Triaromatic the vitamin d analogues, pharmaceutical and cosmetic compositions

 

The invention relates to new triaromatic the vitamin D analogues of General formula (I):

where R1- CH3or-CH2HE, R2-CH2HE, X-Y - linkage of formula (a) or (C)

where R6- H, lower alkyl, W is O, S or-CH2-, Ar1, Ar2the cycles of formula (e), (j), (k), (m)

R8, R9, R11, R12- H, lower alkyl, halogen, HE, CF3,

R3-

where R13, R14- lower alkyl, CF3, R15- H, acetyl, trimethylsilyl, tetrahydropyranyl, or their salts. The compounds I are useful for the treatment of dermatological diseases associated with disorders of keratinization. 3 N. and 8 C.p. f-crystals, 1 tab., 6 Il.

The invention relates to new triaromatic compounds, vitamin D analogues, to a method for their production and to their use in pharmaceutical compositions intended for use in medicine or VETERINARII, or alternatively in cosmetic compositions.

Compounds according to the invention have a pronounced activity in respect of which icenii dermatological (or other) diseases, associated with impaired keratinization, diseases with an inflammatory and/or immunoallergic component and hyperproliferative tissues ectodermal origin (skin, epithelium, ...), both benign and malignant. These compounds can be used, in addition, to prevent aging of the skin caused by exposure to light or age, and for treating disorders in the healing of wounds.

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

Vitamin D is an essential vitamin used in the prophylaxis and treatment of defects of cartilage mineralization (rickets) and bone (osteomalacia) and even some forms of osteoporosis in the elderly. However, currently, it was found that its functions go far beyond the regulation of bone metabolism and calcium homeostasis. Among the new features we can mention the effects on cell proliferation and differentiation and regulation of immune protection. These functions allow you to develop new ways of treatment in dermatology, Oncology, and autoimmune disease and transplant of organs or tissues.

Effective trepetaniem outcome). Some of the synthesized lately structural analogues of vitamin D active only in relation to cell differentiation, but does not affect calcium metabolism.

One of the purposes of the present invention is to provide new compounds which are structural analogues of vitamin D, which have selective activity against cell proliferation and differentiation of cells without showing hypercalcaemia activity.

Another objective of the present invention is to provide new compounds, analogues of vitamin D, which are more easily synthesized and, therefore, they are more economical compared to those known in the prior art.

Thus, the present invention relates to compounds having the following General formula (I):

where:

R1means a hydrogen atom, a radical, CH3or the radical -(CH2)r-OR4;

R2means a radical -(CH2)s-OR5;

moreover, r, s, R4and R5have the meanings stated below;

X-Y represents a bond selected from the relations of the following formulae (a) to(d), which can be read from left to right or Vice versa:

and R6and W them is and R7, R8and R9have the meanings stated below;

Ar2mean cycle following formulas (j)-(n):

and R10, R11and R12have the meanings stated below;

R3means a radical of the formula

moreover, t, R13, R14and R15have the meanings stated below;

and:

r and s are identical or different, denote 1 or 2;

R4and R5identical or different, denote a hydrogen atom, acetyl, benzoyl, trimethylsilyl, tert-butyldimethylsilyl or tetrahydropyranyl;

R6means a hydrogen atom or lower alkyl;

W denotes an oxygen atom, a sulfur, a radical, CH2or an NH radical, which may be substituted by lower alkyl;

R7and R10identical or different, denote a hydrogen atom or lower alkyl;

R8, R9, R11and R12identical or different, denote a hydrogen atom, lower alkyl, halogen atom, radical OR16simple polyester radical, the radical CF3the radical NO2or an amino group which may be substituted by one or two lower alkilani;

and R16has the following values;

t is 0 or 1;

R13and R14the same>

R15means a hydrogen atom, acetyl, trimethylsilyl, tert-butyldimethylsilyl or tetrahydropyranyl;

R16means a hydrogen atom or lower alkyl.

The invention relates also to the optical and geometrical isomers of the above compounds of formula (I) and their salts in the case where X-Y indicate the relationship of the formula (a) and W stands for the radical-NH-, possibly substituted lower alkyl.

When the compounds according to the invention are in the form of salts, it is a pharmaceutically or cosmetically acceptable salts obtained by attaching an inorganic or organic acid, in particular hydrochloric, sulfuric, acetic, fumaric, gementera, maleic or almond acid.

According to the present invention, under a lower alkyl understand linear or branched alkyl radical with 1-6 carbon atoms and preferably methyl, ethyl, isopropyl, tert-butyl and hexyl.

Under cycloalkyl understand cyclic alkanoyl radical of 3-6 carbon atoms. Cycloalkyl preferably chosen among cyclopropyl, cyclopentyl or cyclohexyl.

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

Under ordinary polyester radical see radical with 2 to 5 atoms of psittacines radical.

Of the compounds of formula (I) included in the scope of the present invention include, inter alia, the following:

{5-[4’-(1-ethyl-1-hydroxypropyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{2-hydroxymethyl-5-[4’-(1-hydroxy-1-methylethyl)biphenyl-3-intoximeter]phenyl}methanol;

{5-[4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{2-hydroxymethyl-5-[4’-(1-hydroxy-1-methylethyl)-2’-methylbiphenyl-3-intoximeter]phenyl}methanol;

(5-{2-[3’-(1-ethyl-1-hydroxypropyl)biphenyl-3-yl]ethyl}-2-hydroxymethylene)methanol;

{2-hydroxymethyl-5-[3’-(1-hydroxy-1-methylethyl)biphenyl-3-intoximeter]phenyl}methanol;

{5-[4’-(2-ethyl-2-hydroxybutyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{5-[3’-(2-ethyl-2-hydroxybutyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

1-[3’-(3,4-bishydroxyethyl)biphenyl-3-yl]-2-methylpropan-2-ol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-ylsulphonyl]-2-hydroxymethylene}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-2,2’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{2-hydroxymethyl-4-[4’-(1-hydroxy-1-propinball)-2,2’-dimethylbiphenyl-3-intoximeter]phenyl}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-2-methylbiphenyl-3-intoximeter]-2-hydroxymethyl the l;

(4-{3-[5-(1-ethyl-1-hydroxypropyl)pyridin-2-yl]phenoxymethyl}-2-hydroxymethylene)methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)is 6.2’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)is 6.2’,6’-trimethylphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)2’,6’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

1-{4-[3-(3,4-bishydroxyethyl)phenyl]thiophene-2-yl}propane-1-ol;

(4-{3-[4-(1-ethyl-1-hydroxypropyl)thiophene-2-yl]phenoxymethyl}-2-hydroxymethylene)methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-ylethoxy]-2-hydroxymethylene}methanol;

1-[3’-(3,4-bishydroxyethyl)-2-methylbiphenyl-4-yl]propan-1-ol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-3’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{5-[4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-4-intoximeter]-2-hydroxymethylene}methanol;

{4-[2’-tert-butyl-4’-(1-ethyl-1-hydroxypropyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

1-[3’-(3,4-bishydroxyethyl)-2-methylbiphenyl-4-yl]-2,2-DIMETHYLPROPANE-1-ol;

1-[3’-(3,4-bishydroxyethyl)-2-methylbiphenyl-4-yl]-2-methylpropan-1-ol;

{2-Ki is droxidopa)-2-were]thiophene-2-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{5-[4-(1-ethyl-1-hydroxypropyl)-2-were]thiophene-2-ylethoxy}-2-hydroxymethylene}methanol;

[5-(2-{5-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]thiophene-2-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{5-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]thiophene-2-ylethoxy}-2-hydroxymethylene)methanol;

[5-(2-{5-[4-(1-ethyl-1-hydroxypropyl)-2-were]-4-methylthiophene-2-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{5-[4-(1-ethyl-1-hydroxypropyl)-2-were]-4-methylthiophene-2-ylethoxy}-2-hydroxymethylene)methanol;

[2-hydroxymethyl-5-(2-{5-[methyl(cryptorchidectomy)phenyl]thiophene-2-yl}ethyl)phenyl]methanol;

(2-hydroxymethyl-5-{5-[methyl(cryptorchidectomy)phenyl]thiophene-2-ylethoxy}phenyl)methanol;

[5-(2-{5-[ethyl(cryptorchidectomy)phenyl]thiophene-2-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{5-[ethyl(cryptorchidectomy)phenyl]thiophene-2-ylethoxy}-2-hydroxymethylene)methanol;

[2-hydroxymethyl-5-(2-{methyl[methyl(cryptorchidectomy)phenyl]thiophene-2-yl}ethyl)phenyl]methanol;

(2-hydroxymethyl-5-{methyl[methyl(cryptorchidectomy)phenyl]thiophene-2-ylethoxy}phenyl)methanol;

[5-(2-{5-[4-(1-ethyl-1-hydroxypropyl)-2-were]thiophene-3-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{5-[4-(1-ethyl-1-hydroxypropyl)-the EN-3-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{5-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]thiophene-3-ylethoxy}-2-hydroxymethylene)methanol;

[2-hydroxymethyl-5-(2-{5-[methyl(cryptorchidectomy)phenyl]thiophene-3-yl}ethyl)phenyl]methanol;

(2-hydroxymethyl-5-{5-[methyl(cryptorchidectomy)phenyl]thiophene-3-ylethoxy}phenyl)methanol;

[5-(2-{5-[ethyl(cryptorchidectomy)phenyl]thiophene-3-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{5-[ethyl(cryptorchidectomy)phenyl]thiophene-3-ylethoxy}-2-hydroxymethylene)methanol;

[5-(2-{4-[4-(1-ethyl-1-hydroxypropyl)-2-were]thiophene-2-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{4-[4-(1-ethyl-1-hydroxypropyl)-2-were]thiophene-2-ylethoxy}-2-hydroxymethylene)methanol;

[5-(2-{4-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]thiophene-2-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{4-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]thiophene-2-ylethoxy}-2-hydroxymethylene)methanol;

[5-(2-{4-[4-(1-ethyl-1-hydroxypropyl)-2-were]-5-methylthiophene-2-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{4-[4-(1-ethyl-1-hydroxypropyl)-2-were]-5-methylthiophene-2-ylethoxy}-2-hydroxymethylene)methanol;

[2-hydroxymethyl-5-(2-{4-[methyl(cryptorchidectomy)phenyl]thiophene-2-yl}ethyl)phenyl]methanol;

(2-hydroxymethyl-5-{4-[methyl(Tripolitania the h-2-yl}ethyl)-2-hydroxymethylene]methanol;

(5-{4-[ethyl(cryptorchidectomy)phenyl]thiophene-2-ylethoxy}-2-hydroxymethylene)methanol;

[2-hydroxymethyl-5-(2-{methyl[methyl(cryptorchidectomy)phenyl]thiophene-2-yl}ethyl)phenyl]methanol;

(2-hydroxymethyl-5-{methyl[methyl(cryptorchidectomy)phenyl]thiophene-2-ylethoxy}phenyl)methanol;

{5-[2’-ethyl-4’-(1-ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{5-[4’-(1-ethyl-1-hydroxypropyl)-2’-isopropyl-6-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{5-[2’-tert-butyl-4’-(1-ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{5-[ethylmethyl(cryptorchidectomy)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{2-hydroxymethyl-5-[2’-isopropyl-6-methyl-4’-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)biphenyl-3-intoximeter]phenyl}methanol;

{5-[dimethylaminomethyl(cryptorchidectomy)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{5-[6-ethyl-4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{5-[4’-(1-ethyl-1-hydroxypropyl)-6-methoxy-2’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{5-[6-tert-butyl-4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-intoximeter]-2-HYDR shall fenil}methanol;

{2-hydroxymethyl-5-[6-methoxy-2’-methyl-4’-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)biphenyl-3-intoximeter]phenyl}methanol;

{5-[dimethylaminomethyl(cryptorchidectomy)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

(5-{2-[4’-(1-ethyl-1-hydroxypropyl)is 6.2’-dimethylbiphenyl-3-yl]ethyl}-2-hydroxymethylene)methanol;

(5-{2-[dimethyl(cryptorchidectomy)biphenyl-3-yl]ethyl}-2-hydroxymethylene)methanol;

(5-{[4’-(1-ethyl-1-hydroxypropyl)is 6.2’-dimethylbiphenyl-3-ylamino]methyl}-2-hydroxymethylene)methanol;

(5-{[dimethyl(cryptorchidectomy)biphenyl-3-ylamino]methyl}-2-hydroxymethylene)methanol;

[5-({[4’-(1-ethyl-1-hydroxypropyl)is 6.2’-dimethylbiphenyl-3-yl]methylamino}methyl)-2-hydroxymethylene]methanol;

[5-({[dimethyl(cryptorchidectomy)biphenyl-3-yl]methylamino}methyl)-2-hydroxymethylene]methanol.

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

R1means the radical CH3or CH2OH;

R2means radical, CH2OH;

X-Y represents a relationship of the formula (a) or (C);

R3means the moiety C(R13)(R14Thus, the compounds of formula 1(a) can be obtained (figure 1) by reaction of the halogenated, preferably prosteradlo, the compounds of formula (I) with phenol (Y=OH), thiophenols (Y=SH), aniline (Y=NH-COO-tert-butyl) derivative (3) in the presence of a base, such as2CO3in a solvent such as acetone or methyl ethyl ketone.

The compounds of formula 1(a) can be also obtained (figure 1) by reaction of the halogenated, preferably prosteradlo, the compounds of formula (I) with sodium or potassium salt of phenol (Y=Oh), teotenango (Y=SH), aniline (Y=NH-COO-tert-butyl derivative (3) in a solvent such as dimethylformamide (DMF).

The compounds of formula I(b) can be obtained (figure 1) by reaction lansoprozole (2) phenolic (Y=OH), thiophenols (Y=SH), aniline (Y=NH2) derivative (3) in the presence of carbonyldiimidazole or dicyclohexylcarbodiimide in a solvent such as dichloromethane or tetrahydrofuran (THF).

The compounds of formula I(b) can also be obtained (figure 1) by the reaction of benzoyl chloride (obtained by the interaction lansoprozole (2) with thionyl chloride or oxalidaceae as triethylamine, in a solvent such as dichloromethane or tetrahydrofuran (THF).

Compounds (1), (2) and (3) can be obtained according to the reaction schemes shown in figures 2, 3 and 4. These methods of preparing compounds (1) and (2) have the advantage that the number of stages of obtaining limited.

