CN104447747B - Substituted purin class neuraminidase inhibitor and using method thereof and purposes - Google Patents

Substituted purin class neuraminidase inhibitor and using method thereof and purposes Download PDF

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CN104447747B
CN104447747B CN201410728135.XA CN201410728135A CN104447747B CN 104447747 B CN104447747 B CN 104447747B CN 201410728135 A CN201410728135 A CN 201410728135A CN 104447747 B CN104447747 B CN 104447747B
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compound
acid
present
pharmaceutical composition
methyl
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CN104447747A (en
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任青云
刘辛昌
罗慧超
张健存
张英俊
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Haitong Hengxin International Finance Leasing Tianjin Co ltd
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine

Abstract

The invention provides a kind of substituted purin compounds or its steric isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or prodrug of novelty, for suppressing neuraminidase.Present invention also offers the pharmaceutical composition comprising this compounds, and use the method for the compounds of this invention or pharmaceutical composition prevention or treatment disease of viral infection.

Description

Substituted purin class neuraminidase inhibitor and using method thereof and purposes
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to the substituted purin compounds as neuraminidase inhibitor and pharmaceutical composition thereof, and the purposes in the disease that causes in prevention or treatment influenza virus of described substituted purin compounds and pharmaceutical composition thereof.
Background technology
Influenza, being called for short influenza, is the Acute respiratory infectious disease caused by influenza virus.This disease propagation is strong, and propagating wide, is often endemic conditions, is one of important public health problem expecting at present to solve.
Find, influenza surface has two kinds of glycoprotein: hemagglutinin (HA) and neuraminidase (NA).Wherein neuraminidase (NA) i.e. sialidase, its zymetology code is EC3.2.1.18, influenza virus copy with course of infection in play key enzyme (Calfee, D.P.; Hayden, F.G.Drugs, 1998,56,537.).NA can the sialic acid residues of catalytic pyrolysis host cell surface receptor end and glycoprotein, α-glycosidic link between glycolipid and oligosaccharide, thus promote that the new virus particle formed discharges from the sialic acid residues of host cell, promote that virus particle organizes diffusion towards periphery from the respiratory mucosa infected, and the cohesion after stoping virus to be disengaged from host cell.NA is by the sialic acid in cracking respiratory mucosa simultaneously, stops inactivation of virus, promotes that virus infiltrates airway epithelial cell.In addition, NA, by changing the carbohydrate portions of surface glycoprotein HA, strengthens toxicity, promotes that virus discharges from infected host cell, causes or increase the weight of flu-like symptom.Therefore, the diffusion of virus must rely on the biological activity of NA, by the specific suppression of NA, effectively can suppress the propagation of influenza virus, thus play the effect of anti influenza.
But along with the acceleration variation of influenza virus and the increase of different subtype virus recombination probability between species, influenza, as worldwide seasonal epidemic sexually transmitted disease, increases the threat of human health and sternness just day by day.Neuraminidase (NA) inhibitor has the type compounds such as Zanamivir, Oseltamivir and Peramivir, and wherein Oseltamivir is widely used.But research has found that some virus strain create resistance to Oseltamivir, therefore in the urgent need to studying the medicine of novel resisiting influenza virus.
Summary of the invention
For the deficiencies in the prior art, the present invention finds the novel inhibitors with influenza neuraminidase inhibit activities more, provides the substituted purin compounds of the new resisiting influenza virus neuraminidase activity of a class.
The present invention also provides the method for this compounds of preparation and the pharmaceutical composition containing this compounds.
On the one hand, the present invention relates to a kind of compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug
Wherein:
R 1for-OH or-C (=O) OR 2;
R 2for H or C 1-6alkyl; With
N is 0 or 1.
In one embodiment, R 2for C 1-4alkyl.
In one embodiment, R 2for methyl, ethyl, n-propyl or sec.-propyl.
In one embodiment, R 1for-OH ,-C (=O) OCH 3or-C (=O) OCH 2cH 3.
In one embodiment, compound of the present invention has one of following structure:
or its steric isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug.
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises the compounds of this invention.
In one embodiment, pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable carrier, vehicle, thinner, assistant agent or vehicle further.
In another embodiment, pharmaceutical composition of the present invention its further comprise additional treatment agent, wherein said additional treatment agent is Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, method draw Wei, amantadine, Rimantadine, arbidol, ribavirin, Si Tafulin, ingavirin (Ingavirin), GR-217029 or its combination.
On the other hand, the present invention relates to compound of the present invention or pharmaceutical composition for the preparation of preventing, processing, alleviate or treat the purposes in virus infective medicament.
In one embodiment, virus infection of the present invention is influenza infection.
