CN107286146A - It is used as adenosine A2A4 aminopyridine derivatives of receptor antagonist and application thereof - Google Patents
It is used as adenosine A2A4 aminopyridine derivatives of receptor antagonist and application thereof Download PDFInfo
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Abstract
Adenosine A is used as the invention discloses one kind2A4 aminopyridine derivatives of receptor antagonist, its general structure (I) is as follows：Wherein, R1Selected from halogen, cyano group or trifluoromethyl；R2Selected from pyrazolyl, pyrrolidinyl, or through one or more halogens or C1‑3Alkyl-substituted pyrazolyl or pyrrolidinyl；R3Xuan Zi oxazolyl, oxadiazolyls, triazol radical, or through one or more halogens or C1‑3Wan bases replace oxazolyls.4 aminopyridine derivative provided by the present invention is to people source adenosine A2AAcceptor has obvious antagonism, available for treatment to A2AAntagonism has in the disease of reaction or the composition of illness or combination product, especially treats the diseases such as nerve degenerative diseases, extrapyramidal syndrome, depression, hyperkinetic syndrome, sleep-disorder, anxiety disorder, diabetes or tumour.
Description
Technical field
The present invention relates to medicine and organic chemistry filed, and in particular to one kind is used as adenosine A2AThe 4- amino of receptor antagonist
Pyrimidine derivatives and application thereof.
Background technology
As the endogenous modulator of most physiological functions in maincenter (CNS) and peripheral neverous system, adenosine is widely distributed
In many tissue multiple organs such as nervous system, cardiovascular system, digestive system, respiratory system, the various important physiology of regulation are played
The effect of process.It plays its biological agent by a class film specific receptor, and these acceptors belong to g protein coupled receptor and surpassed
Family, has determined that 4 kinds of adenosine receptor subtypes, they are respectively at present：A1、A2A、A2BAnd A3.Wherein A1And A2AIt is high expression
Acceptor, can be acted under physiological status during low-level adenosine concentration, and A2BAnd A3Expression quantity it is relatively low, only in pathology feelings
Under condition, adenosine can just be activated when rolling up, and produce a series of pathologic effects.A1And A3Acceptor is by them with suppressing adenylate
The G-protein coupling of cyclase carrys out downwards to adjust the level of cell；On the contrary, A2AAnd A2BThe Gs of acceptor and adenosine cyclase of acid
Albumen coupling, and improve intracellular level.By the effect of these acceptors, adenosine can realize that extensive physiological function is adjusted
Section.
A2AAcceptor appears in the region rich in dopamine, the ganglia components of such as substrate, various mammal bags mostly
Include corpus straitum and the globus pallidus of the mankind.Basal ganglion, as center part, participates in cortex, thalamus and marginal convolution with corpus straitum
Information integration is to produce motor behavior.A is had been found that in corpus straitum2AAcceptor and d2 dopamine receptor are closely concentrated on jointly
Corpus straitum globus pallidus GABAergic neuron, so-called indirect output pathway is formed from corpus straitum, and it suppresses with motility
It is relevant.A2AThe neurotransmission that acceptor adjusts γ-aminobutyric acid, dopamine, acetylcholine and glutamate by number of ways promotees
Enter the control of motor behavior.Generally, A2APass through the interaction with D2 acceptors, especially A2AAs the effect of antagonist to controlling
Treating Parkinson's has very big benefit, and it can cause the reduction of dopamine level.A2AAcceptor closely and antagonism with D2 by
Body phase interaction, reduction when causing D2 acceptors stimulated to dopamine affinity.Therefore, A2AIn receptor antagonist can strengthen
The effect of source property dopamine and the dopamine-receptor stimulant of clinical practice and increase the dopaminergic medicine response time limit.
Selective A2AReceptor stimulating agent and antagonist are in the pharmacology of rodent and inhuman primate, behavior and nerve
Existing description extensively in the experiment of protection.In D2 receptor antagonists and A2ACan be clear in the catalepsy model of receptor stimulating agent induction
Chu ground illustration D2 and A2AClose interaction of the acceptor in catalepsy model, it is by A2AReceptor antagonist and D2 receptor agonisms
Agent reaction.At present, many researchers are it has been reported that A2AThe potentiality of receptor antagonist Antiparkinsonian.For example, adenosine A2ABy
Body antagonist SCH58261 and KW-6002, strengthen in the mouse and rat that unilateral 6- hydroxyl dopamines (6-OHDA) are damaged
The bilateral as caused by subdomain dosage levodopa rotates.In addition, widespread reports adenosine A2AReceptor antagonist KW-6002 shows
Write improve in non-human primates because with the long-term treatment of dopamine-receptor stimulant levodopa by 1- methyl 4-phenyl -1,
The injury gained in sports for not causing dyskinesia of 2,3,6- tetrahydropyridines (MPTP) induction.Therefore, because it not only reverses motion to damage
Hinder and disease process, A can be slowed or stopped by extending cell survival2AReceptor antagonist is used as parkinsonian's length
The future drugs of phase medication show very big potentiality.
Several preclinical studies show, adenosine A2AReceptor antagonist for treatment nerve degenerative diseases, such as Parkinson's,
Huntington disease or Alzheimer disease have validity.And have been reported A2AReceptor antagonist is in different nerve degenerative diseases
There is neuroprotection in internal and external model.Sum it up, A2AReceptor antagonist can be protected effectively from various
The different neurons of the nerve retrograde affection of the wound inducement of form.
Studies have found that A2AThe mouse that receptor knockout is removed to " depressant " attack than they the similar sensitiveness of wild type it is lower.
Consistent, the A in mousetail suspension test with this research2AWhen receptor antagonist SCH58261 and KW6002 can reduce total motionless
Between.It has also been found that when in order to there is the high dead time, during the mouse administration screened in advance, antagonist SCH8261 and ZM241385 subtract
Lack immobility, and SCH58261 reduces the motionless of the mouse raised for their " helpless " selectivity in this model
Property.Use A2AThe mice study of knockout shows these animals to incitantia, such as amphetamine and cocaine, slow in reacting.
Therefore existing evidence is it can be shown that adenosine A2AReceptor antagonist by corpus straitum in regulation or in adrenocortical dopaminergic
Approach, may have antidepression and/or antipsychotic function.A2AReceptor activation can aid in a range of nerve of improvement
Psychotic disorder and obstacle, such as depression, sleep too much during the daytime, restless leg syndrome (RLS), attention deficit and hyperactivity disorder and
Cognitive prostration.
