CN110845560B - Phenylalanine amidated nucleotide derivative and preparation method and application thereof - Google Patents

Phenylalanine amidated nucleotide derivative and preparation method and application thereof Download PDF

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CN110845560B
CN110845560B CN201911147426.9A CN201911147426A CN110845560B CN 110845560 B CN110845560 B CN 110845560B CN 201911147426 A CN201911147426 A CN 201911147426A CN 110845560 B CN110845560 B CN 110845560B
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王伟
陆永章
谭进辉
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Shijiazhuang Yiling Pharmaceutical Co Ltd
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Abstract

The invention provides a phenylalanine amidated nucleotide derivative and a preparation method and application thereof. The compound of the invention combines halogenated phenylalanine with amino of nucleoside compound containing amino, phosphorylates, promotes absorption by phosphate and phosphoramide prodrug form, avoids rate-limiting monophosphate synthesis link, reduces or avoids nucleoside deaminase effect to enhance drug effect, and the halogenated phenylalanine has synergistic effect of inhibiting protein synthesis, thereby playing roles of increasing bioavailability, improving drug effect and reducing drug resistance in the aspects of anti-tumor and anti-hepatitis B virus.

Description

Phenylalanine amidated nucleotide derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a phenylalanine amidated nucleotide derivative, and a preparation method and application thereof.
Background
Nucleotides are a class of compounds formed by the linkage of bases (mainly derivatives of purines, pyrimidine bases), pentoses (ribose or deoxyribose), and phosphoric acid. Also called "nucleoside phosphates", are the basic units constituting nucleic acids. Nucleotides are also units that constitute both DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), both present in the cells of an organism.
Cytidine and adenosine are nucleoside compounds containing amino groups, the two compounds comprise antitumor drugs and anti-hepatitis B virus drugs, the antitumor drugs comprise gemcitabine, fludarabine and the like, the anti-hepatitis B virus drugs comprise adefovir, tenofovir and the like, the nucleoside compounds containing the amino groups such as gemcitabine are converted into inactive DFDU by 90 percent under the action of nucleoside deaminase, only a small part of the DFDU is converted into gemcitabine triphosphate to play the drug effect, and gemcitabine is only sold on the market in injection preparations at present.
There is a need to modify the structure of existing cytidine and adenosine to reduce or avoid the effects of nucleoside deaminases and thereby enhance drug efficacy.
Disclosure of Invention
It is an object of the present invention to provide a 4-halogen substituted phenylalanine amidated nucleotide derivative.
The structural formula of the 4-halogen substituted phenylalanine amidated nucleotide derivative provided by the invention is shown as the formula I:
Figure BDA0002282587100000011
in the formula I, X represents halogen, and can be F, Cl, Br or I;
in the above-mentioned formula I, the compound of formula I,
Figure BDA0002282587100000012
represents nucleosides and analogues thereof;
in formula I above, the 4-halo substituted phenylalanine forms an amide bond with an amino group in a nucleoside base, which includes substituted or unsubstituted 4-aminopyrimidines, substituted or unsubstituted 2-aminopurines, substituted or unsubstituted 6-aminopurines, substituted or unsubstituted 2, 6-diaminopurines, substituted or unsubstituted 1H-imidazo [4,5-c ] pyridines, substituted or unsubstituted pyrrolo [2,1-f ] [1,2,4] triazines, where the substituents can be: methyl, methoxy, cyclopropyl, amino, carbonyl, halogen (F, Cl, Br or I).
The base may specifically be any one of the following:
Figure BDA0002282587100000021
in the above formula (I), the 5-hydroxymethyl group of the ribose or deoxyribose of the nucleoside forms an ester bond with the phosphate，R1Can be phenyl or substituted phenyl, naphthyl or substituted naphthyl, C1-C18 unsubstituted alkyl, halogen/alkoxy substituted C1-C18 alkyl, C3-C6 substituted or unsubstituted cycloalkyl, preferably phenyl or naphthyl; r2Can be amino acid side chain (including natural amino acid and unnatural amino acid), and can also be C1-C8 alkyl/cycloalkyl, phenyl; r3Methyl, ethyl, isopropyl, benzyl, preferably benzyl.
The nucleoside and its analogue can be common ribonucleoside or deoxyribonucleoside and its analogue; specifically, the following may be mentioned:
Figure BDA0002282587100000022
Figure BDA0002282587100000031
the 4-halogen substituted phenylalanine amidated nucleotide derivative represented by the formula I can be specifically one of the following compounds:
1、
Figure BDA0002282587100000032
benzyl 2- ((((((2R, 3R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate (gemcitabine derivative);
3、
Figure BDA0002282587100000033
benzyl 2- (((((((2S, 3R,4R,5S) -5- (4- (2-amino-3- (4-fluorophenyl) propanal) -2-oxopyrimidin-1 (2H) -yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate
Figure BDA0002282587100000034
Benzyl 2- (((((((2R, 3R,4R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate;
5、
Figure BDA0002282587100000041
benzyl 2- (((((((2S, 3R,4R,5S) -5- (4- (2-amino-3- (4-fluorophenyl) propanal) -2-oxopyrimidin-1 (2H) -yl) -4-cyano-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate
6、
Figure BDA0002282587100000042
Synthesis of benzyl 2- ((((((2R, 5S) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (zalcitabine derivative)
7、
Figure BDA0002282587100000043
Benzyl 2- ((((2S) -3- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -2-hydroxypropoxy) (phenoxy) phosphoryl) amino) propionate
8、
Figure BDA0002282587100000044
Benzyl 2- ((((((2S, 5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -1, 3-oxathiolan-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Lamivudine derivative)
9、
Figure BDA0002282587100000051
Benzyl 2- ((((((2R, 3S,4R,5R) -5- (2-amino-6- (2-amino-3- (4-fluorophenyl) propylamino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Emtricitabine derivative)
10、
Figure BDA0002282587100000052
Benzyl 2- (((((((2R, 3S,4R,5R) -5- (2-amino-6- (2-amino-3- (4-fluorophenyl) propanal) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000053
Benzyl 2- ((((((2S, 3R,4R,5S) -5- (2- (2-amino-3- (4-fluorophenyl) propylamino) -6-methoxy-1H-purin-9 (6H) -yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Nelarabine derivative)
12、
Figure BDA0002282587100000054
Benzyl 2- ((((((1R, 4S) -4- (2- (2-amino-3- (4-fluorophenyl) propylamino) -6- (cyclopropylamino) -9H-purin-9-yl) cyclopenten-2-en-1-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate
13、
Figure BDA0002282587100000061
