CN104529833B - Cyclobutane-carboxylic acid compounds replaced and uses thereof - Google Patents
Cyclobutane-carboxylic acid compounds replaced and uses thereof Download PDFInfo
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- CN104529833B CN104529833B CN201410758757.7A CN201410758757A CN104529833B CN 104529833 B CN104529833 B CN 104529833B CN 201410758757 A CN201410758757 A CN 201410758757A CN 104529833 B CN104529833 B CN 104529833B
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- 0 *CC(C(C1)(CC1C(O)=O)N*)N* Chemical compound *CC(C(C1)(CC1C(O)=O)N*)N* 0.000 description 2
- CBEFRVOASPHFST-UHFFFAOYSA-N CCC(CC)CC(C(C1)(CC1C(O)=O)NC(C)=O)N Chemical compound CCC(CC)CC(C(C1)(CC1C(O)=O)NC(C)=O)N CBEFRVOASPHFST-UHFFFAOYSA-N 0.000 description 2
- PCBYKGNZDHUVJG-UHFFFAOYSA-N CCC(CC)CC(C(C1)(CC1C(O)=O)NC(N)=N)NC(C)=O Chemical compound CCC(CC)CC(C(C1)(CC1C(O)=O)NC(N)=N)NC(C)=O PCBYKGNZDHUVJG-UHFFFAOYSA-N 0.000 description 2
- LJYGPPHDUGVAOE-UHFFFAOYSA-N CCC(CC)CC(C(C1)(CC1C(O)=O)N)NC(C)=O Chemical compound CCC(CC)CC(C(C1)(CC1C(O)=O)N)NC(C)=O LJYGPPHDUGVAOE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention is cyclobutane-carboxylic acid compounds replaced and uses thereof, relate to cyclobutane-carboxylic acid compounds, or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.The invention still further relates to cyclobutane-carboxylic acid compounds or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or the prodrug purposes as medicine, the application especially in preparation antiviral.
Description
Technical field
The present invention relates to the cyclobutane-carboxylic acid compounds of a class replacement, its preparation method and the application in preparation antiviral thereof, especially prepare the application in prevention and therapy influenza virus relative disease medicine.The invention still further relates to the pharmaceutical composition comprising these compounds, and the application of this pharmaceutical composition in prevention and therapy influenza virus relative disease.
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 new antiviral, its infected by influenza diseases related has preventive and therapeutic action.
Summary of the invention
The present invention relates to the cyclobutane-carboxylic acid compounds that a class replaces, and the application in preparation antiviral.The compounds of this invention or the pharmaceutical composition comprising described compound have certain anti-influenza virus activity, especially have good effect to prevention and therapy influenza virus.
On the one hand, the present invention relates to a kind of compound, its steric isomer for structure shown in the structural formula shown in formula (I) or formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein,
Each R
1and R
2be hydrogen, C independently
1-C
6alkyl-(C=O)-, or amidino groups; And R
3for hydrogen or C
1-C
10alkyl.
In some embodiments, each R
1and R
2be hydrogen, CH independently
3(C=O)-, CH
3cH
2(C=O)-, CH
3cH (CH
3) (C=O)-, CH
3cH
2cH
2(C=O)-, CH
3cH
2cH
2cH
2(C=O)-or amidino groups; With
R
3for hydrogen or C
1-C
6alkyl.
In some embodiments, R
3for hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 1-hexyl, 3-hexyl, 2-amyl group, 3-amyl group, 2-ethyl-butyl or 2-methyl butyl.
In other embodiments, the compounds of this invention pharmacy acceptable salt is hydrochloride, vitriol, nitrate, phosphoric acid salt, metaphosphate, mesylate, esilate, Citrate trianion, benzene sulfonate, tosilate, malate, tartrate, succinate, fumarate, acetate, hydroxyl acetate, isethionate, maleate, lactic acid salt, Lactobionate, trifluoroacetate or its combination.
In other embodiments, the present invention relates to the compound of one of them structure following,
Or the steric isomer of structure shown in it, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.
On the other hand, the present invention relates to a kind of pharmaceutical composition, comprise the arbitrary described compound of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
In certain embodiments, pharmaceutical composition of the present invention its comprise other anti-influenza virus medicament further, 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, the present invention relates to the arbitrary described compound of the present invention or arbitrary described pharmaceutical composition for the preparation of protecting, processing, treat or alleviate the purposes in patient influenza virus diseases related 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 the application of compound of the present invention and steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, its pharmacy acceptable salt or prodrug, and compound of the present invention is producing the application effectively suppressed in influenza virus medicine.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, metaphosphoric acid, nitric acid and phosphoric acid etc.Or use organic acid, lactic acid, lactobionic acid, trifluoroacetic acid, acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxysuccinic acid, 2 hydroxy propanoic 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, hydroxyethylsulfonic 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 obtain inorganic salt from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium.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 " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry " byMichaelB.SmithandJerryMarch, JohnWiley & Sons, description in NewYork:2007, its full content is incorporated to herein by reference.
Except as otherwise noted or in context, have obvious conflict, article used herein " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.
Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, such as, also refer to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.
The present invention says that the term " patient " of use refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.
Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYork; AndEliel, E.andWilen, S., " StereochemistryofOrganicCompounds ", JohnWiley & Sons, Inc., NewYork, 1994.
Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-enantiomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.
The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.
By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, and can with reference to Jacques, etal., Enantiomers, RacematesandResolutions (WileyInterscience, NewYork, 1981); PrinciplesofAsymmetricSynthesis (2
nded.RobertE.Gawley, JeffreyAub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.StereochemistryofCarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S.H.TablesofResolvingAgentsandOpticalResolutionsp.268 (E.L.Eliel, Ed., Univ.ofNotreDamePress, NotreDame, IN1972); ChiralSeparationTechniques:APracticalApproach (Subramanian, G.Ed., Wiley-VCHVerlagGmbH & Co.KGaA, Weinheim, Germany, 2007).
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-c
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.In some embodiments, alkyl group contains 1-10 carbon atom; In another embodiment, alkyl group contains 1-6 carbon atom; In yet another embodiment, alkyl group contains 1-4 carbon atom; In yet another embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH
3), ethyl (Et ,-CH
2cH
3), n-propyl (n-Pr ,-CH
2cH
2cH
3), sec.-propyl (i-Pr ,-CH (CH
3)
2), normal-butyl (n-Bu ,-CH
2cH
2cH
2cH
3), isobutyl-(i-Bu ,-CH
2cH (CH
3)
2), sec-butyl (s-Bu ,-CH (CH
3) CH
2cH
3), the tertiary butyl (t-Bu ,-C (CH
3)
3), n-pentyl (-CH
2cH
2cH
2cH
2cH
3), 2-amyl group (-CH (CH
3) CH
2cH
2cH
3), 3-amyl group (-CH (CH
2cH
3)
2), 2-methyl-2-butyl (-C (CH
3)
2cH
2cH
3), 3-methyl-2-butyl (-CH (CH
3) CH (CH
3)
2), 3-methyl isophthalic acid-butyl (-CH
2cH
2cH (CH
3)
2), 2-methyl-1-butene base (-CH
2cH (CH
3) CH
2cH
3), 2-ethyl-1-butyl (-CH
2cH (CH
2cH
3) CH
2cH
3), n-hexyl (-CH
2cH
2cH
2cH
2cH
2cH
3), 2-hexyl (-CH (CH
3) CH
2cH
2cH
2cH
3), 3-hexyl (-CH (CH
2cH
3) (CH
2cH
2cH
3)), 2-methyl-2-amyl group (-C (CH
3)
2cH
2cH
2cH
3), 3-methyl-2-amyl group (-CH (CH
3) CH (CH
3) CH
2cH
3), 4-methyl-2-amyl group (-CH (CH
3) CH
2cH (CH
3)
2), 3-methyl-3-amyl group (-C (CH
3) (CH
2cH
3)
2), 2-methyl-3-amyl group (-CH (CH
2cH
3) CH (CH
3)
2), 2,3-dimethyl-2-butyl (-C (CH
3)
2cH (CH
3)
2), 3,3-dimethyl-2-butyl (-CH (CH
3) C (CH
3)
3), n-heptyl, n-octyl, etc.
