CN109021056B - Farnesoid X receptor agonists - Google Patents
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- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Abstract
The invention relates to a farnesoid X receptor agonist. The invention discloses a compound shown as the following formula:
the OBN-DAS compound of the invention has the agonistic effect on FXR and EC50The value is comparable to obeticholic acid. The OBN-DAS can obviously reduce the serum ALP and TBIL levels of a cholestatic cirrhosis model rat caused by bile duct ligation, obviously improve the hepatic fibrosis score, and has the effect of treating PBC equivalent to that of obeticholic acid. The OBN-DAS can also obviously reduce serum ALT and AST levels of rats induced by MCD to NASH models, obviously improve the grading of liver pathological NASH, and has the effect of treating NASH equivalent to that of obeticholic acid. The incidence rate of adverse reactions of pruritus caused by OBN-DAS is obviously lower than that of obeticholic acid.
Description
Technical Field
The invention belongs to the field of medicines, relates to a farnesoid X receptor agonist, and particularly relates to a small-molecular farnesoid X receptor agonist, and a preparation method and application thereof.
Background
FXR (farnesoid X receptor), a bile acid receptor expressed in tissues and organs such as the liver and intestine system, can be activated by endogenous ligand bile acid, plays an important role in bile acid metabolism and cholesterol metabolism, can promote adipocyte differentiation in vivo, and regulates adipocyte function in vivo, wherein one very important pathway is the insulin pathway. The primary bile acids chenodeoxycholic acid are the most potent ligands of FXR, and the secondary bile acids lithocholic and deoxycholic acid may also activate FXR. Obeticholic acid is an FXR agonist and a bile acid regulator, increases insulin secretion, improves insulin resistance, enhances lipid storage of adipocytes, promotes adiponectin (an insulin sensitizing hormone, which has been found through studies to improve hepatic injury in NASH patients mediated by bile acid) and leptin (leptin) secretion, and has an anti-fibrotic effect. The most important indications of obeticholic acid include Primary Biliary Cirrhosis (PBC) and non-alcoholic steatohepatitis (NASH), as well as Primary Sclerosing Cholangitis (PSC), portal hypertension, bile acid diarrhea, and the like.
Primary Biliary Cirrhosis (PBC): the disease is a cholestatic liver disease caused by chronic progressive biliary obstruction of unknown cause, and is likely to be related to autoimmunity. PBC often coexists with other immune diseases such as rheumatoid arthritis, sjogren's syndrome, scleroderma, chronic lymphocytic thyroiditis and the like, is frequently seen in middle-aged women, has an insidious onset, is slow in passing, does not obviously reduce appetite and body weight, and does not have any symptom in about 10 percent of patients. PBC is progressive, eventually leading to cirrhosis and liver failure, and liver transplantation is the only effective treatment for end-stage PBC patients.
PBC is characterized by highly specific intrahepatic small bile duct destruction. PBC patients specific serum markers is AMA (anti mitochondrial antibodies), specificity of 90 ~ 95%.
The disease is a rare disease, the global incidence rate is about 0.25-0.33 per thousand, the incidence rate does not change obviously in each region, but the incidence rate is considered to be relatively high in western countries and is rare in Asia and Africa. The majority of the patients with the disease are women, and the patients with the disease are: the ratio of male patients was about 10: 1, the onset age is 40-60 years.
Non-alcoholic steatohepatitis (NASH): NAFLD (non-alcoholic fatty liver disease) is a metabolic stress liver injury closely related to Insulin Resistance (IR) and genetic predisposition, with pathological changes similar to alcoholic liver disease, but without a history of excessive alcohol consumption by patients, with a disease spectrum including non-alcoholic simple fatty liver (NAFL), non-alcoholic steatohepatitis (NASH) and its associated cirrhosis and hepatocellular carcinoma. NAFL is defined as evidence of hepatic steatosis but no damage to hepatocytes (hepatocyte ballooning); NASH is defined as the presence of hepatic steatosis and inflammatory damage of liver cells with or without fibrosis.
