CN112175031A - Uridylic acid mixed phosphoramidate compound, pharmaceutical composition and application thereof - Google Patents
Uridylic acid mixed phosphoramidate compound, pharmaceutical composition and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and discloses a uridylic acid mixed phosphoramidate compound, a pharmaceutical composition thereof and application thereof, in particular application of the compound in treating hepatitis C. Experiments prove that the uridylic acid mixed phosphoramidate compound has the activity of inhibiting HCV virus replication, and simultaneously has the advantages of higher in vitro activity, larger development coefficient and the like compared with the current hepatitis C treatment drug sofosbuvir, and can be used for developing the hepatitis C treatment drug.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a uridylic acid mixed phosphoramidate compound, a pharmaceutical composition and application thereof, which are suitable for treating flaviviridae virus infection, in particular to hepatitis C.
Background
Since the HCV genome is similar in structural and phenotypic characteristics to human flaviviruses and pestiviruses, it is classified as a flaviviridae HCV. Viruses of the flaviviridae family include at least three distinct genera: pestiviruses (pestiviruses), which cause disease in cattle and pigs; flaviviruses (flavivruses), which are the major causes of diseases such as dengue and yellow fever; and hepaciviruses (hepaciviruses), the only member of which is HCV. The flavivirus genus included more than 68 members, grouped based on serological relationship. Clinical symptoms vary and include fever, encephalitis, and hemorrhagic fever. Flaviviruses of global interest in relation to human disease include dengue hemorrhagic fever virus (DHF), yellow fever virus, shock syndrome virus and japanese encephalitis virus. Hepatitis c virus is a positive-stranded RNA virus that surrounds a lipid-containing envelope, with spikes, outside the nucleocapsid.
The world health organization estimates that there are 3-4 million new patients with Hepatitis C Virus (HCV) annually, over 2 billion infected people worldwide, and over 1000 million people in china, where HCV is a virus of the hepacivirus family flaviviridae.
The pathogenesis of hepatitis C is not clear, and when HCV is replicated in hepatocytes to cause structural and functional changes of the hepatocytes or interfere with protein synthesis of the hepatocytes, degeneration and necrosis of the hepatocytes can be caused, which indicates that HCV directly damages the liver to cause pathogenesis.
Chronic hepatitis c virus infection is mild to inflammation, severe to cirrhosis and liver cancer. And various complications can occur when the hepatitis C cirrhosis is in the decompensation stage, such as ascites abdominal infection, upper gastrointestinal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, hepatic failure and the like.
The first treatment for HCV infection was interferon and ribavirin combination therapy, to which only 50% of the patients responded, with interferon having significant side effects such as flu-like symptoms, weight loss and fatigue weakness, and interferon and ribavirin combination therapy producing considerable side effects including hemolysis, anemia and fatigue.
The hepatitis C drug Sofosbuvir (trade name: Sovaldi, common name: Sofosbuvir) from Gilidide Inc. was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with chronic hepatitis C (Hepatitis C) by 6.12.3.2013. Sofosbuvir is the first approved drug for the full oral treatment regimen for hepatitis C, and eliminates the need for the traditional injection of the drug Interferon (IFN) when used in the treatment of chronic hepatitis C of a specific genotype (type 2, type 3).
However, because sofosbuvir has low in vivo bioavailability and requires a large dosage of a drug, and patients with hepatitis c need to be treated for a long time, the problems of viral resistance and long-term safety are not negligible, and therefore, the development of new therapeutic drugs for HCV infection with high bioavailability, longer half-life and high drug efficacy is still an urgent clinical need.
Disclosure of Invention
The invention aims to further modify the structure of the uridylic acid mixed phosphoramidate compound so as to obtain a novel uridylic acid mixed phosphoramidate compound analogue with lower toxicity and higher anti-Hepatitis C Virus (HCV) activity, and lays a foundation for further research and development of antiviral application of the compound.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the invention provides a uridylic acid mixed phosphoramidate compound or a pharmaceutically acceptable salt thereof, wherein the structural formula of the uridylic acid mixed phosphoramidate compound is (Ia):
wherein:
Ra、Rb、Rcand RdEach independently represents (C)1-C12) Alkyl or (C)6-C20) Aryl radical (C)1-C12) Any one of alkyl, ReAnd RfEach independently represents hydrogen or (C)1-C12) Any one of alkyl groups; and when R iscAnd RdBoth being methyl or both being benzyl, and ReAnd RfWhile being hydrogen, RaIs not equal to Rb。
The uridylic acid mixed phosphoramidate compound or the pharmaceutically acceptable salt thereof is provided, wherein ReAnd RfAnd hydrogen at the same time, the amino acid ester connected with the phosphorus atom is in an R configuration or an S configuration, and the structural formula of the uridylic acid mixed phosphoramidate compound is selected from one of the following structural formulas:
wherein: ra、Rb、RcAnd RdEach independently represents (C)1-C12) Alkyl or (C)6-C20) Aryl radical (C)1-C12) Any one of alkyl groups; and when R iscAnd RdWhen both are methyl or when both are benzyl, RaIs not equal to Rb。
The uridylic acid mixed phosphoramidate compound or the pharmaceutically acceptable salt thereof is provided, wherein the phosphorus atom is chiral phosphorus atom, preferably S(P)Configuration or R(P)One or two of the configurations, the structural formula of the uridylic acid mixed phosphoramidate compound is selected from one of the following structural formulas:
wherein: ra、Rb、RcAnd RdEach independently represents (C)1-C12) Alkyl or (C)6-C20) Aryl radical (C)1-C12) Any one of alkyl groups; and when R iscAnd RdWhen both are methyl or when both are benzyl, RaIs not equal to Rb。
The uridylic acid mixed phosphoramidate compound or the pharmaceutically acceptable salt thereof of the present invention, wherein R isaAnd RbEach independently represents any one of isopropyl, ethyl, isobutyl, neopentyl, n-butyl, cyclohexyl, methyl, tert-butyl or 2-ethylbutyl, and R iscAnd RdEach independently represents any one of methyl or benzyl, and the structural formula of the uridylic acid mixed phosphoramidate compound is selected from one of the following structural formulas.
