CN1891710A - L-nucleoside prodrug - Google Patents

L-nucleoside prodrug Download PDF

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CN1891710A
CN1891710A CN 200510040848 CN200510040848A CN1891710A CN 1891710 A CN1891710 A CN 1891710A CN 200510040848 CN200510040848 CN 200510040848 CN 200510040848 A CN200510040848 A CN 200510040848A CN 1891710 A CN1891710 A CN 1891710A
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methyl
fluoro
arabinose
uridine
deoxidation
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CN100577679C (en
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袁建栋
张凯
叶新建
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Brightgene Bio Medical Technology Co Ltd
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Borui Bio-Medical Technology (jiangsu) Co Ltd
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Abstract

The invention relates to the compounds and their salts of type (I), among them R1 and R2 can be the same or different, R1 is the amino acid residue, alkoxyl formyl, organic acid acyl, phosphoryl and alkyl. R2 is H, amino acid residues, alkyloxyethyl formyl, organic carboxylic acid acyl, phosphoryl, and alkyl. These compounds have the function of anti - hepatitis B virus (HBV), anti-EB virus (EBV) and anti - hepatitis D virus (HDV) role. The invention also covers the preparation methods and compounds in the preparation of antiviral drugs.

Description

The prodrug of L-nucleosides
The present invention relates to the prodrug and the application in the preparation antiviral thereof of 2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine (being called for short L-FMAU).The invention still further relates to the preparation method of the prodrug of L-FMAU.The present invention also relates to pharmaceutical composition of the prodrug that contains L-FMAU and preparation method thereof simultaneously.
Background of invention:
(1-(2 '-Deoxy-2 '-fluoro-β-L-arabinofuranosyl)-5-methyluracil be called for short L-FMAU) is a kind of L-type nucleosides that antivirus action is arranged in 2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine.The chemical name of this compound can also be referred to as 2 '-deoxidation-2 '-fluoro-beta-L-arabinose thymidine or N1-(2 '-deoxidation-2 '-fluoro-beta-L-arabinose base)-methyl uracil, and its commodity are called Clevudine.
Chinese patent 95191415.4, United States Patent (USP) 5,567,688 and United States Patent (USP) 5,565,438 disclosed and a series ofly have anti-hepatitis B virus (HBV) and the active L-type of anti-epstein-barr virus (EB) (EBV) nucleosides to comprise L-FMAU.United States Patent (USP) 6670342 has disclosed L-FMAU and has suppressed hepatitis D virus ((Hepatitis delta virus, function HDV) in addition.
According to bibliographical information, the bioavailability of L-FMAU is lower, and the transformation period of internal metabolism is shorter.Antimicrobial medicament and chemotherapy (Antimicrob Agents Chemother.1997Oct; 41 (10): it is reported that 2184-7) oral absorption of L-FMAU in the marmot of America is insufficient, bioavailability is lower, only has an appointment 20%.Also have bibliographical information in addition the L-FMAU oral absorption very slow, % is low for bioavailability (36 ± 13), the transformation period is shorter.
The clinical therapeutic efficacy that short transformation period and lower bioavailability all can influence L-FMAU.The transformation period weak point can make taking at interval of medicine shorten, and the low dosage that can make patient take of bioavailability increases, and increases the weight of the metabolic burden of patient body and the cost of drug manufacture is risen.
Nucleoside medicine is through obtaining the prodrug of nucleosides behind the structural modification.Nucleoside medicine has polytype prodrug, the common amino acid ester that nucleosides is arranged, the carbalkoxyl radical derivative of nucleosides, the carboxylicesters of nucleosides and phosphoric acid ester.
Prodrug often can improve the bioavailability of parent drug, reduces the toxic side effect of medicine, the action time of prolong drug or change medicine distribution situation in vivo.
The prodrug of modal nucleosides is the amino acid ester of nucleosides.Be applied to clinical example valganciclovir (valganciclovir) and valaciclovir have been arranged.Valganciclovir is the L-valine ester of nucleoside medicine ganciclovir (ganciclovir).The bioavailability of oral ganciclovir extremely low (about 6 ~ 9%).The bioavailability of valganciclovir oral absorption is 60%, is 10 times of ganciclovir, and can significantly reduce the toxicity of ganciclovir.Valaciclovir is the left-handed L-valine ester hydrochloride of acyclovir.Valaciclovir changes acyclovir in circulation of first run small intestine and liver metabolism, the bioavailability that changes the back acyclovir is 54%, and is higher 3 ~ 5 times than oral acyclovir.The example of other nucleosides amino acid ester prodrugs can find in following document: antiviral chemistry and chemotherapy (Antiviral Chemistry ﹠amp; Chemotherapy) 14:263-270, U.S. Pat 5198539; Molecular medicine is learned (Mol Pharm.) 2005Mar-Apr; 2 (2): 157-67; Pharmaceutical chemistry magazine (JMed Chem.) 2005 Feb 24; 48 (4): 1274-7; Bioorganic chemistry pharmaceutical chemistry communication (Bioorg Med ChemLett.) 2004Mar 8; 14 (5): 1085-7.; Study of pharmacy (Pharm Res.) 2003 Sep; 20 (9): 1381-8.
The prodrug of another type of nucleoside medicine is the carbalkoxyl radical derivative.An example of such prodrug is an anticancer disease drug capecitabine (Capecitabine).The carbalkoxyl radical derivative can only be formed parent drug by a species specific Procaine esterase (isomerase A) hydrolysis in the liver, and can not be degraded by the enzyme in other organs, so this class prodrug has actual liver target.Example that in addition can reference can find in Chinese patent application 02123469.8.
The prodrug of another type of nucleoside medicine is a carboxylates derivatives.The example of Shi Yonging has Famciclovir (Famciclovir) clinically.Famciclovir is the diacetic acid esters prodrug of Penciclovir (Penciclovir), and Famciclovir can promptly be hydrolyzed deacetylate in vivo and be oxidized to Penciclovir.Famciclovir can improve the bioavailability of Penciclovir greatly.The other example of nucleosides carboxylicesters prodrug can find in following document: pharmaceutical chemistry magazine (J.Med.Chem.) 32,1738 (1989), study of pharmacy (Pharm.Res.) 4 No.2,120 (1987), antimicrobial medicament and chemotherapy (Antimicrob.Agents Chemother.) 33 No.1,110-112 (1989), world patent application W094/24134, W093/07163 and W094/22887, U.S. Pat 6,384,019 and US 5,216,142, European patent EP 343 133.
Also having one type nucleoside medicine prodrug is phosphoric acid ester.An example of such such prodrug is a fludarabine phosphate, and fludarabine phosphate is the phosphoric acid ester prodrug of antitumor nucleosides fludarabine, and the introducing of phosphoric acid ester has improved the solubleness of parent drug, is convenient to be prepared into injection preparation.The more example of nucleoside phosphorylase ester prodrug can find in following document: molecular medicine is learned (Mol Pharm.) 2005May-Jun; 2 (3): 233-41; Nucleosides, Nucleotide and nucleic acid (Nucleosides Nucleotides Nucleic Acids.) 2003May-Aug; 22 (5-8): 899-901; Pharmaceutical chemistry magazine (J Med Chem.) 2003 Oct 9; 46 (21): 4564-71; Modern medicines design (Curr Pharm Des.) 2003; 9 (18): 1441-51.Nucleosides, Nucleotide and nucleic acid (Nucleosides Nucleotides Nucleic Acids.) 2001Apr-Jul; 20 (4-7): 315-21; Bioorganic chemistry pharmaceutical chemistry communication (Bioorg Med Chem Lett.) 2001 Jul9; 11 (13): 1775-7.
Summary of the invention:
The purpose of this invention is to provide one antiviral compound, this compounds can be used for prevention and treat by hepatitis B virus (HBV), and hepatitis D virus (HDV) and epstein-barr virus (EB) (EBV) infect the disease that causes.The structure of this compounds is 3 '-prodrug of 2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine (L-FMAU) suc as formula shown in (I).3 '-prodrug of the L-FMAU that this compounds also comprises is at pharmacy acceptable salt.
Figure A20051004084800071
R in the formula (I) 1And R 2Can be identical or different, R 1=amino-acid residue, alkoxyl formyl, organic carboxyl acid acyl group, phosphoryl and alkyl; R 2=H, amino-acid residue, alkoxyl formyl, organic carboxyl acid acyl group, phosphoryl and alkyl.
