CN100364534C - Use of n-substituted-1,5-di deoxy-1,5-imino-d-glucitol compounds for treating hepatitis virus infections - Google Patents
Use of n-substituted-1,5-di deoxy-1,5-imino-d-glucitol compounds for treating hepatitis virus infections Download PDFInfo
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Abstract
Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immunostimulating agents.
Description
The application be that February 12, application number in 1999 are 99804990.5 the applying date, denomination of invention for " N-replace 1,5-dideoxy-1, the purposes of 5-imino group-D-glucitol compounds for treating hepatitis virus infections " the dividing an application of application for a patent for invention.
Related application
The U.S. Provisional Application (application number 60/074,508) that the application requires to submit to on February 12nd, 1998 is a priority.The application still be the application number submitted on February 12nd, 1998 be the part continuation application of 09/023,401 U.S. Patent application.The content of these applications all is incorporated by reference in this text in this application and examines.
Background of invention
Invention field
The present invention relates to be used for the treatment of mammal, the hepatites virus infections among the mankind especially, especially hepatitis b virus infected method and composition.This method comprise that (1) take separately that N-replaces-1,5-dideoxy-1,5-imino group-D-glucitol chemical compound or it is taken with nucleoside antiviral agent, nucleotide antiviral agent, their mixture or immunomodulator/immunostimulant, or (2) take-1 of N-replacement separately, 5-dideoxy-1,5-imino group-D-glucitol chemical compound, or it is taken with nucleoside antiviral agent, nucleotide antiviral agent or their mixture and immunomodulator/immunostimulant.Hepatitis virus resisting agent this be combined in suppress hepatitis virus in the mammalian cell that is subjected to these viral infection duplicate and the secretion aspect demonstrates unexpected effectiveness.
Association area is introduced
Hepatitis virus
(HBV is the acute and chronic hepatopathy that can cause some death HepB) to hepatitis B virus, comprises the pathogenic thing (Joklik of hepatic fibrosis, liver cirrhosis, inflammatory hepatopathy and hepatocarcinoma, Wolfgang K., virusology (Virology), the third edition, Appleton﹠amp; Lange, Norwark, Connecticut, 1998 (ISBN0-8385-9462-X)).Though effective vaccine is arranged, the whole world still has the people more than 300,000,000, promptly 5% of world population, be subjected to this viral chronic infection (Locarnini, S.A. etc., antiviral chemistry and chemotherapy (Antiviral Chemistry﹠amp; Chemotherapy (1996) I (2): 53-64).For having infected viral patient, these vaccines do not have therapeutical effect.In Europe and North America, the population of 0.1-1% is infected.Estimation has 15-20% to develop into liver cirrhosis in infected people or infects other one caused chronic disability cause because of HBV.
In case become liver cirrhosis, M ﹠ M is very high, and patient's survival period is about 5 years, and (advanced drugs discharges comment (Advanced Drug DeliveryReviews (1995) for Blume, H.E. etc.
17: 321-331).Therefore be necessary and be badly in need of to find improved and effective anti-HBV, anti-hepatitis therapy (Locarnini, S.A. etc., antiviral chemistry and chemotherapy (Antiviral Chenistry﹠amp; Chemotherapy (1996) I (2): 53-64).
Other important hepatitis virus as human disease's thing comprises hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, F type hepatitis and G Hepatitis virus (Coates, J.A.V. etc., the comment of experts of therapy patent (Exp.Opin.Ther.Patents (1995)
5(8): 747-756).In addition, also has animal hepatitis virus to species specificity.This comprises for example hepatitis virus of infected duck, marmot and mouse.
1,5-dideoxy-1,5-imino group-D-glucitol chemical compound
1,5-dideoxy-1,5-imino group-D-glucitol chemical compound (is also referred to as the 1-deoxynojirimycin, DNJ) and inhibitor (Saunier etc., the journal of biological chemistry (J.Biol.Chem.) (1982) of the known N-of being of N-alkyl derivative (being called " iminosugar " together) connection oligosaccharide processive enzyme alpha-Glucosidase I and II
257: 14155-14161; Elbcin comments (Ann.Rev.Biochem. (1987) bioid academic year
56: 497-534).As glucalogue, they also have glucose transport, glucosyltransferase and/or the synthetic effectiveness of glycolipid (Newbrun etc., the Oral Biology archives (Arch.OralBiol.) (1983) of inhibition
28: 516-536; Wang etc., tetrahedron wall bulletin (1993)
34: 403-406).They cause developing these chemical compounds to the inhibition activity of glucosidase and develop into antihyperglycemic agents and antiviral agent.For example see PCT international publication WO87/03903 and United States Patent (USP) 4,065,562,4,182,767,4,533,668,4,639,436,4,849,430,4,957,926,5,011,829 and 5,030,638.
Wherein alkyl contains the alpha-glucosidase inhibitors of 3-6 carbon atom, N-alkyl-1 for example, and 5-dideoxy-1,5-imino group-D-glucitol chemical compound has shown to treatment hepatitis B infection effectively (PCT international publication WO95/19172).For example, N-(normal-butyl)-deoxynojirimycin (N-butyl-DNJ; N-(normal-butyl)-1,5-dideoxy-1,5-imino group-D-glucitol) in this respect effectively (institute of NAS reports (Proc.Natl.Acad.Sci.USA) (1994), 91:2235-2239 for Block, T.M.; Ganem, B. chemistry collected works: organic chemistry (Chemtracts:OrganicChemistry) (1994) 7 (2), 106-107).N-butyl-DNJ also Ceng Zuowei anti-HIV-1 medicine tests in the patient of infected by HIV, and known toleration is fine.Another kind of Alpha-glucosidase inhibitor-deoxynojirimycin (DNJ) once was proposed to use (WO93/18763) together as antiviral agent and N-(phosphono acetyl group)-L-aspartic acid (PALA).But imino group-D-glucitol derivant that N-replaces and other antiviral agent be combined to be used for the treatment of hepatites virus infections and not to report before this or advised.By the result who obtains at the marmot animal model that infects hepatitis virus, Block etc. ((1998), nature medical science (Nature Medicine) 4 (5): 610-614) propose to be used in the alpha-glucosidase inhibitors that disturbs particular step in the N linked glycosylation passage of hepatitis virus glycoprotein, N-nonyl DNJ for example is as the glycosylation processing of leading of the therapeutic inserting of hepatitis B virus.
Nucleoside and nucleotide antiviral agent
Reverse transcriptase inhibitors comprises nucleoside and nucleotide analog, is as for example drug development of HIV (human immunodeficiency virus) (HIV) (the pathogenic thing of acquired immune deficiency syndrome (AIDS)) of treatment retrovirus the earliest.Little by little,, find that these chemical compounds can be used for resisting other virus, comprise RNA and DNA viruses by means such as viral examination and chemical modifications.Nucleoside and nucleotide analog are by suppressing to bring into play its antiviral activity for DNA synthetic corresponding D NA and RNA polymerase viral and that RNA viruses works.Because contain multi-form polymerase in the virus, same nucleoside/nucleotide chemical compound can have effect very inequality for different virus.For example, lamivudine (3TC
TM) as if useful for control HBV infection, and azidothymidine AZT (AZT
TM) for almost not effect (Gish, R.G. etc., the drug research comment of experts (Exp.Opin.Invest.Drugs) (1995) 4 (2): 95-115) of this virus.
The toxicity of some nucleoside analog antiviral agent is obvious.For example, because causing some death, the liver failure relevant with medicine end recently for the clinical trial of the nucleoside analog fialuridine (FIAU) that is used for treating chronic hepatitis B.Therefore, still need to be used for the treatment of safer therapeutic regimen (Mutchnick, M.G. etc., the antiviral agent research (Antiviral Research) (1994) of hepatitis B infection and hepatitis
24: 245-257).
Immunomodulator and immunostimulant
Immunomodulator/immunostimulant, for example alpha-interferon and other cytokine once were used to treat the result that HBV catches a cold and obtained getting a good chance of.Regrettably, its response speed is slower than what require.Interferon therapy now is used for the treatment of B-mode by the FDA approval
Other the immune medicine of influence of hepatitis is studied at present.This comprises the salicylaldehyde derivatives such as the (Gish such as tucaresol, levamisole of the thymosin that is used for the treatment of chronic viral hepatitis B (CHB), inosine pranobex, steroid, formation Schiff's base, R.G etc., experimental period medicine comment of experts (Exp.Opin.Invest.Drugs) (1995) 4 (2): 95-115; Coats, J.A.V. etc., therapy patent comment of experts (Exp.Opin.Ther.patents) (1995)
5(8): 747-765).
Brief summary of the invention
As mentioned above, known to the inventor, do not propose before this or open imino group-D-glucitol chemical compound and derivant thereof of using disclosed N-replacement among the application separately, or its hepatitis virus resisting chemical compound with other used. in view of the M ﹠ M of hepatitis B, preferably use two or more antiviral drugs so that the improvement therapy of treatment hepatitis B to be provided.Adopt combination treatment can make the doctor that the patient is used one or more medicines than low dosage, reduced toxicity, this also is desirable.Combination treatment also helps to prevent patient develop immunity to drugs (Wiltink, E.H., medicament weekly, science version (PharmaceutishWeekblads Scientific Edition) (1992) 14 (4A): 268-274).Improved effectiveness combination combines and will provide improved greatly medication effect with relative low toxicity and Drug resistance.
The present invention finds unexpectedly, uses-1 of N-replacement disclosed herein, 5-dideoxy-1, and 5-imino group-D-glucitol chemical compound is effective for the treatment hepatites virus infections.In addition, these chemical compounds and nucleoside or nucleotide antiviral compound or their mixture and/or immunomodulator/immunostimulant are used in combination, compare with total antiviral activity of each independent chemical compound expection, produce bigger hepatitis virus resisting unexpectedly and render a service.This is because the different actuation gears of the dissimilar medicines that use, still since some other biological phenomenon it be not immediately clear.
Therefore, first aspect present invention provides a kind of method for the treatment of hepatites virus infections in the mammal, this method comprises-1 of the N-replacement of at least a formula I of described administration antiviral effective dose, 5-dideoxy-1, and 5-imino group-D-glucitol chemical compound or its pharmaceutically useful salt:
Wherein R is selected from the straight chained alkyl that chain length is C7-C20, and backbone chain length is the branched alkyl of C3-C20, alkoxyalkyl, and aralkyl and cycloalkyl-alkyl, W wherein, X, Y and Z are selected from hydrogen, alkanoyl, aroyl and trifluoro alkanoyl independently of one another.
