Agent in cosmetic or pharmaceutical compositions intended for the treatment of disorders or diseases associated with sverrehelena receptors rsc and/or hypervitaminosis a, compounds with this activity

 

(57) Abstract:

Describes the application of an effective amount of at least one connection of the retinoid of formula (I) as an active agent in cosmetic or pharmaceutical compositions intended for the treatment of disorders or diseases associated with sverrehelena receptors RSC and or hypervitaminosis A, and this compound corresponds to the General formula (I) in which R1is (i) a radical-CH3(ii) a radical-CH2OH, (iii) a radical-O-R3, (iv) a radical-CO-R4; R3and R4have the meanings stated below; Ar is a radical of the formula (II) (a - d), where R5has the following value; R2is (a) a radical -(X)-(CH2)p-R6(b) a radical -(X)n-(CH2)q-R7(in) a radical-CH=CH-(CH2)s-R6(d) a radical-CH=CH-(CH2)t-R7and R6, R7, X, n, p, q, s and t have the meanings stated below, provided that R3is a hydrogen atom, a lower alkyl radical, a radical -(CH2)m-(CO)n-R8and R8, m and n have the meanings stated below, R4is (a) hydrogen atom, (b) lower alkyl radicale values; R5is a hydrogen atom, halogen, a linear or branched alkyl radical with 1 to 20 carbon atoms, a hydroxyl radical or a radical-OR10or-OCOR10and R10has the following value; R6is a hydrogen atom, a linear or branched alkyl radical with 1 to 20 carbon atoms, alkenyl radical, alkyl radical; R7is aryl radical, a mono - or polyhydroxyethyl radical, a hydroxyl group which, if necessary, protected in the form of a methoxy - or acetoxy or acetonide, radical-COR4provided that R7not a simple polyether radical containing carbon in a-position to the carbon in position 6-afternova radical; R8is a lower alkyl radical or a saturated heterocyclic radical; R9is a hydrogen atom, a linear or branched alkyl radical with 1 to 20 carbon atoms, alkenyl radical, mono - or polyhydroxyalkane radical, aryl radical or Uralkali radical, if necessary substituted (substituted) or a sugar residue, or a residue of an amino acid or peptide; R10is the lowest which are a hydrogen atom, lower alkyl radical, a mono - or polyhydroxyalkane radical, if necessary substituted aryl radical or a residue of an amino acid, peptide or sugar, or alternatively together form a rich heterocycle, m = 1, 2, 3; n = 0 or 1; p = 5 - 12, an integer; q = 0 to 12, an integer; r = 0, 1, or 2; s = 3 to 10, an integer; t = 0 to 10, an integer, as well as their salts and their chiral counterparts. Describes new compounds with the above activity. 2 C. and 22 C.p. f-crystals.

The invention relates to the use of compounds of the type of retinoids as active agents in cosmetic compositions or pharmaceutical compositions intended for the treatment of disorders or diseases associated with sverrehelena receptors PPK and/or hypervitaminosis A.

It is known that retinoic acid and some of its analogues (also known as retinoids) can cause differentiation of the cells (F9) embryonic teratocarcinoma mouse. The secretion of plasminogen activators, which accompanied this differentiation is an indicator of biological response of F9 cells to retinoids. It is also known that the ability of these retinoids stimulate plasminogen activator is acid in F9 cells (Skin Phapmacol, 1990, 3, S. 256-267).

It is also known that dermatological, rheumatic, respiratory, cardiovascular, bone, and eye disorders or diseases associated with, for example, with sverrehelena (overexpression or overactivity) receptors PPK and/or with hypervitaminosis A (the presence in the body of abnormal amounts of vitamin A or its metabolites). Consequently, the clear interest in identifying compounds that can inhibit the biological effects of sverhregulyatsii receptors PPK and/or hypervitaminosis A.

Quite unexpectedly, the applicant has found that some compounds of the type of retinoids do not cause differentiation of these cells F9, but contact PPK, and this connection refers to the type of antagonistas.

This discovery formed the basis of the present invention.

Thus, the present invention relates to the use of an effective amount of at least one connection of the retinoid of formula (I) as an active agent in cosmetic compositions or pharmaceutical compositions, and these compositions intended for the treatment of disorders or diseases associated BR>< / BR>
in which R1is (i) a radical - CH3,

(ii) a radical-CH2OH,

(iii) a radical-O-R3,

(iv) a radical-CO-R4,

R3and R4have the meanings specified below,

Ar is a radical of the formula

< / BR>
< / BR>
R5has the following values,

- R2is (a) a radical -(X)n-(CH2)p-R6(b) a radical -(X)n-(CH2)q-R7(in) a radical-CH=CH-(CH2)s-R6(d) a radical-CH=CH-(CH2)t-R7and R6, R7, X, n, p, q, s and t have the meanings specified below, provided that: R3is a hydrogen atom, a lower alkyl radical, a radical -(CH2)m-(CO)n-R8and

R8, m and n have the previously indicated meanings,

R4is (a) hydrogen atom,

(b) a lower alkyl radical,

(C) a radical of the formula

< / BR>
(d) a radical-OR9,

where R', R" and F9have the following values,

R5is a hydrogen atom, halogen, a linear or branched alkyl radical having 1-20 carbon atoms, a hydroxyl radical, a radical-OR10or - OCOR10and

R10matter megasim 1-20 carbon atoms, alkenyl radical, alkynylaryl radical,

R7is aryl radical, a mono - or polyoxyalkylene radical, hydroxyl group which may be protected in the form of methoxy-, acetoxy - or the acetonide group, amino-alkyl radical, the amine function of which of the possible substituted by one or two lower alkyl groups, simple polyether radical, a radical-COR4saturated or unsaturated heterocyclic radical, or aminoalkyl radical,

R8is a lower alkyl radical or a saturated heterocyclic radical,

R9is a hydrogen atom, a linear or branched alkyl radical having 1-20 carbon atoms, alkenyl radical, mono - or polyoxyalkylene radical, aryl or Uralkali radical, possibly substituted(and) or a sugar residue or an amino acid residue or peptide,

R10is a lower alkyl radical,

X is an oxygen atom or a radical - S(O)r,

R' and R", identical or different, are a hydrogen atom, a lower alkyl radical, a mono - or polyoxyalkylene radical, aryl radical, possibly substituted, or a residue ar>
n = 0 or 1,

p = 5-12, integer,

q = 0-12, integer,

r = 0, 1, or 2,

s = 3-10, integer,

t = 0-10, integer,

as well as their salts and their chiral counterparts.

These compounds of formula (I) can also be salts when R1or R7is a function of the carboxylic acid and when R7is amine function, and chiral analogues and geometric isomers of the above compounds of formula (I). When the compounds of formula (I) are in the form of salts, preferably it is about the salts of alkali or alkaline-earth metals, or salts of zinc or of an organic amine.

According to the present invention, under a lower alkyl radical see radical having 1-6 carbon atoms, preferably methyl, ethyl, ISO-propyl, boutigny, tert-botilony and sexily radicals.

Among the alkyl is linear or branched radicals having 1-20 carbon atoms, can for example be mentioned methyl, ethyl, sawn, 2-ethylhexyl, octillery, dodecylphenyl, hexadecimally and octadecenyl radicals.

Among monoaxially radicals preferred radical having 1-6 carbon atoms, for example oxypropylene, 2-hydroxyethyl, 2-oxidase 3-6 carbon atoms and 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutane, 2,3,4,5-tetrahydroxy-pentelenyi radical or a residue of pentaerythritol.

Among the aryl radicals are preferred phenyl radical, possibly substituted by at least one halogen atom, a hydroxyl or a nitro-group. Thus, among aminoaniline radicals prefer AMINOPHENYL radical, possibly substituted by at least one halogen atom, a hydroxyl or a nitro-group.

Among Uralkalij radicals preferred benzyl or finitely radical, possibly substituted by at least one halogen atom, a hydroxyl or a nitro-group.

Under alkenyl radical see radical containing preferably 2-5 carbon atoms and having one or more ethylene nancysinatra, such as, in particular, allyl radical.

Under the sugar residue understand the remainder occurring, for example, from glucose, galactose or mannose, or glucuronic acid.

Under the balance of amino acids see, for example, a residue derived from lysine, glycine or aspartic acid, and residue peptide understand more specifically the residue of the dipeptide or Tripeptide, which is the PE the new moholynagy, pyrolidine or pieperazinove radical, possibly substituted in position 4 C1-C6-alkyl radical or a mono - or polyoxyalkylene radical such as defined above.

Under unsaturated heterocycle preferably understand pyridine, furan or titanovyi radical.

Under the atoms of halogen understand preferably fluorine atom, chlorine or bromine.

Under aminoalkyl radical see radical, preferably containing 1-6 carbon atoms, such as aminomethyl, 3-aminopropyl, 6-aminohexyl radicals.

Under ordinary polyester radical see radical, preferably containing 1-6 carbon atoms, for example, methoxyethoxy, ethoxyethoxy, methoxyethoxyethoxy-, methoxyethoxymethyl, methoxyethoxymethyl, methoxyacetate radicals.

Under alkynylaryl radical see radical, preferably having 2-6 carbon atoms, such as propargyl radical.

When the radical R5is a halogen atom, the latter is preferably a fluorine atom, bromine or chlorine.

