WO2022225035A1 - Dérivé d'acide biliaire ayant un effet antiviral sur le virus de l'hépatite b - Google Patents

Dérivé d'acide biliaire ayant un effet antiviral sur le virus de l'hépatite b Download PDF

Info

Publication number
WO2022225035A1
WO2022225035A1 PCT/JP2022/018510 JP2022018510W WO2022225035A1 WO 2022225035 A1 WO2022225035 A1 WO 2022225035A1 JP 2022018510 W JP2022018510 W JP 2022018510W WO 2022225035 A1 WO2022225035 A1 WO 2022225035A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
sul
udc
oso
hbv
Prior art date
Application number
PCT/JP2022/018510
Other languages
English (en)
Japanese (ja)
Inventor
清顕 伊藤
彰規 奥村
政志 米田
瑞穂 宇根
裕介 井口
ユキコ 山下
Original Assignee
学校法人愛知医科大学
学校法人常翔学園
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 学校法人愛知医科大学, 学校法人常翔学園 filed Critical 学校法人愛知医科大学
Priority to JP2023515528A priority Critical patent/JPWO2022225035A1/ja
Publication of WO2022225035A1 publication Critical patent/WO2022225035A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • Hepatitis B is hepatitis caused by hepatitis B virus (HBV) infection. Hepatitis B includes acute hepatitis B and chronic hepatitis B. Acute hepatitis B refers to the condition in which an adult is infected with HBV for the first time and develops the disease. It refers to a condition in which high ALT levels persist for more than a month and liver damage is present.
  • HBV hepatitis B virus
  • HBV-infected people There are 2 billion HBV-infected people in the world, of which 257 million are persistently infected.
  • the infected person When infected with HBV during childbirth or infancy, when the immune function is immature, the infected person does not show symptoms of hepatitis, and HBV continues to proliferate in hepatocytes for a long period of time. About 90% of them undergo seroconversion from HBe antigen-positive to HBe antibody-positive, become inactive carriers, and progress to persistent infection. However, in the remaining 10%, viral activity persists and progresses to chronic hepatitis B. As chronic hepatitis B progresses, hepatocytes are destroyed and replaced by fibrous tissue during regeneration, resulting in stiffening of the liver and cirrhosis. Thus, about 2% of chronic hepatitis B patients per year progress to liver cirrhosis, and there are cases where the disease progresses further to develop liver cancer.
  • HBV consists of an approximately 3.2 kb circular, partially double-stranded DNA surrounded by an envelope with a diameter of approximately 42 nm. There are at least 10 genotypes from A to J.
  • the double-stranded DNA contains ORFs encoding HBs antigen proteins (pre-S1, pre-S2 and S), HBc antigen proteins (including pre-C), DNA polymerase, and X protein.
  • HBV is classified into at least four subtypes (adr, adw, ayr, ayw) according to amino acid mutations (d/y, r/w) of the S protein, which is a surface antigen (HBs antigen).
  • SLC10A1 (NTCP; sodium taurocholate co-transport polypeptide) was reported to be a functional receptor for both HBV and HDV (hepatitis D virus), suggesting that bile acids inhibit HBV and HDV infection. It has been reported that it can be inhibited (Elife 1: e00049 (2012); J Virol 87: 7977-7991 (2014); J Virol 88: 3273-3284 (2014); JP 2017-530194).
  • a novel bile acid derivative compound and a pharmaceutical composition for preventing infection with hepatitis B virus (HBV) or treating or preventing hepatitis, cirrhosis, or liver cancer caused by HBV infection are provided.
  • HBV hepatitis B virus
