CN103664908A - Aminopyrimidine heterocyclic compound having adenosine receptor antagonizing activity - Google Patents
Aminopyrimidine heterocyclic compound having adenosine receptor antagonizing activity Download PDFInfo
- Publication number
- CN103664908A CN103664908A CN201310666030.1A CN201310666030A CN103664908A CN 103664908 A CN103664908 A CN 103664908A CN 201310666030 A CN201310666030 A CN 201310666030A CN 103664908 A CN103664908 A CN 103664908A
- Authority
- CN
- China
- Prior art keywords
- aminopyrimidine
- adenosine receptors
- antagonistic activity
- ring
- ring compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- WGHWGHBDYOHJLS-WTIBDHCWSA-N CC1[C@H](C)C(C)NCC1 Chemical compound CC1[C@H](C)C(C)NCC1 WGHWGHBDYOHJLS-WTIBDHCWSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
The present invention proposes that one kind has the active aminopyrimidine heterocyclic compound of adenosine receptor antagonist, including the compound and its pharmaceutically acceptable salt, various isotopes, various isomers and various crystalline structures, has structure shown in general formula I:
It is of the invention that there is the active aminopyrimidine heterocyclic compound of adenosine receptor antagonist, can as effective antagonist of adenosine receptor, can be used in treatment or prevention because adenosine level it is not normal caused by illness.
Description
Technical field
The present invention relates to medical technical field, relate in particular to a kind of aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity.
Background technology
Adenosine is ubiquitous conditioning agent in multiple physiological activity, particularly, in cardiovascular and neural system, by the interaction with specific cell surface receptor, regulates and controls different physiological roles.Known Adenosine Receptors is divided into A1, A2A, A2B and A3 acceptor, belongs to g protein coupled receptor family.Wherein, A1 and A3 acceptor, by suppressing adenylate cyclase with G protein binding, cause that cell cAMP level reduces, A2A and A2B acceptor by with G protein binding activated adenyl cyclase, cause that cell cAMP level raises.
Under normal physiological condition, A1 Adenosine Receptors level is constant.Yet under stressed condition, under local anemia or inflammation condition, A1 Adenosine Receptors level can be raised.For example, in the human airway epithelial cells and bronchial smooth muscle of mankind's asthmatic patient, A1 Adenosine Receptors is raised activation, cause airway hyperreactivity (airway hyperreactivity), inflammation and the medium of airway remodeling (airway remodelling) and the release of cytokine, and cause bronchial tissue that bronchostenosis occurs.Therefore, A1 adenosine receptor antagonists can play potential result for the treatment of in inflammatory disorders and asthma.In addition, in the illness of for example hypertension, congestive heart failure, A1 adenosine receptor antagonists also has treatment potential.
A2B Adenosine Receptors hypotype (referring to Feoktistov, I., Biaggioni, I., Pharmacol.Rev.1997,49,381-402) in various human and murine tissue, identify and regulate multiple physiologically active.For example, the combination meeting of adenosine and A2B acceptor promotes the growth of endotheliocyte, thereby stimulates vasculogenesis.But the high hyperplasia of endotheliocyte can promote diabetic retinopathy, and at tumorigenesis medium vessels, undesirable increase can occur.Therefore, adenosine A 2B receptor antagonist can relax or prevent blood vessel too much, thereby prevents retinopathy and suppress tumour to form.In stomach and intestine and metabolic system, A2B Adenosine Receptors hypotype seems to generate, regulate bowel movement relevant with intestinal secretion with regulating liver glucose.Therefore A2B antagonist may contribute to treat type II diabetes and obesity.In addition, by the A2B receptors bind with mastocyte, can stimulate I type allergy illness, as asthma, spring fever and atopic eczema.Therefore, block these Adenosine Receptorss treatment benefit can be provided such illness.
Research finds, the intensity of activation of A3 acceptor causes mast cell degranulation state, and promotes to discharge vaso-excitor material, causes desensitization and ypotension to be replied, simultaneously with the decline of motion, the desensitization of acceptor is relevant.Therefore, A3 receptor antagonist is recommended as anti-asthmatic medicament exploitation (Fishman and Bar-Yehuda, 2003; Nadeem and Mustafa, 2006).Also studies show that A3 adenosine receptor antagonists is comprising myocardial preservation (Vasc. Pharmacol., 2005,42,271; J.Pharm.Exp.Ther., 2006,319,1200) and in the various diseases of cancer (WO200010391) play therapeutic action.
Adenosine A 2 A receptor is mainly distributed in striatum, regulates the release of GABA in striatum, thereby may regulate the neuronic function of medium-sized many sour jujubes.Research and Pharmacological Analysis to gene modification mouse show; A2A acceptor is treatment central nervous system disease; for example parkinsonism, Huntington Chorea, attention deficit hyperactivity disorder (ADHD), apoplexy, alzheimer's disease (Fredholm; Annu.Rev.Pharmacol.Toxicol.2005,45:385-412; Behav.Brain Res.2007,185:32-42; Dall ' Igna, Exp.Neurol.2007,203 (1): 241-5, Arendash, Neuroscience2006,142:941-52) and various organic sources psychosis (Weiss, Neurology, 2003, treatment target likely 61:S88-93).Therefore, A2A receptor antagonist may contribute to treat neurodegeneration movement disorders as Parkinson's disease and Huntington Chorea (Tuite P., J.Expert Opin.Investig.Drugs2003,12:1335-52; Popoli P., J.Neurosci.2002,22:1967-75), restless legs syndromes (Happe S., Neuropsychobiogy2003,48:82-6) and the dyskinesia disease (Jenner P.J.Neurol.2000, the 247Suppl2: II 43-50) that for example by long-term taking tranquilizer and Dopamine HCL medicine, are caused.In addition, A2A antagonist may have treatment potentiality (Stone TW., the Drug Dev.Res.2001 as neuroprotective; 52:323-330); and be used for the treatment of somnopathy (Dunwiddie TV., Ann.Rev.Neurosci.2001,24:31-55).
Therefore, improve because above-mentioned adenosine level is not normal, cause illness, just effective adenosine receptor antagonists need to be proposed.
