CN103848877B - Nucleoside cyclic phosphate compound and preparation method thereof and its application - Google Patents
Nucleoside cyclic phosphate compound and preparation method thereof and its application Download PDFInfo
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- CN103848877B CN103848877B CN201310688946.7A CN201310688946A CN103848877B CN 103848877 B CN103848877 B CN 103848877B CN 201310688946 A CN201310688946 A CN 201310688946A CN 103848877 B CN103848877 B CN 103848877B
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- sofosbuvir
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- -1 Nucleoside cyclic phosphate compound Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000002777 nucleoside Substances 0.000 title claims abstract description 19
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 17
- 239000010452 phosphate Substances 0.000 title claims abstract description 17
- 125000003118 aryl group Chemical group 0.000 claims abstract description 30
- 239000000460 chlorine Substances 0.000 claims abstract description 18
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 17
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 16
- 239000011737 fluorine Substances 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims abstract description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 10
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000011630 iodine Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
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- SCEZYJKGDJPHQO-UHFFFAOYSA-M magnesium;methanidylbenzene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C1=CC=CC=C1 SCEZYJKGDJPHQO-UHFFFAOYSA-M 0.000 claims description 3
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- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 238000006250 specific catalysis Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
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- 101150012509 sub gene Proteins 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Nucleoside cyclic phosphate compound that the present invention relates to structure shown in formula I and preparation method thereof and its application.The nucleoside cyclic phosphate compound of structure shown in formula I is the prodrug with antivirus action, wherein, X selected from hydrogen, fluorine, chlorine, bromine, iodine any one, Y selected from oxygen, sulfur any one, Z is aromatic ring yl or the aromatic ring yl having 13 substituent groups, described aromatic ring yl selected from phenyl, 2 pyridine radicals, 3 pyridine radicals, 4 pyridine radicals, 2 furyls, 3 furyls, 2 thienyls, 3 thienyls any one, the substituent group on aromatic ring yl be selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, C1‑C3Alkyl, OR any one, R be selected from trifluoromethyl, C1‑C3Any one of alkyl.
Description
Technical field
The invention belongs to technical field of compound preparation, be specifically related to nucleoside cyclic phosphate compound and preparation method thereof and
Its application.
Background technology
Hepatitis C virus (HCV) infects can directly result in liver cirrhosis and hepatocarcinoma, serious threat human health.World health
Tissue (WTO) survey result shows, the whole world has more than the population infection hepatitis C virus of 200,000,000, wherein, there are about the infection of 20%
Crowd relies on self immune system can remove HCV virus, and the HCV virus in remaining HCV virus infection population can hide it
The remaining years, and cause the infection population that there are about 10-20% to develop into liver cirrhosis or hepatocarcinoma and be taken away life.
At present, Peg-IFN alpha-2b (alfa-2a or alfa-2b) and ribavirin (Ribavirin), Bo Saibowei
Or Te Labowei (Telaprevir) drug combination has become acute hepatitis C or chronic hepatitis C (Boceprevir)
Standard regimens, wherein, the HCV infection patient that there are about 50% has response to this therapeutic scheme, but its cure rate is less than 50%,
And interferon therapy is that patient brings great misery.Therefore, exploitation has the specificity HCV-Ab IgG sense of new generation of more high curative rate
Dye medicine is extremely urgent.
HCV virion is single strand plus RNA virus spherical in shape, containing about 9600 codings and is made up of 3010 aminoacid
Polyprotein, its genome array order is: CE1E2/NS1NS2NS3NS4ANS4BNS5ANS5B.HCV viral polyprotein
Through host cell and virus oneself protease effect, it is cracked into the most independent virus protein, (i.e. ties including three kinds of structural protein
Structure PROTEIN C, structural protein E1 and structural protein E2/NS1) and four kinds of non-structural protein (i.e. non-structural protein NS2, non-structural proteins
White NS3, non-structural protein NS4 and non-structural protein NS5).Wherein, structural protein E1 and structural protein E2/NS1 is glycoprotein,
The neutralization of HCV-Ab IgG can be produced.Non-structural protein NS provide catalytic structure for virus replication.At present, it is not yet clear that non-structural
Albumen NS2 and the function of non-structural protein NS4.NS3 gene has a helicase activities, and the HCV-RNA that participates in untwisting divides
Son, and then release NS5B, and NS5B is the RNA polymerase (i.e. HCV NS5B polymerase) depending on RNA, this polymerase participates in
HCV replicative cycle is synthesized the reaction of double-stranded RNA by the single-stranded viral RNA as template.Therefore, compound can suppress effectively
HCV NS5B polymerase just can block double-strand HCV RNA synthesis, then can efficiently control HCV virus and infect.
At present, HCV gene type includes 7 kinds of HCV-I-HCV-VII type.Wherein, HCV-I type patients with viral infections is distributed in
All parts of the world, accounts for the 60% of HCV infection patient, and the Susceptible population that American-European countries crowd is HCV-I type virus.And Asia state
Family HCV infection patient is many to be infected based on HCV-II type virus, is secondly that HCV-III type virus infects.Wherein, HCV-I type virus
The treatment of infected patient is the most difficult.