3 ' of L-FMAU-prodrug has on 3 ' can biological cracked group, and also can optionally have at 5 ' simultaneously can be by biological cracked group.3 ' of L-FMAU-prodrug can be metabolised to 5 '-phosphorylated meta-bolites of parent compound L-FMAU or L-FMAU in vivo.That compound provided by the invention or itself have is antiviral (HBV, HDV, EBV) activity, perhaps becoming by metabolism has 5 '-phosphorylated of the parent compound of antiviral activity L-FMAU and L-FMAU meta-bolites to play antiviral effect.
In a word, the invention provides following material and method:
(a) provide a compounds, said compound is the 3 '-prodrug and the pharmacy acceptable salt thereof of 2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine;
3 '-prodrug of (b) 2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine and pharmacy acceptable salt thereof are in preparation treatment or prevention hepatitis B virus (HBV), the application in the medicine that hepatitis D virus (HDV) and epstein-barr virus (EB) (EBV) infect;
(c) contain 2 '-deoxidation-2 '-fluoro-5-methyl-β-the 3 '-prodrug of L-arabinose uridine or pharmaceutical composition of its pharmacy acceptable salt;
(d) be used to prepare 2 '-deoxidation-2 '-fluoro-5-methyl-β-the 3 '-prodrug of L-arabinose uridine and method of pharmacy acceptable salt thereof,
(e) be used for the method that preparation contains 2 '-deoxidation-2 '-fluoro-5-methyl-β-the 3 '-prodrug of L-arabinose uridine or the pharmaceutical composition of its pharmacy acceptable salt.
Detailed Description Of The Invention:
Term amino acid is meant naturally occurring and α, β, γ or δ amino acid synthetic, and comprises that active group on amino and the side chain is by the amino acid of due care.Natural amino acid includes but not limited to the amino acid that occurs in natural protein, be glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, methionine(Met), phenylalanine, tryptophane, proline(Pro), Serine, Threonine, halfcystine, tyrosine, l-asparagine, glutamine, aspartic acid, L-glutamic acid, Methionin, arginine and Histidine.The example of synthetic or alpha-non-natural amino acid has α-trifluoro leucine, α-para-fluorophenylalanine and α-3-triethyl L-Ala etc. also comprise Beta-alanine, β-Xie Ansuan, β-leucine, β-Isoleucine, β-proline(Pro), β-phenylalanine, β-tryptophane, β-methionine(Met), β-glycine, β-Serine, β-Threonine, β-halfcystine, β-tyrosine, β-l-asparagine acid, β-glutamy amino acid, β-aspartic acid, β-L-glutamic acid, beta-lysine, β-arginine or Betahistidine.
Above-mentioned amino acid can be that the form with single enantiomer exists, and also can be that the form with raceme or mixture of enantiomers exists.Preferred amino acids is the natural amino acid of L-configuration.
The term amino acid residue be meant above-mentioned amino acid remove behind the hydroxyl in the carboxy moiety the remaining group that gets off, include but not limited to: 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; β-arginyl or β-histidyl-.
Alkoxyl formyl is meant the organic group shown in structural formula-C (O)-O-R, wherein R=alkyl;
The organic carboxyl acid acyl group is meant the organic group shown in structural formula-C (O)-R, wherein R=alkyl;
Phosphoryl is meant the group shown in the following structural, Ra wherein, and Rb can be identical or different, Ra, Rb respectively do for oneself H or alkyl;
Figure A20051004084800081
The term alkyl refers to C except that particularly pointing out 1-C 20Saturated or undersaturated straight chain, branch or cyclic aliphatic group, and C 6-C 20Aromatic base and aryl radical.The indefiniteness example comprises methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopentyl, isopentyl, neo-pentyl, hexyl, isohexyl, cyclohexyl, cyclohexyl methyl, 3-methyl amyl, 2,2-dimethylbutyl and 2, the 3-dimethylbutyl, phenyl, phenmethyl, styroyl, naphthyl, p-methylphenyl.Abovementioned alkyl can also have substituting group.Substituent part is selected from: hydroxyl, sulfydryl, halogen, amino, alkylamino, arylamino, alkoxyl group, aryloxy, nitro, cyano group, sulfonic acid, sulfate radical, phosphonic acids, carboxyl, phosphate radical or phosphonate radical.Substituting group part can be as required do not protect or be protected.
The notion of term protection and protecting group is that the technician is known in the organic chemistry filed; can be with reference to " blocking group in the organic synthesis " (Protective Groups in Organic Synthesis of works such as Greene; John Wiley and Sons) second edition, 1991.
The prodrug of L-FMAU is meant the compound that can form (comprising hydrolysis or oxidation) 5 '-phosphoric acid ester of L-FMAU or L-FMAU in vivo by metabolism.
Said herein L-FMAU exists with pure enantiomeric form, is substantially devoid of other steric isomer, and enantiomeric purity is more than 95%.
In one embodiment, the prodrug of L-FMAU only has the cleavable group on 3 '-position, and the indefiniteness example comprises 3 '-amino acid ester, 3 '-organic carboxylic ester, 3 '-alcoxyl manthanoate and 3 '-phosphoric acid ester.
In second kind of embodiment, the prodrug of L-FMAU 3 '-the cleavable group is all arranged on position and the 5 '-position, and 3 '-with 5 '-position on group be identical.The indefiniteness example comprises 3 ', 5 '-diamino acid esters of L-FMAU, 3 ', 5 '-two organic carboxyl acid acid esters and 3 ', 5 '-dialkoxy manthanoate.
In the third embodiment, the L-FMAU prodrug all has the cleavable group on 3 '-position and 5 '-position, and the group on 3 '-position and the 5 '-position is inequality, the indefiniteness example comprises 3 ' of L-FMAU-amino acid ester-5 '-organic carboxyl acid acid esters, 3 '-amino acid ester-5 '-alcoxyl manthanoate, 3 '-organic carboxyl acid acid esters-5 '-amino acid ester, 3 '-alcoxyl manthanoate-5 '-amino acid ester, 3 '-organic carboxyl acid acid esters-5 '-alcoxyl manthanoate, 3 '-alcoxyl manthanoate-5 '-organic carboxyl acid acid esters, also comprise by two kinds different amino acids formed 3 ', 5 '-diamino acid esters, two kinds of 3 ', 5 '-dialkoxy manthanoate or two kinds of 3 ', 5 '-two organic carboxyl acid acid esters that different organic carboxyl acid acid forms that different alcoxyl formic acid forms.
The form of all right salt of above-mentioned L-FMAU prodrug exists.The amino that for example contains on the L-FMAU prodrug of amino-acid residue can form stable salt with the acid with sufficient acidity.Suitable acid can be monoprotic acid or polyprotonic acid, comprises mineral acid, organic sulfonic acid, organic carboxyl acid and the organic compound or the natural product that contain acidic-group.Preferred acid should be nontoxicity or the very low acid of toxicity, and when especially using as medicament active composition behind salify, selected acid needs safety non-toxic.
Suitable mineral acid comprises sulfuric acid, phosphoric acid, and nitric acid, hydrochloric acid, hydroiodic acid HI, Hydrogen bromide, hydrofluoric acid etc., suitable organic sulfonic acid comprises C 6-16Aryl sulfonic acid, C 6-16Heteroaryl sulfonic acid and C 1-16Alkylsulphonic acid; as taurine; Phenylsulfonic acid, tosic acid, α-Nai Huangsuan, beta-naphthalenesulfonic-acid, (S)-camphorsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, positive propanesulfonic acid, different propanesulfonic acid, positive fourth sulfonic acid, Zhong Ding sulfonic acid, isobutyl sulfonic acid, uncle's fourth sulfonic acid, penta sulfonic acid and own sulfonic acid.Organic carboxyl acid can be monobasic or polycarboxylic acid, comprises C 1-16Alkyl carboxylic acid, C 6-16Aryl carboxylic acid and C 4-16Heteroaryl carboxylic acid, as acetate, oxyacetic acid, lactic acid, pyruvic acid, propanedioic acid, pentanedioic acid, tartrate, citric acid, fumaric acid, succsinic acid, oxysuccinic acid, toxilic acid, oxalic acid, hydroxymaleic acid, phenylformic acid, hydroxy-benzoic acid, toluylic acid, styracin, tussol, TRANSCINNAMIC ACID, amygdalic acid, Whitfield's ointment and 1-phenoxy benzoic acid, nicotinic acid, pantothenic acid.Organic carboxyl acid also comprises amino acid, and suitable amino acid has many, the natural amino acid of finding as protein component especially, aspartic acid for example, L-glutamic acid, Xie Ansuan.
