CN115894588A - L-2 '-deoxy-2' -beta-fluorothymidine prodrug derivative and application thereof - Google Patents
L-2 '-deoxy-2' -beta-fluorothymidine prodrug derivative and application thereof Download PDFInfo
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Abstract
The present invention relates to prodrug derivatives of L-2 '-deoxy-2' -beta-fluorothymidine described by the general formula (I), which can be used for the treatment and prevention of hepatitis B virus infection, and also relates to a pharmaceutical composition containing the general formula (I), and the use thereof for the treatment and prevention of hepatitis B infection.
Description
Technical Field
The invention belongs to the field of virus prevention and control. In particular, the present invention relates to a prodrug derivative of L-2 '-deoxy-2' - β -fluorothymidine, a pharmaceutical composition comprising the derivative and its use, in particular for the treatment or prevention of viral diseases such as hepatitis b.
Background
Hepatitis virus infection is a major public health problem affecting approximately 20 million people worldwide. About 3.5 million of these people develop chronic infections that can lead to chronic persistent hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Every year, 50 to 100 million people die from end-stage liver disease caused by hepatitis b virus infection.
Hepatitis B virus is a small virus, which cannot be cured at present, only two drugs of interferon and nucleoside HBV reverse transcriptase inhibitors exist, and nucleoside drugs have no synergistic effect and cannot be used in combination. Therefore, there is still a need in the art to develop drugs for the treatment and prevention of hepatitis b.
Disclosure of Invention
The present invention provides compounds of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof:
wherein the content of the first and second substances,
r1 is selected from C2-C20 aliphatic carboxylic acid acyl, C4-C20 alicyclic carboxylic acid acyl or benzoyl;
r2 is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C8 lipo-heterocycle, C6-C10 aryl, C5-C9 heteroaryl, arylalkyl, heteroarylalkyl, or lipo-heterocyclylalkyl, R2 may be substituted with 1 to 3 independent substituents X, Y or Z replacing 1 to 3 hydrogens;
in one aspect, the nucleoside compound of formula I or a pharmaceutically acceptable salt or ester thereof, is characterized in that the phosphorus atom in the compound is chiral, and the configuration is R-configuration or S-configuration, or a mixture of S-configuration and R-configuration, as shown in Ia and Ib.
In another aspect, the nucleoside compound of formula I, or a pharmaceutically acceptable salt or ester thereof, is characterized in that the alanine ester or amide in formula I has chirality, and the configuration is S-configuration or R-configuration, or a mixture of S-configuration and R-configuration, as Ic and Id.
In another aspect, nucleoside compounds of formulae I, ia, ib, ic and Id, or pharmaceutically acceptable salts or esters thereof, are characterized by: the R1 is selected from C2-C20 fatty carboxylic acid acyl, C4-C20 alicyclic carboxylic acid acyl or benzoyl, preferably, R1 is C2-C20 fatty carboxylic acid acyl, and more preferably, R1 is C5-C7 fatty carboxylic acid acyl. The aliphatic acyl and aromatic acyl groups may be substituted, with 1 to 3 hydrogens above R1 being replaced by X, Y OR Z substituents, X, Y OR Z being selected from halogen, hydroxy, amino, C1-C4 alkyl, C3-C6 cycloalkyl, -C (O) NRR', -C (O) OR; r and R' are each independently selected from H, C, a C4 alkyl, a C3-5 alkenyl, a C3-C5 alkynyl, a C3-C6 cycloalkyl;
in another aspect, nucleoside compounds of formulae I, ia, ib, ic and Id, or pharmaceutically acceptable salts or esters thereof, are characterized by: r2 is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C8 aliphatic heterocycle, C6-C10 aryl, C5-C9 heteroaryl, arylalkyl, heteroarylalkyl or aliphatic heterocyclylalkyl, preferably, R2 is C1-C8 alkyl or benzyl. R2 may be substituted, 1 to 3 hydrogens are replaced with 1-3 independent substituents X, Y or Z, X, Y or Z is selected from halogen, -N3, C1-C4 alkyl, C3-5 alkenyl, C3-C5 alkynyl, C3-C6 cycloalkyl;
in another aspect, nucleoside compounds of formulae 1, ia, ib, ic and Id, or pharmaceutically acceptable salts or esters thereof, characterized by the fact that they may include but are not limited to the following structures:
in another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, which further comprises a combination of other therapeutic agents, such as entecavir, adefovir dipivoxil, an interferon, a hepatitis b virus capsid protein inhibitor, or HBV RNAi.
In another aspect, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of viral infections, in particular hepatitis b virus or herpes virus infections.
In another aspect, the present invention provides a method of treating and/or preventing a viral infection, in particular a hepatitis b virus infection, in a subject comprising administering to said subject a compound of the invention or a composition of the invention.
