WO2021023100A1 - 脱氧胆酸类化合物、药物组合物及其用途 - Google Patents

脱氧胆酸类化合物、药物组合物及其用途 Download PDF

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WO2021023100A1
WO2021023100A1 PCT/CN2020/106117 CN2020106117W WO2021023100A1 WO 2021023100 A1 WO2021023100 A1 WO 2021023100A1 CN 2020106117 W CN2020106117 W CN 2020106117W WO 2021023100 A1 WO2021023100 A1 WO 2021023100A1
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substituted
acid
optionally
group
butyl
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PCT/CN2020/106117
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English (en)
French (fr)
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杜心赟
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杜心赟
黄强
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Priority to US17/632,532 priority Critical patent/US20230146782A1/en
Priority to EP20850984.4A priority patent/EP4011899A4/en
Publication of WO2021023100A1 publication Critical patent/WO2021023100A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals

Definitions

  • the invention relates to a deoxycholic acid compound, a pharmaceutical composition and its use.
  • Non-alcoholic fatty liver disease refers to a clinicopathological syndrome characterized by excessive fat deposition in liver cells caused by alcohol and other clear liver damage factors. It is related to insulin resistance and inheritance. Acquired metabolic stress liver injury closely related to susceptibility. Including simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH) and related cirrhosis. With the globalization of obesity and its related metabolic syndrome, non-alcoholic fatty liver disease has become an important cause of chronic liver disease in developed countries such as Europe and the United States and wealthy areas of my country. The prevalence of NAFLD in ordinary adults is 10%-30%. Among them, 10%-20% are NASH, and the incidence of liver cirrhosis in the latter is as high as 25% within 10 years.
  • SFL simple fatty liver
  • NASH non-alcoholic steatohepatitis
  • Non-alcoholic fatty liver disease can not only directly lead to decompensated liver cirrhosis, hepatocellular carcinoma and recurrence of transplanted liver, but also affect the progress of other chronic liver diseases and participate in the pathogenesis of type 2 diabetes and atherosclerosis. Metabolic syndrome-related malignancies, arteriosclerotic cardiovascular and cerebrovascular diseases, and liver cirrhosis. For this reason, non-alcoholic fatty liver disease is a new challenge in the contemporary medical field. But there is no effective treatment at present.
  • Deoxycholic acid compounds such as chenodeoxycholic acid and the 6-substituted derivative of chenodeoxycholic acid, can activate the farnesoid X receptor (FXR), and have anti-cholestic and anti-fibrotic effects.
  • FXR is a nuclear receptor, a bile acid sensor, which can regulate the synthesis of bile acid and the flow of bile in the liver. It also has an effect on the stability of bile internal environment, lipid metabolism, glucose metabolism, and inflammation/immune response. .
  • OCA 6- ⁇ -ethylchenodeoxycholic acid
  • PBC primary biliary cirrhosis
  • NASH non-alcoholic steatohepatitis
  • Bile acid diarrhea alcoholic hepatitis
  • PSC primary sclerosing cholangitis
  • obeticholic acid is clinically used in the treatment of liver diseases such as fatty liver.
  • the incidence of skin pruritus reaches 63%, and the incidence of rash also reaches 32%.
  • other drugs must be used at the same time to control the effect of obeticholic acid on the skin. Toxic side effects.
  • the clinical application of obeticholic acid is limited.
  • Obeticholic acid is mainly metabolized in the body with glycine (Glycine, Gly) and taurine (Taurine, Tau) into metabolic conjugates OCA-Gly and OCA-Tau.
  • glycine Glycine, Gly
  • taurine Tau
  • obeticholic acid is The above-mentioned metabolic conjugates have the same physiological effects as obeticholic acid.
  • FXR farnesoid X receptor
  • FXR farnesoid X receptor
  • OCA-Gly obeticholic acid glycine conjugate
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are independently selected from: hydrogen, -COR', -CONHR', -CONR'R", or -COOR';
  • R 3 is selected from: hydrogen, methyl, or ethyl
  • R 4 is selected from: hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heteroaryl or substituted hetero Aryl, heterocyclic or substituted heterocyclic group;
  • Linker does not exist or is selected from: alkylene or substituted alkylene, alkenylene or substituted alkenylene, alkynylene or substituted alkynylene, cycloalkylene or substituted cycloalkylene, arylene or substituted Arylene, heteroarylene or substituted heteroarylene, heterocyclylene or substituted heterocyclylene;
  • R 5 and R 6 are independently selected from: hydrogen, alkyl or substituted alkyl; or, R 5 and R 6 are connected to each other, and together with the C atom to which they are connected, they contain 0, 1, or 2 selected from O, 3-7 membered ring of heteroatom of S or N;
  • R is selected from alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, alkylene-aryl, alkylene -Substituted aryl, heteroaryl or substituted heteroaryl, heterocyclic or substituted heterocyclic;
  • R is selected from inorganic cations or organic cations, the inorganic cations are selected from sodium ion, potassium ion, magnesium ion or calcium ion; the organic cations are selected from ammonium, tetramethylammonium, tetraethylammonium, tetrapropylammonium Or tetrabutylammonium;
  • Each R'and R" is independently selected from: hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl , Heteroaryl or substituted heteroaryl, heterocyclic or substituted heterocyclic;
  • substituted alkyl, substituted alkylene, substituted alkenyl, substituted alkenylene, substituted alkynyl, substituted alkynylene, substituted cycloalkyl, substituted cycloalkylene, substituted aryl, substituted arylene, Alkyl-substituted aryl, substituted heteroaryl, substituted heteroarylene, substituted heterocyclyl or substituted heterocyclylene is independently selected from halogen, cyano, amino, nitro, hydroxy , Alkyl, alkoxy, modified alkyl,
  • the compound of formula I is not a compound:
  • R in the compound of formula I is not methyl.
  • halogen is selected from: F, Cl, Br or I;
  • the "alkyl” in the “alkyl” and “alkoxy” is a C 1 -C 20 linear or branched alkyl group, optionally selected from the group consisting of methyl, ethyl, normal Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl;
  • the "alkylene” in the “alkylene”, “alkylene-aryl”, and “alkylene-substituted aryl” is a C 1 -C 10 linear or branched alkylene Group, optionally selected from: methylene, ethylene, n-propylene, isopropylidene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene base;
  • the "modified alkyl group” is any carbon atom of the alkyl group selected from one of -O-, -CO-, -NH 2 , -OH, halogen, -CN, -NO 2 or Groups obtained by substitution of several groups;
  • alkenyl group is a C 2 -C 6 alkenyl group
  • alkenylene group is a C 2 -C 6 alkenylene group
  • alkynyl group is a C 2 -C 6 alkynyl group
  • alkynylene is a C 2 -C 6 alkynylene group
  • cycloalkyl group is a C 3 -C 10 monocyclic or bicyclic cycloalkyl group
  • cycloalkylene is a C 3 -C 10 monocyclic or bicyclic cycloalkylene
  • the "aryl” in the "aryl”, “alkylene-aryl”, and “alkylene-substituted aryl” is a 6-10 membered aryl group; it can optionally be phenyl or naphthalene base;
  • arylene group is a 6-10 membered arylene group; optionally phenylene or naphthylene;
  • heteroaryl group is a 5-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms selected from N, O and S;
  • heteroarylene is a 5-10 membered heteroarylene ring containing 1, 2, or 3 heteroatoms selected from N, O and S;
  • heterocyclic group is a 3-10 membered non-aromatic heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S;
  • heterocyclylene is a 3-10 membered non-aromatic heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S.
  • each R'and R" are each independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl, sec-butyl, n-pentyl ,
  • R 1 and R 2 are independently selected from: hydrogen, acetyl, propionyl, isopropionyl, butyryl, isobutyryl;
  • R 3 is selected from: hydrogen, methyl, or ethyl
  • R 4 is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl;
  • Linker does not exist or is selected from: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, cyclopropylene,
  • R 5 and R 6 are independently selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, or R 5 and R 6 are connected to each other and form any group selected from the following formulas together with the C atom to which they are connected:
  • R is selected from: ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, Heterocyclic group or substituted heterocyclic group, sodium ion, potassium ion, magnesium ion, calcium ion, ammonium, tetramethylammonium, tetraethylammonium, tetrapropylammonium or tetrabutylammonium; each X is independently selected from : 0, 1, 2, or 3 selected from: F, Cl, Br, I, -NH 2 , -OH, -methoxy, ethoxy, propoxy, isopropoxy, -CN , Methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group, or each X is independently any carbon atom of a C 5 -C 10 linear or
  • the compound of formula I is selected from the following compounds of formula II:
  • R 3 and R are as defined above.