Among the compounds of formula (I) can, for example, as follows:

2-hydroxy-4- [7-(1-Adam the slot,

4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl] benzoic acid

5-[7-(1-substituted)- 6-benzyloxy-2-naphthyl]-2-thiencarbazone acid,

4-[7-(1-substituted)-6-benzyloxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - benzyloxycarbonyl-2-naphthyl] benzoic acid

2-hydroxy-4-[7-(1-substituted) -6-(4-terbisil)oxy-2-naphthyl] benzoic acid

6-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl] -nicotinic acid,

4-[7-(1-substituted)-6 - heptyloxy-2-naphthyl] benzoic acid

2-hydroxy-4-[7-(1-substituted) -6-methoxyethoxyethoxy - 2-naphthyl] benzoic acid

2-chloro-4-[7-(1-substituted)- 6-methoxyethoxyethoxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - hydroxyhexyloxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - hydroxypropyl-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - hydroxyethyloxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - hydroxyethyl-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - hydroxyhexyloxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - hydroxyethoxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6- (4-morpholino)-ethyloxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6- (1-piperidino)ethyloxy-2-naphthyl] benzoic, carbonylations-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - ethoxycarbonylmethoxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - carboxymethoxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - carboxymethoxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl]- benzoimidazol,

4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl]- benzaldehyde,

morpholin 4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl] benzoic acid

N-ethyl-4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl]- benzamid,

4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl]-benzamid,

N-[4 oksifenil] -4-[7- (1-of substituted)-6-methoxyethoxyethoxy-2 - naphthyl]-benzamid,

4-[7-(1-substituted)- 6-methoxyethoxyethoxy-2-naphthyl]- benzoylpiperazine,

propyl ester 4-[7- (1-substituted)-6-methoxyethoxyethoxy-2 - naphthyl] benzoic acid

4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl]-phenylacetate,

4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl]-phenol,

hydrochloride 4-[7-(1-substituted) -6-methoxyethoxyethoxy-2-naphthyl] - phenoxyethylamine,

hydrochloride 4-[7-(1-substituted)- 6-methoxyethoxyethoxy-2-naphthyl] - phenoxyethylamine,

hexyl ester of 4-[7-(1-substituted) -6-methoxyethoxyethoxy-2 - naphthyl] benzoic acid is yl)-6-methoxyphenoxy-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - methoxyethoxymethyl-2-naphthyl] benzoic acid

4-[7-(1-substituted)-6 - methoxyethoxymethyl-2-naphthyl] benzoic acid.

In accordance with the present invention is more specifically used by the compounds of General formula (I) are those in which

R1is a radical-CO-R4,

R2is a radical(X)n-(CH2)p-R6or -(X)n-(CH2)q-R7,

Ar is a radical of formula (a) or (b).

More specifically of the compounds of formula (I), preferred compounds of formula (I) in which R7is a simple polyester radical having a carbon-position to the carbon that is in position 6 afternova radical. These compounds proved to be very interesting, because, apparently, they can't be metabolically modified when they are introduced in connection retinoid type that cause the differentiation of these cells F9 and communicating with the PPK, and this connection is the connection agonistic type.

Therefore, the present invention also relates to these specific compounds of formula (I) in which R7is a simple polyester radical having a carbon-poutily radical and methoxyethoxymethyl radical.

Among these new compounds of preferred 4-[7-(1-substituted)- 6-methoxyethoxymethyl-2-naphthyl] benzoic acid and 4-[7-(1-substituted)-6 - methoxyethoxymethyl-2-naphthyl] benzoic acid.

The compounds of formula (I) can be obtained, for example:

or of combination reaction between the halide derivative (1) and halide derivative (2):

< / BR>
where X and Y are chlorine atoms, bromine or iodine. In the first case, the halide compound (1) is transformed into lithium or magnesium derivative, then zinc is derived and combined with a derivative (2) in the presence of Nickel or palladium catalyst in accordance with the terms burilovo combinations described E. Negishi, etc., J. Org. Chem. (1977), 42, 1821,

or of combination reaction between boric acid (3) and halide derivative (2):

< / BR>
The reaction mix is carried out in the presence of a catalyst of palladium, for example, tetrakis/triphenylphosphine/palladium, under the conditions described N. Miyaura et al., Synthetic Communications(1981) 11 (7), 513-519.

A derivative of boric acid (3) can be obtained, for example, from a halide derivative (1) when the first transformation in lithium derivative with subsequent interaction with trimethylboron and hydrolysis.

These form the walking way substituted derivatives, compatible with the terms of the combination.

In particular, when R1is the radical-COOH, connections, receive, protecting R1protecting group of the type alkyl, allyl, benzyl or tert-butilkoi.

The transition to a free form can be made:

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

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

- in the case of the benzyl protecting group by dibenzylamine in the presence of hydrogen using a catalyst such as palladium-on-charcoal,

in case the protecting group is tert-Putilkovo type using trimethylsilane.

When R2is the radical -(CH2)p-R6, -(CH2)q-R7-CH=CH-(CH2)s-R6or-CH=CH-(CH2)t-R7that connection can be obtained from the corresponding phenol derivatives (R2is-OH radical), which in turn triflate derivatives, then spend nucleophilic substitution t al. Tetrahedron Letters, 1986, 27, 3931-3934,

- W. J. Scott et al., J. Org. Chem. 1985, 50, 2302-2308,

- J. K. Stille et al., J. Am. Chem. Soc. 1987, 109, 5478-5486.

Cosmetic or pharmaceutical composition containing at least one compound of formula (I), thus intended for the treatment of disorders or diseases associated with sverrehelena receptors PPK and/or hypervitaminosis A.

Under sverrehelena receptors PPK according to the invention understand the overexpression of receptors PPK and/or biological superactivate receptors PPK.

Biological superactivate receptors PPK may be due to the chemical modification of receptors PPK, or it can be caused by a different factor than the receptor. Thus, biological superactivate may be due to the super-expression of the endogenous gene or expression of the exogenous gene, including item response AORC (item response retinoic acid), which will be recorded heterodimer containing receptor Kurdistan workers party, the latter shall be agonistic ligand. As an example of superexpression endogenous gene that contains the item response EORK, can result in gene CRABP 11 (protein 11 connecting the cell retinova acid), overexpression to the example of the expression of the exogenous gene, contains the item response EORK, you can lead the genome of HIV-I (virus, human immunodeficiency) (Proc. Natl. Sci. USA, Lee et al., so 91, S. 5632-5636, June 1994) or the genome of hepatitis B virus (Retinoid x receptor RXR alpha binds to and trans-activates the hepatite B virus enhancer, B. Huan et al., Pcor. Natl. Acad. Sci. USA, 1992, 89 (19), S. 9059-63).

These disorders or diseases associated with superregular receptors PPK and/or hypervitaminosis A, most often expressed by inflammatory, allergic and/or immunologic component. More specifically, they are present in the following diseases or disorders:

1) acne vulgaris, black acne, polymorphic, red acne, welovejonascause acne, nodular acne, senile acne, secondary acne such as solar, drug or occupational acne,

2) other types of disorders of keratinization, such as ichthyosis, idiotphone condition, disease Daria, Palmar-plantar keratoderma, leukoplakia and liopleurodon status, cutaneous zoster or zoster mucous (buccal),

3) other dermatological disorders associated with impaired keratinization with inflammatory and/or immunoallergic component and, for example, all forms of psoriasis, which are cutaneous, mucous or ungual, the school hypertrophy of the gums,

4) some inflammatory diseases, do not have disorders of keratinization, such as arthritis,

5) termicheskaya and epidermal proliferation, which are benign or malignant, which are of viral origin or not, such as common warts, flat warts and hillocky epidermodysplasia, oral or transient papillomatosis and proliferation, which can be caused by ultraviolet irradiation, for example in the case of basic - and speckletone of epithelium,

6) other skin diseases, such as puzarchaty medicine and diseases of collagen,

7) some eye diseases, such as Corporatio,

8) the aging of the skin, which was caused either by irradiation or age is, or pigmentation and the actinic keratoses, or any pathology associated with age ageing or ageing under irradiation,

9) the stigmata of epidermal and/or termicheskoi atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy,

10) violation of scarring or red scars on the skin,

11) disorders of the sebaceous function, such as Hyperborea acne or simple seborrhoea,

12) rakowiecka immunodeficiency: HIV-I or hepatitis B virus),

14) alopecia,

15) diseases of the circulatory system such as arteriosclerosis.

In the framework of the invention the compounds of formula (I) should be used in combination with other compounds with activity type retinoid, vitamin D, or their derivatives, with corticosteroids, with anti-free radicals, hydroxy - or-keto acid or their derivatives, or even with blockers of ion channels. Under vitamins D and their derivatives see, for example, derivatives of vitamin D2or D3in particular 1,25-dihydroxyvitamin D3. Under tools against free radicals understand, for example-tocopherol, Super Oxide Dismutate, original, or some chelates metals. Under-hydroxy - or-keto acid or their derivatives see, for example, lactic, malic, citric, glycolic, almond, wine, glycerol or ascorbic acid or their salts, amides or esters. Finally, under the blockers of ion channels see, for example, Minoxidil (2,4-diamino-6-piperidinedione-3-oxide) and its derivatives.

