Cyclosporine derivatives for treating ophthalmic and skin diseases and conditions

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound selected from a group consisting of compounds presented by formula:

In the above formula, R1 represents S-Alk-R, wherein Alk represents methylene, C2-C6 polymethylene bond or C3-C6 alkenylene bond, R represents -N=C(NR3R4)(NR5R6) or -NR7[(NR3R4)C=NR5], or -N=C(R8)(NR9R10), wherein R3-R10 represents H, Alk, Ar or (CH2)nAr, wherein Ar represents an aryl group, and n represents an integer from 1 to 13, or R3 and R4, or R4 and R5, or R5 and R7, or R3 and R7, or R9 and R10, or R8 and R9 together can represent -(CH2)x-, wherein x represents an integer from 2 to 5, and R2 is specified in a group consisting of hydroxyl, alkyl having from 1 to 7 carbon atoms, and substituted by alkyl hydroxyl having from 1 to 7 carbon atoms.

EFFECT: preparing new cyclosporine derivatives.

5 cl, 2 ex

 

Cross-reference

In this patent application claimed the priority of provisional patent application U.S. No. 61/134510, filed July 10, 2008, a full description of which is incorporated herein by specific reference.

Prior art

1. The technical field

The invention relates to a method of treatment of eye and/or skin diseases and conditions with the help of new derivatives of cyclosporine. In particular, the present invention relates to a method of treating water-deficit condition of dry eye, phacoanaphylaxis of endophthalmitis and uveitis using some new cyclosporine derivatives.

2. Description of related technology

The open part of the normal eye is covered with a thin tear film. The presence of a continuous tear film is important for normal corneal and conjunctival epithelium and gives the cornea surface with optical quality. Additionally, the aqueous portion of the tear film acts as a lubricant of the eyelids during blinking. In addition, it is known that some enzymes contained in the tear fluid, for example, immunoglobulin A, lysozyme and beta-lysine, have bacteriostatic properties.

Healthy lacrimula the system operates with the formation and maintenance of a properly structured continuous is th tear film. Tear the body consists of a secretory system (source), distribution system and secretion system (runoff). In the secretory system of watery tears are highlighted in the main and accessory lacrimal glands.

The bulk of the tear film is formed such watery tears. Continuous production and drainage of aqueous tears are important for the maintenance of the corneal epithelium and conjunctiva moist nutrients for epithelial breathing, receipts bacteriostatic agents and cleaning of the ocular surface due to the washing action of the movement of tears.

Abnormalities of the tear film include an absolute or partial deficiency of production of watery tears (keratoconjunctivitis sicca or CCM).

In relatively mild cases, the main symptom of the CCM represents a foreign body sensation or mild scratches. Last may progress, become permanent, intense stinging or irritating sensation that can be debilitating for the patient.

More severe forms can progress to the development filamentosa keratitis, representing a painful condition characterized by the appearance of multiple threads or filaments attached to the surface of the cornea. Evidence suggests that these filaments are the breaks nepreryvnosti normal epithelial cells of the cornea. The shift created by the movement of the eyelids, pulling these filaments, causing pain. The treatment of this stage of the CCM is very difficult.

A frequent complication of the CCM represents a secondary infection. Apparently, there are several disorders in the normal protective mechanisms of the eye, possibly related to a decrease in the concentration of antimicrobial lysozyme in aqueous tears of a patient suffering from CCM.

Although the CCM can develop in the absence of any other severe systemic anomalies, there is a frequent Association with CCM systemic disease. The CCM may occur as part of a larger system involvement, known as Sjogren syndrome. He classically consists of dry eyes, dry mouth, and arthritis.

Histologically, the CCM (as part of Sjogren syndrome or yourself) initial changes detected in the lacrimal glands, represent a change of focal lymphocytic and infiltrates of plasma cells in the blood, associated with degeneration of the glandular tissue. These changes resemble the changes detected in autoimmune disease in other tissues, giving rise to the assumption that the CCM has an autoimmune basis.

Sjogren syndrome is considered as a dysfunction of the exocrine glands. Characteristically, the lacrimal gland demonstrate infiltration of mononuclear cells, which in the end is the first account leads to the destruction of the glandular structure.

Traditional treatment CCM is symptomatic. Usually, the state of dryness of the eyes with a water deficit treated by supplementing tears artificial substitutes tears. However, the relief is limited to the retention time of insertion in the eye of the artificial solution of tears. As a rule, the effect of artificial solution of tears, injected eyes, quenched for about thirty to forty-five minutes. Thus, the action of such products as the original soft, does not last long enough. The patient's bothering the need for re-introduction of artificial solution with tears in his eyes, that it is necessary to Supplement the normal tears. In addition, this treatment simply acts to relieve symptoms of a condition of dry eye and does not cure any underlying disorder or cause of the condition of dry eye.

