CN104496918B - Pyrazines derivatives and application thereof - Google Patents
Pyrazines derivatives and application thereof Download PDFInfo
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- CN104496918B CN104496918B CN201410758789.7A CN201410758789A CN104496918B CN 104496918 B CN104496918 B CN 104496918B CN 201410758789 A CN201410758789 A CN 201410758789A CN 104496918 B CN104496918 B CN 104496918B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
- C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
Abstract
The present invention relates to a class pyrazines derivatives, or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug.The invention still further relates to pyrazines derivatives or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or the prodrug purposes as medicine, the especially application in preparation antiviral drugs.
Description
Technical field
The present invention relates to a class pyrazines derivatives, its preparation method and the application in preparation antiviral drugs thereof, especially
It it is the application in preparation prevention and treatment influenza virus relevant disease medicine.The invention still further relates to comprise the medicine of these compounds
Compositions, and the application that this pharmaceutical composition is in prevention and treatment influenza virus relevant disease.
Background technology
Influenza (influenza is called for short influenza) is the acute respiratory infection that influenza virus causes, and is also a kind of
The disease that infectiousness is strong, spread speed is fast.Its mainly by the spittle in air, interpersonal contact or with contaminated thing
The contact transmission of product.Typical clinical symptoms is: anxious high heat, overall pain, the most weak and slight respiratory symptom.Typically
Autumn and winter season is its high-incidence season, and caused complication and the phenomena of mortality are the most serious.
Research to anti-influenza virus medicament in recent years achieves greater advance, and different anti-influenza virus medicaments is in preventing and treating
Effect in influenza is different.M2 ionophorous protein inhibitor (such as Buddha's warrior attendant gastral cavity amine and rimantadine) is that the influenza listed the earliest is faced
Bed medicine, but also exist drug resistance strain ratio increase and to Type B influenza virus unit effect property limitation.Neuraminic acid
It is to explore the breakthrough in resisiting influenza virus grass drug research at present that enzyme inhibitor is succeeded in developing, sick to first, influenza B
Poison all has inhibitory activity, such as, first medication when Oseltamivir is to prevent and treat bird flu and occur Human Influenza popular,
But, in recent years, research worker all over the world is found that H1N1, H5N1, H3N2 that Oseltamivir creates resistance successively
And Type B influenza virus.Other anti-influenza virus medicament roots the most all have preferably to the inhibitory action of virus and disease-resistant
Poison application prospect, but often need demonstration further.
Owing to the extensively application clinically of existing medicine makes influenza virus morph, these medicines are created not
Drug resistance with degree.The most novel anti-influenza virus medicament research and development are very urgent.
The invention provides a kind of new antiviral drugs, its infected by influenza has related disorders to have prevention and treatment is made
With.
Summary of the invention
The present invention relates to a class pyrazines derivatives, its preparation method and the application in preparation antiviral drugs thereof.This
Bright compound or the pharmaceutical composition comprising described compound have certain anti-influenza virus activity, especially to prevention and treatment
Influenza virus has preferable effect.
On the one hand, the present invention relates to a kind of compound, what it was structure shown in the structural formula shown in formula (I) or formula (I) is vertical
Body isomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable
Salt or prodrug,
Wherein,
X is halogen；And R1For hydroxyalkyl.
In some embodiments, X is F, Cl, Br or I；With
R1For C1-C6Hydroxyalkyl.
In some embodiments, R1For 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, methylol, 1-ethoxy, 2-hydroxyl
Ethyl, 1,3-dihydroxy acrylate-2-base, 1,3-dihydroxy-2-(methylol)-propyl-2-base, hydroxyl butyl, 2,4-dihydroxy butyl, hydroxyl amyl group or
Hydroxyl hexyl.
In some embodiments, the compounds of this invention its be structure shown in the structure shown in formula (II) or formula (II) vertical
Body isomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable
Salt or prodrug,
Wherein, R1For C1-C6Hydroxyalkyl.
In some embodiments, R1For 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, methylol, 1-ethoxy, 2-hydroxyl
Ethyl, 1,3-dihydroxy acrylate-2-base, 1,3-dihydroxy-2-(methylol)-propyl-2-base, hydroxyl butyl, 2,4-dihydroxy butyl, hydroxyl amyl group or
Hydroxyl hexyl.
In other embodiments, the present invention relates to the compound of one of structure,
Or the stereoisomer of structure shown in it, geometric isomer, tautomer, nitrogen oxides, hydrate, solvation
Thing, metabolite, pharmaceutically acceptable salt or prodrug.
On the other hand, the present invention relates to a kind of pharmaceutical composition, comprise the arbitrary described compound of the present invention, and pharmacy
Upper acceptable carrier, excipient, diluent, adjuvant, vehicle or combinations thereof.
In certain embodiments, pharmaceutical composition of the present invention its comprise other anti-influenza virus medicament further, its
Described in anti-influenza virus medicament be Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, Favipiravir, diamantane (obsolete)
Amine, rimantadine, arbidol, ribavirin, Si Tafulin, ingavirin (Ingavirin), GR-217029 or a combination thereof.
On the other hand, the present invention relates to the arbitrary described compound of the present invention or arbitrary described pharmaceutical composition is used in preparation
In protecting, process, treat or alleviate patient influenza virus about the purposes in disease medicament.
Another aspect of the present invention relates to the method for the preparation of compound, separation and purification that formula (I) is comprised.
The present invention also comprises compound and stereoisomer, geometric isomer, tautomer, the nitrogen oxidation of the present invention
Thing, hydrate, solvate, metabolite, its pharmaceutically acceptable salt or the application of prodrug, the compound of the present invention is being given birth to
Produce the application effectively suppressed in influenza virus medicine.The compound of the present invention is equally used for producing a kind of pharmaceuticals for alleviating,
Stop, control or treat patient's influenza infection.The present invention comprises pharmaceutical composition, and this pharmaceutical composition includes formula (I) institute
Compound and at least one the pharmaceutically acceptable carrier represented, effectively treats use needed for the combination of adjuvant or diluent
Amount.