  • R 3 is selected from: H, methyl, or ethyl; R is selected from: ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sodium ion, potassium ion, calcium ion, each X is independently selected from: 0, 1, 2, or 3 selected from: F, Cl, Br, I, -NH 2 , -OH, -methoxy , Ethoxy, propoxy, isopropoxy, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl groups, or each X is independently C any carbon atom straight or branched chain alkyl 5 -C 10 is selected from -O -, - CO -, - NH 2, in one or more of the resulting group substituted group.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds:
  • X is 1, 2 or 3 substituents, independently selected from F, Cl, Br, I, -CN, -NH 2 , -NO 2 or -OH, methyl, ethyl , Propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.
  • X is 1, 2 or 3 substituents, independently selected from F, Cl, Br, I, -CN, -NH 2 , -NO 2 or -OH, methyl, ethyl , Propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.
  • the compound of formula I is selected from the compounds listed in the following table:
  • R 3 R 1 R 2 R 4 Linker R 5 R 6 R Et -H -H -H does not exist -H -H -Et, -iPr, -Bn, -Ph Et -H -H -H does not exist -H -CH 3 -Et, -iPr, -Bn, -Ph
  • Et -H -H -H does not exist -H -Et -Et, -iPr, -Bn, -Ph Et -H -H -H does not exist -H -Pr -Et, -iPr, -Bn, -Ph Et -H -H does not exist -H -iPr -Et, -iPr, -Bn, -Ph Et -H -H -H does not exist -H -Bu -Et, -iPr, -Bn, -Ph Et -H -H -H does not exist -H -CH 2 iPr -Et, -iPr, -Bn, -Ph Et -H -H -H does not exist -H -CH(Me)Et -Et, -iPr, -Bn, -Ph Et -H -H
  • Et -H -Ac -H does not exist -H -CH(Me)Et -Et, -iPr, -Bn, -Ph Et -H -Ac -H does not exist -H -nPentyl -Et, -iPr, -Bn, -Ph Et -H -Ac -H does not exist -H -CH(Me)Pr -Et, -iPr, -Bn, -Ph Et -H -Ac -H does not exist -H -CH(Me)iPr -Et, -iPr, -Bn, -Ph Et -H -Ac -H does not exist -H -CH(Me)iPr -Et, -iPr, -Bn, -Ph Et -H -Ac -H does not exist -H -CH 2 tBu
  • Et -H -COEt -H does not exist -H -H -Et, -iPr, -Bn, -Ph Et -H -COEt -H does not exist -H -CH 3 -Et, -iPr, -Bn, -Ph Et -H -COEt -H does not exist -H -Et -Et, -iPr, -Bn, -Ph Et -H -COEt -H does not exist -H -Pr -Et, -iPr, -Bn, -Ph Et -H -COEt -H does not exist -H -Pr -Et, -iPr, -Bn, -Ph Et -H -COEt -H does not exist -H -iPr -Et, -iPr, -Bn, -Ph Et
  • Et -COPr -H -H does not exist -H -Bu -Et, -iPr, -Bn, -Ph Et -COPr -H -H does not exist -H -CH 2 iPr -Et, -iPr, -Bn, -Ph Et -COPr -H -H does not exist -H -CH(Me)Et -Et, -iPr, -Bn, -Ph Et -COPr -H -H does not exist -H -nPentyl -Et, -iPr, -Bn, -Ph Et -COPr -H -H does not exist -H -CH(Me)Pr -Et, -iPr, -Bn, -Ph Et -COPr -H -H does not exist -H -CH(Me)Pr -Et, -
  • Et -COPr -COPr -H does not exist -H -CH(Me)iPr -Et, -iPr, -Bn, -Ph Et -COPr -COPr -H does not exist -H -CH 2 tBu -Et, -iPr, -Bn, -Ph Et -COiPr -H -H does not exist -H -H -Et, -iPr, -Bn, -Ph Et -COiPr -H -H does not exist -H -CH 3 -Et, -iPr, -Bn, -Ph Et -COiPr -H -H does not exist -H -Et -Et, -iPr, -Bn, -Ph Et -COiPr -H -H does not exist -H -Et -Et, -iPr
  • Et -COiPr -COiPr -H does not exist -H -Pr -Et, -iPr, -Bn, -Ph Et -COiPr -COiPr -H does not exist -H -iPr -Et, -iPr, -Bn, -Ph Et -COiPr -COiPr -H does not exist -H -Bu -Et, -iPr, -Bn, -Ph Et -COiPr -COiPr -H does not exist -H -CH 2 iPr -Et, -iPr, -Bn, -Ph Et -COiPr -COiPr -H does not exist -H -CH(Me)Et -Et, -iPr, -Bn, -Ph Et -COiPr -COiPr -
  • the pharmaceutically acceptable salt includes the salt of the compound of formula I, and these cationic salts include alkali metal salts, alkaline earth metal salts, and ammonium salts; alternatively, the alkali metals include sodium, potassium, and lithium. , Cesium, the alkaline earth metals include magnesium, calcium, strontium;
  • the pharmaceutically acceptable salt includes a salt formed by a compound of formula I and an acid; optionally, the acid includes an inorganic acid and an organic acid; optionally, the inorganic acid includes hydrochloric acid and hydrobromic acid , Hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid; alternatively, the organic acids include formic acid, ascorbic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Malic acid, citric acid, citric acid, tartaric acid, gluconic acid, tartaric acid, glucuronic acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, p- Bromobenzenesulfonic acid, glutamic acid, salicylic acid
  • composition comprising a therapeutically effective dose of one or more of the following compounds of formula I or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable Carrier,
  • R 1 and R 2 are independently selected from: hydrogen, -COR', -CONHR', -CONR'R", or -COOR';
  • R 3 is selected from: hydrogen, methyl, or ethyl
  • R 4 is selected from: hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heteroaryl or substituted hetero Aryl, heterocyclic or substituted heterocyclic group;
  • Linker does not exist or is selected from: alkylene or substituted alkylene, alkenylene or substituted alkenylene, alkynylene or substituted alkynylene, cycloalkylene or substituted cycloalkylene, arylene or substituted Arylene, heteroarylene or substituted heteroarylene, heterocyclylene or substituted heterocyclylene;
  • R 5 and R 6 are independently selected from: hydrogen, alkyl or substituted alkyl; or, R 5 and R 6 are connected to each other, and together with the C atom to which they are connected, they contain 0, 1, or 2 selected from O, 3-7 membered ring of heteroatom of S or N;
  • R is selected from alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, alkylene-aryl, alkylene -Substituted aryl, heteroaryl or substituted heteroaryl, heterocyclic or substituted heterocyclic;
  • R is selected from inorganic cations or organic cations, the inorganic cations are selected from sodium ion, potassium ion, magnesium ion or calcium ion; the organic cations are selected from ammonium, tetramethylammonium, tetraethylammonium, tetrapropylammonium Or tetrabutylammonium;
  • Each R'and R" is independently selected from: hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl , Heteroaryl or substituted heteroaryl, heterocyclic or substituted heterocyclic;
  • substituted alkyl, substituted alkylene, substituted alkenyl, substituted alkenylene, substituted alkynyl, substituted alkynylene, substituted cycloalkyl, substituted cycloalkylene, substituted aryl, substituted arylene, Alkyl-substituted aryl, substituted heteroaryl, substituted heteroarylene, substituted heterocyclyl or substituted heterocyclylene is independently selected from halogen, cyano, amino, nitro, hydroxy , Alkyl, alkoxy, modified alkyl.