Summary of the invention
Defect in view of above-mentioned prior art exists, the object of the invention is to propose a kind of aminopyrimidine heterogeneous ring compound, can, as effective antagonist of Adenosine Receptors, can be used in the illness that treatment or prevention cause because adenosine level is not normal.
Object of the present invention will be achieved by the following technical programs:
An aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, comprises this compound, its pharmacy acceptable salt, various isotropic substance, various isomer or various crystalline structure, has the structure shown in general formula I:
Wherein, R1 is included the heterocycle that the one or more substituting groups in low alkyl group, lower alkoxy, halogen and cyano group replace;
R2 is OR5, NR5R6 or heterocycle, and described heterocycle is the heterocycle being replaced by 0-4 R5 group;
R3 is hydrogen atom, alkyl, acyl group or the hetero-aromatic ring that at least contains a nitrogen-atoms, and described hetero-aromatic ring is replaced by 0-4 R5 group;
R4 is halogen, cyano group or alkyl;
R5 is low alkyl group, lower alkoxy, alkoxyalkyl, oxo, cyano group, halogen, hydroxyl,-C (O)-alkyl, low-grade alkenyl, low-grade alkynyl, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle, Heterocyclylalkyl or hydrogen atom are included low alkyl group, halogen, alkoxyalkyl, hydroxyl, cyano group, aryl, the low alkyl group replacing with one or more substituting groups in-C (O)-alkyl, lower alkoxy, alkoxyalkyl, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle or Heterocyclylalkyl,
R6 is hydrogen atom, low alkyl group, lower alkoxy or alkoxyalkyl;
In the above-mentioned aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, preferred:
Described low alkyl group is alkyl or the substituted hydrocarbon radical of saturated straight chain, side chain, ring-type, double-ring or the Spirocyclic of 1-10 carbon atom composition;
Described low-grade alkenyl is alkyl or the substituted hydrocarbon radical of the straight chain that contains at least one carbon-carbon double bond, side chain, ring-type, double-ring or the Spirocyclic of 1-10 carbon atom composition;
Described low-grade alkynyl is alkyl or the substituted hydrocarbon radical of the straight chain, side chain, ring-type, double-ring or the Spirocyclic that contain at least one carbon carbon triple bond of 1-10 carbon atom composition;
Described halogen is fluorine, chlorine, bromine and iodine;
Heteroatoms in described heteroaryl, assorted alkyl, heteroaralkyl, heterocycle, Heterocyclylalkyl is nitrogen, oxygen, sulphur, and the quaternary ammonium salt of various oxidation state and nitrogen;
Described aryl is phenyl ring, naphthalene nucleus and substitutive derivative thereof, or is the derivative cyclic substituents of saturated rings and aromatic ring;
Described heterocycle is monocycle, dicyclo, three ring or the volution substituting groups of the nonaromatic combination that comprises an atom in nitrogen, oxygen and sulphur or a plurality of atoms, and the cyclic substituents of their various oxidation state;
Described heteroaryl is 5-12 former molecular ring of the combination that comprises an atom in nitrogen, oxygen and sulphur or a plurality of atoms and the cyclic substituents of various oxidation state forms thereof, or is the derivative cyclic substituents of saturated rings and hetero-aromatic ring.
In the above-mentioned aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, preferred, R1 comprises:
In the above-mentioned aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, preferred, R2 comprises:
In the above-mentioned aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, preferred, R3 comprises:
In the above-mentioned aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, preferred, R4 comprises:
In the above-mentioned aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, preferred, it comprises following compounds and pharmacy acceptable salt, various isotropic substance, various crystalline structure and various isomer:
In the above-mentioned aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, preferred, isotropic substance comprises but is not only limited to
2h,
3h,
11c,
13c,
14c,
15n,
17o,
18o,
18f,
32p,
35s,
36cl.
In the above-mentioned aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, preferred, various isomer are including, but not limited to steric isomer, cis-trans-isomer, tautomer.
The present invention also provides a kind of combined utilization composition with the aminopyrimidine heterogeneous ring compound of Adenosine Receptors antagonistic activity, and this combined utilization composition is that the composition that combined utilization obtains is carried out in the aminopyrimidine heterogeneous ring compound of the above and one or more the combination in L-DOPA, dopamine agonist, Dopamine HCL decarboxylase inhibitor, catechol-O-methyltransferase inhibitor and oxidase inhibitor.
The present invention also provide there is the aminopyrimidine heterogeneous ring compound of Adenosine Receptors antagonistic activity, the application in the medicine of preparing antagonism Adenosine Receptors of the combined utilization composition of aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity.
The pyridine-heterocyclic compound that compound of the present invention has hedgehog path antagonistic activity has the purposes for the preparation of antitumor drug.
The aminopyrimidine heterogeneous ring compound with adenosine receptor antagonists activity of the present invention has and is used for the treatment of the pathology patient's condition that can be improved by the antagonistic action of Adenosine Receptors (particularly by the antagonistic action of A2A Adenosine Receptors) or the purposes of disease.Improved disease and illness by the antagonistic action of Adenosine Receptors, include but not limited to alzheimer's disease, Parkinson's disease, neuroprotective, schizophrenia, anxiety, pain, respiratory deficiency, depression, asthma, transformation reactions and psychoactive substanceabuse.
Outstanding effect of the present invention is:
The aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity that the present invention proposes, can, as effective antagonist of Adenosine Receptors, can be used in the illness that treatment or prevention cause because adenosine level is not normal.
Below just accompanying drawing in conjunction with the embodiments, is described in further detail the specific embodiment of the present invention, so that technical solution of the present invention is easier to understand, grasp.
Accompanying drawing explanation
Fig. 1 is the nonlinear least square method fitting of a curve figure of the binding ability of compound A-13 0 and A2A Adenosine Receptors;
Fig. 2 is the nonlinear least square method fitting of a curve figure of the binding ability of compound A-13 1 and A2A Adenosine Receptors.
