CN101180053A - Treatment of liver diseases in which iron plays a role in pathogenesis - Google Patents
Treatment of liver diseases in which iron plays a role in pathogenesis Download PDFInfo
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- CN101180053A CN101180053A CNA2006800176178A CN200680017617A CN101180053A CN 101180053 A CN101180053 A CN 101180053A CN A2006800176178 A CNA2006800176178 A CN A2006800176178A CN 200680017617 A CN200680017617 A CN 200680017617A CN 101180053 A CN101180053 A CN 101180053A
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Abstract
The invention relates to the use of 4-[3,5-Bis-(2-hydroxyphenyl)-[1,2,4]-triazol-1-yl]benzoic acid (hereinafter referred to as ''Compound I'') for the manufacture of pharmaceutical compositions for the treatment of liver diseases in humans in which iron plays a role in pathogenesis, including viral diseases, such as chronic hepatitis C, optionally in conjunction with antiviral agents and for the treatment of non viral diseases, such as non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.
Description
Technical field
The present invention relates to for example deferiprone (L1), deferitrin and 4-[3, two (the 2-hydroxy phenyls)-[1 of 5-, 2,4]-and triazol-1-yl] iron chelating agent of benzoic acid (being called " Compound I " hereinafter) or its pharmaceutically acceptable salt is used for preventing and/or treating for example purposes of the pharmaceutical composition of people's hepatopathy in preparation, wherein ferrum plays a role in this sick pathogenesis, described hepatopathy comprises viral disease, as hepatitis B, hepatitis C, hepatitis D, hepatitis G, hepatitis E, chronic hcv infection, cytomegalovirus infection, HIV infects; With the non-viral disease, as non-alcoholic stellato-hepatitis and non-alcoholic fatty liver disease; And hepatocarcinoma, as liver adenocarcinoma (for example hepatocarcinoma is also referred to as hepatocarcinoma), the invention still further relates to the method for the described disease progression of prevention.
Background technology
In the U.S., hepatopathy is one of murderous ten big inducements, causes every year to surpass 30000 people's death, for example referring to people such as Vong S, hepatology (Hepatology); 2004,39:476-483.
The chronic infection of hepatitis C is the main reason that causes hepatopathy, also is to cause the hardened main cause of hepatic fibrosis regulating liver-QI.In the infected individuality of part, it is also relevant with the deterioration of hepatocarcinoma.Adopt current treatment standard, when promptly treating, can only make and make an appointment with the intravital virus of patient of being treated of half to obtain removing with interferon and ribavirin.
Non-alcoholic stellato-hepatitis is a kind of metabolism syndrome relevant with hepatic fibrosis, has about 20% case can develop into liver cirrhosis, for example referring to people such as Ong, and Am.J Gastroenterol2003,98:1915-1917.Current treatment standard is promptly controlled metabolizing parameters and lost weight, and is only effective to small number of patients.Non-alcoholic stellato-hepatitis (or being called NASH) is a kind of common and often be " (silent) that hide " hepatopathy.It and alcoholic liver disease are similar, but this disease incidence is in low alcohol consumption or the crowd that do not drink.The principal character of NASH is a hepatomegaly, and with inflammation and damage.Most of NASH patients liver of not recognizing them of feeling good has problem.Yet NASH may be very serious and can cause liver cirrhosis that in liver cirrhosis, liver permanently is damaged and no longer can works well.2% to 5% American is subjected to the influence of NASH.
Non-alcoholic fatty liver disease (NAFLD) is the common cause that causes liver function test to raise, and shows as on the histology and can see adipopexis, the big vesicle of constitutional in hepatocyte.Although be optimum disease in most of cases, the NAFLD patient up to 20% suffers from non-alcoholic stellato-hepatitis (NASH), and can develop into liver cirrhosis, liver failure and hepatocarcinoma.Some risk factor of NAFLD are firmly established, and comprise that Body Mass Index (BMI) rising, type 2 diabetes mellitus, age increase and hypertriglyceridemia.Think that the pathophysiology basis of NAFLD is an insulin resistant.Most experts think that NAFLD is the liver presentation of metabolic syndrome, comprise that those have the patient of insulin resistant, obesity, hypertension and dyslipidemia simultaneously.NAFLD patient can develop into insulin resistant.
Compound I is 4-[3, two (2-hydroxy phenyl)-[1,2, the 4]-triazol-1-yls of 5-] benzoic acid, its structural formula is as follows:
The Compound I of free acid form, its salt and its crystal form is disclosed among U.S. Patent No. 6465504 B1.Compound I is an active component.
Compound I is a kind of iron chelating agent, and it has demonstrated the ferrum that selectivity is effectively removed model system and philtrum, for example referring to people such as Hershko C, blood (Blood), 2001,97:1115-1122; People such as Nisbet Brown E, lancet (Lancet), 2003,361:1597-1602.
