CN101553228A - Treatment of fibrosing disorders - Google Patents
Treatment of fibrosing disorders Download PDFInfo
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- CN101553228A CN101553228A CNA200780030666XA CN200780030666A CN101553228A CN 101553228 A CN101553228 A CN 101553228A CN A200780030666X A CNA200780030666X A CN A200780030666XA CN 200780030666 A CN200780030666 A CN 200780030666A CN 101553228 A CN101553228 A CN 101553228A
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- chemical compound
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- rapamycin
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- effective dose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- Pharmacology & Pharmacy (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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Abstract
A method for treating liver-associated fibrosing disorders or lupus, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I optionally in conjunction with a co-agent.
Description
The present invention relates to the treatment of fibrosing disorders relevant and lupus (it is the fibrosing disorders relevant with kidney), relate more specifically to the purposes that the specified formula I chemical compound of this paper is used for the treatment of relevant fibrosing disorders of liver or lupus with liver.
Wherein connective tissue has replaced the fibrosis (Fibrosis) or the fibroplasia (fibroplasia) of normal parenchymal tissue, is because infection, autoimmune response, chemical poisoning or machinery attack the pathological process that the tissue that causes or the abnormal reparation during the organ injury cause.
Fibrosing disorders can occur in major organs and the tissue, in liver.Lupus nephritis is a kidney related fibrosis obstacle, i.e. the inflammation of the kidney that is caused by systemic lupus erythematosus (sle) (SLE).The fibrosis that liver is relevant can take place behind the chronic injury that is caused by the various causes of disease such as hepatic fibrosis and sclerosis.The various hepar damnifications that comprise infection (for example hepatitis B virus, hepatitis C virus), ethanol, autoimmune disease or genetic abnormality, the destruction (sclerosis) that can cause liver cell to become scar tissue (fibrosis) or the normal configuration of serious fibrosis variation and liver takes place.Hepatic fibrosis or sclerosis needing can finally cause the liver failure completely of liver transplantation.
The fibrosing disorders that liver is relevant comprises for example infection induced hepatic fibrosis or sclerosis, such as after the hepatitis C or the hepatic fibrosis of hepatitis B after-hardening (hepatic fibrosis), drug-induced hepatic fibrosis or sclerosis, chemical induction or sclerosis (for example ethanol sclerosis), the inductive hepatic fibrosis of autoimmune or sclerosis, the plain thesaurismosis of hereditary hemochromatosis.
Obstacle used herein comprises disease.
Rapamycin is the known macrolide antibiotics that is produced by streptomyces hygroscopicus (Streptomyces hygroscopicus).The chemical compound useful according to the present invention comprises following formula: compound
Wherein
R
1Be CH
3Or C
3-6Alkynyl,
R
2For H ,-CH
2-CH
2-OH ,-CH
2-CH
2-O-CH
2-CH
3,
X is=O, (H, H) or (H, OH),
Condition is to be=O and R as X
1Be CH
3The time, R
2Be not H.
In formula I chemical compound, the substituent group of each single expression can be a preferred substituted, is independent of defined any other substituent group.
The representative example of formula I chemical compound comprises for example 40-O-(2-hydroxyl)-ethyl-rapamycin, 32-deoxidation rapamycin, 16-penta-2-alkynyloxy group-32-deoxidation rapamycin, 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-rapamycin, 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-40-O-(2-hydroxyl)-ethyl-rapamycin and 40-O-(2-ethyoxyl)-ethyl-rapamycin, such as
40-O-(2-hydroxyl)-ethyl-rapamycin, and/or
32-deoxidation rapamycin, and/or
16-penta-2-alkynyloxy group-32-deoxidation rapamycin, and/or
16-penta-2-alkynyloxy group-32 (S or R)-dihydro-rapamycin, and/or
16-penta-2-alkynyloxy group-32 (S or R)-dihydro-40-O-(2-hydroxyl)-ethyl-rapamycin, and/or
40-O-(2-ethyoxyl)-ethyl-rapamycin.
