Vitamin d analogs, pharmaceutical and cosmetic composition containing the same

FIELD: pharmaceutical and cosmetic industries, biological aromatic vitamin D analogs.

SUBSTANCE: invention relates to compounds selected from group containing (E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)phenyl]-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-in-2-ol, (3E,5E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)phenyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol, (E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)ethyl]phenyl}-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-in-2-ol; and (3E,5E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)ethyl]phenyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol, as well as from abovementioned compounds wherein one or more hydroxyl groups have protective group of formula -(C=O)-R, wherein R represents linear or branched C1-C6-alkyl, or C6-C10-aryl, or C7-C11-aralkyl; and aryl and aralkyl radicals may be substituted with one or two hydroxyl groups, C1-C3-alkoxy groups, halogen atoms, nitro or amino groups. Also disclosed are methods for application of said analogs in pharmaceutical composition with cell proliferation and differentiation activity useful in therapy and veterinary (i.e. dermatology, oncology, autoimmune diseases, organ and tissue transplantation), as well as in cosmetic composition.

EFFECT: vitamin D analogs with value pharmaceutical and cosmetic properties.

12 cl, 5 tbl, 6 dwg, 10 ex

 

The invention relates to Bermatingen analogues of vitamin D as new useful products used in industry.

The invention also relates to a method for their production and use in pharmaceutical compositions intended for use in human and veterinary medicine and in cosmetic compositions.

Compounds according to the invention have activity against the proliferation and differentiation of cells and can find application, in particular, when local and systemic treatment of dermatological (or other) diseases associated with disorders of keratinization, or disorders with an inflammatory and/or immunoallergic component, and hyperproliferative tissues ectodermic origin (skin, epithelium...), which can be benign or malignant. These compounds can also be used for anti-aging of the skin under the action of light or from time to time and for the treatment of disorders in scarring.

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

Vitamin D is an important vitamin for the prevention and treatment of deficiency of cartilage mineralization (rickets) and bone (osteomalacia) and even some forms of osteoporosis in elderly patients. But it is now recognised that it is a step beyond the regulation of bone metabolism and calcium homeostasis. So, among the other effects of vitamin D can lead to effects on the proliferation and differentiation of cells, and also monitoring protective functions of the organism. The opening of additional effects led to the development of new therapeutic methods in the field of dermatology, Oncology, in the field of autoimmune diseases, as well as in the field of transplantation of organs or tissues.

The effective therapeutic use of this vitamin for a long time hampered by its toxicity (sometimes reported cases deadly hypercalcemia). Currently synthesized structural analogues of vitamin D, some of which have only differentiating properties and do not affect the metabolism of calcium.

In the patent application WO 00/26167 (D1) the applicant proposed new connections, which are analogues of vitamin D, which have a selective effect on the proliferation and differentiation of cells and do not show hypercalcemia properties. These vitamin D analogues can be synthesized easier and, therefore, are more economical in comparison with known compounds.

Recently, the applicant has unexpectedly discovered that certain compounds, in particular compounds not specifically described in the patent application WO 00/26167 (D1), but the corresponding total the above formula, the times, the t biological activity, far surpassing, in particular, the activity of the known compounds. This activity is so strong that it approaches the activity of natural vitamin D.

Thus, the present invention relates, at least one compound which is selected from the following compounds:

- (4E,6E)-7-{3-[2-(3,4-bis-hydroxymethylene)ethyl]phenyl}-3-ethyl-Nona-4,6-Dien-3-ol,

- (E)-6-[3-(3,4-bis-hydroxymethyl-benzyloxy)phenyl]-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol,

- (3E,5E)-6-[3-(3,4-bis-hydroxymethyl-benzyloxy)phenyl]-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol,

- (E)-6-{3-[2-(3,4-bis-hydroxymethylene)ethyl]phenyl}-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol,

- (3E,5E)-6-{3-[2-(3,4-bis-hydroxymethylene)ethyl]phenyl}-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol,

and their geometric isomers and compounds in which one or more hydroxyl groups have a protective group of the type -(C=O)-R, where R denotes a linear or branched alkyl radical containing from 1 to 6 carbon atoms, or aryl radical containing from 6 to 10 carbon atoms, or Uralkaliy radical containing from 7 to 11 carbon atoms; the aryl radical or Uralkaliy radical can be substituted by one or two hydroxyl groups, alkoxyphenyl containing from 1 to 3 carbon atoms, halogen atoms, neath what about - or amino groups, and to their mixtures.

Under linear or branched alkyl radical containing from 1 to 6 carbon atoms, understand methyl, ethyl, ISO-propyl, tert-botilony or sexily radical.

Under the aryl radical containing from 6 to 10 carbon atoms, understand phenyl or nattily radical.

Under Uralkali radical containing from 7 to 11 carbon atoms, understand benzyl or methyl-nattily radical.

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

The present invention relates also to methods of producing the above compounds.

Figure 1-4 shows a schematic of the reactions, which can be obtained the compounds according to the invention.

Thus, the compound according to example 1 can be obtained (figure 1) derived from (6) by the reaction with utilities at a temperature of -78°in a solvent such as tetrahydrofuran (THF), and then the hydroxyl group is released from the protection in the presence of tetrabutylammonium fluoride.

The compound (6) can be obtained from 3-bromopropiophenone (1) through the progressive implementation of a number of reactions, including:

- The formation of a derivative (2) by protecting ketogroup in the form of a dioxolane and the subsequent formation of aldehyde groups from the corresponding lithium derivative in the presence of dimethylformamide.

- Education is derived (3) by the reaction Horner-Emmons between phosphonate derivative (compound A) and benzaldehyde (2) and subsequent hydrogenation in the presence of palladium on coal.

- The formation of a derivative (4) by reduction of the ester groups in the presence of socialogical, with the subsequent removal of the protective ketogroup in the presence of para-toluenesulfonic acid and protection of the alcohol groups in the form of tert-butyldimethylsilyl.

- The formation of a derivative (5) by the reaction Horner-Emmons with triethylphosphate, the subsequent reduction of the ester group in the presence of socialogical and oxidation of the alcohol group in the presence of manganese dioxide.

- The formation of a derivative (6) by the reaction Horner-Emmons between triethylphosphate and aldehyde derivative (5) or directly by the reaction Horner-Emmons between triethylphosphate and Ketoprofen (4).

The compound a can be obtained from the anhydride trimellitic acid according to the scheme shown in figure 4.

Compounds according to examples 2 and 4 can be obtained (figure 2 and 3), respectively, derived from (13) and derivative (15) by removing the protection of the alcohol groups in the presence of tetrabutylammonium fluoride.

Compounds according to examples 3 and 5 can be obtained (figure 2 and 3), respectively, derived from (13) and derivative (15) by restoring the triple bond to a double bond, having the TRANS configuration, lydialydia in the presence of sodium methylate in a solvent such as THF, and the following is the pressure of the protection of the alcohol groups in the presence of tetrabutylammonium fluoride.

The compound (13) can be obtained from 3-hydroxypropiophenone (7) through the implementation of a number of reactions, including:

- The formation of a derivative (8) by protection of the phenolic group in the form of tert-butyldimethylsilyl.

- The formation of a derivative (9) by the reaction Horner-Emmons with triethylphosphate with subsequent reduction of the ester group in the presence of socialogical and oxidation of the alcohol group in the presence of manganese dioxide.

- The formation of a derivative (10) by the reaction of the Corey-Fuchs (Corey-Fuchs).

- The formation of a derivative (11) by removing the protection of the phenolic group and the subsequent condensation reaction with bromine derivatives (compound) in the presence of sodium hydride in a solvent such as dimethylformamide (DMF).

- The formation of a derivative (12) by removing the protective benzoate groups, and then re protection in the form of tert-butyldimethylsilyloxy.

- The formation of a derivative (13) by reaction with butyllithium, and then HEXAFLUOROACETONE.

The connection can be derived from the anhydride trimellitic acid according to the scheme in figure 4.

The compound (15) can be obtained from the derivative (5) the transformation of the aldehyde group in an acetylene group (14) by the reaction of the Corey-Fuchs followed by the formation of lithium derivative with utility and interaction with HEXAFLUOROACETONE

Protection of the hydroxy groups is carried out in the usual way, described in the literature, for example, by reaction of the corresponding carboxylic acid type RCOCl in a solvent such as THF or dichloromethane, in the presence of a base such as pyridine or triethylamine.

Compounds according to the invention have biological properties similar to properties of vitamin D, in particular the TRANS-activation properties of the elements of the response of the body to the action of vitamin D (VDRE), such as agonistic activity against receptors of vitamin D or its derivatives. Under vitamin D or derivatives of them understand, for example, derivatives of vitamin D2 or D3, and in particular 1,25-dihydroxyvitamin D3 (calcitriol).

