CN116199730A - 4-thiouracil ribonucleoside phosphate compound, and preparation method and application thereof - Google Patents

4-thiouracil ribonucleoside phosphate compound, and preparation method and application thereof Download PDF

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CN116199730A
CN116199730A CN202310446425.4A CN202310446425A CN116199730A CN 116199730 A CN116199730 A CN 116199730A CN 202310446425 A CN202310446425 A CN 202310446425A CN 116199730 A CN116199730 A CN 116199730A
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thiouracil
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鲍甫义
袁仁涛
吴军
杨丽
刘嘉玲
杨梦琪
王伯全
潘永利
施建钢
朱刚
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Guoqing Biomedical Shanghai Co ltd
Guoqing Future Co ltd
Nanjing Yiyuan Biomedical Research Institute Co ltd
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Abstract

The invention discloses a 4-thiouracil ribonucleoside phosphate compound, a preparation method and application thereof, and provides the 4-thiouracil ribonucleoside phosphate compound or pharmaceutically acceptable salt thereof, the structure of which is shown as a structural formula I. The invention proves that the 4-thiouracil ribonucleoside phosphate compound has anti-HBV activity through an in vitro cytotoxicity test and an in vitro anti-HBV drug effect test, has anti-HBV drug development prospect, and provides a potential choice for treating viral hepatitis.
Figure ZY_1