Preferably formula I chemical compound is 40-O-(2-hydroxyl)-ethyl-rapamycin (everolimus).
Make us finding uncannily that formula I chemical compound can be used for the relevant fibrosing disorders of liver and the treatment of lupus according to the present invention, for example formula I chemical compound can for example suppress or reduce fibrotic processes by one or more following mechanism:
The inhibition that-epithelium transforms to a matter,
The minimizing of the expression of-short fibrotic growth factor,
The minimizing that-extracellular matrix generates.
According to special discovery of the present invention, the invention provides following several aspects:
1.1 be used for the treatment of the relevant fibrosing disorders of liver or the method for lupus, comprise to its formula I chemical compound of individual administering therapeutic effective dose of needs.
Lupus used herein comprises lupus nephritis and (general) lupus erythematosus (SLE), is preferably lupus nephritis.
1.2 suppress epithelium to the method that a matter transforms, comprise to its formula I chemical compound of individual administering therapeutic effective dose of needs.
1.3 reduce the method for short fibrotic growth factor expression, comprise to its formula I chemical compound of individual administering therapeutic effective dose of needs.
1.4 reduce the method that extracellular matrix generates, comprise to its formula I chemical compound of individual administering therapeutic effective dose of needs.
1.5 the method for treatment hepatic fibrosis comprises its formula I chemical compound of individual administering therapeutic effective dose of needs.
1.6 the method for treatment liver cirrhosis comprises its formula I chemical compound of individual administering therapeutic effective dose of needs.
1.7 the method for treatment lupus comprises its formula I chemical compound of individual administering therapeutic effective dose of needs.
1.8 the method for treatment lupus nephritis comprises its formula I chemical compound of individual administering therapeutic effective dose of needs.
Another aspect of the present invention also provides
1.9, comprise to its formula I chemical compound of individual administering therapeutic effective dose of needs with the relevant treatment of diseases method of 1.1 to 1.8 indicated any disease conditions.
Treatment used herein comprises treatment or prevention, preferred therapeutic.
Another aspect of the present invention provides
1.10 above 1.1 to 1.9 indicated methods, its Chinese style I chemical compound is selected from, for example be selected from 40-O-(2-hydroxyl)-ethyl-rapamycin, 32-deoxidation rapamycin, 16-penta-2-alkynyloxy group-32-deoxidation rapamycin, 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-rapamycin, 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-40-O-(2-hydroxyl)-ethyl-rapamycin and 40-O-(2-ethyoxyl)-ethyl-rapamycin
Such as 40-O-(2-hydroxyl)-ethyl-rapamycin (everolimus).
Other aspects of the present invention provide:
2. be used for the formula I chemical compound that 1.1 to 1.10 defined any methods are above used.
3. be used for preparing the medicine that 1.1 to 1.10 defined any methods are above used, for example the formula I chemical compound of pharmaceutical composition.
4. be used for the pharmaceutical composition that 1.1 to 1.10 defined any methods are above used, it comprises the formula I chemical compound together with one or more pharmaceutically acceptable diluents or carrier.
Formula I chemical compound can be used as unique active component (agent) or is provided in method or the purposes by the present invention with its second kind of drug substance combination for chemotherapeutic.
Term " chemotherapeutic " represents it is not any chemotherapeutic of formula I chemical compound especially, and it for example provides the benefit of comparing with monotherapy in combination treatment in method provided by the invention or purposes.Preferably such chemotherapeutic is the medicine that beneficial effect is provided in treatment of fibrosis, such as anti-fibrosis medicine, for example comprise can with formula I combination of compounds therapy in synergistic medicine is provided.
