阅读说明：本技术 治疗肝病的方法 (The method for treating hepatopathy ) 是由 J.G.贝茨 D.G.C.布雷肯里奇 G.R.布达斯 J.T.莱尔斯 于 2018-04-11 设计创作，主要内容包括：本公开涉及预防和/或治疗肝病的方法,其包括将ASK1抑制剂与ACC抑制剂和FXR激动剂组合给予需要的患者。(This disclosure relates to the method prevented and/or treat hepatopathy comprising ASK1 inhibitor and ACC inhibitor and FXR agonist combinations are given to the patient of needs.)

1. the method for the treatment of and/or prevention of liver disease in the patient of needs, including pressing down to the ASK1 of patient's dosage treatment effective amount The combination of the FXR agonist of the ACC inhibitor and therapeutically effective amount of preparation and therapeutically effective amount.

2. the method for the treatment of and/or prevention of liver disease in the patient of needs, including pressing down to the ASK1 of patient's dosage treatment effective amount The combination of the FXR agonist of the ACC inhibitor and therapeutically effective amount of preparation and therapeutically effective amount,

Wherein the ASK1 inhibitor is selected from:

Formula (I) compound:

Or its pharmaceutically acceptable salt,

Formula (II) compound:

Or its pharmaceutically acceptable salt,

With formula (VII) compound:

Or its pharmaceutically acceptable salt；

The ACC inhibitor is selected from formula (III) compound:

Or its pharmaceutically acceptable salt,

With formula (IV) compound:

Or its pharmaceutically acceptable salt；

And the FXR agonist is selected from formula (V) compound:

Or its pharmaceutically acceptable salt,

With formula (VI) compound:

Or its pharmaceutically acceptable salt.

3. method according to claim 2, wherein the ASK1 inhibitor is formula (I) compound, which is formula (III) Compound, and the FXR agonist is formula (V) compound.

4. method according to claim 2, wherein the ASK1 inhibitor is formula (I) compound, which is that formula (IV) changes Object is closed, and the FXR agonist is formula (V) compound.

5. method according to claim 2, wherein the ASK1 inhibitor is formula (I) compound, which is formula (III) Compound, and the FXR agonist is formula (VI) compound.

6. method according to claim 2, wherein the ASK1 inhibitor is formula (I) compound, which is that formula (IV) changes Object is closed, and the FXR agonist is formula (VI) compound.

7. method according to claim 2, wherein the ASK1 inhibitor is formula (II) compound, which is formula (III) Compound, and the FXR agonist is formula (V) compound.

8. method according to claim 2, wherein the ASK1 inhibitor is formula (II) compound, which is formula (IV) Compound, and the FXR agonist is formula (V) compound.

9. method according to claim 2, wherein the ASK1 inhibitor is formula (II) compound, which is formula (III) Compound, and the FXR agonist is formula (VI) compound.

10. method according to claim 2, wherein the ASK1 inhibitor is formula (II) compound, which is formula (IV) Compound, and the FXR agonist is formula (VI) compound.

11. method according to claim 2, wherein the ASK1 inhibitor is formula (VII) compound, which is formula (III) compound, and the FXR agonist is formula (V) compound.

12. method according to claim 2, wherein the ASK1 inhibitor is formula (VII) compound, which is formula (IV) compound, and the FXR agonist is formula (V) compound.

13. method according to claim 2, wherein the ASK1 inhibitor is formula (VII) compound, which is formula (III) compound, and the FXR agonist is formula (VI) compound.

14. method according to claim 2, wherein the ASK1 inhibitor is formula (VII) compound, which is formula (IV) compound, and the FXR agonist is formula (VI) compound.

15. any one of -14 method according to claim 1, wherein the ASK1 inhibitor, the ACC inhibitor and FXR excitement Agent is administered together.

16. any one of -14 method according to claim 1, wherein the ASK1 inhibitor, the ACC inhibitor and FXR excitement Agent is separately administered.

17. any one of -14 method according to claim 1, wherein the ASK1 inhibitor, the ACC inhibitor and FXR excitement At least two in agent are administered together.

18. any one of -17 method according to claim 1, wherein the hepatopathy is nonalcoholic fatty liver disease (NASH).

19. pharmaceutical composition, it includes the ASK1 inhibitor of therapeutically effective amount, the ACC inhibitor of therapeutically effective amount, treatment is effective The FXR agonist of amount,

Wherein the ASK1 inhibitor is selected from:

Formula (I) compound:

Or its pharmaceutically acceptable salt,

With formula (II) compound:

Or its pharmaceutically acceptable salt,

With formula (VII) compound:

Or its pharmaceutically acceptable salt；

The ACC inhibitor is selected from formula (III) compound:

Or its pharmaceutically acceptable salt,

With formula (IV) compound:

Or its pharmaceutically acceptable salt；

And the FXR agonist is selected from formula (V) compound:

Or its pharmaceutically acceptable salt,

With formula (VI) compound:

Or its pharmaceutically acceptable salt；

With pharmaceutically acceptable excipient.

20. composition according to claim 19, wherein the ASK1 inhibitor is formula (I) compound, which is formula (III) compound, and the FXR agonist is formula (V) compound.

