CN110041331B - Styrylxanthine derivative and use thereof - Google Patents

Styrylxanthine derivative and use thereof Download PDF

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CN110041331B
CN110041331B CN201910412716.5A CN201910412716A CN110041331B CN 110041331 B CN110041331 B CN 110041331B CN 201910412716 A CN201910412716 A CN 201910412716A CN 110041331 B CN110041331 B CN 110041331B
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CN110041331A (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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Sunshine Lake Pharma Co Ltd
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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

Abstract

The invention discloses styryl xanthine derivatives and application thereof, and particularly relates to novel styryl xanthine derivatives and pharmaceutical compositions containing the same, which can be used as selective adenosine A2AA receptor antagonist. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in therapy with adenosine A2AThe use in the preparation of medicaments for the treatment of receptor-related diseases, in particular Parkinson's disease.

Description

Styrylxanthine derivative and use thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to novel styryl xanthine derivatives, a pharmaceutical composition containing the compounds, and a using method and application of the novel styryl xanthine derivatives. In particular, the novel styrylxanthine derivatives of the present invention are useful as selective adenosine A2AReceptor antagonists for the prevention, treatment or alleviation of adenosine A2AA receptor-associated disease, in particular parkinson's disease.
Background
Parkinson's Disease (PD) is a common chronic degenerative disease of the nervous system, also called parkinsonism, and is common in the elderly, with the average age of about 60 years and the onset of juvenile Parkinson's disease below 40 years being rare. The prevalence rate of PD in people over 65 years old in China is about 1.7%. Most parkinson's disease patients are sporadic cases, with less than 10% of patients having a family history. Parkinson's disease begins with an insidious course and progresses slowly. The first symptoms are often tremors or awkward movements in one limb and further involvement in the contralateral limb. Clinically, the symptoms are static tremor, bradykinesia, muscular rigidity and gait disorder. In recent years, people pay more attention to non-motor symptoms such as depression, constipation and sleep disorder, which are also common complaints of Parkinson patients, and the influence of the non-motor symptoms on the life quality of the patients even exceeds the motor symptoms. PD seriously affects the daily life and social activities of patients, has become a disease that afflicts people and affects the quality of life of millions of people worldwide.
Many of the drugs currently under investigation for PD are primarily directed to the non-dopaminergic system of the basal ganglia, all of which have strong anti-PD activity and do not produce side effects.
The basal ganglia are important subcortical centers that regulate movement. Adenosine A2AReceptor (adenosine A)2Areceptor) is selectively expressed in basal ganglia and is associated with motor behavior, mainly through the regulation of indirect pathways: (1) adenosine A of GABAergic neurons within the striatum2AThe receptor is activated to improve the excitability of GABAergic neurons in striatum, thereby inhibiting lateral GAB of globus pallidusExcitability of a energetic neuron; (2) adenosine A activating striatal GABAergic neuron axon terminals2AThe receptor can promote GABA release and inhibit excitability of GABAergic neurons outside the globus pallidus (Shindou T, Richardson PJ, Mori A et al. Adenosine modulators the structural GABAergic input to the globus pallidus via adenosine A)2Areceptors in rats.NeuroscienceLetters,2003,352(3):167-170.)。
Epidemiological and laboratory studies have shown that adenosine A blockade2AThe receptor can reduce degenerative changes in dopaminergic neurons. Adenosine A2AReceptor antagonists (adenosine A)2Areceptor antagonist) improves PD symptoms while slowing disease progression. Thus, adenosine A2AReceptor antagonists as non-dopamine targets in the basal ganglia may be developed as a novel strategy for the treatment of PD (Pinna A, Wardas J, Simola N, et al. New therapeutics for the treatment of the disease of Parkinson's disease: Adenosine A2Areceptor antagonists[J]L ifeSci,2005,77(26):3259-67.) A number of basic and clinical studies have shown adenosine A2AReceptor antagonists are likely to be a new class of drugs for the treatment of Parkinson's disease. How to look for some adenosine A2AThe medicine with high receptor affinity, good therapeutic effect in vivo and less adverse reaction becomes adenosine A2AAn important topic for the study of receptor antagonists.
Naturally occurring xanthines are the first generation compounds of adenosine receptor antagonists, e.g., caffeine (1,3, 7-caffeine) and theophylline (1, 3-dimethylxanthine, Daly et al, cell. mol. neurobiol.,1983,3, 67.) long known to reverse motor deficiencies in various models of PD and epidemiological investigations suggest that caffeine and theophylline can reduce the incidence of Parkinson's disease, however, studies (Fredholm bb. connection between coffee and coffee production the risk of Parkinson's disease L akartidnin, 2004,101, (34: 2552. Buchner 2555.) found coffee to be a non-selective adenosine a2AReceptor antagonists acting to block adenosine A2AA receptor. They are nonselective and of moderate potency, thus promoting further researchPreparation of Selective adenosine A2AA receptor antagonist.
Adenosine A2AThe receptor antagonist is used as a new medicine for treating PD, has definite effect, safety and better tolerance and has wide application prospect.
Disclosure of Invention
The invention provides a class of adenosine A as selective adenosine2ANovel styrylxanthine derivatives of receptor antagonists useful in therapy with adenosine A2AA receptor-associated disease, in particular for the treatment of parkinson's disease. Experiments show that the styrylxanthine derivative has stable property, good safety, good pharmacodynamics and pharmacokinetic properties, such as good brain/plasma ratio (brain plasma), good bioavailability or good metabolic stability and the like. Therefore, the method has good clinical application prospect.
The invention also provides processes for the preparation of such compounds, pharmaceutical compositions containing them and the use of such compounds and pharmaceutical compositions containing them in the manufacture of medicaments.
In one aspect, the invention relates to a compound of formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,
Figure BDA0002063337660000021
wherein:
R1、R2and R3Each independently is H, D, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, hydroxy-substituted C1-C6Alkyl radical, C3-C8Cycloalkyl, 3-8 membered heterocyclyl, C6-C10Aryl or 5-10 membered heteroaryl;
R4、R5and R8Each independently is 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) - (C)1-C6Alkoxy), -OC (═ O) - (C)1-C6Alkyl group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino, hydroxy-substituted C1-C6Alkyl radical, C3-C8Cycloalkyl, 3-8 membered heterocyclyl, C6-C10Aryl or 5-10 membered heteroaryl;
R9and R10Each independently is H, D, F, Cl, Br, I, C1-C6Alkyl or C1-C6A haloalkyl group;
R6is-O-R0，R7Is 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) - (C)1-C6Alkoxy), -OC (═ O) - (C)1-C6Alkyl group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino, hydroxy-substituted C1-C6Alkyl radical, C3-C8Cycloalkyl, 3-8 membered heterocyclyl, C6-C10Aryl, 5-10 membered heteroaryl or-O-R0(ii) a Or
R6Is 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) - (C)1-C6Alkoxy), -OC (═ O) - (C)1-C6Alkyl group), C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino, hydroxy-substituted C1-C6Alkyl radical, C3-C8Cycloalkyl, 3-8 membered heterocyclyl, C6-C10Aryl or 5-to 10-membered heteroaryl, R7is-O-R0；
R0Is- (CR)aRb)nORc；
RaAnd RbEach independently is H, D, F, Cl, Br, I, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy or hydroxy substituted C1-C4An alkyl group;
Rcis H, D, C1-C6Alkyl radical, C1-C6Haloalkyl, hydroxy-substituted C1-C6Alkyl radical, C3-C8Cycloalkyl, 3-8 membered heterocyclyl, C6-C10Aryl or 5-10 membered heteroaryl;
n is 2,3 or 4.
