WO2016173397A1 - 胆酸衍生物及其制备方法和医药用途 - Google Patents

胆酸衍生物及其制备方法和医药用途 Download PDF

Info

Publication number
WO2016173397A1
WO2016173397A1 PCT/CN2016/079167 CN2016079167W WO2016173397A1 WO 2016173397 A1 WO2016173397 A1 WO 2016173397A1 CN 2016079167 W CN2016079167 W CN 2016079167W WO 2016173397 A1 WO2016173397 A1 WO 2016173397A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pharmaceutically acceptable
acid derivative
stereoisomer
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/079167
Other languages
English (en)
French (fr)
Inventor
杨飞
仝朝龙
李成海
包如迪
喻红平
徐耀昌
吕爱锋
钟慧娟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Original Assignee
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Shanghai Hansoh Biomedical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority to EP16785828.1A priority Critical patent/EP3290429A1/en
Priority to CN201680012567.8A priority patent/CN107250150B/zh
Priority to US15/569,918 priority patent/US20180148470A1/en
Priority to CN201910026222.3A priority patent/CN111116699B/zh
Priority to JP2017552445A priority patent/JP2018519246A/ja
Publication of WO2016173397A1 publication Critical patent/WO2016173397A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • 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
    • 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
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • 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
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to a cholic acid derivative and a preparation method and application thereof.
  • the farnesyl ester derivative X receptor is a member of the hormone nuclear receptor superfamily, which is mainly expressed in the liver, small intestine, kidney, and adrenal gland, and less expressed in adipose tissue and heart. Farnesol was originally thought to be its ligand and was named after it.
  • FXR ligand binds directly to the FXR carboxy terminal ligand binding region (LBD)
  • LBD FXR carboxy terminal ligand binding region
  • RXR retinoid receptor
  • the binding of FXR DNA response elements to regulate the transcription of target genes and participate in the regulation of sugar and lipid metabolism is an important energy regulator.
  • Primary bile acid chenodeoxycholic acid is the most potent ligand for FXR, and secondary bile acid bile acid and deoxycholic acid can also activate FXR.
  • FXR ligands such as 6-ECDCA, GW4064, etc.
  • the main target genes of FXR include bile salt export pump (BSEP), bile acid binding protein (IBABP) and small heterodimeric chaperone receptor (SHP), etc., FXR and FXR response elements on these gene promoters (FXRE) Binding to regulate the expression of these genes.
  • 6-ethyl chenodeoxycholic acid (obeyolic acid) has been completed as a treatment for primary biliary cirrhosis (PBC).
  • PBC primary biliary cirrhosis
  • FXR agonists can both reduce bile acid-dependent bile flow by stimulating the bile salt output pump (BSEP) and also stimulate MRP2 to increase non-biliary acid-dependent bile flow to reduce cholestasis.
  • BSEP bile salt output pump
  • MRP2 biliary acid-dependent bile flow to reduce cholestasis.
  • FXR is expected to be a new drug target for screening and treating other metabolic diseases including cholestatic diseases and nonalcoholic steatohepatitis.
  • FXR agonists may have therapeutic and research value in the following diseases, including atherosclerosis, cholestatic disease caused by bile acid disorders, liver fibrosis, cirrhosis, cancer, etc. (see Table 1).
  • the inventors discovered a class of cholic acid derivatives having the structure of formula (I) during the course of the research. These compounds have significant agonistic effects on FXR activity and can be used to treat FXR-mediated diseases including cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic Liver diseases, gastrointestinal diseases, kidney diseases, cardiovascular diseases, metabolic diseases, cancers (such as colorectal cancer) or nerve signs such as stroke have a wide range of medical applications and are expected to be developed into a new generation of FXR agonists.
  • FXR-mediated diseases including cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic Liver diseases, gastrointestinal diseases, kidney diseases, cardiovascular diseases, metabolic diseases, cancers (such as colorectal cancer) or nerve signs such as stroke have a wide range of medical applications and are expected to be developed into a new generation of FXR agonists.
  • a cholic acid derivative having the structure of the following formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 are selected from hydrogen, fluorine, bromine, trifluoromethyl or C 1-8 alkyl;
  • R 4 is selected from the following structures:
  • X 1 is selected from nitrogen or CR 8 ;
  • X 2 is selected from CR 8 R 9 , NR 10 , oxygen or sulfur;
  • Y 1 and Y 2 are each independently selected from CR 8 R 9 , NR 10 , oxygen or sulfur;
  • Z is selected from CR 8 R 9 , NR 10 , oxygen or sulfur;
  • R 5 is selected from the group consisting of hydrogen, hydroxy, cyano, amino, C 1-8 alkoxy or SO 2 R 11 ;
  • R 6 is selected from the group consisting of SO 2 R 11 , SO 3 R 11 , C(O)OR 11 , C(O)R 12 or C 0-4 -P(O)R 13 R 14 ;
  • R 7 is selected from a hydroxyl group, a hydroxy-substituted C 1-8 alkyl group or a halogen-substituted C 1-8 alkyl group;
  • R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 - 8 -cycloalkyl, C 1-8 alkoxy, C 3-8 cycloalkoxy, SO 2 R 11 , C(O)OR 11 , C(O)R 12 or P(O)R 13 R 14 , Wherein the alkyl group, the cycloalkyl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, halogen substituted C 1-8 alkoxy, C 3-8 Substituted by a substituent of a cycloalkyl or C 3-8 cycloalkoxy group;
  • R 10 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl or C 1-8 alkoxy;
  • R 11 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, phenyl or p-methylphenyl;
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of a hydroxyl group, a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a halogen-substituted C 1-8 alkyl group, a C 1-8 alkoxy group, an amino group or a C group. 1-8 alkyl disubstituted amino group;
  • n is selected from 0 or 1.
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group;
  • C 1-8 alkoxy is preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy;
  • C 3-8 cycloalkyl is preferably C 3-6 cycloalkyl;
  • C 3-8 cycloalkoxy Preferred is a C 3-6 cycloalkoxy group;
  • a C 2-8 alkenyl group is preferably a C 2-4 alkenyl group; and a C 2-8 alkynyl group is preferably a C 2-4 alkynyl group.
  • R 1 is selected from the group consisting of hydrogen, fluorine, methyl, trifluoromethyl, ethyl or isopropyl;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , X 1 , X 2 , Y 1 , Y 2 Z, n are as defined for the compound of formula (I).
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 2 is selected from hydrogen, methyl, ethyl or isopropyl; R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , X 1 , X 2 , Y 1 , Y 2 , Z, n as claimed 1 is defined.
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 3 is selected from H, methyl, ethyl or isopropyl; R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , X 1 , X 2 , Y 1 , Y 2 , Z, n are as defined I) Definition of the compound.
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 3 is selected from H or methyl; R 1 , R 2 , R 4 , R 5 , R 6. R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , X 1 , X 2 , Y 1 , Y 2 , Z, n are as defined for the compound of formula (I).
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following structural compounds of the formula (II):
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof R 1 is selected from H; R 3 is selected from H or methyl; R 2 , R 4 , R 5 And R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , X 1 , X 2 , Y 1 , Y 2 , Z, n are as defined in the compound of formula (I) definition.
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following structural compounds of the formula (III):
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following structural compounds of the formula (IV):
  • R 4 is selected from the following structures:
  • R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , X 1 , X 2 , Y 1 , Y 2 , Z, n is as defined for the compound of formula (I).
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable substance thereof Accept salt is selected from the group consisting of:
  • R 4 is selected from the following structures: When n is 1;
  • R 4 is selected from the following structures: When n is 0;
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following structural compounds of the formula (V):
  • X 1 , X 2 , R 2 , R 8 , R 9 and R 10 are as defined for the compound of formula (I).
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • the cholic acid derivative, the stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following structural compounds of the formula (VI):
  • Y 1 , Y 2 , R 2 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are as defined for the compound of formula (I).
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following structural compounds of the formula (VII):
  • R 2 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and Z are as defined for the compound of the formula (I).
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • R 2 is selected from the group consisting of hydrogen, fluorine, bromine, trifluoromethyl or C 1-8 alkyl.
  • the cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • Another aspect of the present invention provides a process for the preparation of the above-described cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and the preparation method of the corresponding compound comprises one of the following steps:
  • R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , X 1 , X 2 , Y 1 , Y 2 , Z are as defined (I) The definition of the compound.
  • Pg 1 is a hydroxy protecting group, preferably from a C 1-4 alkyl or benzyl group
  • Pg 2 is a hydroxy protecting group, preferably from a C 1-4 alkyl group or an acetyl group.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned bile acid derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the manufacture of a medicament for preventing or treating a FXR-mediated disease or condition application.
  • the FXR mediated disease or condition is selected from the group consisting of cardiovascular disease, hypercholesterolemia, hyperlipidemia chronic hepatitis disease, chronic liver disease, gastrointestinal disease, kidney disease, cerebrovascular disease, metabolic disease or cancer.
  • the chronic liver disease is selected from the group consisting of primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced cholestasis, and intrahepatic bile of pregnancy.
  • PBC primary sclerosis
  • CX cerebral xanthoma
  • PSC primary sclerosing cholecystitis
  • drug-induced cholestasis and intrahepatic bile of pregnancy.
  • PNAC extraintestinal absorption-related cholestasis
  • bacterial overgrowth or sepsis cholestasis autoimmune hepatitis, chronic viral hepatitis
  • alcoholic liver disease nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty Hepatitis (NASH)
  • NASH nonalcoholic fatty Hepatitis
  • liver graft-related graft-versus-host disease live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha 1 anti-membrane protease deficiency.
  • the gastrointestinal disease is selected from the group consisting of inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative enteritis), irritable bowel syndrome (IBS), bacterial overgrowth, nutrient malabsorption, and reflex Posterior colitis or microcolitis.
  • IBD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • bacterial overgrowth bacterial overgrowth
  • nutrient malabsorption nutrient malabsorption
  • reflex Posterior colitis or microcolitis reflex Posterior colitis or microcolitis.
  • the renal disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephropathy, chronic glomerulitis, chronic allograft glomerulopathy, chronic interstitial nephritis Or polycystic kidney disease.
  • FSGS focal segmental glomerulosclerosis
  • hypertensive nephropathy chronic glomerulitis
  • chronic allograft glomerulopathy chronic interstitial nephritis Or polycystic kidney disease.
  • the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, atherosclerosis, dyslipidemia, hypercholesterolemia or hypertriglyceridemia.
  • the metabolic disease is selected from the group consisting of insulin resistance, type I diabetes, type II diabetes, or obesity.
  • the cerebrovascular disease is selected from a stroke.
  • the cancer is selected from the group consisting of colorectal cancer or liver cancer.
  • Another aspect of the present invention provides a method for preventing or treating a FXR-mediated disease or condition comprising administering a therapeutically effective amount of the aforementioned cholic acid derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a combination thereof Things.
  • C 1-8 alkyl means a straight-chain alkyl group having 1 to 8 carbon atoms and a branched alkyl group, and the alkyl group means a saturated aliphatic hydrocarbon group such as methyl, ethyl, n-propyl or different.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent
  • C3-8 cycloalkyl refers to a cycloalkyl group containing from 3 to 8 carbon atoms, for example:
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • Cycloalkane based on the number of shared spiro atoms between the ring and the ring
  • the grouping is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, and a non-limiting example of a spirocycloalkyl group comprises:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:
  • Bridge cycloalkyl refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above.
  • C 1-8 alkoxy refers to an alkyloxy group containing from 1 to 8 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.
  • Cycloalkoxy refers to -O-(unsubstituted cycloalkyl) wherein cycloalkyl is as defined above.
  • C 3-8 cycloalkoxy refers to a cycloalkyloxy group containing from 3 to 8 carbons, and non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. .
  • Halo-substituted C 1-8 alkyl means a hydrogen on the alkyl group optionally substituted with 1-8 carbon alkyl groups substituted by fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloromethyl Base, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • C(O)R 12 refers to a carbonyl group substituted with R 12 .
  • P (O) R 12 R 13 refers to R 12, R 13 is a substituted phosphoryl group, R 12, R 13 may be the same or different substituents.
  • PE means petroleum ether.
  • EA means ethyl acetate
  • THF tetrahydrofuran
  • DCM dichloromethane
  • CDI N,N-carbonyldiimidazole
  • DMF N,N-dimethylformamide
  • Dioxane means 1,4-dioxane.
  • DMAP means 4-dimethylaminopyridine.
  • DIPEA diisopropylethylamine
  • TMSCl refers to trimethylchlorosilane.
  • LDA lithium diisopropylamide
  • Selectflour refers to a selective fluoro reagent.
  • EDC ⁇ HCl refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • TBTU refers to O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate.
  • NBS N-bromosuccinimide
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted means that one or more hydrogen atoms in the group are each independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of TLC is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5. Mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • 6 ⁇ -ethyl-chenodeoxycholic acid (OCA, 42 mg, 0.1 mmol) was weighed and dissolved in 1 mL of N,N-dimethylformamide, then triethylamine (0.03 mL, 0.2 mmol) was added and added to the ice bath.
  • Ethyl chloroformate (0.01 mL, 0.11 mmol) was stirred for 0.5 h.
  • the methoxyamine hydrochloride (9 mg, 0.11 mmol) was dissolved in 1 mL of N,N-dimethylformamide, and then triethylamine (0.03 mL, 0.2 mmol) was added, and the solution was added dropwise to the above reaction vessel.
  • reaction temperature is gradually increased to room temperature, and the basic reaction is complete at 3-4 hours. It was washed with saturated brine and extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate by column to give compound 4 (19.2 mg, 43%).
  • N,N-dimethylformamide dimethyl acetal (2 mL) was added to the above crude product, and the mixture was refluxed for 2 hr. After completion of the reaction, the mixture was cooled to room temperature and concentrated, and the obtained crude product was dissolved in 2 mL of acetic acid, and then hydrazine hydrochloride (21 mg, 0.20 mmol) was added, and the mixture was heated at 90 ° C for 90 minutes. Cool to room temperature and quench with water. The organic layer was washed with saturated aqueous NaHCO3 and dried over anhydrous sodium sulfate. Filtration, concentration, and the crude material was purified eluted elute
  • 6 ⁇ -ethyl-chenodeoxycholamide 12-i (210 mg, 0.50 mmol) was weighed and dissolved in 5 ml of tetrahydrofuran, and triethylamine (0.56 mL, 4.0 mmol) and trifluoroacetic anhydride (0.28) were sequentially added thereto under ice-cooling. mL, 2.0 mmol). After the addition, the reaction was carried out for 3 hours at room temperature. After completion of the reaction, quenched with saturated aqueous NaHCO 3, extracted with ethyl acetate twice.
  • the organic phase was concentrated and dissolved in 5 ml of tetrahydrofuran, and then 5 ml of a 0.5 N aqueous sodium hydroxide solution was added thereto, and the mixture was heated at 60 ° C for 3 hours. After completion of the reaction extracted with ethyl acetate, the organic phase was dried over anhydrous Na 2 SO 4, filtered, concentrated and column chromatography, to obtain a cyano compound 12-ii (167mg, 83% ).
  • N-bromosuccinimide (692 mg, 3.89 mmol) was dissolved in 5 ml of tetrahydrofuran, and added dropwise to the reaction system. After the addition, the mixture was allowed to warm to room temperature overnight. TLC showed that the reaction was completed. EtOAc was evaporated. EtOAc EtOAc EtOAc. .
  • the compound 14-ii was dissolved in 20 ml of ethanol, and then thiourea (443 mg, 5.82 mmol) and sodium acetate (477 mg, 5.82 mmol) were added, and the mixture was heated to reflux overnight. After cooling, 2N hydrochloric acid (20 mL) was added, and reflux was continued for 24 hours. Cool, concentrate under reduced pressure, and remove ethanol. Extract with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated.
  • FXR receptor binding activity test time-resolved fluorescence detection method TR-FRET method
  • FXR receptor binding To test the effect of compounds on FXR receptor binding, we used commercial FXR receptor binding.
  • An activity test kit was used to test the effect of the compound on FXR and its binding protein fragment (the LBD domain binds to the SRC1 fragment) (kit supplier life technology Invitrogen Catalog: PV4835; cisbio Catalog: 610 SAXLA and 61 GSTKLA). See the kit instructions for specific methods. The operation is as follows:
  • SA-APC biotinylated SRC1/streptomycin-allophycocyanin
  • ⁇ X represents the value of 665/615 for each concentration
  • ⁇ Min represents the 665/615 value of the unadded compound
  • ⁇ Max represents the 665/615 value of the reference compound.
  • biochemical activity of the compounds of the present invention was determined by the above test, and the measured EC 50 values are shown in the following table.
  • the cells were digested and cells of appropriate density were planted in 10 ml of complete medium and then incubated for 24 hours at 37 degrees 5% CO2 in humid conditions.
  • Transfection reagent is Fugene HD (Promega#E231A)
  • Firefly luciferase and Renilla luciferase signals were detected by Promega's dual luciferase assay system (Promega #E1980).
  • ⁇ X represents the F/R value for each concentration
  • ⁇ Min represents the F/R value of the unadded compound
  • ⁇ Max represents the F/R value of the reference compound.
  • biochemical activity of the compounds of the present invention was determined by the above test, and the measured EC 50 values are shown in the following table.
  • the pharmacokinetic study of the present invention uses rat as a test animal to study the pharmacokinetic behavior of the positive reference drug INT-747 and representative compounds such as Example 14- ⁇ in rats, and to evaluate its pharmacokinetic characteristics.
  • a 1 mg/ml solution was prepared and the remaining drug solution was used for quantitative analysis.
  • the blood was collected in the mandibular vein ⁇ 0.05ml, placed in the test tube of EDTA-K2 tube, and the collected blood samples were centrifuged at 6500 rpm for 5 min. Plasma was separated and stored at -80 degrees. Eat 4 h after dosing.
  • the test results showed that after the rats were given 10 mg/kg positive reference drug INT-747 by gavage, the blood concentration peak time t max was 0.5 h, the peak concentration C max was 4413 ng/ml, and the plasma concentration-time curve The lower area AUC 0-t was 9028 ng/ml ⁇ h.
  • the rat pharmacokinetic test showed that the exposure amount of the 14- ⁇ compound of the present invention in the test animal was much better than that of the positive reference drug INT-747.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Immunology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及胆酸衍生物及其制备方法和医药用途。具体地，本发明涉及一种具有式(I)结构的胆酸衍生物、其立体异构体或其药学上可接受盐。该系列化合物可以用来治疗用于治疗FXR介导的疾病，包括心血管疾病、动脉粥样硬化、动脉硬化、高胆甾醇血、高血脂慢性肝炎疾病、慢性肝病、胃肠疾病、肾病、心血管疾病、代谢疾病、癌症(例如结直肠癌)或神经迹象如中风等疾病，具有广泛医学应用，有望开发成新一代FXR激动剂。