In second aspect, the invention provides a kind of method for the treatment of hepatites virus infections in the mammal, this method comprises a kind of antiviral composition of described administration, contain in the described compositions that the N-of at least a above-mentioned formula I of antiviral effective dose replaces-1,5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof.
In the third aspect, the invention provides a kind of method for the treatment of hepatites virus infections in the mammal, this method comprises a kind of antiviral composition of described administration, said composition contain mainly that the N-of at least a above-mentioned formula I of antiviral effective dose replaces-1,5-dideoxy-1,5-imino group-D-glucitol chemical compound or its pharmaceutically useful salt.
In fourth aspect, the invention provides a kind of method for the treatment of hepatites virus infections in the mammal, this method mainly comprises-1 of the N-replacement of at least a above-mentioned formula I of described administration antiviral effective dose, 5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof.
Aspect the 5th, the invention provides a kind of method for the treatment of hepatites virus infections in the mammal, this method mainly comprises the antiviral compound to described administration antiviral effective dose, this chemical compound contain mainly that the N-of at least a above-mentioned formula I replaces-1,5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof.
Aspect the 6th, the invention provides a kind of method for the treatment of hepatites virus infections in the mammal, this method mainly comprises-1 of the N-replacement of at least a above-mentioned formula I of the described administration first umber amount, 5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof, antiviral compound with the second umber amount, this antiviral compound is selected from the nucleoside antiviral compound, the nucleotide antiviral compound, immunomodulator, immunostimulant and their mixture, wherein the described chemical compound of first amount and second amount constitutes the described chemical compound of hepatitis virus resisting effective dose together.
On the other hand, the invention provides a kind of method hepatitis b virus infected in the mammal for the treatment of, this method comprise that the N-to the about 0.1-100mg/kg/ of described administration days at least a above-mentioned formula I replaces-1,5-dideoxy-1, a kind of chemical compound that is selected from nucleoside antiviral compound, nucleotide antiviral compound and composition thereof in 5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof and about 0.1-500mg/ people/sky.
On the other hand, the invention provides a kind of hepatitis b virus infected method for the treatment of human patients, this method comprise that N-that described patient was used about 0.1-100mg/kg/ days replaces-1,5-dideoxy-1, (-)-2 '-deoxidation-the 3 '-sulfo-Cytidine-5 in 5-imino group-D-glucitol chemical compound and about 0.1-500mg/ people/sky '-triphosphoric acid, described glucitol chemical compound is to be selected from N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol or its officinal salt, N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol four butyrates or its officinal salt and their mixture.
On the other hand, the invention provides a kind of method for the treatment of hepatites virus infections in the mammal, this method comprises-1 of the N-replacement of at least a above-mentioned formula I of described administration antiviral effective dose, 5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof is not used the antiviral composition that contains nucleoside, nucleotide, immunomodulator or immunostimulant basically.
On the other hand, the invention provides a kind of method for the treatment of hepatites virus infections in the mammal, this method comprises-1 of the N-replacement of at least a above-mentioned formula I of described administration antiviral effective dose, 5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof is not used other antiviral compound except that formula I chemical compound basically.
On the other hand, the invention provides a kind of pharmaceutical composition, contain wherein that the N-of at least a above-mentioned formula I of antiviral effective dose replaces-1,5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof, and a kind of pharmaceutically useful carrier, excipient or diluent.
On the other hand, the invention provides a kind of pharmaceutical composition, contain mainly wherein that the N-of at least a above-mentioned formula I of antiviral effective dose replaces-1,5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof, and a kind of pharmaceutically useful carrier, diluent or excipient.
On the other hand, the invention provides a kind of pharmaceutical composition, contain wherein that the N-of at least a above-mentioned formula I of antiviral effective dose replaces-1,5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof and pharmaceutically useful carrier, diluent or excipient are substantially free of nucleoside, nucleotide, immunomodulator or immunostimulant.
On the other hand, the invention provides a kind of pharmaceutical composition, contain wherein that the N-of at least a above-mentioned formula I of antiviral effective dose replaces-1,5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof and pharmaceutically useful carrier, diluent or excipient are substantially free of other antiviral compound outside the formula I chemical compound.
On the other hand, the invention provides a kind of compositions, contain wherein that the N-of at least a above-mentioned formula I replaces-1,5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof, and a kind of antiviral compound that is selected from nucleoside antiviral compound, nucleotide antiviral compound, immunomodulator, immunostimulant and composition thereof.
On the other hand, the invention provides a kind of pharmaceutical composition, contain wherein that the N-of at least a above-mentioned formula I of first amount replaces-1,5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof, a kind of antiviral compound that is selected from nucleoside antiviral compound, nucleotide antiviral compound, immunomodulator, immunostimulant and composition thereof of second amount, and pharmaceutically useful carrier, diluent or excipient, wherein the chemical compound of first amount and second amount constitutes the chemical compound of antiviral effective dose together.
Aspect another, the invention provides and be used for the treatment of pharmaceutical composition hepatitis b virus infected in the mammal, contain wherein that the N-of at least a above-mentioned formula I of 0.1-100mg that has an appointment replaces-1,5-dideoxy-1,5-imino group-D-glucitol compound or pharmaceutically acceptable salt thereof, about 0.1-500mg is selected from a kind of chemical compound of nucleoside antiviral compound, nucleotide antiviral compound or its mixture, and pharmaceutically useful carrier, diluent or excipient.
On the other hand, the invention provides a kind of hepatitis b virus infected pharmaceutical composition that is used for the treatment of human patients, contain wherein that the N-of the 0.1-100mg that has an appointment replaces-1,5-dideoxy-1,5-imino group-D-glucitol chemical compound, this chemical compound are to be selected from N-(n-nonyl)-1,5-dideoxy-1,-1 of 5-imino group-D-glucitol or its officinal salt, N-(n-nonyl) N-replacement, 5-dideoxy-1,5-imino group-D-glucitol four butyrates or its officinal salt and their mixture; (-)-2 '-deoxidation-3 '-sulfo-Cytidine-5 with about 0.1-500mg '-triphosphoric acid; And pharmaceutically useful carrier, diluent or excipient.
On the other hand, the invention provides a kind of salt, contain wherein that the N-of above-mentioned formula I replaces-1,5-dideoxy-1,5-imino group-D-glucitol chemical compound, and be selected from nucleoside with acidic group and a kind of chemical compound of nucleotide.
Again on the one hand, the salt that the invention provides a kind of method and form thus, described method comprises
Make N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol and (-)-2 '-deoxidation-3 '-sulfo-Cytidine-5 '-triphosphoric acid reacts under salt-forming condition.
By detailed description provided below and accompanying drawing, other scope of application of the present invention will become apparent.Yet be to be understood that, though following detailed description and embodiment have represented the preferred embodiments of the invention, but just the mode with the example explanation provides, because according to these detailed descriptions, those skilled in the art obviously can make various changes and modification within the spirit and scope of the present invention.
Summary of drawings
By detailed description below in conjunction with accompanying drawing, will be better understood above and other objects of the present invention, characteristics and superiority, accompanying drawing and detailed description only for the example explanation, are not limitations of the present invention all, wherein:
Fig. 1 represents independent (-)-2 '-deoxidation-3 '-sulfo-Cytidine-5 '-external anti-hepatitis B virus activity when triphosphoric acid (3TC) and its combine with N-nonyl-DNJ.
Fig. 2 represents the relation of the dosage of the N-nonyl-DNJ plasma concentration of each animal among the embodiment 5 and N-nonyl-DNJ, takes a sample during administration.With specific alphabetical indicator animal, on dose value, added random noise in a small amount, so that can distinguish eclipsed value.
Fig. 3 represents that Log (IPDNA+10) is to the variation with dosage of the slope of all numbers mapping.Every kind of animal is used different letters.Fit line is to derive from four parameter logarithmic models.The parameter and the proximate standard error thereof of matched curve have been marked on the figure.
Detailed Description Of The Invention
Provide following detailed description to implement the present invention to help those skilled in the art.Even so, this detailed description should not be considered to limit the present invention inadequately, because those of ordinary skill in the art can change and revises under condit without departing from the spirit and scope of the present invention embodiment discussed here.
Each patent document of quoting herein and other list of references comprise the literature content of quoting in the original reference document, all are incorporated by reference in this text in this application and examine.
The inventor finds that N-replaces-l, and 5-dideoxy-1,5-imino group-D-glucitol chemical compound are effective for the treatment hepatites virus infections when using separately.The inventor also finds, with N-replace-1,5-dideoxy-1, the nucleoside or the nucleotide of 5-imino group-D-glucitol chemical compound and hepatitis virus resisting, with and/or immunomodulator/immunostimulant be used in combination, also effective to treating hepatites virus infections.Have some evidences to show, some combination system hepatitis virus of being in prison is duplicated the aspect ratio to be used in combination individualized compound desired more effective.
Therefore the invention provides-1 of independent use N-replacement, 5-dideoxy-1,5-imino group-D-glucitol chemical compound or itself and a kind of anti-viral nucleoside, anti-viral nucleoside acid, their mixture and/or immunomodulator or immunostimulant be used in combination and treat hepatites virus infections in the mankind, other mammal and the cell, especially hepatitis b virus infected pharmaceutical composition and method.-1 of N-replacement, 5-dideoxy-1,5-imino group-D-glucitol chemical compound has basic nitrogen atom, and can use with the form of officinal salt.What can be used for nucleoside among the present invention and nucleotide and be replacing floats cool or pyrimidine heterocyclic, in the situation of purine, in formula II-VI in the 9-position further by R
1Replace, and in the situation of pyrimidine, then on the 1-position further by R
1Replace.Can be used for immunomodulator of the present invention and immunostimulant and comprise the chemical compound that can excite effective immune response aspect control or elimination virus or other infectious agent.The limiting examples of this para-immunity modulator and immunostimulant comprises cytokine, peptide agonists, steroid and habitual medicine such as levamisole.Drug regimen of the present invention can be with independence
Pharmaceutically acceptable dosage form is taken or simultaneously or sequentially containing the dosage form of more than one medicines, or form a kind of and multiple pharmaceutical preparation of all kinds takes, and offers cell or human or other mammalian subject.These drug regimens have constituted the component of antiviral effective dose.
