CN116621943A - Long-acting hepatitis virus entry inhibitor - Google Patents

Long-acting hepatitis virus entry inhibitor Download PDF

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CN116621943A
CN116621943A CN202210126681.0A CN202210126681A CN116621943A CN 116621943 A CN116621943 A CN 116621943A CN 202210126681 A CN202210126681 A CN 202210126681A CN 116621943 A CN116621943 A CN 116621943A
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asn
pro
asp
integer
hepatitis
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周述靓
于海宁
高俊萍
邓岚
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Chengdu Aoda Biotechnology Co ltd
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Chengdu Aoda Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to the field of medicine synthesis, and discloses a long-acting hepatitis virus entry inhibitor. The long-acting hepatitis virus entry inhibitor is used for preparing a pharmaceutical composition for treating diseases, and the pharmaceutical composition is used for treating chronic hepatitis B and hepatitis delta.

Description

Long-acting hepatitis virus entry inhibitor
Technical Field
The invention relates to a long-acting hepatitis virus entry inhibitor and application thereof.
Background
Viral hepatitis is an infectious disease caused by a variety of hepatitis viruses, mainly liver lesions. Clinically, it is mainly manifested by anorexia, nausea, epigastric discomfort, pain in liver region and hypodynamia. Some patients may have jaundice fever and liver large with liver function impairment. Some patients may become chronicized, even develop cirrhosis, and a few may develop liver cancer.
The etiology of viral hepatitis is typed, five hepatitis viruses, namely A, B, C, D and E, are currently recognized, and are respectively written as HAV, HBV, HCV, HDV, HEV, and the rest are RNA viruses except that the hepatitis B virus is DNA virus.
Hepatitis A Virus (HAV) is a genus of hepadnaviridae of the picornaviridae family. After HAV infection in humans, most appear as subclinical or recessive infections, and only a few appear as acute hepatitis A. It can be recovered completely without being converted into chronic hepatitis and chronic carrier.
Hepatitis B Virus (HBV) is a causative agent of hepatitis b, belonging to the hepadnaviridae family, which comprises both the genus orthohepadnavirus and the genus avian hepadnavirus, and causes infection of humans with the genus orthohepadnavirus. HBV infection is a global public health problem, and the popularization rate of hepatitis B vaccines is increased year by year and the infection rate is reduced along with the production and the input of genetic engineering vaccines. About 20 million HBV infected patients worldwide, 3.8 million of which are chronically infected, and viruses can be hidden in tissues and organs and cannot be completely cleared by the immune system and drugs.
Hepatitis C Virus (HCV) is transmitted vertically, mainly through blood, sex life, and mother and infant. Unfortunately, however, no vaccine has been developed in the medical community that effectively prevents hepatitis c. Because hepatitis C virus is RNA virus and is very easy to change, the difficulty of developing vaccine is great, and other animals except human and chimpanzee cannot suffer from hepatitis C, so that animal models are difficult to find in vaccine development, but the new generation of oral direct antiviral drugs can cure hepatitis C.
HDV is a defective single-stranded negative-strand RNA virus that must be replicated by providing a shell for hepadnaviruses such as HBV. HDV is present in the nuclei of hepatocytes and in serum of HBsAg positive HDV-infected persons. Mainly replicates in hepatocytes. HDV is prone to variation. After the human is infected with HDV, the synthesis of HBV-DNA can be obviously inhibited, the appearance of the HDAg is consistent with the reduction of HBV-DNA in serum, and the HBV-DNA is restored to the original level along with the negative transfer of the HDAg and the appearance of anti-HD. The transmission is mainly carried out by blood transfusion and blood products, and similar to the transmission mode of hepatitis B, the HDV infection is mostly seen in HBV infected persons, and sporadic HDV infected persons are also seen. After the HDV and HBV are infected in a overlapped way, the liver damage is promoted to be aggravated, and chronic active hepatitis, cirrhosis and severe hepatitis are easy to develop.