The organic compound or the natural product that contain acidic-group comprise xitix, Oleanolic Acid, ursonic acid, ursolic acid, Potenlini, glycyrrhetinic acid, red sage root acid, forulic acid, glucuronic acid, gluconic acid and levulinic acid.
The L-FMAU prodrug that contains acidic-group for example L-FMAU-3 '-glutamate and L-FMAU-3 '-phosplate can with metal ion basic metal for example, alkaline-earth metal and transition metal ion (lithium, sodium, potassium, calcium, magnesium, zinc, aluminium, copper, iron etc.) form salt, can also form salt (single ammonium carbamate, diformazan ammonium salt, triethylammonium salts, two b ammonium salts, monoethanolamine salt, kuh-seng alkali salt) with ammonium or organic ammonium ion, contain a plurality of acidic-groups and maybe can become the prodrug of a polyvalent salt to form mixing salt with above-mentioned more than one ion.
The compound that first kind of embodiment provides can be represented with following formula:
R in the formula (II) 1=amino-acid residue, alkoxyl formyl, the organic carboxyl acid acyl group, the preferred compound of phosphoryl and alkyl has:
3 ' of L-FMAU-amino acid ester; comprise 3 '-O-(L-is valyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine; 3 '-O-(L-isoleucyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine; 3 '-O-(L-alanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine; 3 '-O-(L-phenylalanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine; 3 '-O-(L-lysyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine, 3 '-O-(L-aspartyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine.
3 ' of L-FMAU-organic carboxylic ester; comprise low-grade fatty acid ester; high-grade aliphatic ester and aromatic carboxylates: 3 '-O-benzoyl-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine; 3 '-O-ethanoyl-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine; the anti-oleoyl-2 ' of 3 '-O--deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine; 3 '-O-stearyl--2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
3 ' of L-FMAU-alcoxyl manthanoate, comprise the positive fourth oxygen of 3 '-O-acyl group-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine, 3 '-O-isobutyl oxygen acyl group-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine, positive penta oxygen acyl group-the 2 '-deoxidation-2 ' of 3 '-O--fluoro-5-methyl-β-L-arabinose uridine, the just own oxygen acyl group-2 ' of 3 '-O--deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine;
3 ' of L-FMAU-phosphoric acid ester: 3 ' of L-FMAU-phosplate, 3 '-triguaiacyl phosphate of 3 ' of L-FMAU-bisphosphate and L-FMAU, 3 ' of L-FMAU-single phosphoric acid-di-acetyl mercapto ethyl ester.
The 3 '-prodrug of L-FMAU shown in the formula (II) can prepare with method shown in following reaction equation:
Figure A20051004084800111
At first use suitable blocking group P optionally to protect 5 ' of L-FMAU-hydroxyl to obtain crucial intermediate A.Blocking group P can be a known protecting group arbitrarily in the organic chemistry; the indefiniteness example of the protecting group that can select for use comprises the trityl group of trialkylsilanyl and replacement or non-replacement; preferred protecting group comprises TMS (TMS-); tertiary butyl dimethylsilyl (TBDMS-); tert-butyl diphenyl silylation (TBDPS-), tri isopropyl silane base (TPr iS-), trityl group (Tr-), 4,4 '-dual-methoxy trityl (DMT-) and 4-mono methoxy trityl (MMT-).Can select the reaction conditions of 5 '-hydroxyl of common selective protection nucleosides for use by the reaction conditions of 5 '-hydroxyl of trialkylsilanyl or trityl group selective protection L-FMAU.For example the protection of trialkylsilanyl can be reacted in the presence of imidazoles with trialkylchlorosilane and nucleosides, and reaction solvent is generally dimethyl formamide (DMF), tetrahydrofuran (THF) (THF) or methylene dichloride, and temperature of reaction is generally between-10 ℃ and 30 ℃.The ratio of trialkylchlorosilane and nucleosides is generally between 1.2: 1 to 2: 1.The reaction of trityl group class protecting group protection 5 '-hydroxyl is generally carried out in pyridine, and the triphenylmethyl chloride of using replacement or non-replacement can also be selected for use dimethyl amine yl pyridines (DMAP) as catalyzer as alkylating reagent.Temperature of reaction generally between room temperature to 120 ℃, replace or the ratio of the triphenylmethyl chloride of non-replacement and nucleosides generally 1.2: 1-3: between 1.
After obtaining the intermediate A of 5 '-protection; can using arbitrarily, currently known methods prepares 3 '-hydroxy derivative B; use arbitrarily currently known methods to slough the blocking group that may have on 5 '-protecting group and 3 '-group at last; for example the amino protecting group on the amino-acid residue obtains 3 ' of L-FMAU-prodrug (II).
3 ' of L-FMAU-amino acid ester can prepare by above-mentioned synthetic route.3 '-hydroxyl on the intermediate A can come esterification to obtain 3 '-amino acid ester with the method for any known synthesizing amino acid esters.
A kind of feasible method is that the amino acid with amino due care obtains 3 '-amino acid ester with intermediate A condensation in the presence of condensing agent in appropriate solvent.The indefiniteness example of the condensing agent that can select for use has: Carbodiimides condensing agent such as dicyclohexyl carbodiimide (DCC) or 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (EDCHCl); N, N '-carbonyl dimidazoles (DCI); 1-hydroxyl-benzo-triazole (HOBt) and block special condensing agent (BOP) etc.Amino acid whose protecting group can be selected any known protecting group for use, and the preferred indefiniteness example of protecting group has benzene methoxy carbonyl acyl group (CBZ-), tertiary butyloxycarbonyl acyl group (BOC-) and fluorenes methoxy carbonyl acyl (Fmoc-).The temperature of reaction that the solvent of reaction is selected to reach necessary and any reaction solvent that can the solubilizing reaction composition.Nonrestrictive example is any aprotic solvent, include but not limited to alkane or haloalkane solvent, as hexane, hexanaphthene, methylene dichloride or ethylene dichloride, toluene, acetone, ethyl acetate, dithiane, THF, dioxane, acetonitrile, ether, pyridine, dimethyl formamide (DMF), methyl-sulphoxide (DMSO), N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone (NMP) or their any combination.Reaction can also come accelerated reaction with suitable catalyzer, and the indefiniteness example of catalyzer has 4-dimethyl amine yl pyridines (DMAP), pyridine, imidazoles and acetic acid.Generally between room temperature to 90 ℃, the reaction times is generally between 12 hours-36 hours for temperature of reaction.
The other a kind of preparation method of 3 ' of L-FMAU-amino acid ester comprises the intermediate A of 5 '-protection and amino acid whose N-carbonyl ring inner-acid anhydride (N-carboxyanhydride, NCA) reaction.Amino acid whose N-carbonyl ring inner-acid anhydride (N-carboxyanhydride NCA) has 2-oxygen-4-azepine-1 that the 4-shown in the following array structure formula replaces, 3-diketone cyclopentane structure:
Figure A20051004084800121
Following formula wherein P ' is H or amino protecting group arbitrarily, and R ' is the amino acid side chain group.
Amino acid whose N-carbonyl ring inner-acid anhydride can with hydroxyl reaction freely, form the amino acid ester of hydroxyl, and discharge CO 2As by product.Common amino acid whose N-carbonyl ring inner-acid anhydride reactive behavior is stronger, and the temperature of esterification generally is controlled at about room temperature, and active more weak amino acid whose N-carbonyl ring inner-acid anhydride temperature of reaction can suitably improve, but does not generally surpass 80 ℃.Suitable organic bases such as triethylamine and pyridine can be used for accelerated reaction.
Amino acid whose N-carbonyl ring inner-acid anhydride can reference example such as United States Patent (USP) 6,479,665 disclosed methods prepare.
