CN111393391B - Antiviral agent for hepatitis B virus infection - Google Patents
Antiviral agent for hepatitis B virus infection Download PDFInfo
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- CN111393391B CN111393391B CN202010301579.0A CN202010301579A CN111393391B CN 111393391 B CN111393391 B CN 111393391B CN 202010301579 A CN202010301579 A CN 202010301579A CN 111393391 B CN111393391 B CN 111393391B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/22—Nitrogen atoms not forming part of a nitro radical
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- 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
Abstract
The invention discloses an antiviral agent for hepatitis B virus infection, comprising pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate or isomer form thereof, and application thereof in preparing a medicament for treating or inhibiting hepatitis B virus infection.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to an antiviral agent for hepatitis B virus infection.
Background
Hepatitis B Virus (HBV) infection remains a major public health problem. Currently, there are estimated 3.5 million people worldwide, of which 140 million in the united states have chronic HBV. Without treatment, approximately one-third of these people die from serious liver diseases, such as cirrhosis and liver cancer.
Currently, seven drugs are available for the treatment of chronic hepatitis b, including two α -interferon formulations (standard and peg-modified) and five nucleoside analogs that inhibit HBV DNA polymerase (lamivudine, adefovir, entecavir, telbivudine, and tenofovir). Currently, the first line of treatment options are entecavir, tenofovir or pegylated interferon alpha-2 a. However, even with the first line of treatment option, pegylated interferon alfa-2 a may only be effective in achieving serological milestones in one third of the treated patients, often with severe side effects. Entecavir and tenofovir are highly effective HBV inhibitors, but chronic or potentially lifelong treatment requires continued suppression of HBV replication, and may eventually fail due to the emergence of drug-resistant viruses. Therefore, it is urgently required to introduce a new, safe and effective method for treating chronic hepatitis B.
Therefore, there is still a need for new antiviral drugs that are clinically effective and effective for the treatment of disease relief in patients infected with hepatitis b virus. The invention provides a new choice for treating the disease remission of patients infected with hepatitis B virus and effective new antiviral drugs.
Disclosure of Invention
In one aspect, the present invention discloses compounds having the structure:
in some embodiments, it is a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate, or isomer form.
In another aspect, the invention discloses the use of the aforementioned compounds for the manufacture of a medicament for the treatment or inhibition of hepatitis b virus infection.
In another aspect, the invention discloses the use of the aforementioned compounds for the preparation of a medicament for the prophylactic treatment of hepatitis b virus infection.
In another aspect, the invention discloses the use of the aforementioned compounds for the manufacture of a medicament for reducing the recurrence of hepatitis b virus infection.
In another aspect, the invention discloses the application of the compound in preparing a medicament for inducing and relieving liver injury caused by hepatitis B virus infection
In another aspect, the present invention discloses the use of the aforementioned compounds for the manufacture of a medicament for reducing adverse physiological effects caused by hepatitis b virus infection.
The compounds in the foregoing uses may be in the form of pharmaceutically acceptable salts, esters, prodrugs, complexes, solvates, hydrates, or isomers.
The term "isomer" as used herein includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure. For example, the present application includes R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformers, single stereochemical isomers and mixtures of enantiomers, diastereomers and geometric (or conformational) isomers. Unless otherwise indicated, this application includes all tautomeric forms of the structures described herein. "salts" include acid and base addition salts. It is understood that when the compounds or examples of the present application are shown as particular salts, the present application includes the corresponding free base as well as other salts of the corresponding free base (including pharmaceutically acceptable salts of the corresponding free base). "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present application. Examples of the solvent include water, isopropyl alcohol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.
In another aspect, the invention discloses a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier or excipient. The term "pharmaceutically acceptable carrier or excipient" as used herein refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
In some embodiments, the aforementioned pharmaceutical composition further comprises an additional therapeutic agent that is an HBV polymerase inhibitor, an interferon, or a reverse transcriptase inhibitor.
Detailed Description
Example 1
Step one preparation of 3- (chlorosulfonyl) ethyl benzoate
3- (chlorosulfonyl) benzoic acid (15.18g, 0.069mol, 1.0eq.) was added to DCM (150mL) at room temperature, cooled to 0-5 ℃ with an ice water bath, thionyl chloride (32.74g, 0.27mol, 4.0eq.) and 1.5mL of a catalytic amount of DMF were added, and the reaction was allowed to proceed overnight for 16 hours at room temperature after completion of the addition. Evaporating the reaction solution to dryness, removing the solvent by using toluene for 2 times, pouring the solvent into THF (150mL), cooling the solution to 0-5 ℃ by using an ice water bath, dropwise adding ethanol (30mL), and reacting for 4-6 hours at room temperature after the addition. The reaction mixture was evaporated to dryness and purified by column chromatography (200-300 mesh silica gel, 10: 1-5: 1) to give 12.23g of a yellow oily liquid with a yield of 71.5%.
