Bicyclic aromatic compounds and compositions on their basis

 

(57) Abstract:

The invention relates to new bicyclic aromatic compounds of General formula (I) having the ability to bind RXR, and pharmaceutical compositions based on them, which can be used in medicine, veterinary medicine and in cosmetics. The compounds correspond to the General formula (I), where R1- CH3CH2OR2, R3; R2and R3have the meanings specified below; Ar1represents a group selected from (a-C); R4- R11have the meanings specified below; Ar2means the radical (d); X represents a radical selected from the group (i), (j), (1); R2represents a hydrogen atom, a lower alkyl or a radical CO-R16; R3represents-OR17; R4represents a hydrogen atom, -OR18; R5represents lower alkyl; R6represents tert-butyl; R7is a OR20, lower alkyl; R8represents tert-butyl, substituted; R9and R10taken together, form with the adjacent aromatic ring 6-membered ring, optionally substituted by methyl groups; R11represents a lower alkyl containing from 1 to 9 atoms coal is the mule of the invention. The pharmaceutical composition includes at least one of the compounds of General formula (I) mainly in the amount of from 0.001 to 5 wt.% from the whole composition. 2 c. and 11 C.p. f-crystals, 1 PL.

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>

The invention relates to new and useful industrial products, to Bermatingen connections. It also relates to the use of these new compounds in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.

Compounds according to the invention have a pronounced activity in the field of cell differentiation and proliferation and, more specifically, are used for local and systemic treatment of dermatological diseases associated with impaired scarring, dermatological (or other) diseases with an inflammatory and/or immunoallergic component of dermal or epidermal proliferate of both benign and malignant. These compounds can also be used in the treatment of degenerative diseases of the connective tissue, to fight against skin aging caused by both light and age ageing, and for treating disorders of scarring. The AOC is

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

The present invention relates to compounds that may be represented by the General formula (I) below:

< / BR>
in which R1represents a

(i)- (CH3,

ii) -CH2OR2,

iii) R3,

R2and R3have the meanings given below,

- Ar1represents a radical selected from radicals of formulae (a) to (C) below:

< / BR>
< / BR>
where R4, R5, R6, R7, R8, R9, R10and R11have the meanings given below,

- AG2is a radical (d)

< / BR>
X represents a radical selected from radicals of formulae (i), (j) and (l) below

< / BR>
where R2represents a hydrogen atom, a lower alkyl or a radical CO-R16,

R3represents-OR17,

R4represents a hydrogen atom, -OR18,

R5represents lower alkyl,

R6represents tert-butyl,

R7is a OR20, lower alkyl,

R8represents tert-butyl, substituted,

R
R11represents a lower alkyl containing from 1 to 9 carbon atoms, lower alkoxy, OR21polyester group,

R12represents a hydrogen atom, hydroxyl, alkoxy, OR22polyester group,

R14and R15that may be the same or different, represent a hydrogen atom or lower alkyl,

R16represents lower alkyl,

R17represents a hydrogen atom,

R18and R20may be the same or different and represent lower alkyl,

R20represents a

< / BR>
where R21and R22that may be the same or different, represent monohydroxyethyl, phenyl, optionally substituted C1-C9by alkyl, hydroxyl, C1-C3alkoxygroup or halogen, aralkyl, optionally substituted with halogen, lower alkyl, lower alkoxy, hydroxyl or a polyester group, or a group -(CH2)nR24,

- R24is monohydroxyethyl, COOR25, CON(R26R27, a heterocycle, such as morpholino, piperidino,

- R25represents a lower alkyl, a hydrogen atom,

- R266 carbon atoms and 1 to 3 oxygen atoms,

- n is an integer such that 2n9, provided that:

when AG1represents a radical of formula (C) and X is a radical of the formula (i) or (j), then

R11represents-OR21or a polyester group, or

AG2represents a radical of formula (d), where R12represents-OR22or a polyester group,

the compounds of formula (I) other than those

R11represents methoxyethoxy in ortho-position in relation to the Deputy AG2when Ar1represents a radical of formula (C), X represents a radical of the formula (i), R12represents hydrogen and R1represents R3where R3represents-OR17and R17represents hydrogen,

R12represents methoxyethoxy in ortho - or para-position in relation to the Deputy Ar1when Ar1represents a radical of formula (C), X represents a radical of the formula (i), R11represents methyl in the ortho-position relative to AG2represents R3where R3represents-OR17and R17represents hydrogen,

and optical and gaterade from 1 to 12, preferably, from 1 to 9 carbon atoms, the preferred radicals are methyl, ethyl, isopropyl, butyl, tert-butyl or hexyl.

The term "alkoxy radical" denotes a radical, preferably containing from 1 to 9 carbon atoms, the preferred radicals are methoxy, propyloxy, pentyloxy or heptyloxy.

The term "monohydroxyethyl corresponds to a radical containing 2 or 3 carbon atoms, in particular 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.

The term "polyether group" denotes a radical containing from 1 to 6 carbon atoms and from 1 to 3 atoms of oxygen or sulfur, such as methoxymethyl, methoxyethoxymethyl or methylthiomethyl ether.

Of the compounds of the above formula (I) in the context of the present invention include:

3-(3',5'-di-tert-butyl-2'-methoxy-3-biphenylyl)acrylic acid,

3-(2'-benzyloxy-3', 5'-di-tert-butyl-6-hydroxy-3-biphenylyl)acrylic acid,

3-(3', 5'-di-tert-butyl-6-hydroxy-2'-pentyloxy-3-biphenylyl)acrylic acid,

3-(3',5'-di-tert-butyl-6-hydroxy-2'-methoxy-3-biphenylyl)acrylic acid,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxy the second acid,

[4 methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]propionic acid,

3-[3-(3-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylic acid,

3-[3-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylic acid,

3-(5'-adamantane-1-yl-4'-methoxy-2'-methyl-3-biphenylyl)acrylic acid,

3-(5'-adamantane-1-yl-6-hydroxy-4'-methoxy-2'-methyl-3-biphenylyl)acrylic acid,

3-(5'-adamantane-1-yl-4'-methoxy-6-methoxyethoxy-2'-methyl-3-biphenylyl)acrylic acid,

3-{ 4-methoxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-methoxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 3-[3-(6-hydroxyhexyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]- 4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(7-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(5-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(3-hydroxypropoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-[3-(1-benzylaniline)acrylic acid,

5-[4-methoxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] -3-methylpent-2,4-diene acid,

5-[4-methoxyethoxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]-3-methylpent-2,4-diene acid,

5-[4-hydroxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] -3-methylpent-2,4-diene acid,

3-{ 3-[3-(5-tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(7-tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(7-carboxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(5-carboxypentyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(5-carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(7-carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 4-methoxy-3-[5,5,8,8-tetramethyl-3-(2-morpholine-4-ylethoxy) -5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-methoxy-3-[5,5,8,8-tetramethyl-3-(2-piperidine-1-ylethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-IU is{ 4-methoxy-3-[3-(3-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-methoxy-3-[3-(4-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-methoxy-3-[3-(3-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-[4-fluoro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylic acid,

3-{ 4-hydroxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-hydroxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-hydroxy-3-[3-(4-forbindelse)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-hydroxy-3-[3-(4-chlorobenzoyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-[4-hydroxy-3-(3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid,

3-(3', 5'-di-tert-butyl-6-hydroxy-2'-propyloxy-3-biphenylyl)acrylic acid,

3-(3', 5'-di-tert-butyl-6-hydroxy-2'-Butylochka-3-biphenylyl)acrylic acid,

3-(2'-butoxy-3',5'-di-tert-butyl-6-methoxy-3-biphenylyl)acrylic acid,

3-(3', 5'-di-tert-butyl-6-methoxy-2'-propoxy-3-biphenylyl)acrylic acid,

3-[4-hydroxy-3-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydro-2-Naftowy acid,

ethyl 3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate,

3-methyl-5-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] Penta-2,4-diene acid,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]prop-2-EN-1-ol,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]propenal,

N-ethyl-3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylamide,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]-1-morpholine-4-yl-propenone,

N-(4-hydroxyphenyl)-3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylamide,

5-(5'-adamantane-1-yl-4'-methoxy-2'-methyl-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-[4-methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]-3-methylpent-2,4-diene acid,

5-[4-hydroxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] -3-methylpent-2,4-diene acid,

4-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] Penta-2,4-diene acid,

5-(3',5'-di-tert-butyl-2'-methoxy-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-(3', 5'-di-tert-butyl-2'-propoxy-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-(is droxy-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-(3', 5'-di-tert-butyl-6-hydroxy-2'-propoxy-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-(3', 5'-di-tert-butyl-6-hydroxy-2'-methoxy-3-biphenylyl)-3-methylpentan-2,4-diene acid.

Preferred are compounds where either R11represents-O-R21or R7represents-O-R20.

More preferred are compounds where R11represents-O-R21and R7represents-O-R20.

The compounds of formula (I), in particular, can be obtained according to the reaction scheme shown in the drawing.

Derivatives of formula (Ia) can be obtained (see the drawing) of the aldehyde or ketone derivative (5) by the reaction of the type Horner with the derived phosphonate lithium or sodium (7), carbonyl compounds (5) it is possible to get:

or by reacting boric acid (3) and the derived halogen (4). This reaction is carried out in the presence of a palladium catalyst, such as tetrakis (tri-phenylphosphine) palladium in conditions described by N. Miyaura et al., Synthetic Communications(1981), 11(7), 513-519.

Derivatives of boric acid (3) can be obtained, for example, derived from halogen (1) conversion to a derivative of lithium (2) and then Waimakariri derivative (9) in the presence of a catalyst, for example, a derivative of palladium (NiCl2dppe) with subsequent conversion of the ether functional group (10) in alcohol (11) and oxidation to the aldehyde (5).

The compounds of formula (Ib) can be obtained (see the drawing) of the acetylene derivative (6) by reaction with n-butyllithium and then carboxylation in the presence of CO2.

Acetylene compound (6) can be obtained either:

from the aldehyde derivative (5) (when R3is a hydrogen atom) reaction chetyrehpostovye carbon and triphenylphosphine with the formation of 2', 2'-dibromostyrene, which is converted into acetylene derivative when exposed to a non-nucleophilic base such as n-utility, in an aromatic solvent such as tetrahydrofuran,

from the ketone derivative (5) (when R3is lower alkyl) by a sequence of reactions involving treatment with base such as diisopropylamide lithium chloride then dialkylphosphate and again diisopropylamide lithium.

When R1represents the radical-COOH, connection get:

or protection R1any protecting group of the type of alkyl, allyl or tert-butyl.

Conversion to the free form, you can run:

in the such, as methanol or THF,

in the case of allyl protective group using a catalyst, such as some transition metal complexes in the presence of a secondary amine such as morpholine,

in the case of protective groups such as tert-butyl, using iodine, trimethylsilane.

When R1is functional alcohol group, the compounds can be obtained:

- from the corresponding aldehyde derivatives under the action of a hydride alkalimetal, such as sodium borohydride in an alcohol solvent (e.g. methanol),

from acid derivative when restoring with lithium aluminum hydride.

When R1represents an aldehyde functional group, the compounds can be obtained from alcohol derivatives in the oxidation in the presence of manganese oxide, pyridine dichromate or reagent Swarna.

When R1is an amide functional group, the compounds can be obtained from the corresponding carboxylic derivatives by reaction with aliphatic, aromatic or heterocyclic amines, or by using the acid chloride or in the presence of dicyclohexylcarbodiimide or carbonyl-diimidazole.

Some of these compounds svyazyvayuschii. Preferred compounds are antagonistic activity.

Properties of binding and TRANS-activation, as agonists of RXR receptor can be determined by methods known in this field, such as: Levin et al., Nature, 1992, 355, 359-61; Allenby et al., Proc. Natl. Acad. Sci., 1993, 90, 30-4.

Agonistic activity against RXR can also be determined by the test described in the French patent application 95/07301 filed June 19, 1995. This study includes the following stages: i) a sufficient amount of the compound that is the active ligand of at least one receptor superfamily of steroid/thyroid nuclear receptor other than a ligand specific for RXR receptors, and which may heterodimerization with RXR receptors, such as the molecule RAr-agonist, is applied topically to the skin of a mammal, (ii) molecule having activity of RXR-agonist, is administered systemically or applied to the same portion of the skin of a mammal before, during or after stage (i), and (iii) appreciate the response on the part of the skin of a mammal that has been so processed. Thus, the response to local application of molecules RAr-agonist on the ear of a mammal, manifested in the increase in the thickness of this is ü RXRthe antagonist can be evaluated in the test development when determining the dose (IC50), which gives 50% inhibition transactionmode activity selective for RXR-agonist: 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl] nicotinic acid (CD 3127) according to the following method:

Cells l travelroute together with expressing vector, encoding RXR (p565-RXR), and a reporter plasmid containing the response element 1/2 CRBPII, cloned in the reverse direction heterologous promoter timedancing and reporter gene chloramphenicolchloramphenicol (CAT). After 18 hours after co-transfection of cells treated with CD 3127 constant concentration and increasing concentrations of the molecule, which is appreciated. After treatment for 24 hours in ELISA determine the activity of CAT. Used a constant concentration of CD 3127 equal to 10-8M and corresponds to its EU50.

The object of the present invention, therefore, is a medical product of the compounds of formula (I) as defined above.

Compounds according to the invention is particularly suitable in the following areas of treatment:

1) for treating dermatological diseases associated with impaired runaway polymorphonuclear leukocytes, red acne, nodular acne, prevage tangles, senile acne and secondary acnes such as solar acne, associated with the treatment or occupational disease,

2) for treating other types of violations of scarring, especially ichthyosis, ichtiosnye States, disease Darier, Palmar-plantar keratoderma, lejkokeratoz and leukokeratosis conditions, and cutaneous or mucous (buccal) lichen,

3) for treating other dermatological diseases associated with impaired scarring with inflammatory and/or immunoallergic component, and especially all forms of psoriasis, whether it is cutaneous, mucous or ungual psoriasis, and even psoriatic rheumatism, or alternatively cutaneous atopy, such as eczema or respiratory atopy, or, alternatively, hypertrophy of the gums; the compounds can also be used in certain inflammatory diseases that have no violations scarring,

4) for treating all dermal and epidermal proliferate, both benign and malignant, and if they are viral, or others, such as warts, flat warts and verrucosa epidermodysplasia, it is also possible for oral or red papillomatosis and so the second epithelium,

5) for treating other dermatological diseases such as bullet and collagen diseases,

6) to treat certain eye disorders, in particular, abnormalities of the cornea,

7) to restore or prevent aging of the skin, whether it is induced by light age or aging, or alleviate actinic keratoses and pigmentations, or any pathologies associated with age or actinic aging,

8) for the prevention or treatment of symptoms characteristic of the 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 disturbances of scarring or for the prevention or restoration of strained scars or alternative to promote scarring,

10) for combating disorders of the sebaceous glands, such as Hyperborea for acne or seborrhea,

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

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

13) for the treatment of any General or skin diseases viral nature,

14) for the prevention or treatment of alopecia,

15) for Leche is any cardiovascular system, such as atherosclerosis, hypertension, non-insulin-dependent diabetes and obesity,

17) for the treatment of skin diseases resulting from exposure to UV radiation.

In the above treatment, the compounds according to the invention can be successfully used in combination with other compounds of retinoid-type activity, with vitamin D or its derivatives, with corticosteroids, with agents against free radicals, -hydroxy or-keto acid or their derivatives, or, alternatively, with blockers of ion channels. The term "vitamin D or derivatives thereof, for example, means derivative of vitamin D2or D3and especially 1,25-dihydroxyvitamin D3. The expression "agents against free radicals" means, for example, a-tocopherol, peroxide dismutase, original or some metallochemistry agents. The expression "-hydroxy or keto-acid or derivatives thereof" means, for example, lactic, malic, citric, glycolic, almond, wine, glycerol or ascorbic acid or their salts, amides or esters. Finally, the term "blockers of ion channels" means, for example, Minoxidil (2,4-diamino-6-piperidinedione-3-oxide) and its derivatives.