  • halogen is selected from: F, Cl, Br or I;
  • the "alkyl” in the “alkyl” and “alkoxy” is a C 1 -C 20 linear or branched alkyl group, optionally selected from the group consisting of methyl, ethyl, normal Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl;
  • the "alkylene” in the “alkylene”, “alkylene-aryl”, and “alkylene-substituted aryl” is a C 1 -C 10 linear or branched alkylene Group, optionally selected from: methylene, ethylene, n-propylene, isopropylidene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene base;
  • the "modified alkyl group” is any carbon atom of the alkyl group selected from one of -O-, -CO-, -NH 2 , -OH, halogen, -CN, -NO 2 or Groups obtained by substitution of several groups;
  • alkenyl group is a C 2 -C 6 alkenyl group
  • alkenylene group is a C 2 -C 6 alkenylene group
  • alkynyl group is a C 2 -C 6 alkynyl group
  • alkynylene is a C 2 -C 6 alkynylene group
  • cycloalkyl group is a C 3 -C 10 monocyclic or bicyclic cycloalkyl group
  • cycloalkylene is a C 3 -C 10 monocyclic or bicyclic cycloalkylene
  • the "aryl” in the "aryl”, “alkylene-aryl”, and “alkylene-substituted aryl” is a 6-10 membered aryl group; it can optionally be phenyl or naphthalene base;
  • arylene group is a 6-10 membered arylene group; optionally phenylene or naphthylene;
  • heteroaryl group is a 5-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms selected from N, O and S;
  • heteroarylene is a 5-10 membered heteroarylene ring containing 1, 2, or 3 heteroatoms selected from N, O and S;
  • heterocyclic group is a 3-10 membered non-aromatic heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S;
  • heterocyclylene is a 3-10 membered non-aromatic heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S.
  • each R'and R" are each independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl, sec-butyl, n-pentyl ,
  • R 1 and R 2 are independently selected from: hydrogen, acetyl, propionyl, isopropionyl, butyryl, isobutyryl;
  • R 3 is selected from: hydrogen, methyl, or ethyl
  • R 4 is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl;
  • Linker does not exist or is selected from: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, cyclopropylene,
  • R 5 and R 6 are independently selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, or R 5 and R 6 are connected to each other and form any group selected from the following formulas together with the C atom to which they are connected:
  • R is selected from: ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, Heterocyclic group or substituted heterocyclic group, sodium ion, potassium ion, magnesium ion, calcium ion, ammonium, tetramethylammonium, tetraethylammonium, tetrapropylammonium or tetrabutylammonium; each X is independently selected from : 0, 1, 2, or 3 selected from: F, Cl, Br, I, -NH 2 , -OH, -methoxy, ethoxy, propoxy, isopropoxy, -CN , Methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group, or each X is independently any carbon atom of a C 5 -C 10 linear or
  • the compound of formula I is selected from the following compounds of formula II:
  • R 3 and R are as defined above.
  • R 3 is selected from: H, methyl, or ethyl; R is selected from: ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sodium ion, potassium ion, calcium ion, each X is independently selected from: 0, 1, 2, or 3 selected from: F, Cl, Br, I, -NH 2 , -OH, -methoxy , Ethoxy, propoxy, isopropoxy, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl groups, or each X is independently C any carbon atom straight or branched chain alkyl 5 -C 10 is selected from -O -, - CO -, - NH 2, in one or more of the resulting group substituted group.
  • the compound of formula I is selected from the following compounds:
  • X is 1, 2 or 3 substituents, independently selected from F, Cl, Br, I, -CN, -NH 2 , -NO 2 or -OH, methyl, ethyl , Propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.
  • X is 1, 2 or 3 substituents, independently selected from F, Cl, Br, I, -CN, -NH 2 , -NO 2 or -OH, methyl, ethyl , Propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.
  • the pharmaceutically acceptable salt of the compound of formula I includes a salt formed by the compound of formula I and an acid; optionally, the acid includes an inorganic acid or an organic acid; optionally The inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; alternatively, the organic acid includes formic acid, ascorbic acid, acetic acid, propionic acid, oxalic acid, malonic acid, and succinic acid.
  • Fumaric acid maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, gluconic acid, tartaric acid, glucuronic acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluene Sulfonic acid, benzoic acid, benzenesulfonic acid, p-bromobenzenesulfonic acid, glutamic acid, salicylic acid, pamoic acid.
  • the dosage form of the pharmaceutical composition includes an oral preparation and an injection dosage form;
  • the oral preparations include solid preparations and liquid preparations;
  • the solid preparation includes tablets, powders, granules, and capsules;
  • the liquid preparation includes a water or oil suspension, and syrup.
  • Another aspect provides the use of the above-mentioned pharmaceutical composition, or the above-mentioned compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating non-alcoholic steatohepatitis.
  • the diseases related to bile secretion include: portal hypertension, bile acid diarrhea, alcoholic hepatitis, and primary sclerosing cholangitis.
  • Another aspect provides a method for treating non-alcoholic steatohepatitis by administering a therapeutically effective amount of the above-mentioned compound of formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition to a patient.
  • Another aspect provides a method for treating primary biliary cirrhosis, by administering a therapeutically effective amount of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition to a patient.
  • Another aspect provides a method for treating diseases related to bile secretion, by administering to a patient a therapeutically effective amount of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition;
  • the diseases related to bile secretion include: portal hypertension, bile acid diarrhea, alcoholic hepatitis, and primary sclerosing cholangitis.
  • Preparation and dosage administration accurately weigh an appropriate amount of the test substance and mix it with an appropriate volume of solvent to obtain a clear solution or uniform suspension. Dosing to animals within 4 hours after preparing the formulation. The dosage formulation will be administered by oral gavage in accordance with the facility's standard operating procedures. The dose volume will be determined by the animal body weight collected on the morning of the administration.
  • Each blood collection (about 0.2 ml at each time point) will enter the polypropylene tube from the jugular vein of each animal at each time point. All blood samples will be transferred to pre-chilled commercial EDTA-K2 test tubes and placed on wet ice until centrifugation.
  • Plasma processing blood samples will be centrifuged (3200 rpm, 10 minutes) at about 4°C. The plasma was collected separately and transferred to a pre-labeled PP tube in wet ice at each time point, and then immediately precipitated with ACN (6IS) (the ratio of plasma: ACN was 1:4). Centrifuge again (10 minutes, 12000 rpm) and obtain the supernatant. Quickly freeze on dry ice and keep at -70 ⁇ 10°C until LC/MS/MS analysis.
  • ACN 6IS
  • liver treatment Collect liver tissue at each time point, wash twice with pre-cooled deionized water, and absorb water with filter paper.
  • the liver tissue was immediately homogenized with 10 times the volume of methanol-water solution (1:2, v/v) methanol-water solution (1:2, v/v).
  • a fraction of liver tissue homogenate (such as 200uL) The homogenate) was given to an analytical colleague.
  • the supernatant was centrifuged and stored in a refrigerator at -70 ⁇ 10°C until the LC-MS/MS analysis. Take 800uL of the remaining liver homogenate as a spare.
  • Rats were given the compounds (I-4, I-5, I-6 and OCA, all at 0.0576mmol/kg) by gavage, at 0.25, 0.5, 1, 2, 4, 8, 12, 24h At time points, rat plasma and liver samples were obtained, and the concentration of the active metabolites of the above-mentioned compounds in the plasma and liver was determined by LC-MS/MS according to the above method (see Table 1-4).
  • OCA obeticholic acid
  • the AUC of the effective liver drug reached 142808, which was 3.3 times that of the liver effective drug obtained directly using OCA.
  • the effective drug AUC in the blood was reduced from 48,360 when OCA was used directly to 7634, a reduction of 84%.
  • the enrichment of esterase in the liver may be one of the reasons for the higher liver targeting of benzyl ester I-5. .
  • the total liver and plasma exposure of compound 4 produced by benzyl ester I-5 of 150442 was also significantly increased by 28% compared with 117503 of compound 4 in rats directly gavaged.
  • the compound of the present invention when used to treat corresponding liver diseases, it is expected that while improving the efficacy of the treatment of liver diseases, it is expected that the side effects on the skin will be significantly reduced, and the dosage required to achieve the same therapeutic effect will be significantly reduced.