Specified agonistic activity against receptors of vitamin D or its derivatives can be detected in the test "in vitro" techniques known in the research of gene transcription (Hansen et al., The Society For Investigative Dermatologie, vol.1, No. 1, April 1996).

As an example, the agonistic activity of VDR can be investigated on cell line HeLa by cotransfection vector expression of the receptor VDR human and vehicle plasmids p240Hase-CAT. Agonistic activity can be characterized in this system cotransfection by determining the dose required to achieve 50%of maximal activity is the product (AS). A detailed report of the tests and the results obtained with the use of the compounds according to the invention described in example 7 of the present application.

Biological properties similar to the properties of vitamin D, can also be defined by using the product's ability to inhibit the proliferation of normal human keratinocytes (culture KHN). The product is added to cultured cells KHN under conditions that promote proliferation. The product is left in contact with the cells for five days. The number proliferating cells is measured by the introduction bromodeoxyuridine (BRdU) into DNA. The report about the test and the results obtained with the use of the compounds according to the invention, described in example 8 of the present application.

Biological properties similar to the properties of vitamin D, can also be defined by using the product's ability to induce differentiation of cells promyelocytic leukemia HL60. The report about the test and the results obtained with the use of the compounds according to the invention, described in example 9 of the present application.

Agonistic activity against receptors of vitamin D compounds according to the invention can be evaluated in the test "in vivo induction in mice SKH 24-hydroxylase (Voorhees and al. 1997, 108:513-518). The report of this test, and the results obtained with CA is using the compounds according to the invention, described in example 10 of this application.

The object of the present invention is also the use of the above compounds as a medicine.

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

- dermatological diseases associated with disorders of keratinization, caused by the differentiation and proliferation of cells, such as acne vulgaris, comedones, acne, polymorphic, pink, nodular-cystic, nodular, senile, secondary acne such as solar, drug-induced or caused by occupational diseases;

- ichthyosis, idiotphone States, disease Damiera, palkovicova keratodermia, leukoplasia and makoplasty States, cutaneous or mucosal (oral mucosa) lichen;

inflammatory immune-allergic dermatological diseases, accompanied or not accompanied by disorders of cell proliferation, as well as all forms of psoriasis, cutaneous, mucous or ungual, and even psoriatic rheumatism and skin atopy, such as eczema, respiratory atopy or hypertrophy of the gums;

- benign or malignant dermal or epidermal of proliteracy viral or non-viral origin, such as common warts, flat plane warts is barodawala epidermodysplasia, the oral or floriduh multiple papillomas, symfony T; proliferate caused by ultraviolet exposure, in particular, in the case of basal and spinal cell epithelioma and precancerous skin diseases, such as keratoacanthoma;

- immune dermatoses, such as lupus erythematosus, vesiculating immune diseases or collagen diseases such as scleroderma;

- dermatological or systemic diseases with an immunological component;

- disorders of the sebaceous glands, such as acne affected Hyperborea or simple seborrhoea;

- skin disorders caused by exposure to ultraviolet radiation, aging skin, as under the action of light and age, pigmentations and actinic keratosis, or any pathologies associated with age ageing or aging under the action of radiation;

- abnormalities in the healing of scars or stretch marks;

- inflammatory diseases such as arthritis, skin or systemic diseases of viral origin, such as the syndrome of Kaposia (Kaposis);

- ophthalmological disorders, in particular corporate;

- cancerous or precancerous lesions that can be caused by vitamin D receptors, such as breast cancer, leukemia, myelodysplasia syndromes and lymphomas, carcinomas of epithelial cells and cancer of the gastrointestinal tract is, melanoma and osteosarcoma;

- alopecia of various origins, in particular alopecia caused by chemotherapy or irradiation;

- immune diseases such as autoimmune disease, sugar diabetes, multiple sclerosis, lupus and diseases like lupus, asthma, glomerulonephritis; selective dysfunctions of the immune system such as AIDS, immune rejection;

- diseases of the endocrine system;

- diseases characterized by abnormal control of intracellular calcium, pathologies involving calcium metabolism, such as ischemia of the muscles;

- vitamin D deficiency and other disorders of homeostasis of minerals in plasma or bones, such as rickets, osteomalacia, in particular, women in menopause, renal osteodystrophy or disorders of parathyroid function;

- diseases 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 preferably be used in combination with retinoids, corticosteroids or estrogens, combined with antioxidants, alpha-hydroxy acid, a beta hydroxy acid or alpha-keto acid or their derivatives, with blockers of ion channels, as well as in combination with other known and drugs interacting on the immune system (eg, cyclosporine, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth regulators...).

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

Under the antioxidants understand, for example, alpha-tocopherol, superoxide dismutase, original or some chelates metals.

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

Under a beta hydroxy acid (Aha) see, for example, salicylic acid and its salts, amides or esters.

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

The object of the present invention is a pharmaceutical composition comprising at least one connection, which is defined above.

Introduction compounds according to the invention can be enteral, parenteral, local or intraocular way.

When enteral introduction the pharmaceutical compositions may take the form of tablets, gelatin capsules, pills, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles, involved the gradual selection of medicines. In parenteral administration, the pharmaceutical compositions may take the form of solutions or suspensions for perfusion or for injection. Compounds according to the invention are, in General, a daily dose of approximately from 0.001 μg/kg to 1000 μg/kg, and preferably approximately from 0.01 μg/kg to 100 μg/kg in one or three lots.

The local application, the pharmaceutical compositions based on compounds according to the invention are used to treat skin and mucous membranes in the form of ointments, creams, jelly, sweets, impregnated swabs, solutions, gels, sprays, lotions or suspensions. They may also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric adhesive patches and hydrogels, carrying out a modified release of the active principle. These compositions for topical application in accordance with clinical guidelines can be either in solution or in solid form.

When intraocular method is used mainly eye drops.

These compositions for topical application or for intraocular injection include at least one compound according to the invention, the concentration of which is site is preferably from 0.0001 to 5% and even more preferably from 0.001 to 1% relative to the total weight of the composition.

Compounds according to the invention also find application in the cosmetic field, especially for body care and hair care, in particular for the treatment of skin, prone to acne, for fast hair growth against hair loss, for oily skin or oily hair, for protection against the harmful effects of the sun or for the treatment of physiologically dry skin, for preventing and/or combating aging of the skin under the action of light or time.

In the field of cosmetics compounds according to the invention can be preferably used in combination with retinoids, corticosteroids, in combination with antioxidants, alpha-hydroxy or alpha-keto acid or their derivatives, as well as blockers of ion channels.

Various products used in combination with the compounds according to the present invention described above.

Thus, the present invention relates to a cosmetic composition containing in a cosmetically acceptable medium, at least one connection, which is defined above. Specified cosmetic composition may in particular be in the form of cream, milk, lotion, gel, microspheres or nanospheres or lipid or polymeric vesicles, a soap or shampoo.

Compounds according to the invention are cosmetic compositions in amounts of from 0.001 to 3% of the total weight of the composition.

Pharmaceutical and cosmetic compositions according to the invention can additionally contain inert or pharmacodynamic or cosmetically active additives or combinations thereof and, in particular, wetting; depigmenting agents, such as hydroquinone, azelaic acid, caffeic acid or kojic acid; softeners; hydrating agents such as glycerol, polyethylene glycol PEG 400, thiomorpholine and its derivatives or urea; protivoseborainey or protivougrevoe agents, such as S-carboxymethylcysteine, S-benzylester, 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-isothiazolin-3-ones; agents promoting hair growth, such as Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and phenytoin (5,4-diphenyl-imidazolidin-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and, in particular, β-carotene; protivopolozhnye agents, such as anthralin and its derivatives and, finally, eicosa-5,8,11,14-tetragonia and eicosa-5,8,11-TRINOVA acids, their esters and amides.

Compositions according to the invention can also content the TB agents, improves taste, preservatives such as esters of para-oksibenzoynoy acid, stabilizers, agents, regulators humidity, agents, pH regulators, osmotic pressure modifiers, emulsifiers, filters, UV-a and UV-b, antioxidants, such as alpha-tocopherol, butylhydroxyanisole or equivalent.

As an illustration, examples of preparing compounds according to the invention, which do not limit the invention and various specific compositions based on these compounds and examples of testing the biological activity of the compounds according to the invention.