The present invention comprises the disease of effective influenza virus, or the method sensitive to this disease equally, and the method comprises use
Representated by formula (I), patient is treated by the therapeutically effective amount of compound.
Unless other aspects show, all of stereoisomer of compound of the present invention, geometric isomer, tautomerism
Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug broadly fall into the model of the present invention
Enclose.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes that material or compositions must
Must be to be suitable for chemistry or toxicology, relevant with other components of composition preparation and the mammal for treating.
The salt of the compound of the present invention also includes the intermediate for compound shown in preparation or purification formula (I) or formula (I)
The salt of the enantiomer that shown compound separates, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, the most conceivable salt can by provide on document any suitably
Method prepares, and such as, uses mineral acid, example hydrochloric acid, hydrobromic acid, sulphuric acid, Metaphosphoric acid, nitric acid and phosphoric acid etc..Or make
With organic acid, lactic acid, lactobionic acid, trifluoroacetic acid, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, acetone acid,
Malic acid, 2 hydroxy propanoic acid, citric acid, oxalic acid, glycolic and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid
Acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Aminoacid, such as aspartic acid and glutamic acid；Aromatic acid, such as benzoic acid and meat
Cinnamic acid；Sulfonic acid, as p-methyl benzenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethyl sulfonic acid, hydroxyethylsulfonic acid., trifluoromethanesulfonic acid etc. or they
Combination.
If the compound of the present invention is acid, the most conceivable salt can be prepared by suitable method, e.g.,
Use inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N+(R14)4Salt and alkaline earth gold
Belong to hydroxide, etc..Suitably salt includes, but is not limited to, the organic salt obtained from aminoacid, such as glycine and essence ammonia
Acid, ammonia, such as primaquine, parahelium and tertiary ammonia, N+(R14)4Salt, such as R14It is H, C1-4Alkyl, C6-10Aryl, C6-10Aryl C1-4Alkyl
Deng, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain inorganic salt from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium.
Also the amine cation that suitable, nontoxic ammonium, quaternary ammonium salt and gegenions are formed is included, such as halogenide, hydroxide, carboxylation
Thing, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This
Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition
In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality
Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material
One or more different from the application or conflicting in the case of (include but not limited to defined term, term application, retouched
The technology stated, etc.), it is as the criterion with the application.
It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments
Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity,
Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference
Bright.
Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with
Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined
Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999,
With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John
Description in Wiley&Sons, New York:2007, entire contents is incorporated herein by.
Context except as otherwise noted or has significantly conflict, article used herein " ", " one (kind) "
" described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or
The article of more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to have more than one
Component be taken into account in the embodiment of described embodiment and use or use.
Term used in the present invention " study subject " refers to animal.The most described animal is mammal.Tested right
As, the most also refer to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little
Mus, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described it is subject to
Try liking people.
The present invention says that the term " patient " of use refers to people's (including adult and child) or other animals.Implement at some
In scheme, " patient " refers to people.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise
Content.
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill
Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and
Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,
Inc.,New York,1994。
Many organic compound exist with optical active forms, and i.e. they have and make the plane of linearly polarized light rotate
Ability.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one or more hands
The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound,
Wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete stereoisomerism
Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50:50 mixture of enantiomer
Be referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity time,
May occur in which this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with raceme or enantiomer
Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists
(R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake
Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer
Excess.
According to starting material and the selection of method, the compounds of this invention can with in possible isomer or they
Mixture, the such as form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited
?.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open
Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing dibasic cycloalkanes in compound
Base, the substituent group of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties
Pure or the purest geometric isomer, enantiomer, diastereomer, such as, by chromatography and/or fractional crystallization
Method.
By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art
The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product
Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping
Isomer can be prepared by asymmetric synthesis, such as, refers to Jacques, et al., Enantiomers, Racemates
and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric
Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,
E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables
of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre
Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical
Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,
2007)。
At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special
Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term
“C1-C6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this
Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this
The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively
The alkylidene group connected or arylene group.
Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight chain or
Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described by one or more present invention
Replace.In some embodiments, alkyl group contains 1-10 carbon atom；In another embodiment, alkyl group contains
1-6 carbon atom；In yet another embodiment, alkyl group contains 1-4 carbon atom；In yet another embodiment, alkyl base
Group is containing 1-3 carbon atom.The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-
CH2CH3), n-pro-pyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-
CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-
Bu、-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-amyl group (-CH (CH3)CH2CH2CH3), 3-amyl group (-CH
(CH2CH3)2), 2-methyl-2-butyl (-C (CH3)2CH2CH3), 3-methyl-2-butyl (-CH (CH3)CH(CH3)2), 3-methyl-
1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butene base (-CH2CH(CH3)CH2CH3), 2-ethyl-1-butyl (-CH2CH
(CH2CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3)CH2CH2CH2CH3), 3-hexyl (-
CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-amyl group (-C (CH3)2CH2CH2CH3), 3-methyl-2-amyl group (-CH (CH3)CH
(CH3)CH2CH3), 4-methyl-2-amyl group (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-amyl group (-C (CH3)(CH2CH3)2)、
2-methyl-3-amyl group (-CH (CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C (CH3)2CH(CH3)2), 3,3-diformazan
Base-2-butyl (-CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " hydroxyl " refers to "-OH ".
Term " hydroxyalkyl " or " hydroxy alkyl " represent the alkyl replaced by one or more hydroxyls, wherein oh group and
Alkyl group has implication as described in the present invention.In some of them embodiment, hydroxyalkyl group contains 1-6 carbon atom；
In another embodiment, oh group contains 1-4 carbon atom；In yet another embodiment, oh group contains 1-3 carbon
Atom.Such example includes, but not limited to 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, methylol, 1-ethoxy, 2-hydroxyl
Ethyl, 1,3-dihydroxy acrylate-2-base, 1,3-dihydroxy-2-(methylol)-propyl-2-base, hydroxyl butyl, 2,4-dihydroxy butyl, hydroxyl amyl group or
Hydroxyl hexyl, etc..
Unless other aspects show, structural formula described in the invention includes that all of isomeric forms is (as mapping is different
Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism)): such as contain R, S configuration of asymmetric center, (Z) of double bond,
(E) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or it is right
Reflect isomer, diastereomer, or the mixture of geometric isomer (or conformer) and broadly fall into the scope of the present invention.