As used in this article, term " antiviral effective dose " be meant that the independent N-of effective treatment hepatites virus infections replaces-1,5-dideoxy-1, the amount of 5-imino group-D-glucitol chemical compound, or (1) N-replace-1,5-dideoxy-1,5-imino group-D-glucitol chemical compound and antiviral nucleoside, antiviral nucleotide, the mixture of anti-viral nucleoside and anti-viral nucleoside acid, or the combined amount of immunomodulator/immunostimulant (or its mixture), or (2) N-replace-1,5-dideoxy-1,5-imino group-D-glucitol chemical compound and anti-viral nucleoside, anti-viral nucleoside acid or their mixture, and the combined amount of immunomodulator/immunostimulant (or its mixture).The antiviral efficacy of combinations thereof may with virus to duplicate and assemble relevant many different phenomenons relevant.This comprises that the DNA that for example blocks hepatitis virus is synthetic; Transcribing of blocking virus; The assembling of blocking virus; Blocking-up discharges or secretes virion from infected cell: block or change virus protein function, comprise the function of virus envelope protein; With and/or make jejune or the non-functional virion.Total effect is to suppress virus replication and infect other cell, thereby suppresses patient infection's development.
-1 of N-replacement, 5-dideoxy-1,5-imino group-D-glucitol chemical compound
Can be used for-1 of N-replacement of the present invention, 5-dideoxy-1,5-imino group-D-glucitol chemical compound is represented with following structural formula I:
Wherein R is selected from chain length C7-C20, preferred C8-C20, more preferably C8-C16, more preferably C3-C12, the more preferably C8-C10 straight chained alkyl of C9 most preferably; Backbone chain length is C3-C20, preferred C3-C16, more preferably C3-C14, more preferably C4-C12, more preferably C6-C12, the branched alkyl of C8-C10 most preferably; Alkoxyalkyl; Aralkyl; And cycloalkyl-alkyl.W, X, Y and Z are selected from hydrogen, alkanoyl, aroyl and trifluoro alkanoyl independently of one another.
Short commentary " main chain " is meant in formula I chemical compound the longest the linking to each other or the carbon atom chain of adjacency of being set out by the branched alkyl and the junction point of nitrogen-atoms.
Term " alkoxyl " comprises the oxy radical of straight or branched, has 1 moieties to about 10 carbon atoms in the group.Can be used for alkoxy-alkyl group of the present invention (" alkyl ether " or " oxa-" derivant) and can be C3-C20, preferred C4-C18, more preferably C5-C16, more preferably C6-C12, C8-C12 most preferably, wherein have 1-5 non-terminal carbon, preferred 1-3 non-terminal carbon, more preferably 1-2 non-terminal carbon, most preferably 1 non-terminal carbon can be replaced by oxo.
Term " aryl " when using in independent use or with other moiety combinations, is meant the carbocyclic aromatic system that contains one, two or three ring, and wherein these rings can be bound up with hang, perhaps can condense.Term " aryl " comprises aromatic group, as phenyl, naphthyl, tetrahydro naphthyl, indyl and xenyl.
Term " aralkyl " comprises the alkyl group that aryl replaces.For example benzyl, diphenyl methyl, trityl group, phenethyl and diphenyl-ethyl.
Term " cycloalkyl " includes the 3 saturated carbon ring groups to about 12 carbon atoms.Preferred cycloalkyl is that 3 " low-grade cycloalkyls " to about 8 carbon atoms are arranged.This class examples of groups comprises cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl." cycloalkyl-alkyl " is meant the alkyl that is substituted by cycloalkyl.
The group that the residue behind the hydroxyl forms is removed in term " acyl group " representative from organic acid.The example of this carboxyl groups comprises alkanoyl and aroyl." alkanoyl " is meant the chain alkyl carbonyl of side chain or straight chain, and its chain length is C1-C20, preferred C1-C10, more preferably C1-C5; " aroyl " is meant aryl carbonyl; " trifluoro alkanoyl " is meant the alkanoyl that contains three letter fluoro substituents.The example of these alkanoyls comprises formoxyl, acetyl group, propiono, bytyry, isobutyryl, valeryl, isovaleryl, valeryl, caproyl and the group that is formed by succinic acid, hydroxyacetic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucose aldose, maleic acid, fumaric acid, acetone acid, mandelic acid, pantothenic acid, beta-hydroxy-butanoic acid, galactosaccharic acid and galacturonic acid.
When mentioning when can be used for iminosugar of the present invention, " alkyl " speech that uses with other moiety combinations be meant contain 1 to about 20 carbon atoms, preferred 1 to about 16 carbon atoms, more preferably from about 2-12 carbon atom, the straight or branched alkyl of 3-10 carbon atom most preferably from about.
Term " alkenyl " comprises having " suitable " and negation formula orientation, in other words, and the group of " E " and " Z " type orientation.Term " alkynyl " comprise wherein have at least one carbon-to-carbon ginseng chain 2 to about 20 carbon atoms, preferred 2 straight or branched groups to about 12 carbon atoms.More preferably alkynyl is that 2 " low-grade alkynyls " to about 6 carbon atoms are arranged.The example of alkynyl comprises propargyl, 1-propinyl, 2-propynyl, ethyl acetylene base, 2-butyne base and 1-pentynyl.
Term " cycloalkyl-alkyl " comprises the alkyl that is substituted by cycloalkyl.Preferred cycloalkyl-alkyl group is C4 to C20; Preferred cycloalkyl-alkyl group is C8 to C14." low-grade cycloalkyl alkyl " comprises the low alkyl group that is replaced by low-grade cycloalkyl as defined above.These examples of groups comprise cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl.
The present invention includes any tautomeric form of formula I chemical compound.The present invention also comprises the formula I chemical compound with one or more asymmetric carbon atoms.Those skilled in the art know.The iminosugar that those have asymmetric carbon atom of the present invention can exist with the form of diastereomeric, racemic or optically-active.It is within the scope of the present invention that all these forms all is considered.More particularly, the present invention includes enantiomer, diastereomer, racemic mixture and their other mixture.
Available representational N-replacement-imino group-D-glucitol chemical compound in the present invention includes but not limited to:
N-(n-heptyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-octyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(positive decyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-undecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(dodecyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-tridecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-tetradecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(Pentadecane base)-1,5-dideoxy-1,5-imino group-D-grape sugar alcohol;
N-(n-hexadecyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-heptadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-octadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(AI3-36122 base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(AI3-28404 base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-heptyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-octyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(positive decyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-undecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(dodecyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-tridecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-tetradecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(Pentadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-hexadecyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-heptadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-octadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(AI3-36122 base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(AI3-28404 base)-1,5-dideoxy-1,5-imino group-D-glucitol four butyrates;
N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(5-methyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(3-propyl group hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(1-amyl group amyl group hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(1-butyl butyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(7-Methyl Octyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(8-methyl nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(9-methyl decyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(10-methyl undecyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(6-cyclohexyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(4-cyclohexyl butyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(2-cyclohexyl ethyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(1-cyclohexyl methyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(1-phenyl methyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(3-phenyl propyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(3-(4-methyl)-phenyl propyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(6-phenyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(5-methyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(3-propyl group hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(1-amyl group amyl group hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(1-butyl butyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(7-Methyl Octyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(8-methyl nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(9-methyl decyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(10-methyl undecyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(6-cyclohexyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(4-cyclohexyl butyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(2-cyclohexyl ethyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(1-cyclohexyl methyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(1-phenyl methyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(3-phenyl propyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(3-(4-methyl) phenyl propyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(6-phenyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(the positive decyl of 7-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(the positive decyl of 7-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(the positive decyl of 7-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol, tetracetate;
N-(the positive decyl of 3-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(the positive decyl of 9-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(7-oxa-n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(3-oxa-n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol; Tetracetate;
N-(3-oxa-n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol; With
N-(7,10,13-trioxa n-tetradecane base)-1,5-dideoxy-1,5-imino group-D-glucitol.
Preferred chemical compound is N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol and N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol four butyrates.
Be applicable to imino group-D-glucitol chemical compound that N-of the present invention replaces, comprise its prodrug, can prepare with method well known in the art.For example, United States Patent (USP) 5,144,037 embodiment 13 discloses the method for a kind of N-of preparation nonyl DNJ.At United States Patent (USP) 4,806, go in 650 the 4th hurdle 62, discloses the preparation method of various alkoxide compounds (that is, with alkoxyl substituted alkyl chain).United States Patent (USP) 4,260,622 disclose the preparation method of chemical compound lot.Imino group-D-glucitol the chemical compound that replaces with N-and other relevant document of the preparation of prodrug comprise United States Patent (USP) 4,182,767,4,260,622,4,611,058,4,639,436 and 5,003,072,5,411,970 and 5,151,519; PCT international publication WO95/19172; And Tan etc. (1991), journal of biological chemistry (Journal of BiologicalChemistry
266(22); 14504-14510; The document of wherein quoting.Tan etc. (1994) are at glycobiology (Glycobiology)
4(2): disclose among the 141-149 oxygen is incorporated into method in the alkyl side chain, (1994) such as van den Broek are at Dutch chemical paper collection (Recl.Trav.Chim.Pays-Bas)
113: the preparation method that discloses the DNJ chemical compound that contains ether oxygen among the 107-116.
Listed nonrestrictive example preparation method among the embodiment 1 and 2 below.
In treatment during hepatites virus infections, can be individually or the salt form that forms to derive in combination from mineral acid or organic acid use that N-of the present invention replaces-1,5-dideoxy-1,5-imino group-D-glucitol chemical compound.These salt include but not limited to following salt: acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphorate, camsilate, digluconate, cyclopentane propionate, lauryl sulfate, esilate, gluceptate, glycerophosphate, Hemisulphate, enanthate, caproate, fumarate, hydrochlorate, hydrobromate, the oxygen iodate, the 2-isethionate, lactate, maleate, mesylate, nicotinate, the 2-naphthalene sulfonate, oxalates, palmitate, pectinic acid salt, persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, tartrate, rhodanate, toluene fulfonate, mesylate and hendecane hydrochlorate.
Nitrogenous basic group can be with for example following reagent be quaternized: elementary alkyl halide, as methyl, ethyl, propyl group and butyl chloride, bromide and iodide; Sulphuric acid dialkyl, for example dimethyl sulfate, diethylester, dibutyl ester and diamyl ester; Long-chain halogenide is as decyl, lauryl, myristyl and stearyl chlorination thing, bromide and iodide; Aralkyl halide is as benzyl and phenethyl bromination thing and other.Obtain water solublity, oil-soluble thus as required and maybe can disperse product.These salt are by combining formation with alkali compounds with needed acid.
Nucleoside and nucleotide
Can be used for nucleoside of the present invention and nucleotide is purine (II) alkali cpd or pyrimidine (III) alkali cpd, or its analog for example compound IV or V.