But people also do not know that Compound I is effective to treating above-mentioned hepatopathy.Particularly, need find a kind of Therapeutic Method of alternative hepatopathy, the hepatopathy that described hepatopathy for example plays a role therein for ferrum, for example hepatopathy that causes by viral infection, for example chronic hepatitis C.In addition, also need to find a kind of hepatopathy () Therapeutic Method for example, chronic hepatitis C, with standard treatments such as interferon and ribavirin therapy the time, described hepatopathy is refractory, do not respond or can not cure or be difficult to Sustainable Control fully.
Except as otherwise noted, hereinafter " Compound I " free acid form, its pharmaceutically acceptable salt of being meant Compound I with and crystal form.
Following formula
Deferitrin:(4S)-2-(2, the 4-dihydroxy phenyl)-4-methyl-4,5-dihydro-1,3-thiazoles-4-formic acid and preparation method thereof is disclosed among the disclosed WO00/12493 on March 9th, 2000.
Deferiprone is disclosed among the EP093498 B1: 3-hydroxyl-1,2-dimethyl-4-(1,4) pyridone and pharmaceutically acceptable preparation thereof.
The inventor has confirmed that Compound I can be used for removing intravital ferrum, and to propose to remove intravital ferrum (for example ferrum being removed to nearly deficiency state or deficiency state) will be useful to some hepatopathy, described hepatopathy for example is a viral liver disease, as hepatitis B, hepatitis C, hepatitis D, hepatitis G, hepatitis E, chronic hcv infection, cytomegalovirus infection, HIV infection, non-alcoholic stellato-hepatitis and non-alcoholic fatty liver disease, described benefit can be but be not limited to prevention or reduce hepatic fibrosis and/or liver cirrhosis.
The inventor has confirmed that Compound I can be used in body (for example in the liver) and removes de-iron, and intravital ferrum (for example ferrum being removed to nearly deficiency state or deficiency state) is removed in proposition, and the associating subsequently or the antiviral drugs that gives simultaneously will be useful to some hepatopathy, described antiviral drugs is such as but not limited to biological response modifier (cytokine for example, interferon, alpha-interferon) and/or ucleosides antimetabolite (as ribavirin), described hepatopathy for example is a viral liver disease, hepatitis B for example, hepatitis C, hepatitis D, hepatitis G, hepatitis E, chronic hcv infection, cytomegalovirus infection, HIV infects, non-alcoholic stellato-hepatitis and non-alcoholic fatty liver disease, described benefit can be but be not limited to prevention or reduce hepatic fibrosis and/or liver cirrhosis.
The nearly deficiency state of ferrum or deficiency state are meant that the content of ferrum in the liver is lower than normal value, is meant that especially the content of ferrum in every gram dry weight liver is lower than 0.5mg.Normal value is meant that the content of ferrum in every gram dry weight liver is 0.5 to 1.5mg.For example, according to the present invention, the content of ferrum is 0.4mg/g liver dry weight in the liver, just is equivalent to be in nearly deficiency state or deficiency state.Also can monitor the nearly deficiency state or the deficiency state of ferrum by the level of measuring ferritin.Be equivalent to normal ferritin level when the concentration of ferritin is about 10 to 30ng/ml blood in the blood.Just can think nearly deficiency state or the deficiency state that is equivalent to be in ferrum when for example, the concentration of ferritin is 5ng/ml blood in the blood.
Biological response modifier is also referred to as cytokine, thereby comprises that can change the product that immune defence can improve, commands or recover the ability that health fights back the disease.Described biological response modifier for example comprises:
● colony stimulating factor (granulocyte colony-stimulating factor)--G-CSFs,
● granulocyte macrophage colony stimulating factor--GM-CSFs,
● stem cell factor (SCGF),
● erythropoietin, interferon, interleukin (ILs),
● tumor necrosis factor (TNF) inhibitor, and
● Thymosin alpha 1 is also referred to as thymalfasin, ZADAXIN .
According to the present invention, the preferred interferon of described biological response modifier.
" ucleosides antimetabolite " is meant the ucleosides antimetabolite that can the viral interference hereditary material duplicates.According to the present invention, " ucleosides antimetabolite " for example is but is not limited to ribavirin, its structural formula is 1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-Methanamide, the perhaps viramidine of ValeantPharmaceuticals International company production, be ICN3142, its structural formula is 1-[(2R, 3R, 4S, 5S)-3,4-dihydroxy-5-(methylol) oxa-ring penta-2-yl]-1,2,4-triazole-3-Methanamide (is also referred to as 1-(β-D-ribofuranosyl)-1 usually, 2,4-triazole-3-Methanamide), perhaps be valopicitabine, i.e. NM283 (Indenix Pharmaceutical).