  • bile acid derivatives inhibit the binding of NTCP to the pre-S1 region on the envelope protein of HBV, thereby inhibiting the entry of HBV into hepatocytes. I found it in The present invention includes the following embodiments.
  • compositions for treating or preventing cancer comprising as an active ingredient a bile acid derivative represented by the following formula I or a pharmacologically acceptable salt thereof
  • a bile acid derivative represented by the following formula I or a pharmacologically acceptable salt thereof
  • R 2 is H or an ⁇ -CH 3 group.
  • R 3 is an ⁇ -OH group or a ⁇ -OH group.
  • R 5 is a —[CH(CH 3 )] m —(CH 2 ) q —OSO 3 H group, —(CH 2 ) q —SO 3 H group, —(CH 2 ) q —OH group, —[CH (OH)] p —(CH 2 ) q —COOH group, —CONH—(CH 2 ) q —C 6 H 4 —COOH, and —CONH—CH(CH 2 OH)—COOH group; is a group that m, p are independently 0 or 1, and q is independently selected from 0, 1, 2, 3, 4, and 5; The pharmaceutical composition according to any one of [1] to [3].
  • the bile acid derivative is CDC-sul:
  • a remedy for hepatitis comprising the pharmaceutical composition according to any one of [1] to [5].
  • a drug for treating liver cirrhosis comprising the pharmaceutical composition according to any one of [1] to [5].
  • a drug for treating liver cancer comprising the pharmaceutical composition according to any one of [1] to [5].
  • FIG. 3 shows the results of pre-S1 binding assay in screening bile acid derivatives in one example of the present invention.
  • FIG. 1 shows the results of HBV infection inhibition test (1) using human primary hepatocytes in one example of the present invention. This figure shows the results when the medium was replaced with a liquid medium containing neither the test compound nor the pre-S1 peptide when the liquid medium was replaced on days 1, 2, 7, and 12 after infection. ing.
  • FIG. 1 shows the results of HBV infection inhibition test (1) using human primary hepatocytes in one example of the present invention. This figure shows the results when the medium was replaced with a liquid medium containing the test compound at the time of liquid medium replacement on days 1, 2, 7 and 12 after infection.
  • FIG. 1 shows the results of HBV infection inhibition test (1) using human primary hepatocytes in one example of the present invention. This figure shows the results when the medium was replaced with a liquid medium containing the test compound at the time of liquid medium replacement on days 1, 2, 7 and 12 after infection.
  • FIG. 1 shows the results of HBV infection inhibition test (1) using human primary hepatocytes in one example of the present invention. This figure shows the results when the medium was replaced with a liquid medium containing pre-S1 peptide at the time of liquid medium replacement on days 1, 2, 7 and 12 after infection.
  • FIG. 2 shows the results of HBV infection inhibition test (2) using PXB cells (primary human hepatocytes) in one example of the present invention. HomoUDC-sul has been shown to inhibit HBV infection.
  • Fig. 2 shows the results of HBV infection inhibition test (2) using PXB cells (primary human hepatocytes) in an example of the present invention, showing inhibition of HBV infection by UDC-O-sul.
  • FIG. 2 shows the results of HBV infection inhibition test (2) using PXB cells (primary human hepatocytes) in one example of the present invention. Inhibition of HBV infection by BishomoUDC-sul is shown.
  • FIG. 2 shows the results of a pre-S1 binding assay showing that the bile acid derivative of one example of the present invention acts directly on viral pre-S1.