Cosmetic or pharmaceutical composition contains an effective amount of at least one of the compounds of formula (I), one of his girlsboobs the introduction of the media.

Of course, an effective amount depends on the desired treatment and the nature of the selected connection and, therefore, determined by your doctor.

Introduction compounds according to the invention can be carried out enterline, parenteral, topical or ocular.

When enteral route of administration of the composition, more specifically, the pharmaceutical composition may be in the form of tablets, capsules, pills, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric bubbles bubbles that provide controlled release. When parenteral route, the composition, more specifically, the pharmaceutical composition may be in the form of solutions or suspensions for perfusion or for injection.

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

When local route of administration, the composition is more particularly intended for the treatment of skin and mucosa and then can be in the form of ointments, creams, jelly, lipstick, powder, impregnated swabs, solutions, gels, pulverizing drugs, lotions, suspensions or shampoos. It can also be in the form of microSD controlled release. This composition for topical application, also can be in anhydrous form or in aqueous form.

When the eyepiece way it fundamentally is eye drops.

This composition for local or ocular application contains at least one compound of formula (I) such as defined above, or one of its chiral analogues or one of its salts, at a concentration of, preferably lying between 0.001 and 5% relative to the total weight of the composition.

In addition, the composition according to the invention can contain inert or pharmacodynamically or cosmetically active additives or combinations of these additives, for example wetting agents, depigmentation, such as hydroquinone, azelaic acid, caffeic acid or kojic acid, softeners, hidratante, such as glycerol, PEG 400, diamorphine and its derivatives or urea, protivoseborainey and protivoluchevye agents, such as S-carboxymethylcysteine, S-benzylcyanide, their salts and their derivatives, or benzoyl peroxide, antibiotics, such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines, antifungal agents such as ketoconazole or 4,5-polymethylene-3 - oxide) and its derivatives, diazoxide (7-chloro-3-methyl-1,2,4 - benzothiadiazine-1,1-dioxide) and phenytoin (5,4-diphenylimidazole-2,4 - dione), nonsteroidal anti-inflammatory agents; carotenoids and, for example, -carotene, protivopolozhnye agents, such as anthralin and its derivatives, and finally, eicosa-5,8,11,14-terraenovae and eicosa-5,8,11-TRINOVA acids, their esters and amides.

The composition may also contain agents that enhance the taste, preservatives such as esters of para-oksibenzoynoy acid, stabilizers, humidity regulators, pH regulators, osmotic pressure modifiers, emulsifiers, UV-A and UV-B filters, antioxidants, such as tocopherol, butylacetamide or butylacetyl.

Next will be given as an illustration and without any limiting character a few examples of active compounds of the formula (I), as well as various specific formulations based on these compounds.

EXAMPLE 1

2-Hydroxy-4-[7-(1-substituted) -6-benzyloxy-2-naphthyl]benzoic acid

a) 7-(1-Substituted)-6-benzyloxy-2 does not depend

In a three-neck flask enter 1.26 g (42 mmole) of sodium hydride (80% in oil) and 50 ml of DMF. Added dropwise a solution of 12.5 g (35 mmol) of 7-(1-substituted)-6-hydroxy-2-bromonaphthalene into're asked at room temperature for 2 hours. The reaction medium is poured into water, extracted with diethyl ether, decanted organic phase is dried over magnesium sulfate, and evaporated. The resulting residue is treated with ethanol, heated to boiling under reflux, filtered and dried. Collect 12.5 g (80%) of the desired product with so pl. 150-151oC.

b) 7-(1-Substituted)-6-benzyloxy-2-naftalina acid

Loaded into a three-neck flask in a stream of nitrogen, 3 g (6.7 mmole) of 7-(1-substituted)-6-benzyloxy-2-bromonaphthalene to 50 ml of THF. Added at -78oC dropwise 3.2 ml (8 mmol) of 2.5 M n-utility in hexane and stirred for 15 minutes at the same temperature was added 2.1 g (20 mmol) of triethylborane and stirred for 2 hours. Added at -50oC 23 ml of 1 N. hydrochloric acid and allowed to warm to room temperature. The reaction medium is extracted with diethyl ether, decanted organic phase is dried over magnesium sulfate, and evaporated. The resulting residue is triturated in heptane, filtered and dried. Gather 2.8 g (100%) target boric acid, which is used as such for subsequent synthesis.

C) Methyl ester of 2-hydroxy-4-[7-(1-substituted)-6-benzyloxy - 2-naphthyl] benzoic acid

Loaded into a three-neck flask in a stream of nitrogen at 300 mg (8.8 mmole) of tetr peremeshivayte 20 minutes at room temperature. Then add 5,52 g (a 13.4 mmole) of 7-(1-substituted)-6-benzyloxy-2-afterborn acid and 8.8 ml of 2 N. of an aqueous solution of potassium carbonate and refluxed for 8 hours. The reaction medium is evaporated to dryness, treated with water and diethyl ether, decanted organic phase is dried over magnesium sulfate, and evaporated. The residue is purified by chromatography on a column of silica, elwira a mixture of ethyl acetate with heptane (10-90). Gain of 1.65 g (36%) of methyl ester of 2-hydroxy-4-[7-(1-substituted)-6 - benzyloxy-2-naphthyl]benzoic acid.

g), 2-Hydroxy-4-[7-(1-substituted) -6-benzyloxy-2-naphthyl]benzoic acid

Loaded into the flask 930 mg (1.8 mmole) of methyl ester of 2-hydroxy-4-[7-(1-substituted) -6-benzyloxy-2-naphthyl] benzoic acid and 100 ml of 2 N. methanolic solution of sodium hydroxide and boiled for 1 hour under reflux. The reaction mixture is evaporated to dryness, the residue is treated with water, acidified to pH 1 with concentrated hydrochloric acid and filtered off the solid product. The obtained solid product is triturated in ethyl acetate, filtered and dried. Collect 710 mg (79%) of the target acid with a melting point 263-4oC.

EXAMPLE 2

2-Hydroxy-4-[7-(1-substituted) -6-hexyloxy-2-naphthyl]benzoic acid

a) Matei interaction 430 mg (1 mmole) of methyl ester of 2-hydroxy-4-[7- (1-substituted)-6-hydroxy-2 - naphthyl]benzoic acid with 180 μl (1.2 mmole) of 6-hodgekin get 280 mg (55%) of methyl ester of 2-hydroxy-4-[7-(1-substituted) -6-hexyloxy - 2-naphthyl]benzoic acid.

b) 2-Hydroxy-4-[7-(1-substituted) -6-hexyloxy-2-naphthyl]benzoic acid

Work according to the method of example 1 (d), on the basis of 100 mg (0.2 mmole) of the methyl ester of 2-hydroxy-4-[7- (1-substituted)-6-hexyloxy-2-naphthyl] benzoic acid get 90 mg (92%) of the target acid so pl. 281-3oC.

EXAMPLE 3

4-[7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naphthyl]benzoic acid

a) Methyl ester of 4-[7- (1-substituted)-6-benzyloxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (C), the interaction of 2.6 g (6.7 mmole) of 7-(1-substituted)-6 - benzyloxy-2-afterborn acid with 950 mg (4.4 mmole) of methyl ester of 4-bromobenzoyl acid obtain 1.6 g (72%) of the target product.

b) Methyl ester of 4-[7-(1-substituted)-6-hydroxy-2-naphthyl]benzoic acid

Charged to the reactor to 1.38 g (to 2.75 mmole) of methyl ester of 4-[7-(1-substituted)-6-benzyloxy-2-naphthyl] benzoic acid, 450 mg of 10% palladium-on-coal and 50 ml of dioxane. Add 5 drops of acetic acid and hydronaut at 50oC under a pressure of 6.5 bar of hydrogen for 4 hours. The catalyst is filtered off, washed with 2 times 20 ml of dioxane, the filtrate is evaporated. The resulting residue is purified by chromatography on a column of silica, elwira a mixture of dichloromethane and hexane (50-50). Collect initial ester 4-[7-(1-substituted) -6-methoxyethoxyethoxy-2 - naphthyl] benzoic acid

Work according to the method of example 1 (a), the interaction of 980 mg (2.4 mmole) of methyl ester of 4-[7-(1-substituted)-6-hydroxy-2-naphthyl] benzoic acid with 330 μl (28.6 mmole) of methoxyethoxymethyl get 650 mg (55%) of the desired product in the form of butter.

d) 4-[7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naphthyl]benzoic acid

Work according to the method of example 1 (g), on the basis of 650 mg (1.3 mmole) of methyl ester of 4-[7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl] bonzini acid obtain 580 mg (92%) of the target acid so pl. 234-6oC.

