CN104387288B - As the compound of neuraminidase inhibitor and the application in medicine thereof - Google Patents
As the compound of neuraminidase inhibitor and the application in medicine thereof Download PDFInfo
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- CN104387288B CN104387288B CN201410693099.8A CN201410693099A CN104387288B CN 104387288 B CN104387288 B CN 104387288B CN 201410693099 A CN201410693099 A CN 201410693099A CN 104387288 B CN104387288 B CN 104387288B
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Abstract
The present invention is as the compound of neuraminidase inhibitor and the application in medicine thereof, there is provided some such as formula the tetra-atomic ring compound shown in (I) or its steric isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug, be used for the treatment of the disease of influenza infection.The invention also discloses the pharmaceutical composition containing such compound and use the compounds of this invention or the purposes of its pharmaceutical composition in preparation treatment influenza disease medicine.
Description
Invention field
The invention belongs to pharmaceutical field, be specifically related to the compound and the pharmaceutical composition thereof that are used for the treatment of influenza, relate to described compound or pharmaceutical composition further in the purposes prepared in medicine and using method.Especially, compound of the present invention is neuraminidase inhibitor.
Background of invention
Neuraminidase is also known as sialidase, a kind of glycoprotein be distributed on influenza virus tunicle, it has antigenicities and can be hydrolyzed by catalysis sialic acid, assists ripe influenza virus to depart from the new cell of host cell infected, in the life cycle of influenza virus, plays important role.In influenza A virus, the antigenicity of neuraminidase can morph, and this becomes the foundation dividing subtypes of influenza A virus, has neuraminidase antigen types different in 9 in influenza A virus known at present.
The three-dimensional structure of influenza neuraminidase, after 20th century, the eighties was determined, becomes the target spot of antiviral research, and play important effect in the discovery procedure of two kinds of neuraminidase inhibitor zanamivir and oseltamivir.Neuraminidase inhibitor suppresses the diffusion of influenza virus in body by the effect to neuraminidase, reaches the object of prevention and therapy influenza.
The change of neuraminidase protein amino-acid residue is the important root producing resistance and new virus formation.In succession there is severe side effect and resistance in neuraminidase inhibitor zanamivir and oseltamivir of existing two kinds of listings in recent years, and the research and development of therefore novel neuraminidase inhibitor are very urgent.
The compounds of this invention is used for the treatment of patient's influenza, and this compound selective ground suppresses neuraminidase.
Abstract of invention
The present invention relates to a kind of method of tetra-atomic ring compound and resisiting influenza virus.The compounds of this invention or pharmaceutical composition infected by influenza, particularly Neuraminidase in Influenza Virus have good restraining effect.
On the one hand the present invention relates to a kind of compound, it is for the compound shown in formula (I) or such as formula the steric isomer of compound (I) Suo Shi, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:
Wherein R
1for H or C
1-6alkyl;
R
2for H or C (=NH) NH
2;
R
3for H, C
1-6alkyl or-C (=O)-C
1-6alkyl.
In some embodiments, wherein R
1for H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl.
In some embodiments, wherein R
3for H, methyl, ethyl, propyl group, sec.-propyl, formyl radical or ethanoyl.
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises above-mentioned any one compound and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination.
In some embodiments, it further comprises the medicine of other anti influenza, wherein said Tamiflu 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 the influenza disease that the compounds of this invention or pharmaceutical composition can be used to for the preparation of preventing, processing, treat or alleviate patient.
The present invention relates on the other hand the preparation of compound that formula (I) comprises, the method for abstraction and purification.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.
Circumstantial letter of the present invention
Definition and general terms
Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.
Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.
Unless otherwise indicated, this paper institute should be applied and use to obtain following definition.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can with reference to " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry " byMichaelB.SmithandJerryMarch, JohnWiley & Sons, description in NewYork:2007, its full content is incorporated to herein by 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.
Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, such as, also refer to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.
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.
Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
" 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), geometrical isomer (cis/trans) isomer, atropisomer, etc.
" 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.
" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.
" diastereomer " refers to two or more chiral centre 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.
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-enantiomer 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, JeffreyAub é, 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.
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.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " replacement " represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can 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.
In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be independently " 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.
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 to 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.
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 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 hydroxyl, 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: T.HiguchiandV.Stella, Pro-drugsasNovelDeliverySystems, Vol.14oftheA.C.S.SymposiumSeries, EdwardB.Roche, ed., BioreversibleCarriersinDrugDesign, AmericanPharmaceuticalAssociationandPergamonPress, 1987, J.Rautioetal., Prodrugs:DesignandClinicalApplications, NatureReviewDrugDiscovery, 2008, 7, 255-270, andS.J.Heckeretal., ProdrugsofPhosphatesandPhosphonates, JournalofMedicinalChemistry, 2008, 51, 2328-2345.