Suitable anti-fibrosis medicine for example comprises
-rasied such as renin inhibitor, for example comprises aliskiren, SPP630, SPP635, SPP800, Ro42-5892; Angiotensin receptor antagonist is such as Losartan, valsartan, irbesartan, Eprosartan, Candesartan, Olmesartan (medoxomil), telmisartan; Angiotensin converting enzyme (ACE) inhibitor is such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril;
-Connective Tissue Growth Factor (CTGF) antagonist, antibody such as the antagonism Connective Tissue Growth Factor, or Statins, such as atorvastatin, simvastatin, cerivastatin, Pitavastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin;
-platelet-derived growth factor (PDGF) antagonist is such as Trapidil
, antiplatelet source property somatomedin antibody, pdgf receptor tyrosine kinase inhibitor, for example e.g.SU9518, imatinib, Sutent (malate), AMN107, BMS354825;
-fibroblast growth factor (FGF) antagonist, for example antibody of anti-fibroblast growth factor, FGF receptor tyrosine kinase inhibitors, suramin (sodium) for example,
-tumor necrosis factor (TNF-α) antagonist, such as the TNF-Alpha antibodies, for example English monoclonal antibody of sharp former times, TNF-α receptor Ig construction,
-interferon gamma, relaxin,
-endothelin-receptor antagonists, for example BQ-123, bosentan, clazosentan, SPP301;
-transforming growth factor (TGF-β) antagonist, for example batimastat, or TGF-β antibody, activin acceptor sample inhibitors of kinases, such as SB-431542,
-VEGF (VEGF) antagonist, for example or VEGF antibody; Such as bevacizumab, thunder pearl monoclonal antibody; Vegf receptor tyrosine kinase inhibitor, for example PTK787/ZK 222584, ZD6474, SU5416, ABT-869, AEE788;
-interleukin-13 antagonist, interleukin 3 antagonisies.
Another aspect of the present invention provides:
5.1 drug regimen, pharmaceutical composition for example, for example be used for above 1.1 to 1.10 define, it comprises
A) be formula I chemical compound first kind of medicine and
B) it is second kind of drug substance as combination medicine of chemotherapeutic, and for example anti-fibrosis medicine is as defined herein all.
Drug regimen comprises fixed combination, and wherein two or more pharmaceutically active agents are all suc as formula I chemical compound and chemotherapeutic, are in identical preparation; Medicine box, wherein two or more pharmaceutically active agents are all suc as formula I chemical compound and chemotherapeutic, are to sell in identical packing in independent preparation, for example have co-administered explanation; With free combination, wherein pharmaceutically active agents is all suc as formula I chemical compound and chemotherapeutic, is independent the packing, but has provided the explanation of while or sequential application.
The invention provides on the other hand:
5.2 drug packages, it comprises is first kind of drug substance and at least a second kind of drug substance of formula I chemical compound, and described second kind of drug substance is chemotherapeutic as herein defined, is useful on co-administered explanation in addition;
5.3 drug packages, it comprises is first kind of drug substance of formula I chemical compound, and in addition with the explanation of uniting use of at least a second kind of drug substance, described second drug substance is a chemotherapeutic as herein defined;
5.4 drug packages, it comprises at least a chemotherapeutic as herein defined, in addition also has and the co-administered explanation of formula I chemical compound; For example, be used for any purposes provided by the invention or any method.
6. any method as hereinbefore defined, it comprises co-administered, for example simultaneously or in regular turn formula I chemical compound and second kind of drug substance of administering therapeutic effective dose, described second kind of drug substance are chemotherapeutic as herein defined for example.
Can provide improvement, for example benefit with comparing with single therapy (monotherapy) according to the treatment of combination of the present invention.
Provide in another aspect of this invention
-drug regimen, it comprises a certain amount of all formula I chemical compound and a certain amount of chemotherapeutic as defined herein, wherein said amount be suitable compare with single therapy for example to compare with monotherapy can produce beneficial effect, such as synergistic therapeutic action;
-being used to improve the method for the treatment practicality of formula I chemical compound, it comprises co-administered, for example for example all formula I chemical compound and chemotherapeutic as defined herein of administering therapeutic effective dose simultaneously or in regular turn;
-be used to improve chemotherapeutic, the method for the treatment practicality of for example all chemotherapeutic as defined herein, it comprises co-administered, for example simultaneously or use formula I chemical compound and chemotherapeutic for example defined herein in order.For example, be used for any method provided by the invention or any purposes.
