CN103626741A - Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity - Google Patents

Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity Download PDF

Info

Publication number
CN103626741A
CN103626741A CN201310608492.8A CN201310608492A CN103626741A CN 103626741 A CN103626741 A CN 103626741A CN 201310608492 A CN201310608492 A CN 201310608492A CN 103626741 A CN103626741 A CN 103626741A
Authority
CN
China
Prior art keywords
adenosine receptor
receptor antagonists
amino group
heterocyclic amino
ring
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
Application number
CN201310608492.8A
Other languages
Chinese (zh)
Inventor
郑计岳
杨朝晖
马海阔
李璇
镇学初
张小虎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou University
Original Assignee
Suzhou University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Suzhou University filed Critical Suzhou University
Priority to CN201310608492.8A priority Critical patent/CN103626741A/en
Publication of CN103626741A publication Critical patent/CN103626741A/en
Pending legal-status Critical Current

Links

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
    • 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 a kind of Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity, including the compound and its pharmaceutically acceptable salt, various isotopes, various isomers and various crystalline structures, has structure shown in general formula I: A kind of Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity of the invention, as effective antagonist of adenosine receptor, can be used in treating or preventing because adenosine level it is not normal caused by illness.

Description

The heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity
Technical field
The present invention relates to medical technical field, relate in particular to a kind of heterocyclic amino group pyrimidine compound with adenosine receptor antagonists 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 condition 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; such as parkinsonism, Huntington Chorea, attention deficit hyperactivity disorder (ADHD), apoplexy, the alzheimer's disease (people such as Fredholm; Annu.Rev.Pharmacol.Toxicol.2005,45:385-412; Behav.Brain Res.2007,185:32-42; The people such as Dall ' Igna, Exp.Neurol.2007,203 (1): 241-5, the people such as Arendash, Neuroscience2006,142:941-52) and various organic sources psychosis (people such as 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. etc., J.Expert Opin.Investig.Drugs2003,12:1335-52; Popoli P. etc., J.Neurosci.2002,22:1967-75), restless legs syndromes (Happe S. etc., 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. etc., the Drug Dev.Res.2001 as neuroprotective; 52:323-330); and be used for the treatment of somnopathy (Dunwiddie TV. etc., 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 existence, the object of the invention is to propose a kind of heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, 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:
A heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, comprises this compound and pharmacy acceptable salt thereof, various isotropic substance, various isomer and various crystalline structure, has the structure shown in general formula I:
Figure BDA0000422339770000021
Wherein, R1 is the heterocycle that the one or more groups in the involved low alkyl group of hydrogen atom, lower alkoxy, halogen and cyano group replace;
R2 is OR4, NR4R5, or is the heterocycle that hydrogen atom is replaced by 0-4 R5 group;
R3 is hydrogen, alkyl, haloalkyl, trifluoroethyl, and acyl group or the hetero-aromatic ring that contains a minimum nitrogen, the hydrogen atom of wherein said hetero-aromatic ring is replaced by the R4 group of 0-4;
R4 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 for hydrogen atom be included low alkyl group, halogen, alkoxyalkyl, hydroxyl, cyano group, aryl and-low alkyl group, lower alkoxy, alkoxyalkyl, aryl, heteroaryl, mix alkyl, heteroaralkyl, heterocycle or Heterocyclylalkyl that one or more groups in C (O)-alkyl replace;
R5 is hydrogen atom, low alkyl group, lower alkoxy or alkoxyalkyl.
In the above-mentioned heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, preferred:
Described alkyl 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 thiazolinyl 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 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 heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, preferred, R1 is any in following groups:
Figure BDA0000422339770000031
In the above-mentioned heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, preferred, R2 is any in following groups:
Figure BDA0000422339770000041
In the above-mentioned heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, preferred, R3 is any in following groups:
Figure BDA0000422339770000042
In the above-mentioned heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, preferred, it comprises following compounds and pharmacy acceptable salt, various isotropic substance, various crystalline structure or various isomer:
Figure BDA0000422339770000043