" 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.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Bergeetal., describepharmaceuticallyacceptablesaltsindetailinJ.Pharm aceuticalSciences, described in 1977,66:1-19..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N
+(C
1-4alkyl)
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
1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention 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 and monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Term as used in the present invention " treatment " any disease or illness, some embodiment middle fingers improve disease or illness (namely slow down or stop or palliate a disease or the development of its at least one clinical symptom) wherein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter may not discovered for patient.In other embodiments, " treatment " refer to from health (such as stablizing perceptible symptom) or physiology (such as stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevent or postpone the outbreak of disease or illness, generation or deterioration.
Pharmaceutically useful acid salt can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate, muriate/hydrochloride, chloro theophylline salt, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-semi-lactosi hydrochlorate, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.
Such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. can be comprised by its derivative mineral acid obtaining salt.
Such as acetic acid, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, sulphosalicylic acid etc. can be comprised by its derivative organic acid obtaining salt.
Pharmaceutically acceptable base addition salt can be formed with mineral alkali and organic bases.
Can be comprised by its derivative mineral alkali obtaining salt, the metal of I race to the XII race of such as ammonium salt and periodictable.In certain embodiments, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; Particularly suitable salt comprises ammonium, potassium, sodium, calcium and magnesium salts.
Can comprise primary amine, secondary amine and tertiary amine by its derivative organic bases obtaining salt, the amine of replacement comprises the amine, cyclic amine, deacidite etc. of naturally occurring replacement.Some organic amine comprises, such as, and Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine (meglumine), piperazine and Trometamol.
Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.Generally speaking, such salt can react by making the suitable alkali of the free acid form of these compounds and stoichiometry (oxyhydroxide, carbonate, supercarbonate etc. as Na, Ca, Mg or K), or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared.Such reaction is carried out usually in water or organic solvent or the mixture of the two.Usually, when suitable, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.At such as " Remington ' sPharmaceuticalSciences ", the 20th edition, MackPublishingCompany, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice and application (HandbookofPharmaceuticalSalts:Properties; Selection; andUse) ", StahlandWermuth (Wiley-VCH, Weinheim, Germany, 2002) other can be found to be suitable for the list of salt in.
In addition, compound disclosed by the invention, comprises their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, DMSO, etc.).Compound is come into the open in the present invention can with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of non-solvation.
Any structural formula that the present invention provides is also intended to represent these compounds not by the form of the form of isotopic enrichment and isotopic enrichment.The compound of isotopic enrichment has the structure of the general formula description that the present invention provides, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number.The Exemplary isotopes can introduced in the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as
2h,
3h,
11c,
13c,
14c,
15n,
17o,
18o,
18f,
31p,
32p,
35s,
36cl and
125i.
On the other hand, such as, wherein there is radio isotope in the compound that the present invention that compound of the present invention comprises isotopic enrichment defines, as
3h,
14c and
18those compounds of F, or wherein there is non radioactive isotope, as
2h and
13c.The compound of such isotopic enrichment can be used for metabolism research and (uses
14c), reaction kinetics research (uses such as
2h or
3h), detect or imaging technique, as positron emission tomography (PET) or the SPECT (single photon emission computed tomography) (SPECT) comprising medicine or substrate tissue measure of spread, or can be used in the radiotherapy of patient.
18the compound of F enrichment is desirable especially for PET or SPECT research.Use suitable isotope labeling reagent to substitute original used unmarked reagent described by embodiment in the routine techniques that shown in the formula (I) of isotopic enrichment, compound can be familiar with by those skilled in the art or the present invention and preparation process to prepare.
In addition, particularly deuterium is (that is, for higher isotope
2h or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index improves brings.Should be appreciated that the deuterium in the present invention is seen as the substituting group of formula (I) compound.The concentration of such higher isotope particularly deuterium can be defined by the isotopic enrichment factor.Term used in the present invention " the isotopic enrichment factor " refers to specified ratio between isotopic isotopic abundance and natural abundance.If the substituting group of the compounds of this invention is designated as deuterium, this compound has at least 3500 (each deuterium at D atom place 52.5% of specifying mixes) to each D atom of specifying, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), the isotopic enrichment factor of at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).It can be the such as D that isotropic substance replaces that the pharmaceutically useful solvate of the present invention comprises wherein recrystallisation solvent
2o, acetone-d
6, DMSO-d
6those solvates.
On the other hand, the present invention relates to the intermediate of the compound that preparation formula (I) comprises.
On the other hand, the present invention relates to the preparation of compound that formula (I) comprises, the method for abstraction and purification.
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises the compounds of this invention, pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, solvent, or their combination.In some embodiments, pharmaceutical composition can be liquid, solid, semi-solid, gel or aerosol.