Term " halogen ", refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " carbonyl ", represent-(C=O)-, can be used alone or be used in conjunction with other terms; Term " acyl group ", expression-(C=O)-R, wherein, R is alkyl, and the example of acyl group includes but not limited to ethanoyl, propionyl, butyryl radicals, pentanoyl, etc.
" carboxylic acid halides " is the derivative compound that the hydroxyl of oxygen acid is optionally substituted by halogen.If acid is carboxylic acid, then acetyl halide compound contains-COX a functional group: connect a halogen atom by carbonyl and form.The general formula of this kind of carboxylic acid halides is: RCOX, and wherein, R can be alkyl, and CO represents carbonyl, and X represents halogen as chlorine atom.Carboxylic acid halides can be divided into: acyl fluorides, acyl chlorides, acylbromide and acyl iodides (instability).The hydroxyl of sulfonic acid can be optionally substituted by halogen equally and generate corresponding sulfonic acid halide.In practical application, normally chlorine atom forms SULPHURYL CHLORIDE as halogen substiuted.Such not limiting example comprises Acetyl Chloride 98Min., propionyl chloride, methylsulfonyl chloride, Tosyl chloride etc.
" acid anhydrides " refers to have two acyl groups and is bonded to organic compound on same Sauerstoffatom.If both sides acyl group, by carboxylic acid derivatives of the same race, is called symmetric anhydride, molecular formula can be expressed as: (RC (O))
2o.Symmetric anhydride name depends on that corresponding carboxylic acid is named, and namely affixe " acid " changes into " acid anhydrides ".As (CH
3cO)
2o is called: diacetyl oxide, or acetic anhydride, aceticanhydride).Mixed acid anhydride (or asymmetric acid anhydrides) is named with the carboxylic acid that both sides acyl group is corresponding respectively, as: arboxylic acid acid anhydride.Such not limiting example comprises diacetyl oxide, propionic anhydride, arboxylic acid acid anhydride, acetic acid benzoyl oxide, maleic anhydride etc.
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 compound of the single three-dimensional chemical isomer of compound of the present invention, enantiomer, diastereomer, geometrical isomer, conformer, oxynitride, hydrate, solvate, meta-bolites, 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.
Time term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC; Boc), carbobenzoxy-(Cbz) (CBZ, Cbz) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH
2cH
2sO
2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: TW.Greene, ProtectiveGroupsinOrganicSynthesis, JohnWiley & Sons, NewYork, 1991; AndP.J.Kocienski, ProtectingGroups, Thieme, Stuttgart, 2005.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug
1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.HiguchiandV.Stella, Pro-drugsasNovelDeliverySystems, Vol.14oftheA.C.S.SymposiumSeries, EdwardB.Roche, ed., BioreversibleCarriersinDrugDesign, AmericanPharmaceuticalAssociationandPergamonPress, 1987, J.Rautioetal., Prodrugs:DesignandClinicalApplications, NatureReviewDrugDiscovery, 2008, 7, 255-270, andS.J.Heckeretal., ProdrugsofPhosphatesandPhosphonates, JournalofMedicinalChemistry, 2008, 51, 2328-2345.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
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-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYork; AndEliel, E.andWilen, S., " StereochemistryofOrganicCompounds ", JohnWiley & Sons, Inc., NewYork, 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 " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer, etc.
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.Bergeetal., describepharmaceuticallyacceptablesaltsindetailinJ.Pharm aceuticalSciences, described in 1977,66:1-19..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N
+(C
1-4alkyl)
4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C
1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" 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 AdvancedOrganicChemistry, WileyInterscience, the 4th edition, JerryMarch, 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 (polishcoatingofwax) can be provided.Dyestuff can be added in these coating materials to distinguish different unitary doses.
Oral liquid such as solution, syrup and elixir can be prepared by dosage unit form, thus specified rate contains the compound of predetermined amount.Syrup is prepared by being dissolved in the suitably seasoned aqueous solution by compound, and elixir is prepared by using non-toxic vehicle.Also can add solubilizing agent and emulsifying agent (such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ether), sanitas, flavoring additive (such as spearmint oil or natural sweeteners or asccharin or other artificial sweetners) etc.
If appropriate, the dosage unit preparations micro encapsulation of oral administration can be used for.Also preparation can be made time delay or sustained release, such as, by dressing or be embedded in the microparticle material such as polymkeric substance, wax.
The compounds of this invention, especially formula (I) compound and pharmacy acceptable salt thereof can also give by liposome delivery systems, such as small unilamellar vesicle, large unilamellar liposome and multilamellar liposome.Liposome can be made up of multiple phosphatide (such as cholesterol, octadecylamine or phosphatidylcholine).
The compounds of this invention, especially formula (I) compound and pharmacy acceptable salt thereof are also by using monoclonal antibody to pass medicine as independent carrier (compound molecule is coupled).Compound also can with as can the soluble polymer coupling of target medicine carrier.The polyethylene-oxide polylysine that this base polymer can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide phenol, polyhydroxyethylaspart or be replaced by palmitoyl residues.In addition, compound can with a class Biodegradable polymeric coupling, for reaching the controlled release of medicine, the cross-linking copolymer of this base polymer such as poly(lactic acid), poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate and hydrogel or amphipathic nature block polymer.
The pharmaceutical preparation being suitable for percutaneous dosing can be used as discrete patch (discretepatch) to keep and recipient's epidermis close contact in long-time.Such as, activeconstituents can pass medicine by by iontophoresis patch, usually can see PharmaceuticalResearch1986, and 3 (6), 318.
The pharmaceutical preparation being suitable for topical can be made into ointment, ointment, suspensoid, lotion, powder, solution, paste, gelifying agent, sprays, aerosol, oil formulation or transdermal patch.
The pharmaceutical preparation being suitable for rectal administration can be used as suppository or provides as enema.
The pharmaceutical preparation (wherein carrier is solid) being suitable for nose administration comprises the dust base that particle diameter is such as 20-500 micrometer range, by with the administration of snuffing mode, is namely sucked fast from close to the dust base container of nose by nasal passage.Wherein carrier is liquid, is suitable for the aqueous solution agent or the oily solution agent that comprise activeconstituents as the appropriate formulation of nasal mist or nasal drop administration.
Be suitable for comprising minuteness particle pulvis (dust) or mist agent (mist) by the pharmaceutical preparation of inhalation, the dosage compresed gas aerosol of available dissimilar metering, nebulizer, insufflator or other matters are sent in the device of aerosol spray and are prepared.
The pharmaceutical preparation being suitable for vagina administration can vaginal suppository, vagina plug, ointment, creme, gelifying agent, paste, foaming agent or sprays provide.
The pharmaceutical preparation being suitable for parenteral admin comprises water-based and non-aqueous sterile injection solution and water-based and non-aqueous sterile suspensions, water-based and non-aqueous sterile injection solution can contain antioxidant, buffer reagent, fungistat and make described preparation and the isotonic solute of receptor's blood waiting, and water-based and non-aqueous sterile suspensions can comprise suspension agent and thickening material.Preparation can unitary dose or multi-dose container provide, the triumphant and bottle of the peace such as sealed, and under can being kept at lyophilize (freeze-drying) condition, only need add sterile liquid carrier before use, such as water for injection.The injection solution and the suspensoid that face used time configuration can be prepared by sterile powder injection, granule and tablet.
It should be understood that, except the composition mentioned especially above, preparation also comprises other conventional composition of this area relevant with described preparation type, and this kind of preparation being such as suitable for oral administration can comprise correctives.