The subject of this izobreteny what about the above, one of its optical or geometric isomers or one of its salts.

The object of the present invention, therefore, is a new medical composition, intended in particular for the treatment of the above diseases and is characterized by the fact that it contains pharmaceutically acceptable carrier that is compatible with the assignment method selected for this composition, at least one compound of formula (I), one of its optical and geometric isomers or one of its salts.

Compounds according to the invention can be assigned enterline, parenterally, topically or eyes.

When enteral route, medical products can be in the form of tablets, gelatin capsules, covered with sugar tablets, syrups, suspensions, solutions, powders, granules, emulsions, microcapsules or nanocapsules, or polymeric or lipid vesicles, which make possible controlled release. When parenteral route, the composition can be in the form of solutions or suspensions for infusion or injection.

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

When local route of administration, Farmaceutici mucous membranes and may be in the form of ointments, creams, jelly, balms, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microcapsules or nanocapsules or polymeric or lipid vesicles or polymeric patches or hydrogels, which make possible controlled release. These compositions for topical application can be either in anhydrous form or in aqueous form, depending on clinical indications.

With the introduction in my eyes, they are mostly eye drops.

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 alternatively one of its salts at a concentration of preferably between 0.001 and 5% by weight relative to the total weight of the composition.

The compounds of formula (I) according to the invention also find application in the field of cosmetology, in particular, for the hygiene of the body and hair and especially for the treatment of skin types prone to acne, increased hair growth, preventing hair loss, for combating the greasy type of skin or hair, for protection against the harmful effects of the sun or for the treatment of ptx2">

In the field of cosmetology, in addition, the compounds according to the invention can be successfully used in combination with other compounds of retinoid-type activity, with vitamin D or its derivatives, with corticosteroids, with agents against free radicals-hydroxy - or-keto acid or their derivatives or, alternatively, with blockers of ion channels, all of these different products are as defined above.

The present invention thus also relates to cosmetic compositions, which is characterized by the fact that it contains cosmetically acceptable medium suitable for topical application, at least one compound of formula (I) as defined above, or one of its optical or geometric isomers or one of its salts, it is possible for this cosmetic compositions, in particular in the form of a cream, milk, lotion, gel, microcapsules or nanocapsules, or polymeric or lipid vesicles, a soap or shampoo.

The concentration of the compounds of formula (I) in the cosmetic compositions according to the invention primarily is between 0.001 and 3% by weight relative to the entire composition.

Medical and cosmetic compositions according to the invention is combinatii these additives and, especially: wetting agents; depigmenting tools, such as hydroquinone, azelaic acid, caffeic acid or kojic acid; softeners; moisturizers such as glycerol, PEG 400, thiomorpholine and its derivatives or urea; agents against seborrhea or acne, such as S-carboxymethylcysteine, S-benzylcyanide, their salts and derivatives, or benzoyl peroxide; antibiotics such as erythromycin or its esters, neomycin, clindamycin or its esters and tetracyclines; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolinones; means promotes hair growth, such as Minoxidil (2,4-diamino-6-piperidinylidene 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, in particular, -carotene; anti-psoriatic, such as anthralin and its derivatives, and finally, eicosa-5,8,11,14-Terranova acid and eicosa-5,8,11-TRINOVA acid, their esters and amides.

The composition of the invention may also contain flavoring agents, preservatives such as esters of para-hydroxybenzoic acid, stabilizers, humidity regulators, pH regulators, codecover, butylhydroxyanisole or equivalent.

Further for illustrative purpose, but without intent of limitation, are several examples of active compounds of the formula (I) according to the invention, as well as various specific dosage forms based on these compounds.

A. Examples of compounds

Example 1

3-(3',5'-Decret-butyl-2'-methoxy-3-biphenylyl) acrylic acid

a) 2-Bromo-4,6-decret-butylanisole

6 g (21 mmol) of 2-Bromo-4,6-decret-butylphenol and 60 ml of DMF are placed in a round bottom flask in a stream of nitrogen. Portions add 694 mg (29 mmol) of sodium hydride (80% in oil) and the mixture is stirred until there is no further gas evolution. Then add a 1.45 ml (23.2 mmol) of iodomethane and the mixture is stirred at room temperature for three hours. Reaction medium was poured into ice water and extracted with ethyl acetate, the organic phase after separation is separated, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel, elwira heptane. After evaporation of the solvents will be collected at 6.1 g (98%) of the expected product in the form of a colorless oil.

1H NMR (d, Dl3): 1,3 (, N); 1,4 (, N); a 3.9 (s, 3H); and 7.3 (d, J=2.3 Hz, 1H); 7,4 (d, J=2.3 Hz, 1H).

1H NMR (d, Dl3): 1,3 (, N); 1,4 (, N); and 3.8 (s, 3H); 6,0 (s, 2H); 7.5 (d, J=2.5 Hz, 1H); 7.7 (d, J=2.5 Hz, 1H).

c) 3-(3',5'-Decret-butyl-2'-methoxy-3-biphenylyl)acrylic acid

2.2 g (8.3 mmol) of 2-Methoxy-3',5'-decret-butylaniline acid, 942 mg (4,15 mmol) 3-bromcresol acid and 70 ml of dimethyl ether are placed in a three-neck flask in a stream of nitrogen. Added dropwise to 11.4 ml of an aqueous solution of potassium carbonate (2 M) and the reaction mixture Tegaserod. Then add 144 mg (0.12 mmol) tetranitroaniline (0) and the mixture heated under reflux for 20 hours. To Reu after stratifying separated, washed with water, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel, elwira with a mixture of heptane and ethyl acetate (75/25). After evaporation of the solvents will be collected 990 mg(66%) 3-(3',5'-decret-butyl-2'-methoxy-3-biphenylyl)acrylic acid with a melting point 182-3oC.

1H NMR (d, DMSO): 1,1 (C, N); 1,2 (s, N); 3,0 (s, 3H); at 6.4 (d, J=16 Hz, 1H); 7,0 (d, J=2.3 Hz, 1H); 7,1 (d, J=2.3 Hz, 1H); 7.3 to about 7.6 (m, 5H).

Example 2

3-(2'-Benzyloxy-decret-butyl-6-hydroxy-3-biphenylyl)acrylic acid

a) 2-Bromo-4-hydroxybenzaldehyde

15 g (123 mmol) of 4-Hydroxybenzaldehyde, 687 mg (12.3 mmol) of iron powder, 200 ml of dichloromethane and 10 ml of THF are placed in a 500-ml three-neck flask under nitrogen atmosphere. The mixture is cooled to 0oWith that added dropwise 19,60 g (123 mmol) of bromine and the mixture was stirred at room temperature for one hour. Add a saturated solution of sodium thiosulfate, dichloromethane is evaporated, the residue is extracted with ethyl acetate, the organic phase after separation is separated, washed with water until neutral pH over magnesium sulfate and the solvent is evaporated. The resulting residue is purified by chromatography on a column of silica gel, elwira eluting system sotoyama melting point 121-124oC.

b) 3-Bromo-4-methoxysalicylaldehyde

9 g (of 44.7 mmol) 3-Bromo-4-hydroxybenzaldehyde, 30 ml of THF and 30 ml of DMF was placed in a 250-ml round bottom flask under nitrogen atmosphere. Portions added 1.48 g (up 49.2 mmol) of 80% sodium hydride, the mixture is stirred for 30 minutes at room temperature and added dropwise 4,32 g (52,7 mmol) methoxymethane. The reaction mixture is stirred for one hour at room temperature, acidified with 1 N. hydrochloric acid and extracted with ethyl acetate. The organic phase after separation is separated, washed with water until neutral pH and dried over magnesium sulfate and the solvent is evaporated. Collect of 11.5 g (100%) of orange oil.

c) Ethyl 3-(3-bromo-4-methoxyethoxymethyl)acrylate

12 g (53 mmol) of triethylphosphite and 50 ml of THF are placed in a three-neck flask in a stream of nitrogen. Added in several portions of 2.45 g (81,6 mmol) of sodium hydride (80% in oil) and the mixture is stirred until there is no further gas evolution. Then add a solution of 10 g (of 40.8 mmol) 3-bromo-4-methoxy-methoxybenzaldehyde in 50 ml of THF and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water, acidified with hydrochloric acid and extracted with ethyl acetate, organisatorial on a column of silica gel, elwira with a mixture of heptane and ethyl acetate (90-10). After evaporation of the solvents will be collected 9.6 g (74%) of ethyl 3-(3-bromo-4-methoxyethoxymethyl)acrylate with a melting point of 63-65oC.

d) 2-Benzyloxy-3,5-decret-butylbromide

In a manner analogous to that in example 1(a), by reacting 6 g (21 mmol) of 2-bromo-4,6-decret-butylphenol with 2.8 ml (23.2 mmol) of benzylbromide gain of 7.4 g (94%) of the expected product in the form of a colorless oil.

1H NMR (d, Dl3): 1,3 (, N); 1,4 (, N); to 5.1 (s, 2H); 7,25 was 7.45 (m, 5H); 7,55 and 7.6 (m, 2H).

e) 2-Benzyloxy-3,5-decret-butylaniline acid

In a manner analogous to that in example 1(b), by reacting 7.2 g (19,3 mmol) 2-benzyloxy-3,5-decret-butylperbenzoate from 6.7 ml (29 mmol) of triisopropylsilyl get the 4.29 g (65%) of the expected boronic acid.

1H NMR (d, Dl3): of 1.35 (s, N); 1,45 (s, N); to 5.1 (s, 2H); at 5.9 (s, 2H); 7.3 to at 7.55 (m, 6N); 7.7 (d, J=2.5 Hz, 1H).

(f) Ethyl 3-(2'-benzyloxy-3', 5'-decret-butyl-6'-methoxy-methoxy-3-biphenylyl)acrylate

In a manner analogous to that in example 1(C), by reacting 3,24 g (at 9.53 ml) of 2-benzyloxy-3,5-decret-butylaniline acid 2 g (6,35 mmol )ethyl 3-(3-bromo-4-methoxyethoxymethyl)acrylate, to obtain 2.4 g (71%) of the expected ethyl ester.< 6,3 (d, J=16 Hz, 1H); the 6.9 to 7.0 (m, 2H); 7,15-7,25 (m, 5H); of 7.4-7.5 (m, 2H); about 7.6 to 7.7 (m, 2H).

e) Ethyl 3-(2'-benzyloxy-3', 5'-decret-butyl-6-hydroxy-3-biphenylyl)acrylate

2.14 g (4 mmol) of the above ethyl ester, 10 ml THF and 10 ml of ethanol are placed in a round bottom flask. Add 1 ml of concentrated sulfuric acid and the mixture is stirred at room temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase after separation was separated, washed with water, dried over magnesium sulfate and evaporated. The resulting residue is triturated in heptane, filtered and dried. Collect of 1.93 g (100%) of the expected product.

1H NMR (d, Dl3): 1,3 (t, J=7 Hz, 3H); to 1.35 (s, N); 1,45 (s, N); of 4.25 (q, J= 7 Hz, 2H); 4,5-4,7 (m, 2H); at 6.4 (d, J=16 Hz, 1H); 7,0 (d, J=8 Hz, 1H); to 7.0, and 7.1 (m, 2H); to 7.25 (s, 1H); 7.3 to 7.4 (m, 3H); 7,45 is 7.50 (m, 2H); and 7.6 (s, 1H); 7.7 (d, J=6 Hz, 1H).

h) 3-(2'-Benzyloxy-3',5'-decret-butyl-6-hydroxy-3 - biphenylyl)acrylic acid

of 1.93 g (4 mmol) of Ethyl 3-(2'-benzyloxy-3',5'-decret-butyl-6-hydroxy-3-biphenylyl)acrylate, 20 ml THF, 2 ml of methanol and 4 ml of sodium hydroxide solution (10 BC) placed in a round bottom flask. The reaction medium is heated under reflux for 12 hours, poured into water, acidified to pH 1 hydrochloric KIS the Oia and evaporated. The resulting residue is triturated in heptane, filtered and dried. Collect 1.6 g(87%) 3- (2'-benzyloxy-3', 5'-decret-butyl-6-hydroxy-3-biphenylyl)acrylic acid with a melting point 230-1oC.

1H NMR (d, Dl3): 1,3 (, N), and 1.5 (s, N); and 4.6 (s, 2H); 6,3 (d, J=16 Hz, 1H); to 7.0, and 7.1 (m, 3H); 7,2-7,3 (m, 4H); of 7.4-7.5 (m, 2H); and 7.6 (s, 1H); 7.7 (d, J=16 Hz, 1H); 8,1 (m, 1H).

Example 3

3-(3', 5'-Decret-butyl-6-hydroxy-2'-pentyloxy-3-biphenylyl)acrylic acid

a) 3,5-Decret-butyl-2-Interoceanmetal

In a manner analogous to that in example 1(a), by reacting 6 g (21 mmol) of 2-bromo-4,6-decret-butylphenol with 3 ml (23.2 mmol) of identne gain of 7.3 g (98%) of the expected product in the form of a colorless oil.

1H NMR (d, Dl3): of 0.9 (t, J=7 Hz, 3H); to 1.35 (s, N); 1,45 (s, N); 1.3 to 1.5 (m, 4H); 1,8-2,0 (m, 2H); 4.0 a (kV, J=7 Hz, 2H); and 7.3 (d, J=2.5 Hz, 1H); 7,4 (d, J=2.5 Hz, 1H).

b) 3,5-Decret-butyl-2-interoception acid

In a manner analogous to that in example 1(b), by reacting 7,26 g of 20.5 mmol) of 3,5-decret-butyl-2-Interoceanmetal with 7.1 ml (30,75 mmol) triisopropylsilane obtain 6.4 g (98%) of the expected boronic acid.

1H NMR (d, CDCl3): of 0.9 (t, J=7 Hz, 3H); 1.2 to 1.5 (m, 4H); to 1.35 (s, N); 1,45 (s, N); 1.85 to 1,95 (m, 2H); 3,8-4,0 (m, 2H); 6,1 (s, 1H); of 6.8 to 7.6 (m, 3H).

1H NMR (d, Dl3): 0,7 (t, J=7 Hz, 3H); 1,0 (m, 4H); 1,2 (m, 5H); 1,25 (s, N); to 1.35 (s, N); the 3.2 to 3.3 (m, 2H); at 3.35 (s, 3H); 4,2 (kV, J=7 Hz, 2H); to 5.1 (s, 2H); and 6.25 (d, J=16 Hz, 1H); 7,05 (d, J=2.5 Hz, 1H); to 7.15 (d, J=8.5 Hz, 1H); and 7.3 (d, J=2.5 Hz, 1H); 7,4 (DD, J=8,5 Hz and 2.5 Hz, 1H); 7.5 (d, J= 2.5 Hz, 1H); 7,6 (d, J=16 Hz, 1H).

d) Ethyl 3-(3', 5'-decret-butyl-6-hydroxy-2'-pentyloxy-3-biphenylyl)acrylate

In a manner analogous to that in example 2(g), on the basis of 1.84 g (3.6 mmol) of the above ethyl ester, obtain 1.6 g (88%) of the expected product.