Extrapyramidal syndrome (EPS) is a series of common name of unfavorable nerves reactions relevant with using antipsychotics.
Have the relevant nervous syndromes of the different EPS- of 6 classes, wherein 4 kinds, i.e. dystonia, cathisophobia, pseudoparkinsonism (Parkinson
Syndrome) and Tardive dyskinesia it is particularly common in the patient that Taking Antipsychotics are treated.Dystonia is muscle
Group, the particularly painful spasm of neck, lower jaw, back, pharynx and larynx.It is most commonly in the year with antipsychotic medications
Light male, but also can be with using cocaine, tricyclic antidepressants, lithium salts anticonvulsant (such as benzene English appropriate and carbamazepine)
It is relevant.Pseudoparkinsonism manifest itself by motion can not (tetanic, stiff and slow voltuntary movement, hunchback, walking of shuffling) and
Tremble, and these symptoms occurred after therapy starts in several weeks or several months.Cathisophobiaing, it is how dynamic, main to manifest itself by motion
Feel worried or uncomfortable in seeing, be often misinterpreted as excitement or anxiety, this common syndrome can not often be diagnosed and had to treatment
Minimum reaction.Tardive dyskinesia is that the later stage occurs, the syndrome relevant with ataraxy medicine is used for a long time.It is more
Often betide older patients, and characteristic be face, eyelid, oral area, tongue, four limbs and body it is mechanical, repeatedly, it is nonvoluntary,
Quick choreiform movements.
Cathisophobia is also RLS and PLMS (periodic limb movements in sleep) and PLMD (periodicity legs (or limbs)
Dyskinesia) feature.RLS is general obstacle, and it, which causes patient to have for its mobile leg, can not resist and offending serious hope；
It is often when static and/or night shows, and may upset sleep.Do not have typical RLS symptoms, but intermittent leg can be showed
Patient that is mobile and being adversely affected to Sleeping band is diagnosed as PLMS.RLS and PLMS treatment includes levodopa/card ratio
DOPA, levodopa/benserazide, dopamine agonist (such as Pramipexole and Ropinirole), benzodiazepineClass medicine, Ah
Opiates, anticonvulsant and iron (ferrous sulfate).
In CNS, data display A2AAcceptor is present in basal ganglia with high density, its in the good motion of control very
It is important.In addition, A2AThe selective antagonist of acceptor is pharmacologically critically important, because it shows to reduce the effect of injury gained in sports,
Thus improve the work(in nerve degenerative diseases, such as Parkinson's and associated dyskinesias (such as Huntington's chorea)
Energy.Compared with bringing the current dopaminergic therapies that therapeutic index is improved, A2AAntagonist seems to show to reduce inclining for side effect
To (such as no movement disorder).A2AAntagonist also has antidepression property and stimulates cognitive function.
Therefore, people are to having found new and effective and selective adenosine A2AThe interest of receptor antagonist gradually increases.System
Some effective adenosine As that medicine company finds2AAntagonist has been introduced into clinical test and shows positive findings, shows A2A
Receptor antagonist be not only expected to treat nerve degenerative diseases, such as Parkinson's, Huntington disease or Alzheimer disease, and
It can be used for treating the related diseases of other CNS, such as depression, hyperkinetic syndrome, sleep-disorder and anxiety disorder.
In addition, adenosine A2AAcceptor is also closely related with immunological regulation.Immunological regulation is that body keeps homeostasis, resisted
The important means of external destructive stimulus.Adenosine is as a kind of important mediator of body and quenched, in dysbolism and cellular damage
When can significantly raise, activate adenosine receptor and play biological effect, participate in body immunological regulation.Research table in recent years
It is bright, in many pathologic processes such as hypoxia-ischemia, inflammation, wound, transplanting, adenosine A2AThe activation of acceptor can play important exempt from
Epidemic disease adjustment effect, this may be with A2AAcceptor is in the panimmunity cell such as T cell, B cell, mononuclear macrophage, neutrophil leucocyte
Upper expression is higher relevant.
A2AAcceptor is closely related with tumour.Under normal circumstances, body can rely on complete immunologic mechanism effectively to supervise
Depending on and repel cancerous tumor cell, such as：In terms of cellular immunity, T lymphocytes, antibody-dependent cytotoxicity cell (K cells), NK are thin
Born of the same parents and Macrophages For Tumor have lethal effect.But if cancerous tumor cell is in itself or above-mentioned immune cell function changes
Become, then may escape the removing of body immune system, neoplasm formation tumour.Research is it was demonstrated that A2AThe activation of acceptor can be with
Promote body to produce immune tolerance, the formation of tumour cell " immunologic escape " or " immunosupress " is take part in closely, is tumour
Generation development creates advantage.A2AReceptor activation can be by suppressing the expression of vascular endothelial cell thrombospondin
And be that the growth of blood vessel dependent tumors creates an enabling environment in angiogenesis is dose-dependently promoted；A2AThe activation of acceptor
The killing of PKA suppression of natural killer cells against tumor cells can also be activated by raising cAMP；Melanoma can be promoted
A375 cells, the propagation into the tumour cell such as fibroma NIH3T3 cells and pheochromocytoma PC12 cell.There are some researches show
A2AReceptor antagonist can be applied to treat various tumours, especially such as lung cancer, non-small cell lung cancer.
It is adapted to A2AThe candidate products of receptor antagonist are, it is necessary to potent and A2AAcceptor combine but can not with other adenosines by
The potent combination of body, that is, need higher A2AReceptor subtype-selective, so contributes to reduce potential side effect.It there is now multiple
Small molecule adenosine A2AReceptor antagonist enters the clinical I phases and studied, for treating tumour.Such as the CPI-444 of Corvus companies, show
Show and combine A2AThe affinity (Ki) of acceptor is 3.5nm, A1The affinity (Ki) of acceptor is 192nm, to A1The selection of receptor subtype
Property reaches 54 times.Based on these results, researcher think it is presently contemplated that dosage level, CPI-444 is in rational dosage model
There is enough security and potential curative effect in enclosing.CPI-444 is in 3 mouse models for growing different tumours, i.e. EL-4 lymphs
Knurl model, MC38 colon tumor models and CT26 colon tumor models, in be tested, as a result display or cancer cell at lymph
Tie quantity conspicuousness to reduce, or original site gross tumor volume is substantially reduced, or gross tumor volume is stable or the sound response such as disappear, very
Show and cure completely to some mouse.The AZD4635 of Heptares companies also enters the clinical I phases and treats advanced solid tumor.