Other synthetic method of 3 ' of L-FMAU-amino acid ester comprises amino acid derivative and the intermediate A reaction of using carboxyl to be activated.The amino acid that carboxyl is activated comprises amino acid whose active ester such as amino acid whose pentafluorophenyl esters and amino acid whose N-hydroxy-succinamide ester (NHS ester), amino acid whose acid anhydrides, amino acid whose acyl chlorides etc.
3 ' of L-FMAU-carboxylicesters prodrug can be prepared with any known esterification process by intermediate A.Usually can obtain with intermediate A and activatory carboxylic acid such as reactions such as acid anhydrides and acyl chlorides.For example 3 ' of L-FMAU-benzoic ether just can utilize and slough 5 '-protecting group behind intermediate A and the phenylformic acid acyl chloride reaction and obtain, and 3 ' of L-FMAU-acetic ester can utilize to be sloughed 5 '-protecting group behind intermediate A and the acetic anhydride and obtain.
3 ' of L-FMAU-alcoxyl manthanoate can obtain with removing 5 ' protecting group after intermediate A and the alkyl chloroformate reaction.Reaction is for example carried out under the existence of organic bases (triethylamine, pyridine) among acetonitrile, methylene dichloride, DMF and the NMP at aprotic polar solvent usually.
Alkyl chloroformate
3 ' of L-FMAU-phosphoric acid ester prodrug obtains after can and sloughing protecting group with intermediate A and chemical phosphorylation reagent react rear oxidation:
Figure A20051004084800132
Chemical phosphorylation reagent
The compound that second kind of embodiment provides is 3 ', the 5 '-prodrug of the L-FMAU shown in the formula (III), said compound in 3 '-position and 5 '-have an identical group.
Figure A20051004084800141
R in the formula (III) 1=amino-acid residue, alkoxyl formyl, organic carboxyl acid acyl group, phosphoryl and alkyl
Preferred compound has:
3 ' of L-FMAU-5 '-bis-amino acid ester is 3 '-5 '-two L-L-valine esters of L-FMAU for example, 3 '-5 '-two L-Isoleucine esters, 3 '-5 '-two L-phenylalanine esters;
3 ' of L-FMAU-5 '-double carboxy acid ester is 3 '-5 '-diacetic acid esters of L-FMAU for example, 3 '-5 '-two elaidic acid esters, 3 '-5 '-bilaurate;
3 ' of L-FMAU-5 '-two alcoxyl manthanoate are 3 '-5 '-two normal-butyl oxygen manthanoate of L-FMAU for example, 3 '-5 '-two isobutyl-oxygen manthanoate, 3 '-5 '-two n-pentyl oxygen manthanoate, 3 '-5 '-two n-hexyl oxygen manthanoate.
3 '-5 '-prodrug that 3 '-position and 5 '-position has the L-FMAU of identical group can be that the direct derivatize of raw material obtains with L-FMAU.
3 ' of L-FMAU-5 '-bis-amino acid ester prodrugs can obtain with amino acid condensation in the presence of condensing agent of L-FMAU and due care; also can use L-FMAU and amino acid whose N-carbonyl ring inner-acid anhydride; amino acid whose pentafluorophenyl esters; amino acid whose N-hydroxy-succinamide ester (NHS ester), the reaction of activatory amino acid such as amino acid whose acid anhydrides and amino acid whose acyl chlorides makes.
Generally, the mol ratio of amino acid and L-FMAU reaction was greater than 2: 1, and reaction obtains 3 '-amino acid ester in some cases, the mixture of 5 '-amino acid ester and 3 '-5 '-bis-amino acid ester, and the excessive greatly ability of amino acid needs makes and reacts completely.
3 ' of L-FMAU-5 '-double carboxy acid ester can be that raw material prepares with any known esterification process with L-FMAU.Usually can be with esterifying agents such as acid anhydrides and acyl chlorides and L-FMAU reaction, the twice that the amount of esterifying agent is generally measured greater than L-FMAU is to reduce 3 '-monoesters and 5 '-content of by-products such as monoesters.
3 ' of L-FMAU-5 '-two alcoxyl manthanoate can obtain with L-FMAU and alkyl chloroformate reaction.
The compound that the third embodiment provides is 3 ', the 5 '-prodrug of the L-FMAU shown in the formula (VI), and in 3 '-position and 5 '-position has group inequality.
Figure A20051004084800151
R1 in the formula (IV), R2 are different groups, and R1, R2 are respectively amino-acid residue separately, alkoxyl formyl, organic carboxyl acid acyl group, phosphoryl and alkyl.
Preferred compound has:
The anti-oleoyl-3 ' of 5 '-O--O-(L-is valyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
The anti-oleoyl-3 ' of 5 '-O--O-(L-isoleucyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
The anti-oleoyl-3 ' of 5 '-O--O-(L-phenylalanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-O-normal-butyl oxygen formyl radical-3 '-O-(L-is valyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
5 '-O-normal-butyl oxygen formyl radical-3 '-O-(L-isoleucyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
5 '-O-normal-butyl oxygen formyl radical-3 '-O-(L-phenylalanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
3 '-the 5 '-prodrug of L-FMAU shown in the formula (IV) can prepare with method shown in following reaction equation:
At first use suitable blocking group P optionally to protect 5 ' of L-FMAU-hydroxyl to obtain crucial intermediate A.Prepare 3 '-hydroxy derivative B with currently known methods arbitrarily, use arbitrarily currently known methods to slough 5 '-protecting group then and obtain intermediate C.With obtaining intermediate D behind 5 '-hydroxyl derivatize of currently known methods with intermediate C arbitrarily, the protecting group that may exist of sloughing again on the intermediate D obtains compound (VI).
L-FMAU can synthesize with reference to Chinese patent 95191415 or other document, also can synthesize with the method shown in the following reaction formula:
Figure A20051004084800161
5 ' hydroxyl can also synthesize with the method shown in the following reaction equation with the intermediate A of tert-butyl diphenyl silylation protection:
This method is a raw material with 2-deoxidation-2-fluoro-L-arabinose; in methyl alcohol, be catalyzer Synthetic 2-deoxidation-2-fluoro-α-L-arabinose methyl glucoside, optionally protect with the tert-butyl diphenyl silylation behind the one-level hydroxyl of 5-position again with benzoyl protection 3-position hydroxyl with acid.The thymus pyrimidine of 5-O-tert-butyl diphenyl silylation-3-O-benzoyl-1-O-methyl-2-deoxidation-2-fluoro-L-arabinose and protected silane reacts under lewis acidic catalysis and obtains 5-O-tert-butyl diphenyl silylation-3-O-benzoyl-L-FMAU, and the hydrolysis under weakly alkaline effect of this compound is fallen benzoyl and obtained 5 '-O-tert-butyl diphenyl silylation-L-FMAU.
2-deoxidation-2-fluoro-L-arabinose can reference literature Nucleosides Nucleotides Nucleic Acids.2002; 21 (2): 155-63. synthesizes, also can be by using weak base hydrolysis 1,3, and 5-three-O-benzoyl-2-deoxidation-2-fluoro-α-L-furans pectinose obtains.
The prodrug of L-FMAU provided by the invention can be by any suitable administration for the treatment of disease.Usually, the prodrug of L-FMAU and the administration of physiologically acceptable salt oral administration thereof, but also can be by comprising per rectum, vagina, intranasal, part (comprising eyes, oral cavity and hypogloeeis) and non-stomach and intestine administrations such as (comprising in subcutaneous, muscle, intravenously, intracutaneous, the sheath and exterior dura).
Though the prodrug of L-FMAU and physiologically acceptable salt thereof can be with the form administrations of pure substance, common form administration with pharmaceutical preparation.Pharmaceutical preparation comprises prodrug and physiologically acceptable salt and one or more pharmaceutical carriers of L-FMAU, optionally, also can contain other treatment composition or ancillary component, for example other antiviral agents, immunopotentiating agent and protection liver drug or the like.Pharmaceutical carrier comprises tackiness agent, thinner, disintegrating agent, sanitas, dispersion agent, glidant (antitack agent) and lubricant.
Be fit to oral solid preparation and comprise tablet, capsule, pulvis, granule, dripping pill and powder etc.;
Be fit to oral preparation and also comprise bolus, tincture or paste.
Tablet can be a conventional tablet, also can be dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet or enteric coated tablet.