Description

4-thiouracil ribonucleoside phosphate compound, and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a 4-thiouracil ribonucleoside phosphate compound, and a preparation method and application thereof.
Background
Hepatitis B Virus (HBV) infection is a disease caused after infection of the body with HBV. Hepatitis B virus is a hepadnavirus, mainly exists in liver cells and damages the liver cells, and causes inflammation, necrosis and fibrosis of the liver cells, thereby causing liver cirrhosis and liver cancer. In the last 80 th century, the world of anti-hepatitis B virus drugs have been greatly developed, and clinical antiviral therapy has been a great progress. The anti-HBV medicine mainly comprises interferon and nucleotide, and the nucleotide is used as main chemical medicine for treating HBV, and is successively put into the market. The medicine has certain curative effect on hepatitis B virus. However, the existing nucleoside (nucleotide) anti-hepatitis B virus medicines have the defects of long administration time, easy virus resistance and rebound after stopping the medicine. Therefore, the new anti-hepatitis B virus medicine is continuously innovated, and a new choice is provided for the medicine for treating hepatitis B, thereby having important significance. A 4-thiodeoxythymidine derivative or a pharmaceutically acceptable salt thereof (CN 113461760A) has been proposed in the prior art, in which an in vitro cytotoxicity test and an in vitro anti-HBV virus efficacy test are performed, but in order to solve the drug resistance caused by long-term use thereof, it is required to provide a 4-thiouracil ribonucleoside phosphate compound of more structure.
Disclosure of Invention
The invention aims to: aiming at the prior art, the invention provides a 4-thiouracil ribonucleoside phosphate compound, which has better anti-hepatitis B virus effect than the prior medicine, better ester solubility and easier cell entry, is a high-efficiency hepatitis B therapeutic medicine with a new structure because of being phosphorylated by phosphatase two and three in the cell.
The invention also provides an application of the preparation method of the 4-thiouracil ribonucleoside phosphate compound.
The technical scheme is as follows: the invention relates to a 4-thiouracil ribonucleoside phosphate compound, which has a structure shown in a formula I:
Figure SMS_1
。
preferably, the base moiety of the compound is a natural or synthetic base, and may be replaced with adenine, guanine, cytosine, uracil or thymine in addition to 4-thiouracil.
The invention relates to a method for synthesizing a 4-thiouracil ribonucleoside phosphate compound or pharmaceutically acceptable salt thereof, the synthetic route is as follows:
Figure SMS_2
。
the synthesis method comprises the following steps:
(1) Mixing uracil (2R, 3S,4S, 5S) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-triacetate, BAS and an organic solvent, carrying out reflux reaction, adding TMSOTF, continuously heating and refluxing, naturally cooling the reaction solution to room temperature, filtering, washing, drying, concentrating under reduced pressure to obtain a crude product compound 2, and directly carrying out the next step without purifying the crude product;
(2) Mixing the compound 2 with an organic solvent, heating and stirring until the system is dissolved, adding a Lawson reagent, continuing to react, cooling the reaction liquid to room temperature, filtering, directly concentrating the filtrate under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound 3;
(3) Compound 3 was mixed with an methanolic ammonia solution, stirring and reacting at room temperature, the reaction solution is directly decompressed and concentrated to obtain crude compound 4, and the crude product is directly subjected to the next step without purification;
(4) Mixing the compound 4, p-toluenesulfonic acid monohydrate, 2-dimethylpropane and an organic solvent, stirring at room temperature for reaction, regulating pH value of a reaction solution, directly concentrating the system under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound 5;
(5) Mixing compound 5, (S) -2-ethylbutyl 2- ((((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) amino) propionate, magnesium dichloride and an organic solvent, stirring for reaction, adding DIPEA, continuously stirring for reaction, diluting the reaction solution, washing, drying, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound 6;
(6) And mixing the compound 6 with an organic solvent, stirring at room temperature for reaction, directly concentrating the reaction solution under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a final product Q5.
Wherein step (1) is carried out by mixing compound 1, (2R, 3S,4S, 5S) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-triacetate, BAS and acetonitrile at room temperature, and then under inert gas protection for 90-100 o Reflux reaction for 2-3 hr, adding TMSOTf, and heating reflux is continued for 16-20h.
Preferably, step (1) is carried out by mixing compound 1, (2R, 3S,4S, 5S) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-triacetate, BAS and acetonitrile at room temperature, and then subjecting to 90 under inert gas atmosphere o Reflux reaction of C for 2h, adding TMSOTF, and heating and refluxing for 16h.