Example 1

(4E,6E)-7-{3-[2-(3,4-Bis-hydroxymethyl-phenyl)ethyl]phenyl}-3-ethyl-Nona-4,6-Dien-3-ol

a) 2-(3-Bromophenyl)-2-ethyl-[1,3]dioxolane

15 g (70 mmol) of 3-bromopropiophenone dissolved in 250 ml of toluene and add 20 ml (350 mmol) of ethylene glycol and added 660 mg (3.5 mmol) of paratoluenesulfonyl. Supply installation nozzle Dean-stark, and the reaction mixture is refluxed for 20 hours Cooled, treated with a solution of potassium bicarbonate and extracted the product with ethyl ether; the target product is pure, does not require additional purification and received in the form of a yellowish oil (yield 17.8 g or 99%).

b) 3-(2-Ethyl-[1,3]dioxolane-2-yl)benzaldehyde

17.8 g (70 mmol) of 2-(3-bramp the Nile)-2-ethyl-[1,3]dioxolane was dissolved in 300 ml of THF and cooled the mixture to a temperature of -78° C. Slowly add 34 ml (85 mmol) of a 2.5 M solution of utility and stirred the mixture for 30 minutes. Then add to 8.1 ml (105 mmol) of DMF and heated the mixture to 0°and then treated with a saturated solution of ammonium chloride. After extraction using ethyl ether, and get targeted aldehyde in the form of a yellow oil (yield 14 g or 97%).

(C) Dimethyl ether 4-{(E)-2-[3-(2-ethyl-[1,3]dioxolane-2-yl)phenylphenyl)phthalic acid

10.3 g (30 mmol) of dimethyl 4-(diethoxyphosphoryloxy)phthalic acid are dissolved in 100 ml of anhydrous THF and cooling the mixture to 0°C. Portions added 3.4 g (30 mmol) of potassium tert-butylate and the mixture is stirred for 30 minutes. Then added dropwise a solution of 5.6 g (27,3 mmol) 3-(2-ethyl-[1,3]dioxolane-2-yl)benzaldehyde and the mixture is stirred for 2 hours at a temperature of 0°C. After normal processing of the residue purified by chromatography on a column filled with silica (eluent heptane 80 - ethyl acetate 20). Receive a yellow oil (yield 9.6 g or 89%).

d) Dimethyl 4-{2-[3-(2-ethyl-[1,3]dioxolane-2-yl)phenyl]ethyl}phthalic acid

9.5 g (24 mmol) of dimethyl 4-{(E)-2-[3-(2-ethyl-[1,3]dioxolane-2-yl)phenyl]vinyl}phthalic acid dissolved in a mixture of 120 ml of ethyl acetate and 5 ml of triethylamine. The reaction mixture Tegaserod by blowing with nitrogen for 10 minutes, then we use the t 1 g 5% palladium on coal. Next, the reaction mixture is heated to a temperature of 80°and within 4 hours hydronaut under the hydrogen pressure of 4 bar. The residue is purified by chromatography on a column filled with silica. Receive a colorless oil (yield 7.5 g or 80%).

e) (4-{2-[3-(2-Ethyl-[1,3]dioxolane-2-yl)phenyl]ethyl}-2-hydroxymethylene)methanol

2.9 g (75 mmol) of socialogical suspended in 20 ml of ethyl ether. Add dropwise a solution of 7.5 g (19 mmol) of dimethyl 4-{2-[3-(2-ethyl-[1,3]dioxolane-2-yl)phenyl]ethyl}phthalic acid in 100 ml of ethyl ether. After stirring for 20 minutes at room temperature, the reaction mixture was added 15 ml of water, 1.5 ml 15%aqueous sodium hydroxide solution (4.5 ml of water, then the mixture is filtered and concentrated under reduced pressure. Receive a colorless oil (yield 6.4 g or 99%).

f) 1-{3-[2-(3,4-Bis-hydroxymethylene)ethyl]phenyl}propane-1-he

6.4 g (to 18.7 mmol) (4-{2-[3-(2-ethyl-[1,3]dioxolane-2-yl)phenyl]ethyl}-2-hydroxymethylene)methanol dissolved in a mixture of 40 ml water and 40 ml of acetone. Add 650 mg paratoluenesulfonyl and stirred the mixture for 5 hours. After normal processing of the target product is pure, does not require additional purification; obtained as a colourless oil (yield to 5.57 g or 100%).

g) 1-(3-{2-[3,4-Bis-(tert-butyldimethylsilyloxy)-phenyl]ethyl}phenyl)propane-1-it 5.5 g (18.5 mmol) of 1-{3-[2-(3,4-bis-is hydroxymethylene)ethyl]phenyl}propane-1-dissolve it in 50 ml of anhydrous dimethylformamide and cooled the mixture to 0° C. Add 6.7 g (45 mmol) of tert-butyldimethylchlorosilane and 3.5 g (52 mmol) of imidazole. Allow the mixture to warm to room temperature and stirred for another 2 hours. After treatment with a saturated solution of ammonium chloride and extraction using ethyl acetate the combined organic phases are washed with water, dried and concentrated under reduced pressure. Receive a colorless oil (yield 9.6 g or 99%).

h) Ethyl ester of (E)-3-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)Penta-2-ene acid

11,1 ml (56 mmol) of triethylphosphite dissolved in 100 ml of THF. Then add 2.2 g (55 mmol) of 60%sodium hydride and stirred the mixture for 30 minutes at room temperature. Then was added dropwise a solution of 9.5 g (18 mmol) of 1-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)propane-1-it in 100 ml of THF. The mixture is shaken for 6 hours, then treated with water and extracted using ethyl acetate. The resulting residue is purified by chromatography on silica gel (eluent ethyl acetate 10 - heptane 90). Receive a yellow oil (yield 5.8 g, 56%).

i) (E)-3-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)Penta-2-EN-1-ol

0.75 g (19 mmol) of socialogical suspended in 10 ml of ethyl ether. Was added dropwise a solution of 5.6 g (9.6 mmol) of ethyl ester of (E)-3-(3-{2-[3,4-bis-(tert-butyldimethylsilyl oxymethyl)phenyl]ethyl}phenyl)Penta-2-ene acid in 50 ml of ethyl ether. Stirred for 20 minutes at room temperature and the reaction mixture is treated by adding 0.75 ml of water, 0.75 ml of a 15%aqueous solution of sodium hydroxide in 1.5 ml of water, then filtered and concentrated under reduced pressure. Receive a colorless oil (yield of 5.26 g or 99%).

j) (E)-3-(3-{2-[3,4-Bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)Penta-2-enal

2.8 g (5 mmol) of (E)-3-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)Penta-2-EN-1-ol dissolved in 50 ml of dichloromethane. Added 4.3 g (50 mmol) of manganese dioxide and the mixture is stirred for 12 hours, then filtered and concentrated under reduced pressure. The target product is obtained in the form of a yellow oil (yield 2.8 g or 100%).

k) Diethyl ester of (2E,4E)-5-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)hepta-2,4-diene acid

1.3 ml (6.5 mmol) of triethylphosphite dissolved in 20 ml of THF. Then add 260 mg (6.5 mmol) of 60%sodium hydride and the mixture is stirred for 30 minutes at room temperature. Then add dropwise a solution of 2.8 g (5 mmol) of (E)-3-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]-ethyl}phenyl)Penta-2-inala in 30 ml of THF. The mixture is stirred for 6 hours, then treated with water and extracted with ethyl acetate. The resulting residue is purified by chromatography on silica gel (eluent ethyl acetate 10 - heptane 90). We shall have a yellow oil (yield 2,52 g (81%).

l) (4E,6E)-7-{3-[2-(3,4-Bis-hydroxymethylene)ethyl]phenyl}-3-etylene-4,6-Dien-3-ol

1.7 g of diethyl ether (2.7 mmol) of (2E,4E)-5-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)hepta-2,4-diene acid are dissolved in 120 ml of anhydrous THF and the mixture is cooled to a temperature of -78°C. Type of 13.5 ml (13.5 mmol) of a solution atellite (1.0-1.5 M) and the mixture is stirred at the same temperature for 1 hour, then allow the mixture to warm to 0°and the mixture is treated with a saturated solution of ammonium chloride. The resulting residue is dissolved in 50 ml of THF, are then added to 6.5 ml (6.5 mmol) of a solution of tetrabutylammonium fluoride. After stirring for 30 minutes, and normal processing of the obtained residue is purified by chromatography on a column filled with silica. Get the target product as a colorless oil (yield 200 mg or 18%).

1H NMR (DMSO): of 0.82 (t, 6H, J=7.5 Hz); to 0.89 (t, 3H, J=7.4 Hz); 1.41 to 1,53 (m, 4H); to 2.41 (q, 2H, J=7.4 Hz); and 2.83 (s, 4H); 4,01 (s, 1H); to 4.41 (t, 2H, J=8 Hz); of 4.45 (t, 2H, J=8 Hz); 4,94-to 4.98 (m, 2H); of 6.31 (d, 1H, J=15,0 Hz); 6,46 (d, 1H, J=11,0 Hz); 7,08-7,29 (m, 7H); 7,42 was 7.45 (m, 1H).