The pharmaceutical composition comprises the uridylic acid mixed phosphoramidate compound or pharmaceutically acceptable salt thereof and an auxiliary material, wherein the auxiliary material is a pharmaceutically acceptable carrier or excipient.
The pharmaceutical composition further comprises at least one of Ribavirin (Ribavirin), interferon, hepatitis C NS3 protease inhibitor, HCV reverse transcriptase NS5B non-nucleoside inhibitor, HCV reverse transcriptase NS5B nucleoside inhibitor, NS5A inhibitor, synergist of NS5A inhibitor, entry inhibitor, cyclosporin immunosuppressant, NS4A antagonist, NS4B inhibitor or cyclophilin inhibitor.
The invention provides a preparation method of a uridylic acid mixed phosphoramidate compound, which comprises the following steps:
under the alkaline condition, after amino acid ester hydrochloride HA3ace and amino acid ester hydrochloride HA3bdf react with phosphorus oxychloride of a phosphorylation reagent, pentafluorophenol is added for reaction to obtain a compound FP 3; FP3 was then reacted with nucleoside SOF at-20 ℃ to-80 ℃ to give compound (Ia).
The synthetic route of the preparation method is as follows:
wherein: ra、Rb、RcAnd RdEach independently represents (C)1-C12) Alkyl or (C)6-C20) Aryl radical (C)1-C12) Any one of alkyl, ReAnd RfEach independently represents hydrogen or (C)1-C12) Any one of alkyl groups; and when R iscAnd RdBoth being methyl or both being benzyl, and ReAnd RfWhile being hydrogen, RaIs not equal to Rb。
The invention also provides the application of the uridylic acid mixed phosphoramidate compound or the pharmaceutically acceptable salt thereof in preparing the medicine for treating human Flaviviridae virus infection.
The use of the present invention, wherein the human flaviviridae viral infection is a human HCV viral infection.
The invention also provides application of the pharmaceutical composition in preparing a medicament for resisting human Flaviviridae virus infection, wherein the Flaviviridae virus is HCV virus.
The invention has the beneficial effects that:
the uridylic acid mixed phosphoramidate compound of the present invention has excellent properties required for becoming a medicament for treating hepatitis c as determined by a detection mechanism, and specifically comprises the following:
in an in vitro screening for anti-HCV activity, the EC for compound S34S374S-2, S371S374S-1 or S32S374S-250Is more than 2-5 times of sofosbuvir (positive control), and the selection coefficient of biological activity SI is more than 2-5 times of sofosbuvir (positive control).
This indicates that: the uridylic acid mixed phosphoramidate compound can effectively inhibit HCV infection on a cellular level, and is expected to become a medicament for treating HCV infection.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The present invention will be further illustrated by the following examples, but the present invention is not limited to these examples. The reagents and starting materials used in the examples of the invention were all commercially available.
Example 1
Synthesis of (R) -N- [ (pentafluorophenoxy) (((S) -1- (N-butoxycarbonyl) -2-phenylethyl) amino) phosphoryl ] -D-phenylalanine neopentyl ester (FP374S373R-1) and (S) -N- [ (pentafluorophenoxy) ((((S) -1- (N-butoxycarbonyl) -2-phenylethyl) amino) phosphoryl ] -D-phenylalanine neopentyl ester (FP374S 373R-2).