Benzyl 2- ((((((1S, 3R,5R) -3- (2- (2-amino-3- (4-fluorophenyl) propylamino) -6-oxo-1H-purin-9 (6H) -yl) -5-hydroxy-2-methylenecyclopentyl) methoxy) (phenoxy) phosphoryl) amino) propionate (Entecavir derivative)
14、
Figure BDA0002282587100000062
Benzyl 2- (((((((2R, 3S,4S,5R) -5- (6- (2-amino-3- (4-fluorophenyl) propanal) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
15、
Figure BDA0002282587100000063
Benzyl 2- ((((((2S, 3S,4S,5S) -5- (6- (2-amino-3- (4-fluorophenyl) propanal) -2-fluoro-9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Fludarabine derivative)
16、
Figure BDA0002282587100000071
Benzyl 2- ((((((2R, 3S,4R,5R) -5- (6- (2-amino-3- (4-fluorophenyl) propanal) -2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Clorafarabine derivative)
17、
Figure BDA0002282587100000072
Benzyl 2- (((((((2S, 3S,5S) -5- (6- (2-amino-3- (4-fluorophenyl) propanal) -2-chloro-9H-purin-9-yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Cladibine derivative)
18、
Figure BDA0002282587100000073
Benzyl 2- ((((((2R, 3S,4R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propanal) pyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate
19、
Figure BDA0002282587100000081
Benzyl 2- ((((((2R) -1- (6- (2-amino-3- (4-fluorophenyl) propylamino) -9H-purin-9-yl) propan-2-yl) oxy) (phenoxy) phosphoryl) amino) propanoate (Tenofovir derivative)
20、
Figure BDA0002282587100000082
Benzyl 2- (((2- (6- (2-amino-3- (4-fluorophenyl) propylamino) -9H-purin-9-yl) ethoxy) (phenoxy) phosphoryl) amino) propionate (Adefovir derivative)
The 4-halogen substituted phenylalanine amidated nucleotide derivative shown in the formula I is prepared by a method comprising the following steps according to a flow chart shown in figure 1:
1) reacting the pentafluorophenol phosphate active intermediate shown in the formula II with 5-hydroxymethyl of ribose or deoxyribose in nucleoside to obtain ribose or deoxyribose 5-hydroxymethyl phosphorylated nucleotide;
Figure BDA0002282587100000083
in the formula II, R1、R2And R3Are each as defined for R in formula I1、R2And R3The definition of (1);
2) coupling BOC- (4-X) phenylalanine with amino in the base of the ribose or deoxyribonucleotide obtained in the step 2) to form amido bond;
in the step 1), the molar ratio of the pentafluorophenol phosphate active intermediate represented by the formula II to the nucleoside may be: 1.0-2.0, specifically 1.2: 1;
the reaction is carried out under the catalysis of tert-butyl magnesium chloride;
the molar ratio of nucleoside to tert-butyl magnesium chloride may be: 1:1.0-2.0, specifically 1: 1.2;
the reaction is carried out under the protection of inert gas, and the inert gas can be specifically nitrogen;
the reaction is carried out in an anhydrous organic solvent, and the anhydrous organic solvent can be anhydrous tetrahydrofuran;
the temperature of the reaction may be: -20-10 ℃, in particular 0 ℃, for a time which can be: 8-24 h;
in step 2) of the above method, the amide bond-forming reaction is carried out in the presence of 1-hydroxybenzotriazole;
the reaction for forming the amido bond is carried out in the presence of a carboxyl activating reagent, and the carboxyl activating reagent can be 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride specifically;
the molar ratio of the ribose or the deoxyribonucleotide to the BOC- (4-X) phenylalanine, the 1-hydroxybenzotriazole and the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride can be as follows in sequence: 1.0: 1.0-1.5: 1.0-2.0: 1.0-2.0, specifically 1.0: 1.0: 1.0: 1.3;
the reaction temperature can be room temperature, and the reaction time can be 3-8h, specifically 5 h.
If the ribose or deoxyribose of the nucleoside and its analogues has hydroxyl groups (such as 3-hydroxyl and 4-hydroxyl) at other positions besides 5-hydroxymethyl, then the operation of selectively protecting the hydroxyl groups at other positions is also included before step 1), wherein the protecting groups include, but are not limited to, t-Butyloxycarbonyl (BOC), t-butyldimethylsilyl (TBS);
correspondingly, after the step 2), the method also comprises the operation of removing hydroxyl protection from the product obtained in the step 2) under an acidic condition to obtain the target product.
The application of the 4-halogen substituted phenylalanine amidated nucleotide derivative shown in the formula I in the preparation of antitumor and/or antiviral medicaments also belongs to the protection scope of the invention.
In the application, the tumor may be specifically: human pancreatic cancer tumors; the virus can be hepatitis B virus;
for example, the use of compounds 1,3, 11, 15, 16 and 17 in the preparation of anti-tumor medicaments;
for example, the use of compounds 9, 19, 14 and 20 for the preparation of a medicament against hepatitis B virus.
The compound of the invention combines halogenated phenylalanine with amino of nucleoside compound containing amino, phosphorylates, promotes absorption by phosphate and phosphoramide prodrug form, avoids rate-limiting monophosphate synthesis link, reduces or avoids nucleoside deaminase effect to enhance drug effect, and the halogenated phenylalanine has synergistic effect of inhibiting protein synthesis, thereby playing roles of increasing bioavailability, improving drug effect and reducing drug resistance in the aspects of anti-tumor and anti-hepatitis B virus.
Drawings
FIG. 1 is a flow chart of the present invention for preparing a 4-halogen substituted phenylalanine amidated nucleotide derivative of formula I;
Detailed Description
The present invention will be described below with reference to specific examples, but the present invention is not limited thereto.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, biomaterials, etc. used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 Synthesis of benzyl 2- (((((((2R, 3R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propanal) -2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Gemcitabine derivative)
Figure BDA0002282587100000101
The preparation method comprises the following five steps:
1) synthesis of (2R,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl-tert-butylcarbonate
Figure BDA0002282587100000102
Anhydrous potassium carbonate (11.0g, 79.8mmol, 3.0eq.) was dissolved in water (25mL), and tetrahydrofuran (100mL), gemcitabine (7.0g, 26.6mmol, 1.0eq.), di-tert-butyl dicarbonate (11.5g, 53.2mmol, 2.0eq.) and the reaction were added, respectively, and stirred at room temperature for 24 h. The reaction was monitored by TLC (DCM: MeOH ═ 10: 1). Extracting the reaction solution with ethyl acetate (100 mL. times.2), combining the organic layers, concentrating under reduced pressure, and performing crude column chromatography (DCM: MeOH)Purification 10:1) yielded 6.8g (2R,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl-tert-butyl carbonate as a white solid.1H NMR(CDCl3 400MHz)δ9.16(d,1H),8.61(s,2H),6.33(m,1H),5.44(d,1H),4.92-4.83(m,2H),4.44(s,1H),3.55(m,2H),1.38(s,9H).ESI-MS m/z:364.3[M+H]+.
