Therapeutic agent for improvement of skin properties containing morphinan derivative or any of its pharmacologically acceptable acid-additive salts as active ingredient

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceuticals and concerns a therapeutic agent for improvement of skin properties containing a compound of formula (I): as an active ingredient.

EFFECT: invention provides a medical product effective for prevented dry skin, reduced skin roughness and skin darkening associated with hyperkeratosis ensured by skin moisture preservation, and effective for impaired skin functions for the various reasons.

3 cl, 1 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to the development of new drugs, including derivative morphinane or any of its pharmacologically acceptable acid additive salts applicable to therapies designed to improve the properties of the skin due to the effect of retaining moisture in the skin.

BACKGROUND of the INVENTION

It is known that the coarsening of the skin, dry skin, skin darkening, etc. caused by the weakening of the protective skin barrier, and to improve the properties of skin using toilet water, creams, emulsions, oil, horse chestnut, ointments, etc. as medicines to improve properties of the skin were created agent for external application, including heparinoid, such as hirudoid, Airleet, Kuradoid, Seleloiz and Besoften, urea, hyaluronic acid and collagen for the treatment of diseases such as skin astatos and progressive keratoderma of the palms. Additionally, it was also reported that cosmetics containing as a main ingredient of the extract obtained from the roots, rhizomes or leaves grams; according bambusoides, grams; according nigra or grams; according heterocycle with the use of hydrophilic organic solvent (reference No. 1 to patent literature), as well as cosmetic products, comprising as the main ingredient of the extract is of tabla or branches of bamboo (reference # 2 in patent literature), effective for improving dry skin, followed by a change in its appearance. In addition, it was reported that extracts of some plants contribute to the release of β-endorphins from keratinocytes, which helps retain moisture in the skin (reference No. 1 in non-patent literature).

Mostly healthy corneal layer of the skin intercellular lipids of the stratum corneum to form a double lipid layer that holds water, and because water-soluble low-molecular substances in the keratin cells retain flexibility, subcutaneous fat impedes the evaporation of water through the skin, retaining moisture of the surface layer of the skin. Ceramides play an important role in keeping skin moisture and preserve the protective function of the stratum corneum, and it is believed that in areas with alkaline environment activity increases ceramides, which promotes the reaction of hydrolysis of ceramides to fatty acids and sphingosine, leading to dry skin (reference No. 2 in non-patent literature). Found that approximately 60% of patients were treated with hemodialysis, suffer from itching of the skin (reference No. 3 and 4 in non-patent literature), and on the other hand, found that approximately 90% of them have dry skin and a significant reduction in water content in the stratum corneum and a significant increase in the pH of the skin (reference No. 5 in non-patent literature). Addi is entrusted, in addition, if xerodermia, most often observed in patients treated with hemodialysis, the detected decrease in the number of lipids in the surface layer of the skin (reference No. 6 in non-patent literature), and it was also reported that these patients a higher average pH of the skin, than in healthy people, and they can be itchy, which is reduced when applied to the skin acid cream, in which the aqueous phase is present in the buffer based on lactic acid (reference No. 7 in non-patent literature). Dry skin is often accompanied by aging, atopic dermatitis and xerodermia, which mainly manifests itself in the winter, and there is a need to develop tools to retain water, which has the ability to retain moisture and protective function.

Derivatives morphinan used in the present invention as an active ingredient, are agonists κ-opioid receptor, and to date have disclosed the use of derivatives morphinan based on their analgesic action, diuretic action and antitussive action (reference No. 3 of patent literature). Additionally already disclosed their use as a means to protect brain cells (reference No. 4 of patent literature), anti-itching (reference No. 5 on Pat is NTUU literature), anti-hyponatremia (reference # 6 in the patent literature), antagonist receptor ORL-1 (reference No. 7 in patent literature), funds from neuropathic pain (reference No. 8 in the patent literature), the funds against psychoneurosis (reference No. 9 the patent literature), anti-drug dependence (reference No. 10 of the patent literature), anti-sepsis (reference No. 11 the patent literature), anti itch, itch, caused by multiple sclerosis (reference No. 12 the patent literature), etc. In the application No. 5 from the list patent literature disclosed antipruritic effect of κ-agonist, caused by the activity of the Central nervous system.