Phosphorus oxychloride (5g, 3.04mL, 32.6mmol) and acetonitrile (200mL) were added to a reaction flask, cooled to-70 ℃, and a solution of D-phenylalanine neopentyl ester hydrochloride (D-HA373) (8.86g, 32.6mmol) and triethylamine (3.3 g, 4.53mL, 32.6mmol) in acetonitrile (60mL) was slowly added dropwise, after the addition was complete, the temperature was slowly raised to room temperature, and the reaction was allowed to proceed overnight. Cooling the above mixture to 0 deg.C, adding L-phenylalanine n-butyl ester hydrochloride (L-HA374) (7.57g, 29.4mmol), cooling to-70 deg.C, adding triethylamine (7.3 g, 10mL, 72mmol) in acetonitrile 60mL, heating to 0 deg.C, reacting for 3 hr, adding pentafluorophenol (5.4g, 29.4mmol) and triethylamine (7.3 g, 10mL, 72mmol) in acetonitrile 60mL, stirring at 0 deg.C for 1 hr, heating to room temperature, stirring overnight, adding 100 mL dichloromethane and 100 mL water, separating out organic phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating the residue with silica gel column (0-30% ethyl acetate/hexane) to obtain 8.3g white solid, recrystallizing with 10% tert-butyl methyl ether/hexane to obtain white solid FP374S373R-2(3.5g), the mother liquor is separated by silica gel column (50% ethyl acetate/hexane) to obtain FP374S373R-1(3.1g) and FP374S373R-2(0.3g), wherein the purities of the FP374S373R-1 and the FP374S373R-2 are both more than 98%.
Nuclear magnetic hydrogen spectrum data of FP374S 373R-1: :1H NMR(400MHz，CDCl3)(ppm)：0.80-1.15(12H，m，4×CH3)，1.17-1.42(2H，m，CH2)，1.56-1.70(2H，m，CH2)，3.80-4.01(8H，m，2×CH2，2×NH and2×NCH)，4.13-4.37(4H，m，2×COOCH2) 7.01-7.37(10H, m, hydrogen on both benzene rings).
31P NMR(162MHz,CDCl3)-2.21；
LCMS-ESI+(m/z):685.6(M+H)。
Nuclear magnetic hydrogen spectrum data of FP374S 373R-2:1H NMR(400MHz，CDCl3)(ppm)：0.82-1.15(12H，m，4×CH3)，1.19-1.43(2H，m，CH2)，1.56-1.74(2H，m，CH2)，3.82-4.04(8H，m，2×CH2，2×NH and2×NCH)，4.15-4.38(4H，m，2×COOCH2) 7.02-7.39(10H, m, hydrogen on both benzene rings).
31P NMR(162MHz,CDCl3)-2.33；
LCMS-ESI+(m/z):685.6(M+H)。
Example 2
Synthesis of (R) -N- [ (pentafluorophenoxy) (((R) -1- (neopentyloxycarbonyl) -2-phenylethyl) amino) phosphoryl ] -D-phenylalanine tert-butyl ester (FP373R378R-1) and (S) -N- [ (pentafluorophenoxy) ((((R) -1- (neopentyloxycarbonyl) -2-phenylethyl) amino) phosphoryl ] -D-phenylalanine tert-butyl ester (FP373R 378R-2).
FP373R378R-1 and FP373R378R-2 were synthesized by a similar synthesis method as in example 1.
Nuclear magnetic hydrogen spectrum data of FP373R 378R-1:1H NMR(400MHz，CDCl3)(ppm)：0.80-1.21(18H，m，6×CH3)，3.70-3.97(8H，m，2×CH2，2×NH and 2×NCH)，4.04-4.35(2H，m，COOCH2) 7.02-7.37(10H, m, hydrogen on both benzene rings).
31P NMR(162MHz,CDCl3)-2.03；
LCMS-ESI+(m/z):685.6(M+H)。
Nuclear magnetic hydrogen spectrum data of FP373R 378R-2:1H NMR(400MHz，CDCl3)(ppm)：0.82-1.24(18H，m，6×CH3)，3.72-3.98(8H，m，2×CH2，2×NH and 2×NCH)，4.06-4.37(2H，m，COOCH2) 7.04-7.39(10H, m, hydrogen on both benzene rings).
31P NMR(162MHz,CDCl3)-2.22；
LCMS-ESI+(m/z):685.6(M+H)。
Example 3
Synthesis of (R) -N- [ (pentafluorophenoxy) (((S) -1- (N-butyloxycarbonyl) ethyl) amino) phosphoryl ] -L-phenylalanine N-butyl ester (FP34S374S-1) and (S) -N- [ (pentafluorophenoxy) ((((S) -1- (N-butyloxycarbonyl) ethyl) amino) phosphoryl ] -L-phenylalanine N-butyl ester (FP34S 374S-2).
FP34S374S-1 and
FP34S374S-2。
FP34S374S-11H NMR(400MHz，CDCl3)(ppm)：0.82-1.14(6H，m，2×CH3)，1.19-1.42(7H，m，CH3，2×CH2)，1.53-1.70(4H，m，2×CH2)，3.90-4.08(6H，m，CH2，2×NH and 2×NCH)，4.19-4.39(4H，m，2×COOCH2) 7.01-7.37(5H, m, hydrogen on benzene ring).
31P NMR(162MHz,CDCl3)-1.83；
LCMS-ESI+(m/z):595.5(M+H)。
FP34S374S-21H NMR(400MHz，CDCl3)(ppm)：0.85-1.16(6H，m，2×CH3)，1.19-1.44(7H，m，CH3，2×CH2)，1.54-1.72(4H，m，2×CH2)，3.94-4.11(6H，m，CH2，2×NH and 2×NCH)，4.21-4.40(4H，m，2×COOCH2) 7.05-7.39(5H, m, hydrogen on benzene ring).