Description

胆酸衍生物及其制备方法和医药用途 技术领域
本发明属于药物合成领域，具体涉及一种胆酸衍生物及其制备方法和应用。
背景技术
法尼酯衍生物X受体(FXR)属于激素核受体超家族的一员，其主要在肝脏、小肠、肾脏和肾上腺表达，在脂肪组织和心脏中较少表达。最初认为法尼醇是其配体，并由此得名。当FXR配体与FXR羧基末端配体结合区(LBD)直接结合后,核受体空间构象发生改变并与视黄醛衍生物受体(RXR)形成异源二聚体,最后与靶基因特定FXR DNA反应元件结合从而调节靶基因的转录，参与糖、脂代谢的调控，是重要的能量调节器。初级胆汁酸鹅脱氧胆酸是FXR最有效的配体,次级胆汁酸石胆酸和脱氧胆酸也可以激活FXR。目前还有合成FXR配体(如6-ECDCA、GW4064等),其与FXR结合力比天然配体强数倍。FXR的主要靶基因包括胆盐输出泵(BSEP)、胆酸结合蛋白(IBABP)和小异源二聚体伴侣受体(SHP)等,FXR通过和这些基因启动子上的FXR反应元件(FXRE)结合从而调控这些基因的表达。但如胆固醇7α羟化酶(CYP7α1)等主要FXR调控基因的启动子序列中没有典型FXR结合反应序列,FXR则是间接通过诱导转录抑制因子SHP表达,然后SHP与CYP7α1启动子肝受体同源物(LRH-1)形成抑制性复合物,从而阻断CYP7α1和其它LRH-1靶基因转录。由于FXR在胆汁酸及胆固醇代谢中的重要作用,这将使其和肝脏相关疾病关系日益受到关注。寻找FXR新型激动剂成了治疗包括胆汁淤积综合症等肝脏疾病的研究热点,6-乙基鹅脱氧胆酸(奥贝胆酸)作为治疗原发性胆汁性肝硬化(PBC)已经完成III期临床试验,最早将于2015年上市，而且该化合物在非酒精性脂肪性肝炎患者中也表现出令人满意的治疗效果。FXR激动剂既可以通过刺激胆盐输出泵(BSEP)增加胆汁酸依赖性胆流和也可以刺激MRP2增加非胆汁酸依赖性胆流以减轻胆汁淤积。FXR有望成为筛选治疗包括胆汁淤积性疾病和非酒精性脂肪性肝炎等其它代谢疾病的新的药物靶点。不仅如此，目前的研究已经表明，FXR激动剂可能在以下疾病中具有治疗和研究价值，包括动脉粥样硬化，胆汁酸紊乱引起的胆汁淤积性疾病、肝纤维化、肝硬化，癌症等(见表1)。
表1.FXR激动剂可以对治疗有所帮助的疾病
Figure PCTCN2016079167-appb-000001
Figure PCTCN2016079167-appb-000002
发明内容
发明人在研究过程中发现一类具有式(I)结构的胆酸衍生物。该类化合物对FXR活性具有明显地激动作用，可以用来治疗用于治疗FXR介导的疾病，包括心血管疾病、动脉粥样硬化、动脉硬化、高胆甾醇血、高血脂慢性肝炎疾病、慢性肝病、胃肠疾病、肾病、心血管疾病、代谢疾病、癌症(例如结直肠癌)或神经迹象如中风等疾病，具有广泛医学应用，有望开发成新一代FXR激动剂。
本发明第一方面提供一种具有如下式(I)结构的胆酸衍生物、其立体异构体或其药学上可接受盐：
Figure PCTCN2016079167-appb-000003
其中，
R1、R2、R3选自氢、氟、溴、三氟甲基或C1-8烷基；
R4选自如下结构：
Figure PCTCN2016079167-appb-000004
X1选自氮或CR8；
X2选自CR8R9、NR10、氧或硫；
Y1、Y2各自独立的选自CR8R9、NR10、氧或硫；
Z选自CR8R9、NR10、氧或硫；
R5选自氢、羟基、氰基、氨基、C1-8烷氧基或SO2R11；
R6选自SO2R11、SO3R11、C(O)OR11、C(O)R12或C0-4-P(O)R13R14；
R7选自羟基、羟基取代C1-8烷基或卤取代C1-8烷基；
R8、R9各自独立的选自氢、氘、卤素、羟基、氰基、硝基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、C1-8烷氧基、C3-8环烷氧基、SO2R11、C(O)OR11、C(O)R12或P(O)R13R14，其中烷基、环烷基任选进一步被一个或多个选自卤素、羟基、C1-8烷基、C1-8烷氧基、卤取代C1-8烷氧基、C3-8环烷基或C3-8环烷氧基的取代基所取代；
R10选自氢、C1-8烷基、C3-8环烷基、卤取代C1-8烷基或C1-8烷氧基；
R11选自氢、C1-8烷基、C3-8环烷基、卤取代C1-8烷基、苯基或对甲基苯基；
R12、R13、R14各自独立的选自羟基、C1-8烷基、C3-8环烷基、卤取代C1-8烷基、C1-8烷氧基、氨基或C1-8烷基双取代氨基；
n选自0或1。
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，C1-8烷基优选C1-6烷基，更优选C1-3烷基；C1-8烷氧基优选C1-6烷氧基，更优选C1-3烷氧基；C3-8环烷基优选C3-6环烷基；C3-8环烷氧基优选C3-6环烷氧基；C2-8链烯基优选C2-4链烯基；C2-8链炔基优选C2-4链炔基。
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，R1选自氢、氟、甲基、三氟甲基、乙基或异丙基；R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如式(I)化合物所定义。
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，R2选自氢、甲基、乙基或异丙基；R1、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如权利要求1所定义。
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，R3选自H、甲基、乙基或异丙基；R1、R2、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如式(I)化合物所定义。
作为更进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，R3选自H或甲基；R1、R2、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如式(I)化合物所定义。
作为最优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下式(Ⅱ)结构化合物：
Figure PCTCN2016079167-appb-000005
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，R1选自H；R3选自H或甲基；R2、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如式(I)化合物所定义。
作为最优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下式(Ⅲ)结构化合物：
Figure PCTCN2016079167-appb-000006
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下式(Ⅳ)结构化合物：
Figure PCTCN2016079167-appb-000007
其中，R4选自如下结构：
Figure PCTCN2016079167-appb-000008
R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如式(I)化合物所定义。
作为更进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可 接受盐，
当R4选自如下结构：
Figure PCTCN2016079167-appb-000009
时，n为1；
当R4选自如下结构：
Figure PCTCN2016079167-appb-000010
时，n为0；
R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z如式(I)化合物所定义。
作为最优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：
Figure PCTCN2016079167-appb-000011
或者，选自如下化合物：
Figure PCTCN2016079167-appb-000012
或者，选自如下化合物：
Figure PCTCN2016079167-appb-000013
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下式(Ⅴ)结构化合物：
Figure PCTCN2016079167-appb-000014
其中，X1、X2、R2、R8、R9、R10如式(I)化合物所定义。
作为最优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：
Figure PCTCN2016079167-appb-000015
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下式(Ⅵ)结构化合物：
Figure PCTCN2016079167-appb-000016
其中，Y1、Y2、R2、R8、R9、R10、R11、R12、R13、R14如式(I)化合物所定义。
作为最优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：
Figure PCTCN2016079167-appb-000017
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下式(Ⅶ)结构化合物：
Figure PCTCN2016079167-appb-000018
或表述为：
Figure PCTCN2016079167-appb-000019
包含如下两个异构体：
Figure PCTCN2016079167-appb-000020
其中，R2、R8、R9、R10、R11、R12、R13、R14、Z如式(I)化合物所定义。
作为最优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：
Figure PCTCN2016079167-appb-000021
本发明另一方面提供了式(Ⅷ)结构的胆酸衍生物、其立体异构体或其药学上可接受盐，式(Ⅷ)结构如下：
Figure PCTCN2016079167-appb-000022
Z氧或硫；
R2选自氢、氟、溴、三氟甲基或C1-8烷基。
作为进一步优选的方案，所述的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：
Figure PCTCN2016079167-appb-000023
本发明另一方面提供了前述胆酸衍生物、其立体异构体或其药学上可接受盐的制备方法，相应化合物的制备方法包括如下步骤之一：
Figure PCTCN2016079167-appb-000024
Figure PCTCN2016079167-appb-000025
Figure PCTCN2016079167-appb-000026
其中，R2、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z如式(I)化合物所定义。
Pg1为羟基保护基，优选自C1-4烷基或苄基，Pg2为羟基保护基，优选自C1-4烷基或乙酰基。
本发明另一方面提供一种药物组合物，其包括治疗有效剂量的前述胆酸衍物、其立体异构体或其药学上可接受盐及可药用的载体。
本发明另一方面提供一种前述胆酸衍生物、其立体异构体或其药学上可接受盐，或前述药物组合物在制备用于预防或治疗FXR介导的疾病或状况的药物中的应用。
作为进一步优选的方案，FXR介导的疾病或状况选自心血管疾病、高胆甾醇血症、高血脂慢性肝炎疾病、慢性肝病、胃肠疾病、肾病、脑血管疾病、代谢疾病或癌症。
作为更进一步优选的方案，慢性肝病选自原发性硬化(PBC)、脑脏性黄瘤症(CTX)、原发性硬化性胆囊炎(PSC)、药物导致的胆汁郁积、妊娠肝内胆汁淤积症、肠外吸收相关胆汁郁积(PNAC)、细菌过度生长或脓血症胆汁郁积、自身免疫肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝移植相关移植物抗宿主病、活供体肝移植再生、先天性肝纤维化、胆总管结石、肉芽性肝病、肝内或外恶性肿瘤、Sjogren综合征、结节病、Wilson's疾病、Gaucher's疾病、血色病或α1一抗膜蛋白酶缺乏症。
作为更进一步优选的方案，胃肠疾病选自炎症性肠病(IBD)(包括Crohn's疾病和溃病性肠炎)、肠易激综合征(IBS)、细菌过度生长、营养吸收不良、反射 后结肠炎或微小性结肠炎。
作为更进一步优选的方案，肾病选自糖尿病肾病、局灶节段性肾小球硬化症(FSGS)、高血压肾病、慢性肾小球炎、慢性移植性肾小球病、慢性间质性肾炎或多囊肾病。
作为更进一步优选的方案，心血管疾病选自动脉硬化症、动脉硬化、动脉粥样硬化、血脂障碍、高胆固醇血症或高甘油三酯血症。
作为更进一步优选的方案，代谢疾病选自胰岛素抗性、I型糖尿病、II型糖尿病或肥胖。
作为更进一步优选的方案，脑血管疾病选自中风。
作为更进一步优选的方案，癌症选自结直肠癌或肝癌。
本发明另一方面提供一种预防或治疗FXR介导的疾病或状况的方法，包括施用治疗有效量的前述胆酸衍生物、其立体异构体或其药学上可接受盐，或前述药物组合物。
具体实施方式
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。