US20110251152A1 discloses Sofosbuvir(i.e. GS7977) it is HCV NS5B RNA polymerase inhibitor,
WO2012087596A1 discloses Ledipasvir(i.e. GS5885) it is the HCV anti-protein inhibitor of NS5A interferon.Before 2012
Result of study show, the compound preparation of Sofosbuvir Yu Ribavirin to HCV-II-VII type infect cure rate be 100%,
And the cure rate that HCV-I type is infected by the compound preparation of Sofosbuvir Yu Ledipasvir is 100%.The research in March, 2013
Result shows, the healing that HCV-I-VII type is infected by three compound preparations of Sofosbuvir, Ledipasvir and Ribavirin
Rate is 100%.
Owing to ester hydrolase is the most widely distributed, the medicines such as Sofosbuvir are caused not arrive at before hepatocyte just by many
Number is hydrolyzed to electronegative bioactive ingredients.This bioactive ingredients be difficult to be transported to hepatocyte and by active transport extremely
The proximal tubule of kidney, and then cause nephrotoxicity, and significantly reduce the oral administration biaavailability of Sofosbuvir isoreactivity composition.
Ring-type phosphorus (phosphine) acid esters precursor medicine (4-aryl-2-oxo-1,3,2-dioxaphosphorinane hexamethylene) has excellent
Hepatic targeting, its metabolic mechanism sees document 1(J.Am.Chem.Soc.2004,126 (16), 5154-5163；
J.Pharmacol.Exp.Ther.2005,312 (2), 554-560.) and Fig. 1: the 4-in the most ring-type phosphorus (phosphine) acid esters precursor medicine
Aryl the position of substitution can be by the CYP3A enzyme-specific catalysis hydroxyl in the Cytochrome P450 isozyme family in hepatocyte
Changing, open loop generates single phosphorus (phosphine) acid intermediate with negative charge followed by rapidly.This electronegative intermediate is because being difficult to
It is retained in intracellular through cell membrane.Under phosphodiesterase-catalyzed hydrolysis, there is β-elimination reaction simultaneously, discharge nucleoside
Single phosphorus (phosphine) acid medicine, is then changed into by nucleoside kinase or phosphoribosylpyrophosphate synthetase and has bioactive nucleoside three
Phosphorus (phosphine) acid medicine.Metabolic by-product aryl vinyl ketone can have antioxidation with rich content in hepatocyte and free radical resisting is made
Glutathion quickly occur Isosorbide-5-Nitrae-addition to be eliminated, not yet find that this addition compound product has the relevant report of side effect.
Document 2(J.Med.Chem.2008,51 (3), 666-676.) report, hepatocyte medium ring phosphorus (phosphine) acid esters precursor medicine
Accretion rate have direct relation (see Table 1) with relative configuration and the absolute configuration of chiral centre in its molecule.Can by table 1
Seeing, trans ring-type phosphorus (phosphine) acid esters precursor medicine is very slow to the reaction of CYP3A enzyme-specific catalytic hydroxylation, the acid of cis ring-type phosphorus (phosphine)
The accretion rate of ester precursor medicine is preferable, and wherein, the accretion rate of cis-(2R, 4S) isomer is ideal.
Table 1 ring phosphorus (phosphine) acid esters precursor medicine is accretion rate and the relation of chiral centre absolute configuration in hepatocyte
WO2008045419A1, US20110251152A1 and WO2010135569A1 disclose the preparation of formula II compound
Method；US20110251152A1 discloses the preparation method of Sofobuvir；Chinese patent application CN201310098009.6 is public
Open the preparation method of formula III compound and F-Sofobuvir；WO2006033709A2 discloses the preparation side of formula IV compound
Method, wherein, the Z in formula IV compound is selected from aromatic ring yl or has the aromatic ring yl of 1-3 substituent group, and described aromatic ring yl is selected from benzene
Base, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl any one, virtue
Substituent group in ring group is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, C1-C3Alkyl ,-OR any one, R be selected from trifluoromethyl, C1-
C3Any one of alkyl.
The present invention quotes the technology contents disclosed in document all as the reference of the application.
Summary of the invention
It is an object of the invention to provide the nucleoside cyclic phosphate compound shown in structure shown in formula I,
Wherein, X selected from hydrogen, fluorine, chlorine, bromine, iodine any one, Y selected from oxygen, sulfur any one, Z is aromatic ring yl or has 1-3
The aromatic ring yl of individual substituent group, described aromatic ring yl is selected from phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 2-furyl, 3-
Furyl, 2-thienyl, 3-thienyl any one, the substituent group on aromatic ring yl be selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, C1-
C3Alkyl ,-OR any one, R be selected from trifluoromethyl, C1-C3Any one of alkyl.