Histological examination of the lacrimal glands in patients suffering from Sjogren syndrome, showed some evidence of inflammation of the lacrimal gland. This inflammation can occur simply due to the natural aging of the patient. Suggested that the use of anti-inflammatory drugs could serve to reduce glandular inflammation. Systemic use of corticosteroids promoted under these conditions. However, is it positive effects of systemic corticosteroids in the state of dryness of the eyes has not been proven. In most cases, dry eye risk of long-term use of anti-inflammatory drugs, apparently outweigh their best advantage.

To treat conditions of dryness of the eyes also were offered surgery. In the case of substantial destruction of the conjunctiva, promoted transplantation mucosa. Also suggested that transplantation of a duct of the parotid (salivary) gland could be useful for the treatment of dry eye. However, surgical changes to combat the state of dryness of the eyes are an exceptional remedy, and any benefits arising from these changes is doubtful.

It was also proposed to introduce oral diluted solution of pilocarpine to stimulate the autonomic nervous system, in order to realize increased production of watery tears. This method of treatment is not universal because of the many unpleasant side effects of pilocarpine after it is swallowed.

Model of Sjogren syndrome in animals were the decisive factors for primary ophthalmic research. Disease such as Sjogren syndrome, detected in dogs with systemic superfamicom. This disease, which may be referred to as soba is the third CCM, is a common, chronic, progressive and potentially leading to blindness disease. Many lesions of the cornea and damage the conjunctiva is the result of a condition of dry eye. The reason a dog CCM is often not identified. Usually dog CCM is not a separate ophthalmic disease. In Kaswan et al., Am. J. Vet. Res. 46, 376-383 (1985) discussed that most cases of canine CCM flows through autoimmune mechanisms.

Other eye diseases include phacoanaphylaxis endophthalmitis and uveitis. These diseases can be localized around the eye in the posterior and anterior chambers of the eye, as well as in the vitreous body.

Uveitis, which represents an inflammation of the choroid is responsible for approximately 10% of visual impairment in the United States. Phacoanaphylaxis endophthalmitis is an autoimmune disease in humans.

Proveit refers to the inflammation of the entire uveal (vascular layer of the eye. Uveitis posterior chamber of the eye, usually refers to chorioretinitis, and uveitis anterior chamber of the eye refers to iridocyclitis. Inflammatory products (i.e. cells, fibrin, redundant proteins) of these inflammations usually be detected in the liquid space in the eye, i.e. the anterior chamber of the eye, the posterior chamber of the eye and the vitreous body, and t is the train penetrates into the fabric, closely involved in the inflammatory response. Uveitis may occur after surgical or traumatic injury to the eye; as a component of autoimmune disorders, i.e. rheumatoid arthritis, disease behceta, ankylosing spondylitis, sarcoidosis; in a separate indirect immune system eye disorders, that is, intermediate uveitis, iridocyclitis etc. that are not associated with a known etiology; and after some systemic diseases that cause deposition of complexes of antigen-antibody in uveal tissues. Together, these disorders are non-infectious uveitis.

Normal eyes protected from the immune control blood barriers that do not allow free migration of cells or proteins in the eye. When the eye is damaged or when there is a vasculitis, then the internal eye structures are exposed to General immune system and often cause autoimmune responses.

The compounds of this invention are also useful in the treatment of skin diseases and conditions. Found that the compounds according to this invention can be used for the treatment of balanite, such as nonspecific inflammatory, relapsing balanite. Cm. "Pimecrolimus 1% Cream in Non-Specific Inflammatory Recurrent Balanitis" by S.Georgala et al., Dermatology 2007;215:209-212. Compounds according to this invention m is able to be used for the treatment of psoriasis and atopic dermatitis (see "Cyclosporin Greatly Improves the Quality of Life of Adults with Severe Atopic Dermatitis. A Randomized, Double-Bind, Placebo Controlled Trial" by MS Salek et al., Br J Dermatol 1993:129:422-430 and Physicians' Desk Reference: PDR Gengraf Capsules (Abbot), respectively).

Phacoanaphylaxis is a severe form of uveitis, wherein the lens is a calling antigen. Proteins of the lens in normal separated lens capsule before birth. When these proteins are released into the eye for damage or surgical intervention, or occasionally with the development of cataracts, they can become highly antigenic and induce an autoimmune response. If the answer is moderate, it is detected as chronic uveitis. If he progresses very quickly, the eye becomes severely inflamed in all segments. This last response is called phacoanaphylaxis.

Methylthiazolidine cyclosporine A and other alkylthiophene derivative of cyclosporine As described in PCT application No. 98-379455, 98-379456 and 98-379457 and, as found, are active against retroviruses, in particular AIDS (syndrome acquired immunodeficita) and FCS (associated with AIDS complex) with the introduction of orally, parenterally, rectally or by inhalation.

Additionally, in General, found that they have only very weak immunosupression action and demonstrate antiviral activity when not cytotoxic and do not citest the critical concentrations. It is stated that these compounds have sinergeticheskim action with other agents active against retrovirus (such as reverse transcriptase inhibitors, protease, integrase, HIV replication and nucleocapsid).

These compounds are also claimed for use in the treatment of eye diseases and conditions in U.S. patent No. 6350442 and 6254860.

One of the objectives of this invention is to provide new derivatives of cyclosporine A for the treatment of eye diseases and conditions such as dry eye.

Another object of the invention is to provide new derivatives of cyclosporine A.

Another object of the invention is the treatment of skin diseases and/or conditions such as balanitis.

Another object of the invention is the treatment of skin conditions such as psoriasis and atopic dermatitis.

Other objectives of this invention will become apparent from a reading of the present description of the invention.

Brief description of the invention

In the present invention, a method for treatment of eye disorders or eye condition, for example, water-deficit condition of dry eye, uveitis or phacoanaphylaxis of endophthalmitis, including the stage of introduction into the eye a therapeutically effective amount of a compound selected from the group consisting of the C derivative of cyclosporine A, with the following formula. In the present invention, a method for treatment of skin disorders or skin condition, such as balanite or psoriasis, or atopic dermatitis, comprising the stage of introduction into the eye a therapeutically effective amount of a compound selected from the group consisting of derivatives of cyclosporine A. cyclosporine A Derivative used in the method(s) of the present invention represented by the formula

where R1is an S-Alk-R, where Alk represents alkylenes connection, preferably methylene or polymethene communication, for example, C2-C6polymethene communication or polyalkylene communication, for example, C3-C6alkynylamino bond and R represents-N=C(NR3R4)(NR5R6or

-NR7[(NR3R4)C=NR5], i.e. guanidine or-N=C(R8)(NR9R10therefore amidine, where R3-R10represents H, Alk, Ar or (CH2)nAr, where Ar represents an aryl group, and n represents an integer from 1 to 13, or R3and R4or R4and R5or R5and R7or R3and R7or R9and R10or R8and R9together may represent -(CH2)xwhere x is an integer from 2 to 5, for example,- CH2-CH2- or-CH2-CH2-CH2-, and R2selected from the group consisting of hydroxyl, lower alkyl and substituted by hydroxyl lower alkyl. For example, R1can be a-S(CH2)2N=C(NH2)2and R2may represent-CH2CH(CH3)2, -CH2C(OH)(CH3)2, -CH(CH3)2or-CH(CH3)CH2CH3.

Detailed description of the invention

In the present invention, a method for treatment of uveitis and phacoanaphylaxis of endophthalmitis from suffering from the patient, as well as water-deficit condition of dry eye by topical application to the affected eye a derivative of cyclosporine represented by the following formula

where R1is an S-Alk-R, where Alk represents alkylenes connection, preferably methylene or polymethene communication, for example, C2-C6polymethene communication or polyalkylene communication, for example, C3-C6alkynylamino bond and R represents-N=C(NR3R4)(NR5R6or-NR7[(NR3R4)C=NR5], i.e. guanidine or-N=C(R8)(NR9R10therefore amidine, where R3-R10represents H, Alk, Ar or (CH2)nAr, where Ar represents riloy group, and n is an integer from 1 to 13, or R3and R4or R4and R5or R5and R7or R3and R7or R9and R10together may represent-CH2-CH2- or-CH2-CH2-CH2and R2selected from the group consisting of hydroxyl, lower alkyl and substituted by hydroxyl lower alkyl. R represents-N=C(NR3R4)(NR5R6or-NR7C(NR3)(C=NR5), where R3-R7represents H, Alk, Ar or (CH2)nAr, where Ar represents an aryl group, for example, carbocyclic aryl or heterocyclic aryl, and n is an integer from 1 to 13, for example an integer from 1 to 4, or R3and R4or R4and R5or R5and R7(or R3and R7or R9and R10or R8and R9together may represent -(CH2)xwhere x is an integer from 2 to 5, for example-CH2-CH2- or-CH2-CH2-CH2-, and R2selected from the group consisting of hydroxy and lower alkyl.

For the purposes of describing and writing formulas of the present invention, the following terms have the following meanings.

"Alkyl" refers to pravarasena having a branched chain or cyclic saturated aliphatic uglev is Dorado. Preferably the alkyl group has from 1 to 12 carbon atoms. More preferably it represents a lower alkyl having from 1 to 7 carbon atoms, most preferably from 1 to 4 carbon atoms. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and other Alkyl group may optionally be substituted by one or more than one Deputy, selected from the group consisting of hydroxyl, ceanography, alkoxy, =O, =S, NO2, halogen, dimethylaminopropyl and SH.

"Alkenyl" refers to remotemachine having a branched chain or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond. Preferably Alchemilla group has from 2 to 12 carbon atoms. More preferably it represents a lower alkenyl having from 2 to 7 carbon atoms, most preferably 2 to 4 carbon atoms. Alchemilla group may optionally be substituted by one or more than one Deputy, selected from the group consisting of hydroxyl, cyano, alkoxy, O, S, NO2, halogen, dimethylamino and SH.

"Aryl" refers to an aromatic group that has at least one ring having a conjugate PI-electron system and includes carbocyclic ariline is, heterocyclic aryl and burilnye group. The aryl group may optionally be substituted by one or more than one Deputy, selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO2, Amin, tiefer, ceanography, alkoxy, alkyl and amino.

"Alkaryl" refers to alkyl, which is covalently bonded to the aryl group. Preferably the alkyl is a lower alkyl.

"Alkoxy" refers to an "alkyl" group.

"tBoc" refers to tert-butyloxycarbonyl protective group.

"Carbocyclic aryl" refers to aryl group, where the ring atoms are carbon.

"Heterocyclic aryl" refers to aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms are carbon atoms. Heteroatoms include oxygen, sulfur and nitrogen.

Derivative of cyclosporine A, used in the method according to this invention, was prepared as follows.

Compounds where R4, R5and R6represent hydrogen and R7represent hydrogen, alkyl, substituted alkyl or aryl, can be obtained by reacting the compounds of formula (I), where X is a leaving group and P represents a protective group, with a compound of formula (II) in a suitable process is the, such as methanol, to obtain the compounds of formula (III). For compounds of formula I are typical examples of the protective group are examples, where X=chlorine, MeS, MeSO21-imidazolyl and, in particular, 1-pyrazolyl. The protective group R preferably represents a tertiary butyloxycarbonyl group (tBoc).

Protection from compounds of formula (III) can be removed by applying different conditions to obtain compounds of the formula (IV). For example, when P=tertiary butyloxycarbonyl group (tBoc), they can be removed under acidic conditions using acids such as methanesulfonate acid.

The compounds of formula (V), where R7represents hydrogen, alkyl, substituted alkyl or aryl; R3represents alkyl, substituted alkyl or aryl, can be obtained by reacting the compounds of formula (VI), where X is a leaving group and P represents a protective group, with a compound of formula (II) in a suitable solvent, such as methanol, to obtain the compounds of formula (VII).

For compounds of formula (VI), typical examples of the protective group are examples, where X=chlorine, MeS, MeSO21-imidazolyl and, in particular, 1-pyrazolyl. The protective group R preferably represents a tertiary butyloxycarbonyl group (tBoc).

For example, in WO/2003/051797 N'/N'-di-tBoc-N-methyl-1H-pyrazole-1-carboxamide used to obtain the N-methylguanine in an unrelated chemical family.

Other compounds according to the invention can be obtained by analogy with the use of related synthetic methods, if applicable, with suitable protective groups that are compatible with the method of synthesis.

The compounds of formula (X), where R represents-N=C(R9)-NR9R10(amidine), where R8represents hydrogen, alkyl, substituted alkyl or aryl, and R9and R10can be an alkyl, substituted alkyl or aryl, or R9and R10may form a ring, can be obtained by reacting the compounds of formula (VIII) with the compound of the formula (IX) to give compounds of the formula (X). R11preferably represents lower alkyl and typical examples of the compounds (VIII) are dimethylformamide, dimethylacetal (DMF DMA) and dimethylacetamide, dimethylacetal (DMA DMA).

The following are specific examples of the preparation of some compounds according to the invention using the above General methods.

Guanidine and amidinov analogues of 3-[(2-aminoacetic]-cyclosporin A

Example 1.

3-[(2-Guanidyl)-ethylthio]-cyclosporine A (III)

To a solution of 3-[(2-aminoacetic]-cyclosporine A*(I)) (200 mg, 0.16 mmol) in methanol (20 ml) was added di-tBoc-pyrazole carboxamide (250 mg, 0.8 mmol) and the reagents were stirred together for 18 hours After this was added another portion of di-Tt-pyrazole of carboxamidine (100 mg, 0.32 mmol) and the reaction mixture was stirred for another 3 hours, the Reaction mixture is then evaporated in a vacuum, pererestorani in dichloromethane, washed with 0.5m citric acid and the organic layer was dried over MgSO4and evaporated in vacuum. The product was then purified using a chromatographic column on the cartridge 10 g SPE (solid phase extraction with diethyl ether elution for separation of 90 mg (40%) of the desired product (II).

As the first member of the synthesized guanidine and ajdinovic examples and in view of the difficulties faced in the description of the final product (III), decided to fully and widely to characterize di-tBoc-protected guanidine (II) at this stage and then to convert this substance into the free guanidine (III) by acid hydrolysis. Subsequent analogues in guanidine and medinova subclass, derived from 3-[(2-aminoacetic]-cyclosporine A, then okharakterizovali mainly by MS (mass spectrometry).

The compound (II) was analyzed using1H,13C NMR method undistorted amplification polarization transfer (EPT - Distortionless Enhancement by Polarization Transfer NMR nuclear magnetic resonance) and then using a series of 2-D NMR experiments, HMQC (heteronuclear multiquantum correlation), NMS (heteronuclear multi-band correlation) and DEPT-HMQC.

The presence of 3-[(2-guanidyl)-ethyltoluene] the side chain was confirmed by using the ID & 2D NMR. The analysis was carried out in solution CDCl3at 300 K on a spectrometer Bruker DRX500.

1H NMR of key resonances:

δ=1.50, 1.51 million-1(2 singlets, 2 xBoc, 18H, 6xCH3)

δ=5.89 million-1(singlet, sarcosin, 1H)

2D Spectra

Using experiments 1H detected heteronuclear multiquantum correlation (HMQC), heteronuclear multi-band correlation (NMS) and adjusted heteronuclear odnoslotovoy correlation (DEPT-HSQC) can be estimated for linkages and interpretation, confirming the presence of 3-[(2-guanidyl)-ethylthio] the side chain.

H(3)-2' (multiplet,1H 2,84 million-1, 2H).

2'-3' (multiplet,1H to 3.67 million-1, 2H).

the 3'NH4' (triplet JHH5.8 Hz,1N 8,67 million-1, 1H).

To a solution of di-tBoc-protected 3-[(2-guanidyl)-ethylthio]-cyclosporine A (II) (21 mg, 0,0138 mmol) in dichloromethane (0.3 ml) was added triperoxonane acid (0.3 ml) and the solution was stirred at room temperature for 1 hour. The solution was concentrated to obtain the product (III) in the form of a white TV is Gogo substance (20 mg; 100%).

An analysis by MS (E+demonstrated mass 1320,2 (M+H), agreed with the proposed structure

Example 2

3-[(2-M, g>1-dimethylformamidine)-1-thioethyl]-cyclosporine A (III)

A mixed solution of 3-(1-diethylamino)cyclosporine A (0.64 g, 0.5 mmol) and N,N-dimethylformamide of dimethylacetal in 20 ml of THF was heated under reflux for two hours. After removal of the solvent in vacuo the residue was subjected to chromatography on a column of silica gel using methylene/methanol (10:1) as eluents, received 300 mg of pure product (yield: 45.0%in).

MS (E+demonstrated mass 1332,82 (M+H+)consistent with the proposed structure.

Other ways understandable to experts-chemists, as well as methods of obtaining the starting compounds and intermediate compounds, etc.

In accordance with the present invention a derivative of cyclosporine A can be applied to the affected eye in any effective concentration, for example from 0.01 to saturation (e.g., greater than 20 wt.%) in pharmaceutically acceptable excipient. Can be used from 0.01 to 50 wt.%, preferably from 0.1 to 20 wt.% derivatives of cyclosporine A in a pharmaceutically acceptable excipient. Such pharmaceutically acceptable excipients are, for example, butter, raises the aspects of the oil, suitable organic or aqueous solvent, an artificial solution of tears, a natural or synthetic polymer suitable membrane for encapsulating derived cytosporone A.

Specific examples of pharmaceutically acceptable excipients are olive oil, peanut oil, castor oil, mineral oil, vaseline oil, dimethylsulfoxide, cremophor, Miglyol 182 (commercially available from Dynamit Nobel Kay-Fries Chemical Company, Mont Vale, N.J.), alcohol (e.g. ethanol, n-propyl alcohol or isopropyl alcohol), liposomes or lipoapoptosis products or silicone oil. Preferred excipients are dimethylsulfoxide and olive oil. Can be used a mixture of at least two of any suitable excipients.

Examples of artificial excipients tears, which can be advantageously used in practice of this invention are isotonic sodium chloride, cellulose ethers, such as hypromellose and hydroxyethylcellulose, polyvinyl alcohol and affordable artificial solutions of tea.

An example of a useful polymer excipient is polyoxyethylene castor oil.

Examples of pharmaceutically acceptable membranes, which can be mostly used is a practical implementation of this invention, are microdon representing an artificial lipid membrane, polyvinyl alcohol or methylcellulose.

Derivatives of cyclosporine And mainly administered topically as eye drops (solution or suspension) or ophthalmic ointments containing an effective amount of a derivative. Concentrations of from 0.01 to 50 wt.%, preferably from 0.1 to 20 wt.% derivatives of cyclosporine A are used in the practical implementation of this invention.

In accordance with the method of the present invention at least one of the derivatives of cyclosporin a is administered topically in any quantity required to provide the required degree of treatment. For example, a positive use of 5 microliters to 1 milliliter of solution, suspension or ointment containing an effective amount of a derivative of cyclosporine A, such as from 0.01 to 50 wt.%, preferably from 0.1 to 20 wt.% a derivative of cyclosporine A.

Numerous benefits are added in the practical implementation of the present invention. The method according to the present invention is useful because it may locally prevent activation desisting answer. Local injection of cyclosporine A derivatives in the eye of a patient suffering from a lack of tears, increases the production of tears in the eye. Thus, this treatment will add is Ino serves for correction of disorders of the cornea and conjunctiva, aggravated by a deficiency of tears and the CCM, such as scarring of the cornea, corneal ulceration, inflammation of the cornea or conjunctiva, filamentary keratitis, mucopurulent secretions and vascularization of the cornea. In addition, derivatives of cyclosporine A directly weaken the immune response and granulation and neovascularization.

An additional objective of this invention together with additional features contributing to the invention and the advantages arising from it, is clear from the following examples of the invention.

The preceding description provides detailed information about the specific methods and compositions, which can be used for the practical implementation of the present invention, and represents the best of the proposed method. Thus, although in the above text, you may receive the detailed description, it should not be construed as limiting the overall scope of the invention; rather, the scope of the present invention should be determined only by the lawful construction of the claims. In particular, although the method according to the present invention is described with the use of specific derivative of cyclosporine A the above formula, new cyclosporine derivatives, which can be used in the method according to the present invention include 3-substituted iminal artioposthia cyclosporine A, preferably 3-substituted diaminomaleonitrile cyclosporine A, for example, derivatives of ((R)-(diamino)aminoalkylation-Sar)3-(4'-hydroxy-MeLeu)4cyclosporine A, ((R)-(alkyl)(dialkylamino)aminoalkylation-Sar)3--(4'-hydroxy-MeLeu)4-cyclosporine A, ((R)-(alkyl)(dialkylamino)aminoalkylation-Sar)3-cyclosporin A and derivatives ((R)-(diamino)aminoalkylation-Sar)3-cyclosporine A.

1. A compound selected from the group consisting of compounds represented by formula

where R1is an S-Alk-R, where Alk represents methylene, C2-C6polymethene bond or C3-C6alkynylamino bond, R represents-N=C(NR3R4)(NR5R6or-NR7[(NR3R4)C=NR5], or-N=C(R8)(NR9R10), where R3-R10represents H, Alk, Ar or (CH2)nAr, where Ar represents an aryl group, and n represents an integer from 1 to 13, or R3and R4or R4and R5or R5and R7or R3and R7or R9and R10or R8and R9together may represent -(CH2)x-where x is an integer from 2 to 5, and R2selected from the group consisting of hydroxyl, alkyl having from 1 to 7 carbon atoms, and substituted what eroxia of alkyl, having from 1 to 7 carbon atoms.

2. The compound according to claim 1, where R represents-N=C(NR3R4)(NR5R6or-NR7C(NR3)(C=NR5), where R3-R7represents H, Alk, Ar or (CH2)nAr, where Ar represents an aryl group and n is an integer from 1 to 13 or R3and R4or R4and R5or R5and R7or R3and R7together may represent-CH2-CH2- or-CH2-CH2-CH2-.

3. The compound according to claim 1, which represents a 3-substituted derivative diaminodiphenyldisulfide A.

4. The compound according to claim 1, selected from the group consisting of derivatives of ((R)-(diamino)aminoalkylation-Sar)3-(4'-hydroxy-MeLeu)4cyclosporine A, ((R)-(alkyl)(dialkylamino)monoalkylation-Sar)3(4'-hydroxy-MeLeu)4-cyclosporin A derivatives ((R)-alkyl)(dialkylamino)aminoalkylation-Sar)3-cyclosporin a and derivatives ((R)-diamino)aminoalkylation-Sar)3-cyclosporine A.

5. The compound according to claim 1, where R1represents-S(CH2)2N=C(NH2)2and R2represents-CH2CH(CH3)2, -CH2C(OH)(CH3)2, -CH(CH3)2or-CH(CH3)CH2CH3.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to cyclosporine analogues, which possess antiviral activity with respect to HCV, their pharmaceutical compositions and method of treating viral infection in person.

EFFECT: elaboration of method of treating viral infection in person.

12 cl, 1 tbl, 131 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound and a pharmaceutically acceptable salt thereof to be used as an antifungal agent, particularly, a therapeutic agent for deep fungal disease. The fungus Acremonium persicinum is collected, and a cyclic compound is recovered from its cultural fluid.

EFFECT: what is presented is the compound applicable as an antifungal agent.

10 cl, 16 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to cyclic cationic peptides and use thereof in treating fungal infections.

EFFECT: high efficiency of application.

14 cl, 4 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to biologically active peptides able to inhibit myosin light chain kinase and thereby regulate the variability of vascular endothelial permeability. What is offered is a cyclic nonapeptide of formula cyclo[-Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-].

EFFECT: peptide can find application as a decongestant in various fields of medicine.

2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel cyclic peptide compound of pharmaceutically acceptable salt thereof, having activity against hepatitis C virus, based on inhibiting activity against replication of the hepatitis C virus RNA replicon, a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof, and use of the compounds or pharmaceutically acceptable salt thereof to prepare a medicinal agent with anti-HCV activity.