Summary of the invention
The present invention relates to Compound I or deferitrin or the deferiprone purposes in the hepatopathy that treatment ferrum plays a role in its pathogenesis, for example treatment can cause hepatic fibrosis and/or liver cirrhosis and/or develop into hepatocarcinoma, as liver adenocarcinoma (for example hepatocarcinoma), and the hepatopathy that in its pathogenesis, plays a role of ferrum.
The invention still further relates to Compound I or deferitrin or deferiprone and be used for the treatment of purposes in the medicine of the hepatopathy that ferrum plays a role in its pathogenesis in preparation, described hepatopathy can cause hepatic fibrosis and/or liver cirrhosis and/or hepatitis, for example viral liver disease infects as hepatitis B, hepatitis C, hepatitis D, hepatitis G, hepatitis E, chronic hepatitis C virus (for example 1,2,3,4 or 5 genotype chronic hepatitis viruses) infection, cytomegalovirus infection, HIV.
The invention still further relates to Compound I or deferitrin or the deferiprone purposes in the medicine of the hepatopathy that preparation treatment ferrum plays a role in its pathogenesis, described hepatopathy can cause hepatic fibrosis and/or liver cirrhosis and/or hepatitis, non-viral hepatopathy for example, for example, non-alcoholic stellato-hepatitis and non-alcoholic fatty liver disease.
The invention still further relates to Compound I or deferitrin or the deferiprone purposes in the medicine of the hepatopathy that preparation treatment ferrum plays a role in its pathogenesis, described hepatopathy can cause hepatic fibrosis and/or liver cirrhosis and/or hepatitis such as viral liver disease, hepatitis B for example, hepatitis C, hepatitis D, hepatitis G, hepatitis E, chronic hcv infection, cytomegalovirus infection, HIV infects, and giving antiviral drugs subsequently or simultaneously, the biological example reaction control agent is (as interferon, IFN α, the Polyethylene Glycol interferon) and/or ucleosides antimetabolite (as ribavirin).
Pharmaceutical composition of the present invention can prepare with known method itself, these pharmaceutical compositions are suitable for through enteral (for example oral) and parenteral to homoiothermic animal (comprising the mankind), this pharmaceutical composition comprises the effective ingredient at least a pharmacology who treats effective dose, it can use separately or use with one or more pharmaceutically acceptable carrier combinations, and particularly those are suitable for the carrier of enteral or parenteral use to described carrier.The preferred route of administering of dosage form of the present invention is oral.The oral formulations of Compound I is disclosed in open text WO97/49395 of international patent application and WO 2004/035026.
The present invention relates to treat the method for the homoiothermic animal (for example human) of suffering from the hepatopathy that ferrum plays a role in its pathogenesis, described method comprises Compound I or deferitrin or deferiprone is administered to the animal that needs this kind treatment, dosage is the dosage that can remove de-iron in treatment effectively, under the situation of suffering from hepatitis C (as the third type chronic hepatitis), give antiviral drugs subsequently or simultaneously, perhaps suffering under the situation of non-alcoholic stellato-hepatitis, using or do not using other Therapeutic Method simultaneously.
The present invention relates to Compound I or deferitrin or deferiprone are administered to the method for the human patients of suffering from the hepatopathy that ferrum plays a role in its pathogenesis.
In one embodiment of the invention, Compound I is made into dispersible tablet.
In one embodiment of the invention, Compound I exists with polymorphic A form.
In one embodiment of the invention, Compound I exists with polymorphic A form, and is made into dispersible tablet.
The present invention relates to Compound I or deferitrin or the deferiprone purposes in the medicine of preparation treatment hepatopathy, described hepatopathy is viral liver disease (as chronic hepatitis C) for example, when treating with biological response modifier treatment (as with IFN, IFN-α treatment) or with the combination product of biological response modifier (as IFN) and ucleosides antimetabolite (as ribavirin), described hepatopathy is refractory, that do not respond or that can not control fully or be difficult to persistence and respond.
The present invention relates to the commodity packaging product, this commodity packaging product inclusion compound I and with the operation instructions of described compound administration to the patient who suffers from hepatopathy (as viral liver disease, chronic hepatitis C).
The invention still further relates to combination product, this combination product for example is combination preparation or pharmaceutical composition, and it comprises (a) ferrum intercalating agent and (b) biological response modifier and/or nucleic acid class antimetabolite.
The invention still further relates to combination product, this combination product for example is combination preparation or pharmaceutical composition, and it comprises (a) and is selected from the ferrum intercalating agent of Compound I, deferitrin and deferiprone and (b) biological response modifier and/or nucleic acid class antimetabolite.
The invention still further relates to combination product, this combination product for example is combination preparation or pharmaceutical composition, and it comprises (a) ferrum intercalating agent, and it is Compound I or deferitrin and (b) biological response modifier and/or nucleic acid class antimetabolite.
In one embodiment, the present invention relates to combination product, this combination product comprises (a) Compound I and (b) biological response modifier and/or nucleic acid class antimetabolite.