  • FIG. 2 shows the results of a hepatoprotective effect test of a bile acid derivative against hepatocellular damage induced by taurochenodeoxycholic acid (TCDCA) using human primary hepatocytes in one example of the present invention. Lactose dehydrogenase (LDH) activity in cultures of human primary hepatocytes dosed with each test compound is shown.
  • TCDCA taurochenodeoxycholic acid
  • One embodiment of the present invention is a pharmaceutical composition for preventing hepatitis B virus (HBV) infection or treating hepatitis, cirrhosis, or liver cancer caused by HBV infection, containing a bile acid derivative as an active ingredient. It is a thing.
  • a bile acid derivative or a pharmaceutically acceptable salt thereof has a medical effect because the bile acid derivative binds to HBV, thereby inhibiting the entry of HBV from NTCP into cells, and as a result, causing HBV to enter the liver. This is thought to be for the purpose of inhibiting cell infection.
  • the bile acid derivative compound is preferably represented by Formula I below, more preferably represented by Formula II below, even more preferably represented by Formula III below, and further preferably represented by Formula IV below. is more preferred. These compounds are preferable to conventionally known compounds in that they have the effect of protecting cells from cytotoxicity.
  • R 2 is —H, ⁇ -OH group, ⁇ -OH group, ⁇ -CH 3 group
  • R 3 is —H, an ⁇ -OH group, a ⁇ -OH group, or a ⁇ -OSO 3 H group
  • R 4 is a -H or ⁇ -OH group
  • R 5 is —[CH(CH 3 )] m —(CONH) O —[CH(OH)] p —(CH 2 ) q —R 7 — ⁇ CH[(CH 2 ) n OH] ⁇ r —( CH 2 ) s —R 8 groups
  • o is 0 or 1, when o is 0, R7 is a bond; when o is 1, R 7 is a bond, -C 6 H 4 -, -C 6 H 5 -, -CH(COOH)-, or -CH
  • R 1 is an ⁇ -OH group or a ⁇ -OH group
  • R 2 is a —H, ⁇ -CH 3 group
  • R 3 is -H, an ⁇ -OH group or a ⁇ -OH group
  • R 4 is a -H or ⁇ -OH group
  • R 5 is a —(CONH) O —[CH(OH)] p —(CH 2 ) q —R 7 — ⁇ CH[(CH 2 ) n OH] ⁇ r —(CH 2 ) s —R 8 group
  • o is 0 or 1, when o is 0, R7 is a bond; when o is 1, R 7 is -C 6 H 4 - or -CH(COOH)-;
  • p, q, r, s, n are independently selected from 0, 1, 2, and 3
  • R 8 is a —OSO 3 H group, —SO 3 H group, —OH group, or —COOH group
  • R 6 is a
  • R 1 is an ⁇ -OH group
  • R 2 is H or an ⁇ -CH 3 group
  • R 3 is an ⁇ -OH group or a ⁇ -OH group
  • R 4 is H
  • R 5 is a —[CH(CH 3 )] m —(CH 2 ) q —OSO 3 H group or —[CH(CH 3 )] m —(CH 2 ) q —SO 3 H group
  • m is 0 or 1 and q is independently 0, 1, 2, 3, 4 or 5
  • R 6 is ⁇ -H).
  • R 1 is an ⁇ -OH group
  • R 2 is H or an ⁇ -CH 3 group
  • R 3 is an ⁇ -OH group or a ⁇ -OH group
  • R 4 is H
  • R 5 is a —(CH 2 ) q —OSO 3 H group or a —(CH 2 ) q —SO 3 H group
  • q is 0, 1, 2 or 3
  • R 6 is ⁇ -H
  • the bile acid derivative compounds are CDC-sul, UDC-sul, BishomoCDC-sul, BishomoUDC-sul, 25-Me-bishomo-UDC-sul, Trishomo-UDC-sul, and Tetrakishomo-UDC-sul, HomoCDC-sul. , HomoUDC-sul, CDC-O-sul, UDC-O-sul, UDC-OH, UDC-PABA, UDC-ser, GUDCA and iso-UDCA are preferred.
  • the compounds represented by Formula (III) and Formula (IV) are useful not only for the pharmaceutical composition of the present disclosure, but also as compounds having other uses.
  • Pharmaceutically acceptable salts refer to salts of active compounds prepared with acids or bases, depending on the particular substituents present on the compounds described herein.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or a similar salt.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Salts derived from hydrogensulfuric acid, hydroiodic acid, or phosphoric acid, etc., and organic acids such as acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, Salts derived from mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphate,
