CN103980332A - 2'-fluoro-2'-(fluoromethyl)-2'-deoxynucleoside compound and phosphate potential drug thereof - Google Patents
2'-fluoro-2'-(fluoromethyl)-2'-deoxynucleoside compound and phosphate potential drug thereof Download PDFInfo
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- 0 C*C(C)(C(O*)=O)N(C)P(OC[C@]1O[C@]2[n]3c(nc(N)nc4*)c4nc3)(O[C@]1[C@@]2(CF)F)=O Chemical compound C*C(C)(C(O*)=O)N(C)P(OC[C@]1O[C@]2[n]3c(nc(N)nc4*)c4nc3)(O[C@]1[C@@]2(CF)F)=O 0.000 description 3
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Abstract
The invention discloses a 2'-fluoro-2'-(fluoromethyl)-2'-deoxynucleoside compound represented by formula I, a phosphate potential drug thereof, preparation methods of the 2'-fluoro-2'-(fluoromethyl)-2'-deoxynucleoside compound and the phosphate potential drug, and applications and methods of the 2'-fluoro-2'-(fluoromethyl)-2'-deoxynucleoside compound and the phosphate potential drug in treatment of hepatitis C virus infection.
Description
Technical field
The present invention relates to 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside and phosphoric acid ester pro-drug thereof, their preparation method and be used for the treatment of the purposes of hepatitis c virus infection.
Background technology
The hepatitis c virus infection health problem that become international.According to estimates, the whole world approximately has 200,000,000 people to carry hepatitis C virus.Wherein the infected of 10 to 20 finally can be transformed into liver cirrhosis or liver cancer.For a long time, Interferon, rabbit and Ribavirin drug combination are the standard treatments for the treatment of hepatitis c virus infection., except it has compared with severe side effect, its curative ratio only has 50 percent left and right.The Incivek of Vertex and the Vitrelis of Merck were approval listing in 2011.These two kinds of new drugs still need to share and could obtain good curative effect with Interferon, rabbit and Ribavirin.So its toxic side effect is still similar with standard treatment.Had afterwards many patents to disclose and have the compound that suppresses hepatitis C virus effect, they comprise WO2006/046039, WO2006/046030, WO2006/029912, WO2003/007945, WO2003/010140 etc.Nucleoside compound and phosphoric acid ester pro-drug thereof have suitable advantage to suppressing hepatitis C virus, because they are all effective to various types of hepatitis C virus, and less generation resistance.Nucleosides and the pro-drug thereof of the summary antagonism hepatitis C virus of Sofia have been introduced (Antivir.Chem.Chemother.2011,22,23-49).Up to the present, only Sofosbuvir has reached the stage of new drug declaration.Therefore, be still found and develop the great demand of anti-the third liver medicine of nucleosides.Merck patent application (WO02/057425, WO2004/000858) has disclosed 2 '-(methyl fluoride) nucleosides as anti-the third liver medicine.But its patented invention does not relate to 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside, disclosed technology can not be taught technician and be prepared 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside.Therefore, the present invention discloses 2 for the first time '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside and phosphoric acid ester pro-drug thereof, its preparation method, and they suppress the effect of hepatitis C virus significantly.
Summary of the invention
On the one hand, the invention provides novel 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside and phosphoric acid ester pro-drug thereof.The invention provides on the other hand the preparation method of 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside and phosphoric acid ester pro-drug thereof.The invention provides on the other hand the preparation 2 '-useful intermediate of fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside.The invention provides on the other hand purposes and method that 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside and phosphoric acid ester pro-drug thereof are used for the treatment of hepatitis c virus infection medicine.
In specific embodiment, the invention provides 2 of a kind of formula I '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
R
1and R
2independently selected from H, phosplate, bisphosphate, triguaiacyl phosphate, substituted acyl or " ester of O-binding " comprise the group of formula-C (O) R ', the ester of N-binding " comprise formula-C (O) N (R ')
2group, wherein R ' is independently selected from H, straight chain, branched chain or cyclic alkyl or aryl or heterocyclic aryl.These groups are all optionally with optional substituting group.
X can be selected from O and S, CH
2, C=CH
2, C=CHF, C=CF
2;
B is selected from pyrimidine or the purine bases or derivatives thereof of formula B-1 and B-2:
Wherein:
X
2be selected from H, NH
2, NHMe, NMe
2and halogen (I, Br, Cl, F);
X
4be selected from NH
2or OH;
X
5be selected from H, halogen (I, Br, Cl, F), OH, NH
2, methyl, vinyl, alkyl, 2-bromo vinyl and ethynyl, these groups are all optionally with required substituting group;
X
6can preferentially be selected from (but being not limited to) H, OH, OMe, OEt, O (iPr), N, NH
2, NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).Alkoxyl group, aryloxy, cycloalkyloxy, alkylthio, arylthio, cycloalkylthio, thienyl, furyl, alkylamino, dialkylamino, virtue amino, aryl alkane amino, naphthene amino and cyclopropylamino, these groups are all optionally with optional substituting group;
Z is nitrogen (N) or CX
7;
X
7be selected from H, halogen (I, Br, Cl, F), replace or unsubstituted vinyl or ethynyl;
Wherein any described amino and hydroxyl are all optionally with hydrolyzable blocking group under physiological condition in vivo.
On the other hand, the base B in compound formula I provided by the invention is preferentially selected from VITAMIN B4, guanine, uridylic, thymus pyrimidine, cytosine(Cyt) and its derivative.