31P NMR(162MHz,CDCl3)-1.96；
LCMS-ESI+(m/z):595.5(M+H)。
Example 4
Synthesis of (R) -N- [ (pentafluorophenoxy) (((S) -1- (ethoxycarbonyl) -2-phenylethyl) amino) phosphoryl ] -L-phenylalanine N-butyl ester (FP371S374S-1) and (S) -N- [ (pentafluorophenoxy) ((((S) -1- (ethoxycarbonyl) -2-phenylethyl) amino) phosphoryl ] -L-phenylalanine N-butyl ester (FP371S 374S-2).
FP371S374S-1 and FP371S374S-2 were synthesized by a similar synthesis method as in example 1.
Nuclear magnetic hydrogen spectrum data of FP371S 374S-1:1H NMR(400MHz，CDCl3)(ppm)：1.12-1.40(8H，m，2×CH3 and CH2)，1.54-1.70(2H，m，CH2)，3.81-4.00(8H，m，2×CH2，2×NH and 2×NCH)，4.15-4.36(4H，m，2×COOCH2) 7.02-7.37(10H, m, hydrogen on both benzene rings).
31P NMR(162MHz,CDCl3)-1.62；
LCMS-ESI+(m/z):643.6(M+H)。
Nuclear magnetic hydrogen spectrum data of FP371S 374S-2:1H NMR(400MHz，CDCl3)(ppm)：1.15-1.41(8H，m，2×CH3 and CH2)，1.56-1.71(2H，m，CH2)，3.83-4.05(8H，m，2×CH2，2×NH and 2×NCH)，4.18-4.37(4H，m，2×COOCH2) 7.07-7.37(10H, m, hydrogen on both benzene rings).
31P NMR(162MHz,CDCl3)-1.84；
LCMS-ESI+(m/z):643.6(M+H)。
Example 5
Synthesis of (R) -N- [ (pentafluorophenoxy) (((S) -1- (2-ethylbutyloxycarbonylethyl) amino) phosphoryl ] -L-phenylalanine-2-ethylbutyl ester (FP39S37 379S-1) and (S) -N- [ (pentafluorophenoxy) (((S) -1- (2-ethylbutyloxycarbonyl) ethyl) amino) phosphoryl ] -L-phenylalanine-2-ethylbutyl ester (FP39S 379S-2).
FP39S379S-1 and FP39S379S-2 were synthesized by a similar synthesis method to that of example 1.
Nuclear magnetic hydrogen spectrum data of FP39S 379S-1:1H NMR(400MHz，CDCl3)(ppm)：0.85-1.16(12H，m，4×CH3)，1.21-1.39(11H，m，CH3，4×CH2)，1.95-2.11(2H，m，2×CH)，3.76-3.99(6H，m，CH2，2×NH and 2×NCH)，4.03-4.31(4H，m，2×COOCH2) 7.01-7.40(5H, m, hydrogen on benzene ring).
31P NMR(162MHz,CDCl3)-2.06；
LCMS-ESI+(m/z):651.6(M+H)。
Nuclear magnetic hydrogen spectrum data of FP39S 379S-2:1H NMR(400MHz，CDCl3)(ppm)：0.87-1.18(12H，m，4×CH3)，1.24-1.40(11H，m，CH3，4×CH2)，1.96-2.18(2H，m，2×CH)，3.77-4.00(6H，m，CH2，2×NH and 2×NCH)，4.07-4.35(4H，m，2×COOCH2) 7.07-7.41(5H, m, hydrogen on benzene ring).
31P NMR(162MHz,CDCl3)-2.42；
LCMS-ESI+(m/z):651.6(M+H)。
Example 6
Synthesis of (R) -N- [ (pentafluorophenoxy) (((R) -1- (neopentyloxycarbonyl) ethyl) amino) phosphoryl ] -L-alanine isobutyl ester (FP33R32S-1) and (S) -N- [ (pentafluorophenoxy) ((((R) -1- (neopentyloxycarbonyl) ethyl) amino) phosphoryl ] -L-alanine isobutyl ester (FP33R 32S-2).
FP33R32S-1 and FP33R32S-2 were synthesized by a similar method as in example 1.
Nuclear magnetic hydrogen spectrum data of FP33R 32S-1:1H NMR(400MHz，CDCl3)(ppm)：0.93-1.31(21H，m，7×CH3)，2.36-2.50(1H，m，CH)，3.76-3.92(4H，m，2×NH and 2×NCH)，4.04-4.38(4H，m，2×COOCH2)。
31P NMR(162MHz,CDCl3)-1.77；
LCMS-ESI+(m/z):533.4(M+H)。
nuclear magnetic hydrogen spectrum data of FP33R 32S-2:1H NMR(400MHz，CDCl3)(ppm)：0.94-1.33((21H，m，7×CH3)，2.38-2.50(1H，m，CH)，3.77-3.94(4H，m，2×NH and 2×NCH)，4.06-4.39(4H，m，2×COOCH2)。
31P NMR(162MHz,CDCl3)-1.85；
LCMS-ESI+(m/z):533.4(M+H)。
example 7
Synthesis of (R) -N- [ (pentafluorophenoxy) (((S) -1- (isobutoxycarbonyl) ethyl) amino) phosphoryl ] -L-phenylalanine N-butyl ester (FP32S374S-1) and (S) -N- [ (pentafluorophenoxy) ((((S) -1- (isobutoxycarbonyl) ethyl) amino) phosphoryl ] -L-phenylalanine N-butyl ester (FP32S 374S-2).