21. composition according to claim 19, wherein the ASK1 inhibitor is formula (I) compound, which is formula (IV) compound, and the FXR agonist is formula (V) compound.

22. composition according to claim 19, wherein the ASK1 inhibitor is formula (I) compound, which is formula (III) compound, and the FXR agonist is formula (VI) compound.

23. composition according to claim 19, wherein the ASK1 inhibitor is formula (I) compound, which is formula (IV) compound, and the FXR agonist is formula (VI) compound.

24. composition according to claim 19, wherein the ASK1 inhibitor is formula (II) compound, which is formula (III) compound, and the FXR agonist is formula (V) compound.

25. composition according to claim 19, wherein the ASK1 inhibitor is formula (II) compound, which is formula (IV) compound, and the FXR agonist is formula (V) compound.

26. composition according to claim 19, wherein the ASK1 inhibitor is formula (II) compound, which is formula (III) compound, and the FXR agonist is formula (VI) compound.

27. composition according to claim 19, wherein the ASK1 inhibitor is formula (II) compound, which is formula (IV) compound, and the FXR agonist is formula (VI) compound.

28. composition according to claim 19, wherein the ASK1 inhibitor is formula (VII) compound, which is formula (III) compound, and the FXR agonist is formula (V) compound.

29. composition according to claim 19, wherein the ASK1 inhibitor is formula (VII) compound, which is formula (IV) compound, and the FXR agonist is formula (V) compound.

30. composition according to claim 19, wherein the ASK1 inhibitor is formula (VII) compound, which is formula (III) compound, and the FXR agonist is formula (VI) compound.

31. composition according to claim 19, wherein the ASK1 inhibitor is formula (VII) compound, which is formula (IV) compound, and the FXR agonist is formula (VI) compound.

Technical field

This disclosure relates to the method prevented and/or treat hepatopathy.

Background technique

Duration based on disease, hepatopathy are typically categorized into acute or chronic.Hepatopathy can be by infection, damage, sudden and violent Be exposed to drug or toxic compounds, alcohol, in impurity and blood in food koinomatter abnormal accumulation, autoimmunity Process, genetic defect (such as hemochromatosis) or unknown cause and cause.

Hepatopathy is the main reason for whole world is dead.Particularly, have been observed that high-fat diet to be shockingly similar to The mode liver injury of hepatitis.American Liver Foundation's estimation, the population more than 20% suffer from non-alcohol fatty liver (NAFLD).Have shown that the life style of obesity, unsound diet and sitting may cause the high incidence of NAFLD.When not controlling When treatment, NAFLD can proceed to nonalcoholic fatty liver disease (NASH), cause serious adverse reaction.Once NASH develops, it It will lead to liver and expand and formed scar (i.e. cirrhosis) at any time.

Although preliminary report shows that positive lifestyle change can prevent or reverse hepatic injury, still without effective The drug therapy of NAFLD.Therefore, there is still a need for providing new effective drug to treat hepatopathy.

Summary of the invention

Disclosed herein is the methods for the treatment of and/or prevention of liver disease in the patient of needs, including have to patient's drug treatment Cell proliferation (ASK1) inhibitor of effect amount and acetyl-CoA carboxylase (ACC) inhibitor of therapeutically effective amount and The combination of farnesoid X receptor (farnesoid X receptor, FXR) agonist of therapeutically effective amount.The hepatopathy include but It is not limited to chronic and/or metabolism hepatopathy, non-alcohol fatty liver (NAFLD) and nonalcoholic fatty liver disease (NASH).

In a particular embodiment, provided herein is non-alcoholic fatty liver is treated and/or prevented in the patient of needs The method of scorching (NASH), ACC inhibitor including ASK1 inhibitor and therapeutically effective amount to patient's dosage treatment effective amount and The combination of the FXR agonist of therapeutically effective amount.

In method provided herein, ASK1 inhibitor, ACC inhibitor and FXR agonist can co-administereds.In these realities It applies in scheme, ASK1 inhibitor, ACC inhibitor and FXR agonist can be used as single drug composition and be administered together, or be more than It is separately administered in a kind of pharmaceutical composition.Therefore, the ASK1 inhibitor comprising therapeutically effective amount, therapeutically effective amount is also provided herein ACC inhibitor and therapeutically effective amount FXR agonist pharmaceutical composition.

Pharmaceutical composition is also provided herein, it includes the ASK1 inhibitor of therapeutically effective amount, the ACC of therapeutically effective amount presses down The FXR agonist and pharmaceutically acceptable excipient of preparation and therapeutically effective amount.

Detailed description of the invention

Fig. 1 passes through PSR positive area percentage of the quantitative image analysis in rat CDHFD model.(***p< 0.001, * p < 0.0001 * * * is markedly different from medium by one-way analysis of variance；Examined by t aobvious in &&&&p < 0.0001 It writes and is different from starting to treat；#p < 0.05, ##p < 0.01, ####p < 0.0001 by t inspection be markedly different from shown in two components Combination).Figure shows average value ± SD.