Compound formula I can preferentially be selected from following compound and phosphoric acid ester thereof:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
X
6can preferentially be selected from (but being not limited to) H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
On the other hand, compound formula I provided by the invention is phosplate pro-drug formula II:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
The definition of X and B as mentioned above;
X
1be selected from O and S;
R
3oR
8;
R wherein
4, R
5, R
6, R
7independently selected from H, straight chain, branched chain or cyclic alkyl or aryl or heterocyclic aryl; These groups are all optionally with optional substituting group;
R
4can also be the nonmetallic ion that the ester group of Compound I I is hydrolyzed formation, as NH
4 +or
Organic amine salt comprises (R
8) NH
3 +, (R
8)
2nH
2 +, (R
8)
3nH
+, or (R
8)
4n
+;
R
4can also be to make metal ion, it be preferentially selected from K
+, Na
+, Ca
2+, Mg
2+, etc.
R
8independently selected from (but being not limited to) H, branched chain or cyclic alkyl or aryl or heterocyclic aryl, the phenmethyl that phenyl replaces.These groups are all optionally with optional substituting group.
On the other hand, compound formula II can preferentially be selected from (but being not limited to) following compound and analogue thereof:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
X
6can preferentially be selected from (but being not limited to) H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
On the other hand, compound formula II provided by the invention is phosplate pro-drug formula III:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
R
4, R
8with the definition of B as mentioned above.
On the other hand, compound formula III can preferentially be selected from (but being not limited to) following compound and analogue thereof:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
X
6can preferentially be selected from (but being not limited to) H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
On the other hand, compound formula III provided by the invention is phosplate pro-drug formula IV:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
The definition of B is as mentioned above.
On the other hand, compound formula IV can preferentially be selected from (but being not limited to) following compound and analogue thereof:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
X
6can preferentially be selected from (but being not limited to) H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
On the other hand, compound formula I provided by the invention is cyclic phosphate pro-drug formula V:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
X
1for O or S, the definition of B as mentioned above;
R
9be selected from H, branched chain or cyclic alkyl or aryl or heterocyclic aryl; These groups itself are all optionally with optional substituting group.
On the other hand, compound formula V can preferentially be selected from following compound and analogue thereof:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
R
9definition as mentioned above,
X
6can preferentially be selected from (but being not limited to) H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
On the other hand, compound formula I provided by the invention is cyclic phosphate amine pro-drug formula VI:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
R
4, R
5, R
6, R
7with the definition of B as mentioned above.
Compound formula VI can preferentially be selected from (but being not limited to) following compound:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
R
4, R
5, R
6, R
7with the definition of B as mentioned above.
Compound VI is the cyclic phosphate amine pro-drug of a kind of formula VII:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
The definition of B as mentioned above.
On the other hand, compound VI I can preferentially be selected from (but being not limited to) following cyclic phosphate amine pro-drug and analogue thereof:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
X
6can preferentially be selected from (but being not limited to) H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
Compound I I-VII provided by the invention comprises the arbitrary independent isomer that produced by phosphorus or their mixture.
On the other hand, the arbitrary compound that the invention provides a kind of compound formula I-VII merges the medical composition forming with pharmaceutically acceptable carrier or thinner separately or with other compound again.
On the other hand, the invention provides with arbitrary compound of compound formula I-VII separately merge with other medicines or they with pharmaceutically acceptable carrier or thinner composition composition be used for the treatment of purposes and the method for hepatitis c virus infection.
On the other hand, the invention provides the method for preparation 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside.
Flow process 1-3 provides the method for preparation 2 '-fluoro-2 '-deoxynucleoside of the present invention.Wherein committed step is that intermediate VIII and X are generated to Compound I X and XI through fluoridation:
In VIII and IX, R
10=H or F;
Pg is any protecting group of hydroxyl.(but being not limited to) is preferentially selected from independently:
Work as R
10=H, Pg does not comprise MeCO-; R
11, Ra, Rb and Rc be independently selected from H, straight chain, branched chain or cyclic alkyl or aryl or heterocyclic aryl, these groups are all optionally with optional substituting group.
On the other hand, it is as follows that the present invention also provides the useful synthetic intermediate of preparation 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleoside:
Wherein, Pg can be any protecting group of hydroxyl.
Wherein B preferential (but being not limited to) is selected from:
With reference to following chemical formula and embodiment, will understand better these and other aspect of the present invention.
Definition
Unless otherwise defined, otherwise all technical term of chemistry used herein all adopt their general sense being appreciated by one of skill in the art that, and some term is as given a definition.
As used herein, term " alkyl " comprises common C
1to C
20the hydrocarbon being optionally substituted of saturated straight chain, branched chain or ring-type, and comprise particularly methyl, CF
3, CCl
3, CFCl
2, CF
2cl, ethyl, CH
2cF
3, CF
2cF
3, propyl group, sec.-propyl, cyclopropyl etc.The limiting examples of the part that can replace alkyl is the group that the freely following base of choosing forms: halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkylamino, arylamino, alkoxyl group, aryloxy, nitro, cyano group etc.
" thiazolinyl " comprises that unit price alkene is unsaturated alkyl, has in certain embodiments nearly 11 carbon atoms, it can be straight chain or branched chain and to have at least 1 or 2 alkene be unsaturated site (being C=C key).Exemplary thiazolinyl comprises vinyl (ethenyl) or vinyl (vinyl) (CH=CH
2), allyl group (CH
2cH=CH
2), pseudoallyl (C (CH
3)=CH
2) and the vinyl that is substituted etc.