Unless other aspects show, structural formula described in the invention and described compound include all of isomerism
Form (such as enantiomerism, diastereo-isomerism, geometrical isomerism or conformational isomerism), nitrogen oxides, hydrate, solvate, metabolism
Product, pharmaceutically acceptable salt and prodrug.Therefore, the single three-dimensional chemical isomer of the compound of the present invention, enantiomerism
Body, diastereomer, geometric isomer, conformer, nitrogen oxides, hydrate, solvate, metabolite, pharmacy
The compound of upper acceptable salt and prodrug falls within the scope of the present invention.It addition, unless other aspects show, the present invention is retouched
The structural formula of the compound stated includes the enriched isotope of one or more different atom.
The when that term " blocking group " or " Pg " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance
Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks
Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl
(BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl
The substituent group of base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl
Blocking group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes-
CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-is (to toluene
Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc..For protection
The description that group is general refers to document: T W.Greene, Protective Groups in Organic Synthesis,
John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,
Stuttgart,2005。
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.
Such conversion is hydrolyzed in blood by prodrug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This
Bright prodrug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as prodrug
(C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one
Compound comprises hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form includes
Phosphate ester, if these phosphate compounds are that the di on parent obtains.About complete the begging for of prodrug
Discuss and be referred to documents below: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery
Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible
Carriers in Drug Design,American Pharmaceutical Association and Pergamon
Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature
Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of
Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change
The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention
Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound
Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound
Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
The definition of neutral body of the present invention chemistry and the use of convention are typically referenced to documents below: S.P.Parker, Ed.,
McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New
York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John
Wiley&Sons, Inc., New York, the compound of 1994. present invention can comprise asymmetric center or chiral centre, therefore
There is different stereoisomers.The all of stereoisomeric forms in any ratio of compound of the present invention, include, but not limited to, diastereomeric
Body, enantiomer, atropisomer, and their mixture, such as racemic mixture, constitute the part of the present invention.
A lot of organic compound all exist with optical active forms, and i.e. they are had the ability the plane of Plane of rotation polarized light.Light is being described
When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use
Name the symbol that compound linearly polarized light rotates, (-) or l refer to that compound is left-handed, prefix (+) or d refer to chemical combination
Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.Specific vertical
Body isomer can be enantiomer, and the mixture of isomer is commonly referred to enantiomeric mixture.The enantiomer mixing of 50:50
Thing is referred to as racemic mixture or racemic modification, and this may cause not having stereo selectivity or three-dimensional fixed in chemical reaction process
Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack light
Learn activity.
" stereoisomer " refers to have identical chemical constitution, but the change that atom or group spatially arrangement mode is different
Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer
(cis/trans) isomer, atropisomer, etc..
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy is permissible
Converted mutually by low energy barrier.Such as proton tautomer (the most prototropic tautomer) includes being migrated by proton
Change, such as keto-enol and the isomerization of imine-enamine.Atomicity (quantivalence) tautomer includes
Reassemble into the change of bonding electron.
" 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 image relationship.
" diastereomer " refers to two or more chiral centre and the stereoisomerism of its molecule mirror image the most each other
Body.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomer mixes
Compound can be separated by high resolution analysis operation such as electrophoresis and chromatograph, such as HPLC.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine
On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe
pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,
1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base
The inorganic acid salt that group's reaction is formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid
Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document
Additive method such as ion exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist
Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora sulphur
Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal
Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid
Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalene sulphur
Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, bitterness
Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through
The salt that suitable alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any
The quaternary ammonium salt that the compound of the group of comprised N is formed.Water solublity or oil-soluble or dispersion product can be turned into by quaternary ammonium
With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt farther includes to fit
When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulphuric acid
Compound, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" hydrate " of the present invention refers to that solvent molecule is the associated complex that water is formed.
" nitrogen oxides " of the present invention refers to when compound is containing several amine functional group, can be by 1 or former more than the nitrogen of 1
Son oxidation forms N-oxide.The particular example of N-oxide is N-oxide or the N-oxidation of nitrogen heterocyclic ring nitrogen-atoms of tertiary amine
Thing.Available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine formation N-oxide and (see
Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially
It is that N-oxide can be prepared (Syn.Comm.1977,7,509-514) by the method for L.W.Deady, such as the most molten in inertia
In agent such as dichloromethane, amines is made to react with m-chloroperoxybenzoic acid (MCPBA).
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed
Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second
Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Any disease or disease " treated " in term as used in the present invention, and some embodiment middle fingers improve disease wherein
Disease or disease (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).In other embodiments
In, " treatment " refers to relax or improve at least one body parameter, including the body parameter may not discovered by patient.At another
In a little embodiments, " treatment " refers to (such as stablize perceptible symptom) from health or physiologically (such as stablize health
Parameter) or above-mentioned two aspect regulation disease or diseases.In other embodiments, " treat " and refer to prevention or postpone disease or disease
The outbreak of disease, occur or deteriorate.
Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with
The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many
Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced
Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, such as, and its
In there is radiosiotope, as3H,14C and18Those compounds of F, or wherein there is non radioactive isotope, as2H and13C.The compound of such isotope enrichment can be used for metabolism research and (uses14C), kinetics research (uses such as2H or3H), detection or imaging technique, such as positron emission tomography (PET) or include medicine or substrate tissue measure of spread
SPECT (single photon emission computed tomography) (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichment to PET or
It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art
Embodiment and the preparation process suitable isotope labeling reagent of described use in the routine techniques known or the present invention substitute former
Carry out used unmarked reagent to prepare.
On the other hand, the present invention relates to prepare the intermediate of the compound that formula (I) is comprised.
On the other hand, the method that the present invention relates to the preparation of compound, separation and purification that formula (I) is comprised.
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention, pharmacy
Upper acceptable carrier, excipient, diluent, adjuvant, solvent, or combinations thereof.At some embodiments, pharmaceutical composition
Can be liquid, solid, semi-solid, gel or spray-type.
