the treatment of certain eye disorders, in particular corporate,

7) to restore or to fight skin aging or photo-induced or chronological, or for reducing actinic keratoses and pigmentations, or any pathologies associated with chronological or actinic aging,

8) for the prevention or treatment stigma epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy,

9) for the prevention or treatment of disorders associated with wound healing, or to prevent or to repair abrasions,

10) for combating disorders of the sebaceous function, such as Hyperborea acne or simple seborrhoea,

11) for the treatment or prevention of cancerous or precancerous conditions,

12) for the treatment of inflammatory conditions such as arthritis,

13) for the treatment of any condition of viral origin at skin level or General level,

14) to prevent or treat hair loss,

15) for the treatment of dermatological or oaky as atherosclerosis.

In therapeutic fields mentioned above, the compounds according to the invention can preferably be used in combination with other compounds with the activity of the retinoid type, with vitamin D or other derivatives, corticosteroids, agents for destroying free radicals, hydroxy, or-keto acid, or their derivatives, or alternatively with blockers of ion channels. Vitamin D or derivatives thereof is understood as having a value, for example, derivatives of vitamin D2or D3and in particular 1,25-dihydrovitamin D3. Under the agents for destroying free radicals are understood, for example, a-tocopherol, superoxide dismutase, or SOD, original or certain metalhalide agents. -Hydroxy, or-keto acid, or their derivatives shall be construed as having a value of, for example, lactic acid, malic acid, citric acid, glycolic acid, almond acid, tartaric acid, glyceric acid or ascorbic acid or their salts, amides or esters. Finally, under the blockers of ion channels includes, for example, Minoxidil (2,4-diamino-6-piperidinedione-3-oxide) and its derivatives.

Another object of the present invention are Farin of its optical or geometric isomers or one of its salts.

The pharmaceutical compositions are intended especially for the treatment of the above conditions and are characterized by the fact that they include a pharmaceutically acceptable carrier that is compatible with the selected method of introducing at least one compound of formula (I), one of its optical or geometric isomers or one of its salts.

Introduction compounds according to the invention can be carried out enterline, parenterally, locally or through the eye introduction.

For enteral introduction of the composition can be provided in the form of tablets, hard gelatin capsules, pills, syrups, suspensions, solutions, powders, granules, emulsions or polymer or lipid visicol, or nanospheres or microspheres, which make possible controlled release. For parenteral compositions can be provided in the form of solutions or suspensions for infusion or injection.

Compounds according to the invention is usually administered with a daily dose of approximately 0.01 mg/kg to 100 mg/kg of body weight, and this is at the rate of 1 to 3 injections.

For the local introduction of pharmaceutical compositions based on compounds according to the invention more Konnov, milk, medicinal ointments, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be provided in the form of a polymer or lipid visicol, or nanospheres or microspheres or polymer patches or hydrogels that allow controlled release of the active substance. These compositions for local injection may also be provided either in anhydrous form or in aqueous solutions according to clinical requirements.

Eye of the introduction they are mainly used for washing the eyes.

These compositions for local or ophthalmic use containing at least one compound of formula (I) as defined above, or one of its optical or geometric isomers or one of its salts at a concentration preferably between 0.001 weight. % and 5 weight. % relative to 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 of the body and hair, and especially for the treatment of skin prone to acne, for hair regrowth and to combat hair loss, to combat manifestation Salou skin and for preventing and/or combating photoinduced or chronological aging.

In the field of cosmetics compounds according to the invention may also preferably be used in combination with other compounds with the activity of the retinoid type, with vitamin D or its derivatives with corticosteroids, agents for destroying free radicals,- hydroxy or-keto acid or their derivatives, or alternatively with blockers of ion channels, all of the latter compound are as defined above.

Another object of the present invention is thus a cosmetic composition, which is characterized by the fact that it includes a cosmetically acceptable medium, at least one compound of formula (I) as defined above, or one of its optical or geometric isomers or one of its salts, which makes it possible that this cosmetic composition is provided in the form of cream, milk, lotion, gel, polymer or lipid visicol, or nanospheres or microspheres, soap or shampoo.

The concentration of the compounds of formula (I) in the cosmetic compositions according to the invention are generally between 0.001 weight. percent and 3 weight. % relative to the total weight of the composition.

Pharmaceuricals or cosmetically active additives or combinations of these additives, and especially: wetting agents; depigmenting agents, such as hydroquinone, azelaic acid, caffeic acid or kojic acid; softeners; hydrating agents such as glycerol, PEG 400, thiomorpholine and its derivatives or urea; antisubmarine or protivougrevoe agents, such as S-carboxymethylcysteine, S-benzylester, their salts or their derivatives, or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, or tetracyclines; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolinones; agents accelerating the restoration of hair growth, such as Minoxidil (2,4-diamino-6-piperidinedione-3-oxide) and its derivatives, diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and phenytoin (5,5-diphenylimidazole-2,4-dione); steroidal anti-inflammatory agents; carotenoids and especially-carotene; antipsoriatics agents, such as anthralin and its derivatives; and, finally, eicosa-5,8,11,14-teatrainaya and eicosa-5,8,11-tryeniye acids, their esters and amides.

Compositions according to the invention may also contain amplifiers smell, preservative agents, such as esters of para-hydroxybenzoic acid, stabilizing agents, agents, adjustable lighting angle is UV-a and UV-b, screening agents, and antioxidants, such as tocopherol, bottled hydroxyanisol or bottled hydroxytrol.

Several examples of the preparation of active compounds of the formula (I) according to the invention, and various pharmaceutical and cosmetic compositions based on these compounds will be given as an illustration and without any restrictions.

EXAMPLE 1

Methyl 2-hydroxy-4-[3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoate (a) 4,4-dimethyl-8-iochroma

a 2.00 g (12.3 mmol) of 4,4-DIMETHYLPROPANE and 30 ml of ethyl ether is introduced into the three-neck flask in an argon atmosphere. Added dropwise 2.4 ml (15.9 mmol) of tetramethylethylenediamine (TMEDA) (TAMD), the mixture is cooled to -78oC and added dropwise to 5.9 ml (14.8 mmol) of n-utility (2.5 M in hexane). Allow the temperature to return to -20oC for two hours and then to room temperature and the mixture is stirred for 12 hours. In another three-neck flask is introduced into the argon atmosphere 1.3 ml (16.0 mmol) diiodomethane and 15 ml of ethyl ether. Conduct cooling tooWith and enter the previous solution, pre-cooled to -78oC, then the reaction mixture was allowed to reach room temperature and stirred for 12 cha is observed dried over magnesium sulfate and evaporated. The resulting residue is cleaned using chromatography on a column of silica gel by elution with heptane. After evaporation of the solvents will be collected of 1.30 g (37%) of the expected compound in the form of a pale yellow oil.

1H NMR (CDCl3) to 1.32 (s, 6N), of 1.84 (t, 2H, J= 5.4 Hz), 4,28 (t, 2H, J= 5.4 Hz), 6,62 (t, 1H, J= 7,7 Hz), 7,24 (DD, 1H, J= 7,8/1.5 Hz), 7,56 (DD, 1H, J= 7,7/1.5 Hz) (hereafter s-singlet, s; t-triplet, t; d-doublet, d; dd = double doublet, DD; td-triple doublet, dt; m-multiplet, m).

(b)meticillin

210 ml of 2.5 mol) propargylation ether and 12.00 g (110.0 mmol) of tert-butoxide sodium is introduced into the three-neck flask in an argon atmosphere. The reaction mixture is heated to boiling under reflux for three hours and distilled at atmospheric pressure. Faction Athanasius when 51oWith that collected in order to obtain 153,50 g (88%) of the expected compound in the form of a colourless oil.

1H NMR (CDCl3) to 3.41 (s, 3H), of 5.48 (d, 2H, J= 5,9 Hz), 6,77 (t, 1H, J= 5,9 Hz).

(c) 3-(4,4-DIMETHYLPROPANE-8-yl)-prop-1-in

280 mg (11.5 mmol) of magnesium, activated by a single drop of dibromethane injected into a three-neck flask in an argon atmosphere. Add dropwise a solution of 3.00 g (10.4 mmol) of 4,4-dimethyl-8-iochroma 15 m is> is within 15 minutes. Subsequently, it is cooled to -5oWith add 40 mg (0.2 mmol) Cul and to the solution are added dropwise 1.24 g (17.7 mmol) of metaxylene in 5 ml of ethyl ether. The mixture is stirred for 1 hour at -5oWith, allow to reach room temperature and stirred for two hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. The resulting residue is cleaned using chromatography on a column of silica gel by elution with heptane. After evaporation of the solvents will be collected of 1.30 g (65%) of the expected compound in the form of a yellow oil.

1H NMR (CDCl3) 1.33 (s, 6N), 1.83 (t, 2H, J= 5.4 Hz), 2.15 (t, 1H, J= 2.7 Hz), 3.52 (d, 2H, J= 2.7 Hz), 4.21 (t, 2H, . J= 5.4 Hz), 6.87 (t, 1H, J= 7.6 Hz), 7.18 (DD, 1H, J= 7.9/1.5 Hz), 7.33 (DD, 1H, J= 7.4/1.5 Hz).

(d) methyl 2-hydroxy-4-[3-(4,4-DIMETHYLPROPANE-8-yl)-prop-1-inyl] benzoate

1.18 g (5.9 mmol) of 3-(4,4-DIMETHYLPROPANE-8-yl)-1-propene, 1,60 g (5.9 mmol) of methyl 2-hydroxy-4-iodobenzoate and 60 ml of triethylamine is introduced into the three-neck flask in an argon atmosphere. The reaction mixture Tegaserod by blowing with nitrogen, is injected 332 mg (0,46 mmol) bis(triphenylphosphine)palladium chloride (II) and Tivat dry, the residue is collected with ethyl acetate and hydrochloric acid (1N) and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. The residue is cleaned using chromatography on a column of silica gel by elution with heptane. After evaporation of the solvents receive oil, which slowly crystallizes and is recrystallized from heptane. Collect and 1.00 g (50%) of methyl 2-hydroxy-4-[3-(4,4-DIMETHYLPROPANE-8-yl)-prop-1-inyl] benzoate in the form of a white solid with a melting point 92-93oC.

1H NMR (CDCl3) 1.34 (s, 6N), 1.84 (t, 2H, J= 5.4 Hz), 3.75 (s, 2H), 3.94 (s, 3H), 4.23 (t, 2H, J= 5.4 Hz), 6.89 (t, 1H, J= 7.6 Hz), 6.95 (DD, 1H, J= 8.2/1.5 Hz), 7.06 (d, 1H, J= 1.4 Hz), 7.20 (d, 1H, J= 6.3 Hz), 7.35 (d, 1H, J= 7.4 Hz), 7.75 (d, 1H, J= 8.2 Hz), 10.73 (s, 1H).