As for other medicinal products on the basis of opioids, such as morphine, which differ from those described above, their known actions to improve condition of the skin include the following. It was reported that opioids for external use is effective in disorders of the sebaceous glands, such as for acne and burns (reference No. 13 the patent literature), and that β-endorphin is able to increase the water content in the skin, improving its protective function, helping to update and preventing the early aging process (reference No. 8 in non-patent literature). In 1999 it was discovered that the skin contains β-endorphins, and it was reported that in vitro β-endorphins (1 increase the levels of natural moisturizing factors (amino acids, filaggrin), (2) increase the factors of regulation of metabolism (cytokeratin 1), (3) increase the number of factors, cell adhesion (desmosomes), (4) reinforce the shell of the stratum corneum (involucrin, loricrin) and (5) enhance retention complex (laminin 5). From the point of view of the impact of opioids on the skin cells, it was reported that β-endorphins, as agonists, improve the production of cytokeratin 16 as a marker of differentiation of keratinized cells of the epidermis (reference No. 9 in non-patent literature) and that β-endorphins stimulate the migration of keratinocytes (reference No. 10 in non-patent literature).

It is known that opioids have analgesic properties and, on the other hand, act as chemical mediators of itch, and it was reported that endogenous opioid peptides, such as β-endorphins and enkephalins, cause itching (reference No. 11 in non-patent literature). Although details are not clear, usually it is argued that in suppressing pain and initiating itching participate µ-receptor and δ-receptors, and that κ-receptors participate in the suppression of pain and itching (reference No. 12 in non-patent literature). It was reported that the medicinal product on the basis of opioids, which have antipruritic action include naloxone and naltrexone (reference No. 13 and 14 in non-patent literature), and it was reported that some derivatives morphinan, I have lausiaca active ingredients of the present invention, show antipruritic action (reference No. 15, 16 and 17 in non-patent literature). Additionally, it was reported that some of the medicines, which have the ability to block µ-receptors, was used to prevent chronic itching (reference No. 14 the patent literature), and has a document of the prior art involving the treatment of itching by inhibiting peripheral sensory nerves of the skin due to selective inhibition of glutamic acid receptors (reference # 15 in patent literature).

Itchy skin is defined as "the feeling of needing to comb through the skin". Dryness of the skin and the degree of itching, generally show a positive correlation, and it is well known that the attenuation of the dry skin leads to reduce itching. On the other hand, there is itching of the skin, not involving any anomalous properties of the skin (reference # 18 in non-patent literature), and the relationship between the Central itching and the skin properties is not obvious. Central itching caused by too much reaction to signals resulting from imbalance of the cerebral opioid peptides and has nothing to do with the anomalous properties of the skin.

Thus, in the documents of the prior art not disclosed the ability of active ingredients, which have a characteristic molecular structure is round morphinan, to improve the skin condition.

[Patent literature No. 1] JP 5-124930 A

[Patent literature No. 2] JP 7-187990 A

[Patent literature No. 3] WO 93/015081 A

[Patent literature No. 4] WO 95/003307 A

[Patent literature No. 5] WO 98/023290 A

[Patent literature No. 6] WO 99/005146 And

[Patent literature No. 7] JP 2000-53572 A

[Patent literature No. 8] WO 01/014383 A

[Patent literature No. 9] WO 02/078744 A

[Patent literature No. 10] WO 99/0112B9 A

[Patent literature No. 11] WO 02/089845 A

[Patent literature No. 12] WO 06/095836 A

[Patent literature No. 13] U.S. Patent No. 58344 B0

[Patent literature No. 14] JP 2004-352714 And

[Patent literature No. 15] JP2004-107209A

[Non-patent literature No. 1] "Fundamentals and Clinical Practice of external Preparations for Eczema Dermatitis Group. Moisturizing Agents Used in Dermatological Regions (in Japanese)," (Genji Lmokawa), Journal of Japan Organization of Clinical Dermatologists, Japan Organization of Clinical Dermatologists, April 1998, Vol.56, pages 87-96

[Non-patent literature No. 2] "Purification and Biochemical Characterization of Membrane-bound Epidermal Ceramidases from Guinea Pig Skin," (Yukihiro Yada et al.), The Journal of Biological Chemistry, USA, American Society for Biochemistry and Molecular Biology, 26 may 1995, Vol.270, No. 21, pages 12677-12684

[Non-patent literature No. 3] "Itching up date: Effectiveness of κ-opioid Agonists for Itching of Dialysis Patients (in Japanese)," (Hironari Kumagaya et al.), MB Derma, Zen-Nihon Byoin Shuppan-kai (=Publishing Association of All Japanese Hospitals), 25 August 25 2005, Vol.104, pages 59-64