NAFL histology progresses very slowly, NAFLD not only progresses to fibrosis and liver cirrhosis through NASH, the incidence rate of liver cirrhosis reaches 15% -25% within 10-15 years, NAFLD can further progress to liver failure and primary liver cancer, the mortality rate related to liver diseases is increased, more importantly, NAFLD is used as a component of metabolic syndrome, and the mortality rate of malignant tumors, atherosclerosis and cardiovascular diseases related to metabolic syndrome and the morbidity rate of type 2 diabetes are remarkably increased. These syndromes are important factors affecting the quality of life and life expectancy of NASH patients.
The incidence of NAFLD is high, which is the most common reason for abnormal liver function enzymology and chronic liver disease in western developed countries such as Europe and America, and the prevalence of NAFLD in common adults is 20-33%, wherein NASH and cirrhosis respectively account for 10-20% and 2-3%. The prevalence of NAFLs of obesity patients is 60-90%, NASH is 20-25%, liver cirrhosis is 2-8%, and the prevalence of NAFLs of type II diabetes and hyperlipidemia patients is 28-55% and 27-92%, respectively.
Comprehensive evaluation shows that the NASH prevalence rate of western countries is estimated to be about 3% -5%, and the NASH-related liver cirrhosis prevalence rate is not clear. It is estimated that approximately 600 million adults in the united states develop advanced liver fibrosis or cirrhosis due to NASH. With the global prevalence of obesity and metabolic syndrome, NAFLD in Asian countries increases rapidly and has a low-age incidence trend in recent 20 years, the prevalence rate of developed areas such as Shanghai, Guangzhou and hong Kong in China is about 15%, and the prevalence rate of NASH is about 1.5% -3%. According to the current trend of development, NASH is predicted to become the primary indication for liver transplantation in the next 10 years.
However, pruritus is the most common adverse reaction of obeticholic acid, and in one clinical trial, 68% of patients who are treated by oral administration of 10mg and 56% of patients who are treated by titration of 10mg have pruritus. 12% of the patients in the oral 10mg treatment group and 9% of the patients in the titration 10mg treatment group discontinued study medication.
Disclosure of Invention
The invention aims to provide the FXR agonist with good curative effect and small adverse reaction.
In one aspect, the present invention provides the following compounds:
in a second aspect, the invention provides a pharmaceutical composition comprising OBN-DAS and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition can be tablets, capsules, granules, injections and the like.
The third aspect of the invention provides a preparation method of OBN-DAS, which comprises the following steps:
(1) reacting OBA (obeticholic acid) with taurine to generate OBN (taurine obeticholic acid);
(2) and salifying the OBN and the S-adenosine-L-methionine to obtain the OBN-DAS.
In a fourth aspect, the present invention provides the use of OBN-DAS and pharmaceutical compositions thereof: use in the manufacture of a medicament as an FXR agonist; use in the manufacture of a medicament for the treatment of PBC; use in the manufacture of a medicament for the treatment of NASH; the application in preparing the medicine for treating primary sclerosing cholangitis; use in the manufacture of a medicament for the treatment of portal hypertension; the use in the manufacture of a medicament for the treatment of bile acid diarrhoea.
The OBN-DAS compound of the invention has the agonistic effect on FXR and EC50The value is comparable to obeticholic acid. The OBN-DAS can obviously reduce the serum ALP and TBIL levels of a cholestatic cirrhosis model rat caused by bile duct ligation, obviously improve the hepatic fibrosis score, and has the effect of treating PBC equivalent to that of obeticholic acid. The OBN-DAS can also obviously reduce serum ALT and AST levels of MCD-induced NASH model rats and obviously improve the liverNASH scores for visceral pathology, and the effect of treating NASH is comparable to obeticholic acid. The incidence rate of adverse reactions of pruritus caused by OBN-DAS is obviously lower than that of obeticholic acid.
Drawings
FIG. 1: H-NMR chart
FIG. 2: MS diagram
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The present disclosure is further illustrated and described with reference to specific examples, which, however, are not to be construed as limiting or restricting the scope of the invention.