Additionally, higher isotope particularly deuterium is (i.e.,2H or D) replacement can provide some treat advantage, these advantages are
Brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index obtains improving band
Come.Should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (I) compound.Can determine by the isotope enrichment factor
The concentration of justice such higher isotope particularly deuterium.Term used in the present invention " the isotope enrichment factor " refers to specified same
Ratio between isotope abundance and the natural abundance of position element.If the substituent group of the compounds of this invention is designated as deuterium, this change
Compound for each D-atom specified, have at least 3500 (each specify the deuterium of 52.5% at D-atom to mix), 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
The deuterium of 82.5% (mix), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7
(deuterium of 97% mixes), at least 6600 (deuterium of 99% mixes) or the isotope enrichment of at least 6633.3 (deuterium of 99.5% mixes)
The factor.The pharmaceutically useful solvate of the present invention includes that wherein recrystallisation solvent can be the substituted such as D of isotope2O, acetone-d6、
DMSO-d6Those solvates.
The compounds of this invention and pharmaceutical composition, preparation and administration
Described pharmaceutical composition comprises the compound of any present invention.This pharmaceutical composition can also comprise further
Pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
Described pharmaceutical composition comprises the medicine of resisiting influenza virus further.The medicine of described resisiting influenza virus can be to appoint
Other of the compounds of this invention it are different from for the medicine of influenza known to He.For example, it is possible to be Peramivir, Zha Na meter
Wei, Oseltamivir, that Ni Na meter Wei, Favipiravir, amantadine, rimantadine, arbidol, ribavirin, Si Tafulin,
Ingavirin (Ingavirin), GR-217029 or a combination thereof.
When can be used for treatment, the compounds of this invention of therapeutically effective amount, especially formula (I) compound and pharmaceutically may be used
The salt accepted can give as unprocessed chemical drugs, and the active component being alternatively arranged as pharmaceutical composition provides.Therefore, this
Bright content also provides for pharmaceutical composition, and this pharmaceutical composition includes this compounds of this invention of therapeutically effective amount, especially formula (I)
Compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, diluent or excipient.Herein
The term " therapeutically effective amount " used refers to be enough to demonstrate that significant patient benefit's (such as viral load minimizing) is each
The total amount of active component.When using single active component individually dosed, this term only refers to this composition.When combination application,
No matter this term then refers to combination, when being sequentially or simultaneously administered, all cause the combined amount of the active component of therapeutic effect.The present invention
Compound, especially formula (I) compound and pharmaceutically acceptable salt thereof are described above.From compatible with other compositions of preparation and
To its receiver harmless in the sense that from the point of view of, carrier, diluent or excipient must be acceptable.According to present invention
On the other hand, also providing for the method for preparing pharmaceutical preparation, the method includes the compounds of this invention, and especially formula (I) is changed
Compound or its pharmaceutically acceptable salt mix with one or more pharmaceutically acceptable carriers, diluent or excipient.This
The term " pharmaceutically acceptable " that used of invention refers to such compound, raw material, compositions and/or dosage form, they
In the range of rational medicine judges, it is adaptable to patient tissue contacts and without excessive toxicity, zest, allergy or with rationally
The symmetrical other problems of interests/Hazard ratio and complication, and be effective to given application.
Pharmaceutical preparation can be in unit dosage forms, and each unit dose contains the active component of scheduled volume.The change of present invention
The dosage level of compound is between about 0.01 mg/kg (mg/kg) body weight/day and about 250 mg/kg body weight/day, excellent
Selected introductions, between about 0.05mg/kg body weight/day and about 100mg/kg body weight/day, usually are used for preventing or treating with monotherapy
The disease of influenza virus mediation.Generally can be by every day about 1 to about 5 time or the medicine giving present invention as continuous infusion
Compositions.This kind of dose regimen can be used as long-term or short-term therapy.Mix with carrier material to prepare the active component of single dosage form
Amount by according to disease to be treated, the order of severity of disease, administration time, route of administration, the discharge rate of compound used therefor,
Treatment time and patient age, sex, body weight and situation and change.Preferably unit dosage forms is containing hereinbefore active component
Daily dose or divided dose or the unit dosage forms of its appropriate fraction.The available low dose being already clearly below compound optimal dose starts
Treatment.Hereafter, escalated dose is carried out with less increment until reaching optimum efficiency in this case.It is said that in general, it is the most preferable
To give the concentration level of compound be generally effective result can be provided any harmful without regard to causing at anti-virus aspect
Or poisonous side effect.
When the compositions of present invention comprise the compound of present invention and one or more other treatment medicines or
During the combination of prophylactic agent, the dosage level of compound and other medicine, generally in monotherapy scheme, accounts for normal administration
The about 10-150% of dosage, more preferably accounts for the about 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable to by any suitable way
Footpath is administered, such as by oral (including oral cavity or Sublingual), rectum, nose, locally (include oral cavity, Sublingual or percutaneous), vagina or
Parenteral (in including subcutaneous, Intradermal, intramuscular, intraarticular, intrasynovial, breastbone, in sheath, intralesional, intravenous or corium bet
Penetrate or infusion) approach.This kind of preparation can be prepared by any known method of art of pharmacy, such as by by active component with
Carrier or excipient mixing.Preferred oral is administered or drug administration by injection.
The pharmaceutical preparation being suitable to oral administration is provided by independent unit, such as capsule or tablet；Powder or granule；
Solution in aqueous or non-aqueous liquid or suspensoid；Edible foam formulations or foaming preparations (whip)；Or oil-in-water breast
Liquor or water in oil emulsion liquor.
For example, for oral administration in the form of a tablet or capsule, active medicine component can with pharmaceutically can connect
The oral, non-toxic inert carrier (such as ethanol, glycerol, water etc.) being subject to mixes mutually.By compound powder being broken into suitable fine chi
Very little, and with by as pulverize pharmaceutical carrier (edible saccharide such as such as starch or mannitol etc.) mixing prepare powder.Also
Correctives, preservative, dispersant and coloring agent can be there is.