Preparation of step-bis-3-sulfamoylethyl benzoate
Ethyl 3- (chlorosulfonyl) benzoate (12.20g, 4.9mmol, 1.0eq.) was added to THF (150mL) at room temperature, then brought to-10 ℃ or below, and ammonia (13.67g, 24.5mmol, 5.0eq.) was added dropwise for 1 hour. Adjusting the pH of the reaction solution to 4-5 with 4N hydrochloric acid, distilling part of THF, filtering the precipitated solid, washing the filter cake to neutrality with water, and drying to obtain 10.53g of white solid, wherein the yield is as follows: 93.8 percent.
Step three preparation of Ethyl 3- (N- (tert-Butyldimethylsilyl) sulfamoyl) benzoate
Ethyl 3-sulfamoylbenzoate (3.00g, 13.1mmol, 1.0eq.) was added to DCM (30mL) and THF (15mL) at room temperature, followed by addition of triethylamine (3.97g, 39.3mmol, 3.0eq.) and TBS-Cl (2.37g, 15.7mmol, 1.20eq.) for 12 h. The reaction solution was directly fed to the next reaction.
Step four preparation of 3- (N- (tert-butyldimethylsilyl) -S-chlorosulfonylimido) Ethyl benzoate
Triphenylphosphine dichloride (5.24g, 15.7mmol, 1.2eq.) was added to the reaction solution of the previous step at room temperature (4.50g, 13.1mmol, 1.0eq.) and the reaction was completed at 30-35 ℃ for 10 hours. The reaction solution was directly fed to the next reaction.
Preparation of step five Ethyl 3- (N' - (tert-butyldimethylsilyl) -N- ((S) -tetrahydrofuran-3-yl) sulfonamide Imidilyl) benzoate
(3S) -Oxolan-3-amine (967.0mg, 11.1mmol, 3.0eq.) was added to the reaction solution of the previous step (1.34g, 3.7mmol, 1.0eq.) at room temperature, and the reaction was carried out overnight for 12 hours at room temperature after the addition. The reaction was quenched by addition of saturated brine, extracted with DCM, separated and dried, filtered and evaporated to dryness to give a sand, which was purified by silica gel column chromatography (200-300 mesh silica gel, Heptane/EtOAc ═ 10: 1-5: 1) to give 430.0mg of a pale yellow oily liquid.
Preparation of step hexa 3- (N' - (tert-butyldimethylsilyl) -N- ((S) -tetrahydrofuran-3-yl) sulfonamide diimide-based) benzoic acid
Ethyl 3- (N' - (tert-butyldimethylsilyl) -N- ((S) -tetrahydrofuran-3-yl) sulfonamide diimide-based) benzoate (430.0mg, 1.04mmol, 1.0eq.) was added to THF (10mL) at room temperature, and reacted for 12 hours after adding solid LiOH (87.45mg, 3.2mmol, 2.0eq.) and 5mL of water. Washing the reaction solution with 2N dilute hydrochloric acid until the pH value is 3-4, extracting with EA, washing the organic phase with saturated salt water once, separating, drying, filtering, and evaporating to obtain 400.0mg of yellow liquid, wherein the yield is as follows: 100 percent.
Preparation of step seven 3- (N' - (tert-butyldimethylsilyl) -N- ((S) -tetrahydrofuran-3-yl) sulfonamidoiminoimidoacyl) -N- (3, 4-difluorophenyl) benzamide
Adding 3- (N' - (tert-butyldimethylsilyl) -N- ((S) -tetrahydrofuran-3-yl) sulfonamide diimide) benzoic acid (400.0mg, 1.04mmol, 1.0eq.) to DM (8mL) F at room temperature, cooling the reaction solution to 0-5 ℃ with an ice water bath, adding 3, 4-difluoroaniline (140.0mg, 1.08m mol, 1.1eq.) and DIPEA (410.0mg, 3.12mmol, 3.0eq.) to the reaction solution, reacting the mixture for 30 minutes, and adding HATU (429.5mg, 1.2mmol, 1.2eq.) was reacted overnight at room temperature for 12 hours. 5mL of saturated NaHCO was added to the reaction solution 3 Quenching the aqueous solution, pouring water (30mL) into the solution, extracting with EA, washing the organic phase with saturated brine once, separating, drying, filtering, evaporating to dryness to prepare sand, and purifying by silica gel column chromatography (200-300 mesh silica gel, Heptane/EtOAc 10: 1-5: 1) to obtain 350.0mg of yellow liquid, yield: and (3.6).