The purposes of the compounds of this invention and pharmaceutical composition
The 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 1-6, 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, AldrichChemicalCompany, Inc., ArcoChemicalCompany and AlfaChemicalCompany, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan 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 (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, quartet), dt (doubletoftriplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and aG1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315BDAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS being equipped with G1311A quaternary pump and G1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315DDAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with AgilentZorbaxSB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
| Time (min) | A(CH 3CN，0.1％HCOOH) | B(H 2O，0.1％HCOOH) |
| 0-3 | 5-100 | 95-0 |
| 3-6 | 100 | 0 |
| 6-6.1 | 100-5 | 0-95 |
| 6.1-8 | 5 | 95 |
Compound purifying is evaluated by Agilent1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, ZorbaxSB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
NaBH
4sodium borohydride
DBU1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
CbzCl chloroformic acid benzyl ester
NaOH sodium hydroxide
THF tetrahydrofuran (THF)
EtOH ethanol
EA, EtOAc ethyl acetate
MeOH ethyl acetate
DCM methylene dichloride
DMFN, dinethylformamide
RanyNi Raney's nickel
Ac
2o acetic anhydride
TBAF tetrabutyl ammonium fluoride
Boc tertbutyloxycarbonyl
Ac ethanoyl
Pg
1hydroxy-protective group
Pg
2amido protecting group
H
2hydrogen
TLC tlc
LC-MS liquid chromatograph mass spectrography
H hour
M, mol/L mol/L
ML milliliter
Ul microlitre
Mol mole
Mmol mmole
V/V, v/v volume ratio
Following synthetic schemes describes preparation the present invention and to come into the open the step of compound.
Synthetic schemes (one):
Work as R
2for hydrogen, R
1for C
1-C
6alkyl-(C=O)-time, compound (I) can prepare through synthetic schemes (one), wherein R
3there is implication of the present invention; X is halogen, preferred chlorine, bromine.First, compound (2) is obtained by reacting by compound (1) and Nitromethane 99Min.; Compound (2) forms olefin(e) compound (3) through eliminative reaction; Compound (3) obtains compound (4) through reductive agent (as sodium borohydride) reduction; Compound (4) and compound (5) obtain compound (6) under the effect of tetrabutyl ammonium fluoride; Then compound (6) and hydroxy protecting agent (as diacetyl oxide) are obtained by reacting compound (7); Compound (7) obtains olefin(e) compound (8) through eliminative reaction in the basic conditions; Compound (8) obtains compound (9) with ammonia addition further; Compound (9) again with acid anhydrides R
1oR
1huo Xian Halogen R
1-X is obtained by reacting compound (10); Compound (10) is hydrolyzed in the basic conditions and obtains compound (11); Compound (11) obtains target compound (I) through reductive agent (as Raney's nickel) reduction.
Synthetic schemes (two):
Work as R
2for C
1-C
6alkyl-(C=O)-, R
1during for hydrogen, compound (I) can pass through synthetic schemes (two) and prepare, wherein R
3there is implication of the present invention; X is halogen, preferred chlorine, bromine.First, compound (13) is obtained by reacting by compound (9) and amido protecting agent (as chloroformic acid benzyl ester); Compound (13) obtains compound (14) through reductive agent (as Raney's nickel) reduction again; Compound (14) and acid anhydrides R
2oR
2huo Xian Halogen R
2-X is obtained by reacting compound (15); Compound (15) is hydrolyzed in the basic conditions and obtains compound (16); Compound (16) hydrogen reducing deaminize protecting group under the effect of palladium carbon obtains target compound (I).
Synthetic schemes (three):
Work as R
2for amidino groups, R
1for C
1-C
6alkyl-(C=O)-time, compound (I) can pass through synthetic schemes (three) and prepare, wherein R
3there is implication of the present invention.First, compound (10) obtains compound (18) through reductive agent (as Raney's nickel) reduction; Compound (18) and 1,3-bis-(uncle-butoxy carbonyl)-2-methyl-2-thiocarbamide is obtained by reacting compound (19); Compound 19 obtains compound (20) through hydrolysis in the basic conditions; Compound (20) in acid condition de-Boc protection obtains target compound (I).
Synthetic schemes (four):
Work as R
2for C
1-C
6alkyl-(C=O)-, R
1during for amidino groups, compound (I) can pass through synthetic schemes (four) and prepare, wherein R
3there is implication of the present invention, Pg
2for amino protecting group.First, compound (19) hydrogen reducing deaminize protecting group under the effect of palladium carbon obtains compound (22); Compound (22) and 1,3-bis-(uncle-butoxy carbonyl)-2-methyl-2-thiocarbamide is obtained by reacting compound (23); Compound (23) obtains compound (24) through hydrolysis in the basic conditions; Compound (24) in acid condition de-Boc protection obtains target compound (I).
Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
Embodiment
Embodiment 1:3-acetylaminohydroxyphenylarsonic acid 3-(1-amino-3-ethyl pentyl group) cyclobutane formate
The synthesis of step 1:3-ethyl-1-nitro-1-amylalcohol
At-10 DEG C, to tetrabutyl ammonium fluoride (20.0g, 0.2mol, Nitromethane 99Min. (32mL, 0.6mol, 3.0eq) is slowly dripped in tetrahydrofuran (THF) (100mL) solution 0.2eq), drip and finish, mixed solution continues to stir 1 hour at this temperature.Then in above-mentioned solution, 2-ethyl butyraldehyde (20g, 0.5mol, 1eq) is dripped.After dripping, reaction solution continues to stir, and TLC monitors reaction process, and aftertreatment in about 1 hour is reacted.Saturated ammonium chloride solution is added, separatory in reaction solution.Aqueous phase ethyl acetate (50mLx3) extraction, and merge organic phase.Organic phase anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, purification by silica gel column chromatography (eluent: PE/EA (V/V)=10/1), obtaining product is yellow oil, 18.6g, productive rate 58%.
1HNMR(400MHz,CDCl
3):δ4.40(d,2H),4.31(q,1H),1.45-1.21(m,5H),0.89(t,6H)。
The synthesis of step 2:3-ethyl-1-nitro-1-amylene
At-5 DEG C, to 3-ethyl-1-nitro-1-amylalcohol (5.2g, 32.3mmol, 1.0eq) with the dichloromethane solution (50mL) of triethylamine (11.2mL, 80.7mmol, 2.5eq) drip methylsulfonyl chloride (3.0mL, 38.7mmol, 1.2eq), mixed solution continues stirring reaction at this temperature, and TLC monitors reaction process.In reaction solution, add saturated ammonium chloride solution (10mL), separatory, aqueous phase methylene dichloride (25mLx3) extraction, merges organic phase.Organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure is except desolventizing, and crude product purification by silica gel column chromatography (eluent: PE/EA (V/V)=50/1), obtaining product is yellow oil, 3.1g, productive rate 66%.
1HNMR(400MHz,CDCl
3):δ7.06(q,1H),6.95(d,1H),2.12-2.03(m,1H),1.63-1.37(m,4H),0.89(t,6H)。
The synthesis of step 3:3-ethyl-1-nitropentane
At 0 DEG C, 3-ethyl-1-nitro-1-amylene (4.6g, 32.2mmol, 1.0eq) and silica gel (11.5g is added in the mixing solutions of methylene dichloride (100mL) and Virahol (20mL), 2.5eq), then mix and add NaBH in batches
4(2.45g, 65mmol, 2.0eq), TLC monitors reaction process.Reaction solution sintered filter funnel filters, and filter cake methylene dichloride (30mLx3) washing, removal of solvent under reduced pressure, purification by silica gel column chromatography (eluent: PE), obtaining product is yellow oil, 2.9g, productive rate 62%.