Researchers have found that a protein called liver bile acid transporter (NTCP, sodium taurocholate cotransporter polypeptide) on the surface of hepatocytes can specifically interact with the key receptor binding domain of HBV envelope protein, the receptor required for HBV infection of host cells. Thus, blocking NTCP would be expected to cure hepatitis b.
Bulevirtide is a drug containing 47 amino acids and targeting NTCP, and because Bulevirtide has short half-life in vivo, patients need to take the drug daily and for a long time, and the patient has poor compliance and high clinical cost. The invention aims to provide a long-acting hepatitis virus entry inhibitor for patients, reduce the administration frequency and lower the cost of the patients.
Disclosure of Invention
The invention provides a long-acting hepatitis virus entry inhibitor and application thereof.
To achieve the above object, the present invention provides a compound of the formula I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, a prodrug based on the compound, or a mixture of any of the above forms.
AA1-Gly-Thr-Asn-Leu-Ser-Val-Pro-Asn-Pro-Leu-Gly-Phe-Phe-Pro-
Asp-His-Gln-Leu-Asp-Pro-Ala-Phe-Gly-Ala-Asn-Ser-Asn-Asn-Pro-
Asp-Trp-Asp-Phe-Asn-Pro-Asn-AA2(R)-Asp-His-Trp-Pro-Glu-Ala-
Asn-AA3-Val-Gly-AA4
Structure I
AA1 in structure I is Ac, or H;
AA2 in structure I is Lys, or is Dap, or is Dab, or is Orn, or is Dah, or is Dao;
AA3 in structure I is Arg, or Lys, or gin, or Glu, or Cit;
AA4 in structure I is NH 2 Or is OH;
r in structure I is HO 2 C(CH 2 )n1CO-(AA5)n2-(PEGn3(CH 2 ) n4 CO) n5-, or HO 2 C(CH 2 )n1CO-(AA5)n2-(AA6)n6-；
Wherein: n1 is an integer from 10 to 20;
n2 is an integer from 1 to 5;
n3 is an integer from 1 to 30;
n4 is an integer from 1 to 5;
n5 is 0, or an integer from 1 to 5;
n6 is 0, or an integer from 1 to 10;
AA5 is γglu, or εlys, or β -Ala, or γ -aminobutyric acid, or 5-Ava.
AA6 is Ala, or Leu, or Ser, or Thr, or Tyr, or gin, or Lys, or Dah, or Orn, or Dab, or Dap, or Glu, or Asp, or Ada, or Apm, or Asu.
The long-acting hepatitis virus entry inhibitor comprises a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex formed, a prodrug based on the compound or any mixture of the above forms.
The invention also provides a pharmaceutical composition comprising the compound according to the invention, and the use of the pharmaceutical composition of the compound for preparing a medicament for treating a disease.
Further, the pharmaceutical composition is used for treating chronic hepatitis B and hepatitis D.
Further details of the invention are set forth in the accompanying drawings and the description below, or may be learned by practice of the invention.
Unless otherwise indicated, the amounts of the various components, reaction conditions, and the like, are used herein and are to be construed in any sense as "generally", "about". Accordingly, unless explicitly indicated otherwise, the numerical parameters set forth in the following claims are approximations that may vary depending upon the standard deviation employed under the particular circumstances.
Herein, when the chemical structural formula and chemical name of a compound are divergent or ambiguous, the compound is defined exactly by the chemical structural formula. The compounds described herein may contain one or more chiral centers, and/or double bonds and the like, and stereoisomers, including isomers of double bonds (such as geometric isomers), optical enantiomers or diastereomers, may also be present. Accordingly, any chemical structure within the scope of the description herein, whether partial or whole containing such structures, includes all possible enantiomers and diastereomers of the compound, including any single stereoisomer (e.g., a single geometric isomer, a single enantiomer, or a single diastereomer), and mixtures of any of these isomers. These racemic isomers and mixtures of stereoisomers may also be resolved further into their constituent enantiomers or stereoisomers by methods known to those skilled in the art using continuous separation techniques or chiral molecule synthesis.
