Treating fibrotic diseases. RU patent 2491934.

FIELD: medicine.

SUBSTANCE: present group of inventions refers to medicine, namely therapy, and concerns treating fibrotic diseases. That is ensured by administering 40-O-(2-hydroxy)ethylrapamycin or a pharmaceutical composition thereof in the effective amount.

EFFECT: administering the above compound provides slowing of the hepatic fibrosis development, including following liver transplantation with underlying immunosuppressive therapy.

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The present invention relates to the treatment of violations associated with liver, and brain, which is associated with the kidneys, fibrosing violation, in more detail, to the application of the compounds of formula I, as defined in this context, to ensure violations associated with liver, or lupus.

Fibrosis or by which a normal tissue is replaced by connective tissue, it is the pathological process that develops as a result of damaged healing of damage to the tissue or organ, caused by infections, autoimmune reactions, chemical intoxication or mechanical injuries.

violations may develop in major organs or tissues such as the liver. Lupus nephritis is fibrosing violation associated with the kidneys, namely inflammation of the kidneys caused by systemic lupus erythematosus (SLE). Associated with liver fibrosis, such as liver fibrosis and cirrhosis develops as a result of chronic injuries of different etiology. As a result of various liver lesions, including infection (for example, hepatitis B virus, hepatitis C), alcohol, autoimmune diseases or genetic disorders, hepatocytes secrete the scar tissue (fibrosis), or develop serious fibrous violations and the destruction of the normal structure of the liver (cirrhosis). Liver fibrosis or cirrhosis in some cases leads to the complete liver failure requiring liver transplantation.

Associated with the liver violations include, for example, caused by infection liver fibrosis or cirrhosis, such as cirrhosis (liver fibrosis) as a result of hepatitis C or hepatitis b fibrosis or cirrhosis of the liver, caused by drugs, fibrosis or cirrhosis of the liver, caused by chemical reagents (for example, alcoholic cirrhosis), autoimmune fibrosis or cirrhosis of the liver, genetic hemochromatosis.

Used in this context, the term «violation» includes disease.

Rapamycin is known macrolide antibiotic produced by a strain of Streptomyces hygroscopicus. Compounds that are used in the present invention, include the connection formula

,

where

R 1 means CH 3 or C 3-C 6 ,

R 2 means H-CH 2-CH 2-OH-CH 2 CH 2-O-CH 2 CH 3 ,

X indicates =O (H, H) or (H, OH)

provided that R 2 does not mean Y, if X is =O, a, R 1 means CH 3 .

In connection formula I each specified individual Deputy preferred means Deputy, regardless of any other specified Deputy.

Examples of typical compounds of formula I include, for example, 40-O-(2-hydroxy), 32-, 16-pent-2--32-, 16-pent-2--32(S or R), 16-pent-2--32(S or R)dihydro-40-O-(2-hydroxy) and 40-O-(2-), for example,

40-O-(2-hydroxy) and/or

32- and/or

16-pent-2--32- and/or

16-pent-2--32(S or R) and/or

16-pent-2--32(S or R)dihydro-40-O-(2-hydroxy) and/or

40-O-(2-).

Preferably, the connection formula I mean

40-O-(2-hydroxy) (everolimus).

In the present invention suddenly it was found that the compounds of formula I is suitable for treatment violations associated with liver and lupus, for example, connection the formula I suppress or reduce the fibrous processes, for example, on one or more of the following mechanisms:

- the suppression of epithelial- transition,

- decrease in the expression growth factors

- reduction of the production of extracellular matrix.

In the present invention, first of all, are such objects.

1.1. Method of treatment-related liver violations or lupus, which is that the subject, the needy in the specified treatment is administered a therapeutically efficient quantity of the compounds of formula I.

Used in this context, the term «lupus» includes lupus nephritis and (system) lupus erythematosus (SLE), preferably lupus nephritis.

1.2 Method of suppression of epithelial- transition, which is that the subject, the needy in the specified treatment, impose therapeutically effective amount of the connection formula I.