EXAMPLE 2

2-Hydroxy-4-[3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoic acid

860 mg (2.5 mmole) of the methyl ester obtained in Example 1(d), and 1.00 g (25.0 mmol) of lithium hydroxide and 50 ml of THF is introduced into a round bottom flask. The reaction mixture is heated to boiling under reflux for 18 hours and evaporated to dryness. The residue is collected with water, acidified to pH 1 and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. The remainder Rai acid in the form of a white solid with a melting point 182-183oC.

1H NMR (d6-DMSO) 1.29 (s, 6N), 1.79 (t, 2H, J= 5.2 Hz), 3.72 (s, 2H), 4.20 (t, 2H, J= 5.3 Hz), 6.67 10 (t, 1H, J= 7.6 Hz), 6.76 - 6.79 (m, 2H), 7.05 (d, 2H, J= 7.6 Hz), 7.55 (d, 1H, J= 8.6 Hz).

EXAMPLE 3

Methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-Neil] benzoate.

(a) 4,4-DIMETHYLPROPANE-8-carbaldehyde

14,40 g (50.0 mmol) of 4,4-dimethyl-8-iochroma and 50 ml of THF is introduced into the three-neck flask in a stream of nitrogen. 22 ml (55,0 mmol) n-utility (2.5 M in hexane) was injected dropwise at -78oC, the reaction mixture is stirred for 30 minutes, then add to 4.2 ml (55,0 mmol) of DMF and the mixture was allowed to reach room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. Collect the 10.40 g (100%) of the expected compound in the form of a yellow oil.

1H NMR (Dl3) 1.36 (s, 6N), 1.86 (t, 2H, J= 5.2 Hz), 4.29 (t, 2H, J= 5.6 Hz), 6.91 (t, 1 H, J= 8.4 Hz), 7.50 (DD, 1 H, J= 7.7/1.7 Hz), 7.64 (DD, 1 H, J= 7.9/1,7 Hz), 10.42 (s, 1H).

(b) -ethinyl-4,4-DIMETHYLPROPANE-8-methanol

with 7.6 ml (54.0 mmol) of trimethylsilylacetamide and 50 ml of THF is introduced into the three-neck flask. A solution of 22 ml (54.0 mmol) of n-utility (2.5 M in hexane) is added at cataplasm in a cold (-78oC) a solution comprising of 9.30 g (49,0 mmol) 4,4-DIMETHYLPROPANE-8-carbaldehyde and 50 ml of THF. The reaction mixture was allowed to reach room temperature, poured into saturated aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. Get 14,00 g (100%) of the expected compound in the form of a yellow oil. 3.00 g (10.0 mmol) of this oil mixed with 50 ml of THF and added dropwise 11.5 ml (12.6 mmol) of a solution of tetrabutylammonium fluoride (1.1 M in THF). The reaction mixture was stirred at room temperature for one hour, poured into water and extracted with ethyl ether, and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. Collect 2.30 g (100%) of the expected compound in the form of a colourless oil.

1H NMR (CDCl3) of 1.33 (s, 6N), 1.81-1.88 (m, 2H), 2.59 (d, 1H, J= 2.2 Hz), 4.11 (d, 1H, J= 6.1 Hz), 4.25 (t, 2H, J= 4.7 Hz), 5.68 (DD, 1H, J= 6.1/25 2.0 Hz), 6.90 (t, 1H, J= 7.7 Hz), 7.25 (d, 1H, J= 7.8 Hz), 7.41 (d, 1H, J= 7.7 Hz).

(C) methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoate.

3.00 g (13.9 mmol) ethinyl-4,4-DIMETHYLPROPANE-8-methanol, 3,90 g (13.9 mmol) of methyl 2-hydroxy-4-iodobenzoate and 100 ml of triethylamine is introduced into Trekhgorny the 780 mg (1.1 mmole) of bis(triphenylphosphine)palladium chloride (II) and 320 mg (1.7 mmol) of copper iodide. The reaction mixture was stirred at room temperature for 4 hours and evaporated to dryness, and the residue is collected with water and ethyl ether. The organic phase is separated by settling, dried over magnesium sulfate and evaporated. The resulting residue is cleaned using chromatography on a column of silica gel by elution with a mixture consisting of 50% ethyl acetate and 50% heptane. Collect 2.85 g (56%) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)-prop-1-inyl] benzoate in the form of a white solid with a melting point of 122-123oC.

1H NMR (CDCl3) 1.36 (s, 6N), 1.87-1.90 (m, 2H), 3.18 (d, 1H, J= 6.4 Hz), 3.95 (s, 3H), 4.31 (t, 2H, J= 5.3 Hz), 5.86 (d, 1H, J= 6.4 Hz), 6.89-7.00 (m, 2H), 7.09 (s, 1H), 7.29 (d, 1H, J= 7-9 Hz), 7.40 (d, 1H, J= 7.4 Hz), 7.77 (d, 1H, J= 8.2 Hz).

EXAMPLE 4

2-Hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoic acid.

2,80 g (7,60 mmol) of the compound obtained in Example 3 (C), 3,20 g (76.5 mmol) of lithium hydroxide and 100 ml of THF is introduced into a round bottom flask. The reaction mixture is heated to boiling under reflux for 18 hours and evaporated to dryness. The residue is collected with water, acidified to pH 1 and extracted with ethyl ether, and the organic phase is separated by settling, dried over sulfate MAGN is methylpropan-8-yl)prop-1-inyl] benzoic acid as a white solid with a melting point of 225-227oC.

1H NMR (CDCl3+ 2 drops of d6-DMSO) 1.34 (s, 6N), 1.87 (t, 2H, J= 6.0 Hz), 3,50 (s, 1H), 4.28 (t, 2H, J= 5.7 Hz), 5.90 (s, 1H), 6.88-6.96 (m, 2H), 7.02 (s, 1H 35), 7.27 (d, 1H, J= 7.8 Hz), 7.46 (d, 1H, J= 7.4 Hz), 7.79 (d, 1H, J 8.1 Hz), 11.23 (br s, 1H).

EXAMPLE 5

Methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoate

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

19,30 g (102,0 mmol) of 2-bromothiophene, 160 ml of DMF and 15.50 g (112,0 mmol) of potassium carbonate is introduced into the three-neck flask. 13 ml (112,0 mmol) 1-bromo-3-methyl-2-butene is added and the reaction mixture was stirred at room temperature for two hours. The mixture was poured into water and extracted with ethyl acetate and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. Collect 26,00 g (99%) of the expected compound in the form of an orange oil.

1H NMR (CDCl3) 1.65 (s, 3H), 1.73 (s, 3H), 3.56 (d, 2H, J= 7.7 Hz), 5.32 (dt, 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-brachiation

26,00 g (102,0 mmol) of 2-bromo-1-(3-methylbut-2-initio)benzene, 180 ml of toluene and 23,20 g (122,0 mmol) of para-toluensulfonate acid is introduced into the three-neck flask. The reaction mixture is heated to boiling under reflux for four hours and evaporated on the ABC separated by settling, dried over magnesium sulfate and evaporated. The resulting residue is cleaned using chromatography on a column of silica gel, eluruumi heptane. Collect of 20.00 g (76%) of the expected compound in the form of an orange oil.

1H NMR (CDCl3) 1.33 (s, 6N), 1.94 (t, 2H, J= 6.0 Hz), 3.04 from (t, 2H, J= 6.1 Hz), 6.89 (t, 1H, J= 7.9 Hz), 7.34 (d, 2H, J= 7.9 Hz).

(c) 3-(4,4-dimethylthiochroman-8-yl)prop-1-in

In the same manner as in Example 1(C), from 3.00 g (11.7 mmol) of 4,4-dimethyl-8-pratikramana obtain 710 mg (28%) of the expected compound in the form of a light yellow oil.

1H NMR (CDCl3) 1.34 (s, 6N), 1.95 (t, 2H, J= 6.1 Hz), 2.23 (t, 1H, J= 2.7 Hz), 3.04 (t, 2H, J= 6.2 Hz), 3.53 (d, 2H, J= 2.6 Hz), 7.05 (t, 1H, J= 7.7 Hz), 7.32 (d, 1H, J= 7.8 Hz), 7.38 (d, 1H, J= 7.7 Hz).

(d) methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoate

670 mg (3.1 mmol) of 3-(4,4-dimethylthiochroman-8-yl)prop-1-ins, 860 mg (3.1 mmol) of methyl 2-hydroxy-4-iodobenzoate and 33 ml of triethylamine is introduced into the three-neck flask under argon. The reaction mixture Tegaserod by blowing with nitrogen, is injected 174 mg (0.25 mmole) of bis(triphenylphosphine)palladium chloride (II) and 71 mg of copper iodide and the reaction mixture was stirred at room temperature for eight hours. The reaction mixture is evaporated to dryness, the residue is collected with ethyl acetate and hydrochloric who Yat using chromatography on a column of silica gel by elution with the mixture, consisting of 99% heptane and 1% ethyl acetate. After evaporation of the solvents will be collected 1.50 g (75%) of methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoate as a yellow oil.

1H NMR (CDCl3) 1.35 (s, 6N), 1.97 (t, 2H, J= 6.0 Hz), 3.06 (t, 2H, J= 6.1 Hz), 3.76 (s, 2H), 3.94 (s, 3H), 6.96 (DD, 1H, J= 8.2/1.5 Hz), 7.04-7.10 (m, 2H), 7.33 (d, 1H, J= 6.9 Hz), 7.41 (d, 1H, J= 7.4 Hz), 7.75 (d, 1H, J= 8.2 Hz).

EXAMPLE 6

2-Hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoic acid

In the same manner as in Example 2, from 1.40 g (3.8 mmol) of the compound obtained in Example 5(d) obtain 960 mg (70%) of 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoic acid as a white solid with a melting point 190-191oC.

1H NMR (d6-DMSO) 1.29 (s, 6N), 1.69 (t, 2H, J= 5.9 Hz), 3.04 (t, 2H, J= 6.0 Hz), 3.75 (s, 2H), 6.96-6.99 (m, 2H), 7.06 (t, 1H, J= 7.7 Hz), 7.32 (d, 1H, J= 7.3 Hz), 7.38 (d, 1H, J= 7.8 Hz), 7.76 (d, 1H, J= 8.4 Hz).