[Non-patent literature No. 4] "Uraemic Pruritus," (Idit F.Schwartz et al.), Nephrology, Dialysis, Transplantation, official publication of the European Dialysis and Trnsplant Association - European Renal Association, United Kingdom, Oxford University Press, 1999, Vol.14, No. 4, pages 834-839

[Non-patent literature No. 5] "Cutaneous Lesions of Dialysis Patients. General Remarks (in Japanese)," (Akira Hattori), Rinsho Toseki (=Clinical Dialysis), Nihon Medical Center, October 1995, Vol.11, No. 13, pages 1877-1881

[Non-patent literature No. 6] "Substances Relating to Complications Observed with Uremia and Chronic Dialysis X) Skin Disorders (in Japanese)," (Akira Hattori), Rinsho Toseki (=Clinical Dialysis), Ninon Medical Center, August 10, 2005, Vol.21, No. 9, pages 1237-1242

[Non-patent literature No. 7] "Skin Changes in Hemodialysis Patients (in Japanese)," (Akira Hattori et al.), Rinsho Hifuka (=Clinical Dermatology), Igaku-Shoin Ltd., January 1990, Vol.44, No. 1, pages 21-24

[Non-patent literature No. 8] "New Role of β-endorphin in Skin, (in Japanese)," (Mika Adachi et al.), Fragrance Journal, Fragrance Journal Ltd., June 15, 2005, Vol.33, No. 6, pages 35-38

[Non-patent literature No. 9] "β-endorphin Stimulates Cytokeratin 16 Expression and Downregulates µ-opiate Receptor Expression in Human Epidermis," (Mei Bigliardi-Qi et al.), The Journal of Investigative Dermatology, USA, Nature Publishing Group, March 2000, Vol.114, No. 3, pages 527-532

[Non-patent literature No. 10] "µ-opiate Receptor and Beta-endorphin Expression in Nerve Endings and Keratinocytes in Human Skin," (Mei Bigliardi-Qi et al.), Dermatology, Switzerland, Karger, 2004, Vol.209, No. 3, pages 183-189

[Non-patent literature No. 11] "Experimental and Clinical Pruritus. Studies on Some Putative Peripheral Mediators. The Influence of Ultraviolet Light and Transcutaneous Nerve Stimulation," (B.Fjellner), Acta Dermato-venereologica. Supplementum, Norway, Scandinavian University Press, 1981, Vol.97, pages 1-34

[Non-patent literature No. 12] "Opioid Peptide Targetting Treatment of Pruritus (in Japanese)," (Kenji Takamori), Rinsho Hifuka (=Clinical Dermatology), Igaku-Shoin Ltd., April 10, 2002, Vol.56, No. 5, pages 145-147

[N the patent literature No. 13] "Effects of Naltrexone on Spontaneous Itch-associated Responses in NC Mice with Chronic Dermatitis," (Tatsuya out by Maekawa et al.), Japanese Journal of Pharmacology, The Japanese Pharmacological Society, October 1, 2002, Vol.90, No. 2, pages 193-196

[Non-patent literature No. 14] "Itch-associated Response Induced by Experimental Dry Skin in Mice," (Takayuki Miyamoto et al.), Japanese Journal of Pharmacology, The Japanese Pharmacological Society, March 1, 2002, Vol.88, No. 3, pages 285-292

[Non-patent literature No. 15] "Imbalance in Opioid System as a Cause of Uremic Pruritus and Effect of a Novel κ-Agonist, TRK-820 (in Japanese)," (Hironari Kumagaya et al.), Sogo Rinsho (=General Clinical Medicine), Nagai Shoten Co., Ltd., may 1, 2004, Vol.53, No. 5, pages 1678-1684

[Non-patent literature No. 16] "Involvement of Central µ-opioid System in the Scratching Behavior in Mice, and the Suppression of It by the Activation of κ-opioid System," (Hideo Umeuchi et al.), European Journal of Pharmacology, Netherlands, Elsevier Science, 2003, Vol.447, No. 1, pages 29-35

[Non-patent literature No. 17] "Anti-Pruritic Effect of a Kappa Opioid Receptor Agonist, TRK-820," (Hideo Umeuchi et al.), Journal of Pharmacological Sciences, The Japanese Pharmacological Society, March 1, 2003, Vol.91; Supplement No. 1, page 198

[Non-patent literature No. 18] Knowledge of Diseases Common to Dermatology Necessary for Surgeons 6. Skin Pruritus and Mechanism of Itching (in Japanese)," (Shigeo Kochi), Rinsho Geka (=Clinical Surgery), Igaku-Shoin Ltd., November 20, 2001, Vol.56, No. 12, pages 1522-1524

Description of the INVENTION

Problems, which were to be solved by the present invention

The present invention consisted in the development of new drugs effective for improving the properties of the skin, for example, prevent dryness of the skin, reducing the coarsening of the skin and reduce darkening of the skin associated with hyperkeratosis (thickening of the keratin layer), and the operating against the weakening of the functions of the skin, due to various reasons.