EXAMPLE 4

5-[7-(1-Substituted)-6-benzyloxy - 2-naphthyl]-2-thiencarbazone acid

a) Methyl ester 5-[7-(1-substituted)-6 - benzyloxy-2-naphthyl]- 2-thiophencarboxylic acid

Work according to the method of example 1 (C), the reaction of 1.5 g (3.6 mmole) of 7-(1-substituted)-6-benzyloxy-2-afterborn acid with 400 mg (1.8 mmole) of methyl ester of 5-bromo-2-thiophencarboxylic acid get 600 mg (65%) of the desired product with so pl. 170-1oC.

b) 5-[7-(1-substituted) -6-benzyloxy-2-naphthyl]-2-thiencarbazone acid

Work according to the method of example 1 (g), on the basis of 600 mg (1.2 mmole) of the methyl ester 5-[7-(1-substituted)-6-benzyloxy-2-naphthyl]-2 - thiophencarboxylic acid get 460 mg (79%) of the target acid so pl. 271 - ester of 4-[7-(1-substituted) -6-benzyloxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (b), when interacting with 1.5 g (3.6 mmole) of 7-(1-substituted)-6-benzyloxy-2-afterborn acid 500 mg (1.9 mmole) of methyl ester of 4-identies acid get 320 mg (33%) of the desired product with so pl. 170-3oC.

b) 4-[7-(1-Substituted)-6 - benzyloxy-2-naphthyl]benzoic acid

Work according to the method of example 1 (g), on the basis of 320 mg (0.6 mmole) of methyl ester of 4-[7-(1-substituted)-6-benzyloxy-2-naphthyl] benzoic acid get 195 mg (63%) of the target acid so pl. 305-310oC.

EXAMPLE 6

4-[7-(1-Substituted)-6 - benzyloxycarbonyl-2-naphthyl] benzoic acid

a) Methyl ester of 4-[7- (1-substituted)-6 - tripterocalyx-2-naphthyl] benzoic acid

To a cooled to 78oC to a solution of 5.5 g (13.3 mmole) of methyl ester of 4-[7-(1-substituted)-6-hydroxy-2-naphthyl] benzoic acid, 3.2 ml (40 mmol) of pyridine and 162 mg of 4-dimethylaminopyridine in 100 ml of dichloromethane are added dropwise to 2.7 ml (16 mmol) of anhydride triftormetilfullerenov acid and stirred at room temperature for 12 hours. Reaction medium was poured into ice water, extracted with diethyl ether, decanted organic phase was washed with a saturated solution of sodium chloride, dried over magnesium sulfate, Vetta and heptane (10-90). Collect of 1.94 g (27%) of methyl ester 4-[7-(1-substituted)-6 - tripterocalyx-2-naphthyl] benzoic acid with tons of dps, 226-7oC.

b) Methyl ester of 4-[7-(1-substituted) -6-benzyloxycarbonyl]- 2-naphthyl] benzoic acid

In the reactor sequentially injected solution 1,91 g (3.5 mmole) of methyl ester of 4-[7-(1-substituted)-6-tripterocalyx-2 - naphthyl] benzoic acid in 50 ml of DMF, 980 mg (7 mmol) of triethylamine, 39 mg of palladium acetate, 195 mg (0.35 mmole) of 1,1'-misdefinition-ferrocene and the 3.65 ml (35.1 mmole) of benzyl alcohol. Heated at 80oC under a pressure of 2.5 bar of carbon monoxide for 12 hours. The reaction mixture was poured into a saturated solution of sodium chloride, extracted with diethyl ether, decanted organic phase is dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica gel, elute with a mixture of ethyl acetate and heptane (15-85). After evaporation of the solvents will be collected 720 mg (40%) of the desired product with so pl. 143-4oC.

C) 4-[7-(1-Substituted)-6 - benzyloxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), on the basis of 260 mg (0.5 mmole) of methyl ester of 4-[7-(1-substituted)-6-benzyloxycarbonyl-2-naphthyl] bonzini acid get 200 mg (79%) cementia acid

a) 7-(1-Substituted)-6- (4-terbisil)hydroxy-2 does not depend

Work according to the method of example 1 (a), the interaction of 1.1 g (3 mmol) of 7-(1-substituted)-6 - hydroxy-2-bromonaphthalene with 420 μl (3.3 mmole) of 4-ftorangidridy obtain 1.2 g (86%) of the desired product as a colourless oil.

b) 7-(1-substituted)-6-/4-(tormentil)oxy/-2-naftalina acid

Work according to the method of example 1 (b), according to 1.14 g (of 2.45 mmole) of 7-(1-substituted)-6- (4-terbisil)hydroxy-2-bromonaphthalene obtain 560 mg (57%) target boric acid.

C) Methyl ester of 2-hydroxy-4-[(7- (1-of substituted)-6-(4-terbisil)- hydroxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (b), on the basis of 560 mg (1,41 mmole) of 7-(1-substituted)-6-(4-terbisil)hydroxy-2-afterborn acid and 330 mg (1,17 mmole) of methyl ester of 2-hydroxy-4-identies acid obtain 490 mg (78%) target of ester with so pl. 189-91oC.

g), 2-Hydroxy-4-[7-(1-substituted)-6-(4-terbisil)-hydroxy-2-naphthyl] benzoic acid

Work according to the method of example 1(g), on the basis of 490 mg (of 0.91 mmole) of methyl ester of 2-hydroxy-4-[7- (1-substituted)-6-(4-terbisil)-hydroxy-2 - naphthyl] benzoic acid obtain 440 mg (92%) of the target acid so pl. 240-1oC.

EXAMPLE 8

6-[7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naphthyl]-nicotinic 1-adamantanol and 500 ml of a mixture of dichloromethane and heptane (40-60). Add 15 ml of concentrated sulfuric acid and stirred at room temperature for 48 hours. Filtered the solid product is washed with heptane (3 x 100 ml), dissolved solid product in diethyl ether, washed with water, decanted organic phase is dried over magnesium sulfate, and evaporated. Collect 60.1 g (67%) of the desired product with so pl. 215-6oC.

b) 7-(1-Substituted)-6 - methoxyethoxyethoxy-2 does not depend

Unload in a three-neck flask in a stream of nitrogen 17,85 g (0.05 mmole) of 3-(1-substituted)-6 - bromo-2-naphthol and 200 ml of DMF. Add small portions of 1.8 g (0,06 mole) of sodium hydride (80% in oil) and stirred until cessation of gas evolution. Then added 6.9 ml (0,06 mmole) of methoxyethoxymethyl and stirred for 2 hours at room temperature. Reaction medium was poured into ice water, extracted with diethyl ether, decanted organic phase is dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elute with a mixture of dichloromethane and heptane (40-60). Collect 19.5 g (87%) of the desired product with so pl. 99-100oC.

C) 7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naftalina acid

Work according to the method of example 1 (b), ex is Ciechocinek-2-afterborn acid so pl. 17-4oC.

d) Methyl ester of 6-[7-(1 - substituted)-6-methoxyethoxyethoxy-2 - naphthyl] -nicotinic acid

Work according to the method of example 1 (b), on the basis of 1.3 g (3.1 mmole) of 7-(1-substituted)-6 - methoxyethoxyethoxy-2-afterborn acid and 790 mg (3 mmole) of methyl ester of 6-idnicatively acid obtain 860 mg (57%) of the target air so pl. 166-7oC.

d) 6-[7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naphthyl] - nicotinic acid

Work according to the method of example 1 (g), based on 853 mg (1.7 mmole) obtained earlier methyl ester obtain 790 mg (95%) of the target acid so pl. 247-8oC.

EXAMPLE 9

4-[7-(1-Substituted)-6 - heptyloxy-2-naphthyl] benzoic acid

a) 7-(1-Substituted)-6 - heptyloxy-2 does not depend

Work according to the method of example 8 (b), on the basis of 3.4 g (9.5 mmole) of 3-(1-substituted)to 6-bromo-2-naphthol and of 2.05 g (11.4 mmole) of 1-brometane obtain 3.4 g (79%) of 7-(1-substituted)-6-heptyloxy-2 - bromonaphthalene.

b) 7-(1-Substituted)-6 - heptyloxy-2-naftalina acid

Work according to the method of example 1 (b), on the basis of 3.5 g (17,7 mmole) of 7-(1-substituted)-6-heptyloxy-2-bromonaphthalene get 1,67 g (51%) of 7-(1-substituted)-6 - heptyloxy-2-afterborn acid.

C) Methyl ester of 4-[7-(1-substituted) -6-heptyloxy-2-naphthyl]- benthivores acid and 830 mg (3,17 mmole) of methyl ester of 4-identita get 460 mg (29% ) of the target complex methyl ester.

g) 4-[7-(1-Substituted)-6 - heptyloxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), based on Yves 330 mg (0.65 mmole) of methyl ester of 4-[7-(1-substituted) -6-heptyloxy-2-naphthyl] benzoic acid to obtain 260 mg (81%) of the target acid so pl. 266-7oC.

EXAMPLE 10

2-Hydroxy-2-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl] benzoic acid

a) Methyl ester of 2-hydroxy-4-[7- (1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (b), on the basis of 2.25 g (5.5 mmole) of 7-(1-substituted)-6 - methoxyethoxyethoxy-2-afterborn acid and 1.39 g (5 mmol) of methyl ester of 2-hydroxy-4-identies acid obtain 2.1 g (81%) target of ester with so pl. 101-2oC.

b) 2-Hydroxy-4-[7-(1-substituted) -6-methoxyethoxyethoxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), based on Yves 2,08 g (4 mmol) previously obtained methyl ether complex get 1,72 g (86%) of the target acid so pl. 225-6oC.

EXAMPLE 11

2-Chloro-4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl] benzoic acid

a) Methyl ester of 2-chloro-4- [7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (b), on the basis of 2.25 g (5.5 moltini acid get 2,32 (87%) target of ester with so pl. 112-3oC.

b) 2-Chloro-4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), based on 2,31 g (4.3 mmole) obtained earlier methyl ester gain of 1.97 g (88%) of the target acid so pl. 190-2oC.