Step preparation of octa-N- (3, 4-difluorophenyl) -3- (N- (((S) -tetrahydrofuran-3-yl) sulfonamide diimidazinyl) benzamide
3- (N' - (tert-butyldimethylsilyl) -N- ((S) -tetrahydrofuran-3-yl) sulfonamidoiminoimidoacyl) -N- (3, 4-difluorophenyl) benzamide (350.0mg, 0.7mmol, 1.0eq.) was added to dioxane (5mL) at room temperature and reacted for 6 hours after addition of a 4N dioxane solution of HCl (0.7mL, 2.8mmol, 4.0 eq.). The reaction solution was evaporated to dryness, EA was added to dissolve, washed with water and saturated brine in order once, subjected to liquid separation drying, filtered and evaporated to dryness to obtain 150.6mg of a yellow solid, yield: and 56.3 percent. 1 HNMR(400MHz,DMSO)δ(ppm)1.59-1.84(m,2H),3.58-3.68(m,4H),4.47(m,1H),7.31(brs,1H),7.42-7.49(m,1H),7.55(m,1H),7.71-7.74(t,1H),7.91-7.96(m,1H),8.09-8.15(m,2H),8.44(s,1H),10.66(s,1H)。MS(ESI):m/z([M+H] + )382.50。
Experimental example 1 inhibition of HBV viral replication
DMEM/F12(1:1) medium, PBS (1X), penicillin-streptomycin double antibody, 0.5% pancreatin (10X), qPCR SYBR Green Mix from ThermoFisher (Waltham, MA, USA). Certified Fetal Bovine Serum (FBS) was purchased from Biological Industries (Israel). Hydrocortisone was purchased from Alfa. Insulin was purchased from Sigma. Doxycycline was purchased from Clontech. 96-well and 384-well cell culture plates were purchased from corning (usa). Primers were purchased from Nanjing Kinsrui Biotechnology Ltd. qPCR 384-well plates were purchased from roche. Quickextract DNA extraction reagents were purchased from Lucigen.
"growth medium" was DMEM/F12(1:1), 10% FBS, 1 Xpenicillin-streptomycin diabody, 350nM hydrocortisone, 5ug/mL insulin, 1ug/mL doxycycline. "treatment Medium" was DMEM/F12(1:1), 2% FBS, 1 Xpenicillin-streptomycin double antibody, 350nM hydrocortisone, 5ug/mL insulin.
To evaluate the inhibition of HBV viral replication by the synthetic compounds, HepAD38 cells grown in growth medium were trypsinized, resuspended using treatment medium after centrifugation, and plated at 6000/well in 384-well plates, 40. mu.L/well, placed at 37 ℃ and 5% CO 2 Overnight. Compounds were diluted to 12 point, 3-fold gradient dilutions in DMSO starting at 2 mM. mu.L of DMSO solution from the compound stock plate was added to 199. mu.L of treatment medium (final maximum concentration of compound in assay is 10. mu.M, and final concentration of DMSO is 0.5%). The medium in the cell culture plate was discarded, 40. mu.L of the compound solution was added to each well according to a gradient, and the 384 well plate was placed at 37 ℃ and 5% CO 2 Incubate in incubator for 3 days. After 3 days the medium was discarded from the wells, fresh preparations of the compound medium were added and the 384 well plates were placed in the incubator and incubated for 3 days again. After a total of 6 days of dosing, 4ul of medium was removed from each well of the 384-well cell culture plates and transferred to 384-well qPCR plates. 4ul of quick extract DNA extraction reagent was added to each well, centrifuged and mixed, and DNA was extracted at 65 ℃ for 30min and 95 ℃ for 17min in Roche fluorescent quantitative PCR Lightcycler 480 II.