On the one hand, the present invention includes all suitable isotropic substance change of different compound.The isotropic substance change of the compounds of this invention is defined as: wherein at least one atom is had same atoms ordinal number but different from the atomic mass that usual occurring in nature finds, and preferably enriches most isotopic atom and replaces.The isotopic example can introducing the compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, sulphur, and fluorine and chlorine, such as, be respectively: H 2, H 3, C 11, C 13, C 14, N 15, O 17, O 18, S 35, F 18and Cl 36.Some isotropic substance change of the present invention, such as, those wherein introduce radioisotopic compound, such as: introduce H 3or C 14, very useful in the research that medicine and/or matrix organization distribute.Containing tritium, that is: H 3, and carbon-14, that is: C 14isotropic substance because they are easy to preparation and detectability and particularly preferably.In addition, due to larger metabolic stability, by isotropic substance, such as: deuterium, that is: H 2replace the treatment advantage that can provide certain, such as, the transformation period in vivo increased, the dose demand of minimizing, and be therefore preferred in some cases.The isotropic substance change of the compounds of this invention can be prepared by traditional method substantially, uses the suitable isotropic substance change of suitable agent.
On the other hand, structural formula described in the invention comprises all stereoisomeric forms in any ratio (enantiomerisms, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
On the other hand, all tautomeric forms of compound of the present invention are included within scope of the present invention.
On the other hand, the oxynitride of the compounds of this invention is also contained within scope of the present invention.Can by using conventional oxygenant (such as hydrogen peroxide) at an elevated temperature, under having the acid of such as acetic acid to exist, be oxidized corresponding nitrogenous alkaline matter, or by be applicable to solvent in cross acid-respons, such as react with peracetic acid in methylene dichloride, ethyl acetate or methyl acetate, or react with 3-chloroperoxybenzoic acid in chloroform or methylene dichloride, prepare the oxynitride of the compounds of this invention.
On the other hand, the salt of the compounds of this invention comprises pharmacy acceptable salt; Also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
Definition and general terms
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.The term no matter discussed occurs separately or combination appearance, and definition described herein is all applicable.
According to object of the present invention, chemical element according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, 75, thed, 1994 define.In addition, organic chemistry General Principle is shown in " OrganicChemistry; " Sorrelletal., UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry; " bySmithetal., JohnWiley & Sons, NewYork:2007, therefore all contents have all merged reference.
Except as otherwise noted or in context, have obvious conflict, article used herein " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.
The present invention says that the term " patient " of use refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.
Term " optionally " or " optionally " refer to that the event that describes subsequently or situation may instead of necessarily occur, and this description comprises the situation that wherein said event or situation occur, and situation about not occurring.
Term " replacement " or " replacement ", represent one or more hydrogen atoms in described structure replace by concrete substituting group.Unless other aspects show, a group replaced can have a substituting group to replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.
Term " optionally by .... replaced " or " optionally quilt .... replacement ", can " not replace or quilt ... .. replaced " to exchange with term and use, namely described structure is unsubstituted or is replaced by one or more substituting group of the present invention, substituting group of the present invention comprises, but be not limited to D, F, Cl, N 3,-CN ,-OH ,-SH ,-NH 2, alkyl, alkoxyl group, alkylamino, heterocyclic radical, aryl, heteroaryl, etc.
In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be separately " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.
Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C 1- 6alkyl " refer in particular to independent disclosed methyl, ethyl, C 3alkyl, C 4alkyl, C 5alkyl and C 6alkyl.
At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.
The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1-20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom; In another embodiment, alkyl group contains 1-6 carbon atom; In yet another embodiment, alkyl group contains 1-4 carbon atom; Also in one embodiment, alkyl group contains 1-3 carbon atom.Described alkyl group optionally replace by one or more substituting group described in the invention.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3), n-pentyl (-CH 2cH 2cH 2cH 2cH 3), 2-amyl group (-CH (CH 3) CH 2cH 2cH 3), 3-amyl group (-CH (CH 2cH 3) 2), 2-methyl-2-butyl (-C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (-CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (-CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (-CH 2cH (CH 3) CH 2cH 3), n-hexyl (-CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (-CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (-CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (-C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (-CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (-CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (-C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (-CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (-C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3), n-heptyl, n-octyl, etc.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom.The substituting group that described alkoxy base is optionally described by one or more the present invention replace.
The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH 3), oxyethyl group (EtO ,-OCH 2cH 3), 1-propoxy-(n-PrO, n-propoxy-,-OCH 2cH 2cH 3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH 3) 2), 1-butoxy (n-BuO, n-butoxy ,-OCH 2cH 2cH 2cH 3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH 2cH (CH 3) 2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH 3) CH 2cH 3), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH 3) 3), 1-pentyloxy (n-pentyloxy ,-OCH 2cH 2cH 2cH 2cH 3), 2-pentyloxy (-OCH (CH 3) CH 2cH 2cH 3), 3-pentyloxy (-OCH (CH 2cH 3) 2), 2-methyl-2-butoxy (-OC (CH 3) 2cH 2cH 3), 3-methyl-2-butoxy (-OCH (CH 3) CH (CH 3) 2), 3-methyl-l-butoxy (-OCH 2cH 2cH (CH 3) 2), 2-methyl-l-butoxy (-OCH 2cH (CH 3) CH 2cH 3), etc.
Term " hydroxyalkyl " represents that alkyl group can be optionally substituted with one or more hydroxyl group and replaced, and wherein alkyl group has implication as described in the present invention, and such example comprises, but be not limited to hydroxymethyl, 1-hydroxyethyl, 1,2-dihydroxypropyl, etc.