Example 2

(E)-6-[3-(3,4-Bis-hydroxymethyl-benzyloxy)phenyl]-1,1,1-Cryptor-2-trifluoromethyl-Oct-5-EN-3-in-2-ol

a) 3-(Tert-butyldimethylsilyloxy)benzaldehyde

Get analogously to example 1g, the interaction of 42.7 g (0,275 mol) tert-butyldimethylchlorosilane with 30.5 g (0.2 mol) of 3-hydroxybenzaldehyde and (20.4 g, 0,3 mol is) imidazole. After purification on a column filled with silica (dichloromethane 20 - heptane 80), receive a yellow oil (yield to 55.9 mg or 95%).

b) 1-[3-(Tert-butyldimethylsilyloxy)phenyl]propan-1-ol

50 g (0.21 mol) of 3-(tert-butyldimethylsilyloxy)-benzaldehyde are dissolved in 500 ml of ethyl ether and cooling the mixture to 0°C. Slowly add 80 ml (0.24 mol) 3.0 M solution ethylacetamide and stirred the mixture for 5 hours. After normal processing of the obtained residue is purified by chromatography on a column filled with silica (eluent ethyl acetate 20-heptane 80). Receive a colorless oil (yield of 45.8 g or 82%).

c) 1-[3-(tert-butyldimethylsilyloxy)phenyl]propane-1-he

Get analogously to example 1j, the interaction of 45 g (to 0.17 mol) of 1-[3-(tert-butyldimethylsilyloxy)phenyl]propan-1-ol with 148 g (1.7 mol) of manganese dioxide. Receive a yellow oil (yield 45 g or 100%).

d) Ethyl ester of (E)-3-[3-(tert-butyldimethylsilyloxy)phenyl]Penta-2-ene acid

22.5 ml (113 mmol) of triethylphosphite dissolved in 100 ml of THF. Then add 4.5 g (113 mmol) of 60%sodium hydride and the mixture is stirred for 30 minutes at room temperature. Add dropwise a solution of 20 g (75,6 mmol) of 3-(tert-butyldimethylsilyloxy)propane-1-it in 100 ml of THF. The mixture is stirred for 6 hours, then treated with water and extracted with of etelaat the om. The resulting residue is purified by chromatography on silica gel (eluent ethyl acetate 10 - heptane 90). Receive a yellow oil (yield 7.6 g or 30%).

(e) (E)-3-[3-(tert-butyldimethylsilyloxy)phenyl)Penta-2-EN-1-ol

Get analogously to example 1E, the interaction of 7.6 g (23 mmol) of ethyl ester of (E)-3-[3-(tert-butyldimethylsilyloxy)finalment-2-ene acid of 1.05 g (25 mmol) of socialogical. Receive a colorless oil (yield 6.7 g or 100%).

f) (E)-3-[3-(tert-butyldimethylsilyloxy)phenyl)Penta-2-EN-1-al

Get analogously to example 1j, the interaction of 6.7 g (23 mmol) of (E)-3-[3-(tert-butyldimethylsilyloxy)phenyl)Penta-2-EN-1-ol with 10 g (115 mmol) of manganese dioxide. Receive a yellow oil (yield 4.7 g or 71%).

g) Tert-butyl[3-((E)-4,4-dibromo-1-ethyl-buta-1,3-dienyl)phenoxy]dimethylsilane

1,17 g (18 mmol) of powdered zinc, 4.7 g (18 mmol) of triphenylphosphine and 5.9 g (18 mmol) chetyrehpostovye carbon is stirred for 45 minutes in 150 ml of dichloromethane. Add dropwise a solution of 2.6 g (9 mmol) of (E)-3-[3-(tert-butyldimethylsilyloxy)phenyl)Penta-2-EN-1-al in 10 ml of dichloromethane. The reaction mixture is stirred for 1 hour, then extracted with a mixture of water and dichloromethane. The residue is filtered over a column filled with silica (eluent dichloromethane). Receive a yellow oil (yield of 3.3 g (83%).

h) Tert-butyl[3-((E)-1-ethyl-but-1-EN-3-inyl)phenoxy]dim tensilon

3.2 g (7.2 mmol) of tert-butyl[3-((E)-4,4-dibromo-1-ethyl-buta-1,3-dienyl)phenoxy]dimethylsilane dissolved in 50 ml and cooling the mixture to -78°C. Add 5.7 ml (14.4 mmol) of a 2.5 M solution of utility and stirred the mixture for 2 hours, and then treated her with a saturated solution of ammonium chloride. The residue is purified by chromatography on a column filled with silica. Receive a yellow oil (yield 1.0 g or 49%).

i) 3-((E)-1-ethyl-but-1-EN-3-inyl)phenol

1 g (3.5 mmol) of tert-butyl[3-((E)-1-ethyl-but-1-EN-3-inyl)phenoxy]dimethylsilane dissolved in 50 ml of THF and added dropwise to 3.8 ml (38 mmol) of 1.0 M solution of tetrabutylammonium fluoride. The mixture is stirred for 30 minutes, then treated with a saturated solution of ammonium chloride and extracted with ethyl acetate. Receive a yellow oil (yield 690 mg, or 100%).

j) 2-Benzoyloxymethyl-5-[3-((E)-1-ethyl-but-1-EN-3-inyl)phenoxymethyl]benzyl benzoate

610 mg (3.5 mmol) of 3-((E)-1-ethyl-but-1-EN-3-inyl)of phenol are dissolved in 80 ml of dimethylformamide. Add 150 mg (3.7 mmol) of sodium hydride and stirred the mixture at room temperature. Then add 1.5 g (6.2 mmol) of 2-benzoyloxymethyl-5-bromomethyl-benzyl benzoate and stirred the mixture for 2 hours. After conventional treatment and purification by chromatography on a column of silica gel get colorless oil (yield 1.66 g (88%).

k) 1-(3,4-Bis-tert-buildiers is Maximilianstrasse)-3-((E)-1-ethyl-but-1-EN-3-inyl)benzene

1.6 g (3 mmol) 2-benzoyloxymethyl-5-[3-((E)-1-ethyl-but-1-EN-3-inyl)phenoxymethyl]benzylbenzoate dissolved in 15 ml of 2%aqueous solution of potassium carbonate in methanol. The reaction mixture is stirred for 2 hours, then treated with a saturated solution of ammonium chloride and extracted with ethyl acetate. The resulting residue is dissolved in 20 ml of anhydrous DMF, added 900 mg (6 mmol) of tert-butyldimethylchlorosilane and 450 mg (6.6 mmol) of imidazole. The mixture is stirred for 10 hours at room temperature. After normal processing of the obtained residue is purified by chromatography on a column filled with silica (eluent heptane 85 - ethyl acetate 85). Get an orange oil (yield of 1.16 g or 70%).

l) (E)-6-{3-[3,4-Bis-(tert-butyldimethylsilyloxy)benzyloxy]phenyl}-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol

of 1.16 g (2.1 mmol) of 1-(3,4-bis-tert-butyldimethylsilyloxy-benzyloxy)-3-((E)-1-ethyl-but-1-EN-3-inyl)benzene are dissolved in 30 ml anhydrous THF and cooled the mixture to a temperature of -78°C. is Added dropwise 930 μl (2.3 mmol) of a 2.5 M solution of utility and stirred the mixture for 15 minutes. Through the solution for 10 minutes bubbled HEXAFLUOROACETONE (gaseous) and the reaction mixture was treated with a saturated solution of ammonium chloride. The resulting residue is purified by chromatography on a column filled with silica (E. went heptane 80 - the ethyl acetate 20). Receive a yellow oil (yield 1.35 g or 89%).

m) (E)-6-[3-(3,4-Bis-hydroxymethylbenzene)phenyl]-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol

Get analogously to example 2i, the interaction of 350 mg (0.5 mmol) of (E)-6-{3-[3,4-bis-(tert-butyldimethylsilyloxy)benzyloxy]phenyl}-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol with 1.2 ml (1.2 mmol) of 1.0 M solution of tetrabutylammonium fluoride. Receive a colorless oil (yield 210 mg, or 80%).

1H NMR (CDCl3): of 1.05 (t, 3H, J=7.4 Hz); of 2.72 (q, 2H, J=7.4 Hz); 4,74 (s, 4H); of 5.05 (s, 2H); 5,69 (s, 1H); 6,91-7,01 (m, 3H); from 7.24 (m, 1H); 7,37 (s, 2H); 7,42 (s, 1H).