Another object of the present invention is to provide the preparation method (system of the nucleoside cyclic phosphate compound shown in structure shown in formula I
Standby flow process is shown in Fig. 2), comprise the following steps: under alkaline matter existence condition, formula V compound is with formula VI compound in a solvent
There is ester exchange reaction, prepare type I compound, wherein, formula V compound: the mol ratio of alkali is 1:1-2, formula V compound: formula
The mol ratio of VI compound be 1:1-2, X selected from hydrogen, fluorine, chlorine, bromine, iodine any one, Y selected from oxygen, sulfur any one, Z be fragrant
Ring group or have the aromatic ring yl of 1-3 substituent group, described aromatic ring yl selected from phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl any one, the substituent group on aromatic ring yl selected from fluorine, chlorine, bromine, iodine,
Trifluoromethyl, C1-C3Alkyl ,-OR any one, R be selected from trifluoromethyl, C1-C3Any one of alkyl.
In the preferred technical solution of the present invention, formula V compound: the mol ratio of alkali is 1:1.2-1.5.
In the preferred technical solution of the present invention, formula V compound: the mol ratio of formula VI compound is 1:1.2-1.5.
In the preferred technical solution of the present invention, described alkaline matter is selected from sodium hydride (NaH), lithium diisopropylamine
(LDA), sodium tert-butoxide (NaOBut), potassium tert-butoxide (KOBut), tert-butyl alcohol magnesium ((tBuO)2Mg), tert-butyl group magnesium chloride
(tBuMgCl), any one or a combination thereof of phenyl-magnesium-chloride (PhMgCl), benzylmagnesium chloride (BnMgCl).
In the preferred technical solution of the present invention, described solvent selected from dichloromethane, 1,2-dichloroethanes, oxolane,
2-methyltetrahydrofuran, benzene, any one or a combination thereof of chlorine benzene,toluene,xylene.
In the preferred technical solution of the present invention, transesterification reaction temperature is-10 DEG C～20 DEG C, is preferably-5 DEG C～5 DEG C.
Another object of the present invention is to provide the nucleoside cyclic phosphate compound shown in structure shown in formula I for preparing antiviral
Application in medicine.
In the preferred technical solution of the present invention, described virus selected from hepatitis C virus, hepatitis B virus, HIV appoint
One or a combination thereof.
Formula I-formula Ⅸ compound of the present invention, the chemical name of Sofosbuvir, F-Sofosbuvir be:
Type I compound: 2 '-deoxidation-2 '-fluoro-2 '-C-methyl-cis-5 '-O-[4 (S)-Z-2-Y-1,3,2-dioxy phosphorus
Azacyclohexane-2-base]-5-X uridnine, wherein, X selected from hydrogen, fluorine, chlorine, bromine, iodine any one, Y selected from oxygen, sulfur any one, Z
For aromatic ring yl or the aromatic ring yl that has 1-3 substituent group, described aromatic ring yl is selected from phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine
Base, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl any one, the substituent group on aromatic ring yl selected from fluorine, chlorine, bromine,
Iodine, trifluoromethyl, C1-C3Alkyl ,-OR any one, R be selected from trifluoromethyl, C1-C3Any one of alkyl；
Formula II compound: 2 '-deoxidation-2 '-fluoro-2 '-C-methyluridines；
Formula III compound: 2 '-deoxidation-2 '-fluoro-2 '-C-methyl-5-FUD；
Formula IV compound: (4S)-trans-4-(3-chlorphenyl)-2-(4-nitro-phenoxy)-2-oxygen-1,3,2-dioxy phosphorus
Azacyclohexane；
Formula V compound: 2 '-deoxidation-2 '-fluoro-2 '-C-methyl-5-X uridnine, wherein, X appointing selected from H, F, Cl, Br, I
A kind of；
Formula VI compound: (4S)-trans-4-Z-2-(4-nitro-phenoxy)-2-oxygen-1,3,2-dioxaphosphorinane,
Wherein, Y selected from oxygen, sulfur any one, Z is aromatic ring yl or the aromatic ring yl having 1-3 substituent group, and described aromatic ring yl is selected from benzene
Base, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl any one, virtue
Substituent group in ring group is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, C1-C3Alkyl, OR any one, R be selected from trifluoromethyl, C1-
C3Any one of alkyl；
Formula VII compound: (4S)-trans-4-(3-chlorphenyl)-2-(4-nitro-phenoxy)-2-oxygen-1,3,2-dioxy phosphorus
Azacyclohexane；
Formula VIII compound: 2 '-deoxidation-2 '-fluoro-2 '-C-methyl-cis-5 '-O-[(4S)-(3-chlorphenyl)-2-oxygen-1,
3,2-dioxaphosphorinane-2-base] uridnine；
Formula Ⅸ compound: 2 '-deoxidation-2 '-fluoro-2 '-C-methyl-cis-5 '-O-[(4S)-(3-chlorphenyl)-2-oxygen-1,
3,2-dioxaphosphorinane-2-base]-5-FUD；
Sofosbuvir:2-((S)-(((2R, 3R, 4R, 5R)-5-(2,4-dicarbapentaborane-3,4-dihydro-pyrimidin-1(2H)-
Base)-4-fluoro-3-hydroxy-4-methyl oxolane-2-base) methoxyl group) (phenoxy group) phosphamide)-(S)-isopropyl propionate；
F-Sofosbuvir:2-((S)-(((2R, 3R, 4R, 5R)-5-(2,4-dicarbapentaborane-5-fluoro-3,4-dihydro-pyrimidin-
1-(2H)-yl)-4-fluoro-3-hydroxy-4-methyl oxolane-2-base) methoxyl group) (phenoxy group) phosphamide)-(S)-propanoic acid is different
Propyl ester.