Embodiment
Below by specific embodiment, method of the present invention is described, but the present invention is not limited thereto.Experimental technique described in following embodiment, if no special instructions, is ordinary method; Described reagent and material, if no special instructions, all can obtain from commercial channels.Solvent for use and medicine are analytical pure or chemical pure; Solvent all passes through re-distillation before use; Anhydrous solvent is all processed according to standard method or literature method.Column chromatography silica gel (100-200 order) and tlc silica gel (GF254) are Haiyang Chemical Plant, Qingdao and chemical plant, Yantai product; If not otherwise specified, all adopt sherwood oil (60-90 ℃)/ethyl acetate (v/v) as eluent; The ethanolic soln of iodine or phospho-molybdic acid for developer; All extraction solvent unexplained reference are all used anhydrous Na
2sO
4dry.Bruck-400 type nuclear magnetic resonance analyser record for 1H NMR, TMS is interior mark.U.S. Agilent company 1100 type HPLC-ESI-MSn combined instrument (LC-MSD Trap) records for LC-MS, diode-array detector (DAD), detects wavelength 214nm and 254nm, ion trap mass spectrometry (ESI source).HPLC post is Agela Durashell C18 (4.6 * 50mm, 3.5 μ m); Moving phase is 0.1%NH
4hCO
3the aqueous solution: acetonitrile (in 5 minutes from 5:95 to 95:5); Flow velocity is 1.8mL/min.
Embodiment 1
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A1 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
1) intermediate A 1-2's is synthetic:
By A1-1(500mg, 2.27mmol) and the amino pyrazine of 2-(432mg, 4.54mmol) be dissolved in 5mL anhydrous tetrahydro furan, under condition of ice bath, slowly add sodium hydride (136mg, 4.54mmol, be scattered in the suspension that forms 80wt% in mineral oil), finish, rise to stirring at normal temperature 12h, pour in 150mL water, by the solid suction filtration generating, with a small amount of water and sherwood oil drip washing, obtain a yellow solid (520mg, yield 82%).
2) intermediate A 1-3's is synthetic:
By A1-5(278mg, 1.00mmol) be dissolved in the 5mL tetrahydrofuran (THF) of 0 ℃, slowly add while stirring metachloroperbenzoic acid (459mg, purity 75%, 2.00mmol), after stirring at normal temperature 12h, be spin-dried for, with column chromatography refining (moving phase is petrol ether/ethyl acetate=2:1～1:1), obtain a yellow solid (80mg, yield 26%).
3) product A 1 is synthetic:
Respectively by A1-6(80mg, 0.26mmol), pyrazoles (177mg, 2.60mmol) and Cs
2cO
3(421mg, 1.30mmol) is dissolved in 1mL DMF.Be heated with stirring to 120 ℃, after reaction 6h, be chilled to room temperature, pour 10mL water into, by the solid filtering generating, be dried to obtain a yellow solid (10mg, yield 12%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting solid is compound
Embodiment 2
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A2 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
1) intermediate A 2-2's is synthetic:
In the three-necked bottle of 100mL, add the chloro-2-(methylthio group of 4,6-bis-) pyrimidine (4g, 20mmol), with 40mL anhydrous tetrahydro furan, dissolve, and with nitrogen replacement three times.Under-78 ℃ of conditions, drip while stirring lithium diisopropylamine (15.1mL, 2mol/L, 30.2mmol), finish and be warming up to-50 ℃, after reaction 2h, move to normal temperature, drip the anhydrous tetrahydro furan 40mL that is dissolved with elemental iodine (7.66g, 30.2mmol).Stir after 1h, add saturated NaS
2o
3aqueous solution 20mL, is stirred to organic layer not after fading, and is extracted with ethyl acetate (50mL * 3 time), and organic phase, with being spin-dried for after anhydrous sodium sulfate drying, obtains yellow solid (6g, yield 93%).
2) intermediate A 2-3's is synthetic:
By A2-2(2.04g, 6.34mmol) and the amino pyrazine of 2-(725mg, 7.63mmol) be dissolved in 10mL anhydrous tetrahydro furan, under condition of ice bath, slowly add sodium hydride (380mg, 12.7mmol, be scattered in the suspension that forms 80wt% in mineral oil), finish, rise to after stirring at normal temperature 12h, pour 150mL water into, by the solid filtering generating, with a small amount of water and sherwood oil drip washing, obtain a light brown solid (2.14g, yield 89%).
3) intermediate A 2-4's is synthetic:
By A2-3(2.14g, 5.63mmol) be dissolved in the 150mL tetrahydrofuran (THF) of 0 ℃ after, slowly add while stirring metachloroperbenzoic acid (purity 75%, 2.7g, 11.739mmol), after stirring at normal temperature 12h, add NaHCO
3and NaS
2o
3saturated aqueous solution 250mL, stirring at normal temperature 10min, the solid filtering by generating, with a small amount of water and PE drip washing, is able to light brown solid (1.57g, yield 68%).
4) product A 2 is synthetic:
Respectively by A2-4(780mg, 1.898mmol), pyrazoles (1033mg, 15.19mmol) and Cs
2cO
3(2780mg, 8.533mmol) is dissolved in 5mLN, in dinethylformamide.Be heated with stirring to 120 ℃, after reaction 6h, be chilled to room temperature, pour 250mL water into, by solid filtering, with column chromatography refining (moving phase is 1% ethanol/methylene), obtain a white solid (250mg, yield 30%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting solid is compd A 2
Embodiment 3
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A3 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
1) intermediate A 3-2's is synthetic:
By A3-1(1.0g, 9.6mmol) be dissolved in methyl alcohol 14mL, add sodium methylate (25mg, 0.44mmol), nitrogen protection.This mixed solution stirs and spends the night at normal temperatures, adds ammonium chloride (535mg, 10mmol), stirring at normal temperature 5 hours.Filter, the mixed solvent washing with 50mL Virahol/ethyl acetate=1/10, obtains white solid (1.5g, yield 96%).
2) intermediate A 3-3's is synthetic:
By A3-2(400mg, 2.54mmol) be dissolved in 14mL ethanol, ice bath adds the methanol solution of 2mL28% sodium methylate under stirring, under this mixture ice bath, stir 15 minutes, add the fluoro-diethyl malonate of 2-(1.81g, 10.2mmol), first stirring at normal temperature one hour, then reflux 4 hours.Cool to room temperature adds concentrated hydrochloric acid under ice bath stirs, and regulates PH to 2.Revolve and steam part ethanol, filter, gained solid with ethanol and ether washing, obtains a yellow solid (260mg, yield 49%) successively.