“C1-8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，烷基指饱和的脂族烃基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，“C3-8环烷基”指包括3至8个碳原子的环烷基，例如：
单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷 基分为单螺环烷基、双螺环烷基基或多螺环烷基，螺环烷基的非限制性实施例包含：
Figure PCTCN2016079167-appb-000027
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基的非限制性实施例包含：
Figure PCTCN2016079167-appb-000028
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基的非限制性实施例包含：
Figure PCTCN2016079167-appb-000029
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。“C1-8烷氧基”指含1-8个碳的烷基氧基，非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。
“环烷氧基”指和-O-(未取代的环烷基)，其中环烷基的定义如上所述。“C3-8环烷氧基”指含3-8个碳的环烷基氧基，非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“卤取代的C1-8烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷基基团，例如二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“C(O)R12”指R12取代的羰基。
“P(O)R12R13”指R12、R13取代的磷酰基，R12、R13任选相同或不同的取代基。“PE”指石油醚。
“EA”指乙酸乙酯。
“THF”指四氢呋喃。
“DCM”指二氯甲烷。
“CDI”指N,N-羰基二咪唑
“DMF”指N、N-二甲基甲酰胺。
“Dioxane”指1,4-二氧六环。
“DMAP”指4-二甲氨基吡啶。
“DIPEA”指二异丙基乙胺。
“TMSCl”指三甲基氯硅烷。
“LDA”指二异丙基胺基锂。
“Selectflour”指选择性氟试剂。
“EDC·HCl”指1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
“TBTU”指O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸。
“NBS”指N-溴代丁二酰亚胺。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代甲醇(CD3OD)和氘代氯仿(CDCl3)内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5 mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂。
实施例1
(4R)-4-((3R,4R,5S,6R,7R,10R,13R)-6-乙基-4-氟-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)戊酸的制备
Figure PCTCN2016079167-appb-000030
第一步：
称取6α-乙基-鹅去氧胆酸(OCA，6.0g，14.2mmol)溶解在4N HCl的甲醇溶液中回流搅拌2小时，TLC(PE:EA＝1:2)显示反应完全，旋去甲醇，加入饱和碳酸氢钠调节到碱性，用50mL的乙酸乙酯提取，有机相硫酸钠干燥后旋干得化合物1-ii(6.0g，98％)。
第二步：
称取化合物1-ii(4.0g,9.2mmol)溶解在40mL的甲苯中，依次加入碳酸银(5.0g,18.4mmol)和硅藻土(10g)后回流搅拌24小时，TLC(PE:EA＝2:1)显示反应完全，过滤除去硅藻土，用乙酸乙酯多次洗涤后有机相旋干并经过柱层析得化合物1-iii(1.0g,25％)。
第三步：
称取化合物1-iii(100mg,0.21mmol)溶解在2mL的四氢呋喃中，在-78℃下依次加入TMSCl(200μL,1.05mmol)和LDA(90μL,0.42mmol)，继续搅拌3小时，加入饱和碳酸氢钠淬灭，然后用乙酸乙酯提取，硫酸钠干燥后旋干得中间体。所得产物溶在2mL的乙腈中，selectflour(105mg,0.29mmol)加入后室温搅拌1小时，TLC(PE:EA＝5:1)显示反应完全，加入10mL的水，并用乙酸乙酯提取，有机相旋干得100mg化合物1-iv，粗产品直接用于下步反应。
第四步：
称取化合物1-iv(300mg,0.6mmol)溶解在dioxane/H2O(10mL/0.5mL)中，分批加入硼氢化钠(49mg,1.3mmol)，然后室温搅拌过夜，补加1当量硼 氢化钠，继续搅拌4小时，TLC(PE:EA＝5:1)显示原料消失，加入10mL的水淬灭，用乙酸乙酯提取，有机相用硫酸钠干燥后柱层析得化合物1-v(40mg,15％)。
第五步：
化合物1-v(40mg,0.088mmol)溶解在1mL的四氢呋喃中，加入1mL的1N NaOH后室温搅拌2小时，TLC(PE:EA＝1:1)显示反应完全，加1N HCl调节到酸性，乙酸乙酯提取，有机相硫酸钠干燥后柱层析得化合物1(5mg,12％)。
1H NMR(400MHz,CDCl3)δ5.35–5.13(m,1H),3.75(s,1H),3.56–3.36(m,1H),2.40–2.28(m,1H),2.23–2.11(m,1H),0.90(s,3H),0.88–0.83(m,6H),0.59(s,3H)。
13C NMR(101MHz,CDCl3)δ178.50,99.65(d,J＝168.8Hz),74.89(d,J＝20.0Hz),70.96,55.78,50.45,49.37(d,J＝13.6Hz),42.77,42.10,40.33,39.48,39.00(d,J＝9.4Hz),35.39,35.33,34.44,30.78,29.69,28.15,26.02(d,J＝8.5Hz),24.28(d,J＝8.3Hz),23.60,23.28,20.75,18.23,12.48,11.83。
19F NMR(376MHz,CDCl3)δ-188.73。
实施例2
(4R)-4-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-N-羟基戊酰胺的制备
Figure PCTCN2016079167-appb-000031
称取6α-乙基-鹅去氧胆酸(OCA，100mg，0.24mmol)溶于2毫升N,N-二甲基甲酰胺，再加入N,N-羰基二咪唑(77mg，0.48mmol)，室温搅拌0.5小时。然后加入盐酸羟胺(66mg，0.95mmol)，室温反应0.5小时，反应完全。加水淬灭，乙酸乙酯萃取3次。有机相用无水硫酸钠干燥。过滤，浓缩，柱层析分离，得化合物2(16mg，15％)。
1H NMR(400MHz,DMSO)δ4.29(d,J＝4.2Hz,1H),4.04(d,J＝5.0Hz,1H),3.50(brs,1H),3.20–3.10(m,2H),2.05–1.61(m),1.60–0.76(m),0.60(s,3H)。
13C NMR(101MHz,DMSO)δ169.99,71.08,68.89,56.02,50.60,45.83,42.50,41.77,36.01,35.70,35.42,34.05,33.14,31.94,30.93,29.68,29.44,28.29,23.57,22.63,20.89,18.76,12.22,12.17。
实施例3
(4R)-N-氰基-4-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)戊酰胺的制备
Figure PCTCN2016079167-appb-000032
称取6α-乙基-鹅去氧胆酸(OCA，60mg，0.14mmol)、DMAP(21mg，0.17mmol)、EDC·HCl(38mg，0.20mmol)以及NH2CN(12mg，0.28mmol)，溶于2毫升二氯甲烷，加入DIPEA(50μL，0.28mmol)，室温搅拌过夜，反应完全。加入二氯甲烷稀释，依次用稀盐酸和饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩，柱层析分离，得化合物3(25mg，39％)。
1H NMR(400MHz,DMSO)δ4.28(brs,1H),3.50(brs,1H),3.13(brs,1H),2.30(dd,J＝9.6,5.1Hz,2H),2.20(dd,J＝14.1,5.8Hz,2H),1.96–1.59(m),1.60–0.76(m),0.61(s,3H)。
13C NMR(101MHz,DMSO)δ175.28,71.08,68.89,55.92,50.59,45.82,42.53,41.76,36.02,35.70,35.30,34.04,33.14,32.40,30.92,29.44,28.24,23.57,22.63,20.89,18.69,12.18,12.17。
实施例4
(4R)-4-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-N-甲氧基戊酰胺的制备
Figure PCTCN2016079167-appb-000033
称取6α-乙基-鹅去氧胆酸(OCA，42mg，0.1mmol)溶于1mL N,N-二甲基甲酰胺，再加入三乙胺(0.03mL，0.2mmol)，冰浴下加入氯甲酸乙酯(0.01mL，0.11mmol)搅拌0.5h。称取甲氧基胺盐酸盐(9mg，0.11mmol)溶于1mL N,N-二甲基甲酰胺，再加入三乙胺(0.03mL，0.2mmol)，将此溶液逐滴加入前述反应容器，反应温度逐步提高至室温，3-4h基本反应完全。加入饱和食盐水洗涤，乙酸乙酯萃取三次。合并有机相，无水硫酸钠干燥。过滤，滤液经柱分离浓缩得化合物4(19.2mg，43％)。
1H NMR(400MHz,CDCl3)δ3.69(brs,3H),3.63(brs,1H),3.40–3.27(m,1H),1.96–1.02(m),1.00–0.75(m),0.59(s,3H)。
13C NMR(101MHz,MeOD)δ171.86,71.81,69.79,62.89,55.87,50.29,45.57, 42.38,41.78,40.19,39.66,35.41,35.26,33.15,33.05,31.50,29.88,29.39,27.89,23.18,22.39,22.11,20.60,17.51,10.87,10.66。
实施例5
((4R)-4-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)戊酰氨基)甲磺酸的制备
Figure PCTCN2016079167-appb-000034
称取6α-乙基-鹅去氧胆酸(OCA，42mg，0.10mmol)溶于1mL干燥N,N-二甲基甲酰胺，冰水浴冷却下依次加入三乙胺(28μL，0.20mmol)，氯甲酸乙酯(11μL，0.11mmol)，低温下反应30分钟。再加入氨基甲磺酸(12mg，0.11mmol)，加完后，恢复室温反应5小时。反应完全，浓缩，粗产品经柱层析分离，得化合物5(35mg，68％)。
1H NMR(400MHz,MeOD)δ4.42–4.25(m,2H),3.67(brs,1H),3.33(brs,1H),2.48–2.31(m,1H),2.28–2.13(m,1H),2.11–1.70(m),1.68–0.84(m),0.71(s,3H)。
13C NMR(101MHz,MeOD)δ175.42,71.84,69.86,56.00,55.50,50.30,45.57,42.41,41.75,40.19,39.69,35.59,35.45,35.30,33.15,33.07,32.71,31.59,29.93,27.95,23.25,22.51,22.12,20.64,17.68,11.03,10.77。
实施例6
(((4R)-4-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)戊酰氨基)甲基)膦酸的制备
Figure PCTCN2016079167-appb-000035
第一步：
6α-乙基-鹅去氧胆酸(OCA，40mg，0.046mmoL)溶解在二氯甲烷中，依次 加入碳酸二(N-琥珀酰亚胺基)酯(20mg,0.051mmol)和三乙胺(40L,0.14mmol)，室温搅拌4小时，TLC(PE:EA＝1:2)显示原料消失，加入2mL水和10mL二氯甲烷，有机相硫酸钠干燥并旋干得化合物6-ii。
第二步：
将上述产物6-ii溶在DMF/H2O(1mL/1mL)中，加入碳酸钠(12mg,0.11mmol)和氨甲基磷酸，室温搅拌24小时后TLC(PE:EA＝2:1)显示反应完全，用1N HCl调节到酸性，加入10mL的乙酸乙酯，有机相用2mL水洗涤3次后硫酸钠干燥并旋干得化合物6(5.4mg,22％)。
1H NMR(400MHz,MeOD)δ3.55(s,1H),3.48(d,J＝12.5Hz,2H),3.23–3.19(m,1H),0.88(d,J＝6.4Hz,3H),0.85–0.74(m,6H),0.60(s,3H)。