In some embodiments, R1、R2And R3Each independently is H, D, C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl or hydroxy-substituted C1-C4An alkyl group;
R4、R5and R8Each independently is 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) - (C)1-C4Alkoxy), -OC (═ O) - (C)1-C4Alkyl group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylamino or hydroxy substituted C1-C4An alkyl group;
R9and R10Each independently is H, D, F, Cl, Br, I, C1-C4Alkyl or C1-C4A haloalkyl group.
In some embodiments, R1、R2And R3Each independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, or propynyl;
R4、R5and R8Each independently is 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)CH2CH3Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, or 2-hydroxyethyl;
R9and R10Each independently is H, D, F, ClBr, methyl or ethyl.
In some embodiments, R6is-O-R0，R7Is 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) - (C)1-C4Alkoxy), -OC (═ O) - (C)1-C4Alkyl group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylamino, hydroxy-substituted C1-C4Alkyl or-O-R0(ii) a Or
R6Is 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) - (C)1-C4Alkoxy), -OC (═ O) - (C)1-C4Alkyl group), C1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Alkylamino or hydroxy substituted C1-C4Alkyl radical, R7is-O-R0；
Wherein R is0Have the meaning as described in the present invention.
In some embodiments, R6is-O-R0，R7Is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylthio, ethylthio or-O-R0(ii) a Or
R6Is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylthio or ethylthio, R7is-O-R0；
Wherein R is0Have the meaning as described in the present invention.
In some embodiments, RaAnd RbEach independently H, D, methyl, ethyl, n-propyl, or isopropyl;
Rcis H, D, C1-C4Alkyl radical, C1-C4Haloalkyl or hydroxy-substituted C1-C4An alkyl group.
In some embodiments, RaAnd RbEach independently H, D, methyl or ethyl;
Rch, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxymethyl or hydroxyethyl.
In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of the compound having one of the following structures:
Figure BDA0002063337660000031
Figure BDA0002063337660000041
in another aspect, the present invention relates to a pharmaceutical composition comprising any one of the compounds described herein; further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
In other embodiments, the pharmaceutical compositions of the present invention further comprise an additional therapeutic agent, wherein the additional therapeutic agent is a monoamine oxidase type B inhibitor, a dopamine agonist, an anticholinergic, a glutamate antagonist, levodopa, or any combination thereof.
In a further aspect, the invention relates to the use of a compound of the invention, or a pharmaceutical composition thereof, for the manufacture of a medicament for the prevention, treatment or alleviation of interactions with adenosine A2AA receptor associated disease.
In some embodiments, the peptide is substituted with adenosine A2AThe receptor-associated disease is parkinson's disease, pain, depression, dementia, stroke, myocardial ischemia, asthma, alcohol withdrawal, dyskinetic syndrome, restless legs syndrome, dystonia, catalepsy, a neurodegenerative disorder or osteoporosis.
In a further aspect, the invention relates to the use of a compound of the invention, or a pharmaceutical composition thereof, for the manufacture of a medicament for antagonizing adenosine A2AA receptor.
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Biological test results show that the compound can antagonize adenosine A2AReceptor, and can be used as a better selective adenosine A2AA receptor antagonist.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.
The term "chiral molecule" is a molecule having the property of not overlapping its mirror image; and "achiral molecule" refers to a molecule that can overlap with its mirror image.
The term "enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers, which mixture lacks optical activity.
The term "diastereomer" refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other, diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, and reactivities.
The stereochemical definitions and rules used herein generally follow the general definition and rules of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Elel, E.and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. many Organic Compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical Enantiomers by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof so obtained the racemic products can also be separated by chiral chromatography, e.g., high performance liquid chromatography (HP L C) using a chiral adsorbentndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.
"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including, but 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, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a particular substituent. Unless otherwise indicated, a substituent may be substituted at any reasonable position in the group that it may be substituted for. When more than one position in a given formula can be substituted with one or more particular substituents selected from the group, then the substituents may be substituted identically or differently at each of the possible positions in the formula.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-C6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "D" denotes a single deuterium atom.
The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
The term "oxo" refers to the group ═ O, used interchangeably with "carbonyl".
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR ' (like NR ' in N-substituted pyrrolidinyl, R ' being a substituent as described herein).
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) And so on.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) 1-propenyl (i.e., propenyl, -CH ═ CH-CH)3) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH)3) And so on.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) And so on.
The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1 to 12 carbon atoms. In one embodiment, the alkylthio group contains 1 to 6 carbon atoms; in another embodiment, the alkylthio group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein. Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH)3) Ethylthio (EtS, -SCH)2CH3) And so on.
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like. The alkylamino group is optionally substituted with one or more substituents described herein.
The term "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.
The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, -CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CHFCH3、-CH2CH2F、-CF2CH3、-CH2CF2CHF2And the like. In one embodiment, C1-C6The haloalkyl group containing a fluorine-substituted C1-C6An alkyl group; in another embodiment, C1-C4The haloalkyl group containing a fluorine-substituted C1-C4An alkyl group; in yet another embodiment, C1-C2The haloalkyl group containing a fluorine-substituted C1-C2An alkyl group.
The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, examples of which include, but are not limited to, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCHFCH3、-OCH2CH2F、-OCF2CH3、-OCH2CF2CHF2And the like. In one embodiment, C1-C6Haloalkoxy comprises fluorine substituted C1-C6An alkoxy group; in another embodiment, C1-C4Haloalkoxy comprises fluorine substituted C1-C4An alkoxy group; in yet another embodiment, C1-C2Haloalkoxy comprises fluorine substituted C1-C2An alkoxy group.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl group is optionally substituted with one or more substituents described herein. Examples of cycloalkyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system can include fused, bridged, and spiro rings. Wherein one or more atoms of the ring are independently replaced by a heteroatom having the meaning as described herein. -CH in said heterocyclyl2The group is optionally replaced by-C (═ O) -, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxide. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 8 ring atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give compounds like SO, SO2，PO，PO2The group of (b), for example, a 3-to 8-membered heterocyclic group. The heterocyclyl group is optionally substituted with one or more substituents described herein. The ring atoms of the heterocyclic group may be carbon-based or heteroatom-based. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, and the like.
The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.
The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group consists of 5 to 10 atoms, including 1,2,3, or 4 heteroatoms independently selected from O, S, and N, e.g., a 5-to 10-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, furyl, pyrrolyl, pyridyl, pyrimidinyl, thienyl, and the like.
The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl groupsAcetyl, benzoyl and benzyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene et al, Protective Groups in organic Synthesis, John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salt" refers to the compound of the inventionOrganic and inorganic salts of the compounds. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8Sulphonates and aromaticsA sulfonate compound.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.
The term "treating" any disease or condition, in some embodiments refers to ameliorating the disease or condition (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).
Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed within the scope of the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
The compounds of formula (I) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt need not be a pharmaceutically acceptable salt, and may be an intermediate useful in the preparation and/or purification of a compound of formula (I) and/or in the isolation of an enantiomer of a compound of formula (I).
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable salts.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
pharmaceutical compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or an individual stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic and/or prophylactic ingredients.
Suitable carriers, adjuvants and Excipients are well known to those skilled in The art and are described in detail, for example, in Ansel H.C. et al, Ansel's Pharmaceutical delivery Forms and Drug delivery systems (2004) L ippincott, Williams & Wilkins, Philadelphia, Gennaro A.R.et al, Remington: The Science and Practice of Pharmacy (2000) L ippincott, Williams & Wilkins, Philadelphia, and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
Various carriers for The preparation of pharmaceutically acceptable compositions, and known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, &lTtTtranslation = L "&gTtL &lTt/T &gTtippincott Williams & Wilkins, Philadelphia, and Encyclopedia of pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, Mardecekker, New York, The contents of each of which are incorporated herein by reference.