These results show the A of high selectivity2AReceptor antagonist can be applied to treat tumour.
In addition, A2AImmunoregulation effect of the acceptor in the chronic inflammatory diseases such as asthma, atherosclerosis also gradually by
People recognize and are taken seriously, A2AAcceptor also has close relationship with wound healing or auricular fibrillation.Many researchs it has been shown that
A2AReceptor antagonist applies also for treating diabetes.
Chinese invention patent (CN102892761) provides one kind and is used as adenosine A2AThe 4- aminopyrimidines of receptor antagonist spread out
It is biological：
Wherein R1Represent optionally being replaced by one or two halogen atom or taken by one or two methyl or trifluoromethyl
Pyrazoles, thiazole or the triazole ring in generation.The compound is for adenosine A2AAcceptor has preferably antagonism, shows as it to A2A
Affinity it is stronger, but it is for A1Selectivity it is also very low, cause in A1In the presence of acceptor, it is to A2AThe selectivity of acceptor
It is relatively low.Meanwhile, the Pharmacokinetic Characteristics of the pyrazole compound described in the invention are poor, and plasma clearance is higher, in rat
Internal half-life period is also very short.
The content of the invention
It is an object of the invention to provide be used as adenosine A2AThe 4- aminopyridine derivatives of receptor antagonist, and use it for controlling
Treat to A2AAntagonism has the disease or illness of reaction.
To reach above-mentioned purpose, adenosine A is used as the invention provides one kind2AThe 4- aminopyrimidines of receptor antagonist derive
Thing, its general structure (I) is as follows：
Wherein：
R1Selected from halogen, cyano group or trifluoromethyl；
R2Selected from pyrazolyl, pyrrolidinyl, or through one or more halogens or C1-3Alkyl-substituted pyrazolyl or pyrrolidines
Base；
R3Xuan Zi oxazolyl, oxadiazolyls, triazol radical, or through one or more halogens or C1-3Wan bases replace oxazoles
Base.
Preferably, it is above-mentioned to be used as adenosine A2AThe 4- aminopyridine derivatives of receptor antagonist, wherein, R2Selected from pyrazolyl
Or pyrrolidinyl；R3Xuan Zi oxazolyl, oxadiazolyls, triazol radical, or through a C1-3Wan bases replace oxazolyls.
Preferably, it is above-mentioned to be used as adenosine A2AThe 4- aminopyridine derivatives of receptor antagonist, wherein, the 4- aminopyrimidines
Derivative is selected from following compounds：
Preferably, the 4- aminopyridine derivatives are selected from following compounds：(1)、(5)、(8)、(10)、(13)、(14)、
Or (18) (17).
Prepared present invention also offers a kind of above-mentioned 4- aminopyridine derivatives for treating to A2AAntagonism has
Purposes in the disease of reaction or the medicine of illness.
Further, the disease or illness include nerve degenerative diseases, extrapyramidal syndrome, depression, many dynamic synthesis
Levy, any one or more in sleep-disorder, anxiety disorder, diabetes or tumour.
Further, the tumour is lung cancer, oophoroma, cancer of pancreas, stomach cancer, breast cancer, glioblastoma, melanin
Knurl, clear-cell carcinoma, triple negative breast cancer, colorectal cancer, incidence cancer, carcinoma of urinary bladder, prostate cancer, hepatocellular carcinoma or bile duct
Cancer.
Further, the lung cancer is non-small cell lung cancer.
Present invention also offers a kind of pharmaceutical composition, wherein, it is used as adenosine A comprising above-mentioned2AReceptor antagonist
4- aminopyridine derivatives, and its pharmaceutically acceptable excipient.
Present invention also offers a kind of compound medicine comprising above-mentioned 4- aminopyridine derivatives and can be with
Medicine associated with it.
Further, medicine associated with described is the compound for treating following disease or illness：Nervus retrogression disease
Disease, extrapyramidal syndrome, depression, hyperkinetic syndrome, sleep-disorder, anxiety disorder, diabetes or tumour.
The invention has the advantages that：4- aminopyridine derivatives provided by the present invention are to adenosine A2AAcceptor has
Obvious selectivity antagonism, with preferable Pharmacokinetic Characteristics, can be applied to treatment to A2AAntagonism has reaction
Disease or illness composition or combination product in, in particular for treatment nerve degenerative diseases, extrapyramidal syndrome, suppression
The diseases such as strongly fragrant, hyperkinetic syndrome, sleep-disorder, anxiety disorder, diabetes or tumour or illness.
Embodiment
Below by way of specific embodiment, the invention will be further described, and these embodiments are merely to illustrate the present invention,
It is not limiting the scope of the invention.
Adenosine A is used as the invention provides one kind2AThe 4- aminopyridine derivatives of receptor antagonist, its general structure (I)
It is as follows：
Wherein：
R1Selected from halogen, cyano group or trifluoromethyl；
R2Selected from pyrazolyl, pyrrolidinyl, or through one or more halogens or C1-3Alkyl-substituted pyrazolyl or pyrrolidines
Base；
R3Xuan Zi oxazolyl, oxadiazolyls, triazol radical, or through one or more halogens or C1-3Wan bases replace oxazoles
Base.
Preferably, it is above-mentioned to be used as adenosine A2AThe 4- aminopyridine derivatives of receptor antagonist, wherein, R2Selected from pyrazolyl
Or pyrrolidinyl；R3Xuan Zi oxazolyl, oxadiazolyls, triazol radical, or through a C1-3Wan bases replace oxazolyls.
Preferably, it is above-mentioned to be used as adenosine A2AThe 4- aminopyridine derivatives of receptor antagonist, wherein, the 4- aminopyrimidines
Derivative is selected from following compounds：
Preferably, the 4- aminopyridine derivatives are selected from following compounds：(1)、(5)、(8)、(10)、(13)、(14)、
Or (18) (17).
Prepared present invention also offers a kind of above-mentioned 4- aminopyridine derivatives for treating to A2AAntagonism has
Purposes in the disease of reaction or the medicine of illness.
Further, the disease or illness include nerve degenerative diseases, extrapyramidal syndrome, depression, many dynamic synthesis
Levy, any one or more in sleep-disorder, anxiety disorder, diabetes or tumour.
