Derivatives of cyclosporine, the way they are received and farmcampsite based on them

 

(57) Abstract:

Describes new derivatives of cyclosporine General formula I ,

R is hydrogen, C1-C3-alkyl, C1-C3-alkoxy, galijasevic C1-C3-alkyl, replacement C1-C3-alkyl, (C1-C2)alkylamino or di (C1-C2)alkylamino;

X is oxygen;

x-y represents-CH=CH- (TRANS or-CH2-CH2);

Q is -(D)Ala, (D)Ser, -[0-2-hydroxyethyl (D)Ser]- or -[0-(2-acyloxyacyl)(D)Ser]-,

where each of the acyl residue is physiologically hydrolyzable and acceptable.

Describes how the above compounds and pharmaceutical composition for local administration, used as an immunosuppressive or anti-inflammatory agent with pharmaceutically acceptable diluents or carriers on the basis of compounds of formula I. 3 C. and 6 C.p. f-crystals, 3 tables.

The present invention relates to novel cyclosporin, their use as pharmaceuticals and to contain their pharmaceutical compositions and to methods for their preparation.

Cyclosporine include a class of structurally different, cyclic, poly-N-methylated undecyl protivorahiticheskimi activities, or activity reversion or increase resistance, for example, tumors or other drug therapy, in particular, multilocational resistance. The first dedicated cyclosporine was natural fungal metabolite Ciclosporin (Cyclosporine), also known as cyclosporin A and commercially available under the trademark SANDIMMUNRor SANDIMMUNER. Ciclosporin is the cyclosporin of formula A:

< / BR>
where is MeBmt N-methyl-(4R)-4-but-2E-EN-1-yl-4-methyl-(L) treningowy residue of formula B

< / BR>
where-x-y - is-CH=CH- (TRANS).

After the initial discovery of cyclosporine was isolated and identified a wide range of natural cyclosporine, and received a fully synthetic or semi-synthetic methods or microbiological methods using modified crops many additional non-natural cyclosporin. Thus, the class of cyclosporine currently is extensive and includes, for example, natural cyclosporine A - Z 1) Traber and others; Helv. Chim. Acta, 60, 1247 - 1255 (1977); 2) Traber and others; Helv. Chim. Acta, 65, 1655 - 1667 (1982); 3) Kobel and others; Eupor. J. Applied Microbiology and Biotechnology, 14, 273 - 240, 1982 and von Wartburg and others, Progress in Allergy, 38, 28-45, 1986, as well as various non-natural derivatives of CNT-x-y - residue-MeBmt- (Formula B above) saturate to obtain-x-y - equal-CH2-CH2- derivatives of cyclosporine, in which 3'-0-atom of residue-MeBmt - acelerou or further substituted on carbon atom Sarkisova residue at position 3; and cyclosporine, in which different amino acids linked in a specific peptide sequence. For example, use fully synthetic method of receiving cyclosporine, developed by R. Wenger (1) Traber and others, 2) Traber and others, 3) Kobel and others mentioned earlier); US patents N 4108985, 4220641, 4288431, 4554351, 4396542 and 4798823, EP 34567A, EP 56782A, EP 300784A and EP 300785A, WO 86/02080 and GB 2206119A and 2207678A; Wenger 1, Transpl. Proc., 15, Suppl. 1: 2230 (1983); Wenger 2, Angew. Chem. Int. Ed. 24, 77 (1985) and Wenger 3, Progress in the Chemistry of Organic Natural products, 50, 123 (1986).

Thus, a class that includes cyclosporine, very extensive and includes, for example, [Thr]2-, [Val]2-, [Nva]2and [Nva]2-[Nva]5-ciclosporin (also known as cyclosporin C, D, G and M respectively). [3-0-acetyl-Mebmt] 1ciclosporin (also known as the acetate of cyclosporin A), [dihydro-MeBmt] 1-[Val]2-ciclosporin (also known as dihydrocyclopenta D) [(D)Ser]8-ciclosporin, [Melle]11-ciclosporin, [(D)MeVal]11-ciclosporin (also known as cyclosporin H), [MeAla]6-ciclosporin, [(D)Pro]3-cyclosporine etc.

In accordance with the usual .E. cyclosporine A. This is done, firstly, the indication of those residues in the molecule, which differ from the residues present in the cyclosporine, and then applying the term "Cyclosporin" for the performance of other residues that are identical to residues present in the cyclosporine. So, [MeBmt]1-[Val]2the cyclosporine is cyclosporine containing the sequence represented in the formula A, but where the balance-MeBmt - in position 1 is replaced by MeBmt- (a residue of formula B, above, where-x-y - is-CH2CG2-), and Abu is in the second position is replaced by-Val-.

In addition, amino acid residues, which are referred to in abbreviated form, for example, -Ala-, MeVal-, - Abu - and so on, in accordance with the usual practice should be considered as having (L)-configuration, unless otherwise noted, for example, as in the case of-(D)Ala-". The reduction for the remainder, which is preceded by "Me", as for example, in the case of "-MeLeu -" represents-N-methylated residues. The individual remains cyclosporine molecules are numbered as usual, clockwise, starting with residue-MeBmt-, -dihydro-MeBmt - or residue corresponding to residue in position 1. The same numerical sequence used in the description of the invention and in the flavors of the local application, for example, in the treatment of lung diseases and painful conditions associated with light.