EXAMPLE 12

4-[7-(1-Substituted)-6 - exigencias-2-naphthyl] benzoic acid

a) Methyl ester of 4-[7-(1-substituted) -6-exigencias-2-naphthyl] benzoic acid

Loaded into the flask in a stream of nitrogen of 1.62 g (40 mmol) of methyl ester of 4-[7-(1-substituted)-6 - hydroxy-2-naphthyl] benzoic acid, 830 mg of potassium carbonate and 60 ml of methyl ethyl ketone. Add 1,09 g (60 mmol) of 6-bromo-1-hexanol and boiled for 12 hours under reflux. The reaction mixture is poured into 1 N. hydrochloric acid, extracted with diethyl ether, decanted organic phase is dried over magnesium sulfate,

is evaporated. The residue is purified by chromatography on silica, elwira dichloromethane. After evaporation of the solvents will be collected 1,58 g (77%) of the target methyl ester with so pl. 153-5oC.

C) 4-[7-(1-Substituted)-6 - exigencias-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), from 700 mg (1,36 mmole) of methyl ester of 4-[7-(1-substituted) -6-exigencias-2 - naphthyl) - Rev.)-6 - hydroxypropyl-2-naphthyl] benzoic acid

a) Methyl ester of 4-[7-(1-substituted) -6-allyl-2-naphthyl] benzoic acid

Loaded into a three-neck flask in a stream of nitrogen 4 g (7,34 mmole) of methyl ester of 4-[7-(1-substituted) -6-tripterocalyx-2 - naphthyl] benzoic acid, 2.30 ml (7,9 mmole) allyltrimethylsilane, 630 mg of lithium chloride and 40 ml of DMF. Stirred for 30 minutes at room temperature, was added 104 mg (0,146 mmole) chloride bis/triphenylphosphine/-palladium (II) and heated at 100oC for 3 hours. The reaction mixture was poured into water, extracted with diethyl ether, decanted organic phase is dried over magnesium sulfate, and evaporated. Purify the resulting residue by chromatography on a column of silica gel, elute with a mixture of heptane and dichloromethane (50-50). Collect 1.7 g (53%) of the desired product with so pl. 171-3oC.

b) Methyl ester of 4-[7-(1-substituted) -6-hydroxypropyl-2-naphthyl] benzoic acid

Loaded into the flask in a stream of nitrogen, 1.7 g (3.9 mmole) of methyl ester of 4-[7-(1-substituted) -6-allyl-2-naphthyl] benzoic acid and 40 ml of THF. Added dropwise at 0oC solution of 23.5 ml (11,7 mmole) 9-borabicyclo/3.3.1/nonane (0.5 M in THF) and stirred for 1 hour at room temperature. Then sequentially added at 0oC 12 ml (12 mmole) of a 1 M solution of hydroxide mother was poured into water, extracted with diethyl ether, decanted organic phase is dried over magnesium sulfate, and evaporated. Purify the obtained white powder by chromatography on a column of silica, elute with dichloromethane. Collect 1,67 g (94%) of the desired product with so pl. 184-6oC.

C) 4-[7-(1-Substituted)-6 - hydroxypropyl-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), starting from 500 mg (1.1 mmole) obtained previously complex ether is collected 417 mg(86%) 4-[7-(1-of substituted)-6 - hydroxypropyl-2-naphthyl] benzoic acid so pl. 268-9oC.

EXAMPLE 14

4-[7-(1-Substituted)-6 - hydroxyethyloxy-2-naphthyl] benzoic acid

a) Methyl ester of 4-[7-(1-substituted) -6-hydroxyethyloxy-2 - naphthyl] benzoic acid

Work according to the method of example 12 (a), on the basis of 1.5 g (3.6 mmole) of methyl ester of 4-[7-(1-substituted) -6-hydroxy-2-naphthyl] benzoic acid and 930 ál (of 5.45 mmole) 1-bromo-8-octanol receive 800 mg (41%) of the desired product with so pl. 120-121oC.

b) 4-[7-(1-Substituted)-6 - hydroxyethyloxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), on the basis of 630 mg (1,17 mmole) obtained previously of ester receive 487 mg(79%) 4-[7-(1-of substituted)-6 - hydroxyethyloxy-2-naphthyl] benzoic acid so pl. 242-3
Work according to the method of example 13 (a), based on 4,82 g (8,86 mmole) of methyl ester of 4-[7-(1-substituted-6 - tripterocalyx-2-naphthyl] benzoic acid and 3,90 ml (13.3 mmole) vinyltrimethylsilane receive 805 mg (21.5 per cent) methyl ester 4-[7-(1-substituted) -6-vinyl-2-naphthyl] benzoic acid so pl. 221-2oC.

b) Methyl ester of 4-[7-(1-substituted) -6-hydroxyethyl-2-naphthyl] benzoic acid

Work according to the method of example 13 (b), based on 794 mg (of 1.88 mmole) of methyl ester of 4-[7-(1-substituted) -6-vinyl-2-naphthyl] benzoic acid to obtain 430 mg (54%) target of ester with so pl. 168-70oC.

C) 4-[7-(1-Substituted)-6 - oxyethyl-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), on the basis of 108 mg (0.25 mmole) obtained previously complex ether is collected 60 mg(38%) 4-[7-(1-of substituted)- 6-hydroxyethyl-2-naphthyl] benzoic acid so pl. 276-8oC.

EXAMPLE 16

4-[7-(1-Substituted)-6 - hydroxyethoxy-2-naphthyl] benzoic acid

a) Methyl ester of 4-[7-(1-substituted)-6 - hydroxyethoxy-2 - naphthyl] benzoic acid

Work according to the method of example 12 (a), on the basis of 1.5 g (3.6 mmole) of methyl ester of 4-[7-(1-substituted)-6 - hydroxy-2-naphthyl]benzoic acid and 840 ál (of 5.45 mmole) 1-bromo-7-heptanol get 1 g (52%) a the PTA

Work according to the method of example 1 (g), starting from 1 g (1.9 mmole) obtained previously of ester obtain 830 mg(86%) 4-[7-(1-of substituted)-6 - hydroxyethoxy-2-naphthyl] benzoic acid so pl. 227-228oC.

EXAMPLE 17

4-[7-(1-Substituted)-6 - hydroxyethoxy-2-naphthyl] benzoic acid

a) Methyl ester of 4-[7-(1-substituted)-6 - acetoxymethyl-2 - naphthyl] benzoic acid

Work according to the method of example 12 (a), from 1 g (2.4 mmole) of methyl ester of 4-[7-(1-substituted) -6-hydroxy-2-naphthyl] benzoic acid and 760 mg (3.6 mmole) of 5-bromopentanoate obtain 1.3 g (100%) of the target methyl ether complex with so pl. 132-3oC.

b) 4-[7-(1-Substituted)-6 - oxapentane-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), on the basis of 1.3 g (2.4 mmole) obtained previously of ester receive 1 g (79%) of the target acid so pl. 271-2oC.

EXAMPLE 18

4-[7-(1-Substituted)-6- (4-morpholino)-ethoxy-2-naphthyl] benzoic acid

a) Methyl ester of 4-[7- (1-substituted)-6-(4-morpholino)-ethyloxy-2 - naphthyl] benzoic acid

Work according to the method of example 12 (a), on the basis of 1.5 g (3.6 mmole) of methyl ester of 4-[7-(1-substituted) -6-hydroxy-2-naphthyl] benzoic acid and 5.45 g (the 5.45 mmole) of the hydrochloride of 4-(2-chloroethyl)-the research polucilosi-2-naphthyl] benzoic acid

Work according to the method of example 1 (e) on the basis of 1.45 g (was 2.76 mmole) obtained earlier methyl ether complex receive 956 mg (68%) of the target acid so pl. 280oC with decomposition.

EXAMPLE 19

4-[7-(1-Substituted)-6- (1-piperidino)-ethyloxy-2-naphthyl] benzoic acid

a) Methyl ester of 4-[7-(4-substituted) -6-(1-piperidino)ethyloxy-2 - naphthyl] benzoic acid

Work according to the method of example 12 (a), on the basis of 1.5 g (3.6 mmole) of methyl ester of 4-[7-(1-substituted) -6-hydroxy-2-naphthyl]-benzoic acid and 1 g (of 5.45 mmole) of the hydrochloride of 1-(2-chloroethyl)-piperidine gain of 1.46 g (77%) of the target methyl ester with so pl. 240-1oC.

b) 4-[7-(1-Substituted)-6- (1-piperidino)-ethyloxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), on the basis of a 1.25 g (2.8 mmole) obtained previously difficult methyl ester obtain 640 mg (53%) of the target acid so pl. 250oC with decomposition.

EXAMPLE 20

4-[7-(1-Substituted)-6 - carbamoylphenoxy-2-naphthyl] benzoic acid

a) Methyl ester of 4-[7-(1-substituted) -6-carbamoylphenoxy-2 - naphthyl] benzoic acid

Work according to the method of example 12 (a), on the basis of 640 mg (1,55 mmole) of methyl ester of 4-[7-(1-substituted) -6-hydroxy-2-naphthyl] benzoic acid and 450 mg (2,32 mmole) 6-bromacleanse-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), on the basis of 400 mg (from 0.76 mmole) obtained previously of ester obtain 350 mg (90%) of the target acid so pl. 270-1oC.