EXAMPLE 1 OBN-DAS Synthesis
Synthesis of OBN
OBA (40g, 0.095mol, 1eq) was charged into a 3L three-necked flask, acetone (400ml) was added, stirring was carried out while controlling the temperature between 0 and 10 ℃, HOBT (21.9g, 0.19mol, 2.0eq) was added, DCC (49g, 0.24mol, 2.5eq) and 4-dimethylaminopyridine (1.16g, 0.95mmol, 0.01eq) were added, stirring was carried out for 0.5 to 2 hours, TLC was carried out, 115 disappeared, and an active ester was formed. Adding a taurine aqueous solution (24g of 0.192mol 2eq) and triethylamine (20g of 0.2mol 2eq) into the reaction solution, continuously stirring the solution for 2-5h, adding 6N HCl to adjust the pH of the reaction solution to 1-2, stirring the reaction solution for 1-2h, concentrating the solvent, carrying out suction filtration and precipitation, extracting the filtrate with tetrahydrofuran, drying the organic phase with anhydrous sodium sulfate, carrying out spin drying at 40 ℃ to obtain an OBN (taurocholic acid) crude product, mixing the crude product with silica gel, and eluting with dichloromethane: methanol 20: 1. TLC monitoring, phosphomolybdic acid color development. Mixing the pure products, and carrying out spin drying to obtain 26g of OBN, wherein the yield is as follows: 52 percent.
Synthesis of OBN-DAS (salt formation of OBN and S-adenosyl-L-methionine)
N2Under protection, OBN (1g of 0.0019mol 1eq) and purified water (10ml) are added into a 100ml single-mouth bottle at room temperature, S-adenosine-L-methionine (0.163g of 0.0019mol 1eq) dissolved in 10ml of purified water is added into the reaction solution dropwise, the temperature is controlled in an ice bath, the reaction solution is stirred at room temperature for 2-5 hours after the dropwise addition is finished, and the reaction is stopped. Directly spin-drying the reaction solution, and replacing water with methanol to obtain amorphous substanceOBN-DAS in the form of a disk.
Example 2 FXR agonist Activity assay
The FXR ligand binding domain (amino acids 105 to 472) was fused to COOH-terminal glutathione transferase (GST), and the fused GST-FXR protein was expressed by E.coli and purified by glutathione glass beads. For FRET assay, europium-labeled anti-GST [ anti-GST- (Eu) ] (Wallac, Gaithersburg, Md.) was labeled GST-FXR, steroid receptor co-activator-1 (SRC-1, amino acids 595 to 822) was labeled with 6-polyhistidine, expressed by E.coli, purified by ion chromatography, bioacylated and labeled with allophycocyanin fluorescent protein (APC) and conjugated to streptavidin. When the ligand-mediated affinity of the FXR construct to SRC-1 is changed, so that energy is transferred from europium (337nm excitation wavelength and 620nm emission wavelength) to APC (620nm excitation wavelength and 665nm emission wavelength), fluorescence resonance energy transfer occurs in the solution, and the result is represented by the ratio of the fluorescence of APC to europium. To a black polypropylene 96-well plate, 10nM GST-FXR, 100nM biotin-SRC 1 anti-GST- (Eu) (0.2mg/mL), APC-avidin (1mg/mL) and a compound dissolved in 100mL of a solution [100mM Hepes (pH 7.6), 0.125% CHAPS, and 125mM NaF ] were added per well. The above reactants were mixed and reacted at 4 ℃ for 12 hours. Fluorescence values were read by a Victor II plate reader (Wallac).
ELISA experiments, 1.5mM biotin-labeled peptide fragment (amino acid sequence: Ile-LeuArg-Lys-Leu-Leu-Gln-Glu) was incubated with 100nM GST-FXR and compounds [25mM tris-HCl (pH 7.4) and 150mM NaCl ] in 100mL solution in 96-well plates for 1 h. The 96-well plates were then washed and incubated with rabbit anti-GST antibody. GST-FXR bound to streptavidin was quantified by detection of horseradish peroxidase-labeled anti-rabbit antibody.