More specifically, the present invention relates to a derivative of a cyclosporin of formula I:

< / BR>
where R is hydrogen, (C1- C3)alkyl, (C1- C3)alkoxy, galijasevic (C1- C3)alkyl, replacement (C1- C3)alkyl, (C1- C2)alkylamino or di(C1- C2)alkylamino;

X represents oxygen;

-x-y - represents-CH=CH- (TRANS) or-CH2-CH2-;

Q is -(D)Ala-, -(D)Ser-, [0-(2-hydroxyethyl)(D)Ser]- or - [0-(2-acyloxyacyl)(D) Ser] -, in which the acyl residue is physiologically hydrolyzable and acceptable.

Preferred are derivatives of cyclosporin of formula I, in which

R is methoxy;

X represents oxygen;

-x-y - is-CH=CH-(TRANS);

Q is -(D)Ala-.

Especially preferred are derivatives of cyclosporin of formula I, in which

X represents oxygen;

-x-y - is-CH=CH- (TRANS);

Q is -(D)Ala-;

R means hydrogen, methyl, ethyl, ethoxy, trifluoromethyl, dimethylamino, hydroxymethyl, [S]- hydroxyethyl, [R]- hydroxyethyl

or kotori,

or

X represents oxygen;

-x-y - is-CH=CH- (TRANS);

Q represents a residue of formula III:

< / BR>
and R in formula I and R' in formula III are both stands and both methoxy.

Preferred alkyl groups R are methyl and ethyl. Preferred alkoxy R are methoxy, ethoxy. Galijasevic means chlorine-, bromine-, fluorine - or izlesene. Golozhabernyi group R can be mono-, di - or poly-alojamiento. Suitable Alojamientos(C1- C3)alkyl group as R is trifluoromethyl. Suitable replacement (C1- C3)alkyl groups as R is hydroxymethyl and 1-hydroxyethyl. Suitable mono - and di-alkylaminocarbonyl as R are methylamino, dimethylamino, methylethylamine, and dimethylaminopropan is the most preferred.

In one embodiment of the present invention R is hydrogen, (C1- C2)alkyl, (C1- C2)alkoxy, trifluoromethyl, replacement (C1- C2)alkyl, mono - or di-(C1- C2alkyl)-amino, especially hydrogen, (C1- C2)alkyl, (C1- C2)alkoxy, trifluoromethyl, UB>1- C2)alkyl, (C1- C2)alkoxy, and most preferably the stands or methoxy. The most preferred value of R is a (C1- C2)alkoxy, especially methoxy.

The term "physiologically hydrolyzable and acceptable", as used in the definition of Q determines acyl residues, which can be split under physiological conditions to obtain the acid, which is itself physiologically tolerable at input doses. Suitable acyl residues include benzoyl and salicyl, as well as the remnants of the formula R'-CX'-, where R' has the above values for R, excluding the amino and mono - and di-(C1- C2alkyl)-amino, and X' is oxygen or sulfur.

Preferably, Q was -(D)Ala -, or group III, as indicated previously. Particularly preferably, Q was -(D)Ala-.

The cyclosporine of the present invention, in which R and/or R' is an asymmetric group, for example, one in which R is - hydroxyethyl demonstrate optical isomerism. In this case, the individual isomers can be obtained in the usual way, for example, by synthesis from optically active starting materials (as, for example, in the case of about 10 and 11, below), or raznyh compounds. In those cases, when there are such isomers, note that the present invention covers both the individual isomeric forms, for example, S - and R-enantiomers and their mixtures, e.g. racemic and diastereomeric mixture, unless otherwise noted. However, in General, for pharmaceutical use in accordance with the method of the present invention, the use of individual enantiomers in pure or substantially pure form, for example, containing up to 95% or more pure single enantiomer, will be preferred.

In the present invention proposed a method of obtaining a cyclosporin of formula I, which lies in the interaction of a derivative of formula IV:

< / BR>
where the values of "x-y" and "Q" represent previously indicated, with a compound of formula V:

< / BR>
where Z means tsepliaeva group, R and X have the previously indicated meanings, in this case, if R is a protected by a hydroxy-group replacement (C1- C3)alkyl, remove the protection, and if obtained in this connection Q is [0-(2-hydroxyethyl)(D)Ser], if necessary, carry out the acylation of this compound allermuir agent.

Suitable protective groups vkluchite in accordance with the procedure described by Corey and others J. Am. Chem. Soc., 94, 6190 (1972).

In cyclosporine the source materials of the formula IV 8'-hydroxy-group residue in position 1 is more reactive than the hydroxyl group, which may be present in the residue in position 8, for example, when Q is -(D)Ser-. According to the method, respectively, to introduce the group R-C(= X)-, mainly on the residue in position 1. For example, using 1 equivalent of the compound of formula V can then follow the stage of introduction of a great group R'-C(=X)- residue in position 8. For this purpose, the compound of the formula V R'-C(=X)-Z, where X' is oxygen and R' has the meaning given above for formula III. Z is tsepliaeva group.

If you want to enter the group R'-C(=X) is in position 8, which is identical to the group R-C(= X) is in position 1, the above reaction can be conducted simultaneously, using two equivalents of the compounds of formula V or V'.

Suitable connections V and V' for use in the method include acylhomoserine, for example, those in which Z is chlorine or bromine, and the anhydrides, for example, those in which Z = R-CX-O - or R'-CX'-O. the Reaction is conveniently conducted in the presence of an acid binding agent, for example, 4-dimethylaminopyridine is known or can be obtained analogously to known compounds. Replacement of allhelgona in O-tert. -butylcyclohexanol the form described, for example, in Chem. Abstr. 109-149284 and Bishofsberger and other J. Org. Chem., 53, 3457 (1988).

Cyclosporine starting compound of the formula IV can be obtained in the following sequence of reactions. In this sequence of reactions only residue in position 1 molecule of cyclosporine are presented in detail. The remainder of the molecule is indicated as "(rs2-11)," and is indicated for the formula I, the residue sequence, namely the following sequence: - Abu-Sar-MeLeu-Val-Ala-Q-MeLeu-MeVal-; x-y have the values given for formula I.