EXAMPLE 7

Ethyl 4-[3-hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoate

(a) 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahedronal-1-ol

13,40 g (100.0 mmol) of aluminum chloride and 100 ml of dichloromethane is introduced into the three-neck flask in an argon atmosphere. Added dropwise a solution consisting of 34,60 g (199,0 mmol) 3-bromophenol, tatzati hours at room temperature. The reaction mixture was poured into water and extracted with dichloromethane, the extract washed with water and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. The residue is cleaned using chromatography on a column of silica gel by elution with a mixture consisting of 80% heptane and 20% dichloromethane. After evaporation of the solvents will be collected 30,00 g (53%) of the expected compound in the form of white crystals with a melting point 93oC.

1H NMR (CDCl3) 1.25 (s, 6N), 1.38 (s, 6N), 1.57-1.69 (m, 4H), 4.78 (s, 1H), 6.64 (d, 1H, J= 2.0 Hz), 7.04 (d, 1H, J= 2.0 Hz).

(b) 5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-ol

12,93 g (to 106.0 mmol) of phenylboric acid, of 20.00 g (70,7 mmol) of the compound obtained in Example 7(a), 400 ml of dimethyl ether and 70 ml of an aqueous solution of potassium carbonate (2M) is introduced into the three-neck flask. The reaction mixture Tegaserod by blowing argon, add 4,08 g (3.5 mmol) tetranitroaniline palladium (0) and the reaction mixture is heated to 90oWith over eight hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. The resulting residue is cleaned using chromatography on a column of silica gel by elution with gepatroj melting 121oC.

1H NMR (CDCl3) 1.33 (s, 6N), 1.46 (s, 6N), 1.65-1.73 (m, 4H), 4.77 (s, 1H), 6,69 (d, 1H, J= 1.8 Hz), 7.16 (d, 1H, J= 1.8 Hz), 7.24-7.52 (m, 3H), 7.53 (d, 2H, J= 8.5 Hz).

(c) 5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl triftorbyenzola

13,44 g (47.9 mmol) of the compound obtained in Example 7(b), 100 ml of dichloromethane and 9.95 g (of 81.5 mmol) of N, N-dimethyl-4-aminopyridine is administered in a three-neck flask under argon. The mixture is cooled to 0oC and added dropwise to 12.1 ml (71,9 mmol) triplecore anhydride. Temperature allow to rise to room temperature for sixteen hours and the reaction mixture is evaporated to dryness. Add ethyl acetate and the mixture is acidified to pH 3 with hydrochloric acid (1 N). The product is extracted with ethyl acetate, the organic phase is washed with water and then using a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered, and the solvents evaporated. Get 19,29 g (97%) of the expected compound in the form of a white powder with a melting point of 110oC.

1H NMR (CDCl3) 1.35 (s, 6N), 1.45 (s, 6N), 1.71 (s, 4H), 7.35-7.55 (m, 7H).

(d) methyl-5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahydronaphthalen-1-carboxylate

16,12 g (39.1 mmol) of the triflate obtained in Example 7(C) of 1.61 g (3,9 is mine and 17.1 ml (390,8 mmol) of methanol injected into the hydrogenation unit. The reaction mixture is subjected to pressure of carbon dioxide 4 bars and heated under stirring at 70oWith over seven hours. The mixture is cooled and evaporated as far as possible, the remainder is collected saturated aqueous sodium chloride and extracted with ethyl acetate, and the organic phase is washed using diluted hydrochloric acid and then water, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel, eluruumi heptane. After evaporation of the solvents will be collected of 7.60 g (60%) of the expected compound in the form of a white powder with a melting point 118oC.

1H NMR (CDCl3) 1.35 (s, 6N), 1.40 (s, 6N), 1.65-1.69 (m, 2H), 1.76-1.80 (m, 2H), 3.91 (s, 3H), 7.30 (d, 1H, J= 2.0 Hz), 7.34-7.46 (m, 3H), 7.59 (d, 2H, 35 J= 7.0 Hz), 7.61 (d, 1H, J= 2.0 Hz).

(e) (5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)-methanol

80 ml of ethyl ether and $ 2.68 g (70,7 mmol) of lithium aluminum hydride is introduced into one litre three-neck flask. The reaction mixture was cooled to 0oC and then injected dropwise of 7.60 g (23.5 mmol) of the compound obtained in Example 7(d), in a solution of 80 ml of ethyl ether. The reaction mixture is stirred for sixteen hours at room tempout water and ethyl ether. The product is extracted with ethyl ether, the organic phase is washed with water until neutral pH, dried over magnesium sulfate and filtered, and the solvent is evaporated. 6,82 g (98%) of the expected compound are collected in the form of white crystals with a melting point of 80-82oC.

1H NMR (CDCl3) 1.36 (s, 6N), 1.45 (s, 6N), 1.61 (t, 1H, J= 5.8 Hz), 1.71 (s, 4H), 4.95 (d, 2H, J= 5.7 Hz), 7.30-7.36 (m, 1H), 7.43 (t, 2H, J= 7.7 Hz), 7.53 (d, 1H, J= 2.1 Hz), 7.58-7.61 (m, 3H).

(f) 5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahydronaphthalen-1-carbaldehyde

6,56 g (of 22.2 mmol) of the compound obtained in Example 7(e), 38,73 g (445,6 mmol) of manganese oxide and 500 ml of dichloromethane are mixed in one litre round bottom flask. The reaction mixture is stirred for twenty hours at room temperature and then filtered manganese oxide and washed with dichloromethane. After evaporation of the solvents will be collected 4.44 g (68%) of the expected compound in the form of a yellow powder with a melting point 113oC.

1H NMR (CDCl3) 1.37 (s, 6N), 1.57 (s, 6N), 1.75 (s, 4H), 7.33-7.48 (m, 3H), 7.58-7.62 (m, 2H), 7.77 (d, 1H, J= 2.2 Hz), 7.95 (d, 1H, J= 2.2 Hz).

(g) 1-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)-3-(trimethylsilyl)prop-2-in-1-ol

2,43 ml (17.2 mmol) of trimethylsilylacetamide and 25 ml THF Wade -78oC in nitrogen atmosphere and the reaction mixture was allowed to return to room temperature. This solution is introduced dropwise into a cold (-78oC) a solution consisting of 4,20 g (14.4 mmol) of the compound obtained in Example 7(f), and 25 ml THF. The reaction mixture was allowed to return to room temperature, poured into aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. Collect the ceiling of 5.60 g (100%) of the expected compound in the form of a white powder with a melting point 145oC.

1H NMR (CDCl3) 1.34 (s, 3H), 1.36 (s, 3H), 1.48 (s, 3H), 1.51 (s, 3H), 1.66-1.76 (s, 4H), 2.19 (br s, 1H), 6.13 (s, 1H), 7.30-7.36 (m, 1H), 7.41-7.47 (m, 2H), 7.55 (d, 1H, J= 2.0 Hz), 7.60 (d, 2H, J= 7.1 Hz), 7.90 (d, 1H, J= 2.1 Hz).

(h) 1-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-2-in-1-ol

the ceiling of 5.60 g (14.3 mmol) of the compound obtained in Example 7(g), mixed with 30 ml of THF in a three-neck flask with a volume of 500 ml and added dropwise to 15.8 ml (17.4 mmol) of a solution of tetrabutylammonium fluoride (1.1 M in THF). The reaction mixture was stirred at room temperature for one hour, poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over sulfate mA>) 1.34 (s, 3H), 1.35 (s, 3H), 1.48 (s, 3H), 1.52 (s, 3H), 1.66-1.75 (m, 4H), 2.30 (br s, 1H), 2.59 (d, 1H, J= 2.1 Hz), 6.16 (d, 1H, J= 2.0 Hz), 7.31-7.37 (m, 1H), 7.41-7.47 (m, 2H), 7.55 (d, 1H, J= 2.1 Hz), 7.60 (d, 2H, J= 7.1 Hz), 7.88 (d, 1H, J= 2.1 Hz).

(i) ethyl 4-[3-hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoate

In a manner analogous to Example 3 (C), the reaction 4,07 g (12.8 mmol) of the compound obtained in Example 7(h) of 3.53 g (12,8 by mmol) ethyl 4-iodobenzoate get of 4.57 g (77%) of ethyl 4-[3-hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl-prop-1-inyl] benzoate as an orange powder with a melting point 121oC.

1H NMR (CDCl3) 1.35 (s, 3H), 1.35 (t, 3H, J= 7.1 Hz), 1.37 (s, 3H), 1.53 (s, 3H), 1.56 (s, 3H), 1.67-1.80 (m, 4H), 2.45 (d, 1H, J= 4.9 Hz), 4.35 (d, 2H, J= 7.1 Hz), 6.40 (d, 1H, J= 4.9 Hz), 7.30-7.36 (m, 1H), 7.41-7.49 (m, 4H), 7.57 (d, 1H, J= 2.0 Hz), 7.61 (d, 2H, J= 7.1 Hz), 7.95 (d, 1H, J= 2.0 Hz), 7.96 (d, 2H, J= 6.0 Hz).

EXAMPLE 8

4-[3-Hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid

In a manner analogous to Example 2, of 3.60 g (7.7 mmol) of the compound obtained in Example 7(i) gain of 3.32 g (98%) 4-[3-hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1)yl)prop-1-inyl] benzoic acid as an orange-beige powder with a melting point 250oC.

<, .36 (d, 1H, J= 1.9 Hz), 7.45 (d, 2H, J= 7.3 Hz), 7.68 (d, 1H, J= 2.0 Hz), 7.70 (d, 2H, J= 8.4 Hz), 12.92 (br s, 1H),

EXAMPLE 9

4-[3-(5,5,8,8-Tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid

a 2.00 g (4.6 mmol) of the compound obtained in Example 8, a 1.45 ml (9.1 mmol) of triethylsilane, 30 ml of dichloromethane and 3.5 ml triperoxonane acid is introduced into one litre round bottom flask under nitrogen atmosphere. The reaction mixture is stirred for two hours at room temperature and hydrolyzing using 1N HCl and the product extracted with ethyl ether. The organic phase is washed with water and dried over magnesium sulfate and the solvent is evaporated to dryness. The resulting residue is cleaned using chromatography on a column of silica gel, elution with a mixture consisting of 50% ethyl acetate and 50% heptane. After evaporation of the solvents will be collected 370 mg(19%) 4-[3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid as a white powder with a melting point 228oC.

1H NMR (d6-DMSO) 1.22 (s, 6N), 1.35 (s, 6N), 4.00 (s, 2H), 7.24-7.27 (m, 2H), 7.33-7.41 (m, 4H), 7.46 (s, 1H), 7.53 (d, 2H, J= 7.3 Hz), 7.78 (d, 2H, J= 8.2 Hz).