1H NMR (d, Dl3): of 0.85 (t, J=7 Hz, 3H); 0,9-1,3 (m, 7H); to 1.35 (s, N); 1,45 (s, N); of 1.45 to 1.6 (m, 2H); 3.5 to the 3.65 (m, 2H); 4,3 (kV, J=7 Hz, 2H); 6,35 (d, J= 16 Hz, 1H); 7,05 (d, J=8 Hz, 1H); to 7.15 (d, J=2.4 Hz, 1H); 7,4 (d, J= 2.4 Hz, 1H); 7.5 to about 7.6 (m, 2H); 7.7 (d, J=16 Hz, 1H).

e) 3-(3',5'-Decret-butyl-6-hydroxy-2'-pentyloxy-3 - biphenylyl)acrylic acid

In a manner analogous to that in example 2(h), based on 1,62 g (3.2 mmol) of ethyl 3-(3', 5'-decret-butyl-6-hydroxy - 2'-pentyloxy-3-biphenylyl)acrylate, receive 1.2 g(86%) 3-(3', 5'-decret-butyl-6-hydroxy-2'-pentyloxy-3-biphenylyl)acrylic acid with a point plaln); 3,5-3,6 (m, 2H); at 6.4 (d, J=16 Hz, 1H); 7,1 (d, J=8 Hz, 1H); to 7.2 (s, 1H); to 7.4 (m, 2H); 7.5 to about 7.6 (m, 2H); 7,8 (d, J=16 Hz, 1H).

Example 4

3-(3', 5'-Decret-butyl-6-hydroxy-2'-methoxy-3-biphenylyl) acrylic acid

a) Ethyl 3-(3', 5'-decret-butyl-2'-methoxy-6-methoxyethoxy-3-biphenylyl)acrylate

In a manner analogous to that in example 1(C), by the interaction of 2.18 g (compared to 8.26 mmol) of 3,5-decret-butyl-2-interoceptive acid 2 g (6,35 mmol) ethyl 3-(3-bromo-4-methoxyethoxymethyl)acrylate get 2 g (70%) of the expected ethyl ester.

1H NMR (d, Dl3): 1,2-1,3 (m, 3H); to 1.35 (s, N); 1,45 (s, N); 3,3 (s, 3H); 3,4 (s, 3H); 3,8 (kV, J=7 Hz, 2H); further 5.15 (s, 2H); 6,35 (d, J=16 Hz, 1H); 7,1 (d, J=2 Hz, 1H); 7,2 (d, J=8 Hz, 1H); to 7.35 (d, J=2 Hz, 1H); 7.5 (a DD, J=8 Hz and J=2 Hz, 1H); 7,6 (d, J=2 Hz, 1H); 7.7 (d, J=16 Hz, 1H).

b) Ethyl 3-(3', 5'-decret-butyl-6-hydroxy-2'-methoxy-3-biphenylyl)acrylate

In a manner analogous to that in example 2(g), on the basis of 1.45 g (3,17 mmol) of the above ethyl ester earn 1.25 g (96%) of the expected product.

1H NMR (d, Dl3): 1.1 to 1.2 (m, 4H); to 1.35 (s, N); 1,45 (s, N); 3,5 (s, 3H); 4.25 in (kV, J= 7 Hz, 2H); 6,35 (d, J=16 Hz, 1H); 7,05 (d, J=8 Hz, 1H); to 7.15 (d, J=2.3 Hz, 1H); 7,4 (d, J=2.3 Hz, 1H); 7.5 to about 7.6 (m, 2H); 7.7 (d, J=16 Hz, 1H).

with) 3- (3', 5'-Decret-butyl-6-hydroxy-2'-methoxy-3 - biphenylyl)acrylic acid

By the way, anacleta receive 800 mg(69%) 3-(3',5'-decret-butyl-6-hydroxy-2'-methoxy-3-biphenylyl) acrylic acid with a melting point 166-7oC.

1H NMR (d, Dl3): of 1.35 (s, N); 1,45 (s, N); 3,5 (s, 3H); at 6.4 (d, J=16 Hz, 1H); 7,1 (d, J=8 Hz, 1H); 7,2 (d, J=2.5 Hz, 1H); was 7.45 (d, J=2.5 Hz, 1H); 7.5 to about 7.6 (m, 2H); 7,8 (d, J=16 Hz, 1H).

Example 5

3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2 - naphthyl)-4-methoxyethoxymethyl]acrylic acid

a) 3-Benzyloxy-2-bromo-5,5,8,8-tetramethyl-5,6,7,8 - tetrahydronaphthalen

In a manner analogous to that in example 1(a), by reacting 5 g (25 mmol) of 3-hydroxy-2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene with 3.5 ml (29.5 mmol) of methyl benzyl get 6,15 g (66%) of the expected product.

1H NMR (Dl3): 1,20 (C, 6N); 1,24 (s, 6N); of 1.64 (s, 4H); 5,12 (s, 2H); PC 6.82 (s, 1H Ar); 7,21-to 7.50 (m, 6N Ar).

b) 3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naftalina acid

In a manner analogous to that in example 1(b), by reacting 6,15 g (16.5 mmol) of 3-benzyloxy-2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene with 5.7 ml (24,7 mmol) triisopropylsilane obtain 3.5 g (62%) of the expected boronic acid with a melting point 125-6oC.

1H NMR (Dl3): 1,26 (C, 6N); 1,29 (C, 6N); by 1.68 (s, 4H); 5,12 (s, 2H); of 5.83 (s, 2H); to 6.88 (s, 1H Ar); 7,35-the 7.43 (m, 5H, Ar); 7,80 (s, 1H Ar).

c) Ethyl 3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxy the si-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-afterborn acid 3,17 g (10 mmol) of ethyl 3-(3-bromo-4-methoxyethoxy-phenyl)acrylate receive 3 g (56%) of the expected ethyl ester.

1H NMR (Dl3): of 1.27 (s, N); of 1.33 (t, J=7,1 Hz, 3H); 1.69 in (s, 4H); and 3.31 (s, 3H); 4.25 in (kV, J=7,1 Hz, 2H); free 5.01 (s, 2H); of 5.06 (s, 2H); 6,32 (d, J=15,9 Hz, 1H); 6.89 in (s, 1H Ar); 7,19 (s, 1H Ar); 7,21-7,31 (m, 6N Ar); 7,46 (DD, J=8.6 Hz, J=2.3 Hz, 1H, Ar); 7,52 (d, J=2.3 Hz, 1H, Ar); 7,567 (d, J=15,9 Hz, 1H).

d) 3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl ]acrylic acid

In a manner analogous to that in example 2(h), starting from 1.3 g (2,46 mmol) of the above ethyl ester receive 1 g(90%) 3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl] acrylic acid with a melting point 161-3oC.

1H NMR (Dl3): 1,27 of 1.28 (m, N); 1.69 in (s, 4H); of 3.32 (s,3H); free 5.01 (s, 2H); 5,07 (s, 2H); 6,33 (d, J=16 Hz, 1H); 6,70 (s, 1H Ar); 7,20 (s, 1H Ar); 7,21-7,31 (m, 6N AG); of 7.48 (DD, J=8.6 Hz, J=2.1 Hz, 1H of ar); at 7.55 (d, J=2 Hz, 1H of ar); at 7.55 (d, J=2 Hz, 1H).

13With NMR (Dl3): 10.99, 32.11, 33.91, 34.69, 35.33, 56.20, 70.76, 95.02, 111.13, 115.23, 115.36, 125.11, 126.76, 127.08, 127.61, 127.68, 128.49, 129.25, 129.76, 129.83, 132.29, 137.37, 137.72, 145.74, 147.05, 153.85, 157.49, 172.54.

Example 6

3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxyphenyl]acrylic acid

a) Ethyl 3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxyphenyl]acrylate

In a manner analogous to that in example 2(g), starting from 1.8 g (3,4 IMO is (72%) of ethyl 3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxyphenyl] acrylate.

1H NMR (Dl3): 1,25-of 1.29 (m, N); to 1.31 (t, J=7,1 Hz, 3H); to 1.70 (s, 4H); 4.26 deaths (kV, J=7,1 Hz, 2H); 5,07 (s, 2H); 6,33 (d, J=16 Hz, 1H); for 6.81 (s, 1H, HE); 6,99 (s, 1H Ar); 7,01 (d, J=9.8 Hz, 1H, Ar); of 7.23 (s, 1H Ar); 7,26-to 7.32 (m, 5H, Ar); 7,42 (d, J=2.1 Hz, 1H, Ar); 7,49 (DD, J=8,3 Hz, J=2.1 Hz, 1H, Ar); of 7.69 (d, J=16 Hz, 1H).

b) 3-[3-(3-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxyphenyl]acrylic acid

In a manner analogous to that in example 2(h), from 1.2 g (2,47 mmol) of the above ethyl ester obtain 980 mg(98%) 3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxyphenyl] acrylic acid with a melting point 123-4oC.

1H NMR (Dl3): 1,28-of 1.30 (m, N); to 1.70 (s, 4H); to 5.08 (s, 2H); 6,35 (d, J= 15.7 Hz, 1H); 6,38 (s, 1H); 7,00 (s, 1H Ar);? 7.04 baby mortality (d, J=7.5 Hz, 1H, Ar); from 7.24 (s, 1H Ar); 7,25-7,37 (m, 5H, Ar); was 7.45 (d, J=2 Hz, 1H, Ar); 7,52 (DD, J= 8,4 Hz, J=2 Hz, 1H); 7,80 (d, J=15,9 Hz, 1H).

13With NMR (Dl3): 31.88, 32.02, 34.00, 34.65, 34.99, 35.08, 72.30, 112.66, 114.70, 118.16, 124.49, 127.07, 127.23, 127.64, 128.30, 128.68, 129.22, 130.55, 132.19, 136.06, 139.95, 147.01, 147.08, 152.48, 156.45, 172.75.

Example 7

[4 Methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]propionic acid

a) 2', 2'-Dibromo- [4-methoxyethoxy-3- (3,5,5,8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]ethylene

of 4.95 g (14,71 mmol) [4-Methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-g (29.4 mmol) chetyrehpostovye carbon and 15,45 g (58,94 mmol) of triphenylphosphine and the mixture is stirred at room temperature for two hours. The reaction medium is evaporated and the resulting residue purified by chromatography on a column of silica gel, elwira dichloromethane. Collect of 6.75 g (88%) of the expected product.

b) [4 Methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acetylene

7.6 g (12.9 mmol) of [2',2'-Dibromo-4-methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] ethylene and 50 ml of THF are placed in a three-neck flask in a stream of nitrogen. Added dropwise 11 ml (27,1 mmol) of a solution of n-utility (2.5 M in hexane) at -78oC and the mixture allowed to warm to room temperature. The reaction medium is poured into water and extracted with diethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel, elwira with a mixture of heptane and ethyl acetate (98:2). After evaporation of the solvents will be collected 3,68 g (79%) expected acetylene derivative in the form of a yellow oil.

c) Ethyl [4-methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]propionate

the 3.65 g (10.1 mmol) of the above acetylene derivative and 60 ml of THF are placed in a three-neck flask in a stream of nitrogen. Added dropwise of 4.45 ml (11.1 mmol) of n-utility (2.5 M in hexane) at -78oWith and CME -78oC and the mixture allowed to warm to room temperature. The reaction medium is poured into an aqueous solution of ammonium chloride and extracted with diethyl ether and the organic phase is decanted, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel, elwira with a mixture of heptane and ethyl acetate (98:2). After evaporation of the solvents will be collected to 4.14 g (95%) of ethyl [4-methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] propionate as a yellow oil.

d) [4 Methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]propionic acid

In a manner analogous to that in example 2(h), on the basis of 439 mg (1 mmol) of ethyl [4-methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6, 7,8-tetrahydro-2-naphthyl)phenyl] propionate, get 375 mg (91%) of [4-methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] propionic acid having a melting point of 168-170oC.

Example 8

3-[3-(3-Propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylic acid

a) Ethyl 3-[3-(3-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylate

In a manner analogous to that in example 1(C), by reacting 3 g (10.4 mmol) of (3-prop ethyl (3-bromo-4-methoxyethoxymethyl)acrylate (prepared in example 2(C)), after chromatography on a column of silica gel and elution with a mixture of heptane and ethyl acetate (98:2) to obtain 2.1 g (43%) of the expected ethyl ester.

b) 3-[3-(3-Propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylic acid

In a manner analogous to that in example 2(h), based on 724 mg (1.5 mmol) of ethyl 3-[3-(3-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylate, obtain 620 mg(91%) 3-[3-(3-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl] acrylic acid with a melting point 170-1oC.

Example 9

3-[3-(3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylic acid

a) 2-Bromo-3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8 - tetrahydronaphthalen

In a manner analogous to that in example 1(a), by reacting 25 g (25 mmol) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol with 3.9 ml (29.5 mmol) of 5-identne, get 7 g (79%) of the expected product in the form of a colorless oil.

b) (3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)boric acid

In a manner analogous to that in example 1(b), on the basis of 6,9 g (of 19.5 mmol) of 2-bromo-3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene, produces the rehydro-2-naphthyl)-4-methoxyethoxymethyl]acrylate

In a manner analogous to that in example 1(C), by reacting 4 g (12.6 mmol) (3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)boronic acid of 2.64 ml (8.4 mmol) of ethyl 3-[3-(3-bromo-4-methoxyethoxymethyl] acrylate (prepared in example (2C)), after chromatography on a column of silica gel, elwira with a mixture of heptane and ethyl acetate (98:2), obtain 3.2 g (75%) the expected ethyl ester.

d) 3-[3-(3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylic acid

In a manner analogous to that in example 2(h), starting from 1.7 g (3,26 mmol) ethyl 3-[3-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylate, obtain 1.35 g(86%) 3-[3-(3-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl] acrylic acid with a melting point 178-80oC.

Example 10

3-(5'-Adamantane-1-yl-4'-methoxy-2'-methyl-3-biphenyl)acrylic acid

a) 4-Bromo-3-METHYLPHENOL

80,0 g (740 mmol) 3-METHYLPHENOL and 400 ml of glacial acetic acid are placed in a 2-liter three-neck flask under nitrogen atmosphere. The mixture is cooled to 15oWith that added dropwise 38 ml (742 mmol) of bromine and the mixture was stirred at 15oWith over three hours. Reaction medium was poured into 1 € over magnesium sulfate and the solvent is evaporated. The resulting residue is triturated in heptane, filtered and dried. Collect 70 g (50%) of a white powder with a melting point 55-56oC.

b) 2-(1-Substituted)-4-bromo-3-METHYLPHENOL

70,0 g (376 mmol) of 4-Bromo-3-METHYLPHENOL, 63 g (414 mmol) of 1-adamantanol, 500 ml of heptane and 50 ml of dichloromethane are placed in a 2000-ml round bottom flask under nitrogen atmosphere. Added dropwise 20 ml (376 mmol) of 98% sulfuric acid and the mixture is stirred at room temperature for 3 hours. The reaction medium is poured into water, neutralized to pH 8-9 with sodium bicarbonate solution and extracted with ethylacetate, the organic phase is decanted, washed with water until neutral pH and dried over magnesium sulfate and the solvent is evaporated. The resulting residue is triturated in heptane, filtered and dried. Collect 59 g (49%) pinkish-white powder with a melting point 139-141oC.

c) 2-(1-Substituted)-4-bromo-5-methylanisole

8 g (24,9 mmol) 2-(1-Substituted)-4-bromo-3-METHYLPHENOL, 75 ml of DMF and 25 ml THF was placed in a 250-ml three-neck flask in a stream of nitrogen. Small portions add 880 mg (a 27.4 mmol) of sodium hydride (75% in oil) and the mixture is stirred until there is no further gas evolution. Then add 1.9 ml (30 mmol) of iodomethane and the mixture was stirred at comnation and the organic phase is decanted, dried over magnesium sulfate and evaporated. The resulting residue is triturated in heptane, filtered and dried. Get 6,44 g (77%) of a pale beige powder with a melting point of 129-131oC.

d) 5-(1-Substituted)-4-methoxy-2-methylphenylamine acid

6 g (to 17.9 mmol) of 2-(1-Substituted)-4-bromo-3-methylanisole and 40 ml of THF was placed in a 250-ml three-neck flask in a stream of nitrogen. Added dropwise to 7.9 ml (19,7 mmol) n-utility (2.5 M in hexane) at -78oC and the mixture is stirred for 15 minutes at the same temperature, add 5 ml (21.5 mmol) of triisopropylsilane and the mixture is stirred for 30 minutes. At -50oWith add 20 ml of hydrochloric acid (1 BC) and the mixture allowed to warm to room temperature. The reaction mixture was extracted with diethyl ether and the organic phase is decanted, dried over magnesium sulfate and evaporated. The precipitate triturated in heptane, filtered and dried. Collect of 4.75 g (88%) of the expected boronic acid with a melting point 276-278oWith that use, as it is in the rest of the synthesis.

e) 3-(5'-Adamantane-1-yl-4'-methoxy-2'-methyl-3-biphenylyl)acrylic acid

1.0 g of 3.33 mmol) 5-(1-Substituted)-4-methoxy-2-methylphenylimino acid, obtained above, 580 mg (2.56 mmol) of 3-bromalite is carbonate potassium (2 m) and the reaction medium Tegaserod. Then add 150 mg (0.13 mmol) tetranitroaniline (0) and the mixture heated under reflux for 2 hours. In the reaction environment, which is acidified to pH 1 with hydrochloric acid (1 ad), add water and ethyl acetate. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel, elwira with a mixture of heptane and ethyl acetate (85:15). After evaporation of the solvents will be collected 750 ml thick gel, which leaves yet to crystallize in a stream of nitrogen. Thus obtained yellow crystals re-crystallized from ethanol, filtered and dried to education 452 mg(44%) 3-(5'-adamantane-1-yl-4'-methoxy-2'-methyl-3-biphenylyl)acrylic acid with a melting point 194-6oC.