2) And synthesis of benzyl 2- (((pentafluorophenoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000103
Alanine benzyl ester hydrochloride (8.0g, 37.1mmol, 1.0eq.) was weighed into a 250mL three-necked round bottom reaction flask, protected with nitrogen, and anhydrous dichloromethane (100mL) was added. The reaction solution was cooled to-20 ℃, phenyl dichlorophosphate (7.8g, 37.1mmol, 1.0eq.) was rapidly added, and then a solution of triethylamine (10.3g, 74.2mmol, 2.0eq.) in dichloromethane (20mL) was slowly added dropwise, followed by a constant temperature reaction for 2 hours. The reaction was monitored by TLC (DCM: MeOH ═ 10:1) until the starting alanine benzyl ester hydrochloride was consumed, a solution of pentafluorophenol (6.8g, 37.1mmol, 1.0eq.) in dichloromethane (20mL) was added dropwise, followed by triethylamine (4.1g, 40.8mmol, 1.1eq.) and allowed to react at 0 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (PE: EA ═ 4:1) to give 8.2g of benzyl 2- (((pentafluorophenoxy) (phenoxy) phosphoryl) amino) propionate as a white solid.1H NMR(CDCl3400MHz)δ7.47-7.15(m,10H),5.33(s,2H),4.12(m,1H),1.28(d,3H).ESI-MS m/z:502.2[M+H]+.
3) Synthesis of phenyl 2- (((((((2R, 3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((tert-butoxycarbonyl) oxy) -4, 4-difluorotetrahydrofuran-2-yl) methoxy (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000111
Compound (2R,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl-tert-butyl carbonate (4.8g, 13) was weighed.3mmol, 1.0eq.) in a 250mL round-bottom three-necked reaction flask under nitrogen, and anhydrous tetrahydrofuran (80mL) was added. The reaction solution was cooled to 0 ℃, and a tetrahydrofuran solution of tert-butylmagnesium chloride (16mL, 15.9mmol,1.2eq.,1M) was slowly added dropwise to precipitate a white solid. The reaction solution was stirred at constant temperature for 30min, a solution of benzyl 2- (((pentafluorophenoxy) (phenoxy) phosphoryl) amino) propionate (8.2g, 15.9mmol,1.2 eq.) in tetrahydrofuran (20mL) was added dropwise, the reaction was carried out at constant temperature of 0 ℃ for 16h, and the reaction was monitored by TLC (DCM: MeOH ═ 10: 1). The reaction was quenched by dropwise addition of an aqueous ammonium chloride solution, extracted with ethyl acetate (100 ml. times.2), the organic layers were combined, concentrated under reduced pressure, and purified by crude column chromatography (DCM: MeOH: 10:1) to give 7.7g of phenyl 2- ((((((2R, 3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((tert-butoxycarbonyl) oxy) -4, 4-difluorotetrahydrofuran-2-yl) methoxy (phenoxy) phosphoryl) amino) propionate as a white solid.1H NMR(CDCl3400MHz)δ9.20(d,1H),8.56(s,2H),7.47-7.18(m,10H),6.33(s,1H),5.44(d,1H),5.12(s,2H),4.89(m,2H),4.66(m,2H),4.13(m,1H),1.38(s,9H),1.12(d,3H).ESI-MS m/z:681.2[M+H]+.
4) Synthesis of benzyl 2- (((((((2R, 3R,5R) -5- (4- (2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -3- ((tert-butoxycarbonyl) oxy) -4, 4-difluorotetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000121
Phenyl 2- ((((((2R, 3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((tert-butyloxycarbonyl) oxy) -4, 4-difluorotetrahydrofuran-2-yl) methoxy (phenoxy) phosphoryl) amino) propionate (5.9g, 8.68mmol, 1.0eq.), Boc- (4-F) phenylalanine (2.7g, 9.55mmol, 1.0eq.), 1-hydroxybenzotriazole (1.20g, 8.68mmol, 1.0eq.) was dissolved in tetrahydrofuran (50mL), nitrogen protected, the reaction was cooled in an ice-water bath, 1- (3-dimethylaminopropyl) -3-ethylidenecarbodiimide hydrochloride (2.20g,11.3mmol, 1.3eq.) was added, the reaction was carried out at room temperature for 5h and checked by TLC (DCM: MeOH ═ 20: 1). The reaction mixture was extracted with ethyl acetate (100mL), and the organic phase was concentrated under reduced pressure. Crude product column chromatography (PE: E)A ═ 1:1) purification gave 6.7g of benzyl 2- ((((((((2R, 3R,5R) -5- (4- (2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -3- ((tert-butoxycarbonyl) oxy) -4, 4-difluorotetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate as a white solid.1H NMR(CDCl3 400MHz)δ9.16(d,1H),7.47-7.18(m,14H),6.38(d,1H),5.41(d,1H),5.22(s,2H),4.91(m,2H),4.38(m,2H),4.12(m,2H),3.19(m,2H),1.38(s,18H),1.20(d,3H).ESI-MS m/z:946.3[M+H]+.
5) Synthesis of benzyl 2- (((((((2R, 3R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000122
The compound benzyl 2- ((((((2R, 3R,5R) -5- (4- (2- ((tert-butoxycarbonyl) amino) -3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -3- ((tert-butoxycarbonyl) oxy) -4, 4-difluorotetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (6.7g, 8.66mmol, 1.0eq.) was weighed out dissolved in dichloromethane (15mL), cooled in an ice water bath, trifluoroacetic acid (15mL) was added dropwise, reacted at room temperature for 2H, and the reaction was monitored by TLC (DCM: MeOH ═ 10: 1). The reaction mixture was added with ice water, extracted with ethyl acetate (100 ml. about.2), and the organic layer was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, concentrated under reduced pressure, and purified by column chromatography (PE: EA: 1:10) to give 4.6g of benzyl 2- (((((((2R, 3R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate as a white solid.1H NMR(CDCl3400MHz)δ9.16(d,1H),7.48-7.19(m,14H),6.39(m,1H),5.40(d,1H),5.33(s,2H),5.01(s,2H),4.4-3.95(m,5H),4.21(m,2H),3.32(m,2H),1.21(d,3H).ESI-MS m/z:746.2[M+H]+.