< / BR>
< / BR>
Stage (c) - (f) is conveniently conducted in accordance with the General methods described in example 1 or in a similar way. If the residue at position 8-(rs2-11), i.e., the residue Q is -(D)Ser - or -(0-2-hydroxyethyl)(D)Ser), its free hydroxyl group will also undergo formirovanie at the stage (c) and the subsequent determenirovana on the stage (f).

Cyclosporine starting materials of formula V are known or can be obtained analogously to known cyclosporine. So, if (rs2-11) represents the specified sequence, where Q is -(D)Ala-specified cyclosporine are the CEC is acyl(D)Ser)-, described, for example, in EP 56782A and in the patent GB 2155936A. Appropriate cyclosporine, in which Q is -(0-(2-hydroxyethyl)(D)Ser) or(0)2-acyloxyacyl)(D)Ser) is described, for example, in EP 414632 (application N PO 810567.9).

The cyclosporin of formula IV, where x-y - is-CH=CH- (TRANS), and Q is the (D)Ala-, also known as metabolite cyclosporine A. This metabolite is known to experts as M17.

The following examples illustrate the process of receiving cyclosporin of the present invention.

Example 1

Getting [(8'-methoxycarbonylamino)MeBmt]1-cyclosporine (formula I, where R = CH3O-, X = O, -x-y = -CH=CH (TRANS), Q = -(D)Ala-).

0.33 ml of methylchloroform added to a solution of 4.9 g [(8'-hydroxy)MeBmt]1-cyclosporine and 1.9 g of 4-dimethylaminopyridine in 50 ml of dimethylformamide in anhydrous conditions. The reaction mixture was stirred at room temperature for 18 hours. The solvent is removed in vacuum. The residue is placed in ethyl acetate, washed with aqueous tartaric acid and water Na2CO3. The solvent is removed under reduced pressure and the residue is purified on a chromatographic column with silica gel, using ethyl acetate saturated with water, to obtain the title compound: []2D0= get the following:

Getting [(3'-0-formyl)MeBmt]1-cyclosporine formula VI (process stage c).

15 ml acutiformis added to a solution of 9.6 g of cyclosporine (cyclosporine A) and 3.9 g of 4-dimethylaminopyridine in 100 ml of acetone for 30 minutes at room temperature. The reaction mixture is stirred for 20 hours at room temperature, and the solvent is distilled off under reduced pressure. The residue is placed in ethyl acetate, washed with aqueous Na2SO4. The organic solvent is removed under reduced pressure. The residue is crystallized from boiling hexane to obtain the title compound.

tPL= 195 - 197oC.

Getting [(8'-bromo-3'-0-formyl)MeBmt]1-cyclosporine formula VII (process stage d).

75 g of the product of stage (c) of 11.7 g of N-bromosuccinimide and 1 g of azoisobutyronitrile in suspension in 750 ml of CCl4heated to boiling under reflux for 2 hours. The residue is filtered, washed with aqueous sodium bicarbonate, aqueous tartaric acid and brine, and the organic layer dried over sodium sulfate. The solvent is removed under reduced pressure to obtain the title compound that is introduced into the further reaction without additional LASS="ptx2">

86 g of the product of stage (d), 1 g of NaI and 27 g of tetraethylammonium in 750 ml of methyl ethyl ketone heated to boiling under reflux for 4 hours. The solvent is removed under reduced pressure, the residue is placed in ethyl acetate and washed with aqueous sodium carbonate, aqueous tartaric acid and brine. The organic layer is dried over sodium sulfate, and the solvent is removed under reduced pressure to obtain the title compound that is administered in the following reaction without further purification.

Getting [(8'-hydroxy)MeBmt] 1-cyclosporine M17 formula IIIa (process stage f).

71 g of the product from step (e) is stirred for 18 hours at room temperature in a 0.8 M methylamine ethanol. The solvent is removed under reduced pressure and the residue chromatographic on silica gel using ethyl acetate saturated H2O. the Solvent is removed under reduced pressure, obtaining mentioned in the title compound as a white foam Rf= 0,31 (ethyl acetate saturated with H2O; silica gel).

Following the cyclosporin of formula I indicated earlier, in which the residue A is represented by formula Ia, where R and x-y have the meanings given in table 1 (see end of description),I, where a is a residue of the above formula Ia, where R has the values listed in table 2, and-x-y - is-CH=CH- (TRANS), and Q is a residue of formula IIIa:

< / BR>
where R' has the meanings given hereinafter in table 2 (see end of description), can also be obtained in the same manner but using 2 equivalents of the desired Alliluyeva agent.

The cyclosporine of the present invention have potential immunosuppressors and anti-inflammatory activity. In particular, they inhibit provoked by antigen inflammatory cell infiltration, for example, in the respiratory tract. In vivo, this activity appears after local injection, for example, after local injection in the Airways through inhalation. It was found that the cyclosporine of the present invention on the contrary have significantly reduced or have little or no activity, for example, anti-inflammatory or immunosuppressing activity in vivo with regular admission, for example, after oral administration.

Immunosuppressive and anti-inflammatory properties of cyclosporine of the present invention can be demonstrated in standard test models in vitro and in vivo, for example, sledujushim">

Approximately 0.5 106lymphocytes from the spleen females (8-10) weeks mice strain BaI b/c incubated for 5 days in 0.2 ml of medium for cell growth from approximately 0.5 to 106lymphocytes from the spleen females (8-10 weeks) mouse strain CBA. The test substance is added to the medium at various concentrations. Activity assessed by the ability to suppress the proliferation associated with DNA synthesis, which is determined by the binding radiochango thymidine.