Purine and pyrimidine compound position encoded as shown in structure I I and III.R
1Can be selected from hydroxy alkyl, hydroxyl alkenyl, carboxyalkyl, carboxyl alkenyl, alkylthio, alkyl-thio-alkyl, alkoxyalkyl, alkoxy alkenyl, heterocycle, heterocycle-alkyl, hydroxy alkyl alkoxyalkyl, alkoxyalkyl alkoxyalkyl and cycloalkyl-alkyl.Purine compound can further be substituted 1,2,3,6,7 or 8 of purine heterocycle, and pyrimidine compound can be substituted 2,3,4,5 or 6 of pyrimidine heterocyclic.These substituent groups can be selected from hydroxyl, alkoxyl, halogen, thiol, amino, carboxyl, mono-substituted amino, dibasic amino and alkyl.
Only be applicable to formula II of the present invention, III, IV, V and VI structure to give a definition.When mentioning when can be used for purine of the present invention and pyrimidine, the term " alkyl " that uses with other moiety combinations is meant and contains 1-8 carbon atom, preferably contains the straight or branched alkyl of 1-4 carbon atom.When using with another moiety combinations, term " alkenyl " is meant 1 or the straight or branched alkyl of a plurality of pairs of keys, contains 2-8 the carbon atom of having an appointment, and preferably contains 1-4 carbon atom.When mentioning when can be used for purine of the present invention and pyrimidine, separately the term " alkyl " that uses be meant contain 6-14 carbon atom, preferably contain 7-12 carbon atom, most preferably contain the straight or branched alkyl of 8-11 carbon atom.Use separately or be meant phenyl, naphthyl or indenyl rings, can randomly be selected from alkyl, alkoxyl, halogen, hydroxyl or nitro and replace by one or more with term " aryl " that another moiety combinations is used." alkanoyl " is meant the alkyl-carbonyl of side chain or straight chain, and its chain length is C1 to C20, preferred C2 to C14, more preferably C4 to C10; " aroyl " is meant aryl carbonyl; " trifluoro alkanoyl " is meant the alkyl that contains three fluoro substituents." halogen " is meant fluorine, chlorine, bromine or iodine." thiol " refers to that the sulfur that replaced by hydrogen (SH)." amino " is meant and is with dihydro nitrogen; " mono-substituted amino " and " dibasic amino " is meant further independently by the amino of one or more alkyl or aralkyl replacement." hydroxyalkyl " is meant the alkyl that is replaced by one or more hydroxyls; " hydrocarbyl chain thiazolinyl " refers to the alkenyl that replaced by one or more hydroxyls; " alkylthio " is meant the alkyl that is replaced by one or more thiol (SH); " alkoxyalkyl " refers to by the alkyl of one or more alkane ether replacement; " alkoxy alkenyl " refers to by the alkenyl of one or more alkane ether group replacement; " hydroxyalkyl alkoxyalkyl " is meant the alkoxyalkyl that is replaced by hydroxyalkyl; " alkoxyalkyl-alkoxyalkyl " is meant the alkoxyalkyl that the alkoxy alkyl replaces; " cycloalkyl-alkyl " refers to the alkyl that is substituted by cycloalkyl.Term " heterocycle " independent or that be used in combination is meant saturated or the undersaturated 5 or 6 yuan of rings of part that contain one or more oxygen, nitrogen and/or sulfur heteroatom.This heterocycle can further be replaced by one to four substituent group, and these substituent groups can be hydroxyl, hydroxyalkyl, thiol, alkoxyl, azido, nitro, halogen atom, amino, mono-substituted amino or dibasic amino independently.The Heterocyclylalkyl representative is one or more hydrogen atom substituted or the displaced alkyl of unsubstituted heterocycle wherein.
Also comprise the substituent tautomer on the The compounds of this invention.The limiting examples of these tautomers is ketone/enol change allosomes, imino group/amino tautomer, the amino tautomer that the imino group that N-replaces/N-replaces, thiol/thiocarbonyl tautomer, and encircle a chain isomer, for example 5 and 6 yuan contain oxygen, nitrogen, sulfur or contain oxygen and the thia ring, and contain substituent heterocycle in hetero atom α position.Particularly including the enantiomer that also has chemical compound described herein and diastereomer and racemoid and isomer mixture in the present invention.
Can be used for typical nucleoside of the present invention and nucleotide compound includes but not limited to:
(+)-suitable-5-fluoro-1-[2-(methylol)-[1,3-oxathiolane-5-yl] cytosine;
(-)-2 '-deoxidation-3 '-sulfo-Cytidine-5 '-triphosphoric acid (3TC);
(-)-suitable-5-fluoro-1-[2-(methylol)-[1,3-oxathiolane-5-yl] cytosine (FTC);
(-)-2 ', 3 '-dideoxy-3 '-sulfo-cytidine [(-)-SddC];
1-(2 '-deoxidation-2 '-fluoro-beta-D-arabinofuranosyl base)-5-iodo cytosine (FIAC);
1-(2 '-deoxidation-2 '-fluoro-beta-D-arabinofuranosyl base)-5-iodo cytosine triphosphoric acid (FIACTP);
1-(2 '-deoxidation-2 '-fluoro-beta-D-arabinofuranosyl base)-methyl uracil (FMAU);
1-β-D-ribofuranosyl-1,2,4-triazole-3-Methanamide;
2 ', 3 '-dideoxy-3 '-fluoro-5-methyldeoxycytidine (FddMeCyt);
2 ', 3 '-dideoxy-3 '-chloro-5-methyldeoxycytidine (ClddMeCyt);
2 ', 3 '-dideoxy-3 '-amino-5-methyldeoxycytidine (AddMeCyt);
2 ', 3 '-dideoxy-3 '-fluoro-5-methylcytidine (FddMeCyt);
2 ', 3 '-dideoxy-3 '-chloro-5-methylcytidine (ClddMeCyt);
2 ', 3 '-dideoxy-3 '-amino-5-methylcytidine (AddMeCyt);
2 ', 3 '-dideoxy-3 '-fluorothymidine (FddThd);
2 ', 3 '-dideoxy-β-L-5-fluorine cytidine (β-L-FddC);
2 ', 3 '-dideoxy-β-L-5-sulfo-cytidine;
2 ', 3 '-dideoxy-β-L-5-cytidine (β-L-ddC);
9-(1,3-dihydroxy-2-propoxyl group methyl) guanine;
2 '-deoxidation-3 '-thia-5-flurocytosine;
3 '-amino-5-methyldeoxycytidine (AddMeCyt);
2-amino-1,9-[(2-methylol-1-(methylol) ethyoxyl] methyl]-6H-purine-6-one (gancyclovir);
2-[2-(2-amino-9H-purine-9-yl) ethyl]-1, ammediol diacetate esters (famciclovir);
2-amino-1,9-dihydro-9-[(2-hydroxyl-oxethyl) methyl] 6H-purine-6-one (acyclovir);
9-(4-hydroxyl-3-methylol-Ding-1-yl) guanine (penciclovir);
9-(4-hydroxyl-3-methylol-Ding-1-yl)-6-deoxy-guanine, diacetate esters (famciclovir);
3 '-azido-3 '-deoxyribosylthymine (AZT);
3 '-chloro-5-methyldeoxycytidine (ClddMeCyt);
9-(2-phosphoryl methoxy base ethyl)-2 ', 6 '-diaminopurine-2 ', 3 '-dideoxy ribonucleotide;
9-(2-phosphoryl methoxy base ethyl) adenine (PMEA);
Triphosphoric acid acyclovir (ACVTP);
D-carbocyclic ring-2 '-deoxyguanosine (CdG);
Zalcitabine;
Dideoxy cytosine (ddC);
Dideoxy guanine (ddG);
Didanosine (ddI);
E-5-(2-bromo vinyl)-2 '-deoxyuridine triphosphate;
Fluorine arabinofuranosyl base iodouracil;
1-(2 '-deoxidation-2 '-fluoro-1-β-D-arabinofuranosyl base)-5-iodouracil (FIAU);
Videx;
9-β-D-arabinofuranosyl base-9H-purine-6-amine-hydrate (Ara-A);
9-β-D-arabinofuranosyl base-9H-purine-6-amine-5 '-phosphoric acid-hydrate (Ara-AMP);
2-deoxidation-3 '-thia-5-fluorine cytidine;
2 ', 3 '-dideoxy guanine; With
2 ', 3 '-dideoxy guanosine.
Preferred chemical compound is (-)-2 '-deoxidation-3 '-sulfo-Cytidine-5 '-triphosphoric acid (3TC).
The synthetic method that is applicable to nucleoside of the present invention and nucleotide is well-known to those skilled in the art equally, for example is disclosed in the method in the following document: Polish Biochemical Journal (ActaBiochim.Pol.)
43, 25-36 (1996); Sweden's nucleoside and nucleotide
15, 361-378 (1996); Synthetic (Synthesis)
12, 1465-1479 (1995); Carbohydrate chemistry (Carbohyd.Chem.
27, 242-276 (1995); The chemistry of nucleoside and nucleotide (Chem.Nucleosides Nucleotides)
3, 421-535 (1994); Comment (Ann.Reports in Med.Chem.) medical chemistry year, AcademicPress; And experimental period medicine comment of experts (Exp.Opin.Invest.Drugs)
4, 95-115 (1995).
The chemical reaction of narrating in the above-cited document generally is disclosed to preparing using the most widely of The compounds of this invention according to them.Can respond once in a while and not resemble the described every kind of chemical compound that comprises in the chemical compound scope disclosed by the invention that is applicable to like that.Those skilled in the art are the identification chemical compound that this thing happens easily.In all this situations; or this reaction routine that can use those skilled in the art to understand is revised successfully and is carried out; for example to disturb the group due care, change over other conventional reagent, reaction condition is done customary revise etc., or can use other reaction disclosed herein or popular response to prepare corresponding The compounds of this invention.In ownership Preparation Method, starting material all is known substance or is prepared by known starting material easily.
Though use nucleoside analog itself as antiviral agent usually, nucleotide (phosphoric acid nucleoside) must be changed into nucleoside so that help them to pass cell membrane sometimes.A kind of example of nucleotide of the chemical modification that can enter cell is S-1-3-hydroxyl-2-phosphoryl methoxy base propyl group cytosine (HPMPC, Gilead Science).
Of the present invention itself is that sour nucleoside and nucleotide compound can form salt.The example comprises the salt that forms with alkali metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium), or with the salt of organic base or basic quaternary ammonium salt formation.
Immunomodulator and immunostimulant
The a lot of immunomodulators and the immunostimulant that can be used for the inventive method are the commercial goods now.Listed the list of these chemical compounds in the following table 1.