FP32S374S-1 and FP32S374S-1 were synthesized by a similar synthesis method to that of example 1.
Nuclear magnetic hydrogen spectrum data of FP32S 374S-1:1H NMR(400MHz，CDCl3)(ppm)：0.92-1.40(14H，m，4×CH3 and CH2)，1.58-1.70(2H，m，CH2)，2.38-2.51(1H，m，CH)，3.84-4.05(6H，m，CH2，2×NH and2×NCH)，4.17-4.36(4H，m，2×COOCH2) 7.03-7.39(5H, m, hydrogen on benzene ring).
31P NMR(162MHz,CDCl3)-1.77；
LCMS-ESI+(m/z):595.5(M+H)。
Nuclear magnetic hydrogen spectrum data of FP32S 374S-2:1H NMR(400MHz，CDCl3)(ppm)：0.96-1.41(14H，m，4×CH3 and CH2)，1.58-1.77(2H，m，CH2)，2.39-2.56(1H，m，CH)，3.86-4.09(6H，m，CH2，2×NH and2×NCH)，4.20-4.38(4H，m，2×COOCH2) 7.05-7.41(5H, m, hydrogen on benzene ring).
31P NMR(162MHz,CDCl3)-1.89；
LCMS-ESI+(m/z):595.5(M+H)。
Example 8
Synthesis of (S) -N- [ (((((2R, 3R, 4R, 5R) -5- (2, 4(1H, 3H) -pyrimidinedione-1-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl) oxy) ((((S) -1- (N-butoxycarbonyl) -2-phenylethyl) amino) phosphoryl ] -D-phenylalanine neopentyl ester (S374S 373R-2)):
preparation of nucleoside SOF refer to the preparation method of patent application No. 200880018024.2.
A50 mL flask was charged with nucleoside SOF (260.2mg,1mmol) and 5.0mL anhydrous THF, and the mixture was cooled to 0 ℃ in an ice-water bath. A1.0M in THF solution of tert-butylmagnesium chloride (3.0mL, 3.0mmol) was added dropwise, the reaction mixture stirred at 0 deg.C for 30min, followed by the addition of a solution of phosphorus reagent FP374S373R-2(1.09g, 1.6mmol) in 5mL THF at 0 deg.C. The resulting clear reaction solution was warmed to room temperature, stirred for 20 hours, and then saturated NH was added4Cl (15mL), stirred for 5 min, the mixture was diluted with ethyl acetate (200mL), the organic phase was separated and the aqueous layer was extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with water (30mL), saturated NaHCO3(2X30mL), brine (30mL) and Na2SO4After drying, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to give the product S374S373R-2(280mg) as a white solid.
Nuclear magnetic hydrogen spectrum data of S374S 373R-2:1H NMR(400MHz，CDCl3)(ppm)：0.84-1.12(12H，m，4×CH3)，1.20-1.55(5H，m，CH2and CH at the 2' -position of the sugar ring3)，1.57-1.70(2H，m，CH2)，3.83-4.06(8H，m，2×CH22 × NH and 2 × NCH), 4.11-4.44(7H, m, H at the 3 ' -position of the sugar ring, OH at the 3 ' -position of the sugar ring, H and 2 × COOCH at the 4 ' -position of the sugar ring2) 4.50-4.66(2H, m, H at the 5 '-position of the sugar ring), 5.56-5.74(1H, m, H at the 5-position of the pyrimidine ring), 6.18(1H, s, H at the 1' -position of the sugar ring), 7.02-7.39(11H, m, H at the 6-position of the hydrogen and pyrimidine rings on both benzene rings), 9.78(1H, s, NH at the 3-position of the pyrimidine ring).
31P NMR(162MHz,CDCl3)6.6；
LCMS-ESI+(m/z):761.8(M+H)。
Example 9
Synthesis of (R) -N- [ ((((((2R, 3R, 4R, 5R) -5- (2, 4(1H, 3H) -pyrimidinedione-1-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl) oxy) ((((R) -1- (neopentyloxycarbonyl) -2-phenylethyl) amino) phosphoryl ] -D-phenylalanine tert-butyl ester (S373R 378R-1).
S373R378R-1 was synthesized by a similar synthesis method to that of example 8.
Nuclear magnetic hydrogen spectrum data of S373R 378R-1:1H NMR(400MHz，CDCl3)(ppm)：0.85-1.26(18H，m，6×CH3) 1.38-1.59(3H, s, CH at the 2' -position of the sugar ring)3)，3.75-3.98(8H，m，2×CH2，2×NH and 2×NCH)，4.08-4.44(5H，m，COOCH2H at the 3 ' -position of the sugar ring, OH at the 3 ' -position of the sugar ring, H at the 4 ' -position of the sugar ring), 4.55-4.68(2H, m, H at the 5 ' -position of the sugar ring), 5.55-5.74(1H, m, H at the 5-position of the pyrimidine ring), 6.16(1H, s, H at the 1 ' -position of the sugar ring), 7.06-7.37(11H, m, H at the 6-positions of the two benzene rings and the pyrimidine ring), 9.81(1H, s, NH at the 3-position of the pyrimidine ring).