Example 3

(3E,5E)-6-[3-(3,4-Bis-hydroxymethylbenzene)phenyl]-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol

a) (3E,5E)-6-{3-[3,4-Bis-(tert-butyldimethylsilyloxy)benzyloxy]phenyl}-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol

135 mg (3,55 mmol) lydialydia dissolved in 10 ml anhydrous THF. Add 385 mg (7.1 mmol) of sodium methylate and the mixture is stirred for 10 minutes at room temperature. Add dropwise a solution of 860 mg (1.2 mmol) of (E)-6-{3-[3,4-bis-(tert-butyldimethylsilyloxy)benzyloxy]phenyl}-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol (described in example 21) in 7 ml of THF. The mixture is refluxed for 2 hours, then treated with sequential addition of 120 μl of water, 120 μl of 15%NaOH solution and 35 μl of water. After filtrational viscous yellowish oil (yield 650 mg or 76%).

b) (3E,5E)-6-[3-[3,4-Bis-hydroxymethylbenzene)phenyl]-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol

Get as in example 2m, interaction 640 mg (0.89 mmol) of (3E,5E)-6-{3-[3,4-bis-(tert-butyldimethylsilyloxy)benzyloxy]phenyl}-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol with 2.1 ml (2.1 mmol) of 1.0 M solution of tetrabutylammonium fluoride. Receive a colorless oil (yield 260 mg or 60%).

1NNMR (DMSO): 1,10 (t, 3H, J=7.5 Hz); to 2.65 (q, 2H, J=7.4 Hz); 4,55 (t, 4H, J=5,2 Hz); 5.08 to to 5.17 (m, 4H); 6,05 (d, 1H, J=15.1 Hz); only 6.64 (d, 1H, J=11.2 Hz); of 6.96 (DD, 1H, J1=11.2 Hz, J2=2 Hz); 7,08-7,51 (m, 6H); of 8.27 (s, 1H).

Example 4

(E)-6-{3-[2-(3,4-Bis-hydroxymethylene)ethyl]phenyl}-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol

a) (E)-1-(3-{2-[3,4-Bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)-4,4-dibromo-1-ethyl-buta-1,3-Dien

Get analogously to example 2g, interaction 9 g (16.3 mmol) of (E)-3-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)Penta-2-inala (obtained in example 1j) with 2.1 g (32.5 mmol) of powdered zinc, 8.5 g (32.5 mmol) of triphenylphosphine and 108 g (32.5 mmol) chetyrehpostovye carbon. Receive a yellow oil (yield 11.3 g or 98%).

b) (E)-1-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)-1-ethyl-but-1-EN-3-in

Get analogously to example 2h, interaction 11.3 g (15.9 mmol) of (E)-1-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)-4,4-dibromo-1-ethyl-buta-1,3-dienes 128 ml (32 mmol) of a 2.5 M solution of utility. Receive a yellow oil (yield 8.5 g or 97%).

c) (E)-6-(3-{2-[3,4-Bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol

Get analogously to example 21, the interaction of 5 g (9.1 mmol) of (E)-1-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)-1-ethyl-but-1-EN-3-in with 4 ml (10 mmol) of a 2.5 M solution of utility and bubbling with HEXAFLUOROACETONE. Get the target product as a yellow oil (yield 3.7 g or 57%).

(d) (E)-6-(3-[2-(3,4-Bis-hydroxymethylene)ethyl]phenyl)-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol

Get as in example 2m, interaction 1 g (1.4 mmol) of (E)-6-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol with 3.3 ml (3.3 mmol) of 1.0 M solution of tetrabutylammonium fluoride. Get a solid yellowish substance (TPL=123°s; output 570 mg or 84%).

1NNMR (CDCl3): of 1.05 (t, 3H, J=7.5 Hz); a 2.75 (q, 2H, J=7.5 Hz); 2,92 (s, 4H); 4,69 (s, 4H); 5,67 (s, 1H); 7,05-7,31 (m, 7H).

Example 5

(3E,5E)-6-{3-[2-(3,4-Bis-hydroxymethylene)ethyl]phenyl}-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol

a) (3E,5E)-6-(3-{2-[3,4-Bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol

Get analogously to example 3A, the interaction of 2.5 g (3.5 mmol) of (E)-6-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}Fe who yl)-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol (described in example 4C) from 400 mg (10.4 mmol) of socialogical and 1.13 g (21 mmol) of sodium methylate. Receive a yellow oil (yield 1.27 g or 51%).

b) (3E,5E)-6-{3-[2-(3,4-Bis-hydroxymethylene)ethyl]phenyl}-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol

Get as in example 2m, the interaction of 1.2 g (1,67 mmol) of (3E,5E)-6-(3-{2-[3,4-bis-(tert-butyldimethylsilyloxy)phenyl]ethyl}phenyl)-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol with 4 ml (4 mmol) of 1.0 M solution of tetrabutylammonium fluoride. Get a solid white color (TPL=104°s; output 715 mg or 87%).

1NNMR (DMSO): of 1.02 (t, 3H, J=7.5 Hz); of 2.66 (q, 2H, J=7.5 Hz); at 2.93 (s, 4H); 4,71 (s, 2H); 4.72 in (s, 2H); 5,79 (d, 1H, J=15,0 Hz); 6,24 (d, 1H, J=11,0 Hz); 7,08-7,30 (m, 8H).

Example 6

Examples of composition

1) For oral administration

(a) Prepare the following composition in the form of tablets weighing 0.2 g

The compound according to example 10.005 g
Gelatinizing starch0,065 g
Microcrystalline cellulose0.075 g
Lactose0,050 g
The manganese stearate0.005 g

For the treatment of ichthyosis adult appointed from 1 to 3 tablets per day for 1 to 12 months depending on the complexity of a particular case.

(b) Preparing a suspension for oral administration designed for packaging ampoules of 5 the l

The compound according to example 20,050 mg
Glycerin0,500 g
70%sorbitol0,500 g
The sodium saccharinate0,010 g
Methyl ester parahydroxybenzoic acid0,040 g
Flavouring agent in sufficient quantity
Purified water in sufficient quantity to amount5 ml

To treat acne adult appointed 1 ampoule daily for 1 to 12 months depending on the complexity of a particular case.

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

The compound according to example 40,0001 mg
Corn starchto 0.060 g
Lactose in sufficient quantities to weight0,300 g

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

For the treatment of psoriasis adults appoint 1 gelatin capsule per day for 1 to 12 months.

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

The compound according to example 50.02 mg
Cyclosporine0,050 g
Corn starchto 0.060 g
Lactose in sufficient quantities to weight0,300 g

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

For the treatment of psoriasis adults appoint 1 gelatin capsule per day for 1 to 12 months.

2) For applying topical by

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

The compound according to example 30,100 g
The mixture of emulsifying lanolin alcohols, waxes and
refined oils manufactured by the company BDF
called "Eucurine anhydre"39,900 g
Methyl ester parahydroxybenzoic acid0.075 g
Propyl ester parahydroxybenzoic acid0.075 g
Sterile demineralized water in sufficient
up weight100,000 g

Specified the cream is applied on the skin affected by psoriasis, from 1 to 2 times a day for 1 to 12 m the months.

(b) Preparing a gel by applying the following composition:

The compound according to example 10.001 g
Erythromycin (base)4,000 g
Equivalent0,050 g
Hydroxypropylcellulose, manufactured by the company
Hercules under the name "KLUCEL HF"2,000 g
Ethanol (95°) in sufficient quantity to weight100,000 g

The specified gel applied to the skin affected by dermatitis or acne, from 1 to 3 times a day for 6 to 12 weeks depending on the complexity of a particular case.

(C) Prepare protivoseborainey lotion, applying a mixture of the following ingredients:

The compound according to example 20,030 g
Propylene glycol5,000 g
Equivalent0,100 g
Ethanol (95°) in sufficient quantity to weight100,000 g

Specified lotion is applied 2 times a day on hair affected by seborrhea, and after 2 to 6 weeks to ascertain significant improvement.

(d) Preparing a cosmetic composition intended to use the tion against harmful effects of the sun, applying a mixture of the following ingredients:

The compound according to example 21,000 g
Benzylideneamino4,000 g
Triglycerides of fatty acids31,000 g
Glycerol monostearate6,000 g
Stearic acid2,000 g
Cetyl alcohol1,200 g
Lanolin4,000 g
Preservatives0,300 g
Propylene glycol2,000 g
Triethanolamine0,500 g
Perfume0.400 g
Demineralized water in sufficient
up weight100,000 g

The above composition is applied daily, it helps to fight against aging of the skin under the action of light.