EXAMPLE 21

4-[7-(1-Substituted)-6 - ethoxycarbonylmethoxy-2-naphthyl] benzoic acid

a) Allyl ether of 4-[7-(1-substituted) -6-ethoxycarbonylmethoxy - 2-naphthyl] benzoic acid

Work according to the method of example 12 (a), based on 3 g (6.8 mmole) allyl ether of 4-[7-(1-substituted) -6-hydroxy-2-naphthyl] benzoic acid and 2.3 g (10.2 mmole) ethyl ester 6-Bromhexine acid obtain 2.15 g (55%) of the desired product with so pl. 116-7oC.

b) 4-[7-(1-Substituted)-6-ethoxycarbonylmethoxy-2-naphthyl] benzoic acid

In a three-neck flask is charged in a stream of nitrogen, 1.5 g (2,58 mmole) allyl ether of 4-[7-(1-substituted)-6 - ethoxycarbonylmethoxy-2 - naphthyl] benzoic acid, 50 ml of THF and 90 mg (0.08 mmole) tetrakis/triphenylphosphine/palladium/0/. Added dropwise to 1.13 ml (13 mmol) of the research and stirred for 2 hours at room temperature. Evaporated until dry reaction medium, treated with water, acidified to pH 1 with hydrochloric acid, extracted with diethyl ether, decanted organic phase is dried over magnesium sulfate, and evaporated. The solid product raster-(1-Substituted)-6 - ethoxycarbonylmethoxy-2-naphthyl] benzoic acid

a) Allyl ether of 4-[7-(1-substituted)-6 - ethoxycarbonylmethoxy-2-naphthyl] benzoic acid

Work according to the method of example 12 (a), from 2 g (4.5 mmole) allyl ether of 4-[7-(1-substituted) -6-hydroxy-2 - naphthyl] benzoic acid and 1.4 g (6.7 mmole) ethyl ester 5-bombalurina acid obtain 1.55 g (59%) of the desired product with so pl. 117-8oC.

b) 4-[7-(1-Substituted)-6 - ethoxycarbonylmethoxy-2 - naphthyl] benzoic acid

Work according to the method of example 21 (b), on the basis of 1.48 g (2.6 mmole) obtained previously of ester obtain 1.19 g(87%) 4-[7-(1-of substituted)-6 - ethoxycarbonylmethoxy-2 - naphthyl] benzoic acid so pl. 200oC with decomposition.

EXAMPLE 23

4-[7-(1-Substituted)-6 - carbonylmethyl-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), on the basis of 690 mg (1,28 mmole) 4-[7-(1-substituted)-6-ethoxycarbonylmethoxy-2 - naphthyl] benzoic acid are 250 mg (39%) of the target acid so pl. 305-6oC.

EXAMPLE 24

4-[7-(1-Substituted)-6 - carboxymethoxy-2-naphthyl] benzoic acid

Work according to the method of example 1 (g), on the basis of 730 mg (1.4 mmole) 4-[7-(1-substituted)-6 - ethoxycarbonylmethoxy-2-naphthyl] benzoic acid get 510 mg (90%) of the target acid so pl. 317-8oC.

oC. the Reaction medium was poured into 1 n hydrochloric acid, extracted with ethyl acetate, decanted organic phase is dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elute with a mixture of heptane and ethyl acetate (60-40). Collect 2,44 g(84%) 4-[7-(1-of substituted)-6 - methoxyethoxyethoxy-2-naphthyl]- benzoimidazol with so pl. 131-2oC.

EXAMPLE 26

4-[7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naphthyl]- benzaldehyde

Loaded into the flask 2,63 g (5.9 mmole) 4-[7-(1-substituted)- 6 - methoxyethoxyethoxy-2-naphthyl]-benzoimidazol and 40 ml dichloromethane and added to 4.2 g pyridinylamino. Stirred at room temperature for 12 hours, filter the reaction mixture through silica and the filtrate is evaporated. The obtained solid product is recrystallized from heptane, collect 490 mg(19%) 4-[7-(1-of substituted)-6 - methoxyethoxyethoxy-2-naphthyl]-benzaldehyde with so pl. 83-4oC.

EXAMPLE 27

Morpholin 4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2 - naphthyl] benzoic acid

a) the acid chloride of 4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2 - naphthyl]-binoy acid and 100 ml of dichloromethane and added dropwise to 4.3 ml (21.6 mmole) of dicyclohexylamine. Stirred at room temperature for 1 hour and added dropwise 2.2 ml (21.6 mmole) of thionyl chloride. Stirred for 1 hour, evaporated to dryness, treated with diethyl ether, filtered salt dicyclohexylamine, the filtrate is evaporated. Collect 10.4 g (100%) of a crude carboxylic acid which is used as such in the subsequent syntheses.

b) Morpholin 4-[7-(1-substituted)-6 - methoxyethoxyethoxy - 2-naphthyl] benzoic acid

Loaded into the flask 1.8 ml (to 20.6 mmole) of the research and 40 mg THF. Add dropwise a solution of 3.5 g (6.9 mmole) of the acid chloride of 4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2 - naphthyl] benzoic acid in THF and stirred for 2 hours at room temperature. The reaction medium is poured into water, extracted with ethyl acetate, decanted organic phase is dried over magnesium sulfate, and evaporated. Grind the obtained solid product with hexane, filtered and dried. Obtain 2.8 g (74%), the target amide with so pl. 87-87oC.

EXAMPLE 28

N-Ethyl-4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2 - naphthyl]benzamide

Similarly to the method of example 27 (b) by introducing into the interaction of 3.5 g (6,9 mmol) of acid chloride of 4-[7-(1 - substituted)-6 - methoxyethoxyethoxy-2-naphthyl] benzoic acid with 1.7 ml (20,6 mmolil)-6 - methoxyethoxyethoxy-2 - naphthyl]benzamide

Similarly to the method of example 27 (b) by introducing into the interaction of 3.5 g (6,9 mmol) of acid chloride of 4-[7-(1 - substituted)-6 - methoxyethoxyethoxy-2-naphthyl] benzoic acid with 1.5 ml (26,2 mmol) and ammonia (32%) are obtained 2.9 g (89%), the target amide with so pl. 198-199oC.

EXAMPLE 30

N-[4-(Hydroxyphenyl] -4-[7- (1-of substituted)-6-methoxyethoxyethoxy - 2-naphthyl]benzamide

a) N-(4-Acetoxyphenyl)-4- [7-(1-of substituted)-6 - methoxyethoxyethoxy - 2-naphthyl]benzamide

In the flask is charged with 970 mg (6.4 mmol) of 4-acetoacetanilide, 50 ml THF and 990 μl (7 mmol) of triethylamine. Was added dropwise a solution of 3.2 g (6.4 mmol) of acid chloride of 4-[7-(1-substituted)- 6-methoxyethoxyethoxy-2 - naphthyl]benzoic acid in THF and stirred at room temperature for two hours. The reaction medium is poured into water, extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The obtained residue proscout in heptane, filtered off, dried. Get 3,15 g (81%) of the desired product with so pl. 206-207oC.

b) N-(4-Hydroxyphenyl)-4- [7-(1-of substituted)-6 - methoxyethoxyethoxy-2-naphthyl]benzamide

Similarly to the method of example 1 (g), on the basis of 3.15 g (5.2 mmol) of N-(4-acetoxyphenyl)-4-[7- (1-of substituted)-6 - methoxyethoxyethoxy-2-naphthyl]benzamide is P>C.

EXAMPLE 31

4-[7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naphthyl]-benzoylpiperazine

a) N-Benzyl-4-[7- (1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl] -benzoyl-piperazine

Similarly to the method of example 27 (b) by introducing into the interaction of 7.3 g (14.4 mmol) of acid chloride of 4-[7-(1 - substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzoic acid with 2.5 ml (14.4 mmol) of 4-benzylpiperazine receive 3 g (33%) of the desired product with so pl. 176-177oC.

b) 4-[7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naphthyl]- benzoylpiperazine

In a three-neck flask is charged with 500 mg (0.8 mmol) videolounge amide and 20 ml of methanol. Add 900 mg of Pd/C (10%), then 900 μl of formic acid and stirred at room temperature for 3 hours. The catalyst is filtered off, the filtrate is poured into containing bicarbonate water, extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by column chromatography with silica using a mixture of dichloromethane with methanol (80:20). Obtain 310 mg (72%) of the desired product with so pl. 177-178oC.

EXAMPLE 32

Propyl-4-[7-(1-substituted) -6-mlokosievicsi-2 - naphthyl]benzoate

In a three-neck to the 100 ml of DMF. Add small drops of 200 mg (6.7 mmol) of sodium hydride (80% in oil) and stirred until the cessation of gas evolution. Then add 500 ml (6.1 mmol) of jumproping and stirred for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by column chromatography with silica, elwira mixture of heptane with ethyl acetate (80:20). Get 1 g (33%) complex propyl ether so pl. 121-122oC.

EXAMPLE 33

4-[7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naphthyl]phenyl-acetate

Similarly to the method of example 1 (C) by entering into interaction 5 g (12.8 mmol) of 7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl-boric acid with 2.7 g (10.1 mmol) of 4-iodine-propyl-acetate get 2,88 g (57%) of the desired product with so pl. 117-118oC.