Suitable pharmaceutically acceptable carriers depend on the pharmaceutical form and are known to the person skilled in the art. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents and solvent mixtures, coatings, complexing agents, solid carriers, dispersion media, surface active excipients, antibacterial and antifungal agents, isotonic and absorption delaying agents for pharmaceutically active substances, and mixtures thereof, which are also known in the art.
Non-limiting example packages for pharmaceutically acceptable carriersIncluding those having a composition selected from the group consisting of: lactose, gelatin, sugar alcohols (e.g. starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, colloidal silicon dioxide, carboxymethylcellulose, microcrystalline cellulose, sodium lauryl sulfate, aqueous buffered solutions, copovidone, polysorbates, ethanol, propylene glycol, polyglycols (preferably polyethylene glycols, such as PEG400),
Figure BDA0002063337660000111
(i.e., PEG (20), sorbitol monooleate), DMSO, a mixture of water and a co-solvent, for example, an aqueous solution comprising an alcohol such as ethanol and/or a polyglycol such as polyethylene glycol, an ester of a polyol such as glycerol and/or polyethylene glycol with a fatty acid, a surfactant such as an anionic, cationic, nonionic and amphoteric surfactant, a complexing agent such as a cyclodextrin, for example α -cyclodextrin (α -CD) or hydroxypropyl- β -cyclodextrin (HP- β -CD), a bile acid or lipid, for example a salt of an animal or vegetable phospholipid, a micellizing agent, and an oil such as corn oil, or a mixture of two or more of the aforementioned components.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack publishing company).
Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
The compounds or pharmaceutical compositions of the invention may be administered in a suitable manner, for example, by the buccal, intravenous, subcutaneous, intramuscular or intrathecal routes. Oral, enteral or parenteral administration is preferred. Most preferred is oral administration.
It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.
The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate symptoms of the disease is administered or allowed to equilibrate in vivo. The effective amount required for a particular treatment regimen will depend on a variety of factors including the condition being treated, the severity of the condition, the activity of the particular drug employed, the mode of administration, the clearance rate of the particular drug, the duration of the treatment, the drug combination, the age, body weight, sex, diet and patient health, etc. Other factors that may be considered in The art for a "therapeutically effective amount" are described in Gilman et al, eds., Goodman And Gilman's: The pharmaceutical Bases of Therapeutics,8thed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17thed.,MackPublishing Company,Easton,Pa.,1990。
For convenient and effective administration, the compounds are compounded in an effective amount with suitable pharmaceutically acceptable carriers and optionally other suitable additives and excipients in dosage unit form as described above. The dosage of the compound of formula (I) depends on the route of administration, the age and weight of the patient, the nature and severity of the disease to be treated, and other factors. In various embodiments, the daily dose is typically from 2 to 2000mg/d, such as from 50 to 500 mg/d. Within these ranges, in various embodiments, sub-ranges are selected having a lower limit of 2, 5, 10, 20, 25, 50, 100, 200, 250, or 400mg/d and an upper limit of 50, 100, 200, 250, 500, 600, 750, 1000, 1500, and 2000 mg/d. The lower and upper values may be combined to give suitable dosage ranges, which will depend on various factors such as those described above. The daily dose may be administered in one single dosage unit per day or in two or more dosage units per day.
The term "administering" refers to providing a therapeutically effective amount of a drug to an individual by means including oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. The administration forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pellets, troches, injections, sterile or non-aqueous solutions, suspensions, emulsions, patches and the like. The active ingredient is compounded with non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, pulvis Talci, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).
The compounds of the invention or pharmaceutical compositions comprising the compounds of the invention may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In addition, the appropriate dosage regimen, including the duration of the regimen, of the compound of the invention or of the pharmaceutical composition containing the compound of the invention depends on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan.
The compounds of the present invention may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition. This is selected by the person skilled in the art according to the physical circumstances of the patient, such as health, age, weight, etc. If formulated as a fixed dose, such combination products employ the compounds of the present invention (within the dosage ranges described herein) and the other pharmaceutically active agents (within their dosage ranges).
Accordingly, in one aspect, the present invention includes a combination comprising an amount of at least one compound of the present invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more of the additional therapeutic agents described above.
The compounds of formula (I) may be used in combination with other drugs useful in the prevention, treatment or alleviation of the diseases or conditions for which the compounds of formula (I) are indicated. These other drugs may be administered by their usual routes and amounts, simultaneously or sequentially with the compound of formula (I). When the compound of formula (I) is used contemporaneously with one or more other drugs, a pharmaceutical unit dosage form containing such other drugs as well as the compound of formula (I) is preferred.
In various embodiments, the compounds described in the present invention are combined with other drugs to provide a combination therapy for parkinson's disease or other conditions. The pharmaceutical compositions of the invention include a selective adenosine A as described in the invention2AAt least one of a receptor antagonist and an additional therapeutic agent, examples of which include, but are not limited to:
(1) monoamine oxidase type B inhibitors such as selegiline and rasagiline;
(2) dopamine agonists such as bromocriptine, cabergoline, pergolide, pramipexole, ropinirole and rotigotine (rotigotine);
(3) anticholinergics such as trihexyphenidyl (trihexyphenidyl), benztropine, oxyphennadine and propiconazole;
(4) glutamate antagonists such as amantadine;
(5) levodopa (optionally in combination with carboxylase inhibitors such as carbidopa and benserazide, COMT inhibitors such as tolcapone and entacapone or both carboxylase and COMT inhibitors).
In addition, the compounds of the present invention may be administered in the form of a prodrug. In the present invention, a "prodrug" of a compound of the present invention is a functional derivative that, when administered to a patient, is ultimately released in vivo from the compound of the present invention. When administering the compounds of the present invention in prodrug form, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.
Use of the Compounds and pharmaceutical compositions of the invention
The compound and the pharmaceutical composition provided by the invention can be used for preparing antagonistic adenosine A2AThe pharmaceutical product of the receptor can also be used for preparing a medicament for preventing, treating or alleviating the symptoms of adenosine A2AA pharmaceutical product for a receptor-related disease, in particular parkinson's disease.
In particular, the amount of the compound or compounds in the pharmaceutical compositions of the present invention is effective to detectably and selectively antagonize adenosine A2AA receptor.
The compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment or alleviation of adenosine A by administration to a patient of an effective amount of a compound or a pharmaceutical composition of the present invention2AA receptor associated disease. The compound with adenosine A2AReceptor-related diseases further including, but not limited to, Parkinson's disease, pain, depression, dementia, stroke, myocardial ischemia, asthma, alcohol withdrawal, dyskinesiaSympathy, restless legs syndrome, dystonia, catalepsy, neurodegenerative disorders or osteoporosis. Preferably, the compounds of the present invention are used for the prevention, treatment or alleviation of parkinson's disease and/or dyskinesia.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
1H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer.1H NMR Spectrum in CDC13、DMSO-d6、CD3OD or acetone-d6TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), q (quatets, quartets), m (multiplets ), br (broadpededwideams), brs (broadpedsinglets, wideadlets), dd (doublets, ddles of doublets), ddd (doublets ), ddt (doublets of doublets, doublets), dt (doublets of triplets, doublets), dq (doublets of quatts, doublets), td (triplets of doublets, triplets), tt (triplets of triplets, triplets), triplets (quadruplands ). Coupling constant J, expressed in Hertz (Hz).