EXAMPLE 10

Ethyl 4-[3-(4,4-dimethylthiochroman-5-yl)-3-hydroxyprop-1-inyl] benzoate

(a) 1-methoxy-3-(3-METI the sodium hydroxide is introduced into one litre round bottom flask under nitrogen atmosphere and the mixture is refluxed for three hours. Add dropwise a solution consisting of 53,65 g (360,0 mmol) of 2-methyl-4-bromo-2-butene and 60 ml of acetone. Reflux is maintained for sixteen hours and the reaction mixture is evaporated to dryness. Water is added, extraction was performed with ethyl acetate, the organic phase is washed with water and then saturated sodium chloride solution, dried over magnesium sulfate and filtered, and the solvent is evaporated. The resulting residue is distilled under reduced pressure (510-2bar/113o(C) obtaining 67,81 g (90%) of the expected compound in the form of a pale yellow oil.

1H NMR (CDCl3) 1.62 (s, 3H), 1.72 (s, 3H), 3.55 (d, 2H, J= 7.7 Hz), 3.79 (s, 3H), 5.31 (TT, 1H, J= 7.7/1.3 Hz), 6.71 (dt, 1H, J= 8.3/1.8 Hz), 6.87-6.92 (m, 2H), 7.18 (t, 1H, J= 7.9 Hz).

(b) 5-methoxy-4,4-dimethylthiochroman

62,00 g (298,0 mmol) of the compound obtained in Example 10(a), 85,00 g (446,0 mmol) of para-toluensulfonate acid and 500 ml of toluene is introduced into a round bottom flask. The mixture is heated at the boil under reflux for two hours, cooled, then add water and ethyl acetate and extraction is performed with ethyl acetate. The organic phase is separated by settling, washed with water and then saturated sodium chloride solution, dried over magnesium sulfate and the solvent is evaporated.the group 17,40 g (28%) of the expected compound in the form of a colourless oil.

1H NMR (CDCl3) 1.41 (s, 3H), 2.00-2.05 (m, 2H), 2.86-2.90 (m, 2H), 3.80 (s, 3H), 6.58 (d, 1H, J= 18.1 Hz), 6.72 (DD, 1H, J= 7.9/1.2 Hz), 6.98 (t, 1H, J= 8.0 Hz).

(c) 4,4-dimethylthiochroman-5-ol

17,40 g (83.5 mmol) of the compound obtained in Example 10(b), 28,10 g (333,0 mmol) ethanolate of sodium and 100 ml of DMF is introduced into a round bottom flask. The mixture is heated at a temperature of 150oC for two hours and then stirred for sixteen hours at room temperature, poured into a mixture of 1N HCl/ethyl ether and extracted with ethyl ether. The organic phase is separated by settling, dried over magnesium sulfate and evaporated. The resulting residue is cleaned using chromatography on a column of silica gel by elution with a mixture consisting of 20% ethyl acetate and 80% heptane. Collect 14,07 g (87%) of the expected compound in the form of a light yellow solid with a melting point 48oC.

1H NMR (CDCl3) 1.45 (s, 3H), 2.01-2.07 (m, 2H), 2.86-2.91 (m, 2H), 5.00 (s, 1H), 6.34 (DD, 1H, J= 7.8/1.3 Hz), 6.69 (DD, 1H, J= 7.9/1.2 Hz), 6.84 (d, 1H, J= 7.8 Hz).

(d) 4,4-dimethylthiochroman-5-yl triftorbyenzola

13,63 g (70,1 mmol) 4,4-dimethylthiochroman-5-ol obtained in Example 10(C), 11,14 g (91,2 mmol) of N, N-dimethylaminopyridine and 100 ml of dichloromethane is introduced into a round bottom flask volume anhydride. The reaction mixture is stirred for 30 minutes at room temperature and then add a solution of 1N Hcl and dichloromethane. The product is extracted with dichloromethane and the organic phase is washed with water until neutral pH, dried over magnesium sulfate and filtered. The resulting residue is cleaned using chromatography on a column of silica gel by elution with a mixture consisting of 90% heptane and 10% ethyl acetate. After evaporation of the solvents will be collected 16,32 g (71%) of the expected compound in the form of a yellow oil.

1H NMR (CDCl3) 1.46 (s, 3H), 2.01-2.06 (m, 2H), 2.93-2.98 (m, 2H), 7,00-7.12 (m, 3H).

(e) methyl 4,4-dimethylthiochroman-5-carboxylate

In a manner analogous to Example 7(d), 14,23 g (43.6 mmol) of the compound obtained in Example 10(d) receive 8,81 g (85%) of the expected compound in the form of a yellow oil.

1H NMR (CDCl3) 1.39 (s, 3H), 1.91 (t, 2H, J= 6.1 Hz), 3.05 (t, 2H, J= 6.1 Hz), 3.89 (s, 3H), 6.96 (DD, 1H, J= 7.4/1.8 Hz), 7.03 (t, 1H, J= 7.4 Hz), 7.16 (DD, 1H, J= 7.5/1.8 Hz).

(f) 4,4-dimethylthiochroman-5-methanol

8,81 g (3.3 mmol) of the ester obtained in Example 10(e), and 300 ml of toluene are mixed in a round bottom flask with a volume of 500 ml After cooling to -78oWith poured dropwise a solution of diisobutylaluminium hydride (1M in toluene), at the same time podderjivaet add water paste of magnesium sulfate, the mixture is stirred and extracted with ethyl ether. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated. The resulting residue is cleaned using chromatography on a column of silica gel by elution with a mixture consisting of 70% heptane and 30% of ethyl acetate. After evaporation of the solvents will be collected 4,37 g (56%) of the expected compound in the form of a light yellow powder with a melting point 53oC.

1H NMR (CDCl3) 1.45 (s, 6N), 2.04 (t, 2H, J= 6.4 Hz), 2.95 (t, 2H, J= 6.4 Hz), 4.87 (d, 2H, J= 5.8 Hz), 7.01-7.08 (m, 2H), 7.17-7.22 (m, 1H).

(g) 4,4-dimethylthiochroman-5-carbaldehyde

4,37 g (21,0 mmol) of the alcohol obtained in Example 10(f), 36,47 g (419,5 mmol) of manganese oxide and 300 ml of dichloromethane are mixed in a round bottom flask with a volume of 500 ml. Reaction mixture is stirred for twenty hours at room temperature, then filtered manganese oxide through Celite and the dichloromethane is evaporated. After evaporation of the solvents will be collected 3.25 g (75%) of the expected compound in the form of a yellow oil.

1H NMR (CDCl3) 1.54 (s, 6N), 2.03 (t, 2H, J= 5.9 Hz), 3.01 (t, 2H, J= 6.0 Hz), 7.15 (D. 1H, J= 7.6 Hz), 7.25-7.29 (m, 1H), 7.49 (DD, 1H), J= 7.4/1.4 Hz, of 10.73 (s, 1H).

(h) 1-(4,4-dimethylthiochroman-5-yl)-3-(trimethylsilyl)prop-2-in-1-ol

Spezobtelleoprof-5-yl)-3-(trimethylsilyl)prop-2-in-1-ol as a yellow oil.

1H NMR (CDCl3) 0.16 (s, N), 1.48 (s, 3H), 1.50 (s, 3H), 2.04-2.09 (m, 2H), 2.14 (d, 1H, J= 5.2 Hz), 2.87-2.93 (m, 2H), 6.04 (d, 1H, J= 5.1 Hz), 7.05-7.13 (m, 2H), 7.50-7.54 (d, 1H, J= 3.1 Hz).

(i) 1-(4,4-dimethylthiochroman-5-yl)prop-2-in-1-ol

In a manner analogous to Example 7(h), 4,79 g (15.7 mmol) of the compound obtained in Example 10(h) receive 3,34 g (89%) of 1-(4,4-dimethylthiochroman-5-yl)prop-2-in-1-ol in the form of beige crystals with a melting point 88oC.

1H NMR (CDCl3) 1.49 (s, 3H), 1.51 (s, 3H), 2.04-2.10 (m, 2H), 2.26 (d, 1H, J= 5.1 Hz), 2.59 (d, 1H, J= 2.2 Hz), 2.88-2.94 (m, 2H), 6.07 (br s, 1H), 7.07-7.14 (m, 2H), 7.52-7.55 (d, 1H, J= 3.0 Hz).

(j) ethyl 4-[3-(4,4-dimethylthiochroman-5-yl)-3-hydroxyprop-1-inyl] benzoate

In a manner analogous to Example 3(C), the reaction 3,34 g (14.4 mmol) of the compound obtained in Example 10(i) of 3.97 g (14,4-mmol) ethyl 4-iodobenzoate get of 4.66 g (85%) of ethyl 4-[3-(4,4-dimethylthiochroman-5-yl)-3-hydroxyprop-1-inyl] benzoate as an orange powder with a melting point 108oC.

1H NMR (CDCl3) 1.39 (t, 3H, J= 7.1 Hz), 1.54 (s, 3H), 1.56 (s, 3H), 2.08-2.13 (m, 2H), 2.28 (d, 1H, J= 5.3 Hz), 2.90-2.96 (m, 2H), 4.37 (d, 2H, J= 7.1 Hz), 6.31 (d, 1H, J = 5.3 Hz), 7.09-7.17 (m, 2H), 7.48 (d, 2H, J= 8.3 Hz), 7.60 (DD, 1H, J= 6.4/2.8 Hz), 7.98 (d, 2H, J= 8.4 Hz).

EXAMPLE 11

4-[3-(4,4-Dimethylthiochroman-5-yl)-3-hydroxyprop-1-inyl] benzoin is anxious to 3.41 g(78%) 4-[3-(4,4-dimethylthiochroman-5-yl)-3-hydroxyprop-1-inyl] benzoic acid as a brown solid with a melting point 198oC.

1H NMR (CDCl3) 1.54 (s, 3H), 1.56 (s, 3H), 2.08-2.12 (m, 2H), 2.90-2.94 (m, 2H), 6.29 (s, 1H), 7.10-7,16 (m, 2H), 7.48 (d, 2H, J= 8.2 Hz), 7.61 (DD, 1H, J= 6.7/2.3 Hz), 7.99 (d, 2H, J= 8.3 Hz).

EXAMPLE 12

4-[3-(4,4-Dimethylthiochroman-5-yl)prop-1-inyl] benzoic acid

In a manner analogous to Example 9, from of 2.06 g (5.82 mmol) of the compound obtained in Example 11, the gain of 1.00 g(51%) 4-[3-(4,4-dimethylthiochroman-5-yl)prop-1-inyl] benzoic acid in the form of beige crystals with a melting point of 207oC.

1H NMR (d6-DMSO) 1.51 (s, 6N), 2.05-2.10 (m, 2H), 2.92-2.97 (m, 2H), 4.01 (s, 2H), 7.01-7.03 (m, 2H), 7.25-7.31 (m, 1H), 7.45 (d, 2H, J= 8.3 Hz), 7.97 (d, 2H, J= 8.3 Hz).