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Abstract

一种脱氧胆酸类化合物及其药物组合物和它们在制备治疗肝脏疾病药物中的用途。所述脱氧胆酸类化合物的结构如式I所示，或其药学上可接受的盐。该类化合物具有显著的肝脏靶向特性，其在提高药效的同时，降低循环系统中的药物浓度，从而降低毒副作用。

Description

脱氧胆酸类化合物、药物组合物及其用途 技术领域
本发明涉及一种脱氧胆酸类化合物、药物组合物及其用途。
背景技术
非酒精性脂肪性肝病(Non-Alcohol Fatty Liver Diseases,NAFLD)是指除酒精和其他明确的损肝因素所致的肝细胞内脂肪过度沉积为主要特征的临床病理综合征，与胰岛素抵抗和遗传易感性密切相关的获得性代谢应激性肝损伤。包括单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化。随着肥胖及其相关代谢综合征全球化的流行趋势，非酒精性脂肪性肝病现已成为欧美等发达国家和我国富裕地区慢性肝病的重要病因，普通成人NAFLD患病率10％～30％，其中10％～20％为NASH，后者10年内肝硬化发生率高达25％。
非酒精性脂肪性肝病除可直接导致失代偿期肝硬化、肝细胞癌和移植肝复发外，还可影响其他慢性肝病的进展，并参与2型糖尿病和动脉粥样硬化的发病。代谢综合征相关恶性肿瘤、动脉硬化性心脑血管疾病以及肝硬化。为此，非酒精性脂肪性肝病是当代医学领域的新挑战。但在目前没有有效的治疗方法。
脱氧胆酸类化合物，如鹅脱氧胆酸和鹅脱氧胆酸的6位取代衍生物，可激活法尼醇X受体(FXR)，具有抗淤胆、抗纤维化的效果。FXR是一种核受体，为一种胆酸传感器，可调控胆酸的合成和胆汁在肝内的流动，同时对于胆汁内环境稳定、脂质代谢、糖代谢以及炎症/免疫应答都有作用。研究数据表明，6-α-乙基鹅脱氧胆酸(奥贝胆酸，OCA)可以用于治疗原发性胆汁性肝硬化(PBC)、门静脉高压(Portal hypertension)、非酒精性脂肪肝炎(NASH)、胆汁酸性腹泻(Bile acid diarrhea)、酒精性肝炎、原发性硬化性胆管炎(PSC)等与胆汁分泌有关的疾病(Drug Discovery Today.Volume 17,Numbers 17/18,2012)。
然而奥贝胆酸在临床上治疗肝脏疾病、如脂肪肝时皮肤瘙痒的发生率达到63％，皮疹的发生率也达到32％，有时必须用其它药物同时使用，以控制奥贝胆酸对皮肤的毒副作用。使奥贝胆酸的临床应用受到了限制。
Figure PCTCN2020106117-appb-000001
脱氧胆酸类化合物
奥贝胆酸(OCA)在体内主要与甘氨酸(Glycine,Gly)和牛磺酸(Taurine,Tau)分别代谢成代谢共轭物OCA-Gly和OCA-Tau，已有研究表明，奥贝胆酸的上述代谢共轭物具有与奥贝胆酸同样的生理作用，例如，激活法尼醇X受体(FXR)的活性与奥贝胆酸几乎相同(参考文献：Obeticholic acid,a selective farnesoid X receptor agonist,regulates bile acid homeostasis in sandwich-cultured human hepatocytes.Pharmacology Research&Perspectives.2017,vol.5,iss.4)。
Figure PCTCN2020106117-appb-000002
奥贝胆酸在体内代谢及其产物
发明内容
发明人意外发现，奥贝胆酸甘氨酸共轭物(OCA-Gly)的一类衍生物具有显著的肝脏靶向特性，肝脏中活性药物浓度约为血浆中的20倍。因此，采用该类化合物治疗脂肪肝等肝脏疾病时，由于活性药物在肝脏内的浓度大大提高而提高药效，且因血浆中的有效药物浓度显著降低而减少皮疹等副作用。
鉴于此，本发明提供一种式I所示的化合物或其药学上可接受的盐：
Figure PCTCN2020106117-appb-000003
其中：
R 1和R 2独立地选自：氢、-COR'、-CONHR'、-CONR'R”、或-COOR'；
R 3选自：氢、甲基、或乙基；
R 4选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
Linker不存在或选自：亚烷基或取代亚烷基，亚烯基或取代亚烯基，亚炔基或取代亚炔基，亚环烷基或取代亚环烷基，亚芳基或取代亚芳基，亚杂芳基或取代亚杂芳基，亚杂环基或取代亚杂环基；
R 5和R 6独立地选自：氢、烷基或取代烷基；或者，R 5和R 6相互连接，与它们相连的C原子一起形成含有0个、1个或2个选自O、S或N的杂原子的3-7元环；
R选自烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，亚烷基-芳基、亚烷基-取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
或者R选自无机阳离子或有机阳离子，所述无机阳离子选自钠离子、钾离子、镁离子或钙离子；所述有机阳离子选自铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；
各个R'和R”各自独立地选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
所述取代烷基、取代亚烷基、取代烯基、取代亚烯基、取代炔基、取代亚炔基、取代环烷基、取代亚环烷基、取代芳基、取代亚芳基、亚烷基-取代芳基、取代杂芳基、取代亚杂芳基、取代杂环基或取代亚杂环基中各自的取代基各自独立地选自：卤素，氰基，氨基，硝基，羟基，烷基，烷氧基，改性烷基，
可选地，所述式I化合物不为化合物：
Figure PCTCN2020106117-appb-000004
可选地，所述式I化合物中的R不为甲基。
可选地，所述“卤素”选自：F、Cl、Br或I；
可选地，所述“烷基”、“烷氧基”中的“烷基”为C 1-C 20直链或支链烷基，可选地，选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
可选地，所述“亚烷基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“亚烷基”为C 1-C 10直链或支链亚烷基，可选地，选自：亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基；
可选地，所述“改性烷基”为烷基的任意碳原子被选自-O-、-CO-、-NH 2、-OH、卤素、-CN、-NO 2中的一种或几种基团置换所得的基团；
可选地，所述“烯基”为C 2-C 6的烯基；
可选地，所述“亚烯基”为C 2-C 6的亚烯基；
可选地，所述“炔基”为C 2-C 6的炔基；
可选地，所述“亚炔基”为C 2-C 6的亚炔基；
可选地，所述“环烷基”为C 3-C 10单环或双环环烷基；
可选地，所述“亚环烷基”为C 3-C 10单环或双环亚环烷基；
可选地，所述“芳基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“芳基”为6-10元芳基；可选为苯基或萘基；
可选地，所述“亚芳基”为6-10元亚芳基；可选为亚苯基或亚萘基；
可选地，所述“杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元杂芳环；
可选地，所述“亚杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元亚杂芳环；
可选地，所述“杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香杂环；
可选地，所述“亚杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香亚杂环。
可选地，各个R'和R”各自独立地选自：氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苄基、仲丁基、正戊基、
Figure PCTCN2020106117-appb-000005
Figure PCTCN2020106117-appb-000006
可选地，R 1和R 2独立地选自：氢、乙酰基，丙酰基，异丙酰基，丁酰基，异丁酰基；
可选地，R 3选自：氢、甲基、或乙基；
可选地，R 4选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
可选地，Linker不存在或选自：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、亚环丙基、
Figure PCTCN2020106117-appb-000007
Figure PCTCN2020106117-appb-000008
可选地，R 5和R 6独立地选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，或者R 5和R 6相互连接，与它们相连的C原子一起形成选自下式的任一基团：
Figure PCTCN2020106117-appb-000009
Figure PCTCN2020106117-appb-000010
可选地，R选自：乙基、丙基、丁基、异丙基、异丁基、叔丁基、仲丁基、正戊基、
Figure PCTCN2020106117-appb-000011
Figure PCTCN2020106117-appb-000012
杂环基或取代杂环基、钠离子、钾离子、镁离子、钙离子、铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH 2、-OH、-甲氧基、乙氧基、丙氧基、异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正 丁基或异丁基的基团，或者各个X各自独立地为C 5-C 10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH 2、中的一种或几种基团置换所得的基团。
可选地，式I化合物选自下列式II化合物：
Figure PCTCN2020106117-appb-000013
其中：
R 3、R如上所定义。
可选地，式II中，R 3选自：H、甲基、或乙基；R选自：乙基、正丙基、异丙基、正丁基、异丁基、
Figure PCTCN2020106117-appb-000014
钠离子、钾离子、钙离子，各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH 2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C 5-C 10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH 2、中的一种或几种基团置换所得的基团。
可选地，所述式I化合物或其药学上可接受的盐选自下列化合物：
Figure PCTCN2020106117-appb-000015
Figure PCTCN2020106117-appb-000016
Figure PCTCN2020106117-appb-000017
式I-7中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH 2，-NO 2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
Figure PCTCN2020106117-appb-000018
式I-8中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH 2，-NO 2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