Figure 2: (a) mean reaction with NR3in dioxane; (b) mean reaction with CH3Och2CL in the presence of sodium hydride in dimethylformamide as a solvent; (C) mean reaction with n-butyllithium in the presence of CO2in tetrahydrofuran; (d) mean reaction with n-butyllithium in tetrahydrofuran, followed by reaction with dimethylformamide; (e) means the reduction using sodium borohydride in a mixture of methanol with tetrahydrofuran as solvent; (f) means reaction with tetrabromide carbon in the presence of triphenylphosphine in dichloromethane as solvent.

On the figure 3: (a) mean reaction with NR3in dioxane; (b) mean reaction with methanol in the presence of sulfuric acid; (C) mean reaction with tert-C4H9(CH3)2SiCl in the presence of imidazole in dimethylformamide as a solvent; (a) mean reaction with LiAlH4in diethyl ether; (e) mean reaction NF in tetrahydrofuran; (d) mean reaction with tetrabromide carbon in the presence of triphenylphosphine in dichloromethane as solvent.

Derivative (3) can be obtained as specified on figure 4 reaction scheme. By the reaction of Suzuki type between boron derivative (4) and idealny derivative (5) in the presence of a catalyst, such as tetrakis(triphenylphosphine)-palladium receive ester (6), which in turn is derived (3) by reaction with alkalinisation, cycloalkylation or alkyllithium.

The compounds of formula I(C) can be obtained (figure 5) by reaction type Horner-Emmons between phosphonate derivative (8) (obtained from the corresponding benzylbromide by reaction type Arbuzov) and benzaldehyde (7).

The compounds of formula I(d) can be obtained from compounds 1(C) by hydrogenation of the double bond in the presence of palladium-on-charcoal grill.

The compounds of formula 1(e) can be also obtained (figure 6) by reaction type Sonogashira between acetylene derivative (9) (obtained by reaction of benzaldehyde (7) the type of reaction, Corey-Fuchs) and triflate derivative (X=OSO2CF3or imprisonm (X=1) (10) in the presence of a catalyst based on a transition metal, such ka the formula (I) possess biological properties, similar to those of vitamin D, in particular the TRANS-activation properties of the elements of the response to vitamin D (VDRE), such as agonistic or antagonistic activity against receptors of vitamin D or its derivatives. Under the b group vitamins or their derivatives see, for example, derivatives of vitamin D2or D3and in particular 1,25-dihydroxyvitamin D3(calcitriol).

This agonistic activity against receptors of vitamin D or its derivatives can be detected in vitro using methods known in the study of gene transcription (Hansen and others, The Society For Investigative Dermatologie, 1, No. 1, April 1996).

As an example, the agonistic activity of VDR can be tested using the HeLa cell line by cotransfection expressing vector human receptor VDR and plasmid reporter p240Hase-CAT, which contains the -1399 to +76 promoter of 24-hydroxylase in rats, cloned above phase coding gene chloramphenicolchloramphenicol (CAT). Later, 18 hours after cotransfection in environment type tested product. Later, 18 hours after treatment quantitative determination of CAT activity in cell lysates is carried out using solid-phase immunode and the use of 10-7M calcitriol.

Agonistic activity can also be characterized in this system cotransfection by determining the dose required to achieve 50% of maximal activity product (AS).

Biological properties similar to vitamin D, can also be determined by the ability of the product to inhibit the proliferation of normal human keratinocytes (KHN in culture). Product add to KHN, cultured under conditions conducive to the state of proliferation. The product is kept in contact with the cells for five days. The number of proliferative cells is determined by the embedding of bromosuccinimide (BRdU) into DNA.

Agonistic activity to the receptor of vitamin D compounds according to the invention can also be assessed in vivo by induction of 24-hydroxylase in mouse SKH (Voorhees and others, 108, 513-518 (1997)).

The object of the present invention are also the compounds of formula (I) described above, as a medicinal product.

Compounds according to the invention are particularly well suited in the following areas of treatment:

1) for treating dermatological diseases associated with disorders of keratinization, which manifests itself in the differentiation and proliferation, in particular for the treatment obycejnych acne, such as caused by the sun, medical or occupational acne;

2) for treating other types of disorders of keratinization, such as, in particular ichthyosis, idiotphone condition, disease Daria, Palmar-plantar keratoderma, leukoplakia and leukoplakia status, skin psoriasis, or psoriasis, the mucosa (the mucous membrane of the mouth);

3) for treating other dermatological diseases with inflammatory immunoallergic component, with or without violation of disorders of cell proliferation, and in particular all forms of psoriasis, whether it is a cutaneous, mucous or ungual, and psoriatic rheumatism, or cutaneous atopy, such as eczema, or respiratory atopy or gingival hypertrophy;

4) for treating all dermal or epidermal proliferation, whether they are benign or malignant, whether they have a viral or non-viral origin, such as ordinary simple warts, flat warts and resembling warts epidermodysplasia, oral or multiple intraductal papillomas, lymphoma T; and proliferation, which can be caused by ultraviolet radiation, in particular, in the case of basal cell or STI

5) for treating other dermatological disorders such as immune dermatoses, such as lupus erythematosus, bullous immune diseases and collagen diseases such as scleroderma;

6) in the treatment of dermatological or General diseases with an immunological component;

7) to fight against violations of fat options, such as acne affected Hyperborea or normal seborrhea;

8) in the treatment of skin disorders caused by prolonged exposure to ultraviolet radiation, as well as to restore or fight against skin aging, whether it photoinduced or age, or to reduce pigmentation and actinic keratoses, or any pathologies associated with age or actinic aging;

9) for the prevention or treatment of impaired wound healing or to prevent or eliminate the “stretch marks” on the skin;

10) in the treatment of inflammatory diseases such as arthritis;

11) in the treatment of any skin or generalized, diseases of viral origin, such as the syndrome Kaposi;

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

13) for the treatment or prevention of cancerous or precancerous Sosa D, such as (but not limited to, breast cancer, leukemia, myelodysplastic syndromes and lymphomas, carcinoma cells malpighiales cancer and cancers of the gastrointestinal tract, melanoma and osteosarcoma;

14) for the prevention or treatment of alopecia of various origins, in particular alopecia resulting from chemotherapy or radiation effects;

15) for the treatment of immune diseases such as autoimmune diseases, such as diabetes mellitus type 1, multiple sclerosis, lupus and diseases like lupus, asthma, or glomerulonephritis; selective dysfunctions of the immune system such as AIDS, or to prevent immune rejection reactions such as rejection of transplants of the kidney, heart, bone marrow, liver, pancreatic islets, pancreas, or skin, or to prevent disease graft-versus-host;

16) in the treatment of endocrine diseases, given that the analogues of vitamin D can modulate hormone secretion, such as increasing insulin secretion or selective suppression of secretion of parathyroid hormone, for example, in chronic renal failure and secondary hyperparathyroidism;

17) in the treatment of diseases, x is s, are involved in calcium metabolism, such as muscle ischemia (myocardial infarction);

18) in the treatment and/or prevention of deficiencies of vitamin D and other disturbances of homeostasis of minerals in the plasma and in the bones, such as rickets, osteomalacia, osteoporosis, particularly in women during menopause, osteodystrophy nephrogenic, disorders of the parathyroid gland;

19) in the treatment of lesions of the cardiovascular system such as arteriosclerosis or hypertension and non-insulin-dependent diabetes.

In the above-mentioned therapeutic areas compounds according to the invention can be preferably used in combination with retinoids, corticosteroids or estrogens, in combination with antioxidants-hydroxy - or-keto acid or their derivatives, with blockers of potassium channels or in combination with other known drugs acting at the level of the immune system (eg, cyclosporine, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, ...).

Under the retinoids understand either natural or synthetic ligands of receptors RAR or RXR.

Under agents against free radicals understand allow.

Under-hydroxy - or-keto acid or their derivatives see, for example, lactic, malic, citric, glycolic, almond, wine, glycerin, ascorbic acid, derivatives of salicylic acid and their salts, amides or esters.

Under the blockers of potassium channels see, for example, Minoxidil (2,4-diamino-6-piperidinedione-3-oxide) and its derivatives.

The object of the present invention is also a pharmaceutical composition, comprising at least one compound of formula (I), such as the above.

The object of the present invention is also a pharmaceutical composition, intended in particular for the treatment of the above diseases.

Introduction compounds according to the invention can be carried out enteral, parenteral, local or ocular route.

For administration by enteral pharmaceutical compositions can be in the form of tablets, gelatin capsules, pills, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles, allowing to occur controlled release. For administration by parenteral composizioni is usually administered in a daily dose of about 0.001 μg/kg to 1000 μg/kg, and preferably about from 0.01 μg/kg to 100 μg/kg of body weight for 1-3 reception.

For administration by local pharmaceutical compositions based on compounds according to the invention are for the treatment of skin and mucous membranes and are in the form of ointments, creams, jelly, lipstick, powders, impregnated swabs, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymer "patches and hydrogels allowing to happen controlled release. These compositions for the introduction of a local path can be either in anhydrous form or in aqueous form, depending on clinical indications.

Ocular route of administration is mainly lotions for the eyes.

These compositions for local or ocular route of administration contain at least one compound of formula (I) as defined above, preferably in concentrations of 0.0001-5% and preferably 0.001 to 1% relative to the total weight of the composition.

The compounds of formula (I) according to the invention also find application in cosmetics, in particular for hygiene and hair care products, and, in particular, for treatment of skin with a tendency towards acne, for hair regrowth, against hair loss, to combat vneshnego, for preventing and/or combating photoinduced or age ageing.

In the field of cosmetic compositions according to the invention can be preferably used in combination with retinoids, corticosteroids, in combination with agents against free radicals, with-hydroxy - or-keto acid or their derivatives, or blockers of ion channels, and various products used in combination with the compounds according to the present invention are such as those listed above.

The present invention therefore also relates to cosmetic compositions comprising, in a cosmetically acceptable medium, at least one compound of formula (I) such as defined above. This cosmetic composition can be, in particular, in the form of a cream, a milk, a lotion, a gel, microspheres, or nanospheres or lipid or polymeric vesicles, a soap or shampoo.

The concentration of the compounds of formula (I) in the cosmetic compositions may comprise 0.001 to 3 wt.% in relation to the total weight of the composition.

Pharmaceutical and cosmetic compositions according to the invention, can also contain inert or even pharmacodynamically or County, such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients to soothe; hidratante, such as glycerol, PEG 400, thiomorpholine and its derivatives or urea; protivoseborainey or protivougrevoe supplements 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 polymethylene-4,5-isothiazolinone-3; conducive to regrowth of hair components, such as Minoxidil (2,4-diamino-6-piperidinedione-3-oxide) and its derivatives, diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and phenytoin (5,4-diphenylimidazole-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and, in particular,-carotene; antipsoriatics components, such as anthralin and its derivatives, and finally, eicosa-5,8,11,14-tetralogia and eicosa-5,8,11-TRINOVA acids, their esters and amides.

Compositions according to the invention can also include improving the taste components, preservatives such as esters of p-hydroxybenzoic acid, stabilizers, regulators blaine spectrum a and spectrum B, antioxidants, such as-tocopherol, butylhydroxyanisole or equivalent.

Below, as an explanation and without limiting the scope of protection of the invention of nature, are a few examples of active compounds of the formula (I) according to the invention, as well as various specific preparative forms on the basis of such compounds, as well as an example of assessment of biological activity of compounds of the formula (I) according to the invention.

Example 1

{5-[4’-(1-Ethyl-1-hydroxypropyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) Dimethyl-4-hydroxymetoprolol

50 g (260 mmol) of anhydride 1,2,4-benzotriazoles acid are dissolved in 800 ml of anhydrous dioxane. At room temperature in a period of time approximately 1 hour 30 minutes is added dropwise from a dropping funnel 260 mmol (1 equivalent) NR3THF. Stirring is continued for 12 hours, then the reaction mixture was poured into a mixture containing 600 ml of a saturated solution of ammonium chloride and 2 l of dichloromethane. After decanting, the organic phase is dried and the solvent is evaporated under reduced pressure. The resulting residue is then dissolved in 1 l of methanol and relax after the 18 hours, the reaction medium is cooled to room temperature and poured immediately into a mixture of water with diethyl ether in a ratio of 1 l/2 l After decanting, the aqueous phase is again extracted with two portions of diethyl ether (700 ml), then the combined organic phases, dried and concentrated under reduced pressure. A blend of complex truefire-complex diapir and alcohol is obtained in yields of 80%, which contains 65% of the desired product.

(b) Dimethyl-4-(tert-butyldimethylsilyloxy)phthalate

Obtained in (a) a mixture containing about 135 mmol product obtained above, dissolved in 400 ml of anhydrous dimethylformamide. Then add in one portion of 22.5 g (150 mmol) of tert-butyldimethylsilyloxy. Then in three portions add (slightly exothermic reaction) in General 13.5 g (195 mmol) of imidazole. The reaction medium is stirred for 36 hours and concentrated under reduced pressure. The residue is then dissolved in 500 ml of diethyl ether, and then filtered to remove the formed imidazolecarboxamide. Salt is washed with two portions of 150 ml of diethyl ether, the combined organic phases, dried and concentrated under reduced pressure. The resulting residue is then purified by chromatography on a column of silica. The first received the product (eluting agent: ethyl acetate-heptane in the ratio 10:90) is the target dimethyl-4-(dreidimensionaler)-2-hydroxymethylene]methanol

75 g (220 mmol) obtained above complex diapir dissolved in 1 l of diethyl ether and cooled to a temperature of 0When the nitrogen pressure above atmospheric. Carefully add 4 servings 5 g (527 mmol) of LiAlH4then the mixture is heated at a temperature of 50C. After stirring for 1 hour 30 minutes the reaction mixture is again cooled to a temperature of 0C, then treated sequentially with 20 ml water, 20 ml of 15% NaOH solution, and then 60 ml of water. The reaction mixture is stirred for 30 minutes until, until you find the complete disappearance of aluminum salts gray and their deposition in the form of white flakes. The medium is filtered and after washing the salt with three portions of ethyl acetate (200 ml) the combined organic phases, dried and concentrated under reduced pressure. The yield of the obtained product is 97%.