The present invention obtain hydrogen spectrum (1HNMR), phosphorus spectrum (31PNMR) instrument that data are used is the 400000000 of Brooker company
Conspicuous nuclear magnetic resonance analyser (Bruker Advance II400MHz).Tetramethylsilane (TMS) makees internal standard, and room temperature is collected.Chemical shift
(δ) it is 1/1000000th (ppm).The unimodal s that is denoted as, doublet is denoted as d, and triplet is denoted as t, and quartet is denoted as q, and multiplet is denoted as
M, wide unimodal is denoted as br s.Coupling constant is denoted as j, and unit is Hz.Deuterated solvent is deuterated dimethyl sulfoxide (DMSO-d6).
It is Shimadzu LC-MS instrument (Shimadzu that the present invention obtains the instrument that mass spectrum (MS) data are used
LCMS2010EV), forward (positive), provide the quasi-molecular ions (MH of molecular weight hydrogenation+).
Except as otherwise noted, when the present invention relates to the percentage ratio between liquid and liquid, described percentage ratio is volume/body
Long-pending percentage ratio；When the present invention relates to the percentage ratio between liquid and solid, described percentage ratio is volume/weight percentage ratio；This
Bright relate between solid and liquid percentage ratio time, described percentage ratio is weight/volume percent；Remaining is w/w hundred
Proportion by subtraction.
Compared with prior art, the present invention has a following Advantageous Effects:
1, research confirms, compared with Sofosbuvir, F-Sofosbuvir, and the nucleoside ring phosphorus of structure shown in formula I of the present invention
Ester compound is difficult to be hydrolyzed by internal ester hydrolase in kidney, stomach, intestinal, blood plasma, after oral administration, before arriving hepatocyte
Will not be metabolized, enter the CYP3A specificity just understood behind liver target area by the Cytochrome P450 isozyme family in hepatocyte
Enzymes metabolism and position release, then phosphoribosylpyrophosphate synthetase be catalyzed under be transformed into ribonucleoside triphosphote (hepatitis C NS5B RNA
AG14361) so that the drug level in hepatocyte is higher than normal structure, has more preferable targeting, effectiveness, safety
Property (see figure 3).
2, after the nucleoside cyclic phosphate compound entrance of structure shown in formula I of the present invention is internal, it is possible to optionally at liver
Position is hydrolyzed, and produces antiviral activity composition, thus reduces its distribution organized at intestinal, blood, kidney etc. and accumulation, subtracts
Even avoid Toxicity of Kidney less, improve its bioavailability, there is more preferable targeting, effectiveness, safety.
3, compared with Sofosbuvir, F-Sofosbuvir, the nucleoside cyclic phosphate compound of structure shown in formula I of the present invention
There is preferably antivirus action, especially there is the most anti-hepatitis C virus effect, and there is targeting, effectiveness, dosage
Little, curative effect is high, toxic and side effects is little, safety advantages of higher.
Accompanying drawing explanation
The Liver targeting prodrug metabolic mechanism of nucleotide antiviral agent thing disclosed in Fig. 1 document 1；
The preparation technology flow process of the nucleoside cyclic phosphate compound shown in Fig. 2 structure shown in formula I of the present invention；
Fig. 3 Sofosbuvir, F-Sofosbuvir and type I compound are the process of ribonucleoside triphosphote at intrahepatic metabolism.
Detailed description of the invention
Illustrating the present invention below with reference to embodiment, embodiments of the invention are merely to illustrate the technical side of the present invention
Case, and the essence of the non-limiting present invention.
Reference examples 1The preparation of formula II compound
The present invention is with reference to US20110251152A1(embodiment 1) disclosed in technology contents prepare formula II compound.
δ (1HNMR,DMSO-d6): 1.25(d, J=22.4Hz, 3H), 3.64(m, 1H) and, 3.83(m, 3H), 5.27(m, 1H),
5.64(m, 1H), 5.66(m, 1H), 5.97(d, J=18.8Hz, 1H) and, 9.96(d, J=8.0Hz, 1H), 11.45(s, 1H) and ppm；δ
(19FNMR,DMSO-d6) :-159.9(s) ppm；MS:261(MH+).
Reference examples 2The preparation of Sofosbuvir
The present invention is with reference to US20110251152A1(embodiment 10_7) disclosed in technology contents prepare
Sofosbuvir。
δ (1HNMR,DMSO-d6): 1.15(d, J=6.0Hz, 6H), 1.22(d, J=6.4Hz, 3H) and, 1.25(d, J=
22.3Hz, 3H), 3.80-4.00(m, 3H), 4.11(m, 1H) and, 4.42(m, 1H), 4.52(m, 1H) and, 5.00(m, 1H), 5.30
(d, J=8.0Hz, 1H), 6.20(m, 1H), 7.10-7.30(m, 3H) and, 7.30-7.35(m, 2H), 7.46(d, J=8.2Hz, 1H),
11.45(s, 1H) ppm；δ (19FNMR,DMSO-d6) :-161.68(s) ppm；δ (31PNMR,DMSO-d6): 3.35(s) ppm；MS:
530(MH+).