2. Synthesis of benzyl 2- (((((((2R, 3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (NUC-1031)
Figure BDA0002282587100000131
By combining the preparation method of example 1, gemcitabine was used as a raw material to synthesize a white foamy solid, benzyl 2- (((((((2R, 3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate.1H NMR(CDCl3 400MHz)δ9.16(d,1H),8.58(d,2H),7.46-7.28(m,10H),6.39(m,1H),5.40(d,1H),5.34(s,2H),5.01(s,2H),4.40-3.58(m,6H),1.28(d,3H).ESI-MS m/z:581.1[M+H]+.
3. Synthesis of benzyl 2- (((((((2S, 3R,4R,5S) -5- (4- (2-amino-3- (4-fluorophenyl) propanal) -2-oxopyrimidin-1 (2H) -yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (cytarabine derivative)
Figure BDA0002282587100000132
By combining the preparation methods of example 1, a white foamy solid, benzyl 2- ((((((((2S, 3R,4R,5S) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate, was synthesized using cytarabine as a starting material.1H NMR(CDCl3 400MHz)δ9.18(d,1H),7.47-7.21(m,14H),5.93(m,1H),5.40(d,1H),5.30(s,2H),5.01(s,2H),4.51-3.85(m,7H),3.58-3.77(m,2H),3.37(m,2H),1.28(d,3H).ESI-MS m/z:726.1[M+H]+.
4. Synthesis of benzyl 2- (((((((2R, 3R,4R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propanal) -2-oxopyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000141
By combining the preparation of example 1 with 4-amino-1- ((2R,3R,4R,5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl)Tetrahydrofuran-2-yl) pyridine-2 (1H) -ketone is used as a raw material, and white foamy solid benzyl 2- (((((((2R, 3R,4R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidine-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate is synthesized.1H NMR(CDCl3 400MHz)δ9.16(d,1H),7.38-7.11(m,14H),6.11(m,1H),5.40(d,1H),5.34(s,2H),4.40-3.85(m,7H),3.34-3.16(m,2H),1.47(s,3H),1.22(d,3H).ESI-MS m/z:742.2[M+H]+.
5. Synthesis of benzyl 2- (((((((2S, 3R,4R,5S) -5- (4- (2-amino-3- (4-fluorophenyl) propanal) -2-oxopyrimidin-1 (2H) -yl) -4-cyano-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000142
By following the procedure of example 1, (2S,3R,4R,5S) -2- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-3-carbonitrile was synthesized as a white foamy solid, benzyl 2- ((((((((2S, 3R,4R,5S) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -4-cyano-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate.1H NMR(CDCl3400MHz)δ9.20(d,1H),7.48-7.19(m,14H),5.80(m,1H),5.40(d,1H),5.34(s,2H),4.40-3.65(m,8H),3.34-3.16(m,2H),1.22(d,3H).ESI-MS m/z:735.2[M+H]+.
6. Synthesis of benzyl 2- ((((((2R, 5S) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (zalcitabine)
Figure BDA0002282587100000151
By combining the preparation methods of example 1, zalcitabine was used as a raw material to synthesize a white foamy solid 2- ((((((2R, 5S) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) methoxy) (phenoxy) phenoxy) Phosphoryl) amino) propionic acid benzyl ester.1H NMR(CDCl3 400MHz)δ9.16(d,1H),7.44-7.19(m,14H),5.85(m,1H),5.40(d,1H),5.35(s,2H),4.28-3.36(m,5H),3.34-3.16(m,2H),1.94-1.63(m,6H),1.28(d,3H).ESI-MS m/z:694.2[M+H]+.
7. Synthesis of benzyl 2- (((((2S) -3- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -2-hydroxypropoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000152
The preparation method of the general example 1 was synthesized from (S) -4-amino-1- (2, 3-dihydroxypropyl) pyrimidin-2 (1H) -one as a starting material to obtain benzyl 2- (((((2S) -3- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -2-hydroxypropoxy) (phenoxy) phosphoryl) amino) propionate as a white foamy solid.1H NMR(CDCl3 400MHz)δ9.18(d,1H),7.46-7.19(m,14H),5.40(d,1H),5.35(s,2H),4.29-2.98(m,8H),1.28(d,3H).ESI-MS m/z:668.3[M+H]+.
8. Synthesis of benzyl 2- (((((((2S, 5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -1, 3-oxathiolan-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Lamivudine derivative)
Figure BDA0002282587100000161
According to the preparation method of the comprehensive example 1, lamivudine is used as a raw material, and the white foamy solid benzyl 2- ((((((2S, 5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -2-oxopyrimidin-1 (2H) -yl) -1, 3-oxathiolan-2-yl) methoxy) (methoxy) phosphoryl) amino) propionate is synthesized.1H NMR(CDCl3 400MHz)δ9.16(d,1H),7.48-7.19(m,14H),5.40(d,1H),5.35(s,2H),5.12(m,1H),4.66(m,2H),3.97-2.71(m,7H),1.28(d,3H).ESI-MS m/z:712.1[M+H]+.
9. Synthesis of benzyl 2- (((((((2S, 5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -5-fluoro-2-oxopyrimidin-1 (2H) -yl) -1, 3-oxathiolan-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Emtricitabine derivative)
Figure BDA0002282587100000162
By combining the preparation method of the example 1, the emtricitabine is used as a raw material to synthesize the white foamy solid benzyl 2- (((((((2S, 5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) -5-fluoro-2-oxopyrimidin-1 (2H) -yl) -1, 3-oxathiolan-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate.1H NMR(CDCl3400MHz)δ7.58-7.19(m,15H),5.34(s,2H),5.22(m,1H),5.12(s,2H),4.66(m,2H),3.95-2.71(m,7H),1.28(d,3H).ESI-MS m/z:730.1[M+H]+.
10. Synthesis of benzyl 2- (((((((2R, 3S,4R,5R) -5- (2-amino-6- (2-amino-3- (4-fluorophenyl) propanal) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000171
By combining the preparation methods of example 1,2, 6-diaminopurine nucleoside was used as a raw material to synthesize a white foamy solid, benzyl 2- (((((((2R, 3S,4R,5R) -5- (2-amino-6- (2-amino-3- (4-fluorophenyl) propylamino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate.1H NMR(CDCl3 400MHz)δ8.35(s,1H),7.47-7.18(m,17H),6.99(s,2H),6.16(m,1H),5.34(s,2H),5.11(s,2H),4.75-3.19(m,11H),1.28(d,3H).ESI-MS m/z:765.1[M+H]+.