(d) 2-Benzoyloxymethyl-4-(tert-butyldimethylsilyloxy)benzyl benzoate

60 g (212 mmol) videolounge diol is dissolved in 600 ml of anhydrous tetrahydrofuran and cooled to a temperature of 0C. Then add 74 ml (530 mmol) of triethylamine, then 52 ml (448 mmol) of benzoyl chloride. Then in one portion dobavlyayte temperature. The reaction mixture was then filtered to remove precipitated precipitated salts triethylamine, salt is washed with two portions of 200 ml of ethyl acetate, then the mixture of the organic phases are concentrated under reduced pressure. The resulting residue is treated with dichloromethane, the organic phase is washed with a saturated solution of ammonium chloride, then with water. After drying over magnesium sulfate and concentration under reduced pressure to obtain a residue temnerature color used as is in the next stage.

(e) 2-Benzoyloxymethyl-4-hydroxymethylbenzene

The above residue is dissolved in 600 ml of ethyl acetate and added in one portion 220 ml of 1 M solution of tetrabutylammonium in tetrahydrofuran. After stirring for 30 minutes at room temperature, the reaction medium is then poured into 1 l of saturated solution of ammonium chloride. After separation the aqueous phase is again extracted with 500 ml ethyl acetate, the combined organic phases, dried and evaporated. The product is then purified by chromatography on a column of silica (ethyl acetate/heptane 30:70). Get a solid white color (so pl.: 91-93C).

(f) (3,4-Bisbenzamidoximes)benzylbromide cooled to a temperature of 0With, then add dropwise a solution of 53 g (202 mmol) of triphenylphosphine in 250 ml of dichloromethane. Reaction medium was then heated to room temperature, then stirred for 2 hours. The medium is then treated with 500 ml of water and extracted with dichloromethane. After drying and concentrating the organic phase, the product is purified by chromatography (eluting medium: CH2CL2/ethyl acetate) to give a solid white color (so pl.: 83C) with the release of 93%.

(g) 3-Ethoxymethylenemalonic acid

10 g (of 57.8 mmol) 3-Bromophenol dissolved in 150 ml of anhydrous dimethylformamide. Then add to 2.55 g (of 63.6 mmol) of 60% sodium hydride and the reaction medium is stirred for 1 hour. Then added dropwise a 4.83 ml (63,6 mmol) methoxymethane and the reaction mixture is stirred for 1 hour. After treatment with a saturated solution of ammonium chloride, extraction with diethyl ether and evaporation of the solvent from the organic phase obtained residue is dissolved in 200 ml of anhydrous tetrahydrofuran. The mixture is cooled to a temperature of -78With, then add to 25.4 ml of 2.5 M solution of utility (63,6 mmol). After stirring for recreational medium is stirred for 1 hour, then bring to room temperature, then treated with 1N hydrochloric acid. The medium is then extracted with ethyl acetate, then the combined organic phases, dried, and then concentrated under reduced pressure. After powdering in heptane, then concentration, get a solid brown color (so pl.: 45C; weight = 5.8 g; yield = 67%).

(h) Ethyl-3’-hydroxybiphenyl-4-carboxylate

2 g (13.3 mmol) 3-Ethoxymethylenemalonic acid and 1.86 ml (11 mmol) of ethyl-4-iodobenzoate dissolved in 20 ml of 1,2-dimethoxyethane (DME). Then add a 13.3 ml (to 26.6 mmol) of 2 M potassium carbonate solution and the reaction medium Tegaserod by a current of argon for 10 minutes. After that add 640 mg of PD(P(C6H5)3)4and the mixture is heated at a temperature of 90C for 14 hours. After treatment with a saturated solution of ammonium chloride, extraction with ethyl acetate, and then drying and evaporation of the solvent from the organic phase the residue is dissolved in 25 ml of anhydrous methanol, then add 0.5 ml of sulfuric acid. The reaction medium is refluxed for 15 hours, then cooled and finally treated by adding water. After extras purification by chromatography on a column of silica receive a colorless oil (weight = 2 g; yield = 75%).

(i) Methyl-3’-[3,4-bis(benzoyloxymethyl)benzyloxy]biphenyl-4-carboxylate

1 g (4.1 mmol) of Ethyl-3’-hydroxybiphenyl-4-carboxylate, 1.98 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide and 600 mg of potassium carbonate are dissolved in 40 ml of 2-butanone. The mixture is brought to boiling point under reflux (80C), then stirred for 4 hours. After cooling, the reaction medium is filtered, and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica; get a solid white color (so pl.: 71-72C; weight = 2,18 g; yield = 88%).

(j) {5-[4’-(1-Ethyl-1-hydroxypropyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol

700 mg (1,16 mmol) Ethyl-3’-[3,4-bis(benzoyloxymethyl)-benzyloxy]biphenyl-4-carboxylate are dissolved in 30 ml of anhydrous tetrahydrofuran, then the mixture is cooled to a temperature of 0C. Then add 3,1 ml of 3 M solution ethylacetamide (9.3 mmol), after which the reaction medium was then returned to room temperature and stirred for 1 hour. After treatment with a saturated solution of ammonium chloride, and then extraction with ethyl acetate the combined organic phases, dried and conc is colored oil (weight = 385 mg; yield = 82%).

1H-NMR (CDCl3)(M. D.): 0,78 (6N, t, J=7,3 Hz), 1,77-of 1.93 (4H, m), or 3.28 (2H, ush.C) and 4.68 (2H, s), 4,69 (2H, s), to 5.08 (2H, s), to 6.95 (1H, DD), 7,19-7,42 (8H, m), 7,52 (1H, s), 7,55 (1H, s).

13C-NMR (DEPT)(M. D.): 8,3 (2CH3), 35,3 (CH2), 64,2 (CH2), 64,4 (CH2), 70,0 (CH2), 77,8 (IV), 113,7 (CH), 114,1 (SN), to 120.3 (CH), 126,4 (2CH), 127,1 (2CH), to 127.9 (CH), to 129.2 (CH), is 130.2 (CH), 130,4 (CH), 137,7 (IV), 139,1 (IV), 139,6 (IV), 140,2 (IV), 142,9 (IV), 145,5 (IV), 159,4 (IV).

Example 2

{2-Hydroxymethyl-5-[4’-(1-hydroxy-1-methylethyl)biphenyl-3-intoximeter]phenyl}methanol

Similar to example 1(j) the method by processing 700 mg (1,16 mmol) ethyl-3’-[3,4-bis(benzoyloxymethyl)-benzyloxy]biphenyl-4-carboxylate with the help of 3.1 ml of 3 M solution methylacrylamide (9.3 mmol) obtain, after purification by chromatography on a column of silica, solid white (so pl.: 88-90C; weight = 405 mg; yield = 93%).

1H-NMR (CDCl3)(M. D.): 1,60 (6N, (C), 2,4 (1H, ush.C) of 3.95 (2H, ush.C), 4,70 (2H, s), 4,71 (2H, s), 5,09 (2H, s), 6,92 (1H, DD, J1=2,5 Hz, J2=7,2 Hz), 7,17-7,19 (2H, m), 7,30-7,38 (3H, m), the 7.43 (1H, s), 7,54 (4H, s).

13C-NMR (DEPT)(M. D.): 32,1 (2CH3), 64,1 (CH2), 64,3 (CH<,5 (CIV), 139,6 (IV), 139,9 (IV), to 140.5 (CIV), of 142.8 (CIV), of 149.0 (CIV), 159,4 (IV).

Example 3

{5-[4’-(1-Ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) Ethyl-3’-hydroxy-2-methylbiphenyl-4-carboxylate

Similar to example 1(h) the method by reaction of 2 g (13.3 mmol) 3-ethoxymethylenemalonic acid from 1.9 g (8.9 mmol) of 3-methyl-4-bromobenzoyl acid, obtain 1.6 g (74%) of the target product.

(b) Methyl-3’-[3,4-bis(benzoyloxymethyl)benzyloxy]-2-methylbiphenyl-4-carboxylate

Similar to example 1(i) the method by reaction of 1.6 g (6.6 mmol) of ethyl-3’-hydroxy-2-methylbiphenyl-4-carboxylate with 3,47 g (7.9 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide, obtain 3.7 g (94%) of methyl 3’-[3,4-bis(benzoyloxymethyl)-benzyloxy]-2-methylbiphenyl-4-carboxylate.

() {5-[4’-(1-Ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by processing 800 mg (1,33 mmol) methyl-3’-[3,4-bis(benzoyloxymethyl)benzyloxy]-2-methylbiphenyl-4-carboxylate using 3.6 ml of 3 M solution ethylacetamide (10 mmol). After purification by chromatography on a column of silica receive a colorless oil (weight = 475 mg; yield = 85%).

1H-NMR (WHO 07 (2H, C) 6,91-to 6.95 (3H, m), 7,18 (2H, s), 7,26 (1H, s), 7,29-7,42 (4H, m).

13C-NMR (DEPT)(M. D.): 8,3 (2CH3), 14,5 (CH3), 35,2 (CH2), 64,3 (CH2), 64,6 (CH2), to 69.9 (CH2), with 77.7 (CIV), 113,6 (SN), for 116.2 (CH), 122,6 (CH), 123,3 (CH), 127,8 (SN), to 127.9 (CH), to 129.2 (CH), of 129.5 (CH), 129,7 (CH), 130,4 (CH), 135,1 (IV), 137,8 (IV), 139,5 (IV), 139,9 (IV), 140,1 (IV), 143,8 (IV), 145,3 (IV), 158,7 (IV).

Example 4

{2-Hydroxymethyl-5-[4’-(1-hydroxy-1-methylethyl)-2’-methylbiphenyl-3-intoximeter]phenyl}methanol

Get similar to example 3(C) the method by processing 800 mg (1,33 mmol) methyl-3’-[3,4-bis(benzoyloxymethyl)benzyloxy]-2-methylbiphenyl-4-carboxylate using 3.6 ml of 3 M solution methylacrylamide (10 mmol). After purification by chromatography on a column of silica get a solid white color (so pl.: 45C; weight = 430 mg; yield = 83%).

1H-NMR (CDCl3)(M. D.): 1,61 (6N, C) to 1.82 (1H, s), and 2.26 (3H, s), 2,95 (s, 1H), 2,96 (s, 1H), 4,74 (4H, ush.C) 5,07 (2H, s), 6,91-of 6.96 (3H, m), 7.18 in-7,42 (7H, m).

13C-NMR (DEPT)(M. D.): 21,0 (CH3), 32,2 (2CH3), 64,4 (CH2), 64,6 (CH2), to 69.9 (CH2), 72,8 (IV), 113,7 (SN), FOR 116.2 (CH), 122,2 (CH), 122,6 (SN), TO 126.8 (CH), TO 127.9 (CH), TO 129.2 (CH), OF 129.5 (CH), 130 IV), 158,7 (IV).

Example 5

(5-{2-[3’-(1-Ethyl-1-hydroxypropyl)biphenyl-3-yl]ethyl}-2-hydroxymethylene)methanol

(a) Ethyl-3’-hydroxybiphenyl-3-carboxylate

Similar to example 1(h) the method by reaction of 2 g (13.3 mmol) 3-ethoxymethylenemalonic acid from 1.83 ml (11 mmol) of ethyl-3-iodobenzoate get 1,9 g (72%) of the target complex ethyl ester.

(b) Ethyl-3’-[3,4-bis(benzoyloxymethyl)benzyloxy]biphenyl-3-carboxylate

Similar to example 1(i) the method by reaction of 1 g (4.1 mmol) of ethyl-3’-hydroxybiphenyl-3-carboxylate with 1.98 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide, obtain 2.1 g (85%) ethyl-3’-[3,4-bis(benzoyloxymethyl)benzyloxy] biphenyl-3-carboxylate.

() (5-{2-[3’-(1-Ethyl-1-hydroxypropyl)biphenyl-3-yl]ethyl}-2-hydroxymethylene)methanol

Get similar to example 1(j) the method by processing 400 mg (0.66 mmol) of ethyl-3’-[3,4-bis(benzoyloxymethyl)benzyloxy]biphenyl-3-carboxylate using 1.8 ml of 3 M solution ethylacetamide (5.3 mmol). After purification by chromatography on a column of silica receive a colorless oil (weight = 217 mg; yield = 81%).

1H-NMR (CDCl3)(M. D.): 0,77 (6N, t, J=7.2 Hz), 1,25 (1H, ush.C) 1,79-of 1.88 (4H, m), 3,37 (2H, ush.C) and 4.68 (2H, s), 4,70 (2H, s), 5,11 (2H, s) 6,94 (1H, DD, J1=1,3 G is 3), 35,2 (CH2), 64,2 (CH2), 64,5 (CH2), 70,1 (CH2), 78,0 (IV), 114,1 (SN), to 114.4 (CH), to 120.4 (CH), of 124.8 (CH), 125,1 (CH), output reached 125.5 (CH), 127,8 (SN), of 128.8 (CH), 129,0 (SN), is 130.2 (CH), 130,4 (CH), 137,8 (IV), 139,6 (IV), 140,2 (IV), 141,0 (IV), 143,4 (IV), 146,7 (IV), 159,3 (IV).

Example 6

{2-Hydroxymethyl-5-[3’-(1-hydroxy-1-methylethyl)biphenyl-3-intoximeter]phenyl}methanol

Get similar to example 5(C) the method by processing 380 mg (0,63 mmol) ethyl-3’-[3,4-bis(benzoyloxymethyl)benzyloxy]biphenyl-3-carboxylate using 1.7 ml of 3.0 M solution methylacrylamide (5 mmol). After purification by chromatography on a column of silica get a solid white color (so pl.: 103-104C; weight = 224 mg; yield = 94%).

1H-NMR (CDCl3)(M. D.): 1,60 (6N, (C), 2,96 (1H, ush.C) the 4.29 (1H, t), 4,39 (1H, t), 4,71 (4H, t, J=5.7 Hz), 5,12 (2H, s) 6,94 (1H, DD, J1=2.3 Hz, J2=8,l Hz), 7,18 (2H, m), 7,29-7,47 (8H, m), 7,69 (1H, s).

