CN104402833A - Pyrazine compound containing diethylene substituent and composition and application thereof - Google Patents

Pyrazine compound containing diethylene substituent and composition and application thereof Download PDF

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Publication number
CN104402833A
CN104402833A CN201410667916.2A CN201410667916A CN104402833A CN 104402833 A CN104402833 A CN 104402833A CN 201410667916 A CN201410667916 A CN 201410667916A CN 104402833 A CN104402833 A CN 104402833A
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Prior art keywords
compound
methyl
amino
present
hydroxyl
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CN104402833B (en
Inventor
任青云
刘辛昌
唐昌华
张健存
张英俊
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Haitong Hengxin International Finance Leasing Tianjin Co ltd
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a pyrazine compound containing a diethylene substituent and application thereof as a medicine, particularly application thereof to preparation of medicines for preventing and treating various influenza viruses. Particularly, the invention relates a compound of which the general formula I is shown in the specification, or a stereoisomer, a geometrical isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and all variables are defined in the specification. The invention also relates to application of the compound of which the general formula I is shown in the specification, or the stereoisomer, the geometrical isomer, the tautomer, the nitrogen oxide, the hydrate, the solvate, the metabolite, the pharmaceutically acceptable salt or the prodrug thereof as medicines, particularly application of the compound as a medicine for preventing and treating influenza viruses.

Description

Containing the substituent pyrazine compounds of tetramethylene and composition thereof and purposes
Technical field
The present invention relates to a kind of containing the substituent pyrazine compounds of tetramethylene and the purposes as medicine thereof, the compounds of this invention is applicable to the purposes preparing antiviral.The invention still further relates to the pharmaceutical composition comprising these compounds, and relate to the described compound of use, be used alone or use with other drug combination, the application of the various virus of prevention and therapy, the especially application of prevention and therapy influenza virus.
Background technology
Influenza (influenza is called for short influenza) is the acute respiratory infection that influenza virus causes, and is also the disease that a kind of infectivity is strong, velocity of propagation is fast.It is mainly through the spittle in air, interpersonal contact or the contact transmission with contaminated article.Typical clinical symptom is: anxious high heat, overall pain, significantly weak and slight respiratory symptom.General autumn and winter season is its high-incidence season, and caused complication and the phenomena of mortality are very serious.
Achieve greater advance to the research of anti-influenza virus medicament in recent years, different anti-influenza virus medicaments is preventing and treating the difference of the effect in influenza.M2 ionophorous protein inhibitor (as Buddha's warrior attendant gastral cavity amine and Rimantadine) is the influenza clinical treatment medicine gone on the market the earliest, but there is increasing and the limitation of first validity to Type B influenza virus of resistance strain ratio.It is explore the breakthrough in resisiting influenza virus grass drug research at present that neuraminidase inhibitor is succeeded in developing, all inhibit activities is had to first, Influenza B virus, such as, Oseltamivir be prevention and therapy bird flu and occur Human Influenza popular time first medication, but, in recent years, researchist has all over the world found H1N1, H5N1, the H3N2 and the Type B influenza virus that Oseltamivir are created to resistance successively.Other anti-influenza virus medicaments all have preferably to restraining effect and the antiviral application prospect of virus according to bibliographical information, but normal needs proves further.
Because the widespread use clinically of existing medicine makes influenza virus morph, resistance is in various degree created to these medicines.Therefore novel anti-influenza virus medicament research and development are very urgent.
The invention provides a kind of antiviral drug, it is to various virus, and especially influenza virus has prophylactic effect and therapeutic action.
Summary of the invention
The present invention relates to pyrazine compounds and its pharmaceutical composition of the replacement of a kind of novel tetramethylene, and prepare the various virus of prevention and therapy, the purposes especially in influenza virus medicine.
On the one hand, the present invention relates to a kind of compound, it is for such as formula the compound shown in (I), or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein, R 1for hydroxyl, C 1-3hydroxyalkyl, C 1-3alkyl, C 1-3alkoxyl group, amino or C 1-3alkylamino;
R 2for-CN ,-C (=NH) NH 2,-C (=O) NH 2,-C (=S) NH 2,-C (=NH) NHOH ,-C (=NH) NH-C 1-3alkyl or-C (=O) O-C 1-3alkyl;
R 3for hydrogen or C 1-3alkyl;
R 4for hydrogen, hydroxyl, amino, C 1-3alkylamino, C 1-3alkoxyl group, C 1-3alkyl, F, Cl, Br or I; With
R 5for hydrogen, hydroxyl, C 1-3alkyl or C 1-3hydroxyalkyl.
In some embodiments, wherein
R 1for hydroxyl, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, amino, N-methylamino-, N-ethylamino or N, N-dimethylamino;
R 2for-CN ,-C (=NH) NH 2,-C (=O) NH 2,-C (=S) NH 2,-C (=NH) NHOH ,-C (=NH) NHCH 3,-C (=NH) NHCH 2cH 3,-C (=O) OCH 3or-C (=O) OCH 2cH 3;
R 3for hydrogen, methyl or ethyl;
R 4for hydrogen, hydroxyl, amino, N-methylamino-, N-ethylamino, N, N-dimethylamino, methoxyl group, oxyethyl group, methyl, ethyl, F, Cl, Br or I; With
R 5for hydrogen, hydroxyl, methyl, ethyl, n-propyl, sec.-propyl, hydroxymethyl, hydroxyethyl or 2-hydroxypropyl.
The present invention relates to following one of them compound or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug,
On the one hand, present invention also offers a kind of pharmaceutical composition containing compound of the present invention, this pharmaceutical composition contains compound of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
In certain embodiments, it further comprises other anti-influenza virus medicament, wherein said anti-influenza virus medicament 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, present invention also offers described compound or described pharmaceutical composition for the preparation of preventing, processing, treat or alleviate the purposes in patient influenza virus medicine.
The present invention relates on the other hand the preparation of compound that formula (I) comprises, the method for abstraction and purification.
The present invention also comprises compound of the present invention and steric isomer thereof, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, or the application of its pharmacy acceptable salt, compound of the present invention is producing the application effectively suppressed in influenza virus.Compound of the present invention is used for alleviating for the production of a kind of pharmaceuticals equally, stops, and controls or treatment patient influenza infection.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula (I) and at least one pharmaceutically acceptable carrier, the effective treatment consumption needed for the combination of assistant agent or thinner.