Means for solving the above problems

The authors of the present invention conducted intensive studies to solve the above problems and as a result have found that compounds having a specific molecular structure morphinan, or any of their pharmacologically acceptable acid salt additive is applicable as a therapeutic means to improve properties of the skin. Thus, the work on this invention was completed.

The present invention relates to the following items [1]-[3]. In addition, the present invention relates to a method of improving properties of the skin, including the introduction of effective amounts of compounds described in the following paragraphs[1]-[3].

[1] a Therapeutic tool to improve properties of the skin, comprising as an active ingredient the compound represented by the following General formula (I):

where a double line consisting of a dotted line and a solid line indicates a double bond or a simple bond; R1means cycloalkenyl containing 4-7 carbon atoms; R2means a linear or branched alkyl containing 1-5 carbon atoms; and In the mean fragment-CH=CH-, or any of its pharmacologically acceptable acid additive salts.

[] A therapeutic tool to improve properties of the skin by p.[1], where in the General formula (I) R1means cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl; and R2means methyl, ethyl or propyl.

[3] a Therapeutic tool to improve properties of the skin by p.[1], where the connection represented by the General formula (I)represents the (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

The effect of inventions

In the present invention developed a therapeutic tool to improve properties of the skin, comprising as an active ingredient derived morphinane or any of its pharmacologically acceptable acid additive salts.

The use of such therapeutic agents that improve the properties of skin, can improve the skin condition, for example, can prevent dry skin, reduce the coarsening of the skin and reduce skin darkening associated with hyperkeratosis.

The best way of carrying out the invention

Therapeutic means to improve the properties of the skin according to the present invention includes as an active component a compound represented by the formula (1)and its pharmaceutically acceptable acid additive salt:

R1represents a C1-C5alkyl, C4-C7cycloalkenyl,5With 7cycloalkenyl, C6-C12aryl, C7-C13aralkyl,4-C7alkenyl, allyl, furan-2-illlil (where the number of carbon atoms in the alkyl fragment is from 1 to 5) or thiophene-2-illlil (where the number of carbon atoms in the alkyl fragment is from 1 to 5).

R14represents hydrogen, hydroxy, nitro, C1-C5alkanoyloxy,1-C5alkoxy, C1-C5alkyl or NR9R10where R9represents hydrogen or C1-C5alkyl; R10represents hydrogen, C1-C5alkyl or -(C=O)R11and R11means hydrogen, phenyl or1-C5alkyl.

R3represents hydrogen, hydroxy, C1-C5alkanoyloxy or1-C5alkoxy.

"A" represents-XC(=Y)-, -XC(=Y)Z-, -S - or XSO2- (where X, Y and Z independently represent NR4, S or O, where R4means hydrogen, C1-C5linear or branched alkyl or C6-C12aryl, and when the molecule contains more than one substituent R4these substituents R4may be the same or different).

"B" represents a valence bond, With1-C14linear or branched alkylen (where alkylene may have at least one Deputy, wybran the th group, consisting of C1-C5alkoxy, C1-C5alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifloromethyl, phenoxy, and where 1-3 methylene link in the specified alkylene can be replaced by a carbonyl group (groups))2-C14linear or branched acyclic unsaturated hydrocarbon containing 1-3 double and/or triple bond (where the acyclic unsaturated hydrocarbon may have at least one Deputy, selected from the group consisting of C1-C5alkoxy, C1-C5alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifloromethyl, phenoxy, and where 1-3 methylene groups in unsaturated acyclic hydrocarbon may be replaced by a carbonyl group (groups)), or With1-C14linear or branched saturated or unsaturated hydrocarbon containing from 1 to 5 thioester linkages, ether linkages and/or aminokwasy (where the heteroatom is not directly related to A, and 1 to 3 methylene groups are optionally replaced Cabanillas group (groups)).