13C-NMR (DEPT)(M. D.): 32,2 (CH3), and 63.9 (CH2), 64,1 (CH2), 70,1 (CH2), 72,7 (IV), 114,2 (CH), 114,2 (SN), to 120.3 (CH), 123,8 (SN), of 124.1 (CH), 125,6 (SN), of 127.5 (CH), 128,9 (CH), 129,0 (SN), is 130.2 (CH), 130,3 (CH), 137,4 (IV), 140,0 (IV), 140,7 (IV), 141,1 (IV), br143.3 (IV), of 150.4 (CIV), 159,3 (<3’-hydroxybiphenyl-4-yl)acetate

Similar to example 1(h) the method by reaction 543 mg (3.6 mmol) 3-ethoxymethylenemalonic acid 700 mg (2.4 mmol) of ethyl-4-idgenerator, obtain 630 mg (68%) of the target complex ethyl ester.

(b) Ethyl{3’-[3,4-bis(benzoyloxymethyl)benzyloxy]biphenyl-4-yl}acetate

Similar to example 1(i) the method by reaction of 360 mg (1.4 mmol) of ethyl(3’-hydroxybiphenyl-4-yl)acetate with 676 mg (1.5 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide, obtain 810 mg (94%) of ethyl{3’-[3,4-bis(benzoyloxymethyl)-benzyloxy]biphenyl-4-yl}acetate.

() {5-[4’-(2-Ethyl-2-hydroxybutyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by processing 400 mg (0.66 mmol) of ethyl{3’-[3,4-bis(benzoyloxymethyl)benzyloxy]biphenyl-4-yl}acetate using 1.8 ml of 3.0 M solution ethylacetamide (5.3 mmol). After purification by chromatography on a column of silica receive a colorless oil (weight = 236 mg; yield = 85%).

1H-NMR (CDCl3)(M. D.): 0,94 (6N, t, J=7.5 Hz), 1.27mm (1H, ush.C) to 1.48 (4H, q, J=7.5 Hz), 2,77 (2H, s), 3,17 (2H, ush.C) 4,71 (4H, s), 5,09 (2H, s), 6,91-to 6.95 (1H, m), 7,17-7,20 (2H, m), 7,26-7,42 (6N, m), 7,49 (1H, s), 7,52 (1H, m).

13C-NMR (DEPT)(M. D.): 8,4 (2CH3), 30,9 (CH2), with 44.8 (CH2), 64,3 (CH2), 64,5 (CHIV), 137,7 (IV), to 139.3(CIV), 139,6 (IV), 140,2 (IV), 142,9 (IV), 159,4 (IV).

Example 8

{5-[3’-(2-Ethyl-2-hydroxybutyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) Methyl-[3’-hydroxybiphenyl-3-yl)acetate

Similar to example 1(h) the method by reaction of 2 g (13.3 mmol) 3-ethoxymethylenemalonic acid 2 g (9.3 mmol) of 3-bromoferrocene acid, obtain 1.6 g (72%) of a compound methyl ester.

(b) Methyl-{3’-[3,4-bis(benzoyloxymethyl)benzyloxy]biphenyl-3-yl}acetate

Similar to example 1(i) the method by reaction of 1 g (4.1 mmol) of methyl-(3’-hydroxybiphenyl-3-yl)acetate with 2 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide, obtain 2.2 g (91%) of methyl-{3’-[3,4-bis(benzoyloxymethyl)benzyloxy] biphenyl-3-yl}acetate.

() {5-[3’-(2-Ethyl-2-hydroxybutyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by processing 700 mg (1,16 mmol) of methyl-{3’[3,4-bis(benzoyloxymethyl)benzyloxy]biphenyl-3-yl}acetate with the help of 3.1 ml of 3.0 M solution ethylacetamide (9.3 mmol). After purification by chromatography on a column of silica receive a colorless oil (weight = 419 mg; yield = 86%).

1H-NMR (CDCl3)(M. D.): 0,92 (6N, t, J=7.5 Hz), 1,47 (4H, the p>C-NMR (DEPT)(M. D.): 8,4 (2CH3), 30,8 (CH2), 45,3 (CH2), 64,2 (CH2), 64,4 (CH2), 70,1 (CH2), and 75.2 (CIV), 114,1 (SN), of 114.3 (CH), to 120.4 (CH), 125,6 (SN), of 127.7 (CH), 128,9 (CH), 129,0 (CH), 129,7 (SN), is 130.2 (CH), is 130.2 (CH), 130,4 (CH), 137,8 (IV), 138,3 (IV), 139,6 (IV), 140,3 (IV), 141,2 (IV), 143,0 (IV), 159,3 (IV).

Example 9

1-[3’-(3,4-Bishydroxyethyl)biphenyl-3-yl]-2-methylpropan-2-ol

Receive analogous to example 8(C) methodology, by processing 700 mg (1.13 mmol) of methyl-{3’-[3,4-bis(benzoyloxymethyl)benzyloxy]biphenyl-3-yl}acetate with the help of 3.1 ml of 3 M solution of etimani bromide (9.3 mmol). After purification by chromatography on a column of silica receive a colorless oil (weight = 419 mg; yield = 92%).

1H-NMR (Dl3)(M. D.): 1,24 (6N, (C), of 1.65 (1H, ush.C) 2,80 (2H, s) to 3.38 (1H, ush.C) a 3.50 (1H, ush.C) and 4.68 (2H, s), 4,69 (2H, s), 5,11 (2H, s), 6,94-of 6.96 (1H, m), 7,13-7,19 (3H, m), 7,30-7,44 (7H, m).

13C-NMR (DEPT)(M. D.): 29,6 (2CH3), 50,1 (CH2), 64,2 (CH2), 64,4 (CH2), 70,1 (CH2), 71,3 (IV), 114,2 (SN), to 114.4 (CH), to 120.4 (CH), 125,7 (SN), of 127.7 (CH), 128,9 (CH), 129,0 (SN), of 129.6 (CH), 130,0 (SN), is 130.2 (CH), 130,4 (CH), 137,8 (IV), 138,6 (IV), 139,6 (IV), 140,3 (IV), 141,2 (IV), 142,9 (IV), 159,3 (is Nol

(a) Dimethyl-4-(3-bromophenylacetonitrile)phthalate

5 g (26 mmol) of 3-Bromothiophene and 9.2 g (32 mmol) of dimethyl-4-brometalia dissolved in 150 ml of 2-butanone. Add 4 g (29 mmol) of potassium carbonate and the mixture is refluxed and stirred for 2 hours. The reaction medium is then filtered, concentrated under reduced pressure and the residue purified by chromatography on a column of silica. Receive a yellow oil (10 g) with a yield of 100%.

(b) [5-(3-Bromophenylacetonitrile)-2-hydroxymethylene]methanol

10 g (26 mmol) of Dimethyl-4-(3-bromophenylacetonitrile)-phthalate are dissolved in 120 ml of anhydrous tetrahydrofuran. Then slowly add 2.2 g (100 mmol) of lithium borohydride, then the reaction medium is refluxed for 12 hours. After cooling and treatment with a saturated solution of ammonium chloride reaction medium is extracted with ethyl acetate. The combined organic phases, dried and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica; receive a colorless oil (7.8 g; yield = 89%).

(C) [2-Hydroxymethyl-5-(3-tributylstannyl)phenyl]methanol

6.2 g (18 mmol) [5-(3-Bromophenylacetonitrile)-2-hydroxymethylene]met billaut 18 ml (36 mmol) hexabutylditin and 416 mg (0.36 mmol) of PD(P(C6H5)3)4. Reaction medium was then stirred at a temperature of 120C for 48 hours, cooled, treated with a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic phases, dried, and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica (eluting agent: pure heptane) to give yellow oil (weight = 3,35 g; yield = 34%).

(d) Methyl-3’-(3,4-bishydroxyethyl)-2-methylbiphenyl-4-carboxylate

1,67 g (3 mmol) [2-Hydroxymethyl-5-(3-tributylstannyl)phenyl]methanol was dissolved in 30 ml of toluene and 5 ml of 1,2-dimethoxyethane. Add 970 mg (4.5 mmol) 4-bromo-3-methylbenzoic acid and the mixture Tegaserod by a current of argon for 10 minutes. Then add 175 mg (0.15 mmol) of Pd(P(C6H5)3)4and the reaction mixture is refluxed and stirred for 24 hours. The reaction mixture is then treated with a solution of ammonium chloride, then extracted with ethyl acetate. The combined organic phases, dried, and then concentrated under reduced pressure. The residue is then dissolved in 50 ml of methanol, add 1 ml of sulfuric acid, CI water, the mixture is extracted with ethyl acetate. The combined organic phases, dried, and then concentrated under reduced pressure. The residue is then purified by chromatography on a column of silica. Get colorless oil (weight = 180 mg; yield = 15%).

(e) {4-[4’-(1-Ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-ylsulphonyl]-2-hydroxymethylene}methanol

130 mg (0.3 mmol) of Methyl-3’-(3,4-bishydroxyethyl)-2-methylbiphenyl-4-carboxylate dissolved in 10 ml of anhydrous tetrahydrofuran, then add 0.7 ml of 3 M solution ethylacetamide (2 mmol). The reaction medium is stirred for 1 hour, then treated with a solution of ammonium chloride. After attractie with ethyl acetate the combined organic phases, dried and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica. Get colorless oil (weight = 105 mg; yield = 81%).

1H-NMR (DMSO)(M. D.): 0,46 (6N, t, J=6.8 Hz), 1,40-1,60 (4H, m) of 1.97 (3H, s) 4,08 (2H, s), 4,39 (2H, s), and 4.40 (2H, s), is 4.85 (1H, t), of 4.90 (1H, t), 6,85-of 7.23 (10H, m).

13C-NMR (DEPT)(M. D.): 6,3 (2CH3), 18,7 (CH3), 32,8 (2CH2), 34,7 (CH2), 58,4 (CH2), 58,4 (CH2), 73,7 (IV), to 121.6 (CH), of 124.6 (CH), of 124.8 (CH), 125,0 (CH), 125,1 (SN), and 125.4 (CH), 12up>IV), 140,3 (IV), 144,4 (IV).

Example 11

{4-[4’-(1-Ethyl-1-hydroxypropyl)-2,2’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) 3-Bromo-2-METHYLPHENOL

20 g (107 mmol) of 3-Bromo-2-methylphenylamine dissolved in 150 ml of 1.0 M aqueous sulfuric acid and the mixture is cooled to a temperature of 0C. Slowly add a solution of 8.9 g (129 mmol) of sodium nitrite in 20 ml of water. The medium is stirred for 15 minutes at a temperature of 0With, then add 50 ml of concentrated sulfuric acid. Reaction medium was then heated at 100 ° C for 1 hour, then cooled and diluted with water. After extraction with diethyl ether, the obtained residue will recrystallized from a mixture of heptane and dichloromethane. Get a solid yellow color (so pl.: 89C; weight = 12.3 g; yield = 61%).

(b) 1-Bromo-3-methoxyethoxy-2-methylbenzoyl

of 13.9 g (74 mmol) of 3-Bromo-2-METHYLPHENOL dissolved in 120 ml of dimethylformamide and the mixture is cooled to a temperature of 0C. Then small portions add 3.6 g (90 mmol) of 60% sodium hydride and the medium is stirred for 1 hour. Then slowly add 6.8 ml (90 mmol) of methoxymethane and credoc purify by chromatography on silica gel (eluting agent: heptane-ethyl acetate in the ratio 80:20). The desired product is obtained as a colourless oil (weight = 16.2 g; yield = 95%).

(C) 3 Methoxyethoxy-2-methylbenzol-1-baronova acid

16.2 g (70 mmol) of 1-Bromo-3-methoxyethoxy-2-methylbenzoyl dissolved in 200 ml of anhydrous tetrahydrofuran and the mixture is cooled to a temperature of -78C. Slowly add 33,7 ml of 2.5 M solution of utility (84 mmol), the mixture is then maintained at a temperature of -78C for 1 hour. Then within 15 minutes is added dropwise to 19.4 ml (84 mmol) of triisopropylsilane. The medium is stirred for 30 minutes at the same temperature, then poured into 300 ml of 1N hydrochloric acid. After normal processing of the obtained solid whitish residue was washed with heptane, then dried under reduced pressure. Get flocculent solid white (mass = 11,8 g; yield = 86%).

(d) Methyl-3’-hydroxy-2,2’-dimethylbiphenyl-4-carboxylate

1,03 g (5.2 mmol) of 3-Methoxyethoxy-2-methylbenzol-1-Bronevoy acid, 1 g (4.4 mmol) of methyl 4-bromo-3-methylbenzoate and 4.4 ml of a 2.0 M solution of potassium carbonate dissolved in 20 ml of dimethyl ether of ethylene glycol. The mixture Tegaserod by a current of nitrogen for 10 minutes, then add 250 mg (0.22 mmol) of tetrakis(triphenylphosphine)-palladium is processing the obtained residue is dissolved in 30 ml of methanol and add 0.5 ml of sulfuric acid; the medium is stirred at room temperature for 6 hours, then poured into a mixture of diethyl ether and water. After extraction with diethyl ether the residue is purified by chromatography on silica gel (eluting agent: heptane-ethyl acetate in the ratio 9:1). The desired product is obtained in the form of a thick, colorless oil (weight = 890 mg; yield = 79%).

(e) Methyl-3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2,2’-dimethylbiphenyl-4-carboxylate

Get similar to example 1(i) method by the reaction of 515 mg (2 mmol) of methyl-3’-hydroxy-2,2’-dimethylbiphenyl-4-carboxylate with 880 mg (2 mmol) of 3,4-bis(benzoyloxymethyl)-benzylbromide and 300 mg (2.2 mmol) of potassium carbonate. The desired product is obtained as a colourless oil (weight = 1.22 g; yield =99%).

(f) {4-[4’-(1-Ethyl-1-hydroxypropyl)-2,2’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by reaction 1.22 g (1,98 mmol) methyl-3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2,2’-dimethylbiphenyl-4-carboxylate with 5.3 ml of 3.0 M solution ethylacetamide (16 mmol). The desired product is obtained in the form of a white powder (so-sq: 81-82C; weight = 360 mg; yield = 42%).

1H-NMR (CDCl3)(M. D.): 0,82 (t, J= 7,17 (t, J=7.7 Hz, 2H), 7,26 (s, 1H), 7,37-7,46 (m, 3H).