Treatment comprises treatment and prevention.
For this treatment, suitable dosage will be natch along with all chemical attribute and the attribute of pharmacokinetic data available, each main body, method of application and the disease that will treat and the seriousness and change suc as formula I chemical compound and/or chemotherapeutic of for example activating agent.But usually, in order to obtain satisfied result in bigger mammal, for example human body, specified every day, dosage comprised scope
-from about 0.0001g to about 1.5g, such as 0.0001g to 1.5g;
-from about 0.01mg/kg body weight to about 20mg/kg body weight, to the 20mg/kg body weight, for example use with the maximum four times a day of divided dose such as the 0.01mg/kg body weight.
For example, everolimus can be used from (pact) 0.1mg to the dosage of (pact) 15mg, such as 0.1mg to 10mg, and for example 0.1mg, 0.25mg, 0.5mg, 0.75mg, 1.0mg, 2.5mg, 5mg, 10mg, for example dosage (pact) 1mg to 70mg weekly.
Other chemical compounds of formula I can suitably for example use with the specified similar dosage of everolimus.
Chemotherapeutic as described herein can be suitable dosage use, for example according to, for example with in its monotherapy use similarly described, for example collaborative situation with formula I chemical compound, even use being lower than under such dosage.
Formula I chemical compound, or chemotherapeutic as herein described can any conventional route use, and for example in the intestinal, for example comprises intranasal, buccal mucosa, rectum, Orally administered; Parenteral for example comprises vein, tremulous pulse, muscle, intracardiac, subcutaneous, the interior infusion of bone, transdermal (by the diffusion of intact skin), and saturating mucosa (by the diffusion of mucosa), suction is used, partly; For example comprise in intranasal, the trachea and using; Intraperitoneal (infusion or be injected to intraperitoneal); Epidural (injecting or be infused to the epidural space): in the sheath (injecting or be infused to cerebrospinal fluid); In the vitreous body (using) through eye; Or through medical treatment device, for example local delivery, for example support;
For example, with the form of coating or uncoated tablets, capsule, (injectable) solution, transfusion, solid solution, suspension, dispersion, solid dispersion, for example with the form of ampoule, bottle, with the form of inhalant powder, foaming agent, with the form of suppository;
In each case, activating agent be this paper specified, all suc as formula the I chemical compound, or another kind of chemotherapeutic, for example this paper is specified, any indicated chemical compound inclusion compound, its officinal salt, corresponding isomeric forms, such as racemic modification, diastereomer, enantiomer, tautomer, for example with the pure substance form or with mixture of isomers, and corresponding crystallization change, for example solvate, hydrate and polymorphic.The chemical compound that is used as activating agent in the present invention's combination can be prepared and use according to described in its product description respectively.Equally within the scope of the invention be the combination more than two kinds of independent activating agents of above stipulating, promptly drug regimen within the scope of the present invention can comprise three kinds of activating agents or more.In addition, first composition and co-administered composition are not same compositions.
According to pharmaceutical composition of the present invention can according to, for example similarly prepare, for example by mixing, granulation, coating, dissolving or freeze-dry process preparation with conventional method.Unit dosage forms for example can comprise, from about 0.1mg to about 1500mg, such as 1mg about 1000mg extremely.
The indicated pharmaceutical composition of this paper comprises formula I chemical compound for example as herein described, chemotherapeutic, or according to the present invention the combination of (by provided by the invention) can be suitably for example according to, for example similarly provide with the indicated conventional method of this paper.
Suitable external and body inner model and the mensuration that are used for the relevant fibrosing disorders of liver such as hepatic fibrosis and liver cirrhosis, are known or can be suitably provided, consult for example people such as J.Zhu, Gastroenterology, November 1999,117 (5):, the 1198-1204 page or leaf, people such as N.Shibata, Cell transplant, 2003,12 (5), the 499-507 page or leaf.