1HNMR(400MHz,CDCl
3):δ4.38(t,2H),1.98(m,2H),1.37-1.25(m,5H),0.87(t,6H)。
The synthesis of step 4:3-(3-ethyl-1-nitro amyl group)-3-hydroxycyclobutane carboxylate methyl ester
At-10 DEG C, in THF (60mL) solution of tetrabutyl ammonium fluoride (0.96g, 3.7mmol, 0.4eq), slowly drip 3-ethyl-1-nitropentane (5.36g, 37mmol, 4.0eq).Drip and finish, mixed solution continues to stir 1 hour at this temperature, then in above-mentioned solution, drips 3-oxo cyclobutane-carboxylic acid methyl esters (1.18g, 9.2mmol, 1.0eq).After dripping, reaction solution continues to stir, and TLC monitors reaction process, and aftertreatment in about 1 hour is reacted.In reaction solution, add saturated ammonium chloride solution (5mL), separatory, aqueous phase ethyl acetate (50mLx3) extraction, merges organic phase.Organic phase anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, purification by silica gel column chromatography (eluent: PE) isolates raw material 3-ethyl-1-nitropentane 2.3g, eluent PE/EA (V/V)=10/1 is used to proceed purifies and separates again, obtaining product is yellow oil, 1.42g, productive rate 57%.
1HNMR(400MHz,CDCl
3):δ4.71(dd,1H),3.71(s,3H),2.81(m,1H),2.42-2.31(m,4H),1.45-1.20(m,7H),0.88-0.82(m,6H)。
The synthesis of step 5:3-acetoxy-3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters
Under room temperature, to 3-(3-ethyl-1-nitro amyl group)-3-hydroxycyclobutane carboxylate methyl ester (1.63g, 6.0mmol, 1.0eq) with DMAP (0.88g, 7.2mmol, diacetyl oxide (0.74g, 7.2mmol, 1.2eq) is dripped in methylene dichloride (20mL) solution 1.2eq).Drip and finish, continue to stir at this temperature, TLC monitors reaction process, and aftertreatment in about 1 hour is reacted.
In reaction solution, add saturated ammonium chloride solution (5mL), separatory, aqueous phase methylene dichloride (15mLx3) extraction, merges organic phase.Organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure is except desolventizing.Crude product is with purification by silica gel column chromatography (eluent: PE/EA (V/V)=10/1), and obtaining product is yellow oil, 1.15g, productive rate 61%.
1HNMR(400MHz,CDCl
3):δ5.30(d,1H),3.71(s,3H),3.01(m,1H),2.82-2.21(m,4H),2.03(s,3H),1.61-1.16(m,7H),0.88-0.83(m,6H)。
The synthesis of step 6:3-(3-ethyl-1-nitro pentenyl) cyclobutane-carboxylic acid methyl esters
Under room temperature, DBU (1.11g is dripped in the dichloromethane solution (15mL) of 3-acetoxy-3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters (1.15g, 3.65mmol, 1.0eq), 7.30mmol, 2.0eq).Drip and finish, mixed solution maintains and stirs with this understanding, and TLC monitors reaction process, and aftertreatment in about 1 hour is reacted.Saturated ammonium chloride solution (5mL) is added, separatory in reaction solution.Aqueous phase methylene dichloride (10mLx3) extraction, merges organic phase.Organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure is except desolventizing.Residue purification by silica gel column chromatography (eluent: PE/EA (V/V)=10/1), obtaining product is yellow oil, 0.7g, productive rate 75%.
1HNMR(400MHz,CDCl
3):δ3.74(s,1H),3.54-3.49(m,2H),3.30-3.03(m,3H),2.42-2.27(m,2H),1.51(m,1H),1.31-1.25(m,4H),0.89-0.85(m,6H)。
The synthesis of step 7:3-amino-3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters
Under room temperature, in the tetrahydrofuran solution (30mL) of 3-(3-ethyl-1-nitro pentenyl) cyclobutane-carboxylic acid methyl esters (3.0g, 11.8mmol, 1.0eq), drip strong aqua (8.9mL, 118mmol, 10eq).Drip and finish, stirring at room temperature is reacted, and TLC monitors reaction process, and aftertreatment in about 2 hours is reacted.Saturated ammonium chloride solution (15mL) is added, separatory in reaction solution.Aqueous phase ethyl acetate (10mLx3) extraction, merges organic phase.Organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure is except desolventizing.Residue purification by silica gel column chromatography (eluent: PE/EA/NH
3h
2o (V/V/V)=250/50/1), obtaining product is yellow oil, 2.12g, productive rate 65%.
MS(ESI,pos.ion)m/z:273.2[M+1]
+；
1HNMR(400MHz,CDCl
3):δ4.72(dd,1H),3.69(s,3H),3.30-2.84(m,1H),2.47-2.01(m,4H),1.65(Broad,2H)1.40-1.22(m,7H),0.86-0.82(t,6H)。
The synthesis of step 8:3-acetylaminohydroxyphenylarsonic acid 3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters
Under room temperature, to 3-amino-3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters (0.5g, 1.83mmol, 1.0eq) with triethylamine (0.56mL, 4.04mmol, acetic anhydride (0.38g, 3.68mmol, 2eq) is dripped in methylene dichloride (5mL) solution 2.2eq).Drip and finish, stirring at room temperature is reacted, and TLC monitors reaction process.Saturated ammonium chloride solution (5mL) is added, separatory in reaction solution.Aqueous phase methylene dichloride (10mLx3) extraction, merges organic phase.Organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure is except desolventizing.Residue is with purification by silica gel column chromatography (eluent: PE/EA (V/V)=2/1), and obtaining product is yellow oil, 2.12g, productive rate 65%.
1HNMR(400MHz,CDCl
3):δ5.87(s,1H),5.20(dd,1H),3.70(s,3H),3.26(m,1H),2.63-2.50(m,4H),1.99(s,3H),1.69-1.25(m,7H),0.84(t,6H)。
The synthesis of step 9:3-acetylaminohydroxyphenylarsonic acid 3-(3-ethyl-1-nitro amyl group) cyclobutane formate
Under room temperature, by 3-acetylaminohydroxyphenylarsonic acid 3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters (0.1g, 0.32mmol, 1.0eq) dissolve in tetrahydrofuran (THF)/ethanolic soln (5mL, V/V=1/1) in, open and stir, the NaOH aqueous solution (2mL, 1M) added.Mixed solution reacts 4 hours in stirred at ambient temperature, and TLC monitoring reacts completely.Done by system concentrating under reduced pressure, residue 10mL water dissolution, ethyl acetate (10mLx2) extracts, and organic phase discards.Aqueous phase glacial acetic acid adjusts PH=4 ~ 5, and extracts by ethyl acetate (10mLx5), and organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains white solid, 78mg, yield 82%.
MS(ESI,pos.ion)m/z:301.3[M+1]
+。
The synthesis of step 10:3-acetylaminohydroxyphenylarsonic acid 3-(1-amino-3-ethyl pentyl group) cyclobutane formate 1-12
Under room temperature, by 3-acetylaminohydroxyphenylarsonic acid 3-(3-ethyl-1-nitro amyl group) cyclobutane formate 1-11 (40mg, 0.13mmol, 1.0eq) be dissolved in dehydrated alcohol (5mL), add Raney's nickel (10mg, content 20%), in reaction system, air first uses hydrogen exchange again with after nitrogen replacement.Stirring reaction under atmosphere of hydrogen normal temperature and pressure, TLC monitors reaction process.Suction filtration removing catalyzer, filter cake dehydrated alcohol (10mLx2) washing, concentrating under reduced pressure removing ethanol, residue drains to obtain white solid 20mg.
MS(ESI,pos.ion)m/z:271.3[M+1]
+；
1HNMR(400MHz,CDCl
3):δ5.87(s,1H),5.20(dd,1H),3.70(s,3H),3.26(m,1H),2.63-2.50(m,4H),1.99(s,3H),1.69-1.25(m,7H),0.84(t,6H).