Example 12 {2-Hydroxymethyl-4-[4’-(1-hydroxy-1-propinball)-2,2’-dimethylbiphenyl-3-intoximeter]phenyl}methanol

(a) {2-Hydroxymethyl-4-4’-(1-hydroxy-1-propinball)-2,2’-dimethylbiphenyl-3-intoximeter]phenyl}methanol

Get similar to example 1(j) the method by reaction of 100 mg (0.25 mmol) of methyl 3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2,2’-dimethylbiphenyl-4-carboxylate (described in example 11(e)) with 0.5 ml of 2.0 M solution ethylacetamide (1 mmol). The desired product is obtained in the form of a white powder (so pl.: 118-120C; weight = 64 mg; yield = 56%).

1H-NMR (Dl3)(M. D.): 0,9 (t, J=7.2 Hz, 6N), 1,16-of 1.36 (m, 4H), 1,73-of 1.85 (m, 4H), of 1.97 (s, 3H), of 2.06 (s, 3H), amounts to 4.76 (s, 2H), of 4.77 (s, 2H), 5,11 (s, 2H), 6,77 (d, J=6,9 Hz, 1H), 6.89 in (d, J=6,9 Hz, 1H),? 7.04 baby mortality (d, J=7.9 Hz, 1H), 7,18 (t, J=7.7 Hz, 2H), 7,26 (s, 1H), 7,37-7,46 (m, 3H).

Example 13

{4-[4’-(1-Ethyl-1-hydroxypropyl)-2-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) Methyl-3'-hydroxy-2’-methylbiphenyl-4-carboxylate

Get similar to example 11(d) the method by reaction of 3.3 g (of 16.7 mmol) of 3-methoxyethoxy-2-methylbenzol-1-Bronevoy acid (described in example 11(C)) 3 g (a 13.9 mmol) of ethyl-4-iodobenzoate, and 16.7 ml of a 2.0 M solution of potassium carbonate and 800 mg (0.69 mmol) tetrakis-(triphenylphosphine = 3,07 g; yield = 77%).

(b) Methyl-3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2’-methylbiphenyl-4-carboxylate

Get similar to example 1(1) the method by reaction of 1 g (4.1 mmol) of methyl-3’-hydroxy-2’-methylbiphenyl-4-carboxylate with 2 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)-benzylbromide and 650 mg (4.7 mmol) of potassium carbonate. The desired product is obtained as a colourless oil (weight = 2.4 g; yield = 97%).

() {4-[4’-(1-Ethyl-1-hydroxypropyl)-2-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by reaction of 2.4 g (4 mmol) of methyl 3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2’-methylbiphenyl-4-carboxylate from 10.7 ml of 3.0 M solution ethylacetamide (32 mmol). The desired product is obtained in the form of a white powder (so pl.: 117-118C; weight = 1.1 mg; yield = 60%).

1H-NMR (DMSO)(M. D.): 0,76 (t, J=7.5 Hz, 6N), 1,70-1,90 (m, 4H), to 2.13 (s, 3H), 4,56-br4.61 (m, 5H), to 5.17 (m, 4H), 6,8 (m, 1H), and 7.1 (m, 1H), 7,20-7,30 (m, 3H), 7,40-of 7.60 (m, 4H).

Example 14

{4-[4’-(1-Ethyl-1-hydroxypropyl)-2,2’,6’-trimethylphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) Methyl-3’-hydroxy-2,6,2’-trimethylphenyl-4-carboxylate

Get similar to example 11(d) of the method by the reaction of 1.5 g (7.6 mmol) of 3-methoxyethoxy-2-methylbenzoate, 7.7 ml of 2.0 M potassium carbonate solution and 370 mg (0.32 mmol) of tetrakis(triphenylphosphine)palladium, and then removing the protective group in methanol. The desired product is obtained in the form of a solid white color (so pl.: 149C; weight = 1,34 g; yield = 67%).

(b) Methyl-3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2,6,2’-trimethylphenyl-4-carboxylate

Get similar to example 1(i) the method by reaction 980 mg (3.6 mmol) of methyl-3’-hydroxy-2,6,2’-trimethylphenyl-4-carboxylate from 1.75 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide and 570 mg (4.1 mmol) of potassium carbonate. The desired product is obtained in the form of white crystals (so pl.: 131-132C; weight = 2.16 g; yield = 95%).

with) {4-[4’-1-Ethyl-1-hydroxypropyl}-2,2’,6’-trimethylphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by reaction of 2.1 g (3.3 mmol) of methyl 3’-[3,4-bis(1-phenylmethanesulfonyl) benzyloxy]-2,6,2’-trimethylphenyl-4-carboxylate from 8.9 ml of 3.0 M solution ethylacetamide (27 mmol). The desired product is obtained in the form of a white powder (so pl.: 105-107C; weight = 1.1 mg; yield = 73%).

1H-NMR (Dl3)(M. D.): 0,82 (t, J=7.5 Hz, 6N), 1,81-of 1.85 (m, 4H), to 1.87 (s, 3H), 1,95 (s, 6N the example 15

(4-{3-[5-{1-Ethyl-1-hydroxypropyl)pyridin-2-yl]phenoxymethyl}-2-hydroxymethylene)methanol

(a) Ethyl-6-(3-hydroxyphenyl)nicotinate

Get similar to example 1(h) the method by reaction of 1 g (6.7 mmol) of 3-ethoxymethylenemalonic acid (described in example 1 (d)) and 1.5 g (5.6 mmol) of ethyl-6-etniciteit with 5.6 ml of 2.0 M potassium carbonate solution and 320 mg of tetrakis(triphenylphosphine)palladium, and then removing the protective group in ethanol. The desired product is obtained in the form of a solid white color (weight = 354 mg; yield = 26%).

(b) Ethyl-6-{3-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]phenyl}nicotinate

Get similar to example 1(i) the method by the reaction of 277 mg (1.1 mmol) of ethyl-6-(3-hydroxyphenyl)nicotinate (500 mg (1.1 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide and 166 mg (1.2 mmol) of potassium carbonate. The desired product is obtained in the form of white crystals (so pl.: 118-120C; weight = 500 mg; yield = 73%).

() (4-{3-[5-{1-Ethyl-1-hydroxypropyl)pyridin-2-yl]phenoxymethyl}-2-hydroxymethylene)methanol

Get similar to example 1(j) the method by reaction 410 mg (of 0.68 mmol) of ethyl-6-{3-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]phenyl}nicotinate with 1.8 ml of 3.0 M solution ethylacetamide (5.4 mmol). The desired product is obtained in view of the 6N), 1,65 (ush.s, 1H), 1,73 (ush.s, 1H), 1.85 to of 1.97 (m, 4H), 2,90 (ush.s, 3H), 4,74 (s, 2H), amounts to 4.76 (s, 2H), further 5.15 (s, 2H), 7,01 (d, J=7,6 Hz, 1H), 7,34 was 7.45 (m, 4H), 7,55 (d, J=7.7 Hz, 1H), to 7.67-to 7.77 (m, 2H), 7,78-7,81 (m, 1H), 8,67 (s, 1H).

Example 16

{4-[4’-1-Ethyl-1-hydroxypropyl-6,2’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) 3-Bromo-4-METHYLPHENOL

Get similar to example 11(a) the method by reaction of 20 g (107 mmol) of 3-bromo-4-methylphenylamine from 8.9 g (129 mmol) of sodium nitrite. Get the butter brown, without treatment (weight = 20 g; yield = 100%).

(b) 2-Bromo-4-methoxyethoxy-1-methylbenzol

Get similar to example 11(b) the method by reaction of 20 g (107 mmol) of 3-bromo-4-METHYLPHENOL with 5.6 g (139 mmol) of 60% sodium hydride and 8.9 ml (139 mmol) of methoxymethane. The desired product is obtained in the form of an orange oil (weight = 12.3 g; yield = 50%).

(C) 4 Methoxyethoxy-1-methylbenzol-2-baronova acid

Get similar to example 11(C) the method by reaction of 12.3 g (53 mmol) of 2-bromo-4-methoxyethoxy-1-methylbenzol with 28 ml of 2.5 M solution of utility (69 mmol) and 18.4 ml (80 mmol) of triisopropylsilane. Get a brown oil (weight = 10.4 g; yield = 99%).

(d) Methyl-5’-hydroxy-2,2’-dimethylbiphenyl-4-carboxylate

Get similar to example 11(d) the method by reaction of 3.7 g (18,8 mmol) 4-methoxime the potassium and 1 mg (0.85 mmol) of tetrakis(triphenylphosphine)palladium, then removing the protective group in methanol. The desired product is obtained in the form of a thick, colorless oil (weight = 2,87 mg; yield = 51%).

(e) Methyl-5’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2,2’-dimethylbiphenyl-4-carboxylate

Get similar to example 1(i) the method by reaction of 2.24 g (8,7 mmol) methyl-5’-hydroxy-2,2’-dimethylbiphenyl-4-carboxylate with 4,20 mg (9.6 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide and 1.26 g (9 mmol) of potassium carbonate. The desired product is obtained as a colourless oil (weight = 5.34 g; yield = 99%).

(f) [4-[4’-(1-Ethyl-1-hydroxypropyl)is 6.2’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by reaction of 5.3 g (8.6 mmol) of methyl-5’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2,2’-dimethylbiphenyl-4-carboxylate with 23 ml of a 3.0 M solution ethylacetamide (69 mmol). The desired product is obtained in the form of a white powder (weight = 1.68 g; yield = 45%).

1H-NMR (DMSO)(M. D.): 0,52 (t, J=7,4 Hz, 6N), 1,51 is 1.58 (m, 4H), 1,72 (s, 3H) and 1.83 (s, 3H), or 4.31 (s, 1H), 4,36 (s, 1H), 4,88 (s, 2H), 4,89 to 4.92 (m, 2H), 6,53 (s, 1H), 6,70-6,74 (DD, J1=2,6 Hz, J2=6,7 Hz, 1H), 6,80 (d, J=7.8 Hz, 1H), 6,99? 7.04 baby mortality (m, 2H), and 7.1 (s, 2H), 7,20 (d, J=7,3 Hz, 1H), 7,28 (s, 1H).

Example 17

{4-[4’-(l-Ethyl-l-hydroxypropyl)is 6.2’,6’-trimethylphenyl-3-Elokim the logical example 11(d) of the method, by reaction of 3.7 g (18,8 mmol) 4-methoxyethoxy-1-methylbenzol-2-Bronevoy acid (described in example 16(C)) with 5.3 g (17 mmol) of methyl 3,5-dimethyl-4-triftoratsetilatsetonom, 17 ml of a 2.0 M solution of potassium carbonate and 1 g (0.82 mmol) of tetrakis(triphenylphosphine)palladium, and then removing the protective group in methanol. The desired product is obtained in the form of a yellow oil (weight = 3.0 g; yield = 65%).

(b) Methyl-5’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2,6,2’-trimethylphenyl-4-carboxylate

Get similar to example 1(i) the method by reaction of 1.53 g (5.6 mmol) of methyl-5’-hydroxy-2,6,2’-trimethylphenyl-4-carboxylate with 2,73 g (6.2 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide and 980 mg (5.8 mmol) of potassium carbonate. The desired product is obtained in the form of a yellow oil (weight = 3.5 g; yield = 98%).

(c) {4-[4’-(1-Ethyl-1-hydroxypropyl)is 6.2’,6’-trimethylphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by reaction of 3.5 g (5.8 mmol) of methyl-5’-[3,4-bis[1-phenylmethanesulfonyl)benzyloxy]-2,6,2’-trimethylphenyl-4-carboxylate from 15.3 ml of 3.0 M solution ethylacetamide (46 mmol). The desired product is obtained in the form of a white powder (so pl.: 128C; weight = 1.45 g; yield = 56%).

1H-NMR (DMSO)1=2,6 Hz, J2=6,7 Hz, 1H), 7,13 (s, 2H), 7,25 (d, J=7.5 Hz, 1H), 7,32 (d, J=7.5 Hz, 1H), 7,42 (d, J=7.5 Hz, 1H), 7,49 (s, 1H).

Example 18

{4-[4’-(1-Ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) Ethyl-5’-hydroxy-2’-methylbiphenyl-4-carboxylate

Get similar to example 11(d) the method by reaction of 3.7 g (18,8 mmol) 4-methoxyethoxy-1-methylbenzol-2-Bronevoy acid, described in example 16(C), from 4.7 g (17 mmol) of ethyl-4-iodobenzoate, 17 ml of a 2.0 M solution of potassium carbonate and 1 g (0.8 mmol) of tetrakis(triphenylphosphine)palladium, and then removing the protective group in ethanol. The desired product is obtained as a colourless oil (mass = of 3.07 g; yield = 71%).

(b) Ethyl-5’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2’-methylbiphenyl-4-carboxylate

Get similar to example 1(i) the method by reaction of 3.07 g (12 mmol) attil-5’-hydroxy-2’-methylbiphenyl-4-carboxylate with 6.7 g (15 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide and 2 mg (14 mmol) of potassium carbonate. The desired product is obtained as a colourless oil (weight = 5.7 g; yield = 77%).

() {4-[4’-(1-Ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by reaction of 3.8 g (6.2 mmol) of ethyl-5’-[3,4-bis(1-feel). The desired product is obtained in the form of a white powder (weight = 1,26 mg; yield = 48%).

1H-NMR (DMSO)(M. D.): 0.69 (t, J=7.2 Hz, 6N), 1,74-to 1.77 (m, 4H), of 2.15 (s, 3H), to 4.52 (s, 1H), 4,54 (s, 1H), 4,56 (s, 1H), of 5.05-5,10 (m, 2H), 5,11 (s, 2H), 6,85-6,92 (m, 2H), 7,18 (d, J=8.5 Hz, 1H), 7,25-7,31 (m, 3H), 7,37-of 7.48 (m, 4H).

Example 19

{4-[4’-(1-Ethyl-1-hydroxypropyl)-2’,6’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) Methyl-3’-hydroxy-2,6-dimethylbiphenyl-4-carboxylate

Similar to example 1(h) the method by reaction 4,48 g (24 mmol) of 3-ethoxymethylenemalonic acid (described in example 1(g)) with 7 g (of 22.4 mmol) of methyl 3,5-dimethyl-4-triftoratsetilatsetonom, 24 ml of 2 M potassium carbonate solution and 1.29 g (1.1 mmol) of tetrakis(triphenylphosphine)palladium, and then removing the protective group in methanol, get the target product.