  • the pharmaceutical composition described above can be used as a preventive agent for HBV infection, a therapeutic agent for hepatitis, a therapeutic agent for liver cirrhosis, and a therapeutic agent for liver cancer.
  • these agents may optionally further contain various commonly used ingredients, such as one or more pharmaceutically acceptable excipients, disintegrants, diluents, Lubricants, flavoring agents, coloring agents, sweetening agents, flavoring agents, suspending agents, wetting agents, emulsifying agents, dispersing agents, adjuvants, preservatives, buffering agents, binders, stabilizers, coating agents, etc. obtain.
  • the administration route can be either systemic administration or local administration, oral route or parenteral route.
  • Parenteral routes include usual intravenous administration, intraarterial administration, as well as subcutaneous, intradermal and intramuscular administration.
  • the dosage form is not particularly limited, and various dosage forms, for example, for oral administration, tablets, capsules, powders, granules, pills, liquids, emulsions, suspensions, solutions, alcoholic beverages, Syrups, extracts, and elixirs can be used, and parenteral agents include injections such as subcutaneous injections, intravenous injections, intramuscular injections, and intraperitoneal injections; formulations, ointments or lotions; sublingual agents, buccal patches for buccal administration; and aerosols for nasal administration; suppositories. These formulations can be produced by known methods commonly used in formulation processes. Additionally, the dosage form may be a sustained or sustained release dosage form.
  • the amount of the active ingredient contained in the drug can be appropriately determined according to the dose range of the active ingredient, the number of doses, etc.
  • the dosage is not particularly limited, and the efficacy of the ingredients contained, the dosage form, the route of administration, the type of disease, the nature of the subject (weight, age, medical condition, use of other medicines, etc.), and the doctor in charge It is appropriately selected according to judgment.
  • suitable doses range, for example, from about 0.01 ⁇ g to 100 mg, preferably from about 0.1 ⁇ g to 1 mg per kg body weight of the subject.
  • these doses can be adjusted using routine experimentation well known in the art.
  • the above doses can be administered once to several times daily or in divided doses every other day.
  • the test method according to one embodiment of the present invention is to determine whether a compound according to the following formula (I) inhibits the binding of pre-S1 peptide to cells in vitro, or whether HBV binds to or infects cells. It is a method to check whether or not it hinders doing.
  • a specific test method can be easily conceived by those skilled in the art from routine experimental methods, and examples thereof include the methods described in Examples.
  • R 2 is —H, ⁇ -OH group, ⁇ -OH group, ⁇ -CH 3 group
  • R 3 is —H, an ⁇ -OH group, a ⁇ -OH group, or a ⁇ -OSO 3 H group
  • R 4 is a -H or ⁇ -OH group
  • R 5 is —[CH(CH 3 )] m —(CONH) O —[CH(OH)] p —(CH 2 ) q —R 7 — ⁇ CH[(CH 2 ) n OH] ⁇ r —( CH 2 ) s —R 8 groups
  • o is 0 or 1, when o is 0, R7 is a bond; when o is 1, R 7 is a bond, -C 6 H 4 -, -C 6 H 5 -, -CH(COOH)-, or -CH
