CN111349056A - Antiviral agent for hepatitis B virus infection - Google Patents
Antiviral agent for hepatitis B virus infection Download PDFInfo
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- CN111349056A CN111349056A CN202010301517.XA CN202010301517A CN111349056A CN 111349056 A CN111349056 A CN 111349056A CN 202010301517 A CN202010301517 A CN 202010301517A CN 111349056 A CN111349056 A CN 111349056A
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- C07—ORGANIC CHEMISTRY
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- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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- 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
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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
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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. Approximately one third of these people will die of serious liver diseases, such as cirrhosis and liver cancer, if left untreated.
Currently, there are seven drugs 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 option of choice is entecavir, tenofovir, or pegylated interferon α -2 a. however, even with the first line of treatment option, pegylated interferon α -2a may only be effective in one third of the patients receiving treatment for serological milestones, often accompanied by severe side effects.
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, isopropanol, 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, added with thionyl chloride (32.74g, 0.27mol, 4.0eq.) and 1.5mL of a catalytic amount of DMF, and reacted overnight for 16 hours at room temperature. 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 solution was directly evaporated to dryness and purified by column chromatography (200-300 mesh silica gel, 10: 1-5: 1 Heptane/EtOAc) to give 12.23g of 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 cooled to-10 ℃ or below, and then 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 a filter cake to be neutral with water, and drying to obtain 10.53g of a 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, and triethylamine (3.97g, 39.3mmol, 3.0eq.) and TBS-Cl (2.37g, 15.7mmol, 1.20eq.) were added and reacted for 12 hours. 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- (2-chloroethyl) sulfonamide diimide) benzoate
2-chloroethylamine hydrochloride (4.56g, 39.3mmol, 3.0eq.) was added to DMF (10mL) at room temperature and reacted for 1 hour after addition of TEA (3.98g, 39.3mmol, 3.0 eq.). And cooling the reaction liquid (4.74g, 13.1mmol, 1.0eq.) in the previous step to 0-5 ℃ by using an ice water bath, adding the free 2-chloroethylamine DMF solution after filtration into the reaction liquid, and naturally heating to room temperature for reaction overnight for 12 hours. Adding saturated NaCl aqueous solution to quench the reaction, separating, washing an organic phase with 2N diluted hydrochloric acid until the pH value is 7-8, separating and drying, filtering and evaporating to prepare sand, and purifying by silica gel column chromatography (200-300 meshes silica gel, Heptane/EtOAc (5: 1-2: 1)) to obtain 1.16g of a white solid.
Step preparation of Hexa 3- (N' - (tert-Butyldimethylsilyl) -N- (2-chloroethyl) sulfonamide diimidazinyl) benzoic acid
Ethyl 3- (N' - (tert-butyldimethylsilyl) -N- (2-chloroethyl) sulfonamide diimide) benzoate (660.0mg, 1.6mmol, 1.0eq.) was added to THF (12mL) at room temperature, and reacted for 8 hours after addition of solid LiOH (136.7mg, 3.2mmol, 2.0eq.) and water (6 mL). Washing the reaction solution with 2N diluted hydrochloric acid until the pH value is 3-4, extracting with EA, washing with organic phase saturated saline solution once, separating, drying, filtering, and evaporating to obtain 590.0mg of yellow liquid, wherein the yield is as follows: 97.8 percent.
Preparation of step hepta 3- (N' - (tert-butyldimethylsilyl) -N- (2-chloroethyl) sulfonylimido) -N- (3, 4-difluorophenyl) benzamide
3- (N' - (tert-butyldimethylsilyl) -N- (2-chloroethyl) sulfonamide imido) benzoic acid (590.0mg, 1.56mmol, 1.0eq.) was added to DMF (10mL) at room temperature, the reaction mixture was cooled to 0-5 ℃ in an ice-water bath, DIPEA (403.2mg, 3.10mmol, 2.0eq.) and HATU (889.7mg, 2.30mmol, 1.5eq.) were added, and the mixture was reacted for 1 hour. After addition of 3, 4-difluoroaniline (241.7mg, 1.80mmol, 1.2eq.) the mixture was reacted at room temperature overnight for 12 hours. The reaction solution was quenched into ice water (50mL), extracted with EA, the organic phase was washed once with saturated brine, separated and dried, filtered and evaporated to dryness to make sand, and purified by silica gel column chromatography (200-300 mesh silica gel, Heptane/EtOAc ═ 5: 1-1: 1) to give 400.0mg of a yellow liquid, yield: 52.5 percent.
Step eight preparation of 3- (N- (2-chloroethyl) sulfonamido imino) -N- (3, 4-difluorophenyl) benzamide
(N' - (tert-butyldimethylsilyl) -N- (2-chloroethyl) sulfonamidodiimido) -N- (3, 4-difluorophenyl) benzamide (400.0mg, 0.9mmol, 1.0eq.) was added to dioxane (4mL) at room temperature, and a 4N dioxane HCl solution (0.90mL, 3.6mmol, 4.0eq.) was added and reacted for 6 hours. The reaction solution was evaporated to dryness to prepare sand, which was purified by silica gel column chromatography (200-300 mesh silica gel, Heptane/EtOAc ═ 3: 1-1: 1) to obtain 220.0mg of a yellow solid in yield: 66.3 percent.
Step nine preparation of N- (3, 4-difluorophenyl) -3- (1-oxo-3, 4-dihydro-2H-1 l6,2, 5-thiadiazol-1-yl) benzamide
3- (N- (2-chloroethyl) sulfamino imino) -N- (3, 4-difluorophenyl) benzamide (100mg, 0.27mmol, 1.0eq.) was added to THF (5mL) at room temperature, the reaction was cooled to 0-5 ℃ with an ice water bath, solid 60% sodium hydride (26.75mg, 0.6mmol, 2.5eq.) was added, and after completion of the addition, the mixture was reacted in an ice bath for 1 hour. The reaction solution was adjusted to pH 7 with 1N dilute hydrochloric acid, EA (20mL) and water (10mL) were added, liquid separation was performed after stirring, the organic phase was washed once with saturated saline, the liquid separation was dried, filtered and evaporated to dryness to obtain a crude product, which was separated and purified by preparative silica gel plate to obtain 25.0mg of a white solid, yield: 27.5 percent.1HNMR(400MHz,DMSO)δ(ppm)2.15(m,2H),2.24(m,2H),5.02(s,1H),7.45-7.55(m,2H),7.78(s,1H),7.93(m,1H),8.05-8.23(m,2H),8.49(s,1H),10.71(s,1H)。MS(ESI):m/z([M+H]+)338.51。
Experimental example 1 HBV viral replication inhibition experiment
DMEM/F12(1:1) medium, PBS (1X), penicillin-streptomycin diabody, 0.5% pancreatin (10X), qPCRSBR Green Mix purchased 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 diabody, 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 in treatment medium after centrifugation, and plated at 6000/well in 384-well plates, 40. mu.L per well, placed at 37 ℃ and 5% CO2Overnight in an incubator. Compounds were diluted to 12 points in DMSO, 3-fold gradient dilutions, starting at 2 mM. The compoundStock plates of 1 μ L DMSO solution were added to 199 μ L of treatment medium (final maximum concentration of compound in assay 10 μ M, and final concentration of DMSO 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% CO2Incubate in incubator for 3 days. After 3 days the medium was discarded from the wells, freshly prepared medium of the above compound was added and the 384 well plates were placed in the incubator again and incubated for 3 days. 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 is added into each well, after centrifugation and uniform mixing, DNA is extracted in Roche fluorescence quantitative PCRRight cycler 480 II at 65 ℃ for 30min and at 95 ℃ for 17 min.
The status of virus replication was detected by quantitative qPCR. The detection primers are forward 5'-GAGTGTGGATTCGCACTCC-3' and backward 5'-GAGGCGAGGGAGTTCTTCT-3'. To the above 384 well plates containing the samples, 10ul qPCR SYBR Green Mix, 1ul forward primer, 1ul backward primer were added per well and incubated at 95 ℃ for 10 min. The fluorescent quantitative PCR was carried out in Roche fluorescent quantitative PCR Lightcycler 480 II programmed for 40 cycles at 95 ℃ for 15s and 60 ℃ for 1 min. 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)50Value).
IC of the representative Compounds of the invention50The 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, ester, prodrug, complex, solvate, hydrate, or isomer form.
3. Use of a compound of claim 1 for the manufacture of a medicament for treating or inhibiting hepatitis b virus infection.
4. Use of a compound of claim 1 for the manufacture 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 the 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 3-7, wherein the compound is a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate or isomer form.
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 (9)
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| 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 |
| WO2020016434A1 (en) * | 2018-07-19 | 2020-01-23 | Ospedale San Raffaele S.R.L. | Cyclic inhibitors of hepatitis b virus |
| WO2020016427A1 (en) * | 2018-07-19 | 2020-01-23 | Ospedale San Raffaele S.R.L. | Inhibitors of hepatitis b virus |
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2020
- 2020-04-16 CN CN202010301517.XA patent/CN111349056B/en active Active
Patent Citations (10)
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|---|---|---|---|---|
| US20100056528A1 (en) * | 2006-12-19 | 2010-03-04 | Avihai Yacovan | Sulfonamide derivatives with therapeutic indications |
| 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 |
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| 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 |
| WO2020016434A1 (en) * | 2018-07-19 | 2020-01-23 | Ospedale San Raffaele S.R.L. | Cyclic inhibitors of hepatitis b virus |
| WO2020016427A1 (en) * | 2018-07-19 | 2020-01-23 | Ospedale San Raffaele S.R.L. | Inhibitors of hepatitis b virus |
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