13C NMR(101MHz,MeOD)δ175.22,71.81,69.81,56.01,50.28,45.57,42.36,41.77,40.18,39.67,36.78,35.52,35.39,35.25,33.15,33.04,32.48,31.71,29.87,27.89,23.18,22.36,22.10,20.59,17.52,10.85,10.63。
31P NMR(162MHz,MeOD)δ20.49(s)。
实施例7
(2-((4R)-4-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)戊酰氨基)乙基)膦酸的制备
Figure PCTCN2016079167-appb-000036
第一步：
称取6α-乙基-鹅去氧胆酸(OCA，40mg，0.046mmoL)溶解在二氯甲烷中，依次加入碳酸二(N-琥珀酰亚胺基)酯(20mg,0.051mmol)和三乙胺(40μL,0.14mmol)，室温搅拌4小时，TLC(PE:EA＝1:2)显示原料消失，加入2mL水和10mL二氯甲烷，有机相硫酸钠干燥并旋干得化合物7-ii。
第二步：
将上述产物7-ii溶在DMF/H2O(1mL/1mL)中，加入碳酸钠(12mg,0.11mmol)和氨甲基磷酸，室温搅拌24小时后TLC(PE:EA＝2:1)显示反应完全，用1N HCl调节到酸性，加入10mL的乙酸乙酯，有机相用2mL水洗涤3次后硫酸钠干燥 并旋干得化合物7(1.9mg,7％)。
1H NMR(400MHz,MeOD)δ3.62–3.52(m,1H),3.38–3.27(m,1H),3.24–3.20(m,2H),0.92–0.84(m,3H),0.84–0.76(m,6H),0.60(s,3H)。
13C NMR(101MHz,MeOD)δ175.31,71.81,69.81,60.13,55.96,50.28,45.58,42.36,41.78,40.19,39.66,35.51,35.39,35.25,33.15,33.05,31.79,29.87,29.32,27.90,23.17,22.34,22.10,20.58,17.52,13.05,10.84,10.61。
31P NMR(162MHz,MeOD)δ25.30(s)。
实施例8
(4R)-4-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-N-(2-羟基乙氧基)戊酰胺的制备
Figure PCTCN2016079167-appb-000037
称取6α-乙基-鹅去氧胆酸(OCA，30mg,0.07mmol)和化合物8-ii(6.5mg,0.085mmoL)溶在二氯甲烷中，依次加入TBTU(40mg,0.11mmoL)和DIPEA(30μL,0.21mmoL)，室温下搅拌过夜，TLC检测，原料消失。加水，乙酸乙酯萃取。有机相浓缩，柱层析分离得化合物8(10mg,30％)。
1H NMR(400MHz,MeOD)δ3.95–3.85(m,1H),3.74(dt,J＝16.4,4.7Hz,2H),3.67(s,1H),3.35–3.32(m,1H),1.00(d,J＝6.5Hz,3H),0.95–0.89(m,6H),0.72(s,3H)。
13C NMR(101MHz,MeOD)δ172.75,77.45,71.80,69.78,59.02,55.86,50.29,48.46,45.57,42.37,41.77,40.17,39.65,35.40,35.25,33.15,33.04,31.49,29.87,29.32,27.90,23.17,22.36,22.10,20.59,17.47,10.85,10.64。
实施例9
(3R)-3-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)丁烷-1-磺酸的制备
Figure PCTCN2016079167-appb-000038
第一步：
称取化合物9-i(1.5g,3.58mmol)溶于20mL吡啶，加入15mL乙酸酐，室温搅拌过夜，TLC(PE:EA＝2:1)显示反应完全，减压旋去溶剂并柱层析得化合物9-ii(700mg,42％)。
第二步：
称取化合物9-ii(100mg,0.21mmol)溶于2mL二氯甲烷，滴入一滴DMF，再加入草酰氯(18μL,0.21mmoL)，室温搅拌1小时后TLC(PE:EA＝5:1)显示反应完全。旋干溶剂，然后将粗产品溶在2mL的乙腈中，加入化合物9-iii(38mg,0.25mmol)和DMAP(1mg,0.05％)，置换氮气后回流搅拌2小时，TLC(PE:EA＝5:1)显示反应完全，直接柱层析得化合物9-iv(110mg,90％)。
第三步：
称取化合物9-iv(300mg,0.66mmol)溶在12mL乙醇中，加入12mL亚硫酸钠水溶液(20％)，回流反应24小时。TLC(PE:EA＝10:1)显示反应完全，加20mL水，酸性，用乙酸乙酯提取后硫酸钠干燥并旋干得化合物9-v(200mg,76％)。
第四步：
称取化合物9-v(70mg,0.14mmol)溶在THF/H2O(4mL/0.4mL)中，加入18mg的硼氢化钠后室温搅拌2小时，加水淬灭，乙酸乙酯提取后将有机相旋干，柱层析分离得化合物9-vi(30mg,50％)。
第五步：
称取化合物9-vi(30mg,0.06mmol)溶在THF中，氮气保护下加入氢化铝锂(10mg,0.27mmol)，所得溶液在70℃下搅拌过夜，然后加水淬灭，乙酸乙酯萃取。有机相旋干，柱层析分离，得化合物9(1mg,3％)。
1H NMR(400MHz,CDCl3)δ3.70–3.51(m,3H),3.42–3.27(m,1H),0.91–0.87(m,3H),0.85–0.79(m,6H),0.61(s,3H)。
13C NMR(101MHz,CDCl3)δ72.36 70.93,60.90,56.38,50.58,45.25,42.83,41.23,40.09,39.67,39.02,35.56,34.07,33.29,32.94,30.70,29.69,28.40,23.74, 23.15,22.25,20.77,18.84,11.77,11.65。
实施例10
5-((3R)-3-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)丁基)-1,3,4-噁二唑-2(3H)-酮的制备
Figure PCTCN2016079167-appb-000039
第一步：
称取6α-乙基-鹅去氧胆酸甲酯10-i(96mg，0.22mmol)溶于2.5mL乙醇，再加入水合肼(0.5mL，85％)，加热回流7小时，基本反应完全。冷却后加入饱和水盐水洗涤，乙酸乙酯萃取三次。合并有机相，无水硫酸钠干燥。过滤，滤液浓缩，得化合物10-ii(87mg，91％)。
第二步：
称取上述粗产品(43mg，0.10mmol)溶于2mL干燥四氢呋喃，再加入N,N-羰基二咪唑(19mg，0.12mmol)，室温搅拌过夜。反应完全后加入饱和水盐水洗涤，二氯甲烷萃取三次。合并有机相，无水硫酸钠干燥。过滤，浓缩，粗产品经柱层析分离，得化合物10(20mg，43％)。
1H NMR(400MHz,CDCl3)δ9.64(s,1H),3.65(brs,1H),3.44–3.25(m,1H),2.54(ddd,J＝15.2,10.5,4.5Hz,1H),2.38(ddd,J＝15.7,9.9,6.2Hz,1H),2.12–1.01(m),1.00–0.75(m),0.59(s,3H)。
13C NMR(101MHz,CDCl3)δ158.71,155.39,72.31,71.14,55.62,50.45,45.17,42.78,41.23,39.98,39.60,35.54,35.51,35.30,33.91,33.28,31.38,30.58,28.22,23.67,23.39,23.14,22.23,20.75,18.25,11.79,11.65。
实施例11
(3R,5S,6R,7R,10S,13R)-17-((R)-4-(4H-1,2,4-三唑-3-基)丁烷-2-基)-6-乙基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-3,7-二酚的制备
Figure PCTCN2016079167-appb-000040
第一步：
称取6α-乙基-鹅去氧胆酸(OCA，42mg，0.10mmol)溶于1mL干燥N,N-二甲基甲酰胺，冰水浴冷却下依次加入三乙胺(28μL，0.20mmol)，氯甲酸乙 酯(11μL，0.11mmol)，反应30分钟后加入2.0M氨气甲醇溶液(0.10mL，0.20mmol)。恢复至室温，反应2小时。反应完全，浓缩后直接用于下步反应。
第二步：
在上述粗产品中加入N,N-二甲基甲酰胺二甲基缩醛(2mL)，加热回流2小时。反应完全后，冷却至室温，浓缩，所得粗产品溶于2mL醋酸，再加入盐酸肼(21mg，0.20mmol)，加热90℃反应90分钟。冷却至室温，加水淬灭。乙酸乙酯萃取，有机相再用饱和NaHCO3水溶液洗涤，无水硫酸钠干燥。过滤，浓缩，粗产品经柱层析分离，得化合物11(21mg，47％)。
1H NMR(400MHz,MeOD)δ3.67(brs,1H),2.94–2.80(m,1H),2.73–2.66(m,1H),2.09–0.97(m),0.96–0.85(m,6H),0.70(s,3H)。
13C NMR(101MHz,MeOD)δ124.72,71.80,69.79,55.87,50.28,45.57,42.38,41.77,40.18,39.66,35.40,35.25,34.19,33.15,33.05,29.88,29.52,27.92,23.18,22.37,22.10,20.59,17.50,10.83,10.64。
实施例12
3-((3R)-3-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)丁基)-1,2,4-噁二唑-5(4H)-酮的制备
Figure PCTCN2016079167-appb-000041
第一步：
称取6α-乙基-鹅去氧胆酰胺12-i(210mg，0.50mmol)溶于5毫升四氢呋喃，冰水浴冷却下依次加入三乙胺(0.56mL，4.0mmol)和三氟乙酸酐(0.28mL，2.0mmol)。加完后室温反应3小时。反应完全后，加入饱和NaHCO3水溶液淬灭，乙酸乙酯萃取2次。有机相浓缩后溶于5毫升四氢呋喃，再加入5毫升0.5N氢氧化钠水溶液，加热60℃反应3小时。反应完全后乙酸乙酯萃取，有机相用无水Na2SO4干燥，过滤，浓缩，柱层析分离，得氰基化合物12-ii(167mg，83％)。
第二步：
称取化合物12-ii(20mg，0.05mmol)、盐酸羟胺(4mg，0.055mmol)以及NaHCO3(5mg，0.06mmol)，加入2毫升甲醇中，微波120℃反应15小时，反应约一半。补加盐酸羟胺(4mg，0.055mmol)、NaHCO3(5mg，0.06mmol)，继续微波120℃反应12小时，基本反应完全。浓缩，乙酸乙酯萃取，饱和食盐水洗涤，无水Na2SO4干燥。过滤，浓缩，所得粗产品溶于2毫升1,4-二氧六环，加入CDI(12mg，0.075mmol)，加热至回流，反应2小时，原料消失。加入3毫升0.1N氢氧化钠水溶液，加热50℃反应1小时。冷却后加入稀盐酸中和，再 用乙酸乙酯萃取2次。有机相用饱和食盐水洗涤，无水Na2SO4干燥。过滤，浓缩，柱层析分离，得化合物12(15mg，65％)。
1H NMR(400MHz,CDCl3)δ10.53(s,1H),3.63(brs,1H),3.46–3.30(m,1H),2.62–2.48(m,1H),2.47–2.35(m,1H),2.11–0.71(m),0.60(s,3H)。
13C NMR(101MHz,CDCl3)δ161.06,159.69,72.46,70.93,55.64,50.58,45.14,42.83,41.19,40.03,39.65,35.51,35.34,33.83,33.30,31.94,31.44,30.38,30.21,29.69,28.30,23.69,23.12,22.24,22.09,20.75,18.26,11.80,11.66。
实施例13
5-((3R)-3-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)丁基)-1,3,4-噁二唑-2-羧酸的制备
Figure PCTCN2016079167-appb-000042
第一步：
称取6α-乙基-鹅去氧胆酸甲酯10-ii(43mg，0.10mmol)溶于2mL氯仿，再依次加入吡啶(12μL，0.15mmol，1.5eq.)和草酰氯单乙酯(13μL，0.12mmol，1.2eq.)加热80℃反应2小时，基本反应完全。浓缩后加入饱和食盐水洗涤，乙酸乙酯萃取三次。合并有机相，无水硫酸钠干燥。过滤，滤液浓缩，柱层析分离(CH2Cl2/MeOH 30:1)得化合物13-ii(22mg，43％)。
1H NMR(400MHz,CDCl3)δ4.31(q,J＝7.1Hz,2H),3.63(brs,1H),3.40–3.28(m,1H),2.31(ddd,J＝14.9,10.3,4.8Hz,1H),2.16(ddd,J＝14.7,9.6,4.7Hz,1H),1.94–1.00(m),1.00–0.71(m,H),0.58(s,3H)。
13C NMR(101MHz,CDCl3)δ170.45,158.61,152.39,72.34,70.87,63.61,55.75,50.54,45.21,42.77,41.23,40.06,39.66,35.51,35.41,33.90,33.26,31.34,30.88,30.59,30.33,28.23,23.70,23.15,22.25,20.77,18.37,13.97,11.82,11.67。