(b) Methyl-3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2,6-dimethylbiphenyl-4-carboxylate

Get similar to example 1(i) the method by reaction of 4.49 g (17.5 mmol) of methyl-3’-hydroxy-2,6-dimethylbiphenyl-4-carboxylate with 8,46 g (19 mmol) of 3,4-bis(benzoyloxymethyl)-benzylbromide and 2.54 mg (18 mmol) of potassium carbonate. The desired product is obtained in the form of a yellow oil (weight = 7,4 g; yield = 69%).

(c) {4-[4’-{1-Ethyl-1-hydroxypropyl)-2’,6’-dimethylbiphenyl-3-what mmol) methyl-3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2,6-dimethylbiphenyl-4-carboxylate from 23.3 ml of 3.0 M solution ethylacetamide (70 mmol). The desired product is obtained in the form of a white powder (so pl.: 133C; weight = 2.4 g; yield = 65%).

1H-NMR (DMSO)(M. D.): 0,70 (t, J=7,3 Hz, 6N), 1,67 is 1.75 (m, 4H), to 1.98 (s, 6N), 4,48 (s, 1H), 4,54 (s, 1H), 4,56 (s, 1H), 5,11 (s, 2H), 5,14-5,17 (m, 2H), 6,69-6,77 (m, 2H), 7,00 (d, J=8,2 Hz, 1H), and 7.1 (s, 2H), 7,30-7,42 (m, 3H), 7,49 (s, 1H).

Example 20

1-{4-[3-(3,4-Bishydroxyethyl)phenyl]thiophene-2-yl}propane-1-ol

(a) 1-(4-Bromothiophene-2-yl)propan-1-ol

10 g (52 mmol) of 4-Bromothiophene-2-carbaldehyde are dissolved in 200 ml of diethyl ether and 20 ml of tetrahydrofuran. Slowly add to 26.6 ml of 3.0 M solution ethylacetamide (78 mmol). After incubation for 2 hours at room temperature, the reaction medium is then poured into a saturated solution of ammonium chloride. After extraction will receive a yellow oil (weight = 11,5 g; yield = 99%).

(b) 1-(4-Bromothiophene-2-yl)propane-1-it

11,5 g (52 mmol) of 1-(4-Bromothiophene-2-yl)propan-1-ol are dissolved in 300 ml of dichloromethane. Add 60 g (690 mmol) of manganese dioxide and the reaction medium is stirred for 14 hours, then filtered. The desired product is obtained in the form of an orange oil (weight = 11.4 g; yield = 99%).

(c) 1-[4-(3-Hydroxyphenyl)thiophene-2-yl]propane-1-it

Get similar to example 1(h) the method by reaction of 4.6 g (25 mmol) of 3-label the M potassium carbonate solution and of 1.32 g of tetrakis(triphenylphosphine)palladium, then removing the protective group in methanol. The desired product is obtained in the form of a solid white color (so pl.: 112C; weight = a 3.87 g; yield = 73%).

(d) 1-{4-[3-(3,4-Bis(1-phenylmethanesulfonyl)-benzyloxy)phenyl]thiophene-2-yl}propane-1-it

Get similar to example 1(i) the method by reaction of 3.8 g (16.3 mmol) of 1-[4-(3-hydroxyphenyl)thiophene-2-yl]propane-1-she 16.9 g (18 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide and of 2.36 g (17 mmol) of potassium carbonate. The desired product is obtained in the form of white crystals (so pl.: 117C; weight = 9,1 g; yield = 95%).

(e) 1-{4-[3-(3,4-Bishydroxyethyl)phenyl]thiophene-2-yl}propane-1-ol

to 4.3 g (7.3 mmol) 1-{4-[3-(3,4-Bis(1-phenylmethanesulfonyl)-benzyloxy)phenyl]thiophene-2-yl}propane-1-dissolve it in 10 ml of tetrahydrofuran, is added dropwise to a suspension of 1.1 g (29 mmol) of sociallyengaged and the mixture is stirred for 2 hours. After treating the reaction medium with 1.1 ml of water, 1.1 ml of a 15% aqueous solution of sodium hydroxide and 3.3 ml of water environment filter. After purification by chromatography on silica gel (eluting agent: heptane-ethyl acetate in the ratio 3:7) to get the desired product as colourless oil (weight = 773 mg; yield = 28%).

1H-NMR (DMSO)Example 21

(4-{3-[4-(1-Ethyl-1-hydroxypropyl)thiophene-2-yl]phenoxymethyl}-2-hydroxymethylene)methanol

(and) (4-{3-[4-(1-Ethyl-1-hydroxypropyl)thiophene-2-yl]phenoxymethyl}-2-hydroxymethylene)methanol

Get similar to example 1(j) the method by reaction of 4.3 g (7.3 mmol) 1-{4-[3-(3,4-bis(1-phenylmethanesulfonyl)benzyloxy)phenyl]thiophene-2-yl}propane-1-it (described in example 20 (d) ) with 17 ml of 3.0 M solution ethylacetamide (51 mmol). The desired product is obtained in the form of a solid white color (so pl.: 47C; weight = 1.54 g; yield = 51%).

1H-NMR (DMSO)(M. D.): 0,74 (t, J=7,4 Hz, 6N), 1,68-of 1.78 (m, 4H), 4,54-4,58 (m, 4H), to 4.62 (s, 1H), 5.08 to to 5.13 (m, 1H), 5,16 (s, 2H), 6,92-of 6.96 (DD, J1=2,6 Hz, J2=6.2 Hz, 1H), 7,19 (d, J=7.5 Hz, 2H), 7,27-7,30 (m, 4H), 7,44 (s, 1H), 7,52 (s, 1H).

Example 22

{4-[4’-(1-Ethyl-1-hydroxypropyl)-methylbiphenyl-3-ylethoxy]-2-hydroxymethylene}methanol

(a) 1-(4-Bromo-3-were)propane-1-it

25 g (116 mmol) of 4-Bromo-3-methylbenzoic acid are dissolved in 250 ml of dichloromethane, the mixture is then cooled to a temperature ofC. Slowly add 10.1 ml (116 mmol) of oxalicacid, then add a few drops of dimethylformamide and 16 ml (116 mmol) of triethylamine. After 30 minutes, add 12.5 g (128 mmol is s, then treated with a solution of ammonium chloride and extracted with dichloromethane. The crude residue is then treated with diethyl ether and washed with 1N-sodium hydroxide solution, then dried and concentrated. The obtained intermediate amide is dissolved in 300 ml of anhydrous tetrahydrofuran and cooled to a temperature of -78C. Slowly add 40 ml of 3.0 M solution ethylacetamide (120 mmol) and the reaction medium is brought to a temperature of 0C, then stirred for 18 hours. After conventional treatment and chromatography on silica gel (heptane-ethyl acetate in the ratio 9:1) get the desired product as a thick colorless oil (weight = 17 g; yield = 64%).

(b) 2-(4-Bromo-3-were)-2-ethyl-[1,3]dioxolane

16 g (70 mmol) of 1-(4-Bromo-3-were)propane-1-it is dissolved in 200 ml of toluene. Add 20 ml (350 mmol) of ethylene glycol and 670 mg (3.5 mmol) of p-toluenesulfonic acid. Installation supply distiller type Dean-stark and the reaction medium is heated at a temperature of 130C for 16 hours. The medium is cooled, then poured into a sodium hydrogen carbonate solution and extracted with diethyl ether. The resulting crude product is in the form of a colourless oil (weight = 18.6 g; output is ke, by reaction of 6.6 g (44 mmol) of 3-formylbenzeneboronic acid and 10 g (37 mmol) of 2- (4-bromo-3-were)-2-ethyl-[1,3]dioxolane with 45 ml of 2.0 M potassium carbonate solution and 2.14 g of tetrakis(triphenylphosphine)palladium. The desired product is obtained as a thick oil (weight = 9,1 g; yield = 84%).

(d) [4’-(2-Ethyl-[1,3]dioxolane-2-yl)-2’-methylbiphenyl-3-yl]methane

Get similar to example 20(e) the method by reaction of 4.5 g (15,2 mmol) 4’-(2-ethyl-[1,3]dioxolane-2-yl)-2’-methylbiphenyl-3-carbaldehyde with 760 mg (20 mmol) of sociallyengaged. The desired product is obtained as a colourless oil (weight = 4.4 g; yield = 97%).

(e) Dimethyl-4-[4’-(2-ethyl-[1,3]dioxolane-2-yl)-2’-methylbiphenyl-3-ylethoxy]phthalate 4.4 g (14 mmol) of [4’-(2-Ethyl-[1,3]dioxolane-2-yl)-2’-methylbiphenyl-3-yl]methanol was dissolved in 120 ml of dichloromethane and the mixture is cooled to a temperature of 0C. Type of 2.93 ml (16,8 mmol) Diisopropylamine followed by slow addition of 1.14 ml (14.7 mmol) of methanesulfonamide. After stirring for 30 minutes the reaction medium is poured into a solution of ammonium chloride. After normal processing of the obtained residue is dissolved in 150 ml of 2-butanone. To this solution are successively added: 4,2 g (28 mmol) of sodium iodide, 2,13 g (to 15.4 mmol) of potassium carbonate and of 3.23 g (15,4 mmol) is 8 hours, then filter and concentrate. The resulting residue is purified by chromatography on silica gel (louirouse tool: heptane-ethyl acetate 8:2 ratio). The desired product is obtained as a colourless oil (weight = 6,89 g; yield = 100%).

(f) Dimethyl-4-(2’-methyl-4’-propenylboronic-3-ylethoxy)phthalate

6.8 g (14 mmol) of Dimethyl-4-[4’-(2-ethyl-[1,3]dioxolane-2-yl)-2’-methylbiphenyl-3-ylethoxy]phthalate dissolved in 200 ml of methanol and 50 ml of water. Add 0.5 ml of sulfuric acid and the reaction medium is stirred at room temperature for 10 hours. After normal processing of the desired product is obtained without purification in the form of a colorless oil (weight = 6,05 g; yield = 97%).

(g) Dimethyl-4-[4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-ylethoxy]phthalate

5 g in (11.2 mmol) of Dimethyl-4-(2’-methyl-4’-propenylboronic-3-ylethoxy)phthalate are dissolved in 15 ml of dichloromethane and the mixture is cooled to a temperature of 0C. Type of 1.42 ml in (11.2 mmol) of trimethylsilanol, then 13.4 ml of 1.0 M solution of diethylzinc region (13.4 mmol). The medium is stirred for 6 hours, then treated with 10 ml of methanol. Add 20 ml of 1N hydrochloric acid and continue stirring for 1 hour. After extraction with dichloromethane and purification on a column of silica gel (alue = 3.25 g; yield = 61%).

(h) {4-[4’-(1-Ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-ylethoxy]-2-hydroxymethylene}methanol

Get similar to example 20(e) the method by reaction of 1.5 g (3,15 mmol) dimethyl-4-[4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-ylethoxy]phthalate with 480 mg (12.6 mmol) of sociallyengaged. The desired product is obtained in the form of a solid white color (so pl.: 87C; weight = 1,03 g; yield = 78%).

1H-NMR (DMSO)(M. D.): 0,75 (t, J=7.5 Hz, 6N), a 1.75-to 1.79 (m, 4H), and 2.27 (s, 3H), 4,47 (d, J=5,2 Hz, 2H), 4,56 (d, J=5,2 Hz, 2H), 4,58 (s, 1H), equal to 4.97 (m, 1H), 5,13 (m, 1H), 5,19 (s, 2H), 6.90 to-6,91 (m, 1H), 7,12-7,16 (m, 2H), 7,26-7,35 (m, 4H), 7,46 (m, 3H).

Example 23

1-[3’-(3,4-Bishydroxyethyl)-2-methylbiphenyl-4-yl]propan-1-ol(and) 1-[3’-(3,4-Bishydroxyethyl)-2-methylbiphenyl-4-yl]propan-1-ol

Get similar to example 20(e) the method by reaction of 900 mg (2 mmol) of dimethyl-4-(2’-methyl-4’-propenylboronic-3-ylethoxy)phthalate described in example 22(f), 300 mg (8 mmol) of sociallyengaged. The desired product is obtained in the form of a solid white color (so pl.: 78C; weight = 737 mg; yield = 94%).

1H-NMR (DMSO)(M. D.): 0,90 (t, J=7.5 Hz, 3H), 1,64 by 1.68 (m, 2H), and 2.26 (s, 3H), 3,39 (m, 1H), 4,46 (s, 1H), 4,47 (d, J=5,2 Hz, 2H), 4,56 (d, J=5.3 of sapropel)-3’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) Methyl-3’-hydroxy-3-methylbiphenyl-4-carboxylate

Get similar to example 12(h) the method by reaction 5.35 g (29 mmol) of 3-ethoxymethylenemalonic acid (described in example 1(g)) and 5.7 g (to 26.7 mmol) 4-bromo-2-methylbenzoic acid with 26.7 ml of 2.0 M potassium carbonate solution and 1.54 g of tetrakis(triphenylphosphine)palladium, and then removing the protective group in methanol. The desired product is obtained as a colourless oil (weight = 3,22 g; yield = 50%).

(b) Methyl-3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-3-methylbiphenyl-4-carboxylate

Get similar to example 1(i) the method by reaction of 1.5 g (6.2 mmol) of methyl-3’-hydroxy-3-methylbiphenyl-4-carboxylate with 3 g (6,88 mmol) of 3,4-bis(benzoyloxymethyl)-benzylbromide and 900 mg (6.4 mmol) of potassium carbonate. The desired product is obtained in the form of a yellow oil (weight = 3,69 g; yield = 99%).

() {5-[4’-(1-Ethyl-1-hydroxypropyl)-3’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by reaction of 4.6 g (7.6 mmol) of methyl 3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-3-methylbiphenyl-4-carboxylate with 30,6 ml of 2.0 M solution of ethylmagnesium (61 mmol). The desired product is obtained in the form of a solid white color (so pl.: 76C; mass, N), 4,89 (s, 1H), 4.53-in-of 4.57 (m, 4H), 5,07-5,70 (m, 4H), 6,97 (d, J=5 Hz, 1H), 7,21-the 7.43 (m, 7H), 7,51-7,53 (m, 2H).