In another aspect, the present invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of a viral infection, in particular a hepatitis b virus infection.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.
Detailed Description
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are carried out, prepared, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what is claimed herein.
In the following examples, all water sensitive reactions were carried out under dry conditions. Benzene and tetrahydrofuran are refluxed, dried and distilled in the presence of metal sodium, and 1,2-dichloroethane or dichloromethane is refluxed, dried and distilled in the presence of phosphorus pentoxide, and then is stored for later use. All intermediates were purified by silica gel chromatography to give all final compounds greater than 95% purity. All reported yields were not optimized.
Example 1
Intermediate 2:
compound 1 (10g, 21.6 mmol) was dissolved in 100mL of anhydrous dichloromethane, DAST (9mL, 68.12mmol) was slowly dropped at room temperature, the mixture was refluxed for 24 hours, after cooling, 100mL of dichloromethane was added to dilute the solution, the organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (100 mLx 2), the mixture was dried, filtered and concentrated, and the residue was subjected to silica gel column chromatography (CHCl 2) 3 ) Purification gave intermediate 2 as a colourless foam (10.03g, 81%).
Intermediate 3:
an acetic acid solution (4 mL) of 30% HBr was slowly added to a solution of compound 2 (2.2 g, 4.85mmol) in anhydrous dichloromethane (30 mL) at room temperature, the reaction mixture was stirred at room temperature for 24 hours, the organic phase was washed with a saturated aqueous sodium bicarbonate solution, and the separated organic phase was treated with Na 2 SO 4 Drying, dichloromethane solution was filtered through a short column of silica gel, washed with ethyl acetate, and the filtrate was concentrated and dried to give intermediate 3 (2.05g, 99%).
Intermediate 4:
a solution of thymine (2.9g, 23mmol), ammonium sulfate (0.16g, 0.1mmol), HMDS (12.0g, 74.4mmol) and N, O-bistrimethylsilylacetamide (0.3g, 1.5 mmol) in 1,2-dichloroethane (60 mL) was refluxed to give a clear solution. A solution of intermediate 3 (2.79g, 6.59mmol) in 1,2-dichloroethane (20 mL) was then added to the thymine siliconized solution and the reaction solution was refluxed for an additional 30 hours. After cooling, concentration was carried out under reduced pressure, and the residue was separated by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain product 4 (1.52g, 48%) as a white foam.
Intermediate 5:
compound 4 (1.52g, 3.2mmol) was dissolved in a saturated methanolic ammonia solution (20 mL), the reaction mixture was stirred overnight at room temperature, the solvent was evaporated off by concentration under reduced pressure, and the residue was taken upPurification by silica gel column chromatography (dichloromethane: methanol = 9: 1) gave nucleoside intermediate 5 (0.79g, 95%). 1 H NMR(500MHz，DMSO-d6)δ11.42(s，1H)，7.60(s，1H)，6.10(dd，J＝15.6Hz 1H)，5.86(d，J＝5.1Hz，1H)，5.1(t，J＝5.6Hz，1H)，5.01-5.03(m，1H)，4.21-4.22(m，1H)，3.75-3.77(m，1H，)，3.57-3.68(m，2H)，1.78(s，3H)。
Example 2
Intermediate 7:
to a THF solution (10 mL) of compound 5 (260mg, 1mmol) at 0 ℃ was added dropwise t-butylmagnesium chloride Grignard reagent (1M, 3mL, 3mmol) and stirred for 30 minutes, then a THF solution (10 mL) of compound 6 (680 mg, 1.5mmol) was slowly added to the reaction flask, the reaction mixture was stirred at room temperature for 24 hours, isopropanol (1 mL) was added to quench the reaction, the residue was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give product 7 (262mg, 51%) as a white solid, MS m/z = 530M + H +.