Low resolution Mass Spectrometry (MS) data was determined using Agilent 6120 quadrupole HP L C-MS (column model: Zorbax SB-C18, 2.1X 30 mm,3.5 microns, 6 min, flow rate 0.6m L/min.Mobile phase: 5% -95% (CH containing 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2O) by electrospray ionization (ESI) at 210 nm/254nm, with UV detection.
Pure compounds were detected by UV at 210 nm/254nm using Agilent 1260 pre-HP L C or Calesep pump 250 pre-HP L C (column model: NOVASEP 50/80mm DAC).
The following acronyms are used throughout the invention:
CDC13deuterated chloroform mg
DMSO dimethyl sulfoxide g
DMSO-d6Kg of deuterated dimethyl sulfoxide
CH3OH, MeOH methanol m L, ml
H2Mu L, mu l microliter of O water
HCOONH4Ammonium formate n L, nl nanoliter
FA formic acid s sec
nM, nmol/L nanomole per liter min
Mu M, mu mol/L micromoles per liter h hours
mM, mmol/L mmol/L EDTA-K2 dipotassium ethylenediaminetetraacetate
M, mol/L mol adenosine cyclophosphate per liter cAMP
mmol of PEG400 polyethylene glycol 400
ng nanogram DMA N, N-dimethylacetamide
Mu g microgram Saline physiological Saline
PBS phosphate buffer saline, phosphate buffered saline
HBSS Hank's Balanced Salt Solution, Hank's Balanced Salt Solution
HATU 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
NECA (2S,3S,4R,5S)-5-(6-amino-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-car boxamide、C12H16N6O4Adenosine receptor agonists, 5- (N-ethylcarboxamido) -adenosine
The following intermediate preparation schemes and synthetic schemes describe the steps for preparing the presently disclosed compounds, wherein R is, unless otherwise indicated0And R3Having the definition given in the present invention L is a leaving group, e.g. F, Cl, Br, I.RxIs H, D, F, Cl, Br, I, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylthio radical, C1-C6Alkylamino, hydroxy-substituted C1-C6Alkyl or-O-R0。
Synthesis scheme 1
Figure BDA0002063337660000151
Formula (A), (B) and9) The compound shown can be prepared by the following steps: formula (A), (B) and1) A compound of the formula2) The compound shown in the formula (I) is reacted to obtain3) The product shown; formula (A), (B) and3) Reacting the compound with malonic acid to obtain a compound of the formula (A)4) The product shown; formula (A), (B) and4) A compound of the formula5) The compound is reacted to obtain the compound of the formula (A)6) The product shown; then formula (A), (B), (C), (6) The compound is closed to obtain a compound of the formula (A)7) The products shown. Formula (A), (B) and7) A compound of the formula8) The compound is reacted to obtain the compound of the formula (A)9) The products shown.
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
Examples
Example 1 Synthesis of (E) -1, 3-diethyl-8- (3- (2-methoxyethoxy) styryl) -7-methyl-1H-purine-2, 6(3H,7H) -dione
Figure BDA0002063337660000152
Step 1) Synthesis of 2-methoxyethyl 4-methylbenzenesulfonate
P-toluenesulfonyl chloride (3.0g,15.7mmol) and triethylamine (6.65m L, 47.2mmol) were added to a 100m L single-neck flask at 25 ℃, dichloromethane (10m L) was added, ethylene glycol monomethyl ether (1.56g,20.46mmol) was further added dropwise, the reaction was continued for 12 hours, water (40m L) was added, dichloromethane (20m L) was further added, liquid separation was performed, the organic phase was collected, spin-dried under reduced pressure, and purification by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1-5/1) gave the title compound as a colorless liquid (3.52g, 97.1%).
MS(ESI,pos.ion)m/z:231.1[M+H]+；
1H NMR(400MHz,CDCl3)(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).
Step 2) Synthesis of 3- (2-methoxyethoxy) benzaldehyde
M-hydroxybenzaldehyde (1.5g,12.3mmol), 2-methoxyethyl 4-methylbenzenesulfonate (3.4g,14.7mmol) and DMF (10m L) were charged into a 100m L single neck round bottom flask, potassium carbonate (3.4g,24.6mmol) was added, the mixture was subjected to an oil bath at 100 ℃ for 14 hours, quenched with water (50m L), added with ethyl acetate (30m L), separated, the organic phase collected, dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8/1) to give the title compound as a yellow oil (1.7g, 77%).
MS(ESI,pos.ion)m/z:181.2[M+H]+.
Step 3 Synthesis of) (E) -3- (3- (2-methoxyethoxy) phenyl) acrylic acid
3- (2-methoxyethoxy) benzaldehyde (1.7g,9.4mmol), malonic acid (2.0g,19.2mmol) and pyridine (10m L) were charged into a 100m L single neck round bottom flask, and reacted in an oil bath at 115 ℃ for 5 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, poured into water (50m L), added with hydrochloric acid to adjust pH to 2, and then added with dichloromethane (30m L), separated, collected in an organic phase, and dried under reduced pressure to give the title compound as a white solid (1.8g, 86%).
MS(ESI,pos.ion)m/z:223.2[M+H]+；
1H NMR(400MHz,DMSO-d6)(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-tetrahydropyrimidin-5-yl) -3- Synthesis of (3- (2-methoxyethoxy) phenyl) acrylamide
(E) -3- (3- (2-methoxyethoxy) phenyl) acrylic acid (470mg,2.11mmol) and dichloromethane (20m L) were charged at 0 ℃ into a 100m L single neck round bottom flask, DIPEA (0.9m L, 5mmol) and HATU (805mg,2.11mmol) were added and stirring continued for half an hour, then 5, 6-diamino-1, 3-diethylpyrimidine-2, 4(1H,3H) -dione (350mg,1.76mmol) was added and transferred to 25 ℃ for reaction for 2 hours, water (30m L) was added and the organic phase was separated, collected under reduced pressure and spin-dried and purified (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (0.5g, 70.4%).
MS(ESI,pos.ion)m/z:403.2[M+H]+；
1H NMR(400MHz,CDCl3)(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-methoxyethoxy) styryl) -1H-purine-2, 6(3H, 7H) synthesis of (E) -diketones
(E) -N- (6-amino-1, 3-diethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -3- (3- (2-methoxyethoxy) phenyl) acrylamide (500mg,1.24mmol) and methanol (5m L) were added to a 50m L single-neck round-bottom flask, then water (5m L) and sodium hydroxide (500mg,12.5mmol) were added, the oil bath was stirred at 70 ℃ for 7 hours, the reaction was stopped, spin-dried under reduced pressure, water (20m L) was added and then hydrochloric acid was added to neutralize to pH 2, and the title compound was obtained by filtration and drying as a white solid (0.4g, 82.7%).
MS(ESI,pos.ion)m/z:385.1[M+H]+.
Step 6) (E) -1, 3-diethyl-8- (3- (2-methoxyethoxy) styryl) -7-methyl-1H-purine-2, synthesis of 6(3H,7H) -dione
(E) -1, 3-diethyl-8- (3- (2-methoxyethoxy) styryl) -1H-purine-2, 6(3H,7H) -dione (400mg,1.04mmol) and DMF (10m L) were charged at 0 ℃ into a 100m L single-neck round-bottom flask, sodium hydride (80mg,2.0mmol) was added, the reaction was stirred for 10 minutes, iodomethane (300mg,2.11mmol) was added, the mixture was transferred to 25 ℃ and stirred for 2 hours, the reaction was stopped, water (30m L) was added, ethyl acetate was extracted (50m L), the layers were separated, organic phase was spin-dried under reduced pressure, and column chromatography purification (petroleum ether/ethyl acetate (v/v) ═ 5/1) gave the title compound as a white solid (0.34g, 85.3%).