In another embodiment, the present invention relates to combination product, this combination product comprises (a) Compound I and (b) is selected from the interferon of Intederon Alpha-2a, Interferon Alpha-2b, Interferon Alfacon-1, Polyethylene Glycol Interferon Alpha-2b or Polyethylene Glycol Intederon Alpha-2a and/or be selected from the nucleic acid class antimetabolite of ribavirin, viramidine or valopicitabine.
Term used herein " combination preparation " is defined as " complete product (kit of part) " especially, the meaning is the combination partner (a) of above-mentioned definition and (b) can independent administration, perhaps use with the different fixed combination that contains not commensurability combination partner (a) and (b), above-mentioned use (administration) for example can be carried out at the same time or in different time points.Then can be for example simultaneously or the administration of staggering in chronological order with the each several part in " complete product ", promptly different time points and with identical or different interval with any a part of administration in " complete product ".For example, for the needs of satisfied patient subgroups of being treated or the needs of single patient, in combination preparation, can be changed by the ratio of the total amount of the total amount of the combination partner of administration (a) and combination partner (b).
The invention still further relates to the purposes of described combination product in the medicine of the hepatopathy that preparation treatment ferrum plays a role in its pathogenesis, described hepatopathy can cause hepatic fibrosis and/or liver cirrhosis and/or hepatitis, viral liver disease for example, for example hepatitis B, hepatitis C, hepatitis D, hepatitis G, hepatitis E, chronic hcv infection, cytomegalovirus infection, HIV infect, and are preferably chronic hepatitis C.
The present invention relates to the commodity packaging product, this commodity packaging product inclusion compound I and the antiviral drugs that is selected from biological response modifier (for example interferon, for example interferon-ALPHA) and nucleic acid class antimetabolite (as ribavirin).
The present invention relates to the commodity packaging product, this commodity packaging product inclusion compound I and with Compound I and at least a antiviral drugs that is selected from biological response modifier (for example interferon, for example interferon-ALPHA) and nucleic acid class antimetabolite (as ribavirin) operation instructions of administration together.
The present invention relates to the purposes of deferitrin in the hepatopathy that treatment ferrum plays a role in its pathogenesis, for example being used for the treatment of ferrum plays a role in its pathogenesis, and can cause hepatic fibrosis and/or liver cirrhosis and/or develop into the hepatopathy of hepatocarcinoma, for example liver adenocarcinoma (for example hepatocarcinoma).
The present invention relates to the purposes of deferitrin in treatment viral liver disease (for example chronic hepatitis C).
Detailed Description Of The Invention
Those skilled in the relevant art can select suitable test model fully, to prove the above-mentioned beneficial effect of excessive ferrum to hepatopathy of removing.The pharmacological activity of such chemical compound for example can be by the method for following embodiment, is confirmed by in vitro tests and in vivo test or suitable clinical research.Suitable clinical research is that the ferrum of the open nonrandomness dosage escalation that for example hepatopath carried out is removed research, and the ferrum clearance test of the randomness double blinding placebo that the hepatopath is carried out.
According to the order of severity of excessive degree, the liver disease types that will treat or hepatopathy of the ferrum of employed pharmaceutical composition, administering mode, individual interior existence, the effective dose of Compound I can change.Can also select dosage regimen according to many other factorses of the situation that comprises individual renal function and liver function.Common doctor, clinicist or the veterinary in this area can determine at an easy rate and the place of opening makes the chemical compound of iron deficiency or the nearly effective dose that lacks, thereby reaches effective treatment.
According to described patient's age, individual state, administering mode and clinical presentation, with effective dose, the Compound I that for example with daily dose is 100 to 3000mg active component is administered to the homoiothermic animal (for example human) that body weight is about 70kg, for example 5-40mg/kg body weight/day.Homoiothermic animal is preferably the mankind.Compound I can be with 5-40mg/kg/ days dosed administration.For the child, dosage is preferably the 5-40mg/kg body weight/day.The daily dose of Compound I for example is to arrive the delivery of active ingredients of 3000mg to homoiothermic animal (for example human) with 100 every day.They daily dose are not had enough patients of response, can consider to carry out safely dosage escalation, as long as can access useful treatment and limiting toxicity not occur just passable.
For example with trade mark Copegus
, Rebetol
, Ribasphere
, Vilona
, Virazole
Commercially available ribavirin can carry out administration according to manufacturer's operation instructions, perhaps for example with every day about 200mg, be up to the dosed administration of about 1200mg.Ribavirin is a kind of oral drugs.According to body weight, ribavirin can be with capsule administration every day of 200mg 2 times as total daily dose.For the patient that body weight is less than 75 kilograms (165 pounds), the standard dose of ribavirin for example can be 1000mg, and body weight is surpassed 75 kilograms patient, and the standard dose of ribavirin for example can be 1200mg.In some cases, can advise dosage (every day 2 times, each 400mg) into 800mg.