EXAMPLE 13

Ethyl 4-[3-(3,5-di-tert-butyl-2-(methoxyethoxy)-phenyl)-3-hydroxyprop-1-inyl] benzoate

(a) 1-bromo-3,5-di-tert-butyl-2-(methoxyethoxy)-benzene

40,00 g (140,2 mmol) of 2,4-di-tert-butyl-6-bromophenol and 400 ml of DMF is introduced into one litre three-neck flask. The resulting solution is cooled to 5-10oTo add 4,70 g of sodium hydride and the mixture was stirred at 10oC for 30 minutes. Then added dropwise to 11.7 ml (154,0 mmol) chlormethine methyl ester and the reaction mixture is stirred for 1 hour at room temperature. The reaction mixture was poured into a mixture of 1 N HCl/ethyl afirewall. Collect 46,00 g (100%) of the expected compound in the form of an orange oil.

1H NMR (CDCl3) 1.28 (s, N), 1.43 (s, N), 3.69 (s, 3H), 5.21 (s, 2H), 7.30 (d, 1H, J= 2.4 Hz), 7.39 (d, 1H, J= 2.4 Hz).

(b) 3,5-di-tert-butyl-2-(methoxyethoxy)benzaldehyde

46,00 g (140,0 mmol) of the compound obtained in Example 13(a), and 500 ml of THF is introduced into the three-neck flask under nitrogen atmosphere. Added dropwise to 61.5 ml (154,00 mmol) of a solution of n-utility (2.5 M in hexane) at -78oC and the mixture is stirred for 30 minutes at the same temperature. Then added dropwise 13 ml (168,0 mmol) of DMF and the mixture was allowed to return to room temperature. The reaction mixture is acidified with hydrochloric acid (1N) and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. Collect 46,00 g (100%) of the expected compound in the form of an orange oil.

1H NMR (CDCl3) 1.32 (s, N), 1.44 (s, N), 3.64 (s, 3H), 5.02 (s, 2H), 7.64 (d, 1H, J= 2.6 Hz), 7.72 (d, 1H, J= 2.6 Hz), 10.22 (s, 1H).

(c) 1-(3,5-di-tert-butyl-2-(methoxyethoxy)phenyl)-3-(trimethylsilyl)prop-2-in-1-ol

18,60 g (190,0 mmol) trimethylsilylacetamide and 190 ml of THF is introduced into the three-neck flask under nitrogen atmosphere and the resulting solution cooled to -78oC. Dobavlyayut for 30 minutes at the same temperature and the mixture is brought to a temperature of -20oC. This solution was poured dropwise into a cold (-70oC) a solution consisting of 44,00 g (to 158.0 mmol) of the compound obtained in Example 13(b), in a solution of 550 ml of anhydrous THF. The temperature of the reaction mixture is brought to room temperature for two hours, the reaction mixture is then acidified with hydrochloric acid (1N) and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. Collect 59,00 g (100%) of the expected compound in the form of an orange oil.

1H NMR (CDCl3) 1.12 (s, N), 1.18 (s, N), 3.49 (s, 3H), 3.81 (d, 1H, J= 5.4 Hz), 4.68 (d, 1H, J= 6.3 Hz), 4.88 (d, 1H, J= 6.3 Hz), 5.55 (d, 1H. J= 5.3 Hz), 7.16 (d, 1H, J= 2.5 Hz), 7.56 (d, 1H, J= 2.5 Hz).

(d) 1-(3,5-di-tert-butyl-2-(methoxyethoxy)phenyl)prop-2-in-1-ol

58,00 g (154,0 mmol) of the compound obtained in Example 13(C), and 300 ml of THF is introduced into the three-neck flask under nitrogen atmosphere and poured dropwise a solution of tetrabutylammonium fluoride (1M in THF). The reaction mixture is stirred for two hours at room temperature, then acidified with hydrochloric acid (1N) and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. Collect 6 [lacuna] g (13%) of the expected compound in the form of orange mAH NMR expected connections (CDCl3) 1.32 (s, N), 1.39 (s, N), 2.61 (d, 1H, J= 2.2 Hz), 3.70 (s, 3H), 3.90 (d, 1H, J= 5.5 Hz), 4.90 (d, 1H, J= 6.3 Hz), 5.08 (d, 1H, J= 6.2 Hz), 5.79 (DD, 1H, J= 5.4/2.3 Hz), 7.37 (d, 1H, J= 2.5 Hz), 7.70 (d, 1H, J= 2.5 Hz).

1H NMR of 1-(3,5-di-tert-butyl-2-hydroxyphenyl)prop-2-in-1-ol (CDCl3) 1.30 (s, N), 1.43 (s, N), 2.72 (br s, 1H), 2.80 (d, 1H, J= 2.3 Hz), 4.94 - 5.05 (m, 1H), 5.66 (br s, 1H), 7.27 (d, 1H, J= 2.3 Hz), 7.32 (d, 1H, J= 2.4 Hz).

(e) ethyl 4-[3-(3,5-di-tert-butyl-2-(methoxyethoxy)-phenyl)-3-hydroxyprop-1-inyl] benzoate

6,00 g (19.7 mmol) of the compound obtained in Example 13 (d) of 5.40 g (19.7 mmol) of ethyl 4-iodobenzoate and 40 ml of triethylamine are sequentially introduced into a round bottom flask. The reaction mixture Tegaserod nitrogen for 20 minutes and then add 375 mg Cul and 700 mg of bis(triphenylphosphine)palladium (II) chloride. The reaction mixture was stirred at room temperature for five hours, poured into water, acidified with 1N hydrochloric acid and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulfate and evaporated. The resulting residue is cleaned using chromatography on a column of silica gel, elution with a mixture consisting of 10% ethyl acetate and 90% heptane. After evaporation of the solvents will be collected 6,00 g (69%) of ethyl 4-[3-(3,5-di-tert-butyl-2-(m is oC.

1h NMR (CDCl3) 1.34 (s, N), 1.39 (t, 3H, J= 7.1 Hz), 1.41 (s, N), 3.73 (s, 3H), 4.09 (d, 1H, J= 5.5 Hz), 4.37 (d, 2H, J= 7.1 Hz), 4.93 (d, 1H, J= 6.3 Hz), 5.12 (d, 1H, J= 6.3 Hz), 6.00 (d, 1H, J= 5.5 Hz), 7.40 (d, 1H, J= 2.5. Hz), 7.53 (d, 2H, J= 8.4 Hz), 7,79 (d, 1H, J= 2.5. Hz), 7.99 (d, 2H, J= 8.4 Hz).

EXAMPLE 14

4-[3-(3,5-Di-tert-butyl-2-(methoxyethoxy)phenyl)-3-hydroxyprop-1-inyl] benzoic acid

In a manner analogous to Example 2, from 1.50 g (3.3 mmol) of the compound obtained in Example 13(e) obtain 1.20 g(85%) 4-[3-(3,5-di-tert-butyl-2-(methoxyethoxy)phenyl)-3-hydroxyprop-1-inyl] benzoic acid in the form of a beige powder with a melting point 197oC.

1H NMR (CDCl3) 1.33 (s, N), 1.41 (s, N), 3.73 (s, 3H), 4.35 (br s, 1H), 4.97 (d, 1H, J= 6.1 Hz), 5.12 (d, 1H, J= 6.1 Hz), 6.00 (s, 1H), 7.38 (d, 1H, J= 2.5 Hz), 7.51 (d, 2H, J= 8.4 Hz), 7.78 (d, 1H, J= 2.5 Hz), 8.00 (d, 2H, J= 8.4 Hz).

EXAMPLE 15

Ethyl 4-[3-(3,5-di-tert-butyl-2-hydroxyphenyl)-3-hydroxyprop-1-inyl] benzoate

In a manner analogous to Example 13(e), by reaction of 10.00 g (of 38.4 mmol) of 1-(3,5-di-tert-butyl-2-hydroxyphenyl)prop-2-in-1-ol obtained in Example 13(d), from 10.60 g (38,4 by mmol) ethyl 4-iodobenzoate receive 5,00 g (32%) of ethyl 4-[3-(3,5-di-tert-butyl-2-hydroxyphenyl)-3-hydroxyprop-1-inyl] benzoate in the form of not-quite-white solid with a melting point 142-144< 5.90 (d, 1H, J= 6.2 Hz), 7.34 (s, 2H), 7.37 (s, 1H), 7.53 (d, 2H, J= 8.4 Hz), 8.02 (d, 2H, J= 8.4 Hz).

EXAMPLE 16

Ethyl 4-[3-(3,5-di-tert-butyl-2-hydroxyphenyl)prop-1-inyl] benzoate

In a manner analogous to Example 9, from 3.00 g (7.3 mmol) of the compound obtained in Example 15, the gain of 1.30 g (45%) of ethyl 4-[3-(3,5-di-tert-butyl-2-hydroxyphenyl)prop-1-inyl] benzoate in the form of a white powder with a melting point 113-115oC.

1H NMR (CDCl3) 1.31 (s, N), 1.39 (t, 3H, J= 7.1 Hz), 1.44 (s, N), 3.80 (s, 2H), 4.37 (d, 2H, J= 7.1 Hz), 6.77 (br C. 1H), 7.13 (d, 1H, J= 2.3 Hz), 7.27 (d, 1H, J= 2.3 Hz), 7.48 (d, 2H, J= 8.3 Hz), 7.98 (d, 2H, J = 8.4 Hz).

EXAMPLE 17

Ethyl 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-inyl] benzoate

(a) 1-bromo-3,5-di-tert-butyl-2-methoxybenzoyl

In a manner analogous to Example 13(a), 25,00 g (of 87.6 mmol) of 2,4-di-tert-butyl-6-bromophenol and 13.70 g (96,4 mmol) under the conditions get 27,00 g (100%) 1-bromo-3,5-di-tert-butyl-2-methoxybenzene in the form of an orange oil.

1H NMR (CDCl3) 1.29 (s, N), 1.39 (s, N), 3.91 (s, 3H), 7.27 (d, 1H, J= 2.4 Hz), 7.40 (d, 1H, J= 2.4 Hz).

(b) 3,5-di-tert-butyl-2-methoxybenzaldehyde

In a manner analogous to Example 13(b), 25,00 g (83.5 mmol) of the compound obtained in Example 17(a) receive 21,00 g (100%) of the expected compound in the form of an orange oil.

