CN111620909B - Prodrug of Reidesvir, preparation method and application thereof - Google Patents
Prodrug of Reidesvir, preparation method and application thereof Download PDFInfo
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- CN111620909B CN111620909B CN202010503526.7A CN202010503526A CN111620909B CN 111620909 B CN111620909 B CN 111620909B CN 202010503526 A CN202010503526 A CN 202010503526A CN 111620909 B CN111620909 B CN 111620909B
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a prodrug of Reidesciclovir and a preparation method and application thereof. The structural formula of the prodrug of the Reidesciclovir is shown in a formula I. The concentration of R0 in blood after the obtained compound is subjected to intragastric administration is detected by adopting a liquid chromatography-mass spectrometer, and through contrast study by adopting Reidesciclovir injection and intragastric administration, the modified compound is found to have better bioavailability, and the concentration of R0 in blood exceeds 50 percent of the average value of an injection administration group and exceeds more than 3 times of that of an oral Reidesciclovir hydrochloride administration group.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a prodrug of Reidesvir, and a preparation method and application thereof.
Background
Remdesivir (Remdesivir), also known as Tenedivir, is a novel experimental broad-spectrum antiviral drug developed by Jilide scientific, USA, used against Ebola virus and believed to be effective in inhibiting the replication of SARS and MERS viruses in airway epithelial cells. This is a prodrug of a nucleotide analogue that inhibits RNA-dependent RNA synthetases. A study conducted in 2020 showed that a combination of ridciclovir and interferon IFNB1 had significant therapeutic effects on MERS.
Reidesciclovir is a nucleoside analogue with antiviral activity having an EC50 value of 74nM for SARS-CoV and MERS-CoV in HAE cells and 30nM for murine hepatitis virus in delayed brain tumor cells.
The structure of the Rudexiwei is as follows:
the administration route of the Reidesciclovir is injection administration, the injection administration has certain limitation, the use is inconvenient, and the risk and the side effect are larger than those of oral administration, so the structural modification of the Reidesciclovir can improve the oral bioavailability, and the important practical significance is realized for obtaining a new medicine which can meet the oral requirement.
Disclosure of Invention
An object of the present invention is to provide a prodrug of Reidesciclovir and pharmaceutically acceptable salts, esters and solvates thereof.
The structural general formula of the prodrug of the Reidesciclovir provided by the invention is shown as formula I:
in the formula I, X is CH 2 O or NH; or, X is absent;
r1 is: C1-C30 alkyl, substituent-substituted C1-C30 alkyl, cycloalkyl, substituent-substituted cycloalkyl, arylalkyl, substituent-substituted arylalkyl, aryl, or substituent-substituted aryl; the substituent in the R1 is selected from at least one of the following groups: amino, hydroxyl, carboxyl and halogen;
r2 is: H. C1-C6 alkylcarbonyl, amino-substituted aralkylcarbonyl, amino and/or halogen-substituted arylcarbonyl;
r3 is: C1-C30 alkyl, C1-C30 alkoxyalkyl, aryl, arylalkyl, hydroxy-or halogen-substituted aryl, or hydroxy-or halogen-substituted arylalkyl;
r4 is: C1-C30 alkyl, C1-C30 alkoxyalkyl, aryl, arylalkyl, hydroxy-or halogen-substituted aryl, or hydroxy-or halogen-substituted arylalkyl;
r5 is: C1-C10 alkyl, cycloalkyl, arylalkyl or aryl.
The above-mentioned substituent-containing group may have a substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
Further, the above cycloalkyl group may be a C3-C8 cycloalkyl group; the above arylalkyl group may be a C1-C6 arylalkyl group such as phenylmethyl; the above aralkylcarbonyl group may be a C1-C6 aralkylcarbonyl group; the halogen refers to F, cl, br or I.
In a further preferred embodiment of the process according to the invention,
in formula I, R1 is: C1-C10 alkyl (such as C3 alkyl, C5 alkyl), substituted C1-C10 alkyl (such as hydroxyethyl, aminoethyl, carboxyethyl), aryl (such as phenyl), arylalkyl (such as phenylalkyl or substituted phenylalkyl, wherein the alkyl can be C1-C10 alkyl);
r2 is: H. C1-C6 alkylcarbonyl (e.g., methylcarbonyl);
r3 is: aryl (e.g., phenyl, naphthyl, substituted phenyl or naphthyl);
r4 is: C1-C10 alkyl (such as 2-ethyl butyl), aryl alkyl (such as phenyl alkyl, wherein the alkyl can be C1-C10 alkyl);
r4 is: C1-C10 alkyl (e.g., methyl).