" alkynyl " comprises alkyne series unsaturated alkyl, have in certain embodiments up to about 11 carbon atoms, it can be straight chain or branched chain and there are at least 1 or 2 unsaturated sites of alkynyl (being C ≡ C key).The limiting examples of alkynyl comprises acetylene (acetylenic), ethynyl (ethynyl), propargyl etc.
As used herein, term " aryl " comprises phenyl, biphenyl or naphthyl and phenyl preferably.This term comprises the part that is substituted and is unsubstituted.Aryl can replace through any described part; described part includes, but is not limited to the part of the group of the freely following base composition of one or more choosings: halogen (fluorine, chlorine, bromine or iodine), alkyl, hydroxyl, amino, alkylamino, virtue amino, alkoxyl group, aryloxy, nitro, cyano group, alkylsulfonyl, sulphate groups, phosphono, phosphoric acid foundation or phosphonato, and without protecting or being protected as required.
" cyclic alkyl " or " cycloalkyl " comprises the 3-7 ring of hydrocarbon, and such as cyclopropyl, cyclopentyl, cyclohexyl etc. is all optionally substituted.
" heterocycle " comprises the 3-7 ring in ring with 1-3 heteroatomic carbon compounds such as O, S, N, is all optionally substituted.
" heteroaryl " comprises and contains one to three heteroatomic aromatic rings such as O, S, N, for example pyridyl, pyrimidyl.
" alkoxyl group or alkyl oxy " comprises group-OR, and wherein R is alkyl.
" amino " comprises group-NH
2.
Term " alkylamino " or " arylamino " comprise respectively having the substituent amino of one or two alkyl or aryl.
" halogen " or " halogen " comprises chlorine (Cl), bromine (Br), fluorine (F) or iodine (I).
" alkyl monosubstituted amino " comprises group alkyl-NHR '--, wherein R ' is selected from alkyl or aryl.
" sulfanyl " comprises group--SR, and wherein R is alkyl or aryl.
As used herein and unless otherwise defined, otherwise term " through protection " refers to and is added in oxygen, nitrogen or phosphorus atom to prevent that it from further reacting or reaching the group of other object.The technician in organic synthesis field knows multiple oxygen and nitrogen-protecting group.In any structure, the especially nucleosides or Nucleotide that disclose herein or describe, any hydroxyl or amino can be through protections or without protection.When hydroxyl or amino are called " through protection ", mean that this group is as those skilled in the art understand through such as acyl group, phosphono, the removable radical protection such as phosphate-based.The protecting group that is suitable for prodrug is hydrolyzable under physiological condition in vivo preferably.
It is natural or through nucleosides, non-annularity nucleosides and the C-nucleosides of modification that term " nucleosides " comprises.
Term " C-nucleosides " refer to that glycosyl bond is wherein connected to carbon in the core base of modification and the nucleosides of nitrogen in improper nucleosides (about C-nucleosides summary referring to below with reference to document: nucleosides and Nucleotide chemistry (Chemistry of Nucleosides and Nucleotides), strangle Roy B Townsend (Leroy B Townsend) 1994, science (Science), the 5th chapter, C-nucleosides chemistry (The Chemistry of C-nucleosides), crosses the 421st page, limit respectful (Kyoichi A Watanabe)).C-nucleosides is not limited to the compound of quoting in described summary.
" pharmaceutically acceptable salt " comprises any salt of compound provided herein, and it retains the biological property of described compound and nontoxic or be not or not medicinal use is undesirable in other side.
Term " prodrug " refers to when casting biosystem any compound that produces biologically active cpds due to spontaneous chemical reaction, enzymic catalytic reaction and/or metabolic process or the combination of each as used herein.The prodrug of standard is to use be for example connected to-OH ,-NH
2deng functional group, with medicine, associate and the group of cracking in vivo forms.The prodrug of describing is in the present invention exemplary, but is not restrictive, and those skilled in the art can prepare the prodrug of other Known Species.
It is natural and through the enantiomer of the β-D-of modification nucleoside analog that term " L-nucleosides " refers to.
Term " arbinofuranose yl nucleosides " refers to the nucleoside analog that contains arbinofuranose base sugar, wherein 2 '-hydroxyl of the ribofuranosyl sugar of natural (normally) nucleosides on the opposite of sugar ring.
Term " dioxolane sugar " refers to and contains the sugar that Sauerstoffatom replaces 3 ' carbon of ribofuranosyl sugar.
Term " is fluoridized sugar " and is referred to have the sugar that 1-3 fluorine atom is connected to sugar charcoal.
Term " nucleosides " refers to purine or pyrimidine bases or its analogue that is connected to sugar (comprising its heterocycle and carbocyclic analogs).
Term " treatment significant quantity " refers to aspect treatment disease or symptom, to have the amount of any beneficial effect.
Refer to-O-PO of term " phosphate-based "
3 2-.
Term " phosphoramidic acid ester group " refers to-N-PO
3 2-.
Refer to-CHR-PO of term " phosphonate group "
3 2-.