EXAMPLE 34

4-[7-(1-Substituted)-6 - methoxyethoxyethoxy-2-naphthyl]phenol

Similarly to the method of example 1 (g) on the basis of 2.5 g (5 mmol) 4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2 - naphthyl]phenyl-acetate to obtain 2.2 g(97%) 4-[7-(1-of substituted)-6 - methoxyethoxyethoxy-2-naphthyl] phenol with so pl. 126-127oC.

EXAMPLE 35

Hydrochloride 4-[7-(1-substituted)-6 - the 1-substituted)-6 - methoxyethoxyethoxy-2-naphthyl]phenol, 550 mg (3,96 mmol) of potassium carbonate, and 4 ml of potassium iodide and 60 ml of methyl ethyl ketone. Add 270 mg (1,45 mmol) of the hydrochloride of 4-(2-chloroethyl)the research and refluxed for 12 hours. Reaction medium was poured into 1 N. hydrochloric acid, extracted with diethyl ether, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with ethyl acetate. After evaporation of the solvents receive oil. The hydrochloride is obtained by dissolving the oil in diethyl ether, followed by adding 1 ml of saturated methanolic HCl solution. The salt is filtered off, dried her, obtain 350 mg (44%) of the target hydrochloride with so pl. 123-124oC.

EXAMPLE 36

Hydrochloride 4-[(1-substituted)-6 - methoxyethoxyethoxy - 2-naphthyl]phenoxyethyl-piperidine

Similarly to the method of example 35 by introducing interaction 600 mg (1,32 mmol) 4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2-naphtalene with 310 mg (1.7 mmol) of the hydrochloride of 1-(2-chloroethyl)piperidine obtain 770 mg (85%) of the target hydrochloride with so pl. 126-127oC.

EXAMPLE 37

Hexyl-4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2 - naphthyl]benzoate

Similarly, the method of the example is islote with 800 μl (5.6 mmol) of hodgekin obtain 980 mg (62%) complex hexyl ether so pl. 73-74oC.

EXAMPLE 38

N-{[4-/7-(1-of Substituted)-6 - methoxyethoxyethoxy-2 - naphthyl/benzoyl]}-glutamic acid

a) Diethyl-N-{[4-/7- (1-of substituted)-6 - methoxyethoxyethoxy-2-naphthyl/ benzoyl]}glutamate

In the flask is charged of 1.93 g (7.8 mmol) of the hydrochloride of the ethyl-L-glutamate, 1.13 g (9,24 mmol) of 4-dimethylaminopyridine and 100 ml of THF. Was added dropwise a solution 3,59 g (7.1 mmol) of acid chloride of 4-[7-(1-substituted)-6 - methoxyethoxyethoxy-2 - naphthyl] benzoic acid in THF and stirred at room temperature for 4 hours. The reaction medium is poured into water, extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira mixture of heptane with ethyl acetate (70:30). Obtain 2.8 g (58%) of the desired product in the form of butter.

b) N-{ [4-/7-(1-of Substituted)-6 - methoxyethoxyethoxy - 2-naphthyl/ benzoyl]} -glutamic acid

Similarly to the method of example 1 (g) on the basis of 2.7 g (4.2 mmol) videolounge complex diapir obtain 1.45 g (56%) N-{[4-/7-(1-of substituted)-6 - methoxyethoxyethoxy-2 - naphthyl/ benzoyl] }glutamic acid so pl. 137-138oC.

EXAMPLE 39

4-[7-(1-Substituted)-6 - methoxyphenoxy-2-naphthyl]benzoine 12 (a) by entering into interaction 870 mg (1.7 mmol) of methyl 4-[7-(1-substituted)- 6-hydroxyhexyloxy-2-naphthyl] benzoate with 160 μl (1.7 mmol) of dimethylsulfate receive 100 mg (14%) of the desired product with so pl. 141-143oC.

b) 4-[7-(1-Substituted)-6 - methoxyphenoxy-2-naphthyl] benzoic acid

Similarly to the method of example 1 (g) on the basis of 95 mg (0.18 mmol) videolounge of ester obtain 61 mg (66%) of the target acid so pl. 267-269oC.

EXAMPLE 40

4-[7-(1-Substituted)-6 - methoxyethoxymethyl-2-naphthyl] benzoic acid

a) Methyl-4-[7-(1-substituted)-6 - methoxyethoxymethyl - 2-naphthyl]benzoate

In the flask is charged 541 mg (1.2 mmol) of methyl 4-[7-(1 - substituted)-6 - hydroxypropyl-2-naphthyl] benzoate, 5 ml of dimethoxymethane and add 5 drops of trimethylsilanol. Stirred at room temperature for 24 hours, the reaction medium is poured into water, extracted with diethyl ether, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira mixture with dichloromethane heptane (70:30). Obtain 355 mg (59%) of the desired product with so pl. 137-138oC.

b) 4-[7-(1-Substituted)-6 - methoxyethoxymethyl-2 - naphthyl] benzoic acid

Similarly to the method of example 1 (g) on the basis of 345 mg (0.69 mmol) videolounge of ester obtain 280 mg (83%) of the desired product with so pl. 237-238oC.

EXAMPLE 41

xitil - 2-naphthyl]benzoate

Similarly to the method of example 40 (a) on the basis of 200 mg (0.47 mmol) of methyl 4-[7-(1-substituted)-6 - hydroxyethyl-2 - naphthyl] benzoate obtain 156 mg (68%) of the desired product with so pl. 145-146oC.

b) 4-[7-(1-Substituted)-6 - methoxyethoxymethyl-2 - naphthyl]benzoic acid

Similarly to the method of example 1 (g) on the basis of 149 mg (0.3 mmol) videolounge of ester obtain 101 mg (70%) of the target acid so pl. 225-227oC.

EXAMPLE 42

Antagonistic activity of the compounds of formula (I) evaluate in the test cell differentiation F9 embryonic teratocarcinoma mice (Cancer Research, 43, S. of 5,268, 1983).

These compounds, subjects in a concentration of 10-6M, in this test inactive as agonists and partially or completely inhibit the effects of the retinoid agonist on the morphology and on the secretion activator plasmogen according to the following Protocol.

The F9 cells were seeded in 12-well clusters, connections, experience at a concentration of 10-9- 10-5mol in the presence a11-transretinoic acid or synthetic retinoid agonist (compound A): 4-(5,5,7,8-tetrahydro - 5,5,8,8 - tetramethyl-2-naphthylamine) -benzoic acid (BASF) at a concentration of 10-8mol. After incubation for 3 to whom which inhibits 50% of the effect of the agonist on the secretion activator plasmagene.

Antagonist against compound A (10 nmol) in the test of differentiation of F9 cells, IR50(nmol) is an Example

5 - 1

2 - 3

180 - 5

500 - 6

250 - 14

100 - 20

450 - 39

EXAMPLE 43

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

A. Formulation, administered orally.

(a) Tablets weighing 0.2 g:

The compound obtained in example 6 - 0.001 g

Starch - 0,114 g

The dicalcium phosphate at 0.020 g

Silicon dioxide - 0,020 g

Lactose - 0,030 g

Talc - 0,010 g

Magnesium stearate 0.005 g

(b) potable suspension in ampoules, 5 ml:

The compound obtained in example 5 - 0.001 g

Glycerin - 0,500 g

Sorbitol, 70% - 0,500 g

The sodium saccharinate - 0,010 g

Methyl-parahydroxybenzoate - 0,040 g

Flavouring substance - Enough

Purified water To total 5 ml

(in) Tablets weighing 0.8 g:

Connection example 2 - 0,500 g

Pre gelatinising starch - 0,100 g

Microcrystalline cellulose - 0,115 g

Lactose - 0.075 g

Magnesium stearate - 0,010 g

(g) potable suspension in ampoules of 10 ml:

The compound of example 4 - 0,200 g

Glyceri the Flavoring substance - A sufficient amount of

Purified water To a total volume of 10 ml

B. Language input topical way.

(a) Ointment

The compound of example 6 at 0.020 g

Isopropylmyristate - 81,700 g

Liquid vaseline oil - 9,100 g

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

(b) Ointment

Connection example 2 - 0,300 g

Pharmacopoeial medical vaseline To 100 g

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

The compound of example 7 - 0,100 g

The mixture forming the emulsion of lanolin alcohols, waxes and oils ("Eucerine anhydre, manufactured in the sale of the company BDF) - 39,900 g

Methyl-parahydroxybenzoate - 0.075 g

Propyl-parahydroxybenzoate - 0.075 g

Sterile demineralized water To 100 g

(g) Lotion

The compound of example 8 - 0,100 g

Polyethylene glycol (PEG 400) - 69,900 g

Ethanol, 95% - 30,000 g

(e) Hydrophobic ointment

The compound of example 10 - 0,300 g

Isopropylmyristate - 36,400 g

Silicone oil ("Rhodorsil 47 V 300", manufactured in the sale by the company RHÔNE-POULENC) - 36,400 g

Beeswax - 13,600 g

Silicone oil ("Ab: L 300.300 cst", issued for the sale by the company GOLDSCHMIDT) - Up to 100 g