第二步：
称取13-ii(16mg，0.031mmol)溶于1mL四氢呋喃，再加入1mL氢氧化钠水溶液(0.5N)，加热60℃反应2小时，反应完全后加入稀盐酸酸化，乙酸乙酯萃取。柱层析分离(CH2Cl2/MeOH 5:1)，得化合物13(14mg，93％)。
1H NMR(400MHz,MeOD)δ3.56(brs,1H),2.31–2.17(m,1H),2.17–2.03(m,1H),1.99–0.73(m),0.61(s,3H)。
13C NMR(101MHz,MeOD)δ173.80,160.17,157.52,71.81,69.82,55.97,50.28,45.57,42.38,41.77,40.18,39.67,35.40,35.25,33.15,33.05,31.39,30.36,29.87,27.87,23.18,22.37,22.10,20.59,17.50,10.88,10.64。
实施例14
5-((2R)-2-((3R,5S,6R,7R,10S,13R)-6-乙基-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)丙基)噻唑烷-2,4-二酮的制备
Figure PCTCN2016079167-appb-000043
第一步：
称取6α-乙基-鹅去氧胆酸甲酯1-ii(845mg,1.94mmoL)，溶于10mL干燥四氢呋喃中，干冰-乙醇冷却至-72℃。滴加LDA溶液(4.9mL，9.72mmol，2M)，15分钟加完，继续搅拌15分钟后滴加三甲基氯硅烷(1.0mL，11.7mmol)，维持低温反应4小时。将N-溴代丁二酰亚胺(692mg，3.89mmol)溶于5毫升四氢呋喃，再滴加入反应体系，加完后自然升至室温，反应过夜。TLC显示反应完全，加入10毫升水淬灭，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得粗产品14-ii，直接用于下步反应。
第二步：
化合物14-ii溶于20毫升乙醇，再加入硫脲(443mg,5.82mmol)和乙酸钠(477mg，5.82mmol)，加热回流，反应过夜。冷却后加入2N盐酸(20mL)，继续回流，反应24小时。冷却，减压浓缩，除去乙醇。乙酸乙酯萃取三次。合并有机相，无水硫酸钠干燥，过滤，浓缩，粗产品经柱层析分离，得非对应异构体14-α与14-β的混合物(487mg,52％)。
14-α：1H NMR(400MHz,MeOD)δ4.13(dd,J＝7.4,5.8Hz,1H),3.60(brs,1H),3.31–3.20(m,1H),2.30(ddd,J＝14.3,5.6,3.6Hz,1H),1.96–1.02(m),1.02–0.75(m,12H),0.61(s,3H)。
13C NMR(101MHz,MeOD)δ177.04,172.50,71.95,70.57,56.15,50.36,49.34,45.24,42.90,41.33,40.17,39.91,39.56,35.48,35.44,35.22,33.32,33.14,30.17,28.36,23.53,23.06,22.10,20.71,18.76,11.60,11.46。
14-β：1H NMR(400MHz,CDCl3)δ4.31(dd,J＝11.3,3.3Hz,1H),3.70(brs,1H),3.53–3.37(m,1H),2.02–1.08(m),1.08–0.78(m,12H),0.67(s,3H)。
13C NMR(101MHz,CDCl3)δ176.05,171.36,72.51,71.02,56.25,50.49,50.09,45.10,42.90,41.24,40.20,39.97,39.57,35.54,35.51,35.45,33.60,33.08,30.27,28.39,23.70,23.09,22.21,20.72,17.58,11.81,11.65。
实施例15
5-((2R)-2-((3R,5S,7R,10S,13R)-3,7-二羟基-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)丙基)噻唑烷-2,4-二酮的制备
Figure PCTCN2016079167-appb-000044
第一步：
称取鹅去氧胆酸甲酯15-i(348mg,0.86mmoL)，溶于5mL干燥四氢呋喃中，干冰-乙醇冷却至-72℃。滴加LDA溶液(2.1mL，4.28mmol，2M)，15分钟加完，继续搅拌15分钟后滴加三甲基氯硅烷(0.44mL，5.14mmol)，维持低温反应4小时。将N-溴代丁二酰亚胺(305mg，1.71mmol)溶于5毫升四氢呋喃，再滴加入反应体系，加完后自然升至室温，反应过夜。TLC显示反应完全，加入10毫升水淬灭，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得粗产品15-ii，直接用于下步反应。
第二步：
化合物15-ii溶于10毫升乙醇，再加入硫脲(196mg,2.58mmol)和乙酸钠(222mg，2.58mmol)，加热回流，反应6小时。冷却后加入2N盐酸(10mL)，继续回流，反应过夜。冷却，减压浓缩，除去乙醇。乙酸乙酯萃取三次。合并有机相，无水硫酸钠干燥，过滤，浓缩，粗产品经柱层析分离，得非对映体15-与15-的混合物(220mg,57％)。
15-α：1H NMR(400MHz,CDCl3)δ8.27(s,1H),4.16(dd,J＝7.1,6.1Hz,1H),3.79(d,J＝2.3Hz,1H),3.48–3.35(m,1H),2.32(ddd,J＝14.3,5.8,3.6Hz,1H),2.13(dd,J＝24.6,12.8Hz,1H),1.96–1.02(m),1.02–0.73(m),0.62(s,3H).
13C NMR(101MHz,CDCl3)δ175.14,170.32,72.01,68.54,56.15,50.45,49.20,42.99,41.47,40.25,39.89,39.64,39.41,35.33,35.25,35.05,34.75,32.87,30.67,28.42,23.74,22.75,20.59,18.89,11.76.
15-β：1H NMR(400MHz,CDCl3)δ9.87(s,1H),4.23(dd,J＝11.5,3.8Hz,1H),3.79(brs,1H),3.53–3.28(m,1H),2.32–0.98(m),0.98–0.70(m),0.60(s,3H).
13C NMR(101MHz,CDCl3)δ176.19,171.57,72.12,68.62,56.15,50.33,50.09,42.81,41.42,40.26,39.56,39.31,35.45,35.33,35.06,34.78,32.70,30.37,29.69,28.41,23.67,22.74,20.57,17.58,11.78.
生物学实验例1
FXR受体结合活性测试(时间分辨荧光检测方法TR-FRET法)
为了测试化合物对FXR受体结合的影响，我们选用商业化的FXR受体结合 活性测试试剂盒来测试化合物对FXR与其结合蛋白片段的影响(LBD结构域与SRC1片段结合)(试剂盒供应商life technology Invitrogen Catalog：PV4835；cisbio Catalog：610SAXLA和61GSTKLA)。具体方法见试剂盒说明书。操作如下：
1、准备2x GST标签的FXR-LBD/抗GST的Eu混合液至所需体积，GST-FXR-LBD的浓度为6nM，Eu为50nl/孔。
2、准备2x生物素标记的SRC1/链霉素-别藻蓝素(SA-APC)混合液至所需体积，SRC1浓度为1000nM，链霉素-别藻蓝素为50nl/孔。
3、将2x GST-FXR/Eu和SRC1/SA-APC两种混合液1：1混合。
4、将20μl GST-FXR/Eu和SRC1/SA-APC混合液加到含有待测化合物的384孔板。
5、1000rpm离心1min；室温孵育180min后，
6、时间分辨荧光检测：EnVision读板器读板
7、结果分析：
(1)665nm处数值除以615nm处数值；
(2)计算激动率
激动率＝(X-Min)/(Max-Min)*100％
■X代表每个浓度的665/615值；
■Min代表未加化合物的665/615值；
■Max代表参照化合物的665/615值。
本发明化合物的生化学活性通过以上的试验进行测定，测得的EC50值见下表。
实施例编号 EC50(uM)
1 0.214
2 0.167
3 0.016
4 0.054
5 0.031
6 1.267
7 0.552
8 0.228
9 0.432
10 0.061
11 0.366
12 0.052
13-ii 0.070
13 0.283
14-α 0.013
14-β 0.004
15-α 0.143
15-β 0.312
结论：本发明实施例化合物对FXR活性均有明显地激动作用。
生物学实验例2
FXR报告基因表达测试
为了分析测试化合物对FXR调控的基因表达的影响，我们利用Promega公司的双荧光素酶检测系统(Promega#E1980)在瞬时转染了FXR Gal4报告基因片段的HepG2肝癌细胞株(ATCC#HB-8065)中检测化合物对FXR报告基因的影响。具体实验方法如下：
1.HepG2细胞培养和维护
消化细胞并以10ml完全培养基种植合适密度的细胞，然后37度5％CO2潮湿条件下培养24小时。
2.细胞种植和转染。转染试剂为Fugene HD(Promega#E231A)
(1)根据下表准备转染混合物
pBIND-FXR(ng/孔) 25
pG5Luc(ng/孔) 25
FuGENE HD(μl/孔) 0.15
无血清培养基(μl/孔) 1.85
总混合物(μl/孔) 2.5
(2)剧烈地混匀管内的混合物，室温孵育15分钟；
(3)消化培养皿内的细胞并计数；
(4)稀释细胞混悬液至密度为60万/ml的所需体积(96孔板100μl/孔)；
(5)将所需体积的转染混合物加到细胞混悬液中，然后100μl/孔铺板；
(6)37度5％CO2潮湿条件下孵育24小时。
3.处理化合物
(1)准备10mM的化合物母液，然后用DMSO 3倍连续稀释
(2)加10μl的化合物至90μl完全培养基(10x)
(3)每孔加5μl的化合物溶液(21x)
(4)37度5％CO2潮湿条件下孵育18小时
4.双荧光素酶检测
由Promega公司的双荧光素酶检测系统检测萤火虫荧光素酶和海肾荧光素酶信号(Promega#E1980)。
5.结果分析
(1)检测得到的数值由萤火虫荧光素酶信号(F)除以海肾荧光素酶信号(R)，即F/R。这种数据处理排除了细胞数量和转染效率带来的差异。
(2)计算激动率
激动率＝(X-Min)/(Max-Min)*100％
■X代表每个浓度的F/R值；
■Min代表未加化合物的F/R值；
■Max代表参照化合物的F/R值。
(3)根据GraphPrism 5.0计算EC50
本发明化合物的生化学活性通过以上的试验进行测定，测得的EC50值见下表。
实施例编号 EC50(uM)
1 2.6
2 3.388
3 2.529
4 1.064
8 3.373
10 1.399
11 5.200
12 1.364
13 5.199
14-α 0.063
14-β 0.057
15-β 3.37
结论：本发明实施例化合物对FXR活性均有明显地激动作用。
生物学实验3
(大鼠药代动力学研究试验)
本发明药代动力学研究以大鼠为受试动物，研究阳性参考药物INT-747以及代表性化合物例如实施例14-β在大鼠体内的药代动力学行为，评价其药动学特征。
1.试验方案
(1)每例使用SD大鼠3只，雄性，由西普尔-必凯实验动物有限公司提供，动物生产许可证号SCXK(沪)2008-0016。
(2)称取样品10毫克，加入0.5％CMC-Na水溶液10毫升，充分震荡均匀，
制成1mg/ml溶液，剩余药液留样用于定量分析。
(3)SD大鼠3只，雄性；禁食一夜后分别灌胃给药，剂量为10mg/kg，给药体积10ml/kg。
(4)于给药前和给药后0.5,1.0,2.0,4.0,6.0,8.0,24.0,30.0h下颌静脉采血～0.05ml，置于EDTA-K2试管中试管中，收集血样均6500rpm离心5min分离血浆，于-80度保存。给药后4h进食。
2.分析方法
(1)仪器设备：API 4000三重四级杆质谱仪，美国Applied Biosystems公司；Shimadzu LC-20AD高效液相色谱系统，日本Shimadzu公司。
(2)色谱条件：色谱柱采用Phenomenex gemiu 5um C18 50X4.6mm；流动相为乙腈：0.1％TFA水溶液(梯度洗脱)；流速(ml/min)为0.8ml/min。
(3)质谱条件：
入口电位 10psi
碰撞池出口电位 12psi
气帘气 15psi
碰撞气 中等
扫描方式 ESI(+),MRM
离子喷雾电压 5500V
温度 550℃
离子源气1 50psi
离子源气2 50psi
3.药物代谢实验结果：
(1)试验结果表明，大鼠灌胃给予10mg/kg阳性参考药物INT-747后，血药浓度达峰时间tmax为0.5h，峰浓度Cmax为4413ng/ml，血药浓度-时间曲线下面积 AUC0-t为9028ng/ml·h。
(2)试验结果表明，大鼠灌胃给予10mg/kg实施例14-β后，血药浓度达峰时间tmax为1h，峰浓度Cmax为7577ng/ml，血药浓度-时间曲线下面积AUC0-t为41796ng/ml·h。
大鼠药代试验表明，本发明实施例14-β化合物在受试动物体内暴露量要大大优于阳性参考药物INT-747。