1.3 Way to reduce the expression of growth factors, which is that the subject, the needy in the specified treatment is administered a therapeutically efficient quantity of the compounds of formula I.

1.4 Way to reduce production extracellular matrix, which is that the subject, the needy in the specified treatment is administered a therapeutically efficient quantity of the compounds of formula I.

1.5 the Method of treatment of liver fibrosis, which is that the subject, the needy in the specified treatment is administered a therapeutically effective number of the compounds of formula I.

1.6 Method of treatment of cirrhosis of the liver, which is that the subject, the needy in the specified treatment is administered a therapeutically efficient quantity of the compounds of formula I.

1.7 Method of treatment of lupus, which is that the subject, the needy in the specified treatment is administered a therapeutically efficient quantity of the compounds of formula I.

1.8 Method of treatment of lupus nephritis, which is that the subject, the needy in the specified treatment is administered a therapeutically efficient quantity of the compounds of formula I.

In another object of the present invention also proposes the following way.

1.9 Way treatment of disease associated with any pathological condition, as specified in paragraph 1.1-1.8 above, which is that the subject, the needy in the specified treatment is administered a therapeutically efficient quantity of the compounds of formula I.

Used in this context, the term «treatment» includes treatment or prophylaxis, preferably treatment.

In yet another object of the present invention is offered the following way.

1.10 Way, as indicated in paragraph 1.1-1.9 above where the connection formula I choose, for example, from the group consisting of 40-O-(2-hydroxy), 32-, 16-pent-2--32-, 16-pent-2--32(S or R), 16-pent-2--32(S or R)dihydro-40-O-(2-hydroxy) and 40-O-(2-),

for example, 40-O-(2-hydroxy) (everolimus).

In other objects of the present invention provides the following options.

2. The connection formula I for application in any way by paragraph 1.1-1.10.

3. The connection formula I of the medicinal product, for example, pharmaceutical composition, intended for use in any fashion by paragraph 1.1-1.10.

4. Pharmaceutical composition, intended for application in any way by paragraph 1.1-1.10, including the connection formula I in the mixture with one or more pharmaceutically acceptable diluent or media.

Compound of formula I can be used in any way or for the application of the proposed in the present invention, in the form of the active ingredient (agent) individually or in combination with a second drug, which is a chemotherapeutic agent.

The term «chemotherapy agent» means, first and foremost, any chemotherapeutic agent, in contrast to the compounds of formula I, which has a favorable effect of combination therapy compared with treatment only one drug, for example, in the way or to apply, proposed in the present treatment. Preferably specified chemotherapeutic agent is the agent that has a beneficial effect in the treatment of fibrosis, such as agent, for example, including the agent who showed a synergistic effect when affair in combination with the connection formula I.

Suitable agents include, for example:

- inhibitors of angiotensin-renin, such as inhibitors of the renin, for example, including , SPP630, SPP635, SPP800, Ro 42-5892 antagonists angiotensin receptor, such as losartan, , irbesartan, eprosartan, candesartan, olmesartan (medoxomil), , inhibitors of angiotensin converting enzyme (ACE), such as benazepril, captopril, enalapril, , lisinopril, moeksipril, , , ramipril, ,

antagonists of connective tissue growth factor (CTGF), such as antibodies against the connective tissue growth factor, or statins, such as atorvastatin, simvastatin, cerivastatin, , fluvastatin, lovastatin, pravastatin, rosuvastatin,

antagonists platelet-derived growth factor (PDGF), such as Trapidil®antibodies against platelet-derived growth factor, receptor tyrosine kinase inhibitors PDGF, for example, SU9518 imatinib, (malate, AMN107, BMS354825,

antagonists of fibroblast growth factor (FGF), such as antibodies against factor of fibroblast growth inhibitors FGF receptor tyrosine kinase, for example, suramin (sodium salt),

- antagonists of tumor necrosis factor-alpha (TNF-alpha), such as antibodies against TNF-alpha, for example, infliximab, constructs Ig-receptor TNF-alpha,

interferon-g, ,

antagonist of endothelin receptor, for example, BQ-123, , , SPP301,

antagonists of transforming growth factor b (TGF-beta), for example, , or antibodies against the TGF-B, inhibitors activin- kinases, such as SB-431542,

antagonists endothelial growth factor (VEGF), for example, the anti-VEGF antibody, such as bevacizumab, inhibitors VEGF receptor tyrosine kinase, for example, PTK787/ZK 222584, ZD6474, SU5416, AVT-869, 788,

antagonist of interleukin 13, antagonist of interleukin 33.