The present invention comprises the disease of effective influenza virus equally, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises the representative compound of use formula (I) is treated patient.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.Term " pharmaceutically acceptable " comprises material or composition must be applicable to chemistry or toxicology, relevant with the Mammals be used for the treatment of with other components of composition preparation.
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, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxysuccinic acid, Lactic acid Citric 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, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or their combination.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide, ammonium, N +(R 14) 4salt and alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, N +(R 14) 4salt, as R 14h, C 1-4alkyl, C 6-10aryl, C 6-10aryl C 1-4alkyl etc., and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.Also suitable, nontoxic ammonium is comprised, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
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 " Organic Chemistry ", ThomasSorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley & Sons, description in New York: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.
Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-Hill Dictionary of ChemicalTerms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of OrganicCompounds ", John Wiley & Sons, Inc., New York, 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, can with reference to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles ofAsymmetric Synthesis (2 nded.Robert E.Gawley, Jeffrey Aub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H.Tables of Resolving Agents andOptical Resolutions p.268 (E.L.Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972); Chiral SeparationTechniques:A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim, Germany, 2007).
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), etc.
Term " hydroxyalkyl " groups separately replace by one or two oh group, wherein alkyl group has implication as described in the present invention, and the example of hydroxyalkyl groups comprises, but is not limited to, hydroxymethyl (HOCH 2-), hydroxyethyl (HOCH 2cH 2-), 2-hydroxypropyl (CH 3cHOHCH 2-), etc.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom.The substituting group that described alkoxy base can optionally be described by one or more the present invention replace.
The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH 3), oxyethyl group (EtO ,-OCH 2cH 3), 1-propoxy-(n-PrO, n-propoxy-,-OCH 2cH 2cH 3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH 3) 2), 1-butoxy (n-BuO, n-butoxy ,-OCH 2cH 2cH 2cH 3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH 2cH (CH 3) 2), etc.
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group.Some of them embodiment is, alkylamino is one or two C 1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C 1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, etc.
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Unless other aspects show, structural formula described in the invention and described compound comprise all isomeric forms (as enantiomerism, diastereo-isomerism, rotamerism or conformational isomerism), oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt and prodrug.Therefore, the single three-dimensional chemical isomer of compound of the present invention, enantiomer, diastereomer, geometrical isomer, conformer, oxynitride, hydrate, solvate, meta-bolites, the compound of pharmacy acceptable salt and prodrug also belongs to scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises 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.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of theA.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, J.Rautio et al., Prodrugs:Design and ClinicalApplications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al., Prodrugs of Phosphatesand Phosphonates, Journal of Medicinal Chemistry, 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.
The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary ofChemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry ofOrganic Compounds ", John Wiley & Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, enantiomer, atropisomer, and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Steric isomer " refer to that there is 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.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can be transformed mutually by low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) comprises the change by proton shifting, as the isomerization of keto-enol and imine-enamine.Valence (valency) tautomer comprises the change reassembling into 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.
" 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.
" 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.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 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.
" hydrate " of the present invention refers to that solvent molecule is the associated complex that water is formed.
" oxynitride " of the present invention refers to when compound is containing several amine functional group, 1 or the nitrogen-atoms oxidation being greater than 1 can be formed N-oxide compound.The particular example of N-oxide compound is the N-oxide compound of tertiary amine or the N-oxide compound of nitrogen heterocyclic ring nitrogen-atoms.Available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine and form N-oxide compound (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).Especially, N-oxide compound can be prepared (Syn.Comm.1977,7,509-514) by the method for L.W.Deady, wherein such as in inert solvent such as methylene dichloride, amine compound and m-chloroperoxybenzoic acid (MCPBA) is reacted.
" 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.
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.
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.
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.
The compounds of this invention and pharmaceutical composition, 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 (polish coating of wax) 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 (discrete patch) to keep and recipient's epidermis close contact in long-time.Such as, activeconstituents can pass medicine by by iontophoresis patch, usually can see Pharmaceutical Research 1986, 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 feature of pharmaceutical composition of the present invention comprises the compound of formula (I), the compound listed by the present invention, or the compound of embodiment 1-14, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, compound effectively can suppress the ability of influenza virus, is applicable to the prevention and therapy of influenza virus.
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.
The general synthetic method of this compound
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 Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, 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 is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, N,N-dimethylacetamide and sherwood oil 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 3or DMSO-d 6for solvent (reporting in units of ppm), with TMS (0 ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, 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 a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6120 being equipped with G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with Agilent Zorbax SB-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 purifying is evaluated by Agilent 1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-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:
BOC, Boc tert-butoxycarbonyl
Bz benzoyl
NBu 4br Tetrabutyl amonium bromide
CDC1 3deuterochloroform
CD 3oD deuterated methanol
H 2o water
Et 3n triethylamine
EtOAc ethyl acetate
UL microlitre
ML, m milliliter
N 2nitrogen
NH 2oH azanol
Pd/C palladium/carbon
PE sherwood oil (60 – 90 DEG C)
DCM methylene dichloride
MeOH methyl alcohol
DMSO methyl-sulphoxide
DMSO-d 6deuterated dimethyl sulfoxide
DMF DMF
DIPEA diisopropylethylamine
H 2o 2hydrogen peroxide
THF tetrahydrofuran (THF)
NaOMe sodium methylate
NH 4cl ammonia chloride
H hour
TBAF tetrabutyl ammonium fluoride
HPLC high performance liquid chromatography
MS mass spectrum
POCl 3phosphorus oxychloride
KF Potassium monofluoride
SOCl 2sulfur oxychloride
Pd/C palladium/carbon
NaOH sodium hydroxide
H 2o 2hydrogen peroxide
Na 2sO 4.10H 2o Disodium sulfate decahydrate
Min minute
Synthetic schemes
Synthetic method 1
Compound (c) can be prepared by synthetic method 1, wherein R 1, R 3, R 4, R 5have implication of the present invention, compound (a) and compound (b) obtain target compound 3 by nucleophilic reaction under alkali (as triethylamine, salt of wormwood etc.) acts on.
Synthetic method 2
Compound (d) can be prepared by synthetic method 2, wherein R 1, R 3, R 4, R 5have implication of the present invention, compound (c) and azanol reaction obtain target compound (d).
Synthetic method 3
Compound (c) can be prepared by synthetic method 3, wherein R 1, R 3, R 4, R 5have implication of the present invention, compound (c) and ammonium chloride are obtained by reacting target compound (e) under the effect of alkali.