Cyclosporine according to the method of the present invention inhibit the binding of thymidine at concentrations of about 0.005 to 0.025 µg/ml.

1.2 Test Michel-Dutton

Approximately 107lymphocytes from the spleen of female mice of the strain OFI cultivate together with about 3 to 107the sheep red blood cells within 3 days. The test substance is added to inkubiruemykh environment in various concentrations. Lymphocytes collected and placed on the agar with fresh sheep red blood cells as antigen. Sensitized lymphocytes secrete antibodies, which cover the red blood cells, and lysis occurs with the formation of plaques in the presence of additives. Activity assessed by reduction of the resulting plaques, i.e., cells that produce antibodies. Cyclosporine this out/P> 2. The impact caused by allergens pulmonary eosinophilia (in vivo)

Male Himalayan spotted Guinea pigs (300 g, BRL) sensibiliser with ovalbumin (OA) by intraperitoneal injection of 1 ml of suspension OA (10 mg) with Al(OH)3(100 mg) and B vaccine-pertussis (0.25 ml) in physiological solution (0.9% wt./volume). For oral studies, the procedure was repeated 1 time in 2 weeks, and animals used in another week. For inhalation studies, the procedure was repeated 2 times with intervals of 3 weeks, and animal use in the week after the last injection.

Immunization is done using saline OA sprayed in the experimental chamber. Test animals exposed to OA only inhalation through the nose for 60 minutes. For oral studies, the OA solution is used at a concentration of 0.05%. For inhalation studies using OA solution at a concentration of 0.01%.

The test substance is administered (a) oral and (b) by inhalation. For oral studies, the test substance is administered orally (R.) olive oil 1 times a day for 3 days or powder with methylcellulose once to OA immunization. On the third day of the test animals receiving the test substance for the hollowed out for the introduction of test animals in the liquid paste is only through the nose. Introduction by inhalation carry out 15 minutes before OA immunization.

The efficiency of insertion of the test compounds determine bronchoalveolar lavage (BAL) and counting cells. For this purpose, animals kill Na-pentobarbitone (100 mg/kg intraperitoneally) and extract the trachea and kanyoro. Then injected into the light 5 consecutive aliquot of 10 ml of Ca2+and Mg2+free balanced salt solution, Henk (HBSS) containing bovine serum albumin (BSA, 0.3%) and EDTA (10 mm) and HEPES (10 mm), and immediately sucked off by gently squeezing lung tissue. The total number of cells in the collected eluates determined using an automatic cell counter. The lavage fluid centrifuged at 200 rpm for 10 minutes and the cell sediment is re-suspended in 1 ml additional HBSS. 10 μl of cell suspension is added to 190 μl of a solution Turk (1:20 dilution). Spend dierential counts of cells on smears, tinted Chiff-Quick. Cells identify and consider immersing in oil (x1000). Consider the minimum of 500 cells per smear and appreciate the full population of each cell type.

Untreated animals OA infection causes an increase in the content of the cells of all types bretania by inhalation at doses of the order of from 1.0 to 15.0 mg/kg reduces eosinophils in BAL depending on dose, compared with untreated control experiments. The number of cells of other leukocytes (macrophages, neutrophils) also decreases. On the contrary, repeated oral introduction of cyclosporine present invention does not have a significant effect on the number of cells compared to untreated control.

Cyclosporine present invention accordingly suitable for the treatment of diseases or medical conditions that respond to or require local anti-inflammatory, immunosuppressing or family therapy, for example, by local injection for the treatment of such diseases or morbid conditions of the eye, nasal cavity, oral cavity, skin, rectum, or, especially, respiratory tract or lungs. In particular, the cephalosporins of the present invention allow local anti-inflammatory, immunosuppressing or family therapy while reducing or excluding unwanted side effects, for example, the total system immunosuppressive.

The cyclosporine of the present invention is particularly suitable for the treatment of diseases or medical conditions of the Airways or lungs, in particular inflammatory disease or obstructive diseases of the respiratory tract. Olivani, associated with or characterized by inflammatory cell infiltration or other inflammatory phenomena accompanying inflammation cells, for example, the accumulation of eosinophils and/or neutrophils. They are particularly suitable for the treatment of asthma.

The cyclosporine of the present invention is suitable for treatment of asthma of any type and origin, including both endogenous and exogenous asthma. They are suitable for the treatment of atopic or diatopically asthma, including allergic asthma, bronchial asthma, caused by stress, asthma, associated with place of residence, asthma, bacterial infections, and other asthma non-allergic origin. Treatment of asthma also includes treatment "striding child syndrome", i.e. the treatment of children under the age of 4-5 years, with symptoms of stridor, particularly at night, with a diagnosis of strigamia children" belonging to the category of regular patients, and lately, more correctly classified as prone to asthma or asthma patients in the early stages. The cyclosporine of the present invention, particularly useful in the treatment of asthma in patients, asthmatic status of which depends on steroids or resistant to steroids.

The cyclosporine of the present invention, moreover, useful in the treatment of lung diseases (e.g., inflammation, usually associated with a place, diseases of the lungs, frequently accompanied by inflammation of the respiratory tract, both chronic and acute, and caused frequent inhalation of various dusts), of any type and origin, including, for example, aluminas, antraks, asbestosis, beryllos, helicos, files, sideros, silicosis, tabacos and, especially, bessines.