(c) 1-(3,5-di-tert-butyl-2-methoxyphenyl)-3-(trimethylsilyl)prop-2-in-1-ol

In a manner analogous to Example 13(C), from 21,00 g (85,0 mmol) of the compound obtained in Example 17(b), receive 30,00 g (100%) of the expected compound in the form of a beige powder with a melting point 104-106oC.

1H NMR (CDCl3) 1.13 (s, N), 1.20 (s, N), 2.39 (d, 1H, J= 4.7 Hz), 3.69 (s, 3H), 5.59 (d, 1H, J= 4.0 Hz), 7.15 (d, 1H, J= 2.5 Hz), 7.43 (d, 1H, J= 2.5 Hz).

(d) 1-(3,5-di-tert-butyl-2-methoxyphenyl)prop-2-in-1-ol

In a manner analogous to Example 13(d), from 23,00 g (66.0 mmol) of the compound obtained in Example 17(C), receive a 25.00 g (100%) of the expected compound in the form of an orange oil.

1H NMR (CDCl3) 1.32 (s, N), 1.40 (s, N), 2.63 (d, 1H, J= 2.2 Hz), 3.88 (s, 3H), 5.81 (d, 1H, J= 2.2 Hz), 7.35 (d, 1H, J= 2.5 Hz), 7.58 (d, 1H, J= 2.5 Hz).

(e) ethyl 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-inyl] benzoate

In a manner analogous to Example 13(e), by reaction 23,30 g (85,0 mmol) of the compound obtained in Example 17(d), 23,50 g (85,0 by mmol) ethyl 4-iodobenzoate get 20,00 g (55%) of ethyl 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-inyl] benzoate in the form of a gray powder with a melting point 101-103oC.

1H NMR (CDCl3) 1.34 (s, N), 1.39 (t, 3H, J= 5.2 Hz), 1.42 (s, N), 2.74 (d, 1H, J= 5.4 Hz), 3.93">

EXAMPLE 18

4-[3-(3,5-Di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-inyl] benzoic acid

In a manner analogous to Example 2, from 5,00 g (11.8 mmol) of the compound obtained in Example 17(e) receive 4,50 g(96%) 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-inyl] benzoic acid as a pale yellow solid with a melting point 208-209oC.

1H NMR (CDCl3) 1.29 (s, N), 1.37 (s, N), 3.83 (s, 3H), 5.80 (d, 1H, J= 5.0 Hz), 6.19 (d, 1H, J= 5.6 Hz), 7.27 (d, 1H, J= 2.5 Hz), 7.53 (d, 2H, J= 8.3 Hz), 7.62 (d, 1H, J= 2.4 Hz), 7.93 (d, 2H, J= 8.3 Hz), 13.14 (br s, 1H).

EXAMPLE 19

4-[3-(3,5-Di-tert-butyl-2-methoxyphenyl)prop-1-inyl] benzoic acid

In a manner analogous to Example 9, from 1.50 g (3.8 mmol) of the compound obtained in Example 18, to obtain 1.40 g(97%) 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)prop-1-inyl] benzoic acid as a white powder with a melting point 237-239oC.

1H NMR (CDCl3) 1.33 (s, N), 1.41 (s, N), 3.83 (s, 3H), 3.87 (s, 2H), 7.27 (d, 1H, J= 2.2 Hz), 7.46 (d, 1H, J= 2.2. Hz), 7.47 (D, 2H, J= 8.2 Hz), to 7.99 (d, 2H, J= 8.2 Hz).

EXAMPLE 20

Ethyl 4-[3-(5-tert-butyl-4-(methoxyethoxy)biphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate

(a) 2-tert-butyl-4-bromophenol

80,00 g (426,0 mmol) of 4-bromophenol and 8.00 g of Dowex 50WX8 resin sulfonic acid, smna for 30 hours. The reaction mixture is cooled and the residue purified by passing through a column of silica gel, which elute with a mixture consisting of 95% dichloromethane and 5% heptane. Collect 88 g (90%) of the expected compound in the form of a yellow oil.

1H NMR (CDCl3) 1.38 (s, N), 4.79 (s, 1H), 6.55 (d, 1H, J= 8.4 Hz), 7.16 (DD, 1H, J= 8.4/2.4 Hz), 7.35 (d, 1H, J= 2.4 Hz).

(b) 3-(tert-butyl)biphenyl-4-ol

In a manner analogous to Example 7(b), the reaction 40,00 g (175,0 mmol) of the compound obtained in Example 20(a), with 34,60 g (283,0 by mmol) of phenylboric acid get 27,00 g (68%) of the expected compound in the form of a brown oil.

1H NMR (CDCl3) 1.46 (S, N), 4.99 (s, 1H), 6.74 (d, 1H, J= 8.1 Hz), 7.28 (d, 1H, J= 2.3 Hz), 7.31 (d, 1H, J= 2.4 Hz), 7.41 (t, 2H, J= 7.2 Hz), 7.50 (d, 1H, J= 2.2 Hz), 7.53 (s, 1H), 7.56 (d, 1H, J= 1.4 Hz).

(c) 5-bromo-3-(tert-butyl)biphenyl-4-ol

27,00 g (120,0 mmol) of the compound obtained in Example 20(b), and 120 ml of dichloromethane is introduced into a round bottom flask. The mixture is cooled to 0oC, is added dropwise to 6.4 ml (131.0 mmol) of bromine and the mixture is stirred for ten minutes at 0oC. Add a saturated solution of sodium thiosulfate, the extraction is carried out with dichloromethane and the organic phase is separated by settling, washed with water until neutral pH, dried over sulfating>3) 1.45 (s, N), 5.83 (s, 1H), 7.28-7.34 (m, 1H), 7.40 (d, 2H, J= 7.6 Hz), 7.44 (d, 1H, J= 1.9 Hz), 7.49-7.53 (d, 2H, J= 8.6 Hz), 7.57 (d, 1H, J= 2.2 Hz).

(d) 5-bromo-3-tert-butyl-4-(methoxyethoxy)biphenyl -

In a manner analogous to Example 13(a), the reaction 7.30 g (24.0 mmol) of the compound obtained in Example 20(C), 2 ml (26,4-mmol) chlormethine methyl ester receive 8.00 g (100%) of the expected compound in the form of an orange oil.

1H NMR (CDCl3) 1.48 (s, N), 3.71 (s, 3H), 5.16 (s, 2H), 7.34-7.46 (m, 3H), 7.51-7.54 (m, 3H), 7.64 (d, 1H, J= 2.0 Hz).

(e) 5-tert-butyl-4-(methoxyethoxy)biphenyl-3-carbaldehyde

In a manner analogous to Example 3(a), 7,80 g (23.0 mmol) of the compound obtained in Example 20(d) receive or 4.31 g (63%) of the expected compound in the form of a yellow solid with a melting point 92-94oC.

1H NMR (CDCl3) 1.49 (s, N), 3.66 (s, 3H), 5.09 (s, 2H), 7.38 (d, 1H, J= 8.5 Hz), 7.44 (t, 2H, J= 7.0 Hz), 7.58 (d, 2H, J= 8.5 Hz), 7.82 (d, 1H, J= 2.5 Hz), 7.94 (d, 1H, J= 2.4 Hz), 10.27 (s, 1H).

(f) 1-(5-tert-butyl-4-(methoxyethoxy)biphenyl-3-yl)-3-(trimethylsilyl)prop-2-in-1-ol

In a manner analogous to Example 7(g), 4,30 g (14.4 mmol) of the compound obtained in Example 20(e), gain of 4.00 g (70%) of the expected compound in the form of a yellow solid with a melting point 90-91oS.

(g) 1-(5-tert-butyl-4-(methoxyethoxy)biphenyl-3-yl)prop-2-in-1-

In a manner analogous to Example 7(h), out of 4.00 g (10.1 mmol) of the compound obtained in Example 20(f), gain of 3.27 g (100%) of the expected compound in the form of an orange oil.

1H NMR (CDCl3) 1.37 (s, N), 2.55 (d, 1H, J= 2.3 Hz), 3.66 (s, 3H), 4.89 (d, 1H, J= 6.3 Hz), 5.07 (d, 1H, J= 6.2 Hz), 5.79 (d, 1H, J= 2.1 Hz), 7.24-7.46 (m, 3H), 7.50-7.54 (m, 3H), 7.85 (d, 1H, J= 2.3 Hz).

(h) ethyl 4-[3-(5-tert-butyl-4-(methoxyethoxy)biphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate

In a manner analogous to Example 3(C), the reaction 3,20 g (9.9 mmol) of the compound obtained in Example 20(g), 3.00 g (10,8 by mmol) ethyl 4-iodobenzoate obtain 3.00 g (65%) of ethyl 4-[3-(5-tert-butyl-4-(methoxyethoxy)biphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate as a brown oil.

1H NMR (CDCl3) 1.39 (t, 3H, J= 7.1 Hz), 1.46 (s, N), 3.76 (s, 3H), 3.99 (d, 1H, J= 5.5 Hz), 4.37 (d, 2H, J= 7.2 Hz), 4.99 (d, 1H, J= 6.3 Hz), 5.17 (d, 1H, J= 6.3 Hz), 7.35 (d, 1H, J= 7.1 Hz), 7.44 (t, 1H, J= 7.5 Hz), 7.53 (d, 2H, J= 8.3 Hz). 7.57-7.61 (m, 4H), 7.96 (s, 1H), 7.98 (d, 2H, J= 8.1 Hz).

EXAMPLE 21

4-[3-(5-tert-Butyl-4-(methoxyethoxy)biphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoic acid

In a manner analogous to Example 2, from 1.50 g (3.2 mmol) connect the-inyl] benzoic acid in the form of a beige powder with a melting point 162-164oC.

1H NMR (d6-DMSO) 1.44 (s, N), 3.63 (s, 3H), 5.11 (d, 1H, J= 5.2 Hz), 5.18 (d, 1H, J= 5.2 Hz), 5.94 (d, 1H, J= 6.2 Hz), 6.30 (d, 1H, J= 6.3 Hz), 7.37 (d, 1H, J= 7.3 Hz), 7.46 (d, 2H, J= 7.6 Hz), 7.52-7.55 (m, 3H), 7.62 (d, 2H. J= 7.5 Hz), 7.85 (d, 1H, J= 2.0 Hz), 7.91 (d, 2H, J= 8.1 Hz), 13,14 (s, 1H).

EXAMPLE 22

Ethyl 4-[3-(5-tert-butyl-4-(methoxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate

(a) 5-bromo-3-tert-butyl-4-methoxybiphenyl

In a manner analogous to Example 13(a), by reaction of 4.00 g (13.0 mmol) of the compound obtained in Example 20(C), 890 μl (14,3 by mmol) methyl iodide obtain 4.09 g (98%) of the expected compound in the form of a yellow oil.