R5represents hydrogen or an organic group having a structure selected from the following formulas:

Q: N, O, S
T: CH2, N, S, O
l=0-5
m,n≧0
m+n≦5

Organic groups represented by R5(where Q is an atom of N, O or S; T mean CH2, NH, S or O; l is an integer from 0 to 5; and m and n independently represent integers from 0 to 5, where the sum of m and n may not exceed 5; each of these organic groups may have at least one Deputy, selected from the group consisting of C1-C5of alkyl, C1-C5alkoxy, C1-C5alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifloromethyl, triptoreline, methylendioxy).

R6represents hydrogen; R7represents hydrogen, hydroxy, C1-C5/sub> alkoxy or1-C5alkanoyloxy; or R6and R7taken together form-O-, -CH2- or-S-.

R8represents hydrogen, C1-C5alkyl or C1-C5alkanoyl.

R12and R13both represent hydrogen, or one of them represents hydrogen and the other represents hydroxy, or they, taken together, represent an oxo.

The compounds of formula (1) include (+)-, (-)- and (±)-isomers.

The dotted line in the formula (1) means a double bond or a simple link, the latter is preferred.

Among the compounds represented by formula (1), a means to improve properties of the skin according to the present invention preferably comprise as an active component the compound represented already shown above formula (I)or their pharmaceutically acceptable acid salt additive. The dotted line in formula (I) means a double bond or a simple link, the latter is preferred.

In the formula (I) R1means cycloalkenyl containing 4-7 carbon atoms. First of all, it is preferable that R1was cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl. Particularly preferably, R1was cyclopropylmethyl.

R2iznachaliniy or branched alkyl, comprising 1-5 carbon atoms. Preferably, R2represented a methyl, ethyl or propyl. Particularly preferably, R2represented a methyl.

In means-CH=CH-. Preferably, In was a TRANS-form-CH=CH-.

Especially preferably, the compound represented by formula (I), was a compound in which R1means cyclopropylmethyl; R2means methyl; and means TRANS-form-CH=CH-, namely (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4, 5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan, although the compounds of formula (I) is not limited to this specific connection.

The above compounds of formula (I) can be obtained by the method described in Japan patent No. 2525552. Among the compounds represented by formula (1), compounds in which both of the substituent R12and R13are hydrogen atoms, can be obtained by the method described in Japan patent No. 2525552. Among the compounds represented by formula (1), compounds in which both of the substituent R12and R13together form oxo, may be, for example, obtained by the method described in Chem. Pharm. Bull., 52, 664(2004) and the Japan patent No. 2525552 using the compounds, including the 10-oxo and obtained by the method known from the literature (Heterocycle, 63, 865(2004); Bioorg. Med. Chem. Lett., 5, 1505 (1995)) as the source of the second substance. In addition, among the compounds represented by formula (1), compounds in which R12represents hydroxyl, and R13is hydrogen, can be obtained by the method described in Chem. Pharm. Bull., 52, 664 (2004).

Additionally, it is preferable that a therapeutic tool to improve properties of the skin according to the present invention was used as a means to retain moisture, helping to restore the protective functions of the skin, means for preventing dryness of the skin, and means for preventing the coarsening of the skin. Preferably, a therapeutic tool to improve properties of leather was applied in the form of oral preparation, but it is not limited to such compounds, and can be used in the form of skin preparations for external application, etc. if the result of this is not getting worse.

Pharmacologically acceptable acid salt additive of the present invention include salts of inorganic acids, such as hydrochloride, sulfates, nitrates, hydrobromide, hydroiodide and phosphates, organic carboxylates such as acetates, lactates, citrates, oxalates, glutarate, malate, tartratami, fumarate, mandelate, maleate, benzoate and phthalates, organic sulfonates, such as methanesulfonate, econsultancy, bansilalpet, p-toluensulfonate and camphorsulfonic what you etc. In the first place preferably can be used hydrochloride, hydrobromide, phosphates, tartratami, methansulfonate etc., although the acid additive salts are certainly not limited to.

Optionally, the compound represented by formula (I) or any of its pharmacologically acceptable acid additive salts, purified for applications in medicine and subjected to a mandatory test security, and connection, since this test can be administered orally in pure form or in pharmaceutical compositions obtained by mixing this compound with well-known pharmacologically acceptable acids, carriers, fillers, etc. Dosage form for oral administration may be selected from tablets, capsules, powder, granules, etc., although certainly not limited to these forms. These dosage forms can be obtained by well known methods, usually used for getting medicines. The proper dosage of a therapeutic agent to improve the properties of the skin according to the present invention can be established based on the symptoms, age and body weight of the patient, the route of administration, etc. As a rule, the amount of active ingredient, administered to the adult patient in the course of the day, is from about 0.1 μg to approx the tion of 100 mg in the case of oral administration and from about 0.01 μg to about 10 mg in the case refererlog introduction.