Claims (26)

  1. 一种具有如下式(I)结构的胆酸衍生物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2016079167-appb-100001
    其中，
    R1、R2、R3选自氢、氟、溴、三氟甲基或C1-8烷基；
    R4选自如下结构：
    Figure PCTCN2016079167-appb-100002
    X1选自氮或CR8；
    X2选自CR8R9、NR10、氧或硫；
    Y1、Y2各自独立的选自CR8R9、NR10、氧或硫；
    Z选自CR8R9、NR10、氧或硫；
    R5选自氢、羟基、氰基、氨基、C1-8烷氧基或SO2R11；
    R6选自SO2R11、SO3R11、C(O)OR11、C(O)R12或C0-4-P(O)R13R14；
    R7选自羟基、羟基取代C1-8烷基或卤取代C1-8烷基；
    R8、R9各自独立的选自氢、氘、卤素、羟基、氰基、硝基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、C1-8烷氧基、C3-8环烷氧基、SO2R11、C(O)OR11、C(O)R12或P(O)R13R14，其中烷基、环烷基任选进一步被一个或多个选自卤素、羟基、C1-8烷基、C1-8烷氧基、卤取代C1-8烷氧基、C3-8环烷基或C3-8环烷氧基的取代基所取代；
    R10选自氢、C1-8烷基、C3-8环烷基、卤取代C1-8烷基或C1-8烷氧基；
    R11选自氢、C1-8烷基、C3-8环烷基、卤取代C1-8烷基、苯基或对甲基苯基；
    R12、R13、R14各自独立的选自羟基、C1-8烷基、C3-8环烷基、卤取代C1-8烷基、C1-8烷氧基、氨基或C1-8烷基双取代氨基；
    n选自0或1。
  2. 根据权利要求1所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，C1-8烷基优选C1-6烷基，更优选C1-3烷基；C1-8烷氧基优选C1-6烷氧基，更优选C1-3烷氧基；C3-8环烷基优选C3-6环烷基；C3-8环烷氧基优选C3-6环烷氧基；C2-8链烯基优选C2-4链烯基；C2-8链炔基优选C2-4链炔基。
  3. 根据权利要求1所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，R3选自H、甲基、乙基或异丙基；R1、R2、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如权利要求1所定义。
  4. 根据权利要求1所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，R3选自H或甲基；R1、R2、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如权利要求1所定义。
  5. 根据权利要求1所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅱ)结构化合物：
    Figure PCTCN2016079167-appb-100003
  6. 根据权利要求1所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，R1选自H；R3选自H或甲基；R2、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如权利要求1所定义。
  7. 根据权利要求1所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅲ)结构化合物：
    Figure PCTCN2016079167-appb-100004
  8. 根据权利要求1所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅳ)结构化合物：
    Figure PCTCN2016079167-appb-100005
    其中，R4选自如下结构：
    Figure PCTCN2016079167-appb-100006
    R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z、n如权利要求1所定义。
  9. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，
    当R4选自如下结构：
    Figure PCTCN2016079167-appb-100007
    时，n为1；
    当R4选自如下结构：
    Figure PCTCN2016079167-appb-100008
    时，n为0；
    R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z 如权利要求1所定义。
  10. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2016079167-appb-100009
  11. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2016079167-appb-100010
  12. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2016079167-appb-100011
  13. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅴ)结构化合物：
    Figure PCTCN2016079167-appb-100012
    其中，X1、X2、R2、R8、R9、R10、R11、R12、R13、R14如权利要求1所定义。
  14. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2016079167-appb-100013
  15. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅵ)结构化合物：
    Figure PCTCN2016079167-appb-100014
    其中，Y1、Y2、R2、R8、R9、R10、R11、R12、R13、R14如权利要求1所定义。
  16. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2016079167-appb-100015
  17. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅶ)结构化合物：
    Figure PCTCN2016079167-appb-100016
    其中，R2、R8、R9、R10、R11、R12、R13、R14、Z如权利要求1所定义。
  18. 根据权利要求8所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2016079167-appb-100017
  19. 式(Ⅷ)结构的胆酸衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：
    Figure PCTCN2016079167-appb-100018
    Z氧或硫；
    R2选自氢、氟、溴、三氟甲基或C1-8烷基。
  20. 根据权利要求19所述的胆酸衍生物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物
    Figure PCTCN2016079167-appb-100019
  21. 根据权利要求1-20任一项所述的胆酸衍生物、其立体异构体或其药学上可接受盐的制备方法，包括如下步骤：
    Figure PCTCN2016079167-appb-100020
    Figure PCTCN2016079167-appb-100021
    Figure PCTCN2016079167-appb-100022
    其中，R2、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、X1、X2、Y1、Y2、Z如权利要求1所定义；Pg1为羟基保护基，优选自C1-4烷基或苄基，Pg2为羟基保护基，优选自C1-4烷基或乙酰基。
  22. 药物组合物，其包括治疗有效剂量的权利要求1-20任一项所述的胆酸衍生物、其立体异构体或其药学上可接受盐及可药用的载体。
  23. 根据权利要求1-20任一项所述的胆酸衍生物、其立体异构体或其药学上可接受盐，或权利要求22所述的药物组合物在制备用于预防或治疗FXR介导的疾病或状况的药物中的应用。
  24. 根据权利要求23所述的应用，其特征在于，FXR介导的疾病或状况选自心血管疾病、高胆甾醇血症、高血脂慢性肝炎疾病、慢性肝病、胃肠疾病、肾病、脑血管疾病、代谢疾病或癌症。
  25. 根据权利要求24所述的应用，其特征在于，慢性肝病选自原发性硬化(PBC)、脑脏性黄瘤症(CTX)、原发性硬化性胆囊炎(PSC)、药物导致的胆汁郁积、妊娠肝内胆汁淤积症、肠外吸收相关胆汁郁积(PNAC)、细菌过度生长或脓血症胆汁郁积、自身免疫肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝移植相关移植物抗宿主病、活供体肝移植再生、先天性肝纤维化、胆总管结石、肉芽性肝病、肝内或外恶性肿瘤、Sjogren综合征、结节病、Wilson's疾病、Gaucher's疾病、血色病或α1一抗膜蛋白酶缺乏症；胃肠疾病选自炎症性肠病(I BD)、肠易激综合征(IBS)、细菌过度生长、营养吸收不良、反射后结肠炎或微小性结肠炎，炎症性肠病优选克罗恩疾病(Crohn’s Disease)或溃病性肠病；肾病选自糖尿病肾病、局灶节段性肾小球硬化症(FSGS)、高血压肾病、慢性肾小球炎、慢性移植性肾小球病、慢性间质性肾炎或多囊肾病；心血管疾病选自动脉硬化症、动脉硬化、动脉粥样硬化、血脂障碍、高胆固醇血症或高甘油三酯血症；代谢疾病选自胰岛素抗性、I型糖尿病、II型糖尿病或肥胖；脑血管疾病选自中风；癌症选自结直肠癌或肝癌。
  26. 一种预防或治疗FXR介导的疾病或状况的方法，包括施用治疗有效量的权利要求1-20任一项所述的胆酸衍生物、其立体异构体或其药学上可接受盐，或权利要求22所述的药物组合物。
PCT/CN2016/079167 2015-04-28 2016-04-13 胆酸衍生物及其制备方法和医药用途 Ceased WO2016173397A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP16785828.1A EP3290429A1 (en) 2015-04-28 2016-04-13 Cholic acid derivative, and preparation method and medical use thereof
CN201680012567.8A CN107250150B (zh) 2015-04-28 2016-04-13 胆酸衍生物及其制备方法和医药用途
US15/569,918 US20180148470A1 (en) 2015-04-28 2016-04-13 Cholic acid derivative, and preparation method and medical use thereof
CN201910026222.3A CN111116699B (zh) 2015-04-28 2016-04-13 胆酸衍生物及其制备方法和医药用途
JP2017552445A JP2018519246A (ja) 2015-04-28 2016-04-13 コール酸誘導体、及びその製造方法及び医薬用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510204748 2015-04-28
CN201510204748.8 2015-04-28