" associating " represents the medicine box of the fixed Combination in single dosage unit form or the part for combined administration, wherein the present invention come into the open compound and combined partner capable can individual application or can use respectively in certain time interval at one time, particularly make to combine and close companion and show cooperation, such as act synergistically." co-administered " or " Combined Preparation " etc. are intended to include the single individuality (such as patient) selected COMBINATION OF THE INVENTION being applied to and needing it as the term is employed herein, and be intended to comprise wherein material need not by identical route of administration or the treatment plan used simultaneously." pharmaceutical combination product " represents the mixing of more than one activeconstituentss or combines the product obtained as the term is employed herein, and the fixed Combination both having comprised activeconstituents also comprises non-fixed combinations.Term " fixing joint " represents that activeconstituents such as come into the open compound and COMBINATION OF THE INVENTION of the present invention is applied to patient with the form of single entities or dosage simultaneously.Term " on-fixed associating " represent activeconstituents as the present invention come into the open chelate compound and COMBINATION OF THE INVENTION all as separate entity simultaneously, common or be successively applied to patient without specified time restriction, wherein this is applied in patient body the treatment level of significance providing two kinds of compounds.The latter is also applicable to drug cocktail therapy (treatment), such as, use 3 kinds or more and plant activeconstituents.
The description of the compounds of this invention
On the one hand the present invention relates to a kind of compound, it is for the compound shown in formula (I) or such as formula the steric isomer of compound (I) Suo Shi, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:
Wherein R
1for H or C
1-6alkyl;
R
2for H or C (=NH) NH
2;
R
3for H, C
1-6alkyl or-C (=O)-C
1-6alkyl.
In some embodiments, wherein R
1for H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl.
In some embodiments, wherein R
3for H, methyl, ethyl, propyl group, sec.-propyl, formyl radical or ethanoyl.
In some embodiments, it has one of them structure following,
or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate or pharmacy acceptable salt or prodrug.
Compound of the present invention (in this article, form of presentation " formula (I) compound and steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate and pharmacy acceptable salt and prodrug " can be referred to as " compound of the present invention "), may be used for producing pharmaceutical prod treatment influenza disease, comprise that those are described in the invention.Further, compound of the present invention may be used for the medicine of production anti influenza disease.Thus, compound of the present invention may be used for producing a kind of pharmaceuticals and is used for alleviating, control or treat the illness that influenza virus mediates, the disease of particularly neuraminidase protein mediation.Thus, compound of the present invention can be used as the activeconstituents of pharmaceutical composition, and this pharmaceutical composition can comprise the compound representated by formula (I), can also comprise the pharmaceutically acceptable carrier of at least one, assistant agent or thinner further.
Specifically, salt is pharmacy acceptable salt.The implication of term " pharmaceutically acceptable " is, the material adopted or composition must be applicable to chemistry or toxicity mate with the Mammals be used for the treatment of with other components of composition preparation.Those skilled in the art can according to adopt the object such as people of other components and used treatment, specifically select material or the composition of " pharmaceutically acceptable ".
The salt of compound of the present invention 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 or organic acid.Wherein, the example of mineral acid includes but not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Organic acid example includes but not limited to 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 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, ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and obtain inorganic salt from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium.
The composition of the compounds of this invention, preparation and administration
Described pharmaceutical composition comprises any one compound of the present invention.This pharmaceutical composition can also comprise pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination further.
Described pharmaceutical composition comprises the medicine of resisiting influenza virus further.The medicine of described resisiting influenza virus can be any known other medicines for anti influenza being different from the compounds of this invention.Such as, Wei, amantadine, Rimantadine, arbidol, ribavirin, Si Tafulin, ingavirin (Ingavirin), GR-217029 or its combination can be drawn for Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, method.
When can be used for treatment, the compounds of this invention for the treatment of significant quantity, especially formula (I) compound and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give, and the activeconstituents that also can be used as pharmaceutical composition provides.Therefore, content of the present invention also provides pharmaceutical composition, this pharmaceutical composition comprises this compounds of this invention for the treatment of significant quantity, especially formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle.Term as used herein " treatment significant quantity " refers to the total amount being enough to each active ingredient demonstrating significant patient benefit (such as viral load minimizing).When using independent activeconstituents individually dosed, this term only refers to this composition.When Combination application, no matter this term then refers to combination, successively or simultaneously administration time, all cause the combined amount of the activeconstituents of result for the treatment of.The compounds of this invention, especially formula (I) compound and pharmacy acceptable salt described above.From compatible with other compositions of preparation and harmless to its recipient meaning, carrier, thinner or vehicle must be acceptable.According to the another aspect of content of the present invention, also be provided for the method for useful in preparing drug formulations, the method comprises the compounds of this invention, and especially formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle mix.Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, 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.
Pharmaceutical preparation can be unit dosage, and each unitary dose contains the activeconstituents of predetermined amount.The dosage level of the compound of content of the present invention is between about 0.01 mg/kg (mg/kg) body weight/day and about 250 mg/kg body weight/day, preferably between about 0.05mg/kg body weight/day and about 100mg/kg body weight/day, usually with the disease that monotherapy mediates for preventing or treat influenza virus.Usually can by every day about 1 to about 5 times or give the pharmaceutical composition of content of the present invention as continuous infusion.This kind of dose regimen can be used as long-term or short-term therapy.The discharge rate of the severity according to disease to be treated, disease, administration time, route of administration, compound used therefor, treatment time and patient age, sex, body weight and situation change by the amount mixing the activeconstituents preparing single formulation with solid support material.Preferred unit dosage is the unit dosage of per daily dose containing hereinbefore activeconstituents or divided dose or its appropriate fraction.Available obviously lower than the low dose of begin treatment of compound optimal dose.After this, escalated dose is carried out until reach best effect in this case with less increment.Generally speaking, the concentration level most desirably giving compound usually can provide effective result and don't as causing any harmful or poisonous side effect at anti-virus aspect.