Further, the tumour is lung cancer, oophoroma, cancer of pancreas, stomach cancer, breast cancer, glioblastoma, melanin
Knurl, clear-cell carcinoma, triple negative breast cancer, colorectal cancer, incidence cancer, carcinoma of urinary bladder, prostate cancer, hepatocellular carcinoma or bile duct
Cancer.
Further, the lung cancer is non-small cell lung cancer.
Present invention also offers a kind of pharmaceutical composition, wherein, it is used as adenosine A comprising above-mentioned2AReceptor antagonist
4- aminopyridine derivatives, and its pharmaceutically acceptable excipient.
Present invention also offers a kind of compound medicine comprising above-mentioned 4- aminopyridine derivatives and can be with
Medicine associated with it.
Further, medicine associated with described is the compound for treating following disease or illness：Nervus retrogression disease
Disease, extrapyramidal syndrome, depression, hyperkinetic syndrome, sleep-disorder, anxiety disorder, diabetes or tumour.
It is provided by the present invention to be used as adenosine A2AThe 4- aminopyridine derivatives of receptor antagonist can be synthesized by the following way
One of route is synthesized：
Synthetic route 1：
Reagent and condition：(a), acetic anhydride, backflow；(b), pyrazoles, cesium carbonate, dimethylformamide (DMF), 80 DEG C；
(c), trans- β-stvrYlboronic acid, sodium carbonate, dioxane, room temperature；Tetrakis triphenylphosphine palladium (Pd (PPh3)4), 90 DEG C；(d) it is, smelly
Oxygen, methanol (MeOH)/dichloromethane (CH2Cl2), -78 DEG C；(e), to Methyl benzenesulfonyl methyl isocyanide (TOSMIC), potassium carbonate
(K2CO3), MeOH, 80 DEG C；(f), N- bromo-succinimides, DMF.
Compound (1)-(3), (6)-(8), (11)-(13), the preparation of (15)-(17) is implemented by synthetic route 1.It is specific real
Applying method is referring to embodiment 1.The compound of wherein 5 fluorine substitutions of pyrimidine can also be prepared since the initiation material containing fluorine atom.
Synthetic route 2：
Reagent and condition：(a), m- chlorine benzylhydroperoxide, dichloromethane, room temperature；(b), N-bromosuccinimide (NBS),
DMF, room temperature；(c), 1. oxazole, butyl lithium (n-BuLi), tetrahydrofuran (THF), -78 DEG C~-20 DEG C, 2.Pd (PPh3)4, 80
℃；(d), 1H- pyrazoles, cesium carbonate, DMF, 90 DEG C；(e), pyrrolidines, cesium carbonate, DMF, 90 DEG C.
Using DMF as solvent, in the presence of alkali (such as cesium carbonate or butyl lithium), sulfoxide and the different business of formula (G)
Five-ring heterocycles (for example, pyrazoles, oxazole, oxadiazoles or triazole) derivative of industry sale reacts under room temperature or low temperature, generation 2
The derivative that position is replaced by five-ring heterocycles.For example, the intermediate of formula (G) reacts under these conditions Yu oxazole, then formula (H) is obtained
Derivative.
Further use DMF as solvent in the presence of alkali (such as cesium carbonate or sodium methoxide), derived by five-ring heterocycles
Thing (for example, pyrazoles or pyrrolidines) carrys out 6 chlorine atoms of substituted pyrimidines derivative.For example, derivative (H) and pyrazoles or pyrrolidines
Compound (19) and (23) can be made in reaction under these conditions.
Compound (19), (20), the preparation of (23-25) is implemented by synthetic route 2.Specific implementation method is referring to embodiment
15。
Synthetic route 3：
Reagent and condition：(a), cuprous cyanide, pyridine, microwave (MW), reaction is carried out 20 minutes at 250 DEG C.(b), it is fluorinated
Potassium (KF), double (dibenzalacetone) palladium (Pd (dba)2), 2- (dicyclohexyl phosphorus) -3,6- dimethoxys -2', 4', 6'- tri- is different
Propyl group -1,1'- biphenyl, trimethyl (trifluoromethyl) silane, dioxane, 20h, 140 DEG C.
In order to synthesize wherein pyrimidine 5- bit substituents R as defined above1It is the pyrimidine derivatives of cyano group or trifluoromethyl,
Can respectively it be prepared using the method described in synthetic route 3 using the similar precursor compound as shown in compound (1).
Compound (4), (5), (9), (10), (14), (18), (21), the preparation of (22) is implemented by synthetic route 3.Specifically
Implementation is referring to embodiment 4 and embodiment 5.