In some embodiments, the prodrug of ridciclovir of the invention can be enumerated by the following structures, but is not limited to the following structures:
the term "alkyl" as used herein refers to a group consisting of only carbon and hydrogen atoms, and having no unsaturation (e.g., double bonds, triple bonds, or rings), which encompasses a wide variety of possible geometric and stereoisomeric groups. This group is connected to the rest of the molecule by a single bond. By way of non-limiting examples of alkyl groups, mention may be made of the following linear or branched groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and seven further isomers thereof, n-hexyl and sixteen further isomers thereof, n-heptyl and various isomers thereof, n-octyl and various isomers thereof, n-nonyl and various isomers thereof, and n-decyl and various isomers thereof.
The term "cycloalkyl" as used herein refers to a saturated non-aromatic ring system consisting of at least 3 carbon atoms, which may be monocyclic, bicyclic, polycyclic, fused, bridged, or spiro. As non-limiting examples of cycloalkyl groups, the following groups may be cited: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl; and fused, bridged or spiro ring groups formed from two or more of the above monocyclic rings via a common edge and a common carbon atom.
The term "aryl" as used herein, alone or as part of an "arylalkyl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing a total of 6 to 14 membered rings, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 membered rings and only one attachment point is attached to the rest of the molecule.
The term "arylalkyl" as used herein, refers to an alkyl group having one or more hydrogen atoms independently replaced by an aryl group, wherein the aryl and alkyl groups are as defined above. Examples include benzyl, phenylethyl, and the like.
It is a further object of the present invention to provide a process for the preparation of the compounds of formula I as described above.
The invention provides a preparation method of a compound of formula I, which comprises the following steps:
1) Carrying out coupling reaction on 7-bromopyrrolo [1,2-f ] [1,2,4] triazine-4-amine shown in a formula III and acid to obtain an amide compound 4 shown in a formula IV;
wherein the structural formula of the acid is shown as a formula III-1, wherein X and R1 are defined as a formula I;
in the formula IV, X and R1 are defined as the formula III-1;
2) Performing halogen exchange on an amide compound 4 shown in a formula IV and isopropyl magnesium chloride, and performing nucleophilic substitution reaction on the amide compound 4 and 2,3, 5-tribenzyl-D-arabinose-1, 4-lactone to obtain a compound 5 shown in a formula V;
wherein X and R1 in the formula V are defined as the formula IV;
3) Carrying out cyanation reaction on a compound 5 shown in a formula V to obtain a compound 6 shown in a formula VI;
wherein X and R1 in the formula VI are defined as the formula V;
4) Removing benzyl ether from a compound 6 shown in a formula VI by using boron trichloride to obtain a compound 7 shown in a formula VII; protecting 3, 4-dihydroxy by using 2, 2-dimethoxypropane to obtain a compound 8 shown in a formula VIII; then carrying out condensation reaction with an active compound 2 shown in a formula II to obtain a fully protected nucleotide compound 9 shown in a formula IX;
wherein X and R1 in the formula VII are defined as the formula VI; in the formula VIII, X and R1 are defined as the formula VII;
in the formula II, R3, R4 and R5 are defined as the formula I;
x and R1 in the formula IX are defined as in the formula VIII, and R3, R4 and R5 in the formula IX are defined as in the formula II;
5) Carrying out acidolysis deprotection on a fully protected nucleotide compound 9 shown in a formula IX to obtain a compound 10 shown in a formula X; and then carrying out esterification reaction on the compound 10 shown in the formula X to obtain the compound shown in the formula I.
X, R1, R3, R4, R5 in the formula X are as defined for formula IX.
In step 1), the acid is at least one of: pentylcarbonic acid, butyric acid, benzoic acid, 2-amino-3- (4-fluorophenyl) propionic acid, 2-hydroxyethylcarbonic acid, 2-aminoethylcarbonic acid, 3- (carboxylamino) propionic acid, and succinic acid.
The reaction conditions of the coupling reaction are as follows: the reaction temperature is 0 to 25 ℃, and the reaction time is 2 to 8 hours.
In step 2), the reaction conditions of the halogen exchange reaction are as follows: the reaction temperature is-30 to 0 ℃, and the reaction time is 1 to 8 hours; the molar ratio of the amide compound 4 shown in the formula IV to isopropyl magnesium chloride is 1:1-2.