As a result: see Table 1, EC of OBA and OBN-DAS50The values are comparable.
TABLE 1 FXR agonistic Activity
| Chemical combinationArticle (A) | EC50(μM) |
| OBA | 0.11 |
| OBN-DAS | 0.099 |
Example 3 PBC model
32 SPF-grade 6-8 week-old SD rats purchased from Beijing Wittingle laboratory animal technology, Inc. The experimental animals are raised in an SPF animal room, the animal room is well ventilated, an air conditioner is arranged, the temperature is kept at 20-25 ℃, the humidity is kept at 40% -70%, the ventilation frequency is 10-15 times/h, the light and the dark illumination are respectively 12 hours, the experimental animals eat and drink water freely, and each rat is marked with an ear tag. Rats were randomly divided into 2 groups by weight: bile duct ligation group 24, sham operation group 8. After overnight fasting, the bile duct ligated rats were shaved on their abdomens, anesthetized by inhalation with isoflurane, disinfected on their abdomens and incised along the ventral midline, exposing and freeing the common bile duct, ligating three segments of their distal ends, cutting between the second and third ligatures at the distal end, and suturing the abdomens. The sham group only incised the abdominal cavity along the midline of the abdomen, dissociated the common bile duct, and sutured the abdomen. One week after surgery, bile duct ligated rats were randomized into three groups according to body weight: model group, OBA group and OBN-DAS group. The model group and the sham operation group are intragastrically administered with 10mL/kg of 0.5% CMC-Na, the OBA group is intragastrically administered with 5mg/kg of OBA, and the OBN-DAS group is intragastrically administered with 11mg/kg of OBN-DAS (with the molar dose equal to that of the OBA). 4 weeks after administration, the animals were anesthetized with 2% sodium pentobarbital, and serum was separated after blood drawing from the inferior vena cava to determine ALP (alkaline phosphatase) and TBIL (total bilirubin). Taking the right liver lobe, fixing the right liver lobe in 10% neutral formalin, dehydrating, embedding, slicing, making HE and collagen staining, and scoring the hepatic fibrosis degree: fibrous tissue in the portal area is not hyperplastic "-"; the area of hyperplasia below the lobule 1/3 is "+"; the liver-occupying lobules 1/3-2/3 are "+"; above 2/3, it occupies the lobule of the liver by "+ + +". Each "+" score 1, each specimen score a total score. Comparisons between groups were performed using one-way analysis of variance (ANOVA) with SPSS software.
As a result: the OBA and the OBN-DAS have significant difference compared with a model group, can significantly reduce the ALP and TBIL levels of serum of a cholestatic cirrhosis model rat caused by bile duct ligation, and significantly improve the hepatic fibrosis score, and have no significant difference compared with the OBA and the OBN-DAS, and the PBC treatment effect is equivalent.