Any of therapeutic agents to improve the properties of the skin according to the present invention can be entered by itself or, alternatively, in combination with another drug, for example, means for holding moisture, itching remedy intended for external application, or steroid ointment, etc. are Examples of means for moisture retention include petrolatum, urea, ointments containing heparinoid, ointments based on Artemisia princes, ceramiaceae creams and lotions are oil-based Camellia japonica. Examples of anti-itching for external application include antihistamine ointments and crotamiton ointment. In the case of severe itching in combination with the above means you can also use a steroid ointment. Therapeutic means to improve properties of the skin according to the present invention can be used as a means to retain moisture, tools that help restore the protective functions of the skin, prevent dryness, and means for preventing the coarsening of the skin.

Hereinafter the present invention will be disclosed in more detail using an example.

Example 1

2.5 mg of hydrochloride of (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan (compound 1), represented by the following structural formula (II), was sealed in a soft who apsule, made of gelatin film, receiving a drug for oral administration. Two capsules (5,0 µg) received oral drug was administered to two patients with itching, which were hemodialysis and who would not yield to treatment with conventional ways. After the beginning of the introduction of one patient (woman, aged 79 years) felt the reduction of itching, and the smoothness of her skin grew throughout the body (especially the legs), resulting managed to achieve beautiful skin. Another patient (male aged 69 years), who had a very bad complexion and skin texture, after the start of oral administration of the drug showed a reduction in dry skin and have gained a good complexion. After about 4-5 days after the start of oral administration of the drug, one of the patients had relief of itching on the skin areas from the wrists to the shoulders and chest, and the patient's skin is damp, but after the introduction of the drug when the patient began again to feel itchy, his skin started to get dry.

INDUSTRIAL APPLICABILITY

Compounds according to the present invention is applicable as a therapeutic means of improving properties of the skin, which can prevent the coarsening of the skin, dry skin, skin darkening, etc. and to provide the effect of saving the owner the guy in the leather.

1. A therapeutic tool to prevent dryness of the skin, reducing the coarsening of the skin or reduce darkening of the skin associated with hyperkeratosis, comprising as an active ingredient the compound represented by the following formula (I):

[where a double line consisting of a dotted line and a solid line indicates a double bond or a simple bond; R1means cycloalkenyl, containing 4-7 carbon atoms; R2means a linear or branched alkyl comprising 1 to 5 carbon atoms; and means-CH=CH-], or any of its pharmacologically acceptable acid additive salts.

2. Therapeutic agent according to claim 1, where in formula (I) R1means cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl; and R is methyl, ethyl or propyl.

3. Therapeutic agent according to claim 1, where the compound represented by formula (I)represents the (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.



 

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16 cl, 9 ex, 16 dwg

FIELD: medicine.

SUBSTANCE: invention refers to cosmetic skin and/or scalp and/or hair care compositions, particularly deodorant and antiperspirant compositions. The offered cosmetic composition contains, in an acceptable cosmetic carrier, at least one hydrated silica ester selected from a group of esters of certain composition, where at least one residue R is formed of at least one alcohol, which is selected from a group consisting of (Z)-2-hexen-1-ole, (E)-2-hexen-1-ole, (Z)-3-hexen-1-ole (leaf alcohol), (E)-3-hexen-1-ole, (Z)-4-hexen-1-ole, (E)-4-hexen-1-ole and 5-hexen-1-ole, while the other residues R are hydrogen atom, and also their mixtures. The cosmetic composition involves the specified hydrated silica ester in total 0.05 to 0.1 wt % per weight of the cosmetic composition.

EFFECT: use of hydrated silica esters of such composition as a part of the cosmetic agent provides higher intensity and long-lasting scent release.

6 cl, 28 tbl

FIELD: medicine.

SUBSTANCE: invention refers to cosmetic skin and/or scalp and/or hair care compositions, particularly deodorant and antiperspirant compositions. The offered cosmetic composition contains, in an acceptable cosmetic carrier, at least one hydrated silica ester selected from a group of esters of certain composition, where at least one residue R is formed of at least one alcohol, which is selected from a group consisting of (Z)-2-hexen-1-ole, (E)-2-hexen-1-ole, (Z)-3-hexen-1-ole (leaf alcohol), (E)-3-hexen-1-ole, (Z)-4-hexen-1-ole, (E)-4-hexen-1-ole and 5-hexen-1-ole, while the other residues R are hydrogen atom, and also their mixtures. The cosmetic composition involves the specified hydrated silica ester in total 0.05 to 0.1 wt % per weight of the cosmetic composition.