Capsule can be the conventional capsule preparation, also can be slow releasing capsule, controlled release capsule or enteric coated capsule.
The prodrug of L-FMAU and physiologically acceptable salt thereof can also be with the mode administrations of injection, and preparation comprises powder pin and injecting fluid.
The preparation of embodiment 1 1-O-methyl-L-ribofuranose
0 ℃ in the methyl alcohol (250ml) logical HCl gas saturated to solution, then L-ribose (50g) is dissolved in wherein, continue logical HCl solid/liquid/gas reactions 3hr.
, filter to pH=7 with solid sodium carbonate neutralization reaction liquid, the reaction solution evaporated under reduced pressure is got yellow syrupy shape 1-O-methyl-L-ribofuranose 60 grams, be directly used in the next step.
Embodiment 2 1-O-methyl-2,3, the preparation of 5-three-O-benzoyl-L-ribofuranose
Figure A20051004084800192
1-O-methyl-L-ribofuranose 60 grams are dissolved in the pyridine (800ml), and 0 ℃ is stirred down, drips Benzoyl chloride (200ml), and reaction solution is by the faint yellow pink that becomes, and have a large amount of solids (pyridine hydrochloride) to occur, recover room temperature stirring reaction 17hr then.
To discard solid and evaporated under reduced pressure filtrate behind the above-mentioned reaction solution suction filtration, residue adds CH 2Cl 2(500ml) dissolving, successively with 1%HCl solution (500ml * 3), the aqueous solution (500ml * 3), KHCO 3Solution (500ml * 2) washing.Organic layer adds gac (50g), reflux 0.5hr decolouring, liquid cooling to the room temperature with anhydrous Na 2SO 4Dewater, cross the filtering look by layer of silica gel and sand bed then.At last the filtrate evaporate to dryness is got yellow syrupy shape 1-O-methyl-2,3,5-three-O-benzoyl-L-ribofuranose is directly used in the next step.
Embodiment 3 1-O-ethanoyl-2,3, the preparation of 5-three-O-benzoyl-β-L-ribofuranose
Figure A20051004084800193
With the 1-O-methyl-2,3 that the reaction of last step obtains, 5-three-O-benzoyl-L-ribofuranose is with 72mlAcOH and 167mlAc 2O is dissolved in the 1000ml round-bottomed flask, and 0 ℃ is stirred and drip 24mlconc-H 2SO 4, solution is by the orange red brownish black that becomes, and after dripping, reaction solution is placed to the recovery room temperature, places refrigerator overnight again.
In the reaction solution impouring 350ml frozen water, stir evenly and leave standstill, the liquid layering adds the 1000ml ethyl acetate, respectively with the aqueous solution (500ml * 3), KHCO 3Solution (500ml * 2), salt solution (500ml * 2) extraction.Divide and get organic layer with anhydrous Na SO 4After dewatering, add gac (50g), reflux 0.5hr, liquid cooling is crossed the filtering look by layer of silica gel and sand bed to room temperature.With the filtrate decompression evaporate to dryness, add recrystallizing methanol and get (92 gram) canescence 1-O-ethanoyl-2,3,5-three-O-benzoyl-β-L-ribofuranose at last.
Embodiment 41, and 3, the preparation of 5-three-O-benzoyl-α-L-ribofuranose
With CH 2Cl 2(1000ml) place the 3000ml three-necked flask, 0 ℃ of logical HBr gas makes solution saturated, disposable adding 1-O-ethanoyl-2,3, and 5-three-O-benzoyl-β-L-ribofuranose (90g) is at 1000mlCH 2Cl 2In solution, mixed solution is at 0 ℃ of following stirring reaction 3.5hrs.At normal temperatures reaction solution is concentrated then, reduction vaporization is to half of original volume.Concentrated solution adds 550mlH 2Stirring reaction 2hrs under the normal temperature behind the O, solution is become colorless by orange red.
Divide and get organic layer, add anhydrous Na 2SO 4Remove residual moisture, evaporated under reduced pressure organic layer then, resistates CH 2Cl 2Get (48 gram) white solid 1,3 with the mixture recrystallization of sherwood oil, 5-three-O-benzoyl-α-L-ribofuranose.
Embodiment 51, and 3, the preparation of 5-three-O-benzoyl-2-O-imidazoles sulfonic group-α-L-furans pectinose
Figure A20051004084800202
1,3,5-three-O-benzoyl-α-L-ribofuranose (46g) is with anhydrous CH 2Cl 2(390ml) and dry DMF (120ml) be dissolved in the 1000ml three-necked flask and logical N 2This reaction solution is in-15 ℃ of stirrings, drip SULPHURYL CHLORIDE (25ml) simultaneously, dropwise afterreaction and continue to stir 0.5hr, slowly rise to room temperature and continue reaction 4h at low temperature, in 0 ℃ of following minute three times adding imidazoles (imidazole 67g), return to room temperature reaction 17hr then.
In the reaction solution impouring frozen water (1500ml), and with CH 2Cl 2(500ml * 3) extraction divides then and gets organic layer, washes with water, again with anhydrous Na 2SO 4Dry back concentrates, and (EtOAc: Hexane/1: 5-1: get yellowish white solid (32g) 6) is 1,3 to concentrated solution, 5-three-O-benzoyl-2-O-imidazoles sulfonic group-α-L-ribofuranose with the silicagel column separation and purification.
Embodiment 61, and 3, the preparation of 5-three-O-benzoyl-2-deoxidation-2-fluoro-α-L-furans pectinose
1,3,5-three-O-benzoyl-2-O-imidazoles sulfonic group-α-L-ribofuranose (30g) and KHF 2(20g) in 500ml tetrafluoroethylene crucible with 2,3-butyleneglycol (330ml) dissolving, logical N 2Following stirring reaction adds HF/H after being heated to 150 ℃ 2O (40%12ml), mixed solution continue to be warming up to 160 ℃, stirring reaction 1hr.
With the icy salt solution termination reaction, add CH 2Cl 2(500ml * 4) extraction divides and gets organic layer more successively with salt solution, water, NaHCO 3Solution is washed, and uses anhydrous Na then 2SO 4Remove remaining moisture, evaporated under reduced pressure gets liquid syrup, adds 95% ethyl alcohol recrystallization and gets the solid shape 1,3 of (18g) white, 5-three-O-benzoyl-2-deoxidation-2-fluoro-α-L-furans pectinose.
Embodiment 7 1-bromo-2-deoxidation-2-fluoro-3, the preparation of 5-two O-benzoyl-α-L-furans pectinose
1,3,5-three-O-benzoyl-2-deoxidation-2-fluoro-α-L-ribofuranose (15g) is dissolved in CH 2Cl 2(330ml) add HBr/AcOH (45%w/v 46ml) simultaneously, mixed solution is lucifuge stirring reaction 24hr under room temperature.
Add CH after the reaction solution evaporated under reduced pressure 2Cl 2(500ml) respectively with water, NaHCO 3Solution is washed, and divides and gets the organic layer anhydrous Na 2SO 4Remove remaining moisture, evaporated under reduced pressure gets liquid syrup, and (perhaps directly add toluene behind the reaction solution evaporate to dryness and repeat to revolve steaming 3 times), being 1-bromo-2-deoxidation-2-fluoro-3,5-two O-benzoyl-α-L-furans pectinose are directly used in the next step.
Embodiment 8 N 1The preparation of-(3 ', 5 '-two O-benzoyl-2 '-deoxidations-2 '-fluoro-beta-L-furans pectinose)-methyl uracil
Thymus pyrimidine (5g) and a little ammonium sulfate lead to N in HMDS (hexamethyldisilazane 100ml) and 1 in the 2-ethylene dichloride (100ml) 2Back flow reaction 17hrs treats that white solid disappears, and solution becomes is clarified the back evaporated under reduced pressure, gets the thymus pyrimidine solution of silanization.With 1-bromo-2-deoxidation-2-fluoro-3 that the reaction of last step obtains, 5-two O-benzoyl-α-L-ribofuranose adds the thymus pyrimidine solution of silanization, logical N 2Back flow reaction 36 hours.