Compound 8:
to a solution of intermediate 7 (200mg, 0.37mmol) and DMAP (5mg, 40. Mu. Mol) in tetrahydrofuran (10 mL) at 0 ℃ was added Et 3 N (0.16mL, 1.12mmol), was stirred at 0 ℃ for 5 minutes, and isobutyryl chloride (40mg, 0.37mmol) was slowly added to the reaction mixture. After 60 min of reaction the reaction was quenched by addition of aqueous HCl (1M, 50mL), the mixture was extracted with EtOAc (2X 50 mL), and the combined organic phases were washed with water and brine, over MgSO 4 Drying, filtering and concentrating. The residue was purified by silica gel column chromatography (10% MeOH/DCM) to give product 8 as a white solid (167mg, 75%). 1 H NMR(400MHz，DMSO-d6)δ7.65(t，J＝1.4Hz，1H)，7.35-7.41(m，2H)，7.20-7.31(m，3H)，6.15(dd，J＝15.4，4.3Hz，1H)，5.61-5.64(m，1H)，4.94-5.09(m，2H)，3.76-4.06(m，3H)，3.33-3.45(m，1H)，2.46-2.37(m，1H)，1.82(m，3H)，1.35-1.44(m，6H)，1.10-1.16(m，9H)； 31 P NMR(162MHz，MeOH-d4)δ3.22；MS m/z＝600[M+H] + 。
Example 3
Intermediate 10:
to a THF solution (10 mL) of compound 5 (260mg, 1mmol) at 0 ℃ was added dropwise t-butylmagnesium chloride Grignard reagent (1M, 3mL, 3mmol) and stirred for 30 minutes, followed by slowly adding a THF solution (10 mL) of compound 9 (680 mg, 1.5mmol) to the reaction flask, the reaction mixture was stirred overnight at room temperature, isopropanol (1 mL) was added to quench the reaction, after concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give a white solid product 10 (226mg, 44%), MS m/z =530 ], (M + H + C)] + 。
Compound 11:
DCC (116mg, 0.56mmol) was added to a dioxane solution (10 mL) of isobutyric acid (50mg, 0.56mmol) at 0 deg.C, and the mixture was stirred at room temperature for 30min and then cooled to 0 deg.C. To the above reaction solution were added intermediate 10 (200mg, 0.37mmol), DMAP and Et 3 N (0.16mL, 1.12mmol), and the reaction was carried out at room temperature for 24h. The reaction was taken up in water (40 mL), the mixture was extracted with EtOAc (3X 50 mL), and the combined organic phases were washed with water and brine, over MgSO 4 Drying, filtering and concentrating. The residue was purified by column chromatography on silica gel (10% MeOH/DCM) to give product 11 as a white solid (100mg, 45%). 1 H NMR(400MHz，DMSO-d6)δ7.66(t，J＝1.4Hz，1H)，7.34-7.40(m，2H)，7.20-7.32(m，3H)，6.14(dd，J＝15.4，4.3Hz，1H)，5.61-5.64(m，1H)，4.92-5.07(m，2H)，3.79-4.05(m，3H)，3.35-3.45(m，1H)，2.49-2.37(m，1H)，1.81(m，3H)，1.35-1.43(m，6H)，1.10-1.16(m，9H)； 31 P NMR(162MHz，MeOH-d4)δ3.29；MS m/z＝600[M+H] + 。
Example 4 in vitro activity assay for HBV
The experimental method comprises the following steps:
HepG2.2.15 cells were seeded in 96-well microplates at a density of 3X 104 cells per well of 0.1mL medium and the plates were incubated overnight at 37 ℃. The next day will beTest compounds were serially diluted in DMSO to different concentrations, and then 100 μ L of decreasing compound DMSO solution was added to the wells on the plate such that the final concentration of DMSO in each well was 0.5%. Five days after compound exposure, culture supernatants were collected for further analysis. For extracellular HBV DNA quantitative detection by PCR, 100. Mu.L of culture supernatant was collected and subjected to viral DNA extraction in the Magna Pure 96 nucleic acid purification system. The extracted samples were quantified for HBV DNA by qPCR and the concentration of the compound (EC) at which 50% of HBV replication was inhibited was determined 50 )。
The experimental results are as follows:
the compounds of the invention were tested for their ability to inhibit HBV replication in vitro as described above and the results are shown in the following table:
| compound (I) | EC 50 (μM) | Compound (I) | EC 50 (μM) | Compound (I) | EC 50 (μM) |
| 5 | 0.1 | 7 | 0.3 | 8 | 0.02 |
| 10 | 3.6 | 11 | 0.5 | 3TC | 0.1 |
Conclusion of the experiment
In vitro activity experiments demonstrated that, by comparing response compounds 7 and 8, and 10 and 11, it can be seen that when 3' -hydroxyl of nucleoside prodrug 7 and 10 is protected by isobutyrate esterification, the HBV activity of the resulting novel prodrug compounds 8 and 11 is increased by 15-fold and 7-fold, respectively. The above results are mutually confirmed with the pharmacokinetic experiments in rats.