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

The compound of example 5 to 1,000 g
Propylene glycol - 2,000 g

Methyl-parahydroxybenzoate - 0.075 g

Propyl-parahydroxybenzoate - 0.075 g

Sterile demineralized water To 100 g

1. Applying an effective amount of at least one connection of the retinoid of formula (I) as an active agent in cosmetic or pharmaceutical compositions intended for the treatment of disorders or diseases associated with sverrehelena receptors RSC and/or hypervitaminosis A, and this compound corresponds to the General formula (I)

< / BR>
in which R1is (i) a radical-CH3(ii) a radical-CH2OH, (iii) a radical-O-R3, (iv) a radical-CO-R4;

R3and R4have the meanings stated below;

Ar is a radical of the formula

< / BR>
< / BR>
where R5below value,

R2is (a) a radical -(X)-(CH2)p-R6(b) a radical -(X)n- (CH2)q-R7(in) a radical-CH=CH-(CH2)5-R6(d) a radical-CH=CH-(CH2)t-R7and R6, R7, X, n, p, q, s, t have the meanings stated below, provided that R3is a hydrogen atom, a lower alkyl radical, a radical - (CH2)m
< / BR>
(d) a radical-OR9and the radicals R1, R11and R9have the following values;

R5is a hydrogen atom, halogen, a linear or branched alkyl radical with 1 to 20 carbon atoms, a hydroxyl radical or a radical-OR10or-OCOR10and R10has the following value;

R6is a hydrogen atom, a linear or branched alkyl radical with 1 to 20 carbon atoms, alkenyl radical, alkyl radical;

R7is aryl radical, a mono - or polyhydroxyethyl radical, a hydroxyl group which, if necessary, protected in the form of a methoxy or acetoxy group or acetonide, radical-COR4provided that R7not a simple polyether radical containing carbon in a - position to the carbon in position 6-afternova radical;

R8is a lower alkyl radical or a saturated heterocyclic radical;

R9is a hydrogen atom, a linear or branched alkyl radical with 1 to 20 carbon atoms, alkenyl radical, mono - or polyhydroxyalkane) or a sugar residue, or a residue of an amino acid, or peptide;

R10is a lower alkyl radical;

X is an oxygen atom or a radical-S(O)2;

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

m = 1, 2, or 3;

n = 0 or 1;

p = 5 - 12, integer;

q = 0 to 12, an integer;

r = 0,1 or 2;

s = 3 to 10, an integer;

t = 0 to 10, an integer;

as well as their salts and their chiral counterparts.

2. Application under item 1, characterized in that compounds of the formula (I) are in the form of salts of alkali or alkaline earth metal, or alternative zinc, or organic amine.

3. Application under item 1 or 2, characterized in that the lower alkyl radicals are selected from the group consisting of methyl, ethyl, ISO-propyl, Putilkovo, tert-Putilkovo and exiling radicals.

4. The use according to any one of paragraphs.1 to 3, characterized in that the linear or branched alkyl radicals with 1 to 20 carbon atoms selected from the group so octadecyl radicals.

5. The use according to any one of paragraphs.1 to 4, characterized in that monohydrocalcite radicals selected from the group consisting of hydroxymethylene, 2-hydroxyethylene, 2-hydroxypropyl or 3-hydroxypropyl radicals.

6. The use according to any one of paragraphs.1 to 5, characterized in that polyhydroxyalkane radicals selected from the group consisting of 2,3-dihydroxypropyl, 2,3,4-trihydroxybutane, 2,3,4,5-tetrahydroxyphenyl radical or residue of pentaerythritol.

7. The use according to any one of paragraphs.1 - 6, characterized in that the aryl radical is a phenyl radical, if necessary substituted by at least one halogen atom, a hydroxyl or a nitro-group.

8. The use according to any one of paragraphs.1 to 7, characterized in that kalkilya radicals chosen in the group consisting of benzyl or phenyl radicals, if necessary substituted by at least one halogen atom, a hydroxyl or amino group.

9. The use according to any one of paragraphs.1 to 8, characterized in that alkeneamine radicals selected from the group consisting of radicals with 2 to 5 carbon atoms and having one or more ethylene nancysinatra, especially as allyl s, consisting of residues of glucose, galactose, mannose or glucuronic acid.

11. The use according to any one of paragraphs.1 to 10, characterized in that the amino acid residues is chosen from the group consisting of a residue derived from lysine, glycine, or aspartic acid.

12. The use according to any one of paragraphs.1 - 11, characterized in that the peptide residues is chosen from the group consisting of the residue of the dipeptide or Tripeptide.

13. The use according to any one of paragraphs.1 - 12, characterized in that the unsaturated heterocyclic radicals selected from the group formed piperidino, morpholino-, pyrrolidino or piperazinediones, if necessary substituted in position 4 alkyl radical with 1 to 6 carbon atoms or mono - or polyhydroxyalkane radical.

14. The use according to any one of paragraphs.1 - 13, characterized in that the unsaturated heterocycles are selected from the group consisting of pyridine, furan or thiophene radical.

15. The use according to any one of paragraphs.1 to 14, characterized in that the halogen atoms are selected from the group consisting of fluorine, chlorine and bromine.

16. Application under item 1, characterized in that the compounds are selected from the group consisting of:

2-hydroxy-4-/7-(oinoi acid,

4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/-benzoic acid,

4-/7-(1-substituted)-6-benzyloxy-2-naphthyl/-2-thiophencarboxylic acid,

4-/7-(1-substituted)-6-benzyloxy-2-naphthyl/-benzoic acid,

4-/7-(1-substituted)-6-benzyloxycarbonyl-2-naphthyl/-benzoic acid,

2-hydroxy-4-/7-(1-substituted)-6-(4-terbisil)oxy-2-naphthyl/benzoic acid,

6-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/nicotinic acid,

4-/7-(1-substituted)-6-heptyloxy-2-naphthyl/-benzoic acid,

2-hydroxy-4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzoic acid,

2-chloro-4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-hydroxyhexyloxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-hydroxypropyl-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-hydroxyethyloxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-hydroxyethyl-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-hydroxyethyl-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-hydroxyethoxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-hydroxyethoxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-hydroxyethoxy-2-naphthyl/benzoic acid,

4-/7-(1-ad is l/benzoic acid,

4-/7-(1-substituted)-6-carbamoylphenoxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-ethoxycarbonylmethoxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-ethoxycarbonylmethoxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-carboxymethoxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-carboxymethoxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzoic of benzoimidazole,

4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzaldehyde, morpholine 4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzoic acid,

N-ethyl-4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzamide,

4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzamide,

N-(4-hydroxyphenyl)- 4-/7-(1-of substituted)-6-methoxyethoxyethoxy-a-naphthyl/benzamide,

4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzoylpiperazine,

propyl-4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzoate,

4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/phenylacetate,

4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/phenol,

the hydrochloride 4-/7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl/-phenoxyethylamine,

the hydrochloride 4-/7-(1-substituted)-6-methoxybenzoate,

N-{ [4-/7-(1-of substituted)-6-methoxyethoxyethoxy-2-naphthyl/benzoyl] } -glutamic acid,

4-/7-(1-substituted)-6-methoxyphenoxy-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-methoxyethoxymethyl-2-naphthyl/benzoic acid,

4-/7-(1-substituted)-6-methoxyethoxymethyl-2-naphthyl/benzoic acid.

17. Application under item 1, characterized in that the compounds correspond to the formula (I) in which R1- radical-CO-R4, R2- radical -(X)n-(CH2)pR6or -(X)n-(CH2)q-R7, Ar is a radical of formula (a) or (b).

18. The use according to any one of paragraphs.1 - 17, wherein the disorder or disease associated with sverrehelena receptors RSC and/or hypervitaminosis A, are expressed by inflammatory, allergic and/or immunologic component.

19. The use according to any one of paragraphs.1 to 18, characterized in that compounds of the formula (I) is combined with other compounds having retinoid activity type, 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.

20. Use one lead interline or parenteral.

21. Use one of the PP.1 to 19, characterized in that the cosmetic or pharmaceutical composition is administered tapicerki or ocular.

22. Application under item 21, characterized in that compounds of the formula (I) used at a concentration of 0.001 - 5% based on the total weight of the composition.

23. Connection type retinoids General formula (I)

< / BR>
in which R1- radical-CO-R4;

Ar is a radical of the formula

< / BR>
R2- radical -(X)n-(CH2)q-R7;

R4(a) a hydrogen atom,

(b) a lower alkyl radical, (d) radical OR9;

R5is a hydrogen atom, halogen, a linear or branched alkyl radical with 1 to 20 carbon atoms, a hydroxyl radical, a radical - OR10or OCOR10;

R7is simple polyether radical containing carbon in a - position to the carbon in position 6 afternova radical;

X is an oxygen atom or a radical S(O)r;

n, q or r = 0;

R9is a hydrogen atom, a linear or branched alkyl radical with 1 to 20 carbon atoms;

R10lower alkyl radical,

or their salts, or chiral analogs that have activity in the treatment of the composition of cosmetic or pharmaceutical compositions.

24. Connection on p. 23, characterized in that they are chosen among 4-[7-(1-substituted)-6-methoxyethoxymethyl-2-naphthyl] benzoic acid and 4-[7-(1-substituted)-6-methoxyethoxymethyl-2-naphthyl]benzoic acid.

 

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