The reaction water stops, with CHCl 3Extraction.Divide and get organic layer more successively with salt solution, anhydrous Na is used in washing then 2SO 4Remove remaining moisture.Organic layer evaporated under reduced pressure gained crude product is with silicagel column separation and purification (MeOH: CH 2Cl 2/ 0 ~ 5%) obtaining white solid (12.45g) after is N 1-(3 ', 5 '-two O-benzoyl 2 '-deoxidation-2 '-fluoro-betas-L-furans pectinose)-methyl uracil.
The preparation of embodiment 9 L-FMAU
Figure A20051004084800221
N 1-(3 ', 5 '-two O-benzoyl 2 '-deoxidation-2 '-fluoro-betas-L-furans pectinose)-methyl uracil (12g) is dissolved in NH 3/ CH 3OH (200ml), stirring at room reaction 24hr.
The reaction solution concentrating under reduced pressure is with silicagel column separation and purification (MeOH: CH 2Cl 2/ 5%) obtains white solid after, obtain the L-FMAU4.6 gram after the recrystallizing methanol.Mass spectrum (FAB-MS): 261 (M+1), nuclear magnetic data conforms to bibliographical information.
Embodiment 10 5 '-preparation of O-tert-butyl diphenyl silylation-L-FMAU:
Take by weighing 2.77gL-FMAU and 2.13g imidazoles, after the 60mlDMF dissolving, place ice-water bath, at rare gas element (N 2) protection adds down 3.73ml tert-butyl diphenyl chlorosilane (TBDPS-Cl), react to show to TLC and to react completely.Decompressing and extracting, CH 2Cl 2Dissolving, washing is again with anhydrous Na SO 4Dewater, drain and obtain a small amount of CH of product 2Cl 2Recrystallization gets solid 5.2g.Mass spectrum (FAB-MS): 499 (M+1).
Embodiment 11 5 '-preparation of O-tertiary butyl dimethylsilyl-L-FMAU:
Figure A20051004084800223
Take by weighing 1.3gL-FMAU and 1.02g imidazoles, after the 20mlDMF dissolving, place ice-water bath, at rare gas element (N 2) protection adds down 0.85g gram TERT-BUTYL DIMETHYL CHLORO SILANE (TBDMS-Cl), react to show to TLC and to react completely.Decompressing and extracting, CH 2Cl 2Dissolving, washing is again with anhydrous Na SO 4Dewater, drain and obtain product 1.53g.Mass spectrum (FAB-MS): 375 (M+1).
Embodiment 12 5 '-preparation of O-(4,4 '-dual-methoxy trityl)-L-FMAU:
Figure A20051004084800231
Take by weighing 1.3g FMAU, be dissolved in the 20ml pyridine, add 3.8g DMT-Cl, 50mgDMAP reacts 48hr in 90 ℃ of oil baths, drain pyridine, uses CH 2Cl 2Dissolving is crossed silicagel column and is obtained 5 '-O-DMT-L-FMAU 1.63g.Mass spectrum (FAB-MS): 563 (M+1).
Embodiment 13 3 '-O-(L-is valyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine hydrochloride.
Figure A20051004084800232
5 '-O-tert-butyl diphenyl silylation-L-FMAU1.0g dissolves with the 20ml dry DMF, add 1.1g Boc-L-Xie Ansuan (L-Boc-Val) and 0.87g DCC, reaction mixture places 50 ℃ of water-baths to react 48h, show to TLC and to react completely, filter, filtrate, dewaters with the sodium bicarbonate aqueous solution washing with methylene dichloride 100ml dilution back, drains solvent and obtains 1.32g oily matter.Gained oily matter is dissolved among the 15mlTHF, adds " the CH of 2ml 2M 3(CH 2) 3" 4The THF solution of NF, reaction 120min, the TLC demonstration reacts completely, and reaction solution washes with water after diluting with methylene dichloride 100ml, dewaters, and drains solvent.Residue is dissolved among the anhydrous THF10ml, is cooled to 0 ℃, add the saturated solution of 3ml hydrogenchloride THF, react that the TLC demonstration reacts completely after 4 hours.Add ether 20ml, the adularescent solid is separated out.Solid collected by filtration is used the small amount of methanol recrystallization, filters, and obtains white crystal 0.32 gram after the vacuum-drying.
Mass spectrum (FAB-MS): 360 (M+1); UV (MeOH) λ max=261nm; Ultimate analysis C15H23ClFN 3O 6
Calculated value: C, 45.52; H, 5.86; N, 10.62; F, 4.80; Cl, 8.96
Measured value: C, 45.76; H, 5.83; N, 10.57; F, 4.78; Cl, 9.01
Embodiment 14 3 '-O-(L-isoleucyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine hydrochloride.
Figure A20051004084800241
Get 1.5g 5 '-O-tert-butyl diphenyl silylation-L-FMAU, dissolve with 40mlDMF, add 50 milligrams of DMAP, 2.1gN-Cbz-L-Isoleucine carbonyl ring inner-acid anhydride (making) with reference to U.S. Pat 6479665, reaction mixture slowly is warming up to 50 ℃, reacts to gas release to stop and TLC shows and to react completely.Solvent removed in vacuo, residue dissolves with methylene dichloride 100ml, and hydrochloric acid and the sodium bicarbonate aqueous solution washing final vacuum with 1M obtains oily matter except that desolvating respectively.Gained oily matter is dissolved among the 20mlTHF, adds " the CH of 3ml 2M 3(CH 2) 3" 4The THF solution of NF, reaction 120min, the TLC demonstration reacts completely.Reaction solution washes with water after diluting with methylene dichloride 100ml, dewaters, and drains solvent.Residue is dissolved in the 50ml methyl alcohol, splashes into the 0.2ml concentrated hydrochloric acid, add to stir behind 50 milligrams of the Pd/C catalyzer and feed till hydrogen shows that to TLC reaction is finished.Filter, vacuum concentration adds the 20ml ether and obtains white solid to original volume 1/5th, filters the collection back and obtains crystal 0.55 gram with recrystallizing methanol.
Mass spectrum (FAB-MS): 374 (M+1); UV (MeOH) λ max=259nm; Ultimate analysis C16H25ClFN3O6
Calculated value: C, 46.89; H, 6.15; N, 10.25; F, 4.64; Cl, 8.65
Measured value: C, 46.70; H, 6.17; N, 10.21; F, 4.66; Cl, 8.70
Embodiment 15 3 '-O-(L-phenylalanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine hydrochloride.
Figure A20051004084800242
Get 1.5g 5 '-O-tert-butyl diphenyl silylation-L-FMAU, dissolve with 40mlDMF, add 50 milligrams of DMAP, 2.5gN-Boc-L-phenylalanine carbonyl ring inner-acid anhydride (making) with reference to U.S. Pat 6479665, reaction mixes and slowly to be warming up to 50 ℃, reacts to gas release to stop and TLC shows and reacts completely.Solvent removed in vacuo, residue dissolves with methylene dichloride 100ml, and hydrochloric acid and the sodium bicarbonate aqueous solution washing final vacuum with 1M removes the oily matter that desolvates respectively.Gained oily matter is dissolved among the 20mlTHF, adds " the CH of 3ml 2M 3(CH 2) 3" 4The THF solution of NF, reaction 120min, the TLC demonstration reacts completely.Reaction solution washes with water after diluting with methylene dichloride 100ml, dewaters, and drains solvent.Residue is dissolved among the anhydrous THF15ml, is cooled to 0 ℃, add the saturated solution of 5ml hydrogenchloride THF, react that the TLC demonstration reacts completely after 4 hours.Add ether 40ml, the adularescent solid is separated out.Solid collected by filtration is used the small amount of methanol recrystallization, filters, and obtains white crystal 0.62 gram after the vacuum-drying.