Fig. 2 passes through α-SMA positive area percentage of the quantitative image analysis in rat CDHFD model.(**p< 0.01, * p < 0.0001 * * p < 0.001, * * * * is markedly different from medium by one-way analysis of variance；&&&&p < 0.0001 is logical It crosses t inspection and is markedly different from and start to treat；##p < 0.01, ###p < 0.001, ####p < 0.0001 are markedly different from by t inspection Shown in two groups of subassemblys).Figure shows average value ± SD.

Fig. 3 measures the Timp1 albumen in the blood plasma of rat CDHFD model by ELISA.(*p<0.05,**p< 0.01, * p < 0.001 * * is markedly different from medium by one-way analysis of variance；It is examined significantly not by t &&&&p < 0.0001 It is same as starting to treat；##p < 0.01 by t inspection be markedly different from shown in two groups of subassemblys).Figure shows average value ± SD.

Detailed description of the invention

Definition and general parameter

The following term and phrase that this specification uses are generally intended to the meaning being such as set forth below, but context In addition except the case where illustrating.

As it is used herein, the term " about " used under the background of quantitative measurment refers to indicatrix ± 10%, or Indicatrix ± 5% or ± 1%.

Term " pharmaceutically acceptable salt " refers to the salt of compound disclosed herein, keeps the biology of basic compound Validity and property, and be not on biology or other aspects are undesirable.There are acid-addition salts and base addition salts.Pharmaceutically may be used The acid-addition salts of receiving can be from the preparation of inorganic and organic acid.

Pharmaceutically acceptable salt (respectively acid-addition salts or base addition salts) is formed for reacting with basic compound Bronsted lowry acids and bases bronsted lowry is known to the skilled in the art.It, can be with if compound as described herein is obtained as acid-addition salts Free alkali is obtained by the solution for the acid salt that alkalizes.On the contrary, if product is free alkali, it can be by the way that free alkali be dissolved The solution is handled in suitable organic solvent and with acid, prepares and adds according to the conventional method for preparing acid-addition salts from alkali cpd At salt, especially pharmaceutically acceptable addition salt.Those skilled in the art will appreciate that can be used for preparing it is nontoxic pharmaceutically The various synthetic methods of acceptable addition salt.Pharmaceutically acceptable acid-addition salts can be prepared by inorganic acid and organic acid. Salt from inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..Salt from organic acid includes acetic acid, propionic acid, second Alkyd, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cortex cinnamomi Acid, mandelic acid, methanesulfonic acid, ethane sulfonic acid, to toluene-sulfonic acid, salicylic acid, etc..Equally, pharmaceutically acceptable base addition salts can From the preparation of inorganic and organic base.Salt from inorganic base includes only being used as example, sodium, potassium, lithium, ammonium, calcium and magnesium salts.From having The salt of machine alkali includes, but are not limited to the salt of primary, secondary and tertiary amine, if alkylamine is (that is, NH₂(alkyl)), dialkylamine is (that is, HN (alkyl)₂), trialkylamine is (that is, N (alkyl)₃), replace alkylamine (that is, NH₂(substituted alkyl)), two (substituted alkyl) Amine is (that is, HN (substituted alkyl)₂), three (substituted alkyl) amine are (that is, N (substituted alkyl)₃), alkenyl amine is (that is, NH₂(alkene Base)), dialkylene amine is (that is, HN (alkenyl)₂), trialkenyl amine is (that is, N (alkenyl)₃), replace alkenyl amine (that is, NH₂(substituted alkene Base)), two (substituted alkenyl) amine are (that is, HN (substituted alkenyl)₂), three (substituted alkenyl) amine are (that is, N (substituted alkenyl)₃、 Mono-, two- or three-Cycloalkyl amines are (that is, NH₂(naphthenic base), HN (naphthenic base)₂, N (naphthenic base)₃), mono-, two- or three-arylamines (that is, NH₂(aryl), HN (aryl)₂, N (aryl)₃) or mixed amine, etc..The specific example of suitable amine includes, only as real Example, isopropylamine, Trimethylamine, diethylamide, three (isopropyl) amine, three (n-propyl) amine, ethanol amine, 2- dimethylaminoethyl Alcohol, piperazine, piperidines, morpholine, N-ethylpiperidine etc..Similarly, the method for preparing pharmaceutically acceptable salt from basic compound (when open) is known to the skilled in the art, and is disclosed in such as Berge et al., Journal of The sources such as Pharmaceutical Science, Jan.1977vol.66, No.1.

As used herein, " pharmaceutically acceptable carrier " includes the figuration harmless to disclosed compound or its purposes Agent or reagent, such as solvent, diluent, decentralized medium, coating, antibacterial agent and antifungal agent, isotonic agent and absorption delaying agent Deng.Using the composition that such carrier and reagent prepare pharmaceutically active substance be it is well known in the art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA17th Ed(1985)；With Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S.Banker& C.T.Rhodes, Eds.).

Term " therapeutically effective amount " and " effective quantity " are used interchangeably, and are referred to when one or more dosage deliver medicine to need It wants to be enough to realize the amount of the compound such as undefined treatment when patient (for example, people) of this treatment.Therapeutically effective amount is by root It is true according to patient, the disease treated, the weight of patient and/or age, the seriousness of disease or by qualified pharmacist or care-giver Fixed administration mode and change.