Synthetic method 4
Compound (f) can be prepared by synthetic method 4, wherein R 1, R 3, R 4, R 5have implication of the present invention, compound (c) is obtained by reacting target compound (f) under alkaline condition (as salt of wormwood).
The synthesis of intermediate
Intermediate 1:3,6-bis-Calmazine-2-formonitrile HCN
The synthesis of the bromo-3-HYDROXYPYRAZINE of step 1:6--2-methane amide
By 2,6-lutidine (4.2mL, 35.97mmol, 1eq.) join 3-HYDROXYPYRAZINE-2-methane amide (5g, 35.97mmol, 1eq.) with Tetrabutyl amonium bromide (19g, 39.57mmol, in DMF (50mL) solution 1.1eq.), reaction solution at room temperature stirs 17h, after having reacted, the sodium chloride solution of 10% is added in reaction system, separate out solid, the solid of collection is joined in the mixing solutions of 30mL water and 30mL EtOAc, then stir ten minutes.Be separated organic phase saturated aqueous common salt (the 20mL x 2) washing obtained, use anhydrous sodium sulfate drying again, concentrating under reduced pressure, residue obtains titled compound as white solid (4g, 51%) through silica gel column chromatography column chromatography (eluent: PE/EtOAc (V/V)=2/1) purifying.
MS:(ESI,pos.ion)m/z:219.1[M+1] +.
The synthesis of the bromo-3-chloropyrazine of step 2:6--2-formonitrile HCN
At 0 DEG C, by POCl 3(5.3mL, 57.33mmol, 3.5eq.) with DIPEA (11.4mL, 65.52mmol, 4eq.) join the bromo-3-HYDROXYPYRAZINE of 6--2-methane amide (3.57g, 16.38mmol, in chlorobenzene (70mL) solution 1eq.), reaction solution is heated to 100 DEG C and stirs 17h, after having reacted, by reaction solution concentrating under reduced pressure, concentrated crude on silica gel column chromatography (eluent: PE/EtOAc (V/V)=10/1) purifying obtained obtains white solid title compound (2.2g, 62%).
ESI:(ESI,pos.ion)m/z:219.4[M+1] +.
Step 3:3,6-bis-synthesis of Calmazine-2-formonitrile HCN
By KF (5.7g, 98.44mmol, 3.7eq.) and NBu 4br (1.72g, 5.32mmol, 0.2eq.) join in the anhydrous DMSO of 10mL, reaction mixture is heated to 100 DEG C of reaction 1h, then be cooled to 70 DEG C, then add the bromo-3-chloropyrazine of compound 6--2-formonitrile HCN (5.8g, 26.6mmol, dry toluene (20mL) solution 1eq.), gained mixture continues to react 3h at this temperature.After having reacted, add 10mL water, then be separated organic phase and aqueous phase, the organic phase of separation is washed with saturated aqueous common salt 20mL, and organic phase adds concentrated hydrochloric acid again and is adjusted to pH about 1.6, and then washs with saturated nacl aqueous solution 20mL.After organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, the concentrated thick product obtained obtains white solid title compound (1.85g, 49%) through silica gel column chromatography (eluent: PE/EtOAc (V/V)=30/1) purifying.
1H NMR(400MHz,CDCl 3):δ8.34-8.31(d,1H).
Intermediate 2:(3-(amino methyl)-3-hydroxycyclobutyl) methyl benzoic acid ester
The synthesis of step 1:3-oxygen cyclobutane-carboxylic acid methyl esters
0 DEG C and stir under, by SOCl 2(3.1mL, 0.045mol, 0.5eq.) joins the CH of 3-oxygen cyclobutane formate (10.0g, 0.09mol, 1.0eq.) 3in OH (50mL) solution, concentrating under reduced pressure after reaction solution backflow 4.0h, residue by silicagel column chromatography (eluent: PE/EtOAc (V/V)=10/1) purifying obtains colorless oil title compound (10.0g, 90%).
1H NMR(400MHz,CDCl 3):δ3.77(s,3H),3.23-3.46(s,5H).
The synthesis of step 2:3,3-bi-methoxy cyclobutane-carboxylic acid methyl esters
By trimethyl orthoformate (25.7mL, 234.4mmol, 2eq.) and tosic acid (0.75g, 5%) 3-oxygen cyclobutane-carboxylic acid methyl esters (15g is joined, 117.19mmol, 1eq.) 50mL dichloromethane solution in, reaction solution reacts 5h at being placed in 45 DEG C.After having reacted, in reaction solution, add 50mL water, and extract with DCM (20mL x 2).The organic phase merged saturated aqueous common salt (40mL x 2) washing, then anhydrous sodium sulfate drying, then filter, last concentrating under reduced pressure obtains colorless oil title compound (19.6g, 96%).
Step 3:(3,3-bi-methoxy tetramethylene base) synthesis of methyl alcohol
At 0 DEG C, by anhydrous 3,3-bi-methoxy cyclobutane-carboxylic acid methyl esters (18.6g, 106.78mmol, THF (50mL) solution 1eq.) joins lithium aluminium hydride (4.06g, 106.78mmol, 1eq.) anhydrous THF (150mL) suspension in, reaction mixture continue at 0 DEG C stir 17h.Then in reaction solution, add the Na of 1mL 2sO 4.10H 2the saturated solution of O, refilters, and filtrate obtains colorless oil title compound (10.7g, 69%) through concentrating under reduced pressure.
1H NMR(400MHz,CD 3OD):δ3.60(d,2H),3.12(s,3H),3.10(s,3H),2.27(m,1H),2.24(s,1H),2.23(m,2H)；1.85(m,2H).
Step 4:(3,3-bi-methoxy tetramethylene base) synthesis of methyl benzoic acid ester
By (3,3-bi-methoxy tetramethylene base) methyl alcohol (10.7g, 73.2mmol, 1eq.) be dissolved in DCM (100mL), and add triethylamine (25.4mL wherein, 183mmol, 2.5eq.) with DIPEA (1.28mL, 7.32mmol, 0.1eq.), then at 0 DEG C, drip Benzoyl chloride (10.2mL again, 87.84mmol, 1.2eq.), gained reaction solution at room temperature stirs 16h, then adds 100mL saturated sodium bicarbonate solution wherein.The organic phase be separated uses saturated ammonium chloride solution (60mL) and saturated nacl aqueous solution (60mL) washing respectively, then uses dried over sodium sulfate, finally filters.Filtrate obtains colorless oil title compound (16.83g, 92%) through concentrating under reduced pressure.