Reference examples 3The preparation of formula III compound
The present invention is with reference to Chinese patent application CN201310098009.6(embodiment 4) disclosed in technology contents prepare
Formula III compound.
δ (1HNMR,DMSO-d6): 1.35(d, J=22.4Hz, 3H), 3.71(m, 1H) and, 3.98(m, 1H), 4.13(m, 1H),
4.93(m, 1H), 5.72(m, 1H), 6.05(d, J=20.4Hz, 1H) and, 7.76(d, J=6.8Hz, 1H), 11.88(s, 1H) and ppm；δ
(19FNMR,DMSO-d6) :-168.06(s) ,-176.03(s) ppm；MS:279(MH+).
Reference examples 4The preparation of F-Sofosbuvir
The present invention is with reference to Chinese patent application CN201310098009.6(embodiment 5) disclosed in technology contents prepare
F-Sofosbuvir。
δ (1HNMR,DMSO-d6): 1.13(d, J=6.0Hz, 6H), 1.22(d, J=6.4Hz, 3H) and, 1.25(d, J=
22.3Hz, 3H), 3.80-4.00(m, 3H), 4.11(m, 1H) and, 4.42(m, 1H), 4.52(m, 1H) and, 5.00(m, 1H), 6.20
(m, 1H), 7.10-7.30(m, 3H), 7.30-7.35(m, 2H) and, 7.46(d, J=8.1Hz, 1H), 11.50(s, 1H) and ppm；δ
(19FNMR,DMSO-d6) :-161.68(s) ,-167.58(s) ppm；δ (31PNMR,DMSO-d6): 3.35(s) ppm；MS:548
(MH+).
Reference examples 5The preparation of formula VII compound
The present invention is with reference to WO2006033709A2(embodiment 11) disclosed in technology contents prepare formula IV compound.
δ (1HNMR,CDCl3): 2.00-2.21(m, 1H), 2.21-2.62(m, 1H) and, 4.40-4.72(m, 2H), 5.56(d,
J=11.7,1H), 7.20-7.52 (m, 6H), 8.26 (s, J=9.7,2H) ppm.
Embodiment 1The preparation of formula VIII compound
The preparation method of the present embodiment formula VIII compound, comprises the steps:
1) anhydrous, anaerobic ,-5 DEG C, under stirring condition, 20g formula II compound is suspended in 300ml anhydrous tetrahydro furan
In, prepare formula II compound suspension, then drip 1M tert-butyl group magnesium chloride (tBuMgCl) tetrahydrofuran solution 160ml,
Under the conditions of-5 DEG C, after stirring 0.5h, it is warming up to 20 DEG C, continues stirring 0.5h, reactant mixture is cooled to 5 DEG C, drip 34
Gram formula VII compound is dissolved in the solution of 200ml oxolane, under the conditions of 5 DEG C, after stirring 20h, reactant mixture is cooled to-
5 DEG C, drip 2N aqueous hydrochloric acid solution 80ml, under stirring, be warming up to room temperature, prepare reactant liquor；
2) vacuum rotary steam removing step 1) prepare the oxolane in reactant liquor after, with 400ml toluene by distillation leftover
It is transferred to separatory funnel, takes organic layer；
3) by organic layer successively with 1N aqueous hydrochloric acid solution (2x40ml), water (40ml), 0.3N sodium hydrate aqueous solution
(4x40ml), water (40ml) and saturated aqueous common salt (40ml) washing, dried through anhydrous sodium sulfate, vacuum rotary steam removes organic layer
In solvent after, prepare rotation steam residue；
4) adding 80ml dichloromethane in residue is steamed in rotation, 20h is stirred at room temperature, reduce pressure sucking filtration, filter cake tert-butyl group first
After the mixture (1:1, v/v) washing (2x40ml) of base ether and dichloromethane, it is dried, prepares crude product；
5), by prepared crude product thermosol in 200ml dichloromethane, after 20h is stirred at room temperature, reduce pressure sucking filtration, filter cake 20ml cold two
Chloromethanes washs, and is dried, and prepares formula VIII pure compounds 29g, white solid.
δ (1HNMR,DMSO-d6): 1.25 (d, J=22.3Hz, 3H), 1.98-2.18 (m, 1H), 2.18-2.56 (m, 1H),
3.65 (m, 1H), 3.83 (m, 1H), 4.13 (m, 1H), 4.4-4.70(m, 2H), 5.27(m, 1H), 5.56 (d, J=11.7Hz,
1H), 5.64 (m, 1H), 5.66(m, 1H), 5.97 (d, J=18.8Hz, 1H), 7.20-7.55 (m, 4H), 9.98(d, J=8.1Hz,
1H), 11.46(s, 1H) ppm；δ (19FNMR,DMSO-d6) :-161.68(s) ppm；MS:491(MH+).