Mass spectrum (FAB-MS): 408 (M+1);
Ultimate analysis C19H23ClFN3O6
Calculated value: C, 51.41; H, 5.22; N, 9.47; F, 4.28; Cl, 7.99;
Measured value: C, 51.15; H, 5.25; N, 9.51; F, 4.25; Cl, 7.96
Also synthesized following compounds with embodiment 15 identical methods:
3 '-O-(L-alanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
3 '-O-glycyl-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
3 '-O-(L-leucyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
Embodiment 16 3 '-O-benzoyl-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
Figure A20051004084800251
5 '-O-tert-butyl diphenyl silylation-L-FMAU is dissolved in the 5ml pyridine for 250 milligrams, is cooled to 0 ℃ under the nitrogen protection, adds Benzoyl chloride 0.15ml, slowly rises to room temperature continuation stirring reaction and finishes until TLC demonstration reaction.Vacuum is removed pyridine, and residue washs with the hydrochloric acid and the sodium bicarbonate aqueous solution of methylene dichloride 20ml dissolving back with 1M.Remove methylene dichloride after the drying, add " the CH of 5ml 1M 3(CH 2) 3" 4The THF solution of NF, reaction is monitored with TLC.React completely the back except that desolvating, separate obtaining title compound with silicagel column (the methylene dichloride wash-out of 5% methyl alcohol).Mass spectrum (FAB-MS): 365 (M+1).
Embodiment 17 3 '-the anti-oleoyl-2 ' of O--deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
Figure A20051004084800261
5 '-O-tert-butyl diphenyl silylation-L-FMAU is dissolved in the 5ml pyridine for 250 milligrams, is cooled to 0 ℃ under the nitrogen protection, adds anti-oleoyl chloride 0.2ml, slowly rises to room temperature continuation stirring reaction and finishes until TLC demonstration reaction.Vacuum is removed pyridine, and residue washs with the hydrochloric acid and the sodium bicarbonate aqueous solution of methylene dichloride 20ml dissolving back with 1M.Remove methylene dichloride after the drying, add " the CH of 2ml 1M 3(CH 2) 3" 4The THF solution of NF, reaction is monitored with TLC.React completely the back except that desolvating, separate obtaining title compound with silicagel column (the methylene dichloride wash-out of 2% methyl alcohol).Mass spectrum (FAB-MS): 525 (M+1).
Embodiment 18 3 '-the positive fourth oxygen of O-formyl radical-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
Figure A20051004084800262
250 milligrams of 5 '-O-tert-butyl diphenyl silylation-L-FMAU and DMAP30 milligram are dissolved in 5mlDMF.Be cooled to 0 ℃ under the nitrogen protection, add triethylamine 0.20ml, add butyl chloroformate 0.12ml subsequently, slowly rise to room temperature continuation stirring reaction and finish until TLC demonstration reaction.Vacuum is removed DMF, and residue washs with the hydrochloric acid and the sodium bicarbonate aqueous solution of methylene dichloride 20ml dissolving back with 1M.Remove methylene dichloride after the drying, add " the CH of 3ml 1M 3(CH 2) 3" 4The THF solution of NF, reaction is monitored with TLC.React completely the back except that desolvating, separate obtaining title compound with silicagel column (the methylene dichloride wash-out of 5% methyl alcohol).Mass spectrum (FAB-MS): 361 (M+1).
Embodiment 19 5 '-3 '-O-two (L-is valyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine hydrochloride,
L-FMAU 1.3g is dissolved in the 20ml dry DMF, adds 50 milligrams of DMAP then, the 2ml pyridine.Reaction mixture is cooled to 0 ℃ under nitrogen protection, add N-Boc-L-Xie Ansuan carbonyl ring inner-acid anhydride 2.5 grams, react that gas release stops after 3 hours, and TLC shows and reacts also incomplete.In reaction solution, add N-Boc-L-Xie Ansuan carbonyl ring inner-acid anhydride 2.5 grams again and be heated to 55 ℃, react after 5 hours, solvent removed in vacuo, residue dissolves with methylene dichloride 100ml, and hydrochloric acid and the sodium bicarbonate aqueous solution washing final vacuum with 1M removes the oily matter that desolvates respectively.Oily matter is dissolved among the anhydrous THF10ml, is cooled to 0 ℃, add the saturated solution of 10ml hydrogenchloride in THF, react that the TLC demonstration reacts completely after 4 hours.Add ether 40ml, the adularescent solid is separated out.Solid collected by filtration is used the small amount of methanol recrystallization, filters, and obtains white crystal 1.42 grams after the vacuum-drying.
Mass spectrum (FAB-MS): 459 (M+1); UV (MeOH) λ max=264nm; Ultimate analysis C20H33Cl2FN4O7
Calculated value: C, 45.20; H, 6.26; N, 10.54; F, 3.58; Cl, 13.34;
Measured value: C, 45.42; H, 6.22; N, 10.49; F, 3.60; Cl, 13.29;
Also synthesized following compounds with embodiment 19 identical methods:
5 '-3 '-O-two (L-isoleucyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-two (L-phenylalanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
Embodiment 20 5 '-3 '-O-diacetyl-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
Figure A20051004084800271
L-FMAU 0.13g is dissolved in the 2ml pyridine, is cooled to 0 ℃ under nitrogen protection, slowly rises to room temperature reaction 5 hours behind adding diacetyl oxide 200 microlitres.Vacuum is removed pyridine, and residue washs with the hydrochloric acid and the sodium bicarbonate aqueous solution of methylene dichloride 20ml dissolving back with 1M.Remove methylene dichloride after the drying, separate obtaining title compound 0.15g with silicagel column (the dichloromethane solution wash-out of 2% methyl alcohol).Mass spectrum (FAB-MS): 345 (M+1).
Embodiment 21 5 '-3 '-O-di-n-butyl oxygen formyl radical-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine
Figure A20051004084800272
L-FMAU 0.13g is dissolved in the 2ml pyridine, is cooled to 0 ℃ under nitrogen protection, adds the DMAP20 milligram and drips butyl chloroformate 0.42ml then.Finish reaction solution and slowly rise to room temperature continuation reaction 16 hours.Vacuum is removed pyridine, and residue washs with the hydrochloric acid and the sodium bicarbonate aqueous solution of methylene dichloride 20ml dissolving back with 1M.Remove methylene dichloride after the drying, separate obtaining title compound 0.18g with silicagel column (the dichloromethane solution wash-out of 1% methyl alcohol).Mass spectrum (FAB-MS): 461 (M+1).
Also synthesized following compounds with embodiment 21 identical methods:
5 '-3 '-O-diisobutyl oxygen formyl radical-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-, two n-pentyl oxygen formyl radical-2 '-deoxidations-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-di-n-hexyl oxygen formyl radical-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine.
Embodiment 22 5 '-(L-is valyl)-3 '-O-normal-butyl oxygen formyl radical-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine hydrochloride
Figure A20051004084800281
The positive fourth oxygen of 3 '-O-formyl radical-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine is dissolved in 2mlDMF for 180 milligrams and dissolves; add 10 milligrams of DMAP; 0.5g N-Cbz-L-Xie Ansuan carbonyl ring inner-acid anhydride (making) with reference to U.S. Pat 6479665; reaction mixture slowly is warming up to 50 ℃, react to gas release stop and TLC show react completely till.Solvent removed in vacuo, residue dissolves with methylene dichloride 10ml, and hydrochloric acid and the sodium bicarbonate aqueous solution washing final vacuum with 1M removes the oily matter that desolvates respectively.Oily matter is dissolved in 10ml contains in the methyl alcohol of 1%HCl, add 5 milligrams of Pd/C catalyzer, till stirring feeding hydrogen shows that to TLC reaction is finished.Filter, vacuum concentration adds the 10ml ether and obtains white solid to original volume 1/5th, obtains crystal 0.15 gram after filtration is collected.Mass spectrum (FAB-MS): 460 (M+1).
Embodiment 23 contains the tablet of 3 '-O-(L-is valyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine hydrochloride
Prescription (by 1000): 3 '-O-(L-is valyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine hydrochloride 50g, lactose 300g,, carboxymethylstach sodium 2g, polyvidone (K30) 20g, Magnesium Stearate 0.8g, talcum powder 1.2g.
Method for making: with 3 '-O-(L-is valyl)-L-FMAU hydrochloride, lactose, carboxymethylstach sodium, polyvidone (K30), Magnesium Stearate, talcum powder is crossed 80 mesh sieves respectively, and is standby.3 ' of full dose-O-(L-the is valyl)-L-FMAU hydrochloride of will writing out a prescription then, lactose, carboxymethylstach sodium, polyvidone (K30), the Magnesium Stearate of recipe quantity 50%, talcum powder are crossed 18 mesh sieves with Drygranulatemachine and are granulated so that the addition thorough mixing is even equally; Add remaining Magnesium Stearate, talcum powder, thorough mixing is even, and compressing tablet promptly gets every tablet of tablet that contains 50 milligrams of 3 '-O-(L-is valyl)-L-FMAU hydrochloride.