  • HepG2-hNTCP-C4 cells stably expressing human NTCP (Iwamoto M et al. Biochem Biophys Res Commun 2014;443:808-813) were provided by the National Institute of Infectious Diseases.
  • uPA/SCID humanized chimeric mice (PXB mice) with livers composed of more than 90% human hepatocytes were purchased from PhoenixBio Co., Ltd. (Hiroshima, Japan).
  • Human hepatocytes (PXB cells) from PXB mice were purchased from PhoenixBio Co., Ltd. (Hiroshima, Japan) and cultured according to the manufacturer's instructions.
  • ⁇ Detection method> The amount of extracellular HBV DNA and the amount of intracellular cccDNA were quantified using real-time PCR using the LightCycler96 system (Roche Diagnostics, Mannheim, Germany). DNA in the culture supernatant and cell DNA were extracted using QIAamp DNA Blood Mini kit and QIAamp DNA Mini kit (Qiagen, Valencia, CA, USA), respectively. Primer and probe sequences used for quantification are shown below.
  • HBV DNA (Fw): 5'-CTT CAT CCT GCT GCT ATG CCT-3' (SEQ ID NO: 2)
  • HBV DNA (Rev): 5'-AAA GCC CAG GAT GAT GGG AT-3' (SEQ ID NO: 3)
  • HBV DNA (Probe): 5'-FAM-ATG TTG CCC GTT TGT CCT CTA ATT CCA G-TAMRA-3' (SEQ ID NO: 4)
  • HBVcccDNA (Fw): 5'-CGT CTG TGC CTT CTC ATC TGC-3' (SEQ ID NO: 5)
  • HBVcccDNA (Rev): 5'-GCA CAG CTT GGA GGC TTG AA-3' (SEQ ID NO: 6)
  • HBVcccDNA (Probe): 5'-FAM-CTG TAG GCA TAA ATT GGT-MGB-3' (SEQ ID NO: 7)
  • HBs antigen and HBe antigen were quantified using HISCL HBsAg reagent (Sysmex, Kobe, Japan) and HISCL HBeAg reagent (Sysmex), respectively, using an automated chemiluminescent enzyme immunoassay system (HISCL-800; Sysmex). .
  • Cytotoxicity was evaluated by quantifying lactose dehydrogenase (LDH) activity in the culture medium using a cytotoxicity detection kit (LDH) (Sigma-Aldrich, St. Louis, MO, USA).
  • reaction solution was adjusted to pH 3 by adding HCl aqueous solution (2N), extracted with ethyl acetate, and washed with H 2 O and saturated sodium bicarbonate aqueous solution.
  • the resulting organic layer was dehydrated with magnesium sulfate, filtered through a cotton plug, and then ethyl acetate was distilled off under reduced pressure.
  • the resulting residue was purified with a silica gel column and dried under vacuum to obtain compound 7 (485 mg, yield: 64%).
  • Compound 7 (485 mg, 0.864 mmol) was dissolved in acetone (30 ml) followed by sodium iodide (648 mg, 4.32 mmol) and stirred at 40° C. for 15 hours.
  • Trifluoroacetic acid 50 ml was added to the obtained compound 10, trifluoroacetic anhydride (5.41 ml, 38.4 mmol) was added under an argon gas stream, and the mixture was stirred at 0°C for 1 hour. Subsequently, sodium nitrite (636 mg, 9.22 mmol) was added to the reaction solution, and the mixture was stirred at 0°C for 1 hour, warmed to 50°C, and further stirred for 1 hour. Thereafter, the reaction solution was returned to room temperature, and the desired product was precipitated in ice water to obtain compound 11. A 10% KOH solution (50% EtOH aqueous solution) was added to the obtained compound 11, and the mixture was stirred at 80°C for 15 hours.
  • Homo-UDCA (12) (2.56 g, 6.33 mmol) was dissolved in THF (65 ml), and TEA (4.10 ml, 31.5 mmol) and ethyl chloroformate (3.00 ml, 31.5 mmol) were dissolved under an argon gas stream. 5 mmol) was added and stirred at 0° C. for 3 hours. After that, 10% NaBH 4 /H 2 O (5 g/50 ml) was further added and stirred at 0° C. for an hour.
  • pre-S1 binding assay HepG2-hNTCP-C4 cells were treated with 40 nM TAMRA-labeled N-terminal myristoylated peptide corresponding to amino acids 2-48 of the pre-S1 domain (TAMRA-pre- S1-lipopeptide).
  • the N-terminal myristoylated peptide has the following sequence.