The reaction conditions of the nucleophilic substitution reaction are as follows: the reaction temperature is-30 to 0 ℃, and the reaction time is 2 to 8 hours; the molar ratio of the amide compound 4 shown in the formula IV to the 2,3, 5-tribenzyl-D-arabinose-1, 4-lactone is 1:1-1.5.
In step 3), the reaction conditions of the cyanation reaction are as follows: the reaction temperature is-78 to-50 ℃, and the reaction time is 2 to 8 hours.
In the step 4) of the method, the molar ratio of the compound 6 shown in the formula VI to the boron trichloride is 1:3-4; the debenzylation ether conditions are as follows: the reaction temperature is-10 to 10 ℃, and the reaction time is 3 to 8 hours; the molar ratio of the compound shown in the formula VII to the 2, 2-dimethoxypropane is 1:1-2; the molar ratio of the compound 8 shown in the formula VIII to the active compound 2 shown in the formula II is 1:1-2, the reaction conditions of the condensation reaction are as follows: the reaction temperature is-10 to 10 ℃, and the reaction time is 2 to 8 hours.
In step 5), the acid used in the esterification reaction is R2OH, and R2 is as defined in formula I, such as acetic acid, propionic acid, 2-aminopropionic acid.
The active compound 2 represented by the formula II is prepared according to the following method: condensing phenyl dichlorophosphate, amino acid ester hydrochloride and 4-nitrophenol at ultralow temperature to obtain the compound.
Another object of the present invention is to provide the use of the compounds of formula I as described above.
The application provided by the invention is the application of the compound shown in the formula I in the preparation of antiviral drugs.
The virus comprises at least one of the following: coronavirus, filovirus, flavivirus, enterovirus, influenza virus, parainfluenza virus, HIV virus and hepatitis virus.
The coronavirus specifically includes SARS virus, MERS virus and COVID-19.
The filoviruses specifically include Ebola virus and Marburg virus.
The flavivirus specifically includes Zika virus.
The influenza virus specifically includes H1N1, H7N9.
The antiviral drug prepared by using the compound shown in the formula I as an active ingredient also belongs to the protection scope of the invention.
The antiviral drug can be introduced into body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other substances and introduced into body.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The above medicine can be made into tablet, powder, granule, capsule, oral liquid, paste, cream, injection, etc.; the medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The administration route of the Reidesciclovir is injection administration, the injection administration has certain limitation, the use is inconvenient, and the risk and the side effect are larger than those of oral administration. After a series of compound screens, the compound with the general formula I has better bioavailability, and can generate an active metabolite R0 which is the same as the Rudexilevir in vivo in a shorter time, wherein the R0 has the following structural formula:
r0 is an intermediate process of the Reidesciclovir in blood, a reference method is adopted for detecting the concentration of R0 in blood, the reference method is used for verification research under the condition of Reidesciclovir injection and oral administration contrast, the concentration of R0 in blood after the obtained compound is subjected to intragastric gavage is detected by adopting a liquid chromatograph-mass spectrometer, and contrast research is carried out by adopting Reidesciclovir injection and intragastric administration, the modified compound is found to have better bioavailability, the concentration of R0 in blood exceeds 50 percent of the average value of an injection administration group, and exceeds more than 3 times of the average value of an oral Reidesciclovir hydrochloride administration group.
Drawings
FIG. 1 is a scheme showing the preparation of the compound of formula I according to the present invention.
Detailed Description
The present invention is described below with reference to specific embodiments, but the present invention is not limited thereto, and any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
In the quantitative tests in the following examples, three replicates were set up and the results averaged.
Examples of preparation of Compounds
Example 1: synthesis of (2S) -2-ethylbutyl 2- ((((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (formula I-1)
1) Synthesis of (2S) -2-ethylbutyl 2- (((4-nitrophenyl) (phenoxy) phosphoryl) amino) propionate
Alanine-2-ethylbutyl ester hydrochloride (21.0 g,100mmol,1.0 eq.) was weighed into a 500mL three-necked round bottom reaction flask, blanketed with nitrogen, and anhydrous dichloromethane (200 mL) was added. The reaction mixture was cooled to-70 ℃ and phenyl dichlorophosphate (21.0 g,100mmol,1.0 eq.) was added, then TEA (20.0 g,200mmol,2.0 eq.) was slowly added dropwise and the reaction was allowed to proceed at constant temperature for 2 hours. TLC was followed until the starting alanine-2-ethylbutyl ester hydrochloride was consumed, and a solution of 4-nitrophenol (14.0 g,100mmol,1.0 eq.) in dichloromethane (20 mL) was added dropwise and reacted at a constant temperature of 0 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure, and the solid was purified by direct flash column chromatography to give (2S) -2-ethylbutyl 2- (((4-nitrophenyl) (phenoxy) phosphoryl) amino) propionate as a white solid (22.5 g, 50.0%). ESI-MS m/z of 451.5[ 2] M + H ] +.