Term " treatment (treatment) " or " treatment (treating) " refer to the compound or pharmaceutically of administration formula (I) Acceptable salt is used for following purpose: (i) postpones the breaking-out of disease, that is, causes the clinical symptoms of disease not occur or postpone it and go out It is existing；(ii) inhibit disease, that is, prevent the development of clinical symptoms；And/or (iii) alleviates disease, that is, causes clinical symptoms or it is tight The recession of principal characteristic.

Hepatopathy

Hepatopathy is the acute or chronic damage during continuing disease to liver.Hepatic injury can be by infection, damage, exposure Abnormal accumulation, the autoimmunity mistake of koinomatter in impurity, blood in drug or toxic compounds such as alcohol or food Journey, genetic defect (such as hemochromatosis) or other unknown causes cause.Exemplary hepatopathy includes but is not limited to cirrhosis, Liver fibrosis, non-alcohol fatty liver (NAFLD), nonalcoholic fatty liver disease (NASH), alcoholic fatty liver are scorching (ASH), Ischemia-reperfusion Injury in Rat, primary biliary cirrhosis (PBC) and hepatitis, including viral and alcoholic hepatitis.

Non-alcohol fatty liver (NAFLD) is the accumulation of not extra fat in the liver cell as caused by alcohol. NAFLD may cause liver swelling (i.e. steatohepatitis), this may cause scar (i.e. cirrhosis) with the time again, and can It can lead to liver cancer or hepatic failure.NAFLD is characterized in that accumulation of the fat in liver cell, and usually and metabolic syndrome The some aspects of (such as diabetes B, insulin resistance, hyperlipidemia, hypertension) are related.The frequency of this disease has become Must be increasingly common, this is because consumption is rich in carbohydrate and high-fat diet.NAFLD patient a subgroup (~ 20%) development is nonalcoholic fatty liver disease (NASH).

NASH is the hypotype of Fatty Liver Disease, is more serious NAFLD form.It is characterized in that Macrovesicular steatosis, The sacculus of liver cell is denaturalized and/or inflammation, eventually leads to liver cicatrization (i.e. fibrosis).The patient progress for being diagnosed as NASH arrives Advanced stage liver fibrosis and final cirrhosis.It is at present liver transfer operation to the treatment of the cirrhosis NASH patient with terminal illness.

Another common hepatopathy is primary sclerotic cholangitis (PSC).It is chronic or long-term hepatopathy, is slowly damaged The inside and outside bile duct of liver.In the patient with PSC, bile is accumulated in due to bile duct occlusion in liver, gradually Damage liver cell simultaneously causes cirrhosis or liver cicatrization.Currently, curing PSC without effective treatment method.Many trouble There is the patient of PSC since hepatic failure finally needs liver transfer operation, usually after being diagnosed with the disease about 10 years.PSC can also It can lead to cholangiocarcinoma.

Liver fibrosis is the mistake of the extracellular matrix protein (including collagen) occurred in most types of chronic liver disease Degree accumulation.Advanced stage liver fibrosis leads to cirrhosis, hepatic failure and portal hypertension, and usually requires liver transfer operation.

Method

Disclosed herein is the methods for the treatment of and/or prevention of liver disease in the patient of needs, including have to patient's drug treatment The combination of the ASK1 inhibitor of effect amount and the ACC inhibitor of therapeutically effective amount and the FXR agonist of therapeutically effective amount.Active hepatopathy Presence can be detected by the presence of enzyme level raised in blood.Specifically, it is known that higher than clinically receiving just The alanine aminotransferase (ALT) of normal range and the blood level of aspartate transaminase (AST) indicate ongoing hepatic injury. To the routine monitoring of the blood level of the ALT and AST of hepatopath be used clinically for measuring in medical therapy hepatopathy into Exhibition.Raised ALT and AST are reduced in the normal range (NR) of receiving as clinical evidence, the ongoing liver damage of reflection patient The reduction of the seriousness of wound.

In some embodiments, hepatopathy is chronic liver disease.Chronic liver disease, which is related to hepatic parenchymal progressive, to be destroyed, and fibre is caused Dimensionization and cirrhosis.In general, chronic liver disease can be by virus (such as hepatitis B, hepatitis C, cytomegalovirus (CMV) Or epstein-Barr virus (Epstein Barr Virus, EBV)), toxic agents or drug (such as alcohol, methotrexate (MTX) or Furantoin), metabolic disease (such as non-alcohol fatty liver (NAFLD), nonalcoholic fatty liver disease (NASH), Hemochromatosis or Wilson's disease), autoimmune disease (such as autoimmune chronic hepatitis, primary biliary Cholangitis (being formerly referred to as primary biliary cirrhosis) or primary sclerotic cholangitis) or other reasons (such as right heart failure Exhaust) cause.

In one embodiment, there is provided herein the methods for reducing cirrhosis level.In one embodiment, Cirrhosis is in the loss that feature pathologically is normal small leaflet structure, fibrosis and tubercle regeneration.Measure degree of cirrhosis Method be well known in the art.In one embodiment, cirrhosis level reduces about 5% to about 95%.Implement at one In scheme, cirrhosis level reduces at least about 5%, at least about 10%, at least about 15%, at least about 20% in subject, until Few about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least 50%, at least about 55%, at least About 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least About 95%.In one embodiment, the fibrosis score of patient can be reduced from baseline, such as be reduced to F3 from F4, from F3 It is reduced to F2, or is reduced to F1 from F2.