Interferon for example is Intederon Alpha-2a (Roferon-A; Hoffmann-La Roche); Interferon Alpha-2b (Intron-A; Schering-Plough); Interferon Alfacon-1 (Infergen; Intermune); And Polyethylene Glycol interferon (peginterferon) (being also referred to as Polyethylene Glycol interferon (pegylatedinterferon) sometimes), for example Polyethylene Glycol Interferon Alpha-2b (Peg-Intron; Schering-Plough) and Polyethylene Glycol Intederon Alpha-2a (Pegasys; Hoffmann-La Roche); Interferon ω (Intarcia); Multiferon (Viragen), Jellyfish interferon (Flamel Technologies) and Albuferon (Human genome Sciences).For example can subcutaneous administration Polyethylene Glycol Intederon Alpha-2a, for example with fixed dosage, 180 micrograms (mcg) weekly for example.For example can be with based on the weekly subcutaneous administration Polyethylene Glycol of the dosage of weight Interferon Alpha-2b, 1.5mcg/ kilogram/week for example is for example weekly 75 to 150mcg.
For example according to body weight, can with every days 100 ten thousand to 1,000 ten thousand unit dose with the interferon administration.Can be continuous 2 every days in week be administered once, subsequently weekly administration 3 times or for example weekly 3 times with the interferon administration.The Polyethylene Glycol interferon-ALPHA for example can be administered once weekly.
The present invention relates to will be pharmaceutically the Compound I of effective dose be administered to the method for the human patients of suffering from hepatopathy once a day, described hepatopathy is relevant with the inducement of for example chronic hepatitis C infection or non-alcoholic stellato-hepatitis.
The present invention relates to will be pharmaceutically the Compound I of effective dose and biological response modifier and/or ucleosides antimetabolite be administered to the method for the human patients of suffering from hepatopathy, described liver disease is relevant with the inducement of for example chronic hepatitis C infection or non-alcoholic stellato-hepatitis, described biological response modifier is interferon for example, for example be selected from Intederon Alpha-2a, Interferon Alpha-2b, Interferon Alfacon-1, Polyethylene Glycol Interferon Alpha-2b or Polyethylene Glycol Intederon Alpha-2a, described ucleosides antimetabolite for example is selected from ribavirin, viramidine or valopicitabine.
The present invention be more particularly directed to a kind of like this method, wherein give adult or child dose every day and be 50 to 4000mg Compound I.In the situation of hepatitis C infection is arranged, when giving Compound I or can give antiviral drugs (biological example reaction control agent subsequently, for example interferon, for example interferon-ALPHA) and/or ucleosides antimetabolite (for example viramidine, valopicitabine or ribavirin).
The present invention can be particularly related to from the individuality of suffering from hepatopathy and remove ferrum, and removing ferrum is useful to these individualities, and these are individual because it suffers from anemia or other contraindication simultaneously, can not adopt venesection to treat.In addition, the present invention can be particularly related to the hepatitis C patients that standard antiviral therapy method is not responded.
The invention still further relates to once a day the human patients method of the Compound I of effective dose pharmaceutically of periodically suffering from hepatopathy, the described cycle is preferably per 2 months or administration in 3 months 14 days or 2 weeks or administration in every month 7 days.The present invention be more particularly directed to a kind of like this method, dosage every day that wherein gives adult or child's Compound I is 50 to 4000mg, is preferably 1000mg.
The present invention relates to:
-the purposes of Compound I in the medicine of the hepatopathy that preparation treatment ferrum plays a role in its pathogenesis with following formula,
The purposes of-Compound I in the medicine of the hepatopathy that preparation treatment ferrum plays a role in its pathogenesis, described hepatopathy is chronic hepatitis C or non-alcoholic stellato-hepatitis,
The purposes of-Compound I in the medicine of the hepatopathy that preparation treatment ferrum plays a role in its pathogenesis, described hepatopathy such as chronic hepatitis C or non-alcoholic stellato-hepatitis, wherein ferrum is in shortage or nearly deficiency state after described treatment,
The purposes of-Compound I in the medicine of the hepatopathy that the excessive ferrum of preparation treatment plays a role in its pathogenesis.
-such use, wherein with the daily dose that is equivalent to 50mg to 4000mg Compound I with the Compound I administration.
-treatment suffers from the mammiferous method of the hepatopathy that ferrum plays a role in its pathogenesis, described method comprises the mammal that the Compound I of the effective dose that can remove excessive iron is administered to needs this kind treatment.
-combination product, this combination product inclusion compound I and biological response modifier and/or ucleosides antimetabolite, described biological response modifier for example is an interferon, for example is selected from Intederon Alpha-2a, Interferon Alpha-2b, Interferon Alfacon-1, Polyethylene Glycol Interferon Alpha-2b or Polyethylene Glycol Intederon Alpha-2a.