MS(ESI,pos.ion)m/z:399.2[M+H]+；
1H NMR(600MHz,CDCl3)(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).
Example 2 Synthesis of (E) -1, 3-diethyl-8- (4- (2-methoxyethoxy) styryl) -7-methyl-1H-purine-2, 6(3H,7H) -dione
Figure BDA0002063337660000171
Step 1) Synthesis of 4- (2-methoxyethoxy) benzaldehyde
The title compound was prepared as described in example 1, step 2 by reacting 2-methoxyethyl 4-methylbenzenesulfonate (2.07g,9.0mmol) and p-hydroxybenzaldehyde (1.0g,8.2mmol) in DMF (10m L) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a clear oil (1.4g, 94.7%).
MS(ESI,pos.ion)m/z:181.2[M+H]+.
Step 2) Synthesis of (E) -3- (4- (2-methoxyethoxy) phenyl) acrylic acid
The title compound was prepared as described in example 1, step 3 by reacting 4- (2-methoxyethoxy) benzaldehyde (1.4g,7.8mmol), malonic acid (2.44g,23.4mmol) in pyridine (5m L) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound as a yellow oil (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-tetrahydropyrimidin-5-yl) -3- Synthesis of (4- (2-methoxyethoxy) phenyl) acrylamide
The title compound was prepared as described in example 1, step 4 by reacting 5, 6-diamino-1, 3-diethylpyrimidine-2, 4(1H,3H) -dione (0.6g,3.03mmol), (E) -3- (4- (2-methoxyethoxy) phenyl) acrylic acid (900mg,4.05mmol), HATU (1.8g,4.5mmol) and DIPEA (2.7m L, 15.4mmol) in dichloromethane (10m L) and purifying the crude by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a 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-methoxyethoxy) styryl) -1H-purine-2, 6(3H, 7H) synthesis of (E) -diketones
The title compound was prepared as described in example 1, step 5 by reacting (E) -N- (6-amino-1, 3-diethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -3- (4- (2-methoxyethoxy) phenyl) acrylamide (500mg,1.24mmol) and sodium hydroxide (200mg,5.0mmol) in methanol (6m L) and water (3m L) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a yellow solid (0.45g, 92.2%).
MS(ESI,pos.ion)m/z:385.3[M+H]+.
Step 5) (E) -1, 3-diethyl-8- (4- (2-methoxyethoxy) styryl) -7-methyl-1H-purine-2, synthesis of 6(3H,7H) -dione
The title compound was prepared as described in example 1, step 6 by reacting (E) -1, 3-diethyl-8- (4- (2-methoxyethoxy) styryl) -1H-purine-2, 6(3H,7H) -dione (450mg,1.17mmol), methyl iodide (443mg,3.12mmol) and sodium hydride (50mg,1.25mmol) in DMF (5m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a white solid (0.35g, 75.0%).
MS(ESI,pos.ion)m/z:399.1[M+H]+；
1H NMR(400MHz,CDCl3)(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).
Example 3 Synthesis of (E) -8- (3, 4-bis (2-methoxyethoxy) styryl) -1, 3-diethyl-7-methyl-1H-purine-2, 6(3H,7H) -dione
Figure BDA0002063337660000181
Step 1) Synthesis of 3, 4-bis (2-methoxyethoxy) benzaldehyde
The title compound was prepared as described in example 1, step 2 by reacting 2-methoxyethyl 4-methylbenzenesulfonate (1.83g,7.96mmol) and 3, 4-dihydroxybenzaldehyde (1.0g,7.2mmol) in DMF (10m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a yellow solid (1.78g, 96.7%).
MS(ESI,pos.ion)m/z:255.0[M+H]+.
Step 2 Synthesis of (E) -3- (3, 4-bis (2-methoxyethoxy) phenyl) acrylic acid
The title compound was prepared as described in example 1, step 3, by reacting 3, 4-bis (2-methoxyethoxy) benzaldehyde (1.8g,7.1mmol), malonic acid (2.24g,21.5mmol) and piperidine (0.6m L) in DMF (10m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a 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-tetrahydropyrimidin-5-yl) -3- Synthesis of (3, 4-bis (2-methoxyethoxy) phenyl) acrylamide
The title compound was prepared as described in example 1, step 4 by reacting 5, 6-diamino-1, 3-diethylpyrimidine-2, 4(1H,3H) -dione (0.6g,3.03mmol), (E) -3- (3, 4-bis (2-methoxyethoxy) phenyl) acrylic acid (500mg,1.69mmol), HATU (0.8g,2.1mmol) and DIPEA (1.3m L, 7.7mmol) in dichloromethane (10m L) and purifying the crude by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a yellow solid (0.62g, 77.1%).
MS(ESI,pos.ion)m/z:477.4[M+H]+.
Step 4) (E) -1, 3-diethyl-8- (3, 4-bis (2-methoxyethoxy) styryl) -1H-purine-2, 6 Synthesis of (3H,7H) -diones
The title compound was prepared as described in example 1, step 5 by reacting (E) -N- (6-amino-1, 3-diethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -3- (3, 4-bis (2-methoxyethoxy) phenyl) acrylamide (0.6g,1.26mmol) and sodium hydroxide (200mg,5.0mmol) in methanol (6m L) and water (3m L), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a yellow solid (0.41g, 69.6%).
MS(ESI,pos.ion)m/z:459.1[M+H]+.
Step 5) (E) -1, 3-diethyl-8- (3,4-bis (2-methoxyethoxy) styryl) -7-methyl-1H-purine Synthesis of pterin-2, 6(3H,7H) -diketone
The title compound was prepared as described in example 1, step 6 by reacting (E) -1, 3-diethyl-8- (3, 4-bis (2-methoxyethoxy) styryl) -1H-purine-2, 6(3H,7H) -dione (0.4g,0.87mmol), methyl iodide (0.37g,2.62mmol) and sodium hydride (68mg,1.7mmol) in DMF (5m L) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a yellow solid (0.35g, 85%).
MS(ESI,pos.ion)m/z:473.1[M+H]+.
EXAMPLE 4 Synthesis of (E) -1, 3-diethyl-8- (4-methoxy-3- (2-methoxyethoxy) styryl) -7-methyl-1H-purine-2, 6(3H,7H) -dione
Figure BDA0002063337660000182
Step 1) Synthesis of 4-methoxy-3- (2-methoxyethoxy) benzaldehyde
The title compound was prepared as described in example 1, step 2 by reacting 2-methoxyethyl 4-methylbenzenesulfonate (2.73g,11.9mmol), potassium carbonate (4.47g,32.3mmol) and 3-hydroxy-4-methoxybenzaldehyde (1.64g,10.8mmol) in DMF (10m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a pale yellow oil (2.0g, 88.3%).
MS(ESI,pos.ion)m/z:211.2[M+H]+.
Step 2 Synthesis of) (E) -3- (4-methoxy-3- (2-methoxyethoxy) phenyl) acrylic acid
The title compound was prepared as described in example 1, step 3 by reacting (4-methoxy-3- (2-methoxyethoxy) benzaldehyde (2.1g,10mmol), malonic acid (3.12g,29.96mmol) in pyridine (2.4m L) and DMF (20m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound as a pale yellow oil (1.53g,6 g) as a crude oil1％)。MS(ESI,pos.ion)m/z:253.1[M+H]+；
1H NMR(400MHz,CDCl3)(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-tetrahydropyrimidin-5-yl) -3- Synthesis of (4-methoxy-3- (2-methoxyethoxy) phenyl) acrylamide
The title compound was prepared as described in example 1, step 4 by reacting 5, 6-diamino-1, 3-diethylpyrimidine-2, 4(1H,3H) -dione (1.0g,5.04mmol), (E) -3- (4-methoxy-3- (2-methoxyethoxy) phenyl) acrylic acid (1.5g,5.9mmol), HATU (2.26g,5.94mmol) and DIPEA (3.2m L, 18.3mmol) in dichloromethane (10m L) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a yellow solid (2g, 91.7%).