1H NMR (CDCl3): 1,76 (ush, 6N); 2,05 (ush, 3H); 2,10 (ush, 6N); and 2.26 (s, 3H); 3,88 (s, 3H); 6,48 (d, J=15,8 Hz, 1H); is 6.78 (s, 1H Ar); 7,07 (s, 1H Ar); 7,35-7,51 (m, 4H Ah); to 7.84 (d, J=15,8 Hz, 1H of ar).

Example 11

3-(5'-Adamantane-1-yl-6-hydroxy-4'-methoxy-2'-methyl-3-biphenylyl)acrylic acid

a) Ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate

In a manner analogous to that in example 2(g), by the interaction of 10.1 g (20.3 mmol) of ethyl 3-(3-bromo-4-methoxyethoxymethyl)acrylate obtained white powder with a melting point 112-3oC.

b) Ethyl 3-(5'-adamantane-1-yl-6-hydroxy-4'-methoxy-2'-methyl-3-biphenylyl)acrylate

In a manner analogous to that in example 1(C), by reacting 3.0 g (10 mmol) 5-(1-substituted)-4-methoxy-2-methylphenylimino acid obtained in example 10 (d), 2.25 g (8,33 mmol) ethyl 3-(3-bromo-4-hydroxyphenyl) acrylate obtained above, obtain 570 mg (15%) of a white powder with a melting point 164-6oC.

c) 3-(5'-Adamantane-1-yl-6-hydroxy-4'-methoxy-2'-methyl-3-biphenylyl)acrylic acid

In a manner analogous to that in example 2(h), based on 270 g (0.6 mmol) of ethyl 3-(5'-adamantane-1-yl-6-hydroxy-4'-methoxy-2'-methyl-3-biphenylyl)acrylate obtained above, obtain 190 mg (76%) of white powder, which decomposes, starting with the 120oC.

1H NMR (Dl3): 1,76 (ush, 6N), 2,07 (ush, N) by 2.13 (s, 3H), with 3.89 (s, 3H), 5,20 (ush, 1H), of 6.31 (d, J=of 15.75 Hz, 1H), 6,83 (s, 1H), 7,00 (d, J=a 9.25 Hz, 1H), of 7.48 (DD, J1=a 9.25 Hz, J2=2.0 Hz, 1H), 7,74 (d, J=of 15.75 Hz, 1H).

Example 12

3- (5'-Adamantane-1-yl-4'-methoxy-6-methoxyethoxy-2'-methyl-3-biphenylyl)acrylic acid

a) Ethyl 3-(5'-adamantane-1-yl-4'-methoxy-6-methoxyethoxy-2'-methyl-3-biphenylyl) acrylate

In a manner analogous to that in example 2(b), by reacting 300 mg (0.67 mmol) of ethyl 3-(5'-adamantane-1-yl-6-hydroxy-4'-methox whom (97%) white gel.

1H NMR (Dl3): of 1.32 (t, J= 7,00 Hz, 3H), 1,75 (ush, 6N), 2,04+2,09 (ush+ush, 6N+3N), and 2.14 (s, 3H), 3,37 (s, 3H), a 3.87 (s, 3H), 4,25 (kV, J=7,0 Hz, 2H), 5,11 (s, 2H), 6,33 (d, J=15,8 Hz, 1H), 6,76 (s, 3H), 7,00 (s, 1H), then 7.20 (d, J= 8.5 Hz, 1H), was 7.36 (d, J=2.25 Hz, 1H), 7,46 (DD, J1=8.5 Hz, J2= 2.25 Hz, 1H), 7,66 (d, J=15,8 Hz, 1H).

b) 3-(5'-Adamantane-1-yl-4'-methoxy-6-methoxyethoxy-2'-methyl-3-biphenylyl)acrylic acid

In a manner analogous to that in example 2(h), starting from 300 mg (0.61 mmol) of ethyl 3-(5'-adamantane-1-yl-4'-methoxy-6-methoxyethoxy-2'-methyl-3-biphenylyl) acrylate obtained above, receive 200 mg (71%) of white powder, which decomposes, starting with 113oC.

1H NMR (Dl3): 1,76 (ush, 6N), 2,04 (ush, 3H), 2,09 (ush, 6N), and 2.14 (s, 3H), 3,38 (s, 3H), a 3.87 (s, 3H), 5,13 (s, 2H), 6,34 (d, J=of 15.75 Hz, 1H), 6,76 (s, 1H), 7,00 (s, 1H), 7,22 (d, J=8.5 Hz, 1H), 7,39 (d, J=2.25 Hz, 1H), 7,49 (DD, J1=8.5 Hz, J2=2.25 Hz, 1H), 7,76 (d, J=of 15.75 Hz, 1H).

Example 13

3-{ 4-Methoxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) 2-Bromo-3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen

In a manner analogous to that in example 1 (a), by reacting 100 g (353 mmol) 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol with 32 ml (406 mmol) of methoxymethane receive 100 g (86%) of the expected product in the form of beige is boric acid

In a manner analogous to that in example 1 (b), by reacting 90 g (275 mmol) of 2-bromo-3-methoxyethoxy-5,5,8,8, -tetramethyl-5,6,7,8-tetrahydronaphthalene obtained above, will receive 70 g (87%) of the expected product in the form of a white powder with a melting point of 130-132oC.

c) 3-Bromo-4-methoxybenzaldehyde

In a manner analogous to that in example 1(a), by reacting 50 g (270 mmol) of 3-bromo-4-hydroxybenzaldehyde (obtained in accordance with example 2 (a)) and 20.2 ml (338 mmol) of iodomethane receive 48 g (83%) of the expected product in the form of a white powder with a melting point 48-50oC.

d) Ethyl 3-(3-bromo-4-methoxyphenyl)acrylate

In a manner analogous to that in example 2 (C), by interacting 46 g (214 mmol) of 3-bromo-4-methoxybenzaldehyde obtained above, and 55.2 ml (278 mmol) of triethylphosphite obtain 47 g (77%) of the expected product in the form of white flakes with a melting point of 76-78oC.

e) Ethyl 3-[4-methoxy-3-(3-methoxyethoxy-5, 5,8,8-8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylate

In a manner analogous to that in example 1(C), by reacting 53,3 g (182 mmol) of 3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl-boric acid, obtained in example 13 (b), and 40 g (140 mmol) of ethyl 3-(3-ultralights.

1H NMR (Dl3): of 1.23 and 1.35 (m, 15 NM), to 1.70 (s, 4H), to 3.34 (s, 3H), 3,81 (s, 3H), 4,25 (kV, J=7,25 Hz, 2H), to 5.03 (s, 2H), 6,32 (d, J=of 15.75 Hz, 1H), 9,95 (d, J= 9.0 Hz, 1H), 7,13 (s, 1H), 7,42-7,66 (m, 2H), to 7.67 (d, J=of 15.75 Hz, 1H).

(f) Ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate

In a manner analogous to that in example 2(g), by reacting 63 g (140 mmol) of ethyl 3-[4-methoxy-3-(3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylate obtained above, and 22 ml (420 mmol) of sulfuric acid to obtain 42.5 g (75%) of the expected product in the form of a pale yellow powder with a melting point 147-149oC.

g), Ethyl 3-{ 4-methoxy-3-[3-(3-methoxybenzyloxy) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic

In a manner analogous to that in example 1(a), by reacting 1 g (2.45 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-phenyl] acrylate obtained above, 4 ml (3 mmol) of 3-methoxybenzylamine, gain of 1.30 g (100%) of the expected product in the form of a yellow oil.

1H NMR (Dl3): 1,24-of 1.35 (m, 15 NM), was 1.69 (s, 4H), of 3.69 (s, 3H), 3,76 (s, 3H), 4,25 (kV, J=7,0 Hz, 2H), 5,0 (s, 2H), 6,30 (d, J=16.0 Hz, 1H), 6.75 in-of 6.96 (m, 5H), 7,16-7,22 (m, 2H), 7,45-7,51 (m, 2H), to 7.67 (d, J=16.0 Hz, 1H).

h) 3-{4-Methoxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-Tetra is I'm from 1.3 g (2.45 mmol) of ethyl 3-{ 4-methoxy-3-[3-(3-methoxy-benzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] phenyl}acrylate, obtained above, obtain 830 mg (67%) of the expected product in the form of a white powder with a melting point of 168-170oC.

Example 14

3-{ 4-Methoxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) Ethyl 3-{ 4-methoxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate

In a manner analogous to that in example 1(a), by the interaction of 1.23 g (3 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-phenyl]acrylate obtained in example 13(f), with 490 μl (3.6 mmol) of 4-methoxybenzylamine get 1,58 g (100%) of the expected product in the form of a yellow oil.

1H NMR (Dl3): to 1.21 and 1.35 (m, 15 NM), was 1.69 (s, 4H), of 3.75 (s, 3H), of 3.77 (s, 3H), 4,25 (kV, J=7,0 Hz, 2H), is 4.93 (s, 2H), 6,29 (d, J=16.0 Hz, 1H), 6,80-6,94 (m, 4H), 7,15-to 7.18 (m, 2H), 7,31 (d, J=8.5 Hz, 1H), 7,44 is 7.50 (m, 2H), 7,66 (d, J=16,25 Hz, 1H).

b) 3-{4-Methoxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), based on 1,58 g (3 mmol) of ethyl 3-{ 4-methoxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] phenyl}acrylate obtained above, receiving 1.1 mg (71%) of the expected product in the form of a white powder with a melting point of 201 toxigenic}acrylic acid

a) Ethyl 3-{3-[3-(6-hydroxyhexyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate

In a manner analogous to that in example 1 (a), by reacting 1.4 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl] acrylate obtained in example 13(f), with 540 μl (4.1 mmol) of 1-Bromhexine receive 850 mg (50%) of the expected product in the form of a yellow oil.

1H NMR (Dl3): of 1.23 and 1.35 (m, N), 1,43 is 1.70 (m, 8H), of 3.56 (q, J=5.5 Hz, 2H), 3,81 (s, 3H), 3,90 (t, J=5.0 Hz, 2H), 4,25 (kV, J=7,25 Hz, 2H), of 6.31 (d, J=16.0 Hz, 1H), 6,85 (s, 1H), of 6.96 (d, J=8.5 Hz, 1H), 7,20 (s, 1H), 7,47 (DD, J1=8,25 Hz, J2=2.25 Hz, 1H), 7,52 (d, J=2.25 Hz, 1H), to 7.67 (d, J= 16.0 Hz, 1H).

b) 3-{ 3-[3-(6-Hydroxyhexyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 850 mg (1,67 mmol) of ethyl 3-{3-[3-(6-hydroxyhexyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxy-phenyl} acrylate obtained above, obtain 510 mg (63%) of the expected product in the form of a white powder with a melting point of 118-120oC.

Example 16

3-{ 3-[3-(7-Hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

a) Ethyl 3-{3-[3-(7-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-it-2-naphthyl)-4-methoxyphenyl] acrylate, obtained in example 13(f), 440 mg (3.2 mmol) of potassium carbonate, 540 μl (3.5 mmol) of 1-bromoheptanoate and 30 ml butanone placed in a round bottom flask. The mixture is heated under reflux for 8 hours, the reaction medium is poured into water, acidified to pH 1 with hydrochloric acid and extracted with diethyl ether, and the organic phase is decanted, dried over magnesium sulfate and evaporated. Collect of 1.57 g (100%) of the expected product in the form of a yellow oil.

1H NMR (Dl3): 1,26 (C, 6N), 1,32 (C, 6N), 1,08-1,7 (m, 17H), of 3.5-3.7 (m, 2H), 3,81 (s, 3H), with 3.89 (t, J=6.25 Hz, 2H), 4,24 (kV, J=7,0 Hz, 2H), and 6.3 (d, J= 16.0 Hz, 1H), 6,84 (s, 1H), 6,95 (d, J=of 8.25 Hz, 1H), 7,19 (s, 1H), 7,47 (DD, J1=8,25 Hz, J2=2.25 Hz, 1H), 7,50 (d, J=2.25 Hz, 1H), to 7.67 (d, J= 16.0 Hz, 1H).

b) 3-{ 3-[3-(7-Hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of of 1.57 g (3 mmol) of ethyl 3-{3-[3-(7-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate obtained above, obtain 700 mg (47%) of the expected product in the form of a white powder with a melting point of 105-107oC.

Example 17

3-{ 3-[3-(5-Hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

a) Ethyl 3-{3-[3-(5-g the m to that in example 1(a), by the interaction of 1.20 g (2,90 mmol) ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-phenyl] acrylate obtained in example 13 (f), 727 mg (3,48 mmol) 5-bromopentanoate, obtain 1.42 g (92%) of the expected product in the form of a yellow oil.

1H NMR (CDCl3): of 1.26 to 1.37 (m, 17H), 1,50-to 1.67 (m, 4H), to 1.70 (s, 4H), for 2.01 (s, 3H), of 3.80 (s, 3H), of 3.80-4.00 points (m, 4H), 4,25 (kV, J=7,25 Hz, 2H), 6,30 (d, J= of 15.75 Hz, 1H), 6,84 (s, 1H), 6,94 (d, J=of 8.25 Hz, 1H), 7,17 (s, 1H), 7,44-of 7.48 (m, 2H), 7,66 (d, J=16.0 Hz, 1H).

b) 3-{ 3-[3-(5-Hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 1.42 g (to 2.65 mmol) of ethyl 3-{3-[3-(5-acetoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxy-phenyl} acrylate obtained above, obtain 730 mg (60%) of the expected product in the form of a white powder with a melting point 115-117oC.

Example 18

3-{ 3-[3-(3-Hydroxypropoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

a) Ethyl 3-{3-[3-(3-hydroxypropoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate

In a manner analogous to that in example 16(a), by reacting 1.2 g (2.9 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetrameth is getting 632 mg (47%) of the expected product in the form of a yellow oil.