Example 25

{4-[4’-(1-Ethyl-1-hydroxypropyl)-2’-methylbiphenyl-4-intoximeter]-2-hydroxymethylene}methanol

(a) 4-Ethoxymethylenemalonic acid

Get similar to example 1(g) the method by reaction of 10 g (of 57.8 mmol) of 4-bromophenol with 2.55 g (of 63.6 mmol) of 60% sodium hydride and a 4.83 ml (63,6 mmol) methoxymethane, then 25,4 ml of 2.5 M solution of utility (63,6 mmol) and 15 ml (65 mmol) of triisopropylsilane. Get a solid brown color (so pl.: 65C; weight = 6.2 g; yield = 73%).

(b) Methyl-4’-hydroxy-2-methylbiphenyl-4-carboxylate

Get similar to example 1(h) the method by reaction of 1.61 g (8,7 mmol) 4-ethoxymethylenemalonic acid and 1.8 g (9.7 mmol) of 4-bromo-3-methylbenzoic acid with 26.7 ml of 2.0 M potassium carbonate solution and 1.54 g of tetrakis(triphenylphosphine)palladium, and then removing the protective group - esterification in methanol. The desired product is obtained as a colourless oil (mass = of 2.06 g; yield = 98%).

(C) Methyl-4’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-2-methylbiphenyl-4-carboxylate

Get similar to example 1(i) the method by the reaction of 2.0 g (8,7 mmol) of methyl-4’-hydroxy-2-methylbiphenyl-4-carboxylate with 4.3 g (9,8 is e oil yellow (weight = 4,88 g; yield = 91%).

(d) {4-[4’-{1-Ethyl-1-hydroxypropyl)-2’-methylbiphenyl-4-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1(j) the method by reaction of 4.9 g (8 mmol) of methyl-4’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-

2-methylbiphenyl-4-carboxylate with 35 ml of 2.0 M solution ethylacetamide (70 mmol). The desired product is obtained in the form of a solid white color (so pl.: 97C; weight = 426 mg; yield = 13%).

1H-NMR (DMSO)(M. D.): 0,76 (t, J=7,34 Hz, 6N), a 1.75-of 1.84 (s, 3H), 4,56 (s, 1H), 4,60 with 4.64 (m, 4H), 5,14-5,24 (m, 4H), 7,10-to 7.18 (m, 3H), 7,25 is 7.50 (m, 7H), 7,53 (s, 1H).

Example 26

{4-[2’-tert-Butyl-4’-(1-ethyl-1-hydroxypropyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol

(a) Ethyl-3’-hydroxy-2-tert-butylbiphenyl-4-carboxylate

Get similar to example 1(h) the method by reaction of 6.8 g (37 mmol) of 3-ethoxymethylenemalonic acid (described in example 1(g)) with 11 g (31 mmol) of ethyl-3-tert-butyl-4-triftoratsetilatsetonom, 37 ml of 2 M potassium carbonate solution and 1.8 g of tetrakis(triphenylphosphine)-palladium, and then removing the protective group in ethanol. The desired product is obtained in the form of crystals pink (so pl.: 118-120C; weight = 5,3 g; yield = 57%).

(b) Ethyl-3’-[3,4-bis(1-phenylmethane is by the reaction of 5.3 g (17,7 mmol) methyl-3’-hydroxy-2-tert-butylbiphenyl-4-carboxylate with 8,46 g (19 mmol) of 3,4-bis(benzoyloxymethyl)benzylbromide and 2.54 g (18 mmol) of potassium carbonate. The desired product is obtained in the form of a yellow oil (weight = 11 g; yield = 94%).

(c) {4-[4’-(1-Ethyl-1-hydroxypropyl)-2’-tert-butylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol

Get similar to example 1 (j) the method by reaction of 3 g (4.6 mmol) of methyl 3’-[3,4-bis(1-phenylmethanesulfonyl)benzyloxy]-

2-tert-butylbiphenyl-4-carboxylate with 12 ml of 3.0 M solution ethylacetamide (36 mmol). The desired product is obtained in the form of a white powder (so pl.: 133C; weight = 1.7 g; yield = 80%).

1H-NMR (CDCl3)(M. D.): or 0.83 (t, J=7,4 Hz, 6N), of 1.18 (s, N), 1,82-1,90 (m, 4H), 2.05 is (ush.s, 3H), 4,74 (s, 4H), 5,07 (s, 2H), 6,88-6,97 (m, 4H), 7,12-7,24 (m, 2H), 7,37 (s, 2H), 7,42 (s, 1H), 7,52 (d, J=1.7 Hz, 1H).

Example 27

1-[3’-(3,4-Bishydroxyethyl)-2-methylbiphenyl-4-yl]-2,2-DIMETHYLPROPANE-1-ol

(a) 4 Brom-2’-methylbiphenyl-3-ol

Get similar to example 1(h) the method by reaction of 15.3 g (84 mmol) of 3-ethoxymethylenemalonic acid (described in example 1(g) and 25 g (84 mmol) of 2-bromo-5-iodotoluene with 84 ml of 2.0 M potassium carbonate solution and 4.8 g of tetrakis(triphenylphosphine)palladium, and then removing the protective group in methanol. The desired product is obtained as a colourless oil (weight = 11,8 g; yield = 50%).

(b) Dimethyl-4-bromethalin

36 g (176 mmol) Dimetho slowly add a solution of 55.3 g (211 mmol) of triphenylphosphine in 200 ml of dichloromethane and the reaction mixture is stirred for 3 hours at room temperature. After treatment with water and extraction with dichloromethane, the residue is purified by chromatography on a column of silica (eluting agent: dichloromethane). The desired product is obtained as a colourless oil (weight = 25 g; yield = 50%).

(C) Dimethyl-4-(4’-bromo-2’-methylbiphenyl-3-intoximeter)phthalate

Get similar to example 1(i) the method by reaction of 11.8 g (44,8 mmol) of 4’-bromo-2’-methylbiphenyl-3-ol with 14.2 g (49 mmol) of dimethyl-4-brometalia and 6.5 g (47 mmol) of potassium carbonate. The desired product is obtained in the form of a yellow oil (weight = 16,4 g; yield = 78%).

(d) [4-(4’-Bromo-2’-methylbiphenyl-3-intoximeter)-2-hydroxymethylene]methanol

16.4 g (35 mmol) of Dimethyl-4-(4’-bromo-2’-methylbiphenyl-3-intoximeter)phthalate are dissolved in 200 ml of anhydrous tetrahydrofuran and added 1.5 g (70 mmol) of lithium borohydride. The reaction medium is refluxed for 3 hours, then cooled and poured on ice, then diluted with a saturated solution of ammonium chloride. After extraction, the desired product is obtained as a colourless oil (weight = 13.3 g; yield = 100%).

(e) 3’-[3,4-Bis(tert-butyldimethylsilyloxy)-

benzyloxy]-4-bromo-2-methyl-biphenyl -

13.3 g (34.8 mmol) [4-(4’-Bromo-2’-methylbiphenyl-3-intoximeter)-

2-hydroxymethylene]metal) imidazole. The medium is stirred for 10 hours, then diluted with 400 ml of diethyl ether and filtered. The filtrate is then treated with a saturated solution of ammonium chloride and washed with water. After chromatography on a column of silica get the desired product as colourless oil (weight = 20,4 g; yield = 91%).

(f) 1-{3’-[3,4-Bis(tert-butyldimethylsilyloxy)-benzyloxy]-

2-methylbiphenyl-4-yl}-2,2-DIMETHYLPROPANE-1-ol

2 g (3 mmol) of 3’-[3,4-Bis(tert-butyldimethylsilyloxy)-

benzyloxy]-4-bromo-2-methylbiphenyl dissolved in 30 ml of anhydrous tetrahydrofuran and the mixture is cooled to a temperature of -78C. Slowly added to 1.4 ml of 2.5 M solution of utility (3.5 mmol) and the mixture was kept at a temperature of -78C for 1 hour. Added dropwise to 400 ml (3.7 mmol) of 2,2-dimethylpropanamide and environment slowly bring back to room temperature, then treated according to normal processing. The desired product is obtained as a colourless oil (weight = 2 g; yield = 100%).

(g) 1-[3’-(3,4-Bishydroxyethyl)-2-methylbiphenyl-4-yl]-2,2-

DIMETHYLPROPANE-1-ol

2 g (3 mmol) 1-{3’-[3,4-Bis(tert-butyldimethylsilyloxy)benzyloxy]

2-methylbiphenyl-4-yl}-2,2-dimethyldi (7.7 mmol). After stirring for 1 hour at room temperature, then normal processing, the obtained residue is purified by chromatography on silica gel. The desired product is obtained as a colourless oil (weight = 1,15 g; yield = 90%).

1H-NMR (CDCl3)(M. D.): 0,97 (s, N), 2,09 (ush.with 2N in), 2.25 (s, 3H), and 4.40 (s, 1H), and 4.75 (s, 2H), amounts to 4.76 (s, 2H), 5,09 (s, 2H), 6,91-of 6.96 (m, 3H), 7,17-7,19 (m, 3H), 7,28-7,44 (m, 4H).

Example 28

1-[3’-(3,4-Bishydroxyethyl)-2-methylbiphenyl-

4-yl]-2-methylpropan-1-ol

(and) 1-{3’-[3,4-Bis(tert-butyldimethylsilyloxy)-

benzyloxy]-2-methylbiphenyl-4-yl}-2-methylpropan-1-ol

Get similar to example 27(f) the method by reaction of 2 g (3.1 mmol) of 3’-[3,4-bis(tert-butyldimethylsilyloxy)benzyloxy]-

4-bromo-2-methylbiphenyl with 1.4 ml of 2.5 M solution of utility (3.5 mmol) and 400 ml (37 mmol) of 2-methylpropionamidine. The desired product is obtained as a colourless oil (weight = 1.1 g; yield = 56%).

(b) 1-[3’-(3,4-Bishydroxyethyl)-2-methylbiphenyl-

4-yl]-2-methylpropan-1-ol

Get similar to example 27(g) the method by reaction of 1.1 g (1.7 mmol) 1-{3’-[3,4-bis(tert-butyldimethylsilyloxy)benzyloxy]-2-methylbiphenyl-4-yl}-2-methylpropan-1-ol with 3.8 ml of a 1.0 M solution of tetrabutylammonium (3.8 mmol). Desired promd> (M. D.): 0,85 (d, J=6,7 Hz, 3H), of 1.03 (d, J=6.6 Hz, 3H), 1,99 (m, 1H), of 2.25 (s, 3H), 4,35 (d, J=6,9 Hz, 1H), to 4.73 (s, 2H), 4,74 (s, 2H), to 5.08 (s, 2H), 6,92-to 6.95 (m, 3H), 7,14-7,20 (m, 3H), 7,28-the 7.43 (m, 4H).

Example 29

{2-Hydroxymethyl-4-[methyl(cryptorchidectomy)-

biphenyl-3-intoximeter]phenyl}methanol(and) 2-{3’-[3,4-Bis(tert-butyldimethylsilyloxy)benzyloxy]

2-methylbiphenyl-4-yl}-1,1,1,3,3,3-hexaferrite-2-ol

Get similar to example 27(f) the method by reaction of 4 g (6.2 mmol) of 3’-[3,4-bis(tert-butyldimethylsilyloxy)benzyloxy]-4-bromo-2-methylbiphenyl with 2.7 ml of 2.5 M solution of utility (6.8 mmol) and HEXAFLUOROACETONE used in excess. The desired product is obtained as a colourless oil (weight = 2,35 g; yield = 52%).

(b) {2-Hydroxymethyl-4-[methyl(triptolide-trifloromethyl)biphenyl-3-intoximeter]phenyl}methanol

Get similar to example 27(g) the method by reaction of 2.3 g (3.2 mmol) 2-{3’-[3,4-bis(tert-butultimately-silyloxy)benzyloxy]-2-methylbiphenyl-4-yl}-1,1,1,3,3,3-hexaferrite-2-ol with 7 ml of a 1.0 M solution of tetrabutylammonium (7 mmol). The desired product is obtained as a colourless oil (weight = 1.2 g; yield = 75%).

1H-NMR (CDCl3)(M. D.): 2,28 (s, 3H), 2,37 (ush.s, 2H), 4,74 (s, 4H), to 5.08 (s, 2H), 6,91-of 6.99 (m, 3H), 7,26-the 7.43 (m, 5H), 7,53-to 7.59 (m, 3H).

When the weave weighing 0.2 g:

The compound of example 1 0.005 g

Pre -

gelatinizing starch 0,065 g

Microcrystalline cellulose 0.075 g

Lactose 0,050 g

Magnesium stearate 0.005 g

For the treatment of ichthyosis adult patient is administered 1-3 tablets a day for 1-12 months depending on the severity of treatable cases.

b) Prepare a suspension in the form of a drink, designed for packaging in vials with a capacity of 5 ml of:

The compound of example 2 0,050 mg

Glycerin 0,500 g

70% sorbitol 0,500 g

The sodium saccharinate 0,010 g

Methyl-p-hydroxybenzoate 0,040 g

Aromatized Enough

Purified water To total

number 5 ml

For the treatment of acne adult patient is given 1 ampoule a day for 1-12 months depending on the severity of treatable cases.

c) Prepare the following composition intended for packaging in gelatin capsules:

The compound of example 4 of 0.0001 mg

Corn starch to 0.060 g

Lactose Up to the total number 0,300 g

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

In the treatment of psoriasis adult patient is given 1 gelatin capsule a day for 1-12 months.

d) Prepare the following composition intended for packaging in gelatin capsules:

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

In the treatment of psoriasis adult patient is given 1 gelatin capsule a day for 1-12 months.

2) For entering local path:

(a) Prepare the following non-ionic cream water-in-oil:

The compound of example 9 0,100 g

The mixture of emulsifying alcohols

lanolin, waxes and

refined oils,

produced by BDF

called "Eisige

anhydre" 39,900 g

Methyl-p-hydroxybenzoate 0.075 g

Propyl-p-hydroxybenzoate 0.075 g

Sterile demineralized

water To total

the number 100,000 g

This cream is applied to psoriatic skin 1-2 times a day

for 1-12 months.

(b) Prepare the gel by implementing the following composition:

The compound of example 28 0.001 g

Erythromycin in basic form 4,000 g

Equivalent 0,050 g

Hydroxypropylcellulose,

produced by

Hercules under the name of

"KLUGEL HF" 2,000 g

Ethanol (95) To common

the number 100,000 g

This gel is to be applied to the affected skin skin or skin with acne 1-3 times a day for 6-12 weeks depending on the severity of treatable cases.