The amino cyclobutane formate of embodiment 2:3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-
The synthesis of step 1:3-benzyloxycarbonyl amino-3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters
At 0 DEG C, to 3-amino-3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters (0.5g, 1.83mmol, 1.0eq) with triethylamine (0.56mL, 4.04mmol, CbzCl (0.38g, 2.2mmol, 1.2eq) is dripped in methylene dichloride (5mL) solution 2.2eq).Drip and finish, mixed solution 0 DEG C of stirring reaction, TLC monitors reaction process.Saturated ammonium chloride solution (5mL) is added, separatory in reaction solution.Aqueous phase methylene dichloride (10mLx3) extraction, merges organic phase.Organic phase anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure is except desolventizing, and purification by silica gel column chromatography, eluent PE/EA (V/V)=5/1, obtaining product is yellow oil, 0.44g, productive rate 61%.
The synthesis of step 2:3-benzyloxycarbonyl amino-3-(1-amino-3-ethyl pentyl group) cyclobutane-carboxylic acid methyl esters
Under room temperature, Raney's nickel (20mg, content 20%) is added to 3-benzyloxycarbonyl amino-3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters (0.4g, 1mmol, in methanol solution (5mL) 1.0eq), reaction system is replaced as H
2system, TLC monitors reaction process.Use diatomite filtration reaction system, filter cake methyl alcohol (10mL) washing, filtrate reduced in volume is except desolventizing, residue purification by silica gel column chromatography (eluent: PE/EA (V/V)=3/1), obtaining product is yellow oil, 360mg, productive rate 90%.
MS(ESI,pos.ion)m/z:377.3[M+1]
+.
The synthesis of step 3:3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(benzyloxycarbonyl amino) cyclobutane-carboxylic acid methyl esters
Under room temperature, by 3-benzyloxycarbonyl amino-3-(1-amino-3-ethyl pentyl group) cyclobutane-carboxylic acid methyl esters (360mg, 0.95mmol, 1.0eq) be dissolved in methylene dichloride (10mL), then add triethylamine (193mg, 1.9mmol, 2eq), drip diacetyl oxide (116mg, 1.14mmol, 1.2eq).Mixed solution stirring at room temperature is reacted, and TLC monitors reaction process.In reaction solution, add saturated ammonium chloride solution (5mL) cancellation reaction, ethyl acetate (10mLx3) extracts, and anhydrous sodium sulfate drying, is spin-dried for.Residue column chromatography purification (eluent: PE/EA (V/V)=5/1), obtaining product is yellow oil, 300mg, productive rate 71.8%.
The synthesis of step 4:3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(benzyloxycarbonyl amino) cyclobutane formate
Under room temperature, to 3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(benzyloxycarbonyl amino) cyclobutane-carboxylic acid methyl esters (300mg, 0.71mmol, tetrahydrofuran (THF) 1.0eq)/ethanol (5mL, V/V=1/1) NaOH solution (1mol/L is added in solution, 2mL), stirring at room temperature is reacted, TLC and LC-MS monitors reaction process.In reaction system, add 10mL water, with ethyl acetate (15mLx2) extraction, organic phase discards.About pH to 5.0 adjusted by aqueous phase Glacial acetic acid, then uses ethyl acetate (15mLx6) to extract, and merges organic phase, and dry, concentrating under reduced pressure desolventizes, and obtains white solid product 210mg, productive rate 73.1%, is directly used in next step reaction.
The synthesis of the amino cyclobutane formate of step 5:3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-
Under room temperature, 3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(benzyloxycarbonyl amino) cyclobutane formate (210mg, 0.52mmol, 1.0eq) is dissolved in the dehydrated alcohol of 10mL, add wet palladium carbon (content 10%, 40mg).Air in reaction system first uses nitrogen replacement five times, then uses hydrogen exchange five times, and stirring at room temperature reaction about 4 hours, LC-MS monitors reaction process.
Decompress filter removing palladium carbon, with dehydrated alcohol (10mLx2) washing, merging filtrate.Filtrate reduced in volume, drains to obtain white solid product 80mg, yield 57.1%.
MS(ESI,pos.ion)m/z:271.1[M+1]
+；
1HNMR(400MHz,CDCl
3):δ4.1(m,1H),2.9-3.3(m,1H),2.2-2.6(m,4H),1.99(s,3H),1.2-1.5(m,7H),0.83-0.88(m,6H)。
Embodiment 3:3-acetylaminohydroxyphenylarsonic acid 3-(3-ethyl-1-guanidine radicals amyl group)-cyclobutane formate
The synthesis of step 1:3-acetylaminohydroxyphenylarsonic acid 3-(1-amino-3-ethyl pentyl group) cyclobutane-carboxylic acid methyl esters
Under room temperature, Raney's nickel (20mg, content 20%) is added to 3-acetylaminohydroxyphenylarsonic acid 3-(3-ethyl-1-nitro amyl group) cyclobutane-carboxylic acid methyl esters (0.1g, 0.32mmol, in methanol solution (5mL) 1.0eq), reaction system is replaced as H
2system, TLC monitors reaction process.Use diatomite filtration reaction solution, filter cake methyl alcohol (10mL) washing, removal of solvent under reduced pressure, purification by silica gel column chromatography (eluent DCM/MeOH (V/V)=8/1), obtaining product is yellow oil, 56mg, productive rate 62%.
MS(ESI,pos.ion)m/z:285.2[M+1]
+。
The synthesis of step 2:3-(1-(two (tert-butoxycarbonyl) guanidine radicals of 2,3-)-3-ethyl pentyl group)-3-kharophen cyclobutane-carboxylic acid methyl esters
Under room temperature, by 3-acetylaminohydroxyphenylarsonic acid 3-(1-amino-3-ethyl pentyl group) cyclobutane-carboxylic acid methyl esters (140mg, 0.49mmol, 1.0eq) be dissolved in N, dinethylformamide (10mL), add triethylamine (76mg successively again, 0.75mmol, 3.8eq), 1,3-bis-(uncle-butoxy carbonyl)-2-methyl-2-thiocarbamide (160mg, 0.55mmol, 1.1eq) with mercury chloride (150mg, 0.55mmol, 1.1eq), mixture stirring at room temperature is reacted, and TLC monitors reaction process.Ethyl acetate (30mL) dilution is added in reaction solution, diatomite filtration, filtrate water (10mLx3) washs, dry, purification by silica gel column chromatography (eluent: PE/EA (V/V)=5/1), obtaining product is yellow oil, 113mg, productive rate 44%.
MS(ESI,pos.ion)m/z:527.3[M+1]
+；
1HNMR(400MHz,CDCl
3):δ11.36(s,1H),9.04(d,1H),8.61(s,1H),4.15(m,1H),3.67(s,3H),3.18(m,1H),2.56-2.27(m,4H),1.98(s,3H),1.49(s,9H),1.45(s,9H),1.32-1.16(m,7H),0.83-0.78(m,6H).
The synthesis of step 3:3-(1-(two (tert-butoxycarbonyl) guanidine radicals of 2,3-)-3-ethyl pentyl group)-3-kharophen cyclobutane formate
Under room temperature, to 3-(1-(2, two (tert-butoxycarbonyl) guanidine radicals of 3-)-3-ethyl pentyl group)-3-kharophen cyclobutane-carboxylic acid methyl esters (110mg, 0.21mmol, aqueous sodium hydroxide solution (2mL is added in tetrahydrofuran (THF) (5mL) solution 1.0eq), 1M), stirring at room temperature is reacted, TLC and LC-MS monitors reaction process.10mL water is added in reaction system, extract by ethyl acetate (15mLx2), about pH to 5.0 adjusted by aqueous phase Glacial acetic acid, ethyl acetate (15mLx6) is used to extract again, merge organic phase, dry, decompression desolventizes, obtain yellow oily product liquid 90mg, be directly used in next step reaction.