2) Synthesis of pentyl (7-bromopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate
7-bromopyrrolo [1,2-f ] [1,2,4] triazin-4-amine (21.2g, 100mmol, 1.0eq.) was dissolved in dichloromethane (200 mL), pyridine (15.8g, 200mmol, 2.0eq.) was added, and pentyl chloroformate (15.1g, 100mmol, 1.0eq.) was added dropwise in an ice-water bath and reacted for 5 hours at constant temperature. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give pentyl (7-bromopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate (27.7g, 85.0%) as a white solid. ESI-MS m/z:326.1[ 2] M ] +,328.1[ 2] M +2] +.
3) Synthesis of pentyl (7- ((3R, 4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino carbonate
Pentyl (7-bromopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate (27.0g, 82.8mmol, 1.0eq.) was dissolved in anhydrous tetrahydrofuran, anhydrous lithium chloride (3.48g, 82.8mmol, 1.0eq.) was added, the mixture was cooled to-20 ℃ under nitrogen protection, a tetrahydrofuran solution of isopropylmagnesium chloride (42mL, 82.8mmol,1.0eq., 2M) was added dropwise, the mixture was stirred at constant temperature for 1 hour, a tetrahydrofuran solution of (3R, 4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) dihydrofuran-2 (3H) -one (34.6g, 82.8mmol, 1.0eq.) was further added dropwise, and the mixture was stirred at constant temperature at 0 ℃ for 5 hours. The reaction mixture was added dropwise with a protected aqueous ammonium chloride solution, and the organic phase was concentrated under reduced pressure and purified by column chromatography to give a white solid, pentyl (7- ((3R, 4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) aminocarbonate (34.7g, 63.0%). ESI-MS m/z of 667.1, 2 [ m ] +.
4) Synthesis of pentyl (7- ((2R, 3R,4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-cyanotetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate
Pentyl (7- ((3R, 4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) aminocarbonate (34.0g, 51.0mmol, 1.0eq.) was dissolved in anhydrous dichloromethane (200 mL), cooled to-78 ℃, boron trifluoride diethyl ether (26mL, 51.0mmol,1.0eq., 2M) solution was added dropwise, after stirring for 0.5h, trimethylsilyl (5.0g, 51.0mmol, 1.0eq.) was further added dropwise, and stirring at constant temperature for 3h. The reaction was quenched by addition of saturated sodium bicarbonate, the organic phase was concentrated under reduced pressure, and purified by column chromatography to give pentyl (7- ((2R, 3R,4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-cyanotetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate as a white solid (30.3g, 88.0%). ESI-MS m/z of 676.1[ 2] M ] +.
5) Synthesis of pentyl (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate
Pentyl (7- ((2R, 3R,4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-cyanotetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate (30.0g, 44.4mmol, 1.0eq.) was dissolved in dichloromethane (200 mL), cooled to-10 ℃, and a solution of boron trichloride (66mL, 133mmol,3.0eq, 2M) in dichloromethane was added dropwise and stirred at constant temperature for 5 hours. The reaction was neutralized with a saturated sodium bicarbonate solution, the organic phase was concentrated under reduced pressure, and purified by column chromatography to give pentyl (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate (16.2g, 90.0%) as a white solid. ESI-MS m/z:406.1[ 2] M ] +.
6) Synthesis of pentyl (7- ((4R, 6R) -4-cyano-6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxo-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate
Pentyl (7- ((2R, 3R,4S, 5R) -2-cyano-3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate (1691, 39.5mmol, 1.0eq.) was dissolved in acetone (150 mL), and 2, 2-dimethoxypropane (4.1g, 39.5mmol, 1.0eq.) was added dropwise at room temperature with stirring for 5 hours at constant temperature. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give pentyl (7- ((4R, 6R) -4-cyano-6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxo-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate as a white solid (16.7g, 95.0%). ESI-MS m/z:446.1[ 2] M ] +.