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

The compound according to example 30,500 g
Retinology acid0,020 g
Cetyl alcohol4,000 g
Glycerol monostearate2,500 g
Propyl ether Parag what droxybenzoic acid 0.075 g
Stearate PEG 502,500 g
Oil Karitu9,200 g
Propylene glycol2,000 g
Methyl ester parahydroxybenzoic acid0.075 g
Sterile demineralized water
sufficient quantity to weight100,000 g

Specified the cream is applied on the skin affected by psoriasis, from 1 to 2 times a day for 30 days to treat acute and unlimited time to maintain the skin in good condition.

(f) Preparing a gel for topical application, using a mixture of the following ingredients:

The compound according to example 40,050 g
Ethanol43,000 g
Alpha-tocopherol0,050 g
Carboxyvinyl polymer produced under
the name "Carbopol 941" by the company "Goodrich"0,500 g
20%aqueous solution of triethanolamine3,800 g
Water9,300 g
Propylene glycol in sufficient quantities to weight100,000 g

The specified gel is used to treat acne 1 to 3 times on the HB within 6 to 12 weeks depending on the complexity of a particular case.

(g) Prepare a lotion against hair loss and for fast hair growth by applying a mixture of the following ingredients:

The compound according to example 30.05 g
The compound, produced under the name "Minoxidil"1,00 g
Propylene glycol20,00 g
Ethanol34,92 g
Polyethylene glycol (molecular weight=400)40,00 g
Butylhydroxyanisole0.01 g
Equivalent0.02 g
Water in sufficient quantity to weight100,00 g

Specified lotion is applied to hair, prone to hair loss, from 1 to 2 times a day for 3 months and unlimited time to maintain the hair in good condition.

(h) Prepare the cream against acne by applying a mixture of the following ingredients:

The compound according to example 50,050 g
Retinology acid0,010 g
A mixture of glycerol stearates and polyethylene glycol
(75 mol)sold under the name
"Gelot 64" company is th "GATTEFOSSE" 15,000 g
Stone fruit oil, polyoxyethylenated
6 moles of ethylene oxide, marketed under the name
"Labrafil M2 130 CS" by the company "GATTEFOSSE"8,000 g
Perhydrosqualene10,000 g
Preservatives in sufficient quantity
Polyethylene glycol (molecular weight=400)8,000 g
The disodium salt of ethylenediaminetetraacetic acid0,050
Purified water in sufficient quantities to weight100,000 g

Specified the cream is applied on the skin affected by dermatitis or acne, from 1 to 3 times a day for 6 to 12 weeks.

(i) Prepare the cream of type oil-in-water, using the following structure:

The compound according to example 40,020 g
17-valerate betamethasone0,050 g
S-carboxymethylcysteine3,000 g
The polyoxyethylene stearate
(40 mol of ethylene oxide)released
under the name "Myrj 51" company "ATLAS"4,000 g
Monolaurate sorbitan, Polyak ethylenically
20 moles of ethylene oxide, marketed under the name
"Tween 20" by "ATLAS"1,800 g
A mixture of mono - and distearate glycerol produced
called "Guluol" by the company "GATTEFOSSE"4,200 g
Propylene glycol10,000 g
Butylhydroxyanisole0,010 g
Equivalent0,020 g
Cetostearyl alcohol6,200 g
Preservatives in sufficient quantity
Perhydrosqualene18,000 g
Kapralova-mixture of capric triglyceride,
marketed under the name "Miglyol 8 12"
company "DYNAMIT NOBEL"4,000 g
Triethanolamine (99% wt.)2,500 g
Water in sufficient quantity to weight100,000 g

Specified the 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:

Lactic acid5,000 g
Conn is out according to example 1 0,020 g
The polyoxyethylene stearate (40 mol of oxide
ethylene), marketed under the name "Myrj 52"
the company "ATLAS"4,000 g
Monolaurate sorbitan, polyoxyethylenated
20 moles of ethylene oxide, sold under the
the name "Tween 20" by "ATLAS"1,800 g
A mixture of mono - and distearate glycerol
marketed under the name "Guluol"
the company "GATTEFOSSE"4,200 g
Propylene glycol10,000 g
Butylhydroxyanisole0,010 g
Equivalent0,020 g
Cetostearyl alcohol6,200 g
Preservatives in sufficient quantity
Perhydrosqualene18,000 g
Kapralova-mixture of capric triglyceride,
marketed under the name "Miglyol 8 12"
company "DYNAMIT NOBEL"4,000 g
Water in sufficient quantity to weight100,000 g

Specified the cream is applied 1 time per day; it helps to fight aging of the skin under the action of light or time.

(k) Prepare the following anhydrous ointment:

The compound according to example 15,000 g
Vaseline oil50,00 g
Butylhydroxytoluene0,050 g
White petrolatum in sufficient quantity100 g

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

3) To implant in the site of lesion

(a) Prepare the following composition:

The compound according to example 20.002 g
Etiloleat in sufficient quantity10 g

In the treatment of malignant melanoma composition is administered to an adult person with a frequency from 1 to 7 times per week for 1 to 12 months.

(b) Prepare the following composition:

The compound according to example 10,050 g
Olive oil in sufficient quantity2 g

In the treatment of basal cell carcinoma composition is administered to an adult person with a frequency from 1 to 7 times per week in ECENA from 1 to 12 months.

(c) Prepare the following composition:

The compound according to example 30.1 mg
Sesame oil in sufficient quantity2 g

In the treatment of spinal cell carcinoma composition is administered to an adult person with a frequency from 1 to 7 times per week for 1 to 12 months.

(d) Prepare the following composition:

The compound according to example 40.001 mg
Methylbenzoate in sufficient quantity10 g

In the treatment of carcinoma of the colon composition is administered to an adult person with a frequency from 1 to 7 times per week for 1 to 12 months.

4) For intravenous injection

(a) Prepare the following lipid emulsion for injection:

The compound according to example 40.001 mg
Soybean oil10,000 g
The phospholipid eggs1,200 g
Glycerin2,500 g
Water for injection
in sufficient quantity to weight100,000 g

In the treatment of psoriasis, the composition is administered to an adult person with a frequency from 1 to 7 RA is a week for 1 to 12 months.

(b) Prepare the following lipid emulsion for injection:

The compound according to example 10,010 g
Cottonseed oil10,000 g
Soy lecithin0,750 g
Sorbitol5,000 g
DL-alpha-tocopherol0,100 g
Water for injection
in sufficient quantity to weight100,000 g

In the treatment of ichthyosis, the composition is administered to an adult person with a frequency from 1 to 7 times per week for 1 to 12 months.

(C) Prepare the following lipid emulsion for injection:

The compound according to example 20.001 g
Soybean oil15,000 g
Acetylene monoglycerides10,000 g
Pluronic F-1081,000 g
Glycerin2,500 g
Water for injection
in sufficient quantity to weight100,000 g

In the treatment of leukemia, the composition is administered to an adult person with a frequency from 1 to 7 times per week for 1 to 12 months.

(d) Prepare the following mixed micellar to the impositio:

The compound according to example 20.001 g
Lecithin16,930 g
Glikoholeva acid8,850 g
Water for injection
in sufficient quantity to weight100,000 g

In the treatment of malignant melanoma composition is administered to an adult person with a frequency from 1 to 7 times per week for 1 to 12 months.

(e) Prepare the following composition based on cyclodextrin:

The compound according to example 30.1 mg
β-cyclodextrin0,100 g
Water for injection
in sufficient quantity to weight100,00 g

To prevent rejection of the graft composition is administered to an adult person with a frequency from 1 to 7 times per week for 1 to 12 months.

(f) Prepare the following composition based on cyclodextrin:

The compound according to example0,010 g
2-hydroxypropylcellulose0,100 g
Water for injection
in d is quite up weight 100,00 g

In the treatment of kidney cancer, the composition is administered to an adult person with a frequency from 1 to 7 times per week for 1 to 12 months.

Example 7

Example testing the biological activity of the compounds according to the invention: the potential of transactivate

Agonistic activity of VDR was investigated on cell line HeLa by contrastedly vector expression of the receptor VDR and plasmid-carrier p240Hase-CAT, which contains the region from -1399 to +76 promoter of 24-hydroxylase in rats, cloned before gene encoding chloramphenicol-acetyl-transferase (CAT). After 18 hours after cotransfection on Wednesday introduced the investigational product. After 18 hours of processing carried out analysis of CAT activity in the cell lysate by the method of enzyme-linked immunosorbent assay ELISA (Enzyme Linked Measurement Sorbent Essay, test drug produced by the company Roche Molecular Biochemicals).