MS(ESI,pos.ion)m/z:513.3[M+1]
+。
The synthesis of step 4:3-acetylaminohydroxyphenylarsonic acid 3-(3-ethyl-1-guanidine radicals amyl group) cyclobutane formate
Under room temperature, to 3-(1-(2, two (tert-butoxycarbonyl) guanidine radicals of 3-)-3-ethyl pentyl group)-3-kharophen cyclobutane formate (90mg, 0.18mmol, 1.0eq) methylene dichloride (5mL) solution in drip trifluoroacetic acid (0.5mL).Drip and finish, stirring at room temperature reaction about 4 hours, LC-MS monitors reaction process.Concentrating under reduced pressure is except desolventizing and trifluoroacetic acid, and residue methylene dichloride (10mLx2) washing, is spin-dried for (removing trifluoroacetic acid) with revolving steaming instrument, then uses methylene dichloride (10mLx2) to wash.Product is insoluble to methylene dichloride, pours out solvent, remains in the thick product vacuum-drying in flask walls, and obtaining product is yellow solid, 45mg, productive rate 80%.
MS(ESI,pos.ion)m/z:313.2[M+1]
+；
1HNMR(400MHz,CDCl
3):δ3.93(d,1H),3.12(m,1H),2.47-2.17(m,4H),2.03(s,3H),1.39-1.18(m,7H),0.88-0.77(m,6H)。
Embodiment 4:3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-guanidine radicals cyclobutane formate
The synthesis of the amino cyclobutane-carboxylic acid methyl esters of step 1:3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-
By compound 3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(benzyloxycarbonyl amino) cyclobutane-carboxylic acid methyl esters (500mg, 1.0eq) be dissolved in 20mL methyl alcohol, add palladium carbon (content 10%, 50mg), hydrogen exchange air.Mixed solution stirring at normal temperature, TLC monitors.After reacting completely, filter, concentrating under reduced pressure is except desolventizing, and the oil pump degree of depth takes out solvent, obtains yellow oily target compound 320mg, productive rate 72%.
The synthesis of step 2:3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(two (tert-butoxycarbonyl) guanidine radicals of 2,3-) cyclobutane-carboxylic acid methyl esters
By the amino cyclobutane-carboxylic acid methyl esters of compound 3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(160g, 1.0eq, 0.56mmol) be dissolved in 10mLN, in dinethylformamide, add 1 successively, 3-bis-(uncle-butoxy carbonyl)-2-methyl-2-thiocarbamide (179mg, 1.1eq, 0.61mmol), mercury chloride (168mg, 1.1eq, 0.61mmol), triethylamine (199mg, 3.5eq, 1.97mmol), stirring at room temperature two hours, TLC monitors reaction.A large amount of ethyl acetate (30mL) is added in reaction solution, filter, then add water (30mL), separatory, organic phase is dry, revolve steaming solvent, residue purification by silica gel column chromatography (eluent: PE/EA (V/V)=20/1) obtains yellow oily target compound 160mg, yield 50%.
The synthesis of step 3:3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(two (tert-butoxycarbonyl) guanidine radicals of 2,3-) cyclobutane formate
By compound 3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(2, two (tert-butoxycarbonyl) guanidine radicals of 3-) cyclobutane-carboxylic acid methyl esters (150mg, 1.0eq, 1.9mmol) be dissolved in 10mL ethanol, hydro-oxidation sodium solution (10%, 10mL) under ice bath.Mixed solution stirring at room temperature 2 hours, TLC monitors reaction.After complete reaction, 35 DEG C revolve the most of ethanol of steaming removing, add water (10mL) and ethyl acetate (20mL) in residue, and extraction separatory, stays aqueous phase.Aqueous phase is adjusted between pH to 1 to 2, adds ethyl acetate (15mLx3) extraction, merges organic phase, dry, revolves and steams except desolventizing.Oil pump is transferred residue and is obtained yellow oily target compound, 140mg, yield 90%.
The synthesis of step 4:3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-guanidine radicals cyclobutane formate
By 3-(1-acetylaminohydroxyphenylarsonic acid 3-ethyl pentyl group)-3-(2, two (tert-butoxycarbonyl) guanidine radicals of 3-) cyclobutane formate (140mg, 1.0eq, 0.27mmol) be dissolved in the dichloromethane solution (5mL of 10% trifluoroacetic acid, 0.5mmol), stirring at room temperature 3 hours, TLC monitors reaction, revolves and steams except desolventizing.The residue oil pump degree of depth takes out 10 minutes, adds ethyl acetate 10mL, after white solid settles down, topples over and falls supernatant liquid, adds ethyl acetate (10mL) washing, repeats operation above three times, revolve and evaporate partial solvent.Residue scavenge oil pump is taken out and within 20 minutes, is obtained white solid target compound 60mg, yield 72%.
MS(ESI,pos.ion)m/z:313.1[M+1]
+；
1HNMR(400MHz,CDCl
3):δ0.91-0.92(m,6H),1.40-1.50(m,7H),2.01(d,3H),2.40-2.42(m,2H)，2.53-2.59(m,2H),3.01-3.11(m,1H),4.08-4.18(m,1H),7.96(d,1H),8.12(dd,1H)。
Embodiment 5:3-acetylaminohydroxyphenylarsonic acid 3-(1-aminopropyl) cyclobutane formate. trifluoroacetate
The synthesis of step 1:3-oxo cyclobutane-carboxylic acid methyl esters
In 100mL round-bottomed flask, add methyl alcohol (50mL) solution of 3-oxo cyclobutane formate (10.0g, 0.088mol, 1.0eq), under 0 DEG C of stirring, be slowly added dropwise to thionyl chloride (3.1mL, 0.045mol, 0.5eq).Add rear reaction solution to reflux 4.0 hours.Reaction solution concentrating under reduced pressure is except desolventizing, and residue over silica gel column chromatography purification (eluent: PE/EA (V/V)=10/1) obtains target compound 10.0g, colourless oil liquid, yield 89%.
1HNMR(400MHz,CDCl
3):δ3.77(s,3H),3.23-3.46(s,5H)。
The synthesis of step 2:3-hydroxyl-3-(1-nitropropyl) cyclobutane-carboxylic acid methyl esters
In 25mL round-bottomed flask, add tetrahydrofuran (THF) (10mL) solution of tetrabutyl ammonium fluoride (1.1g, 4.2mmol, 0.9eq), at 0 DEG C, drip 1-nitropropane (1.25g, 14.0mol, 2.5eq).Mixed solution stirs 1 hour at 0 DEG C, then adds 3-oxo cyclobutane-carboxylic acid methyl esters (0.6g, 4.66mmol, 1eq), and mixture continues stirring at room temperature 4 hours.After completion of the reaction, add saturated ammonium chloride solution (10mL), reaction solution ethyl acetate (20mLx3) extracts in TLC monitoring.The organic phase anhydrous sodium sulfate drying merged, then underpressure distillation is except desolventizing, and residue uses purification by silica gel column chromatography (eluent: PE/EA (V/V)=10/1) to obtain colourless oil liquid 1.3g, yield 30% further.
The synthesis of step 3:3-(1-nitropropenyl) cyclobutane-carboxylic acid methyl esters
In 50mL round-bottomed flask, add 3-hydroxyl-3-(1-nitropropyl) cyclobutane-carboxylic acid methyl esters (0.7g, 3.22mmol, 1.0eq) methylene dichloride (20mL) solution, 0 DEG C stir under slowly drip methylsulfonyl chloride (0.37g, 3.22mmol, 1.0eq), then add triethylamine (0.9mL, 6.44mmol, 2.0eq), rear mixed solution stirring at room temperature 2 hours are added.Add saturated ammonium chloride solution (20mL) subsequently, with methylene dichloride (20mLx3) extractive reaction liquid, use anhydrous sodium sulfate drying organic phase, residue uses purification by silica gel column chromatography (eluent: PE/EA (V/V)=10/1) to obtain colourless oil liquid 0.36g, yield 56% further.