Figure BDA0000422339770000051
Figure BDA0000422339770000061
In the above-mentioned heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, preferred, isotropic substance comprises but is not only limited to 2h, 3h, 11c, 13c, 14c, 15n, 17o, 18o, 18f, 32p, 35s, 36cl etc.
In the above-mentioned heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, preferred, various isomer, including, but not limited to, steric isomer, cis-trans-isomer, tautomer etc.
The present invention also provides a kind of combined utilization composition with the heterocyclic amino group pyrimidine compound of adenosine receptor antagonists activity, and this combined utilization composition is that the composition that combined utilization obtains is carried out in the heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity 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 heterocyclic amino group pyrimidine compound of adenosine receptor antagonists activity, the application in the medicine of preparing antagonism Adenosine Receptors of the combined utilization composition of heterocyclic amino group pyrimidine compound with adenosine receptor antagonists 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 heterocyclic amino group pyrimidine 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:
A kind of heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity that the present invention proposes, 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 compd A 12 and A2A Adenosine Receptors;
Fig. 2 is the nonlinear least square method fitting of a curve figure of the binding ability of compd A 17 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 heterocyclic amino group pyrimidine compound A1 with adenosine receptor antagonists activity, and it synthesizes by the following method:
1) intermediate A 1-1's is synthetic:
By compound S M(1.38g, 7.05mmol) and the amino pyrazine of 2-(807mg, 8.49mmol) be dissolved in 10mL anhydrous tetrahydro furan, under condition of ice bath, slowly add hmds sodium (7.0mL, 14.0mmol, the tetrahydrofuran solution of 2N), 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 white solid A1-1(1.43g, 80%).
2) intermediate A 1-2's is synthetic:
By A1-1(1.4g, 5.51mmol) be dissolved in 20mL tetrahydrofuran (THF)/water (10:1), under condition of ice bath, slowly add potassium hydrogen persulfate (3.45g, 11.2mmol), 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 white solid A1-2(1.03g, 66%).
3) intermediate A 1-3's is synthetic:
Respectively by A1-2(500mg, 1.75mmol) and 3，5-dimethylpyrazole (336mg, 3.50mmol) be dissolved in 10mL anhydrous tetrahydro furan, under condition of ice bath, slowly add sodium hydride (80% is scattered in mineral oil, 135mg, 4.50mmol).Finish, after stirring at normal temperature 6h, pour the 20mL shrend reaction of going out into, with ethyl acetate (25mL*3) extraction, organic phase is spin-dried for, and column chromatography is refined (0.5% ethanol/methylene), obtains a white solid A1-3(370mg, 70%).
4) compd A 1 is synthetic:
Respectively by A1-3(50mg, 0.16mmol) with 1,2,3,4-tetrahydroisoquinoline (64mg, 0.48mmol) be dissolved in 1mL tetrahydrofuran (THF), be heated to 50 ℃, after reaction 8h, be spin-dried for solvent, solute, with column chromatography refining (moving phase is 0.5% ethanol/methylene), obtains a white solid (51mg, 80%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting compound is A1
Embodiment 2
The present embodiment provides a kind of heterocyclic amino group pyrimidine compound A2 with adenosine receptor antagonists activity, and it synthesizes by the following method:
Figure BDA0000422339770000092
Respectively by A1-3(50mg, 0.16mmol), pyrazoles (90mg, 1.32mmol) and Cs 2cO 3(241mg, 0.74mmol) is dissolved in 1mL N-Methyl pyrrolidone, is heated to 95 ℃, after reaction 12h, pours 15mL water into, and the solid filtering by generating, with a small amount of water and sherwood oil drip washing, obtains a white solid (15mg, 29%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting compound is A2
Figure BDA0000422339770000093
Embodiment 3
The present embodiment provides a kind of heterocyclic amino group pyrimidine compound A3 with adenosine receptor antagonists activity, and it synthesizes by the following method:
Figure BDA0000422339770000094
1) intermediate A 3-1's is synthetic:
By compound S M(1.38g, 7.05mmol) and 2,2,2-trifluoro ethamine (1.40g, 14.1mmol) be dissolved in 5mLN-methyl-2-pyrrolidone, add diisopropyl ethyl amine (1.82g, 14.1mmol), be heated to 100 ℃ of reaction 10h, pour 100mL water into, by the solid filtering generating, with a small amount of water and sherwood oil drip washing, obtain a white solid A3-1(1.38g, 76%).
2) intermediate A 3-2's is synthetic:
By A3-1(1.42g, 5.51mmol) be dissolved in 20mL tetrahydrofuran (THF)/water (10:1), under condition of ice bath, slowly add potassium hydrogen persulfate (3.45g, 11.2mmol), 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 white solid A3-2(1.20g, 75%).
3) intermediate A 3-3's is synthetic:
Respectively by A3-2(500mg, 1.72mmol) and 3，5-dimethylpyrazole (336mg, 3.50mmol) be dissolved in 10mL anhydrous tetrahydro furan, under condition of ice bath, slowly add sodium hydride (80% is scattered in mineral oil, 135mg, 4.50mmol).Finish, after stirring at normal temperature 6h, pour the 20mL shrend reaction of going out into, with ethyl acetate (25mL*3) extraction, organic phase is spin-dried for, and column chromatography is refined (ethyl acetate/petroleum ether=3/1), obtains a white solid A3-3(400mg, 71%).
4) compound A-13 is synthetic:
Respectively by A3-3(50mg, 0.16mmol) with 1,2,3,4-tetrahydroisoquinoline (64mg, 0.48mmol) be dissolved in 1mL tetrahydrofuran (THF), be heated to 50 ℃, after reaction 8h, be spin-dried for solvent, solute, with column chromatography refining (moving phase is 0.5% ethanol/methylene), obtains a white solid (33mg, 51%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting compound is A3
Figure BDA0000422339770000101
Embodiment 4
The present embodiment provides a kind of heterocyclic amino group pyrimidine compound A4 with adenosine receptor antagonists activity, and it synthesizes by the following method:
Figure BDA0000422339770000102
Respectively by A3-3(50mg, 0.16mmol), pyrazoles (90mg, 1.32mmol) and Cs 2cO 3(241mg, 0.74mmol) is dissolved in 1mL N-Methyl pyrrolidone, is heated to 95 ℃, after reaction 12h, pours 15mL water into, and the solid filtering by generating, with a small amount of water and sherwood oil drip washing, obtains a white solid (10mg, 19%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting compound is A4
Figure BDA0000422339770000111
Embodiment 5
The present embodiment provides a kind of heterocyclic amino group pyrimidine compound A5 with adenosine receptor antagonists activity, and it synthesizes by the following method:
Figure BDA0000422339770000112
1) intermediate A 5-1's is synthetic:
By compound S M(1.95g, 10.0mmol) and thiazolamine (1.20g, 12.0mmol) be dissolved in 20mL anhydrous tetrahydro furan, under condition of ice bath, slowly add hmds sodium (10.0mL, 20.0mmol, the tetrahydrofuran solution of 2N), 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 gray solid A5-1(1.63g, 64.6%).
2) intermediate A 5-2's is synthetic:
By A5-1(1.0g, 3.88mmol) be dissolved in 20mL tetrahydrofuran (THF)/water (10:1), under condition of ice bath, slowly add potassium hydrogen persulfate (3.88g, 12.6mmol), 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 white solid A5-2(1.0g, 94%).
3) intermediate A 5-3's is synthetic:
Respectively by A5-2(500mg, 1.83mmol) and 3，5-dimethylpyrazole (527mg, 5.49mmol) be dissolved in 15mL anhydrous tetrahydro furan, under condition of ice bath, slowly add sodium hydride (80% is scattered in mineral oil, 165mg, 5.49mmol).Finish, after stirring at normal temperature 6h, pour in 50mL water, the solid filtering by generating, with a small amount of water and sherwood oil drip washing, obtains a purplish grey solid A5-3(421mg, 75%).
4) compound A-45 is synthetic:
By A5-3(100mg, 0.32mmol) be dissolved in 2mL dioxane, add 80% hydrazine hydrate (100mg, 1.6mmol), after reflux 5h, be spin-dried for solvent, be dissolved in methylene dichloride 5mL, saturated aqueous common salt 2mL washes, dry being spin-dried for, is dissolved in ethanol 3mL, adds 1,1,3,3-tetramethoxy propane (262mg, 1.60mmol) and an acetic acid, reflux 8h, pours in 20mL water, by the solid filtering generating, with a small amount of water and sherwood oil drip washing, obtain a faint yellow solid (16mg, 15%).Through mass spectrum and nuclear magnetic spectrum, resolve (spectrum data is in Table 1), resulting compound is A5
Table 1 has been listed analytic structure and the spectral data of the compound that embodiment 1-5 obtains, and according to embodiment 1 and 2 the compd A 6-A20 that obtains of similar step.
Table 1
Figure BDA0000422339770000122
Figure BDA0000422339770000141
Embodiment 6
The binding ability of the compound that the present embodiment his-and-hers watches 1 are listed and A2A Adenosine Receptors is measured.
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, PH7.4EDTANa25mM, EGTA5mM, PMSF1:1000) cracking 30min on ice, on ice bath, cross syringe needle (1ml syringe needle) 15 times, by high speed centrifugation (40000 * g, 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 MgCl2) ice bath played syringe needle (1ml syringe needle) 15 times, by high speed centrifugation (40000 * g, 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.Take compd A 12 and A17 as example, and as depicted in figs. 1 and 2, Data1 and Data2 are twice repeating datas under same experimental conditions.IC50 can directly read from curve.Can be in the hope of K according to formula Ki=IC50/ (1+L/Kd) ivalue, wherein L is actual isotopes concentration.
The A2A binding ability measurement result of the compound of synthesized is as shown in table 2:
Table 2
Figure BDA0000422339770000151
Figure BDA0000422339770000161
Figure BDA0000422339770000171
Therefore, the heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity of embodiment, as effective antagonist of Adenosine Receptors, can be combined strongly with acceptor, effectively blocking-up 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 (9)