-combination product, this combination product inclusion compound I and biological response modifier and/or ucleosides antimetabolite, described biological response modifier for example is an interferon, for example be selected from Intederon Alpha-2a, Interferon Alpha-2b, Interferon Alfacon-1, Polyethylene Glycol Interferon Alpha-2b or Polyethylene Glycol Intederon Alpha-2a, described ucleosides antimetabolite for example is selected from ribavirin, viramidine or valopicitabine.
-combination product, this combination product inclusion compound I and biological response modifier and/or ucleosides antimetabolite, described biological response modifier for example is an interferon, for example be selected from Intederon Alpha-2a, Interferon Alpha-2b, Interferon Alfacon-1, Polyethylene Glycol Interferon Alpha-2b and Polyethylene Glycol Intederon Alpha-2a, described ucleosides antimetabolite for example is selected from ribavirin, viramidine and valopicitabine.
-combination product, this combination product inclusion compound I and biological response modifier and/or ucleosides antimetabolite, described biological response modifier for example is an interferon, for example be selected from Intederon Alpha-2a, Interferon Alpha-2b, Interferon Alfacon-1, Polyethylene Glycol Interferon Alpha-2b or Polyethylene Glycol Intederon Alpha-2a, described ucleosides antimetabolite for example is selected from ribavirin.
The purposes of the combination product of-inclusion compound I and biological response modifier and/or ucleosides antimetabolite in the chronic hepatitis C patient's that the preparation treatment does not respond standard treatments medicine, described biological response modifier for example is an interferon, for example be selected from Intederon Alpha-2a, Interferon Alpha-2b, Interferon Alfacon-1, Polyethylene Glycol Interferon Alpha-2b or Polyethylene Glycol Intederon Alpha-2a, described ucleosides antimetabolite for example is selected from ribavirin, viramidine or valopicitabine.
The purposes of the combination product of-inclusion compound I and biological response modifier and/or ucleosides antimetabolite in the chronic hepatitis C patient's that the preparation treatment does not respond standard treatments medicine, described biological response modifier for example is an interferon, for example be selected from Intederon Alpha-2a, Interferon Alpha-2b, Interferon Alfacon-1, Polyethylene Glycol Interferon Alpha-2b and Polyethylene Glycol Intederon Alpha-2a, described ucleosides antimetabolite for example is selected from ribavirin, viramidine and valopicitabine.
Following embodiment is in order to illustrate the present invention.But, should be appreciated that the present invention has more than and be limited to certain conditions described in these embodiment or details.
Embodiment
Embodiment 1: confirm the clinical research of Compound I ferrum chelation
In 24 adult β-thalassemia patients to Compound I carry out at random, the dosage escalation test of double blinding, placebo, the accumulation iron balance amount (10mg/kg (n=5), 20mg/kg (n=6), 40mg/kg (n=7), placebo (n=6)) of the in test safety of assessing compound I, toleration, PK and 12 days.
After the Compound I administration, it is absorbed very soon, and is present in the blood in whole interval always.Behind the single dose administration, the exposed amount (C of Compound I
MaxAnd AUC) can increase a little pro rata with the dosage of Compound I, but during steady statue, still be approximated to direct ratio.When all dosage levels, compare C during the steady statue of pharmacokinetics with behind the single dose administration
MaxImproved approximately 25% to 40%, the exposed amount of Compound I has improved 1.8 times to 2.2 times.With compare the average elimination half-life t of Compound I and iron complex thereof when steady statue behind the single dose administration
1/2Be tending towards prolonging.On the whole, in steady statue, the t of Compound I
1/2Be about 12 to 13 hours, the t of iron complex
1/2Usually more longer (12 to 21 hours).In whole collection interval, the homaluria of Compound I and iron complex very low (be Compound I dosage 0.04% to 0.15%).
In this test, iron balance studies show that the drainage of ferrum is dose dependent and increases, and almost all falls from defecate.Chelation percent is based on the clean excretion of average every day of ferrum and comes, can be calculated chelation percent by the ratio of the amount of the ferrum of sequestration and the amount of in fact excretory ferrum in theory with respect to body weight.Think that iron atom of sequestration needs the Compound I of 2 molecules, thereby obtain the theoretical amount of ferrum.The molecular weight of Compound I is 373.4, and ferrum is 55.85.Therefore the sequestration rate can be calculated by following formula:
Sequestration rate=(ferrum
Drain* 2*373.4)/(dosage
Chemical compound* 55.85) * 100%
Dosage
Chemical compoundAnd ferrum
DrainUnit be the mg/kg body weight.
Whole 3 dosage at active medicine all obtain minus iron balance, on average are about 0.127mg/kg/ days during 10mg/kg dosage, on average are about 0.343mg/kg/ days during 20mg/kg dosage, on average are about 0.564mg/kg/ days during 40mg/kg dosage.Observe significant difference in 40mg/kg dosage group.