As used herein, " as nucleoside phosphoramidate or the amido phosphonate of therapeutical agent " comprises nucleosides (comprising non-annularity nucleosides and the C-nucleosides) therapeutical agent that is derivatized into phosphoramidate and amido phosphonate, and described phosphoramidate and amido phosphonate have the substituent phenmethyl that contains the following base of one or more being selected from (but being not limited to): amino, C
1-C
20acyloxy, C
1-C
20alkyl, aryl, C
1-C
20alkyl oxy, aryloxy or aralkyl oxy, be all optionally substituted.Therapeutical agent is for example to comprise or derived to change into comprising that for example hydroxyl isoreactivity group is for connecting the antiviral agent of phosphoramidate or aminophosphonic acid ester moiety.These therapeutical agents include, but is not limited to nucleosides, nucleoside analog (comprising non-annularity nucleosides, C-nucleosides) and contain alcohol medicine.In certain embodiments, also provide the phosphoramidate of nucleosides and nucleotide analog, for example 1 '-, 2 '-, 3 '-and the phosphoramidate of 4 '-branched chain or dibasic nucleosides.These compounds can cast by treatment significant quantity, for example, to treat infectious diseases, liver illness (comprise cancer and infectious diseases, viral hepatitis type b and C type virus infection, comprise its resistance virus strain).
Term " parent drug " refers to nucleosides, non-annularity nucleosides and its phosplate medicine (M-O-PO
3 2-).
Term " parent drug " also refers to the medicine [R-CH that contains phosphonate group
2-P (O) (OH)
2].
Term " medicine of biologic activity or medicament " refers to the chemical entities that produces biological effect.In the present invention, the medicament of biologic activity refers to nucleosides (M-OH), single-nucleotide phosphate (M-O-PO
3 2-), nucleoside diphosphate ester (M-O-P
2o
6 3-), ribonucleoside triphosphote ester (M-O-P
3o
9 4-), nucleoside phosphate ester [M-CH
2p (O) (OH)
2, M-CH
2pO
3 2-], non-nucleoside phosphate ester, phosplate (M-CH
2p
2o
6 3-) or its bisphosphate (M-CH
2p
3o
9 4-), containing alkylol cpd.
Term " alkaryl " or " alkylaryl " comprise the aryl with alkyl substituent.Term aralkyl or arylalkyl comprise the alkyl with aryl substituent.
Term " purine " or " pyrimidine " base include, but is not limited to VITAMIN B4, N
6-alkyl-adenine, N
6-acyl group-adenine (wherein acyl group is C (O) (alkyl, aryl, alkylaryl or arylalkyl)), N
6-phenmethyl-adenine, N
6-vinyl-adenine, N
6-ethynyl-adenine, 6-ring aminopurine, 7-deazapurine, through the 7-of modification deazapurine, thymus pyrimidine, cytosine(Cyt), N
4-acyl group cytosine(Cyt), 5-flurocytosine, 5-methylcytosine, 6-azepine cytosine(Cyt), uridylic, 5 FU 5 fluorouracil, 5-alkyl urea pyrimidine, 5-vinyl pyrimidine, 5-ethinyluracil, 5-hydroxylmethyluracil, 5-amide group uridylic, 5-cyanouracil, 5-iodouracil, 5-Br-vinyl uridylic, 5-azepine cytosine(Cyt), 5-azauracil, Triazolopyridine, imidazopyridine, pyrrolo-pyrimidine radicals and pyrazolopyrimidine base.Purine bases include, but is not limited to guanine, VITAMIN B4,2-fluoroadenine, 2-chloroadenine, inferior Yellow purine, 7-deazaguanine, 7-denitrogenation VITAMIN B4,2,6-diaminopurine and 6-chloropurine, 6-alkoxyl group purine, 6-deoxy-guanine, 6-alkyl sulfenyl purine.Functionality oxygen in base and nitrogen groups can as required or require to be protected.Applicable protecting group is known by those skilled in the art, and comprises TMS, dimethyl hexyl silane base, tertiary butyl dimethylsilyl and tert-butyl diphenyl silylation, trityl, alkyl and acyl groups such as ethanoyl and propionyl, methylsulfonyl and p-toluenesulfonyl.
Term " acyl group " or " ester of O-binding " comprise the group of formula-C (O) R ', and wherein R ' is straight chain, branched chain or cyclic alkyl or aryl.
Term " amino acid " comprise natural existence and synthetic α-, β-, γ-or δ-amino acid, and the amino acid that includes, but is not limited to find in protein, i.e. glycine, L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, methionine(Met), phenylalanine, tryptophane, proline(Pro), Serine, Threonine, halfcystine, tyrosine, l-asparagine, glutamine, aspartic acid, L-glutamic acid, Methionin, arginine and Histidine.In a preferred embodiment, amino acid is to be L-configuration.Or, amino acid can be alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophyl, methionyl, glycyl, seryl, Threonyl, cysteinyl, tyrosyl, asparagyl, glutaminyl, aspartyl, glutamyl, lysyl, arginyl, histidyl-, β-alanyl, β-valyl, β-leucyl, β-isoleucyl, β-prolyl, β-phenylalanyl, β-tryptophyl, β-methionyl, β-glycyl, β-seryl, β-Threonyl, β-cysteinyl, β-tyrosyl, β-asparagyl, β-glutaminyl, β-aspartyl, β-glutamyl, β-lysyl, the derivative of β-arginyl or β-histidyl-.
" solvate " comprises and further comprising by the stoichiometric quantity of non-covalent Intermolecular Forces combination or the compound or its salt provided herein of the solvent of calculated amount non-chemically.In the situation that solvent is water, solvate is hydrate.
As used herein, term " part " refers to the part-structure of molecule, is often in molecule, to retain the integral part of the characteristic element of described molecule.In some cases, it and term " group " or " substituting group " are tradable.For instance, " sugar moieties " meaning is at the Sauerstoffatom by glycan molecule from hydroxyl loses hydrogen atom or from carbon atom loses hydroxyl, by this carbon atom, by covalent linkage, is being connected to the glycosyl group of dependency structure.