The cyclosporine of the present invention can also be used for treatment of respiratory diseases associated with eosinophils (for example, including morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia and its effect on the respiratory tract and/or lungs, as well as, for example, associated with eosinophils diseases of the respiratory tract, accompanied by the syndrome Leffler, eosinophilic pneumonia, parasitic (in particular, METAS the key syndrome Churg-Strauss), eosinophilic granuloma and associated with eosinophils diseases of the respiratory tract, caused by a reaction to medications.

Under the wording of "treatment," as it is used on the treatment of diseases of the respiratory tract or lungs, and, in particular asthma, you should understand covering both symptomatic and prophylactic treatment, i.e. immediate treatment, for example, acute inflammation (symptomatic treatment), and prior treatment for preventing, improving or limiting long-term symptomatology (prophylactic treatment). The term "treatment" as used in the present description and the claims about such diseases should be understood, respectively, as including both symptomatic and prophylactic treatment, for example, in the case of asthma symptomatic treatment to relieve acute inflammatory attack and prophylactic treatment to limit the ongoing inflammatory condition and to reduce further related exacerbations.

The cyclosporine of the present invention can also be used to treat any diseases or illnesses of the respiratory tract and is(for example, for the treatment of sarcoidosis, alveolitis or chronic hypersensitive pneumonia) or to maintain allogeneic lung transplant, for example, after lung transplantation or heart.

As mentioned previously, for the above purposes, the cyclosporine of the present invention must be entered locally in the respiratory tract, for example, by inhalation. As mentioned previously, having the potential to be effective at the local introduction, the cyclosporine of the present invention do not possess or demonstrate relatively low system activity, for example, after oral administration. Thus, the cyclosporine of the present invention provide a means for the treatment of diseases and painful conditions of the lungs, as mentioned earlier, while allowing to avoid undesirable systemic side effects, for example, related to involuntary ingestion of drugs in the treatment of inhalation. (It is estimated that during the course of inhalation when the necessary manipulations up to 90% or more of the drug is usually eaten, not is inhaled).

By offering cyclosporine, which is active in the local introduction, i.e., effective the mi for patients for which otherwise such treatment would be excluded, for example, due to systematic risk, especially immunosuppressing, side effects.

The cyclosporine of the present invention is also suitable for treatment of other diseases or medical conditions, in particular diseases or medical conditions with an autoimmune or inflammatory component, and which can be practiced local therapy, such as treatment of diseases or morbid conditions of the eye, such as conjunctivitis, keratoconjunctivitis, vernal conjunctivitis and maintain corneal transplants, and diseases associated with the nose including allergic rhinitis, diseases and painful skin conditions, including psoriasis, atopic dermatiti, pemphigus and contact dermatitis, diseases of the colon, for example, disease Cronin's and ulcerative colitis.

For the previously mentioned purposes, the cyclosporine of the present invention can be used in any dose forms suitable for local injection in the right place. So, for the treatment of diseases of the respiratory tract or lungs cyclosporine present invention can be activated by inhalation or inhalation of the corresponding raspredeljal finely chopped or thin-dispersed form, suitable for introduction into the respiratory tract or lungs, for example, in the form of fine dry particles or in the form of a dispersion or solution in any suitable (i.e., the potential for introduction into the respiratory tract) solid or liquid media. For administration in the form of dry particles, the cyclosporine of the present invention can, for example, be used as they are, i.e. in microtrenching form without additional materials, diluted with additional materials - micronized inert solid carriers or diluents (e.g., glucose, lactose, mannitol, sorbitol, ribose, mannose or xylose), in the form of particles with a coating or in any other form known in the art for introduction into the respiratory tract finely ground solids.

Introduction to light can be carried out using any suitable system known in the art for administration of drugs in a dry or liquid form by inhalation, for example, the atomizer, a nebulizer, an inhaler for dry powder or similar device. Preferably the device with a measuring device, with which you can enter a predetermined number of cyclosporine in each act. Such is the updated enter in liquid form from the appropriate device for instillation into the nose. Suitable forms for local injection for the treatment of diseases or medical conditions related to the skin include, for example, creams, gels, ointments, pastes, cataplasma, plasters, transdermal patches, etc., Compositions for dermal applications usually contain the appropriate agents promoting penetration through the skin, for example, well-known specialists azone. Form suitable for ophthalmic application, include lotions, tinctures, gels, ointments and eye liners, also known in the art. For rectal administration, for example, for local therapy of the rectum, the cyclosporine of the present invention can be introduced in the form of suppositories or enemas, in particular in solutions, for example solutions of vegetable oil or similar oil systems for use in the form of withholding enemas.

Accordingly, the present invention provides:

A. a Method of treating diseases or medical conditions requiring anti-inflammatory, immunosuppressing or family therapy in need of the patient, and the method includes the local introduction of an effective amount of cyclosporine of the present invention.

B. Cyclosporine nastoyashtego, immunosuppressing or family therapy, for example, for use in method A, described above, especially for local injection into the respiratory tract.

The method described in paragraph A applies, in particular, for the treatment of diseases or morbid conditions of the eye, nose, throat, oral cavity, skin, colon, or, especially, respiratory tract or lungs. It is also applicable to diseases or morbid conditions listed above, in particular, to any diseases or morbid conditions of the Airways or lungs, requiring anti-inflammatory or family therapy, especially any diseases or morbid conditions of the Airways or lungs, different inflammatory cell infiltration, and especially for the treatment of asthma.