Observed sequestration rate is 16% (10mg/kg dosage group), 22% (20mg/kg dosage group), 15% (40mg/kg dosage group), referring to Nisbet-Brown etc., lancet, 361:1597-1602.
Embodiment 2: confirm the safety of Compound I removal ferrum and the clinical research of effectiveness
This clinical research is one and is divided into two-part test that Compound I is brought down below the ability of 100mcg/L with serum ferritin (storing the index of ferrum in the body) level when being 5 to 40mg/kg in order to the test day dosage.In the first of this test, select best safety and effective dose; At the second portion of this test, the Compound I that gives this dosage every day with mg/kg and every day give the Compound I of about similar dosage with mg, and itself and safety and effectiveness of adopting venesection to reduce the therapy of ferrum are compared.
Embodiment 3: Compound I is alleviated the spontaneous hepatitis of LEC rat
Long-Evans cinnamon (LEC) rat is a kind of mutant strain that shows heritability hepatitis and spontaneous hepatocarcinoma.Compound I is tested the effectiveness of LEC rat acute hepatitis model.
Method: give Compound I with male LEC rat through tube feed, dosage is 0,14 and 28mg/kg/ days, since 6 ages in week and lasted till for 18 ages in week.When the 9th, 12,14,16 and 18 ages in week, in chemical compound 1 processed group and matched group, put to death 4 rats respectively.
After rat is put to death, collect peripheral blood to detect biochemical indicator (comprising serum alanine transaminase (ALT)).Hepatic tissue is carried out histological examination.
The result: the rat of non-processed group (matched group), Serum ALT increased since the 16th age in week, reached 250 UI/L in the 18th age in week.Compare with matched group, the meansigma methods ± SD (standard deviation) of the Serum ALT when 18 ages in week of the rat in the Compound I processed group significantly reduces.With the accumulated amount of ferrum in the prussian blue staining method mensuration liver, compare with matched group, the accumulated amount of ferrum significantly reduces in the liver of Compound I processed group.
Compound I can effectively be alleviated the acute hepatitis that is caused by ferrum in the LEC rat.
Embodiment 4: to the test of hepatitis rat model
Long-Evans cinnamon (LEC) rat is a kind of mutant strain that shows heritability hepatitis and spontaneous hepatocarcinoma.Whether test compounds I is to the favourable effect of hepatitis progress of LEC rat model.
Method and material:
1) animal varieties and quantity
Long-Evans cinnamon (LEC) rat (n=45/group).When the 12nd, 13,14,16,20,24 weeks, respectively put to death 6 rats respectively.
2) administering mode: oral
3) dosage and persistent period: 14mg/kg and 28mg/kg, 24 weeks of as many as.
Embodiment 5: Compound I improves the ALT value in people's liver
ALT (glutamate pyruvate transaminase is also referred to as SGPT, i.e. serum glutamic pyruvic transminase) is the special identifier thing of hepatic injury.ALT is a kind of enzyme that liver cell (for example hepatocyte) produces; Compare with other enzyme, ALT more has specificity to the diagnosis of hepatopathy.When liver has damage, for example when hepatitis, for example cell membrane damage, ALT can increase usually.In the general patient of no hepatic injury, the ALT value is about zero.
The patient of iron overload can develop into hepatic injury, thereby causes that the ALT value raises.Appended result of the test shows that the patient's that Compound I can raise the ALT value ALT level rolls back the baseline values value.
Above-mentioned patient is the patient of iron overload, and treats 1 year with the Compound I of various dose.
Adopt conventional biomedical technology to measure ALT, for example use Brinkmann T, DreierJ, Diekmann J, Gotting C, Klauke R, Schumann G, the described International Federation of Clinical Chemistry of Kleesiek K reference method (International Federation of ClinicalChemistry reference method).With the cutoff value (cut-offvalue) of new International Federation of Clinical Chemistry's reference method, see Vox Sang, 2003,85 (3): 159-64 at 37 ℃ of time screening blood donors' glutamate pyruvate transaminase.
Appended result of the test shows that the Compound I of suitable dosage can make the ALT value of the patient with ALT parameter remain on baseline value, that is to say, makes its ALT value be no more than baseline ALT value.
Baseline ALT value is defined as the patient's that the patient by the clinical trial registration phase determines ALT value, that is to say that the ALT baseline value is the ALT value of patient before beginning with chemical compound 1 treatment.
The patient accepts the Compound I of various dosage, when a suitable dosage, its intravital iron content reduce (as follows, dosage be 20 and the ALT value during the 30mg/kg body weight/day).The ALT value remains on about baseline value or is lower than baseline value.