When the composition of content of the present invention comprises the combination of the compound of content of the present invention and one or more other treatment medicines or prophylactic agent, the dosage level of compound and other medicine is usually in monotherapy scheme, account for the about 10-150% of bio-occlusion pharmaceutical quantities, more preferably account for the about 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable for by any suitable administration, such as by oral (comprising oral cavity or sublingual), rectum, nose, locally (comprise oral cavity, sublingual or through skin), vagina or parenteral (comprise in subcutaneous, intracutaneous, intramuscular, intraarticular, synovial membrane, in breastbone, in sheath, intralesional, intravenously or intradermal injection or infusion) approach.This kind of preparation can be prepared, such as, by by activeconstituents and carrier or mixed with excipients by any currently known methods of art of pharmacy.Preferred oral administration or drug administration by injection.
The pharmaceutical preparation being suitable for oral administration provides by independently unit, such as capsule or tablet; Powder or granule; Solution in water-based or non-aqueous liquid or suspensoid; Edible foam formulations or foaming preparations (whip); Or O/w emulsion agent or water in oil emulsion liquor.
For example, for oral administration in the form of a tablet or capsule, active medicine component can mix mutually with pharmaceutically acceptable oral, non-toxic inert support (such as ethanol, glycerine, water etc.).By compound powder is broken into suitable fine sizes, and mix to prepare powder with by the same pharmaceutical carrier (edible carbohydrate such as such as starch or N.F,USP MANNITOL etc.) pulverized.Also can there is correctives, sanitas, dispersion agent and tinting material.
By preparing pulverulent mixture as above, and being loaded in the gelatin shell of shaping, preparing capsule.Before filling operation, glidant and lubricant (such as colloidal silica, talcum powder, Magnesium Stearate, calcium stearate or solid polyethylene glycol) can be added in pulverulent mixture.Also can add and will improve disintegrating agent or the solubilizing agent (such as agar, calcium carbonate or sodium carbonate) of medicine utilizability when taking lower capsule.
In addition need or required time, also suitable tackiness agent, lubricant, disintegrating agent and tinting material can be mixed in mixture.Suitable tackiness agent comprises starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthetic gum (such as Sudan Gum-arabic, tragakanta or sodiun alginate), carboxymethyl cellulose, polyoxyethylene glycol etc.Lubricant for these formulations comprises sodium oleate, sodium-chlor etc.Disintegrating agent includes, but are not limited to starch, methylcellulose gum, agar, bentonite, xanthan gum etc.Such as, by making pulverulent mixture, granulating or pre-compressing tablet, adding lubricant and disintegrating agent, tabletted, thus make tablet.By the compound suitably pulverized and thinner as described above or base-material, optional with tackiness agent (such as carboxymethyl cellulose, alginate, gelatin or polyvinylpyrrolidone), dissolve hold back agent (such as paraffin), absorb accelerator (quaternary salt) and/or absorption agent (such as bentonite, kaolin or Si Liaodengji dicalcium phosphate feed grade) mixes, prepare pulverulent mixture.After useful binders (such as syrup, starch slurry, mucialga of arabic gummy (acadiamucilage) or cellulose materials or polymeric material solution) is wetting, pressurization is sieved, and is granulated by pulverulent mixture.An alternative method of granulating is, can by pulverulent mixture by tabletting machine, and result is smashed by the not good agglomerate of formation to make particle again.By adding stearic acid, stearate, talcum powder or mineral oil make particle lubrication to prevent from adhering on the punch die of tabletting machine.Then by the mixture tabletted through lubrication.The compound of content of the present invention also can mix with free-pouring inert support, without the need to by granulate or pre-tableting step just can tabletted.Transparent or the opaque protectiveness coating material be made up of shellac seal coat, sugar-coat or polymeric material clothing and wax polishing clothing (polishcoatingofwax) can be provided.Dyestuff can be added in these coating materials to distinguish different unitary doses.
Oral liquid such as solution, syrup and elixir can be prepared by dosage unit form, thus specified rate contains the compound of predetermined amount.Syrup is prepared by being dissolved in the suitably seasoned aqueous solution by compound, and elixir is prepared by using non-toxic vehicle.Also can add solubilizing agent and emulsifying agent (such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ether), sanitas, flavoring additive (such as spearmint oil or natural sweeteners or asccharin or other artificial sweetners) etc.
If appropriate, the dosage unit preparations micro encapsulation of oral administration can be used for.Also preparation can be made time delay or sustained release, such as, by dressing or be embedded in the microparticle material such as polymkeric substance, wax.
The compounds of this invention, especially formula (I) compound and pharmacy acceptable salt thereof can also give by liposome delivery systems, such as small unilamellar vesicle, large unilamellar liposome and multilamellar liposome.Liposome can be made up of multiple phosphatide (such as cholesterol, octadecylamine or phosphatidylcholine).