In another object of the present invention is offered the following option.

5.1 Pharmaceutical combination, for example, pharmaceutical composition, for example, intended for use as specified in paragraph 1.1-1.10 above, including:

a) the first agent, which is a compound of formula I, and

b) the second drug as a co-agent, which is a chemotherapeutic agent, for example, agent, as defined in this context.

Pharmaceutical combinations include fixed combinations in which two or more pharmaceutically active agent, such as the connection formula I and chemotherapeutic agent, presented in the same composition; sets in which two or more pharmaceutically active agent, such as the connection formula I and chemotherapeutic agent, presented in the individual formulations and are available in one package, for example, with instructions on how to cooperate on the introduction; and available combinations in which pharmaceutically active agents, such as the connection formula I and chemotherapeutic agent is Packed separately, but attached instructions simultaneously or serial introduction.

In yet another object of the present invention offers the following options.

5.2 Pharmaceutical packaging, including the first drug, which is a compound of the formula I, and at least one second medicinal product, in this case, the second drug is chemotherapeutic agent, for example, as defined in this context as well as instructions on the combined introduction.

5.3 Pharmaceutical packaging, including the first the drug, which is a compound of formula I, as well as instructions on the combined introduction of at least one second of the medicinal product, in this case, the second drug is chemotherapeutic agent, for example, as defined in this context.

5.4 Pharmaceutical packaging, including at least one chemotherapeutic agent, for example, as defined in this context as well as instructions on the combined introduction with the compound of formula I, for example, for the application of or in any way, proposed in the present invention.

6. Any way, as defined above, which is that a therapeutically efficient quantity of the compounds of formula I and second of a medicinal product, which is a chemotherapeutic agent, for example, as defined in this context, administered jointly, for example, simultaneously or consistently.

In the treatment of combinations according to the present invention is observed enhanced effect of, for example, favorable action, compared with treatment with the introduction of only one drug (monotherapy).

In another object of the present invention is invited to:

- pharmaceutical combination, including the number of the compounds of formula I and the number of chemotherapeutic agent, for example, such, as defined in this context, the number of which have a positive effect compared with treatment with the introduction of only one medicinal means, for example, compared with treatment as monotherapy, such as the synergistic therapeutic effect,

- a way to strengthen the therapeutic effects of the compounds of formula I, which is that a therapeutically efficient quantity of the compounds of formula I and chemotherapy agent, for example, such, as defined in this context, administered jointly, for example, simultaneously or successively,

- a way to strengthen the therapeutic effects of chemotherapeutic agent, for example such, as defined in this context, which is that the connection formula I and chemotherapeutic agent, for example, such, as defined in this context, administered jointly, for example, simultaneously or successively,

for example, for use in any way or for any application, as suggested in the present invention.

The term «treatment» includes treatment and prevention.

During this treatment the dose change depending on, for example, from the chemical nature and pharmacokinetic data of the active ingredient, such as the connection formula I and/or chemotherapeutic agent, a specific subject, method introduction, as well as the nature and severity of the conditions to be treated. However, in General, satisfactory results in the treatment of large mammals, for example, a person required daily dose amounts in the range

- from about 0.0001 g to approximately 1.5 g, for example, from 0.0001 grams to 1.5 g,

from approximately 0.01 mg/kg body weight up to approximately 20 mg/kg body weight, for example, from 0.01 mg/kg body weight up to 20 mg/kg body weight, which is injected, for example, divided doses up to four times a day.