1H NMR(400MHz,CD 3OD):δ8.06(d,2H),7.56(m,1H),7.45(m,2H),4.36(d,2H),3.18(d,6H),2.52(m,1H),2.37(m,2H),2.01(m,2H).
Step 5:(3-oxygen cyclobutyl) synthesis of methyl benzoic acid ester
(3,3-bi-methoxy tetramethylene base) methyl benzoic acid ester (20.15g, 80.6mmol, 1eq.) is dissolved in CH 3in CN (100mL), and add 1M sulfuric acid (40mL, 40.3mmol, 0.5eq.) wherein.Reaction solution at room temperature reacts about 2h, then with saturated sodium bicarbonate, reaction solution is adjusted its pH to 7, then concentrating under reduced pressure, adds 60mL saturated nacl aqueous solution in residue.Gained mixture EtOAc (50mL x 2) extracts, organic phase saturated nacl aqueous solution (50mL x 2) washs, anhydrous sodium sulfate drying, concentrating under reduced pressure again, residue obtainedly obtain colorless oil title compound (16.7g, 98%) through purification by silica gel column chromatography (eluent: PE/EtOAc (V/V)=7/1).
1H NMR(400MHz,CD 3OD):δ8.02(m,2H),7.57(m,1H),7.45(m,2H),4.49(d,2H),3.26-3.21(m,2H),3.03-2.97(m,3H).
Step 6:(3-hydroxyl-3-(nitromethyla) cyclobutyl) synthesis of methyl benzoic acid ester
At-10 DEG C, by Nitromethane 99Min. (8mL, 89mmol) slowly join TBAF (3.2g, in THF solution (10mL) 42mmol), stir about 30min, and then add (3-oxygen cyclobutyl) tolyl acid)) THF (5mL) solution of ester (2.8g, 9mmol), reaction solution stirs at such a temperature and spends the night.After completion of the reaction, add saturated ammonium chloride solution (20mL), then use EtOAc (20mL x 3) to extract, the organic phase anhydrous sodium sulfate drying of merging, then concentrating under reduced pressure.Residue obtainedly obtain colorless oil title compound (3.1g, 91%) through silica gel column chromatography (eluent: PE/EtOAc (V/V)=5/1) purifying.
MS:(ESI,pos.ion)m/z:266.3[M+1] +.
Step 7:(3-(amino methyl)-3-hydroxycyclobutyl) synthesis of methyl benzoic acid ester
By Pd/C (0.1g, 10%) (3-hydroxyl-3-(nitromethyla) cyclobutyl) methyl benzoic acid ester (3.1g is joined, in 15mL methanol solution 45mmol), with hydrogen balloon as hydrogen source, then at room temperature reaction is spent the night.After having reacted, by reacting liquid filtering, gained filtrate reduced in volume obtains colorless oil title compound (2.9g, 99%).
MS:(ESI,pos.ion)m/z:236.3[M+1] +.
Intermediate 3:(3-(amino methyl) cyclobutyl) methyl benzoic acid ester
Step 1:(3-(nitro methene) cyclobutyl) synthesis of methyl benzoic acid ester
By triethylamine (11mL, 78.64mmol, 2eq.) with Methanesulfonyl chloride (3.65mL, 47.18mmol, 1.2eq.) join (3-hydroxyl-3-(nitromethyla) cyclobutyl) methyl benzoic acid ester (8.1g, 39.32mmol, in DCM (100mL) solution 1eq.), reaction solution is placed in 0 DEG C of reaction 5h, then saturated ammonium chloride solution 60mL is added, the organic phase be separated saturated nacl aqueous solution (50mL x 2) washing, with anhydrous sodium sulfate drying and concentrating under reduced pressure.Gained residue silica gel column chromatography (eluent: PE/EtOAc (V/V)=5/1) purifying obtains colorless oil title compound (7.5g, 81%).
MS:(ESI,pos.ion)m/z:285.3[M+1] +.
Step 2:(3-(amino methyl) cyclobutyl) synthesis of methyl benzoic acid ester
By (3-(nitro methene) cyclobutyl) methyl benzoic acid ester (10g, 35mmol) be dissolved in 100mL methyl alcohol, and then add Pd/C (10%, 1.03g), reaction solution under 1 atmospheric hydrogen and stirred at ambient temperature be about 2h, after completion of the reaction, diatomite filtration obtains 9.54g crude product, can be directly used in next step reaction.
MS:(ESI,pos.ion)m/z:285.3[M+1] +.
Embodiment 1:3-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-formonitrile HCN
The synthesis of step 1:3-chloropyrazine-2-formonitrile HCN
At 0 DEG C, in chlorobenzene (20mL) solution of 3-HYDROXYPYRAZINE-2-methane amide (5g, 37mmol), successively drip phosphorus oxychloride (2mL, 40mmol) and diisopropylethylamine (3.5mL, 80mmol).Reaction solution is placed in 90 DEG C of stirrings and spends the night.After completion of the reaction, concentrating under reduced pressure reaction solution, gained residue 20mL water dilutes, gained mixture EtOAc (20mL x 3) extracts, the organic phase anhydrous sodium sulfate drying merged, reduce pressure after filtration removing, residue obtains white solid title compound (4.5g, 79%) through silica gel column chromatography (eluent: PE/EtOAc (V/V)=10/1) purifying.
1H NMR(400MHz,CD 3OD):δ8.67(d,1H),8.63(d,1H).
Step 2:(3-((3-cyanopyrazine-2-base amino) methyl) cyclobutyl) synthesis of methyl benzoic acid ester
Under room temperature, by (3-(amino methyl) cyclobutyl) methyl benzoic acid ester (0.3g, 5mmol) with triethylamine (0.2mL, 12mmol) join 3-chloropyrazine-2-formonitrile HCN (0.5g, in THF (10mL) 6mmol), reaction solution was 25 DEG C of reactions two hours, after completion of the reaction, concentrating under reduced pressure, residue obtained through purification by silica gel column chromatography (eluent: PE/EtOAc (V/V)=5/1) white solid title compound (0.32g, 54%).
1H NMR(400MHz,DMSO-d 6):δ8.62(d,1H),8.02(d,1H),7.38-7.82(m,5H),5.42(s,1H),3.63(m,2H),3.54(m,2H),2.68(m,2H),2.28-2.29(m,1H),2.26-2.28(m,2H),1.68-1.70(m,1H).