Further object of the present invention is:

C. Pharmaceutical composition for local administration, i.e. suitable for local injection in the form of containing cyclosporin present invention as immunosuppressing or anti-inflammatory agent together with a pharmaceutically acceptable diluent or carrier, or cyclosporine of the present invention in the form of, or means, or device, obeso, mentioned previously, are diluents or carriers acceptable to the local introduction of the desired treatment area, for example, diluents or carriers acceptable to the local introduction of the respiratory tract, skin, through the nose, eyes, or rectally. Forms for local administration, for example, facilitate or provide local introduction, include, for example, preparations of dry powders of the active ingredient (e.g., cyclosporine of the present invention in virtually pure form, for example, those that are used by specialists for any inhalation device for the introduction of powder. Tools or devices that provide or facilitate local introduction, include, in particular, devices for inhalation, as well as containers, etc. from which the active ingredients can be submitted in a form suitable for local administration. The preferred option described in paragraph C will be such that allow local entry into the respiratory tract or lungs, for example, by inhalation.

Dose cyclosporin of the present invention used to practice the method of the present invention, of course, will depend on the application, a specific state depending on the desired effect. In General, for the treatment of diseases or medical conditions of the Airways or lungs, for example, for use in the treatment of inflammation or complications of respiratory diseases, such as asthma, cyclosporine present invention should be introduced locally in the respiratory tract or lungs, i.e., through inhalation, in doses of from 20 to 400 mg/day, for example, from 50 or 100 to 300, or for example, from 200 to 300 mg/day. Doses should be through a measuring system for a number of consecutive breaths from 1 to 5 for each reception, and the reception can be repeated one to four times per day. Thus, the dose at each introduction will be of the order of from about 5 to 100 mg, more conveniently, from 12.5 or 25 to 100 mg, i.e., in a volumetric flow device will be supplied, for example, from 1 to 25 mg at one time.

For the treatment of diseases of the eyes and nose cyclosporine of the present invention is usually administered in the form of appropriate compositions, for example, eye drops, gels, liquids, or so forth, or nose drops, spray in the nose or etc., containing from about 0.05 to about 10%, and especially from about 0.05 to about 5%, more preferably from about 0.1 to about 2.5% by weight of cyclosporine, acceptable for introduction into the eyes or nose diluent or HP, from about 0.05 to about 0.1 ml of the composition once or two to three times a day.

For the treatment of diseases or medical conditions of the colon is usually a suitable daily dose of cyclosporine of the present invention is on the order of from about 0.5 to about 15,0, preferably from about 2.5 to about 10.0 mg/kg and usually introduced as held enema, administered once or in half dose twice a day. Thus, each dose should contain from about 17.5 to about 1000, and preferably from about 35 to about 700, more preferably from about 87.5 to about 550 mg of cyclosporine of the present invention along with the corresponding rectal applicable diluent or carrier. Suitable concentrations of cyclosporine for use in such held the enema be on the order of from about 0.5 to about 12.0, and preferably from about 1.0 to about 10.0, and more preferably, from about 2.0 to about 7.0 mg/ml

For application to the skin for the treatment of diseases or painful skin conditions cyclosporine of the present invention is usually administered in an appropriate, i.e., acceptable for the skin, containing from about 1 to 10 wt.% cyclosporine together in an acceptable skin razbavitelyami 0.005 to 0.05 g/cm2, 1, 2 or 3 times a day.

The preferred cyclosporine of the present invention is the product of example 1, namely [(8'-methoxy-carbonyloxy)MeBmt]1- cyclosporine. Specific results for this cyclosporine in a series of tests carried out according to the methods described in p. p. 1.1, 1.2 and 1.3 and 2 above are shown in table 3.

1. Derivatives of cyclosporine General formula I

< / BR>
where R is hydrogen, (C1-C3)alkyl, (C1-C3)alkoxy, galijasevic (C1-C3)alkyl, replacement (C1-C3)alkyl, (C1-C3)alkylamino or di(C1-C2)alkylamino;

X is oxygen;

-x-y - represents-CH=CH-(TRANS) or-CH2-CH2-;

Q is -(D)Ala-, -(D)Ser-, -[0-(2-hydroxyethyl)(D)Ser]- or -[0-(2-acyloxyacyl)(D)Ser]-, in which the acyl residue is physiologically hydrolyzable and acceptable.

2. Derivative of a cyclosporin of formula I under item 1, in which R is methoxy; X is oxygen; -x-y - is-CH=CH-(TRANS); Q - -(D)Ala-.

3. Derivative of a cyclosporin of formula I under item 1, in which X is oxygen; -x-y - is-CH= CH-(TRANS); Q - -(D)Ala-; R is hydrogen, methyl, ethyl, ethoxy, trifluoromethyl, dimethylamino, hydroxymethyl, [S]-hydroxyethyl, [R]-g-x-y - is-CH=CH-(TRANS); Q is a residue of formula III

< / BR>
and R in formula I and R' in formula III are both stands or both methoxy.

4. The method of obtaining the derivative of a cyclosporin of formula I under item 1, which consists in the interaction of a derivative of formula IV

< / BR>
where the values of-x-y - and Q correspond to those specified in paragraph 1 of the claims,

with the compound of the formula V

< / BR>
in which Z - tsepliaeva group,

R and X have the meanings specified in paragraph 1,

in this case, if R is protected by a hydroxy-group replacement (C1-C3)alkyl, remove the protection, and, if received in this connection Q is [0-(2-hydroxyethyl)(D)Ser] , if necessary, carry out the acylation of this compound allermuir agent.

5. Derivative of a cyclosporin of formula I according to any one of paragraphs.1 to 3, having the properties immunosuppressing or anti-inflammatory agent.

6. Derivatives of cyclosporine on p. 5, which are intended for use in the composition of medicines for the treatment of diseases or medical conditions that require immunosuppressing or anti-inflammatory therapy.

7. Derivatives of cyclosporine on p. 6, which are intended for use in the composition lekarstvennyye for use in the composition of medicines for local injection into the respiratory tract or lungs in the treatment of asthma.