Embodiment 1：
The preparation of compound (1), its structural formula is as follows：
The preparation of compound (1) is implemented by said synthesis route 1：
The first step, prepares intermediate (A)
4- amino -2,6- dichloro pyrimidine (DCAP, 4g, 24.4mmol) is suspended in acetic anhydride (80mL, 860mmol),
It is heated to reflux under stirring 4 hours.After reaction solution cooling, it is concentrated in vacuo, remaining acetic anhydride is distilled off after adding toluene.Residue
It is dissolved in ethyl acetate and water, adds 10% NaHCO3Solution to solution PH is 7.Organic layer is washed with saturated common salt, is reclaimed
Residue is dissolved at acetic anhydride (40mL), 0-5 DEG C and stirred 2 hours after solvent, is collected by filtration to be dried in vacuo at precipitation, 40 DEG C and obtains
Mesosome (A).MS m/z(ESI):206.0[M+1]+。
Second step, prepares intermediate (B)
Intermediate (A) (1g, 5mmol) is dissolved in dry DMF (15mL), pyrazoles (340mg, 5mmol) and carbon is added
Sour caesium (1.6g, 5mmol).Mixture is extracted in 80 DEG C of stirrings are fallen back for 2 hours with ethyl acetate.Organic layer is used successively
After washing, saturated common salt water washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Residue is through silica gel column chromatography (3% methanol：
Dichloromethane) isolate and purify to obtain product (B).MS m/z(ESI):238.0[M+1]+。
3rd step, prepares intermediate (C)
By intermediate (B) (0.4g, 1.68mmol), trans- β-stvrYlboronic acid (0.5g, 3.36mmol) and sodium carbonate
(1.08g, 10.1mmol) is added in dioxane/water solution, is passed through after nitrogen about 30min, adds Pd (PPh3)4(0.2g,
0.16mmol), mixture be heated to 90 DEG C stirring 20 hours after be poured into water, ethyl acetate extract.Organic layer uses water successively
Wash, saturated common salt water washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Residue silica gel column chromatography (3% methanol：Dichloromethane
Alkane) isolate and purify to obtain product (C).MS m/z(ESI):306.1[M+1]+。
4th step, prepares intermediate (D)
Intermediate (C) (0.4g, 1.6mmol) is dissolved in ethanol/methylene (4/1,20ml) mixed solution, cooled down
To -78 DEG C, ozone is passed through 10 minutes.Nitrogen being passed through after completion of the reaction 20 minutes, adding methyl ether, reaction solution is warming up to after room temperature again
Being passed through nitrogen makes to obtain crude product (D) after solvent volatilization is complete.MS m/z(ESI):232.1[M+1]+。
5th step, prepares intermediate (E)
Intermediate (D) (460mg, 2mmol), TOSMIC (tolysulfonyl methyl isocyanide, 50mg, 4mmol), potassium carbonate
(860mg, 6mmol) mixture is added in methanol, is heated to 80 DEG C, after reacting 16 hours, reclaims methanol, and residue pours into water
In, ethyl acetate is extracted.Organic layer washing, saturated common salt water washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Residue
Silica gel column chromatography (5% methanol：Dichloromethane), obtain product (E).MS m/z(ESI):229.1[M+1]+。
5th step, prepare compound (1)
0.2g (1.25mmol) NBS (N- bromo-succinimides) is slowly added into and is suspended with 0.2g intermediates (E)
In cold DMF solution.After stirring 1 hour at room temperature, removal of solvent under reduced pressure.Residue is poured into water, and ethyl acetate is extracted.Organic layer
Washing, saturated common salt water washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Residue silica gel column chromatography (5% methanol：Two
Chloromethanes) purifying, compound (1) is made.MS m/z(ESI):307.1[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.55
(d,1H),8.32(s,1H),7.84(d,1H),7.53(s,1H),7.58(s,2H),6.58(dd,1H)。
Embodiment 2：
The preparation of compound (2), its structural formula is as follows：
The preparation of compound (2) is implemented by synthetic route 1, specific method reference implementation example 1.6th step uses NCS when reacting
(N- chlorosuccinimides) replaces NBS (N- bromo-succinimides) progress chloros and obtains compound (2).MS m/z(ESI):
263.0[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.53(d,1H),8.26(s,1H),7.82(d,1H),7.49(s,1H),
7.54(s,2H),6.55(dd,1H)。
Embodiment 3
The preparation of compound (3), its structural formula is as follows：
Implement that compound (3) is made by synthetic route 1.MS m/z(ESI):247.0[M+1]+,1HNMR(400MHz,
DMSO-d6)δ8.51(d,1H),8.27(s,1H),7.83(d,1H),7.48(s,1H),7.55(s,2H),6.54(dd,1H)。
Embodiment 4：
The preparation of compound (4), its structural formula is as follows：
Containing 11.3mg (20 μm of ol) Pd (dba)2With 15.8mg (29.4 μm of ol) 2- (dicyclohexyl phosphorus) -3,6- dimethoxies
The mixed solution of base -2', 4', 6'- triisopropyl -1,1'- biphenyl is added in 3ml dioxane, is then added mixed solution
Enter to containing 0.1g (0.33mmol) compound (1) (embodiment 1), in the mixture of 0.04g (0.65mmol) potassium fluoride, add
0.093g (0.65mmol) trimethyl (trifluoromethyl) silane, reaction solution stirring reaction at 140 DEG C uses diatom after 20 hours
Soil filtering, filter vacuum concentration.Residue silica gel column chromatography (dichloromethane：Methanol) purifying obtain compound (4).MS m/z
(ESI):297.1[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.51(d,1H),8.31(s,1H),7.85(d,1H),7.52
(s,1H),7.55(s,2H),6.58(dd,1H)。
Embodiment 5：
The preparation of compound (5), its structural formula is as follows：
Prepared by synthetic route 3.The cuprous cyanide of compound (1) and 0.06g (0.72mmol) is added in pyridine, mixed
Compound is placed in microwave reactor 250 DEG C and reacted 20 minutes.After thin-layer chromatography (TLC) monitoring reaction completely, ethyl acetate is added
Filtered afterwards with diatomite, successively with saturated sodium bicarbonate solution and saturated common salt water washing, organic layer is dried with anhydrous magnesium sulfate,
It is concentrated to give product (5).MS m/z(ESI):254.1[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.52(d,1H),8.29(s,
1H),7.83(d,1H),7.51(s,1H),7.57(s,2H),6.59(dd,1H)。
Embodiment 6:
The preparation of compound (6), its structural formula is as follows：
Compound (6) is prepared by synthetic route 1, wherein with methyl-tolysulfonyl methyl isocyanide during the reaction of the 5th step
(Me-TOSMIC) analog that tolysulfonyl methyl isocyanide (TOSMIC) prepares compound (E) is replaced.MS m/z
(ESI):261.1[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.55(d,1H),8.36(s,1H),7.84(d,1H),7.57
(s,2H),6.61(dd,1H),2.16(s,3H)。
Embodiment 7:
The preparation of compound (7), its structural formula is as follows：
Prepared by synthetic route 1.When 5th step is reacted the similar of TOSMIC prepare compounds (E) is replaced with Me-TOSMIC
Thing, then carries out chloro with NCS (N- chlorosuccinimides) replacement NBS (N- bromo-succinimides) and obtains compound (7).