  • Myristoyl-GTNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANKVG SEQ ID NO: 1 After incubation for 30 minutes at 37°C, cells were washed and fixed with 4% paraformaldehyde solution.
  • CDC-sul, UDC-sul, LC-sul, BishomoCDC-sul, Cyprinol sulfate, Ssymnol sulfate, 25-Me-bishomo-UDC-sul, Trishomo-UDC-sul, Tetrakishomo-UDC-sul are pre -has the activity of inhibiting the binding of the S1 peptide to cells.
  • HBV infection inhibition test using PXB cells human primary hepatocytes
  • PXB cells human primary hepatocytes
  • the test compound (10 ⁇ M) was pretreated with the respective test compound (10 ⁇ M) for 3 hours and then infected with genotype C HBV at 5 genome equivalents/cell in the presence of 4% polyethylene glycol 8000 and the same test compound (10 ⁇ M). rice field. Twenty hours after infection, the medium was replaced with a liquid medium containing no test compound, and then on the 2nd, 7th and 12th days, the medium was replaced with a liquid medium containing no test compound. Culture supernatants were collected 17 days after infection and the concentrations of HBs antigen, HBe antigen, extracellular HBV DNA and intracellular cccDNA were measured.
  • the same experiment was performed using DMSO alone or Cyclosporin A (4 ⁇ M) instead of the test compound, and the control value was set to 1 for HBs antigen, HBe antigen, extracellular HBV DNA and intracellular cccDNA. It was represented in a graph as a relative value when Furthermore, the test was performed under the same conditions except that the liquid medium was replaced with a liquid medium containing the test compound when the liquid medium was replaced on the 1st, 2nd, 7th and 12th days after infection. Antigen, extracellular HBV DNA and intracellular cccDNA were measured (Fig. 2B).
  • UDC-OH, UDC-PABA, UDC-ser, GUDCA, and iso-UDCA also observed particularly strong suppression of the expression of both HBs antigen and HBe antigen.
  • HomoUDC-sul, UDC-O-sul, BishomoUDC-sul, UDC-OH, UDC-PABA, UDC-ser, GUDCA, and iso-UDCA strongly inhibited HBV cell infection in human primary hepatocytes. do.
  • HBV infection inhibition test using PXB cells human primary hepatocytes
  • PXB cells human primary hepatocytes
  • PXB cells were pretreated with serially diluted HomoUDC-sul, UDC-O-sul, or BishomoUDC-sul for 3 hours and then genotyped at 5 genome equivalents/cell in the presence of 4% polyethylene glycol 8000. infected with HBV of C. On days 1 and 2 after infection, the medium was replaced with a liquid medium containing no test compound and cultured.
  • Binding test to pre-S1 peptide Cultured HepG2-hNTCP-C4 cells were used to prepare the following groups (A) to (C).
  • A Group to which test compound and peptide were added at the same time 40 nM TAMRA-pre-S1-lipopeptide was added to HepG2-hNTCP-C4 cells, and in the presence of 30 ⁇ M test compound, it was incubated at 37° C. for 30 minutes. Then washed.
  • B Group treated with test compound and then added with the peptide 30 ⁇ M test compound and 40 nM TAMRA-pre-S1-lipopeptide were mixed in advance, incubated at 37° C. for 30 minutes, and fractionated.
  • HomoUDC-sul, UDC-O-sul, and BishomoUDC-sul have the activity of inhibiting the binding of HBV to hepatocytes by binding to pre-S1 of HBV.
  • the present invention provides novel bile acid derivative compounds and pharmaceutical compositions for preventing infection with hepatitis B virus (HBV), or treating or preventing hepatitis, cirrhosis, or liver cancer caused by HBV infection. be able to.
  • HBV hepatitis B virus