As used herein, term " individuality " and " patient " commutative use.Term " individuality " refers to animal, and for example Mammals, comprises non-human primate animal (for example ox, pig, horse, cat, dog, rat and mouse) and primate (for example monkey, for example cynomolgus monkey (cynomolgous monkey), chimpanzee).In one embodiment, individuality is the mankind.
As used herein, term " therapeutical agent (therapeutic agent and therapeutic agents) " refers to any medicament that can be used for the treatment of or prevent illness or its one or more symptoms.In certain embodiments, term " therapeutical agent " comprises compound provided herein.In one embodiment, therapeutical agent is the known medicament that is applicable to or or has at present been used for treatment or prevention illness or its one or more symptoms.
" treatment significant quantity " comprises when be enough to realize the amount to the compound of this treatment of described disease or composition when individuality casts to treat disease." treatment significant quantity " can change, and especially depends on compound, disease and its severity and has individual age to be treated, body weight etc.
" treatment (Treating or treatment) " of any disease or illness refers in one embodiment and improves individual disease or the illness existing.In another embodiment, " treatment " comprises and improves at least one body parameter, and described body parameter may be individual undistinguishable.In yet another embodiment, " treatment " be for example included on health, on (make recognizable symptom stable) or physiology (for example make body parameter stable) or regulate disease or illness aspect two.In yet another embodiment, " treatment " comprise the outbreak that postpones disease or illness.
The preparation method of compound
The exemplary preparation of flow process 1 explanation 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxyuridine.Compound 1 is pressed literature method synthetic (ARKIVOC2006,114).Compound 1 under TMSOTf exists with the uridylic reacting generating compound 2 of silanization.Compound 2 obtains nucleosides 3 with ammonia methyl alcohol Deprotection after catalytic hydrogenation.3 ', 5 '-OH TIPSCl
2protection is processed and is generated compound 5 by DAST.Other protecting group, RCO-, Tr, DMTr, can adopt.Other silylation protecting group can adopt.Compound 5 generates compound 6 through basic hydrolysis.Compound 6 generates nucleosides 8 with TBAF Deprotection after DAST processes.
Present method also can be applied to the synthetic of 2 '-methyl-2 '-alpha-fluoro nucleosides.Therefore the useful synthetic intermediate general formula that, compound 6 provided by the invention is relevant is as follows:
R wherein
10preferentially be selected from H or F;
Pg preferential (but being not limited to) is selected from:
Work as R
11during=H, Pg does not comprise MeCO-.The preferential R that selects
11protecting group beyond CO-, because these protecting groups can prevent that its ortho position from participating in effect and producing the by product containing 2 '-α-OH;
Wherein B is preferentially selected from (but being not limited to):
The another kind of method of the exemplary preparation of flow process 2 explanation 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxyuridines.Compound 9 passes through KMnO
4or OsO
4catalysis bishydroxy generates compound 10.With dimethoxy trityl chloride, react with compound 10 and generate 11.TBAF after processing 11 again with BzCl reacting generating compound 13.Compound 13 use DAST process and produce compound 14.With trifluoroacetic acid/CH
2cl
2process 14 and generate compound 15.With DAST, react with compound 15 and generate fluorochemical 16.TIPSCl after compound 16 use NaOH hydrolysis
2protection generates intermediate 6.Compound 6 Deprotection after DAST processes generates nucleosides 8.
The another kind of method of the exemplary preparation of flow process 3 explanation 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleosides.The ketone 17 and alkynyl Lithium reacting generating compound 18 of TIPS protection.DAST fluoridizes 18 generation compounds 19.In methyl alcohol, use K
2cO
3slough TMS and produce compound 20.Pd catalytic hydrogenation 20 generates compound 21.With after TBAF Deprotection with BzCl reacting generating compound 23.Compound 23 passes through KMnO
4or OsO
4catalysis bishydroxy generates compound 24.NaIO
4naBH after oxidation
4reduction generation compound 25. use DAST fluoridize 25 and with ammonia methyl alcohol, process and obtain compound 26 again.Compound 26 deprotections generate difluoride 27.
The method of the exemplary preparation of the phosphoric acid ester pro-drug of flow process 4 explanation 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxynucleosides.Phosphoric acid ester pro-drug 28-32 can be prepared according to literature method.
Flow process 1. is from 2-methyl fluoride sugar precursor 1 preparation 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxyuridine 8
Flow process 2. is prepared intermediate 5 from 2 '-methylene radical uridine precursor 9
Flow process 3. is from 2 '-one, 17 preparation 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxyuridines 27
Wherein the B in compound 17-26 is preferentially selected from:
X
6preferentially be selected from, but be not limited to, H, OEt, O (iPr), NH
2, NHMe, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
Wherein the B in compound 27 is preferentially selected from:
X
6preferentially be selected from, but be not limited to, H, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, N (Et)
2, SMe, SEt, S (iPr).
The preparation of the pro-drug of flow process 4.2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxyuridine 27
Wherein B is preferentially selected from (but being not limited to):
Embodiment
Compound provided herein can be by the apparent any method preparation of those skilled in the art, separated or acquisition.Exemplary preparation method describes in detail in following instance part.
1。Prepare compound 2.
According to document (ARKIVOC2006,114) method, prepare intermediate 1.