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

Table I
ConnectionAS nm
Example 139
Example 59 document D1124
Example 2 77
Example 80 document D1746
Example 37
Example 92 document D179
Example 416
Example 80 document D1746
Example 53
Example 60 document D1319

Each connection according to the invention compared with the connection, the closest in structure to the compound described in patent application WO 00/26167 (D1). To facilitate comparison, figure 5 and 6 are grouped structure of the compounds according to the invention and comparative examples of document D1. The results show significantly stronger activity of the compounds according to the invention in comparison with the compounds according to document D1. The difference between the two values IS considered as significant if it has a factor 3, preferably a factor of 5 and more preferably a factor of 10.

Example 8

Example of tests for determining the biological activity of compounds according to the invention: activity against proliferation of human keratinocytes

It is known that 1,25-dihydroxyvitamin according to document D3, called calcitriol, which corresponds to the natural vitamin D inhibits proliferation of cultured ke is atenolol person. Use the following method: normal human keratinocytes were seeded with a low density on the plate with 24 cells. After 4 hours the culture type of the investigated compounds. The culture is grown for 5 days and then determine the proliferation of keratinocytes by incorporating 5-bromo-2-deoxyuridine (BRdU) into DNA. Then the number of built-in 5-bromo-2-deoxyuridine determined by the method of enzyme-linked immunosorbent assay ELISA (preparation for the test is manufactured by Roche Molecular Biochemicals).

Data on the degree of inhibition effect of the compounds according to the invention and of calcitriol used as compounds for comparison on the proliferation of keratinocytes are shown in table II. The IC50 value represents the concentration of tested compound, which is 50% inhibited proliferation of keratinocytes.

These results allow us to detect for the compounds according to the invention inhibitory activity against proliferation of keratinocytes in the same range of values as for calcitriol (natural vitamin D). In addition, the results show significant differences between the compounds according to the invention and compounds most similar in structure to the compounds of the patent application D1. The difference is considered as significant between the two values AS if is and is, at least a factor 3, preferably a factor of 5 and more preferably a factor of 10.

Table II
ConnectionThe inhibition of proliferation AS*(nm)
Calcitriol14
Example 145
Example 59 document D11029
Example 2153
Example 80 document D1>10000 (not active)
Example 335
Example 92 document D199
Example 429
Example 80 document D1>10000 (not active)
Example 58
Example 60 document D11506
* Composition, for which there is 50%inhibition of proliferation of keratinocytes.

Example 9

Example of tests for determining the biological activity of compounds according to the invention: activity against HL60 cell differentiation

Calcitriol initiates the differentiation of promyelocytic leukaemia cells (HL60) on monocytes/macrophages. Specified inductive effect on differentiation is the I marker well characterize the cellular activity of vitamin D. One of the most important antibacterial products macrophages is hydrogen peroxide, which can be analyzed experimentally recovery NBT (tetrazole nitro-blue).

Use the following method: HL60 cells were seeded on a plate with 6 cells and then immediately treated with the studied compounds. The culture is grown for 4 days, the cells are then incubated together with turbolover ether ATP and NBT in a short period, and then calculate the differentiated cells, i.e. cells, positive action NBT.

Data on the extent of inducing impacts of the compounds according to the invention, as well as calcitrol used as a connection to compare the effects on differentiation of HL60 cells are shown in the following table.

Table III
ConnectionActivation of differentiation AU50*(nm)
Calcitriol7
(n=5)
Example 156
(n=3)
Example 59 document D1310
Example 37
(=2)
Example 55
(n=2)
* The concentration at which there is 50% of maximum response activation of differentiation.

These results show that examples 3 and 5 according to the invention have an activity of inducing differentiation of HL60 cells, similar to calcitriol.

Example 10

Example of tests for determining the biological activity of compounds according to the invention: induction of 24-hydroxylase in the test in vivo in mice SKH

24-hydroxylase is a cytochrome P450 enzyme, which hydroxylase 1,25-dihydroxyvitamin D3 (calcitriol) in position 24 and receive metabolite, 1,24,25-trihydroxybutane D3. The authors Voorhees and al. it has been shown (JID 1997. 108:513-518)that the gene expression of 24-hydroxylase was caused by calcitriol on human skin.

Therefore, agonistic activity to the receptor of vitamin D compounds according to the invention can be assessed in vivo by introduction of 24-hydroxylase SKH mouse.

Use the following method: mice XII only topical applied by a solution of the compound in ethanol with increasing concentrations.

Volume of 50 µl sample of the product or only a solvent is applied on the back of the mouse with a pipette.

Other mice SKH only topices who put them through a solution of calcitriol in ethanol with increasing concentrations. Volume of 50 µl sample of the product or only a solvent is applied on the back of the mouse with a pipette.

After 8 hours after local application of mouse death, take away the treated skin and the epidermis separated from the dermis. The number of ARNm 24-hydroxylase determined by the method of semi-quantitative PCR analysis. The results are normal, compared with expression of ARNm GAPDH, and values for different concentrations of calcitriol and for different investigated compounds according to the invention is expressed in the coefficient of induction compared to calcitriol.

The results are summarized in the following table IV:

Table IV

Expression of ARNm 24-hydroxylase
Analyzed

connection
Concentration % (weight/volume)The coefficient of induction in relation to ethanol
Calcitriol0,00016,7
Calcitriol0,00110,3
Calcitriol0,0120,1
Calcitriol0,126

These results show that calcitriol, administered by topical application, induces the mouse dose-dependent expression of ARNm 24-hydroxylase in the epidermis.

Biol the strategic activity of the compounds according to the invention is evaluated by comparing the coefficients of induction with the compounds according to the invention and of the coefficients of induction, received calcitriol. The results are presented in the following table V:

Table V
Analyzed

connection
Concentration, % (weight/volume)Induction, %, relative to the induction of calcitriol with a concentration of 0.01%
Calcitriol0,01100
Example 10,1108
Example 20,0158
Example 30,00159
Example 40,0189
Example 50,0003106

Thus, the results show that the examples according to the invention have activity comparable or superior (example 3) and 5) the activity of calcitriol.

1. Analogues of vitamin D, representing a compound selected from the group consisting of

-(E)-6-[3-(3,4-Bis-hydroxymethylbenzene)phenyl]-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol,

-(3E,5E)-6-[3-(3,4-Bis-hydroxymethylbenzene)phenyl]-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol,

-(E)-6-{3-[2-(3,4-Bis-hydroxymethylene)ethyl]phenyl}-1,1,1-Cryptor-2-trifloromethyl-5-ene-3-in-2-ol,

- (3E,5E)-6-{3-[2-(3,4-Bis-hydroxymethylene)ethyl]FeNi is}-1,1,1-Cryptor-2-cryptometrics-3,5-Dien-2-ol,

and the above compounds in which one or more hydroxyl groups have a protective group of the type -(C=O)-R, where R denotes a linear or branched alkyl radical containing 1-6 carbon atoms, or aryl radical containing 6 to 10 carbon atoms, or Uralkaliy radical containing 7 to 11 carbon atoms; the aryl radical or Uralkaliy radical may be substituted by one or two hydroxyl groups, alkoxygroup containing 1-3 carbon atoms, halogen atoms, nitro or amino groups.

2. Compounds according to claim 1, wherein the linear or branched alkyl radical containing 1-6 carbon atoms, selected from methyl, ethyl, ISO-propyl, tretbutylphenol or exiling radical.

3. Compounds according to claim 1, characterized in that the aryl radical containing 6 to 10 carbon atoms, selected from phenyl or afternova radical.

4. Compounds according to claim 1, characterized in that Aracely radical containing 7 to 11 carbon atoms, selected from benzyl or methylnaphthalene radical.

5. Compounds according to claim 1, characterized in that the halogen atom selected from a fluorine atom, bromine or chlorine.

6. Compounds according to any one of claims 1 to 5, with activity against the proliferation and differentiation of cells.