The compounds of this invention, especially formula (I) compound and pharmacy acceptable salt thereof are also by using monoclonal antibody to pass medicine as independent carrier (compound molecule is coupled).Compound also can with as can the soluble polymer coupling of target medicine carrier.The polyethylene-oxide polylysine that this base polymer can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide phenol, polyhydroxyethylaspart or be replaced by palmitoyl residues.In addition, compound can with a class Biodegradable polymeric coupling, for reaching the controlled release of medicine, the cross-linking copolymer of this base polymer such as poly(lactic acid), poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate and hydrogel or amphipathic nature block polymer.
The pharmaceutical preparation being suitable for percutaneous dosing can be used as discrete patch (discretepatch) to keep and recipient's epidermis close contact in long-time.Such as, activeconstituents can pass medicine by by iontophoresis patch, usually can see PharmaceuticalResearch1986, and 3 (6), 318.
The pharmaceutical preparation being suitable for topical can be made into ointment, ointment, suspensoid, lotion, powder, solution, paste, gelifying agent, sprays, aerosol, oil formulation or transdermal patch.
The pharmaceutical preparation being suitable for rectal administration can be used as suppository or provides as enema.
The pharmaceutical preparation (wherein carrier is solid) being suitable for nose administration comprises the dust base that particle diameter is such as 20-500 micrometer range, by with the administration of snuffing mode, is namely sucked fast from close to the dust base container of nose by nasal passage.Wherein carrier is liquid, is suitable for the aqueous solution agent or the oily solution agent that comprise activeconstituents as the appropriate formulation of nasal mist or nasal drop administration.
Be suitable for comprising minuteness particle pulvis (dust) or mist agent (mist) by the pharmaceutical preparation of inhalation, the dosage compresed gas aerosol of available dissimilar metering, nebulizer, insufflator or other matters are sent in the device of aerosol spray and are prepared.
The pharmaceutical preparation being suitable for vagina administration can vaginal suppository, vagina plug, ointment, creme, gelifying agent, paste, foaming agent or sprays provide.
The pharmaceutical preparation being suitable for parenteral admin comprises water-based and non-aqueous sterile injection solution and water-based and non-aqueous sterile suspensions, water-based and non-aqueous sterile injection solution can contain antioxidant, buffer reagent, fungistat and make described preparation and the isotonic solute of receptor's blood waiting, and water-based and non-aqueous sterile suspensions can comprise suspension agent and thickening material.Preparation can unitary dose or multi-dose container provide, the triumphant and bottle of the peace such as sealed, and under can being kept at lyophilize (freeze-drying) condition, only need add sterile liquid carrier before use, such as water for injection.The injection solution and the suspensoid that face used time configuration can be prepared by sterile powder injection, granule and tablet.
It should be understood that, except the composition mentioned especially above, preparation also comprises other conventional composition of this area relevant with described preparation type, and this kind of preparation being such as suitable for oral administration can comprise correctives.
The purposes of the compounds of this invention and pharmaceutical composition
The invention provides compound of the present invention or pharmaceutical composition is preparing the purposes in medicine, described medicine may be used for effectively suppressing influenza virus, particularly effectively suppresses neuraminidase.Arbitrary compound of the present invention or pharmaceutical composition may be used for preventing, process, treat or alleviate influenza disease.
Comprise the methods for the treatment of of the compounds of this invention or pharmaceutical composition administration, comprise the medicine to other anti influenza of patient's administration further, thus, the medicine of compound of the present invention and other anti influenza can be carried out combination therapy, the medicine of wherein said anti influenza 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.
And comprise the methods for the treatment of of the compounds of this invention or pharmaceutical composition administration, comprise the administration of other Tamiflu further, wherein, other Tamiflu can with the compounds of this invention or its pharmaceutical composition Combined Preparation, the compounds of this invention or pharmaceutical composition are as single formulation, or the compound separated or pharmaceutical composition are as a part for multi-form.Other Tamiflu can from the compounds of this invention simultaneously administration or different time administration.The situation of the latter, administration can be staggered and be carried out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months carries out.
" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.
General building-up process
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.