1. a heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity, comprises this compound and pharmacy acceptable salt thereof, various isotropic substance, various isomer and various crystalline structure, has the structure shown in general formula I:
Figure FDA0000422339760000011
Wherein, R1 is the heterocycle that the one or more groups in the involved low alkyl group of hydrogen atom, lower alkoxy, halogen and cyano group replace;
R2 is OR4, NR4R5, or is the heterocycle that hydrogen atom is replaced by 0-4 R5 group;
R3 is hydrogen, alkyl, haloalkyl, trifluoroethyl, and acyl group or the hetero-aromatic ring that contains a minimum nitrogen, the hydrogen atom of wherein said hetero-aromatic ring is replaced by the R4 group of 0-4;
R4 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 for hydrogen atom be included low alkyl group, halogen, alkoxyalkyl, hydroxyl, cyano group, aryl and-low alkyl group, lower alkoxy, alkoxyalkyl, aryl, heteroaryl, mix alkyl, heteroaralkyl, heterocycle or Heterocyclylalkyl that one or more groups in C (O)-alkyl replace;
R5 is hydrogen atom, low alkyl group, lower alkoxy or alkoxyalkyl.
2. the heterocyclic amino group pyrimidine compound with adenosine receptor antagonists 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 heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity according to claim 1 and 2, is characterized in that R1 is any in following groups:
Figure FDA0000422339760000021
4. the heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity according to claim 1 and 2, is characterized in that R2 is any in following groups:
Figure FDA0000422339760000022
5. the heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity according to claim 1 and 2, is characterized in that R3 is any in following groups:
6. according to the heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity described in claim 1-5 any one, it comprises following compounds and pharmacy acceptable salt, various isotropic substance, various crystalline structure or various isomer:
Figure FDA0000422339760000031
Figure FDA0000422339760000041
Figure FDA0000422339760000051
7. a combined utilization composition with the heterocyclic amino group pyrimidine compound of adenosine receptor antagonists activity, this combined utilization composition is that the composition that combined utilization obtains is carried out in the heterocyclic amino group pyrimidine compound with adenosine receptor antagonists 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.
8. the application in the medicine of preparing antagonism Adenosine Receptors according to the heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity described in claim 1-6 any one.
9. the application of the combined utilization composition of the heterocyclic amino group pyrimidine compound with adenosine receptor antagonists activity according to claim 7 in the medicine of preparing antagonism Adenosine Receptors.
CN201310608492.8A 2013-11-26 2013-11-26 Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity Pending CN103626741A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310608492.8A CN103626741A (en) 2013-11-26 2013-11-26 Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310608492.8A CN103626741A (en) 2013-11-26 2013-11-26 Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity

Publications (1)

Publication Number Publication Date
CN103626741A true CN103626741A (en) 2014-03-12

Family

ID=50208229

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310608492.8A Pending CN103626741A (en) 2013-11-26 2013-11-26 Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity

Country Status (1)

Country Link
CN (1) CN103626741A (en)

Cited By (8)

* Cited by examiner, † Cited by third party
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
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
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
CN109651358A (en) * 2017-10-11 2019-04-19 上海迪诺医药科技有限公司 4-aminopyridine derivative, its pharmaceutical composition, preparation method and application
US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
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
CN114539265A (en) * 2022-03-02 2022-05-27 中山大学 Targeting A2ABenzimidazole pyrazine-3-formamide and tumor immune function thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006110884A2 (en) * 2005-04-11 2006-10-19 Neurocrine Biosciences, Inc. 2, 6-di (hetero) aryl -4-amido-pyrimidines as adenosine receptor antagonists
CN101304996A (en) * 2005-09-16 2008-11-12 阿斯利康(瑞典)有限公司 Pyrimidine derivatives for the inhibition of IGF-1R tyrosine kinase activity
CN101679371A (en) * 2006-12-04 2010-03-24 艾美罗股份公司 Substituted pyrimidines as adenosine receptor antagonists
CN102892761A (en) * 2010-03-31 2013-01-23 帕罗生物制药有限公司 4 - aminopyrimidine derivatives and their as as adenosine a2a receptor antagonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006110884A2 (en) * 2005-04-11 2006-10-19 Neurocrine Biosciences, Inc. 2, 6-di (hetero) aryl -4-amido-pyrimidines as adenosine receptor antagonists
CN101304996A (en) * 2005-09-16 2008-11-12 阿斯利康(瑞典)有限公司 Pyrimidine derivatives for the inhibition of IGF-1R tyrosine kinase activity
CN101679371A (en) * 2006-12-04 2010-03-24 艾美罗股份公司 Substituted pyrimidines as adenosine receptor antagonists
CN102892761A (en) * 2010-03-31 2013-01-23 帕罗生物制药有限公司 4 - aminopyrimidine derivatives and their as as adenosine a2a receptor antagonists

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US10125144B2 (en) 2013-10-07 2018-11-13 Kadmon Corporation, Llc Rho kinase inhibitors
WO2015085909A1 (en) * 2013-12-10 2015-06-18 苏州大学 Aminopyrimidine heterocyclic compound with adenosine receptor antagonist activity
US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
US10717728B2 (en) 2017-01-23 2020-07-21 Cadent Therapeutics, Inc. Potassium channel modulators
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
US10351553B2 (en) 2017-01-23 2019-07-16 Cadent Therapeutics, Inc. Potassium channel modulators
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
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
CN109651358A (en) * 2017-10-11 2019-04-19 上海迪诺医药科技有限公司 4-aminopyridine derivative, its pharmaceutical composition, preparation method and application
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
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
CN114539265A (en) * 2022-03-02 2022-05-27 中山大学 Targeting A2ABenzimidazole pyrazine-3-formamide and tumor immune function thereof
WO2023165165A1 (en) * 2022-03-02 2023-09-07 中山大学 Benzoimidazopyrazine-3-carboxamide compound targeting a2a and anti-tumor immunological function thereof

Similar Documents

Publication Publication Date Title
CN103626741A (en) Heterocyclic aminopyrimidine compound with adenosine receptor antagonist activity
CN103664908A (en) Aminopyrimidine heterocyclic compound having adenosine receptor antagonizing activity
ES2729630T3 (en) Heteroaromatic compounds and their use as dopamine D1 ligands
CN110869357A (en) Compounds and methods of use thereof for treating cancer
WO2017172979A1 (en) Substituted quinazoline compounds and methods of use
JP2018511631A (en) Fused tricyclic inhibitors of KRAS and methods of use thereof
JP2018533611A (en) 2-Substituted quinazoline compounds containing substituted heterocyclic groups and methods of using the same
JP6334577B2 (en) Imidazo [4,5-C] pyridine derivatives and pyrrolo [2,3-C] pyridine derivatives as SSAO inhibitors
JP2018520195A (en) Substituted quinazoline compounds and their use as inhibitors of G12C mutant KRAS, HRAS and / or NRAS proteins
JP2018513853A (en) Substituted quinazoline compounds and methods of use thereof
CN104844566B (en) A kind of kinase inhibitor of new structure
Chenard et al. Quinazolin-4-one α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonists: Structure− Activity Relationship of the C-2 Side Chain Tether
KR20200081424A (en) Antagonist of muscarinic acetylcholine receptor M4
CA2876969A1 (en) Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mglur5 receptors
CN108026046B (en) Substituted quinazoline compounds and their use as inhibitors of G12C mutant KRAS, HRAS and/or NRAS proteins
Elsner et al. Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists
JP6779867B2 (en) Pyrimidine compounds and how to use them
CA3129516A1 (en) Low affinity poly(ad-ribose) polymerase 1 dependent cytotoxic agents
CA2592457A1 (en) Triazolopyrimidine derivatives as glycogen synthase kinase 3 inhibitors
US9138494B2 (en) Radiolabeled PDE10A ligands
WO2017088755A1 (en) Aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity
EP3134405B1 (en) Heteroaromatic compounds and their use as dopamine d1 ligands
EP3122744B1 (en) Diazaspiroalkaneone-substituted oxazole derivatives as spleen tyrosine kinase inhibitors
CN106565674A (en) Octahydrocyclopentano[c]pyrrole derivatives, and preparation methods and medicinal application thereof
EP3137469B1 (en) Heterocyclic compounds and their use as dopamine d1 ligands

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C12 Rejection of a patent application after its publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20140312