(C) Prepare protivoseborainey lotion by mixing the following ingredients:

The compound of example 12 0,030 g

Propylene glycol 5,000 g

Butylhydroxytoluene fur skull, affected by seborrhea, and establish a significant improvement during the 2-6 weeks.

d) Prepare a cosmetic composition against the harmful effects of the sun by mixing the following ingredients:

The compound of example 7 1,000 g

Benzylideneamino 4,000 g

Triglycerides of fatty acids 31,000 g

Glycerylmonostearate 6,000 g

Stearic acid 2,000 g

Cetyl alcohol 1,200 g

Lanolin 4,000 g

Preservatives 0,300 g

Propylene glycol 2,000 g

Triethanolamine 0,500 g

Odorant 0.400 g

Demineralized water Until the General

the number 100,000 g

This composition is applied daily, it helps to fight against photoinductive aging.

(e) Prepare the following non-ionic cream oil-in-water:

The compound of example 23 0,500 g

Retinoic acid 0,020 g

Cetyl alcohol 4.000 g

Glycerylmonostearate 2,500 g

Stearate PEG-50 2,500 g

Oil Karite 9,200 g

Propylene glycol 2,000 g

Methyl-p-hydroxybenzoate 0.075 g

Propyl-p-hydroxybenzoate 0.075 g

Sterile demineralized water Until the General

the number 100,000 g

This cream is applied to psoriatic skin 1-2 times a day for 30 days for a treatment episode and constantly to care for her.

(f) Prepare the gel for local application by mixing the following ingredients:

The compound of example 19 0,05

Goodrich under the name of

"Carbopol 941" 0,500 g

Triethanolamine as

aqueous 20 wt.%-tion

solution 3,800 g

Water 9,300 g

The propylene glycol To total

the number 100,000 g

This gel is to be applied for the treatment of acne 1-3 times a day for 6-12 weeks depending on the severity of treatable cases.

(g) Prepare a lotion against hair loss and growing hair by mixing the following ingredients:

The compound of example 13 0.05 g

The connection produced

called "Minoxidil" 1,00 g

Propylene glycol 20,00 g

Ethanol 34,92 g

The glycol

(molecular weight = 400) 40,00 g

Butylhydroxyanisole 0.01 g

Equivalent 0.02 g

Water To total amount of 100.00 g

This lotion is applied 1-2 times a day for 3 months fur skull undergoing hair loss, and continually to take care of them.

(h) Prepare a cream against acne by mixing the following ingredients:

The compound of example 5 0,050 g

Retinoic acid 0,010 g

A mixture of glycerol stearates

poly (ethylene glycol)

(75 mol), produced

the company Gattefosse

called "Gelot 64" 15,000 g

Stone fruit oil,

polyoxyethylenated

using 6 mol

of ethylene oxide produced

the company Gattefosse

under the name "Labrafil

M2130 CS 8,000 g

Perhydrosqualene salt Ethylenediamine-

tetraoxane acid 0,050 g

Purified water To total

the number 100,000 g

This cream is applied on the skin affected by dermatitis, or skin with acne 1-3 times within 6-12 weeks.

(i) Prepare a cream oil-in-water by implementing the following composition:

The compound of example 14 0,020 g

-metadon-17-valerate 0,050 g

S-carboxymethylcysteine 3,000 g

Polyoxyethylenated

(40 mol of ethylene oxide),

manufactured by Atlas

under the name "Myrj 52" 4,000 g

Sorbitanoleat,

polyoxyethylenated

using 20 mol

of ethylene oxide produced

company Atlas under

the name "Tween 20" 1,800 g

A mixture of glycerine and

distearate manufactured

the company Gattefosse

under the name "Geleol" 4,200 g

Propylene glycol 10,000 g

Butylhydroxyanisole 0,010 g

Equivalent 0,020 g

Cetostearyl alcohol 6,200 g

Preservatives Enough

Perhydrosqualene 18,000 g

A mixture of triglycerides

Caprylic and capric

acids produced

the company Dynamit Nobel

called

"Miglyol 812" 4,000 g

Triethanolamine (99 wt.%-tion) 2,500 g

Water To total

the number 100,000 g

This cream is applied 2 times a day on skin that is affected by inflammatory dermatosis, within 30 days.

(j) Prepare the following cream of type oil-in-water:

Molochnoe Atlas

under the name "Myrj 52" 4,000 g

Sorbitanoleat,

polyoxyethylenated

using 20 mol

of ethylene oxide produced

company Atlas under the name of

"Tween 20" 1,800 g

A mixture of glycerine and

distearate manufactured

the company Gattefosse under the

the name "Geleol" 4,200 g

Propylene glycol 10,000 g

Butylhydroxyanisole 0,010 g

Equivalent 0,020 g

Cetostearyl alcohol 6,200 g

Preservatives Enough

Perhydrosqualene 18,000 g

A mixture of triglycerides

Caprylic and capric acids,

produced by

Dynamit Nobel under the name of

"Miglyol 812" 4,000 g

Water To total

the number 100,000 g

This cream is applied 1 time per day, it helps to fight aging, whether it photoinduced or age.

(k) Prepare the following anhydrous ointment:

The compound of example 25 5,000 g

Vaseline oil 50,00 g

Equivalent 0,050 g

White petrolatum To General

the quantity of 100 g

This ointment is applied 2 times a day on skin that is affected by scaly dermatosis, within 30 days.

3) For administration by injection:

(a) Prepare the following composition:

The compound of example 16 0,002 grams

Etiloleat To a total of 10 g

In the treatment of malignant melanoma adult patient the composition is administered by injection with a frequency of 1 to 7 times a weeks is about the total number of 2 g

In the treatment of basal cell carcinoma adult patient the composition is administered by injection with a frequency of 1 to 7 times a week for 1-12 months.

(c) Prepare the following composition:

The compound of example 6 0.1 mg

Sesame oil Until General

number 2 grams

In the treatment spinocellular carcinoma adult patient the composition is administered by injection with a frequency of 1 to 7 times a week for 1-12 months.

(d) Prepare the following composition

The compound of example 2 0.001 mg

Methylbenzoate To a total of 10 g

In the treatment of carcinoma of the colon adult patient the composition is administered by injection with a frequency of 1 to 7 times a week for 1-12 months.

4) For intravenous injection by means of:

(a) Prepare the following injected by the injection of a lipid emulsion:

The compound of example 7 0.001 mg

Soybean oil 10,000 g

Egg phospholipid 1,200 g

Glycerin 2,500 g

Water for injection To a total

the number 100,000 g

In the treatment of psoriasis adult patient the composition is administered by injection with a frequency of 1 to 7 times a week for 1-12 months.

(b) Prepare the following injected by the injection of a lipid emulsion:

The compound of example 3 0,010 g

Cottonseed oil 10,000 g

Soy lecithin 0,750 g

Sorbitol 5,000 g

DL--t is the position is administered by injection with a frequency of 1 to 7 times a week for 1-12 months.

(f) Prepare the following injected by the injection of a lipid emulsion:

The compound of example 21 0.001 g

Soybean oil 15,000 g

Acetilsalicilic 10,000 g

Pluronic F-108 1,000 g

Glycerin 2,500 g

Water for injection To a total

the number 100,000 g

In the treatment of leukemia adult patient the composition is administered by injection with a frequency of 1 to 7 times a week for 1-12 months.

(d) Prepare the following mixed micellar composition:

The compound of example 29 0.001 g

Lecithin 16,930 g

Glikoholeva acid 8,850 g

Water for injection To a total

the number 100,000 g

In the treatment of malignant melanoma adult patient the composition is administered by injection with a frequency of 1 to 7 times a week for 1-12 months.

(e) Prepare the following cyclodextrines composition:

The compound of example 11 0.1 mg

-cyclodextrin 0,100 g

Water for injection To a total

the number 10,000 g

In the treatment in the case of transplant rejection adult patient the composition is administered by injection with a frequency of 1 to 7 times a week for 1-12 months.

(f) Prepare the following cyclodextrines composition:

The compound of example 4 0,010 g

2-Hydroxypropyl--

cyclodextrin 0,100 g

Water for injection To a total

the number 10,000 to gradely within 1-12 months.

Example 31

An example of assessment of biological activity of compounds according to the invention

Agonistic activity of VDR tested using the HeLa cell line by cotransfection expressing vector human receptor VDR and plasmid reporter p240Hase-CAT, which contains the -1399 to +76 promoter of 24-hydroxylase in rats, cloned above phase coding gene chloramphenicolchloramphenicol (CAT). Later, 18 hours after cotransfection in medium were added to test the product. Later, 18 hours after treatment quantitative determination of CAT activity of cell lysates was performed using enzyme-linked immunosorbent assay (Elisa method). The results were expressed in percentage in relation to action, usually observed when using 10-7M calcitriol.

Agonistic activity in this system cotransfection was characterized by determining the dose required to achieve 50% of maximal activity product (AS) (see table).

Claims

1. Triaromatic the vitamin D analogues of General formula I

in which R1means the radical CH3or for which l (a) or (C), which can be read from left to right or Vice versa:

where R6means a hydrogen atom or lower alkyl;

W denotes an oxygen atom, a sulfur or a radical-CH2-;

Ar1means a cycle of formula (e)

R8and R9have the meanings stated below;

AG2means a cycle of formula (j), (k) or (m)

where R11and R12have the meanings stated below;

R3means a radical of the formula

where R13and R14identical or different, represent lower alkyl or a group of CF3;

R8, R9, R11, R12identical or different, denote a hydrogen atom, lower alkyl, halogen atom, radical, CF3;

R15denotes a hydrogen atom, acetyl, trimethylsilyl, tert-butyldimethylsilyl or tetrahydropyranyl, as well as their salts.

2. Connection on p. 1, characterized in that they are in the form of salts of inorganic or organic acids, in particular hydrochloric, sulfuric, acetic, fumaric, gementera, maleic or almond acid.

3. Connection under item 1 or 2, characterized in that the lower alkyl radicals chosen what about the halogen atom corresponds to a fluorine atom, chlorine or bromine.

5. Connection on p. 1, characterized in that individually or in mixtures, are selected from the group consisting of

{5-[4’-(1-ethyl-1-hydroxypropyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{2-hydroxymethyl-5-[4’-(1-hydroxy-1-methylethyl)biphenyl-3-intoximeter]phenyl}methanol;

{5-[4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{2-hydroxymethyl-5-[4’-(1-hydroxy-1-methylethyl)-2’-methylbiphenyl-3-intoximeter]phenyl}methanol;

(5-{2-[3’-(1-ethyl-1-hydroxypropyl)biphenyl-3-yl]ethyl}-2-hydroxymethylene)methanol;

{2-hydroxymethyl-5-[3’-(1-hydroxy-1-methylethyl)biphenyl-3-intoximeter]phenyl}methanol;

{5-[4’-(2-ethyl-2-hydroxybutyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{5-[3’-(2-ethyl-2-hydroxybutyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

1-[3’-(3,4-bishydroxyethyl)biphenyl-3-yl]-2-methylpropan-2-ol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-ylsulphonyl]-2-hydroxymethylene}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-2,2’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{2-hydroxymethyl-4-[4’-(1-hydroxy-1-propinball)-2,2’-dimethylbiphenyl-3-intoximeter]phenyl}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-2-metalbite Ketil]-2-hydroxymethylene}methanol;

(4-{3-[5-(1-ethyl-1-hydroxypropyl)pyridin-2-yl]phenoxymethyl}-2-hydroxymethylene)methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)is 6.2’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)is 6.2’,6’-trimethylphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-2’,6’-dimethylbiphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

1-{4-[3-(3,4-bishydroxyethyl)phenyl]thiophene-2-yl}propane-1-ol;

(4-{3-[4-(1-ethyl-1-hydroxypropyl)thiophene-2-yl]phenoxymethyl}-2-hydroxymethylene)methanol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-3-ylethoxy]-2-hydroxymethylene}methanol;

1-[3’-(3,4-bishydroxyethyl)-2-methylbiphenyl-4-yl]propan-1-ol;

{4-[4’-(1-ethyl-1-hydroxypropyl)-3’-methylbiphenyl-3-intoximeter]-2-hydroxymethylene} methanol;

{5-(4’-(1-ethyl-1-hydroxypropyl)-2’-methylbiphenyl-4-intoximeter]-2-hydroxymethylene}methanol;

{4-[2’-tert-butyl-4’-(1-ethyl-1-hydroxypropyl)biphenyl-3-intoximeter]-2-hydroxymethylene}methanol;

1-[3’-(3,4-bishydroxyethyl)-2-methylbiphenyl-4-yl]-2,2-DIMETHYLPROPANE-1-ol;

1-[3’-(3,4-bishydroxyethyl)-2-methylbiphenyl-4 -} methanol.

6. Connection on p. 1, characterized in that they possess at least one and preferably all of the following characteristics: R1means the radical CH3or CH2HE; R2means radical, CH2OH; X-Y represents a relationship of the formula (a) or (C); R3means the moiety C(R13) (R14)OH.

7. Compounds according to any one of paragraphs. 1-6 as a medicinal product intended for the treatment of dermatological diseases associated with disorders of keratinization, which manifests itself in the differentiation and proliferation, such as ordinary, youth, polymorphic, rosacea; nodular-cystic, nodular acne; senile acne, secondary acne such as caused by sun medical or occupational acne; other types of disorders of keratinization, such as ichthyosis, idiotphone state; other dermatological diseases with inflammatory immuno-allergic component, with or without violation of disorders of cell proliferation and in particular all forms of psoriasis; disorders of fat options, such as acne affected Hyperborea or normal seborrhea; alopecia different lineages, in particular alopecia, resulting from chemotherapy or exposure to audacia fact, she includes a pharmaceutically acceptable carrier at least one of the compounds listed in any of paragraphs. 1-6.

9. The composition according to p. 8, characterized in that the concentration of compounds (compounds) according to any one of paragraphs. 1-6 is 0.0001-5% by total weight of the composition.

10. Cosmetic composition for care of the body, and hair care products, characterized in that it comprises in a cosmetically acceptable medium, at least one of the compounds specified in any of paragraphs. 1-6.

11. The composition according to p. 10, characterized in that the concentration of compounds (compounds) is 0.001-3% by total weight of the composition.

 

Same patents:

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< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

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

< / BR>
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< / BR>
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Q is

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