Embodiment 2The preparation of formula Ⅸ compound
The preparation method of formula Ⅸ compound, comprises the steps:
1) anhydrous, anaerobic ,-5 DEG C, under stirring condition, 20g formula III compound is suspended in 300ml anhydrous tetrahydro furan
In, prepare formula II compound suspension, then drip 1M tert-butyl group magnesium chloride (tBuMgCl) tetrahydrofuran solution 150ml ,-5 DEG C
After lower stirring 0.5h, it is warming up to 20 DEG C, stirs 0.5h, reactant mixture is cooled to 5 DEG C, drips 34 grams of formula VII compounds and be dissolved in
The solution of 200ml oxolane, after 5 DEG C of stirring 20h, is cooled to reactant mixture-5 DEG C, drips 2N aqueous hydrochloric acid solution 80ml,
Under stirring, it is warming up to room temperature, prepares reactant liquor；
2) vacuum rotary steam removing step 1) prepare the oxolane in reactant liquor after, with 400ml toluene by distillation leftover
It is transferred to separatory funnel, takes organic layer；
3) by organic layer successively with 1N aqueous hydrochloric acid solution (2x40ml), water (40ml), 0.3N sodium hydrate aqueous solution
(4x40ml), water (40ml) and saturated aqueous common salt (40ml) washing, dried through anhydrous sodium sulfate, vacuum rotary steam removes organic layer
In solvent, prepare rotation steam residue；
4) adding 80ml dichloromethane in residue is steamed in rotation, 20h is stirred at room temperature, reduce pressure sucking filtration, filter cake tert-butyl group first
Base ether and the mixture (1:1, v/v) washing (2x40ml) of dichloromethane, be dried, prepare crude product；
5), by prepared crude product thermosol in 200ml dichloromethane, after 20h is stirred at room temperature, reduce pressure sucking filtration, filter cake 20ml cold two
Chloromethanes washs, and is dried, and prepares formula Ⅸ pure compounds 28g, white solid.
δ (1HNMR,DMSO-d6): 1.30(d, J=22.3Hz, 3H), 2.00-2.20(m, 1H), 2.20-2.61 (m, 1H),
3.71 (m, 1H), 3.98(m, 1H), 4.13(m, 1H) and, 4.94(m, 1H), 5.72(m, 1H) and, 6.05(d, J=20.4Hz, 3H),
7.76(d, J=6.8Hz, 1H), 11.80(s, 1H) ppm；δ (19FNMR,DMSO-d6) :-161.68(s) ,-167.58(s) ppm；
MS:509(MH+).
Embodiment 3Testing compound hepatic targeting evaluation in Mice Body
Method disclosed in reference literature 3 (Clin.Chem.1992,38,480-485.), comparative study testing compound
(Sofosbuvir, formula VIII, F-Sofosbuvir, formula Ⅸ) hepatic targeting in Mice Body.
By testing compound (Sofosbuvir, formula VIII, F-Sofosbuvir and formula Ⅸ) with after dmso solution, use
Phosphate buffer is diluted to desired concn, prepares the testing compound solution of desired concn respectively.
Take the BACLB/c mice 48 of body weight 20-25 gram, be randomly divided into four groups, often group 12.After fasting 12h, gavage is given
Give testing compound (i.e. compound Sofosbuvir, formula VIII, F-Sofosbuvir and the formula Ⅸ) solution of 30 milligrams/Kg dosage；
After being administered 60 minutes (min) and 120min, often organize and take 6 mices at random, gather its small intestinal, kidney, liver, be respectively prepared even
Slurry, homogenate, after high speed centrifugation, takes supernatant, measures the content of active medicine in small intestinal, kidney, liver.The results are shown in Table 2.
The evaluation result of hepatic targeting in table 2 Mice Body
From table 2, compared with Sofosbuvir and F-Sofosbuvir, the formula VIII of the present invention, formula Ⅸ compound are more easy to
It is transported to liver, there is hepatic targeting, safety and the effectiveness become apparent from.
Embodiment 4The oral administration biaavailability research of testing compound
Reference literature 4 (J.Med.Chem.1994,37,1857-1864) and document 3(Clin.Chem.1992,38,480-
485.) method disclosed in, by testing compound in urine after mensuration Mouse oral administration and intravenous administration
The content of (Sofosbuvir, formula VIII, F-Sofosbuvir and formula Ⅸ), comparative study testing compound (Sofosbuvir, formula
VIII, F-Sofosbuvir and formula Ⅸ) oral administration biaavailability.
By testing compound (Sofosbuvir, formula VIII, F-Sofosbuvir and formula Ⅸ) with after dmso solution, use
Phosphate buffer is diluted to desired concn, prepares testing compound (Sofosbuvir, formula VIII, the F-of desired concn respectively
Sofosbuvir and formula Ⅸ) solution.
Take the BACLB/c mice 48 of body weight 20-25 gram, be randomly divided into four groups, often group 12.After mice fasting 12h, will
Intravenous testing compound (Sofosbuvir, formula VIII, F-Sofosbuvir and formula Ⅸ) solution is made into 15 mg/ml
Normal saline solution, after being administered by tail vein injection；Testing compound (Sofosbuvir, formula VIII, the F-of oral administration
Sofosbuvir and formula Ⅸ) solution is made into the aqueous solutions that concentration is 3 mg/ml containing 5% dimethyl sulfoxide, gastric infusion.To be measuredization
The intravenous administration amount of compound and oral administration amount are equivalent to the tenofovir of 30 milligrams/Kg.