7) Synthesis of (2S) -2-ethylbutyl 2- (((((3aR, 4R,6R, 6aR) -6-cyano-2, 2-dimethyl-6- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuro [3,4-d ] [1,3] dioxo-4-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate
Pentyl (7- ((4R, 6R) -4-cyano-6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxo-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) carbamate (16.0g, 36.0mmol, 1.0eq.) was weighed into a 250mL round-bottomed three-necked reaction flask, and anhydrous THF (100 mL) was added thereto under nitrogen protection. The reaction solution was cooled to 0 ℃, t-BnMgCl in tetrahydrofuran (44ml, 43.2mmol,1.2eq, 1M) was slowly added dropwise, the reaction solution was stirred at constant temperature for 30min, a solution of (2S) -2-ethylbutyl 2- (((4-nitrophenyl) (phenoxy) phosphoryl) amino) propionate (19.4g, 43.2mmol, 1.2eq) in THF (50 mL) was added dropwise, and the reaction was carried out at constant temperature of 0 ℃ for 16h. The reaction was quenched by dropwise addition of aqueous ammonium chloride, extracted by EA, and the organic layer was concentrated under reduced pressure and purified by column chromatography to give (2S) -2-ethylbutyl 2- ((((((3aR, 4R,6R, 6aR) -6-cyano-2, 2-dimethyl-6- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuro [3,4-d ] [1,3] dioxo-4-yl) methoxy) (phenoxy) phosphoryl) amino) propionate as a white solid (19.0 g, 70.0%). ESI-MS m/z:757.1[ 2] M ] +.
8) Synthesis of (2S) -2-ethylbutyl 2- ((((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
(2S) -2-ethylbutyl 2- (((((3aR, 4R,6R, 6aR) -6-cyano-2, 2-dimethyl-6- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuro [3,4-d ] [1,3] dioxo-4-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (18.0g, 23.9mmol, 1.0eq.) was dissolved in dichloromethane (100 mL), concentrated hydrochloric acid (20 mL) was added and stirred at room temperature for 3h. The organic layer was separated from the reaction mixture, concentrated under reduced pressure, and purified by column chromatography to give (2S) -2-ethylbutyl 2- ((((((2r, 3s,4r, 5r) -5-cyano-3, 4-dihydroxy-5- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate as a white foamy solid (15.4g, 90.0%). 1H NMR (CDCl 3 400 MHz) delta 9.65 (s, 1H), 7.37-7.21 (m, 5H), 5.95-5.73 (d, 2H), 4.33-3.35 (m, 10H), 2.21-0.98 (m, 22H). ESI-MS m/z:717.5[ m ] + ].
EXAMPLE 2 Synthesis of (2S) -benzyl 2- ((((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (formula I-2)
According to the preparation method of the comprehensive literature, 7-bromopyrrolo [1,2-f ] [1,2,4] triazin-4-amine is used as a raw material, and white foamy solid (2S) -benzyl 2- (((((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate is synthesized.
1 H NMR(CDCl 3 400MHz)δ9.67(s,1H),7.47-7.18(m,10H),5.89-5.72(d,2H),5.34(s,2H),4.53-3.65(m,8H),1.62-0.90(m,12H).ESI-MS m/z:723.5[M+H]+.
EXAMPLE 3 Synthesis of (2R, 3R,4R, 5R) -2-cyano-5- (((((((S) -1- (2-ethylbutoxy) -1-propanoid-2-yl) amino) (phenoxy) phosphoryl) oxy) methyl) -2- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-3, 4-diacetate (formula I-3)
Comprehensive textThe preparation method is disclosed, and 7-bromopyrrolo [1,2-f ] is adopted][1,2,4]Triazine-4-amine is used as a raw material to synthesize white foam solid (2R, 3R,4R, 5R) -2-cyano-5- (((((((S) -1- (2-ethylbutoxy) -1-propionate-2-yl) amino) (phenoxy) phosphoryl) oxy) methyl) -2- (4- (((pentyloxy) carbonyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) tetrahydrofuran-3, 4-diacetate. 1 H NMR(CDCl 3 400MHz)δ9.67(s,1H),7.37-7.21(m,5H),5.89-5.72(d,2H),5.33-3.65(m,10H),2.21-0.98(m,29H).ESI-MS m/z:801.5[M+H]+.
EXAMPLE 4 Synthesis of (2S) -2-ethylbutyl 2- ((((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-butanamido-pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoramide) amino) propanoate (formula I-4)
Synthesis of a literature preparation with 7-bromopyrrolo [1,2-f][1,2,4]Triazine-4-amine is taken as a raw material, and white foam solid (2S) -2-ethylbutyl 2- (((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4-butanamide pyrrolo [2, 1-f) is synthesized][1,2,4]Triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoramide) amino) propanoate. 1 H NMR(CDCl 3 400MHz)δ9.78(s,1H),7.27-7.22(m,5H),5.85-5.73(d,2H),4.33-3.35(m,8H),2.21-0.98(m,21H).ESI-MS m/z:673.5[M+H]+.