1H NMR (CDCl3): of 1.27 and 1.35 (m, N), to 1.70 (s, 4H), 1.85 to of 1.92 (m, 2H), 1,96 (ush, 1H), to 3.64 (m, 2H), 3,82 (s, 3H), 4.09 to (t, J=5.5 Hz, 2H), 4,25 (kV, J= 7,25 Hz, 2H), of 6.31 (d, J=16.0 Hz, 1H), 6.87 in (s, 1H), of 6.96 (d, J=8.5 Hz, 1H), 7,15 (s, 1H), 7,44 (d, J=2.25 Hz, 1H), 7,49 (DD, J1=8.5 Hz, J2=2.25 Hz, 1H), 7,66 (d, J=16.0 Hz, 1H).

b) 3-{ 3-[3-(3-Hydroxypropoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 632 mg (1.35 mmol) of ethyl 3-{3-[3-(3-hydroxypropoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxy-phenyl} acrylate obtained above, receive 449 mg (75%) of the expected product in the form of a white powder with a melting point of 198-200oC.

Example 19

3-[3-(1-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylic acid

a) 1-Methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-Tetra-hydronephrosis

In a manner analogous to that in example 1(a), by reacting 8.65 g (42,4 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol with 3.55 ml (with 46.6 mmol) methoxymethane, receive a 10.5 g (100%) of the expected product.

b) 1-Methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naftalina acid

1 g (4 mmol) of 1-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene and 12 ml of THF are placed in a round bottom KGO - ByLi (1.3 M). The mixture was stirred at -78oC for 1 hour and then added to 1.4 ml (6 mmol) of triisopropylsilane and the mixture is allowed to warm to room temperature. At -40oWith add 3 ml of hydrochloric acid (5%) and the mixture is stirred at room temperature for 1 hour. The reaction medium is poured into water and extracted with ethyl acetate and the organic phase is decanted, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel, elwira a mixture of dichloromethane and methanol (98: 2). Collect 900 mg (77%) of the expected derivative of boric acid in the form of a pale yellow oil.

c) 3-[3-(1-Methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid

In a manner analogous to that in example 1(C), by reacting 3,4 g (11.6 mmol) of 1-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalene-boric acid from 1.32 g (5.8 mmol) of 3-bromcresol acid, pounding in heptane, to obtain 1.4 g(62%) 3-[3-(1-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylic acid in the form of a white powder with a melting point 188-9oC.

d) Methyl 3-[3-(1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8 - tetrahydro-2-naphthyl)phenyl]acrylate

1.24 g (3,15 mmol) 3-[3-(1-mitocnol and 15 ml of THF are placed in a round bottom flask. Add 620 μl of concentrated sulfuric acid and the mixture is stirred at room temperature for eight hours and heated under reflux for two hours. The reaction medium is poured into water and extracted with diethyl ether and the organic phase is decanted, dried over magnesium sulfate and evaporated. Gather 1.1 g (100%) of methyl 3-[3-(1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylate with a melting point 197-8oC.

e) Methyl 3-[3-(1-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylate

In a manner analogous to that in example 1(a), by reacting 500 mg (1.37 mmol) of methyl 3-[3-(1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylate with 180 μl (1.5 mmol) of benzyl bromide, get 550 mg (88%) of the expected product in the form of a yellow oil.

f) 3-[3-(1-Benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid

In a manner analogous to that in example 2(h), on the basis of 498 mg (1.01 mmol) of ethyl 3-[3-(1-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylate, get 360 mg(82%) 3-[3-(1-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylic acid with a melting point 153-4oC.

Example 20

3-{ TA

a) Tert-butyl - 6-bromopropyl

1,95 g (10 mmol) of 6-Bromophenol acid, dissolved in 10 ml of dichloromethane are placed in a round bottom flask in a stream of nitrogen. Added dropwise a solution 4,37 g (20 mmol) of tert-butyl 2,2,2-trichloroacetimidate in 20 ml of cyclohexane, and immediately 200 ál of Cryptosporidium. The mixture is stirred at room temperature for 5 minutes, add 5 g of sodium bicarbonate and the mixture is stirred for 1 minute. The resulting suspension was placed on a column of silica gel, which is pre-moistened with cyclohexane, and the last elute with a mixture of 8: 2 cyclohexane /ethyl acetate. After evaporation of the solvents to obtain 1.63 g (65%) of colorless oil.

1H NMR (CDCl3): 1,45 (s, N), 1,44 is 1.70 (m, 4H), to 1.87 (m, 2H), 2,33 (t, J=7.5 Hz, 2H), 3,41 (t, J=6.75 Hz, 2H).

b) Ethyl 3-{3-[3-(5-tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxy-phenyl}acrylate

In a manner analogous to that in example 1(a), by the interaction of 2.36 g (5.8 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-phenyl]acrylate obtained in example 13(f), 1.6 g (6.3 mmol) of tert-butyl 6-bromhexina received higher gain of 3.3 g (100%) of the expected product in the form of a yellow oil.

< is), 6,38 (s, 1H), 6,94 (d, J=8,75 Hz, 1H), 7,16 (s, 1H), 7,44-of 7.48 (m, 2H), 7,66 (d, J=16.0 Hz, 1H).

with) 3-{ 3-[3-(5-Tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

A solution of 1.0 g (1.7 mmol) 3-{3-[3-(5-tert-butoxy-carbonylmethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxyphenyl} acrylate obtained above, and dissolved in 25 ml of THF are placed in a round bottom flask and add 730 mg (17 mmol) of lithium hydroxide and 2 ml of water. The mixture is heated under reflux in THF for 8 hours and stirred at room temperature for 48 hours, the reaction medium is poured into water, acidified to pH 1 with hydrochloric acid and extracted with diethyl ether, the organic phase is decanted, dried over magnesium sulfate, filtered and evaporated. The obtained residue chromatographic on a column of silica gel, elwira mixture 8:2 heptane/ethyl acetate. After evaporation of the solvents will be collected 126 mg (14%) of a white powder with a melting point of 130-132oC.

Example 21

3-{ 3-[3-(7-Tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl} acrylic acid

a) Tert-butyl-6-bromooctanoate

In a manner analogous to that in example 21 (a), based on 3 g to 1.37 (m, 6N), the 1.44 (s, N), 1,50-1,75 (m, 2H), 1,75-of 1.95 (m, 2H), measuring 2.20 (t, J=7.5 Hz, 2H), 3,40 (t, J=6.75 Hz, 2H).

b) Ethyl 3-{3-[3-(7-tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate

In a manner analogous to that in example 1(a), by reacting 3,82 g (9,34 mmol) ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-phenyl]acrylate obtained in example 13(f), 3 g (about 10.7 mmol) of tert-butyl 8-bromooctanoate obtained above, get 4,36 g (77%) of the expected product in the form of a yellow oil.

1H NMR (CDCl3): 1,26-of 1.13 (m, N), the 1.44 (s, N), 1,43-of 1.65 (m, 4H), to 1.70 (s, 4H), of 2.16 (t, J=7,25 Hz, 2H), 3,80 (s, 3H), 3,88 (t, J=6.5 Hz, 2H), 4,24 (kV, J=7,0 Hz, 2H), 6,30 (d, J=of 15.75 Hz, 1H), 6,84 (s, 1H), 6,93 (d, J= of 8.25 Hz, 1H), 7,17 (s, 1H), 7,43-7,49 (m, 2H), 7,66 (d, J=of 15.75 Hz, 1H).

c) 3-{ 3-[3-(7-Tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

In a manner analogous to that in example 20 (C), on the basis of 1,15 g (1.9 mmol) 3-{ 3-[3-(7-tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxyphenyl} acrylate obtained above, receive 363 mg (33%) of the expected product in the form of a white powder with a melting point of 126-128oC.

Example 22

3-{ 3-[3-(7-Carboxymethoxy)-5,5,8,8-tetrame amatil-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate

A solution of 3.75 g (6,18 mmol) of ethyl 3-{3-[3-(7-tert-butoxycarbonyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2 - naphthyl] -4-methoxyphenyl} acrylate obtained in example 21(b), dissolved in 60 ml of dichloromethane are placed in a round bottom flask, add value of 4.76 ml (61,8 mmol) triperoxonane acid, the mixture is stirred at room temperature for four hours. The reaction medium is poured into water and extracted with diethyl ether, and the organic phase is decanted, dried over magnesium sulfate, filtered and evaporated. Obtain 3.4 g (100%) of the expected product in the form of a white foam.

1H NMR (CDCl3): of 1.26 and 1.35 (m, N), 1,50-to 1.67 (m, 4H), to 1.70 (s, 4H), 2,30 (t, J=7.5 Hz, 2H), 3,80 (s, 3H), 3,88 (t, J=6.25 Hz, 2H), 4,25 (kV, J= 7,25 Hz, 2H), of 6.31 (d, J=of 15.75 Hz, 1H), 6,84 (s, 1H), 6,94 (d, J=of 8.25 Hz, 1H), 7,17 (s, 1H), 7,44-7,49 (m, 2H), to 7.67 (d, J=16.0 Hz, 1H).

b) 3-{3-[3-(7-Carboxymethoxy)-5,5,8,8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

In a manner analogous to that in example 2(h), starting from 1 g (1.8 mmol) of ethyl 3-{3-[3-(7-carboxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxy-phenyl} acrylate obtained above, obtain 830 mg (88%) of the expected product in the form of a white powder with a melting point 212-214oC.

Example 23

3-{ 3-[3-(5-Carboxypentyl is Loxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate

In a manner analogous to that in example 22(a), on the basis of 2.3 g (of 3.97 mmol) of ethyl 3-{ 3-[3-(5-tert-butoxy-carbonylmethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxyphenyl} acrylate obtained in example 20(b) obtain 2.1 g (100%) of the expected product in the form of a white foam.

1H NMR (CDCl3): 1,24-of 1.42 (m, 17H), 1,55-1,70 (m, 8H), 2,28 (t, J=7,0 Hz, 2H), 3,80 (s, 3H), 3,91 (t, J=5,75 Hz, 2H), 4,25 (kV, J=7,25 Hz, 2H), 6,32 (d, J= of 15.75 Hz, 1H), 6,84 (s, 1H), 6,95 (d, J=9.0 Hz, 1H), 7,19 (s, 1H), 7,46 is 7.50 (m, 2H), 7,69 (d, J=16.0 Hz, 1H).

b) 3-{ 3-[3-(5-Carboxypentyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

In a manner analogous to that in example 2 (h), on the basis of 900 mg (1,72 mmol) of ethyl 3-{3-[3-(5-carboxypentyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate obtained above, receive 647 mg (76%) of the expected product in the form of a white powder with a melting point 166-168oC.

Example 24

3-{ 3-[3-(5-Carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

a) Ethyl 3-{ 3-[3-(5-carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate

A solution of 1.27 g (2,43 mmol) of ethyl 3-{ 3-[3-(5-carboxypentyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxy what type 505 μl (2.55 mmol) of dicyclohexylamine, the mixture is stirred for 10 minutes. Then added dropwise 186 μl (2.55 mmol) of thionyl chloride and the mixture is stirred at room temperature for 10 minutes. The reaction medium is evaporated to dryness, the resulting residue was transferred to diethyl ether, the suspension filtered and the filtrate dried. The resulting residue is dissolved in 15 ml of THF and the solution dropwise placed under nitrogen in a three-neck flask containing 20 ml of THF, 405 μl (2,92 mmol) of triethylamine and 160 μl of 34% aqueous solution of ammonia or 2.67 mmol). The mixture is stirred at room temperature for 30 minutes, the reaction medium is poured into water, acidified to pH 1 of 1 N. hydrochloric acid and extracted with diethyl ether, and the organic phase is decanted, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel, elwira with a mixture of heptane and ethyl acetate (80:20). After evaporation of the solvents receive 750 mg (60%) of the expected product in the form of a white powder with a melting point of 133-135oC.

b) 3-{ 3-[3-(5-Carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 900 mg (1.4 mmol) of ethyl 3-{ 3-[3-(5-carbamoylphenoxy)-5,5,8,8-reducta in the form of a white powder with a melting point 179-181oC.

Example 25

3-{ 3-[3-(7-Carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

a) Ethyl 3-{ 3-[3-(7-carbamoylphenoxy)-5,5,8,8-Tetra-methyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate

In a manner analogous to that in example 24(a), on the basis of 1.5 g (2,70 mmol) of ethyl 3-{3-[3-(7-carboxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxyphenyl } acrylate obtained in example 22(a), receive 1 g (68%) of the expected product in the form of a beige powder with a melting point 132-134oC.

b) 3-{ 3-[3-(7-Carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid

In a manner analogous to that in example 2(h), starting from 1 g (1.8 mmol) of ethyl 3-{ 3-[3-(7-carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] -4-methoxy-phenyl} acrylate obtained above, obtain 700 mg (74%) of the expected product in the form of a white powder with a melting point 199-201oC.

Example 26

3-{ 4-Methoxy-3-[5,5,8,8-tetramethyl-3-(2-morpholine-4-yl-ethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) Ethyl 3-{4-methoxy-3-[5,5,8,8-tetramethyl-3-(2-morpholine-4-yl-ethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate

In a manner analogous to the fact that the methoxy-phenyl]acrylate, obtained in example 13(f), with 760 mg (4,08 mmol) of 4-(2-chloroethyl)morpholine hydrochloride receive 1.5 g (85%) of the expected product in the form of a yellow oil.

1H NMR (CDCl3): 1,27 (C, 6N), of 1.29 and 1.35 (m, N), to 1.70 (s, 4H), is 2.37 (m, 4H), 2,60 (t, J=5,75 Hz, 2H) and 3.59 (m, 4H), 3,81 (s,3H), of 4.05 (t, J=5.50 Hz, 2H), 4,25 (kV, J= 7,0 Hz, 2H), 6,30 (d, J=of 15.75 Hz, 1H), 6,85 (s, 1H), 6,91-to 6.95 (m, 1H), 7,16 (s, 1H), 7,44-7,49 (m, 2H), 7,65 (d, J=16.0 Hz, 1H).

b) 3-{ 4-Methoxy-3-[5,5,8,8-tetramethyl-3-(2-morpholine-4-yl-ethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), starting from 1.5 g (2.9 mmol) of ethyl 3-{4-methoxy-3-[5,5,8,8-tetramethyl-3-(2-morpholine-4-yl-ethoxy)-5,6,7,8-tetrahydro-2-naphthyl] phenyl}acrylate obtained above, get 1,17 g (83%) of the expected product in the form of a white powder, which decomposes ranging from 140oC.

1H NMR (CD3OD (Ref.: kV if =2,85 ppm)): 0,79 (C, 6N), 0,87 (C, 6N), of 1.26 (s, 4H), 1,90 (m, 4H), to 2.18 (t, J=5.0 Hz, 2H), of 3.07 (m, 4H), and 3.31 (s, 3H), 3,61 (t, J=5.0 Hz, 2H), 5,91 (d, J=of 15.75 Hz, 1H), 6,45 (s, 1H), 6,56 (d, J=8.5 Hz, 1H), 6,62 (s, 1H), 6.87 in (d, J=1.75 Hz, 1H), 7,01-to 7.09 (m, 2H).

Example 27

3-{ 4-Methoxy-3-[5,5,8,8-tetramethyl-3-(2-piperidine-1-yl-ethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) Ethyl 3-{ 4-methoxy-3-[5,5,8,8-tetramethyl-3-(2-piperidine-1-yl-ethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) -4-methoxyphenyl]acrylate, obtained in example 13(f) and 760 mg (4,08 mmol) 1-(2-chloroethyl)piperidine hydrochloride, gain of 1.57 g (89%) of the expected product in the form of a colorless oil.