By preparing pulverulent mixture as above, and it is loaded in the gelatin shell of shaping, prepares capsule.At dress
Before filling out operation, can be by fluidizer and lubricant (such as colloidal silica, Pulvis Talci, magnesium stearate, calcium stearate or solid-state
Polyethylene Glycol) it is added in pulverulent mixture.Also can add when the lower capsule of clothes by improve medicine utilizability disintegrating agent or
Solubilizing agent (such as agar, calcium carbonate or sodium carbonate).
When needing in addition or be required, it is possible to suitable binding agent, lubricant, disintegrating agent and coloring agent are mixed mixture
In.Suitably binding agent includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthesis
Natural gum (such as Radix Acaciae senegalis, tragakanta or sodium alginate), carboxymethyl cellulose, Polyethylene Glycol etc..For these dosage forms
Lubricant includes enuatrol, sodium chloride etc..Disintegrating agent includes, but are not limited to starch, methylcellulose, agar, Bentonite, xanthan
Glue etc..Such as, by making pulverulent mixture, pelletize or pre-tabletting, add lubricant and disintegrating agent, tabletted, thus make
Piece agent.By the compound suitably pulverized and diluent as described above or base material, optional and binding agent (such as carboxymethyl fibre
Dimension element, alginate, gelatin or polyvinylpyrrolidone), dissolve inhibitor (such as paraffin), absorption accelerator (quaternary salt) and/or
Absorbent (such as Bentonite, Kaolin or dicalcium phosphate) mixes, and prepares pulverulent mixture.Useful binders (such as syrup, shallow lake
Slurry, mucialga of arabic gummy (acadiamucilage) or cellulosic material or polymeric material solution) pressurize after moistening and sieve, by powder
Shape granulating mixture.The alternative method pelletized is, can be by pulverulent mixture by tablet machine, and result is the best by formation
Agglomerate smashes and makes granule.Can be by adding stearic acid, stearate, Pulvis Talci or mineral oil make particle lubrication to prevent from gluing
On the punch die of tablet machine.Then by the mixture tabletted through lubrication.The compound of present invention also can be with free stream
Dynamic inert carrier mixing, it is not necessary to just can tabletted by granulation or pre-tableting step.Can provide transparent or opaque by
The protectiveness bag that Lac seal coat, sugar-coat or polymeric material clothing and waxiness polishing clothing (polish coating of wax) form
Clothing material.Can be added to dyestuff in these coating materials distinguish different unit dose.
Oral liquid such as solution, syrup and elixir can be prepared with dosage unit form, thus specified rate contains
There is the compound of scheduled volume.Syrup can be prepared by being dissolved in suitably seasoned aqueous solution by compound, and elixir can lead to
Cross use non-toxic vehicle to prepare.Also can add solubilizing agent and emulsifying agent (such as ethoxylated isostearyl alcohols and polyoxyethylene mountain
Pears alcohol ether), preservative, taste masking additive (such as Oleum menthae or natural sweetener or saccharin or other artificial sweeteners) etc..
If appropriate, the dosage unit preparations micro encapsulation of oral administration can be used for.Also preparation can be made and prolong
Time or sustained release, such as by coating or be embedded in the microparticle material such as polymer, wax.
The compounds of this invention, especially formula (I) compound and pharmaceutically acceptable salt thereof can pass medicine system with liposome
System gives, such as small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can (such as gallbladder be solid by multiple phospholipid
Alcohol, octadecylamine or phosphatidylcholine) constitute.
The compounds of this invention, especially formula (I) compound and pharmaceutically acceptable salt thereof also can be by using monoclonal
Antibody passs medicine as single carrier (compound molecule is coupled).Compound also can with as can target medicine carrier can
Soluble polymer coupling.This base polymer can include polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide
Phenol, polyhydroxyethylaspart or the polyethylene-oxide polylysine replaced by palmitoyl residues.Additionally, compound can
With a class Biodegradable polymeric coupling, for reaching the controlled release of medicine, this base polymer such as polylactic acid, poly-ε-oneself in
Ester, poly butyric, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and the cross-linked copolymer of hydrogel or
Amphipathic nature block polymer.
The pharmaceutical preparation being suitable to percutaneous dosing can be as discrete patch (discrete patch) to protect in a long time
Hold and receiver's epidermis close contact.Such as, active component can be passed medicine by by iontophoresis patch, generally can be found in
Pharmaceutical Research 1986,3(6),318。
The pharmaceutical preparation being suitable to topical can be made into ointment, ointment, suspensoid, lotion, powder, solution, paste
Agent, gel, spray, aerosol, oil formulation or transdermal patch.
The pharmaceutical preparation being suitable to rectally can be as suppository or as enema offer.
The pharmaceutical preparation (wherein carrier is solid) being suitable to nose administration includes that particle diameter is such as 20-500 micrometer range
Pulvis grossus, by being administered in snuffing mode, is i.e. quickly sucked from close to the pulvis grossus container of nose by nasal passage.Wherein carry
Body is liquid, be adapted as nasal mist or appropriate formulation that nasal drop is administered includes aqueous solution agent or the oil of active component
Property solution.
Be suitable to the pharmaceutical preparation by inhalation and include minuteness particle powder (dust) or mist agent (mist), can use not
Dosage compresed gas aerosol, nebulizer, insufflator or other matters with type metering deliver the device of aerosol spray
Middle preparation.
The pharmaceutical preparation being suitable to vagina administration can be with vaginal suppository, vagina plug, ointment, cream, gel, paste, foam
Agent or spray provide.
Be suitable to the pharmaceutical preparation of parenteral and include aqueous and non-aqueous sterile injection solution and aqueous and non-aqueous
Sterile suspensions, aqueous and non-aqueous sterile injection solution can contain antioxidant, buffer agent, antibacterial and make described preparation
The solute isotonic with receptor's blood waiting, aqueous and non-aqueous sterile suspensions can include suspending agent and thickening agent.Preparation is permissible
Unit dose or multi-dose container provide, and the peace such as sealed is triumphant and bottle, and under the conditions of lyophilization (lyophilizing) can be saved in,
Only need to add sterile liquid carrier, such as water for injection before use.The injection solution and the suspensoid that face used time configuration can be by
Prepared by sterile powder injection, granule and tablet.