TABLE 2 serum ALP, ALT, AST and TBIL levels in rats
| Group of | Dosage (mg/kg) | ALP(U/L) | TBIL(μmol/L) |
| Artificial operation group | NA | 120 | 1.2 |
| Model set | NA | 295 | 5.3 |
| OBA | 5 | 184** | 2.5** |
| OBN-DAS | 11 | 193**# | 2.5**# |
". compared with the model group, p is less than 0.01, and the difference is significant
"#" compared to OBA, p > 0.05, there was no significant difference
TABLE 3 hepatic fibrosis score
| Group of | Dosage (mg/kg) | Scoring |
| Artificial operation group | NA | 0 |
| Model set | NA | 9.3 |
| OBA | 5 | 5.5** |
| OBN-DAS | 11 | 5.2**# |
". compared with the model group, p is less than 0.01, and the difference is significant
"#" compared to OBA, p > 0.05, there was no significant difference
Example 4NASH model
32 male SPF grade C57BL/6 mice were purchased from Shanghai Spiker laboratory animals, Inc. The experimental animals are raised in an SPF animal room, the animal room is well ventilated, an air conditioner is arranged, the temperature is kept at 20-25 ℃, the humidity is kept at 40% -70%, the ventilation frequency is 10-15 times/h, the light and the dark illumination are respectively 12 hours, the experimental animals eat and drink water freely, and each mouse is marked by an ear tag. 8 mice were randomly selected as a blank group, and fed with MCS (methionine-choline deficient control feed purchased from Nantong Telofia feed science Co., Ltd.) in a feed-matched manner, and the feed was administered to the mice in the blank group at the first 48 hours of the feed intake of the model group. The remaining 24 mice were given MCD (methionine-choline deficient feed, purchased from south tone toffee, ltd) feed to replicate the nonalcoholic steatohepatitis model. Model replication was given to the first week of acclimatization, the experiment started on days 1 and 2 (MCD diet: MCS diet: 1:2), the experiment started on days 3 and 4 (MCD diet: MCS diet: 1), the experiment started on days 5 and 6 (MCD diet: MCS diet: 2:1), and the experiment started on day 7 with MCD diet completely. The experimental feed was not discarded after all 48 hours. After 2 weeks of molding, 24 animals were divided into 3 groups according to body weight using a randomized block method: model group, OBA group and OBN-DAS group. The blank control group and the model group are intragastrically administered with 10mL/kg of 0.5% CMC-Na, the OBA group is intragastrically administered with 5mg/kg of OBA, and the OBN-DAS group is intragastrically administered with 11mg/kg of OBN-DAS (with the same molar dose of OBA). After 4 weeks of administration, the animals were anesthetized with 2% sodium pentobarbital, and serum was separated after blood drawing from the inferior vena cava to measure AST (glutamic oxaloacetic transaminase) and ALT (glutamic pyruvic transaminase). The collected right lobe of liver tissue is dissected along the median line, and a part of the tissue is cut along the outer edge to obtain 2 tissue blocks with the size of about 5mm multiplied by 5mm, the tissue blocks are placed in 10% neutral buffered formalin solution for fixation, the liver tissues of all the animals are removed from the 10% neutral buffered formalin solution for taking materials, dehydrating, paraffin embedding, slicing, HE staining and microscopic examination. And cutting 2 tissue blocks with the size of about 5mm multiplied by 5mm from the outer edge of the other part of the liver tissue, fixing the tissue blocks in liquid nitrogen, taking the liver tissue of all the animals out of the liquid nitrogen, freezing and slicing the liver tissue (the thickness of 10 mu m), rinsing the liver tissue for 2min by 60 percent of isopropanol, staining the liver tissue for 10min by oil red O working solution, differentiating and rinsing the liver tissue by 60 percent of isopropanol, washing the liver tissue by water, and sealing the liver tissue by fluorocount-G water-soluble sealing agent. The histopathological scoring criteria was based on the criteria established by the national institutes of health non-alcoholic steatohepatitis clinical research net pathology working group 2005, namely the non-alcoholic fatty liver disease (NAFLD) activity score (NAS). The specific scoring criteria are as follows: the histological scoring system included 14 pathological changes, of which 4 indices were semi-quantitatively evaluated: hepatic steatosis (steatosis): 0-3 points, endoplasmic reticulum inflammation (hepatocyte balling): 0-2 points, hepatocyte ballooning change (lobular inflammation): 0-2 points, hepatic fibrosis: 0 to 4 points, and the other indicators are "presence or absence (1/0)". The NAS value is calculated from the first 3. Comparisons between groups were performed using one-way analysis of variance (ANOVA) with SPSS software.
As a result: in tables 4 and 5, OBA and OBN-DAS were able to significantly reduce serum ALT and AST levels in MCD-induced NASH model rats and significantly improve the liver pathology NASH score.