MS(ESI,pos.ion)m/z:433.1[M+H]+；
1H NMR(400MHz,CDCl3)(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-methoxy-3- (2-methoxyethoxy) styryl) -1H-purine- Synthesis of 2,6(3H,7H) -dione
The title compound was prepared as described in example 1, step 5 by reacting (E) -N- (6-amino-1, 3-diethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -3- (4-methoxy-3- (2-methoxyethoxy) phenyl) acrylamide (766mg,1.77mmol) and sodium hydroxide (213mg,5.33mmol) in methanol (6m L) and water (2m L), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1) to give the title compound as a yellow solid (0.41g, 56%).
MS(ESI,pos.ion)m/z:415.1[M+H]+；
1H NMR(400MHz,DMSO-d6)(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-methoxy-3- (2-methoxyethoxy) styryl) -7-methyl- Synthesis of 1H-purine-2, 6(3H,7H) -dione
The title compound was prepared as described in example 1, step 6 by reacting (E) -1, 3-diethyl-8- (4-methoxy-3- (2-methoxyethoxy) styryl) -1H-purine-2, 6(3H,7H) -dione (410mg,0.99mmol), methyl iodide (0.28g,2.0mmol) and sodium hydride (80mg,2.0mmol) in DMF (10m L), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a white solid (0.347g, 82%).
MS(ESI,pos.ion)m/z:429.1[M+H]+；
1H NMR(400MHz,CDCl3)(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).
EXAMPLE 5 Synthesis of (E) -1, 3-diethyl-8- (3-methoxy-4- (2-methoxyethoxy) styryl) -7-methyl-1H-purine-2, 6(3H,7H) -dione
Figure BDA0002063337660000201
Step 1) Synthesis of 3-methoxy-4- (2-methoxyethoxy) benzaldehyde
The title compound was prepared as described in example 1, step 2 by reacting 2-methoxyethyl 4-methylbenzenesulfonate (2.07g,9.0mmol), potassium carbonate (2.24g,16.2mmol) and 4-hydroxy-3-methoxybenzaldehyde (1.0g,6.57mmol) in DMF (10m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a colourless oil (1.18g, 85.4%).
MS(ESI,pos.ion)m/z:211.2[M+H]+.
Step 2 Synthesis of) (E) -3- (3-methoxy-4- (2-methoxyethoxy) phenyl) acrylic acid
The title compound was prepared as described in example 1, step 3 by reacting (3-methoxy-4- (2-methoxyethoxy) benzaldehyde (1.18g,5.61mmol), malonic acid (2.1g,20.2mmol) in pyridine (2.0m L) and DMF (10m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound as a white solid (1.25g, 88.3%).
MS(ESI,pos.ion)m/z:253.1[M+H]+；
1H NMR(400MHz,CDCl3)(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-tetrahydropyrimidin-5-yl) -3- Synthesis of (3-methoxy-4- (2-methoxyethoxy) phenyl) acrylamide
The title compound was prepared as described in example 1, step 4 by reacting 5, 6-diamino-1, 3-diethylpyrimidine-2, 4(1H,3H) -dione (0.6g,3.2mmol), (E) -3- (3-methoxy-4- (2-methoxyethoxy) phenyl) acrylic acid (1.0g,3.96mmol), HATU (1.5g,3.96mmol) and DIPEA (3.2m L, 18.3mmol) in dichloromethane (10m L) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a yellow solid (0.85g, 61.3%).
MS(ESI,pos.ion)m/z:433.1[M+H]+.
Step 4) (E) -1, 3-diethyl-8- (3-methoxy-4- (2-methoxyethoxy) styryl) -1H-purine- Synthesis of 2,6(3H,7H) -dione
The title compound was prepared as described in example 1, step 5 by reacting (E) -N- (6-amino-1, 3-diethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -3- (3-methoxy-4- (2-methoxyethoxy) phenyl) acrylamide (0.8g,1.85mmol) and sodium hydroxide (300mg,7.5mmol) in methanol (6m L) and water (2m L), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1) to give the title compound as a yellow solid (0.71g, 97.3%).
MS(ESI,pos.ion)m/z:415.4[M+H]+；
1H NMR(400MHz,CDCl3)(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-methoxy-4- (2-methoxyethoxy) styryl) -7-methyl- Synthesis of 1H-purine-2, 6(3H,7H) -dione
The title compound was prepared as described in example 1, step 6 by reacting (E) -1, 3-diethyl-8- (3-methoxy-4- (2-methoxyethoxy) styryl) -1H-purine-2, 6(3H,7H) -dione (0.7g,1.69mmol), methyl iodide (0.28g,2.0mmol) and sodium hydride (80mg,2.0mmol) in DMF (10m L), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a yellow solid (0.62g, 88.5%).
MS(ESI,pos.ion)m/z:429.2[M+H]+；
1H NMR(400MHz,CDCl3)(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).
Example 6 Synthesis of (E) -1, 3-diethyl-8- (3-fluoro-4- (2-methoxyethoxy) styryl) -7-methyl-1H-purine-2, 6(3H,7H) -dione
Figure BDA0002063337660000211
Step 1) Synthesis of 3-fluoro-4- (2-methoxyethoxy) benzaldehyde
The title compound was prepared as described in example 1, step 2 by reacting 2-methoxyethyl 4-methylbenzenesulfonate (1.8g,7.82mmol), potassium carbonate (2.49g,17.8mmol) and 3-fluoro-4-hydroxybenzaldehyde (1.0g,7.14mmol) in DMF (10m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a pale yellow solid (1.4g, 99%).
MS(ESI,pos.ion)m/z:199.1[M+H]+；
1H NMR(400MHz,CDCl3)(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).
Step 2) Synthesis of (E) -3- (3-fluoro-4- (2-methoxyethoxy) phenyl) acrylic acid
The title compound was prepared as described in example 1, step 3 by reacting 3-fluoro-4- (2-methoxyethoxy) benzaldehyde (1.4g,7.06mmol), malonic acid (2.21g,21.19mmol) in pyridine (3.5m L) and DMF (10m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound as a pale yellow solid (0.918g, 54.07%).
MS(ESI,pos.ion)m/z:241.3[M+H]+；
1H NMR(400MHz,CDCl3)(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-tetrahydropyrimidin-5-yl) -3- Synthesis of (3-fluoro-4- (2-methoxyethoxy) phenyl) acrylamide
The title compound was prepared as described in example 1, step 4 by reacting 5, 6-diamino-1, 3-diethylpyrimidine-2, 4(1H,3H) -dione (0.3g,1.6mmol), (E) -3- (3-fluoro-4- (2-methoxyethoxy) phenyl) acrylic acid (0.4g,1.67mmol), HATU (0.551g,1.41mmol) and DIPEA (1.35m L, 7.67mmol) in dichloromethane (10m L) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a pale yellow solid (0.45g, 83.7%).
MS(ESI,pos.ion)m/z:421.1[M+H]+；
1H NMR(400MHz,CDCl3)(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- (3-fluoro-4- (2-methoxyethoxy) styryl) -1H-purine-2, 6 Synthesis of (3H,7H) -diones
The title compound was prepared as described in example 1, step 5 by reacting (E) -N- (6-amino-1, 3-diethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -3- (3-fluoro-4- (2-methoxyethoxy) phenyl) acrylamide (0.45g,1.07mmol) and sodium hydroxide (500mg,11.9mmol) in methanol (6m L) and water (3m L), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a white solid (0.396g, 91.9%).