1H NMR (CDCl3): 1,22-to 1.38 (m, N), 1,46-of 1.55 (m, 4H), 1.69 in (m, 5H), a 2.36 (m, 4H), 2,60 (t, J=6.25 Hz, 2H), 3,81 (s, 3H), of 4.05 (t, J=6.0 Hz, 2H), 4,24 (kV, J=7,25 Hz, 2H), 6,30 (d, J=16.0 Hz, 1H), 6,85 (s, 1H), 6,93 (d, J= a 9.25 Hz, 1H), 7,16 (s, 1H), 7,44-of 7.48 (m, 2H), 7,66 (d, J=16.0 Hz, 1H).

b) 3-{ 4-Methoxy-3-[5,5,8,8-tetramethyl-3-(2-piperidine-1-yl-ethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of of 1.57 g (3 mmol) of ethyl 3-{ 4-methoxy-3-[5,5,8,8-tetramethyl-3- (2-piperidine-4-yl-ethoxy)-5,6,7,8-tetrahydro-2 - naphthyl]phenyl}acrylate obtained above, receive 900 mg (61%) of the expected product in the form of a white powder with a melting point 251-253oC.

Example 28

3-{ 4-Methoxy-3-[3-(2-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) 2-Methoxysalicylaldehyde

In a manner analogous to that in example 1 (a), by reacting 30 g (245 mmol) of 2-hydroxybenzaldehyde with 21 ml (270 mmol) of methoxymethane get 40,7 g (100%) of the expected product in the form of not-quite-white oil.

1H NMR (CDCl3): of 3.53 (s, 3H), 5,31 (s, 2H), to 7.09 (t, J=7 is oxyphenyl)methanol

A solution of 40 g (241 mmol) of 2-methoxysalicylaldehyde dissolved in 250 ml of THF are placed in a 2-l round-bottom

the flask in a stream of nitrogen and add small portions of 3.65 g (96 mmol) of lithium aluminum hydride. The reaction medium is stirred at room temperature for 15 minutes, before the slow hydrolysis with a saturated solution of ammonium chloride and then acidified to pH 1 of 1 N. hydrochloric acid. The reaction medium is extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate and the filtrate is evaporated. Collect of 39.2 g (96%) of colorless oil.

1H NMR (CDCl3): to 2.29 (m, 1H), 3,49 (s, 3H), 4,80 (d, J=6.0 Hz, 2H), 5.25 in (s, 2H), 6,98 for 7.12 (m, 2H), 7.23 percent-7,34 (m, 2H).

c) 2-Methoxyethoxymethyl

5.0 g (29.7 mmol) (2-methoxyethoxymethyl)methanol obtained above, 90 ml of dichloromethane and of 8.27 ml (59.5 mmol) of triethylamine are sequentially placed in a 250-ml three-neck flask in a stream of nitrogen. Then added dropwise 2.76 g (35,7 mmol) methanesulfonanilide and the mixture is stirred at room temperature for 1 hour. Reaction medium hydrolyzing with hydrochloric acid and extracted with dichloromethane, the organic phase is dried over magnesium sulfate and filtered and the filtrate is evaporated. The obtained orange is Ariane solvents gather 3.0 g (55%) of the expected product in the form of a yellow oil.

1H NMR (CDCl3): 3,50 (s, 3H), of 4.67 (s, 2H), 3,25 (s, 2H), 6,99 (TD, J1= 7.5 Hz, J2=1.0 Hz, 1H), 7,11 (d, J=7,75 Hz, 1H), 7.24 to 7,38 (m, 2H).

d) Ethyl 3-{ 4-methoxy-3-[3-(2-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate

In a manner analogous to that in example 1 (a), by reacting 2.5 g (6.12 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in example 13(f), 1.26 g (of 6.73 mmol) of 2-methoxyethoxymethyl obtained above, obtain 3.2 g (94%) of the expected product in the form of a yellow oil.

1H NMR (CDCl3): of 1.27 and 1.35 (m, 15 NM), was 1.69 (s, 4H), 3.43 points (s, 3H), 3,74 (s, 3H), 4,25 (kV, J=7,0 Hz, 2H), 5,07 (s, 2H), by 5.18 (s, 2H), 6,29 (d, J=16.0 Hz, 1H), 6.90 to-to 6.95 (m, 3H), 7,06 (d, J=7.5 Hz, 1H), 7,15-7,21 (m, 3H), 7,47 (DD, J1= 8.5 Hz, J2=2.25 Hz, 1H), 7,52 (d, J=2.25 Hz, 1H), 7,66 (d, J=16.0 Hz, 1H).

e) 3-{ 4-Methoxy-3-[3-(2-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 1.0 g (1.8 mmol) of ethyl 3-{4-methoxy-3-[3-(2-methoxyethoxyethoxy) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate obtained above, obtain 760 mg (80%) of the expected product in the form of a white powder with a melting point 159-161oC.

Example 29

3-{ 4- a) 3-Methoxysalicylaldehyde

In a manner analogous to that in example 1(a), by reacting 30 g (245 mmol) of 3-hydroxybenzaldehyde with 21 ml (270 mmol) of methoxyethoxymethyl get 40,7 g (100%) of the expected product in the form of a chestnut-brown oil.

1H NMR (CDCl3): to 3.49 (s, 3H), 5,23 (s, 2H), 7,27-7,32 (m, 1H), 7,42-of 7.55 (m, 3H), becomes 9.97 (s, 1H).

b) (3-Methoxyethoxymethyl)methanol

In a manner analogous to that in example 28(b), by reacting 40 g (240 mmol) of 3-methoxysalicylaldehyde with the 3.65 g (96 mmol) of lithium aluminum hydride, get 40,7 g (100%) of the expected product in the form of a colorless oil.

1H NMR (CDCl3): 1,83 (br, 1H), 3,48 (s, ZN), of 4.67 (s, 2H), by 5.18 (s, 2H), 6,94-7,06 (m, 3H), 7.24 to 7,31 (m, 1H).

c) 3-Methoxyethoxymethyl

In a manner analogous to that in example 28(C), by reacting 5.0 g (29.7 mmol) (3-methoxyethoxymethyl) methanol with 8,27 ml (59.5 mmol) of triethylamine and 2.76 ml (35,7 mmol) metatarsalphalangeal receive 2.66 g (48%) of the expected product in the form of a yellow oil.

1H NMR (CDCl3): of 3.48 (s, 3H), 4,55 (s, 2H), with 5.22 (s, 2H), 6,97-7,07 (m, 3H), 7.24 to 7,30 (m, 1H).

d) Ethyl 3-{ 4-methoxy-3-[3-(3-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl} acrylate

In a manner analogous to that in priceifinal] acrylate, obtained in example 13(f), 1.26 g (of 6.73 mmol) 3-methoxyethoxymethyl obtained above, get 2,90 g (85%) of the expected product in the form of a yellow oil.

1H NMR (CDCl3): of 1.27 and 1.35 (m, 15 NM), was 1.69 (s, 4H), 3.43 points (s, 3H), of 3.77 (s, 3H), 4,24 (kV, J=7,25 Hz, 2H), 4,99 (s, 2H), 5,09 (s, 2H), of 6.31 (d, J=of 15.75 Hz, 1H), 6,88-of 6.96 (m, 5H), 7,16-of 7.23 (m, 2H), 7,45-7,51 (m, 2H), to 7.67 (d, J=of 15.75 Hz, 1H).

e) 3-{ 4-Methoxy-3-[3-(3-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 1.0 g (1,79 mmol) ethyl 3-{4-methoxy-3-[3-(3-methoxyethoxyethoxy) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate obtained above, get 813 mg (85%) of the expected product in the form of a white powder with a melting point of 144-146oC.

Example 30

3-{ 4-Methoxy-3-[3-(4-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) 4-Methoxysalicylaldehyde

In a manner analogous to that in example 1 (a), by reacting 30 g (245 mmol) of 4-hydroxybenzaldehyde with 21 ml (270 mmol) of methoxyethoxymethyl get 40,7 g (100%) of the expected product in the form of an orange oil.

1H NMR (CDCl3): to 3.49 (s, 3H), 5,28 (s, 2H), 7,15 (d, J=8,75 Hz, 2H), to 7.84 (d, J=8,75 ), by reacting 40 g (240 mmol) of 4-methoxysalicylaldehyde with the 3.65 g (96 mmol) of lithium aluminum hydride, to obtain 15 g (37%) of the expected product in the form of a colorless oil.

1H NMR (CDCl3): 1,71 (t, J=5,75 Hz, 1H), 3,47 (s, 3H), br4.61 (d, J=5,75 Hz, 2H), 5,17 (s, 2H), 7,02 (d, J=8.5 Hz, 2H), 7,29 (d, J=8.5 Hz, 2H).

c) 4-Methoxyethoxymethyl

In a manner analogous to that in example 28(C), by reacting 5.0 g (29.7 mmol) (4-methoxyethoxymethyl) methanol with 8,27 ml (59.5 mmol) of triethylamine and 2.76 ml (35,7 mmol) metatarsalphalangeal receive 2.66 g (48%) of the expected product in the form of a yellow oil.

1H NMR (CDCl3): 3,47 (s, 3H), 4,56 (s, 2H), 5,17 (s, 2H), 7,02 (d, J= 8,75 Hz, 2H), 7,31 (d, J=8,75 Hz, 2H).

d) Ethyl 3-{ 4-methoxy-3-[3-(4-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl} acrylate

In a manner analogous to that in example 1(a), by reacting 2.5 g (6.12 mmol) of ethyl 3-[3-(3-hydroxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in example 13 (f), 1.26 g (of 6.73 mmol) of 4-methoxyethoxymethyl obtained above, obtain 3.0 g (87%) of the expected product in the form of a white powder with a melting point 106-108oC.

e) 3-(4-Methoxy-3-[3-(4-methoxyethoxyethoxy)-5,5,8,(h), on the basis of 1.0 g (1,79 mmol) ethyl 3-{4-methoxy-3-[3-(4-methoxyethoxyethoxy) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate obtained above, receive 877 mg (91%) of the expected product in the form of a white powder with a melting point of 184-186oC.

Example 31

3-{ 4-Methoxy-3-[3-(3-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) Ethyl 3-{ 4-methoxy-3-[3-(3-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate

In a manner analogous to that in example 2(g), but in ethanol as solvent, on the basis of the 1.9 g (3.4 mmol) of ethyl 3-{4-methoxy-3-[3-(3-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] phenyl} acrylate obtained in example 29(a), gain of 1.38 g (79%) of the expected product in the form of a white powder with a melting point 131-133oC.

b) 3-{ 4-Methoxy-3-[3-(3-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 1,11 g (of 2.16 mmol) ethyl 3-{ 4-methoxy-3-[3-(3-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate obtained above, obtain 1.0 g (95%) of the expected product in the form of a white powder with a melting point 229-231oC.

oC.

Example 33

3-{ 4-Hydroxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) 2-Bromo-3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen

In a manner analogous to that in example 1(a), by reacting 5.0 g (about 17.7 mmol) of 2-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene with 3.0 g (to 19.4 mmol) of 3-methoxybenzylamine get 7,14 g (100%) of the expected product in the form of a chestnut-brown oil.

1H NMR (CDCl3): 1,21 (C, 6N), 1,24 (s, 6N), of 1.64 (s, 4H), 3,82 (s, 3H), 5,09 (s, 2H), 6,83-6,87 (m, 2H), 7.03 is-was 7.08 (m, 2H), 7,29 (m, 1H), 7,43 (s, 1H).

b) 3-(3-Methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naftalina acid

In a manner analogous to that in example 1(b), on the basis of 7,10 g (17.6 mmol) of 2-bromo-3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene obtained above, get 4,85 g (74%) of the expected product in V (s, 2H), 6,85-7,0 (m, 3H), 7,31 (t, J=7,75 Hz, 1H), 7,78 (s, 1H).

c) Ethyl 3-(3-bromo-4-methoxyethoxymethyl)acrylate

In a manner analogous to that in example 2(C), by reacting 30 g (122 mmol) of ethyl 3-(3-bromo-4-methoxyethoxymethyl)acrylate obtained above, with 30,27 g (135 mmol) of triethylphosphite get 34,6 g (90%) of the expected product in the form of white crystals with a melting point 64-66oC.

d) Ethyl 3-(3-bromo-hydroxyphenyl)acrylate

In a manner analogous to that in example 2(g), on the basis of 30 g (95 mmol) of ethyl 3-(3-bromo-4-methoxyethoxymethyl)acrylate obtained above, the gain of 25.8 g (100%) of the expected product in the form of a white powder with a melting point of 113-115oC.

(e) Ethyl 3-{ 4-hydroxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate

In a manner analogous to that in example 1(C), by reacting 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained above, from 1.77 g (4.8 mmol) of 3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-afterborn acid obtained in example 33(C), obtain 630 mg (33%) of the expected product in the form of a colorless oil.

1H NMR (CDCl3): 1,25-of 1.36 (m, 15 NM), to 1.70 (s, 4H), of 3.78 (s, 3H), 4.26 deaths (kV, J=7,25 Hz, 2H), 4,99 (s, 2H), 6,32 (d, J=of 15.75 Hz, 1H), 6,84 (d, the C-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 600 mg (1,16 mmol) ethyl 3-{4-hydroxy-3-[3-(3-methoxybenzyloxy) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] phenyl}acrylate obtained above, receive 539 mg (95%) of the expected product in the form of a white powder with a melting point 197-199oC.

Example 34

3-{ 4-Hydroxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) 2-Bromo-3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen

In a manner analogous to that in example 1(a), by reacting 5.0 g (17,7 mmol) 3-hydroxy-2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene with 3.0 g (to 19.4 mmol) of 4-methoxybenzylamine get 7,14 g (100%) of the expected product in the form of a chestnut-brown oil.

1H NMR (CDCl3): 1,21 (C, 6N), 1,24 (s, 6N), of 1.64 (s, 4H), 3,81 (s, 3H), 5,04 (s, 2H), 6,83 (s, 1H), 6,92 (d, J=7.5 Hz, 2H), 7,39 (d, J=7.5 Hz, 2H), 7,43 (s, 1H).

b) 3-(4-Methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naftalina acid

In a manner analogous to that in example 1(b), on the basis of 7,14 g (about 17.7 mmol) of 2-bromo-3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene obtained above, get 3,55 g (54%) of the expected product in the form of an orange oil.

<78 (s, 1H).

c) Ethyl 3-{ 4-hydroxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate

In a manner analogous to that in example 1(C), by reacting 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in example 33(d) with 2.0 g (5.5 mmol) of 3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-afterborn acid, obtained above, obtain 930 mg (49%) of the expected product in the form of a colorless oil.

1H NMR (CDCl3): of 1.29 (s, N), of 1.34 (t, J=7.0 Hz, 3H), of 1.70 (s, 4H), and 3.72 (s, 3H), 4.26 deaths (kV, J=7,25 Hz, 2H), 5,02 (s, 2H), 6,33 (d, J=of 15.75 Hz, 1H), 6,70 (s, 1H), 6,80-6,87 (m, 3H), 7,02 (d, J=7,25 Hz, 2H), 7.18 in-7,25 (m, 2H), 7,42 (d, J=2.25 Hz, 1H), of 7.48 (d, J=8.5 Hz, 1H), 7,69 (d, J=16.0 Hz, 1H).

d) 3-{ 4-Hydroxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 930 mg (1.8 mmol) of ethyl 3-{ 4-hydroxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] phenyl} acrylate obtained above, receive 800 mg (91%) of the expected product in the form of a white powder with a melting point of 170-172oC.

Example 35

3-{ 4-Hydroxy-3-[3-(4-forbindelse)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) 2-Bromo-3-(4-terbisil the actions of 5.0 g (17,7 mmol) 3-hydroxy-2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene from 3.67 g (to 19.4 mmol) of methyl 4-Formentera, obtain 4.3 g (62%) of the expected product in the form of a bright chestnut-brown crystals with a melting point of 74-76oC.

b) 3-(4-Forbindelse)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naftalina acid

In a manner analogous to that in example 1 (b), on the basis of 4.3 g (11.0 mmol) of 2-bromo-3-(4-forbindelse)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene obtained above, get 3,24 g (83%) of the expected product in the form of an orange oil.