Table 1
AA-2G
Adamantyl amide dipeptides
Adenosine deamination acyl, Enzon
adjuvant，Alliance
adjuvants，Ribi
adjuvants，Vaxcel
Adjuvax
agelasphin-11
AIDS thcrapy，Chiron
algal glucan，SRI
a1gamulin，Anutech
Anginlyc
Antibacterial agent, Yeda
Anticort
Anti-gastrin-17 immunogen, Ap
The antigen delivery systme, Vac
Antigen preparation, IDBC
Anti-GnRH immunogen, Aphton
Antiherpin
Arbidol
Aviron
azarole
Bay-q-8939
Bay-r-1005
BCH-1393
Betafectin
Biostim
BL-001
BL-009
Broncostat
Cantastim
CDRI-84-246
Cefodizime
CFI, ICOS
The CMV peptide, City of Hope
CN-5888
The release of cytokines agent, St
DHEAS，Paradigm
DISC TA-HSV
J07B
I01A
I01Z
Ditiocarb Sodium
ECA-10-142
ELS-1
Endotoxin, Novartis
FCE-20696
FCE-24089
FCE-24578
The FLT-3 part, Immunex
FR-900483
FR-900494
FR-901235
FTS-Zn
G-protein, Cadus
gludaPcin
Glutaurine
glyeophosphopeptical
GM-2
GM-53
GMDP
The somatomedin vaccine, EntreM
H-BIG，NABI
H-CIG，NABI
HAB-439
Helicobacter pylori vaccine,
The herpes specific immune factor
The HIV preparation, United Biomcd
HyperGAM+CF
ImmuMax
Immun BCG
Immunotherapy, Connective
Immunomodulator, Evans
Immunomodulator, Novacell
imreg-1
imreg-2
Indomune
Inosine pranobex
Interferon, Dong-A (alpha2)
Interferon, Genentech (gamma)
Interferon, Novartis (alpha)
Interleukin-15, Immunex
Interleukin-1 6, Research Cor
ISCAR-1
J005X
L-644257
Welkstoff. acid
LipoTber
LK-409
LK-410
LP-2307
LT(R1926)
LW-50020
MAF，Shionogi
MDP derivatives，Merck
Between-enkephalin, TNl
Methylfuran base butyrolactone
MIMP
Mirimostim
The mixed cell vaccine, Tem
MM-1
moniliastat
MPLA，Ribi
MS-705
English Latin ester
English Latin ester, Vacsyn
The muramyldipeptide derivant
The muramyl peptide derivant
myelopid
N-563
NACOS-6
NH-765
NISV，Proteus
NPT-16416
NT-002
PA-485
PEFA-814
Peptide, Scios
Peptidoglycan, Pliva
Perthon，Advanced Plant
PGM derivative，Pliva
Pharmaprojects No.1099
Pharmaprojects No.1426
Pharmaprojects No.1549
Pharmaprojects No.1585
Pharmaprojects No.1607
Pharmaprojects No.1710
Pharmaprojects No.1779
Pharmaprojects No.2002
Pharmaprojects No.2060
Pharmaprojects No.2795
Pharmaprojects No.3088
Pharmaprojects No.3111
Pharmaprojects No.3345
Pharmaprojects No.3467
Pharmaprojects No.3668
Pharmaprojects No.3998
Pharmaprojects No.3999
Pharmaprojects No.4089
Pharmaprojects No.4188
Pharmaprojects No.4451
Pharmaprojects No.4500
Pharmaprojects No.4689
Pharmaprojects No.4833
Pharmaprojects No.494
Pharmaprojects No.5217
Pharmaprojects No.530
Axil
Pimelautide
Pinafide
PMD-589
Podophyllotoxin, Conpharm
POL-509
poly-ICLC
poly-ICLC，Yamasa Shoyu
PolyA-PolyU
Polysaccharide A
Protein A, Berlox Biosciencc
PS34WO
Pseudomonas MAbs, Teijin
Psomaglobin
PTL-78419
Pyrexol
pyriferone
Retrogen
Retropep
RG-003
Rhinostat
Rifamexil (rifamaxil)
RM-06
Rollin
Romurtide
RU-40555
RU-41821
Rubella antibody, ResCo
S-27609
SB-73
SDZ-280-636
SDZ-MRL-953
SK&F-107647
SL04
SL05
SM-4333
Solutein
SRI-62-834
SRL-172
ST-570
ST-789
staphage lysate
Stimulon
suppressin
T-150RI
T-LCEF
tabilautide
temurtide
Theradigm-HBV
Theradigm-HPV
Theradigm-HSV
THF，Pharm&Upjohn
THF，Yeda
thymalfasin
The thymosin fraction
Thymocartin
thymolymphotropin
Thymopentin
The Thymopentin analog
Thymopentin, Peptech
Thymostimulin
Thymotrinan
TMD-232
TO-115
Transfer factor, Viragen
tuftsin，Selavo
Bestatin
Ulsastat
ANGG-
CD-4+
Collag+
COLSF+
COM+
DA-A+
GAST-
GF-TH+
GP-120-
IF+
IF-A+
IF-A-2+
IF-B+
IF-G+
IF-G-1B+
IL-2+
IL-12+
IL-15+
IM+
LHRH-
LIPCOR+
LYM-B+
LYM-NK+
LYM-T+
OPI+
PEP+
PHG-MA+
RNA-SYN-
SY-CW-
TH-A-1+
TH-5+
TNF+
UN
Dosage
Be applicable to-1 of N-replacement of the present invention, 5-dideoxy-1,5-imino group-D-glucitol chemical compound can be about 0.1-100mg/kg/ days to the mankind's dosage, more preferably from about 1-75mg/kg/ days, most preferably from about 5-50mg/kg/ days.
Nucleoside or nucleotide antiviral compound or its mixture, consumption to the mankind can be about 0.1-500mg/ people/sky, preferably about 10-300mg/ people/sky, more preferably from about 25-200mg/ people/sky, more preferably from about 50-150mg/ people/sky, most preferably from about 1-50mg/ people/sky.
Be applicable to that immunomodulator of the present invention and immunostimulant can be to be lower than the amount administration of this area convention amount.Dosage was generally about 900 μ g/m when for example, thymosin and thymosin fraction 5 were used for the treatment of people's hepatitis B virus infection
2, 2 times weekly (hepatology (Hepatology)
8, 1270 (1988),
10, 575 (1989),
14, 409 (1991); Gastroenterology (Gastroenterlogy)
108: A 1127 (1995)).In method and composition of the present invention, this dosage can be about 10 μ g/m
2, weekly twice, to about 750 μ g/m
2, weekly twice, be more preferably about 100-600 μ g/m
2, weekly twice, preferably about 200-400 μ g/m
2, weekly twice, dosage was generally about 1 * 10 when interferon-ALPHA was used for people's hepatitis C infection
6-10 * 10
6Unit/people, time (Simon etc. (1997) hepatology (Hepatology) on every Wendesdays
25, 445-448).In method and composition of the present invention, this dosage can be about 0.1 * 10
6-7.5 * 10
6Unit/people, on every Wendesdays time, more preferably from about 0.5 * 10
6-5 * 10
6Unit/people, on every Wendesdays time, most preferably from about 1 * 10
6-3 * 10
6Unit/people, inferior on every Wendesdays.
Because the effectiveness of the hepatitis virus resisting of these immunomodulators and immunostimulant is being applicable to-1 of N-replacement of the present invention, 5-dideoxy-1,5-imino group-D-glucitol chemical compound can improve when existing, so in method and composition disclosed by the invention, can use other the immunomodulator/immunostimulant that reduces dosage.Monitor by hepatitis virus, can determine the dosage of this minimizing the infected patient that treated.This can use the hepatitis virus DNA among slit engram method, dot blotting or the round pcr monitoring patients serum, perhaps measures hepatitis surface antigen or other antigen in the serum, and for example e antigen carries out.Hoofnagle etc. is seen in the discussion of these methods, (1997), New England Journal of Medicine (New Engl.Jour.Med.)
336(5): 347-356 and F.B.Hollinger are at Fields Virolohy, and the third edition the 2nd is rolled up (1996), volumes such as Bernard N.Fields, the 86th chapter " hepatitis B virus " 2738-2807 page or leaf, Lippincott-Raven, Philadelphia, PA and the document of wherein quoting.
Adopting-1 of N-replacement, 5-dideoxy-1 during 5-imino group-D-glucitol chemical compound and nucleoside and/or the nucleotide antiviral agent combination treatment, can be monitored the patient similarly to determine minimum effective dose separately.
Above-mentioned dosage can be with single dose or pro rata repeatedly sub-doses to patient's medication.In back one situation, dosage unit compositions can contain its sub-doses of some, constitutes daily dose altogether.According to prescriber's wish, every day, multiple dosing also can increase accumulated dose every day.
Pharmaceutical composition
The compounds of this invention can be mixed with pharmaceutical composition.These pharmaceutical compositions can, parenteral administration oral with the form of dosage unit preparations, or suction, spraying, rectum, Intradermal, percutaneous or topical, can contain conventional pharmaceutically useful non-toxic carrier, adjuvant and excipient in the preparation as required.Topical also may relate to and utilizes percutaneous dosing, for example transdermal patch or iontophoresis device.Here that said parenteral route one speech comprises is subcutaneous, intravenous, intramuscular or breastbone inner injection or infusion techniques.See for example Hoover about the discussion of pharmaceutical preparation, JohnE " Remington pharmaceutical science " Mack Publishihg Co.Easton, Pennsylrania (1975), and Liberman, H.A and Lachman, L. compiles " pharmaceutical dosage form " (MarcelDecker, New York, N.Y. (1980).
Injectable preparation, for example, injectable water base or oil-based suspension can be utilized suitable dispersion or wetting agent and suspending agent preparation according to known technology.Injectable sterile preparation also can be diluent or injectable sterile solution or the suspension in the solvent, for example solution in 1,3 butylene glycol that uses at nontoxic parenteral route.Among available excipient and solvent, operable have water, Ringer's mixture and an isoosmotic sodium chloride solution.In addition, also use aseptic fixedness oils as solvent or suspension media usually.For this reason, any bland fixedness oils be can use, synthetic monoglyceride or diglyceride comprised.In addition, fatty acid such as oleic acid can be used for preparing ejection preparation.Can use dimethyl acetylamide, surfactant comprises ion-type and non-ionic detergent, and polyethylene glycols.Mixture such as solvent discussed above and wetting agent also can use.
The suppository that is used for the chemical compound rectally of this paper discussion can pass through active agents and suitable nonirritant excipient such as cocoa butter, synthetic monoglyceride, diester or three esters, mixing such as fatty acid or Polyethylene Glycol prepares, described excipient is solid at normal temperatures, but under rectal temperature, be liquid, thereby fusing and discharge medicine in rectum.
The solid dosage forms of oral administration can comprise capsule, tablet, pill, powder and granule.In these solid dosage formss, one or more adjuvant combinations of the route of administration shown in The compounds of this invention is common and suitable.If per os medication, chemical compound can mix with cellulose esters, cellulose Arrcostab, Talcum, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and vitriolic sodium and calcium salt, gelatin, arabic gum, sodium alginate, polyvinylpyrrolidone and/or the polyvinyl alcohol of lactose, sucrose, starch, alkanoic acid, then tabletting or seal for conventional administration with capsule.These capsules or tablet can comprise the preparation of controllable release, and be for example formed by the dispersion of reactive compound in hydroxypropyl emthylcellulose.In the situation of capsule, tablet and pill, also can contain buffer agent in the dosage form, for example sodium citrate, the perhaps carbonate of magnesium or calcium or bicarbonate.Tablet and pill can be made in addition and have enteric coating.
In order to be used for the treatment of, the preparation of parenteral administration can be the form of water base or non-water base isotonic sterile injection solution or suspension.These solution and suspension can be used for the carrier that oral preparation mentions or the sterile powder or the preparation of granules of diluent by containing one or more.Chemical compound can be dissolved in water, Polyethylene Glycol, propylene glycol, ethanol, Semen Maydis oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum sesami, benzyl alcohol, sodium chloride and/or the various buffer.Other adjuvant and medicining mode are well-known in the drug world.
The liquid dosage form of oral administration can comprise pharmaceutically useful Emulsion, solution, suspension, slurry agent and elixir, wherein contains this area inert diluent commonly used, for example water.These compositionss also can contain adjuvant, for example wetting agent, emulsifying agent and suspending agent, and sweeting agent, flavoring agent and flavouring agent.
The amount that can combine with carrier mass with the active component that forms single dosage form will become with patient and concrete application method.
Some medical compounds of taking according to the inventive method of the present invention can play the prodrug of other chemical compound of the present invention.Prodrug is the medicine that can chemically change into one or more reactive derivatives in external or body by living things system.Prodrug is taken to go up identical mode substantially with other medicines chemical compound of the present invention.Non-limiting instance is that N-of the present invention replaces-1,5-dideoxy-1, the ester of 5-imino group-D-glucitol chemical compound.
Chemical compound in the combination of the present invention, N-(n-nonyl)-1 for example, 5-dideoxy-1,5-imino group-D-glucitol and various nucleoside or nucleotide can be acid or alkali.Therefore, they can be used for acting on each other formation salt.Nucleoside is purine or the pyrimidine compound that lacks phosphate ester.The formula II of this paper, III, IV, V or VI chemical compound do not have phosphate ester but contain carboxylic moiety, they can with N-of the present invention replace-1,5-dideoxy-1,5-imino group-D-glucitol compound formation salt.Nucleotide is purine or the pyrimidine compound as phosphate monoester, diester or three esters.These phosphate esters contain tart freedom-OH group, can form salt with inorganic base or organic base.Depend on the pKa of bronsted lowry acids and bases bronsted lowry with the organic base salify.-1 of N-replacement disclosed by the invention, 5-dideoxy-1,5-imino group-D-glucitol chemical compound is alkaline, can form pharmaceutically useful salt.In this situation, not only with pharmaceutically useful acid, and also sour with biological activity as nucleoside disclosed herein and nucleotide, all can form suitable salt.These salt can prepare with the mode of the preparation salt of routine well-known in the art.For example, can handle-1 of N-replacement with the nucleotide analog of formula II, III, IV, V or VI, 5-dideoxy-1,5-imino group-D-glucitol chemical compound is to form salt.This can be used as independent chemical reaction and carries out, or carries out as the part of preparation process.Restriction reagent in the salt-forming reaction is acid or the alkali that the technical staff selects to be used for obtaining suitable biological result.The mixture that can contain as required, different salt, acid or free alkali in the preparation.For example, (-)-2 ' of phosphoric acid-deoxidation-3 '-sulfo-Cytidine-5 '-triphosphoric acid can with the N-(n-nonyl)-1 of alkali form, 5-dideoxy-1,5-imino group-D-glucitol or N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol four butyrates form salt.This class salt can be used as pure independent salt, or as the part of mixture, offers the patient with the form of pharmaceutically useful preparation.
In some situation, these salt also can be used as separation, purification or the fractionation that auxiliary agent is used for The compounds of this invention.
Therapeutic scheme
Scheme with The compounds of this invention and/or combination treatment hepatites virus infections patient will be selected according to many factors, these factors comprise patient's age, body weight, sex, diet and medical conditions, the order of severity that infects, route of administration, pharmacological consideration is as activity, effectiveness, pharmacokinetics and the toxicology property of the particular compound used, and whether adopts drug delivery system.
Take drug regimen disclosed by the invention and generally should continue several thoughtful several months or several years, reach acceptable level up to virus titer, expression is infected and is controlled or eradicates.As mentioned above, the patient who treats with pharmaceutical composition disclosed by the invention can be by measuring the hepatitis virus DNA among the patients serum with slit engram method, dot blotting or round pcr, or the hepatitis antigen in the mensuration serum, for example hbs antigen (HBsAg) and hepatitis B e antigen (HBeAg) carry out routine monitor, to determine the effectiveness of treatment.For example, in chronic viral hepatitis B, the feature of alleviation is that hepatitis B virus DNA disappears, that is, be reduced to can detect in every ml serum 〉=10
5The level that genomic cross experiment can not detect, and HBeAg disappears in the serum, although HBsAg exists.These serum are the improvement of the biochemistry and the histological characteristic of disease after changing.In most of antiviral therapies, the terminal point of successful treatment is HBeAg and viral DNA disappearance in the serum.In the patient that e antigen disappears, the alleviation process continues usually, causes the HBsAg carrier state of inactivation.A lot of patients finally become the HBsAg-feminine gender and (see Hoofnagle etc., (1997), New England Journal of Medicine (New Engl.Jour.Med.), 336 (5): the commentary of 347-356).
Continuing to analyze gained data with these methods can make amendment to the therapeutic scheme during the treatment, so that each component in the compositions is with the optimised quantity administration, and can determine persistent period for the treatment of.So, therapeutic scheme/medication schedule can reasonably be revised during treating, so that can take with minimum flow and in compositions, demonstrate the various antiviral compounds that gratifying hepatitis virus resisting is renderd a service altogether, just and just infect for treatment successfully must the time continue to take the antiviral compound of these combinations.
Following non-limiting example is in order to illustrate various aspects of the present invention.
1,5-(butyl imino group)-1, the preparation of 5-dideoxy-D-glucitol
With 1,5-dideoxy-1,5-imino group-D-glucitol (5.14g, 0.0315mol), butyraldehyde (3.35ml, 0.0380mol) and the solution hydrogenation (60psi/29 ℃/21 hour) of palladium black (1g) in 200ml methanol.After the mixture filtration that forms, vacuum concentrated filtrate becomes grease.Make title compound crystallization in acetone, recrystallization in methanol/acetone, about 132 ℃ of fusing point.NMR, infrared and elementary analysis supporting structure identification.
C
10H
21NO
4The analysis theories value: C, 54.78; H, 9.65; N, 6.39.Experiment value: C, 54.46; H, 9.33; N, 6.46.
1,5-(butyl imino group)-1, the preparation of 5-dideoxy-D-glucitol tetracetate
With acetic anhydride (1.08g, 0.0106mol) be added to embodiment 1 title compound in the 5ml pyridine (0.50g, 0.0023mol) in, stirred 17 days under the room temperature.Product is evaporated under nitrogen.The title compound silica gel chromatography purification that forms.NMR, infrared spectrum and elementary analysis supporting structure are assert.
C
18H
29NO
8Analysis theories value: C, 55.80; H, 7.54; N, 3.62.Experiment value: C, 55.42; H, 7.50; N, 3.72.
-1 of various N-replacements, 5-dideoxy-1, the external anti-hepatitis B activity of 5-imino group-D-glucitol chemical compound
Use the Hep G 2.2.15 cell of long-term secretion hepatitis B virus,-1 of some different N-replacements have been measured with the in vitro tests method, 5-dideoxy-1, the 5-imino group-anti-hepatitis B activity of D-glucitol chemical compound and the influence of pair cell viability. used method basically as Block etc. at institute of NAS newspaper (Proc.Natl. Acad.Sci.USA)
91(1994): described in the 2235-2239.The results are shown in table 2 and 3.
Table 2
-1 of N-replacement, 5-dideoxy-1,5-imino group-D-glucitol chemical compound is to the hepatitis B virus secretion of HepG2.2.15 cell and the influence of viability
| Chemical compound and [concentration] | Survival %+/-1S.D. 2 | Excretory HBV relative populations, the % of sample in contrast 3 | |
| Contrast NBDNJ 4 NBDNJ 4 1 1 2 2 3 3 | [200] [1000] [200] [1000] [200] [1000] [200] [1000] | 90+/-7(n＝4)94+/-6(n＝10)88+/-8(n＝10)90+/-2(n＝4)87+/-3(n＝4)90+/-6(n＝4)89+/-4(n＝4)n.d. 3n.d. 3 | 10037.0+/-13(n＝15)3.2+/-5(n＝15)85.0+/-5(n＝8)35.0+/-6(n＝8)107.0+/-12(n＝3)38.0+/-15(n＝3)45.0+/-30(n＝3)5.0+/-20(n＝3) |
1The 2.2.15 cell (about 500,000 of every hole) of long-term secretion HBV shown in chemical compound in the presence of cultivation 3 days.
2Chemical compound exist or not in the presence of cultivate 3 days after, utilize the trypsin treatment emigrated cells, cultivate with trypan blue, microscopically visualize dyestuff repels.Numerical value is the percent of the cell (the trypan blue repulsion is considered to be equivalent to survival) of repulsion trypan blue with respect to the total cellular score of being checked.
3Chemical compound exist or not in the presence of cultivate 3 days after, by containing to preceding S
1Immunoprecipitation goes out excretory virion (the international virusology of Meisel etc. (1995) (Intervirology) in the culture medium of the monoclonal antibody of antigen-specific
37: 330-339; Lu etc. (1995) virusology (Virology)
213: 660-665).Use the photodensitometric quantitation of the dna segment of the appropriate size that forms by the polymerase chain reaction to measure the viral DNA that exists in the detection immunoprecipitate.By to (do not accept the cell of chemical compound) in the same old way the amplification DNA quantity be assumed to 100%.
4NBDNJ:N-(normal-butyl)-1,5-dideoxy-1,5-imino group-D-glucitol; N-butyl DNJ.
5As if though do not carry out the dye test of trypan blue viability, cell is no abnormal (health) under rough microscopy.
S.D: standard deviation.
Chemical compound:
1:N-(3-phenylpropyl)-1,5-dideoxy-1,5-imino group-D-glucitol
2:N-(normal-butyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates
3:N-(2-ethyl-butyl)-1,5-dideoxy-1,5-imino group-D-glucitol
Table 3
-1 of N-replacement, 5-dideoxy-1,5-imino group-D-glucitol chemical compound is to the hepatitis B virus secretion of HepG2.2.15 cell and the influence of survival
| Chemical compound | Cause 90%HBV to secrete repressed concentration 1 | In MTT, cause 50% concentration that reduces 2 |
| 1 2 | 0.5-1.0* ＞200** | 100-200 n.d. 3 |
1The μ g number of every ml is according to the multiple PCR result of secondary.
2The μ g number of every ml, MTT:3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide.Colorimetric analysis based on MTT is (Heo etc. (1990), the cancer research (Cancer Research) measured of cell viability
50: 3681-3690).
3Undetermined.
* Shi Yan least concentration.
* does not see inhibitory action at used maximum concentration (200 μ g/ml).
Chemical compound:
1:N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol
2:N-(normal-butyl)-1,5-dideoxy-1,5-imino group-D-glucitol, 3,4-diacetate esters
Embodiment 4
Independent or with the anti-hepatitis B activity of (-)-2 '-deoxidation-3 '-sulfo-cytidine (3TC)-the 5 '-triphosphoric acid (3TC) of N-nonyl-DNJ combination
Independent or with the anti-HBV effect of (-)-2 '-deoxidation-3 '-sulfo-cytidine (3TC)-the 5 '-triphosphoric acid (3TC) of N-nonyl-DNJ combination according to Korba ((1996) antiviral research (Antiviral Research) 29 (1): 49-51), " Combostat " method of employing (Comstat Program, Combostat Corp., Duluth MN) measures.The Combostat method comprises each chemical compound that dilutes IC-90 serially.The IC-90 of N-nonyl-DNJ is 4-10 μ g/ml (T.Block and G.Jacob, the observed result of not delivering) after measured.In HepG 2.2.15 (2.2.15) cell, acceptable IC-90 is 300-500nM (Doong etc. (1991), institute of a NAS newspaper (Proc.Natl.Acad.Sci.USA) for 3TC
88: 8495-8499).
2.2.15 cell that Sells etc. is described in newspaper (Proc.Natl.Acad.Sci.USA) 84:1005-1009 of institute of (1987) NAS remain on RPMI 1640 culture medium of having added 10% hyclone, 200 μ g/ml G418 (Gibco BRL 066-1811) (Gibco BRL, #31800-022) in.Cell is inoculated into 25cm with 80% fusion rate
2Flask in.After five days, flask repeats sample or does not add the serial dilutions that chemical compound only adds 3TC with three parts, or adds the serial dilutions of 3TC and N-nonyl-DNJ.Behind 2,4 and 6 days of adding chemical compound (carrying out culture medium in those skies replaces), measure the quantity of hepatitis B virus (HBV) DNA in the culture medium with the pcr analysis method of Polyethylene Glycol sedimented particle.Therefore, in these experiments, do not distinguish tunicary granule and virus nucleocapsid body.The product of pcr amplification splits with agarose gel electrophoresis (1.5% agarose), utilizes bands of a spectrum scanning method (HP Jet Imager) quantitative assay 538 nucleotide fragments.Suppose that the HBV amount that reclaims is 100% from untreated cell.Data when figure 1 illustrates 6 days, they are that standard error never surpasses 20% by at least three meansigma methodss of obtaining of flask independently, mean error is 12%.
For three time point series being tested, it is all more more effective significantly than arbitrary independent chemical compound that being combined in of 3TC and N-nonyl-DNJ suppressed HBV secretion aspect.Only the conclusion that obtains by pcr analysis is difficult to determine IC-50 value accurately.For example, the high sensitivity of PCR and variable person's character may be only also to reach the reason of HBV suppression ratio more than 90% with 3TC even when the 300nM.Each experiment all comprises being that DNA in reaction yield and sample measures in proportional DNA concentration range and carries out so that guarantee PCR in the same old way.Resolution is about 3 times,, can detect 3 times of difference of DNA concentration that is.The difference that can not detect consistently below 3 times may be that independent 3TC can't reach 90% reason that suppresses.This shows, detects inhibitory action for PCR, must meet very high inhibition standard.Therefore, it is obvious to separate trend as a result constantly based on three: 3TC adds the combined effect of N-nonyl-DNJ greater than any independent chemical compound, also greater than each chemical compound adduction of effect separately.These data show that when N-nonyl-DNJ of 0.016 μ g/ml existed, the IC-50 of 3TC faded to about 0.48nM by about 60nM.
The antivirus action of independent N-nonyl-DNJ in the marmot model
Render a service for the anti-hepatitis virus that is combined in the marmot animal model of estimating N-nonyl-DNJ and 3TC (or other nucleoside or nucleotide analog), at first carry out the monotherapy experiment with independent N-nonyl-DNJ.Be necessary to determine N-nonyl-DNJ in marmot, whether have any anti--whether HBV effect and N-nonyl-DNJ play beneficial effect, so that composite design is studied on the basis of dosage one response relation of this independent medicine.
Therefore, four every group five treated animals (all each group all has two kinds of sexes, and except that in the same old way, every kind of sex all has two) are specified with twice oral mode administration 0,12.5,25,50 every day and 100mg/kg/ days.This is the wild animal of laboratory rearing.All animals are all as infection of newborn woodchuck hepatitis virus (WHV), and are positive in the serum test to the WHV surface antigen.After (1,2,3 and 4 week) and medication finish weekly during (0 week), the medication in medication the last week (1 week), before facing medication (5,6,8 and 10 week) take a blood sample.
The methods that two kinds of tolerance pharmaceutical efficacies are arranged: the minimizing (recording) of total HBV DNA and have the minimizing (recording) of HBV DNA of the virocapsid (it is the activity form of virus) of complete surface glycoprotein by the immunoprecipitation analysis method of similar ELISA and quantitative PCR subsequently by quantitative PCR.The cell culture experiments of carrying out with N-nonyl-DNJ shows that this chemical compound is very little or do not have to the influence of total HBV DNA, but the DNA (IPDNA) of immunoprecipitation is had appreciable impact.No wonder be that IPDNA test is quite variable; For partly offsetting this kind influence, carry out four-wheel experiment, whenever take turns the sample that experiment all comprises all animals, but all number differences of research.
The summary result of study, N-nonyl-DNJ offers medicine before and medication all dosages partly the equal substantially constant of measured value under study for action for the not influence of total HBV DNA measured value.On the other hand, the IPDNA level is non-constant during studying.During medication (0-4 week), the low dosage animal tends to the IPDNA level and increases, and reduces and the high dose animal tends to the IPDNA level during same.Each week response of every animal is fitted to straight line, and these collinear slopes are owing to the dosage or the plasma concentration difference of medicine demonstrate remarkable difference.The plasma concentration of medicine also is quite variable: the animal that plasma concentration is minimum in dosage group is also lower than the plasma concentration of the animal that has maximum plasma concentration in the next more low dose group.In all are measured, there is not difference between the male and female response.
Plasma concentration
The plasma concentration of N-nonyl-DNJ change with all numbers of medication that may be relevant or medication last time after time between do not have clear and definite related pattern.Because as if the plasma concentration in the animal reasonably remain unchanged during medication, so use the intermediate value plasma concentration of each animal to carry out subsequently modelling.With during each animal-use drug weekly plasma concentration for dosage mapping (add the random noise of an a small amount of on dosage level, therefore the point that overlaps each other on figure is distinguished) (Fig. 2).
HBV DNA
Total HBV dna level of each animal does not become (not video data) basically in time.Except 3 animals have the very high virus levels at maximum dose level, there is fuzzy sign to show and exists virus levels to increase the dosage-response relation that reduces with dose.Can not conclude between N-nonyl-DNJ and the total HBV DNA whether any relation is arranged.May there be two animal populations: responder (for example animal γ) and non-responder (animal i, m or d), but also need more data about the reliable conclusion of this point.
The HBV DNA of immunoprecipitation
In the IPDNA test, all there be significant change (data not shown goes out) within the test with every the wheel between each wheel test.Even so, also can observe in 0-4 week slope and with its modelling, this slope increases for the low dosage animal usually, animal then reduces high dose.This variation of slope is statistically significant (P＜0.005).
Before with model and data fitting, adopt the log conversion, because: 1) variation of IPDNA increases with the IPDNA value; The log conversion obtains changing near constant numerical value and 2) the expected drug effect will occur from the form of the constant multiple of IPDNA level.Because IPDNA has null value, so before carrying out the log conversion, all numerical value added a fractional value (be about minimum nonzero value 1/2).
Use two kinds of methods to simulate: linear analogue method and non-linear simulation method to the variation of the slope of all numbers with N-nonyl-DNJ dosage.Two kinds of methods suppose that all (linearity) pace of change of log (IPDNA) numerical value during medication is that the reflection medicine was measured " correctly " of virus function.Two kinds of all substep matches of method, the first step is identical to two kinds of methods.At first, by round combination, with the simple linear regression model (LRM) of data fitting in 0-4 week so that every animal is indicated log (IPDNA+10) respectively.In second step, response variable is the slope that simulates in the first step.
For this linear method, regard every experimental data of taking turns as a data set, with in response and model of match with respect to the slope of all numbers, dosage has remarkable influence (this influence almost all be result from slope with respect to dosage), and the corresponding error of test dose influence is the variation (to after making adjustment as each round of data set) between the animal of handling with the same manner.This is similar to and utilizes correction data earlier the data of each round to be adjusted to a common viral DNA concentration in each round; Its difference is, what carry out here using when round is regulated is to derive from the data of marmot and be not only correction data.
For nonlinear method, one four parameter logarithmic model of match, with in response to the slope of all numbers, with dosage as desired value.Equally, each round is taken as data set, but comprises all each weeks because there is not to take turns experiment, the blocking in the therefore impossible nonlinear method of reflection comprehensively.Even so, nonlinear model also obtains the EC50 of a 7.88mg/kg/BID dosage.The average greatest gradient that observes is to exceed log (IPDNA μ g/ml)/week 2.71, or the increase in about 150%/week; With the observed average minimum slope of N-nonyl-DNJ is to be lower than log (IPDNA μ g/ml)/week 0.31, or about 25%/all reducing.Slope, the model of match, the parameter estimation that obtains by model, and the approximate test error of these parameters all is shown among Fig. 3.Data show that the proximate effective monotherapy dosage of N-nonyl-DNJ in marmot is about 16mg/kg/ days.No matter be in marmot or in the people, the nucleoside or the nucleotide antiviral agent of N-alkyl-DNJ that takes and combination with it can be divided into two equal bu dosed administrations (that is, B.I.D).
Fig. 2 and 3 has listed the letter of expression animal.Code, sex and the dosage of table 4 expression animal.
Table 4
Animal code, sex and dosage
| Number of animals | Letter code | Sex | Dosage |
| F95343 M96364 F96304 F96301 M96285 F96283 F96391 M96305 F96271 M96256 M96404 r96392 F96163 M96414 F96393 M95322 M96286 F96231 F96402 M96363 | b n k j h g o l f c s p c t q a i d r m | |
0 0 0 0 6.25 6.25 6.25 6.25 12.5 12.5 12.5 12.5 25 25 25 25 50 50 50 50 |
Embodiment 6
Test is studied with the active antiviral of N-nonyl-DNJ in marmot hepatitis B virus infection model of 3TC combination
The combined activity of N-nonyl-DNJ and nucleoside analog 3TC can be estimated with the marmot model of hepatitis B virus infection.Use the marmot of 28 persistent infection woodchuck hepatitis virus (WHV).Each organizes marmot can be only with 3TC (s.i.d.), only with N-nonyl-DNJ (b.i.d.), or with the combination oral medication of two kinds of medicines.The antiviral activity of single medicine and composition of medicine can be by measuring the serum WHV DNA during treating and the matched group of treatment group and placebo treatment being made comparisons definite.
The marmot of WHV of can having used 28 definite persistent infections, they all infect WHV with experimental technique in first week of life.When the research beginning is the WHsAg positive entirely.
Use and amount to 8 experimental grouies.Marmot in every group can be divided into different levels according to sex, body weight and age.3TC can Epivir (Glaxo-Wellcome) tablet water slurry form oral administration every day once.N-nonyl-DNJ also can be divided into two parts of sub-doses oral administrations with the aqueous solution form.With taking the semisynthetic liquid marmot of 4-5ml food after two kinds of Drug therapys to guarantee that medicine is swallowed fully.
Experimental group can be following situation:
| Group ID | Number | 3TC (mg/kg/ days) | N-nonyl-DNJ (mg/kg/ days) |
| 1 2 3 4 5 6 7 8 | 4 3 3 3 3 4 4 4 | 0.0 3.0 9.0 0.0 0.0 1.5 4.5 9.0 | 0.0 0.0 0.0 4.0 12.0 2.0 6.0 12.0 |
Marmot can be anaesthetized (50mg/kg ketamine, 5mg/kg Zylazine), weigh, and before begin treatment, in six weeks of treatment phase, take a blood sample during 1,2 and 4 weeks week about and after treatment.Collect serum and be divided into aliquot.Analyze WHV DNA with a serum with speckle slit hybrid method, obtain CBC and clinical biochemistry pattern when finishing with treating with elisa assay WHsAg and before treatment.Preserve second duplicate samples as the filing sample.Other each part serum can be used for pharmaceutical analysis and special WHV DNA analysis.
The present invention is described, obviously it can change in a lot of modes.These change the isolation that is not considered to the spirit and scope of the present invention, and all these changes and equivalent are conspicuous for those skilled in the art, and will be included within the scope of following claim.
Claims (10)
1. salt, comprising the N-of formula I replace-1,5-dideoxy-1,5-imino group-D-glucitol and be selected from nucleoside (-)-2 with acidic moiety '-deoxidation-3 '-the sulfo-Cytidine-5 '-triphosphoric acid and nucleotide (-)-2 '-deoxidation-3 '-the sulfo-Cytidine-5 '-a kind of chemical compound of triphosphoric acid:
Wherein R is selected from and has chain length C
7To C
20Straight chained alkyl, backbone chain length C
3To C
16Branched alkyl, C
4-C
18The C that alkoxyalkyl, phenyl replace
1-C
16Straight or branched alkyl and C
8-C
14Cycloalkyl-alkyl, W, X, Y and Z are selected from hydrogen and C independently of one another
1-C
10Alkanoyl.
2. the salt of claim 1, wherein R is that chain length is C
7To C
20Straight chained alkyl, W, X, Y and Z are hydrogen.
3. the salt of claim 2, wherein R is a nonyl.
4. the salt of claim 1, wherein R is chain length C
7To C
20Straight chained alkyl, W, W, Y and Z are C
1-C
10Alkanoyl.
5. the salt of claim 4, wherein R is a nonyl.
6. the salt of claim 5, wherein said alkanoyl is a bytyry.
7. the salt of claim 1, N-wherein replace-1,5-dideoxy-1,5-imino group-D-glucitol chemical compound is to be selected from following chemical compound:
N-(n-heptyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-octyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(positive decyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-undecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(dodecyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-tridecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-tetradecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(Pentadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-hexadecyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-heptadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-octadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(AI3-36122 base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(AI3-28404 base)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(n-heptyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-octyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(positive decyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-undecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(dodecyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-tridecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-tetradecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(Pentadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-hexadecyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-heptadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(n-octadecane base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(AI3-36122 base)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(AI3-28404 base)-1,5-dideoxy-1,5-imino group-D-glucitol four butyrates;
N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(5-methyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(3-propyl group hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(1-amyl group amyl group hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(1-butyl butyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(7-Methyl Octyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(8-methyl nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(9-methyl decyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(10-methyl undecyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(6-cyclohexyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(4-cyclohexyl butyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(2-cyclohexyl ethyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(1-cyclohexyl methyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(1-phenyl methyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(3-phenyl propyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(3-(4-methyl)-phenyl propyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(6-phenyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(5-methyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(3-propyl group hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(1-amyl group amyl group hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(1-butyl butyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(7-Methyl Octyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(8-methyl nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(9-methyl decyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(10-methyl undecyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(6-cyclohexyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(4-cyclohexyl butyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(2-cyclohexyl ethyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(1-cyclohexyl methyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(1-phenyl methyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(3-phenyl propyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(3-(4-methyl) phenyl propyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(6-phenyl hexyl)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(the positive decyl of 7-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(the positive decyl of 7-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol, four butyrates;
N-(the positive decyl of 7-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol, tetracetate;
N-(the positive decyl of 3-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(the positive decyl of 9-oxa-)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(7-oxa-n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol;
N-(3-oxa-n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol; Tetracetate;
N-(3-oxa-n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol; With
N-(7,10,13-trioxa n-tetradecane base)-1,5-dideoxy-1,5-imino group-D-glucitol.
8. the salt of claim 1, wherein
-1 of described N-replacement, 5-dideoxy-1,5-imino group-D-glucitol are to be selected from N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol and N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol four butyrates; And
Described nucleotide be (-)-2 '-deoxidation-3 '-the sulfo-Cytidine-5 '-triphosphoric acid.
9. method, comprising making N-(n-nonyl)-1,5-dideoxy-1,5-imino group-D-glucitol and (-)-2 '-deoxidation-3 '-the sulfo-Cytidine-5 '-triphosphoric acid reacts under salt-forming condition.
10. pass through the salt of the method formation of claim 9.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7450898P | 1998-02-12 | 1998-02-12 | |
| US60/074508 | 1998-02-12 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99804990 Division CN1202824C (en) | 1998-02-12 | 1999-02-12 | Use of N-substituted-1,5-dideoxy -1,5-imino-D-glucitol compounds for treating hepatitis virus |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1679568A CN1679568A (en) | 2005-10-12 |
| CN100364534C true CN100364534C (en) | 2008-01-30 |
Family
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99804990 Expired - Fee Related CN1202824C (en) | 1998-02-12 | 1999-02-12 | Use of N-substituted-1,5-dideoxy -1,5-imino-D-glucitol compounds for treating hepatitis virus |
| CNB2005100626425A Expired - Fee Related CN100364534C (en) | 1998-02-12 | 1999-02-12 | Use of n-substituted-1,5-di deoxy-1,5-imino-d-glucitol compounds for treating hepatitis virus infections |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99804990 Expired - Fee Related CN1202824C (en) | 1998-02-12 | 1999-02-12 | Use of N-substituted-1,5-dideoxy -1,5-imino-D-glucitol compounds for treating hepatitis virus |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN1202824C (en) |
| AR (1) | AR019532A1 (en) |
| ZA (1) | ZA991142B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011389B (en) * | 2003-09-19 | 2012-09-19 | 石药集团中奇制药技术（石家庄）有限公司 | Application of arbidol in preparing medicaments for preventing and/or treating hepatitis B |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0350012A2 (en) * | 1988-07-08 | 1990-01-10 | Meiji Seika Kaisha Ltd. | Antiviral composition |
| US5003072A (en) * | 1988-11-03 | 1991-03-26 | G. D. Searle & Co. | 1,5-dideoxy-1,5-imino-D-glucitol derivatives |
| EP0449026A2 (en) * | 1990-03-24 | 1991-10-02 | Bayer Ag | Desoxynojirimycin derivatives, process for their preparation and their use in drugs |
| US5622972A (en) * | 1994-02-25 | 1997-04-22 | G. D. Searle & Co. | Method for treating a mammal infected with respiratory syncytial virus |
-
1999
- 1999-02-12 ZA ZA9901142A patent/ZA991142B/en unknown
- 1999-02-12 CN CN 99804990 patent/CN1202824C/en not_active Expired - Fee Related
- 1999-02-12 CN CNB2005100626425A patent/CN100364534C/en not_active Expired - Fee Related
- 1999-02-12 AR ARP990100609 patent/AR019532A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0350012A2 (en) * | 1988-07-08 | 1990-01-10 | Meiji Seika Kaisha Ltd. | Antiviral composition |
| US5003072A (en) * | 1988-11-03 | 1991-03-26 | G. D. Searle & Co. | 1,5-dideoxy-1,5-imino-D-glucitol derivatives |
| EP0449026A2 (en) * | 1990-03-24 | 1991-10-02 | Bayer Ag | Desoxynojirimycin derivatives, process for their preparation and their use in drugs |
| US5622972A (en) * | 1994-02-25 | 1997-04-22 | G. D. Searle & Co. | Method for treating a mammal infected with respiratory syncytial virus |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1202824C (en) | 2005-05-25 |
| CN1328457A (en) | 2001-12-26 |
| ZA991142B (en) | 2000-02-14 |
| CN1679568A (en) | 2005-10-12 |
| AR019532A1 (en) | 2002-02-27 |
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