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Steroid Compounds (AREA)

Abstract

Le but de la présente invention est de fournir un dérivé d'acide biliaire ayant un effet antiviral sur le virus de l'hépatite B. L'invention concerne spécifiquement une composition pharmaceutique destinée à prévenir une infection par le virus de l'hépatite B (VHB) ou à traiter ou à prévenir une hépatite, une cirrhose du foie, ou un cancer du foie résultant d'une infection par le VHB, la composition pharmaceutique contenant, en tant que principe actif, un dérivé d'acide biliaire représenté par la formule I ou un sel pharmacologiquement acceptable de celui-ci. (I)　(Ici, chaque groupe est indépendant, et R1 est un groupe α–OH, un groupe β–OH, un groupe α–OSO3H, ou =O ; R2 est –H, un groupe α–OH, un groupe β–OH, ou un groupe α–CH3 ; R3 est –H, un groupe α–OH, un groupe β–OH, ou un groupe β–OSO3H ; R4 est –H ou un groupe α–OH ; R5 est un groupe –[CH(CH3)]m–(CONH)O–[CH(OH)]p–(CH2)q–R7–{CH[(CH2)nOH]}r–(CH2)s–R8 ; o est 0 ou 1, et si o est 0, R7 est une liaison, et si o est 1, R7 est une liaison, –C6H4–, –C6H5–, –CH(COOH)–, ou –CH(CH2OH)–; m, p, q, r, s, et n sont indépendamment choisis parmi 0, 1, 2, 3, 4, et 5 ; R8 est un groupe –OSO3H, un groupe –SO3H, un groupe –OH, ou un groupe –COOH ; et R6 est α–H ou β–H.)
PCT/JP2022/018510 2021-04-22 2022-04-22 Dérivé d'acide biliaire ayant un effet antiviral sur le virus de l'hépatite b WO2022225035A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2023515528A JPWO2022225035A1 (fr) 2021-04-22 2022-04-22

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021072888 2021-04-22
JP2021-072888 2021-04-22

Publications (1)

Publication Number Publication Date
WO2022225035A1 true WO2022225035A1 (fr) 2022-10-27

Family

ID=83723044

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/018510 WO2022225035A1 (fr) 2021-04-22 2022-04-22 Dérivé d'acide biliaire ayant un effet antiviral sur le virus de l'hépatite b

Country Status (2)

Country Link
JP (1) JPWO2022225035A1 (fr)
WO (1) WO2022225035A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019139126A1 (fr) * 2018-01-11 2019-07-18 国立大学法人東京大学 Inhibiteur de ntcp
WO2020063632A1 (fr) * 2018-09-25 2020-04-02 Yichang Humanwell Pharmaceutical Co., Ltd Régulateur de la signalisation tgr5 en tant qu'agent immunomodulateur
WO2021070883A1 (fr) * 2019-10-07 2021-04-15 国立研究開発法人理化学研究所 Anticorps de liaison au ntcp humain pouvant inhiber l'infection par le virus de l'hépatite b (vhb) d'hépatocytes humains

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019139126A1 (fr) * 2018-01-11 2019-07-18 国立大学法人東京大学 Inhibiteur de ntcp
WO2020063632A1 (fr) * 2018-09-25 2020-04-02 Yichang Humanwell Pharmaceutical Co., Ltd Régulateur de la signalisation tgr5 en tant qu'agent immunomodulateur
WO2021070883A1 (fr) * 2019-10-07 2021-04-15 国立研究開発法人理化学研究所 Anticorps de liaison au ntcp humain pouvant inhiber l'infection par le virus de l'hépatite b (vhb) d'hépatocytes humains

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CLAUDIO D’AMORE, FRANCESCO SAVERIO, DI LEVA, VALENTINA SEPE, BARBARA RENGA, CHIARA DEL GAUDIO, MARIA VALERIA, D ' AURIA, ANG: "Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 57, no. 3, 13 February 2014 (2014-02-13), pages 937 - 954, XP055165457, ISSN: 00222623, DOI: 10.1021/jm401873d *
ISHIZUKA SATOSHI: "Variation of Molecular Species of Bile Acids: Structure, Metabolism, and Physiological Influence", KAGAKU TO SEIBUTSU - CHEMISTRY AND BIOLOGY, GAKKAI SHUPPAN SENTA / JAPAN SCIENTIFIC SOCIETIES PRESS, JP, vol. 52, no. 5, 1 May 2014 (2014-05-01), JP , pages 301 - 306, XP055979040, ISSN: 0453-073X, DOI: 0.1271/kagakutoseibutsu.52.301 *
KIHIRA KENJI, YOSHII MICHIKO, OKAMOTO AKIRA, IKAWA SEIICHIRO, ISHII HISAKO, HOSHITA TAKAHIKO, KKIHIRA -, K, YOSHII M, OKAMOTO A, : "Synthesis of new bile salt analogues, sodium 3a ,7a-di hyd roxy-5p-c holane-24-sulfonate and sodium 3a ,7p-d i hyd roxy-5p-c holane-24-su lfonate", JOURNAL OF LIPID RESEARCH, vol. 31, no. 7, 1 July 1990 (1990-07-01), pages 1323 - 1326, XP055979017, DOI: 10.1016/S0022-2275(20)42642-2 *
MIKAMI, T. et al. 15α-Hydroxylation of a bile acid analogue, sodium 3α,7α-dihydroxy-25,26-bishomo-5β-cholane-26-sulfonate in the hamster. Journal of Lipid Research. 1996, vol. 37, pp. 1189-1197 *
MIKI SHIGEO, ET AL: "Sulfonate analogs of chenodeoxycholic acid: metabolism of sodium 3.alpha.,7.alpha.-dihydroxy-25-homo-5.beta.-cholane-25-sulfonate and sodium 3.alpha.,7.alpha.-dihydroxy-24-nor-5.beta.-cholane-23- sulfonate in the hamster", JOURNAL OF LIPID RESEARCH, AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, INC., US, vol. 33, no. 11, 1 November 1992 (1992-11-01), US , pages 1629 - 1637, XP002520342, ISSN: 0022-2275, DOI: 10.1016/S0022-2275(20)41385-9 *