EFFECT: use of hydrated silica esters of such composition as a part of the cosmetic agent provides higher intensity and long-lasting scent release.

6 cl, 28 tbl

FIELD: medicine.

SUBSTANCE: invention refers to cosmetic skin and/or scalp and/or hair care compositions, particularly deodorant and antiperspirant compositions. The offered cosmetic composition contains, in an acceptable cosmetic carrier, at least one hydrated silica ester selected from a group of esters of certain composition, where at least one residue R is formed of at least one alcohol, which is selected from a group consisting of (Z)-2-hexen-1-ole, (E)-2-hexen-1-ole, (Z)-3-hexen-1-ole (leaf alcohol), (E)-3-hexen-1-ole, (Z)-4-hexen-1-ole, (E)-4-hexen-1-ole and 5-hexen-1-ole, while the other residues R are hydrogen atom, and also their mixtures. The cosmetic composition involves the specified hydrated silica ester in total 0.05 to 0.1 wt % per weight of the cosmetic composition.

EFFECT: use of hydrated silica esters of such composition as a part of the cosmetic agent provides higher intensity and long-lasting scent release.

6 cl, 28 tbl

FIELD: medicine.

SUBSTANCE: invention refers to cosmetology, and represents a complex cosmetic agent with rejuvenating and lifting effect, containing hyaluronic acid, emulsion wax and water, differing by the fact that the cosmetic agent contains a matrix peptide recovered from hyaluronic acid hydrogel during photochemical nanopatterning, at wave length equal to 280 nm, and hyaluronic acid is nanopatterned at an individual chain diameter 5 nm; the ingredients are taken in certain proportions, wt %.

EFFECT: invention provides intensified cellular turnover of epidermic tissue, provides higher skin self-repair and self-renew ability.

1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to make-up products and represents a cosmetic agent for creating a fancy look, presented in the form of a colourless luminescent make-up product containing organic phosphor of abnormally high Stockes shift more than 100 nm, colourless in daylight and luminescing in a visible spectral region when exposed to UV radiation, differing by the fact that specified phosphor is introduced in the cosmetic agent in the form of a powdered pigment forming suspension with a colourless binding substance not absorbing long-wave UV radiation in the range of 365-420 nm.

EFFECT: invention provides improved visual perception of the fancy look at the distance due to higher make-up contrast and brightness under UV radiation, and better stability, homogeneity and segregation resistance of the cosmetic agents containing phosphors.

16 cl, 3 ex, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of medicine and deals with development of medications for acceleration of wound healing and tissue regeneration after damaging individual's tissues. Claimed is composition for acceleration of wound healing, which contains at least one polypeptide, consisting of 4-30 sequential amino acids of carboxy-end of alpha-connexin or its conservative version, where at least one said alpha-connexin polypeptide is bound on amino-end with carrier of cellular internalisation. Also claimed is composition for acceleration of tissue healing, composed for local application, containing polypeptide, which consists of 4-30 sequential amino acids of carboxy-end of alpha-connexin protein or its conservative version, and material for wound treatment for acceleration of tissue healing, covered by such polypeptide. Set for wound healing acceleration can contain mentioned above compositions or material for wound treatment and instruction for their application. Also claimed is application of mentioned above compositions and material for obtaining medicine, which accelerates tissue healing.

EFFECT: application of polypeptide, which consists of 4-30 sequential amino acids of carboxy-end of alpha-connexin protein or its conservative version ensures reduction of inflammation after tissue damaging, acceleration of healing, reduction of scarring, intensification of compound tissue regeneration.

31 cl, 2 tbl, 5 ex, 17 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is application of allopurinol or its pharmaceutically acceptable salt for treating or preventing palmoplantar erythrodysesthesia (PPE) induced by fluoropyrimidine chemotherapy, a related method of treating and a pharmaceutical composition for skin application of the same purpose, and the composition does not contain methyl sulphonyl methane or cetomacrogol.

EFFECT: relief, and in 66% of patients - delitescence of PPE symptoms in the absence of toxic effects on allopurinol and compliance of the patients is shown.