Term " steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometry (cis/trans) isomer, atropisomer, etc.
Term " diastereomer " refers to two or more chiral centres and the steric isomer of its molecule not mirror image each other.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture is by high resolution analysis operation as electrophoresis and chromatogram, and such as HPLC is separated.
Term " enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.
Term " racemoid " or " racemic mixture " be optically active two the corresponding isomer species of hypodactylia etc. molar mixture.
Term " chirality " is that have can not the molecule of overlapping character with its mirror image; And " achirality " refer to can be overlapping with its mirror image molecule.
Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYork; AndEliel, E.andWilen, S., " StereochemistryofOrganicCompounds ", JohnWiley & Sons, Inc., NewYork, 1994.
Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.
The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.
By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, and can with reference to Jacques, etal., Enantiomers, RacematesandResolutions (WileyInterscience, NewYork, 1981); PrinciplesofAsymmetricSynthesis (2 nded.RobertE.Gawley, JeffreyAube, Elsevier, Oxford, UK, 2012); Eliel, E.L.StereochemistryofCarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S.H.TablesofResolvingAgentsandOpticalResolutionsp.268 (E.L.Eliel, Ed., Univ.ofNotreDamePress, NotreDame, IN1972); ChiralSeparationTechniques:APracticalApproach (Subramanian, G.Ed., Wiley-VCHVerlagGmbH & Co.KGaA, Weinheim, Germany, 2007).
Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (lowenergybarrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropictautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valencetautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.
" pharmaceutically acceptable " refers to some compounds, raw material, composition and/or formulation like this, they are in the scope that rational medicine judges, to be applicable to patient tissue contacts and without excessive toxicity, pungency, transformation reactions or the other problems symmetrical with rational interests/Hazard ratio and complication, and to be effective to given application.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises OH group, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: Higuchietal., Pro-drugsasNovelDeliverySystems, Vol.14, A.C.S.SymposiumSeries; Rocheetal., ed., BioreversibleCarriersinDrugDesign, AmericanPharmaceuticalAssociationandPergamonPress, 1987; Rautioetal., Prodrugs:DesignandClinicalApplications, NatureReviewsDrugDiscovery, 2008,7,255-270, andHeckeretal, ProdrugsofPhosphatesandPhosphonates, J.Med.Chem., 2008,51,2328-2345, every section of document is contained in this by reference.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
Term " pharmacy acceptable salt " refers within the scope of reliable medical judgment, is suitable for not occurring excessive toxicity, stimulation, anaphylaxis etc. with the mankind and zootic contact tissue, and the salt matched with rational effect/Hazard ratio.Pharmacologically acceptable salts is well known in the art.Such as, S.M.Berge, etal., J.PharmaceuticalSciences, be described in detail pharmacologically acceptable salts in 1977,66:1.
The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, acetate, adipate, alginates, Citrate trianion, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, maleate, lauroleate, lauryl sulfate, malate, malonate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, stearate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate, undecane hydrochlorate, valerate etc.The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-C 4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-C 8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Term " solvate " refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, thanomin or its mixture.
When described solvent is water, term " hydrate " can be used.In certain embodiments, a compounds of this invention molecule can combine with a water molecules, such as monohydrate; In other embodiment, a compounds of this invention molecule can combine with more than one water molecules, such as dihydrate, also has in some embodiments, a compounds of this invention molecule can combine with the water molecules being less than, such as semihydrate.It should be noted that hydrate of the present invention remains with the biological effectiveness of the described compound of nonhydrated form.
Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; benzoyl, ethoxy carbonyl, tertbutyloxycarbonyl (BOC); carbobenzoxy-(Cbz) (CBZ), the sub-methoxycarbonyl (Fmoc) of 9-fluorenes and benzyl.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises trialkylsilkl, ethanoyl, benzoyl and benzyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: Greeneetal., ProtectiveGroupsinOrganicSynthesis, JohnWiley & Sons; NewYork, 1991andKocienskietal., ProtectingGroups; Thieme, Stuttgart, 2005.
Term " prevents " or " prevention " refers to that the minimizing of the risk obtaining disease or obstacle (that is: makes at least one clinical symptom of disease in main body, stop development, this main body may in the face of or in advance tendency in the face of this disease, but also do not experience or show the symptom of disease).
Term " treatment significant quantity " refers to when delivering medicine to main body and carrying out disease therapy, and the component of compound is enough to the treatment onset of this disease." treatment significant quantity " can along with compound, disease and severity, and the condition having main body to be treated, the age, body weight, sex etc. and changing.
" treatment " of morbid state comprises: (i) preventing disease state, that is, make to be exposed to or susceptible disease state but also do not experience or show the clinical symptom not developing deeply of morbid state of experimenter of symptom of morbid state; (ii) suppress morbid state, that is, stop the development of morbid state or its clinical symptom, or (iii) alleviates morbid state, that is, make morbid state or its clinical symptom temporarily or forever disappear.
The composition of the compounds of this invention, preparation and administration
The invention provides a kind of pharmaceutical composition, comprise compound or its independent steric isomer of formula (I), the racemize of isomer or non-racemic mixture or its pharmacy acceptable salt or solvate.In an embodiment of the invention, described pharmaceutical composition comprises the pharmaceutically acceptable carrier of at least one, assistant agent or vehicle further, and optionally, other treat and/or prevent composition.