3) intermediate A 3-4's is synthetic:
By A3-3(1.70g, 8.14mmol) be dissolved in 20mL toluene, under ice bath, add successively triethylamine (3.30g, 32.6mmol) and phosphorus oxychloride (12.5g, 81.4mmol), this mixture refluxes 2 hours at 110 ℃.Vacuum rotary steam, removes toluene and phosphorus oxychloride, in solute, slowly adds frozen water and saturated sodium bicarbonate aqueous solution, to no longer including bubble, emerges.Add ethyl acetate (200mL), saturated aqueous common salt for organic phase (40mL) is washed, and anhydrous sodium sulfate drying revolves desolventizing after filtration, through column chromatography, refining (moving phase is sherwood oil to solute: ethyl acetate=5:1) obtain white solid (1.0g, yield 65%).
4) intermediate A 3-5's is synthetic:
By A3-4(1.0g, 4.1mmol), the amino pyrazine (584mg of 2-, 6.15mmol) be dissolved in 50mL tetrahydrofuran (THF), ice bath adds sodium hydride (300mg, 10.0mmol under stirring, be scattered in the suspension that forms 80wt% in mineral oil), this mixed solution stirs and spends the night at normal temperatures.Vacuum rotary steam, remove tetrahydrofuran (THF), under stirring in solute, slowly add 40mL water and 300mL ethyl acetate, saturated sodium-chloride washing (40mL) for organic layer, after anhydrous sodium sulfate drying filters, revolve desolventizing, through column chromatography, refining (moving phase is methyl alcohol to solute: methylene dichloride=1:60) obtain yellow solid (700mg, yield 53%).
5) compound A-13 is synthetic:
By A3-5(20mg, 0.063mmol) be dissolved in 1mL tetrahydrofuran (THF), add Pyrrolidine (12.3mg, 0.173mmol), this mixed solution reacts 8 hours at 60 ℃.Cooling, vacuum rotary steam, removes tetrahydrofuran (THF) and Pyrrolidine.Solute is through column chromatography (methylene dichloride: methyl alcohol=150:1) obtain a white solid (12mg, yield 60%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting solid is compound A-13
Embodiment 4
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A7 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
By A3-5(40mg, 0.13mmol) be dissolved in 1.5mL ethanol, add anhydrous hydrazine (13mg, 0.26mmol).Being heated to 90 ℃ refluxes 22 hours.Reaction solution is cooled to 0 ℃, slowly adds methyl ethyl diketone (26mg, 0.26mmol), reheat 90 ℃ and reflux 2 hours.Vacuum rotary steam, removes ethanol.Thick product is dissolved in 10mL methylene dichloride, washes twice with water, and salt wash once, organic layer dried over sodium sulfate, and vacuum rotary steam, solute refines through column chromatography that (moving phase is sherwood oil: ethyl acetate=1:1) must a white solid (25mg, yield 52%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting solid is compd A 7
Embodiment 5
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A8 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
1) intermediate A 8-1's is synthetic:
By thiocarbamide (2.2g, 28.9mmol), the fluoro-diethyl malonate of 2-(5g, 26.4mmol) and sodium methylate (1.6g, 29.6mmol) be dissolved in respectively in 50mL methyl alcohol, be heated to reflux, after reaction 5h, be chilled to room temperature, suction filtration, a small amount of sherwood oil drip washing for solid, obtains a white solid (3.19g, yield 68%).
2) intermediate A 8-2's is synthetic:
By A8-1(3.19g, 19.63mmol) be dissolved in 100mL water, under ice bath, add methyl-sulfate (2.73g, 21.67mmol), finish after stirring at normal temperature 12h, with 6N dilute hydrochloric acid, regulate PH to 1, filter the solid generating, a small amount of sherwood oil drip washing for solid, obtains a white solid (2.73g, yield 67%).
3) intermediate A 8-3's is synthetic:
By A8-2(2.37g, 13.49mmol) add in 10mL phosphorus oxychloride under normal temperature, be heated to 95 ℃, after reaction 12h, be chilled to room temperature, be spin-dried for solvent, sherwood oil solute for/water extracts, and organic phase is spin-dried for, and obtains a yellow crude product (2.33g, 81%).
4) intermediate A 8-4's is synthetic:
Respectively by A8-3(1.5g, 7.04mmol), the amino pyrazine (1.2g of 2-, 12.63mmol) be dissolved in 20mL anhydrous tetrahydro furan, under condition of ice bath, slowly add sodium hydride (400mg, 13.3mmol, is scattered in the suspension that forms 80wt% in mineral oil), finish stirring at normal temperature 12h.In system, pour 200mL water into again, by the solid filtering of separating out, with a small amount of sherwood oil drip washing, obtain a light yellow solid (1.7g, yield 89%).
5) intermediate A 8-5's is synthetic:
By A8-4(1.1g, 4.049mmol) be dissolved in 10mL tetrahydrofuran (THF), (2.04g, purity 75% 8.869mmol), after stirring at normal temperature 6h, are poured the saturated NaHCO of 200mL in system under condition of ice bath, slowly to add metachloroperbenzoic acid
3and NaS
2o
3the aqueous solution, cross filter solid, a small amount of sherwood oil drip washing for solid, obtains a white solid (890mg, yield 73%).
6) product A 8 is synthetic:
Respectively by A8-5(50mg, 0.1646mmol), pyrazoles (90mg, 1.3235mmol) and Cs
2cO
3(241mg, 0.7397mmol) be dissolved in 1mL N, in dinethylformamide, be heated to 95 ℃, after reaction 12h, pour in 150mL ethyl acetate, water (3 * 50mL) extraction, organic phase is spin-dried for, with column chromatography refining (moving phase is 0.5% ethanol/methylene), obtain a white solid (10mg, yield 19%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting solid is compound A-28
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A9 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
1) intermediate A 9-1's is synthetic:
Respectively by A8-5(500mg, 1.65mmol) and pyrazoles (200mg, 2.94mmol) be dissolved in 20mL anhydrous tetrahydro furan, under condition of ice bath, slowly add sodium hydride (140mg, 4.67mmol are scattered in the suspension that forms 80wt% in mineral oil).Finish, after stirring at normal temperature 6h, in system, pour 200mL water into, cross filter solid, a small amount of sherwood oil drip washing for solid, obtains a white solid (310mg, yield 63%).