Wherein step (2) is carried out by reacting compound 2 with toluene at room temperature at 90-100 o C, heating and stirring until the system is dissolved, adding Lawson reagent, and carrying out 90-100 o C continues to react for 2-3h.
Preferably, step (2) is performed by reacting compound 2 with toluene at room temperature at 100 o C, heating and stirring until the system is dissolved, adding Lawson reagent, and 100 o C the reaction was continued for 2h.
Wherein, in the step (4), the compound 4, acetone, p-toluenesulfonic acid monohydrate and 2, 2-dimethylpropane are mixed at room temperature, stirred at room temperature for reaction for 2-3h, and the pH of the reaction solution is regulated to 7-8.
Preferably, in the step (4), the compound 4, acetone, paratoluenesulfonic acid monohydrate and 2, 2-dimethylpropane are mixed at room temperature, stirred at room temperature for 2 hours, and triethylamine is slowly added dropwise to the reaction solution to adjust the pH to 8.
Wherein step (5) is a mixture of compound 5, (S) -2-ethylbutyl 2- ((((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) amino) propionate, magnesium dichloride, and acetonitrile at room temperature, 50-60 o C stirring for reacting for 10-15 min, adding DIPEA, and continuing for 50-60 min o C, stirring and reacting for 15-16h.
Preferably, step (5) is a mixture of compound 5, (S) -2-ethylbutyl 2- ((((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) amino) propionate, magnesium dichloride, and acetonitrile at room temperature, 50 o C stirring and reacting for 15min, adding DIPEA, and continuing for 50 min o C, stirring and reacting for 16h.
And (3) mixing the compound 6 with a formic acid solution at room temperature, stirring at room temperature for reaction for 15-16h, directly concentrating the reaction solution under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a final product Q5.
Preferably, in the step (6), the compound 6 and the formic acid solution are mixed at room temperature, stirred at room temperature for reaction for 16 hours, the reaction solution is directly concentrated under reduced pressure to obtain a crude product, and the crude product is separated by column chromatography to obtain a final product Q5.
The pharmaceutical composition comprises the 4-thiouracil ribonucleoside phosphate compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The invention relates to 4-thiouracil ribonucleoside phosphate or pharmaceutically acceptable salt thereof, or application of the pharmaceutical composition in preparation of medicaments for treating hepatitis virus.
The pharmaceutical composition comprises an effective amount of the 4-thiouracil ribonucleoside phosphate or pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, solvate or crystal form thereof, and pharmaceutically acceptable excipient.
Wherein the medicine or the medicine combination is prepared into any dosage form in pharmacy, including capsules, powder, tablets, granules, pills, injection, syrup, oral liquid, inhalants, ointments, suppositories or patches.
The invention provides a 4-thiouracil ribonucleoside phosphate compound with a novel structure, which has very good HBV inhibition rate and novel structure, and can solve the problem of drug resistance of the existing compound.
The beneficial effects are that: compared with the prior art, the invention has the following advantages:
the invention discloses 4-thiouracil ribonucleoside phosphate or pharmaceutically acceptable salt thereof, and designs a synthetic method route thereof, wherein the route has simple steps and high product yield.
The compound of the invention has anti-HBV activity through in vitro cytotoxicity test and in vitro anti-HBV drug effect test, and has better effect than positive control and the compound with the existing similar structure, and has anti-HBV drug development prospect.
Drawings
FIG. 1 is a diagram of compound Q5 1 HNMR spectra.
Fig. 2 is a mass spectrum of compound Q5.
Detailed Description
The present invention will be described in detail with reference to the following examples.
Example 1
The synthetic route is as follows:
Figure SMS_3
the first step of synthesis:
to a 1L three-necked flask, a reaction mixture of compound 1 (2 g,78.55 mmol, michael), (2R, 3S,4S, 5S) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-triacetate (26.4 g,235.64 mmol, ramboo), BSA (48 g,235.64 mmol, taan) and acetonitrile (380 mL, taan) was sequentially added at room temperature under argon substitution and argon protection, the oil bath was heated to 90℃and heated to reflux for 2h, TMSOTF (26 g,116.25 mmol,adamas) was added, and the heating reflux was continued for 16h, followed by sampling TLC detection, and the reaction of the starting materials was completed. Post-treatment: the reaction solution was cooled to room temperature naturally, a saturated sodium hydrogencarbonate (200 mL) solution and ethyl acetate (500 mL) were added, the filtrate was filtered to separate an aqueous phase, the organic phase was washed with water (100 mL) twice, saturated brine was washed once, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give crude compound 2 (32.3 g, yellow oil). The crude product was carried forward directly to the next step without purification.
Second step and (3) synthesis:
compound 2 (14 g, 37.81 mmol) and toluene (300 mL, national medicine) are sequentially added into a 500 mL three-mouth bottle at room temperature, the temperature of an oil bath is raised to 100 ℃ and stirred until the system is dissolved, then Lawson reagent (16.8 g,415.87 mmol,adamas) is added, the reaction is continued for 2 hours at 100 ℃, the detection is carried out by sampling TLC, and the reaction of the raw materials is completed. Post-treatment: the reaction solution was naturally cooled to room temperature, filtered, and the filtrate was directly concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give compound 3 (11.1 g, yellow oil, yield: 76%).
And thirdly, synthesizing:
to a 500 mL single-vial was added compound 3 (11.1 g, 28.73 mmol) and methanolic ammonia (250 mL, meyer, 7M) at room temperature, stirred at room temperature for 16h, detected by sample TLC, and the reaction was complete. Post-treatment: the reaction solution was concentrated directly under reduced pressure to give crude 4 (12.2. 12.2 g, deep yellow oil), which was carried forward directly without purification.
Fourth step of synthesis:
to a 500 mL three-necked flask were added compound 4 (12.2 g,46.88 mmol) and acetone (250 mL, tetan), and p-toluenesulfonic acid monohydrate (8.9 g,46.88 mmol, lesion) and 2, 2-dimethylpropane (48.8 g,468.76mmol, michael) at room temperature, followed by stirring at room temperature for 2 hours, and sampling TLC detection was performed to complete the reaction of the starting materials. Post-treatment: triethylamine is slowly added dropwise to the reaction solution, the pH=8 is regulated, the system is directly concentrated under reduced pressure to obtain a crude product, and the crude product is separated by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain a compound 5 (5.5 g, yellow solid).
Fifth step of synthesis:
to a 100 mL single vial was added compound 5 (1.2 g,3.99 mmol), (S) -2-ethylbutyl 2- ((((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) amino) propionate (4.5 g,9.99 mmol, after completion), magnesium dichloride (570 mg,3.99 mmol, microphone) and acetonitrile (800 mL, tautan) at room temperature, the oil bath was warmed to 50 ℃ and stirred for 15min, DIPEA (2.58 g,19.98 mmol,adamas) was further added, the reaction mixture was stirred for 16h at 50 ℃, sampling TLC was detected, the reaction mixture was worked up after completion, diluted with ethyl acetate (200 mL), washed once with 1M citric acid, twice with water, saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, which was separated by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1-1/1) to give compound 6 (2.3 g, yellow solid).
Sixth step of synthesis:
to a 25 mL single vial was added compound 6 (2.3 g,3.78 mmol) and 80% formic acid solution (25 mL, adamas) at room temperature, stirred at room temperature for 16h, and sampled for TLC detectionAnd (5) measuring the reaction of the raw materials. Post-treatment: the reaction solution was concentrated directly under reduced pressure to give a crude product, which was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1-1/2) to give the final product Q5 (1.1 g, yellow solid). 1 The HNMR spectrum is shown in FIG. 1, and the mass spectrum is shown in FIG. 2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.71 (s,1H), 7.50 (d, 1H), 7.37 (t, 2H), 7.23 – 7.17 (m, 3H), 6.20 (d, 1H), 6.10 (dd, 1H), 5.73 (d,1H), 5.56 (d, 1H), 5.30 (d, 1H), 4.22-4.20 (m, 1H), 4.14-4.02 (m, 1H), 4.01-3.867 (m,6H), 1.47-1.44 (m, 1H), 1.31-1.24 (m,7H), 0.82 (t,6H)。
Example 2
In vitro anti-HBV Activity assay
Tibifdine (available from Shanghai taitan technologies Co., ltd.), hepG2.2.15 cells (supplied from the institute of antiviral drugs, university of double denier pharmaceutical Co., ltd.), fetal Bovine Serum (FBS) (available from Sairo Feisha Biochemical Co., ltd.), DMEM medium (Sairo Feisha Biochemical Co., ltd.), carbon dioxide incubator (Sairo Feisha Biochemical Co., ltd.), fluorescent quantitative PCR (Sairo Feisha Biochemical Co., ltd.).
The test medicine prepared by the embodiment of the invention is used for in-vitro anti-HBV drug effect evaluation test, and comprises the following steps:
detection of antiviral activity of the drug: taking 1 bottle of HepG2.2.15 cells with good growth, digesting with pancreatin to obtain single cell suspension, counting with cell counting plate, adjusting cell density to 2×10 with DMEM medium containing 10% FBS serum 5 Each mL was inoculated into a culture plate (96 wells, 100uL per well). Placing in a carbon dioxide incubator in 5% CO 2 Incubation at 37 ℃ to 80% contact inhibition. The supernatant was aspirated, and test drug broth was added, together with a positive control drug, telbivudine broth, at the corresponding concentration, and cell blank control wells were also provided. 3 duplicate wells were set per concentration gradient and cell blank. Placing in a carbon dioxide incubator, culturing at 37deg.C for 6d, sucking supernatant, centrifuging, and detecting HBV-DNA content in supernatant by fluorescent quantitative PCR method, and the result is shown in Table 1.
TABLE 1 in vitro anti-HBV Activity assay
Figure SMS_4
From Table 1, it can be seen that the inhibition rate of compound Q5 to HBV is significantly better than that of the positive control drug telbivudine and compound Q21 in the prior art, and the inhibition effect is improved by about 371%.