Suitable carrier, assistant agent and vehicle agent be for those skilled in the art know and be described in detail in such as AnselH.C.etal., Ansel ' sPharmaceuticalDosageFormsandDrugDeliverySystems (2004) Lippincott, Williams & Wilkins, Philadelphia; GennaroA.R.etal., Remington:TheScienceandPracticeofPharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; And in RoweR.C., HandbookofPharmaceuticalExcipients (2005) PharmaceuticalPress, Chicago.
Compound of the present invention or composition can by any suitable method administrations, comprise oral (comprise containing clothes and sublingual), locally, rectum, vagina, transdermal, parenteral (intramuscular, intravenously, intra-arterial, intraperitoneal or subcutaneous), in lung, intracutaneous, in sheath and in epidural and nose, and if need for topical therapeutic, intralesional administration.Preferred mode is oral administration, to Intraperitoneal medication or intravenous injection.
For Orally administered, described pharmaceutical composition can adopt such as following form: the tablet prepared by the pharmaceutically acceptable vehicle of ordinary method or capsule, and described vehicle is tackiness agent (such as pregelatinized corn starch, Polyvinylpyrolidone (PVP) or Vltra tears) such as; Weighting agent (such as lactose, Microcrystalline Cellulose or calcium phosphate); Lubricant (such as Magnesium Stearate, talcum or silicon-dioxide); Disintegrating agent (such as yam starch or sodium starch glycolate); Or wetting agent (such as Sodium Lauryl Sulphate BP/USP).Tablet can dressing by means commonly known in the art.
Orally administered liquid preparation can adopt such as following form: solution, syrup or suspension, or can the form of desciccate exist, with the carrier reconstruct be applicable to water or other before use.These liquid preparations can adopt pharmaceutically acceptable additive to prepare by ordinary method, and described additive is suspension agent (edible fat of such as sorbitol syrup, methylcellulose gum or hydrogenation) such as; Emulsifying agent (such as Yelkin TTS and Sudan Gum-arabic); Nonaqueous carrier (such as Prunus amygdalus oil, oily ester or ethanol) and sanitas (as methyl p-hydroxybenzoate or propylparaben or Sorbic Acid).
For sucking and using, described composition can adopt the form of tablet or the lozenge prepared in conventional manner.
The composition being suitable for parental injection can comprise physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion agent, suspensoid or emulsion, and for reconstructing the sterile powders of sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agent and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., can guarantee the effect preventing microorganism.Also expect to comprise isotonic agent, such as carbohydrate, sodium-chlor etc.Such as, by using the material that can postpone to absorb, aluminum monostearate and gelatin, the prolongation that can reach injectable drug form absorbs.
Also suspension agent can be contained in addition to the active compound, the mixture etc. of such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, partially aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials in suspensoid.
In some cases, be the effect of prolong drug, expect absorption that is subcutaneous or intramuscular injection of drugs of slowing down.This realizes by using the crystal of poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.
Injectable depot formulations form is by preparing at the microcapsule matrix of biodegradable polymer as formed medicine in polylactide-polyglycolide (polylactide-polyglycolide).According to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopted, drug releasing rate can be controlled.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can be prepared in the liposome compatible with bodily tissue or micro emulsion by pharmaceutical pack being embedded in.
Injectable formulation can such as by filtering with bacterial filter or carrying out sterilizing by the disinfectant mixing aseptic solid composite form, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention can be prepared as paste, creme or lotion or be used for epidermis topical as pasting through skin.Paste and creme such as use or oil binder (base) can add suitable thickening material and/or jelling agent preparation.Lotion can use or oil binder preparation, and usually also will containing one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material.Be suitable for the formulation of topical in mouth to comprise: lozenge, it is included in flavouring base, the promoting agent in usually sucrose and Acacia or tragacanth gum; Pastille, it is included in the activeconstituents in inertia base-material such as gelatin and glycerine or sucrose and Acacia; And collutory, it is included in the activeconstituents in suitable liquid vehicle.In addition, the pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.
The pharmaceutically acceptable composition of the present invention can with the form rectum of suppository or vagina administration.These can form by reagent and suitable non-perfusing adjuvant being mixed with, and this adjuvant is at room temperature solid but is then liquid at the temperature of rectum or vagina, thus melts in rectum or vagina and discharge medicine.Such material comprises cocoa butter, beeswax, and polyethylene glycols.
For using for intranasal administration or by suction, active compound of the present invention is sent easily with the form of the aerosol spray in pressurizing vessel or atomizer or in the capsule of employing sucker or insufflator.In the case of a pressurized aerosol, suitable propellent (such as Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other gas be applicable to) and unitary dose can be determined by the amount providing valve to send through metering.The medicine of pressurizing vessel or atomizer can comprise solution or the suspension of active compound, concerning then its preferred powder type capsule.The capsule and cartridge case (being made up of such as gelatin) that are used for sucker or insufflator can be mixed with the powdered mixture comprising the compounds of this invention and suitable powdered substrate (such as lactose or starch).