Contain uracil (1.60g, 15mmol), HMDS (20mL) and (NH
4)
2sO
4(20mg) mixture heats and the 5h that refluxes.The solution evaporate to dryness generating.Residuum is dissolved in CH
2cl
2(50mL).By TMSOTf(20mmol) add in solution.The solution producing is poured NaHCO into after 25-30 ℃ of stirring 20h
3the mixture of the aqueous solution and EtOAc (100mL).Organic solution Na
2sO
4evaporate to dryness after dry.Separated (the 0-5%MeOH/CH of silica gel column chromatography for residuum
2cl
2) obtain compound 2.LC-MS(ESI):451(M+H
+)。
2。Prepare compound 5.
Compound 2(4.50g, 10mmol) be dissolved in ammonia methyl alcohol (20mL).Evaporate to dryness after reaction solution stirs and spends the night.Residuum is dissolved in methyl alcohol (50mL).Pd/C (5%, 50mg) add.Reaction mixture filters after the lower stirring of hydrogen (1atm) 5h.Filtrate evaporate to dryness.Gained compound 3 is dissolved in pyridine (20mL).TIPSCl
2(11mmol) at 0 ℃, slowly add reaction solution.Evaporate to dryness after reaction solution stirs and spends the night.Residuum is dissolved in EtOAc (100mL).After organic solution washing, use Na
2sO
4dry.Solvent evaporated.Residuum is dissolved in CH
2cl
2(50mL).Reaction solution is cooled to-20 ℃.DAST (2,4g, 15mmol) is slowly added to reaction solution at-20 ℃.Reaction solution adds EtOAc (100mL) after-20 ℃ of stirring 1h.Organic solution NaHCO
3the aqueous solution is used Na after washing
2sO
4dry.Boil off solvent, the separated (0-5%MeOH/CH of silicagel column for residuum
2cl
2) generation compound 5.LC-MS(ESI):501(M+H
+)。
3。Prepare compound 8.
By 2N NaOH(7.5mL, 15mmol) at 0 ℃ of methyl alcohol (10mL) solution that adds compound 5 (5.0g, 10mmol).Reaction solution is at stirring at room 1h.EtOAc (100mL) adds.Organic solution washes with water, Na
2sO
4dry.After solvent evaporated, residuum is through the separated (0-5%MeOH/CH of silicagel column
2cl
2) generation compound 6.By DAST(3.22g, 20mmol) at-20 ℃ of CH that add compound 6 (5.18g, 10mmol)
2cl
2(50mL) solution.Reaction solution stirs 2h at-20 ℃.Add EtOAc (100mL).Organic solution NaHCO
3washing, Na
2sO
4dry, solvent evaporated.Separated (the 0-5%MeOH/CH of silicagel column for residuum
2cl
2) generation compound 7.The THF (15mL) that the THF solution of TBAF (15mL, 1M, 15mmol) is added to compound 7 (10mmol).Reaction solution at room temperature stirs 2h.Solvent evaporate to dryness, the separated (0-10%MeOH/CH of silicagel column for residuum
2cl
2) generation compound 8.δ
H(400MHz,DMSO-d
6):11.45(s,1H),7.83(d,J=8.0Hz,1H),6.12(d,J=19.2Hz,1H),5.82(d,J=7.2H,1H),5.63(d,J=8.0Hz,1H),5.24(br.s,1H),4.40-4.60(m,2H),4.05-4.16(m,1H),3.55-3.85(m,3H).LC-MS(ESI):279(M+H
+)。
Compound 27b-e can be prepared by similar approach.
4。Prepare compound 28a.
The hydrochloride (1.67g, 10mmol) of amino acid isopropyl ester is added to PhOP (O) Cl at-20 ℃
2the solution of the THF of (2.11g, 10mmol) (40mL).By Et
3n (2.02g, 20mmol) adds reaction solution at-20 ℃.Reaction solution is in stirred overnight at room temperature.Evaporate to dryness.Add ether (50mL) to filter.Filtrate evaporate to dryness.Residuum phosphorus reagent is dissolved in CH
2cl
2(10mL) stand-by.Compound 8 (27a, 331mg, 1mmol) is added to CH
2cl
2(10mL).By phosphorus reagent (1.5mL, 1.5mmol) at 0 ℃ of mixture that adds 8 (27a).N-methylimidazole (NMI, 0.5mL) is added, and reaction solution stirs 2h at 0 ℃.EtOAc (100mL) adds.Na after organic solution washing
2sO
4dry.Solvent evaporated, the separated (0-5%MeOH/CH of silicagel column for residuum
2cl
2) generation compound 28a.LC-MS(ESI):548(M+H
+)。
Same method is prepared into compound 28b-e from compound 27b-e.
5。Prepare compound 29a.
By 2-xylyl alcohol (1.22g, 10mmol) and Et
3the CH of N (1.01g, 10mmol)
2cl
2(5mL) solution adds the Cl containing P (O) at-78 ℃
3the CH of (1.53g, 10mmol)
2cl
2(10mL) solution.Reaction solution stirs 5h at-78 ℃.The hydrochloride (1.67g, 10mmol) of amino acid isopropyl ester is added at-20 ℃.By Et
3n (2.02g, 20mmol) adds reaction solution at-20 ℃.Reaction solution is in stirred overnight at room temperature.Evaporate to dryness.Add ether (50mL) to filter.Filtrate evaporate to dryness.Residuum phosphorus reagent is dissolved in CH
2cl
2(10mL) stand-by.Compound 8 (27a, 331mg, 1mmol) is dissolved in to CH
2cl
2(10mL).By phosphorus reagent (1.5mL, 1.5mmol) at 0 ℃ of solution that adds 8 (27a).NMI (2mL) is added, and reaction solution stirs 1h at 0 ℃.EtOAc (100mL) adds.Na after organic solution washing
2sO
4dry.Solvent evaporated, the separated (0-5%MeOH/CH of silicagel column for residuum
2cl
2) generation compound 29a.LC-MS(ESI):576(M+H
+)。
Same method is prepared into compound 29b-e from compound 27b-e.