可选地，所述式I化合物选自下表所列化合物：
R 3 R 1 R 2 R 4 Linker R 5 R 6 R
Et -H -H -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -H -H -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -Ac -H -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -H -Ac -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -Ac -Ac -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -COEt -H -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -H -COEt -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -COEt -COEt -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -COPr -H -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -H -COPr -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -COPr -COPr -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -COiPr -H -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -H -COiPr -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -H -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -CH 3 -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -Et -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -Pr -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -iPr -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -Bu -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -CH 2iPr -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -CH(Me)Et -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -nPentyl -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -CH(Me)Pr -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -CH(Me)iPr -Et，-iPr,-Bn,-Ph
Et -COiPr -COiPr -H 不存在 -H -CH 2tBu -Et，-iPr,-Bn,-Ph
可选地，所述药学上可接受的盐包括式I化合物的盐，这些阳离子盐包括碱金属的盐、碱土金属的盐、铵盐；可选地，所述碱金属包括钠、钾、锂、铯，所述碱土金属包括镁、钙、锶；
可选地，所述药学上可接受的盐包括式I化合物与酸形成的盐；可选地，所述酸包括无机酸、有机酸；可选地，所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸；可选地，所述有机酸包括甲酸、抗坏血酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、双羟萘酸。
本发明另一方面，提供一种药物组合物，其包含治疗有效剂量的下述式I化合物或其药学上可接受的盐中的一种或多种，以及任选存在的药学上可接受的载体，
Figure PCTCN2020106117-appb-000019
式I中：
R 1和R 2独立地选自：氢、-COR'、-CONHR'、-CONR'R”、或-COOR'；
R 3选自：氢、甲基、或乙基；
R 4选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
Linker不存在或选自：亚烷基或取代亚烷基，亚烯基或取代亚烯基，亚炔基或取代亚炔基，亚环烷基或取代亚环烷基，亚芳基或取代亚芳基，亚杂芳基或取代亚杂芳基，亚杂环基或取代亚杂环基；
R 5和R 6独立地选自：氢、烷基或取代烷基；或者，R 5和R 6相互连接，与它们相连的C原子一起形成含有0个、1个或2个选自O、S或N的杂原子的3-7元环；
R选自烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，亚烷基-芳基、亚烷基-取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
或者R选自无机阳离子或有机阳离子，所述无机阳离子选自钠离子、钾离子、镁离子或钙离子；所述有机阳离子选自铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；
各个R'和R”各自独立地选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
所述取代烷基、取代亚烷基、取代烯基、取代亚烯基、取代炔基、取代亚炔基、取代环烷基、取代亚环烷基、取代芳基、取代亚芳基、亚烷基-取代芳基、取代杂芳基、取代亚杂芳基、取代杂环基或取代亚杂环基中各自的取代基各自独立地选自：卤素，氰基，氨基，硝基，羟基，烷基，烷氧基，改性烷基。
可选地，所述的药物组合物中，可选所述“卤素”选自：F、Cl、Br或I；
可选地，所述“烷基”、“烷氧基”中的“烷基”为C 1-C 20直链或支链烷基，可选地，选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
可选地，所述“亚烷基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“亚烷基”为C 1-C 10直链或支链亚烷基，可选地，选自：亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基；
可选地，所述“改性烷基”为烷基的任意碳原子被选自-O-、-CO-、-NH 2、-OH、卤素、-CN、-NO 2中的一种或几种基团置换所得的基团；
可选地，所述“烯基”为C 2-C 6的烯基；
可选地，所述“亚烯基”为C 2-C 6的亚烯基；
可选地，所述“炔基”为C 2-C 6的炔基；
可选地，所述“亚炔基”为C 2-C 6的亚炔基；
可选地，所述“环烷基”为C 3-C 10单环或双环环烷基；
可选地，所述“亚环烷基”为C 3-C 10单环或双环亚环烷基；
可选地，所述“芳基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“芳基”为6-10元芳基；可选为苯基或萘基；
可选地，所述“亚芳基”为6-10元亚芳基；可选为亚苯基或亚萘基；
可选地，所述“杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元杂芳环；
可选地，所述“亚杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元亚杂芳环；
可选地，所述“杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香杂环；
可选地，所述“亚杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香亚杂环。
可选地，各个R'和R”各自独立地选自：氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苄基、仲丁基、正戊基、
Figure PCTCN2020106117-appb-000020
Figure PCTCN2020106117-appb-000021
可选地，R 1和R 2独立地选自：氢、乙酰基，丙酰基，异丙酰基，丁酰基，异丁酰基；
可选地，R 3选自：氢、甲基、或乙基；
可选地，R 4选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
可选地，Linker不存在或选自：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、亚环丙基、
Figure PCTCN2020106117-appb-000022
Figure PCTCN2020106117-appb-000023
可选地，R 5和R 6独立地选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，或者R 5和R 6相互连接，与它们相连的C原子一起形成选自下式的任一基团：
Figure PCTCN2020106117-appb-000024
Figure PCTCN2020106117-appb-000025
Figure PCTCN2020106117-appb-000026
可选地，R选自：乙基、丙基、丁基、异丙基、异丁基、叔丁基、仲丁基、正戊基、
Figure PCTCN2020106117-appb-000027
Figure PCTCN2020106117-appb-000028
杂环基或取代杂环基、钠离子、钾离子、镁离子、钙离子、铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH 2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C 5-C 10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH 2、中的一种或几种基团置换所得的基团。
可选地，所述的药物组合物中，所述式I化合物选自下列式II化合物：
Figure PCTCN2020106117-appb-000029
其中：
R 3、R如上述定义。
可选地，所述的药物组合物中，R 3选自：H、甲基、或乙基；R选自：乙基、正丙基、异丙基、正丁基、异丁基、
Figure PCTCN2020106117-appb-000030
钠离子、钾离子、钙离子，各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH 2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C 5-C 10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH 2、中的一种或几种基团置换所得的基团。
可选地，所述药物组合物中，所述式I化合物选自下列化合物：
Figure PCTCN2020106117-appb-000031
Figure PCTCN2020106117-appb-000032
Figure PCTCN2020106117-appb-000033
式I-7中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH 2，-NO 2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