" often spraying (puff) " that aerosol formulation for treating above-mentioned illness in average adult is preferably prepared as each dosing or aerosol comprises the compounds of this invention of 20 μ g to 1000 μ g.Every TDD of aerosol is in the scope of 100 μ g to 10mg.Can use several times in one day, such as 2,3,4 or 8 times, give such as 1,2 or 3 dosage at every turn.
Pharmaceutical preparation is preferably unit dosage.In this form, preparation is subdivided into the unitary dose containing appropriate active ingredient.Unit dosage can be the preparation of packaging, and this packaging contains the preparation of discrete magnitude, as tablet, capsule and the powder in bottle or ampoule packed.In addition, unit dosage can be capsule, tablet, cachet or lozenge itself, or can be the packaged form of these formulations any of proper amt.
It should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, the dosage that formula (I), (II), (III) or (IV) compound are used for Mammals particularly people can be 0.1-1000mg/kg/day, be preferably 1-100mg/kg/day, taking can be once a day or for several times, and takes medicine for each time and can comprise 1,2 or 3 dosage.
The purposes of the compounds of this invention and composition
Above-claimed cpd provided by the invention and pharmaceutical composition can be used for for the preparation of prevention, the medicine treating or alleviate patient's disease of viral infection, and preferably, described virus infection is influenza infection.
The present invention also provides above-claimed cpd or its pharmaceutical composition preparing the purposes in neuraminidase inhibitor class medicine.
The invention provides a kind of method being used for the treatment of, preventing or delaying the infection caused by virus, described method comprises above-claimed cpd or its pharmaceutical composition of the bacterium having treatment needs.Wherein said virus is influenza virus.Further, above-claimed cpd provided by the invention or its pharmaceutical composition can be used jointly with other therapies or therapeutical agent.Method of application can for simultaneously, order or carry out with certain hour interval.
Implement treatment, prevent or the dosage of the compound that to delay etc. needed for effect or pharmaceutical composition usually depend on use particular compound, patient, disease specific or illness and severity, route of administration and frequency etc., and need to be judged as the case may be by attending doctor.Such as, when by using compound provided by the invention or pharmaceutical composition through intravenous route, can even use with longer time interval once in a week.
In sum, the invention provides a kind of novel cpd, described compound can be used as neuraminidase inhibitor.Compound of the present invention is applicable to the medicine making multiple formulation, can be widely used in treatment seasonal influenza, bird flu, porcine influenza and Tamiflu be had to the influenza virus mutant strain of resistance.
Compound of the present invention and pharmaceutical composition, except useful to human treatment, also can be applicable to the Mammals in veterinary treatment pet, the animal of introduced variety and the animal on farm.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.
the synthetic method of compound
For describing the present invention, below list embodiment.But need be appreciated that and the invention is not restricted to these embodiments, only be to provide and put into practice method of the present invention.
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as AldrichChemicalCompany, ArcoChemicalCompanyandAlfaChemicalCompany, unless other aspects show, all not through being further purified during use.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemical reagent factory in morning, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited and Haiyang Chemical Plant, Qingdao buy and obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, quartet), dt (doubletoftriplets, two triplet).Coupling constant, represents with hertz (Hz).
The condition of Algorithm (MS) data is: (3.5 microns, 6min, flow velocity is 0.6mL/min to Agilent1200 or Agilent6120SeriesLCMS for pillar model: ZorbaxSB-C18,2.1 × 30mm.Moving phase: 5-95% is (containing the CH of 0.1% formic acid 3cN) (containing the H of 0.1% formic acid 2o) ratio in, detects at 210/254nm UV, by low-response EFI pattern (ESI).
The characteristic manner of pure compound is: Agilent1100Series high speed liquid chromatography (HPLC), detects at 210nm and 254nm UV.Pillar operates usually at 40 DEG C.
The use of brief word below runs through the present invention:
Aq. the aqueous solution
SOCl 2sulfur oxychloride
HCl hydrochloric acid
Pd (OH) 2palladium hydroxide
CH 2cl 2, DCM methylene dichloride
CDC1 3deuterochloroform
DMFN, dinethylformamide
DMSO dimethyl sulfoxide (DMSO)
EtOAc, EA ethyl acetate
Et 3n, TEA triethylamine
G gram
H hour
H 2sO 4sulfuric acid
K 2cO 3salt of wormwood
KI potassiumiodide
KCl Repone K
MeOH, CH 3oH methyl alcohol
MgSO 4magnesium sulfate
ML, ml milliliter
Min minute
N 2nitrogen
RT, rt, r.t. room temperature
NaBH 4sodium borohydride
NH 4c1 ammonia chloride
NaHCO 3sodium bicarbonate
NaCl sodium-chlor
Na 2sO 4sodium sulfate
PE sherwood oil (60-90 DEG C)
THF tetrahydrofuran (THF)
Following synthetic schemes describes preparation the present invention and to come into the open the step of compound.Unless otherwise indicated, n and R1 has definition as described in the present invention.