31P NMR(162MHz,CDCl3)5.5；
LCMS-ESI+(m/z):761.8(M+H)。
Example 10
Synthesis of (S) -N- [ ((((((2R, 3R, 4R, 5R) -5- (2, 4(1H, 3H) -pyrimidinedione-1-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl) oxy) ((((S) -1- (N-butyloxycarbonyl) ethyl) amino) phosphoryl ] -L-phenylalanine N-butyl ester (S34S 374S-2).
Synthesized in a similar manner to example 8 to give S374R 374S-2.
S34S374S-2Nuclear magnetic hydrogen spectrum data:1H NMR(400MHz，CDCl3)(ppm)：0.83-1.12(6H，m，2×CH3)，1.19-1.37(7H，m，CH3 and 2×CH2) 1.42-1.53(3H, s, CH at the 2' -position of the sugar ring)3)，1.57-1.70(4H，m，2×CH2)，3.90-4.08(6H，m，CH2，2×NH and 2×NCH)，4.13-4.42(7H，m，2×COOCH2H at the 3 ' -position of the sugar ring, OH at the 3 ' -position of the sugar ring, H at the 4 ' -position of the sugar ring), 4.50 to 4.66(2H, m, H at the 5 ' -position of the sugar ring), 5.55 to 5.74(1H, m, H at the 5-position of the pyrimidine ring), 6.18(1H, s, H at the 1 ' -position of the sugar ring), 7.07 to 7.36(6H, m, hydrogen at the benzene ring, H at the 6-position of the pyrimidine ring), 9.77(1H, s, NH at the 3-position of the pyrimidine ring).
31P NMR(162MHz,CDCl3)4.9；
LCMS-ESI+(m/z):671.7(M+H)。
Example 11
Synthesis of (R) -N- [ ((((((2R, 3R, 4R, 5R) -5- (2, 4(1H, 3H) -pyrimidinedione-1-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl) oxy) ((((S) -1- (ethoxycarbonyl) -2-phenylethyl) amino) phosphoryl ] -L-phenylalanine N-butyl ester (S371S 374S-1).
S371S374S-1 was synthesized by a similar synthesis method to that of example 8.
Nuclear magnetic hydrogen spectrum data of S371S374S-1:1H NMR(400MHz，CDCl3)(ppm)：1.15-1.39(8H，m，2×CH3 and CH2) 1.41-1.55(3H, s, CH at the 2' -position of the sugar ring)3)，1.59-1.71(2H，m，CH2)，3.85-4.04(8H，m，2×CH2，2×NH and 2×NCH)，4.10-4.42(7H，m，2×COOCH2H at the 3 ' -position of the sugar ring, OH at the 3 ' -position of the sugar ring, H at the 4 ' -position of the sugar ring), 4.52 to 4.64(2H, m, H at the 5 ' -position of the sugar ring), 5.56 to 5.73(1H, m, H at the 5-position of the pyrimidine ring), 6.18(1H, s, H at the 1 ' -position of the sugar ring), 7.06 to 7.39(11H, m, hydrogen on both benzene rings, H at the 6-position of the pyrimidine ring)H) 9.72(1H, s, NH at position 3 of the pyrimidine ring).
31P NMR(162MHz,CDCl3)5.2；
LCMS-ESI+(m/z):719.7(M+H)。
Example 12
Synthesis of (S) -N- [ ((((((2R, 3R, 4R, 5R) -5- (2, 4(1H, 3H) -pyrimidinedione-1-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl) oxy) ((((S) -1- (2-ethylbutyloxycarbonyl) ethyl) amino) phosphoryl ] -L-phenylalanine-2-ethylbutyl ester (S39S37 379S-2).
S39S379S-2 was synthesized in a similar manner to example 8.
Nuclear magnetic hydrogen spectrum data of S39S 379S-2:1H NMR(400MHz，CDCl3)(ppm)：0.87-1.16(12H，m，4×CH3)，1.21-1.37(11H，m，CH3，4×CH2) 1.39-1.57(3H, s, CH at the 2' -position of the sugar ring)3)，1.93-2.11(2H，m，2×CH)，3.75-3.99(6H，m，CH2，2×NH and 2×NCH)，4.08-4.44(7H，m，2×COOCH2H at the 3 ' -position of the sugar ring, OH at the 3 ' -position of the sugar ring, H at the 4 ' -position of the sugar ring), 4.52 to 4.64(2H, m, H at the 5 ' -position of the sugar ring), 5.58 to 5.77(1H, m, H at the 5-position of the pyrimidine ring), 6.19(1H, s, H at the 1 ' -position of the sugar ring), 7.08 to 7.40(6H, m, hydrogen at the benzene ring, H at the 6-position of the pyrimidine ring), 9.78(1H, s, NH at the 3-position of the pyrimidine ring).