Figure PCTCN2020106117-appb-000034
式I-8中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH 2，-NO 2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
可选地，所述的药物组合物中，所述式I化合物药学上可接受的盐包括式I化合物与酸形成的盐；可选地，所述酸包括无机酸、有机酸；可选地，所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸；可选地，所述有机酸包括甲酸、抗坏血酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、 碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、双羟萘酸。
可选地，所述药物组合物的剂型包括口服制剂，注射剂型；
可选地，所述口服制剂包括固体制剂、液体制剂；
可选地，所述固体制剂包括片剂、粉剂、粒剂、胶囊；
可选地，所述液体制剂包括水或油悬浮剂、糖浆。
另一方面提供上述的药物组合物，或者上述的式I化合物或其药学上可接受的盐在制备治疗非酒精性脂肪肝炎药物中的用途。
另一方面提供上述的药物组合物，或者上述的式I化合物或其药学上可接受的盐在制备治疗原发性胆汁性肝硬化药物中的用途。
另一方面提供上述的药物组合物，或者上述的式I化合物或其药学上可接受的盐药物组合物在制备治疗胆汁分泌相关的疾病药物中的用途；
可选地，所述胆汁分泌相关的疾病包括：门静脉高压、胆汁酸性腹泻、酒精性肝炎和原发性硬化性胆管炎。
另一方面提供一种治疗非酒精性脂肪肝炎的方法，对患者施用治疗有效量的上述的式I化合物或其药学上可接受的盐，或者上述的药物组合物。
另一方面提供一种治疗原发性胆汁性肝硬化的方法，对患者施用治疗有效量的上述的式I化合物或其药学上可接受的盐，或者上述的药物组合物。
另一方面提供一种治疗胆汁分泌相关的疾病的方法，对患者施用治疗有效量的上述的式I化合物或其药学上可接受的盐，或者上述的药物组合物；
可选地，所述胆汁分泌相关的疾病包括：门静脉高压、胆汁酸性腹泻、酒精性肝炎和原发性硬化性胆管炎。
具体实施方式
以下对本发明的具体实施方式进行详细的说明。应当理解的是，此处所描述的具体实施方式仅用于示例性地对本发明进行说明，并不用于限制本发明。
实施例1化合物的制备
1、制备化合物4：
Figure PCTCN2020106117-appb-000035
A、将原料1(0.8g,1.90mmol,1.0eq)，甘氨酸甲酯盐酸盐(2，356mg,2.85mmol)，EDCI(546mg,2.85mmol)，DMAP(696mg,5.70mmol)溶于DCM(10mL)中，氮气保护，室温反应过夜，TLC检测反应完毕，旋蒸除去DCM，加EtOAC溶解，用1N HCl 5mL×2洗，除去过量的DMAP，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到化合物3(900mg，96％)。 1H NMR(400MHz,CDCl 3)δ5.94(s,1H),4.0(d,J＝5.1Hz,2H),3.76(s,3H),3.70(s,1H),3.44-3.36(m,1H),2.34-2.27(m,1H),2.18-2.10(m,1H),1.97-0.89(m,36H),0.65(s,3H)。
Figure PCTCN2020106117-appb-000036
B、将化合物3(900mg,1.83mmol)，NaOH(111mg,2.78mmol)加入到CH 3OH-H 2O(4mL，V:V＝1:1)中，回流反应3h，TLC检测反应完毕，旋蒸除去甲醇，加EtOAC萃取，除去有机杂质，水相用1N HCl调pH至5左右，有白色固体析出，加EtOAC溶解萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到化合物4(795mg，91％)。 1H NMR(400MHz,DMSO)δ12.4(s,1H),8.1(t,J＝5.9Hz,1H),4.3(s,1H),4.05(d,J＝4.9Hz,1H),3.7(d,J＝5.9Hz,2H),3.5(s,1H),3.16-3.10(m,1H),2.18-2.11(m,1H),2.07-2.01(m,1H),1.97-0.89(m,34H),0.61(s,3H)；m/z(ESI)[M-H] -＝476.4。
2、制备化合物I-4：
Figure PCTCN2020106117-appb-000037
将原料4(1.3g,2.72mmol)，异丙醇(245mg,4.08mmol)，EDCI(782mg,4.08mmol)，DMAP(498mg,4.08mmol)溶于DCM(10mL)中，氮气保护，室温反应过夜,TLC检测反应完毕，旋蒸除去DCM，加EtOAc溶解，用1N HCl 10mL×2洗，除去过量的DMAP，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，过柱(DCM:MeOH＝20:1)得到化合物I-4(653mg，46％)。 1H NMR(400MHz,CDCl 3)δ5.94(s,1H),5.10-5.04(m,1H),4.0(d,J＝5.0Hz,2H),3.7(s,1H),3.44-3.36(m,1H),2.34-2.27(m,1H),2.17-2.07(m,1H),1.97-0.89(m,42H),0.65(s,3H)。
3、制备化合物I-5：
Figure PCTCN2020106117-appb-000038
将原料4(2.27g,4.75mmol)，苯甲醇(770mg,7.12mmol)，EDCI(1.36g,7.12mmol)，DMAP(870mg,7.12mmol)溶于DCM(30mL)中，氮气保护，室温反应过夜，TLC检测反应完毕，旋蒸除去DCM，加EtOAc溶解，用1N HCl 10mL×2洗，除去过量的DMAP，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，过柱(DCM:MeOH＝20:1)得到化合物I-5(1.72g，64％)。 1H NMR(400MHz,CDCl 3)δ7.39-7.32(m,5H),5.94(t,J＝4.8Hz,1H),5.18(s,2H),4.08(d,J＝5.2Hz,2H),3.7(s,1H),3.44-3.36(m,1H),2.34-2.27(m,1H),2.17-2.07(m,1H),1.97-0.89(m,36H),0.65(s,3H)；m/z(ESI)[M+Na] +＝590.5。
4、制备化合物I-6：
Figure PCTCN2020106117-appb-000039
A、将原料4(2.27g,4.75mmol)，化合物5(2.20g,7.12mmol)，EDCI(1.36g,7.12mmol)，DMAP(870mg,7.12mmol)溶于DCM(30mL)中，氮气保护，室温反应过夜，LC-MS检测反应完毕，加水淬灭，萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，过柱(DCM:MeOH＝20:1)得化合物6(750mg，21％)。 1H NMR(400MHz,CDCl 3)δ7.15(d,J＝8.5Hz,2H),7.03(d,J＝8.5Hz,2H),5.98(t,J＝5.2Hz,1H),5.0(d,J＝8.0Hz,1H),4.54(dd,J＝6.3Hz,J＝13.8Hz,1H),4.28(d,J＝5.2Hz,2H),4.15(t,J＝7.2Hz,2H),3.70(s,1H),3.40(s,1H),3.13-3.02(m,2H),2.37-2.29(m,1H),2.21-2.13(m,1H),1.97-0.89(m,48H),0.65(s,3H)。
Figure PCTCN2020106117-appb-000040
B、将化合物6(750mg，0.98mmol)溶于DCM(10mL)中，室温下通入HCl气体，溶液由澄清变为浑浊，TLC检测反应完毕，旋蒸除去溶剂，乙醚带2次变为泡沫状固体，得到化合物I-6(550mg，84％)。 1H NMR(400MHz,DMSO)δ8.67(d,J＝4.2Hz,3H),8.45(t,J＝5.7Hz,1H),7.30(d,J＝8.5Hz,2H),7.07(d,J＝8.5Hz,2H),4.24(dd,J＝6.8Hz,J＝12.4Hz,1H),4.14-4.08(m,4H),3.49(s,1H),3.24-3.03(m,3H),2.22-2.16(m,1H),2.12-2.05(m,1H),1.97-0.89(m,39H),0.59(s,3H)；m/z(ESI)[M-HCl+H] +＝669.5。
5、制备化合物I-1：
化合物3用NaOH水解或者化合物4用NaOH水溶液处理得到化合物I-1。
试验例1药代动力学试验
1、制剂配制和剂量给药：将适量的供试品精确称重，并与适当体积的溶媒混合，以获得清晰的溶液或均匀的悬浮液。在制备制剂后4小时内给动物给药。剂量制剂将按照设施标准操作规程通过口服管饲进行给药。剂量体积将由给药当天早上收集的动物体重决定。
2、采血：每次采血(每一时间点约0.2毫升)将在每一时间点从每只动物的颈静脉点穴进入聚丙烯管。所有血液样本将被转移到预冷的商业EDTA-K2试管中，并置于湿冰上，直到离心分离。
3、血浆处理：血液样本将在约4℃下离心(3200转/分，10分钟)处理。分别收集血浆，并在每个时间点将其转移到湿冰中的预先标记的PP管中，然后立即使用ACN(6IS)沉淀(血浆：ACN的比例为1:4)。再次离心(10分钟，12000转/分)并获得上清液。在干冰上快速冷冻，并保持在-70±10℃，直到进行LC/MS/MS分析。
4、肝脏处理：每个时间点采集肝组织，用预冷去离子水洗两次，滤纸吸干水分。肝组织立即采用10倍体积的甲醇-水溶液(1:2，v/v)甲醇-水溶液(1:2，v/v)匀浆，匀浆完立即取一分部肝组织匀浆液(比如200uL匀浆液)给到分析同事，在湿冰上沉淀样品之后，离心取上清，于-70±10℃冰箱贮存，直至LC-MS/MS分析。剩余肝匀浆液取800uL作为备用。
大鼠分别灌胃服用化合物(I-4、I-5、I-6和OCA，给药剂量均为0.0576mmol/kg)，分别在0.25、0.5、1、2、4、8、12、24h时间点取得大鼠血浆和肝脏样品，按照上述方法，用LC-MS/MS测试，分别测定上述化合物的体内活性代谢产物在血浆和肝脏中的浓度(见表1-4)。
大鼠灌胃化合物I-4后，测得大鼠体内活性化合物为化合物4，其在血浆和肝脏中的浓度见表1。
表1
Figure PCTCN2020106117-appb-000041
Figure PCTCN2020106117-appb-000042
血浆和肝脏总AUC＝110506，AUC Ratio＝肝脏/血浆＝105664/4845＝21.8。
大鼠灌胃化合物I-5后，测得大鼠体内活性化合物为化合物4，其在血浆和肝脏中的浓度见表2。
表2
Figure PCTCN2020106117-appb-000043
血浆和肝脏总AUC＝150442，AUC Ratio＝肝脏/血浆＝142808/7634＝18.7。
大鼠灌胃化合物I-6后，测得大鼠体内活性化合物为化合物4，其在血浆和肝脏中的浓度见表3。
表3
Figure PCTCN2020106117-appb-000044
Figure PCTCN2020106117-appb-000045
血浆和肝脏总AUC＝87730，AUC Ratio＝肝脏/血浆＝83872/3858＝21.7。
大鼠灌胃奥贝胆酸后，测得大鼠体内活性化合物为奥贝胆酸(OCA)和化合物4，其在血浆和肝脏中的浓度见表4。
表4
Figure PCTCN2020106117-appb-000046
血浆和肝脏总AUC＝91386；AUC Ratio＝肝脏/血浆＝43030/48356＝0.89。
大鼠灌胃化合物4后，测得大鼠体内活性化合物为化合物4，其在血浆和肝脏中的浓度见表5。
表5
Figure PCTCN2020106117-appb-000047
Figure PCTCN2020106117-appb-000048
血浆和肝脏总AUC＝117503，AUC Ratio＝肝脏/血浆＝14.7。
从表1、2、3和4的数据可以看出，灌胃大鼠化合物OCA后，大量的药物OCA(血浆中OCA的AUC+OCA-Gly的AUC总量为48360)在血液中循环，这可能导致其引起的皮肤副作用，而肝脏的总有效药物(肝脏OCA的AUC+OCA-Gly的AUC总量为43030)相应减少。而本发明所述化合物I-4、I-5和I-6分别同摩尔剂量灌胃大鼠后，肝脏的总有效药物量显著增加。尤其是，化合物I-5，肝脏有效药物AUC达到142808，是直接用OCA得到的肝脏有效药物的3.3倍。而血液中的有效药物AUC从直接用OCA的48360减少到7634，减少了84％。比较相同摩尔剂量奥贝胆酸-甘氨酸共轭物4与其苄酯I-5灌胃大鼠后，苄酯I-5产生的奥贝胆酸-甘氨酸共轭物4在肝脏/血浆的暴露量比达到18.7，而直接用奥贝胆酸-甘氨酸共轭物4产生的相应暴露量比只有14.7，酯酶富集于肝脏可能是苄酯I-5的肝靶向性更高的原因之一。苄酯I-5产生的化合物4的肝脏和血浆的总暴露量150442也较直接灌胃大鼠化合物4的117503显著提高28％。
因此，使用本发明所述的化合物治疗相应的肝脏疾病时，可望在提高治疗肝脏疾病药效的同时，显著减少对皮肤的副作用，而且达到同样疗效所需的用药剂量显著减少。

Claims (22)

  1. 一种式I所示的化合物或其药学上可接受的盐：
    Figure PCTCN2020106117-appb-100001
    其中：
    R 1和R 2独立地选自：氢、-COR'、-CONHR'、-CONR'R”、或-COOR'；
    R 3选自：氢、甲基、或乙基；
    R 4选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
    Linker不存在或选自：亚烷基或取代亚烷基，亚烯基或取代亚烯基，亚炔基或取代亚炔基，亚环烷基或取代亚环烷基，亚芳基或取代亚芳基，亚杂芳基或取代亚杂芳基，亚杂环基或取代亚杂环基；
    R 5和R 6独立地选自：氢、烷基或取代烷基；或者，R 5和R 6相互连接，与它们相连的C原子一起形成含有0个、1个或2个选自O、S或N的杂原子的3-7元环；
    R选自烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，亚烷基-芳基、亚烷基-取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
    或者R选自无机阳离子或有机阳离子，所述无机阳离子选自钠离子、钾离子、镁离子或钙离子；所述有机阳离子选自铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；
    各个R'和R”各自独立地选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
    所述取代烷基、取代亚烷基、取代烯基、取代亚烯基、取代炔基、取代亚炔基、取代环烷基、取代亚环烷基、取代芳基、取代亚芳基、亚烷基-取代芳基、 取代杂芳基、取代亚杂芳基、取代杂环基或取代亚杂环基中各自的取代基各自独立地选自：卤素，氰基，氨基，硝基，羟基，烷基，烷氧基，改性烷基。
  2. 根据权利要求1所述的式I化合物或其药学上可接受的盐，其中，所述式I化合物不为化合物：
    Figure PCTCN2020106117-appb-100002
    可选地，所述式I化合物中的R不为甲基。
  3. 根据权利要求1或2所述的式I化合物或其药学上可接受的盐，其特征在于，
    可选地，所述“卤素”选自：F、Cl、Br或I；
    可选地，所述“烷基”、“烷氧基”中的“烷基”为C 1-C 20直链或支链烷基，可选地，选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
    可选地，所述“亚烷基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“亚烷基”为C 1-C 10直链或支链亚烷基，可选地，选自：亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基；
    可选地，所述“改性烷基”为烷基的任意碳原子被选自-O-、-CO-、-NH 2、-OH、卤素、-CN、-NO 2中的一种或几种基团置换所得的基团；
    可选地，所述“烯基”为C 2-C 6的烯基；
    可选地，所述“亚烯基”为C 2-C 6的亚烯基；
    可选地，所述“炔基”为C 2-C 6的炔基；
    可选地，所述“亚炔基”为C 2-C 6的亚炔基；
    可选地，所述“环烷基”为C 3-C 10单环或双环环烷基；
    可选地，所述“亚环烷基”为C 3-C 10单环或双环亚环烷基；
    可选地，所述“芳基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“芳基”为6-10元芳基；可选为苯基或萘基；
    可选地，所述“亚芳基”为6-10元亚芳基；可选为亚苯基或亚萘基；
    可选地，所述“杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元杂芳环；
    可选地，所述“亚杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元亚杂芳环；
    可选地，所述“杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香杂环；
    可选地，所述“亚杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香亚杂环。
  4. 根据权利要求1-3任一项所述的式I化合物或其药学上可接受的盐，其特征在于，
    可选地，各个R'和R”各自独立地选自：氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苄基、仲丁基、正戊基、
    Figure PCTCN2020106117-appb-100003
    Figure PCTCN2020106117-appb-100004
    可选地，R 1和R 2独立地选自：氢、乙酰基，丙酰基，异丙酰基，丁酰基，异丁酰基；
    可选地，R 3选自：氢、甲基、或乙基；
    可选地，R 4选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
    可选地，Linker不存在或选自：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、亚环丙基、
    Figure PCTCN2020106117-appb-100005
    Figure PCTCN2020106117-appb-100006
    可选地，R 5和R 6独立地选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，或者R 5和R 6相互连接，与它们相连的C原子一起形成选自下式的任一基团：
    Figure PCTCN2020106117-appb-100007
    Figure PCTCN2020106117-appb-100008
    可选地，R选自：乙基、丙基、丁基、异丙基、异丁基、叔丁基、仲丁基、正戊基、
    Figure PCTCN2020106117-appb-100009
    Figure PCTCN2020106117-appb-100010
    杂环基或取代杂环基、钠离子、钾离子、镁离子、钙离子、铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH 2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C 5-C 10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH 2、中的一种或几种基团置换所得的基团。
  5. 根据权利要求1-4任一项所述的式I化合物或其药学上可接受的盐，其特征在于，式I化合物选自下列式II化合物：
    Figure PCTCN2020106117-appb-100011
    其中：
    R 3、R如权利要求1-3任一项所定义。
  6. 根据权利要求5所述的式I化合物或其药学上可接受的盐，其特征在于，R 3选自：H、甲基、或乙基；R选自：乙基、正丙基、异丙基、正丁基、异丁基、
    Figure PCTCN2020106117-appb-100012
    钠离子、钾离子、钙离子，各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH 2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C 5-C 10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH 2、中的一种或几种基团置换所得的基团。
  7. 根据权利要求1-6任一项所述的式I化合物或其药学上可接受的盐，其特征在于，选自下列化合物：
    Figure PCTCN2020106117-appb-100013
    Figure PCTCN2020106117-appb-100014
    式I-7中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH 2，-NO 2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
    Figure PCTCN2020106117-appb-100015
    式I-8中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH 2，-NO 2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
  8. 根据权利要求1-7任一项所述的式I化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐包括式I化合物与酸形成的盐；可选地，所述酸包括无机酸、有机酸；可选地，所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸；可选地，所述有机酸包括甲酸、抗坏血酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、双羟萘酸。
  9. 一种药物组合物，其特征在于，包含治疗有效剂量的下式I化合物或其药学上可接受的盐中的一种或多种，以及任选存在的药学上可接受的载体：
    Figure PCTCN2020106117-appb-100016
    式I中：
    R 1和R 2独立地选自：氢、-COR'、-CONHR'、-CONR'R”、或-COOR'；
    R 3选自：氢、甲基、或乙基；
    R 4选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
    Linker不存在或选自：亚烷基或取代亚烷基，亚烯基或取代亚烯基，亚炔基或取代亚炔基，亚环烷基或取代亚环烷基，亚芳基或取代亚芳基，亚杂芳基或取代亚杂芳基，亚杂环基或取代亚杂环基；