In some embodiments, the hepatopathy is Metabolic liver disease.In one embodiment, the hepatopathy is non-wine Essence fatty liver disease (NAFLD).NAFLD and insulin resistance and metabolic syndrome (obesity, combined hyperlipidemia familial, sugar Urinate sick (II type) and hypertension) it is related.Think that NAFLD covers a series of disease activities, and starts as the accumulation of fat in liver (hepatic steatosis).

It has been shown that fat and insulin resistance may play strong effect in the lysis of NAFLD.In addition to drink Eat it is bad except, there are also several other known reasons by NAFLD.For example, NAFLD can be caused by some drugs, such as amiodarone, Antiviral drugs (such as nucleoside analog), aspirin is (seldom as children's Reye syndrome (Reye's syndrome) A part), corticosteroid, methotrexate (MTX), tamoxifen or tetracycline.NAFLD also passes through the presence of high-fructose corn syrup Related to the consumption of soft drink, this may cause fat in the increased deposition of abdomen, although the consumption of sucrose shows similar effect Fruit (may be since it resolves into fructose).Science of heredity is recognized as the effect of having played, because having determined that this neurological susceptibility Two genetic mutations.

If do not treated, NAFLD can develop into nonalcoholic fatty liver disease (NASH), be the most extreme of NAFLD Form, wherein state of the steatosis in conjunction with inflammation and fibrosis.The main reason for NASH is considered as cirrhosis.Therefore, Provided herein is the methods that nonalcoholic fatty liver disease (NASH) is treated and/or prevented in the patient of needs, including to patient The group of the ASK1 inhibitor of dosage treatment effective amount and the ACC inhibitor of therapeutically effective amount and the FXR agonist of therapeutically effective amount It closes.

The method that liver fibrosis is treated and/or prevented in the patient of needs is also provided herein, including is controlled to patient's administration Treat the combination of the ACC inhibitor of a effective amount of ASK1 inhibitor and therapeutically effective amount and the FXR agonist of therapeutically effective amount.Liver is fine Dimensionization is building up for extracellular matrix protein (including the collagen) occurred in most types of chronic liver disease.Some In embodiment, advanced stage liver fibrosis leads to cirrhosis and hepatic failure.Method for measuring liver histological, such as fibrosis journey The variation of bridging necrosis is well known in the art around degree, lobular hepatitis and portal vein.

In one embodiment, the horizontal drop of liver fibrosis (it is fibr tissue formation, fibroma or fibre modification) It is low to be more than about 90%.In one embodiment, the water of liver fibrosis (it is fibr tissue formation, fibroma or fibre modification) Pancake low at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least About 30%, at least about 20%, at least about 10%, at least about 5% or at least about 2%.

Some embodiments as described herein are related to treating the method for hepatopathy, and the method includes dosage treatment effective amounts The form (form) of compound I as described herein or pharmaceutical composition as described herein.Hepatopathy can be divided into 4 stages: F0 is indicated Without fibrosis；F1 indicates mild fibrosis；F2 indicates moderate fibrosis；F3 indicates has severe fibrosis；Cirrhosis is indicated with F4.In In one embodiment, the fiber that compound provided herein reduces in liver forms level.The formation of liver fiber is to cause to be known as The process that excess extracellular matrix component deposits in the liver of fibrosis.It is in such as chronic type B viral hepatitis and the third type liver Inflammation, alcoholic liver disease, drug-induced hepatopathy, hemochromatosis, oneself immunity hepatitis, Wilson's disease, primary gallbladder It is seen in juice cholangitis (being formerly referred to as primary biliary cirrhosis), sclerosing cholangitis, hepatic schistosomiasis and other illnesss It observes.In one embodiment, fiber forms horizontal reduce more than about 90%.In one embodiment, fiber forms water Pancake low at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least 40%, at least about 30%, at least about 20%, at least about 10%, at least about 5% or at least 2%.Some embodiments as described herein are related to treating The method of hepatopathy, the method includes the form of the compound I as described herein of dosage treatment effective amount or medicines as described herein Compositions.Hepatopathy can be divided into 4 stages: F0 indicates no fibrosis；F1 indicates mild fibrosis；F2 indicates moderate fibrosis； F3 indicates has severe fibrosis；Cirrhosis is indicated with F4.

In other embodiments, provided herein is primary sclerotic bile duct is treated and/or prevented in the patient of needs The method of scorching (PSC), ACC inhibitor including ASK1 inhibitor and therapeutically effective amount to patient's dosage treatment effective amount and is controlled Treat the combination of a effective amount of FXR agonist.

Have been observed that the patient with NASH average specific healthy patients about 2.8 years old in epigenetic test.Therefore, In one embodiment, it can be used for slowing down for treating the compound of NASH, improve or reverse and apparently lost as caused by NASH Pass the influence of age or aging.In another embodiment, for treating the combination treatment of NASH, for example, it is disclosed herein The combination of ASK1 inhibitor compound and ACC inhibitor compound and FXR agonist, can be used for improving or reverse is caused by NASH Aging effect.