It will be appreciated that in addition to the composition being particularly mentioned above, preparation also includes relevant with described preparation type
Other composition commonly used in the art, this kind of preparation being for example suitable for oral administration can include correctives.
The compounds of this invention and the purposes of pharmaceutical composition
The feature of the pharmaceutical composition of the present invention includes the compound of formula (I), the compound listed by the present invention, or implements
The compound of example 1-2, and pharmaceutically acceptable carrier, adjuvant, or excipient.In the compositions of the present invention, compound can be effective
The ability of suppression influenza virus, it is adaptable to the prevention of influenza virus and treatment.
Comprise the compounds of this invention or the Therapeutic Method of pharmaceutical composition administration, farther include that patient is administered other and resist
The medicine of influenza, thus, it is possible to the medicine of the compound of the present invention Yu other influenza to be carried out therapeutic alliance, wherein said anti-
The medicine of influenza be Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, Favipiravir, amantadine, rimantadine,
Arbidol, ribavirin, Si Tafulin, ingavirin (Ingavirin), GR-217029 or a combination thereof.
And comprise the compounds of this invention or the Therapeutic Method of pharmaceutical composition administration, comprise other antiviral drugs further
The administration of thing, wherein, other Tamiflu can be with the compounds of this invention or its pharmaceutical composition administering drug combinations, of the present inventionization
Compound or pharmaceutical composition are as single dosage form, or separate compound or pharmaceutical composition are as a part for multi-pharmaceutics.Its
He can be administered simultaneously with the compounds of this invention or not be administered simultaneously Tamiflu.The situation of the latter, administration can stagger into
Row as carried out for 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
The compound of the present invention or " effective dose " of pharmaceutically acceptable compositions or " effective dose " refer to process or
Alleviate the effective dose that one or more present invention is previously mentioned the severity of disease.The method according to the invention, compound and combination
Thing can be any dosage and any route of administration is efficiently used for the order of severity that processes or palliate a disease.Required standard
Situation according to patient is changed by true amount, and this depends on race, the age, the generic condition of patient, the order of severity of infection,
Special factor, administering mode, etc..Compound or compositions can with one or more other therapeutic agents administering drug combinations, as
The present invention is discussed.
The general synthetic method of this compound
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further
Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this
The content of invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to prepare perhaps suitably
Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention
Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art
Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention
, or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business
Product supplier such as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa
Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is from Shantou
Chemical plant, western Gansu Province, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao is risen
Dragon chemical reagent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.
Anhydrous tetrahydro furan is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride and chloroform are to return through calcium hydride
Fluidized drying obtains.Ethyl acetate, N,N-dimethylacetamide and petroleum ether are to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects
Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with
CDC13Or DMSO-d6For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.
When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, bimodal), t
(triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of
Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data
DEG C) the spectrogrph of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector
Being applied to analyze, ESI source is applied to LC-MS spectrogrph.
Algorithm (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C)
The spectrogrph of Agilent 6120 series LC-MS measure, G1329A automatic sampler and G1315D DAD detector should
For analyzing, ESI source is applied to LC-MS spectrogrph.
Both the above spectrogrph is provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Note
Beam is long-pending is to be determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm
UV-Vis wavelength records reading.Flowing be mutually 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water-soluble
Liquid (phase B).Condition of gradient elution is as shown in table 1:
Table 1
| Time (min) | A(CH3CN, 0.1%HCOOH) | B(H2O, 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 purification is evaluated by Agilent 1100 series of high efficiency liquid chromatograph (HPLC), wherein UV detection
At 210nm and 254nm, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, and flow velocity is 0.6mL/min,
(0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of brief word below runs through the present invention:
V/V, v/v volume ratio
Ul microlitre
Mol/L, M mol/L
Mol mole
Mmol mM
ML milliliter
PE petroleum ether (60-90 DEG C)
EA, EtOAc ethyl acetate
DIPEA N, N-diisopropylethylamine
TLC thin layer chromatography
Following synthetic schemes describes the preparation present invention and comes into the open the step of compound.
Synthetic schemes (one)
Compound (I) can pass through synthetic schemes () and prepare, wherein R1, X there is implication of the present invention.Change
Compound (1) and compound (2), at alkali, obtain target compound by a step necleophilic reaction under acting on such as triethylamine, potassium carbonate etc.
(3), compound (3) reaction under alkalescence condition such as potassium carbonate effect obtains target compound 4.
The compound, pharmaceutical composition and the application thereof that there is provided the present invention below in conjunction with embodiment are further described.
Embodiment
Embodiment 1:3-((1,3-dihydroxy acrylate-2-yl) amino)-6-Calmazine-2-Methanamide
The synthesis of step 1:6-bromo-3-HYDROXYPYRAZINE-2-Methanamide
By 3-hydroxyl piperazine-2-Methanamide (5g, 35.97mmol, 1eq.) and tetrabutyl ammonium bromide (19g, 39.57mmol,
1.1eq.) it is dissolved in DMF (50mL), is subsequently adding 2,6-lutidines (4.2mL, 35.97mmol, 1
eq.).Mixture is stirred at room temperature 17 hours, and TLC monitoring reaction is until complete.In reaction system, 10% is added after having reacted
Sodium-chloride water solution (100mL), separates out solid.In collecting solid and adding the mixed solution of 30mL water and 30mL ethyl acetate,
Stir 10 minutes, isolated organic facies.Organic facies saturated aqueous common salt (20mL x 2) washs, then does with anhydrous sodium sulfate
Dry, it is concentrated under reduced pressure to give residue crude product, subsequently crude product silica gel column chromatography (eluant: PE/EA (V/V)=5/1-2/1) purification
Obtain white solid compound 4g, yield 51%.