The compounds of formula I include, but are not limited to, optical isomers, racemates and/or other mixtures of these compounds. In the above cases, single enantiomers or diastereomers, such as optical isomers, may be obtained by asymmetric synthesis or resolution of racemates. Resolution of the racemate can be accomplished in various ways, such as recrystallization with conventional resolution-aiding reagents, or by chromatographic methods. In addition, the compounds of the formula I also contain cis-and/or trans-isomers with double bonds.
The compounds of the present invention include, but are not limited to, the compounds of formula I and all of their various pharmaceutically acceptable forms. Pharmaceutically useful different forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above, and mixtures of any of these forms.
Detailed Description
The invention discloses a long-acting hepatitis virus entry inhibitor and application thereof, and a person skilled in the art can properly improve relevant parameters by referring to the content of the present disclosure. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the process of the present invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the compounds and methods of preparation described herein, or in appropriate combinations, without departing from the spirit and scope of the invention.
The Chinese names corresponding to the English abbreviations in the invention are shown in the following table:
english abbreviations Chinese name English abbreviations Chinese name
Fmoc 9-fluorenylmethoxycarbonyl OtBu Tert-butoxy radical
tBu Tert-butyl group Boc Boc acid tert-butyl ester
Trt Trityl radical Pbf (2, 3-dihydro-2, 4,6, 7-pentamethylbenzofuran-5-yl) sulfonyl
Ala Alanine (Ala) Leu Leucine (leucine)
Arg Arginine (Arg) Lys Lysine
Asn Asparagine derivatives Met Methionine
Asp Aspartic acid Phe Phenylalanine (Phe)
Cys Cysteine (S) Pro Proline (proline)
Gln Glutamine Ser Serine (serine)
Glu Glutamic acid Thr Threonine (Thr)
Gly Glycine (Gly) Trp Tryptophan
His Histidine Tyr Tyrosine
Ile Isoleucine (Ile) Val Valine (valine)
Aib Amino isobutyric acid Dah 2, 7-diaminoheptanoic acid
5-Ava 5-Aminopentanoic acid Dao 2, 8-diamino octanoic acid
Dap 2, 3-diaminopropionic acid Ada 2-aminoadipic acid
Dab 2, 4-diaminobutyric acid Apm 2-Aminopimelic acid
Orn Ornithine Asu 2-amino-suberic acid
Example 1 preparation of Compounds
The preparation method comprises the following steps: preparing peptide resin by adopting a solid-phase polypeptide synthesis method, acidolysis is carried out on the peptide resin to obtain a crude product, and finally, the crude product is purified to obtain a pure product; wherein the step of preparing peptide resin by solid-phase polypeptide synthesis method comprises the steps of sequentially accessing corresponding protected amino acid or fragment in the following sequence on carrier resin by solid-phase coupling synthesis method to prepare peptide resin:
in the preparation method, the dosage of the Fmoc-protected amino acid or the protected amino acid fragment is 1.2-6 times of the total mole number of the resin; preferably 2.5 to 3.5 times.
In the preparation method, the substitution value of the carrier resin is 0.2-1.0 mmol/g resin, and the preferred substitution value is 0.3-0.5 mmol/g resin.
As a preferred scheme of the invention, the solid phase coupling synthesis method is as follows: the protected amino acid-resin obtained in the previous step is subjected to Fmoc protecting group removal and then is subjected to coupling reaction with the next protected amino acid. The deprotection time for Fmoc deprotection is 10 to 60 minutes, preferably 15 to 25 minutes. The coupling reaction time is 60 to 300 minutes, preferably 100 to 140 minutes.
The coupling reaction needs to add a condensation reagent, wherein the condensation reagent is selected from DIC (N, N-diisopropyl carbodiimide), N, N-dicyclohexylcarbodiimide, benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate, 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate or O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate; n, N-diisopropylcarbodiimide is preferred. The molar amount of the condensing agent is 1.2 to 6 times, preferably 2.5 to 3.5 times, the total molar amount of the amino groups in the amino resin.
The coupling reaction needs to add an activating reagent, and the activating reagent is selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, and is preferably 1-hydroxybenzotriazole. The amount of the activating agent to be used is 1.2 to 6 times, preferably 2.5 to 3.5 times, the total mole number of the amino groups in the amino resin.