MS m/z(ESI):277.1[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.52(d,1H),8.33(s,1H),7.82(d,
1H),7.55(s,2H),6.60(dd,1H),2.14(s,3H)。
Embodiment 8:
The preparation of compound (8), its structural formula is as follows：
Prepared by synthetic route 1.When 5th step is reacted the similar of TOSMIC prepare compounds (E) is replaced with Me-TOSMIC
Thing, then obtains compound (8) with NBS (N- bromo-succinimides) bromo.MS m/z(ESI):321.0[M+1]+,1HNMR
(400MHz,DMSO-d6)δ8.53(d,1H),8.34(s,1H),7.82(d,1H),7.56(s,2H),6.59(dd,1H),2.12
(s,3H)。
Embodiment 9：
The preparation of compound (9), its structural formula is as follows：
Compound (1) is replaced with compound (8), as described in Example 4 prepare compound (9).MS m/z(ESI):
311.1[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.50(d,1H),8.31(s,1H),7.79(d,1H),7.55(s,2H),
6.57(dd,1H),2.13(s,3H)。
Embodiment 10：
The preparation of compound (10), its structural formula is as follows：
Compound (1) is replaced with compound (8), as described in Example 5 prepare compound (10).MS m/z(ESI):
268.1[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.51(d,1H),8.30(s,1H),7.81(d,1H),7.53(s,2H),
6.58(dd,1H),2.16(s,3H)。
Embodiment 11：
The preparation of compound (13), its structural formula is as follows：
Prepared by synthetic route 1.The analog that pyrazoles obtains intermediate (B) is replaced with pyrrolidines when second step reacts, then
Compound (13) is made through the reaction such as coupling, cyclization, bromo.MS m/z(ESI):310.0[M+1]+,1HNMR(400MHz,
DMSO-d6)δ8.51(d,1H),7.82(d,1H),6.90(s,2H),3.51-3.74(m,4H),1.82-1.85(m,4H)。
Embodiment 12：
The preparation of compound (14), its structural formula is as follows：
Compound (1) is replaced with compound (13), compound (14) is made as described in Example 5.MS m/z(ESI):
257.1[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.50(d,1H),7.81(d,1H),6.94(s,2H),3.53-3.75
(m,4H),1.83-1.87(m,4H)。
Embodiment 13：
The preparation of compound (17), its structural formula is as follows：
Prepared by synthetic route 1.The analog that pyrazoles prepares intermediate (B), the 5th step are replaced in 2nd step reaction with pyrrolidines
The analog that TOSMIC prepares intermediate (E) is replaced with Me-TOSMIC during reaction, then with NBS (N- bromo-succinimides)
Bromo obtains compound (17).MS m/z(ESI):324.0[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.50(s,1H),
7.70(s,2H),3.52-3.76(m,4H),2.16(s,3H),1.82-1.86(m,4H)。
Embodiment 14：
The preparation of compound (18), its structural formula is as follows：
Compound (17) replaces compound (1), and compound (18) is made as described in Example 5.MS m/z(ESI):
271.1[M+1]+,1HNMR(400MHz,DMSO-d6)δ8.52(d,1H),7.69(s,2H),3.53-3.77(m,4H),1.82-
1.86(m,4H)。
Embodiment 15：
The preparation of compound (19), its structural formula is as follows：
Prepared by synthetic route 2.
The first step：Prepare intermediate 6- chloro- 2- (methylsulfinyl) pyrimidine -4- amine (F)
It is molten to the 50ml dichloromethane dissolved with 1.0g (5.7mmol) 6- chloro- 2- (methyl mercapto) pyrimidine -4- amine in 30 minutes
M- chlorine benzylhydroperoxide (77%) solution of 1.5g (6.9mmol) for being dissolved in 30ml dichloromethane is added in liquid.By the reactant mixture
It is stirred at room temperature 4 hours.The white precipitate of generation is filtered, is washed with dichloromethane for several times, is dried, obtain 1.0g intermediates
(F)。MS m/z(ESI):192.0[M+1]+。
Second step：Prepare the bromo- 6- of intermediate 5- chloro- 2- (methylsulfinyl) pyrimidine -4- amine (G)：By 1.12g
(it is phonetic that 6.3mmol N- bromo-succinimides (NBS) are slowly added into the chloro- 2- of 1.0g (5.3mmol) 6- (methylsulfinyl)
In the suspension of the 30ml DMF coolings of pyridine -4- amine.After stirring 50 minutes at room temperature, filtering precipitation is washed with cold DMF, with cold
For several times, vacuum drying is obtained (G) water washing.MS m/z(ESI):271.9[M+1]+。
3rd step：Prepare the chloro- 2- (oxazoles -2- bases of the bromo- 6- of intermediate 5-) pyrimidine -4- amine (H)：
Oxazole (260mg, 3.7mmol) is dissolved in anhydrous THF in the of -78 DEG C, nBuLi (1.6M is dissolved in n-hexane) is added and stirs
Mix 15 minutes, warm naturally to -20 DEG C.By 1g (3.7mmol) intermediate (G) and Pd (PPh3)4It is added in anhydrous THF.Again plus
Enter into Shang Shu oxazole solution.After mixed liquor reacts 2 hours at 80 DEG C, by solution down in 1N hydrochloric acid, ethyl acetate is carried
Take, organic layer washing, saturated common salt washing, anhydrous sodium sulfate drying, silica gel column chromatography (dichloromethane solution of 5% methanol)
Required product.MS m/z(ESI):276.9[M+1]+。
4th step：Prepare compound (19)
Into the 3ml DMF solutions dissolved with 0.15g intermediates (H) add 0.11g (1.64mmol) 1H- pyrazoles and
0.18g (0.55mmol) cesium carbonate.The mixture is stirred 24 hours at 90 DEG C.Be concentrated under reduced pressure solvent DMF.It is washed with water
Crude product, dry compound (19).MS m/z(ESI):307.1[M+1]+。
Embodiment 16：
The preparation of compound (25), its structural formula is as follows：
Prepared by said synthesis route 2, specific method is referring to embodiment 15.In three-step reaction, intermediate (G) and 1H-
Triazole is changed in the case where cesium carbonate is acted on, and reaction a few hours are stirred at room temperature in DMF solution, and to prepare corresponding intermediate (H) similar
Thing.Again compound (25) is obtained with the similar approach of embodiment 15 with 6 chlorine of pyrazoles substituted pyrimidines.MS m/z(ESI):307.1[M+
1]+,1HNMR(400MHz,DMSO-d6)δ9.14(s,1H),8.60(s,1H),8.45(d,1H),7.64(d,1H),6.55(dd,
1H)。
Pharmacological activity：
(1) to adenosine A2AAcceptor binding affinity assays：
Using standard technique, by determining people source adenosine A2AReceptor selective radioligand
[3H] CGS-21680 conversion come determine the compounds of this invention in vitro combine people source adenosine A2AThe combination parent of acceptor
And power, as a result it is summarised in table 1.