2) product A 9 is synthetic:
Respectively by A9-1(40mg, 0.14mmol) and Pyrrolidine (35mg, 0.49mmol) be dissolved in 1mL tetrahydrofuran (THF), be heated to 45 ℃, after reaction 2h, be spin-dried for solvent, solute, with column chromatography refining (moving phase is 0.5% ethanol/methylene), obtains a white solid (17mg, yield 38%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting solid is compd A 9
Embodiment 7
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A17 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
At 0 ℃, in cyclopentanol (2mL), add sodium hydride (8mg, 0.2667mmol, be scattered in the suspension that forms 80wt% in mineral oil), stir after 10min, add A9-1(60mg, 0.2058mmol), finish and be warming up to 120 ℃, after reaction 12h, add water (50mL) cancellation reaction, and extract by ethyl acetate (50mL * 3 time), organic phase merging is spin-dried for, and solute is refined (moving phase is 0.5% ethanol/methylene) with column chromatography, obtain a white solid (7mg, yield 10%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting solid is compd A 17
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A19 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
In the three-necked bottle of 25mL, add respectively A9-1 (60mg, 0.21mmol), 5-methoxypyridine-3-boric acid (38mg, 0.25mmol), Na
2cO
3(63mg, 0.62mmol), 1, two (diphenylphosphine) the ferrocene palladium chlorides (15mg, 0.021mmol) of 1'-and glycol dimethyl ether/water (volume ratio 5:1,10mL) are also with after nitrogen replacement three times, be heated to 90 ℃, reaction 12h, is chilled to room temperature, filters, filtrate is spin-dried for, and with column chromatography refining (moving phase is 1% ethanol/methylene), obtain a white solid (14mg, yield 18%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting solid is compd A 19
Embodiment 9
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A25 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
1) intermediate A 25-1's is synthetic:
Respectively by A8-3(800mg, 3.76mmol), A15-2(860mg, 5.63mmol) and triethylamine (910mg, 9.0mmol) be dissolved in 1, in 4-dioxane (20mL), be heated to 50 ℃, after reaction 12h, be spin-dried for solvent, with column chromatography, refining (moving phase is sherwood oil to solute: ethyl acetate=5:1), obtain a white solid (1g, yield 91%).
2) intermediate A 25-2's is synthetic:
By A25-1(1.0g, 3.43mmol) be dissolved in 10mL tetrahydrofuran (THF)/water (10:1), under condition of ice bath, slowly add potassium hydrogen persulfate (2.7g, 8.88mmol), after stirring at normal temperature 12h, be spin-dried for solvent, the extraction of ethyl acetate for solute/water, organic phase is spin-dried for, and obtains a colorless oil (1.2g, crude product).
3) intermediate A 25-3's is synthetic:
Respectively by A25-2(1.2g, 3.70mmol) and 3，5-dimethylpyrazole (350mg, 3.65mmol) be dissolved in 20mL anhydrous tetrahydro furan, (140mg, 80% is scattered in mineral oil, 4.67mmol) under condition of ice bath, slowly to add sodium hydride.Finish, after stirring at normal temperature 6h, pour the 20mL shrend reaction of going out into, with ethyl acetate (50mL * 3 time) extraction, organic phase is spin-dried for, and column chromatography is refined (0.5% ethanol/methylene) (890mg, yield 71%).
4) product A 25 is synthetic:
In the three-necked bottle of 25mL, add respectively A25-2(60mg, 0.18mmol), PA (30mg, 0.32mmol), sodium tert-butoxide (36mg, 0.37mmol), two (dibenzalacetone) palladium (25mg, 0.043mmol), 2-dicyclohexyl phosphorus-2', 4', 6'-tri isopropyl biphenyl (45mg, 0.094mmol) and toluene (10mL) with after nitrogen replacement three times, be heated to 110 ℃, reaction 12h, be chilled to room temperature, filter, filtrate is spin-dried for, and refine (moving phase is 1% ethanol/methylene) with column chromatography, obtain a yellow oil (50mg, yield 71%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting oily matter is compd A 25
The present embodiment provides a kind of aminopyrimidine heterogeneous ring compound A30 with Adenosine Receptors antagonistic activity, and it synthesizes by the following method:
1) intermediate A 30-1's is synthetic:
A8-3(800mg, 3.76mmol), be dissolved in Isosorbide-5-Nitrae-dioxane (5mL) and ammoniacal liquor (5mL), be heated to 100 ℃, after reaction 12h, pour in 30mL water ethyl acetate extraction into, organic phase is dry concentrated, with column chromatography, refining (moving phase is sherwood oil to solute: ethyl acetate=5:1), obtain a white solid (662mg, yield 91%).
2) intermediate A 30-2's is synthetic:
With reference to the synthesis step of A25-2, by A30-1(650mg, 3.35mmol) must a white solid (750mg, crude product).
3) intermediate A 30-3's is synthetic:
With reference to the synthesis step of A25-3, by A30-2(500mg, 2.21mmol) obtain a white solid (271mg, yield 51%).
4) intermediate A 30-4's is synthetic:
A30-3 (120mg, 0.50mmol) is dissolved in acetic acid 5mL, adds acetic anhydride (510mg, 5.0mmol), reflux 6h.Be cooled to normal temperature, ethyl acetate dilution, saturated sodium bicarbonate (5mL) is washed, dry concentrated, obtains a white solid (132mg, yield 93%).
5) product A 30 is synthetic:
With reference to the synthesis step of A25-1, by A30-4(50mg, 0.18mmol) obtain a white solid (22mg, yield 35%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting solid is compound A-13 0
Table 1 has been listed analytic structure and the spectral data of the compound that embodiment 1-11 obtains and the compd A 1-A31 obtaining according to similar step.
Table 1
Embodiment 11
The binding ability of the compound that the present embodiment his-and-hers watches 1 are listed and A2A Adenosine Receptors is measured, and comprises the steps:
1. film preparation
By the HEK293(G418 resistance of the stably express adenosine A 2 A of collecting) cell is dissolved in lysis buffer(5mM Tris base, PH7.4, EDTANa25mM, EGTA5mM, PMSF1:1000) cracking 30min on ice, on ice bath, cross syringe needle (1mL syringe needle) 15 times, by high speed centrifugation (40000r/min, 4 ℃, 20min) obtain HEK293/A2A cell crude product film, gained crude product film is dissolved in to reaction buffer Reaction buffer(50mM Tris, PH7.4,2mM MgCl
2) ice bath played syringe needle (1mL syringe needle) 15 times, by high speed centrifugation (40000r/min, 4 ℃, 20min) obtain the membranin of HEK293/A2A, be dissolved in 500 μ L reaction buffer Reaction buffer ice baths and played syringe needle (1mL syringe needle) 10 times.By BCA method, record protein concentration, be stored in-80 ℃ of refrigerators.
2. in conjunction with measuring
Membranin solution adds 1U/mL adenosine deaminase, under NECA (10 μ M) exists, measures non-specific binding.Under the competitive part of different concns exists, [3H] ZM241385(50.00Ci/mmol of membranin (50 μ g) and 0.1nM) in 37 ℃ of water-baths, hatch 30min.Ice-water bath termination reaction.Use 12 hole Millipore cell sample collectors, by vacuum filtration, binding partner and free ligand are separated to GF/B glass fiber filter paper, then with ice-cold 50mM Tris-HCL, rinse three times, film is taken off to dry and put into EP pipe and add 540 μ L scintillation solutions.Use Beckman LS-6500 type full-service fluid scintillation counter to measure the radioligand of combination.Use GraphPad Prism, by the analysis of nonlinear least square method curve fitting algorithm, in conjunction with data, record IC50 and K
ivalue.It is example that the compound of take is lifted A30, A31, and as shown in Figure 1 and Figure 2, Data1 and Data2 are twice repeating datas under same experimental conditions, and two secondary data are more approaching, and two curves more overlap, and illustrative experiment error is less, and experimental repeatability is better.IC50 can directly read from curve.According to formula K
i=IC50/ (1+L/Kd) can be in the hope of K
ivalue, K
ibe worth littlely, in conjunction with better, wherein L is actual isotopes concentration, and Kd is isotopic binding constant used, is a fixed value, can in document and database, find.
The A2A binding ability measurement result of the compound of synthesized is as shown in table 2:
Table 2
Therefore, K
ibe worth all very littlely, the aminopyrimidine heterogeneous ring compound of embodiment, as effective antagonist of Adenosine Receptors, can be combined strongly with acceptor, effectively blocks Adenosine Receptors, can be used in the illness that treatment or prevention cause because adenosine level is not normal.
The present invention still has numerous embodiments, and all employing equivalents or equivalent transformation and all technical schemes of forming, within all dropping on protection scope of the present invention.
Claims (10)
1. an aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity, comprises this compound, its pharmacy acceptable salt, various isotropic substance, various isomer or various crystalline structure, has the structure shown in general formula I:
Wherein, R1 is included the heterocycle that the one or more substituting groups in low alkyl group, lower alkoxy, halogen and cyano group replace;
R2 is OR5, NR5R6 or heterocycle, and described heterocycle is the heterocycle being replaced by 0-4 R5 group;
R3 is hydrogen atom, alkyl, acyl group or the hetero-aromatic ring that at least contains a nitrogen-atoms, and described hetero-aromatic ring is replaced by 0-4 R5 group;
R4 is halogen, cyano group or alkyl;
R5 is low alkyl group, lower alkoxy, alkoxyalkyl, oxo, cyano group, halogen, hydroxyl,-C (O)-alkyl, low-grade alkenyl, low-grade alkynyl, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle, Heterocyclylalkyl or hydrogen atom are included low alkyl group, halogen, alkoxyalkyl, hydroxyl, cyano group, aryl, the low alkyl group replacing with one or more substituting groups in-C (O)-alkyl, lower alkoxy, alkoxyalkyl, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle or Heterocyclylalkyl,
R6 is hydrogen atom, low alkyl group, lower alkoxy or alkoxyalkyl.
2. the aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity according to claim 1, is characterized in that:
Described low alkyl group is alkyl or the substituted hydrocarbon radical of saturated straight chain, side chain, ring-type, double-ring or the Spirocyclic of 1-10 carbon atom composition;
Described low-grade alkenyl is alkyl or the substituted hydrocarbon radical of the straight chain that contains at least one carbon-carbon double bond, side chain, ring-type, double-ring or the Spirocyclic of 1-10 carbon atom composition;
Described low-grade alkynyl is alkyl or the substituted hydrocarbon radical of the straight chain, side chain, ring-type, double-ring or the Spirocyclic that contain at least one carbon carbon triple bond of 1-10 carbon atom composition;
Described halogen is fluorine, chlorine, bromine and iodine;
Heteroatoms in described heteroaryl, assorted alkyl, heteroaralkyl, heterocycle, Heterocyclylalkyl is nitrogen, oxygen, sulphur, and the quaternary ammonium salt of various oxidation state and nitrogen;
Described aryl is phenyl ring, naphthalene nucleus and substitutive derivative thereof, or is the derivative cyclic substituents of saturated rings and aromatic ring;
Described heterocycle is monocycle, dicyclo, three ring or the volution substituting groups of the nonaromatic combination that comprises an atom in nitrogen, oxygen and sulphur or a plurality of atoms, and the cyclic substituents of their various oxidation state;
Described heteroaryl is 5-12 former molecular ring of the combination that comprises an atom in nitrogen, oxygen and sulphur or a plurality of atoms and the cyclic substituents of various oxidation state forms thereof, or is the derivative cyclic substituents of saturated rings and hetero-aromatic ring.
3. the aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity according to claim 1 and 2, is characterized in that R1 comprises:
4. the aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity according to claim 1 and 2, is characterized in that R2 comprises:
5. the aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity according to claim 1 and 2, is characterized in that R3 comprises:
6. the aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity according to claim 1 and 2, is characterized in that R4 comprises:
7. according to the aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity described in claim 1-6 any one, it comprises following compounds and pharmacy acceptable salt, various isotropic substance, various crystalline structure and various isomer:
8. a combined utilization composition with the aminopyrimidine heterogeneous ring compound of Adenosine Receptors antagonistic activity, this combined utilization composition is that the composition that combined utilization obtains is carried out in the aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity described in claim 1-6 any one and one or more the combination in L-DOPA, dopamine agonist, Dopamine HCL decarboxylase inhibitor, catechol-O-methyltransferase inhibitor and oxidase inhibitor.
9. the application in the medicine of preparing antagonism Adenosine Receptors according to the aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity described in claim 1-7 any one.
10. the application of the combined utilization composition of the aminopyrimidine heterogeneous ring compound with Adenosine Receptors antagonistic activity according to claim 8 in the medicine of preparing antagonism Adenosine Receptors.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310666030.1A CN103664908A (en) | 2013-12-10 | 2013-12-10 | Aminopyrimidine heterocyclic compound having adenosine receptor antagonizing activity |
| CN201410620592.7A CN104447708B (en) | 2013-12-10 | 2014-11-06 | A kind of aminopyrimidine heterocyclic compound with adenosine receptor antagonist activity |
| PCT/CN2014/093397 WO2015085909A1 (en) | 2013-12-10 | 2014-12-09 | Aminopyrimidine heterocyclic compound with adenosine receptor antagonist activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310666030.1A CN103664908A (en) | 2013-12-10 | 2013-12-10 | Aminopyrimidine heterocyclic compound having adenosine receptor antagonizing activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103664908A true CN103664908A (en) | 2014-03-26 |
Family
ID=50303777
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310666030.1A Pending CN103664908A (en) | 2013-12-10 | 2013-12-10 | Aminopyrimidine heterocyclic compound having adenosine receptor antagonizing activity |
| CN201410620592.7A Active CN104447708B (en) | 2013-12-10 | 2014-11-06 | A kind of aminopyrimidine heterocyclic compound with adenosine receptor antagonist activity |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410620592.7A Active CN104447708B (en) | 2013-12-10 | 2014-11-06 | A kind of aminopyrimidine heterocyclic compound with adenosine receptor antagonist activity |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN103664908A (en) |
| WO (1) | WO2015085909A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015085909A1 (en) * | 2013-12-10 | 2015-06-18 | 苏州大学 | Aminopyrimidine heterocyclic compound with adenosine receptor antagonist activity |
| JP2016534038A (en) * | 2013-10-07 | 2016-11-04 | カドモン コーポレイション，リミティド ライアビリティ カンパニー | RHO kinase inhibitor |
| CN106749190A (en) * | 2015-11-23 | 2017-05-31 | 苏州云轩医药科技有限公司 | Aminopyrimidine heterocyclic compound and its application with adenosine receptor antagonist activity |
| CN107286146A (en) * | 2017-07-05 | 2017-10-24 | 上海肇钰医药科技有限公司 | It is used as adenosine A2A4 aminopyridine derivatives of receptor antagonist and application thereof |
| WO2019141096A1 (en) * | 2018-01-19 | 2019-07-25 | 四川科伦博泰生物医药股份有限公司 | Substituted urea compound and preparation method and use thereof |
| WO2021159993A1 (en) * | 2020-02-14 | 2021-08-19 | Pharmablock Sciences (Nanjing) , Inc. | Inhibitors of interleukin-1 receptor associated kinase (irak) /fms-like receptor tyrosine kinase (flt3), pharmaceutical products thereof, and methods thereof |
| TWI781136B (en) * | 2017-01-20 | 2022-10-21 | 美商阿克思生物科學有限公司 | Azolo-pyrimidine for the treatment of cancer-related disorders |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113620981A (en) * | 2016-10-05 | 2021-11-09 | 结核病药物开发全球联盟公司 | Heteroaryl trifluoroborate compounds for the treatment of mycobacterial infections |
| CN109651358B (en) * | 2017-10-11 | 2023-04-07 | 上海迪诺医药科技有限公司 | 4-aminopyridine derivative, pharmaceutical composition, preparation method and application thereof |
| GB201908511D0 (en) * | 2019-06-13 | 2019-07-31 | Adorx Therapeutics Ltd | Hydroxamate compounds |
| WO2022202537A1 (en) * | 2021-03-22 | 2022-09-29 | ユニマテック株式会社 | Fluorinated pyrimidine compound and method for producing same |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2234433B1 (en) * | 2003-12-15 | 2006-11-01 | Almirall Prodesfarma, S.A. | 4-AMINOPIRIMIDINS AS ANTAGONISTS OF ADENOSINE RECEPTORS. |
| EP1888565B1 (en) * | 2005-04-11 | 2011-03-23 | Almirall, S.A. | 2, 6-di (hetero) aryl -4-amido-pyrimidines as adenosine receptor antagonists |
| US20100234341A1 (en) * | 2006-12-04 | 2010-09-16 | Marion Lanier | Substituted pyrimidines as adenosine receptor antagonists |
| US20080221103A1 (en) * | 2007-03-09 | 2008-09-11 | Orchid Research Laboratories Ltd. | New heterocyclic compounds |
| EP2132197A2 (en) * | 2007-03-21 | 2009-12-16 | Almirall, S.A. | Substituted pyrimidines as adenosine receptor antagonists |
| ES2365960B1 (en) * | 2010-03-31 | 2012-06-04 | Palobiofarma, S.L | NEW ANTAGONISTS OF ADENOSINE RECEPTORS. |
| CN103626741A (en) * | 2013-11-26 | 2014-03-12 | 苏州大学 | Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity |
| CN103664908A (en) * | 2013-12-10 | 2014-03-26 | 苏州大学 | Aminopyrimidine heterocyclic compound having adenosine receptor antagonizing activity |
-
2013
- 2013-12-10 CN CN201310666030.1A patent/CN103664908A/en active Pending
-
2014
- 2014-11-06 CN CN201410620592.7A patent/CN104447708B/en active Active
- 2014-12-09 WO PCT/CN2014/093397 patent/WO2015085909A1/en active Application Filing
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10125144B2 (en) | 2013-10-07 | 2018-11-13 | Kadmon Corporation, Llc | Rho kinase inhibitors |
| JP2016534038A (en) * | 2013-10-07 | 2016-11-04 | カドモン コーポレイション，リミティド ライアビリティ カンパニー | RHO kinase inhibitor |
| WO2015085909A1 (en) * | 2013-12-10 | 2015-06-18 | 苏州大学 | Aminopyrimidine heterocyclic compound with adenosine receptor antagonist activity |
| CN106749190B (en) * | 2015-11-23 | 2019-05-17 | 苏州云轩医药科技有限公司 | With the active aminopyrimidine heterocyclic compound of adenosine receptor antagonist and its application |
| WO2017088755A1 (en) * | 2015-11-23 | 2017-06-01 | Suzhou Yunxuan Yiyao Keji Youxian Gongsi | Aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity |
| CN106749190A (en) * | 2015-11-23 | 2017-05-31 | 苏州云轩医药科技有限公司 | Aminopyrimidine heterocyclic compound and its application with adenosine receptor antagonist activity |
| TWI781136B (en) * | 2017-01-20 | 2022-10-21 | 美商阿克思生物科學有限公司 | Azolo-pyrimidine for the treatment of cancer-related disorders |
| TWI812494B (en) * | 2017-01-20 | 2023-08-11 | 美商阿克思生物科學有限公司 | Azolo-pyrimidine for the treatment of cancer-related disorders |
| CN107286146A (en) * | 2017-07-05 | 2017-10-24 | 上海肇钰医药科技有限公司 | It is used as adenosine A2A4 aminopyridine derivatives of receptor antagonist and application thereof |
| CN107286146B (en) * | 2017-07-05 | 2020-07-31 | 上海肇钰医药科技有限公司 | 4-aminopyrimidine derivatives as adenosine A2A receptor antagonists and uses thereof |
| WO2019141096A1 (en) * | 2018-01-19 | 2019-07-25 | 四川科伦博泰生物医药股份有限公司 | Substituted urea compound and preparation method and use thereof |
| WO2021159993A1 (en) * | 2020-02-14 | 2021-08-19 | Pharmablock Sciences (Nanjing) , Inc. | Inhibitors of interleukin-1 receptor associated kinase (irak) /fms-like receptor tyrosine kinase (flt3), pharmaceutical products thereof, and methods thereof |
| CN115151534A (en) * | 2020-02-14 | 2022-10-04 | 南京药石科技股份有限公司 | Inhibitors of interleukin-1 receptor-related kinase (IRAK)/FMS-like receptor tyrosine kinase (FLT 3), pharmaceutical products thereof, and methods thereof |
| CN115151534B (en) * | 2020-02-14 | 2024-02-06 | 南京药石科技股份有限公司 | Inhibitors of interleukin-1 receptor associated kinase (IRAK)/FMS-like receptor tyrosine kinase (FLT 3), pharmaceutical products thereof and methods of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015085909A1 (en) | 2015-06-18 |
| CN104447708A (en) | 2015-03-25 |
| WO2015085909A8 (en) | 2015-08-06 |
| CN104447708B (en) | 2017-07-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103664908A (en) | Aminopyrimidine heterocyclic compound having adenosine receptor antagonizing activity | |
| CN103958480B (en) | Imidazolines derivative, its preparation method and in application pharmaceutically | |
| JP6845939B2 (en) | Isoquinoline and naphthidrin compounds | |
| CN105120864B (en) | 2-aminopyrimidin-6-ones and analogs exhibiting anti-cancer and anti-proliferative activities | |
| CN104540809A (en) | Inhibitors of the fibroblast growth factor receptor | |
| CN102093364B (en) | 2,4-diamido-6,7-dihydro-5H-pyrrolo [2,3] pyrimidine derivative as focal adhesion kinase/pyruvate kinase 2 (FAK/Pyk2) inhibitor | |
| CN105503827B (en) | EGFR inhibitor and its preparation method and application | |
| JP2023516291A (en) | Methods of treating estrogen receptor-related disorders | |
| CN103626741A (en) | Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity | |
| CN101948425A (en) | As the compound of glucocorticoid ligands, the pharmaceutical composition that comprises them, test kit and preparation method thereof | |
| CN102731492B (en) | Cyclohexanes derivant, its preparation method and in application pharmaceutically | |
| EA023137B1 (en) | Alpha-7 nicotinic receptor modulators for the treatment of pain, a psychotic disorder, cognitive impairment or alzheimer's disease | |
| CN104844566B (en) | A kind of kinase inhibitor of new structure | |
| CN103420977A (en) | Acetylene derivative with anti-tumor activity | |
| BR112015020772B1 (en) | Pyrimidine and pyridine compounds and their use | |
| CN103619841A (en) | Heteroaryl compounds and methods of use thereof | |
| CN106103432B (en) | Substituted thiazole or oxazole P2X7 receptor antagonist | |
| JP5631009B2 (en) | Novel 2-heteroaryl-substituted benzothiophenes and benzofurans 709 | |
| JP2022516882A (en) | MAT2A aza complex bicyclic inhibitor and its use for the treatment of cancer | |
| CN105669564A (en) | Urea compound and preparation method, medicine composition, intermediate and application thereof | |
| KR102356040B1 (en) | Ligand compounds of α7 nicotinic acetylcholine receptors and their applications | |
| WO2013056015A1 (en) | Isoindolinone and pyrrolopyridinone derivatives as akt inhibitors | |
| TW202102505A (en) | A pyrroloheterocyclic derivative and preparation method and medical use thereof | |
| CN110386932A (en) | For the dual ATM and DNA-PK inhibitor in antitumor therapy | |
| JP6941900B2 (en) | Aldehyde group pyridine derivative showing FGFR4 inhibitory activity, its production method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140326 |