Publications (1)

Publication Number Publication Date
WO2016173397A1 true WO2016173397A1 (zh) 2016-11-03

Family

ID=57198149

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/079167 Ceased WO2016173397A1 (zh) 2015-04-28 2016-04-13 胆酸衍生物及其制备方法和医药用途

Country Status (6)

Country Link
US (1) US20180148470A1 (zh)
EP (1) EP3290429A1 (zh)
JP (1) JP2018519246A (zh)
CN (2) CN111116699B (zh)
TW (1) TW201638067A (zh)
WO (1) WO2016173397A1 (zh)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017129125A1 (zh) * 2016-01-28 2017-08-03 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂
WO2018054300A1 (zh) * 2016-09-20 2018-03-29 江苏豪森药业集团有限公司 胆酸衍生物游离碱，晶型及其制备方法和应用
JP2018518537A (ja) * 2015-06-19 2018-07-12 インターセプト ファーマシューティカルズ， インコーポレイテッド Ｔｇｒ５修飾物質およびその使用方法
CN109134572A (zh) * 2017-06-19 2019-01-04 中国科学院上海药物研究所 胆酸衍生物及其制备方法和用途
EP3431486A1 (en) * 2017-07-18 2019-01-23 Bionice, S.L.U. Process and intermediates for the synthesis of obeticholic acid and derivatives thereof
WO2020025942A1 (en) 2018-07-30 2020-02-06 NZP UK Limited Fluorinated bile acid derivatives
CN111440223A (zh) * 2020-04-09 2020-07-24 江苏海悦康医药科技有限公司 奥贝胆酸杂质的制备方法
WO2021009332A1 (en) 2019-07-18 2021-01-21 Enyo Pharma Method for decreasing adverse-effects of interferon
EP3660031A4 (en) * 2017-07-26 2021-03-31 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. CRYSTALLINE OR AMORPHIC FORM OF STEROID DERIVATIVE FXR AGONIST, METHOD OF MANUFACTURING THEREOF AND USE THEREOF
WO2021083336A1 (zh) * 2019-11-01 2021-05-06 北京大学 胆汁酸及其衍生物在制备gpr39激动剂中的用途
WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
EA038580B1 (ru) * 2016-05-18 2021-09-17 Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. Агонист fxr, представляющий собой производное стероидов
WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
WO2022229302A1 (en) 2021-04-28 2022-11-03 Enyo Pharma Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment
CN116178473A (zh) * 2018-12-10 2023-05-30 江西青峰药业有限公司 一种奥贝胆酸的制备方法
RU2800751C2 (ru) * 2017-07-26 2023-07-27 Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. Кристаллическая или аморфная форма агонистов fxr, представляющих собой производные стероидов, способ их получения и их применение