The synthesis of step 3:3-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-formonitrile HCN
By (3-((3-cyanopyrazine-2-base is amino) methyl) cyclobutyl) methyl benzoic acid ester (0.21g, 4mmol) be dissolved in anhydrous methanol (8mL), add the aqueous solution (2mL) of NaOH (0.01g, 5mmol) again.Reaction mixture is stir about 1h at room temperature.After having reacted, concentrated by reaction solution, gained residue obtains white solid title compound (30mg, 28%) through silica gel chromatography (eluent: PE/EtOAc (V/V)=5/1).
1H NMR(400MHz,DMSO-d 6):δ8.21(d,1H),7.38(d,1H),3.45(m,2H),3.34(m,2H),2.36(m,1H),2.01-1.99(m,3H),1.77(m,1H),1.69(m,1H).
Embodiment 2:3-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-carbonamidine
Step 1:3-((3-amidino pyrazine-2-base amino) methyl) cyclobutyl) synthesis of methyl benzoic acid ester
(3-((3-cyanopyrazine-2-base is amino) methyl) cyclobutyl) methyl benzoic acid ester (0.2g, 3mmol) is dissolved in 10mL methyl alcohol, then adds NaOMe (0.04g, 6mmol).Reaction solution at room temperature stirs 1h, then adds NH 4cl (0.03g, 5mmol), gained reaction solution at room temperature continues stirring and spends the night.After having reacted, concentrating under reduced pressure, the residue obtained obtains white solid title compound (0.12g, 79%) through silica gel column chromatography (eluent: DCM/MeOH=10/1) purifying.
MS:(ESI,pos.ion)m/z:268.3[M+1] +.
The synthesis of step 2:3-((3-(methylol) cyclobutyl) methylamino) pyrazine-2-carbonamidine
By 3-((3-amidino pyrazine-2-base is amino) methyl) cyclobutyl) methyl benzoic acid ester (0.25g, 4mmol) be dissolved in anhydrous methanol (8mL), add NaOH (0.01g again, the aqueous solution (2mL) 5mmol), reaction mixture is stir about 1h at room temperature.After having reacted, by reaction solution concentrating under reduced pressure, residue obtainedly obtain white solid title compound (40mg, 48%) through purification by silica gel column chromatography (eluent: DCM/MeOH (V/V)=7/1).
1H NMR(400 MHz,DMSO-d 6):δ9.04(s,2H),8.21(s,1H),7.88(s,1H),7.79(s,1H),4.42(s,1H),3.29-3.34(m,4H),2.38(m,1H),2.23(m,1H),2.17-2.19(m,2H),2.01-1.99(m,2H).
Embodiment 3:3-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-methane amide
Step 1:(3-((3-formamido-pyrazine-2-base amino) methyl) cyclobutyl) synthesis of methyl benzoic acid ester
By salt of wormwood (3.8mg, 0.02mmol, 0.1eq) join (3-((3-cyanopyrazine-2-base is amino) methyl) cyclobutyl) tolyl acid (0.12g, 2mmol, in DMSO solution 1eq) (10mL), mixture stirs 30min, add 10mL hydrogen peroxide again, gained mixture continues to add after normal-temperature reaction 2h 5mL shrend and to go out reaction, solids removed by filtration product, filtrate reduced in volume obtains residue, is directly used in next step reaction.
MS:(ESI,pos.ion)m/z:268.3[M+1] +.
The synthesis of step 2:3-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-methane amide
By (3-((3-formamido-pyrazine-2-base is amino) methyl) cyclobutyl) methyl benzoic acid ester (0.05g, 0.8mmol) be dissolved in anhydrous methanol (8mL), add NaOH (0.03g again, water (2mL) solution 1.2mmol), mixture is stir about 6h at room temperature.After having reacted, by reaction solution concentrating under reduced pressure, residue obtainedly obtain white solid title compound (30mg, 57%) through purification by silica gel column chromatography (eluent: DCM/MeOH (V/V)=7/1).
MS:(ESI,pos.ion)m/z:253.2[M+1] +；
1H NMR(400 MHz,DMSO-d 6):δ8.21(d,1H),7.38(d,1H),3.45(m,2H),3.34(m,2H),2.36(m,1H),2.01-1.99(m,3H),1.77(m,1H),1.69(m,1H).
Embodiment 4:N-hydroxyl-3-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-carbonamidine
Step 1:(3-(((3-(N-hydroxy formamidine base) pyrazine-2-base) amino) methyl) cyclobutyl) synthesis of methyl benzoic acid ester
(3-((3-cyanopyrazine-2-base is amino) methyl) cyclobutyl) methyl benzoic acid ester (0.2g, 3mmol) is dissolved in 10mL methyl alcohol, then adds sodium methylate (0.04g, 6mmol).Reaction mixture at room temperature stirs 1h, then adds NH 2oH (0.18g, 5mmol), gained mixture at room temperature reacts and spends the night.After completion of the reaction, by reaction solution concentrating under reduced pressure, residue by silicagel column chromatography (eluent: DCM/MeOH (V/V)=10/1) purifying obtains white solid title compound (0.12g, 79%).
MS:(ESI,pos.ion)m/z:268.2[M+1] +.
The synthesis of step 2:N-hydroxyl-3-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-carbonamidine
At (3-(((3-(N-hydroxy formamidine base) pyrazine-2-base) is amino) methyl) cyclobutyl) methyl benzoic acid ester (0.08g, in 10mL methanol solution 1mmol), add sodium hydroxide (0.02g, 2mmol), then reaction system at room temperature stirs 1h.After having reacted, by reaction solution concentrating under reduced pressure, residue by silicagel column chromatography (eluent: DCM/MeOH (V/V)=7/1) purifying obtains white solid title compound (7mg, 32%).
MS:(ESI,pos.ion)m/z:253.2[M+1] +；
1H NMR(400MHz,DMSO-d 6):δ8.21(d,1H),7.38(d,1H),3.45(m,2H),3.34(m,2H),2.36(m,1H),2.01-1.99(m,3H),1.77(m,1H),1.69(m,1H).