Table 1: the Compound I of usefulness various dose was treated after 1 year, thalassemia patient's ALT value (independent trials is with result's comparison of table 1)
| Compound I | Patient's number | The meansigma methods of ALT (units per liter) |
| 5mg/kg/ days | 2 | 35.25 |
| 10mg/kg/ days | 8 | 26.62 |
| 20mg/kg/ days | 21 | 3.17 |
| 30mg/kg/ days | 52 | -23.56 |
Table 2: use the Compound I of various dose to treat after 1 year, seldom anemia patient's ALT value
| Compound I | Patient's number | The meansigma methods of ALT (units per liter) |
| 5mg/kg/ days | 4 | 67.42 |
| 10mg/kg/ days | 10 | 14.22 |
| 20mg/kg/ days | 24 | -3.27 |
| 30mg/kg/ days | 41 | -14.19 |
Embodiment 6:
Compound I is administered to the suffer from chronic hepatitis C patient of (for example 1 genotype), described patient does not respond Therapeutic Method (comprising interferon (as glycol interferon) and ribavirin) maybe can not continue response.
Tested the Compound I of 2 to 3 various dose.
Every group of patient's number: 8-12.
Embodiment 7:
Give the patient:
The combination product of-Compound I and biological response modifier (for example interferon-ALPHA),
The combination product of-Compound I and biological response modifier (for example interferon-ALPHA) and ucleosides antimetabolite (for example ribavirin),
The combination product of-Compound I and ribavirin.
Claims (17)
1. the purposes of the Compound I of following formula in the medicine of the hepatopathy that preparation treatment ferrum plays a role in its pathogenesis:
2. according to the purposes of claim 1, wherein said hepatopathy is chronic hepatitis C, non-alcoholic stellato-hepatitis or non-alcoholic fatty liver disease.
3. according to the purposes of claim 2, wherein said hepatopathy is a chronic hepatitis C.
4. according to the purposes of claim 1 or 2, wherein the ferrum state reaches shortage or nearly deficiency state after treating.
5. according to any one purposes among the claim 1-4, wherein Compound I exists with the dispersible tablet form.
6. according to any one purposes among the claim 1-5, wherein Compound I is a polymorphic A form.
7. according to any one purposes among the claim 1-6, wherein with the daily dose of the Compound I that is equivalent to 50mg to 4000mg with the Compound I administration.
8. according to any one purposes among the claim 1-7, wherein per 2 or give Compound I once a day 3 at least 2 weeks of the middle of the month.
9. according to the purposes of claim 1-8, wherein gave Compound I per month at least 7 days once a day.
10. the purposes of the hepatopathy that the purposes of the Compound I of any one in requiring according to aforesaid right, this purposes play a role in its pathogenesis for the excessive ferrum of treatment.
11. treatment suffers from the mammiferous method of the hepatopathy that ferrum plays a role in its pathogenesis, described method comprises the mammal that the Compound I of the effective dose that can remove excessive iron is administered to needs this kind treatment.
12. combination product, this combination product comprise (a) Compound I and (b) biological response modifier and/or ucleosides antimetabolite.
13. according to the combination product of claim 12, wherein said (b) biological response modifier is an interferon.
14. according to the combination product of claim 13, wherein said interferon is selected from Intederon Alpha-2a, Interferon Alpha-2b, Interferon Alfacon-1, Polyethylene Glycol Interferon Alpha-2b or Polyethylene Glycol Intederon Alpha-2a.
15. according to the combination product of claim 14, wherein said ucleosides antimetabolite is selected from ribavirin, viramidine or valopicitabine.
16. according to the combination product of claim 14, wherein said ucleosides antimetabolite is a ribavirin.
17. according to any one the purposes of combination product in the medicine of the chronic hepatitis C that preparation treatment does not respond standard care among the claim 12-16.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68584805P | 2005-05-31 | 2005-05-31 | |
| US60/685,848 | 2005-05-31 | ||
| US60/692,808 | 2005-06-22 | ||
| US60/746,786 | 2006-05-09 |
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| Publication Number | Publication Date |
|---|---|
| CN101180053A true CN101180053A (en) | 2008-05-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800176178A Pending CN101180053A (en) | 2005-05-31 | 2006-05-30 | Treatment of liver diseases in which iron plays a role in pathogenesis |
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| Country | Link |
|---|---|
| CN (1) | CN101180053A (en) |
| UA (1) | UA92912C2 (en) |
| ZA (1) | ZA200708895B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114073772A (en) * | 2020-08-18 | 2022-02-22 | 上海市公共卫生临床中心 | Use of an iron chelator for the treatment or prevention of polyoma viral infections |
-
2006
- 2006-05-30 UA UAA200713361A patent/UA92912C2/en unknown
- 2006-05-30 CN CNA2006800176178A patent/CN101180053A/en active Pending
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- 2007-10-17 ZA ZA200708895A patent/ZA200708895B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114073772A (en) * | 2020-08-18 | 2022-02-22 | 上海市公共卫生临床中心 | Use of an iron chelator for the treatment or prevention of polyoma viral infections |
Also Published As
| Publication number | Publication date |
|---|---|
| UA92912C2 (en) | 2010-12-27 |
| ZA200708895B (en) | 2008-10-29 |
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