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112017009657A2 (pt) 2014-11-06 2018-01-23 Enanta Pharmaceuticals, Inc análogos de ácidos biliares como agonistas de fxr/tgr5 e métodos de uso dos mesmos
US10208081B2 (en) 2014-11-26 2019-02-19 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
RU2017121457A (ru) 2014-11-26 2018-12-26 Энанта Фармасьютикалс, Инк. Аналоги желчной кислоты в качестве агонистов fxr/tgr5 и способы их применения
WO2016086115A1 (en) 2014-11-26 2016-06-02 Enanta Pharmaceuticals, Inc. Tetrazole derivatives of bile acids as fxr/tgr5 agonists and methods of use thereof
AU2016219266A1 (en) 2015-02-11 2017-08-10 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
RU2712099C2 (ru) 2015-03-31 2020-01-24 Энанта Фармасьютикалс, Инк. Производные желчных кислот в качестве агонистов fxr/tgr5 и способы их применения
DK3310801T3 (da) 2015-06-19 2021-06-21 Intercept Pharmaceuticals Inc Tgr5-modulatorer og fremgangsmåder til anvendelse deraf
US10323060B2 (en) * 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Benzoic acid derivatives of bile acid as FXR/TGR5 agonists and methods of use thereof
WO2017147174A1 (en) 2016-02-23 2017-08-31 Enanta Pharmaceuticals, Inc. Heteroaryl containing bile acid analogs as fxr/tgr5 agonists and methods of use thereof
AU2017368069B2 (en) 2016-11-29 2021-07-08 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonylurea bile acid derivatives
US10472386B2 (en) 2017-02-14 2019-11-12 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR agonists and methods of use thereof
MX388300B (es) 2017-04-07 2025-03-19 Enanta Pharm Inc Proceso para la preparación de derivados de ácidos biliares de sulfonil carbamato
EP3844156A4 (en) * 2018-08-30 2022-06-08 Terns Pharmaceuticals, Inc. TREATMENT OF LIVER DISEASES
CN112409435B (zh) * 2019-08-23 2023-07-18 深圳云合医药科技合伙企业(有限合伙) 胆汁酸衍生物及其组合物和应用
CN114276402B (zh) * 2022-01-05 2023-11-14 厦门大学 一种甾体衍生物及其在制备抗肿瘤药物中的应用
CN114524857B (zh) * 2022-02-22 2023-06-30 中国科学院微生物研究所 胆酸衍生物及其应用
CN116554252A (zh) * 2023-04-07 2023-08-08 华南理工大学 一种高结晶度别胆酸及其在制备预防和治疗胆汁淤积性肝病药物中的应用
TW202508555A (zh) * 2023-07-27 2025-03-01 大陸商珂闌(上海)醫藥科技有限公司 甾類化合物、其製備方法和應用
CN119371475B (zh) * 2023-07-27 2025-11-04 珂阑(上海)医药科技有限公司 甾类化合物、其制备方法和应用
WO2025020190A1 (zh) * 2023-07-27 2025-01-30 珂阑(上海)医药科技有限公司 甾类化合物、其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466815A (en) * 1993-05-08 1995-11-14 Hoechst Aktiengesellschaft Tetrazole derivatives of bile acids, and their use as lipid level lowering medicaments
US20140206657A1 (en) * 2013-01-18 2014-07-24 City Of Hope Bile acid analog tgr5 agonists
WO2015017813A2 (en) * 2013-08-01 2015-02-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibitors of the farnesoid x receptor and uses in medicine
CN104672290A (zh) * 2015-01-05 2015-06-03 北京普禄德医药科技有限公司 一种用于预防或治疗fxr-介导的疾病的药物及其制备方法和用途

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5646316A (en) * 1994-04-08 1997-07-08 Osteoarthritis Sciences, Inc. Bile acid inhibitors of metalloproteinase enzymes
WO2005089316A2 (en) * 2004-03-12 2005-09-29 Intercept Pharmaceuticals, Inc. Treatment of fibrosis using fxr ligands
HUE039171T2 (hu) * 2008-11-19 2018-12-28 Intercept Pharmaceuticals Inc TGR5 modulátorok és azok alkalmazási eljárása
WO2013037482A1 (en) * 2011-09-15 2013-03-21 Phenex Pharmaceuticals Ag Farnesoid x receptor agonists for cancer treatment and prevention
BR112017009657A2 (pt) * 2014-11-06 2018-01-23 Enanta Pharmaceuticals, Inc análogos de ácidos biliares como agonistas de fxr/tgr5 e métodos de uso dos mesmos
RU2017121457A (ru) * 2014-11-26 2018-12-26 Энанта Фармасьютикалс, Инк. Аналоги желчной кислоты в качестве агонистов fxr/tgr5 и способы их применения
TW201704251A (zh) * 2015-04-29 2017-02-01 正大天晴藥業集團股份有限公司 鵝去氧膽酸衍生物
TW201700447A (zh) * 2015-06-19 2017-01-01 英特賽普醫藥品公司 Tgr5調控劑及其用法
CN109021054B (zh) * 2017-06-09 2021-04-09 博瑞生物医药（苏州）股份有限公司 一种fxr激动剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466815A (en) * 1993-05-08 1995-11-14 Hoechst Aktiengesellschaft Tetrazole derivatives of bile acids, and their use as lipid level lowering medicaments
US20140206657A1 (en) * 2013-01-18 2014-07-24 City Of Hope Bile acid analog tgr5 agonists
WO2015017813A2 (en) * 2013-08-01 2015-02-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibitors of the farnesoid x receptor and uses in medicine
CN104672290A (zh) * 2015-01-05 2015-06-03 北京普禄德医药科技有限公司 一种用于预防或治疗fxr-介导的疾病的药物及其制备方法和用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D'AMORE, C. ET AL.: "Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, no. 3, 4 January 2014 (2014-01-04), pages 937 - 954, XP055165457 *
HONORIO, K.M. ET AL.: "Hologram QSAR studies on farnesoid X receptor activators", LETTERS IN DRUG DESIGN & DISCOVERY, vol. 3, no. 4, 31 December 2006 (2006-12-31), pages 261 - 267, XP008082458, DOI: doi:10.2174/157018006776743206 *
NGUYEN, T.T.H. ET AL.: "Synthesis of 24-(piperidin-1-yl, morpholin-4-yl and 4-methylpiperazin-1-yl)-5beta-cholan-3alpha-ols and four hydroxylated 23-(4,5-dihydroimidazol-2-yl)-24-nof--5beta-cholanes", COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, vol. 62, no. 3, 31 December 1997 (1997-12-31), pages 471 - 478, XP055326306 *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018518537A (ja) * 2015-06-19 2018-07-12 インターセプト ファーマシューティカルズ， インコーポレイテッド Ｔｇｒ５修飾物質およびその使用方法
US10875888B2 (en) 2016-01-28 2020-12-29 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Steroid derivative FXR agonist
CN109071593A (zh) * 2016-01-28 2018-12-21 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂
US11667667B2 (en) 2016-01-28 2023-06-06 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Steroid derivative FXR agonist
WO2017129125A1 (zh) * 2016-01-28 2017-08-03 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂
EP3409684A4 (en) * 2016-01-28 2019-10-09 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. STEROID DERIVATIVE-FXR AGONIST
EA038580B1 (ru) * 2016-05-18 2021-09-17 Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. Агонист fxr, представляющий собой производное стероидов
WO2018054300A1 (zh) * 2016-09-20 2018-03-29 江苏豪森药业集团有限公司 胆酸衍生物游离碱，晶型及其制备方法和应用
CN109134572A (zh) * 2017-06-19 2019-01-04 中国科学院上海药物研究所 胆酸衍生物及其制备方法和用途
JP2020527148A (ja) * 2017-07-18 2020-09-03 バイオニス、ソシエダッド、リミターダ、ウニペルソナルＢｉｏｎｉｃｅ，Ｓ．Ｌ．Ｕ オベチコール酸およびその誘導体の合成法、並びにその中間体
WO2019015914A1 (en) * 2017-07-18 2019-01-24 Bionice, S.L.U. METHODS AND INTERMEDIATES FOR THE SYNTHESIS OF OBETICHOLIC ACID AND DERIVATIVES THEREOF
EP3431486A1 (en) * 2017-07-18 2019-01-23 Bionice, S.L.U. Process and intermediates for the synthesis of obeticholic acid and derivatives thereof
JP7286615B2 (ja) 2017-07-18 2023-06-05 クリスタル ファルマ、エセ、ア、ウ オベチコール酸およびその誘導体の合成法、並びにその中間体
US11104702B2 (en) 2017-07-18 2021-08-31 Crystal Pharma, S.A.U. Process and intermediates for the synthesis of obeticholic acid and derivatives thereof
RU2800751C2 (ru) * 2017-07-26 2023-07-27 Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. Кристаллическая или аморфная форма агонистов fxr, представляющих собой производные стероидов, способ их получения и их применение
EP3660031A4 (en) * 2017-07-26 2021-03-31 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. CRYSTALLINE OR AMORPHIC FORM OF STEROID DERIVATIVE FXR AGONIST, METHOD OF MANUFACTURING THEREOF AND USE THEREOF
WO2020025942A1 (en) 2018-07-30 2020-02-06 NZP UK Limited Fluorinated bile acid derivatives
CN116178473A (zh) * 2018-12-10 2023-05-30 江西青峰药业有限公司 一种奥贝胆酸的制备方法
WO2021009332A1 (en) 2019-07-18 2021-01-21 Enyo Pharma Method for decreasing adverse-effects of interferon
US20230091702A1 (en) * 2019-11-01 2023-03-23 Peking University Use of bile acids and derivatives thereof in preparation of gpr39 agonist
WO2021083336A1 (zh) * 2019-11-01 2021-05-06 北京大学 胆汁酸及其衍生物在制备gpr39激动剂中的用途
US12569502B2 (en) * 2019-11-01 2026-03-10 Peking University Use of bile acids and derivatives thereof in preparation of GPR39 agonist
WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
CN111440223A (zh) * 2020-04-09 2020-07-24 江苏海悦康医药科技有限公司 奥贝胆酸杂质的制备方法
WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
WO2022229302A1 (en) 2021-04-28 2022-11-03 Enyo Pharma Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment

Also Published As

Publication number Publication date
CN111116699A (zh) 2020-05-08
CN107250150A (zh) 2017-10-13
EP3290429A1 (en) 2018-03-07
CN111116699B (zh) 2023-02-28
JP2018519246A (ja) 2018-07-19
CN107250150B (zh) 2019-11-22
TW201638067A (zh) 2016-11-01
US20180148470A1 (en) 2018-05-31

Similar Documents

Publication Publication Date Title
CN111116699B (zh) 胆酸衍生物及其制备方法和医药用途
AU2018311198B2 (en) Selective inhibitors of NLRP3 inflammasome
CN111138448B (zh) 抑制rip1激酶的杂环酰胺及其用途
CN107771180B (zh) Tgr5调节剂及其使用方法
CN103958480B (zh) 咪唑啉类衍生物、其制备方法及其在医药上的应用
CN106518946A (zh) 磺酰脲衍生物、其药物组合物及应用
EP4208465A1 (en) Medium- or macro-cyclic benzyl-substituted heterocycle derivatives and their uses as orexin-2 receptor agonists
CN107106575A (zh) 作为fxr/tgr5激动剂的胆汁酸衍生物及其使用方法
CN104844678B (zh) 具有神经保护和增强记忆活性的受体调节剂
CN106103432B (zh) 被取代的噻唑或噁唑p2x7受体拮抗剂
WO2018133730A1 (zh) 一种杂环化合物及其制备方法和用途
WO2016173493A1 (en) Sulfonylaminocarbonyl derivative, pharmaceutical composition and uses thereof
CN114656514A (zh) 一种甾族类衍生物调节剂及其制备方法和应用
CN107231795A (zh) 作为fxr/tgr5激动剂的胆汁酸类似物及其使用方法
WO2020088194A1 (zh) 抑制rip1激酶的杂环酰胺及其用途
EP1758854A1 (en) Pyrrolidin-3-yl compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease
JP4648303B2 (ja) 選択的非ステロイド系糖質コルチコイド受容体調節剤
WO2015135449A1 (zh) 五环三萜类化合物及其制备方法、药物组合物和用途
JP2025121901A (ja) ファルネソイドｘ受容体アゴニストの結晶質形態
EP3983387A1 (en) Sulfonylurea derivatives and uses thereof
WO2020157069A1 (en) Amino heterocyclic compounds and uses thereof
US20210171527A1 (en) Compounds as modulators of ror gamma
WO2021047406A1 (zh) 一种三并环类化合物，包含其的药物组合物，其制备方法及其用途
CN120641402A (zh) 杂环化合物和其用途
WO2024012532A1 (zh) 一种gpr139受体激动剂及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16785828

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017552445

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 15569918

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE