CN1312254A - Novel nucleoside - Google Patents

Novel nucleoside Download PDF

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Publication number
CN1312254A
CN1312254A CN00121912A CN00121912A CN1312254A CN 1312254 A CN1312254 A CN 1312254A CN 00121912 A CN00121912 A CN 00121912A CN 00121912 A CN00121912 A CN 00121912A CN 1312254 A CN1312254 A CN 1312254A
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administration
nucleosides
cell
compound
term
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R·谭
王广义
D·阿维雷特
K·拉马萨米
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Valeant Pharmaceuticals International Inc USA
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ICN Pharmaceuticals Inc
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom

Abstract

Novel nucleosides having the structure of Formula 1 and Formula 2 are contemplated. In one aspect of the invention, controlled release dosage forms are particularly contemplated. Further, alternative routes of administration of the nucleosides having the structure of Formula 1 or Formula 2 are contemplated.

Description

New nucleosides
Invention field
The invention belongs to the nucleosides field.
Background of invention
Immune system comprises two kinds of main lymphocytes: bone-marrow-derived lymphocyte (B cell), and it derives from marrow, and T lymphocyte (T cell), and it derives from thymus gland.The B cell mainly is responsible for humoral immunization (promptly producing antibody), and the T cell mainly is responsible for cell-mediated immunity.
It is generally acknowledged that the T cell can be divided into two subclass, helper cell and cytotoxic T cells.Helper cell participates in cell-mediated immunity by discharging, and is called as the soluble protein medium of cytokine, activates other lymphocyte and the scavenger cell that comprise B cell and cytotoxic T cell.As used herein, lymphokine is the subgroup of cytokine.
It is generally acknowledged that helper cell also can be divided into two subclass, Th1 subclass and Th2 subclass.Th1 cell (being also referred to as 1 type cell) produces interleukin-22 (IL-2), tumour necrosis factor (TNF α) and gamma-interferon (IFN γ), main responsible cell-mediated immunity such as delayed hypersensitivity and antiviral immunity, different with it, Th2 cell (being also referred to as 2 type cells) produces interleukin I L4, IL-5, IL-6, IL-9, IL-10 and IL-13 relate generally to and assist humoral immune reaction as in the immune response of arriving seen in allergenic response, conversion (the Mosmann of IgE and IgG4 antibody isotype for example, 1989, immunity is commented academic year, 7:145-173).
Noun Th1 as used herein and Th2 " reaction " mean and comprise by Th1 and Th2 lymphocyte are induced the whole effects that caused respectively.Wherein, these reactions comprise by transcribing, translation, the change of the corresponding cytokine production that secretion and other may mechanism cause increases corresponding lymphocytic propagation, and with increase other relevant effect of cytokine production, comprise the motility effect.
The mechanism that nucleosides and some other compound are regulated Th1 and Th2 reacting phase mutual relation so as to selectivity it be unclear that.A kind of possibility of present inventor's imagination is, effectively nucleosides can change GTP (guanosine triphosphate) (GTP) storehouse, then influence the speed that cytokine produces so again, according to this theory, can utilize the relatively large change of GTP, be enough to the concentration of Th1 and Th2 cytokine is all exerted an influence, and can utilize the less relatively change of GTP, tending to concentration to Th1 and Th2 cytokine has in various degree influence.
These discoveries have the meaning of particularly important, because for above-named numerous disease, present treatment countermeasure or only limited effect are significantly paid effect, perhaps do not have producing effect and significant side effects is arranged.For example to the treatment of autoimmune disorder, it usually is the standard that is confined to alleviate, remove toxicity antibody (as to Therapy for Myasthemia Gravis), and comprise reflunomide, chloroquine derivative, with antimetabolic or antitumor drug at interior dangerous medicine, and act on the medicine such as the cyclosporins of immune system cell.
Summary of the invention
The application is about new nucleosides.The nucleosides that the present invention discusses is corresponding to formula 1 and 2.
Following term will be used for this specification sheets, they will by as the use of giving a definition.
Term " α " and " β " are meant in the chemical structural drawing, substituent specific three-dimensional chemical configuration on the unsymmetrical carbon.
Term " aryl " refers to the unit price unsaturation aromatic carbon ring base of have monocycle (for example phenyl) or two condensed ring (for example naphthyl), and it can randomly be replaced by hydroxyl, low alkyl group, chlorine and/or cyano group.
Term " enantiomorph " refer to a pair of mutually can not eclipsed mirror shadow steric isomer.A pair of enantiomorph is " racemize " mixture in the mixture of 1: 1 ratio.
Term " heterocycle " is meant and contains at least one heteroatoms such as N, saturated or the undersaturated carboatomic ring atom of the unit price of O or S group, wherein in each utilized position of its ring, can randomly independently be replaced: hydroxyl, oxygen base, amino, imino-by following group, low alkyl group, bromine, chlorine and/or cyano group.Purine, pyrimidine are also included within this substituting group.
Term " isomer " is meant the different compounds with same molecular formula." steric isomer " be only atom at the different isomer of spatial disposition mode.
Term " L-configuration " is used to describe the chemical structure of the ribofuranose base section of the compound that is connected in core skeleton in whole the present invention.The L-configuration of The compounds of this invention glycosyl part and naturally occurring nucleosides compare as the D-form of the ribosyl of cytidine, adenosine, thymidine, guanosine and uridine part.
Term " low alkyl group " be meant methyl, ethyl, just-propyl group, sec.-propyl, just-butyl, tert-butyl, different-butyl or just-hexyl.The example of this term can further comprise endless chain, branched chain or the straight chain of 1-6 carbon atom.
Term " monocycle " is meant and contains at least one heteroatoms such as O, N, S, the unit price saturated carbon ring atomic group of Se or P, in the ring, its each utilized position all can randomly be replaced independently, for example with glycosyl part or any other group such as bromine, chlorine and/or cyano group replace, and make this single-loop system at last by aromizing like this.
Term " C-nucleosides " is used to describe in whole detailed description, formed connection type between ribose part and heterocyclic base.For the C-nucleosides, connect and originate from ribose partial C-1 position, combine with the carbon atom of heterocyclic base.The key that forms in the C-nucleosides is that carbon atom is to the carbon atom type.
Term " D-nucleosides " is meant the nucleoside compound (for example thymidine) that contains D-ribose part.
Term " L-nucleosides " is meant the nucleoside compound that contains L-ribose part.
Term " N-nucleosides " is used to describe in whole detailed description, formed connection type between ribose part and heterocyclic base.For the N-nucleosides, connect and originate from ribose partial C-1 position, combine with the nitrogen-atoms of heterocyclic base.The key that forms in the N-nucleosides is that carbon atom is to the nitrogen-atoms type.
Term " Nucleotide " is meant substituted phosphoric acid ester on nucleosides 5-position.
Term " purine " is meant Fig. 1 at this, the nitrogenous bicyclic heterocycle structure of being described in 2.
Be used for examples for compounds formula of the present invention in formula 1 and 2.
Structural formula 1 compound has following structure:
Figure A0012191200051
Structural formula 2 compounds have following structure:
Figure A0012191200052
Administration
Expect that compound of the present invention can be with any suitable pharmaceutical dosage forms administration, and can be by any suitable scheme administration.The existing statement in PDR to preferred single therapeutic dose of this class medicine and scheme perhaps can obtain from maker and seller at least.
Certainly, the ordinary person of this area should know that the treatment effective dose will change with following multiple factor: infection to be treated or disease, its severity, the therapeutic modality that adopts, the pharmacokinetics of institute's with medicament, and the object of being treated (animal or human).Therefore, effective dose can be about 1mg/kg body weight-25mg/kg body weight dosage range.This dosage range generally can make the concentration level of active compound in patient's blood reach the scope of about 0.04-100 μ g/cc.But, can design by giving low dose earlier, increase dosage then, until or side effect reverse fully, perhaps reached predetermined effect, and set up the patient-specific mode that is fit to.
Compound of the present invention can be taked the various ways administration: oral, the parenteral administration (comprises subcutaneous injection, intravenous injection, intramuscular injection, intrathoracic injection or infusion administration), by sucking sprays, rectal administration, topical or the like, and can be to contain the dosage unit preparations form administration of pharmaceutically acceptable conventional carrier adjuvant of non-toxicity and vehicle.
Can design compound of the present invention with pharmaceutically acceptable carrier mixed preparing.For example, compound of the present invention can become pharmaceutically useful salt oral administration.Because compound of the present invention nearly all is water miscible, they can administration in physiological saline (for example being buffered to the about 7.2-7.5's of pH) medium sized vein.Conventional buffer reagent such as phosphoric acid salt, supercarbonate or citrate buffer agent can be used for this purpose.Certainly, those of ordinary skill in the art can make amendment to preparation by the guidance of the present invention's detailed description, so that be provided for the several formulations of specific administration approach, and does not destroy the stability of the present composition, does not perhaps sacrifice their therapeutic activity.Becoming after particularly making this compound modified more can water-soluble or other vehicle, for example, modifies (forming salt pref, esterification etc.) a little by means of the method that those of ordinary skills know and just is easy to achieve the goal.What those skilled in the art knew equally is, in order to control the pharmacokinetics of this compound, makes it that the patient is had best beneficial effect, can make amendment to the route of administration and the formulation of specific compound.
In addition, be included in the compound in the present composition, can separate administration, perhaps administration together can give by any order when separate administration.In order to reach desirable synergistic therapeutic effect, can be to the content of activeconstituents and pharmaceutics promoting agent, and the relative time arrangement of administration is selected.
The medication of The compounds of this invention can be successive administration (intravenous drip) or every day oral administration (as every day 4 times) several times, wherein can comprise oral, local, parenteral, intramuscular, intravenously, subcutaneous injection, transdermal administration (may comprise penetration enhancers) contains agent and suppository dose regimen.
Being as the criterion is ready for use on therapeutics of the present invention, preferably will treat the compound of significant quantity, and the pharmaceutics adjustment technology according to routine is uniformly mixed into a dosage with pharmaceutically useful carrier.Carrier can be extensive different form, depends on the dosage form of wishing to be used for administration, as form oral or parenteral.When the medicament composition of preparation oral dosage form, can use any common pharmaceutics matrix.Therefore, for liquid oral medicine such as suspension, elixir and solution can use to comprise water, glycol, oil, alcohol, perfume compound, sanitas, the suitable carrier and the additive of tinting material etc.For solid orally ingestible such as pulvis, tablet, capsule, and for solid preparation such as suppository, can use to comprise starch, sugar carrier such as glucose, N.F,USP MANNITOL, lactose and relevant carrier, thinner, granulation agent, lubricant, tackiness agent, the suitable carrier and the additive of disintegrating agent etc.If desired, also can make enteric coating to tablet or capsule, perhaps make sustained release dosage by means of standard techniques.
For the preparation of parenteral administration, carrier generally includes aseptic water or sodium chloride aqueous solution, though also may comprise other composition that promotes dissemination.Certainly, when using sterilized water and will keep aseptic, said composition and carrier also must be aseptic.Injection suspension can also be mixed with, suitable liquid vehicle, suspension agent etc. can be used in the case.
What also should fully understand is that in general, the most preferred purposes of the present invention is that active compound wherein has less relatively cytotoxicity to the non-target cell of host, and target cell is had higher relatively activity.
Except the explanation by means of claims, these embodiments do not limit the scope of the invention.

Claims (2)

1. the nucleosides that has formula 1 structure
Figure A0012191200021
2. the nucleosides that has formula 2 structures.
Figure A0012191200022
CN00121912A 1997-01-14 2000-07-22 Novel nucleoside Pending CN1312254A (en)

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US60/036094 1997-01-14
US3609497P 1997-01-17 1997-01-17
US4397497P 1997-04-23 1997-04-23
US2858697P 1997-04-23 1997-04-23
US60/028586 1997-04-23
US60/043974 1997-04-23
US5548797P 1997-08-12 1997-08-12
US60/055487 1997-08-12

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