The fluoro-3-of embodiment 5:6-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-methane amide
Step 1:(3-(((3-cyano group-5-Calmazine-2-base) amino) methyl) cyclobutyl) synthesis of methyl benzoic acid ester
Under room temperature, by 3,6-bis-Calmazine-2-methane amide (1.0g, 70mmol, 1eq.) is dissolved in THF (10mL), add (3-(amino methyl) cyclobutyl) methyl benzoic acid ester (2.16g again, 92mmol, 1.3eq.) and triethylamine (1.8g, 182mmol, 2.6eq.), reaction solution reacts 2 hours at 25 DEG C.After having reacted, saturated nacl aqueous solution (30mL) is added in reaction mixture, extract with EtOAc (30mL x 2), the organic phase merged saturated nacl aqueous solution washing (30mLx2), with anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains crude product, and crude product obtains white solid title compound (1.8g, 85%) through purification by silica gel column chromatography (eluent: PE/EtOAc (V/V)=5/1).
MS:(ESI,pos.ion)m/z:341.3[M+1] +.
Step 2:(3-(((3-formamido--5-Calmazine-2-base) amino) methyl) cyclobutyl) synthesis of methyl benzoic acid ester
By salt of wormwood (3.8mg, 0.02mmol, 0.1eq) join (3-(((3-cyano group-5-Calmazine-2-base) is amino) methyl) cyclobutyl) methyl benzoic acid ester (100mg, 0.28mmol, in DMSO (10mL) solution 1eq.), reaction solution stirring at room temperature reacts about 30min, add 10mL hydrogen peroxide again, gained mixture continues to add after insulation reaction 2h 5mL shrend and to go out reaction, solids removed by filtration product, filtrate is directly used in next step reaction through the residue that concentrating under reduced pressure obtains.
The synthesis of the fluoro-3-of step 3:6-(((3-(hydroxymethyl) cyclobutyl) methyl) is amino) pyrazine-2-methane amide
By raw material (3-(((3-formamido--5-Calmazine-2-base) is amino) methyl) cyclobutyl) methyl benzoic acid ester (200mg, 0.27mmol, 1.0eq.) be dissolved in anhydrous methanol (8mL), add NaOH (11.17mg again, 0.27mmol, the aqueous solution (2mL) 1.0eq.), mixture is stir about 3h at room temperature.After having reacted, concentrated by reaction solution, gained residue is separated (eluent: PE/EtOAc (V/V)=1/1) purifying through silica gel column chromatography and obtains white solid title compound (108mg, 59%).
MS:(ESI,pos.ion)m/z:255.3[M+1] +；
1H NMR(400MHz,CD 3OD):δ8.16-8.13(dd,1H),3.56-3.53(m,2H),3.46-3.44(m,2H),2.56-2.50(m,2H),2.48-2.46(m,1H),2.17-2.13(m,2H),2.10-1.96(m,1H).
The fluoro-N-hydroxyl of embodiment 6:6--3-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-carbonamidine
By salt of wormwood (3.8mg, 0.02mmol, 0.1eq) join (3-(((3-cyano group-5-Calmazine-2-base) is amino) methyl) cyclobutyl) methyl benzoic acid ester (100mg, 0.28mmol, in MeOH (10mL) solution 1eq.), reaction solution is stir about 30min at room temperature, then adds NH 2oH (0.1mL, 1.2mmol) is in reaction system, and gained reaction mixture at room temperature continues to stir 2h.After completion of the reaction, add 20mL water, mixture EtOAc (20mL x 2) extracts, organic phase saturated nacl aqueous solution (15mL) washs, the organic phase anhydrous sodium sulfate drying merged, concentrating under reduced pressure again, gained residue obtains white solid title compound (57mg, 75%) through silica gel column chromatography (eluent: PE/EtOAc (V/V)=1/1) purifying.
MS:(ESI,pos.ion)m/z:270.3[M+1] +；
1H NMR(400MHz,DMSO-d 6):δ7.86(dd,1H),3.56-3.44(m,2H),3.42-3.30(m,2H),2.20-2.23(m,2H),2.20-2.18(m,2H),1.79-1.76(m,2H).
The fluoro-3-of embodiment 7:6-(((3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-carbonamidine
By (3-(((3-cyano group-5-Calmazine-2-base) is amino) methyl) cyclobutyl) methyl benzoic acid ester (80mg, 0.24mmol, 1eq.) be dissolved in MeOH (3mL), add sodium methylate (24mg again, 0.44mmol, 1.8eq.) methyl alcohol (1mL) solution.Mixture at room temperature stirs 3.5h, then adds ammonium chloride (29mg, 0.54mmol, 2.2eq.), and gained mixture continues at room temperature to stir 12h.After having reacted, concentrating under reduced pressure, residue obtains 50mg crude product through silica gel column chromatography (eluent DCM/MeOH (V/V)=10/1) purifying, and this crude product obtains white solid title compound (7mg, 11%) through preparative HPLC purifying.
MS:(ESI,pos.ion)m/z:254.1[M+1] +；
1H NMR(400MHz,CD 3OD):δ8.00-7.98(dd,1H),3.56-3.44(m,2H),3.30-3.29(m,2H),2.56-2.50(m,2H),2.48-2.47(m,1H),2.37-2.33(m,2H),2.11-2.09(m,1H).
Embodiment 8:3-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-formonitrile HCN
Step 1:(3-((3-cyanopyrazine-2-base amino) methyl) cyclobutyl) synthesis of methyl benzoic acid ester
Under room temperature, by 3-chloropyrazine-2-formonitrile HCN (0.5g, 6mmol) be dissolved in THF (10mL), add (3-(amino methyl)-3-hydroxycyclobutyl) methyl benzoic acid ester (0.3g again, 5mmol) with triethylamine (0.2mL, 12mmol), reaction mixture was 25 DEG C of reactions two hours, after having reacted, concentrating under reduced pressure, residue obtains white solid target compound (0.32g, 54%) through purification by silica gel column chromatography (eluent: PE/EtOAc (V/V)=5/1).
MS:(ESI,pos.ion)m/z:339.4[M+1] +.
The synthesis of step 2:3-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-formonitrile HCN
By raw material (3-((3-cyanopyrazine-2-base is amino) methyl) cyclobutyl) methyl benzoic acid ester (0.32g, 5.3mmol) be dissolved in anhydrous methanol (10mL), add NaOH (0.41g again, water (2mL) solution 10mmol), mixture is stir about 1h at room temperature.After having reacted, concentrating under reduced pressure, residue obtainedly obtains white solid target compound (120mg, 46%) through silica gel chromatography (eluent: PE/EtOAc (V/V)=4/1).
MS:(ESI,pos.ion)m/z:235.3[M+1] +；
1H NMR(400MHz,CD 3OD):δ8.17(d,1H),7.90(d,1H),5.84(s,1H),3.69(d,2H),3.67(s,2H),2.62(m,1H),2.28(m,2H),2.17(m,2H).
Embodiment 9:N-hydroxyl-3-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-carbonamidine
By salt of wormwood (3.8mg, 0.02mmol, 0.1eq) join (3-((3-cyanopyrazine-2-base is amino) methyl) cyclobutyl) methyl benzoic acid ester (100mg, 0.28mmol, in MeOH (10mL) solution 1eq.), reaction solution stirring at room temperature is about 30min.Then NH is added 2oH (0.1mL, 1.2mmol) is in reaction system, and reaction solution at room temperature continues to react 2h.After completion of the reaction, add 20mL water, extract with EtOAc (20mL x 2), organic phase saturated nacl aqueous solution (15mL) washs, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained residue obtains white solid target compound (0.03g, 57%) through purification by silica gel column chromatography (eluent: DCM/MeOH (V/V)=7/1).
MS:(ESI,pos.ion)m/z:268.3[M+1] +；
1H NMR(400MHz,DMSO-d 6):δ8.21(d,1H),7.38(d,1H),3.45(m,2H),3.34(m,2H),2.36(m,1H),2.01-1.99(m,3H),1.77(m,1H),1.69(m,1H).
Embodiment 10:3-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-carbonamidine
The synthesis of step 1:3-((3-(benzyloxymethyl)-1-hydroxycyclobutyl) methylamino) pyrazine-2-carbonamidine
Raw material (3-((3-cyanopyrazine-2-base is amino) methyl) cyclobutyl) methyl benzoic acid ester (0.2g, 1.4mmol) is dissolved in 10mL methyl alcohol, then adds NaOMe (0.02g, 3mmol).Mixture at room temperature stirs 1h, then adds NH 4cl (0.03g, 5mmol), gained reaction mixture continues at room temperature reaction and spends the night.After having reacted, by reaction solution concentrating under reduced pressure, residue obtainedly obtain white solid title compound (0.12g, 68%) through silica gel column chromatography (eluent: DCM/MeOH (V/V)=10/1) purifying.
MS:(ESI,pos.ion)m/z:356.3[M+1] +.
The synthesis of step 2:3-((1-hydroxyl-3-(methylol) cyclobutyl) methylamino) pyrazine-2-carbonamidine
By 3-((3-(benzyloxymethyl)-1-hydroxycyclobutyl) methylamino) pyrazine-2-carbonamidine (0.12g, 1mmol) be dissolved in anhydrous methanol (8mL), add NaOH (0.08g again, water (2mL) solution 2mmol), reaction mixture is stir about 6h at room temperature, after having reacted, concentrating under reduced pressure will be reacted, gained residue obtains titled compound as white solid (30mg, 39%) through purification by silica gel column chromatography (eluent: DCM/MeOH (V/V)=10/1).
MS:(ESI,pos.ion)m/z:252.1[M+1] +；
1H NMR(400MHz,DMSO-d 6):δ8.21(d,1H),7.38(d,1H),3.45(m,2H),3.34(m,2H),2.36(m,1H),2.01-1.99(m,3H),1.77(m,1H),1.69(m,1H).
Embodiment 11:3-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-methane amide
Step 1:(3-((3-formamido-pyrazine-2-base amino) methyl)-3-hydroxycyclobutyl) synthesis of methyl benzoic acid ester
By salt of wormwood (100mg, 4mmol, 0.1eq) join (3-((3-cyanopyrazine-2-base is amino) methyl) cyclobutyl) methyl benzoic acid ester (0.32g, 5.3mmol, in DMSO (10mL) solution 1eq), mixture stirring at room temperature is about 30min, add hydrogen peroxide (0.2mL again, 6mmol), after gained mixture continues insulated and stirred 1h, add 10mL shrend to go out reaction, solids removed by filtration product, by filtrate reduced in volume, residue obtains white solid title compound (0.21g through purification by silica gel column chromatography (eluent: PE/EtOAc (V/V)=2/1), 52%).
MS:(ESI,pos.ion)m/z:357.3[M+1] +。
The synthesis of step 2:3-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-methane amide
By (3-((3-formamido-pyrazine-2-base is amino) methyl)-3-hydroxycyclobutyl) methyl benzoic acid ester (0.21g, 2.7mmol) be dissolved in anhydrous methanol (10mL), add NaOH (0.08g again, water (2mL) solution 2mmol), mixture is stir about 6h at room temperature, after having reacted, reaction mixture is concentrated, gained residue obtains white solid title compound (50mg, 51%) through purification by silica gel column chromatography (eluent: DCM/MeOH (V/V)=7/1).
MS:(ESI,pos.ion)m/z:253.3[M+1] +；
1H NMR(400MHz,DMSO-d 6):δ8.21(d,1H),7.38(d,1H),3.45(m,2H),3.34(m,2H),2.36(m,1H),2.01-1.99(m,3H),1.77(m,1H),1.69(m,1H).
The fluoro-3-of embodiment 12:6-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-methane amide
Step 1:(3-(((3-cyano group-5-Calmazine-2-base) amino) methyl)-3-hydroxycyclobutyl) synthesis of methyl benzoic acid ester
By 3, 6-bis-Calmazine-2-methane amide (1.0g, 70mmol, 1eq.), (3-(amino methyl)-3-hydroxycyclobutyl) methyl benzoic acid ester (2.16g, 92mmol, 1.3eq.) with Et3N (1.8g, 182mmol, 2.6eq.) join in the THF of 20mL, reaction mixture stirs 2 hours at 25 DEG C, after having reacted, add 20mL saturated nacl aqueous solution, gained mixture EtOAc (20mL x 2) extracts, the organic phase merged is washed with saturated aqueous common salt 20mL, with anhydrous sodium sulfate drying, concentrating under reduced pressure again, residue obtains white solid title compound (1.8g through silica gel column chromatography (eluent: PE/EtOAc (V/V)=5/1) purifying, 85%).
MS:(ESI,pos.ion)m/z:357.3[M+1] +.
Step 2:(3-(((3-formamido--5-Calmazine-2-base) amino) methyl)-3-hydroxycyclobutyl) synthesis of methyl benzoic acid ester
By salt of wormwood (3.8mg, 0.02mmol, 0.1eq) join (3-(((3-cyano group-5-Calmazine-2-base) is amino) methyl)-3-hydroxycyclobutyl) methyl benzoic acid ester (100mg, 0.28mmol, in DMSO (10mL) solution 1eq.), mixture is stir about 30min at room temperature, then adds 30%H 2o 2(0.1mL, 1.2mmol), gained mixture at room temperature continues to stir 2h.After having reacted, add 20mL water, filter and obtain titled compound as white solid (83mg, 80%).