Synthetic schemes 1
Compound 4 can be prepared by synthetic schemes 1, and wherein-Bn is benzyl, and MsO-is mesyloxy.Compound 1 and compound 2 reacting generating compound 3 under sodium hydride effect, compound 3 is sloughed benzyl protecting group through palladium carbon catalytic reduction further and is obtained target compound 4.
Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
Embodiment
Embodiment 12-amino-9-((3-hydroxycyclobutyl) methyl)-3H-purine-6 (9H)-one
Step 1) 3-oxygen cyclobutane-carboxylic acid methyl esters
In methyl alcohol (50mL) solution of 3-oxygen cyclobutane formate (10.0g, 0.088mol), slowly SOCl is dripped at 0 DEG C 2(3.1mL, 0.045mol), adds rear reaction solution and refluxes 4 hours.Reaction solution concentrating under reduced pressure is except desolventizing, and it is colourless oil liquid (10.0g, >90%) that residue over silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) obtains target compound.
MS-ESI:(ESI,pos.ion)m/z:129.2[M+H] +；
1HNMR(400MHz,CDCl 3)δ(ppm):3.77(s,3H),3.23-3.46(m,5H)。
Step 2) 3,3-dimethoxy cyclobutane-carboxylic acid methyl esters
By 3-oxygen cyclobutane-carboxylic acid methyl esters (15g, 117.19mmol) be dissolved in methylene dichloride (50mL), add trimethyl orthoformate (25.7mL, 234.4mmol) with tosic acid (0.75g, 5%), react 5 hours at reaction solution is placed in 45 DEG C, TLC monitoring after completion of the reaction.Water (50mL) is added in reaction solution, and extract with methylene dichloride (20mLx2), then organic phase saturated aqueous common salt (40mLx2) washs, with anhydrous sodium sulfate drying, it is colourless oil liquid (19.6g, 96%) that concentrating under reduced pressure obtains target compound.
MS-ESI:(ESI,pos.ion)m/z:175.3[M+H] +。
Step 3) (3,3-dimethoxy tetramethylene base) methyl alcohol
By lithium aluminium hydride (4.06g, 106.78mmol) be placed in the anhydrous tetrahydro furan (150mL) of 0 DEG C, add anhydrous 3,3-bi-methoxy cyclobutane-carboxylic acid methyl esters (18.6g, tetrahydrofuran (THF) (50mL) solution 106.78mmol), reaction mixture stirs 17 hours at 0 DEG C.Then in reaction solution, Na is added 2sO 4.10H 2o also filters, and it is colourless oil liquid (10.7g, 69%) that filtrate concentrating obtains target compound.
MS-ESI:(ESI,pos.ion)m/z:147.2[M+H] +；
1HNMR(400MHz,CD 3OD)δ(ppm):3.60(d,2H),3.12(s,3H),3.10(s,3H),2.27(m,1H),2.24(s,1H),2.23(m,2H)；1.85(m,2H)。
Step 4) (3,3-dimethoxy cyclobutyl) methylmethanesulfonate ester
By (3,3-dimethoxy tetramethylene base) methyl alcohol (5.7g, 38.99mmol) be dissolved in methylene dichloride (150mL), add triethylamine (16.2mL, 116.97mmol) with Methanesulfonyl chloride (3.62mL, 46.79mmol), rear maintenance 0 DEG C reaction 12 hours are added.Reaction solution adds saturated ammonium chloride solution (50mL) washing, separatory again, dichloromethane solution saturated nacl aqueous solution washing (50mLx2) obtained, organic phase uses anhydrous sodium sulfate drying again, concentrating under reduced pressure obtains crude product, it is colourless oil liquid (6.25g, 72%) that crude product uses purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) to obtain target compound further.
MS-ESI:(ESI,pos.ion)m/z:225.3[M+H] +。
Step 5) 6-(benzyloxy)-9-((3,3-dimethoxy cyclobutyl) methyl)-6,9-dihydro-3H-purine-2-ammonia
By 6-(benzyloxy)-6,9-dihydro-3H-purine-2-ammonia (1.0g, 4.11mmol) be dissolved in dry N, in dinethylformamide (30mL) solution, NaH (164mg is dripped at 0 DEG C, N 4.11mmol), dinethylformamide (10mL) solution, drip off rear reaction solution in stirred at ambient temperature 30 minutes, then (3 are added under room temperature, 3-dimethoxy tetramethylene base) anhydrous tetrahydro furan (1mL) solution of methyl alcohol (920mg, 4.11mmol).Reaction continues stirring 12 hours, and TLC monitors reaction.Add saturated ammonium chloride solution (20mL) after completion of the reaction, then ethyl acetate (50mLx2) is used to extract, dry, pressure reducing and steaming solvent obtains residue, obtaining target compound with purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) is white solid (700mg, 53%).