6。Prepare compound 30a.
Methyl alcohol (10mL) solution that 2N NaOH (1.5mL, 3mmol) is added to compound 29a (575mg, 1mmol).Reaction solution is at stirring at room 2h.Solvent evaporate to dryness obtains compound 30a.LC-MS(ESI):534(M+H
+)。
Same method is prepared into compound 30b-e from compound 27b-e.
7。Pro-drug 31a-e and 32a-e can be prepared according to literature method.
Example 11.HCV replicon is analyzed
The anti-HCV activity of exemplary compound and toxicity can be two bioanalysiss, and the HCV replicon based on cell is analyzed and the middle test of cytotoxicity analysis (WO 2007/027248).
I. anti-HCV analyzes
Use contains the anti-HCV activity that the human hepatocytes oncocyte system (Huh-7) of copying HCV sub-genome duplication with luciferase reporter gene (luc-ubi-neo) assesses compound.In this analysis, luciferase signal level directly copies relevant with viral RNA.HCV replicon-report clone (NK/luc-ubi-neo) is cultivated in the DMEM substratum that is supplemented with 10% foetal calf serum and 0.5mg/ml Geneticin (G418).Cell maintains under subconfluent state synthetic to guarantee high-caliber HCV replicon rna.
In order to assess the antiviral activity of compound, the serial dilution of preparation concentration in the scope of 0.14 to 300 μ M.The compound of dilution is transferred in 96 porose discs, then adds replicon cell (6000, every hole cell).Cell is cultivated together with compound 48 hours, then measured luciferase activity.The reduction of luciferase signal has reflected the minimizing of HCV replicon rna in treated cell and in order to determine EC
50value (making luciferase activity reduce by 50% concentration).
II. cytotoxicity analysis
The Huh-7 clone that use carries the luciferase reporter gene (by HIV LTR promoters driven) being stably attached in karyomit(e) is analyzed the cytotoxic effect of selected compound.This clone (LTR-luc) maintains in the DMEM substratum with 10%FBS.The design class of cytotoxicity analysis is similar to the design that HCV replicon is analyzed.The reduction of luciferase activity and the cytotoxic effect of test compounds is relevant and in order to calculate CC in treated cell
50value (concentration that suppresses 50% Growth of Cells).
Use the biological activity of subgene group genotype 1a replicon and the cytotoxicity of selected compounds to be summarized in table 2.
The activity of exemplary compound in the analysis of table 2. replicon
| Compound | EC 50（μM） | CC 50（μM） |
| 28a | <1.0 | >100 |
| 29a | <1.0 | >100 |
In table, EC
50representative suppresses the needed drug level of half hepatitis C virus.CC
50representative suppresses the needed drug level of half Growth of Cells.
The present invention synthesized 2 first '-fluoro-2 '-(methyl fluoride)-2 '-deoxyuridine and phosphoric acid ester pro-drug thereof.
2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxyuridine provided by the invention and phosphoric acid ester pro-drug thereof have the activity of significant anti-hepatitis C virus, and within the scope of test concentrations, do not produce cytotoxicity.
2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxyuridine provided by the invention and phosphoric acid ester pro-drug thereof can merge the infection that is used for the treatment of hepatitis C virus separately or with other medicines.
The present invention provides 2 first '-fluoro-2 '-(methyl fluoride)-2 ' synthetic method of-deoxyuridine and useful synthetic intermediate.
The synthetic method of 2 '-fluoro-2 '-(methyl fluoride)-2 '-deoxyuridine that the present invention provides first can be used for the synthetic of 2 '-fluoro-2 '-methyl-2 '-deoxyuridine.
Claims (17)
1. the compound of a formula I and phosphoric acid ester pro-drug thereof:
Or its pharmaceutically acceptable salt, ester, hydrate, solvate, crystalline form or prodrug, wherein: R
1and R
2independently selected from H, phosplate, bisphosphate, triguaiacyl phosphate, substituted acyl or " ester of O-binding " comprise the group of formula-C (O) R ', the ester of N-binding comprises formula-C (O) N (R ')
2group; R ' is independently selected from H, straight chain, branched chain or cyclic alkyl, and aryl or heterocyclic aryl, these groups are all optionally with optional substituting group.
X is selected from O and S, CH
2, C=CH
2, C=CHF, C=CF
2;
B is selected from pyrimidine or the purine bases or derivatives thereof of formula B-1 and B-2:
Wherein:
X
2be selected from H, NH
2, NHMe, N (Me)
2and halogen;
X
4be selected from NH
2or OH;
X
5be selected from H, halogen, OH, NH
2, methyl, vinyl, alkyl, 2-bromo vinyl and ethynyl, these groups are all optionally with optional substituting group;
X
6be selected from H, OH, OMe, OEt, SMe, N, NH
2, NHMe, N (Me)
2, NHEt, N (Et)
2, alkoxyl group, aryloxy, cycloalkyloxy, alkylthio, arylthio, cycloalkylthio, thienyl, furyl, alkylamino, dialkylamino, virtue amino, aryl alkane amino, naphthene amino and cyclopropylamino, these groups are all optionally with optional substituting group;
Z is nitrogen or CX
7;
X
7be to be selected from H, halogen, replace or unsubstituted vinyl or ethynyl;
Wherein any described amino and hydroxyl are all optionally with hydrolyzable blocking group under physiological condition in vivo.