11. Synthesis of benzyl 2- ((((((2S, 3R,4R,5S) -5- (2- (2-amino-3- (4-fluorophenyl) propanal) -6-methoxy-1H-purin-9 (6H) -yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Nelarabine derivative)
Figure BDA0002282587100000172
By combining the preparation method of example 1, the white foamy solid benzyl 2- ((((((2S, 3R,4R,5S) -5- (2- (2-amino-3- (4-fluorophenyl) propylamino) -6-methoxy-1H-purin-9 (6H) -yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate was synthesized using nelarabine as a raw material.1H NMR(CDCl3 400MHz)δ7.92(s,1H),7.47-7.18(m,14H),6.16(m,1H),5.34(s,2H),5.26(s,1H),5.11(s,2H),4.75-3.44(m,11H),3.30(s,3H),1.28(d,3H).ESI-MS m/z:782.1[M+H]+.
12. Synthesis of benzyl 2- (((((((1R, 4S) -4- (2- (2-amino-3- (4-fluorophenyl) propylamino) -6- (cyclopropylamino) -9H-purin-9-yl) cyclopenten-2-en-1-yl) methoxy) (phenoxy) phosphoryl) amino) propionate ()
Figure BDA0002282587100000181
By integrating the preparation method of example 1, abacavir is used as a raw material to synthesize a white foamy solid benzyl 2- ((((((1R, 4S) -4- (2- (2-amino-3- (4-fluorophenyl) alanine) -6- (cyclopropylamino) -9H-purin-9-yl) cyclopentene-2-en-1-yl) methoxy) (phenoxy) phosphoryl) amino) propionate.1H NMR(CDCl3 400MHz)δ8.05(s,1H),7.47-7.18(m,14H),6.05-5.60(m,2H),5.34(s,2H),5.11(s,2H),4.48-3.19(m,7H),2.36-2.17(m,3H),1.35(m,1H),1.28(d,3H),0.88(m,4H).ESI-MS m/z:769.1[M+H]+.
13. Synthesis of benzyl 2- (((((((1S, 3R,5R) -3- (2- (2-amino-3- (4-fluorophenyl) propylamino) -6-oxo-1H-purin-9 (6H) -yl) -5-hydroxy-2-methylenecyclopentyl) methoxy) (phenoxy) phosphoryl) amino) propionate (Entecavir derivative)
Figure BDA0002282587100000182
By combining the preparation methods of example 1, entecavir was used as a starting material to synthesize 2- (((((1S,3R,5R) -3- (2- (2-amino-3- (4-fluorophenyl) propylamino) -6-oxo-1H-purin-9 (6H) -yl) -5-hydroxy-2-methylenecyclopentyl) methyl-2-carboxylate as a white foamy solidOxy) (phenoxy) phosphoryl) amino) benzyl propionate.1H NMR(CDCl3 400MHz)δ7.97(s,1H),7.47-7.18(m,14H),5.34(s,2H),5.26-5.11(d,3H),4.37-3.19(m,9H),2.33-2.01(m,3H),1.28(d,3H).ESI-MS m/z:760.1[M+H]+.
14. Synthesis of benzyl 2- (((((((2R, 3S,4S,5R) -5- (6- (2-amino-3- (4-fluorophenyl) propanal) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000191
By combining the preparation method of example 1, a white foamy solid, benzyl 2- (((((((2R, 3S,4S,5R) -5- (6- (2-amino-3- (4-fluorophenyl) propylamino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate, was synthesized using vidarabine as a starting material.1H NMR(CDCl3 400MHz)δ8.60(s,1H),8.35(s,1H),7.47-7.18(m,14H),6.16(m,1H),5.34(s,2H),5.11(s,2H),4.75-3.19(m,11H),1.28(d,3H).ESI-MS m/z:750.1[M+H]+.
15. Synthesis of benzyl 2- ((((((2S, 3S,4S,5S) -5- (6- (2-amino-3- (4-fluorophenyl) propanal) -2-fluoro-9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Fludarabine derivative)
Figure BDA0002282587100000192
By combining the preparation method of the embodiment 1, the fludarabine is used as a raw material, and the white foamy solid benzyl 2- ((((((((2S, 3S,4S,5S) -5- (6- (2-amino-3- (4-fluorophenyl) propylamino) -2-fluoro-9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate is synthesized.1H NMR(CDCl3 400MHz)δ8.35(s,1H),7.47-7.18(m,14H),6.16(m,1H),5.34(s,2H),5.11(s,2H),4.75-3.19(m,11H),1.28(d,3H).ESI-MS m/z:768.1[M+H]+.
16. Synthesis of benzyl 2- ((((((2R, 3S,4R,5R) -5- (6- (2-amino-3- (4-fluorophenyl) propanal) -2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Clofarabine derivative)
Figure BDA0002282587100000201
By combining the preparation method of example 1, the clorfarabine is used as a raw material, and the white foamy solid benzyl 2- ((((((2R, 3S,4R,5R) -5- (6- (2-amino-3- (4-fluorophenyl) propylamino) -2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate is synthesized.1H NMR(CDCl3 400MHz)δ8.35(s,1H),7.47-7.18(m,14H),6.22(m,1H),5.34(s,2H),5.11(s,2H),4.40-3.19(m,10H),1.28(d,3H).ESI-MS m/z:786.1[M+H]+.
17. Synthesis of benzyl 2- (((((((2S, 3S,5S) -5- (6- (2-amino-3- (4-fluorophenyl) propanal) -2-chloro-9H-purin-9-yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate (Cladibine derivative)
Figure BDA0002282587100000202
By combining the preparation methods of example 1, cladribine was used as a starting material to synthesize a white foamy solid, benzyl 2- (((((((2S, 3S,5S) -5- (6- (2-amino-3- (4-fluorophenyl) propylamino) -2-chloro-9H-purin-9-yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate.1H NMR(CDCl3 400MHz)δ8.35(s,1H),7.47-7.18(m,14H),5.95(m,1H),5.34(s,2H),5.11(s,2H),4.40-3.19(m,9H),2.56(m,2H),1.28(d,3H).ESI-MS m/z:768.1[M+H]+.
18. Synthesis of benzyl 2- (((((((2R, 3S,4R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) pyrr-olidine [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate
Figure BDA0002282587100000211
By combining the preparation methods of example 1 with (2R,3R,4S,5R) -2- (4-aminopyrrole [2,1-f ]][1,2,4]Triazine-7-yl) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile is used as a raw material to synthesize white foam solid 2- (((((2R,3S,4R,5R) -5- (4- (2-amino-3- (4-fluorophenyl) propylamino) pyrrole [2, 1-f)][1,2,4]Triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) benzyl propionate.1H NMR(CDCl3 400MHz)δ9.78(s,1H),7.47-7.18(m,14H),5.89-5.72(m,2H),5.34(s,2H),5.11(s,2H),4.51-3.19(m,11H),1.28(d,3H).ESI-MS m/z:774.1[M+H]+.
