CN110041331A - Styryl xanthine derivative and application thereof - Google Patents

Styryl xanthine derivative and application thereof Download PDF

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CN110041331A
CN110041331A CN201910412716.5A CN201910412716A CN110041331A CN 110041331 A CN110041331 A CN 110041331A CN 201910412716 A CN201910412716 A CN 201910412716A CN 110041331 A CN110041331 A CN 110041331A
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alkyl
alkoxy
compound
base
chf
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CN110041331B (en
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金传飞
钟文和
张英俊
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Guangdong HEC Pharmaceutical
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Ruyuan Yongxing Technical Service Co Ltd
Guangdong HEC Pharmaceutical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

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Abstract

The invention discloses styryl xanthine derivatives and application thereof, in particular it relates to which a kind of novel styryl xanthine derivative and the pharmaceutical composition comprising such compound, can be used as selective adenosine A2AReceptor antagonist.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and they preparation treatment and adenosine A2APurposes in the relevant disease of receptor, the especially drug of Parkinson's disease.

Description

Styryl xanthine derivative and application thereof
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to novel styryl xanthine derivative and include these change The pharmaceutical composition and its application method and purposes of conjunction object.Particularly, novel styryl xanthine of the present invention spreads out Biology can be used as selective adenosine A2AReceptor antagonist, for preventing, treating or mitigating and adenosine A2AThe relevant disease of receptor, Especially Parkinson's disease.
Background technique
Parkinson's disease (Parkinson ' s disease, PD) is a kind of common nervous system chronic degenerative diseases, again Claim shaking plasy, the elderly is common, and average age of onset is 60 years old or so, and the young Parkinson's disease of 40 years old or less onset is less See.The illness rate of China over-65s crowd PD is about 1.7%.Most of Parkinsonian is Sporadic cases, only not Patient to 10% has family history.Parkinson's disease insidious onset, makes slow progress.Onset symptoms be usually side limbs tremble or It is movable clumsy, and then involve contralateral limbs.Clinically it is mainly shown as static tremor, bradykinesia, myotonia and posture step State obstacle.People more and more notice that the non-motor symptoms such as depression, constipation and sleep disturbance are also Parkinson's disease in recent years The common main suit of patient, their influences to patients ' life quality are even more than motor symptoms.PD seriously affects the daily of patient Life and social activities, it has also become the big disease for perplexing people affects the quality of life of whole world millions of people.
The drug of many treatment PD of recent studies at present primarily directed to basal ganglion non-dopaminergic system, they There is stronger anti-PD activity, and does not generate side effect.
Basal ganglion is the important subcortical center for adjusting movement.Adenosine A2AReceptor (adenosine A2A Receptor) in basal ganglion selective expression and related with motor behavior, mainly pass through the adjusting to indirect pathway and play Effect: (1) in corpus straitum GABA serotonergic neuron adenosine A2AReceptor is activated, and to can be improved striatal GABAergic neurons emerging Putting forth energy property, to inhibit the excitability of GABA serotonergic neuron on the outside of globus pallidus；(2) striatal GABAergic neurons aixs cylinder end is activated Adenosine A2AReceptor can promote the release of GABA, inhibit GABA serotonergic neuron on the outside of globus pallidus excitability (Shindou T, Richardson PJ,Mori A et al.Adenosine modulates the striatal GABAergic inputs to the globus pallidus via adenosine A2A receptors in rats.Neuroscience Letters,2003,352(3):167-170.)。
Epidemiological study and laboratory research show to block adenosine A2AMitigated dopaminergic neuron by physical efficiency to be moved back Row venereal disease becomes.Adenosine A2AReceptor antagonist (adenosine A2AReceptor antagonist) improving the same of PD symptom When can also slow down the process of disease.Therefore, adenosine A2AReceptor antagonist may be sent out as the non-dopamine target spot of basal ganglion It transforms into treat new strategy (Pinna A, Wardas J, Simola N, the et al.New therapies for the of PD treatment of Parkinson’s disease:Adenosine A2A receptor antagonists[J] .LifeSci,2005,77(26):3259-67.).A large amount of bases and clinical research show adenosine A2AReceptor antagonist is possible into For the kind new medicine for treating Parkinson's disease.How some pair adenosine As are found2AReceptor affinity is high, can also play very well in vivo Curative effect, the drug that adverse reaction is few, becomes adenosine A2AOne important topic of receptor antagonist research.
Naturally occurring xanthine is the first generation compound of adenosine receptor antagonists, for example, caffeine (1,3,7- coffee Alkali) and theophylline (1,3- dimethyl xanthine, Daly et al., Cell.Mol.Neurobiol., 1983,3,67).For a long time with Come, it is known that these xanthine have reversed poverty of movement in various PD models.Moreover, epidemiological survey prompt caffeine and tea Alkali can reduce the incidence probability of Parkinson's disease.But research (Fredholm BB.Connection between caffeine, adenosine receptors and dopamine.Coffee reduces the risk of Parkinson’ Sdisease.Lakartidningen, 2004,101 (34): 2552-2555.) find that coffee is non-selective adenosine A2AReceptor Antagonist, effect are to have blocked adenosine A2AReceptor.Since they are non-selectivities and effect is medium, to promote people Further developing selective adenosine A2AReceptor antagonist.
Adenosine A2AA kind of new drug of the receptor antagonist as treatment PD, definite effect, safety, tolerance are preferable, have wide Wealthy application prospect.
Summary of the invention
The present invention provides a kind of alternatively property adenosine As2AThe novel styryl xanthine of receptor antagonist is derivative Object can be used for treatment and adenosine A2AThe relevant disease of receptor, especially for treating Parkinson's disease.And pass through experiment hair Existing, the property of styryl xanthine derivative of the invention is stablized, good security, has good pharmacodynamics and medicine generation dynamic Mechanical property, such as good brain/blood plasma ratio (brain plasmaratio), good bioavilability or good metabolism Stability etc..Therefore, has good potential applicability in clinical practice.
The present invention also provides prepare the method for this kind of compound, the pharmaceutical composition containing this kind of compound and this kind of Compound and the purposes of pharmaceutical composition in medicine preparation comprising this kind of compound.
On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Its prodrug,
Wherein:
R1、R2And R3It is each independently H, D, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, hydroxyl Substituted C1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Aryl or 5-10 unit's heteroaryl；
R4、R5And R8It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy) ,-OC (= O)-(C1-C6Alkyl), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Alkyl halide Oxygroup, C1-C6Alkylthio group, C1-C6The C that alkylamino, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Virtue Base or 5-10 unit's heteroaryl；
R9And R10It is each independently H, D, F, Cl, Br, I, C1-C6Alkyl or C1-C6Halogenated alkyl；
R6For-O-R0, R7For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2、-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy) ,-OC (=O)- (C1-C6Alkyl), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Haloalkoxy Base, C1-C6Alkylthio group, C1-C6The C that alkylamino, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Virtue Base, 5-10 unit's heteroaryl or-O-R0；Or
R6For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3、- C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy) ,-OC (=O)-(C1-C6Alkyl), C1- C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6The C that alkylamino, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Aryl or 5-10 member heteroaryl Base, R7For-O-R0；
R0For-(CRaRb)nORc；
RaAnd RbIt is each independently H, D, F, Cl, Br, I, C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1- C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl；
RcFor H, D, C1-C6Alkyl, C1-C6The C that halogenated alkyl, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 member are miscellaneous Ring group, C6-C10Aryl or 5-10 unit's heteroaryl；
N is 2,3 or 4.
In some embodiments, R1、R2And R3It is each independently H, D, C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4The C that halogenated alkyl or hydroxyl replace1-C4Alkyl；
R4、R5And R8It is each independently H, D, F, Cl, Br, I ,-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (= O)NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy) ,-OC (=O)-(C1-C4 Alkyl), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1- C4Alkylthio group, C1-C4The C that alkylamino or hydroxyl replace1-C4Alkyl；
R9And R10It is each independently H, D, F, Cl, Br, I, C1-C4Alkyl or C1-C4Halogenated alkyl.
In some embodiments, R1、R2And R3It is each independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl Base, acrylic, propargyl or propinyl；
R4、R5And R8It is each independently H, D, F, Cl, Br ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-CH3,-C (=O)-OCH3,-OC (=O) CH3,-OC (=O) CH2CH3, it is methyl, ethyl, n-propyl, different Propyl, allyl, acrylic, propargyl, propinyl ,-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、- CH2CF2CHF2, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、-OCF3、-OCHFCH2F、- OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol or 2- Hydroxyethyl；
R9And R10It is each independently H, D, F, Cl, Br, methyl or ethyl.
In some embodiments, R6For-O-R0, R7For H, D, F, Cl, Br, I ,-NH2,-OH ,-SH ,-COOH ,-C (= O)NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy) ,-OC (=O)-(C1-C4Alkyl), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogen For alkoxy, C1-C4Alkylthio group, C1-C4The C that alkylamino, hydroxyl replace1-C4Alkyl or-O-R0；Or
R6For H, D, F, Cl, Br, I ,-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy) ,-OC (=O)-(C1-C4Alkyl), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkane The C that amino or hydroxyl replace1-C4Alkyl, R7For-O-R0；
Wherein, R0With meaning of the present invention.
In some embodiments, R6For-O-R0, R7For H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, Allyl, acrylic, propargyl, propinyl ,-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2, first Oxygroup, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、- OCH2CF2CHF2, methyl mercapto, ethylmercapto group or-O-R0；Or
R6For H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propine Base ,-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2, it is methoxyl group, ethyoxyl, n-propyl oxygroup, different Propyl oxygroup ,-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2, methyl mercapto or ethylmercapto group, R7 For-O-R0；
Wherein, R0With meaning of the present invention.
In some embodiments, RaAnd RbIt is each independently H, D, methyl, ethyl, n-propyl or isopropyl；
RcFor H, D, C1-C4Alkyl, C1-C4The C that halogenated alkyl or hydroxyl replace1-C4Alkyl.
In some embodiments, RaAnd RbIt is each independently H, D, methyl or ethyl；
RcFor H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxymethyl or hydroxyethyl.
In some embodiments, compound of the present invention is for the compound with one of following structure or under having One of the column stereoisomer of the compound of structure, tautomer, nitrogen oxides, hydrate, solvate, metabolite, Pharmaceutically acceptable salt or its prodrug:
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes of the present invention any Compound；Further include pharmaceutically acceptable excipient, carrier, adjuvant or their any combination.
In other embodiments, pharmaceutical composition of the present invention further includes additional therapeutic agent, wherein institute The additional therapeutic agent stated is monoamine oxidase B type inhibitor, dopamine agonist, anticholinergic drug, glutamate antagonist, left-handed DOPA or their any combination.
Another aspect, the present invention relates to the use of compound of the present invention or its pharmaceutical composition in medicine preparation On the way, the drug is for preventing, treating or mitigating and adenosine A2AThe relevant disease of receptor.
In some embodiments, described and adenosine A2AThe relevant disease of receptor is Parkinson's disease, pain, depression, is crazy about Slow-witted, apoplexy, myocardial ischemia, asthma, abstinence from alcohol, dyskinetic syndrome, restless legs syndrome, dystonia, catalepsy, nerve Neuodegenerative disorder or osteoporosis.
In another aspect, the use the present invention relates to compound of the present invention or its pharmaceutical composition in medicine preparation On the way, the drug is used for Adenosine A2AReceptor.
On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I).
Biological results show that the compounds of this invention can be with Adenosine A2AReceptor, and can be used as preferable selectivity Adenosine A2AReceptor antagonist.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its Content in terms of him will make more specific complete description below.All bibliography in this specification pass through whole reference In this.When the disclosure of the specification and citation are variant, it is subject to the disclosure of the specification.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case where (including but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.
It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With the periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry Description in March, John Wiley&Sons, New York:2007, entire contents are incorporated by reference into the present invention.
There is apparent conflict unless otherwise indicated or in context, the article " one " used in the present invention, " one (kind) " and " described " are intended to include "at least one" or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more It uses or uses in the embodiment that one component is taken into account in the embodiment.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different Structure body (cis/trans isomers), atropisomer, etc..
Term " chiral molecules " be with its mirror image cannot be overlapped property molecule；And " achiral molecule " refers to and it The molecule that mirror image can be overlapped.
Term " enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
Term " racemate " or " racemic mixture " refer to the equimolar mixture of two enantiomters, the mixing Object lacks optical activity.
Term " diastereoisomer " refer to there are two or multiple chiral centers and its molecule not solid of mirror image each other Isomers.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereo-isomerism Body mixture can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis and be separated.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face rotates.When describing optically active compound, indicate molecule about one using prefix D and L or R and S A or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are revolved for linearly polarized light caused by appointed compound The symbol turned, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or three-dimensional spy When anisotropic, such case may occur in which.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to compounds some in this way, raw material, composition and/or dosage form, they are cured rationally Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced .. " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is not limited to D, F, Cl, Br, I, N3、-CD3、-CN、-NO2、-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-alkyl ,-C (=O)-alkoxy, alkyl, alkenyl, alkynyl, halogenated alkyl, alcoxyl Base, halogenated alkoxy, alkylthio group, alkylamino, the alkyl of hydroxyl substitution, naphthenic base, heterocycle, aryl, heteroaryl etc..
In general, term it is " substituted " indicate specifically replaced to one or more hydrogen atoms in structure or group Replaced base.Unless otherwise indicated, a substituent group can be replaced in each substitutive reasonable position of group. Replaced the specific substituent group of one or more that more than one position can be selected from given structural formula, then substituent group It can each reasonable position be replaced in structural formula identical or differently.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.
Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by Trying object is people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-C6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Term " D " indicates single D-atom.
Term " halogen " and " halogenated " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Term " oxo " refers to group=O, is used interchangeably with " carbonyl ".
Term " hetero atom " refers to O, S, N, P and Si, the form including any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole base N), (NR ' in pyrrolidinyl replaced as N-, R ' are substitution of the present invention by NH (as the NH in pyrrolidinyl) or NR ' Base).
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 A carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention Replaced the substituent group stated comprising the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".In an embodiment In, alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another reality It applies in scheme, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH= CH2), allyl (- CH2CH=CH2), 1- acrylic is (that is, acrylic ,-CH=CH-CH3), etc..
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention Replaced the substituent group stated.In one embodiment, alkynyl group includes 2-8 carbon atom；In another embodiment, alkynyl Group includes 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example packet of alkynyl group It includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyl is (that is, propinyl ,-C ≡ C-CH3), Etc..
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more Replaced the substituent group that the present invention describes.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), etc..
Term " alkylthio group " indicates that alkyl group is connected by sulphur atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkylthio radicals contain 1-12 carbon atom.In an embodiment party In case, alkylthio radicals contain 1-6 carbon atom；In another embodiment, alkylthio radicals contain 1-4 carbon atom；? In another embodiment, alkylthio radicals contain 1-3 carbon atom.The alkylthio radicals can be optionally one or more Replaced the substituent group that the present invention describes.The example of alkylthio radicals includes, but is not limited to, methyl mercapto (MeS ,-SCH3), second Sulfenyl (EtS ,-SCH2CH3) etc..
Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.It closes Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first ammonia Base (methylamino), N- ethylamino (ethylamino), N, N- dimethylamino (dimethylamino), N, N- lignocaine (lignocaine) etc. Deng.The alkylamino radicals are optionally replaced one or more substituent groups described in the invention.
Term " alkyl that hydroxyl replaces " indicates alkyl group replaced one or more hydroxyls, and wherein alkyl group has There is meaning as described in the present invention；Such example includes, but is not limited to, methylol, 2- hydroxyethyl, 2- hydroxyl -1- third Base, 3- hydroxyl -1- propyl, 2,3- dihydroxypropyl etc..
Term " halogenated alkyl " indicates alkyl group replaced one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to ,-CHF2、-CF3、-CHFCH2F、-CF2CHF2、- CH2CF3、-CHFCH3、-CH2CH2F、-CF2CH3、-CH2CF2CHF2Deng.In one embodiment, C1-C6Halogenated alkyl includes fluorine Substituted C1-C6Alkyl；In another embodiment, C1-C4Halogenated alkyl includes fluorine-substituted C1-C4Alkyl；In another implementation In scheme, C1-C2Halogenated alkyl includes fluorine-substituted C1-C2Alkyl.
Term " halogenated alkoxy " indicate alkoxy base replaced one or more halogen atoms, wherein alkoxy base Group has meaning as described in the present invention, and such example includes, but is not limited to ,-OCHF2、-OCF3、-OCHFCH2F、- OCF2CHF2、-OCH2CF3、-OCHFCH3、-OCH2CH2F、-OCF2CH3、-OCH2CF2CHF2Deng.In one embodiment, C1-C6 Halogenated alkoxy includes fluorine-substituted C1-C6Alkoxy；In another embodiment, C1-C4Halogenated alkoxy includes fluorine-substituted C1-C4Alkoxy；In yet another embodiment, C1-C2Halogenated alkoxy includes fluorine-substituted C1-C2Alkoxy.
Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.Bicyclic or three-ring system may include condensed ring, bridged ring and loop coil.In one embodiment, naphthenic base includes that 3-10 carbon is former Son；In another embodiment, naphthenic base includes 3-8 carbon atom；In yet another embodiment, naphthenic base includes 3-6 carbon Atom.The group of naphthene base is optionally replaced one or more substituent groups described in the invention.Group of naphthene base Example further comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..
Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to comprising 3-12 annular atom, non-aromatic The unsaturated monocyclic, bicyclic or tricyclic system of saturation or part of property, wherein described bicyclic or three-ring system may include thick Ring, bridged ring and loop coil.One or more atoms are independently replaced by hetero atom in its middle ring, and the hetero atom has such as this hair The bright meaning.- CH in the heterocycle2Group is optionally substituted by-C (=O)-, and the sulphur atom of ring is optionally by oxygen It is melted into S- oxide, the nitrogen-atoms of ring is optionally oxidized to N- oxygen compound.In one embodiment, heterocycle is 3-8 Annular atom composition monocyclic heterocycles base (2-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, this S or P optionally It is obtained replaced one or more oxygen atoms as SO, SO2, PO, PO2Group), for example, 3-8 circle heterocyclic ring base.The heterocycle Group is optionally replaced one or more substituent groups described in the invention.The annular atom of heterocycle can be carbon-based or miscellaneous Atom base.The example of heterocycle includes, but are not limited to Oxyranyle, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperazine Piperidinyl, morpholinyl, piperazinyl etc..
Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original Molecular ring.Aryl group by the armaticity ring of aryl group with parent molecule in general, but unnecessarily connect.Term " aryl " can be used interchangeably with term " aromatic rings " or " aromatic ring ".The example of aryl group may include phenyl, naphthalene and anthracene Base.The aryl group is optionally replaced one or more substituent groups described in the invention.
Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring system are aromatic, and at least one ring system includes one or more miscellaneous Atom, wherein each ring system includes 5-7 former molecular ring.Heteroaryl groups are in general, but unnecessarily pass through heteroaryl The armaticity ring of base group is connect with parent molecule.Term " heteroaryl " can be with term " hetero-aromatic ring ", " heteroaromatic " or " heteroaryl Compounds of group " is used interchangeably.The heteroaryl groups are optionally replaced one or more substituent groups described in the invention. In one embodiment, heteroaryl is made of 5-10 atom, wherein being independently selected from the miscellaneous original of O, S and N comprising 1,2,3 or 4 Son, for example, 5-10 unit's heteroaryl.The example of heteroaryl groups includes, but is not limited to, furyl, pyrrole radicals, pyridyl group, phonetic Piperidinyl, thienyl etc..
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used to block or protect the functionality of hydroxyl, suitable blocking group includes trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general Carboxyl-protecting group includes-CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy Ylmethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro second Base, etc..Description general for blocking group can refer to document: Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-C8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate；In yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
Any disease of term " treatment " or illness refer to that improving disease or illness (slows down in some of these embodiments Or prevent or mitigate disease or the development of its at least one clinical symptoms).In other embodiments, " treatment " refer to mitigation or Improve at least one body parameter, including the body parameter that may not be discovered by patient.In other embodiments, it " controls Treat " refer in terms of (such as stablizing perceptible symptom) on body or physiologically (such as parameter of stable body) or above-mentioned two Adjust disease or illness.In other embodiments, " treatment " refers to the breaking-out, generation or evil for preventing or delaying disease or illness Change.
Term " preventing " or " prevention " refer to that the reduction for obtaining the risk of disease or obstacle (that is: makes at least one clinical condition of disease Shape stops development in main body, which may face or be inclined in advance in face of this disease, but without undergoing or show The symptom of disease).
Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
Compound shown in formula (I) can exist in a salt form.In one embodiment, the salt refers to and can pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refer to substance or composition must with other ingredients comprising preparation and/or use it The mammal for the treatment of is compatible chemically and/or in toxicology.In another embodiment, the salt, which is not necessarily, pharmaceutically may be used The salt of receiving can be and be used to prepare and/or purify compound shown in formula (I) and/or for separating compound shown in formula (I) The intermediate of enantiomer.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, including compound shown in formula (I) or its individual stereoisomer, isomery The racemic or non-racemic mixture of body or its pharmaceutically acceptable salt or solvate.In one embodiment of the present invention In formula, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally Ground, others treatment and/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al., Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and will lead to not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.It is some suitable Excipients example include lactose, glucose, sucrose, D-sorbite, mannitol, starch, Arabic gum, calcium phosphate, alginic acid Salt, tragacanth, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose.
In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy,Lippincott Williams &Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Well-known technique, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object effect, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of compound, pays close attention to its application and belong to the scope of the present invention.
Suitable pharmaceutically acceptable carrier depends on medicament forms and is known to those skilled in the art.Such as this Used in invention, " pharmaceutically acceptable carrier " includes any and whole solvent and solvent mixture, coating, complexing Agent, solid carrier, dispersion medium, surface active excipient, antibacterium and antifungal, for the isotonic of pharmaceutically active substance And absorption delaying agent and its mixture, these are equally known in the art.
Non-limiting example for pharmaceutically acceptable carrier includes having selected from those of following component: lactose, Gelatin, sugar alcohol (such as starch, mannitol, cornstarch etc.), vegetable oil, talcum, magnesium stearate, colloidal silicon dioxide, carboxylic first Base cellulose, microcrystalline cellulose, sodium dodecyl sulfate, buffered aqueous solution, copolyvidone, polysorbate, ethyl alcohol, propylene glycol, Polyglycols (preferably polyethylene glycol, such as PEG400),(i.e. PEG (20), D-sorbite monooleate), DMSO, The mixture of water and cosolvent, the aqueous solution for example including alcohol such as ethyl alcohol and/or polyglycols such as polyethylene glycol, polyalcohol such as glycerol And/or the ester of polyethylene glycol and fatty acid, surfactant such as anion, cation, nonionic and amphoteric surfactant, network Mixture such as cyclodextrin, such as alpha-cyclodextrin (α-CD) perhaps hydroxypropyl-β-cyclodextrin (HP- β-CD) bile acid or lipid, example Such as animal or the salt of plant phosphatide, at micellar, and oil such as corn oil or two or more aforementioned components is mixed Close object.
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination, the technique include that mixing is each Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix under such as environment temperature and atmospheric pressure to make It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
The compound of the present invention or pharmaceutical composition can be administered in an appropriate manner, for example, by oral cavity, vein It is interior, subcutaneously, intramuscular or intrathecal route.Preferably in oral cavity, enteral or parenteral administration.Most preferably given in oral cavity Medicine.
It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
Term " therapeutically effective amount " used in the present invention refers to each active group for being enough to show beneficial therapeutic effect The total amount divided.For example, being administered or making the amount for the symptom for being enough to treat, curing or mitigating disease for reaching balance in vivo.Special Effective quantity needed for therapeutic scheme depends on many factors, the disease including treatment, the severity of disease, the particular drug used The activity of object, administration mode, the clearance rate of certain drug, duration for the treatment of, drug combination, age, weight, gender, diet With the health of patient etc..This field description as described in " therapeutically effective amount " other factors in need of consideration can be found in Gilman et al.,eds.,Goodman And Gilman’s:The Pharmacological Bases of Therapeutics, 8thed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17th ed.,Mack Publishing Company,Easton,Pa.,1990。
It is administered for convenience and effectively, with effective quantity by compound and suitable pharmaceutically acceptable carrier and optionally Other suitable additives and excipient are come mixed with dosage unit form as described above.The agent of formula (I) compound represented Amount depends on administration route, the age of patient and weight, the property and severity and other factors of disease to be treated.? In various embodiments, daily dose is usually 2-2000mg/d, such as 50-500mg/d.In these ranges, in various embodiment party It is 2,5,10,20,25,50,100,200,250 or 400mg/d and upper limit value for 50 with lower limit value in case, 100,200,250, 500,600,750,1000,1500 and 2000mg/d selects subrange.Lower limit value and upper limit value can be combined to provide conjunction It is for example those of as described above will to depend on various factors for suitable dosage range.Daily dose can be with daily one single dose Amount unit is administered with daily two or more dosage units.
Term " administration " shows individual and provides the drug of therapeutically effective amount, and administration mode includes oral, sublingual, vein, skin Under, it is percutaneously, intramuscular, it is intradermal, it is intrathecal, on dura mater, intraocularly, and encephalic, sucking, rectum, vagina etc..Form of administration includes paste, is washed Agent, tablet, capsule, pill, dustability powder agent, granule, suppository, sublimed preparation, pastille, injection, sterile solution or non-aqueous Solution, suspending agent, emulsion, patch agent etc..Active component and nontoxic pharmaceutically acceptable carrier (such as glucose, lactose, Gum arabic, gelatin, mannitol, gelatinized corn starch, magnesium trisilicate, talcum powder, cornstarch, keratin, silica gel, potato starch, Urea, dextran etc.) it is compound.
The compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be with once dailies, or according to administration Scheme, at the appointed time in section, doses at intervals is several times in different times.For example, be administered once a day, twice, three times or Four times.In addition, the appropriate dosage regimen of the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention, including implementing should The duration of scheme, depending on treated disease, the severity of disease being treated, the age of patient under consideration and body Situation, the medical history of patient under consideration while property, desired therapeutic effect of therapy etc. are in technical staff's knowledge and experience model Enclose interior factor.
The compounds of this invention can be administered simultaneously, or before it or later with one or more other therapeutic agents.This hair Bright compound can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with same pharmaceutical composition Form administration.This is selected by those skilled in the art according to the actual conditions of the bodies such as the health of patient, age, weight.If Be formulated as fixed dosage, this combination product using the compound of the present invention (within dosage range described in the invention) and Other forms of pharmacologically active agents (within its dosage range).
Correspondingly, in one aspect, the present invention includes drug combination comprising a certain number of at least one of the invention Compound or pharmaceutically acceptable salt thereof, solvate, ester or pro-drug and a effective amount of one or more above-mentioned additional therapeutic agents.
Formula (I) compound represented can with for preventing, treating or mitigating the applicable disease of formula (I) compound represented Or the other medicines combination of symptom.These other medicines can be same with formula (I) compound represented by its common approach and amount When or in succession administration.When formula (I) compound represented and one or more other medicines are simultaneously in use, contain this kind of other medicines The pharmaceutical unit dosage forms of object and formula (I) compound represented are preferred.
In various embodiments, heretofore described compound provides in conjunction with other medicines for Parkinson's disease Or the combination therapy of other situations.Pharmaceutical composition of the invention includes heretofore described selective adenosine A2AReceptor antagonist The example of at least one of agent and additional therapeutic agent, additional therapeutic agent includes but is not limited to:
(1) monoamine oxidase B type inhibitor such as selegiline and Rasagiline；
(2) dopamine agonist such as bromocriptine, Cabergoline, pergolide, Pramipexole, Ropinirole and rotigotine (rotigotine)；
(3) anticholinergic drug such as benzhexol (trihexphenidyl), benzatropine, Orphenadrine and procyclidine；
(4) glutamate antagonist such as amantadine；
(5) levodopa is (optionally in conjunction with following substance: carboxylase inhibitor such as carbidopa and benserazide, COMT Inhibitor such as Tolcapone and Entacapone or both carboxylase inhibitor and COMT inhibitor).
In addition, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is When administering to a patient, the functional derivatives of the compounds of this invention can be finally released in vivo.This hair is given with prodrug forms When bright compound, one of implementable following manner of those skilled in the art or more: the internal action of compound (a) is changed Time；(b) the internal acting duration of compound is changed；(c) the internal conveying or distribution of compound are changed；(d) modification Close the internal solubility of object；And the side effect or other difficult points for (e) overcoming compound to be faced.It is used to prepare the typical of prodrug Functional derivatives, comprising in vivo chemically or the variant of compound that cracks of the mode of enzyme.Comprising prepare phosphate, Amide, ester, monothioester, carbonate and carbaminate these variants be well-known to those skilled in the art.
The purposes of the compounds of this invention and pharmaceutical composition
Compound provided by the invention and pharmaceutical composition can be used for preparing for Adenosine A2AThe drug of receptor, can also To be used to prepare for preventing, treating or mitigating and adenosine A2AThe relevant disease of receptor, the especially drug of Parkinson's disease.
Specifically, the amount of compound effectively can be selected detectably in the compound of the present invention or pharmaceutical composition Property ground Adenosine A2AReceptor.
The compound of the present invention can be applied to, but be not limited to, and use the compound of the present invention or pharmaceutical composition Effective quantity administers to a patient to prevent, treat or mitigate and adenosine A2AThe relevant disease of receptor.Described and adenosine A2AReceptor phase The disease of pass further comprises but is not limited to, Parkinson's disease, pain, depression, dementia, apoplexy, myocardial ischemia, asthma, ring Wine, dyskinetic syndrome, restless legs syndrome, dystonia, catalepsy, neurodegenerative disorders or osteoporosis.It is excellent Selection of land, the compound of the present invention is for preventing, treating or mitigating Parkinson's disease and/or dyskinesia.
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.
The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy is recorded using 400 MHz of Bruker or 600 MHz nuclear magnetic resonance spectrometers.1H H NMR spectroscopy is with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0 ppm) or chloroform (7.26 ppm) as reference Standard.When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), brs (broadened singlet, wide is unimodal), dd (doublet of doublets, double doublet), ddd (doublet of Doublet of doublets, in pairs doublet), and ddt (doublet of doublet of triplets, it is triple in pairs Peak), dt (doublet of triplets, double triplets), dq (doublet of quartets, double quartets), td (triplet of doublets, three doublets), tt (triplet of triplets, three triplets), qd (quartet of Doublets, four doublets).Coupling constant J is indicated with hertz (Hz).
The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-MS of Agilent (column model: 30 mm of Zorbax SB-C18,2.1 x, 3.5 microns, 6 min, flow velocity is 0.6 mL/min.Mobile phase: 5%-95% (contains The CH of 0.1% formic acid3CN) in (H containing 0.1% formic acid2O the ratio in), using electrospray ionisation (ESI), in 210 nm/254 Under nm, detected with UV.
Pure compound uses 1260 pre-HPLC or Calesep pump of Agilent, 250 pre-HPLC (pillar type Number: NOVASEP 50/80mm DAC), detected in 210 nm/254 nm with UV.
The use of logogram word below is through the present invention:
CDC13Mg milligrams of deuterated chloroform
G grams of DMSO dimethyl sulfoxide
DMSO-d6Kg kilograms of deuterated dimethyl sulfoxide
CH3ML, ml milliliters of OH, MeOH methanol
H2O water μ L, μ l microlitres
HCOONH4Ammonium formate nL, nl nanoliter
FA formic acid s seconds
NM, nmol/L nanomole every liter of min minutes
μM, μm ol/L micromole every liter of h hours
MM, mmol/L mMs of every liter of EDTA-K2 EDTAP dipotassium ethylene diamine tetraacetates
M, mol/L moles of every liter of cAMP cyclic adenosine monophosphate
Mmol mMs of PEG400 polyethylene glycol 400
Ng nanogram DMA DMAC N,N' dimethyl acetamide
μ g microgram Saline physiological saline
PBS phosphate buffer saline, phosphate buffered saline solution
HBSS Hank's Balanced Salt Solution, Hank's balanced salt solution
HATU 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphate
NECA (2S,3S,4R,5S)-5-(6-amino-9H-purin-9-yl)-N-ethyl-3,4- dihydroxytetrahydrofuran-2-car boxamide、C12H16N6O4Adenosine Receptor stimulating agent, 5- (N- ethyl carboxamide base)-adenosine
Following intermediate preparation method and synthetic schemes describe the step of preparation disclosed compound of present invention, unless in addition Illustrate, wherein R0And R3With definition of the present invention.L is leaving group, such as F, Cl, Br, I.RxFor H, D, F, Cl, Br, I, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkane sulphur Base, C1-C6The C that alkylamino, hydroxyl replace1-C6Alkyl or-O-R0。
Synthetic schemes 1
Formula (9) compound represented can be prepared by following process: formula (1) compound represented and formula (2) institute The compound shown react to obtain formula (3) shown in product；Formula (3) compound represented react to obtain with malonic acid formula (4) shown in Product；Formula (4) compound represented and formula (5) shown in compound reaction, obtain formula (6) shown in product；Then formula (6) institute The compound cyclization shown obtain formula (7) shown in product.Formula (7) compound represented and formula (8) shown in compound react to obtain Formula (9) shown in product.
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1 (E) -1,3- diethyl -8- (3- (2- methoxy ethoxy) styryl) -7- methyl-1 H- purine - The synthesis of 2,6 (3H, 7H)-diketone
The synthesis of step 1) 2- methoxy ethyl 4- oluene sulfonic acides ester
Paratoluensulfonyl chloride (3.0g, 15.7mmol) and triethylamine (6.65mL, 47.2mmol) are added at 25 DEG C In 100mL single-necked flask, it is added methylene chloride (10mL), then be added dropwise to ethylene glycol monomethyl ether (1.56g, 20.46mmol), is further continued for Reaction 12 hours；It is added water (40mL), adds methylene chloride (20mL), liquid separation, collect organic phase, decompression is spin-dried for, column chromatography Isolate and purify (petrol ether/ethyl acetate (v/v)=10/1~5/1) obtain title compound be colourless liquid (3.52g, 97.1%).
MS(ESI,pos.ion)m/z:231.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.78 (d, J=8.2Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 4.14–4.12(m,2H),3.56–3.54(m,2H),3.28(s,3H),2.42(s,3H).
The synthesis of step 2) 3- (2- methoxy ethoxy) benzaldehyde
By m-hydroxybenzaldehyde (1.5g, 12.3mmol), 2- methoxy ethyl 4- oluene sulfonic acides ester (3.4g, It 14.7mmol) is added in 100mL single necked round bottom flask, is added potassium carbonate (3.4g, 24.6mmol), oil bath with DMF (10mL) It is reacted 14 hours at 100 DEG C；Water (50mL) is added to be quenched, adds ethyl acetate (30mL), liquid separation, collects organic phase, decompression It is spin-dried for, it is yellow oil that column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=8/1), which obtains title compound, (1.7g, 77%).
MS(ESI,pos.ion)m/z:181.2[M+H]+.
The synthesis of step 3) (E) -3- (3- (2- methoxy ethoxy) phenyl) acrylic acid
By 3- (2- methoxy ethoxy) benzaldehyde (1.7g, 9.4mmol), malonic acid (2.0g, 19.2mmol), pyridine (10mL) is added in 100mL single necked round bottom flask, and 115 DEG C of oil bath are reacted 5 hours.It is cooled to room temperature after reaction, it will be anti- It answers liquid to pour into water (50mL), hydrochloric acid is added and adjusts pH=2, adds methylene chloride (30mL), liquid separation, collects organic phase, subtracts Pressure is spin-dried for obtaining title compound being white solid (1.8g, 86%).
MS(ESI,pos.ion)m/z:223.2[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm) 7.55 (d, J=16.0Hz, 1H), 7.29 (dt, J=25.8, 7.6Hz, 3H), 6.99 (d, J=7.9Hz, 1H), 6.56 (d, J=16.0Hz, 1H), 4.18-4.09 (m, 2H), 3.73-3.61 (m,2H),3.42(s,3H).
Step 4) (E)-N- (6- amino -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- The synthesis of (3- (2- methoxy ethoxy) phenyl) acrylamide
By (E) -3- (3- (2- methoxy ethoxy) phenyl) acrylic acid (470mg, 2.11mmol) and dichloromethane at 0 DEG C Alkane (20mL) is added in 100mL single necked round bottom flask, be added DIPEA (0.9mL, 5mmol) and HATU (805mg, 2.11mmol), continue to stir half an hour；Then 5,6- diaminostilbene, -2,4 (1H, 3H)-diketone of 3- diethyl yl pyrimidines is added (350mg, 1.76mmol) is transferred at 25 DEG C and reacts 2 hours.It being added water (30mL), liquid separation, collects organic phase, decompression is spin-dried for, It is white solid (0.5g, 70.4%) that column chromatographic purifying (methylene chloride/methanol (v/v)=20/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:403.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.84 (s, 1H), 7.58 (d, J=15.6Hz, 1H), 7.26 (d, J= 7.9Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 7.05 (s, 1H), 6.97-6.91 (m, 1H), 6.69 (d, J=15.6Hz, 1H), 5.78 (s, 2H), 4.18-4.12 (m, 2H), 3.98 (q, J=6.0Hz, 4H), 3.80-3.75 (m, 2H), 3.47 (s, 3H), 1.32 (t, J=7.2Hz, 3H), 1.21 (t, J=7.0Hz, 3H)
Step 5) (E) -1,3- diethyl -8- (3- (2- methoxy ethoxy) styryl) -1H- purine -2,6 (3H, The synthesis of 7H)-diketone
By (E)-N- (6- amino -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- (3- (2- Methoxy ethoxy) phenyl) acrylamide (500mg, 1.24mmol) and methanol (5mL) is added to 50mL single necked round bottom flask In, water (5mL) and sodium hydroxide (500mg, 12.5mmol) is then added, continues to be stirred to react 7 hours at 70 DEG C of oil bath；Stop Reaction, decompression are spin-dried for, and water (20mL) is added, and then addition hydrochloric acid is neutralized to pH=2, and it is white that filtration drying, which obtains title compound, Color solid (0.4g, 82.7%).
MS(ESI,pos.ion)m/z:385.1[M+H]+.
Step 6) (E)-1,3- diethyl-8- (3- (2- methoxy ethoxy) styryl) purine-2-7- methyl-1 H-, The synthesis of 6 (3H, 7H)-diketone
By (E) -1,3- diethyl -8- (3- (2- methoxy ethoxy) styryl) -1H- purine -2,6 at 0 DEG C (3H, 7H)-diketone (400mg, 1.04mmol) and DMF (10mL) are added in 100mL single necked round bottom flask, and sodium hydride is added (80mg, 2.0mmol) is stirred to react after ten minutes, is added iodomethane (300mg, 2.11mmol), is transferred to 25 DEG C and continues to stir Reaction 2 hours；Stop reaction, be added water (30mL), ethyl acetate extracts (50mL), liquid separation, and organic phase decompression is spin-dried for, column chromatography It is white solid (0.34g, 85.3%) that purifying (petrol ether/ethyl acetate (v/v)=5/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:399.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm) 7.75 (d, J=15.7Hz, 1H), 7.32 (t, J=7.7Hz, 1H), 7.19 (d, J=7.4Hz, 1H), 7.16 (s, 1H), 6.95 (d, J=7.6Hz, 1H), 6.91 (d, J=15.7Hz, 1H), 4.25- 4.20(m,2H),4.18(brs,2H),4.12–4.08(m,2H),4.06(s,3H),3.79(brs,2H),3.48(s,3H), 1.39 (t, J=6.7Hz, 3H), 1.27 (t, J=6.3Hz, 3H)
Embodiment 2 (E) -1,3- diethyl -8- (4- (2- methoxy ethoxy) styryl) -7- methyl-1 H- purine - The synthesis of 2,6 (3H, 7H)-diketone
The synthesis of step 1) 4- (2- methoxy ethoxy) benzaldehyde
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- methoxy ethyl 4- oluene sulfonic acides ester (2.07g, 9.0mmol) and parahydroxyben-zaldehyde (1.0g, 8.2mmol) the reaction system in DMF (10mL) Standby, it is transparent that crude product, which obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=10/1), Grease (1.4g, 94.7%).
MS(ESI,pos.ion)m/z:181.2[M+H]+.
The synthesis of step 2) (E) -3- (4- (2- methoxy ethoxy) phenyl) acrylic acid
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 4- (2- methoxyl group Ethyoxyl) benzaldehyde (1.4g, 7.8mmol), malonic acid (2.44g, 23.4mmol) reaction preparation in pyridine (5mL) are thick to produce It is yellow oil that object, which obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=4/1), (1.01g, 58.3%).
MS(ESI,pos.ion)m/z:223.2[M+H]+.
Step 3) (E)-N- (6- amino -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- The synthesis of (4- (2- methoxy ethoxy) phenyl) acrylamide
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 5,6- diamino- - 2,4 (1H, 3H)-diketone (0.6g, 3.03mmol) of 1,3- diethyl yl pyrimidines, (E) -3- (4- (2- methoxy ethoxy) phenyl) Acrylic acid (900mg, 4.05mmol), HATU (1.8g, 4.5mmol) and DIPEA (2.7mL, 15.4mmol) are in methylene chloride Reaction preparation, crude product obtain title through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) in (10mL) Compound is yellow solid (0.65g, 72.2%).
MS(ESI,pos.ion)m/z:403.2[M+H]+.
Step 4) (E) -1,3- diethyl -8- (4- (2- methoxy ethoxy) styryl) -1H- purine -2,6 (3H, The synthesis of 7H)-diketone
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by (E)-N- (6- ammonia Base -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- (4- (2- methoxy ethoxy) phenyl) third Acrylamide (500mg, 1.24mmol) and sodium hydroxide (200mg, 5.0mmol) the reaction system in methanol (6mL) and water (3mL) Standby, crude product obtains title compound through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) and consolidates for yellow Body (0.45g, 92.2%).
MS(ESI,pos.ion)m/z:385.3[M+H]+.
Step 5) (E)-1,3- diethyl-8- (4- (2- methoxy ethoxy) styryl) purine-2-7- methyl-1 H-, The synthesis of 6 (3H, 7H)-diketone
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (E) -1,3- diethyl Base -8- (4- (2- methoxy ethoxy) styryl) -1H- purine -2,6 (3H, 7H)-diketone (450mg, 1.17mmol), iodine The reaction preparation in DMF (5mL) of methane (443mg, 3.12mmol) and sodium hydride (50mg, 1.25mmol), crude product is through silica gel Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=3/1) obtain title compound be white solid (0.35g, 75.0%).
MS(ESI,pos.ion)m/z:399.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.75 (d, J=15.7Hz, 1H), 7.54 (d, J=8.5Hz, 2H), 6.97 (d, J=8.5Hz, 2H), 6.79 (d, J=15.7Hz, 1H), 4.28-4.20 (m, 2H), 4.21-4.16 (m, 2H), 4.10 (q, J=7.1Hz, 2H), 4.06 (s, 3H), 3.89-3.70 (m, 2H), 3.48 (s, 3H), 1.39 (t, J=7.0Hz, 3H), 1.27(s,3H).
Embodiment 3 (E) -8- (bis- (2- methoxy ethoxy) styryls of 3,4-) -1,3- diethyl -7- methyl-1 H- is fast The synthesis of purine -2,6 (3H, 7H)-diketone
The synthesis of bis- (2- methoxy ethoxy) benzaldehydes of step 1) 3,4-
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- methoxy ethyl 4- oluene sulfonic acides ester (1.83g, 7.96mmol) and 3,4- 4-dihydroxy benzaldehyde (1.0g, 7.2mmol) are anti-in DMF (10mL) It should prepare, crude product obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=10/1) and is Yellow solid (1.78g, 96.7%).
MS(ESI,pos.ion)m/z:255.0[M+H]+.
The synthesis of step 2) (E) -3- (bis- (2- methoxy ethoxy) phenyl of 3,4-) acrylic acid
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by bis- (the 2- first of 3,4- Oxygroup ethyoxyl) benzaldehyde (1.8g, 7.1mmol), malonic acid (2.24g, 21.5mmol) and piperidines (0.6mL) be in DMF Reaction preparation, crude product are marked through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=2/1) in (10mL) Topic compound is yellow oil (1.81g, 86.1%).
MS(ESI,pos.ion)m/z:297.2[M+H]+.
Step 3) (E)-N- (6- amino -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- The synthesis of (bis- (2- methoxy ethoxy) phenyl of 3,4-) acrylamide
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 5,6- diamino- - 2,4 (1H, 3H)-diketone (0.6g, 3.03mmol) of 1,3- diethyl yl pyrimidines, (E) -3- (bis- (2- methoxy ethoxy) benzene of 3,4- Base) acrylic acid (500mg, 1.69mmol), HATU (0.8g, 2.1mmol) and DIPEA (1.3mL, 7.7mmol) be in methylene chloride Reaction preparation, crude product obtain title through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) in (10mL) Compound is yellow solid (0.62g, 77.1%).
MS(ESI,pos.ion)m/z:477.4[M+H]+.
Step 4) (E) -1,3- diethyl -8- (bis- (2- methoxy ethoxy) styryls of 3,4-) -1H- purine -2,6 The synthesis of (3H, 7H)-diketone
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by (E)-N- (6- ammonia Base -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- (bis- (2- methoxy ethoxy) benzene of 3,4- Base) reaction in methanol (6mL) and water (3mL) of acrylamide (0.6g, 1.26mmol) and sodium hydroxide (200mg, 5.0mmol) Preparation, crude product obtain title compound through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) as Huang Color solid (0.41g, 69.6%).
MS(ESI,pos.ion)m/z:459.1[M+H]+.
Step 5) (E) -1,3- diethyl -8- (bis- (2- methoxy ethoxy) styryls of 3,4-) -7- methyl-1 H- is fast The synthesis of purine -2,6 (3H, 7H)-diketone
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (E) -1,3- diethyl Base -8- (bis- (2- methoxy ethoxy) styryls of 3,4-) -1H- purine -2,6 (3H, 7H)-diketone (0.4g, 0.87mmol), The reaction preparation in DMF (5mL) of iodomethane (0.37g, 2.62mmol) and sodium hydride (68mg, 1.7mmol), crude product is through silica gel Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=3/1), obtain title compound be yellow solid (0.35g, 85%).
MS(ESI,pos.ion)m/z:473.1[M+H]+.
Embodiment 4 (E) -1,3- diethyl -8- (4- methoxyl group -3- (2- methoxy ethoxy) styryl) -7- methyl - The synthesis of 1H- purine -2,6 (3H, 7H)-diketone
The synthesis of step 1) 4- methoxyl group -3- (2- methoxy ethoxy) benzaldehyde
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- methoxy ethyl 4- oluene sulfonic acides ester (2.73g, 11.9mmol), potassium carbonate (4.47g, 32.3mmol) and 3- hydroxyl -4-methoxybenzaldehyde (1.64g, 10.8mmol) reaction preparation in DMF (10mL), crude product is through silica gel column chromatography separating purification (petroleum ether/acetic acid Ethyl ester (v/v)=10/1), obtaining title compound is light yellow oil (2.0g, 88.3%).
MS(ESI,pos.ion)m/z:211.2[M+H]+.
The synthesis of step 2) (E) -3- (4- methoxyl group -3- (2- methoxy ethoxy) phenyl) acrylic acid
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by (4- methoxyl group -3- (2- methoxy ethoxy) benzaldehyde (2.1g, 10mmol), malonic acid (3.12g, 29.96mmol) are in pyridine (2.4mL) and DMF Reaction preparation, crude product are marked through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=4/1) in (20mL) Topic compound is light yellow oil (1.53g, 61%).MS(ESI,pos.ion)m/z:253.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.71 (d, J=15.9Hz, 1H), 7.15 (d, J=7.7Hz, 2H), 6.89 (d, J=8.1Hz, 1H), 6.32 (d, J=15.9Hz, 1H), 4.29-4.15 (m, 2H), 3.91 (s, 3H), 3.87-3.77 (m,2H),3.47(s,3H).
Step 3) (E)-N- (6- amino -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- The synthesis of (4- methoxyl group -3- (2- methoxy ethoxy) phenyl) acrylamide
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 5,6- diamino- - 2,4 (1H, 3H)-diketone (1.0g, 5.04mmol) of 1,3- diethyl yl pyrimidines, (E) -3- (4- methoxyl group -3- (2- methoxyl group ethoxy Base) phenyl) acrylic acid (1.5g, 5.9mmol), HATU (2.26g, 5.94mmol) and DIPEA (3.2mL, 18.3mmol) be two Reaction preparation in chloromethanes (10mL), crude product through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1), Obtaining title compound is yellow solid (2g, 91.7%).
MS(ESI,pos.ion)m/z:433.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.63-7.48 (m, 2H), 7.15-7.05 (m, 2H), 6.85 (d, J= 8.3Hz, 1H), 6.58 (d, J=15.5Hz, 1H), 4.24-4.18 (m, 2H), 3.98 (q, J=6.9Hz, 4H), 3.90 (d, J= 5.6Hz, 3H), 3.84-3.78 (m, 2H), 3.47 (s, 3H), 1.33 (t, J=7.2Hz, 3H), 1.21 (t, J=7.0Hz, 3H)
Step 4) (E) -1,3- diethyl -8- (4- methoxyl group -3- (2- methoxy ethoxy) styryl) -1H- purine - The synthesis of 2,6 (3H, 7H)-diketone
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by (E)-N- (6- ammonia Base -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- (4- methoxyl group -3- (2- methoxyl group ethoxy Base) phenyl) acrylamide (766mg, 1.77mmol) and sodium hydroxide (213mg, 5.33mmol) be in methanol (6mL) and water Reaction preparation, crude product are marked through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) in (2mL) Topic compound is yellow solid (0.41g, 56%).
MS(ESI,pos.ion)m/z:415.1[M+H]+；
1H NMR(400MHz,DMSO-d6) δ (ppm) 7.58 (d, J=16.3Hz, 1H), 7.28 (s, 1H), 7.14 (d, J= 8.3Hz, 1H), 7.0 (d, J=8.0Hz, 1H), 6.95 (d, J=16.0Hz, 1H), 4.21-4.12 (m, 2H), 4.06 (q, J= 6.8Hz, 2H), 3.93 (q, J=6.7Hz, 2H), 3.80 (s, 3H), 3.73-3.64 (m, 2H), 3.33 (s, 3H), 1.26 (t, J =7.0Hz, 3H), 1.13 (t, J=6.9Hz, 3H)
Step 5) (E) -1,3- diethyl -8- (4- methoxyl group -3- (2- methoxy ethoxy) styryl) -7- methyl - The synthesis of 1H- purine -2,6 (3H, 7H)-diketone
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (E) -1,3- diethyl Base -8- (4- methoxyl group -3- (2- methoxy ethoxy) styryl) -1H- purine -2,6 (3H, 7H)-diketone (410mg, 0.99mmol), iodomethane (0.28g, 2.0mmol) and sodium hydride (80mg, 2.0mmol) the reaction preparation in DMF (10mL), slightly For product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=3/1), obtaining title compound is white solid (0.347g, 82%).
MS(ESI,pos.ion)m/z:429.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.72 (d, J=15.7Hz, 1H), 7.19 (d, J=8.5Hz, 2H), 6.90 (d, J=8.1Hz, 1H), 6.76 (d, J=15.7Hz, 1H), 4.27-4.18 (m, 4H), 4.13-4.08 (m, 2H), 4.06 (s, 3H), 3.91 (s, 3H), 3.85-3.80 (m, 2H), 3.48 (s, 3H), 1.39 (t, J=7.1Hz, 3H), 1.27 (t, J= 7.0Hz,3H).
Embodiment 5 (E) -1,3- diethyl -8- (3- methoxyl group -4- (2- methoxy ethoxy) styryl) -7- methyl - The synthesis of 1H- purine -2,6 (3H, 7H)-diketone
The synthesis of step 1) 3- methoxyl group -4- (2- methoxyl group ethoxy) benzaldehyde
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- methoxy ethyl 4- oluene sulfonic acides ester (2.07g, 9.0mmol), potassium carbonate (2.24g, 16.2mmol) and 3-methoxy-4-hydroxybenzaldehyde (1.0g, 6.57mmol) reaction preparation in DMF (10mL), crude product is through silica gel column chromatography separating purification (petroleum ether/acetic acid second Ester (v/v)=10/1), obtaining title compound is colorless oil (1.18g, 85.4%).
MS(ESI,pos.ion)m/z:211.2[M+H]+.
The synthesis of step 2) (E) -3- (3- methoxyl group -4- (2- methoxy ethoxy) phenyl) acrylic acid
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by (3- methoxyl group -4- (2- methoxy ethoxy) benzaldehyde (1.18g, 5.61mmol), malonic acid (2.1g, 20.2mmol) in pyridine (2.0mL) and Reaction preparation, crude product are obtained through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=4/1) in DMF (10mL) It is white solid (1.25g, 88.3%) to title compound.
MS(ESI,pos.ion)m/z:253.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.73 (d, J=16.0Hz, 1H), 7.17 (d, J=7.9Hz, 2H), 6.90 (d, J=8.0Hz, 1H), 6.33 (d, J=15.9Hz, 1H), 4.31-4.16 (m, 2H), 3.92 (s, 3H), 3.88-3.77 (m,2H),3.46(s,3H).
Step 3) (E)-N- (6- amino -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- The synthesis of (3- methoxyl group -4- (2- methoxy ethoxy) phenyl) acrylamide
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 5,6- diamino- - 2,4 (1H, 3H)-diketone (0.6g, 3.2mmol) of 1,3- diethyl yl pyrimidines, (E) -3- (3- methoxyl group -4- (2- methoxyl group ethoxy Base) phenyl) acrylic acid (1.0g, 3.96mmol), HATU (1.5g, 3.96mmol) and DIPEA (3.2mL, 18.3mmol) be two Reaction preparation in chloromethanes (10mL), crude product through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1), Obtaining title compound is yellow solid (0.85g, 61.3%).
MS(ESI,pos.ion)m/z:433.1[M+H]+.
Step 4) (E) -1,3- diethyl -8- (3- methoxyl group -4- (2- methoxy ethoxy) styryl) -1H- purine - The synthesis of 2,6 (3H, 7H)-diketone
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by (E)-N- (6- ammonia Base -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- (3- methoxyl group -4- (2- methoxyl group ethoxy Base) phenyl) acrylamide (0.8g, 1.85mmol) and sodium hydroxide (300mg, 7.5mmol) be in methanol (6mL) and water (2mL) Middle reaction preparation, crude product obtain title compound through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) Object is yellow solid (0.71g, 97.3%).
MS(ESI,pos.ion)m/z:415.4[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.70 (d, J=15.7Hz, 1H), 7.66 (d, J=1.8Hz, 1H), 7.42 (dd, J=8.5,1.8Hz, 1H), 6.99 (d, J=8.5Hz, 1H), 6.80 (d, J=15.7Hz, 1H), 4.25 (d, J= 4.5Hz, 2H), 4.20 (d, J=7.1Hz, 2H), 4.14-4.09 (m, 2H), 4.07 (s, 3H), 3.87-3.82 (m, 2H), 3.51 (s, 3H), 1.39 (t, J=7.0Hz, 3H), 1.29 (d, J=7.1Hz, 3H)
Step 5) (E) -1,3- diethyl -8- (3- methoxyl group -4- (2- methoxy ethoxy) styryl) -7- methyl - The synthesis of 1H- purine -2,6 (3H, 7H)-diketone
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (E) -1,3- diethyl Base -8- (3- methoxyl group -4- (2- methoxy ethoxy) styryl) -1H- purine -2,6 (3H, 7H)-diketone (0.7g, 1.69mmol), iodomethane (0.28g, 2.0mmol) and sodium hydride (80mg, 2.0mmol) the reaction preparation in DMF (10mL), slightly For product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=3/1), obtaining title compound is yellow solid (0.62g, 88.5%).
MS(ESI,pos.ion)m/z:429.2[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.72 (d, J=15.9Hz, 1H), 7.17 (d, J=8.1Hz, 2H), 6.91 (d, J=8.3Hz, 1H), 6.77 (d, J=15.7Hz, 1H), 4.27-4.19 (m, 4H), 4.14-4.09 (m, 2H), 4.06 (s, 3H), 3.93 (s, 3H), 3.87-3.81 (m, 2H), 3.49 (s, 3H), 1.38 (t, J=7.0Hz, 3H), 1.27 (t, J= 7.0Hz,3H).
Embodiment 6 (E) -1,3- diethyl -8- (the fluoro- 4- of 3- (2- methoxy ethoxy) styryl) -7- methyl-1 H- The synthesis of purine -2,6 (3H, 7H)-diketone
The synthesis of the fluoro- 4- of step 1) 3- (2- methoxy ethoxy) benzaldehyde
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- methoxy ethyl 4- oluene sulfonic acides ester (1.8g, 7.82mmol), potassium carbonate (2.49g, 17.8mmol) and the fluoro- 4- hydroxy benzaldehyde of 3- (1.0g, 7.14mmol) the reaction preparation in DMF (10mL), crude product is through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/ V)=10/1), obtaining title compound is faint yellow solid (1.4g, 99%).
MS(ESI,pos.ion)m/z:199.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 9.85 (d, J=1.9Hz, 1H), 7.62-7.58 (m, 2H), 7.10 (t, J =8.2Hz, 1H), 4.28-4.26 (m, 2H), 3.82-3.80 (m, 2H), 3.46 (s, 3H)
The synthesis of step 2) (E) -3- (the fluoro- 4- of 3- (2- methoxy ethoxy) phenyl) acrylic acid
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 3- fluoro- 4- (2- first Oxygroup ethyoxyl) benzaldehyde (1.4g, 7.06mmol), malonic acid (2.21g, 21.19mmol) is in pyridine (3.5mL) and DMF Reaction preparation, crude product are marked through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=4/1) in (10mL) Topic compound is faint yellow solid (0.918g, 54.07%).
MS(ESI,pos.ion)m/z:241.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.66 (d, J=16.0Hz, 1H), 7.30 (d, J=12.0Hz, 1H), 7.24 (s, 1H), 6.99 (t, J=8.4Hz, 1H), 6.30 (d, J=15.9Hz, 1H), 4.24-4.22 (m, 2H), 3.81-3.78 (m,2H),3.46(s,3H).
Step 3) (E)-N- (6- amino -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- The synthesis of (the fluoro- 4- of 3- (2- methoxy ethoxy) phenyl) acrylamide
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 5,6- diamino- - 2,4 (1H, 3H)-diketone (0.3g, 1.6mmol) of 1,3- diethyl yl pyrimidines, (E) -3- (the fluoro- 4- of 3- (2- methoxy ethoxy) benzene Base) acrylic acid (0.4g, 1.67mmol), HATU (0.551g, 1.41mmol) and DIPEA (1.35mL, 7.67mmol) be in dichloro Reaction preparation, crude product are obtained through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in methane (10mL) It is faint yellow solid (0.45g, 83.7%) to title compound.
MS(ESI,pos.ion)m/z:421.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.81 (s, 1H), 7.49 (d, J=15.5Hz, 1H), 7.22-7.17 (m, 2H), 6.94 (t, J=8.4Hz, 1H), 6.55 (d, J=15.5Hz, 1H), 5.71 (s, 2H), 4.21-4.19 (m, 2H), 3.99- 3.95 (m, 4H), 3.79-3.76 (m, 2H), 3.45 (s, 3H), 1.31 (t, J=7.2Hz, 3H), 1.18 (t, J=7.0Hz, 3H).
Step 4) (E) -1,3- diethyl -8- (the fluoro- 4- of 3- (2- methoxy ethoxy) styryl) -1H- purine -2,6 The synthesis of (3H, 7H)-diketone
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by (E)-N- (6- ammonia Base -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- (the fluoro- 4- of 3- (2- methoxy ethoxy) benzene Base) acrylamide (0.45g, 1.07mmol) and sodium hydroxide (500mg, 11.9mmol) be anti-in methanol (6mL) and water (3mL) It should prepare, through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1), obtain title compound is crude product White solid (0.396g, 91.9%).
MS(ESI,pos.ion)m/z:403.3[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm)13.54(s,1H),7.59(s,1H),7.55(s,1H),7.37(d,J =8.5Hz, 1H), 7.21 (t, J=8.7Hz, 1H), 6.95 (d, J=16.4Hz, 1H), 4.23-4.21 (m, 2H), 4.06 (q, J =6.9Hz, 2H), 3.93 (q, J=6.9Hz, 2H), 3.70-3.68 (m, 2H), 3.32 (s, 3H), 1.26 (t, J=7.0Hz, 3H), 1.14 (t, J=7.0Hz, 3H)
Step 5) (E) -1,3- diethyl -8- (the fluoro- 4- of 3- (2- methoxy ethoxy) styryl) -7- methyl-1 H- is fast The synthesis of purine -2,6 (3H, 7H)-diketone
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (E) -1,3- diethyl Base -8- (the fluoro- 4- of 3- (2- methoxy ethoxy) styryl) -1H- purine -2,6 (3H, 7H)-diketone (0.39g, 0.97mmol), iodomethane (0.121mL, 1.93mmol) and sodium hydride (39mg, 0.98mmol) the reaction system in DMF (10mL) Standby, crude product obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=2/1) as white Solid (0.354g, 87.7%).
MS(ESI,pos.ion)m/z:417.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.67 (d, J=15.7Hz, 1H), 7.33 (dd, J=12.1,1.7Hz, 1H), 7.25 (d, J=7.7Hz, 1H), 6.99 (t, J=8.5Hz, 1H), 6.75 (d, J=15.7Hz, 1H), 4.20 (dt, J= 14.1,5.9Hz,4H),4.10–4.06(m,2H),4.04(s,3H),3.80–3.77(m,2H),3.45(s,3H),1.36(t,J =7.1Hz, 3H), 1.25 (t, J=7.0Hz, 3H)
Embodiment 7 (E) -1,3- diethyl -8- (the chloro- 4- of 3- (2- methoxy ethoxy) styryl) -7- methyl-1 H- The synthesis of purine -2,6 (3H, 7H)-diketone
The synthesis of the chloro- 4- of step 1) 3- (2- methoxy ethoxy) benzaldehyde
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by 2- methoxy ethyl 4- oluene sulfonic acides ester (1.8g, 7.82mmol), cesium carbonate (4.16g, 12.77mmol) and 3- chloro-4-hydroxyl benzaldehyde (1.0g, 6.38mmol) reaction preparation in DMF (10mL), crude product is through silica gel column chromatography separating purification (petroleum ether/acetic acid second Ester (v/v)=10/1), obtaining title compound is light yellow oil (0.65g, 47%).
MS(ESI,pos.ion)m/z:215.1[M+H]+.
The synthesis of step 2) (E) -3- (the chloro- 4- of 3- (2- methoxy ethoxy) phenyl) acrylic acid
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 3- chloro- 4- (2- first Oxygroup ethyoxyl) benzaldehyde (0.65g, 3.0mmol), malonic acid (0.47g, 4.5mmol) reaction system in pyridine (6.0mL) Standby, crude product obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=4/1) as white Solid (0.68g, 87%).
MS(ESI,pos.ion)m/z:257.0[M+H]+.
Step 3) (E)-N- (6- amino -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- The synthesis of (the chloro- 4- of 3- (2- methoxy ethoxy) phenyl) acrylamide
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 5,6- diamino- - 2,4 (1H, 3H)-diketone (0.35g, 1.8mmol) of 1,3- diethyl yl pyrimidines, (E) -3- (chloro- 4- of 3- (2- methoxy ethoxy) Phenyl) acrylic acid (0.6g, 2.33mmol), HATU (0.8g, 2.05mmol) and DIPEA (1.35mL, 7.67mmol) be in dichloro Reaction preparation, crude product are obtained through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in methane (10mL) It is yellow solid (0.55g, 71%) to title compound.
MS(ESI,pos.ion)m/z:437.1[M+H]+.
Step 4) (E) -1,3- diethyl -8- (the chloro- 4- of 3- (2- methoxy ethoxy) styryl) -1H- purine -2,6 The synthesis of (3H, 7H)-diketone
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by (E)-N- (6- ammonia Base -1,3- diethyl -2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- base) -3- (the chloro- 4- of 3- (2- methoxy ethoxy) benzene Base) reaction in methanol (6mL) and water (3mL) of acrylamide (0.5g, 1.14mmol) and sodium hydroxide (400mg, 10mmol) Preparation, crude product obtain title compound through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1) as Huang Color solid (0.385g, 80.3%).
MS(ESI,pos.ion)m/z:419.2[M+H]+.
Step 5) (E) -1,3- diethyl -8- (the chloro- 4- of 3- (2- methoxy ethoxy) styryl) -7- methyl-1 H- is fast The synthesis of purine -2,6 (3H, 7H)-diketone
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (E) -1,3- diethyl Base -8- (the chloro- 4- of 3- (2- methoxy ethoxy) styryl) -1H- purine -2,6 (3H, 7H)-diketone (0.35g, 0.84mmol), iodomethane (0.12mL, 1.9mmol) and sodium hydride (40mg, 1.0mmol) the reaction preparation in DMF (5mL), slightly For product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=2/1), obtaining title compound is white solid (0.28g, 77%).
MS(ESI,pos.ion)m/z:433.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm) 7.70 (d, J=15.7Hz, 1H), 7.66 (d, J=1.8Hz, 1H), 7.42 (dd, J=8.5,1.8Hz, 1H), 6.99 (d, J=8.5Hz, 1H), 6.80 (d, J=15.7Hz, 1H), 4.25 (t, J= 4.5Hz, 2H), 4.20 (q, J=7.1Hz, 2H), 4.14-4.09 (m, 2H), 4.07 (s, 3H), 3.87-3.82 (m, 2H), 3.51 (s, 3H), 1.39 (t, J=7.0Hz, 3H), 1.29 (d, J=7.1Hz, 3H)
Biologic test
Embodiment A: evaluation the compounds of this invention is to people's adenosine A2AThe antagonism of receptor
Experimental method
Experimental system uses people's recombinant adenosine A2AReceptor, stabilization are expressed in HEK-293 cell line.HEK-293 is inoculated in training It supports in plate, density is 1.25 × 105cell/ml.Modified HBSS solution is replaced medium to, pH 7.4 is added different The test compound and solvent (PBS containing 0.1%DMSO) of concentration, 37 DEG C of incubation 10min test the concentration difference of compound Are as follows: 10 μM, 1 μM, 0.1 μM, 10nM, 1nM, 0.1nM.Using cAMP (cyclic adenosine monophosphate) in TR-FRET method detection culture medium Concentration.Using NECA as positive control drug, (1) first exclusive use test compound stimulation cell generates a certain amount of for this experiment CAMP, (0.1 μM) stimulation cell of NECA is then used alone again and also generates a certain amount of cAMP.If test chemical combination is used alone Object stimulate cell generate cAMP amount be higher than be used alone (0.1 μM) of NECA stimulation cell generate cAMP amount 50%, then this Test compound is considered to have adenosine A2AReceptor agonist activity.(2) all cells first use test compound incubation cell again Cell is stimulated with NECA (3nM), NECA (3nM) stimulation cell is in addition used alone and generates a certain amount of cAMP, if test chemical combination The amount that object is incubated for the cAMP generated again with the cell of NECA (3nM) stimulation is generated lower than NECA (3nM) stimulation cell is used alone The 50% of the amount of cAMP, i.e. test compound then illustrate this test to amount inhibiting rate >=50% of NECA (3nM) cAMP generated Compound has adenosine A2AThe antagonism of receptor.IC50Using MathIQTM(ID Business Solutions Ltd., UK it) is got by non-linear, least square method regression equation analytical calculation.Experimental result is shown in Table As.
Table A: the compounds of this invention is to people's adenosine A2AThe antagonism experimental result of receptor
Example No. IC50(μM)
Embodiment 1 5.0
Embodiment 2 3.3
Embodiment 3 3.2
Embodiment 4 3.8
Embodiment 5 3.1
Embodiment 6 2.81
Experimental result shows that the compounds of this invention has stronger adenosine A2AThe antagonism of receptor.
Embodiment B: Pharmacokinetic Evaluation of the rat after intravenous or stomach-filling quantify the compounds of this invention
(1) animal subject
Animal subject is rat, and concrete condition is as shown in table 1:
Table 1
Germline Grade Gender Weight Week old Source
SD rat Cleaning grade Male 180~220g 8 weeks Changzhou Cavan this
(2) analysis method
The LC-MS/MS system of analysis includes the serial vacuum degassing machine of Agilent 1200, quaternary pump, and orifice plate is adopted automatically Sample device, thermostatted column compartment, the triple level four bars mass spectrographs of the API4000Qtrap of charged spray ionization source (ESI).Quantitative analysis exists It is carried out under MRM mode, wherein the source parameter of MRM conversion is as shown in table 2:
Table 2
Gas curtain gas/CUR: 30psi
Atomization gas/GS1: 55psi
Auxiliary heating gas/GS2: 60psi
Ion transmits voltage/IS: 5000V
Atomization temperature/TEM: 500℃
Analysis uses the Waters ACQUITY UPLC CSH μm column of C18,2.1 × 50mm, 1.7, injects 0.8 μ L sample. Analysis condition: mobile phase H2O+2mM HCOONH4(ammonium formate)+0.1%FA (formic acid) (mobile phase A) and MeOH (methanol)+ 2mMHCOONH4(ammonium formate)+0.1%FA (formic acid) (Mobile phase B).Flow velocity is 0.7mL/min.Column temperature is 40 DEG C, mobile phase ladder Degree is as shown in table 3:
Table 3
Time The gradient of Mobile phase B
0.4min 10%
0.6min 95%
1.6min 95%
1.61min 10%
2.50min Stop
(3) experimental method
The intracorporal pharmcokinetic evaluation of rat is carried out to the compounds of this invention, the specific steps are as follows:
Experiment is divided into two groups: one groups by intravenous injection administration, and one group passes through gastric infusion.By the compounds of this invention with The form of 10%DMA (heating)+60%PEG400+30%Saline solution is administered animal subject (fasting 12h overnight). For be injected intravenously administration group, dosage 1mg/kg, then time point upon administration be 0.083,0.25,0.5,1.0, 2.0,5.0,7.0 and for 24 hours when venous blood sampling (0.3mL), anti-coagulants EDTA-K2 is added into blood, and 3,000 or 4, It is centrifuged 10 minutes under 000rpm, collects plasma solutions, and save at -20 DEG C or -70 DEG C.For gastric infusion group, medicament is given Amount be 5mg/kg, then time point upon administration be 0.25,0.5,1.0,2.0,5.0,7.0 and for 24 hours when venous blood sampling (0.3mL) anti-coagulants EDTA-K2 is added into blood, and is centrifuged 10 minutes at 3,000 or 4,000rpm, and it is molten to collect blood plasma Liquid, and saved at -20 DEG C or -70 DEG C.
20 μ L blood plasma are taken, 120 μ L IS working solutions, vortex 2min is added.Then by the mixed solution in 12,000rpm item 2min is centrifuged under part.100 μ L supernatants are taken, 110 μ L MeOH/H are added2After O (v/v=1/1), vortex 2min, 5 μ L sample introductions are taken LC-MS/MS system.Using the concentration of LC-MS/MS method detection target compound, medicine is calculated for power using non-compartment model Learn parameter.Analysis the result shows that, the compounds of this invention in rat body have preferable pharmacokinetic property.
Embodiment C: Pharmacokinetic Evaluation of the mouse/dog after intravenous or stomach-filling quantify the compounds of this invention
(1) animal subject: animal subject is mouse and/or dog, and concrete condition is as shown in table 4:
Table 4
Germline Grade Gender Quantity Weight Week old Source
ICR mouse Cleaning grade Male 6 18-22g 8 weeks Changzhou Cavan this
Beasle dog Regular grade Male 4 6-8kg The 6-8 month Beijing Ma Si biotech firm
(2) analysis method:
The LC/MS/MS system of analysis includes the serial vacuum degassing machine of Agilent 1200, quaternary pump, and orifice plate is adopted automatically Sample device, thermostatted column compartment, the triple level four bars mass spectrographs of the API4000Qtrap of charged spray ionization source (ESI).Quantitative analysis exists It is carried out under MRM mode, wherein the source parameter of MRM conversion is as shown in table 5:
Table 5
Gas curtain gas/CUR: 20psi
Atomization gas/GS1: 60psi
Auxiliary heating gas/GS2: 70psi
Ion transmits voltage/IS: 4500V
Atomization temperature/TEM: 550℃
Analysis uses waters xbridge C18UPLC, 2.1x 50mm, and 3.5 μM of columns inject 0.5 μ L sample.Analyze item Part: mobile phase H2O+2mM HCOONH4(ammonium formate)+0.1%FA (formic acid) (mobile phase A) and MeOH (methanol)+2mM HCOONH4(ammonium formate)+0.1%FA (formic acid) (Mobile phase B).Flow velocity is 0.7mL/min.Eluent gradient is as shown in table 6:
Table 6
Time The gradient of Mobile phase B
0.3min 20%
0.7min 95%
1.8min 95%
1.81min 20%
2.8min Stop
(3) test method
1) the intracorporal pharmcokinetic evaluation of mouse is carried out to the compounds of this invention, the specific steps are as follows:
Experiment is divided into two groups: one groups by intravenous injection administration, and one group passes through gastric infusion.By the compounds of this invention with The form of 10%DMA+60%PEG400+30%Saline solution is administered animal subject.For being injected intravenously administration group, Dosage is 2mg/kg, and then time point upon administration is 0.083,0.25,0.5,1.0,2.0,5.0,7.0 and 24 hour When venous blood sampling (0.3mL), and be centrifuged 10 minutes at 3,000 or 4,000rpm, collect plasma solutions (anti-coagulants EDTA- K2 it), and at -20 DEG C or -70 DEG C saves.For gastric infusion group, dosage 5mg/kg, then time upon administration Venous blood sampling (0.3mL) when point is 0.083,0.25,0.5,1.0,2.0,5.0,7.0 and 24 hour, and 3,000 or 4, It is centrifuged 10 minutes, collects plasma solutions (anti-coagulants EDTA-K2), and saved at -20 DEG C or -70 DEG C under 000rpm.
10 μ L blood plasma are taken, 130 μ L IS working solutions, vortex 5min is added.Then mixed solution under the conditions of 4000rpm from Heart 5min.100 μ L supernatants are taken, 150 μ L H are added2After O, vortex 2min, 2.5 μ L sample introduction LC-MS/MS systems are taken.Using LC- MS/MS method detects the concentration of target compound, calculates pharmacokinetic parameter using non-compartment model.Analysis the result shows that, The compounds of this invention has preferable pharmacokinetic property in Mice Body.
2) the intracorporal pharmcokinetic evaluation of beasle dog is carried out to the compounds of this invention, the specific steps are as follows:
Experiment is divided into two groups: one groups by intravenous injection administration, and one group passes through gastric infusion.By the compounds of this invention with The form of 10%DMA+60%PEG400+30%Saline solution is administered animal subject.For being injected intravenously administration group, Dosage is 1mg/kg, and then time point upon administration is 0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 Hour when venous blood sampling (0.3mL), and be centrifuged 10 minutes at 3,000 or 4,000rpm, (anti-coagulants is collection plasma solutions EDTA-K2 it), and at -20 DEG C or -70 DEG C saves.For gastric infusion group, dosage 5mg/kg, then upon administration Time point venous blood sampling (0.3mL) when being 0.25,0.5,1.0,2.0,5.0,7.0 and 24 hour, and 3,000 or 4, It is centrifuged 10 minutes, collects plasma solutions (anti-coagulants EDTA-K2), and saved at -20 DEG C or -70 DEG C under 000rpm.
10 μ L blood plasma are taken, 120 μ L IS working solutions, vortex 2min is added.Then mixed solution under the conditions of 12000rpm from Heart 2min.80 μ L supernatants are taken, 140 μ L methanol solution (methanol: H are added2O=1:1), after vortex 2min, 1.0 μ L sample introductions are taken LC-MS/MS system.Using the concentration of LC-MS/MS method detection target compound, medicine is calculated for power using non-compartment model Learn parameter.The experimental results showed that the compounds of this invention has preferable pharmacokinetic property in beasle dog body.
In the description of this specification, reference term " one embodiment ", " embodiment ", " some embodiments ", " show The description of example ", specific examples or " some examples " etc. means to combine the specific spy of the embodiment, embodiment or example description Sign, structure, material or feature are contained at least one embodiment of the present invention, embodiment or example.In this specification In, schematic expression of the above terms are necessarily directed to identical embodiment, embodiment or example.Moreover, description Particular features, structures, materials, or characteristics can be in any one or more embodiments, embodiment or example with suitable Mode combines.In addition, without conflicting with each other, those skilled in the art can be by difference described in this specification Embodiment, embodiment or example and different embodiments, embodiment or exemplary feature are combined.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (10)

1. a kind of compound, the stereoisomer for being compound shown in formula (I) compound represented or formula (I), mutually variation Structure body, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein:
R1、R2And R3It is each independently H, D, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, hydroxyl replace C1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Aryl or 5-10 unit's heteroaryl；
R4、R5And R8It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2、- C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy) ,-OC (=O)- (C1-C6Alkyl), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Haloalkoxy Base, C1-C6Alkylthio group, C1-C6The C that alkylamino, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Aryl Or 5-10 unit's heteroaryl；
R9And R10It is each independently H, D, F, Cl, Br, I, C1-C6Alkyl or C1-C6Halogenated alkyl；
R6For-O-R0, R7For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy) ,-OC (=O)-(C1-C6Alkane Base), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6 Alkylthio group, C1-C6The C that alkylamino, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Aryl, 5-10 member Heteroaryl or-O-R0；Or
R6For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (= O)N(CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy) ,-OC (=O)-(C1-C6Alkyl), C1-C6Alkane Base, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6 The C that alkylamino, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Aryl or 5-10 unit's heteroaryl, R7 For-O-R0；
R0For-(CRaRb)nORc；
RaAnd RbIt is each independently H, D, F, Cl, Br, I, C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4It is halogenated The C that alkoxy or hydroxyl replace1-C4Alkyl；
RcFor H, D, C1-C6Alkyl, C1-C6The C that halogenated alkyl, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Aryl or 5-10 unit's heteroaryl；
N is 2,3 or 4.
2. compound according to claim 1, wherein R1、R2And R3It is each independently H, D, C1-C4Alkyl, C2-C4Alkene Base, C2-C4Alkynyl, C1-C4The C that halogenated alkyl or hydroxyl replace1-C4Alkyl；
R4、R5And R8It is each independently H, D, F, Cl, Br, I ,-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy) ,-OC (=O)-(C1-C4Alkane Base), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4 Alkylthio group, C1-C4The C that alkylamino or hydroxyl replace1-C4Alkyl；
R9And R10It is each independently H, D, F, Cl, Br, I, C1-C4Alkyl or C1-C4Halogenated alkyl.
3. compound according to claim 1 or 2, wherein R1、R2And R3It is each independently H, D, methyl, ethyl, positive third Base, isopropyl, allyl, acrylic, propargyl or propinyl；
R4、R5And R8It is each independently H, D, F, Cl, Br ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-CH3,-C (=O)-OCH3,-OC (=O) CH3,-OC (=O) CH2CH3, it is methyl, ethyl, n-propyl, different Propyl, allyl, acrylic, propargyl, propinyl ,-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、- CH2CF2CHF2, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、-OCF3、-OCHFCH2F、- OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol or 2- Hydroxyethyl；
R9And R10It is each independently H, D, F, Cl, Br, methyl or ethyl.
4. compound according to claim 1 to 3, wherein R6For-O-R0, R7For H, D, F, Cl, Br, I ,- NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy) ,-OC (=O)-(C1-C4Alkyl), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4It is halogenated Alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4The C that alkylamino, hydroxyl replace1-C4Alkyl or- O-R0；Or
R6For H, D, F, Cl, Br, I ,-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy) ,-OC (=O)-(C1-C4Alkyl), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkane The C that amino or hydroxyl replace1-C4Alkyl, R7For-O-R0。
5. compound according to any one of claims 1-4, wherein R6For-O-R0, R7For H, D, F, Cl, Br, I, first Base, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propinyl ,-CHF2、-CF3、-CHFCH2F、- CF2CHF2、-CH2CF3、-CH2CF2CHF2, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、-OCF3、- OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2, methyl mercapto, ethylmercapto group or-O-R0；Or
R6For H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propinyl ,- CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl Oxygroup ,-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2, methyl mercapto or ethylmercapto group, R7For- O-R0。
6. compound described in -5 any one according to claim 1, wherein RaAnd RbBe each independently H, D, methyl, ethyl, N-propyl or isopropyl；
RcFor H, D, C1-C4Alkyl, C1-C4The C that halogenated alkyl or hydroxyl replace1-C4Alkyl.
7. compound described in -6 any one according to claim 1, wherein RaAnd RbIt is each independently H, D, methyl or second Base；
RcFor H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxymethyl or hydroxyethyl.
8. compound described in -7 any one according to claim 1 for the compound with one of following structure or has The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug:
9. a kind of pharmaceutical composition includes compound described in claim 1-8 any one；With
The pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or their times Meaning combination.
10. compound described in claim 1-8 any one or pharmaceutical composition as claimed in claim 9 are in medicine preparation Purposes, the drug is for preventing, treating or mitigating and adenosine A2AThe relevant disease of receptor；
Described in wherein and adenosine A2AThe relevant disease of receptor be Parkinson's disease, pain, depression, dementia, apoplexy, myocardial ischemia, Asthma, abstinence from alcohol, dyskinetic syndrome, restless legs syndrome, dystonia, catalepsy, neurodegenerative disorders or sclerotin are dredged Loose disease.
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CN110981876A (en) * 2018-12-21 2020-04-10 广东东阳光药业有限公司 8-substituted styrylxanthine derivatives and uses thereof
CN110981876B (en) * 2018-12-21 2021-10-01 广东东阳光药业有限公司 8-substituted styrylxanthine derivatives and uses thereof
CN111333648A (en) * 2019-04-24 2020-06-26 东莞市东阳光新药研发有限公司 8-substituted aromatic ring vinyl xanthine derivative and application thereof
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CN111333648B (en) * 2019-04-24 2021-05-11 东莞市东阳光新药研发有限公司 8-substituted aromatic ring vinyl xanthine derivative and application thereof
CN112409360A (en) * 2019-08-22 2021-02-26 广东东阳光药业有限公司 Heteroaryl vinyl xanthine derivatives and uses thereof
CN112409360B (en) * 2019-08-22 2022-12-23 广东东阳光药业有限公司 Heteroaryl vinyl xanthine derivatives and uses thereof
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CN111072663A (en) * 2019-12-12 2020-04-28 广东东阳光药业有限公司 8-substituted styrylxanthine derivatives and uses thereof
CN115884973A (en) * 2020-03-10 2023-03-31 奇迹生物技术公司 Purine compounds for the treatment of diseases
WO2022174351A1 (en) * 2021-02-19 2022-08-25 Marvel Biotechnology Purine compounds for treating disorders
WO2023097402A1 (en) * 2021-12-03 2023-06-08 Marvel Biotechnology Purine compounds for treating disorders

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