MS(ESI,pos.ion)m/z:403.3[M+H]+；
1H NMR(400MHz,DMSO-d6)(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- (3-fluoro-4- (2-methoxyethoxy) styryl) -7-methyl-1H-purine Synthesis of pterin-2, 6(3H,7H) -diketone
The title compound was prepared as described in example 1, step 6 by reacting (E) -1, 3-diethyl-8- (3-fluoro-4- (2-methoxyethoxy) styryl) -1H-purine-2, 6(3H,7H) -dione (0.39g,0.97mmol), methyl iodide (0.121m L, 1.93mmol) and sodium hydride (39mg,0.98mmol) in DMF (10m L) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (0.354g, 87.7%).
MS(ESI,pos.ion)m/z:417.1[M+H]+；
1H NMR(400MHz,CDCl3)(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).
Example 7 Synthesis of (E) -1, 3-diethyl-8- (3-chloro-4- (2-methoxyethoxy) styryl) -7-methyl-1H-purine-2, 6(3H,7H) -dione
Figure BDA0002063337660000221
Step 1) Synthesis of 3-chloro-4- (2-methoxyethoxy) benzaldehyde
The title compound was prepared as described in example 1, step 2 by reacting 2-methoxyethyl 4-methylbenzenesulfonate (1.8g,7.82mmol), cesium carbonate (4.16g,12.77mmol) and 3-chloro-4-hydroxybenzaldehyde (1.0g,6.38mmol) in DMF (10m L) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a pale yellow oil (0.65g, 47%).
MS(ESI,pos.ion)m/z:215.1[M+H]+.
Step 2 Synthesis of) (E) -3- (3-chloro-4- (2-methoxyethoxy) phenyl) acrylic acid
The title compound was prepared as described in example 1, step 3 by reacting 3-chloro-4- (2-methoxyethoxy) benzaldehyde (0.65g,3.0mmol), malonic acid (0.47g,4.5mmol) in pyridine (6.0m L) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound as a 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-tetrahydropyrimidin-5-yl) -3- Synthesis of (3-chloro-4- (2-methoxyethoxy) phenyl) acrylamide
The title compound was prepared as described in example 1, step 4 by reacting 5, 6-diamino-1, 3-diethylpyrimidine-2, 4(1H,3H) -dione (0.35g,1.8mmol), (E) -3- (3-chloro-4- (2-methoxyethoxy) phenyl) acrylic acid (0.6g,2.33mmol), HATU (0.8g,2.05mmol) and DIPEA (1.35m L, 7.67mmol) in dichloromethane (10m L) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a yellow solid (0.55g, 71%).
MS(ESI,pos.ion)m/z:437.1[M+H]+.
Step 4) (E) -1, 3-diethyl-8- (3-chloro-4- (2-methoxyethoxy) styryl) -1H-purine-2, 6 Synthesis of (3H,7H) -diones
The title compound was prepared as described in example 1, step 5 by reacting (E) -N- (6-amino-1, 3-diethyl-2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -3- (3-chloro-4- (2-methoxyethoxy) phenyl) acrylamide (0.5g,1.14mmol) and sodium hydroxide (400mg,10mmol) in methanol (6m L) and water (3m L), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a yellow solid (0.385g, 80.3%).
MS(ESI,pos.ion)m/z:419.2[M+H]+.
Step 5) (E) -1, 3-diethyl-8- (3-chloro-4- (2-methoxyethoxy) styryl) -7-methyl-1H-purine Synthesis of pterin-2, 6(3H,7H) -diketone
The title compound was prepared as described in example 1, step 6 by reacting (E) -1, 3-diethyl-8- (3-chloro-4- (2-methoxyethoxy) styryl) -1H-purine-2, 6(3H,7H) -dione (0.35g,0.84mmol), methyl iodide (0.12m L, 1.9mmol) and sodium hydride (40mg,1.0mmol) in DMF (5m L) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (0.28g, 77%).
MS(ESI,pos.ion)m/z:433.1[M+H]+；
1H NMR(400MHz,CDCl3)(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).
Biological assay
Example A: evaluation of the Compounds of the invention on human adenosine A2AAntagonism of receptors
Experimental methods
The experimental system adopts human recombinant adenosine A2AReceptor stably expressed in HEK-293 cell line HEK-293 was plated at a density of 1.25 × 105cell/ml. The medium was changed to Modified HBSS solution at pH 7.4, test compounds and solvents (PBS containing 0.1% DMSO) were added at different concentrations, and incubation was carried out at 37 ℃ for 10min, with the test compounds at the respective concentrations: 10. mu.M, 1. mu.M, 0.1. mu.M, 10nM, 1nM, 0.1 nM. The concentration of cAMP (cyclic adenosine monophosphate) in the medium was detected by TR-FRET method. This experiment used NECA as a positive control, (1) the test compound alone stimulated cells to produce a certain amount of cAMP, and then NECA alone (0.1. mu.M) stimulated cells to also produce a certain amount of cAMP. A test compound is considered to have adenosine A if the amount of cAMP production stimulated by the test compound alone is higher than 50% of the amount of cAMP production stimulated by the NECA alone (0.1. mu.M)2AReceptor agonistic activity. (2) All cells were incubated with test compound and then cells were stimulated with NECA (3nM), and further with NECA alone (3nM) to produce an amount of cAMP that is less than 50% of the amount of cAMP produced by NECA alone (3nM), i.e., the test compound inhibited cAMP production by NECA (3nM) by greater than or equal to 50%, indicating that the test compound has adenosine A2AAntagonism of the receptor. IC (integrated circuit)50By using MathIQTM(ID Business Solutions Ltd.,UK)Calculated by nonlinear least square regression equation analysis. The results are shown in Table A.
Table a: the compounds of the invention are human adenosine A2AResults of receptor antagonism experiments
Example No. 2 IC50(μM)
Example 1 5.0
Example 2 3.3
Example 3 3.2
Example 4 3.8
Example 5 3.1
Example 6 2.81
The experimental result shows that the compound has stronger adenosine A2AAntagonism of the receptor.
Example B: pharmacokinetic evaluation of rats after intravenous injection or gavage of a quantitative Compound of the invention
(1) Test animal
The test animals are rats, and the specific conditions are shown in table 1:
TABLE 1
Germling Grade Sex Body weight The week of the year Origin of origin
SD rat Cleaning stage Male sex 180～220g 8 weeks Changzhou Kavens
(2) Analytical method
The L C-MS/MS system used for the analysis included an Agilent 1200 series vacuum degasser, quaternary pump, orifice plate autosampler, thermostatted column oven, API4000Qtrap triple quadrupole mass spectrometer with charged spray ionization source (ESI). quantitative analysis was performed in MRM mode, where the source parameters of the MRM conversions are shown in Table 2:
TABLE 2
Air curtain air-based or air-based deviceCUR: 30psi
Atomizing gas/GS 1: 55psi
auxiliary heating gas/GS 2: 60psi
ion transmission voltage/IS: 5000V
atomization temperature/TEM: 500℃
analysis was performed using a Waters ACQUITY UP L C CSH C18,2.1 × 50mm, 1.7 μm column, and injecting a 0.8 μ L sample under the conditions of H as the mobile phase2O+2mM HCOONH4(ammonium formate) + 0.1% FA (formic acid) (mobile phase A) and MeOH (methanol) +2mM MHCOONH4(ammonium formate) + 0.1% FA (formic acid) (mobile phase B), flow rate 0.7m L/min, column temperature 40 ℃, mobile phase gradient as shown in table 3:
TABLE 3
Time of day Gradient of mobile phase B
0.4min 10％
0.6min 95％
1.6min 95％
1.61min 10％
2.50min Stop
(3) Experimental methods
The compound of the invention is evaluated by pharmacokinetics in rats, and the specific steps are as follows:
the experiments were divided into two groups, one group administered intravenously and one group administered intragastrically, the compounds of the present invention were administered to the test animals (12 h overnight fasted) as 10% DMA (heat) + 60% PEG400+ 30% Saline solutions, for the intravenous group, the dose was 1mg/kg, then blood was taken intravenously (0.3m 26) at the time points 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h after administration, the anticoagulant EDTA-K2 was added to the blood, and centrifuged at 3,000 or 4,000rpm for 10 minutes, the plasma solution was collected, and stored at-20 ℃ or-70 ℃, for the intragastrically group, the dose was 5mg/kg, then blood was taken intravenously (0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (0.3m L m) at the time points 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h after administration, the anticoagulant was taken intravenously (0.3 m) and blood was collected at 3,000 ℃ or 35 rpm.
Adding 120 μ L IS working solution into 20 μ L plasma, swirling for 2min, centrifuging the mixed solution at 12,000rpm for 2min, collecting 100 μ L supernatant, adding 110 μ L MeOH/H2And O (v/v is 1/1), swirling for 2min, taking 5 mu L sample injection L C-MS/MS system, detecting the concentration of the target compound by adopting a L C-MS/MS method, and calculating pharmacokinetic parameters by adopting a non-atrioventricular model.
Example C: pharmacokinetic evaluation of mice/dogs after intravenous or intragastric dosing of the Compounds of the invention
(1) The test animals were: the tested animals are mice and/or dogs, and the specific conditions are shown in table 4:
TABLE 4
Germling Grade Sex Number of Body weight The week of the year Origin of origin
ICR mice Cleaning stage Male sex 6 are 18-22g 8 weeks Changzhou Kavens
Beagle dog Common stage Male sex 4 are 6-8kg 6-8 months Beijing Mas Biotech Ltd
(2) The analysis method comprises the following steps:
the L C/MS/MS system used for the analysis included an Agilent 1200 series vacuum degasser, quaternary pump, orifice plate autosampler, thermostatted column oven, API4000Qtrap triple quadrupole mass spectrometer with charged spray ionization source (ESI). quantitative analysis was performed in MRM mode, where the source parameters of the MRM conversions are shown in Table 5:
TABLE 5
Air curtain air/CUR: 20psi
atomizing gas/GS 1: 60psi
auxiliary heating gas/GS 2: 70psi
ion transmission voltage/IS: 4500V
atomization temperature/TEM: 550℃
analysis was performed using waters xbridge C18UP L C, 2.1X 50mm, 3.5. mu.M column, injected with 0.5. mu. L sample under conditions of H as mobile phase2O+2mM HCOONH4(ammonium formate) + 0.1% FA (formic acid) (mobile phase A) and MeOH (methanol) +2mM MHCOONH4(ammonium formate) + 0.1% FA (formic acid) (mobile phase B) flow rate 0.7m L/min mobile phase gradient as shown in table 6:
TABLE 6
Time of day 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 compound of the invention is subjected to pharmacokinetic evaluation in mice, and the specific steps are as follows:
the experiments were divided into two groups, one group administered intravenously and one group administered intragastrically, the compounds of the present invention were administered to the test animals as 10% DMA + 60% PEG400+ 30% Saline solutions, for the intravenous administration group, the dose was 2mg/kg, then blood was taken intravenously at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours after administration (0.3m L) and centrifuged at 3,000 or 4,000rpm for 10 minutes, the plasma solution was collected (EDTA-K2) and stored at-20 ℃ or-70 ℃, for the intragastrically anticoagulant group, the dose was 5mg/kg, then blood was taken intravenously at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours (0.3m L) and stored at 3,000 or 4,000rpm for 2 minutes after administration (EDTA-20 ℃ or-70 ℃), and the plasma solution was collected at 3,000 rpm for 2 minutes.
Adding 130 μ L IS working solution into 10 μ L plasma, vortexing for 5min, centrifuging the mixed solution at 4000rpm for 5min, collecting 100 μ L supernatant, adding 150 μ L H2And O, after vortex for 2min, taking 2.5 mu L sample feeding L C-MS/MS system, detecting the concentration of the target compound by adopting a L C-MS/MS method, and calculating pharmacokinetic parameters by adopting a non-atrioventricular model.
2) The pharmacokinetic evaluation of the compounds of the invention in beagle dogs was carried out by the following specific steps:
the experiments were divided into two groups, one group administered intravenously and one group administered intragastrically, the compounds of the present invention were administered to the test animals as 10% DMA + 60% PEG400+ 30% Saline solutions, for the intravenous administration group, the dose was 1mg/kg, then blood was taken intravenously at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration (0.3m L) and centrifuged at 3,000 or 4,000rpm for 10 minutes, the plasma solution was collected (anticoagulant is EDTA-K2) and stored at-20 ℃ or-70 ℃, for the intragastrically administered group, the dose was 5mg/kg, then blood was taken intravenously at time points of 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours after administration (0.3m L) and stored at 3,000 or 4,000rpm for 2 minutes at 3,000 ℃ or-70 ℃ after administration, and the plasma solution was collected at 6332 ℃ or at 10 minutes.
Adding 120 μ L IS working solution into 10 μ L plasma, vortexing for 2min, centrifuging the mixed solution at 12000rpm for 2min, collecting 80 μ L supernatant, and adding 140 μ L methanol solution (methanol: H)2O1: 1), swirling for 2min, taking 1.0 mu L sample feeding L C-MS/MS system, detecting the concentration of the target compound by adopting a L C-MS/MS method, and calculating pharmacokinetic parameters by adopting a non-compartmental model.
In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (6)

1. A compound, which is a compound represented by formula (I), or a pharmaceutically acceptable salt of the compound represented by formula (I),
Figure FDA0002456502400000011
wherein:
R1、R2and R3Each independently is H, D, C1-C4Alkyl or C1-C4A haloalkyl group;
R4、R5and R8Each independently is H;
R9and R10Each independently is H;
R6is-O-R0，R7Is F, Cl, Br, I, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy or-O-R0(ii) a Or
R6Is H, D, F, Cl, Br, I, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4Haloalkoxy, R7is-O-R0；
R0Is- (CR)aRb)nORc；
RaAnd RbEach independently is H;
Rcis methyl;
n is 2.
2. The compound of claim 1, wherein R1、R2And R3Each independently H, D, methyl, ethyl, n-propyl or isopropyl.
3. The compound of claim 1, wherein R6is-O-R0，R7Is F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl or-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2or-O-R0(ii) a Or
R6Is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl or-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3or-OCH2CF2CHF2，R7is-O-R0。
4. The compound of claim 1, which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:
Figure FDA0002456502400000012
Figure FDA0002456502400000021
5. a pharmaceutical composition comprising a compound of any one of claims 1-4; and
the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the prevention, treatment or alleviation of the interaction with adenosine a2AA receptor-associated disease;
wherein said peptide is substituted with adenosine A2AThe receptor-associated disease is parkinson's disease, pain, depression, dementia, stroke, myocardial ischemia, asthma, alcohol withdrawal, dyskinetic syndrome, restless legs syndrome, dystonia, catalepsy, a neurodegenerative disorder or osteoporosis.
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