Also Published As

Publication number Publication date
JPWO2022225035A1 (fr) 2022-10-27

Similar Documents

Publication Publication Date Title
Locarnini et al. The hepatitis B virus and common mutants
JP4040578B2 (ja) Ｃ型肝炎ウイルスに対して活性な大環状ペプチド
JP4060801B2 (ja) Ｎｓ３（ｃ型肝炎）の抑制のための置換キノリンのヒドロキシプロリンエーテルを有するトリペプチド
Bozdayi et al. Complete genome sequence and phylogenetic analysis of hepatitis B virus isolated from Turkish patients with chronic HBV infection
US6642204B2 (en) Hepatitis C inhibitor tri-peptides
US20030224977A1 (en) Macrocyclic peptides active against the hepatitis C virus
CA3017020A1 (fr) Agents antiviraux contre l'hepatite b
US20040002448A1 (en) Macrocyclic peptides active against the hepatitis C virus
US20170022150A1 (en) Hepatitis b antiviral agents
EP2624837A2 (fr) Nouveaux inhibiteurs de la sécrétion d'antigènes du virus de l'hépatite b
US6306899B1 (en) Inhibition and treatment of Hepatitis B virus and Flavivirus by Helioxanthin and its analogs
CN106902347A (zh) 亲环孢素抑制剂的用途
CN106565785A (zh) 一种具有抗hbv/hiv活性的核苷氨基磷酸酯类化合物及其盐和用途
CA2475446A1 (fr) Variants viraux presentant une sensibilite modifiee par rapport aux analogues nucleosidiques et leurs applications
WO2022225035A1 (fr) Dérivé d'acide biliaire ayant un effet antiviral sur le virus de l'hépatite b
CN106902346A (zh) 药物组合物及其制药用途
JPH09502453A (ja) オキサチオランと、その製造方法と、それを含む医薬組成物
AU2006230802A1 (en) Variants of hepatitis B virus with resistance to anti-viral nucleoside agents and applications thereof
AU2019382521B2 (en) Crystal form of hepatitis B surface antigen inhibitor
CN105461773B (zh) 索非布韦的制备方法及其中间体
WO2021188414A1 (fr) Composés hétérocycliques fonctionnalisés utiles en tant qu'agents antiviraux
WO2024114709A1 (fr) Forme cristalline d'un composé dérivé d'hétérocycle fusionné
Lee et al. Recent Research and Knowledge on Treatment for Hepatitis B
WO2023151358A1 (fr) Inhibiteur durable d'entrée du virus de l'hépatite
US20060106070A1 (en) Novel pyridine-based metal chelators as antiviral agents

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: 22791806

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2023515528

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22791806

Country of ref document: EP

Kind code of ref document: A1