9. Pharmaceutical composition for topical administration, comprising an effective amount of the derivative of a cyclosporin of formula I according to any one of paragraphs.1 to 3, as immunosuppressing or anti-inflammatory agent with pharmaceutically acceptable diluents or carriers.

 

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The invention relates to the field of medicine

FIELD: medicine.

SUBSTANCE: the present innovation deals with cyclosporin-containing and practically oil-free compositions being of immunosuppressive action. The composition contains a hydrophilic surface-active substance, a lipophilic component, a lipophilic surface-active substance and ethanol. As a hydrophilic surface-active substance this composition contains ether of fatty acid and polyoxyethylene sorbitane and product of either natural or hydrogenised castor oil and ethylenoxide; as a lipophilic component and lipophilic surface-active substance it contains ether of fatty acid and sorbitane. The suggested composition has been designed as a gelatinous capsule with solid covering. The present innovation solves the problem dealing with stability of galena compositions with cyclosporin: at treating with water the composition develops practically stable microemulsion.

EFFECT: higher efficiency of application.

11 cl, 2 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: pharmaceutical composition comprises efficient amount of lipophilic medicament in combination with pharmaceutical carrier. The latter consists of propylene glycol esters of C6-C18-fatty acid with 90 wt % monoester and nonionic surfactant, whose hydrophilic/lipophilic balance exceeds 10 and is suitable to solubilize lipophilic medicament. Above-mentioned surfactant is present in amount high enough to form microemulsion with ester and medicament when in contact with aqueous medium. Preferably medicament is cyclosporine.

EFFECT: increased stability of composition to provide desired pharmacokinetics and biological accessibility of lipophilic drugs essentially non soluble in water.

34 cl, 10 ex

FIELD: antibiotics, pharmacology of peptides.

SUBSTANCE: invention relates to high-active crystalline preparation of cyclosporine A and a method for its preparing. Invention relates to high-active crystalline preparation of cyclosporine A representing cyclic undecapeptide prepared from fungus of genus Tolypocladium inflatum subsporum blastosporum grown in cultural medium containing additionally rubomycin in the concentration 2 mcg/ml and zinc sulfate in the concentration 5 mg/ml. The fermentation medium comprises maltex and D,L-valine as main components wherein the final concentration of preparation in medium is 2.0-2.5 mg/ml. Product is isolated from fungus dried mycelium by extraction with petroleum ether before and after purification by chromatography method on silica gel and crystallized in system hexane - acetone (4:1). Invention provides the development of effective cyclosporine preparation wherein the content of cyclosporine A is 80-85%.

EFFECT: improved preparing method.

2 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to microemulsion preconcentrate comprising active ingredient, oil, surfactant and hydrophilic solvent selected from group containing propylene glycol diacetate, propylene glycol acetate and salts thereof. Microemulsion preconcentrate optionally contains as active ingredient not only hydrophobic compounds but also hydrophilic compounds and proteins.

EFFECT: microemulsion preconcentrate of improved quality.

6 cl, 6 tbl, 3 dwg, 14 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical composition comprising the following components, %: hydrophobic active component representing cyclosporine and/or taxane, 0.1-60.0; one or some gelatinizing substances chosen from fatty acid polyglycerol esters, 0.1-60.0; one or some gel-forming substances chosen from oleic acid polyglycerol-3-esters, 1.0-60.0; one or some substances chosen from triglyceride macrogol glycerol esters, partial glycerides or fatty acids, or fatty acid macrogol esters. In dilution with water the composition forms dispersion of polymorphous nonspherical gel particles of size from 0.2 to 500 mcm. Invention provides acceptable availability of therapeutically active cyclosporines and taxanes showing difficult water solubility.

EFFECT: improved and valuable properties of composition.

14 cl, 1 tbl, 8 dwg, 20 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises the following components, %: hydrophobic active component representing cyclosporine and/or taxane, 0.1-30.0; one or some gelatinizing substances chosen from fatty acid polyglycerol esters, 0.1-60.0; one or some gel-forming substances chosen from fatty acid polyglycerol esters and/or unsaturated fatty acids, 0.1-60.0; one or some substances chosen from triglyceride macrogol glycerol esters, partial glycerides or fatty acids, or fatty acid macrogol esters, 1.0-60.0, and ethanol, 5.0-30.0. In dilution with water the composition forms dispersion of polymorphous nonspherical gel particles having size from 0.2 to 500 mcm. Invention provides acceptable bioavailability of therapeutically active cyclosporines and taxanes showing difficult solubility in water.

EFFECT: improved and valuable properties of pharmaceutical compositions.

13 cl, 8 dwg, 1 tbl, 20 ex

FIELD: medicine, pharmacology, pharmacy, antibiotics.

SUBSTANCE: invention relates to a prodrug representing a cyclic undecapeptide wherein its peptide chain comprises at least one amino acid residue of the general formula (I) given in the invention description wherein carbon atom Ca form one bond among bonds in the undecapeptide ring; each substitute among Y substitutes represents hydrogen atom, or they form a bond in common; substitutes R1 and R3 represent independently of one another hydrogen atom, the group aralkyl, alkaryl, heteroalkyl, heterocycle, alkylheterocycle, heterocycloalkyl or direct or branched alkyl comprising 1-6 carbon atoms wherein indicated groups are substituted optionally with at least one group chosen from: -COOH, -CONHR8, -NHC=NH(NH2), - NHC=NR8(NH2), -NH2, -NHR8, -NR82, -N+R83, -OH, -OPO(OR)2, -OPO(OH)(OR8), -OPO(OH)2, -OSO(OR8)2, -0SO(OH)(OR8), -OSO(OH)2 and different saline forms of these groups wherein each group among substitutes R8 independently of one another represents a direct or branched alkyl comprising 1-6 carbon atoms; substitutes R2 and R4 represent independently of one another hydrogen atom, alkaryl group or direct or branched alkyl comprising 1-6 carbon atoms; substitutes R and R6 represent independently of one another hydrogen atom, aralkyl group or direct or branched alkyl comprising 1-6 carbon atoms; substitute R7 represents the group aralkyl, alkaryl, heteroalkyl, heterocycle, alkylheterocycle, heterocycloalkyl, or direct or branched alkyl. Also, invention relates to using the indicated prodrug for preparing a medicinal agent used in treatment of pathological states of mucous membranes. Invention provides enhancing availability of the drug in its using.