1H NMR (Dl3): 1,27 (C, 6N), 1,29 (C, 6N), to 1.67 (s, 4H), to 5.08 (s, 2H), of 5.81 (s, 2H), 7,06-7,13 (m, 2H), 7,38-the 7.43 (m, 2H), 7,80 (s, 1H).

c) Ethyl 3-{ 4-hydroxy-3-[3-(4-forbindelse)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate

In a manner analogous to that in example 1(C), by reacting 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in example 33(d) of 1.97 g (5.5 mmol) of 3-(4-forbindelse)-5,5,8,8-tetramethyl-5,6,7, 8-tetrahydro-2-afterborn acid, obtained above, get 825 mg (44%) of the expected product in the form of a white precipitate with a melting point of 123-125oC.

d) 3-{ 4-Hydroxy-3-[3-(3-forbindelse)-5,5,8,8 - tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 800 mg (1.6 mmol) of ethyl 3-{ 4-hydroxy-3-[3-( expected product in the form of a white powder with a melting point of 157-159oC.

Example 36

3-{ 4-Hydroxy-3-[3-(4-chlorobenzoyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) 2-Bromo-3-(4-chlorobenzoyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen

In a manner analogous to that in example 1(a), by reacting 5.0 g (17,7 mmol) 3-hydroxy-2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene with 3.12 g (to 19.4 mmol) of 4-chlorobenzylchloride get 7,22 g (100%) of the expected product in the form of a pale chestnut-brown crystals with a melting point of 108-110oC.

b) 3-(4-Chlorobenzoyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naftalina acid

In a manner analogous to that in example 1(b), on the basis of 7,14 g (17.5 mmol) of 2-bromo-3-(4-chlorobenzoyloxy)-5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydronaphthalene obtained above, obtain 3.50 g (54%) of the expected product in the form of an orange oil.

1H NMR (Dl3): 1,26 (C, 6N), 1,29 (C, 6N), to 1.67 (s, 4H), 5,09 (s, 2H), 5,72 (s, 2H), at 6.84 (s, 1H), 7,37 (m, 4H), 7,80 (s, 1H).

c) Ethyl 3-{ 4-hydroxy-3-[3-(4-chlorobenzoyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate

In a manner analogous to that in example 1(C), by reacting 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-HYDR oksifenil)acrylate obtained in example 33(d) from 2.05 g (5.5 mmol) of 3-(4-Klooga product in the form of a white precipitate with a melting point of 152-154oC.

d) 3-{ 4-Hydroxy-3-[3-(4-chlorobenzoyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), on the basis of 580 mg (1.12 mmol) of ethyl 3-{ 4-hydroxy-3-[3-(4-chlorobenzoyloxy) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] phenyl}acrylate obtained above, get 382 mg (70%) of the expected product in the form of a white powder with a melting point 147-149oC.

Example 37

3-[4-Hydroxy-3-(3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid

a) Ethyl 3-[4-hydroxy-3-(3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylate

In a manner analogous to that in example 1(C), by reacting 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in example 33(d) with 1.6 g (5.5 mmol) of 3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-afterborn acid obtained in example 13(b), 150 mg (9%) of the expected product in the form of a white precipitate with a melting point of 101-103oC.

d) 3-{ 4-Hydroxy-3-[3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2(h), starting from 150 mg (0.34 mmol) of ethyl 3-{4-hydroxy-3-[3-methoxyethoxy)-5,5,8,8-tetr is a white powder with a melting point 191-193oC.

Example 38

3-(3', 5'-Decret-butyl-6-hydroxy-2'-propyloxy-3-biphenylyl) acrylic acid

a) 1-Bromo-3,5-decret-butyl-2-proproxyphene

In a manner analogous to that in example 1(a), by reacting 15 g (for 52.6 mmol) 6-bromo-2,4-decret-butyl-phenol with 7.4 g (57,9 mmol) of 1-bromopropane, gain of 17.2 g (100%) of the expected product in the form of orange crystals with a melting point 41-43oC.

b) 2-Propyloxy-3,5-decret-butylaniline acid

In a manner analogous to that in example 1(b), on the basis of 16.0 g (48,9 mmol) 1-bromo-3,5-decret-butyl-2-propyl-oxybenzone received higher gain of 9.1 g (63%) of the expected product in the form of a white powder with a melting point of 104-106oC.

c) Ethyl 3-(3', 5'-decret-butyl-6-hydroxy-2'-propyloxy-3-biphenylyl)acrylate

In a manner analogous to that in example 1(C), by reacting 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxy-phenyl)acrylate obtained in example 33(d), 2.14 g (7,33 mmol) 2-propyloxy-3,5-decret-butylaniline acid, obtained above, will receive 70 mg (4%) of the expected product in the form of a colorless oil.

1H NMR (Dl3): of 0.85 (t, J=7.5 Hz, 3H), of 1.34 (s, N), of 1.40 (t, J=7,75 Hz, 3H), 1,45 (s, N), 1,55-to 1.59 (m, 2H), 3.43 points-of 3.65 (m, 2H), 4,27 (kV, J= of 8.25 Hz, 2H), 6,37 (d, J=of 15.75 Hz, 1 is t-butyl-6-hydroxy-2'-propyloxy-3-biphenylyl)acrylic acid

In a manner analogous to that in example 2(h), starting from 70 mg (0.16 mmol) of ethyl 3-(3', 5'-decret-butyl-6-hydroxy-2'-propyloxy-3-biphenylyl)acrylate obtained above, receive 50 mg (75%) of the expected product in the form of a white powder with a melting point 187-189oC.

Example 39

3-(3',5'-Decret-butyl-6-hydroxy-2'-Butylochka-3-biphenylyl)acrylic acid

a) 1-Bromo-3,5-decret-butyl-2-butylacetate

In a manner analogous to that in example 1(a), by reacting 15 g (for 52.6 mmol) of 2-bromo-4,6-decret-butylphenol with of 7.93 g (57,9 mmol) 1-bromobutane get to 17.7 g (100%) of the expected product in the form of an orange oil.

1H NMR (Dl3): 0,99 (t, J=7.5 Hz, 3H), 1.28 (in C, N), of 1.39 (s, N), 1,45-to 1.60 (m, 2H), 1,80-of 1.92 (m, 2H), a 4.03 (t, J=7,0 Hz, 2H), 7,27 (d, J=2.5 Hz, 1H), 7,39 (d, J=2.5 Hz, 1H).

b) 2-Butylochka-3,5-decret-butylaniline acid

In a manner analogous to that in example 1(b), on the basis of 16.0 g (46.8 mmol) of 1-bromo-3,5-decret-butyl-2-butyl-oxybenzone obtained above, obtain 14 g (97%) of the expected product in the form of a white powder with a melting point 92-94oC.

c) Ethyl 3-(3', 5'-decret-butyl-6-hydroxy-2'-Butylochka-3-biphenylyl)acrylate

In a manner analogous to that in example 1(C), by reacting 6.2 g (of 22.8 mmol) of ethyl 3-(3-br is islote, obtained above, obtain 700 mg (7%) of the expected product in the form of a yellow oil.

1H NMR (Dl3): 0,78 (t, J=7.5 Hz, 3H), 1,31-of 1.56 (m, 25N), 3,20-3,66 (m, 2H), 4,27 (kV, J=7,25 Hz, 2H), 6,37 (d, J=16.0 Hz, 1H), 7,06 (d, J=of 8.25 Hz, 1H), 7,16 (d, J= 2.5 Hz, 1H), 7,30 (s, 1H), 7,43 (d, J=2.25 Hz, 1H), 7,49-of 7.55 (m, 2H), 7,72 (d, J=16.0 Hz, 1H).

d) 3-(3',5'-Decret-butyl-6-hydroxy-2'-Butylochka-3-Biff-nilil)acrylic acid

In a manner analogous to that in example 2(h), on the basis of 430 mg (0.95 mmol) of ethyl 3-(3', 5'-decret-butyl-6-hydroxy-2'-Butylochka-3-biphenylyl)acrylate obtained above, receive 300 mg (74%) of the expected product in the form of a white powder with a melting point 194-196oC.

Example 40

3-(2'-Butoxy-3', 5'-Decret-butyl-6-methoxy-3-biphenylyl) acrylic acid

a) Ethyl 3-(2'-butoxy-3',5'-decret-butyl-6-methoxy-3-biphenylyl)acrylate

In a manner analogous to that in example 1(a), by reacting 230 mg (0.5 mmol) of ethyl 3-(3',5'-decret-butyl-6-hydroxy-2'-Butylochka-3-biphenylyl) acrylate obtained in example 39(s), with 82 mg (of 0.58 mmol) of iodomethane, obtain 230 mg (100%) of the expected product in the form of a yellow oil.

1H NMR (Dl3): of 0.67 (t, J=of 7.25 Hz, 3H), of 1.07 (m, 2H), 1,25-of 1.36 (m, 14N), USD 1.43 (s, N), 3,40 (ush, 2N), of 3.84 (s, 3H), 4,25 (kV, J=7,0 Hz, 2H), 6,33 (d, J= 15,5 Hz, 1H), 6,98 (d, J=8.5 Hz, 1H), 7,11 (d, J=2.25 Hz, et-butyl-6-methoxy-3-biphenylyl)acrylic acid

In a manner analogous to that in example 2(h), starting from 230 mg (0.51 mmol) of ethyl 3- (2'-butoxy-3',5'-decret-butyl-6-methoxy-3-biphenylyl)acrylate obtained above, obtain 120 mg (55%) of the expected product in the form of a white powder with a melting point 204-206oC.

Example 41

3-(3', 5'-Decret-butyl-6-methoxy-2'-propoxy-3-biphenylyl)acrylic acid

a) Ethyl 3-(3',5'-decret-butyl-6-methoxy-2'-propoxy-3-biphenylyl)acrylate

In a manner analogous to that in example 1(C), by reacting 1.0 g (3.5 mmol) of ethyl 3-(3-bromo-4-methoxyphenyl)acrylate obtained in example 13(d), 1.54 g (5,26 mmol) 2-propyloxy-3,5-decret-butylaniline acid obtained in example 38(b) obtain 1.20 g (76%) of the expected product in the form of a white powder with a melting point of 107-109oC.

b) 3-(3', 5'-Decret-butyl-6-methoxy-2'-propoxy-3-biphenylyl)acrylic acid

In a manner analogous to that in example 2 (h), on the basis of 1.0 g (2.2 mmol) of ethyl 3-(3',5'-decret-butyl-6-methoxy-2'-propoxy-3-biphenylyl)acrylate obtained above, receive 800 mg (85%) of the expected product in the form of a white powder with a melting point 207-209oC.

Example 42

3-[4-Hydroxy-3-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid

a) 3A 2-l three-neck flask in a stream of nitrogen and added dropwise a solution of 25 g (145 mmol) of 3-bromophenol in 100 ml of dichloromethane, the mixture is stirred at room temperature for 15 minutes. Then pour the solution 26,2 g (143 mmol) of 2,5-dichloro-2,5-dimethylhexane in 100 ml of dichloromethane and the mixture is stirred at room temperature for 1 hour. Then added in four portions a solution of 40 g (218 mmol) of 2,5-dichloro-2,5-dimethylhexane in 200 ml of dichloromethane under stirring for one hour between each addition and the mixture is stirred for 15 hours. Dichloromethane is evaporated from the reaction medium, the remainder is transferred to the ethyl acetate and water and the organic phase is decanted, dried over magnesium sulfate, filtered and evaporated. The resulting residue is purified by chromatography on silica gel, elwira first with heptane and then with a mixture of 95:5 heptane/ethyl acetate. After evaporation of the solvents receive 30 g (73%) of the expected product in the form of oily black crystals.

1H NMR (Dl3): 1,25 (C, 6N), to 1.38 (s, 6N), 1,58-to 1.67 (m, 4H), 4,99 (s, 1H), and 6.25 (d, J=2.0 Hz, 1H),? 7.04 baby mortality (d, J=2.0 Hz, 1H).

b) 2-Bromo-4-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen

In a manner analogous to that in example 1(a), by interaction of 18 g (63,6 mmol) 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahedronal-1-ol, obtained in the preceding example, from 8.61 g (70 mmol) of 1-bromopropane, polyoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naftalina acid

In a manner analogous to that in example 1(b), on the basis of 16.0 g (up 49.2 mmol) of 2-bromo-4-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene obtained above, obtain 6.2 g (46%) of the expected product in the form of a white powder with a melting point 230-232oC.

d) Ethyl 3-[4-hydroxy-3-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylate

In a manner analogous to that in example 1(C), by reacting 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in example 33(d), from 1.61 g (5.5 mmol) of 4-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-Tetra-hydro-2-afterborn acid obtained in example 42(C), obtain 640 mg (40%) of the expected product in the form of a white powder with a melting point of 114-116oC.

e) 3-[4-Hydroxy-3-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid

In a manner analogous to that in example 2(h), on the basis of 640 mg (1,47 mmol) ethyl 3-[4-hydroxy-3-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylate obtained above, obtain 270 mg (45%) of the expected product in the form of a white powder with a melting point 209-211oC.

Example 43

3-{ 4-Methoxy-3-[3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

a) Ethyl 3-{4-method in example 1(a), by the interaction of 1.40 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-phenyl]acrylate obtained in example 13(f), with 450 ál (of 3.77 mmol) benzyl bromide, obtain 1.64 g (97%) of the expected product in the form of a yellow oil.

1H NMR (Dl3): of 1.28 and 1.35 (m, 15 NM), was 1.69 (s, 4H), 3,76 (s, 3H), 4,25 (kV, J= 7,0 Hz, 2H), 5,02 (s, 2H), 6,30 (d, J=of 15.75 Hz, 1H), 6.89 in (s, 1H), 6,93 (d, J=of 8.25 Hz, 1H), 7,19 (s, 1H), 7,20-to 7.35 (m, 5H), 7,43-7,52 (m, 2H), to 7.67 (d, J=16.0 Hz, 1H).

b) 3-{4-Methoxy-3-[3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid

In a manner analogous to that in example 2 (h), on the basis of 1.64 g (3.3 mmol) of ethyl 3-{4-methoxy-3-[3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate obtained above, obtain 1.27 g (82%) of the expected product in the form of a white powder with a melting point 200-202oC.

Example 44

3-Methyl-5-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]Penta-2,4-diene acid

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

In a manner analogous to that in example 1(C), by reacting 2.0 g (8,12 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-afterborn acid (prepared in example 5(a) on patent application WO 97/33881) and 1.89 g (10,15 mmol) 3-bromo-benzaldehyde tag-5-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]Penta-2,4-dienoate

In a manner analogous to that in example 2(C), by reacting 2.0 g (6,53 mmol) of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)benzaldehyde, obtained in the previous example, and 1.90 g (7.20 mmol) of triethyl 3-methyl-4-phosphorothionate, gain of 1.80 g (66%) of the expected product in the form of a white powder with a melting point 83-85oC.

C) 3-Methyl-5-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-Tetra-hydro-2-naphthyl)phenyl]Penta-2,4-diene acid

In a manner analogous to that in example 2(h), based on a 1.00 g (2.4 mmol) of ethyl 3-methyl-5-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] Penta-2,4-dienoate obtained above, and after separation of the isomers by column with fine-grained silica gel (7-35 μm), elwira a mixture of 95:5 heptane/ethyl acetate, to obtain 420 mg (45%) of the expected product in the form of a white powder with a melting point of 218-220oC.

Century Examples test

Performed biological tests described in this application. The results are compared in the following table:

C. Examples of dosage forms

1) introduction through the mouth

a) Prepare the following composition in the form of 0.8-g tablet:

connection example 3 - 0,005 grams

pre gelatinizing starch - 0,265 g

microcrystalline whole who will be assigned 1-3 tablets a day for 3-6 months, depending on the severity of injury.

b) Suspension, suitable for drinking, for packaging in 5-ml vials prepared:

connection example 2 - 0,050 g

glycerin - 0,500 g

70% sorbitol - 0,500 g

sodium saccharinate - 0,010 g

methyl para-hydroxybenzoate - 0,040 g

flavoring substance - qs

purified water qs 5 ml

To treat acne adult individual will be assigned to 1 bottle a day for 3 months, depending on the severity of injury.

c) Prepare the following composition for inclusion in gelatin capsules:

the compound from example 5 - 0,025 g

corn starch - to 0.060 g

lactose qs - 0,300 g

Used gelatin capsule consists of gelatin, titanium oxide and preservative.