12 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to dermatology, and represents a hydrogel composition for treating burns, containing immobilised active and auxiliary ingredients and a gelling ingredients, differing by the fact that as an active component it contains a drug substance of 2-allyloxyethanol in amount 0.1 to 10.0 (wt %), as auxiliary ingredients it contains a drug substance of lidocaine in amount 0.1 to 5.0 (wt %) or drug substances of lidocaine in amount 0.1 to 5.0 (wt %) or dezoxynate in amount 0.1 to 5.0 (wt %), as a gelling ingredient it contains hydroxypropyl cellulose in amount 0.1 to 5.0 (wt %).

EFFECT: invention provides enhancement of first-aid treatment of local burns of various aetiologies, including radiation ones, at all the stages of the first-aid treatment, also application in emergency medicine as a all-purpose drug in treating granulating wounds of various aetiologies: continuous ones; for inflammation relief in skin diseases, and also for treatment of insect bites.

5 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacology, and represents ointment for treating infected wounds in purulo-necrotic wound process, containing as active substances an antimicrobial agent and lidocaine, and an ointment base, characterised by the fact that it additionally contains as an active substance, dibunol, as an antimicrobial agent - furacilin, and as an ointment base a styrene maleic anhydride copolymer, lutrol F-127 and purified water, and the ointment ingredients are taken in certain proportions, wt %.

EFFECT: invention provides antimicrobial, anesthetic, anti-inflammatory, regenerating, antioxidant, antiviral and drainage effect, exhibits good fixation, evident and prolonged action, and also ensures usability and hygienic application.

7 ex, 2 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to dermatology and can be used for treating atopic dermatitis in children being residents of technogenic chemical environments with increased body biological environment contamination. This is ensured by standard background therapy together with intravenous drop-by-drop administration of cytoflavinum every day at 1 ml per 10 kg of child's body weight, dissolved in 150-200 ml of 0.9 % sodium chloride at 30-40 drops a minute for 3-7 days.

EFFECT: method provides higher clinical effectiveness ensured by reduced intensity of systemic inflammatory process in the body, improved metabolic processes, activated enzyme system, normalised immunogram values.

2 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: what is described is a composition for fistula treatment in an individual, including stromal stem cells of fatty tissue where at least approximately 50 % of stromal stem cells of fatty tissue making a composition, express CD9, CD10, CD13, CD29, CD44, CD49A, CD51, CD54, CD55, CD58, CD59, CD90 and CD105 markers and where the contents of the stromal stem cells of fatty tissue in the composition makes at least approximately 3×106 cells/ml.

EFFECT: invention extends the range of products for fistula treatment.

8 cl, 7 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to methods of producing herbal therapeutic agents. The method of producing an antifungal agent of herbal raw materials involves extraction of an elevated part of Maltese cross campion (Lychnis chalcedonica L.) in distilled water and removal of an extractant in a rotary evaporator. The extraction process is carried out in a microwave (microwave heating) seven times for 1.5 hours.

EFFECT: agent exhibits evident antifungal action with respect to widespread fungus infectious agents.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to transporting filler for introduction of biologically active compounds, which contains one or more C1-C4 alcohols, water and combination of one or more diphosphate derivatives of electronic transfer agents and one or more monophosphate derivatives of electronic transfer agents. C1-C4 alcohols are present in amount from 0.5 to 50% by weight. Preferably C1-C4 alcohol represents ethanol. Transporting filler can have the shape of vesicles.

EFFECT: transporting filler in accordance with invention increases bioavailability of biologically active compounds, in particular, pharmaceutical preparations, including cosmetic ones.

33 cl, 4 dwg, 1 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to agent for skin bleaching, representing pyrimidyl pyrazole compound of formula (1), where R1, R3, R4 and R6 each independently represents C1-3alkyl and R2 and R5 each independently represents hydrogen atom or C1-3alkyl, or its pharmacologically acceptable salt. Said agent inhibits production of melanin, possesses low cytotoxicity and can be used as bleaching agent for improvement or prevention of pigment spots, freckles, skin darkening, etc. Invention also relates to composition for skin bleaching for external application, which contains effective amount of said pyrimidyl pyrazole compound of formula (1), described in any of items 1-3, or its pharmacologically acceptable salt. Preferable composition represents cosmetic preparation.

EFFECT: obtaining agent for skin bleaching.

6 cl, 3 tbl, 17 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary science. The combination preparation Praziotrem at praziquantel 75 mg and polytrem 100 mg per 1 kg of animal's weight is once prescribed for oral use that is followed by introduction of the hepatoprotector Tykveol 100 mg/kg of weight for 5 days running.

EFFECT: method is effective in treating opisthorchiasis with no adverse action of animal's body, normalised hepatic function, accelerated regeneration of parasite damaged areas.

4 tbl, 4 ex

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