Those skilled in the art will realize that: 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, Inc., ArcoChemicalCompany and AlfaChemicalCompany, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether are through sodium Metal 99.5 backflow drying and obtain.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), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, two bimodal), dt (doubletoftriplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and aG1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315BDAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS being equipped with G1311A quaternary pump and G1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315DDAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with AgilentZorbaxSB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
| Time (min) | A(CH 3CN，0.1％HCOOH) | B(H 2O，0.1％HCOOH) |
| 0-3 | 5-100 | 95-0 |
| 3-6 | 100 | 0 |
| 6-6.1 | 100-5 | 0-95 |
| 6.1-8 | 5 | 95 |
Compound purity is evaluated by Agilent1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, ZorbaxSB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
Ac
2o diacetyl oxide
BOC, Boc tert-butoxycarbonyl
CDC1
3deuterochloroform
Et
2o ether
DMFN, dinethylformamide
DMAP4-Dimethylamino pyridine
DMSO dimethyl sulfoxide (DMSO)
EtOAc ethyl acetate
EA ethyl acetate
Et
3n triethylamine
HBr Hydrogen bromide
HCl hydrochloric acid
H
2hydrogen
HgCl
2mercury chloride
MgSO
4magnesium sulfate
MeOH, CH
3oH methyl alcohol
MsCl methylsulfonyl chloride
CH
2cl
2, DCM methylene dichloride
NMPN-methyl-2-pyrrolidone
NaNO
2sODIUMNITRATE
ML, m milliliter
N
2nitrogen
PE sherwood oil (60 – 90 DEG C)
Pd (PPh
3)
4four triphenyl phosphorus palladiums
Pd (OH)
2palladium hydroxide
K
2cO
3salt of wormwood
KOH potassium hydroxide
RT, rt room temperature
Rt retention time
NaOH sodium hydroxide
NaCl sodium-chlor
Na
2sO
4sodium sulfate
THF tetrahydrofuran (THF)
Et
3n, TEA triethylamine
TFA trifluoroacetic acid
Tf
2o trifluoromethanesulfanhydride anhydride
TBAF tetrabutyl fluoride amine
HCl.EA hydrogenchloride ethyl acetate
DIPEA diisopropyl ethyl amine
DME glycol dimethyl ether
TsOH tosic acid
I
2iodine
IPA Virahol
Synthetic method
Synthetic method 1
Compound 7 can be prepared by synthetic method 1, wherein R
2, R
3there is implication of the present invention, compound 1 is obtained by reacting compound 2 with aminoderivative and Phenylsulfonic acid, compound 2 and Nitromethane 99Min. are obtained by reacting compound 3 under the effect of alkali, compound 3 is obtained by reacting oxazole compounds 4 with vinylbenzene and phenylcarbimide, compound 4 reductive ring open obtains compound 5, obtain compound 6 after compound 5 amino derivatization, compound 6 obtains compound 7 through hydrolysis.
Embodiment
Embodiment 1: the synthesis of the amino cyclobutane-carboxylic acid methyl esters of compound 3-(1-acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-phenyl propyl)-3-
Synthetic route:
Step 1: the synthesis of compound 3-oxygen cyclobutane-carboxylic acid methyl esters (1-2)
At 0 DEG C, SOCl
2(3.1ml, 0.045mol) slowly instills the CH of 3-oxygen cyclobutane formate (1-1) (10.0g, 0.088mol)
3in OH (50ml) solution, after adding, reaction solution backflow 4.0h, removal of solvent under reduced pressure, resistates obtains colourless oil liquid (10.0g, 90%) through column chromatographic isolation and purification (eluent: PE:EtOAc (V:V)=10:1).
1HNMR(400MHz,CDCl
3):δ3.77(s,3H),3.23-3.46(s,5H)ppm.
Step 2: the synthesis of compound 3-(t-butoxycarbonyl amino)-3-(benzenesulfonyl) cyclobutane-carboxylic acid methyl esters (1-3)
Under room temperature, by 3-oxygen cyclobutane-carboxylic acid methyl esters (1-2) (25g195.1mmol) and t-butyl carbamate (22.86g, 195.1mmol) be dissolved in DCM (350mL), 1h is stirred under nitrogen atmosphere, then 30 molecular sieves and Phenylsulfonic acid (30.51g is added, 214.6mmol), continue to stir 48h.Reaction system is filtered, and reaction solution is concentrated obtains 55g crude product, is directly used in the next step.
Step 3: the synthesis of compound 3-(t-butoxycarbonyl amino)-3-(Nitromethylene) cyclobutane-carboxylic acid methyl esters (1-4)
Under room temperature, t-BuOK (50.03g, 446.7mmol) is dissolved in anhydrous THF (350mL), at 0 DEG C, slowly adds CH
3nO
2(32.7g; 536mmol); mixture stirs 1h; then crude product (the 55g of 3-(t-butoxycarbonyl amino)-3-(benzenesulfonyl) cyclobutane-carboxylic acid methyl esters (1-3) is added; THF (150mL) solution 148.9mmol), mixture continues stirring at room temperature 3h.The most of solvent of mixture decompression removing, add saturated ammonium chloride solution (100ml), add ethyl acetate (100mlx2) extraction again, merge organic phase, with anhydrous sodium sulfate drying, concentrate and obtain crude product, thick product obtains colourless oil liquid (19.5g, 45.5%) through column chromatographic isolation and purification (eluent: PE:EtOAc (V:V)=10:1).
MS(ESI,pos.ion)m/z:289.3[M+H]
+.