With encoding human source adenosine A2AThe plasmid of acceptor stable transfection on HEK-293 cells, using the cell in three (hydroxyl first
Base) film prepared using standard technique in aminomethane (Tris-HCl) buffer solution (pH=7.4).About 15 μ g memebrane protein and 50nM
Radioligand [3H] CGS-21680,10 μM of testing compounds mix and are incubated altogether at 25 DEG C 90 minutes.50 μM of addition
NECA (adenosine -5 '-N- alkylcarboxies acid amides) determine non-specific binding.By membrane filtration and wash 3 times it is uncombined to remove
Radioligand.Filter determines the part combined with scintillation counter.Determined by analyzing multiple different concentration concentration-
Respond binding competition curve.IC is calculated using nonlinear fitting program50Value.Counted by Cheng-Prusoff equatioies (II)
Calculate the inhibition constant (Ki) of compound.
Ki=IC50/(1+[L]/KD) (Ⅱ)
Wherein IC50It is the compound concentration when radioligand of conversion 50% is combined, [L] is the free of radioligand
Concentration, KD is the dissociation constant of radioligand.IC50Value is obtained by the Prism softwares nonlinear regression and fitting data
Arrive.The smaller explanation compound of Ki numerical value is to people source adenosine A2AThe antagonism of acceptor is more obvious.
(2) to adenosine A1Acceptor binding affinity assays：
Compound DPCPX (the 1,3- dipropyl-xanthine of ring penta) is the adenosine A of known high activity1Receptor antagonist (text
Offer and report its Ki=0.45nM).Using standard technique, by determining people source adenosine A1Receptor selective radioligand [3H]DPCPX
Conversion come determine the compounds of this invention in vitro combine people source adenosine A1The binding affinity of acceptor, to judge chemical combination of the present invention
Thing is to A2AThe selective intensity of acceptor.As a result it is summarised in table 1.
With encoding human source adenosine A1The plasmid of acceptor stable transfection on Chinese hamster ovary celI, using the cell improvement HEPES
Film is prepared using standard technique in buffer solution (pH=7.4).About 10 μ g memebrane protein and 1nM radioligands [3H]DPCPX、10
μM testing compound is mixed and is incubated altogether at 25 DEG C 90 minutes.100 μM of R (-)-PIA (R- Phenylisopropyladenosines) of addition determine
Non-specific binding.By membrane filtration and 3 times are washed to remove uncombined radioligand.Filter is determined with scintillation counter
With reference to part.Concentration-response binding competition curve is determined by analyzing multiple different concentration.Calculated by preceding method
The inhibition constant (Ki) of compound.
(3) to people source adenosine A2AAcceptor platelet aggregation inhibitory activity is analyzed：
CGS-21680 is adenosine A2AThe high activity activator of acceptor, can act on adenosine A2AAcceptor promotes platelet aggregation
Collection.The platelet aggregation for suppressing CGS-21680 inductions by test compound can obtain the compounds of this invention on a cellular level
To adenosine A2AThe antagonistic activity of acceptor.As a result it is summarised in table 1.
At 37 DEG C, the blood plasma rich in human blood platelets is in thromboxane A2Under (10 μM) effects of receptor stimulating agent U-46619, upper strata
Rich in hematoblastic blood plasma (6 × 108Blood platelet/milliliter) aggregation is produced, detected with optics aggregometer.With 1 μM of CGS-21680
As comparison medicine, if platelet aggregation reaches 50% or more (>=50%) in test compound (30 μM) system in 5 minutes,
Show that test substances there may be adenosine A2AReceptor agonist activity.
When not observing obvious agonist activity under a certain tester concentration, it reduces (1 μM) induction of CGS-21680
Suppression reaction reach 50% or more (>=50%), then show that test compound has adenosine A2AReceptor antagonist activity.Before pressing
The inhibition constant (Ki) that method calculates compound is stated, the smaller explanation compound of Ki numerical value is to people source adenosine A2AThe antagonism of acceptor
It is more obvious.
The compound of table 1. (1)-(25) obtained in affinity analysis and to platelet aggregation set analysis to people source adenosine A2A
And A1The inhibition constant of acceptor ("/" represents not test)
As shown in Table 1, the compound prepared by the present invention can be to people source adenosine A in nM concentration ranks2AAcceptor has
Obvious antagonism.And work as R1The suction of group electrically strengthens, and such as halogen atom is changed into chlorine from bromine, or is changed into cyanogen from halogen atom
During base, the compounds of this invention is to people source adenosine A2AThe antagonistic activity of acceptor is significantly improved.
In addition, above-claimed cpd VI is the compound of embodiment 1 in CN102892761, it is pyrazole compound, structural formula
It is as follows：
Now it regard it as positive control in the present invention.In patent CN102892761, it was recently reported that VI pairs of the compound
People source A2AThe affinity Ki values of acceptor are 12nM, in CHO-A2AIt is 25nM to cAMP Ki values on cell.Present invention employs upper
The method of testing stated, the antagonistic activity for surveying compound VI is more poor than the result of CN102892761 patent report (being shown in Table 1).
In 4 kinds of receptor subtypes of adenosine, due to A1And A2AIt is high expressed receptor, low-level adenosine is dense under physiological status
It can be acted when spending, and A2BAnd A3Expression quantity it is relatively low, only in pathological conditions, adenosine roll up when can just activate production
Raw pathologic effect.This invention Suo Shu oxazole compounds are relative to A1Acceptor, to A2AAcceptor has the (selection of obvious high selectivity
Property coefficient is compound in table 1 to people source adenosine A1The inhibition constant of receptor affinity and to people source adenosine A2AReceptor affinity
The ratio of inhibition constant), and compound VI choosing is reported in 3-4 times of CN102892761 of selectivity factor of part of compounds
Property coefficient is selected, significant progress can be considered to have in the art.
By the compounds of this invention to people source adenosine A2AThe analysis of acceptor platelet aggregation inhibitory activity, demonstrates them thin
Antagonism A in born of the same parents' level2AThe function of acceptor.The compounds of this invention of most of tests is shown than in CN102892761
Cytoactive stronger described pyrazole compound VI, the cytoactive of such as compound (5) is stronger than VI about 4.5 times.
Thus, compared to the pyrazole compound VI described in CN102892761, this invention Suo Shu oxazole compounds
To people source adenosine A2AThe antagonistic activity and functional activity of acceptor are suitable or more excellent, and to people source adenosine A1The affinity of acceptor is obvious
Reduction, shows to A2AThe high selectivity of acceptor.
Pharmacokinetic Evaluation：
Test the compounds of this invention (1), (5), (8), (10), the pharmacokinetics of (13).