The synthesis of step 4:3-(1-nitropropyl)-3-((R)-1-phenylethylcarbamate) cyclobutane-carboxylic acid methyl esters
3-(1-nitropropenyl) cyclobutane-carboxylic acid methyl esters (0.4g, 2mmol, 1.0eq) and tetrahydrofuran (THF) (10mL) is added in 50mL round-bottomed flask.Mixed solution is cooled to-10 DEG C, adds (R)-1-phenyl-ethyl amine (0.24mL, 2mmol, 1.0eq) under stirring, and continues stirring 2 hours.It is colourless oil liquid that reaction solution concentrating under reduced pressure obtains crude product, 0.53g, yield 80%.
MS(ESI,pos.ion)m/z:321.1[M+1]
+。
The synthesis of step 5:3-(1-aminopropyl)-3-((R)-1-phenylethylcarbamate) cyclobutane-carboxylic acid methyl esters
At room temperature, 3-(1-nitropropyl)-3-((R)-1-phenylethylcarbamate) cyclobutane-carboxylic acid methyl esters (0.4g is added in the round-bottomed flask of 25mL, 4.44mmol, 1.0eq) and ethanol (5mL), in mixture, Raney's nickel (100mg is added under stirring, content 20%), then add hydrogen balloon as sources of hydrogen.Mixture continues stir about 2 hours.After completion of the reaction, by reaction solution concentrating under reduced pressure, except desolventizing, to obtain crude product be colourless oil liquid, 0.9g, yield 70% in TLC monitoring.
MS(ESI,pos.ion)m/z:291.1[M+1]
+。
The synthesis of step 6:3-(1-(tertbutyloxycarbonylamino) propyl group)-3-((R)-1-phenylethylcarbamate) cyclobutane-carboxylic acid methyl esters
Under room temperature, 3-(1-aminopropyl)-3-((the R)-1-phenylethylcarbamate) cyclobutane-carboxylic acid methyl esters (0.9g in step reaction is added in the round-bottomed flask of 25mL, 3mmol), add the triethylamine (0.3g of equivalent, 3mmol) and tetrahydrofuran (THF) (5mL), add the tert-Butyl dicarbonate (0.66g, 3mmol) of equivalent under stirring, continue reaction 2 hours at this temperature.Reaction solution concentrating under reduced pressure after completion of the reaction, is removed desolventizing and obtains colourless oil liquid crude product 0.93g, yield 80% by TLC monitoring.
MS(ESI,pos.ion)m/z:391.2[M+1]
+.
The synthesis of step 7:3-amino-3-(1-(tertbutyloxycarbonylamino) propyl group) cyclobutane-carboxylic acid methyl esters
Under room temperature, 3-(1-(tertbutyloxycarbonylamino) propyl group)-3-((the R)-1-phenylethylcarbamate) cyclobutane-carboxylic acid methyl esters (0.93g in the reaction of upper step is added in the round-bottomed flask of 25mL, 2.4mmol), and ethanol (5mL), in mixture, add palladium hydroxide (200mg) under stirring, then add hydrogen balloon as sources of hydrogen.Mixture continues stir about 2 hours.After completion of the reaction, by reaction solution concentrating under reduced pressure, except desolventizing, to obtain crude product be colourless oil liquid, 0.62g, yield 90% in TLC monitoring.
MS(ESI,pos.ion)m/z:287.1[M+1]
+。
The synthesis of step 8:3-acetylaminohydroxyphenylarsonic acid 3-(1-(tertbutyloxycarbonylamino) propyl group) cyclobutane-carboxylic acid methyl esters
Under room temperature, 3-amino-3-(1-(tertbutyloxycarbonylamino) propyl group) cyclobutane-carboxylic acid methyl esters (100mg is added in the round-bottomed flask of 50mL, 0.439mmol, 1.0eq), triethylamine (44mg, 0.439mmol, 2eq) and DMAP (catalytic amount) and tetrahydrofuran (THF) (5mL), in mixed solution, add tert-Butyl dicarbonate (39.0mg under stirring, 0.18mol, 1.0eq).Under room temperature, mixed solution stirs and spends the night, and TLC monitors extent of reaction.In reaction solution, add saturated ammonium chloride solution (5mL), be extracted with ethyl acetate (20mLx3).The organic phase anhydrous sodium sulfate drying merged, concentrating under reduced pressure steams and desolventizes.Remaining residue uses purification by silica gel column chromatography (eluent: PE/EA (V/V)=1/1) to obtain colorless oil target compound 100mg, yield 69.4% further.
MS(ESI,pos.ion)m/z:329.4[M+1]
+。
The synthesis of step 9:3-acetylaminohydroxyphenylarsonic acid 3-(1-(tertbutyloxycarbonylamino) propyl group) cyclobutane formate
Under room temperature, 3-acetylaminohydroxyphenylarsonic acid 3-(1-(tertbutyloxycarbonylamino) propyl group) cyclobutane-carboxylic acid methyl esters (100mg is added in the round-bottomed flask of 50mL, 0.3mmol, 1eq) and tetrahydrofuran (THF)/ethanol (v/v=1/1, mixing solutions 30mL), at room temperature be added dropwise to the NaOH aqueous solution (5mL, 1M) again.Mixed solution at room temperature continues stirring 4 hours.Mixed solution concentrating under reduced pressure, residue is dissolved in 20mL water, and adds acetic acid to pH=2-3, continues with ethyl acetate (20mLx3) extraction.The organic phase anhydrous sodium sulfate drying merged, underpressure distillation obtains colourless oil liquid product 80mg, yield 88.9%.
MS(ESI,pos.ion)m/z:215.3[M+1]
+。
Step 10:3-acetylaminohydroxyphenylarsonic acid 3-(1-aminopropyl) cyclobutane formate. the synthesis of trifluoroacetate
Under room temperature, in the round-bottomed flask of 50mL, add 3-acetylaminohydroxyphenylarsonic acid 3-(1-(tertbutyloxycarbonylamino) propyl group) cyclobutane formate (40mg, 0.14mmol, 1eq) and methylene dichloride (5mL).In mixed solution, trifluoroacetic acid (0.5mL) is dropwise added under stirring at room temperature.It is complete that mixture stirs TLC monitoring reaction after 14 hours, except desolventizing adopts ether making beating to obtain white solid product 30mg, yield 65%.
MS(ESI,pos.ion)m/z:215.1[M+1]
+；
1HNMR(400MHz,CD
3OD):δ3.69(m,1H),3.13(m,1H),2.21-2.79(m,4H),1.98(s,3H),1.41-1.82(m,2H),1.01(t,3H)。
The amino cyclobutane formate of embodiment 6:3-(1-kharophen propyl group)-3-. trifluoroacetate
The synthesis of step 1:3-(1-kharophen propyl group)-3-((R)-1-phenylethylcarbamate) cyclobutane-carboxylic acid methyl esters
Under room temperature, 3-(1-aminopropyl)-3-((R)-1-phenylethylcarbamate) cyclobutane-carboxylic acid methyl esters (1.16g is added in the round-bottomed flask of 25mL, 4mmol), acetic anhydride (0.1mL) is added under stirring, continue stirring 2 hours, underpressure distillation, except desolventizing, obtains reaction residues, directly drops into next step reaction.
MS(ESI,pos.ion)m/z:333.4[M+1]
+。
The synthesis of the amino cyclobutane-carboxylic acid methyl esters of step 2:3-(1-kharophen propyl group)-3-
Under room temperature, 3-(1-kharophen propyl group)-3-((R)-1-phenylethylcarbamate) the cyclobutane-carboxylic acid methyl esters in the reaction of upper step and ethanol (5mL) is added in the round-bottomed flask of 25mL, add palladium hydroxide (200mg) under stirring, then add hydrogen balloon as sources of hydrogen.Mixture continues stir about 2 hours.Reaction solution concentrating under reduced pressure after completion of the reaction, is obtained crude product by TLC monitoring, adopts purification by silica gel column chromatography (eluent: PE/EA (V/V)=3/1) to obtain colorless oil target product 0.1g, yield 11.1%.
MS(ESI,pos.ion)m/z:229.1[M+1]
+。
The synthesis of step 3:3-(1-kharophen propyl group)-3-(t-butoxycarbonyl amino) cyclobutane-carboxylic acid methyl esters
Under room temperature, the amino cyclobutane-carboxylic acid methyl esters of 3-(1-kharophen propyl group)-3-(100mg is added in the round-bottomed flask of 50mL, 0.439mmol, 1.0eq), triethylamine (44mg, 0.439mmol, 2eq), DMAP (catalytic amount) and tetrahydrofuran (THF) (5mL).In mixed solution, add tert-Butyl dicarbonate (39.0mg, 0.18mol, 1.0eq) under stirring, continue reaction under mixed solution room temperature and spend the night.TLC monitoring after completion of the reaction, adds saturated ammonium chloride solution (5mL), is extracted with ethyl acetate (20mLx3) in reaction flask.The organic phase anhydrous sodium sulfate drying merged, concentrating under reduced pressure is except desolventizing.Remaining residue uses purification by silica gel column chromatography (eluent: PE/EA (V/V)=1/1) to obtain colorless oil target compound 120mg, yield 83.3% further.
MS(ESI,pos.ion)m/z:329.4[M+1]
+。
The synthesis of step 4:3-(1-kharophen propyl group)-3-(t-butoxycarbonyl amino) cyclobutane formate
Under room temperature, 3-(1-kharophen propyl group)-3-(t-butoxycarbonyl amino) cyclobutane-carboxylic acid methyl esters (100mg is added in the round-bottomed flask of 50mL, 0.3mmol, 1eq) and the mixing solutions of tetrahydrofuran (THF)/ethanol (V/V=1/1,30mL).At room temperature be added dropwise to the NaOH aqueous solution (5mL, 1M) to mixing solutions again, mixed solution at room temperature continues stirring 4 hours.Reaction solution concentrating under reduced pressure, residue is dissolved in 20mL water, and adds acetic acid to pH=2-3, continues to be extracted with ethyl acetate (20mLx3).The organic phase anhydrous sodium sulfate drying merged, concentrating under reduced pressure obtains colourless oil liquid product 80mg, yield 85.1%.
MS(ESI,pos.ion)m/z:315.1[M+1]
+。
The amino cyclobutane formate of step 5:3-(1-kharophen propyl group)-3-. the synthesis of trifluoroacetate
Under room temperature, in the round-bottomed flask of 50mL, add 3-(1-kharophen propyl group)-3-(t-butoxycarbonyl amino) cyclobutane formate (43mg, 0.14mmol, 1eq) and methylene dichloride (5mL).Dropwise add trifluoroacetic acid (0.5mL) under stirring at room temperature, it is complete that mixture stirs TLC monitoring reaction after 14 hours.Mixture concentrating under reduced pressure, it is white solid that residue adopts ether making beating to obtain product, 26mg, yield 60%.
MS(ESI,pos.ion)m/z:215.1[M+1]
+；
1HNMR(400MHz,CD
3OD):δ3.99(m,1H),3.03(m,1H),2.21-2.74(m,4H),2.1(s,3H),1.51-1.92(m,2H),0.99(t,3H)。
Anti-influenza virus activity measures
96 orifice plate CPE assay method steps:
Spread 96 orifice plates, 5000 mdck cells are inoculated in every hole, 37 DEG C, 5%CO
2, incubated overnight.
By DMSO and serum free medium diluted compounds to suitable concn, DMSO final concentration is 1%.
With the influenza virus H1N1 (A/weiss/43) that substratum dilution-80 DEG C is frozen.
Every hole adds the virus liquid (final MOI=0.01) after the compound after 50ul dilution and 50ul dilution.
96 orifice plates are placed in 37 DEG C, 5%CO
2, cultivate 3 days.
Every hole adds 20ulMTT, is placed in 37 DEG C, hatches 4 hours.
Measure the first a ceremonial jade-ladle, used in libation amount that MTT is generated by viable cell reduction, and the per-cent that the monitored compound of CPE calculating influenza virus mediation accordingly suppresses.
96 orifice plates measure cytotoxicity step:
Spread 96 orifice plates, 5000 mdck cells are inoculated in every hole, 37 DEG C, 5%CO
2, incubated overnight.
By DMSO and serum free medium diluted compounds to suitable concn, DMSO final concentration is 1%.
Every hole adds the compound after 50ul dilution and 50ul nutrient solution.
96 orifice plates are placed in 37 DEG C, 5%CO
2, cultivate 3 days.
Every hole adds 20ulMTT, is placed in 37 DEG C, 4 hours.
Measure the first a ceremonial jade-ladle, used in libation amount that MTT is generated by viable cell reduction, and calculate the cytotoxicity of test compound accordingly.
Data analysis: % inhibiting rate=(OD
t– OD
v)/(OD
c– OD
v) x100%
% cytotoxicity=OD
t/ OD
cx100%
% activity=% suppression Shuai – % cytotoxicity
OD
t, OD
v, and OD
crepresent the specific absorbance of test compounds respectively, virus-infected controls (without compound ,+1%DMSO), and cell blank contrast (virus-free, without compound ,+1%DMSO)
ODvalue＝OD
570–OD
630(MTT)
Table 2: part of compounds infected by influenza H1N1 (A/weiss/43) experiment in vitro activity value of the present invention
As seen from the above table, the compounds of this invention has obvious anti-influenza virus activity.
It will be apparent to one skilled in the art that content of the present invention is not limited to foregoing illustrative embodiment, and can be embodied in other specific form and don't depart from its essential characteristics.Therefore, expect that each embodiment is all considered in all respects illustrative and nonrestrictive, should with reference to appended claims, instead of these embodiments aforementioned, therefore, all changes in the implication and scope of appended claims equivalents are all included in herein.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, limitation of the present invention can not be interpreted as, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification, and scope of the present invention is by claim and equivalents thereof.
Claims (8)
1. a compound, it is steric isomer, tautomer, the pharmacy acceptable salt of structure shown in the structural formula shown in formula (I) or formula (I),
Wherein,
Each R
1and R
2be hydrogen, C independently
1-C
6alkyl-(C=O)-, or amidino groups; With
R
3for hydrogen or C
1-C
10alkyl.
2. compound according to claim 1, wherein,
Each R
1and R
2be hydrogen, CH independently
3(C=O)-, CH
3cH
2(C=O)-, CH
3cH (CH
3) (C=O)-, CH
3cH
2cH
2(C=O)-, CH
3cH
2cH
2cH
2(C=O)-or amidino groups; With
R
3for hydrogen or C
1-C
6alkyl.
3. compound according to claim 1, wherein, R
3for hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, 1-amyl group, 1-hexyl, 3-hexyl, 2-amyl group, 3-amyl group, 2-ethyl-butyl or 2-methyl butyl.
4. compound according to claim 1, wherein said pharmacy acceptable salt is hydrochloride, vitriol, nitrate, phosphoric acid salt, metaphosphate, mesylate, esilate, Citrate trianion, benzene sulfonate, tosilate, malate, tartrate, succinate, fumarate, acetate, hydroxyl acetate, isethionate, maleate, lactic acid salt, Lactobionate, trifluoroacetate or its combination.
5. compound according to claim 1, it has one of them structure following,
Or the steric isomer of structure shown in it, tautomer, pharmacy acceptable salt.
6. pharmaceutical composition comprises the compound described in any one of claim 1-5, and pharmaceutically acceptable vehicle, assistant agent or their combination.
7. pharmaceutical composition according to claim 6, it comprises other anti-influenza virus medicament further, 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) or its combination.
8. the compound described in an any one of claim 1-5 or the pharmaceutical composition described in any one of claim 6-7 are for the preparation of protecting, processing, treat or alleviate and the purposes in the medicine of influenza virus diseases related.
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