In one embodiment, ASK1 inhibitor, ACC inhibitor and FXR agonist can in combination preparation or It is applied together in individual pharmaceutical composition, wherein every kind of inhibitor can be configured to any suitable dosage form.In certain implementations In scheme, method provided herein includes that application respectively includes ASK1 inhibitor and pharmaceutically acceptable carrier or excipient Pharmaceutical composition and pharmaceutical composition comprising ACC inhibitor and pharmaceutically acceptable carrier or excipient and swash comprising FXR The pharmaceutical composition of dynamic agent and pharmaceutically acceptable carrier or excipient.Combination preparation according to the present invention inhibits comprising ASK1 Agent, ACC inhibitor and FXR agonist and one or more pharmaceutically acceptable carriers or excipient and optional other are controlled Treat agent.Alternatively, any two in ASK1 inhibitor, ACC inhibitor or FXR agonist can be combined into single formulation, It is administered with the third with individual pharmaceutical compositions.Combination preparation containing active constituent can be suitable for expected administration Any form of method.

ASK1 inhibitor

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is with formula (I) compound of structure:

Or its pharmaceutically acceptable salt.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is with formula (II) compound of structure:

Or its pharmaceutically acceptable salt.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is with formula (VII) compound of structure:

Or its pharmaceutically acceptable salt.

Method known to those skilled in the art synthesis and table can be used in the compound of formula (I), formula (II) and formula (VII) Sign, the method as described in U.S. Patent Application Publication No. 2011/0009410 and 2013/0197037.In an embodiment In, the ASK1 inhibitor is the compound or its pharmaceutically acceptable salt of formula (I).In one embodiment, described ASK1 inhibitor is the compound or its pharmaceutically acceptable salt of formula (II).In one embodiment, the ASK1 inhibits Agent is the compound or its pharmaceutically acceptable salt of formula (V).

ACC inhibitor

In certain embodiments of method disclosed herein and pharmaceutical composition, the ACC inhibitor is with formula (III) compound of structure:

Or its pharmaceutically acceptable salt.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ACC inhibitor is with formula (IV) compound of structure:

Or its pharmaceutically acceptable salt.

Method known to those skilled in the art synthesis and characterization, such as state can be used in the compound of formula (III) and formula (IV) Method described in the application publication number WO/2013/071169 of border.

FXR agonist

In certain embodiments of method disclosed herein and pharmaceutical composition, the FXR agonist is with formula (V) The compound of structure:

Or its pharmaceutically acceptable salt.

In certain embodiments of method disclosed herein and pharmaceutical composition, FXR agonist is tied with formula (VI) The compound of structure:

Or its pharmaceutically acceptable salt.

It can be used method known to those skilled in the art, such as described in the US publication 2014/0221659 Those methods synthesize and characterize the compound of formula (V) and formula (VI).

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is that formula (I) changes Object is closed, the ACC inhibitor is formula (III) compound, and the FXR agonist is formula (V) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is that formula (I) changes Object is closed, the ACC inhibitor is formula (IV) compound, and the FXR agonist is formula (V) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is that formula (I) changes Object is closed, the ACC inhibitor is formula (III) compound, and the FXR agonist is formula (VI) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is that formula (I) changes Object is closed, the ACC inhibitor is formula (IV) compound, and the FXR agonist is formula (VI) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is that formula (II) changes Object is closed, the ACC inhibitor is formula (III) compound, and the FXR agonist is formula (V) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is that formula (II) changes Object is closed, the ACC inhibitor is formula (IV) compound, and the FXR agonist is formula (V) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is that formula (II) changes Object is closed, the ACC inhibitor is formula (III) compound, and the FXR agonist is formula (VI) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is that formula (II) changes Object is closed, the ACC inhibitor is formula (IV) compound, and the FXR agonist is formula (VI) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is formula (VII) Compound, the ACC inhibitor is formula (III) compound, and the FXR agonist is formula (V) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is formula (VII) Compound, the ACC inhibitor is formula (IV) compound, and the FXR agonist is formula (V) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is formula (VII) Compound, the ACC inhibitor is formula (III) compound, and the FXR agonist is formula (VI) compound.

In certain embodiments of method disclosed herein and pharmaceutical composition, the ASK1 inhibitor is formula (VII) Compound, the ACC inhibitor is formula (IV) compound, and the FXR agonist is formula (VI) compound.

Administration and application

Although active constituent can be administered alone, it is preferred that as pharmaceutical preparation or pharmaceutical composition as described below Object provides.The preparation of the disclosure used for animal doctor and the mankind include at least one active constituent and it is one or more can The carrier of receiving and optional other therapeutic components.Carrier must be " acceptable ", mean other at split-phase with preparation Hold and is physiologically harmless to its recipient.