MS-ESI:(ESI,pos.ion)m/z:372.3[M+H] +。
Step 6) 3-((2-amino-6-(benzyloxy)-3H-purine-9 (6H)-Ji) methyl) cyclobutanone
By tosic acid (345mg, 2mmol) drop to 6-(benzyloxy)-9-((3,3-dimethoxy cyclobutyl) methyl)-6,9-dihydro-3H-purine-2-ammonia (370mg, ethanol/water (v/v=10/1 1mmol), in mixing solutions 33mL), reaction system at room temperature stirs 2 hours.Then add saturated sodium bicarbonate solution, adjust ph, to 7, then concentrates and obtains crude product.Crude product use water (20mL) disperses and uses ethyl acetate (30mLx2) to extract, and ethyl acetate uses saturated nacl aqueous solution (30mLx2) to wash mutually, anhydrous sodium sulfate drying, concentrates and obtains crude product.It is white solid (210mg, 68%) that crude product uses silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying to obtain target compound further.
MS-ESI:(ESI,pos.ion)m/z:326.1[M+H] +；
1HNMR(400MHz,DMSO)δ(ppm):7.19-7.53(m,6H),5.48(s,2H),4.83(s,2H),3.05-3.12(m,2H),2.85-2.94(m,1H+2H)。
Step 7) 3-((2-amino-6-(benzyloxy)-3H-purine-9 (6H)-Ji) methyl) cyclobutanol
By sodium borohydride (160mg, at 0 DEG C, 4.3mmol) be added to 3-((2-amino-6-(benzyloxy)-3H-purine-9 (6H)-Ji) methyl) cyclobutanone (700mg, in methanol solution (10mL) 2.15mmol), continue stirring 2 hours at this temperature.After reaction terminates, add 5%HCl adjust ph to 7, removal of solvent under reduced pressure, then obtaining target compound by purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) is white solid (500mg, 71%).
MS-ESI:(ESI,pos.ion)m/z:328.1[M+H] +；
1HNMR(400MHz,DMSO)δ(ppm):7.29-7.57(m,6H),5.55(s,2H),4.83(s,2H),2.40-2.46(m,2H),2.10-2.28(m,1H+1H)，1.69-1.74(m,2H)。
Step 8) 2-amino-9-((3-hydroxycyclobutyl) methyl)-3H-purine-6 (9H)-one
By 3-((2-amino-6-(benzyloxy)-3H-purine-9 (6H)-Ji) methyl) cyclobutanol (100mg, 3.05mmol) and Pd (OH) 2(20mg) be dissolved in methyl alcohol (10mL), pass into hydrogen stirred overnight at room temperature.TLC monitors, and after completion of the reaction, cross and filter methyl alcohol, it is white solid (400mg, 57%) that residue over silica gel column chromatography (methylene chloride/methanol=10/1) obtains target compound.
MS-ESI:(ESI,pos.ion)m/z:236.1[M+H] +；
1HNMR(400MHz,DMSO)δ(ppm):10.57(s,1H),7.63(s,1H),6.64(s,2H),5.01-5.06(m,1H),4.11(d,J＝2.4Hz,2H),1.99-2.21(m,5H)。
Embodiment 23-(2-amino-6-oxygen-3H-purine-9 (6H)-Ji) cyclobutane-carboxylic acid methyl esters
Step 1) 3-hydroxycyclobutane carboxylate methyl ester
3-oxygen cyclobutane-carboxylic acid methyl esters (8g, 62.5mmol) is dissolved in THF/MeOH (v/v=1/2,240mL), at 0 DEG C, adds sodium borohydride (4.75g, 125mmol), continue at such a temperature to stir 2h.After reaction terminates, saturated aqueous ammonium chloride (50mL) is added in mixture, removal of solvent under reduced pressure obtains thick product, in crude product, add ethyl acetate (150ml) pull an oar and filter, filtrate reduced in volume obtains crude product, crude product purified by silica gel column chromatogram chromatography (petrol ether/ethyl acetate (v/v)=3/1) purifying obtains target compound (3.2g, 39%).
MS-ESI:(ESI,pos.ion)m/z:131.2[M+1] +。
Step 2) 3-(mesyloxy) cyclobutane-carboxylic acid methyl esters
By 3-hydroxycyclobutane carboxylate methyl ester (3.2g, 24.61mmol) be dissolved in DCM (100mL), triethylamine (10.25mL is added at-10 DEG C, 73.83mmol) with first sulphur SULPHURYL CHLORIDE (2.29mL, 29.54mmol), mixture continues to react 3h at this temperature.After reaction terminates, saturated aqueous ammonium chloride (60mL) is added in reaction solution, washing separatory, the DCM phase obtained is further with saturated sodium-chloride water solution washing (50mlx2), organic phase uses anhydrous sodium sulfate drying subsequently, decompression removing organic phase obtains crude product, and crude product uses silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purifying to obtain target compound (4.9g, 95.7%) further.
MS-ESI:(ESI,pos.ion)m/z:209.1[M+1] +。
Step 3) 3-(2-amino-6-(benzyloxy)-3H-purine-9 (6H)-Ji) cyclobutane-carboxylic acid methyl esters
By compound 6-(benzyloxy)-6,9-dihydro-3H-purine-2-ammonia (3.01g, 12.73mmol) be dissolved in anhydrous DMSO (150mL), add 3-(mesyloxy) cyclobutane-carboxylic acid methyl esters (2.65g, 12.73mmol), salt of wormwood (2.1g, 15.28mmol) and cuprous iodide (485mg, 2.546mmol), reaction solution stirs 23h at 130 DEG C.After reaction terminates, reaction solution is added in water (200mL), and be extracted with ethyl acetate (150mlx2), organic phase saturated sodium-chloride water solution washing (150mlx2), use anhydrous sodium sulfate drying again, filtering and concentrating obtains crude product, and crude product continuation preparative HPLC purifying obtains target compound (181mg, 4.2%).