Step 4: the synthesis of compound 3-(t-butoxycarbonyl amino)-3-(5-phenyl-4,5-dihydro-isoxazole-3-base) cyclobutane-carboxylic acid methyl esters (1-5)
By 3-(t-butoxycarbonyl amino)-3-(Nitromethylene) cyclobutane-carboxylic acid methyl esters (1-4) (6.6g, 22.92mmol), vinylbenzene (2.38g, 22.92mmol), parachlorobenzyl isocyanic ester (14.03g, 91.68mmol) be dissolved in toluene (250mL) with triethylamine (636uL, 4.584mmol), reaction system is heated to 110 DEG C of reaction 14h.Reaction system adopts diatomite filtration, filtrate is concentrated obtains crude product, crude product is dissolved in methylene dichloride (50ml) solution and again passes through diatomite filtration, colourless oil liquid (3.9g, 45.3%) is obtained through column chromatographic isolation and purification (eluent: PE:EtOAc (V:V)=15:1) after filtrate is concentrated.
MS(ESI,pos.ion)m/z:375.4[M+H]
+.
Step 5: the synthesis of compound 3-(1-amino-3-hydroxyl-3-phenyl propyl)-3-(t-butoxycarbonyl amino) cyclobutane-carboxylic acid methyl esters (1-6)
At-30 DEG C, by 3-(t-butoxycarbonyl amino)-3-(5-phenyl-4,5-dihydro-isoxazole-3-base) cyclobutane-carboxylic acid methyl esters (1-5) (2.5g, 6.684mmol) with Nickel dichloride hexahydrate (4.732g, 20.05mmol) be dissolved in MeOH/THF (3:1,50mL), 10min is stirred.Then sodium borohydride (2.54g, 66.84mmol) is joined in reaction system, stirring reaction 2h at-30 DEG C.Reaction solution adds ammoniacal liquor (10ml), then filter, filtrate extracts by ethyl acetate (60mlx2), organic phase saturated nacl aqueous solution (60mlx2) washing, then uses anhydrous sodium sulfate drying, filters, filtrate is concentrated obtains crude product, crude product obtains colourless oil liquid, (1.1g, 43.5%) through column chromatographic isolation and purification (eluent: PE:EtOAc (V:V)=4:1).
MS(ESI,pos.ion)m/z:379.5[M+H]
+.
Step 6: the synthesis of compound 3-(1-acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-phenyl propyl)-3-(t-butoxycarbonyl amino) cyclobutane-carboxylic acid methyl esters (1-7)
Under room temperature, 3-(1-amino-3-hydroxyl-3-phenyl propyl)-3-(t-butoxycarbonyl amino) cyclobutane-carboxylic acid methyl esters (1-6) (1g, 2.646mmol) is dissolved in following mixing solutions (Ac
2o:DIPEA:DMF (V:V:V)=1:1:8,250mL), reaction solution stirred overnight at room temperature.Reaction solution adds saturated nacl aqueous solution (100ml), extract by ethyl acetate (150mlx2), organic phase saturated nacl aqueous solution (150mlx2) washs, then anhydrous sodium sulfate drying is used, filter, filtrate is concentrated obtains crude product, and crude product obtains colourless oil liquid (362mg, 43.5%) through column chromatographic isolation and purification (eluent: PE:EtOAc (V:V)=4:1).
MS(ESI,pos.ion)m/z:421.5[M+H]
+；
1HNMR(400MHz,CDCl
3):δ8.21(s,1H),7.26-7.32(m,5H),4.92(s,1H),4.82(s,1H),4.42(s,1H),4.12(s,1H),3.68(s,3H),2.96(d,1H),2.45(d,1H),2.40(d,1H),2.28(d,2H)；2.14-2.16(d,3H),1.96-1.98(m,2H),1.32(s,9H)ppm.
Step 7: the synthesis of amino cyclobutane-carboxylic acid methyl esters (1-8) of compound 3-(1-acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-phenyl propyl)-3-
Under room temperature, by 3-(1-acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-phenyl propyl)-3-(t-butoxycarbonyl amino) cyclobutane-carboxylic acid methyl esters (1-7) (65mg, 0.1548mmol) be dissolved in TFA/DCM (V:V) (1:9,5mL), stirring at room temperature 2.5h.Concentration response system obtains crude product, and crude product uses reverse column chromatography (eluent: H further
2o/CH
3cN (V:V)=95:5) be separated obtain colourless oil liquid (32.8mg, 66%).
MS(ESI,pos.ion)m/z:321.3[M+H]
+；
1HNMR(400MHz,CDCl
3):δ7.26-7.32(m,5H),4.71(d,1H),3.94(d,1H),3.67(s,3H),2.93(d,1H),2.45(d,1H),2.29(d,3H)；2.14-2.15(d,2H),2.11-2.12(d,1H),1.98-2.00(m,3H)ppm.
The synthesis of the amino cyclobutane formate of embodiment 2 compound 3-(1-acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-phenyl propyl)-3-
Synthetic route:
Step 1: the synthesis of compound 3-(1-acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-phenyl propyl)-3-(t-butoxycarbonyl amino) cyclobutane-carboxylic acid (2-1)
Under room temperature, 3-(1-acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-phenyl propyl)-3-(t-butoxycarbonyl amino) cyclobutane-carboxylic acid methyl esters (1-7) (175mg, 416mmol) is dissolved in EtOH/H
2o (2:1,15mL), then adds sodium hydroxide solution (1mol/L, 10mL), and reaction system stirred at ambient temperature is about 2h.Mixture concentrates, extract by ethyl acetate (30ml), aqueous phase acetic acid regulates pH=4 ~ 5 and then extracts with EtOAc, organic phase washed with water (30mlx2) washs, anhydrous sodium sulfate drying, obtain thick product (160mg, 95%) after concentrated organic phase, crude product is directly used in the next step.