EXAMPLE 5 Synthesis of (2S) -2-ethylbutyl 2- ((((((2R, 3S,4R, 5R) -5- (4-benzamide pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (formula I-5)
Synthesis of a literature preparation with 7-bromopyrrolo [1,2-f][1,2,4]Triazine-4-amine is taken as a raw material, and white foamy solid (2S) -2-ethylbutyl 2- (((((2R, 3S,4R, 5R) -5- (4-benzamide pyrrolo [2, 1-f) is obtained by synthesis][1,2,4]Triazin-7-yl) -5-cyano3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate. 1 H NMR(CDCl 3 400MHz)δ9.40(s,1H),8.03-7.21(m,10H),5.89-5.72(d,2H),4.31-3.65(m,8H),2.21-0.98(m,14H).ESI-MS m/z:707.5[M+H]+.
EXAMPLE 6 Synthesis of (2S) -2-ethylbutyl 2- ((((((2R, 3S,4R, 5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (formula I-6)
Synthesis of a literature preparation with 7-bromopyrrolo [1,2-f][1,2,4]Triazine-4-amine is taken as a raw material, and white foamy solid (2S) -2-ethylbutyl 2- (((((2R, 3S,4R, 5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) pyrrolo [2, 1-f) is obtained by synthesis][1,2,4]Triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate. 1 H NMR(CDCl 3 400MHz)δ9.83(s,1H),7.28-7.17(m,9H),5.85-5.66(d,2H),4.50-3.19(m,9H),2.01(m,1H),1.29-0.90(m,9H).ESI-MS m/z:768.6[M+H]+.
EXAMPLE 7 Synthesis of (2S) -2-ethylbutyl 2- ((((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((2-hydroxyethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (formula I-7)
Synthesis of the literature preparation with 7-bromopyrrolo [1,2-f ]][1,2,4]Triazine-4-amine is taken as a raw material, and white foam solid (2S) -2-ethylbutyl 2- (((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((2-hydroxyethoxy) carbonyl) amino) pyrrolo [2, 1-f) is obtained by synthesis][1,2,4]Triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate. 1 H NMR(CDCl 3 400MHz)δ9.67(s,1H),7.28-7.21(m,5H),5.98-5.83(d,2H),4.33-3.35(m,13H),1.89-0.88(m,14H).ESI-MS m/z:691.5[M+H]+.
EXAMPLE 8 Synthesis of (2S) -2-ethylbutyl 2- ((((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((2-aminoethoxy) carbonyl) amino) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (formula I-8)
Synthesis of a literature preparation with 7-bromopyrrolo [1,2-f][1,2,4]Triazine-4-amine is taken as a raw material, and white foamy solid (2S) -2-ethylbutyl 2- ((((2R, 3S,4R, 5R) -5-cyano-3, 4-dihydroxy-5- (4- (((2-aminoethoxy) carbonyl) amino) pyrrolo [2, 1-f) is obtained by synthesis][1,2,4]Triazin-7-yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate. 1 H NMR(CDCl 3 400MHz)δ9.66(s,1H),7.25-7.23(m,5H),5.94-5.73(d,2H),4.21-3.25(m,13H),1.69-0.88(m,14H).ESI-MS m/z:690.5[M+H]+.
Example 9 Synthesis of 3- (3- (7- ((2R, 3R,4S, 5R) -2-cyano-5- (((((((S) -1- (2-ethylbutyl) -1-propanoic acid-2-yl) amino) (phenoxy) phosphoryl) oxy) methyl) -3, 4-dihydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) urea) propanoic acid (formula I-9)
Synthesis of a literature preparation with 7-bromopyrrolo [1,2-f][1,2,4]Triazine-4-amine is taken as a raw material, and white foamy solid 3- (3- (7- ((2R, 3R,4S, 5R) -2-cyano-5- ((((((((S) -1- (2-ethylbutyl) -1-propionic acid-2-group) amino) (phenoxy) phosphoryl) oxy) methyl) -3, 4-dihydroxy tetrahydrofuran-2-group) pyrrolo [2, 1-f) is synthesized][1,2,4]Triazin-4-yl) urea) propionic acid. 1 H NMR(CDCl 3 400MHz)δ11.2(s,1H),9.40(s,1H),7.28-7.21(m,5H),5.97-5.76(d,2H),4.56-3.35(m,10H),2.49-0.88(m,16H).ESI-MS m/z:718.6[M+H]+.