The status of virus replication was detected by quantitative qPCR. The detection primer is forward: 5'-GAGTGTGGATTCGCACTCC-3' and backward: 5'-GAGGCGAGGGAGTTCTTCT-3'. To the above 384 well plates containing samples, 10ul of qPCR SYBR Green Mix, 1ul of forward primer, 1ul of backward primer were added per well and incubated at 95 ℃ for 10 min. The fluorescent quantitative PCR was performed in Roche fluorescent quantitative PCR Lightcycler 480 II, and the program was set to 95 ℃ for 15s,60 ℃ for 1min,40 cycles. Viral load was calculated from a standard curve. Concentration (IC) at which a compound inhibits viral load by 50% (IC) was determined in Prism 7(LaJolla, CA) using a sigmoidal dose response model (variable slope, four parameters) 50 Value).
IC of the representative Compounds of the invention 50 Values are shown in Table 1。
TABLE 1
Claims (10)
1. A compound having the structure:
2. the compound of claim 1, which is a pharmaceutically acceptable salt.
3. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment or inhibition of hepatitis b virus infection.
4. Use of a compound of claim 1 for the preparation of a medicament for the prophylactic treatment of hepatitis b virus infection.
5. Use of a compound of claim 1 for the manufacture of a medicament for reducing recurrence of hepatitis b virus infection.
6. Use of a compound of claim 1 for the manufacture of a medicament for inducing remission of liver damage caused by hepatitis b virus infection.
7. Use of a compound of claim 1 for the manufacture of a medicament for reducing adverse physiological effects caused by hepatitis b virus infection.
8. The use according to any one of claims 3 to 7, wherein the compound is a pharmaceutically acceptable salt.
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
10. The pharmaceutical composition of claim 9, further comprising an additional therapeutic agent that is an HBV polymerase inhibitor, an interferon, or a reverse transcriptase inhibitor.
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Citations (8)
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|---|---|---|---|---|
| CN103889953A (en) * | 2011-07-01 | 2014-06-25 | 肝炎与病毒研究所 | Sulfamoylbenzamide derivatives as antiviral agents against hbv infection |
| CN104144913A (en) * | 2011-12-21 | 2014-11-12 | 诺维拉治疗公司 | Hepatitis b antiviral agents |
| CN104812743A (en) * | 2012-08-28 | 2015-07-29 | 爱尔兰詹森科学公司 | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b |
| CN105209031A (en) * | 2012-12-27 | 2015-12-30 | 德雷克塞尔大学 | Novel antiviral agents against HBV infection |
| WO2019046287A1 (en) * | 2017-08-30 | 2019-03-07 | Arbutus Biopharma Corporation | Compounds, compositions, and methods for treating or preventing hepatitis b |
| WO2019206072A1 (en) * | 2018-04-24 | 2019-10-31 | 浙江海正药业股份有限公司 | Sulfamide aryl formamide derivative and preparation method therefor and uses thereof |
| WO2020016427A1 (en) * | 2018-07-19 | 2020-01-23 | Ospedale San Raffaele S.R.L. | Inhibitors of hepatitis b virus |
| WO2020016434A1 (en) * | 2018-07-19 | 2020-01-23 | Ospedale San Raffaele S.R.L. | Cyclic inhibitors of hepatitis b virus |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008075353A1 (en) * | 2006-12-19 | 2008-06-26 | Pharmos Corporation | Sulfonamide derivatives with therapeutic indications |
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Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103889953A (en) * | 2011-07-01 | 2014-06-25 | 肝炎与病毒研究所 | Sulfamoylbenzamide derivatives as antiviral agents against hbv infection |
| CN104144913A (en) * | 2011-12-21 | 2014-11-12 | 诺维拉治疗公司 | Hepatitis b antiviral agents |
| CN106957282A (en) * | 2011-12-21 | 2017-07-18 | 诺维拉治疗公司 | Viral hepatitis type b antivirotic |
| CN104812743A (en) * | 2012-08-28 | 2015-07-29 | 爱尔兰詹森科学公司 | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b |
| CN105209031A (en) * | 2012-12-27 | 2015-12-30 | 德雷克塞尔大学 | Novel antiviral agents against HBV infection |
| WO2019046287A1 (en) * | 2017-08-30 | 2019-03-07 | Arbutus Biopharma Corporation | Compounds, compositions, and methods for treating or preventing hepatitis b |
| WO2019206072A1 (en) * | 2018-04-24 | 2019-10-31 | 浙江海正药业股份有限公司 | Sulfamide aryl formamide derivative and preparation method therefor and uses thereof |
| WO2020016427A1 (en) * | 2018-07-19 | 2020-01-23 | Ospedale San Raffaele S.R.L. | Inhibitors of hepatitis b virus |
| WO2020016434A1 (en) * | 2018-07-19 | 2020-01-23 | Ospedale San Raffaele S.R.L. | Cyclic inhibitors of hepatitis b virus |
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