1H NMR (CDCl3) 1.44 (s, N), 3.97 (s, 3H), 7.34-7.54 (m, 5H), 7.47 (d, 1H, J= 2.1 Hz), 7.65 (d, 1H, J= 2.0 Hz).

(b) 5-tert-butyl-4-methoxybiphenyl-3-carbaldehyde

In a manner analogous to Example 3(a), 3.80 g (12.0 mmol) of the compound obtained in Example 22(a), get to 2.29 g (71%) of the expected compound in the form of a yellow solid with a melting point 45oC.

1H NMR (CDCl3) 1.47 (s, N), 3.99 (s, 3H), 7.32-7.59 (m, 5H), 7.79 (d, 1H, J= 2.1 Hz), 7.93 (d, 1H, J= 2.2 Hz), 10.40 (s, 1H).

(c) 1-(5-tert-butyl-4-methoxybiphenyl-3-yl)-3-trimethylsilyl)prop-2-in-1-ol

In a manner analogous to Example 7(g), to 2.29 g (8.5 mmol) of the compound obtained in PARAGRAPH 94-96oC.

1H NMR (CDCl3) 0.21 (s, N), 1.46 (s, 3H), 2.56 (d, 1H, J= 5.3 Hz), 3.96 (s, 3H), 5.86 (d, 1H, J= 5.2 Hz), 7.37 (d, 1H, J= 7.1 Hz), 7.46 (t, 2H, J= 7.0 Hz), 7.56 (d, 1H, J= 2.4 Hz), 7.60 (d, 2H, J= 7.6 Hz), 7.83 (d, 1H, J= 2.3 Hz).

(d) 1-(5-tert-butyl-4-methoxybiphenyl-3-yl)prop-2-in-1-ol

In a manner analogous to Example 7(h), 2.00 g (5.5 mmol) of the compound obtained in Example 22(C), obtain 1.52 g (95%) of the expected compound in the form of a yellow oil.

1H NMR (CDCl3) 1.38 (s, N), 2.57 (d, 1H, J= 2.3 Hz), 3.87 (s, 3H), 5.79 (br s, 1H), 7.24-7.40 (m, 6N), 7.74 (d, 1H, J= 2.3 Hz).

(e) ethyl 4-[3-(5-tert-butyl-4-methoxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate

In a manner analogous to Example 3(C), by reaction of 1.50 g (5.1 mmol) of the compound obtained in Example 22(d), 1.55 g (5,6-mmol) ethyl 4-iodobenzoate receive 1.88 g (83%) of ethyl 4-[3-(5-tert-butyl-4-methoxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate in the form of a reddish oil.

1H NMR (CDCl3) 1.39 (t, 3H, J= 7.2 Hz), 1.46 (s, N), 2.67 (d, 1H, J= 5.3 Hz), 3.99 (s, 3H), 4.37 (d, 2H, J= 7.1 Hz), 6.10 (d, 1H, J= 5.2 Hz), 7.34-7.60 (m, 8H), 7.85 (d, 1H, J= 2.3 Hz), 7.98 (d, 2H, J= 8.4 Hz).

EXAMPLE 23

4-[3-(5-tert-Butyl-4-methoxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoic acid

In a manner analogous to Example 2, from 1.88 g (4.2 mmol) of the compound obtained in Example 22(SW powder with a melting point 165-167oC.

1H NMR (d6-DMSO) 1.42 (s, N), 3.90 (s, 3H), 5.88 (br s, 1H), 6.32 (br s, 1H), 7.37 (d, 1H, J= 7,2 Hz), 7.45-7.51 (m, 3H), 7.54 (d, 2H, J= 8.3 Hz), 7.62 (d, 2H, J= 7.2 Hz), 7.83 (d, 1H, J= 2.3 Hz), 7.91 (d, 2H, J= 8.3 Hz).

EXAMPLE 24

Ethyl 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-methoxypropan-1-inyl] benzoate

(a) 1-(3,5-di-tert-butyl-2-methoxyphenyl)-1-methoxypropan-2-in

In a manner analogous to Example 13(a), by reaction of 1.30 g (5.0 mmol) 1-(3,5-di-tert-butyl-2-hydroxyphenyl)prop-2-in-1-ol obtained in Example 13(d), with 340 μl (5.5 mmol) of methyl iodide receive 600 mg (41%) of the expected compound in the form of a yellow solid with a melting point 68-70oC.

1H NMR (CDCl3) 1.32 (S, N), 1.39 (s, N), 2.58 (d, 1H, J= 2.2 Hz), 3.47 (s, 3H), 3.82 (s, 3H), 5.34 (d, 1H, J= 2.2 Hz), 7.34 (d, 1H, J= 2.5 Hz), 7.54 (d, 1H, J= 2.5 Hz).

(b) ethyl 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-methoxypropan-1-inyl] benzoate

In a manner analogous to Example 3(C), by reaction of 220 mg (0.8 mmol) of the compound obtained in Example 24(a), 220 mg (0.8 mmol) of ethyl 4-iodobenzoate obtain 260 mg (74%) of ethyl 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-methoxypropan-1-inyl] benzoate as an orange oil.

1H NMR (CDCl3) 1.33 (s, N), 1.38 (t, 3H, J= 7.1 Hz), 1.41 (s, N), 3.53 (s, 3H), 3.88 (s, 3H), 4.37 (d, 2H. J= 7.1 Hz), 5.57 (s, 1H), 7.36 (d, 1H is fenil)-3-methoxypropan-1-inyl] benzoic acid

In a manner analogous to Example 2, from 260 mg (0.6 mmol) of the compound obtained in Example 24(b), 180 mg get(73%) 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-methoxypropan-1-inyl] benzoic acid in the form of a beige powder with a melting point 162-164oC.

1H NMR (CDCl3) 1.33 (s, N), 1.41 (s, N), 3.54 (s, 3H), 3.88 (s, 3H), to 5.58 (s, 1H), 7.36 (d, 1H, J= 2.5 Hz), 7.55 (d, 1H, J= 8.3 Hz), 7.62 (d, 1H, J= 2.5 Hz), 8.06 (D. 1H, J= 8.4 Hz).

EXAMPLE 26

Methyl 4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] -benzoate

In a manner analogous to Example 3(C), by reaction of 4.00 g (18.5 mmol) of the compound obtained in Example 5(C), 3.88 g (14,8 by mmol) of methyl 4-iodobenzoate obtain 1.66 g (25%) of methyl 4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] -benzoate as a yellow powder with a melting point 92oC.

1H NMR (CDCl3) 1.35 (s, 6N), 1.96 (t, 2H, J= 6.0 Hz), 3.05 (t, 2H, J= 6.2 Hz), 3.77 (s, 2H), 3.91 (s, 3H), 7.07 (t, 1H, J= 7.7 Hz), 7.33 (d, 1H, J= 7.0 Hz), 7.42 (d, 1H, J= 7.3 Hz), 7.51 (d, 2H, J= 8.4 Hz), 7.97 (d, 2H, J= 8.4 Hz).

EXAMPLE 27

Ethyl 6-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] nicotinate

In a manner analogous to Example 3(C), reaction of 1.00 g (4.6 mmol) of the compound obtained in Example 5(C) of 1.41 g (5.1 mmol) of ethyl 6-iodopyridine-3-carboxylate receive 50 mg (3%) of ethyl 6-[3-(4,4-dimethylthiochroman-8-yl)prop-1-0 Hz), 3.06 (t, 2H, J= 6.1 Hz), 3.82 (s, 2H), 4.41 (d, 2H, J= 7.1 Hz), 7.06 (t, 1H, J= 7.7 Hz), 7.34 (d, 1H, J= 7.9 Hz), 7.42 (d, 1H, J= 7.4 Hz), 7.51 (d, 1H, J= 8.2 Hz), 8.23 (DD, 1H, J= 8.1/2.1 Hz), 9.16 (d, 1H, J= 1.8 Hz).

EXAMPLE 28

4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-inyl] benzaldehyde

In a manner analogous to Example 3(C), by reaction of 2.00 g (9.3 mmol) of the compound obtained in Example 5(C), 1.88 g (10,2 by mmol) of 4-bromobenzaldehyde receive 90 mg(5%) 4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzaldehyde as a yellow powder with a melting point of 55 to 63oC.

1H NMR (CDCl3) 1.34 (s, 6N), 1.95 (t, 2H, J= 6.1 Hz), 3.05 (t, 2H, J= 6.2 Hz), 7.00 (t, 1H, J= 8.6 Hz), 7.17 (DD, 1H, J= 7.5/1.2 Hz), 7.29 (DD, 1H, J= 7.1/1.3 Hz), 7.58 (d, 2H, J= 8.2 Hz), 7.80 (d, 2H, J= 8.2 Hz), 9.94 (s, 1H).

EXAMPLE 29

4-[3-(4,4-Dimethylthiochroman-8-yl)prop-1-inyl] phenol

In a manner analogous to Example 3(C), reaction of 1.00 g (4.6 mmol) of the compound obtained in Example 5(C), 880 mg (5.1 mmol) of 4-bromophenol receive 286 mg(20%) 4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] phenol as a yellow powder with a melting point 95oC.

1H NMR (CDCl3) 1.33 (s, 6N), 1.94 (t, 2H, J= 6.0 Hz), 3.03 (t, 2H, J= 6.1 Hz), 3.72 (s, 2H), 6.75 (d, 2H, J= 8.7 Hz), 7.07 (t, 1H, J= 7.7 Hz), 7.27-7.34 (m, 3H), 7.46 (d, 1H, J= 7.4 Hz).

EXAMPLE 30

Ethyl 4-[3-(5-tert-butyl-4-hydroxybiphenyl-3-yl)-3b three-neck flask with a volume of 100 ml in a nitrogen atmosphere. Added dropwise 830 μl (15 mmol) of concentrated sulfuric acid. The reaction mixture is stirred for three hours at room temperature, then add water, extraction is carried out with ethyl ether, the organic phase is washed with water until neutral pH, dried over magnesium sulfate and filtered, and the solvent is evaporated. Collect of 1.25 g (100%) of ethyl 4-[3-(5-tert-butyl-4-(hydroxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate in the form of a reddish oil.

1H NMR (CDCl3) 1.40 (t, 3H, J= 7.2 Hz), 1.48 (s, N), 4.38 (d, 2H, J= 7.2 Hz), 5.69 (s, 1H), 7.31 (d, 1H, J= 7.1 Hz), 7.38-7.44 (m, 3H), 7.52-7.56 (m, 5H), of 7.97 (s, 1H), 8.00 (d, 2H, J= 8.4 Hz).