Example 10 Synthesis of 4- ((7- ((2R, 3R,4S, 5R) -2-cyano-5- (((((((S) -1- (2-ethylbutyl) -1-propanoid-2-yl) amino) (phenoxy) phosphoryl) oxy) methyl) -3, 4-dihydroxytetrahydrofuran-2-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) amino) -4-oxobutanoic acid (formula I-10)
Synthesis of a literature preparation with 7-bromopyrrolo [1,2-f][1,2,4]Triazine-4-amine is taken as a raw material, and white foamy solid 4- ((7- ((2R, 3R,4S, 5R) -2-cyano-5- (((((((((S) -1- (2-ethylbutyl) -1-propionyloxy) amino) (phenoxy) phosphoryl) oxy) methyl) -3, 4-dihydroxy tetrahydrofuran-2-yl) pyrrolo [2, 1-f) is synthesized][1,2,4]Triazin-4-yl) amino) -4-oxobutanoic acid. 1 H NMR(CDCl 3 400MHz)δ11.0(s,1H),9.78(s,1H),7.29-7.21(m,5H),5.85-5.66(d,2H),4.51-3.63(m,8H),2.72-2.49(d,4H),2.07(m,1H),1.29-0.90(m,9H).ESI-MS m/z:703.6[M+H]+.
Effect test
Example 11: detection of R0 concentration in blood
Solvent 1:15% solutol HS15+85% PEG400
Heating Solutol HS15 to liquid in water bath at 50-60 ℃, sucking 1.8mL Solutol HS15 to 15mL centrifuge tubes, adding 10.2mL PEG400, vortex shaking and mixing uniformly to prepare a mixed preparation containing 15% Solutol HS15 and 85% PEG400.
Preparation of drug delivery formulation
Control sample:
group 01: ZONK1802-0 (Reidesvir hydrochloride) was administered in a molar dose of 285mM/kg in physiological saline. The administration route is intravenous injection.
Group 02: ZONK1802-1 (Darcy's acid hydrochloride) was prepared in a molar dose of 285mM/kg in the solvent 1 described above. The administration route is intragastric administration.
Groups 1-6: the compounds of examples 1-6 were used in a molar dose of 285mM/kg for each group, in the solvent 1 described above. The administration route is intragastric administration.
Male SD rats 48 in each group, 6 in each group, oral groupFasted for about 14 hours before administration. The feed was restored after about 4 hours after dosing. Intravenous group at 0.083,0.5,1,4,8,12,18,24,32 and 48 hours before and after administration, oral group at 0.5,1,2,4,8,12,18,24,32 and 48 hours before and after administration, blood collected via jugular vein of about 0.25mL, heparin sodium anticoagulation, blood sample collection on ice, and plasma centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 4 ℃). The collected plasma was stored at-80 ℃ before analysis. Fasting was for more than 12 hours before administration, and fasting was for 4 hours after administration, with free water. Anticoagulant: EDTA-K 2 。
The experiment adopts a LC-MS method to determine the drug concentration of the ridciclovir triphosphate (R0) in the plasma of male rats. At least one standard curve at least comprising 6 standard concentration points is established for each analysis batch, the concentration of the substance to be detected in the samples of the analysis batch is calculated, and the samples are subjected to quality control. The accuracy of the concentration points of more than 3/4 of the standard curve of the plasma and the tumor is within 80-120%. If the quantitative lower limit or the quantitative upper limit exceeds the acceptance range, rejecting the point and reestablishing a new linear range. And each analysis batch is provided with quality control samples (QC) with high, medium and low concentrations, each concentration is at least parallel to double samples, and the quantity of the quality control samples is more than or equal to 5 percent of that of each batch. The concentration of the quality control sample was calculated from the standard curve of each analysis batch. The plasma quality control sample can be allowed to exceed the theoretical value by +/-20% at most 1/3 and different concentrations.
High performance liquid system: SHIMADZU LC30AD
And (3) chromatographic column: thermo SCINTIFIC Hypersil GOLD C8 50 x 2.1mm
Column temperature: room temperature;
flow rate: 0.5mL/min;
mobile phase: phase A: aqueous solution containing 2mM ammonium acetate, phase B: acetonitrile solution.
The average values of the areas under the time-concentration curves of the ridiflower triphosphate drug measured for each group are shown in the following table.
Table 1 mean value of area under time-concentration curve of each group of measured raschel triphosphates
As can be seen from Table 1, the R0 concentration in blood after intragastric administration of the drugs in groups 1-6 is higher than that in the Redeseivir intragastric administration group of group 02, and the absolute bioavailability (F) is more than 50%.