Suitable body inner model that is used for lupus and mensuration are known or can suitably provide, for example consult people such as J Gavalchin, The Journal of Immunology, the 138th volume, 1987, the 1st phase, 128-137 page or leaf and 138-148 page or leaf, Alan D.Salama, Drug Discovery Today:Disease Models, the 1st volume, the 4th phase, in December, 2004, p.457-463, ML Stoll, JGavalchin, Rheumatology (Oxford), in January, 2000, the 39th volume, the 1st phase, 18-27 page or leaf.
Formula I chemical compound randomly with one or more for example all combinations of chemotherapeutic as disclosed herein, demonstrates activity in these models.
Claims (15)
1. the treatment fibrosing disorders relevant with liver or the method for lupus, it comprises its following formula: compound of individual administering therapeutic effective dose of needs
Wherein
R
1Be CH
3Or C
3-6Alkynyl,
R
2For H ,-CH
2-CH
2-OH ,-CH
2-CH
2-O-CH
2-CH
3,
X is=O, (H, H) or (H, OH),
Condition is to be=O and R as X
1Be CH
3The time, R
2Be not H.
2. suppress epithelium to the method that a matter transforms, comprise to needs its individual administering therapeutic effective dose as the defined formula I chemical compound of claim 1.
3. reduce the method for short fibrotic growth factor expression, comprise to needs its individual administering therapeutic effective dose as the defined formula I chemical compound of claim 1.
4. reduce the method that extracellular matrix generates, comprise to needs its individual administering therapeutic effective dose as the defined formula I chemical compound of claim 1.
5. according to any method that is used for the treatment of hepatic fibrosis of claim 1 or 4.
6. according to the method that is used for the treatment of liver cirrhosis of claim 5.
7. according to any method that is used for the treatment of lupus of claim 1 or 4.
8. according to the method that is used for the treatment of lupus nephritis of claim 7.
9. be used for the treatment of the method with any indicated any disease condition diseases associated of claim 1 to 8, comprise to needs its individual administering therapeutic effective dose as the defined formula I chemical compound of claim 1.
10. according to any one method of claim 1 to 9, formula I chemical compound wherein is selected from 40-O-(2-hydroxyl)-ethyl-rapamycin, 32-deoxidation rapamycin, 16-penta-2-alkynyloxy group-32-deoxidation rapamycin, 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-rapamycin, 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-40-O-(2-hydroxyl)-ethyl-rapamycin and 40-O-(2-ethyoxyl)-ethyl-rapamycin.
11. according to any one method of claim 1 to 10, formula I chemical compound wherein is 40-O-(2-hydroxyl)-ethyl-rapamycin.
12. be used for as any defined any method of claim 1 to 11 as the defined formula I chemical compound of claim 1.
13. be used to prepare the formula I chemical compound that is used for as any defined any method of claim 1 to 11 as claim 1 is defined.
14. be used for the pharmaceutical composition as any defined any method of claim 1 to 11, it comprises as the defined formula I chemical compound of claim 1 and one or more acceptable diluents or carrier.
15. be used for the drug regimen as any defined any method of claim 1 to 11, it comprises
A) be formula I chemical compound first kind of medicine and
B) it is second kind of drug substance as combination medicine of chemotherapeutic.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06119311 | 2006-08-22 | ||
| EP06119311.6 | 2006-08-22 | ||
| EP06121903.6 | 2006-10-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101553228A true CN101553228A (en) | 2009-10-07 |
Family
ID=37670639
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200780030666XA Pending CN101553228A (en) | 2006-08-22 | 2007-08-20 | Treatment of fibrosing disorders |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101553228A (en) |
| BR (1) | BRPI0716580A2 (en) |
-
2007
- 2007-08-20 CN CNA200780030666XA patent/CN101553228A/en active Pending
- 2007-08-20 BR BRPI0716580-3A2A patent/BRPI0716580A2/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0716580A2 (en) | 2013-10-08 |
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Open date: 20091007 |