EXAMPLE 31

4-[3-(5-tert-Butyl-4-methoxybiphenyl-3-yl)prop-1-inyl] benzoic acid

In a manner analogous to Example 9, from 700 mg (1.7 mmol) of the compound obtained in Example 23, receive 508 mg(75%) 4-[3-(5-tert-butyl-4-methoxybiphenyl-3-yl)prop-1-inyl] benzoic acid as a white powder with a melting point 229-231oC.

1H NMR (CDCl3) 1.45 (s, N), 3.89 (s, 3H), 3.94 (s, 2H), 7.34 (d, 1H, J= 7.1 Hz), 7.40-7.49 (m, 5H), 7.56-7.60 (m, 2H), 7.66 (d, 1H, J= 2.2 Hz), 7.98 (d, 2H, J= 8.3 Hz).

Examples of pharmaceutical and cosmetic compositions

Various pharmaceutical and cosmetic compositions based INITIAL METHOD of APPLICATION

(a) 0.2 g Tablet

The compound prepared in Example 2 - 0.001 g

Starch - 0,114 g

Dicalcium phosphate - 0,020 g

Silicon dioxide - 0,020 g

Lactose - 0,030 g

Talc - 0,010 g

Magnesium stearate 0.005 g

The compound according to Example 2 can preferably be replaced by the same amount of one of the compounds according to Examples 4, 6, 11, 12, 21, 25 or 31.

(b) Oral suspension in 5 ml vials

The compound prepared in Example 4 - 0.001 g

Glycerin - 0,500 g

70% Sorbitol - 0,500 g

The sodium saccharinate - 0,010 g

Methyl p-hydroxybenzoate - 0,040 g

Odorant q. s.

Distilled water q. s. to 5 ml

The compound according to Example 4 can preferably be replaced by the same amount of one of the compounds according to Examples 8, 12, 18, and 19.

(c) 0.8 g Tablet

The compound of Example 6 - 0,500 g

Pre gelatinizing starch - 0,100 g

Microcrystalline cellulose - 0,115 g

Lactose - 0.075 g

Magnesium stearate - 0,010 g

(d) Oral suspension in 10 ml vials

The compound of Example 6 - 0,200 g

Glycerin - 1,000 grams

70% Sorbitol - 1,000 grams

The sodium saccharinate - 0,010 g

Methyl p-hydroxybenzoate - 0,080 g

Odorant q to change by the same amount of one of the compounds according to Examples 11, 12, 14, 23 or 25.

IN THE LOCAL METHOD OF APPLICATION

(a) Ointment

The compound of Example 4 at 0.020 g

Isopropyl myristate - 81,700 g

Liquid paynova oil - 9,100 g

Silicon dioxide("Ayrosil 200" sold by the company Degussa) - 9,180 g

(b) Ointment

Connection Example 1 - 0,300 g

White petrolatum pharmaceutical marks - 100 g

In this example, the compound of Example 1 can preferably be replaced by the same amount of one of the compounds according to Examples 28 and 29.

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

Connection Example 2 - 0,100 g

The mixture emulsive lanolin alcohols, waxes and oils ("Anhydrous eucerin" marketed by the company BDF) - 39,900 g

Methyl p-hydroxybenzoate - 0.075 g

Propyl p-hydroxybenzoate - 0.075 g

Sterile demineralized water q. s. on - 100g

(d) Lotion

The compound of Example 4 - 0,100 g

Polietilenglikol (PEG 400) - 69,900 g

95% ethanol - 30,000 g

In the above examples (C) and (d) compound according to Example 4 can preferably be replaced by the same amount of one of the compounds according to Examples 6, 9, 11, 14, 21, 23 and 31.

(e) Hydrophobic ointment

Connection Example 2 - 0,300 g

Isopropyl myristate - 36,400 g

Silicone oil ("Rhodorsil 47V300"e company Goldschmidt) - 100 g

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

The compound of Example 5 to 1,000 g

Cetyl alcohol - 4,000 grams

Glycerol monostearate - 2,500 grams

Stearate PEG-50 - 2,500 grams

Seed oil butyrospermum Parkii - 9,200 g

Propylene glycol - 2,000 g

Methyl p-hydroxybenzoate - 0.075 g

Propyl p-hydroxybenzoate - 0.075 g

Sterile demineralized water q. s. on - 100g

In this example, the compound according to Example 5 can preferably be replaced by the same amount of one of the compounds according to Examples 7, 10, 13, 15, 17, 20 or 22.

1. Baromedicine connection connected via propylenebis communication, characterized in that they correspond to the following General formula (I)

< / BR>
where Ar represents a radical according to formula (a) or (b)

< / BR>
< / BR>
R1is-OR6or-COR7;

R2polyester radical, comprising from 1 to 6 carbon atoms and from 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar communication;

R3represents lower alkyl,

or R2and R3taken together form a 6-membered ring, neobythites is R>R4represents H, linear or branched C1-C20alkyl or aryl;

R5represents H or-OR8;

R6is N;

R7represents H, -or SIG10or

< / BR>
where r' and r" are H, lower alkyl or taken together with the nitrogen atoms forming the ring of morpholino;

R8represents H or lower alkyl;

R10represents N or C1-C20alkyl which may be linear or branched;

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

< / BR>
R11represents H or-OR8;

R12represents H,

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

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

3. Connection under item 1 or 2, characterized in that the lower alkyl radical is selected from the group consisting of methyl, ethyl, ISO-propyl, Budilnik, tert-Budilnik and hexylene radicals.

5. Compounds according to any one of the preceding paragraphs, characterized in that the polyether radical is selected from the radicals methoxymethyl ether, methoxyethoxymethyl ether or methylthiomethyl ether.

6. Compounds according to any one of the preceding paragraphs, wherein the substituted phenyl is substituted by at least one halogen atom, one hydroxyl, one nitro functional group, a single lower alkyl, one CF3radical, one aminosalicylate not necessarily protected acetyl functional group or optionally substituted by one or two lower alkyl(Lamy), one alkoxy radical or one polyether radical.

7. Compounds according to any one of the preceding paragraphs, characterized in that they correspond to the following General formula

< / BR>
in which Ar represents a radical of the following formula (a) or (b)

< / BR>
< / BR>
where R1is-COR7;

R5and R7have the meanings as defined in paragraph 1;

X IS R12represent H;

R13and R14that are the same or different, represent N or CH3;

Y represents oxygen atom or sulfur, or a methylene, ethylene or isopropylidene divalent radical;

n = 1 or 2.

8. Compounds according to any one of the preceding paragraphs, characterized in that they are selected from the group consisting of:

methyl 2-hydroxy-4-[3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoate,

2-hydroxy-4-[3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoic acid,

methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoate,

2-hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoic acid,

methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoate,

2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoic acid,

ethyl 4-[3-hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoate,

4-[3-hydroxy-3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid,

4-[3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid,

ethyl 4-[3-(4,4-dimethylthiochroman-5-yl)-3-hydroxyprop-1-inyl] benzoate,

4-[3-(4,4-dimethylthiochroman-5-yl)-3-hydroc is-(3,5-di-tert-butyl-2-(methoxyethoxy)-phenyl)-3-hydroxyprop-1-inyl] benzoate,

4-[3-(3,5-di-tert-butyl-2-(methoxyethoxy)phenyl)-3-hydroxyprop-1-inyl] benzoic acid,

ethyl 4-[3-(3,5-di-tert-butyl-2-hydroxyphenyl)-3-hydroxyprop-1-inyl] benzoate,

ethyl 4-[3-(3,5-di-tert-butyl-2-hydroxyphenyl)prop-1-inyl] benzoate,

ethyl 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-inyl] benzoate,

4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-hydroxyprop-1-inyl] benzoic acid,

4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)prop-1-inyl] benzoic acid,

ethyl 4-[3-(5-tert-butyl-4-(methoxyethoxy)biphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate,

4-[3-(5-tert-butyl-4-(methoxyethoxy)biphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoic acid,

ethyl 4-[3-(5-tert-butyl-4-(methoxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoate,

4-[3-(5-tert-butyl-4-methoxybiphenyl-3-yl)-3-hydroxyprop-1-inyl] benzoic acid,

ethyl 4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-methoxypropan-1-inyl] benzoate,

4-[3-(3,5-di-tert-butyl-2-methoxyphenyl)-3-methoxypropan-1-inyl] benzoic acid,

methyl 4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] -benzoate,

ethyl 6-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] -nicotinate,

4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzaldehyde,

4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] phenol,

ethyl 4-[3-(5-tert-is l] benzoic acid,

4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] -benzoic acid,

4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-naphthyl)prop-1-inyl] benzoic acid,

2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-naphthyl)prop-1-inyl] benzoic acid,

methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoate,

2-hydroxy-4-[3-hydroxy-3-(4,4-DIMETHYLPROPANE-8-yl)prop-1-inyl] benzoic acid,

2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoic acid,

4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzamid,

N-ethyl-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzamid,

N-(4-hydroxyphenyl)-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzamid,

morpholin-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-inyl] benzoic acid

4-[3-(4,4-dimethylthiochroman-8-yl)prop-2-inyl] benzoic acid,

4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahedronal-1-yl)prop-2-inyl] benzoic acid,

4-[3-(4,4-dimethyl-6-panitikan-8-yl)prop-1-inyl] benzoic acid,

4-[3-(4,4-dimethyl-6-phenylpropan-8-yl)prop-1-inyl] benzoic acid,

4-[3-(4,4-dimethyl-6-panitikan-8-yl)prop-2-inyl] benzoic acid,

4-[3-(4,4-dimethyl-6-(p-tolyl)thiochroman-8-yl)prop-1-inyl] benzoic acid,

4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahedronal-1-Eli acid,

4-(3-[3-(4-methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid,

2-hydroxy-4-[3-(5,5,8,8-tetramethyl-3-(p-tolyl)-5,6,7,8-tetrahedronal-1-yl)prop-1-inyl] benzoic acid

3-hydroxy-4-[3-(5,5,8,8-tetramethyl-3-phenyl-5,6,7,8-tetrahydrogen-1-yl)prop-1-inyl] benzoic acid.

9. Compounds according to any one of the preceding paragraphs, which has antagonistic activity against receptors of retinoic acid.

10. Pharmaceutical composition having antagonistic activity against receptors retinoic acid, characterized in that it contains a pharmaceutically acceptable carrier, at least one of the compounds as defined according to any of paragraphs. 1-8.

11. The composition according to p. 10, characterized in that the concentration of at least one of the compounds according to any of paragraphs. 1-8 is 0.001 - 5 weight. % relative to the total weight of the composition.

12. Cosmetic composition having antagonistic activity against receptors retinoic acid, characterized in that it contains in a cosmetically acceptable medium, at least one of the compounds as defined according to any of paragraphs. 1-8.

 

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