19. Synthesis of benzyl 2- (((((((2R) -1- (6- (2-amino-3- (4-fluorophenyl) propylamino) -9H-purin-9-yl) propan-2-yl) oxy) (phenoxy) phosphoryl) amino) propionate (Tenofovir derivative)
Figure BDA0002282587100000212
By combining the preparation methods of example 1, benzyl 2- (((((2R) -1- (6- (2-amino-3- (4-fluorophenyl) propylamino) -9H-purin-9-yl) propan-2-yl) oxy) (phenoxy) phosphoryl) amino) propionate was synthesized as a white foamy solid using (R) -1- (6-amino-9H-purin-9-yl) propyl-2-ol as a starting material.1H NMR(CDCl3 400MHz)δ8.60(s,1H),8.05(s,1H),7.47-7.18(m,14H),5.34(s,2H),5.11(s,2H),4.18-3.19(m,7H),1.28(d,3H),1.18(d,3H).ESI-MS m/z:676.1[M+H]+.
20. Synthesis of benzyl 2- (((2- (6- (2-amino-3- (4-fluorophenyl) propylamino) -9H-purin-9-yl) ethoxy) (phenoxy) phosphoryl) amino) propionate (Adefovir derivative)
Figure BDA0002282587100000221
By synthesizing the preparation method of the comprehensive example 1 by using 2- (6-amino-9H-purin-9-yl) ethanol as a raw material, white foamy solid 2- (((2- (6- (2-amino-3- (4-fluorophenyl) propylamino) -9H-purin-9-yl) ethoxy) (phenoxy) phosphoryl) amino) was obtainedYl) propionic acid benzyl ester.1H NMR(CDCl3 400MHz)δ8.60(s,1H),8.05(s,1H),7.47-7.18(m,14H),5.34(s,2H),5.11(s,2H),4.51(m,4H),3.95(m,1H),3.63(m,1H),3.44-3.19(m,2H),1.28(d,3H).ESI-MS m/z:662.1[M+H]+.
Example 21
Compounds of examples 1,2, 3, 11, 15, 16, 17 and gemcitabine in vivo antitumor activity experiments the antitumor activity of compounds of the ZONK1802 series was evaluated in the PANC-1 xenograft model. PANC-1 cells were implanted into female nude mice. On day 8 (8 days post-implantation) the mean tumor volume reached about 247mm3. On day 8 (8 days post-implantation), tumor-bearing mice were randomly divided into 9 groups according to tumor volume and were combined with a blank control, gemcitabine (ip, 285mM/kg), example 1(po, 285mM), example 2(ip, 285mM/kg), example 3(po, 285mM), example 11(po, 285mM), example 15(po, 285mM), example 16(po, 285mM), example 17(po, 285 mM). Tumor volume and body weight were observed and recorded twice weekly for 21 days. At the end of the study (d29), animals were euthanized and vehicle-controlled tumors dissected and weighed. The tumor T/C (%) value (relative tumor increment rate) was calculated as T/C (%). 100% times RTVT/RTVC
RTVTRelative tumor volume after administration
RTVCRelative tumor volume before administration
Solvent: solutol HS15 Beijing coupled technologies, Inc., lot No. 20180226
PEG 400 Damas-beta, batch No. P1471409 physiological saline, Sichuan Koran pharmaceutical Co.Ltd, batch No. A18111004-2
Animals: 72 animals: female BALB/c nude mice, 6 weeks old, were housed in plastic cages (3-5 mice/cage) containing corncobs and kept in a specific pathogen free facility (20-26 ℃, 40-70% humidity), 12 hours light and dark cycles, with food ad libitum access and filtered water.
Human tumor cell lines: PANC-1
Implanting the cell suspension into a athymic BALB/c nude mouse in the flank to establish a tumor model;
the control group used: 15% Solutol HS15+ 85% PEG 400
The experimental drug group was dissolved in physiological saline (5ml)
When the mean tumor volume reached about 247mm3Meanwhile, tumor-bearing mice were randomly divided into 8 groups according to the tumor volume and treated; tumor size and body weight were measured twice weekly; during the observation period, the animals were observed for any clinically relevant abnormalities and recorded; end point: with CO2Animals were sacrificed and vehicle control tumors were dissected and weighed. Experimental groups and dosages (mM/kg)
Group of Medicine Dosage form Route of administration Dosing regimens Number of animals
A Blank control PO BIW is multiplied by 6 times 6
B Gemcitabine 285 ip BIW is multiplied by 6 times 6
C Example 2 285 ip BIW is multiplied by 6 times 6
D Example 1 285 PO BIW is multiplied by 6 times 6
E Example 3 285 PO BIW is multiplied by 6 times 6
F Example 11 285 PO BIW is multiplied by 6 times 6
G Example 15 285 PO BIW is multiplied by 6 times 6
H Example 16 285 PO BIW is multiplied by 6 times 6
I Example 17 285 PO BIW is multiplied by 6 times 6
Relative tumor proliferation rate T/C%
Figure BDA0002282587100000231
Figure BDA0002282587100000241
As can be seen from the above table, the compound of example 2 (group C) was not significantly different from gemcitabine (group B), the compounds of examples 1,3, 11, 15, 16 and 17 were significantly different from gemcitabine (group B), and the relative tumor increment rate was significantly lower than that of the positive control gemcitabine.
The weight of each group is reduced by percentage%
Group of Day 8 Day 12 Day 15 Day 19 Day 22 Day 26 Day 29
A -1.57％ -1.86％ -1.86％ -2.25％ -2.35％ -2.35％ -1.57％
B 1.10％ 2.58％ 2.20％ 1.10％ 1.96％ 1.14％ 1.10％
C 0.10％ 1.58％ 1.31％ 1.22％ 2.25％ 1.50％ 1.15％
D -0.20％ -0.40％ -1.99％ -3.58％ -4.77％ -4.57％ -2.20％
E -0.10％ -0.50％ -1.66％ -2.50％ -3.66％ -3.42％ -0.86％
F -0.30％ -0.35％ -1.35％ -2.88％ -3.67％ -3.88％ -0.97％
G -0.21％ -0.36％ -2.33％ -3.78％ -4.21％ -4.56％ -1.20％
H -0.55％ -0.64％ -1.88％ -3.67％ -3.96％ -4.23％ -1.56％
I -0.32％ -0.54％ -2.99％ -2.58％ -3.69％ -4.78％ -1.25％
d8 day 8 after tumor implantation; "-": the animal gained weight.
Example 22
Drug ZONK1802-5, dfdu and dfdctp drug concentrations in male BALB/c nude mouse plasma and tumors.