MS(ESI,pos.ion)m/z:407.5[M+H]
+.
Step 2: the synthesis of the amino cyclobutane-carboxylic acid (2-2) of compound 3-(1-acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-phenyl propyl)-3-
Under room temperature, by 3-(1-acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-phenyl propyl)-3-(t-butoxycarbonyl amino) cyclobutane-carboxylic acid (2-1) (115mg, 0.28mmol) be dissolved in TFA/DCM (V:V) (1:15,20mL), stirring at room temperature 2.5h.After reaction solution is concentrated, obtain white solid (90mg, 83%) with EtOAc (10ml) making beating.
MS(ESI,pos.ion)m/z:307.4[M+1]
+
1HNMR(400MHz,CDCl
3):δ7.25-7.33(m,5H),4.72(d,1H),3.95(d,1H),2.94(d,1H),2.46(d,1H),2.30(d,3H)；2.13-2.15(d,2H),2.10-2.12(d,1H),1.99-2.01(m,3H)ppm.
Biological activity:
Anti-influenza virus activity measures
96 orifice plate CPE assay method steps:
spread 96 orifice plates, 5000 mdck cells are inoculated in every hole, 37 DEG C, 5%CO
2, incubated overnight.
by DMSO and serum free medium diluted compounds to suitable concn, DMSO final concentration is 1%.
with the influenza virus H1N1 (A/weiss/43) that substratum dilution-80 DEG C is frozen.
every hole adds the virus liquid (final MOI=0.01) after the compound after 50ul dilution and 50ul dilution.
96 orifice plates are placed in 37 DEG C, 5%CO
2, cultivate 3 days.
every hole adds 20ulMTT, is placed in 37 DEG C, hatches 4 hours.
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.
96 orifice plates measure cytotoxicity step:
spread 96 orifice plates, 5000 mdck cells are inoculated in every hole, 37 DEG C, 5%CO
2, incubated overnight.
by DMSO and serum free medium diluted compounds to suitable concn, DMSO final concentration is 1%.
every hole adds the compound after 50ul dilution and 50ul nutrient solution.
96 orifice plates are placed in 37 DEG C, 5%CO
2, cultivate 3 days.
every hole adds 20ulMTT, is placed in 37 DEG C, 4 hours.
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.
Data analysis: % inhibiting rate=(OD
t– OD
v)/(OD
c– OD
v) × 100%
% cytotoxicity=OD
t/ OD
c× 100%
% activity=% inhibiting rate-% cytotoxicity
OD
t, OD
v, and 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)
Table one: part of compounds infected by influenza H1N1 (A/weiss/43) experiment in vitro activity value of the present invention
As seen from the above table, compound involved in the present invention has obvious anti-influenza virus activity.
It will be apparent to one skilled in the art that content of the present invention is not limited to foregoing illustrative embodiment, and can be embodied in other specific form and don't depart from its essential characteristics.Therefore, expect that each embodiment is all considered in all respects illustrative and nonrestrictive, should with reference to appended claims, instead of these embodiments aforementioned, therefore, all changes in the implication and scope of appended claims equivalents are all included in herein.
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, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, limitation of the present invention can not be interpreted as, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification, and scope of the present invention is by claim and equivalents thereof.
Claims (8)
1. a compound, it is the pharmacy acceptable salt of the compound shown in the compound shown in formula (I) or formula (I),
Wherein R
1for H or C
1-6alkyl;
R
2for H or-C (=NH) NH
2;
R
3for H, C
1-6alkyl or-C (=O)-C
1-6alkyl.
2. compound according to claim 1, wherein R
1for H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl.
3. compound according to claim 1, wherein R
3for H, methyl, ethyl, propyl group, sec.-propyl, formyl radical or ethanoyl.
4. compound according to claim 1, it has one of them structure following:
or pharmacy acceptable salt.
5. a pharmaceutical composition, it comprises compound described in any one of claim 1-4 and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
6. pharmaceutical composition according to claim 5, it comprises the medicine of other anti influenza further, wherein said Tamiflu is Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, method draw Wei, amantadine, Rimantadine, arbidol, ribavirin, Si Tafulin, ingavirin (Ingavirin) or its combination.
7. the compound described in any one of claim 1-4 and the pharmaceutical composition described in any one of claim 5-6 are preparing the purposes in medicine, and wherein said medicine is used for effectively suppressing neuraminidase.
8. the compound described in any one of claim 1-4 and the pharmaceutical composition described in any one of claim 5-6 are preparing the purposes in medicine, and wherein said medicine is for preventing, processing, treat or alleviate the influenza disease of patient.
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| EP1087938A1 (en) * | 1998-04-23 | 2001-04-04 | Abbott Laboratories | Inhibitors of neuraminidases |
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