MS-ESI:(ESI,pos.ion)m/z:219.1[M+1]+。
The synthesis of step 2:6-bromo-3-chloropyrazine-2-formonitrile HCN
Bromo-for 6-3-HYDROXYPYRAZINE-2-Methanamide (3.57g, 16.38mmol, 1eq.) is dissolved in chlorobenzene (70mL), 0 DEG C
Lower addition phosphorus oxychloride (5.3mL, 57.33mmol, 3.5eq.) and N, N-diisopropylethylamine (11.4mL, 65.52mmol,
4eq.).Mixed liquor is heated to 100 DEG C and stirs 17 hours, and TLC observes reaction process.Reactant liquor is concentrated under reduced pressure to give crude product, slightly
Product silica gel column chromatography (eluant: PE/EA (V/V)=15/1-10/1) purification obtains white solid compound 2.2g, receives
Rate 62%.
The synthesis of step 3:3,6-bis-Calmazine-2-formonitrile HCN
Potassium fluoride (5.7g, 98.44mmol, 3.7eq.) and tetrabutyl ammonium bromide (1.72g, 5.32mmol, 0.2eq.) add
Entering in 10mL anhydrous dimethyl sulfoxide, mixed liquor is heated to 100 DEG C and reacts 1 hour.It is cooled to 70 DEG C, adds 6-bromo-3-chlorine pyrrole
The anhydrous toluene solution 20mL of piperazine-2-formonitrile HCN (5.8g, 26.6mmol, 1eq.), mixture reacts 3 hours at this temperature.TLC
Monitoring after completion of the reaction, adds 10mL water, separates organic facies.Organic facies saturated aqueous common salt 20mL washs, and adds hydrochloric acid and adjusts
Saving to pH about 1.6, organic facies continues to wash with saturated nacl aqueous solution 20mL, and dried with anhydrous sodium sulfate, concentrating under reduced pressure obtains
To thick product.Crude product obtains white solid product 1.85g with silica gel column chromatography (eluant: PE/EA=30/1) purification further,
Yield 49%.
1H NMR(400MHz,CDCl3):δ8.34-8.31(d,1H)。
The synthesis of step 4:3-((1,3-dihydroxy acrylate-2-yl) amino)-6-Calmazine-2-formonitrile HCN
By 3,6-bis-Calmazine-2-formonitrile HCN (200mg, 1.42mmol), 2-aminopropan-1,2-glycol (142mg,
1.56mmol) adding in 30mL dichloromethane with triethylamine (0.43mL, 3.12mmol), mixed liquor is stirred at room temperature 2 hours, TLC
Monitoring reaction is until reacting complete.Adding the washing of 20mL water, organic facies is washed with saturated aqueous common salt 20mL, and anhydrous sodium sulfate is done
Dry, concentrating under reduced pressure.Residue silica gel column chromatography (eluant: PE/EA=2/1) purification obtains 55mg white solid targeted
Compound, yield 19%.
MS-ESI:(ESI,pos.ion)m/z:213.1[M+1]+。
The synthesis of step 5:3-((1,3-dihydroxy acrylate-2-yl) amino)-6-Calmazine-2-Methanamide
Potassium carbonate (66mg, 0.48mmol) is dissolved in water (0.66mL), this solution is joined at 10 DEG C 3-((1,
3-dihydroxy acrylate-2-yl) amino)-6-Calmazine-2-formonitrile HCN (55mg, 0.24mmol) dimethyl sulfoxide (4mL) solution in, so
Rear reactant liquor is stirred at room temperature 30 minutes.Add 30% hydrogen peroxide solution (0.1mL, 1.2mmol) in reaction system, mix liquid chamber
Temperature is lower continues reaction 2 hours.Then TLC monitors after completion of the reaction, adds ethyl acetate and each 20mL of water, separatory, and organic facies is used
Saturated aqueous common salt (15mL x 2) washs, and anhydrous sodium sulfate is dried, concentrating under reduced pressure.Residue silica gel column chromatography (eluant: PE/
EA=4/1) white solid target compound 8.5mg, yield 14% are obtained.
MS-ESI:(ESI,pos.ion)m/z:231.2[M+1]+；
1H NMR(400MHz,DMSO):δ8.75(d,1H),8.33(d,1H),8.00(s,1H),7.68(s,1H),4.79
(t,1H),4.03(dd,2H),3.53(m,4H)。
The fluoro-3-of embodiment 2:6-((3-hydroxypropyl) amino) pyrazine-2-Methanamide
The synthesis of the fluoro-3-of step 1:6-((3-hydroxypropyl) amino) pyrazine-2-formonitrile HCN
By 3,6-bis-Calmazine-2-formonitrile HCN (100mg, 0.70mmol), 3-aminopropan-1-ols (58mg, 0.78mmol) and
Triethylamine (0.21mL, 1.1mmol) is placed in 50mL dichloromethane, and mixed liquor is stirred at room temperature about 2 hours, and TLC monitors reaction
After, concentrating under reduced pressure removes dichloromethane.Residue over silica gel column chromatography (eluant: PE/EA=2/1) purification, obtains
83mg white solid target compound, yield 56%.
MS-ESI:(ESI,pos.ion)m/z:197.1[M+1]+。
The synthesis of the fluoro-3-of step 2:6-((3-hydroxypropyl) amino) pyrazine-2-Methanamide
Fluoro-for 6-3-((3-hydroxypropyl) amino) pyrazine-2-formonitrile HCN (77mg, 0.39mmol) is dissolved in dimethyl sulfoxide
(4mL), solution adds the aqueous solution (1mL) of potassium carbonate (107mg, 0.78mmol) at 10 DEG C, adds rear mixed liquor and rises to room
Temperature reaction 30 minutes.Being subsequently adding the hydrogen peroxide solution (221mg, 1.95mmol) of 30%, it is little that mixed liquor room temperature continues stirring 2
Time.TLC monitors after completion of the reaction, adds ethyl acetate and each 20mL of water, separatory.Organic facies is with saturated aqueous common salt (15mL x 2)
Washing, anhydrous sodium sulfate is dried, concentrating under reduced pressure.Residue silica gel column chromatography (eluant is PE:EA=2:1) purification obtains white
Solid, shaped target compound 42mg, yield 50%.