Claims (6)
1. A compound having the general structural formula shown in formula I:
(formula I)
The compound shown in the formula I is selected from any one of the following compounds:
2. A compound of formula I as claimed in claim 1, wherein R 2 A process for the preparation of a compound of = H comprising the steps of:
1) Carrying out coupling reaction on a compound shown as a formula III and acid to obtain an amide compound shown as a formula IV;
wherein X and R1 in the formula IV are defined as the formula I;
2) Performing halogen exchange on an amide compound shown in a formula IV and isopropyl magnesium chloride, and performing nucleophilic substitution reaction on the amide compound and 2,3, 5-tribenzyl-D-arabinose-1, 4-lactone to obtain a compound shown in a formula V;
wherein X and R1 in the formula V are defined as the formula IV;
3) Carrying out cyanation reaction on the compound shown in the formula V to obtain a compound shown in a formula VI;
wherein X and R1 in the formula VI are defined as the formula V;
4) Removing benzyl ether from the compound shown in the formula VI by using boron trichloride to obtain a compound shown in a formula VII; protecting 3, 4-dihydroxy by using 2, 2-dimethoxypropane to obtain a compound shown as a formula VIII; then carrying out condensation reaction with an active compound 2 shown in a formula II to obtain a full-protection nucleotide compound shown in a formula IX;
wherein X and R1 in the formula VII are defined as the formula VI; in the formula VIII, X and R1 are defined as the formula VII;
in the formula II, R3, R4 and R5 are defined as the formula I;
x and R1 in the formula IX are defined as in the formula VIII, and R3, R4 and R5 in the formula IX are defined as in the formula II;
5) Acid hydrolysis deprotection of the fully protected nucleotide compound of formula IX to yield R 2 A compound of formula I of = H.
3. A process for the preparation of a compound according to claim 2, characterized in that: in the step 1), the acid is
R 1 -X-COOH, wherein X, R1 are as defined for formula iv;
the reaction conditions of the coupling reaction are as follows: the reaction temperature is 0 to 25 ℃, and the reaction time is 2 to 8 hours;
in the step 2), the reaction conditions of the halogen exchange reaction are as follows: the reaction temperature is-30 to 0 ℃, and the reaction time is 1 to 8 hours; the molar ratio of amide compound represented by formula iv to isopropyl magnesium chloride is 1:1.0-2.0;
the reaction conditions of the nucleophilic substitution reaction are as follows: the reaction temperature is-30 to 0 ℃, and the reaction time is 2 to 8 hours; the molar ratio of the amide compound shown in the formula IV to the 2,3, 5-tribenzyl-D-arabinose-1, 4-lactone is 1:1-1.5;
in the step 3), the reaction conditions of the cyanation reaction are as follows: the reaction temperature is-78 to-50 ℃, and the reaction time is 2 to 8 hours;
in the step 4), the molar ratio of the compound shown in the formula VI to the boron trichloride is 1:3-4; the debenzylation ether conditions are as follows: the reaction temperature is-10 to 10 ℃, and the reaction time is 3 to 8 hours; the molar ratio of the compound shown in the formula VII to the 2, 2-dimethoxypropane is 1:1-2; the molar ratio of the compound shown in the formula VIII to the active compound shown in the formula II is 1:1-2, the reaction conditions of the condensation reaction are as follows: the reaction temperature is-10 to 10 ℃, and the reaction time is 2 to 8 hours.
4. The compound of claim 1, wherein R is 2 A process for the preparation of a compound which is a group other than H comprising the steps of: r in claim 1 2 Carrying out esterification reaction on a compound shown as a formula I of = H to obtain R 2 A compound of formula I which is a radical other than H.
5. Use of a compound as claimed in claim 1 for the preparation of an antiviral medicament;
the virus is selected from at least one of the following: coronavirus, filovirus, flavivirus, influenza virus;
the coronavirus is selected from SARS virus, MERS virus and COVID-19;
the filovirus is selected from the group consisting of ebola virus and marburg virus;
the flavivirus is selected from Zika virus;
the influenza virus is selected from H1N1 and H7N9.
6. An antiviral agent whose active ingredient comprises the compound of claim 1;
the virus is selected from at least one of the following: coronavirus, filovirus, flavivirus, influenza virus;
the coronavirus is selected from SARS virus, MERS virus and COVID-19;
the filovirus is selected from the group consisting of ebola virus and marburg virus;
the flavivirus is selected from the group consisting of Zika virus;
the influenza virus is selected from H1N1 and H7N9.
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