Dfdu is the main metabolite of gemcitabine in animals and is also an ineffective component, and dfdctp is the main active component of gemcitabine in animals, so that the reduction of Dfdu means that the oxidation of amino part of nucleotide structure is reduced, the active component of dfdctp is increased, and the action mechanism is changed.
1.1.1 test article and internal standard Compound
And (3) testing the sample: ZONK1802-3, ZONK1802-4, ZONK1802-5, dfdu and dfdctp, molecular weights 745.6, 788.7, 299.7, 264 and 505, respectively, were provided by Guangdong Central medicine research, Inc.
Internal standard compound:
tolbutamide, batch MKBR6717V, purchased from Sigma.
Propranolol hydrochloride, lot No. BCBD8251V, purchased from Sigma.
Dichlorophenolic acid, batch No. BCBK6371V, available from Sigma.
1.1.2 test reagents
Dimethyl sulfoxide (DMSO): lot number L1712018, available from Aladdin.
Acetonitrile: lot number 175164, available from Fisher Scientific.
Formic acid: lot number L0980250, available from CNW Technologies.
Ultrapure water: prepared by a water purifier and taken at present after being used.
Blank mouse plasma and tumors: mice were collected in the home portosystemic group.
Animal sources:
is provided in vivo.
Animals and groups: 18 BALB/c nude mice were obtained from the organism, 6 mice/group;
the administration mode comprises the following steps: IP and PO
Solvent formulation
Solvent I: 15% Solutol HS15+ 85% PEG 400
Heating Solutol HS15 (polyethylene glycol 15 hydroxystearate) to liquid in water bath at 50-60 ℃, sucking 1.8mL Solutol HS15 to 15mL centrifuge tubes, adding 10.2mL PEG 400, vortex, shaking and mixing uniformly to prepare a mixed preparation containing 15% Solutol HS15 and 85% PEG 400, and storing at 2-8 ℃ for later use, wherein the preparation is prepared once a week.
Preparation of drug delivery preparation
Control sample: ZONK1802-5 (gemcitabine hydrochloride) is formulated with a formulation for administration at a molar dose of 285mM/kg (75mg/kg) (test concentration of 8.56mg/mL)
Weighing a proper amount of ZONK1802-5 test sample, placing the test sample into a 5mL centrifuge tube, adding a proper amount of normal saline, carrying out vortex oscillation until the drug is completely dissolved, and preparing into an administration preparation with the test sample concentration of 8.56mg/mL, wherein the administration preparation is used for animal administration and is ready for use.
And (3) testing a sample: ZONK1802-3 (Compound of example 1) was formulated with a dose of 570mM/kg (423mg/kg) as a drug delivery formulation (test concentration 42.3mg/mL)
Weighing an appropriate amount of ZONK1802-3 sample, placing the sample into a 5mL centrifuge tube, adding an appropriate amount of solvent I, performing vortex oscillation until the drug is completely dissolved, and preparing into an administration preparation with the sample concentration of 42.3mg/mL for animal administration. It is prepared as before use.
And (3) testing a sample: ZONK1802-4 (Compound of example 2) was formulated with a dose of 570mM/kg (450mg/kg) (test sample concentration 45.3mg/mL)
Weighing an appropriate amount of ZONK1802-4 test sample, placing the test sample into a 5mL centrifuge tube, adding an appropriate amount of solvent I, performing vortex oscillation until the drug is completely dissolved, and preparing into an administration preparation with the test sample concentration of 45.3mg/mL for animal administration. It is prepared as before use.
Solvent comparison: 15% Solutol HS15+ 85% PEG 400
Animal numbers, administered dose volumes are as follows:
Figure BDA0002282587100000261
eating/drinking conditions:
fasting was for more than 12 hours before administration, and fasting was for 4 hours after administration, with free water.
Anticoagulant: EDTA-K2
Sample collection time point: animals 1h, 2h and 4h after administration, wherein 101-102, 201-202 and 301-302 are 1 h; 103, 203, 204 and 303, 304 are 2h animals; 105, 205, 206 and 305, 306 were 4h animals, plasma and tumors were collected and weighed. Collecting Whole blood to EDTA-K2Adding tetrahydrouridine (25ug/mL) into anticoagulation tube, placing blood sample on crushed ice before centrifugation, centrifuging within half an hour, collecting plasma (6000 rpm, 8 min, 4 deg.C), and freezing dry ice for use. Tumors were washed three times with ice-cold physiological saline, blotted with filter paper, and weighed.
All samples were collected and stored frozen in a-80 freezer for analysis.
Analytical method and assay
In the experiment, the concentrations of ZONK1802-5, dfdu and dfdctp drugs in the plasma and tumors of male BALB/c nude mice are measured by a liquid chromatography-mass spectrometry method. 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 above 3/4 in the plasma and tumor standard curves was 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. Each analysis batch is provided with quality control samples (QC) with different concentrations, wherein each concentration is at least parallel to two samples, and the quantity of the quality control samples is more than or equal to 5 percent of that of each batch. And calculating the concentration of the quality control sample according to the standard curve of each analysis batch. The sample with 1/3 allowed at most and different concentration in the plasma quality control sample is more than 20% of the theoretical value, otherwise the data of the batch is not accepted and re-determined.
Preparation of Standard Curve and quality control sample
Taking 45 mu L of blank male BALB/c nude mouse plasma and tumor respectively, adding 5 mu L of the prepared standard curve working solution and quality control working solution respectively, and vortex and uniformly mixing to obtain a standard curve and a quality control sample corresponding to each compound. For the compounds needing to be diluted in blood samples, 57 μ L of male BALB/c nude mouse plasma and tumor are respectively taken, 3 μ L of diluted quality control working solution of the corresponding compound with the concentration of 100 μ g/mL is respectively added, vortex mixing is carried out, Quality Control (QC) samples with the concentration of 5000ng/mL are respectively obtained, then 5 μ L of the quality control samples are taken and added into 45 μ L of male BALB/c nude mouse plasma and tumor, vortex mixing is carried out, a diluted quality control sample with the concentration of 500ng/mL is obtained (N is 3), and the dilution factor is: 10.