As a preferred scheme of the invention, the Fmoc protection removing reagent is PIP/DMF (piperidine/N, N-dimethylformamide) mixed solution, and the mixed solution contains 10-30% (V) of piperidine. The Fmoc-removing protective agent is used in an amount of 5-15 mL per gram of amino resin, preferably 8-12 mL per gram of amino resin.
Preferably, the peptide resin is subjected to acidolysis and simultaneously the resin and side chain protecting group are removed to obtain a crude product:
further preferably, the acidolysis agent used in acidolysis of the peptide resin is a mixed solvent of trifluoroacetic acid (TFA), 1, 2-Ethanedithiol (EDT) and water, and the volume ratio of the mixed solvent is as follows: 80-95% of TFA, 1-10% of EDT and the balance of water.
Still more preferably, the volume ratio of the mixed solvent is: 89-91% TFA, 4-6% EDT and the balance water. Optimally, the volume ratio of the mixed solvent is as follows: TFA 90%, EDT 5%, balance water.
The dosage of the acidolysis agent is 4-15 mL of acidolysis agent required by each gram of peptide resin; preferably, 7 to 10mL of acidolysis agent is required per gram of peptide resin.
The time for cleavage with acidolysis agent is 1 to 6 hours, preferably 3 to 4 hours, at room temperature.
Further, purifying the crude product by high performance liquid chromatography, and lyophilizing to obtain pure product.
1. Synthesis of peptide resins
And (3) taking Rink Amide BHHA resin as carrier resin, and sequentially accessing corresponding protected amino acid through Fmoc removal protection and coupling reaction.
(1) Access to backbone 1 st protected amino acid
Taking 0.03mol of 1 st protected amino acid and 0.03mol of HOBt, and dissolving the 1 st protected amino acid and the HOBt with a proper amount of DMF; and (3) adding 0.03mol of DIC into the protected amino acid DMF solution slowly under stirring, and stirring and reacting for 30 minutes in a room temperature environment to obtain an activated protected amino acid solution for later use.
0.01mol of Rink amide MBHA resin (substitution value about 0.4 mmol/g) was taken and deprotected with 20% PIP/DMF solution for 25 min, washed and filtered to give Fmoc-removed resin.
And adding the activated 1 st protected amino acid solution into Fmoc-removed resin, performing coupling reaction for 60-300 minutes, and filtering and washing to obtain the resin containing 1 protected amino acid.
(2) Accessing the 2 nd to 49 th protected amino acids of the main chain
The same method of accessing the 1 st protected amino acid of the main chain is adopted, and the corresponding 2 nd to 49 th protected amino acids are sequentially accessed to obtain the resin containing 49 amino acids of the main chain.
(3) Access to side chain 1 st protected amino acid
Taking 0.03mol of 1 st protected amino acid of a side chain and 0.03mol of HOBt, and dissolving the protected amino acid and the HOBt with a proper amount of DMF; and adding 0.03mol of DIC into the protected amino acid DMF solution under stirring, and stirring and reacting for 30 minutes in a room temperature environment to obtain an activated protected amino acid solution.
2.5mmol of tetraphenylphosphine palladium and 25mmol of phenylsilane are taken, dissolved with a proper amount of dichloromethane, deprotected for 4 hours, filtered and washed to obtain dealloc resin for later use.
Adding the 1 st protective amino acid liquid of the side chain after the activation into the dealloc-removed resin, carrying out coupling reaction for 60-300 minutes, and filtering and washing to obtain the resin containing the 1 st protective amino acid of the side chain.
(4) Accessing the 2 nd to 4 th protected amino acids of the side chain
The same method of accessing the 1 st protected amino acid of the main chain is adopted, and the 2 nd to 4 th protected amino acids and the single protected fatty acid corresponding to the side chains are sequentially accessed to obtain the peptide resin.