For the treatment of psoriasis, an adult individual will be assigned 1 gelatin capsule per day within 30 days.

2) Local path

a) Prepare the following does not contain ions cream water-in-oil:

the compound from example 6 - 0,100 g

the mixture of emulsifying lanolin alcohols, waxes and refined oils sold by BDF called "anhydrous Eucerin" - 39,900 g

methyl para-hydroxybenzoate - 0.075 g

propyl para-hydroxybenzoate - 0.075 g

sterile times a day for 30 days.

b) Preparing a gel, making the following composition:

the compound from example 18 - 0,050 g

erythromycin base - 4,000 grams

equivalent - 0,500 g

hydroxypropylcellulose sold by the company Hercules under the name "Klucel HF" - 2,000 g

ethanol (95o) qs - 100,000 g

This gel will be applied to the skin affected by dermatitis, or skin with acne, 1-3 times a day for 6-12 weeks, depending on the severity of injury.

c) Prepare antiseborrheic lotion by mixing the following components:

the compound of example 4 - 0,030 g

propylene glycol - 5,00 g

equivalent - 0,100 g

ethanol (95o) qs - 100,000 g

This lotion should be applied twice daily to the scalp seborrhea, and significant improvement was observed in the period between 2-6 weeks.

d) a Cosmetic composition against the harmful effects of the sun are prepared by mixing the following components:

the compound from example 24 - 1,000 grams

benzylideneamino - 4,000 grams

triglycerides of fatty acids - 31,000 g

glycerylmonostearate - 6,000 g

stearic acid - 2,000 g

cetyl alcohol - 1,200 g

lanolin - 4,000 grams

preservatives - 0,300 g

propylene glycol - 2,000 g

triethanolamine - 0,500 g

aromatise is possible to deal with induced light - skin aging.

e) Prepare the following does not contain ions cream oil-in-water:

the compound from example 37 - 0,500 g

vitamin D3at 0.020 g

cetyl alcohol - 4,000 grams

glycerylmonostearate - 2,500 grams

PEG-50 stearate - 2,500 grams

Carinae oil - 9,200 g

propylene glycol - 2,000 g

methyl para-hydroxybenzoate - 0.075 g

propyl para-hydroxybenzoate - 0.075 g

sterile deionized water qs - 100,000 g

This cream will be applied to the psoriatic skin, once or twice a day for 30 days.

(f) Gel for topical application is prepared by mixing the following components:

the compound from example 19 - 0,050 g

ethanol - 43,000 g

-tocopherol - 0,050 g

carboxyvinyl polymer sold under the name "Carbopol 941" by the company "Goodrich" - 0,500 g

triethanolamin in the form of an aqueous solution at 20% by weight - 3,800 g

water - 9,300 g

propylene glycol qs - 100,000 g

This gel will be applied in the treatment of acne 1-3 times a day for 6-12 weeks depending on the severity of injury.

(g) hair Lotion against hair loss and enhance hair growth is prepared by mixing the components:

the compound of example 40 - 0.05 g

the compound sold under the weight=400) - 40,00 g

butylhydroxyanisole - 0.01 g

equivalent - 0.02 g

water qs - 100,00 g

This lotion is to be applied twice a day for 3 months on the scalp of an individual suffering from significant hair loss.

h) Cream against acne is prepared by mixing the following components:

the compound from example 13 - 0,050 g

retinoic acid - 0,010 g

a mixture of glitzenstein and polietilenglikolmonostearat (75 mol) sold under the name "Gelot 64" by the company "Gattefosse" - 15,000 g

palm kernel oil, polypolystyrene 6 moles of ethylene oxide, sold under the name "Ladrafil M CS" by the company "Gattefosse" - 8,000 g

perhydrosqualene - 10,000 g

preservatives qs

polyethylene glycol (molecular weight=400) - 8,000 g

the disodium salt of ethylendiaminetetraacetic acid - 0,05

purified water - 100,000 g

This cream will be applied to the skin affected by dermatitis, or acne skin 1-3 times a day for 6-12 weeks.

i) Cream oil-in-water is prepared by preparing the following composition:

the compound from example 28 - 0,020 g

betamethasone 17-valerat - 0,050 g

S-carboxymethylcysteine - 3,000 grams

polyoxyethylenated (40 mol of ethylene oxide) sold supplied under the name "Tween 20" by "Atlas" - 1,800 g

a mixture of glycerine and distearate sold under the name "Geleol" by "Gattefosse" - 4,200 g

propylene glycol - 10,000 g

butylhydroxyanisole - 0,010 g

equivalent - 0,020 g

cetostearyl alcohol - 6,200 g

conservancy - qs

perhydrosqualene - 18,000 g

a mixture of triglycerides of Caprylic/capric acids, sold under the name "Miglyol 812" by the company "Dynamit Nobel" - 4,000 grams

triethanolamine (99 mass%) - 2,500 grams

water qs - 100,000 g

This cream should be applied twice daily on the skin affected by dermatitis within 30 days.

j) Prepare the following cream oil-in-water:

lactic acid - 5,000 g

the compound from example 32 - 0,020 g

polyoxyethylenated (40 mol of ethylene oxide) sold under the name "Myrj 52" by "Atlas" - 4,000 grams

sorbitanoleat, polyoxyethylene 20 moles of ethylene oxide, sold under the name "Tween 20" by "Atlas" - 1,800 g

a mixture of glycerine and distearate sold under the name "Geleol" by "Gattefosse" - 4,200 g

propylene glycol - 10,000 g

butylhydroxyanisole - 0,010 g

equivalent - 0,020 g

cetostearyl alcohol - 6,200 g

preservatives qs

perhydrosqualene - 18,000 g

a mixture of triglycerides ka
This cream should be applied once a day, and it will help to fight aging, as induced by light or associated with age.

1. Compounds characterized in that they correspond to the General formula (I)

< / BR>
in which R1represents (i)- (CH3ii) -CH2OR2iii) -R3;

R2and R3have the meanings given below;

Ar1represents a radical selected from radicals of formulae (a) to(C) below

< / BR>
< / BR>
< / BR>
R4, R5, R6, R7, R8, R9, R10and R11have the meanings given below;

AG2is a radical (d)

< / BR>
X represents a radical selected from radicals of formulae (i), (j) and (l) below

< / BR>
< / BR>
R2represents a hydrogen atom, a lower alkyl or a radical CO-R16,

R3represents-OR17;

R4represents a hydrogen atom, -OR18,

R5represents lower alkyl;

R6represents tert-butyl;

R7is a OR20, lower alkyl;

R8represents tert-butyl, substituted;

R9and R10, Satyabhama;

R11represents a lower alkyl containing from 1 to 9 carbon atoms, lower alkoxy, OR21polyester group,

R12represents a hydrogen atom, hydroxyl, alkoxy, OR22polyester group;

R14and R15that may be the same or different, represent a hydrogen atom or lower alkyl;

R16represents lower alkyl;

R17represents a hydrogen atom;

R18and R20may be the same or different and represent lower alkyl;

R20represents a

< / BR>
R21and R22that may be the same or different, represent monohydroxyethyl, phenyl, optionally substituted C1-C9by alkyl, hydroxyl, C1-C3alkoxygroup or halogen, aralkyl, optionally substituted with halogen, lower alkyl, lower alkoxy, hydroxyl or a polyester group, or a group -(CH2)nR24;

R24is monohydroxyethyl, COOR25, CON(R26R27, a heterocycle, such as morpholino, piperidino;

R25represents a lower alkyl, a hydrogen atom;

R26and R27 what kind and from 1 to 3 oxygen atoms;

n is an integer such that 2n9, provided that when Ar1represents a radical of formula (C) and X is a radical of the formula (i) or (j), then R11represents-OR21or a polyester group, or AG2represents a radical of formula (a), where R12represents-OR22or a polyester group,

the compounds of formula (I) are different from those where R11represents methoxyethoxy in anthopology in relation to the Deputy AG2; when Ar1represents a radical of formula (C), X represents a radical of the formula (i), R12represents hydrogen and R1represents R3where R3represents-OR17and R17represents hydrogen;

R12represents methoxyethoxy in ortho - or paraprotein against the Deputy Ar1; when Ar1represents a radical of formula (C), X represents a radical of the formula (i), R11represents methyl in anthopology against AG2, R1represents R3where R3represents-OR17and R17represents hydrogen.

2. Connection on p. 1, otlichayushiesya one of the preceding paragraphs, wherein the alkoxy is selected from methoxy, propyloxy, pentyloxy or heptyloxy.

4. Join one of the preceding paragraphs, characterized in that monohydroxyethyl corresponds to a radical containing 2 or 3 carbon atoms, in particular 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.

5. Join one of the preceding paragraphs, characterized in that the polyester selected from the group methoxymethanol, methoxyethoxymethyl or methylthiomethyl ether.

6. Join one of the preceding paragraphs, characterized in that they are selected from a group including:

3-(3',5'-di-tert-butyl-2'-methoxy-3-biphenylyl)acrylic acid,

3-(2'-benzyloxy-3', 5'-di-tert-butyl-6-hydroxy-3-biphenylyl)acrylic acid,

3-(3', 5'-di-tert-butyl-6-hydroxy-2'-pentyloxy-3-biphenylyl)acrylic acid,

3-(3',5'-di-tert-butyl-6-hydroxy-2'-methoxy-3-biphenylyl)acrylic acid,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylic acid,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxyphenyl]acrylic acid,

[4 methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] ash acid,

3-[3-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyethoxymethyl]acrylic acid,

3-(5'-adamantane-1-yl-4'-methoxy-2'-methyl-3-biphenylyl)acrylic acid,

3-(5'-adamantane-1-yl-6-hydroxy-4'-methoxy-2'-methyl-3-biphenylyl)acrylic acid,

3-(5'-adamantane-1-yl-4'-methoxy-6-methoxyethoxy-2'-methyl-3-biphenylyl)acrylic acid,

3-{ 4-methoxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-methoxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 3-[3-(6-hydroxyhexyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-(3-[3-(7-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(5-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(3-hydroxypropoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-[3-(1-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylic acid,

3-(3'-adamantane-1-yl-4'-hydroxy-3-biphenylyl)acrylic acid,

5-[4-methoxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)primatelit-2,4-diene acid,

5-[4-hydroxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] -3-methylpent-2,4-diene acid,

3-{ 3-[3-(5-tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(7-tert-butoxycarbonylmethylene)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(7-carboxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(5-carboxypentyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(5-carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 3-[3-(7-carbamoylphenoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylic acid,

3-{ 4-methoxy-N-[5,5,8,8-tetramethyl-3-(2-morpholine-4-ylethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-methoxy-3-[5,5,8,8-tetramethyl-3-(2-piperidine-1-ylethoxy)-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-methoxy-3-[3-(2-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-methoxy-3-[3-(3-methoxyethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl)acrylic Owego acid,

3-{ 4-methoxy-3-[3-(3-hydroxyethyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-[4-fluoro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] acrylic acid,

3-{ 4-hydroxy-3-[3-(3-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-hydroxy-3-[3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

-3-{ 4-hydroxy-3-[3-(4-forbindelse)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylic acid,

3-{ 4-hydroxy-3-[3-(4-chlorobenzoyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl)acrylic acid,

3-[4-hydroxy-3-(3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid,

3-(3', 5'-di-tert-butyl-6-hydroxy-2'-propyloxy-3-biphenylyl)acrylic acid,

3-(3', 5'-di-tert-butyl-6-hydroxy-2'-Butylochka-3-biphenylyl)acrylic acid,

3-(2'-butoxy-3',5'-di-tert-butyl-6-methoxy-3-biphenylyl)acrylic acid,

3-(3', 5'-di-tert-butyl-6-methoxy-2'-propoxy-3-biphenylyl)acrylic acid,

3-[4-hydroxy-3-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]akrilovye-5-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] Penta-2,4-diene acid,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]prop-2-EN-1-ol,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]propenal,

N-ethyl-3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylamide,

3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]-1-morpholine-4-yl-propenone,

N-(4-hydroxyphenyl)-3-[3-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylamide,

5-(5'-adamantane-1-yl-4'-methoxy-2'-methyl-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-[4-methoxyethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]-3-methylpent-2,4-diene acid,

5-[4-hydroxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] -3-methylpent-2,4-diene acid,

4-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl] Penta-2,4-diene acid,

5-(3',5'-di-tert-butyl-2'-methoxy-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-(3', 5'-di-tert-butyl-2'-propoxy-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-(2'-butoxy-3',5'-di-tert-butyl-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-(2'-butoxy-3', 5'-di-tert-butyl-6-hydroxy-3-biphenylyl)-3-methylpentan-2,4-diene acid,

5-(3', 5'-di-tert-methoxy-3-biphenylyl)-3-methylpentan-2,4-diene acid.

7. Connection on p. 1, wherein R11preferably represents-O-R21or R7preferably represents-O-R20and more preferably R11represents-O-R21and R7represents-O-R20.

8. Join one of the preceding paragraphs, having the ability to bind RXR.

9. Pharmaceutical composition having the ability to bind RXR, characterized in that it contains pharmaceutically acceptable carrier at least one of the compounds listed in one of the paragraphs.1-7.

10. The composition according to p. 9, characterized in that the concentration of the compound(s) according to one of paragraphs. 1-7 is from 0.001 to 5% by weight relative to the entire composition.

11. The composition according to p. 9 or 10 as cosmetic compositions.

12. The composition according to p. 11, characterized in that the concentration of the compound(s) according to one of paragraphs.1-7 is 0.001 to 3% by weight relative to the entire composition.

13. The composition according to p. 11 or 12 as a cosmetic composition for care of the body and hair.

 

Same patents:

The invention relates to a new process for the preparation of 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanol acid of the formula (I)

OCOOH

(I) This connection is used for regulating the level of blood lipids

The invention relates to new derivatives of benzofuran-2-ones of formula 1, where a value of substituents specified in paragraph (1 formulas that can be used as stabilizers for organic polymers susceptible to oxidative, thermal or induced light decay

The invention relates to a new process for the preparation of 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanol acid of the formula (I)

OCOOH

(I) This connection is used for regulating the level of blood lipids

The invention relates to a method for producing new derivatives benzocycloheptene acids

The invention relates to the field of medicine and for the application of at least one extract of non-photosynthetic filamentous bacteria as an antagonist of substance P for the treatment of diseases associated with excessive synthesis and/or release of substance P
The invention relates to medicine, and more specifically to photodynamic therapy, and can be used in Oncology and dermatology

The invention relates to the field of veterinary medicine
The invention relates to medicine, in particular to surgery and can be used for the treatment of nonhealing wounds

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

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

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

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to medicine, dermatology, to methods for treating microbial eczema

The invention relates to pharmacology and for the treatment of burn wounds
The invention relates to medicine, refers to antiexudative drug for infusion and irrigation vessels and tissues of the human body, which contains phospholipids, and/or their derivatives cetanol, and/or their derivatives and membrane glycopeptides and/or their derivatives, salt buffer with a pH of 7.2-7.4 and osmolarity 200-400 and water at a certain ratio
The invention relates to medicine, balneotherapy
The invention relates to medicine, in particular to surgery, and can be used for the treatment of pancreatic necrosis

to increase the rate of apoptosis" target="_blank">

The invention relates to medicine, specifically to pharmacology and dermatology and cosmetology
The invention relates to medicine, and more specifically to photodynamic therapy, and can be used in Oncology and dermatology
Up!