For example, everolimus can be administered in a dose of (approximately) 0.1 mg up to (approximately) 15 mg, for example, from 0.1 to 10 mg, for example, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 2.5 mg, 5 mg, 10 mg, for example, in a weekly dose of (approximately) 1 mg up to 70 mg

You can use other compounds of formula I, for example, in similar doses as prescribed for the everolimus.

Chemotherapeutic agents, as described in this context, is used in appropriate doses, for example, in the same way as described for their introduction as monotherapy, for example, in the case of synergies with the compound of formula I and even below the indicated doses.

The connection formula I, or chemotherapeutic agent, as described in this context, you can enter any standard method, for example, way, for example, including (nasal, buccal, rectal, oral administration, parenteral way, for example, including intravenous, intraarterial, intramuscular, , subcutaneous administration, infusion, percutaneous (diffusion through the intact skin), diffusion through the mucous membrane), inhalation introduction, local manner, for example, including intranasal, introduction, intra-peritoneal way (infusion or injection in the abdominal cavity), epidural () method (injection or infusion into the epidural space), way (injection or infusion into the spinal fluid), introduction into the vitreous body (introduction in the eye), or with the use of medical devices, for example, for local delivery, for example, with the use of stents,

for example, in the form of tablets coated or uncoated, capsules, solutions (for injection), solutions for injections, solid solutions, suspensions, dispersions, solid dispersions, for example, in the form of ampoules, bottles, in the form of powder for inhalations, pins, the form of suppositories.

In each case, if this description are active agents, such as the connection of the formulas I or other chemotherapeutic agent, for example, as stated in this context, any designated compound includes a connection, its pharmaceutically acceptable salts, relevant isomeric forms, such as racemates, , enantiomers, , for example, in pure form or in the form of isomeric mixtures, as well as the corresponding crystal modifications of, for example, , hydrates and polymorphic form. Compounds used as active ingredients in combination of the present invention, receive and administered, as described in the accompanying instructions. In the scope of the present invention also included a combination of more than two separate active ingredients, as listed above, namely, pharmaceutical combination included in the scope of the present invention may include three active ingredients or more. In addition, the first agent and joint agent are not identical ingredients.

Pharmaceutical compositions of the present invention receive, for example, similarly to the standard method, for example, mixing, granulation, coating, dissolution or lyophilization. Standard dosage forms contain, for example, of approximately 0.1 mg to 1500 mg, for example, from 1 mg to about 1000 mg

Pharmaceutical compositions specified in this description, include the connection formula I, chemotherapeutic agent, for example, as described in this the context, or a combination of the present invention (as proposed in the present invention) receive, for example, similarly to the standard method, or as specified in the present description.

Appropriate models and tests in vitro and in vivo for related liver violations, such as liver fibrosis and cirrhosis of the liver, known or offered as an appropriate models, see, for example, article Zhu, J. and others, Gastroenterology, 117, 5, .1198-1204 (November 1999), Shibata N. and others, Cell transplant, 12, 5, .499-507 (2003).

Appropriate models and analyses in vivo for lupus known or offered as an appropriate models, see, for example, article Gavalchin J. and others, The Journal of Immunology, .138, issue 1, .128-137 (1987), Alan D. Salama, Drug Discovery Today: Disease Models, vol. 1, issue 4, .457-463 (December 2004), Stoll M.L., Gavalchin J., Rheumatology (Oxford), V. 39, issue 1, .18-27 (January 2000).

The compounds of formula I, not necessarily in combination with one or more of chemotherapeutic agents, such as described in this context, are active in these models/analyses.

1. The use of 40-O-(2-hydroxy) for the treatment of violations associated with liver.

2. The use of 40-O-(2-hydroxy) according to claim 1, where fibrosing violation associated with the liver, a liver fibrosis.

3. The pharmaceutical composition comprising 40-O-(2-hydroxy) designed for use according to claim 1 and 2, in a mixture with one or more pharmaceutically acceptable diluents, or carriers.