2. Preparation of crude product
Adding a cracking reagent (10 mL/g resin) with a volume ratio of TFA to water to EDT=95 to 5 into the peptide resin, uniformly stirring, stirring at room temperature for reaction for 3 hours, filtering a reaction mixture by using a sand core funnel, collecting filtrate, washing the resin with a small amount of TFA for 3 times, combining the filtrates, concentrating under reduced pressure, adding anhydrous diethyl ether for precipitation, washing the precipitation with anhydrous diethyl ether for 3 times, and pumping to obtain white-like powder which is a crude product.
3. Preparation of pure product
Mixing the crude product with water, adjusting pH to 8.0 with ammonia water to dissolve completely, filtering the solution with 0.45 μm mixed microporous membrane, and purifying;
purifying by high performance liquid chromatography, wherein the chromatographic packing for purification is reverse phase C18 with the size of 10 μm, the mobile phase system is 0.1% TFA/water solution-0.1% TFA/acetonitrile solution, the flow rate of a chromatographic column with the size of 30mm or 250mm is 20mL/min, eluting by a gradient system, circularly sampling and purifying, sampling the crude product solution into the chromatographic column, starting mobile phase eluting, collecting main peaks, evaporating acetonitrile, and obtaining purified intermediate concentrated solution;
filtering the purified intermediate concentrate with 0.45 μm filter membrane for use, changing salt by high performance liquid chromatography, wherein the mobile phase system is 1% acetic acid/water solution-acetonitrile, the chromatographic column flow rate of purification column is 20mL/min (corresponding flow rate can be adjusted according to chromatographic columns of different specifications) with reversed phase C18 of 10 μm and 30mm x 250 mm; adopting a gradient elution and cyclic loading method, loading in a chromatographic column, starting mobile phase elution, collecting a spectrum, observing the change of absorbance, collecting a salt-exchange main peak, analyzing the liquid phase to detect purity, combining the salt-exchange main peak solutions, concentrating under reduced pressure to obtain a pure acetic acid aqueous solution, and freeze-drying to obtain a pure product.
The following compounds were prepared using the above procedure:
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example 2 measurement of the effect of inhibiting HBV infection
The test group comprises blank group, solvent group, positive control and compound to be tested, the test concentration is 0.5nM, the positive drug is Myrcludex B, and the detection time is that the supernatant HBeAg/HBsAg is detected every 3 days after infection
1. Virus concentration
(1) Culturing hepAD38 cells and collecting culture supernatant, and subjecting the collected hepAD38 cell culture supernatant to centrifugation at 4000rpm at 4 ℃ for 30min to remove cell debris;
(2) Adding the centrifuged virus supernatant into 6 XPEG 8000 (Poly (ethylene glycol), sigma, SLBZ 3934) solution to dilute it into 1 XPEG 8000, and standing on a horizontal shaking table at 4deg.C and 20rpm/min overnight;
(3) The next day, the virus concentrate was centrifuged at 7000g for 30min at 4℃and the supernatant was discarded; the pellet was resuspended in serum-free, double-antibody-free DMEM medium and the resuspended concentrated virus solution was stored at 4 ℃.
(4) The multiplicity of viral concentrate infection (Multiplicity ofinfection, MOI) was calculated: mu.L of the virus concentrate was taken, diluted with 180. Mu.L of PBS, digested with DNase (to reduce the effect of residual plasmid), column-extracted with a Viral DNA/RNA Kit, and HBV DNA was quantified by detection of S-region primer qPCR with a standard, in order to calculate the multiplicity of virus infection, i.e., the ratio of the number of infected viruses to the number of cells.