MS-ESI:(ESI,pos.ion)m/z:356.4[M+1] +。
Step 4) 3-(2-amino-6-oxygen-3H-purine-9 (6H)-Ji) cyclobutane-carboxylic acid methyl esters
By 3-(2-amino-6-(benzyloxy)-3H-purine-9 (6H)-Ji) cyclobutane-carboxylic acid methyl esters (711mg, 2mmol) and Pd (OH) 2(15mg) be dissolved in methyl alcohol (10mL), pass into hydrogen stirred overnight at room temperature.After completion of the reaction, cross and filter methyl alcohol, it is white solid (253mg, 48%) that residue over silica gel column chromatography (methylene chloride/methanol=10/1) obtains target compound in TLC monitoring.
MS-ESI:(ESI,pos.ion)m/z:264.5[M+1] +；
1HNMR(400MHz,DMSO)δ(ppm):9.57(s,2H),7.63(s,1H),4.24(s,1H),3.87(s,3H),3.31(s,1H),2.65-2.87(m,4H)。
Activity test
A. anti-influenza virus activity measures
1.96 orifice plate CPE assay methods
1) spread 96 orifice plates, 5000 mdck cells are inoculated in every hole, 37 DEG C, 5%CO 2, incubated overnight.
2) use DMSO and serum free medium diluted compounds to suitable concn, DMSO final concentration is 1%.
3) with the influenza virus H1N1 (A/weiss/43) that substratum dilution-80 DEG C is frozen.
4) virus liquid (final MOI=0.01) after the compound after every hole adds 50 μ l dilutions and 50 μ l dilute.
5) 96 orifice plates are placed in 37 DEG C, 5%CO 2, cultivate 3 days.
6) every hole adds 20 μ lMTT, is placed in 37 DEG C, hatches 4 hours.
7) measure the first a ceremonial jade-ladle, used in libation amount that MTT is generated by viable cell reduction, and the CPE calculating influenza virus mediation is accordingly detected the per-cent that compound suppresses.
2.96 orifice plates measure cytotoxicity
1) spread 96 orifice plates, 5000 mdck cells are inoculated in every hole, 37 DEG C, 5%CO 2, incubated overnight.
2) use DMSO and serum free medium diluted compounds to suitable concn, DMSO final concentration is 1%.
3) every hole add 50 μ l dilute after compound and 50 μ l nutrient solutions.
4) 96 orifice plates are placed in 37 DEG C, 5%CO 2, cultivate 3 days.
5) every hole adds 20 μ lMTT, is placed in 37 DEG C, 4 hours.
6) measure the first a ceremonial jade-ladle, used in libation amount that MTT is generated by viable cell reduction, and calculate the cytotoxicity of test compound accordingly.
3. data analysis
% inhibiting rate=(OD t– OD v)/(OD c– OD v) × 100%, % cytotoxicity=OD t/ OD c× 100%, % activity=% inhibiting rate-% cytotoxicity, wherein OD t, OD vand OD crepresent the specific absorbance of test compounds respectively, virus-infected controls (without compound ,+1%DMSO), and cell blank contrast (virus-free, without compound ,+1%DMSO).
ODvalue＝OD 570–OD 630(MTT)
4. experimental result
The compounds of this invention anti-influenza virus activity result is as shown in table 1.
Table 1 the compounds of this invention infected by influenza H1N1 (A/weiss/43) experiment in vitro activity value
As shown in Table 1, compound involved in the present invention has obvious anti-influenza virus activity.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.

Claims (10)

1. a compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), tautomer or pharmacy acceptable salt,
Wherein:
R 1for-C (=O) OR 2;
R 2for H or C 1-6alkyl; With
N is 0.
2. compound according to claim 1, wherein R 2for C 1-4alkyl.
3. compound according to claim 1, wherein R 2for methyl, ethyl, n-propyl or sec.-propyl.
4. compound according to claim 1, wherein R 1for-C (=O) OCH 3or-C (=O) OCH 2cH 3.
5. the compound according to claim 1-4 any one, wherein said compound has one of following structure:
or its steric isomer, tautomer or pharmacy acceptable salt.
6. a pharmaceutical composition, comprises the compound described in claim 1-5 any one.
7. pharmaceutical composition according to claim 6, comprises the pharmaceutically acceptable carrier of at least one further, or vehicle.
8. pharmaceutical composition according to claim 7, it comprises additional treatment agent further, wherein said additional treatment agent is Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, method draw Wei, amantadine, arbidol, ribavirin, Si Tafulin, ingavirin (Ingavirin), GR-217029 or its combination.
9. one kind uses the compound described in claim 1-5 any one or the pharmaceutical composition described in claim 6-8 any one for the preparation of preventing, processing, alleviate or treat the purposes in virus infective medicament.
10. purposes according to claim 9, wherein said virus infection is influenza infection.
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