After being administered 48h, collect the urine of each group of mice respectively, and measure testing compound in urine (Sofosbuvir, formula
VIII, F-Sofosbuvir and formula Ⅸ) content.
Calculate the bioavailability of oral administration according to following formula, the results are shown in Table 3.
Bioavailability=[M1]0-48h/[M2]0-48hX100%。
Wherein, [M1]0-48hFor the total amount of homaluria medicine, [M in 48h after oral administration2]0-48hAfter intravenous administration
The total amount of homaluria medicine in 48h.
The comparison of table 3 oral administration biaavailability
From table 3, compared with Sofosbuvir and F-Sofosbuvir, the formula VIII of the present invention, formula Ⅸ compound have
Preferably oral administration biaavailability, and then there is preferably safety and effectiveness.
Embodiment 5Testing compound is in the research that rat hepatocytes intracellular metabolite is ribonucleoside triphosphote (NTP)
One, material
1, rat hepatocytes: list of references 5 (J.Cell.Biol.1969,43,506-520) and document 6
Method disclosed in (Eur.J.Biochem.1982,122,87-93.), select oneself to look for food, body weight 250-300 gram male
Sprague Dawley rat prepares rat hepatocytes 20mg/ml(weight in wet base), more than 85% trypan blue (Trypan Blue) activity；
2, buffer solution: containing 20mM concentration of glucose and the kerbs of 1mg/ml bovine serum albumin (BSA)
(Krebs) sodium bicarbonate buffer solution；
3, precursor medicine solution: dimethyl sulfoxide (DMSO) solution of 10mM concentration；
4, acetonitrile solution: containing 0.1mg/ml dicyclohexylcarbodiimide (DCCD) and 0.1% (volume ratio) ammonium hydroxide
60% acetonitrile solution.
Two, method
1, under the conditions of 37 DEG C, by 10 μMs of testing compounds (formula II, formula III, Sofosbuvir, formula VIII, F-
Sofosbuvir and formula Ⅸ), 2ml buffer solution and rat hepatocytes cultivate 2h, wherein, by testing compound (formula II, formula III,
Sofosbuvir, formula VIII, F-Sofosbuvir and formula Ⅸ) with after dmso solution, it is diluted to phosphate buffer
Desired concn, prepares testing compound (formula II, formula III, Sofosbuvir, formula VIII, the F-Sofosbuvir of desired concn respectively
With formula Ⅸ) solution；
2, by step 1) cell suspending liquid of gained, carry out 1600 μ l decile and centrifugations.Abandoning supernatant, it is heavy to retain
Shallow lake thing, is separately added into 500 μ l acetonitrile solutions, violent vortex oscillation；14000 revs/min are centrifuged 10 minutes；
3, take supernatant and carry out LC-MS/MS analysis.Use MS/MS mode detection, with lamivudine-5 '-triphosphoric acid standard phase
Relatively, testing compound in detection by quantitative rat hepatocytes (formula II, formula III, Sofosbuvir, formula VIII, F-Sofosbuvir and
Formula Ⅸ) it is metabolized to the content of ribonucleoside triphosphote (NTP), the results are shown in Table 4.
Table 4 testing compound is in the research that rat hepatocytes intracellular metabolite is ribonucleoside triphosphote (NTP)
From table 4, compared with formula II compound, formula III compound, Sofosbuvir and F-Sofosbuvir, the present invention
Formula VIII, formula Ⅸ compound is the easiest becomes active constituents of medicine at liver metabolism, there is preferably targeting, safety, have
Effect property and higher bioavailability.
Embodiment 6The antivirus action research of testing compound
One, material
Cell: HCV subgenomic replicons cell (Shanghai Fudan-Yueda Bio-Tech Co., Ltd.'s offer).
Structure basic process is:
1, isolate HCV genome (HCVlb) from the liver organization of hepatitis C virus infection, and it is cloned
Rebuild；Deletion HCV part core gene, to NJISZ district, inserts neomycin phosphotransferase gene (noeR), makes sub-gene group obtain
The gene of phosphoric acid neomycin (G418) must be resisted；Insert the IRES of murine encephalomyocarditis virus gene；
2, by HCV Subgenomic replicon transfected with human hepatoma carcinoma cell H-hu7 of synthesis, with the culture medium culturing people containing G418
Hepatoma carcinoma cell H-hu7, to obtain the clone of anti-phosphoric acid neomycin, these clones can express replicon rna [4I].
Two, method
With Sofosbuvir as positive control, and virus control group (only adding virus, be not added with medicine), cell controls group are set
(being not added with virus, medicine), comparative study F-Sofosbuvir, formula VIII compound, the antivirus action of formula Ⅸ compound.
After Sofosbuvir, F-Sofosbuvir, formula VIII compound, formula Ⅸ compound dmso solution, use
Phosphate buffer is diluted to table 5 and is recorded concentration, prepares the Sofosbuvir of desired concn, F-Sofosbuvir, formula respectively
VIII compound, formula Ⅸ compound solution.