According to a conventional method, using SD rats as animal subject, determine rat intravenous injection using LC/MS/MS methods and give this hair
Drug concentration behind bright compound (1), (5), (8), (10), (13) not in the same time in blood plasma, research the compounds of this invention is big
Pharmacokinetics behavior in mouse body, evaluates its characteristics of pharmacokinetics.The compound VI that now patent CN102892761 is reported as
Positive control, is tested simultaneously using the above method.Its result is summarized in table 2.
The compounds of this invention of table 2. (1), (5), (8), (10), pharmacokinetic parameter (the SD rat intravenous injections of (13)
1.0mg/kg)
From the result of table 2, this invention Suo Shu oxazole compounds have more preferable Pharmacokinetic Characteristics, than
Pyrazole compound VI described in CN102892761 has significantly lower plasma clearance, so as to remain higher
Blood concentration and longer effective time；Half-life period of the oxazole compounds that this invention is stated in rat body is compound VI
More than 3 times of half-life period, and Increased Plasma Half-life 20%-40% is it is believed that more excellent, to extend more than 1 times in the art
I.e. it is believed that with significant progressive；Thus the compounds of this invention is compared to the pyrazole compound described in CN102892761
VI is in the higher blood concentration of maintenance and has on longer effective treatment time significant progressive.
In summary, 4- aminopyridine derivatives provided by the present invention are to people source adenosine A2AAcceptor has obvious antagonism
Effect, and show the A of height2AReceptor-selective, while the metabolic adsorption in rat body is good, can be applied to treatment pair
A2AAntagonism has in the disease of reaction or the composition of illness or combination product, in particular for treatment nervus retrogression disease
The diseases such as disease, extrapyramidal syndrome, depression, hyperkinetic syndrome, sleep-disorder, anxiety disorder, diabetes or tumour or illness.
Although present disclosure is discussed in detail by above preferred embodiment, but it should be appreciated that above-mentioned
Description is not considered as limitation of the present invention.After those skilled in the art have read the above, for the present invention's
A variety of modifications and substitutions all will be apparent.Therefore, protection scope of the present invention should be limited to the appended claims.
Claims (10)
1. one kind is used as adenosine A2AThe 4- aminopyridine derivatives of receptor antagonist, it is characterised in that general structure (I) is as follows：
Wherein：
R1Selected from halogen, cyano group or trifluoromethyl；
R2Selected from pyrazolyl, pyrrolidinyl, or through one or more halogens or C1-3Alkyl-substituted pyrazolyl or pyrrolidinyl；
R3Xuan Zi oxazolyl, oxadiazolyls, triazol radical, or through one or more halogens or C1-3Wan bases replace oxazolyls.
2. it is used as adenosine A as claimed in claim 12AThe 4- aminopyridine derivatives of receptor antagonist, it is characterised in that R2Choosing
From pyrazolyl or pyrrolidinyl；R3Xuan Zi oxazolyl, oxadiazolyls, triazol radical, or through a C1-3Wan bases replace oxazoles
Base.
3. it is used as adenosine A as claimed in claim 12AThe 4- aminopyridine derivatives of receptor antagonist, it is characterised in that the 4-
Aminopyridine derivative is selected from following compounds：
4. the 4- aminopyridine derivatives in a kind of 1-3 such as claim as described in any one are being prepared for treating to A2AAntagonism
Effect has the purposes in the disease of reaction or the medicine of illness.
5. purposes as claimed in claim 4, it is characterised in that the disease or illness include nerve degenerative diseases, cone
Any one or more in outer syndrome, depression, hyperkinetic syndrome, sleep-disorder, anxiety disorder, diabetes or tumour.
6. purposes as claimed in claim 5, it is characterised in that the tumour is lung cancer, oophoroma, cancer of pancreas, stomach cancer, mammary gland
Cancer, glioblastoma, melanoma, clear-cell carcinoma, triple negative breast cancer, colorectal cancer, incidence cancer, carcinoma of urinary bladder, prostatitis
Gland cancer, hepatocellular carcinoma or cholangiocarcinoma.
7. purposes as claimed in claim 6, it is characterised in that the lung cancer is non-small cell lung cancer.
8. a kind of pharmaceutical composition, it is characterised in that it includes and is used as adenosine A as described in any one in claim 1-32A
The 4- aminopyridine derivatives of receptor antagonist, and its pharmaceutically acceptable excipient.
9. a kind of compound medicine, it is characterised in that derive comprising the 4- aminopyrimidines as described in any one in claim 1-3
Thing and can be with medicine associated with it.
10. compound medicine as claimed in claim 9, it is characterised in that medicine associated with described is for treating following disease
Or the compound of illness：Nerve degenerative diseases, extrapyramidal syndrome, depression, hyperkinetic syndrome, sleep-disorder, anxiety disorder, sugar
Urine disease or tumour.
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| CN109662966A (en) * | 2017-10-16 | 2019-04-23 | 北京莱科金基因科技有限责任公司 | Purposes of the istradefylline in the drug that preparation is used for oncotherapy |
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| WO2021085540A1 (en) | 2019-11-01 | 2021-05-06 | ユニマテック株式会社 | Fluorine-containing pyrimidine compound and manufacturing method for same |
| WO2021246095A1 (en) | 2020-06-01 | 2021-12-09 | ユニマテック株式会社 | Fluorine-containing fused ring pyrimidine compound and method for producing same |
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| CN109662966A (en) * | 2017-10-16 | 2019-04-23 | 北京莱科金基因科技有限责任公司 | Purposes of the istradefylline in the drug that preparation is used for oncotherapy |
| CN113874397A (en) * | 2019-03-29 | 2021-12-31 | 艾库斯生物科学有限公司 | Treatment of cancer using identified adenosine fingerprints |
| CN111943938A (en) * | 2019-05-17 | 2020-11-17 | 上海再极医药科技有限公司 | Synthetic method of A2A adenosine receptor antagonist |
| WO2021085540A1 (en) | 2019-11-01 | 2021-05-06 | ユニマテック株式会社 | Fluorine-containing pyrimidine compound and manufacturing method for same |
| WO2021246095A1 (en) | 2020-06-01 | 2021-12-09 | ユニマテック株式会社 | Fluorine-containing fused ring pyrimidine compound and method for producing same |
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| WO2019007140A1 (en) | 2019-01-10 |
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