TABLE 4 ALT and AST levels in rat serum
| Group of | Dosage (mg/kg) | ALT(U/L) | AST(U/L) |
| Artificial operation group | NA | 38.6 | 113 |
| Model set | NA | 85.4 | 259 |
| OBA | 5 | 62.1** | 183** |
| OBN-DAS | 11 | 56.6**# | 174**# |
". compared with the model group, p is less than 0.01, and the difference is significant
"#" compared to OBA, p > 0.05, there was no significant difference
TABLE 5 NASH Scoring
| Group of | Dosage (mg/kg) | Scoring |
| Artificial operation group | NA | 0.6 |
| Model set | NA | 5.6 |
| OBA | 5 | 3.1** |
| OBN-DAS | 11 | 3.0**# |
". compared with the model group, p is less than 0.01, and the difference is significant
"#" compared to OBA, p > 0.05, there was no significant difference
Example 5 model of pruritus
32 male ICR mice of SPF grade were purchased from shanghai slaike laboratory animals llc. The experimental animals are raised in an SPF animal room, the animal room is well ventilated, an air conditioner is arranged, the temperature is kept at 20-25 ℃, the humidity is kept at 40% -70%, the ventilation frequency is 10-15 times/h, the light and the dark illumination are respectively 12 hours, the experimental animals eat and drink water freely, and each mouse is marked by an ear tag. Mice were randomly divided into four groups according to body weight: blank set, model set, OBA set, and OBN-DAS set. The animals in the blank group and the model group are gavaged with 10mL/kg of 0.5% CMC-Na, the OBA group is gavaged with 150mg/kg of OBA, and the OBN-DAS group is gavaged with 331.5mg/kg of OBN-DAS (equimolar dose with OBA), and the administration is carried out for 1 time every day and is continuously carried out for 7 days. Animals in the model group, OBA group and OBN-DAS group were injected with 48/80 compound (stimulating mast cell degranulation) subcutaneously at 10 μ g/mouse in the neck and back and the blank control group was injected with the same volume of PBS buffer in the neck and back 2h after administration on days 4 and 7. Following subcutaneous injection of 48/80 compound, each mouse was videotaped in a single cage for 30min, and the number of scratching was recorded and statistically analyzed. Note that: and during video recording, the user is careful about closing the room, and any interference is avoided, so that the mouse behavior is not influenced. Comparisons between groups were performed using one-way analysis of variance (ANOVA) with SPSS software.
As a result: compared with the OBA group, the OBN-DAS group can obviously reduce the scratching times of 48/80-induced pruritus model mice.
TABLE 6 number of scratches
| Group of | Dosage (mg/kg) | Scratching times (day 4) | Scratching times (day 7) |
| Artificial operation group | NA | 12 | 14 |
| Model set | NA | 31 | 37 |
| OBA | 150 | 122 | 143 |
| OBN-DAS | 331.5 | 55** | 67** |
". compared with OBA group, p < 0.01, there was a significant difference.
Claims (7)
1. A compound having an agonistic effect on FXR, having the structure shown below:
2. use of a compound according to claim 1 for the manufacture of a medicament as an FXR agonist.
3. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of primary biliary cirrhosis; the application in preparing the medicine for treating the non-alcoholic steatohepatitis; the application in preparing the medicine for treating primary sclerosing cholangitis; the use in the manufacture of a medicament for the treatment of portal hypertension; the application in preparing the medicine for treating bile acid diarrhea.
4. A process for the preparation of a compound according to claim 1 which is:
(1) reacting obeticholic acid with taurine to generate OBN;
(2) and salifying the OBN and the S-adenosine-L-methionine to obtain the OBN-DAS.
5. A pharmaceutical composition comprising a compound of claim 1 and optionally a pharmaceutically acceptable carrier.
6. Use of a composition of claim 5 in the manufacture of a medicament as an FXR agonist.
7. Use of a composition according to claim 5 for the manufacture of a medicament for the treatment of primary biliary cirrhosis; the application in preparing the medicine for treating the non-alcoholic steatohepatitis; the application in preparing the medicine for treating primary sclerosing cholangitis; the use in the manufacture of a medicament for the treatment of portal hypertension; the application in preparing the medicine for treating bile acid diarrhea.
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| CN109021056A (en) | 2018-12-18 |
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