EFFECT: valuable medicinal properties of drug.

17 cl, 5 tbl, 3 dwg, 5 ex

FIELD: chemical-pharmaceutical industry, medicine.

SUBSTANCE: invention relates to a pharmaceutical preparation comprising a lipophilic phase in the amount 1-10% by mass, mixture of a surface-active substance and an accessory surface-active substance wherein a surface-active substance is chosen from polyoxyethylene glycerol esters and fatty acids and polyoxyethylene sorbitan esters and fatty acids, and an accessory surface-active substance is chosen from poloxamers, block-copolymers of polyoxyethylene and polyoxypropylene in the amount 1-50% by mass, hydrophilic phase in the amount 40-80% by mass, and ciclosporin or its derivatives as an active component in the concentration 0.1-20% by mass. Proposed pharmaceutical preparation is made in colloidal formulation for topical using and designated for treatment and prophylaxis of skin pathological alterations, and/or skin adventitious, and/or mucous envelopes including mucous envelopes in digestive tract, urogenital ways and bronchial system, and/or conjunctives.

EFFECT: valuable medicinal properties of pharmaceutical preparation.

17 cl, 5 tbl, 11 dwg

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes immunosuppressive pharmaceutical compositions containing the following components: (a) ISATx247 taken in the pharmaceutically effective amount; (b) vitamin E TPGC (d-α-tocopheryl-polyethylene glycol(1000)-succinate); (c) MCT oil; (d) emulsifier chosen from group consisting of Tween-40 and Tween-80, and (e) ethanol. This pharmaceutical composition forms a clear microemulsion after contact with aqueous medium. Compositions provide high biological availability of drug and/or decrease one or more adverse effects associated with administration of ciclosporin. Also, invention discloses methods for using and preparing these compositions.

EFFECT: valuable medicinal and pharmaceutical properties of compositions.

39 cl, 7 tbl, 5 dwg, 7 ex

FIELD: chemical-pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to a composition in form of microemulsion concentrate designated for oral using, for example, in gelatin capsule. Proposed pharmaceutical composition provides high bioavailability of preparation. Pharmaceutical composition in form of microemulsion concentrate comprises ciclosporin and accessory components: (a) propanediol monocaprylate as a solvent; (b) monocaprylate glyceryl; (c) polyethylene glycol 40, hydrogenated castor oil and linoleic acid glycerides polyethylene glycol as surfactants; (d) 1,2-propylene glycol as a hydrophilic component; (e) alpha-tocoferol acetate as an antioxidant wherein in dilution microemulsion concentrate forms microemulsion to be easily dosed with particles size 15-20 nm.

EFFECT: improved and valuable properties of pharmaceutical composition.

1 tbl, 5 ex

FIELD: biochemistry.

SUBSTANCE: method relates to new cyclopeptides of general formula cyclo(R1-Arg-Ile-Lys-Pro-His-R2) selected from group containing: P11: cyclo(DPhe-Pro-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly-Glu) (SEQ ID NO:5), P16: cyclo(Arg-Ile-Lys-Pro-His-Gln-Gly (SEQ ID NO:8), P17: cyclo(Pro-Arg-Ile-Lys-Pro-His-Gln-Gly) (SEQ ID NO:9), P19: cyclo(Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly-Glu) (SEQ ID NO:10), P20: cyclo(Dphe-Pro-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly) (SEQ ID NO:11), P23: cyclo(DPhe-Pro-Arg-Ile-Lys-Pro-His-Gln) (SEQ ID NO:13), P24: cyclo(Gly-Arg-Ile-Lys-Pro-His) (SEQ ID NO:25), as well as P11, P20 and P23 with DPhe substituted by DTyr. Cyclopeptides are useful in systems for angiogenesis inhibition. System includes substrate with cyclopeptides attached by organic spacer arm optionally containing group cleavable by any fermentation system.

EFFECT: angiogenesis inhibiting cyclopeptides.

23 cl, 4 dwg, 2 tbl, 2 ex

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes agonists of somatostatin of the formula (I): X-A1-cyclo-(D-Cys-A3-A4-Lys-A6-A7)-A8-Y or its pharmaceutically acceptable salt wherein X represents hydrogen atom (H); A1 represents L-Cpa, L-Phe, L-Trp or L-Nal; A3 represents L-3-Pal or L-4-Pal; A4 represents D-Trp; A6 represents -NH-(CHR1)n-CO- wherein n = 2, 3 or 4; A7 represents L- or D-Cys; A8 represents D- or L-isomer of amino acid taken among the group consisting of Nal, Phe, Cpa and Trp; Y represents NH2; R1 represents hydrogen atom (H), and Cys in A3 is bound by disulfide bong in A wherein this disulfide bond is formed by thiol groups of each Cys residue.

EFFECT: valuable biological properties of compounds.

9 cl, 2 ex

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