2. compound claimed in claim 1 and phosphoric acid ester pro-drug thereof, wherein base B is selected from VITAMIN B4, guanine, uridylic, thymus pyrimidine, cytosine(Cyt) and its derivative.
3. compound claimed in claim 1 and phosphoric acid ester pro-drug thereof, be selected from following compound and phosphoric acid ester thereof:
Or its pharmaceutically acceptable salt, ester, hydrate, solvate, crystalline form or pro-drug, wherein:
X
6be selected from H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
4. compound claimed in claim 1 and phosphoric acid ester pro-drug thereof, be selected from the phosplate pro-drug of formula II:
Or its pharmaceutically acceptable salt, ester, hydrate, solvate, crystalline form or pro-drug, wherein:
The definition of B is described in right 1.
X
1be selected from O and S;
R
3amino, amino acid based, amino acid ester group or OR
8,
R wherein
4, R
5, R
6, R
7independently selected from H, straight chain, branched chain or cyclic alkyl or aryl or heterocyclic aryl, these groups are all optionally with optional substituting group;
R
4also be selected from nonmetallic ion, it is preferentially selected from NH
4 +or (R
8) NH
3 +, (R
8)
2nH
2 +, (R
8)
3nH
+, or (R
8)
4n
+,
R
4also be selected from metal ion, it is preferentially selected from K
+, Na
+, Ca
2+, Mg
2+, etc.,
R
8independently selected from H, branched chain or cyclic alkyl or aryl or heterocyclic aryl, the phenmethyl that phenyl replaces.These groups are all optionally with optional substituting group.
5. compound claimed in claim 4 and phosphoric acid ester pro-drug thereof, the phosplate pro-drug of formula II is selected from following compound:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
Ar can preferentially be selected from and replace or unsubstituted phenyl or naphthyl and its derivative, X
6h can be preferentially selected from, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
6. compound claimed in claim 4 and phosphoric acid ester pro-drug thereof, the phosplate pro-drug of formula II is selected from the phosplate pro-drug of following compound formula III:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
R
4, R
8with the definition of B described in right 4 or 1.
7. compound claimed in claim 6 and phosphoric acid ester pro-drug thereof, compound formula III is selected from following compound:
Wherein, X
6be selected from H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
8. compound claimed in claim 6 and phosphoric acid ester pro-drug thereof, compound III is the phosplate pro-drug that is selected from compound formula IV:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
The definition of B is described in right 1.
9. compound claimed in claim 8 and phosphoric acid ester pro-drug thereof, compound formula IV is selected from following compound:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
X
6can preferentially be selected from (but being not limited to) H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
10. compound claimed in claim 1 and phosphoric acid ester pro-drug thereof, compound formula I is selected from the cyclic phosphate pro-drug of formula V:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
The definition of B is described in right 1.
X
1for O or S;
R
9be selected from H, branched chain or cyclic alkyl or aryl or heterocyclic aryl; These groups itself are all optionally with optional substituting group.
11. compounds claimed in claim 1 and phosphoric acid ester pro-drug thereof, be selected from the cyclic phosphate amine pro-drug of formula VI:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
R wherein
4, R
5, R
6, R
7independently selected from H, straight chain, branched chain or cyclic alkyl or aryl or heterocyclic aryl, these groups are all optionally with optional substituting group;
R
4also be selected from nonmetallic ion, as NH
4 +or (R
8) NH
3 +, (R
8)
2nH
2 +, (R
8)
3nH
+, or (R
8)
4n
+;
R
4also be selected from metal ion, it is preferentially selected from K
+, Na
+, Ca
2+, Mg
2+, etc.
The definition of B is described in right 1.
Compound described in 12. claims 11 and phosphoric acid ester pro-drug thereof, compound formula VI is selected from formula VII cyclic phosphate amine pro-drug:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
The definition of B is described in right 1.
Compound described in 13. claims 12 and phosphoric acid ester pro-drug thereof, compound formula VII is optional from following cyclic phosphate amine pro-drug:
Or its pharmaceutically acceptable salt, solvate or pro-drug, wherein:
X
6can be selected from H, OMe, OEt, O (iPr), NH
2, NHMe, N, N (Me)
2, (Me) NEt, N (Et)
2, SMe, SEt, S (iPr).
Arbitrary compound described in 14. 1 kinds of claim 1-13 separately or both above in conjunction with or merge then the composition forming with pharmaceutically acceptable carrier or thinner with other compound.
Arbitrary compound described in 15. 1 kinds of claim 1-13 separately merge with other medicines or claim 14 described in the application of composition in treatment hepatitis c virus infection.
16. prepare the method for formula I compound described in claim 1, comprise fluoridizing of following intermediate:
A: intermediate VIII is fluoridized into Compound I X:
B: intermediate X is fluoridized generation and fluoridized into compounds X I:
Wherein, R
10=H or F; Pg is any protecting group of hydroxyl, is preferentially selected from:
Work as R
10=H, Pg does not comprise MeCO-;
R
11, Ra, Rb and Rc be independently selected from H, straight chain, branched chain or cyclic alkyl or aryl or heterocyclic aryl, these groups are all optionally with optional substituting group;
B is preferentially selected from:
17. suc as formula the intermediate described in VIII or formula X:
Wherein, Pg can be any protecting group of hydroxyl;
B is preferentially selected from:
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