Claims (10)

1. A 4-thiouracil ribonucleoside phosphate compound or a pharmaceutically acceptable salt thereof, which is characterized by having a structure as shown in formula I:
Figure QLYQS_1
。
2. the 4-thiouracil ribonucleoside-phosphate compound according to claim 1, wherein the base moiety of the compound is a natural or synthetic base, other than 4-thiouracil, or adenine, guanine, cytosine, uracil or thymine, or a pharmaceutically acceptable salt thereof.
3. A method of synthesizing a 4-thiouracil ribonucleoside phosphate compound according to claim 1, or a pharmaceutically acceptable salt thereof, which comprises the following synthetic routes:
Figure QLYQS_2
；
the synthesis method comprises the following steps:
(1) Mixing uracil (2R, 3S,4S, 5S) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-triacetate, BSA and an organic solvent, carrying out reflux reaction, adding TMSOTF, continuously heating and refluxing, cooling the reaction liquid to room temperature, filtering, washing, drying, concentrating under reduced pressure to obtain a crude product compound 2, and directly carrying out the next step without purifying the crude product;
(2) Mixing the compound 2 with an organic solvent, heating and stirring until the system is dissolved, adding a Lawson reagent, continuing to react, cooling the reaction liquid to room temperature, filtering, directly concentrating the filtrate under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound 3;
(3) Mixing the compound 3 with an ammonia methanol solution, stirring at room temperature for reaction, directly concentrating the reaction solution under reduced pressure to obtain a crude product compound 4, and directly carrying out the next step without purifying the crude product;
(4) Mixing the compound 4, p-toluenesulfonic acid monohydrate, 2-dimethylpropane and an organic solvent, stirring at room temperature for reaction, adjusting pH after the reaction is finished, directly concentrating the system under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound 5;
(5) Mixing compound 5, (S) -2-ethylbutyl 2- ((((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) amino) propionate, magnesium dichloride and an organic solvent, stirring for reaction, adding DIPEA, continuously stirring for reaction, diluting the reaction solution, washing, drying, concentrating under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound 6;
(6) And mixing the compound 6 with an organic solvent, stirring at room temperature for reaction, directly concentrating the reaction solution under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a final product Q5.
4. The synthesis method according to claim 3, wherein step (1) comprises mixing uracil, (2R, 3S,4S, 5S) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-triacetate, BSA and acetonitrile at room temperature, and then subjecting to 90-100 under inert gas atmosphere o And C, carrying out reflux reaction for 2-3h, adding TMSOTF, and continuously heating and refluxing for 16-20h.
5. The synthetic method according to claim 3, wherein the step (2) comprises mixing the compound 2 with toluene at room temperature at 90 to 100 o C, heating and stirring until the system is dissolved, adding Lawson reagent, and carrying out 90-100 o C continues to react for 2-3h.
6. The method according to claim 3, wherein the step (4) is carried out by mixing the compound 4, p-toluenesulfonic acid monohydrate, 2-dimethylpropane and acetone at room temperature, stirring at room temperature, reacting for 2-3 hours, and adjusting pH to 7-8 after the reaction.
7. The method of synthesis according to claim 3, wherein step (5) is a mixture of compound 5, (S) -2-ethylbutyl 2- ((((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) amino) propionate, magnesium dichloride and acetonitrile at room temperature, 50-60 o C stirring for reacting for 10-15 min, adding DIPEA, and continuing for 50-60 min o C, stirring and reacting for 15-16h.
8. The synthesis method according to claim 3, wherein in the step (6), the compound 6 and the formic acid solution are mixed at room temperature, stirred at room temperature for reaction for 15-16 hours, the reaction solution is directly concentrated under reduced pressure to obtain a crude product, and the crude product is separated by column chromatography to obtain a final product Q5.
9. A pharmaceutical composition comprising the 4-thiouracil ribonucleoside phosphate compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. Use of a 4-thiouracil ribonucleoside phosphate compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of hepatitis virus.
CN202310446425.4A 2023-04-24 2023-04-24 4-thiouracil ribonucleoside phosphate compound, and preparation method and application thereof Pending CN116199730A (en)

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CN114230623A (en) * 2022-02-24 2022-03-25 南京颐媛生物医学研究院有限公司 2-thio-N-hydroxyl cytosine ribonucleoside phosphate and antiviral drug application thereof

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