Example 5 rat pharmacokinetic experiments
Pharmacokinetic experiments with CD-1 mice, dosing was a single gavage with 25mg/kg equivalents of the parent nucleoside 5, i.e., 50mg/kg for prodrugs 7 and 10 and 58mg/kg for prodrugs 8 and 11. Liver samples were taken at 0.5, 1,2, 4, 6, 12, 24 hours post-dose. When sampling, mice were first CO-administered 2 Sacrificed, livers washed with ice cold saline through the hepatic portal vein, cut into small pieces of approximately 0.2 grams of liver samples, snap frozen in liquid nitrogen, and stored at-80 ℃. The liver samples were analyzed by LC-MS/MS for active species nucleoside triphosphates. Detecting and quantifying the sample to be detected on a liquid chromatograph-mass spectrometer, detecting the exposure of the active compound, and calculating to obtain C max (ng/g)、t max (h)、AUC(0-t)(ng.h/g)、AUC(inf)(ng.h/g)。
| Compound (I) | Unit of | 5 | 7 | 8 | 10 | 11 |
| T max | hr | 3 | 3 | 4 | 4 | 6 |
| C max | ng/g | 1560 | 1780 | 2970 | 2210 | 5260 |
| AUC last | ng.h/g | 9940 | 11026 | 17869 | 14507 | 27362 |
| AUC inf | ng.h/g | NA | NA | 18753 | NA | NA |
Pharmacokinetic studies have shown that for nucleoside parent compound 5, the corresponding phosphoramidate prodrug 7 and 10 are compared, and that the D-alanine ester prodrug 10 has greater stability and liver targeting properties; after the 3' -hydroxyl is protected by isobutyrate, the generated double prodrugs 8 and 11 have better stability and liver targeting compared with corresponding phosphoramidate prodrugs 7 and 10. In combination with the results of the in vitro HBV activity test described above, the compounds 8 and 10 claimed in this patent had better drugability.
Claims (9)
1. A compound for use in treating a viral infection, the method comprising administering to a patient a therapeutically effective amount of a nucleoside compound represented by formula I:
wherein the content of the first and second substances,
R 1 selected from C2-C20 aliphatic carboxylic acid acyl, C4-C20 alicyclic carboxylic acid acyl or benzoyl;
R 2 selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C8 aliphatic heterocycle, C6-C10 aryl, C5-C9 heteroaryl, arylalkyl, heteroarylalkyl, or aliphatic heterocyclylalkyl, R2 may be substituted with 1 to 3 independent substituents X, Y or Z having 1 to 3 hydrogens replaced.
2. The nucleoside compound according to claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein the phosphorus atom in the compound of formula I is chiral, and the configuration thereof is R-configuration or S-configuration, or a mixture of S-configuration and R-configuration, as shown in Ia and Ib.
3. The nucleoside compound according to claim 1, or a pharmaceutically acceptable salt or ester thereof, characterized in that the alanine ester or amide of formula I has chirality, the configuration is S-configuration or R-configuration, or a mixture of S-configuration and R-configuration, as indicated by Ic and Id.
4. A nucleoside compound according to claims 1 to 3, or a pharmaceutically acceptable salt or ester thereof, wherein: the R is 1 Selected from C2-C20 aliphatic carboxylic acid acyl, C4-C20 alicyclic carboxylic acid acyl or benzoyl, preferably, R 1 Is C2-C20 fatty carboxylic acyl. The aliphatic acyl and aromatic acyl groups may be substituted, R may be replaced by a substituent X, Y or Z 1 The above 1 to 3 hydrogens, X, Y OR Z is selected from the group consisting of halogen, hydroxy, amino, C1-C4 alkyl, C3-C6 cycloalkyl, -C (O) NRR', -C (O) OR; r and R' are each independently selected from H, C1-C4 alkyl, C3-5 alkenyl, C3-C5 alkynyl, C3-C6 cycloalkyl.
5. A nucleoside compound according to claims 1-3, or a pharmaceutically acceptable salt or ester thereof, wherein: r2 is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C8 aliphatic heterocycle, C6-C10 aryl, C5-C9 heteroaryl, arylalkyl, heteroarylalkyl or aliphatic heterocyclylalkyl, preferably R2 is selected from C1-C8 alkyl or benzyl. R2 may be substituted by 1 to 3 independent substituents X, Y or Z replacing 1 to 3 hydrogens, X, Y or Z is selected from halogen, -N 3 C1-C4 alkyl, C3-C5 alkenyl, C3-C5 alkynyl, C3-C6 cycloalkyl.
6. A nucleoside compound according to claims 1 to 5, or a pharmaceutically acceptable salt or ester thereof, characterized by comprising the structure but not limited to:
7. use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of viral infections, in particular hepatitis b or herpes viral infections.
8. A pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and a pharmaceutically acceptable excipient; it may also contain other therapeutic agents such as entecavir, adefovir dipivoxil, interferon, hepatitis b virus capsid protein inhibitor, or HBV RNAi.
9. A method of treating and/or preventing a viral infection, in particular a hepatitis b virus infection, in a subject, the method comprising administering to the subject a compound of any one of claims 1-6 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition of claim 8.
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