Every kind of active constituent can be prepared together with conventional carrier and excipient, will select according to the common practice It selects.Tablet can contain excipient, glidant, filler, adhesive etc..Aqueous formulation is prepared with sterile form, and is worked as and beaten It usually will be isotonic when calculating for by delivering in addition to oral administration.All formulations will optionally contain excipient, example Those of as described in Handbook of Pharmaceutical Excipients (1986).Excipient includes ascorbic acid With other antioxidants, chelating agent such as EDTA, carbohydrate such as dextrin, hydroxy alkyl cellulose, hydroxyalky methyl celluloses, hard Resin acid etc..The pH range of preparation is about 3 to about 11, but typically about 7 to 10.

In general, active constituent will be administered with 0.01 milligram to 2 grams of dosage.In one embodiment, dosage is about 10 Milligram is to 450 milligrams.In another embodiment, dosage is about 25 to about 250 milligrams.In another embodiment, agent Amount is about 50 or 100 milligrams.In one embodiment, dosage is about 100 milligrams.Expection activity ingredient can be with daily administration one It is secondary, twice or thrice.In addition, active constituent can once a week or twice, once every two weeks, once every three weeks, every four weeks one Secondary, every five Zhou Yici is administered once every six weeks.In one embodiment, 18 milligrams of ASK1 inhibitor are administered and 20 millis are administered Simultaneously 20 milligrams of FXR agonists are administered in gram ACC inhibitor.

Pharmaceutical composition for active constituent may include being suitable for those of above-mentioned administration route.Preparation can be convenient Ground exists with unit dosage forms, and can be prepared by any method known to pharmaceutical field.Technology and preparation usually referring to Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).Such method Include the steps that making active constituent and constitutes the carrier association of one or more auxiliary elements.In general, preparation by by activity at Point with liquid-carrier or solid carrier fine crushing or both are uniform closely mixes, then if desired, making formed product Preparation.

The preparation for being suitable for oral administration can be used as discrete unit presence, such as capsule, cachet or tablet, Mei Gehan There is the active constituent of predetermined amount；As powder or particle；As the solution or suspension in aqueous or non-aqueous liquid；Or make For oil-in-water liquid emulsion or water-in-oil liquid emulsion.Active constituent is also used as bolus, electuary or paste administration.In In specific embodiment, active constituent can be used as subcutaneous administrations.

Tablet can optionally be prepared using one or more auxiliary elements by compressing or moulding.Compressed tablets can be with By in suitable machine compress free-flowing form active constituent such as powder or particle, optionally with adhesive, lubricant, Inert diluent, preservative or surfactant mixing are to prepare.Molded tablet can be used by moulding in suitable machine It is prepared by the mixture of the powder active ingredient of inert liquid diluent wetting.Tablet can be optionally coated or indentation, And it is optionally formulated in order to provide the slow of active constituent or control release.

Active constituent can be administered by being suitable for any approach of the illness.Suitable approach include oral, rectum, nose, Part (including cheek and sublingual), vagina and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and Epidural cavity) etc..It answers Work as understanding, preferred approach can change with the situation of such as recipient.In a particular embodiment, active constituent is oral Bioavailable, therefore can be taken orally.In one embodiment, patient is people.

When being applied in combination in method disclosed herein, ASK1 inhibitor, ACC inhibitor and FXR agonist can be Administration or separately (simultaneously or sequentially) administration in more than one pharmaceutical composition together in single drug composition.In some realities It applies in scheme, ASK1 inhibitor, ACC inhibitor and FXR agonist are administered together.In other embodiments, ASK1 inhibitor, ACC inhibitor and FXR agonist are separately administered.In some respects, ACC is first administered before ASK1 inhibitor and FXR agonist Inhibitor.In some respects, FXR agonist is first administered before ASK1 inhibitor and ACC inhibitor.When being administered respectively, ASK1 inhibitor, ACC inhibitor and FXR agonist can deliver medicine to patient by identical or different route of delivery.

Pharmaceutical composition

Pharmaceutical composition of the invention includes a effective amount of selected from formula (I) compound, formula (II) compound and formula (VII) change Close the ASK1 inhibitor of object, a effective amount of ACC inhibitor and effective quantity selected from formula (III) compound and formula (IV) compound The FXR agonist selected from formula (V) compound and formula (VI) compound.

When for such as tablet, lozenge, pastille, aqueous or oily suspensions, dispersible when being administered orally, can be prepared Powder or particle, emulsion, hard or soft capsule, syrup or elixir.Composition for oral use can be according to known in the art Be used to prepare pharmaceutical composition any method preparation, and this composition can contain one or more reagents, including Sweetener, flavoring agent, colorant and preservative, in order to provide palatable preparations.Containing with nontoxic pharmaceutically acceptable figuration The tablet of the active constituent of agent (it is suitable for preparing tablet) mixing, is acceptable.It is dilute that these excipient can be such as inertia Release agent, such as calcium carbonate or sodium carbonate, lactose, a Lactose hydrate, croscarmellose sodium, povidone, calcium phosphate or phosphorus Sour sodium；Granulation agent and disintegrating agent, such as cornstarch or alginic acid；Adhesive, such as cellulose, microcrystalline cellulose, starch, gelatin Or Arabic gum；And lubricant, such as magnesium stearate, stearic acid or talcum.Tablet can be uncoated, or can pass through Known technology includes microencapsulation to be coated, to postpone disintegration and absorption in the gastrointestinal tract, to provide continuing for longer time Effect.It is, for example, possible to use time delay materials, such as individual or glycerin monostearate or glycerol disterate together with wax Ester.