MS-ESI:(ESI,pos.ion)m/z:215.2[M+1]+；
1H NMR(400MHz,CDCl3):δ8.54(s,1H),8.10(dd,1H),7.38(s,1H),5.60(s,1H),
3.61-3.67(m,4H),2.33-2.35(d,2H),1.80-1.86(m,2H)。
Anti-influenza virus activity measures
96 orifice plate CPE algoscopy steps:
Spread 96 orifice plates, 5000 mdck cells of every hole inoculation, 37 DEG C, 5%CO2, incubated overnight.
By DMSO and serum-free medium diluted compounds to suitable concn, DMSO final concentration of 1%.
-80 DEG C of frozen influenza virus H1N1 (A/weiss/43) are diluted by culture medium.
Every hole adds the compound after 50ul dilution and the virus liquid (final MOI=0.01) after 50ul dilution.
96 orifice plates are placed in 37 DEG C, 5%CO2, cultivate 3 days.
Every hole adds 20ul MTT, 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 living cells reduction, and the CPE calculating influenza virus mediation accordingly is detected chemical combination
The percentage ratio of thing suppression.
96 orifice plates mensuration cytotoxicity steps:
Spread 96 orifice plates, 5000 mdck cells of every hole inoculation, 37 DEG C, 5%CO2, incubated overnight.
By DMSO and serum-free medium diluted compounds to suitable concn, DMSO final concentration of 1%.
Every hole adds the compound after 50ul dilution and 50ul culture fluid.
96 orifice plates are placed in 37 DEG C, 5%CO2, cultivate 3 days.
Every hole adds 20ul MTT, is placed in 37 DEG C, 4 hours.
Measure the first a ceremonial jade-ladle, used in libation amount that MTT is generated by living cells reduction, and calculate the cytotoxicity of test compound accordingly.
Data analysis: % suppression ratio=(ODT–ODV)/(ODC–ODV) × 100%
% cytotoxicity=ODT/ODC× 100%
% activity=% suppression ratio % cytotoxicity
ODT,ODV, and ODCRepresent the specific absorbance of test compound respectively, and virus-infected controls (without compound ,+1%
DMSO),
And cell blank comparison (virus-free, without compound ,+1%DMSO)
OD value=OD570–OD630(MTT)
Table 2: 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, the compounds of this invention has obvious anti-influenza virus activity.
It will be apparent to one skilled in the art that present invention is not limited to foregoing illustrative embodiment, and
And can be embodied in other concrete form without departing from its essential characteristics.It is therefore contemplated that each embodiment is the most all
It is considered illustrative and nonrestrictive, should refer to appended claims rather than these embodiments aforementioned, therefore,
All changes in the implication of appended claims equivalents and scope are included in herein.
In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specifically show
Example " or the description of " some examples " etc. means to combine this embodiment or example describes specific features, structure, material or feature
It is contained at least one embodiment or the example of the present invention.In this manual, the schematic representation of above-mentioned term is differed
Surely identical embodiment or example are referred to.And, the specific features of description, structure, material or feature can be any
One or more embodiments or example combine in an appropriate manner.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example
Property, it is impossible to be interpreted as limitation of the present invention, those of ordinary skill in the art is without departing from the principle of the present invention and objective
In the case of above-described embodiment can be changed within the scope of the invention, revise, replace and modification, the scope of the present invention
Limited by claim and equivalent thereof.
Claims (9)
1. a compound, it is the stereoisomer of structure shown in the structural formula shown in formula (I) or formula (I), geometric isomer,
Tautomer, pharmaceutically acceptable salt,
Wherein,
X is halogen；With
R1For C1-C6Hydroxyalkyl.
Compound the most according to claim 1, wherein,
X is F, Cl, Br or I；With
R1For C1-C6Hydroxyalkyl.
Compound the most according to claim 1, wherein, R1For 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, methylol, 1-
Ethoxy, 2-ethoxy, 1,3-dihydroxy acrylate-2-base, 1,3-dihydroxy-2-(methylol)-propyl-2-base, hydroxyl butyl, 2,4-dihydroxy fourth
Base, hydroxyl amyl group or hydroxyl hexyl.
Compound the most according to claim 1, it is different for the solid of structure shown in the structure shown in formula (II) or formula (II)
Structure body, geometric isomer, tautomer, pharmaceutically acceptable salt,
Wherein, R1For C1-C6Hydroxyalkyl.
Compound the most according to claim 4, wherein, R1For 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, methylol, 1-
Ethoxy, 2-ethoxy, 1,3-dihydroxy acrylate-2-base, 1,3-dihydroxy-2-(methylol)-propyl-2-base, hydroxyl butyl, 2,4-dihydroxy fourth
Base, hydroxyl amyl group or hydroxyl hexyl.
Compound the most according to claim 1, has the structure of one of,
Or the stereoisomer of structure shown in it, geometric isomer, tautomer, pharmaceutically acceptable salt.
7. pharmaceutical composition comprises the compound described in claim 1-6 any one, and pharmaceutically acceptable load
Body, excipient, diluent or combinations thereof.
Pharmaceutical composition the most according to claim 7, it comprises other anti-influenza virus medicament, Qi Zhongsuo further
The anti-influenza virus medicament stated be Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, Favipiravir, amantadine,
Rimantadine, arbidol, ribavirin, Si Tafulin, ingavirin (Ingavirin) or a combination thereof.
9. the compound described in a claim 1-6 any one or the drug regimen described in claim 7-8 any one
Thing has the purposes in the medicine of related disorders in preparation for protecting, treat or alleviating with influenza virus.
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| CN101268064A (en) * | 2005-07-29 | 2008-09-17 | 奥米罗实验室有限公司 | Pyrazine derivatives useful as adenosine receptor antagonists |
| CN101610772A (en) * | 2007-02-16 | 2009-12-23 | 富山化学工业株式会社 | The method that comprises pharmaceutical composition with the drug combination that uses pyrazines derivatives of pyrazines derivatives |
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| CN101268064A (en) * | 2005-07-29 | 2008-09-17 | 奥米罗实验室有限公司 | Pyrazine derivatives useful as adenosine receptor antagonists |
| CN101610772A (en) * | 2007-02-16 | 2009-12-23 | 富山化学工业株式会社 | The method that comprises pharmaceutical composition with the drug combination that uses pyrazines derivatives of pyrazines derivatives |
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