The external anti-HBV activity experiment of the prodrug of embodiment 24 L-FMAU:
Get the 2.2.15 cell (from the HepG2 cell transfecting, secretion HBsAg, HBeAg and HBV DNA), with DMEM nutrient solution (GIBCO), nutrient solution adds 10% foetal calf serum, 100mg/L penicillin, the 100mg/L Streptomycin sulphate, G418 380mg/L (GIBCO), the 0.3g/L glutaminase transfers pH to 6.8. with 0.6g/L trypsinase the 2.2.15 cell to be dispersed into 3 * 10 with 2.38g/L Hepes 7/ L, every hole 0.1ml use the pastille nutrient solution in 96 orifice plates instead after 2 days, and all testing compounds are diluted to 11,3.7,1.2,0.4 respectively, 0.137 and 0.045 μ M, and each concentration adds 6 holes, establishes simultaneously not contain the medicine control group; Renewed bright pastille nutrient solution totally 4 times in per 3 days, with cytosis after 12 days, the cell conditioned medium liquid that swaps out, with HBV DNA concentration in the HBV DNA of preventive medicine institute of the Shanghai Medical Univ kit detection cell supernatant liquor, calculate inhibiting rate, obtain the 503nhibiting concentration of compound HBV DNA.The cytotoxicity of medicine is measured with mtt assay.The results are shown in the table one:
Table one
Figure A20051004084800291
Illustrate: EC 50The effective concentration 50 of-inhibition HBV-DNA
IC 50-cytotoxicity index, the 503nhibiting concentration of cell growth
The bioavailability of the prodrug of embodiment 25 L-FMAU
The bioavailability of the prodrug of L-FMAU and L-FMAU is measured with the AUC ratio method.
10 of rats are divided into two groups at random, 5 every group, gastric infusion or intravenous injection give the L-FMAU of 50mg/kg or the prodrug of L-FMAU respectively, after administration 0.083,0.25,0.5,0.75,1,2,4,6,8h blood sampling 0.3ml respectively uses the reversed-phase HPLC technology for detection to obtain the Plasma Concentration of L-FMAU, draws Plasma Concentration-time curve of L-FMAU and tries to achieve area under curve AUC.Lower area of blood concentration-time curve (the AUC of L-FMAU behind the drug oral PO) and intravenous injection after the lower area of blood concentration-time curve (AUC of L-FMAU Iv) ratio be the oral administration biaavailability of this medicine.
The concentration of the prodrug of L-FMAU and L-FMAU in blood can be measured with HPLC, measuring method is as follows: blood sample 0.3ml joins in the acetonitrile (2M) of the 1.8ml that is chilled to 4 ℃ in advance after (D4T20mg/ml) mixes with interior the marking of 50ul, vibration shakes up 30s, ultracentrifugation (4500g) 30min again.Take out supernatant liquor, dry up with nitrogen.Residue 75ul dissolved in distilled water is got the 50ulHPLC sample introduction.The HPLC stationary phase adopts C 18Reversed-phase column, moving phase is with the phosphate sodium dihydrogen buffer solution that contains acetonitrile, at 260nm place ultraviolet detection.According to L-FMAU on the HPLC collection of illustrative plates, the prodrug of L-FMAU and interior target calculated by peak area medicine/interior target peak area ratio are tried to achieve drug level on the drug level typical curve.
The concentration standard curve of the 0.5-50ug/ml of all medicines to be measured obtains with standard addition method in the barren rat plasma.
All prodrugs just can't detect in blood behind intravenous injection 5min and show that all prodrugs can both be metabolised to L-FMAU rapidly in blood, all said medicine just can't detect in blood behind oral back 0.75h, and table two has been listed the bioavailability of L-FMAU and its prodrug.
Table two
Figure A20051004084800301

Claims (10)

1. suc as formula compound and the salt thereof shown in (I):
R 1And R 2Can be identical or different, R 1=amino-acid residue, alkoxyl formyl, organic carboxyl acid acyl group, phosphoryl and alkyl;
R 2=H, amino-acid residue, alkoxyl formyl, organic carboxyl acid acyl group, phosphoryl and alkyl.
2. compound as claimed in claim 1 and salt thereof is characterized by described compound and have suc as formula the structure shown in (II):
Figure A2005100408480002C2
R 1=amino-acid residue, alkoxyl formyl, organic carboxyl acid acyl group, phosphoryl and alkyl;
3. compound as claimed in claim 1 and salt thereof is characterized by described compound and have suc as formula the structure shown in (III):
Figure A2005100408480002C3
R 1=amino-acid residue, alkoxyl formyl, organic carboxyl acid acyl group, phosphoryl and alkyl
4. compound as claimed in claim 1 and salt thereof is characterized by described compound and have suc as formula the structure shown in (VI):
Figure A2005100408480003C1
R 1, R 2Be different groups, R 1, R 2Be respectively amino-acid residue separately, alkoxyl formyl, organic carboxyl acid acyl group, phosphoryl and alkyl.
5. compound as claimed in claim 2 is characterized by described compound and is:
3 '-O-(L-is valyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
3 '-O-(L-isoleucyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
3 '-O-(L-alanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
3 '-O-(L-phenylalanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
3 '-O-(L-lysyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
3 '-O-(L-aspartyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
3 '-O-benzoyl-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
3 '-O-ethanoyl-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
The anti-oleoyl-2 ' of 3 '-O--deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
3 '-O-stearyl--2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
The positive fourth oxygen of 3 '-O-acyl group-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
3 '-O-isobutyl oxygen acyl group-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
Positive penta oxygen acyl group-the 2 '-deoxidation-2 ' of 3 '-O--fluoro-5-methyl-β-L-arabinose uridine,
The just own oxygen acyl group-2 ' of 3 '-O--deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine;
6. compound as claimed in claim 3 is characterized by described compound and is:
5 '-3 '-O-two (L-is valyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-two (L-isoleucyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-two (L-phenylalanyl)-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-diacetyl-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-, two anti-oleoyl-2 '-deoxidations-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-, two bay acyl group-2 '-deoxidations-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-di-n-butyl oxygen formyl radical-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-diisobutyl oxygen formyl radical-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-, two n-pentyl oxygen formyl radical-2 '-deoxidations-2 '-fluoro-5-methyl-β-L-arabinose uridine,
5 '-3 '-O-di-n-hexyl oxygen formyl radical-2 '-deoxidation-2 '-fluoro-5-methyl-β-L-arabinose uridine.
7. the application of any described compound in the preparation antiviral among the claim 1-6, described antiviral is anti-hepatitis B virus (HBV) medicine, anti-epstein-barr virus (EB) (EBV) medicine and anti-hepatitis D virus (HDV) medicine.
8. pharmaceutical composition contains the compound described in any one claim 1-6 of significant quantity.
9. the midbody compound that is used for the synthetic described compound of claim 1 that is shown below.
P is blocking group arbitrarily
10. midbody compound as claimed in claim 9; it is characterized by protecting group P and be selected from trityl group trialkylsilanyl and replacement or non-replacement; particularly preferred protecting group has TMS; tertiary butyl dimethylsilyl; the tert-butyl diphenyl silylation, tri isopropyl silane base, trityl group; 4,4 '-dual-methoxy trityl and 4-mono methoxy trityl.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105254695A (en) * 2014-11-10 2016-01-20 南京曼杰生物科技有限公司 Nucleoside phosphoramidate ramification and application thereof
CN114404391A (en) * 2022-02-16 2022-04-29 深圳厚存纳米药业有限公司 Nano particle, preparation method and application thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105254695A (en) * 2014-11-10 2016-01-20 南京曼杰生物科技有限公司 Nucleoside phosphoramidate ramification and application thereof
WO2016074596A1 (en) * 2014-11-10 2016-05-19 南京曼杰生物科技有限公司 Nucleoside phosphoramidate derivative and application thereof
CN105254695B (en) * 2014-11-10 2019-01-18 南京曼杰生物科技有限公司 Nucleoside phosphoramidate derivative and its application
CN114404391A (en) * 2022-02-16 2022-04-29 深圳厚存纳米药业有限公司 Nano particle, preparation method and application thereof

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