EFFECT: high efficiency of the compounds.

9 cl, 19 tbl, 259 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new cyclic peptide compound or its pharmaceutically acceptable salt which shows a hepatitis C virus activity based on an inhibiting activity of RNA replication of a hepatitis C virus replicon, to a method of producing it involving regrouping in a soft acid medium followed by amino acid exchange reactions, to a pharmaceutical composition containing said compound.

EFFECT: preparation of the drug exhibiting the anti-HCV activity.

16 cl, 44 tbl, 228 ex

FIELD: chemistry.

SUBSTANCE: in cyclosporine derivatives of general formula A, B, R1, R2 and X are defined in the description, for use in treating viral hepatitis C.

EFFECT: more effective treatment.

23 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel anti-tumour compounds which are kahalalide F derivatives, pharmaceutical compositions containing said derivatives and their use in preparing an anti-tumour medicinal agent.

EFFECT: obtaining novel anti-tumour compounds.

4 cl, 9 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the method for preparation of the cyclic somostatin analogues of formula I and to the intermediates used in the claimed method. The method is implemented by the cyclisation of somostatin having formula II where R1 is -C2-C6 alkylene -NR3R4, R3 and R4 independently of each other are H or acyl, R2 is , where R5 is phenyl, R11 and R12 independently of each other are amino protective groups. If R1 contains the amino end-group the latter is also protected with amino protective group, if necessary the amino protective group(s) is (are) eliminated and thus obtained compound of formula I is reduced in free or salt form.

EFFECT: improvement of method for preparation of somostatin peptides.

6 cl, 4 ex

FIELD: medicine.

SUBSTANCE: method provides interaction of cells of a medullary carcinoma of a thyroid gland with agonist SSTR2 representing bond of the formula of cyclo [Tic-Tyr-D-Trp-Lys-Abu-Phe].

EFFECT: reduction of rate of proliferation of cells of thyroid gland medullary carcinoma.

3 cl, 8 dwg, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: eyelid care is performed daily twice a day for one month in the form of a 1-2-minute Blepharowipe stupe. That is followed by a 1-2-minute eyelid self-massage with Blepharogel 1 or Blepharogel 2. Systane Balance artificial tear drops are instilled into a conjunctival cavity every 4 hours 3 times a day. The instillations are alternated with eye blinking exercises for 15 seconds 3 times a day. The therapeutic course is repeated one month later.

EFFECT: recovered functional state of the lipid layer of the tear film with an increase in the protective function of tears and relevant reduction of the clinical manifestations of the degenerative and inflammatory processes in the eyelids, conjunctiva and cornea due to an interaction of the procedures of the method each of which enhances the effect of the following one.

2 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to ophthalmology. The ophthalmic preparations are used in ophthalmic diseases as a lacrimal substitute, and they contain a combination of hyaluronic acid and a polysaccharide known as TSP (a Tamarindus indica seed polysaccharide). The ophthalmic preparations suggested to be used in treating a dry eye syndrome contain in a combination of 0.05 to 2 wt % of the tamarind seed polysaccharide and 0.05 to 1 wt % of hyaluronic acid in the aqueous solution.

EFFECT: when administered in a combination of hyaluronic acid and TSP, the invention provides a synergistic effect in stimulating the normal conjunctival mucosa recovery if affected by the dry eye syndrome, thereby inducing a noticeable improvement of the number and morphology of the conjunctival microvilli.

16 cl, 9 tbl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a multidose ophthalmic composition containing prostaglandin as a therapeutic ingredient, mannitol or sorbitol 0.15-0.5 wt/vol %, propylene glycol or glycerol 0.2-1.8, borate 0.25-0.5 wt/vol %, an antimicrobial preserving agent 0.0003-0.003 wt/vol % representing a polymer quaternary ammonium compound and water. Said composition has pH 6.4-7.2 and is benzalconium chloride free. Besides, the invention refers to the use of said ophthalmic composition for preparing a drug for treating glaucoma, eye infections, allergies and inflammations.

EFFECT: preparing the ophthalmic composition which exhibits improved antimicrobial preserving activity and improved buffer properties.

16 cl, 8 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of invention refers to ophthalmic compositions containing protease inhibition peptide substrates. The ophthalmic compositions contains a peptide substrate in a solution in the amount of approximately 0.01 wt/vol. % to 10 wt/vol. %, and said substrate is specified in a group consisting of gelatin, ovomacroglobulin, collagen and casein in an ophthalmically acceptable carrier. The composition additionally contains galactomannan and borate. The invention also describes a method for using the composition for treating dry eye.

EFFECT: group of invention provides higher viability and lower water loss of corneal epitheliocytes.

12 cl, 12 dwg, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an aqueous pharmaceutical suspension which contains a fine rebamipide of particle size 0.2-5 mcm and polyvinyl alcohol. The invention also refers to a method for preparing said rebamipide suspension which involves mixing water and polyvinyl alcohol to prepare an aqueous solution, adding fine rebamipide particles to said solution, and mixing to produce the aqueous rebamipide suspension.

EFFECT: invention provides preparing the suspension wherein rebamipide may be stably dispersed as fine particles without agglutination that enables store the suspension for a long time.

6 cl, 1 dwg, 1 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, in particular, to ophthalmology. Ophthalmologic compositions contain from 0.1 ppm to 10 ppm of cationic antimicrobial component, selected from group, consisting of biguanides, polymer biguanides, quaternary ammonium compounds and any their mixture; 0.005-0.15 wt % of hyaluronic acid; and 0.01-1.0 wt % of amphoteric surface-active substance of formula I, where R1 represents R or -(CH2)n-NHC(O)R, where R represents C8-C18 alkyl, which can be replaced by hydroxyl group and equals 2, 3 or 4; R2 and R4 each is independently selected from methyl, ethyl, propyl or isopropyl; and R4 represents C2-C8 alkylene, which can be substituted by hydroxyl group.

EFFECT: invention ensures application of ophthalmologic compositions for purification and disinfection of contact lenses and, in particular, soft silicon hydrogel contact lenses.

12 cl, 15 tbl, 5 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, particularly to ophthalmology. An aqueous liquid ophthalmic composition contains hyaluronic acid in the concentration of 0.05-0.4% or its pharmaceutically acceptable salt, and additionally contains gluconic acid and its salt with a metal, but does not contain chlorhexidine or its salt. A method for improving the viscosity stability of the aqueous eye-drop ophthalmic composition containing hyaluronic acid is conditioned by introducing gluconic acid and its salt with the metal.

EFFECT: invention provides slowed-down viscosity reduction of the aqueous ophthalmic composition.

6 cl, 6 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology, and may be used in treating eyelid cancer for prevention of obliteration of the lachrymal ducts. That is ensured by irrigation of the nasolachrymal duct twice a day before each session radiation therapy and in 10-12 days after the session. A solution containing 0.1% dexamethasone min. 2.0 ml and methotrexate 5 mg is injected in the nasolachrymal duct in a lower nasal point through a blunt-ended cannula on a syringe.

EFFECT: method provides prevention of such bothersome symptom as permanent lachrymation, as well as maintenance of light-refringent, protective function of the lachrymal organs, and finally - maintenance of visual functions.

2 ex

Eye drops // 2431470

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and medicine, and concerns a lachrymal substitute preparation which can be used for local therapy in an ocular surface disease. The invention has a composition (g/l): hydroxypropyl methylcellulose 2.5-5.0; disodium phosphate 5.5-16.5; sodium dihydrogen phosphate 0.8-1.5; sodium chloride 2.0-8.0; disodium edetate 0.1-0.5; benzalkonium chloride 0.03-0.09; dextrane 0.5-1.5; water for injections up to 1 l. The composition has the balanced proportions providing the pH value within 6.5 to 7.8, contains a polymeric composition containing hydroxypropyl methylcellulose and dextrane. As dextrane, either dextrane 40, or dextrane 60, or dextrane 70 is used.

EFFECT: invention provides ocular surface moistening that allows relieving or eliminating irritation symptoms caused by the ocular surface disease.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, ophthalmology, and can be used in diagnostics and surgical treatment of vision organ diseases. In realisation of the method instruments, products of medicinal purpose and liquids introduced into eye are used heated to +37°C. Open eyeball is irrigated from above with 0.9% of sodium chloride at temperature +37°C continuously by means of dropper with frequency 12 drops per minute, and illuminated by yellow dispersed light with wavelength 570-590 nm. Light formation is provided by light filter. Light brightness is increased under control of visibility of selected eye structures to minimal value, ensuring their visibility.

EFFECT: method eliminates injury of retina by light and injury of conjunctiva by dehydration and cooling.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: application of (R)-5-[3-chloro-4-(2,3-dihydroxypropoxy)benz[2]ylidene]-2-([2]-propylimino)-3-ortho-tolylthiazolidin-4-one (compound 1) or its salt for obtaining a medication for prevention and/or treatment of a disease or disorder, associated with the immune system activation, where the medication represents a set of Compound 1 doses; with the dose inducing the heart desensitisation in an initial phase of treatment and being lower than the final dose; with the said initial phase of treatment the dose is introduced with a frequency ensuring support of the heart desensitisation until the next acute reduction of heart rate occurs, after which the dose is titrated with increase to the final dose of Compound 1; a corresponding method of treatment and the set of doses.

EFFECT: invention ensures reduction and minimisation of undesirable side effects of Compound 1 (acute reduction of heart rate, atrioventricular conduction, or fatigue and dizziness) aimed at increase of Compound 1 tolerance and safety, as well as minimises problems, associated with monitoring at the initial phase of treatment or after interruption of treatment in the period of repeated treatment.

22 cl, 1 tbl

Up!