31P NMR(162MHz,CDCl3)7.2；
LCMS-ESI+(m/z):727.8(M+H)。
Example 13
Synthesis of (R) -N- [ ((((((2R, 3R, 4R, 5R) -5- (2, 4(1H, 3H) -pyrimidinedione-1-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl) oxy) ((((R) -1- (neopentyloxycarbonyl) ethyl) amino) phosphoryl ] -L-alanine isobutyl ester (S33R 32S-1).
S33R32S-1 was synthesized in a similar manner to example 8.
Nuclear magnetic hydrogen spectrum data of S33R 32S-1:1H NMR(400MHz，CDCl3)(ppm)：0.90-1.30(21H，m，7×CH3) 1.38-1.59(3H, s, CH at the 2' -position of the sugar ring)3)，2.38-2.50(1H，m，CH)，3.74-3.92(4H，m，2×NH and 2×NCH)，4.08-4.40(7H，m，2×COOCH2H at the 3 ' -position of the sugar ring, OH at the 3 ' -position of the sugar ring, H at the 4 ' -position of the sugar ring), 4.50 to 4.66(2H, m, H at the 5 ' -position of the sugar ring), 5.53 to 5.77(1H, m, H at the 5-position of the pyrimidine ring), 6.16(1H, s, H at the 1 ' -position of the sugar ring), 7.11 to 7.24(1H, m, H at the 6-position of the pyrimidine ring), 9.81(1H, s, NH at the 3-position of the pyrimidine ring).
31P NMR(162MHz,CDCl3)6.6；
LCMS-ESI+(m/z):609.6(M+H)。
Example 14
Synthesis of (S) -N- [ ((((((2R, 3R, 4R, 5R) -5- (2, 4(1H, 3H) -pyrimidinedione-1-yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methyl) oxy) ((((S) -1- (isobutoxycarbonyl) ethyl) amino) phosphoryl ] -L-phenylalanine N-butyl ester (S32S 374S-2).
Synthesized in a similar manner to example 8 to give S32S 374S-2.
Nuclear magnetic hydrogen spectrum data of S32S 374S-2:1H NMR(400MHz，CDCl3)(ppm)：0.97-1.37(14H，m，4×CH3，CH2) 1.40-1.57(3H, s, CH at the 2' -position of the sugar ring)3)，1.60-1.70(2H，m，CH2)，2.39-2.50(1H，m，CH)，3.82-4.07(6H，m，CH2，2×NH and 2×NCH)，4.10-4.41(7H，m，2×COOCH2H at the 3 ' -position of the sugar ring, OH at the 3 ' -position of the sugar ring, H at the 4 ' -position of the sugar ring), 4.51-4.66(2H, m, H at the 5 '-position of the sugar ring), 5.54 to 5.74(1H, m, H at the 5-position of the pyrimidine ring), 6.18(1H, s, H at the 1' -position of the sugar ring), 7.05 to 7.39(6H, m, hydrogen at the benzene ring, H at the 6-position of the pyrimidine ring), 9.77(1H, s, NH at the 3-position of the pyrimidine ring).
31P NMR(162MHz,CDCl3)5.8；
LCMS-ESI+(m/z):671.6(M+H)。
Example 15
Biological evaluation
1. Detection of antiviral Activity of Compounds of the present invention in HCV replicon (HCVpp) System
HCV replicon assay procedure
General procedure Huh-7 derived cell lines (ZLuc) bearing HCV genotype 1b replicon and luciferase reporter genes were grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 2mM GlutaMAX, 1% MEM nonessential amino acids, 100IU/mL penicillin, 100. mu.g/mL streptomycin, and 0.5mg/mL (G418). Zluc cells were transiently transfected with human carboxylesterase 1(CES1) by using a lipid/histone based transfection procedure. 24 and 48 hours after transfection, expression of CES1 was confirmed by Western blotting (Western blot) using anti-CES 1 and anti-tag antibodies. For dose response testing, cells were seeded in 96-well plates at 7.5xl03 cells/well in a volume of 50 μ L and at 37 ℃/5% CO2And (4) incubating. Drug solutions were freshly prepared in Huh-7 medium as 2X stock solutions. 10 additional 5-fold dilutions were prepared from these stocks in DMEM without G418. At least 3 hours after seeding with the Huc cells, drug treatment was started by adding 50 μ Ι _ of drug dilution to the plates in duplicate. The final concentration of the drug ranges from 100nM to 0.0000512n μm. Cells were then incubated at 37 ℃/5% CO2And (4) incubating. Alternatively, compounds were tested at two concentrations (10nM and 100 nM). In all cases, Huh-7 (which does not carry an HCV replicon) was used as a negative control. Inhibition of HCV replication was measured by quantifying the photons emitted by the singlet oxidation of 5' -fluoroluciferin to oxyfluoroluciferin (oxyiuoroluteciferin) by firefly luciferase after 72 hours of incubation. For this purpose, 50. mu.l of ONE-glo luciferase assay reagents were added to each well. The plate was gently shaken for 3 minutes at room temperature and the luminescence measured on a Victor3V1420 multiple mark counter (PerkinElmer) with a 1 second read-out time using a 700nm cut-off filter. EC was calculated from the dose-response curve of the resulting best-fit equation, as determined by Microsoft Excel and XLFit4.1 software50The value is obtained.