1.1.3 liquid chromatography conditions
For dfdu
High-performance liquid phase system: SHIMADZU LC30AD
A chromatographic column: phenomenex Gimini C185 μm 4.6 x 50mm
Column temperature: room temperature;
flow rate: 0.8 mL/min;
mobile phase: phase A: 0.1% formic acid in water, phase B: acetonitrile solution containing 0.1% formic acid;
high-performance liquid phase system: SHIMADZU LC30AD
A chromatographic column: thermo SCINTIFIC Hypersil GOLD C850 x 2.1mm
Column temperature: room temperature;
flow rate: 0.5 mL/min;
mobile phase: phase A: aqueous solution containing 2mM ammonium acetate, phase B: acetonitrile solution;
test concentration of dfdu drug in plasma of Male BALB/c nude mice (ng/mL)
Figure BDA0002282587100000271
Figure BDA0002282587100000281
EXAMPLE 23 comparison of pharmacodynamic experiment of 4-fluorophenylalanine acylated derivative of amino group-containing nucleotide drug against hepatitis B virus
In vivo assay for hepatitis B Virus (DHBV-DNA) inhibition by Compounds of the examples
Reagent:
positive control drug:
lamivudine
alpha-32P-Dctp (Beijing Furui biotechnology engineering Co., Ltd.)
Gap translation kit (Promega corporation)
The milt DNA and bovine serum albumin were purchased from the Biophysical institute of Chinese academy of sciences
Experimental animals and viruses: the weight of the 1-day-old Beijing sheldrake is 60-100 g; DHBV-DNA strong positive serum collected from Nanjing sheldrake and stored at-70 deg.C.
The test method comprises the following steps: 1 day old Beijing duck, through leg intravenous injection DHBV-DNA positive serum 0.2 ml/one, duckling infection day 7 through DHBV randomly divided into groups, respectively: virus control group (saline, PO); example 9, example 19, example 20, example 14, positive control lamivudine group (LA), each experimental group was orally gavaged with the same molar amount dissolved in DMSO at a dose of 300 mM/kg. Administration was started on day 7 (i.e., time T0) after DHBV infection, 2 times per day, and continued for 10 days. Blood was collected from the vein of duck leg before administration on the seventh day (T0) after HDBV infection, on the 5 th day, on the 10 th day, and on the 3 rd day after discontinuation of the drug, and serum was centrifuged and stored at-70 deg.C for testing. Serum DHBV-DNA levels were determined strictly according to the notch translation kit instructions. DHBV-DNA density was labeled with 32P, and the OD of the hybridization spots was used as the DHBV-DNA level in the specimen. The inhibition rate of the medicine on the animal serum DHBV-DNA at each time point is calculated according to the following formula:
DNA inhibition (%) — OD value before administration (T0) -OD value after administration/OD value before administration (T0) × 100%
The experimental results are as follows: after DHBV infection, DHBV-DNA in the blood serum of the ducks at the time points of T0, T5, T10 and P3 is determined by a dot blot hybridization method, and after all 4 groups of experimental animals are infected with DHBV, the DHBV-DNA in the blood serum is strong positive. OD values of all experimental samples at 490nm detected by a microplate reader show that the concentration of DHBV-DNA in animal serum is extremely reduced remarkably after the compound of the embodiment is orally taken for 5-10 days, and the compound of the embodiment has obvious advantages compared with lamivudine and the compound of other embodiments has advantages compared with the compound of the embodiment 2. DHBV-DNA can be still obviously inhibited after 3 days of drug withdrawal. The OD values for each set of different time points are given in the table below:
point in time T0 T5 T10 P3
Virus control group 1.83±0.21 1.76±0.15 1.66±0.23 1.75±0.25
LA 1.86±0.31 1.56±0.21 1.26±0.35 1.61±0.28
Example 9 1.91±0.36 1.50±0.21 1.11±0.25 1.12±0.32
Example 19 1.79±0.29 1.45±0.24 1.10±0.11 1.02±0.16

Claims (8)

1. A 4-halo-substituted phenylalanine amidated nucleotide derivative of formula I:
Figure FDA0003147739800000011
in formula I, X represents F;
in the formula I, the compound is shown in the specification,
Figure FDA0003147739800000012
represents a nucleoside;
in formula I, the 4-halo substituted phenylalanine forms an amide bond with an amino group in a nucleobase, which is any one of the following:
Figure FDA0003147739800000013
Figure FDA0003147739800000021
in the formula (I), the 5-hydroxymethyl group in the ribose or deoxyribose of the nucleoside forms an ester bond with the phosphate,
R1is phenyl;
R2is C1-C8 alkyl;
R3is benzyl.
2. A process for preparing the nucleotide derivative of claim 1, comprising the steps of: 1) reacting the pentafluorophenol phosphate active intermediate shown in the formula II with 5-hydroxymethyl of ribose or deoxyribose in nucleoside to obtain ribose or deoxyribose 5-hydroxymethyl phosphorylated nucleotide;
Figure FDA0003147739800000022
in the formula II, R1、R2And R3Are each as defined in claim 1 wherein R is1、R2And R3The definition of (1);
2) coupling BOC- (4-X) phenylalanine, wherein X represents F, with amino in the basic group of the ribose or deoxyribonucleotide obtained in the step 2) to form amido bond, thus obtaining the final product.
3. The method of claim 2, wherein: in the step 1), the molar ratio of the pentafluorophenol phosphate active intermediate shown in the formula II to the nucleoside is as follows: 1.0-2.0;
the reaction is carried out under the catalysis of tert-butyl magnesium chloride;
the molar ratio of nucleoside to tert-butyl magnesium chloride is: 1: 1.0-2.0;
the reaction is carried out under the protection of inert gas;
the reaction is carried out in an anhydrous organic solvent;
the reaction temperature is as follows: -20-10 ℃ for: 8-24 h.
4. The method of claim 3, wherein: the inert gas is nitrogen, and the anhydrous organic solvent is anhydrous tetrahydrofuran.
5. The method of claim 2, wherein: in the step 2), the reaction for forming the amido bond is carried out in the presence of 1-hydroxybenzotriazole;
the reaction for forming the amido bond is carried out in the presence of a carboxyl activating reagent, and the carboxyl activating reagent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;
the molar ratio of the ribose or deoxyribose 5-hydroxymethyl phosphorylated nucleotide to the BOC- (4-X) phenylalanine, the 1-hydroxybenzotriazole and the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is as follows in sequence: 1.0: 1.0-1.5: 1.0-2.0: 1.0-2.0;
the reaction temperature is room temperature, and the reaction time is 3-8 h.
6. The method of claim 2, wherein: if the ribose or deoxyribose of the nucleoside has hydroxyl groups at other positions in addition to the 5-hydroxymethyl group, the step 1) may be preceded by an operation of selectively protecting the hydroxyl groups at other positions,
correspondingly, after the step 2), the method also comprises the operation of removing hydroxyl protection from the product obtained in the step 2) under an acidic condition to obtain the target product.
7. Use of the 4-halogen substituted phenylalanine amidated nucleotide derivative of formula I as defined in claim 1 for the preparation of an antitumor and/or antiviral medicament.
8. Use according to claim 7, characterized in that: the tumor is a human pancreatic cancer tumor;
the virus is hepatitis B virus.
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