Centrifugal collection virocyte liquid, adds the cell suspending liquid 100 μ l of desired concn in each hole of 96 orifice plates.Press
Recording according to table 5, in each test group, addition Sofosbuvir solution, F-Sofosbuvir solution, formula VIII compound solution, formula Ⅸ are changed
Polymer solution, and virus control group (only adding virus, be not added with medicine), cell controls group (being not added with virus, medicine) are set, often group sets
Put 4 repeating holes.After adding, 96 orifice plates are placed in 37 DEG C, 5%CO2Hatch cultivation 5 days.96 orifice plates, after high speed centrifugation, take
Clear liquid.According to the method measuring p24 antigen, the content of detection supernatant p24 antigen.Calculate Sofosbuvir, F-
Sofosbuvir, formula VIII compound, the viral suppression of formula Ⅸ compound and EC50, the results are shown in Table 5.
From table 5, compared with Sofosbuvir, F-Sofosbuvir, formula VIII, formula Ⅸ compound are to hepatitis C virus
(HCV) there is more preferable inhibitory action.
To sum up, the experimental data of embodiment 3-6 showing, the formula VIII of the present invention, formula Ⅸ compound have preferably targeting
Property, bioavailability, safety and effectiveness, and then perform better than ground antivirus action.
The antivirus action result of study of table 5 testing compound
Claims (12)
1. the nucleoside cyclic phosphate compound shown in structure shown in formula I,
Wherein, X selected from hydrogen, fluorine, chlorine, bromine, iodine any one, Y is oxygen, and Z is aromatic ring yl or the aromatic ring yl having 1-3 substituent group,
Described aromatic ring yl be selected from phenyl, the substituent group on aromatic ring yl selected from fluorine, chlorine, bromine, iodine any one.
Nucleoside cyclic phosphate compound the most according to claim 1, wherein X selected from fluorine, chlorine, bromine, iodine any one.
Nucleoside cyclic phosphate compound the most according to claim 1, it is selected from 2 '-deoxidation-2 '-fluoro-2 '-C-methyl-suitable
Formula-5 '-O-[(4S)-(3-chlorphenyl)-2-oxygen-1,3,2-dioxaphosphorinane-2-base] uridnine or 2 '-deoxidation-2 '-fluoro-
2 '-C-methyl-cis-5 '-O-[(4S)-(3-chlorphenyl)-2-oxygen-1,3,2-dioxaphosphorinane-2-base]-5-fluorine urine
Glycosides.
4. a preparation method for the nucleoside cyclic phosphate compound shown in structure shown in formula I, comprises the following steps: deposit at alkaline matter
Under conditions, there is ester exchange reaction in formula V compound and formula VI compound in a solvent, prepares type I compound, wherein, formula V
Compound: the mol ratio of alkali is 1:1-2, formula V compound: the mol ratio of formula VI compound is 1:1-2,
Compound of formula I is
Formula V compound is
Formula IV compound is
Wherein: X selected from hydrogen, fluorine, chlorine, bromine, iodine any one, Y is oxygen, and Z is aromatic ring yl or the aromatic ring yl having 1-3 substituent group,
Described aromatic ring yl be selected from phenyl, the substituent group on aromatic ring yl selected from fluorine, chlorine, bromine, iodine any one.
Preparation method the most according to claim 4, formula V compound: the mol ratio of alkali is 1:1.2-1.5.
6. according to the preparation method described in claim 4 or 5, formula V compound: the mol ratio of formula VI compound is 1:1.2-
1.5。
7. according to the preparation method described in claim 4 or 5, described alkaline matter selected from sodium hydride, lithium diisopropylamine,
Sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol magnesium, tert-butyl group magnesium chloride, phenyl-magnesium-chloride, any one or its group of benzylmagnesium chloride
Close.
8. according to the preparation method described in claim 4 or 5, described solvent selected from dichloromethane, 1,2-dichloroethanes, tetrahydrochysene
Furan, 2-methyltetrahydrofuran, benzene, any one or a combination thereof of chlorine benzene,toluene,xylene.
9., according to the preparation method described in claim 4 or 5, transesterification reaction temperature is-10 DEG C～20 DEG C.
Preparation method the most according to claim 9, transesterification reaction temperature is-5 DEG C～5 DEG C.
Nucleoside cyclic phosphate compound or any one of claim 4-10 described in 11. any one of claim 1-3 prepare institute
The nucleoside cyclic phosphate compound obtained is for preparing the application in antiviral drugs.
12. application according to claim 11, described virus selected from hepatitis C virus, hepatitis B virus, HIV appoint
One or a combination thereof.
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| US9109001B2 (en) | 2012-05-22 | 2015-08-18 | Idenix Pharmaceuticals, Inc. | 3′,5′-cyclic phosphoramidate prodrugs for HCV infection |
| WO2013177195A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphate prodrugs for hcv infection |
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| WO2014165542A1 (en) | 2013-04-01 | 2014-10-09 | Idenix Pharmaceuticals, Inc. | 2',4'-fluoro nucleosides for the treatment of hcv |
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