2. Infection experiments and detection
(1) HepG2-NTCP cells were cultured for 4 days with 10% FBS DMEM medium supplemented with 4. Mu.g/mL Doxycycline to induce NTCP expression;
(2) Spreading HepG2-NTCP cells into a type I rat tail collagen-coated 48-well petri dish (200. Mu.L collagen solution) 4 x 10≡4 cells per well one night prior to the fourth day of culture;
(3) The next day, the culture medium is replaced by HCM (HBMTM, LONZA, CC-3199\single quats, LONZA, CC-4182) to induce the proliferation retardation of HepG2-NTCP cells, and Doxycycline is added, and meanwhile, the drug to be tested is added;
(4) After 24h incubation with HCM, the HCM was discarded, concentrated virus solution was added to the petri dish at 1600MOI, the HCM was used to make up to 150. Mu.L, the drug to be tested was added simultaneously, then 8% PEG 8000150. Mu.L, 2% DMSO, 4. Mu.g/mL Doxycycline was added, and after gentle mixing, the mixture was allowed to infect overnight with a 37℃incubator;
(5) After 16h of infection, the supernatant was discarded, washed 5 times with PBS, and continued culture with 300. Mu.L of DMEM (containing 10% FBS, 2% DMSO, 4. Mu.g/mL doxycline);
(6) After that, the culture medium was replaced every three days, 300ul of cell culture supernatant at the corresponding time point was collected, centrifuged for 3min to remove cell pellet, and the supernatant was subjected to detection of HBsAg and HBeAg by a full-automatic chemiluminescence immunoassay system MAGLUMI X3 (New organism).
2. Test results
The test results are shown in the following table.
EXAMPLE 3 determination of Primary drug substitution Properties
The test animals were cynomolgus monkeys, 2 male cynomolgus monkeys per compound group were subcutaneously administered at a dose of 0.1mg/kg, respectively, blood was collected intravenously at 1h, 2h, 3h, 4h, 8h, 12h, 18h, 24h, 48h, 96h, 144h, 168h before administration (0 h), and after administration, plasma samples were centrifuged, and plasma concentrations of the corresponding compounds in the plasma samples were measured by liquid chromatography-mass spectrometry, respectively, and the Subcutaneous (SC) administration half lives of the compounds were shown in the following table:
compounds of formula (I) t 1/2 (h)
Compound 6 68.3

Claims (4)

1. A long-acting hepatitis virus entry inhibitor having the structural formula i:
AA1-Gly-Thr-Asn-Leu-Ser-Val-Pro-Asn-Pro-Leu-Gly-Phe-Phe-Pro-Asp-His-Gln-Leu-Asp-Pro-Ala-Phe-Gly-Ala-Asn-Ser-Asn-Asn-Pro-Asp-Trp-Asp-Phe-Asn-Pro-Asn-AA2(R)-Asp-His-Trp-Pro-Glu-Ala-Asn-AA3-Val-Gly-AA4
structure I
AA1 in structure I is Ac, or H;
AA2 in structure I is Lys, or is Dap, or is Dab, or is Orn, or is Dah, or is Dao;
AA3 in structure I is Arg, or Lys, or gin, or Glu, or Cit;
AA4 in structure I is NH 2 Or is OH;
r in structure I is HO 2 C(CH 2 )n1CO-(AA5)n2-(PEGn3(CH 2 ) n4 CO) n5-, or HO 2 C(CH 2 )n1CO-(AA5)n2-(AA6)n6-；
Wherein: n1 is an integer from 10 to 20;
n2 is an integer from 1 to 5;
n3 is an integer from 1 to 30;
n4 is an integer from 1 to 5;
n5 is 0, or an integer from 1 to 5;
n6 is 0, or an integer from 1 to 10;
AA5 is γglu, or εlys, or β -Ala, or γ -aminobutyric acid, or 5-Ava.
AA6 is Ala, or Leu, or Ser, or Thr, or Tyr, or gin, or Lys, or Dah, or Orn, or Dab, or Dap, or Glu, or Asp, or Ada, or Apm, or Asu.
2. The long acting hepatitis virus entry inhibitor of claim 1, comprising a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex of the analog, a prodrug based on the compound, or a mixture of any of the foregoing forms.
3. A long acting hepatitis virus entry inhibitor according to claim 1 and claim 2 for use in the preparation of a pharmaceutical composition for the treatment of a disease.
4. A pharmaceutical composition according to claim 3 for the treatment of chronic hepatitis b and hepatitis delta.
CN202210126681.0A 2022-02-10 2022-02-10 Long-acting hepatitis virus entry inhibitor Pending CN116621943A (en)

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Application Number Priority Date Filing Date Title
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CN116621943A true CN116621943A (en) 2023-08-22

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