    R 5和R 6独立地选自：氢、烷基或取代烷基；或者，R 5和R 6相互连接，与它们相连的C原子一起形成含有0个、1个或2个选自O、S或N的杂原子的3-7元环；
    R选自烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，亚烷基-芳基、亚烷基-取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基。
    或者R选自无机阳离子或有机阳离子，所述无机阳离子选自钠离子、钾离子、镁离子或钙离子；所述有机阳离子选自铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；
    各个R'和R”各自独立地选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
    所述取代烷基、取代亚烷基、取代烯基、取代亚烯基、取代炔基、取代亚炔基、取代环烷基、取代亚环烷基、取代芳基、取代亚芳基、亚烷基-取代芳基、取代杂芳基、取代亚杂芳基、取代杂环基或取代亚杂环基中各自的取代基各自独立地选自：卤素，氰基，氨基，硝基，羟基，烷基，烷氧基，改性烷基。
  10. 根据权利要求9所述的药物组合物，其特征在于，
    可选地，所述“卤素”选自：F、Cl、Br或I；
    可选地，所述“烷基”、“烷氧基”中的“烷基”为C 1-C 20直链或支链烷基，可选地，选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
    可选地，所述“亚烷基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“亚烷基”为C 1-C 10直链或支链亚烷基，可选地，选自：亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基；
    可选地，所述“改性烷基”为烷基的任意碳原子被选自-O-、-CO-、-NH 2、-OH、卤素、-CN、-NO 2中的一种或几种基团置换所得的基团；
    可选地，所述“烯基”为C 2-C 6的烯基；
    可选地，所述“亚烯基”为C 2-C 6的亚烯基；
    可选地，所述“炔基”为C 2-C 6的炔基；
    可选地，所述“亚炔基”为C 2-C 6的亚炔基；
    可选地，所述“环烷基”为C 3-C 10单环或双环环烷基；
    可选地，所述“亚环烷基”为C 3-C 10单环或双环亚环烷基；
    可选地，所述“芳基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“芳基”为6-10元芳基；可选为苯基或萘基；
    可选地，所述“亚芳基”为6-10元亚芳基；可选为亚苯基或亚萘基；
    可选地，所述“杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元杂芳环；
    可选地，所述“亚杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元亚杂芳环；
    可选地，所述“杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香杂环；
    可选地，所述“亚杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香亚杂环。
  11. 根据权利要求9或10所述的药物组合物，其特征在于，
    可选地，各个R'和R”各自独立地选自：氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苄基、仲丁基、正戊基、
    Figure PCTCN2020106117-appb-100017
    Figure PCTCN2020106117-appb-100018
    可选地，R 1和R 2独立地选自：氢、乙酰基，丙酰基，异丙酰基，丁酰基，异丁酰基；
    可选地，R 3选自：氢、甲基、或乙基；
    可选地，R 4选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
    可选地，Linker不存在或选自：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、亚环丙基、
    Figure PCTCN2020106117-appb-100019
    Figure PCTCN2020106117-appb-100020
    可选地，R 5和R 6独立地选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，或者R 5和R 6相互连接，与它们相连的C原子一起形成选自下式的任一基团：
    Figure PCTCN2020106117-appb-100021
    Figure PCTCN2020106117-appb-100022
    可选地，R选自：乙基、丙基、丁基、异丙基、异丁基、叔丁基、仲丁基、正戊基、
    Figure PCTCN2020106117-appb-100023
    Figure PCTCN2020106117-appb-100024
    杂环基或取代杂环基、钠离子、钾离子、镁离子、钙离子、铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH 2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C 5-C 10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH 2、中的一种或几种基团置换所得的基团。
  12. 根据权利要求9-11任一项所述的药物组合物，其特征在于，所述式I化合物选自下列式II化合物：
    Figure PCTCN2020106117-appb-100025
    其中：
    R 3、R如权利要求9-11任一项所定义。
  13. 根据权利要求12所述的药物组合物，其特征在于，R 3选自：H、甲基、或乙基；R选自：乙基、正丙基、异丙基、正丁基、异丁基、
    Figure PCTCN2020106117-appb-100026
    钠离子、钾离子、钙离子，各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH 2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C 5-C 10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH 2、中的一种或几种基团置换所得的基团。
  14. 根据权利要求9-13任一项所述的药物组合物，其特征在于，所述式I化合物选自下列化合物：
    Figure PCTCN2020106117-appb-100027
    Figure PCTCN2020106117-appb-100028
    Figure PCTCN2020106117-appb-100029
    式I-7中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH 2，-NO 2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
    Figure PCTCN2020106117-appb-100030
    式I-8中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH 2，-NO 2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
  15. 根据权利要求9-14任一项所述的药物组合物，其特征在于，所述式I化合物药学上可接受的盐包括式I化合物与酸形成的盐；可选地，所述酸包括无机酸、有机酸；可选地，所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸；可选地，所述有机酸包括甲酸、抗坏血酸、乙酸、丙酸、草酸、丙 二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、双羟萘酸。
  16. 根据权利要求9-15任一项所述的药物组合物，其特征在于，所述药物组合物的剂型包括口服制剂，注射剂型；
    可选地，所述口服制剂包括固体制剂、液体制剂；
    可选地，所述固体制剂包括片剂、粉剂、粒剂、胶囊；
    可选地，所述液体制剂包括水或油悬浮剂、糖浆。
  17. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐，或者权利要求9-16任一项所述的药物组合物所述的在制备治疗非酒精性脂肪肝炎药物中的用途。
  18. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐，或者权利要求9-16任一项所述的药物组合物在制备治疗原发性胆汁性肝硬化药物中的用途。
  19. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐，或者权利要求9-16任一项所述的药物组合物在制备治疗胆汁分泌相关的疾病药物中的用途；
    可选地，所述胆汁分泌相关的疾病包括：门静脉高压、胆汁酸性腹泻、酒精性肝炎和原发性硬化性胆管炎。
  20. 一种治疗非酒精性脂肪肝炎的方法，其特征在于，对患者施用治疗有效量的权利要求1-8任一项所述的式I化合物或其药学上可接受的盐，或者权利要求9-16任一项所述的药物组合物。
  21. 一种治疗原发性胆汁性肝硬化的方法，其特征在于，对患者施用治疗有效量的权利要求1-8任一项所述的式I化合物或其药学上可接受的盐，或者权利要求9-16任一项所述的药物组合物。
  22. 一种治疗胆汁分泌相关的疾病的方法，其特征在于，对患者施用治疗有效量的权利要求1-8任一项所述的式I化合物或其药学上可接受的盐，或者权利要求9-16任一项所述的药物组合物；
    可选地，所述胆汁分泌相关的疾病包括：门静脉高压、胆汁酸性腹泻、酒精 性肝炎和原发性硬化性胆管炎。
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WILLEMEN HENDRA M, VERMONDEN TINA, MARCELIS ANTONIUS T M, SUDHÖLTER ERNST J R: "N-Cholyl Amino Acid Alkyl Esters - A Novel Class of Organogelators", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, WILEY-VCH, DE, 18 January 2001 (2001-01-18), DE, pages 2329 - 2335, XP055780293, ISSN: 1434-193X, DOI: 10.1002/1099-0690(200106)2001:12<2329::AID-EJOC2329>3.0.CO;2-N *

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CN112341514A (zh) 2021-02-09
CN112341514B (zh) 2023-11-21
EP4011899A4 (en) 2022-09-28
US20230146782A1 (en) 2023-05-11

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