For cytotoxicity evaluation, Zluc cells were treated with the above compounds, and cell viability was monitored by adding 20 μ L of assay solution to each well using CellTiter-Blue cell viability assay (Promega). The plates were then incubated at 37 deg.C/5% CO2And incubating for at least 3 hours. Fluorescence of the plates was detected in a Victor3V1420 multiple-marker register (Perkin Elmer) using excitation and emission wavelengths of 560 and 590nm, respectively, and the CC was determined using Microsoft Excel and XLFit4.1 software50The value is obtained.
2. The compounds provided in the table below were determined according to the replicon assay described above
, + ++ refers to 1-10 nM; + represents 10-100 nM; + represents 0.1-1. mu.M;
sofosbuvir was prepared according to reference j
While the present invention has been described in considerable detail and with particular reference to a few illustrative embodiments thereof, it is not intended to be limited to any such details or embodiments or any particular embodiments, but it is to be construed as effectively covering the intended scope of the disclosure by providing broad, potential interpretations of such claims in view of the prior art with reference to the appended claims. Furthermore, the foregoing describes the disclosure in terms of embodiments foreseen by the inventor for which an enabling description was available, notwithstanding that insubstantial modifications of the disclosure, not presently foreseen, may nonetheless represent equivalent modifications thereto.
Claims (9)
1. A uridylic acid mixed phosphoramidate compound or a pharmaceutically acceptable salt thereof, wherein the uridylic acid mixed phosphoramidate compound has the structural formula (Ia):
wherein:
Ra、Rb、Rcand RdEach independently represents (C)1-C12) Alkyl or (C)6-C20) Aryl radical (C)1-C12) Any one of alkyl, ReAnd RfEach independently represents hydrogen or (C)1-C12) Any one of alkyl groups; and when R iscAnd RdBoth being methyl or both being benzyl, and ReAnd RfWhile being hydrogen, RaIs not equal to Rb。
2. The uridylic acid mixed phosphoramidate compound or pharmaceutically acceptable salt thereof of claim 1 wherein R iseAnd RfMeanwhile, the compound is hydrogen, the amino acid ester connected with the phosphorus atom is in an R configuration or an S configuration, and the structural formula of the uridylic acid mixed phosphoramidate compound is selected from one of the following structural formulas:
wherein: ra、Rb、RcAnd RdEach independently represents (C)1-C12) Alkyl or (C)6-C20) Aryl radical (C)1-C12) Any one of alkyl groups; and when R iscAnd RdWhen both are methyl or when both are benzyl, RaIs not equal to Rb。
3. The uridylic acid mixed phosphoramidate compound or pharmaceutically acceptable salt thereof of claim 2 wherein the phosphorgen isThe atom being a chiral phosphorus atom, preferably S(P)Configuration or R(P)One or two of the configurations, the structural formula of the uridylic acid mixed phosphoramidate compound is selected from one of the following structural formulas:
wherein: ra、Rb、RcAnd RdEach independently represents (C)1-C12) Alkyl or (C)6-C20) Aryl radical (C)1-C12) Any one of alkyl groups; and when R iscAnd RdWhen both are methyl or when both are benzyl, RaIs not equal to Rb。
4. The uridylic acid mixed phosphoramidate compound or pharmaceutically acceptable salt thereof of claim 3 wherein R isaAnd RbEach independently represents any one of isopropyl, ethyl, isobutyl, neopentyl, n-butyl, cyclohexyl, methyl, tert-butyl or 2-ethylbutyl, and R iscAnd RdEach independently represents any one of methyl or benzyl, and the structural formula of the uridylic acid mixed phosphoramidate compound is selected from one of the following structural formulas:
5. a pharmaceutical composition comprising the uridylic acid mixed phosphoramidate compound of any of claims 1-4 or a pharmaceutically acceptable salt thereof, and an excipient, wherein the excipient is a pharmaceutically acceptable carrier or excipient.
6. The pharmaceutical composition of claim 5, further comprising at least one of ribavirin, interferon, a hepatitis C NS3 protease inhibitor, a HCV reverse transcriptase NS5B non-nucleoside inhibitor, a HCV reverse transcriptase NS5B nucleoside inhibitor, a NS5A inhibitor, and a potentiator of a NS5A inhibitor, an entry inhibitor, a cyclosporin immunosuppressant, a NS4A antagonist, a NS4B inhibitor, or a cyclophilin inhibitor.
7. Use of a uridylic acid mixed phosphoramidate compound of any of claims 1-4 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a human flaviviridae virus infection.
8. The use according to claim 7, wherein the human Flaviviridae viral infection is a human HCV viral infection.
9. Use of a pharmaceutical composition according to any one of claims 5 to 6 for the manufacture of a medicament against infection by a virus of the flaviviridae family of humans, wherein said virus of the flaviviridae family is the HCV virus.
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