The preparation being administered orally is also possible to hard gelatin capsule, wherein active constituent and inert solid diluent such as phosphoric acid Calcium or kaolin mixing, or as Perle, wherein active constituent is mixed with water or oil medium, such as peanut oil, liquid Paraffin or olive oil.

The aqueous suspension of the disclosure contains the mixture of active material with the excipient for being suitable for preparing aqueous suspension.This The excipient of sample includes suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, mosanom, poly- Vinylpyrrolidone, bassora gum and Arabic gum and dispersing agent or wetting agent, such as naturally occurring phosphatide is (for example, lecithin Rouge), the condensation product (for example, Myrj 45) of alkylene oxide and fatty acid, the contracting of ethylene oxide and long-chain fatty alcohol It closes product (such as 17 carbon ethyleneoxy group cetanols), ethylene oxide and the contracting derived from fatty acid and the partial ester of hexitan It closes product (for example, polyoxyethylene sorbitan monooleate).Aqueous suspension can also contain one or more preservatives, Such as ethyl-para-hydroxybenzoate or n-propyl, one or more colorants, one or more flavoring agents and one or more sweet teas Taste agent, for example, sucrose or saccharin.

Oil suspension can be by being suspended in vegetable oil (such as peanut oil, olive oil, sesame oil or coconut for active constituent Oil) in or prepare in the mineral oil (such as atoleine).Oral administration mixed suspension can contain thickener, for example, beeswax, hard paraffin or Cetanol.Sweetener can be added, as escribed above those and flavoring agent, to provide palatable oral preparation.These combinations Object can be saved by the way that antioxidant such as ascorbic acid is added.

Dispersible powder and particle suitable for preparing the disclosure of aqueous suspension by addition water provide and dispersion or profit The active constituent of humectant, suspending agent and the mixing of one or more preservatives.Suitable dispersing agent or wetting agent and suspending agent are by upper Face those disclosed illustrates.There may also be other excipient, such as sweetener, flavoring agent and colorant.

The pharmaceutical composition of the disclosure is also possible to the form of oil-in-water emulsion.Oil mutually can be vegetable oil, such as olive Oil or peanut oil, mineral oil, such as atoleine or these mixture.Suitable emulsifier includes naturally occurring natural gum, Such as gum arabic and bassora gum, naturally occurring phosphatide, such as soybean lecithin, derived from fatty acid and hexitan Ester or partial ester, such as the condensation product of Sorbitan Monooleate and these partial esters and ethylene oxide, such as polyoxyethylene Sorbitan Monooleate.Emulsion can also contain sweetener and flavoring agent.Syrup and elixir can use sweetener, such as sweet Oil, sorbierite or sucrose are prepared.Such preparation can also contain moderator, preservative, corrigent or colorant.

The pharmaceutical composition of the disclosure can be the form of sterile injectable preparation, such as sterile injection is aqueous or oily Property suspension.The suspension can be prepared according to known technology using above-mentioned suitable dispersing agent or wetting agent and suspending agent. Sterile injectable preparation can also be sterile injectable solution in the nontoxic acceptable diluent of parenteral or solvent or Suspension, such as solution in 1,3-BDO or it is prepared as freeze-dried powder.The acceptable carrier and solvent that can be used It is water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterile non-volatile oil usually can be used as solvent or suspension media. For this purpose, any mild expressed oi can be used, monoglyceride or diglyceride including synthesis.In addition, fatty acid Such as oleic acid can be used for preparing injection.

The amount that the active constituent of single formulation can be combined to produce with carrier material will be according to the host and tool treated The administration mode (such as oral administration or subcutaneous injection) of body and change.For example, the time for being intended for mankind's oral administration releases About 1 to 1000mg active material can be contained by putting preparation, be mixed with suitable and the amount of convenience carrier material, carrier material can For about 5 to about 95% (weight: weight) of total composition.Pharmaceutical composition can be prepared to provide the dosage for being easy to measure. For example, the active constituent of every milliliter of about 3 to 500 μ g of solution can be contained for the aqueous solution of intravenous infusion, so as to The suitable volume of the rate infusion of about 30mL/hr.When being formulated for subcutaneous administration, usually within the time of about 2 to about 4 months Monthly about drug-delivery preparation twice.

Preparation suitable for parenteral administration includes aqueous and non-aqueous sterile injection solution, can contain antioxidant, delay Electuary, bacteriostatic agent and the solute for keeping preparation isotonic with the blood of expected recipient；It, can with aqueous and non-aqueous sterile suspensions To include suspending agent and thickener.

Preparation can reside in unit dose or multi-dose container, such as in the ampoule and bottle of sealing, and can be with It is stored under freeze-drying (freeze-drying) state for only needing that sterile liquid carrier (such as water for injection) is added immediately before use. Extemporaneous injection solutions and suspension are prepared by the aseptic powdery, particle and tablet of aforementioned type.Preferably unit dose formulations are Those of the daily sub-doses of daily dose or unit as described above containing active constituent or its appropriate part.

Embodiment