7. The use of compounds according to any one of claims 1 to 5 for the prigotovleniya drugs used to treat the following diseases:

dermatological diseases associated with disorders of keratinization, which is caused by the differentiation and proliferation of cells, such as acne vulgaris, comedones, acne, polymorphic, pink, nodular-cystic, nodular, senile, secondary acne such as solar, drug-induced or caused by occupational diseases, ichthyosis, idiotphone States, disease Daria (Darrier), Palmar-plantar keratoderma, leukoplakia and leukoplakia States, cutaneous or mucosal (oral mucosa) lichen;

dermatological diseases with inflammatory immuno-allergic component, accompanied or not accompanied by disorders of cell proliferation, as well as all forms of psoriasis, cutaneous, mucous or ungual, and psoriatic rheumatism and skin atopy, such as eczema, respiratory atopy or hypertrophy of the gums;

benign or malignant dermal or epidermal of proliteracy viral or non-viral origin, such as common warts, flat plane warts and barodawala epidermodysplasia, oral or flowering of multiple papillomas, lymphoma T; proliferate, which can be caused by UV radiation, in private the tee, in the case of basal and spinal cell epithelioma and precancerous skin diseases, such as keratoacanthoma;

immune dermatoses, such as lupus erythematosus, vesiculating immune diseases or collagen diseases, such as scleroderma;

dermatological or systemic diseases with an immunological component;

disorders of the sebaceous glands, such as acne affected Hyperborea or simple seborrhoea;

skin disorders caused by exposure to ultraviolet radiation, aging of the skin under the action of light or from time to time, pigmentations and actinic keratoses, or any pathologies associated with age ageing or aging under UV irradiation;

violations in the healing of scars or stretch marks;

inflammatory diseases such as arthritis, skin or systemic diseases of viral origin, such as the syndrome Kaposi (Kaposis);

ophthalmological disorders, in particular, Corporatio;

cancerous or precancerous lesions that can be caused by vitamin D receptors, such as breast cancer, leukemia, myelodysplasia syndrome and syndrome lymphoma, carcinoma cells malpighiales epithelium and cancer of the gastrointestinal tract, melanoma and osteosarcoma;

alopecia different origin is, in particular, alopecia caused by chemotherapy or radiation;

immune diseases such as autoimmune disease, sugar diabetes, multiple sclerosis, lupus and diseases like lupus, asthma, glomerulonephritis; selective dysfunctions of the immune system, for example, AIDS, immune rejection; diseases of the endocrine system;

diseases characterized by abnormal control of intracellular calcium, pathologies involving calcium metabolism, such as ischemia of the muscles;

vitamin D deficiency and other disorders of homeostasis of minerals in plasma or bones, such as rickets, osteomalacia, osteoporosis, particularly in women during menopause, renal osteodystrophy or disorders of parathyroid function;

diseases of the cardiovascular system such as arteriosclerosis or hypertension and non-insulin-dependent diabetes.

8. Pharmaceutical composition having activity against the proliferation and differentiation of cells, characterized in that it contains a pharmaceutically acceptable carrier, at least one of the compounds defined according to any one of claims 1 to 5.

9. The composition according to claim 8, characterized in that the amount of compound(s) according to claim 1 is 0.001-5% relative to the total weight of the composition.

10. Kosmet is ical composition, possessing activity against the proliferation and differentiation of cells, characterized in that it contains in a cosmetically acceptable medium, at least one of the compounds defined according to any one of claims 1 to 5.

11. The composition of claim 10, wherein the amount of compound(s) is 0.001-3% relative to the total weight of the composition.

12. The use of compounds as defined in any one of claims 1 to 5, as a cosmetic agent for body care and hair care.



 

Same patents:

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 invention relates to new tricyclic derivative of the formula (I), (Ia'), (Ib'), (Ig'), (If'), their salts and hydrates, which have immunosuppressive or anti-allergic activity, pharmaceutical compositions based on these compounds and to a method of suppressing immune response or treatment and/or prevention of allergic diseases

The invention relates to a method for separation of the enantiomers of racemic 3-(2-methoxyphenoxy)-1,2-propane diol and 3-(2-methylphenoxy)-1,2-propane diol, which can be used in the pharmaceutical industry in obtaining narramissic drugs

The invention relates to a method for producing 1,5-bis(2-hydroxyphenoxy)-3-oxapentane monohydrate, which is an intermediate product in the synthesis of crown ethers used as extractants cesium

The invention relates to trehzameshchenny phenyl derivative of the General formula (1) in which Y represents a group or SIG1where R1represents a C1-C6alkyl group, optionally substituted by up to three halogen atoms; R2represents a C1-C6alkyl or C3-C8cycloalkyl provided that Y and-OR2are not both methoxypropane; R3represents a hydrogen atom or a hydroxy-group; R4and R5that may be the same or different, represent a group -(CH2)nAr, where n = 0 or 1 and Ar is a phenyl or heteroaryl group containing one or two 5 - and/or 6-membered ring containing up to three heteroatoms selected from oxygen, sulfur and nitrogen, where Ar is optionally substituted with halogen, C1-C6the alkyl, C1-C6hydroxyalkyl,1-C6alkoxy, C1-C6alkoxy-C1-C6the alkyl, C1-C6halogenation, amino,

di-(C1-C6)alkylamino-C1-C6by alkyl, hydroxyl, formyl, carboxyla,1-C6alkoxycarbonyl,1-C6alkanoyloxy, thiol, carboxamido,1-C6alkanolamine,

The invention relates to new derivatives of cyclohexane and tetrahydropyrane, the way they are received, fungicidal compositions on their basis and use of this composition for combating fungi

The invention relates to methods of obtaining monoamino of pyrocatechin, namely nanometrology ester pyrocatechin guaiacol and monoecious ester pyrocatechin of guadala used as raw material in the synthesis of aromatic substances, in particular, in the synthesis of vanillin and vanillal, and medicinal substances

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to a spontaneously dispersing composition comprising N-benzoylstaurosporin, a hydrophilic component, a lipophilic component and a surface-active substance taken in the definite ratio of components. Also, invention relates to a method for treatment of the patient needing administration of N-benzoylstautosporin as a component of the spontaneously dispersing composition. The composition possesses the enhanced level of biological availability or diminished variability of the biological availability levels and effectiveness.

EFFECT: improved and valuable properties of composition.

13 cl, 3 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new heteroaryl derivatives, in particular, derivatives of quinoline of he general formula (I): wherein R, R1, R2 and R3 are similar or different and mean independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl, halogen atom, aryl-(C1-C8)-alkoxy-group, aryl. Except for, R and R1 or R2 and R3 can form six-membered aromatic ring condensed with quinoline residue; X means oxygen atom; p, Q mean in each case -CH2-; X means nitrogen atom; n = 2; m = 0; R4 means phenyl or pyridyl. Also, invention relates to their pharmaceutically acceptable salts, in particular, acid-additive salts. Compounds are useful as antitumor agents. Also, invention describes a method for preparing compounds and medicinal agent based on thereof.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

11 cl, 2 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: medicine.

SUBSTANCE: one should perform the following stages: a) removal of contaminants out of plant; b) plant's reducing; c) treatment of reduced plant with laser radiation; d) suspending the mixture obtained at stage c) in water; e) maceration of suspension obtained at stage d) and f) separation of liquid developed. Composition should be obtained due to this technique. It should be applied at treating hepatitis C as an aqueous extract. It should be applied as aqueous extract as immunostimulant. Pharmaceutical preparation includes aqueous extract as an active constituent.

EFFECT: increased biological activity of the product.

43 cl, 16 ex, 1 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating malignant tumors of mammary gland in case no tumor penetration into thoracic fasciae. The method suggested includes autohemochemotherapy. Moreover, on the 1st d of therapy it is necessary to sample 30 ml blood out of patient's peripheral vein into the 1st vial to combine its content with 500 mg 5-fluorouracil and 600 mg cyclophosphan; then one should sample 20 ml blood into the 2nd vial to combine its content with 40 mg doxorubicin; both vials should be incubated at 37-37.5 C for 20-30 min, afterwards its necessary to inject the mixtures out of both vials under the tumor and along its circumference. On the 8th d of therapy one should repeat impact procedures at the same dosages of anti-tumor preparations and at the same order. The innovation suggested enables to develop the largest concentration of anti-tumor preparations in lesion focus, divide into fragments, decrease tumor's size and its inflammatory component and border it against surrounding tissues for performing radical surgical treatment.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with applying fulvestrant as a curative preparation of the third line in treating patients with resistant cancer of mammary gland after failed application of tamoxifen and aromatase inhibitor. The innovation shows positive therapeutic result in 41% cases.

EFFECT: higher sensitivity to fulvestrant.

5 cl, 1 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry of natural compounds, medicine.

SUBSTANCE: invention relates to new taxanes with carbonate substitute at C7 of the general formula (I) given in the invention description wherein R2 means benzoyloxy group; R7 means -COO; R9 means -CO; R10 means -OH; R14 means hydrogen atom (H); X3 means (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom; X5 means -COX10, -COOX10 wherein X10 means (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl or 5-membered heteroaromatic group wherein heteroatom is represented by oxygen (O) or sulfur (S) atom, and Ac means acetyl. Proposed compounds possess an anti-tumor activity.

EFFECT: valuable medicinal properties of compounds.

61 cl, 1 tbl, 5 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: pharmaceutics.

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EFFECT: higher efficiency of application.

13 cl, 14 ex, 2 tbl

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