MS:(ESI,pos.ion)m/z:375.3[M+1] +.
The synthesis of the fluoro-3-of step 3:6-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-methane amide
By (3-(((3-formamido--5-Calmazine-2-base) is amino) methyl)-3-hydroxycyclobutyl) methyl benzoic acid ester (200mg, 0.27mmol, 1.0eq.) be dissolved in anhydrous methanol (8mL), add NaOH (11.17mg again, 0.27mmol, water (2mL) solution 1.0eq.), reaction solution at room temperature stirs 3h.After having reacted, by reaction solution concentrating under reduced pressure, residue obtains titled compound as white solid (108mg, 59%) through silica gel column chromatography (eluent: PE/EtOAc (V/V)=1/1) purifying.
MS:(ESI,pos.ion)m/z:271.1[M+1] +；
1H NMR(400MHz,CD 3OD):δ8.12-8.09(dd 1H),3.64(s,2H),3.53-3.52(d,2H),2.23-2.18(m,2H),2.08-2.06(m,1H),62.04-61.74(m,2H).
The fluoro-N-hydroxyl of embodiment 13:6--3-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-methane amide
By salt of wormwood (3.8mg, 0.02mmol, 0.1eq) join (3-(((3-cyano group-5-Calmazine-2-base) is amino) methyl)-3-hydroxycyclobutyl) methyl benzoic acid ester (100mg, 0.28mmol, in MeOH (10mL) solution 1eq.), reaction solution is stir about 30min at room temperature.Add NH again 2oH (0.1mL, 1.2mmol) is in reaction system, and gained mixture continues under room temperature to stir 2h again.After having reacted, add 20mL water, with EtOAc (20mL x 2) extraction, organic phase saturated nacl aqueous solution (15mL) washing, then use dried over sodium sulfate, then concentrating under reduced pressure.Gained residue obtains titled compound as white solid (69mg, 87%) through silica gel column chromatography (eluent: PE/EtOAc (V/V)=1/1) purifying.
MS:(ESI,pos.ion)m/z:286.1[M+1] +；
1H NMR(400MHz,DMSO-d 6):δ7.89-7.86(dd,1H),3.64(s,2H),3.53-3.52(m,2H),2.23-2.18(m,2H),2.08-2.04(m,1H),1.79-1.77(m,2H).
The fluoro-3-of embodiment 14:6-(((1-hydroxyl-3-(methylol) cyclobutyl) methyl) is amino) pyrazine-2-carbonamidine
By 3-(((3-cyano group-5-Calmazine-2-base) is amino) methyl)-3-hydroxycyclobutyl) methyl benzoic acid ester (80mg, 0.24mmol, 1eq.) be dissolved in MeOH (3mL), add sodium methylate (24mg again, 0.44mmol, 1.8eq.) methyl alcohol (1mL) solution.Mixture at room temperature stirs 3.5h. and adds ammonium chloride (29mg, 0.54mmol, 2.2eq.) again, and gained mixture continues at room temperature to stir 12h.After having reacted, concentrating under reduced pressure, residue through silica gel column chromatography (eluent: DCM/MeOH (V/V)=10/1) purifying, then obtains titled compound as white solid (13mg, 20%) through preparative HPLC purifying.
MS:(ESI,pos.ion)m/z:270.1[M+1] +；
1H NMR(400MHz,CD 3OD):δ8.00-7.98(dd,1H),5.04(br,6H),3.56-3.44(m,2H),3.30-3.29(m,2H),2.56-2.50(m,2H),2.48-2.47(m,1H),2.37-2.33(m,2H).
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.
Virus liquid (final MOI=0.01) after compound after every hole adds 50 μ L dilutions and 50 μ L dilute.
96 orifice plates are placed in 37 DEG C, 5%CO 2, cultivate 3 days.
Every hole adds 20 μ L 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 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 50 μ L dilutions and 50 μ L nutrient solutions.
96 orifice plates are placed in 37 DEG C, 5%CO 2, cultivate 3 days.
Every hole adds 20 μ L 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 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)
OD value＝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 (6)

1. a compound, has such as formula the compound shown in (I), or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug,
Wherein, R 1for hydroxyl, C 1-3hydroxyalkyl, C 1-3alkyl, C 1-3alkoxyl group, amino or C 1-3alkylamino;
R 2for-CN ,-C (=NH) NH 2,-C (=O) NH 2,-C (=S) NH 2,-C (=NH) NHOH ,-C (=NH) NH-C 1-3alkyl or-C (=O) O-C 1-3alkyl;
R 3for hydrogen or C 1-3alkyl;
R 4for hydrogen, hydroxyl, amino, C 1-3alkylamino, C 1-3alkoxyl group, C 1-3alkyl, F, Cl, Br or I; With
R 5for hydrogen, hydroxyl, C 1-3alkyl or C 1-3hydroxyalkyl.
2. compound as claimed in claim 1, wherein
R 1for hydroxyl, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, amino, N-methylamino-, N-ethylamino or N, N-dimethylamino;
R 2for-CN ,-C (=NH) NH 2,-C (=O) NH 2,-C (=S) NH 2,-C (=NH) NHOH ,-C (=NH) NHCH 3,-C (=NH) NHCH 2cH 3,-C (=O) OCH 3or-C (=O) OCH 2cH 3; With
R 3for hydrogen, methyl or ethyl;
R 4for hydrogen, hydroxyl, amino, N-methylamino-, N-ethylamino, N, N-dimethylamino, methoxyl group, oxyethyl group, methyl, ethyl, F, Cl, Br or I; With
R 5for hydrogen, hydroxyl, methyl, ethyl, n-propyl, sec.-propyl, hydroxymethyl, hydroxyethyl or 2-hydroxypropyl.
3. the compound according to any one of claim 1-2, have following one of them structure or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug,
4. a pharmaceutical composition, comprises the arbitrary described compound of claim 1-3, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combine arbitrarily.
5. pharmaceutical composition according to claim 4, it further comprises anti-influenza virus medicament, wherein said anti-influenza virus medicament 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.
6. the arbitrary described compound of claim 1-3 or the arbitrary described pharmaceutical composition of claim 4-5 are preparing the purposes prevented, process, treat or alleviate in patient influenza virus medicine.
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