WO2015085909A1 - 一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物 - Google Patents

一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物 Download PDF

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WO2015085909A1
WO2015085909A1 PCT/CN2014/093397 CN2014093397W WO2015085909A1 WO 2015085909 A1 WO2015085909 A1 WO 2015085909A1 CN 2014093397 W CN2014093397 W CN 2014093397W WO 2015085909 A1 WO2015085909 A1 WO 2015085909A1
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adenosine receptor
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heterocyclic compound
aminopyrimidine
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马海阔
郑计岳
杨朝晖
李克煌
李璇
镇学初
张小虎
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苏州大学
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Definitions

  • the invention relates to the technical field of medicine, in particular to an aminopyrimidine heterocyclic compound having an adenosine receptor antagonist activity.
  • Adenosine is a ubiquitous regulator of various physiological activities, particularly in the cardiovascular and nervous systems, regulating a variety of physiological functions through interaction with specific cell surface receptors.
  • the known adenosine receptors are classified into the A1, A2A, A2B and A3 receptors and belong to the G protein coupled receptor family.
  • A1 and A3 receptors inhibit adenylate cyclase by binding to G protein, causing a decrease in cellular cAMP levels
  • A2A and A2B receptors activate adenylate cyclase by binding to G protein, causing cellular cAMP levels. Raise.
  • the A1 adenosine receptor level is constant. However, under stress conditions, such as local anemia or inflammatory conditions, A1 adenosine receptor levels are up-regulated. For example, in airway epithelial cells and bronchial smooth muscle of human asthma patients, A1 adenosine receptors are up-regulated to induce mediators and cytokines that cause airway hyperreactivity, inflammation, and airway remodelling. Release and cause bronchoconstriction in bronchial tissue. Therefore, the A1 adenosine receptor antagonist can have potential therapeutic effects in inflammatory conditions and asthma. In addition, A1 adenosine receptor antagonists also have therapeutic potential in conditions such as hypertension and congestive heart failure.
  • the A2B adenosine receptor subtype (see Feoktistov, I., Biaggioni, I., Pharmacol. Rev. 1997, 49, 381-402) has identified and regulated a variety of physiological activities in a variety of human and murine tissues. .
  • binding of adenosine to the A2B receptor promotes the growth of endothelial cells, thereby stimulating angiogenesis.
  • hyperproliferation of endothelial cells promotes diabetic retinopathy, and an undesired increase in blood vessels occurs during neoplasia. Therefore, the adenosine A2B receptor antagonist can alleviate or prevent excessive blood vessels, thereby preventing retinopathy and inhibiting tumor formation.
  • A2B adenosine receptor subtype appears to be involved in the regulation of hepatic glucose production, regulation of intestinal movement, and secretion of the small intestine. Therefore, A2B antagonists may help treat type 2 diabetes and obesity.
  • type I hypersensitivity disorders such as asthma, hay fever, and atopic eczema can be stimulated by binding to the A2B receptor of mast cells. Thus, blocking these adenosine receptors provides a therapeutic benefit for such conditions.
  • A3 receptor antagonists have been proposed as anti-asthmatic drug development (Fishman and Bar-Yehuda, 2003; Nadeem and Mustafa, 2006). Studies have also shown that A3 adenosine receptor antagonists include myocardial protection (Vasc. Pharmacol., 2005, 42, 271; J. Pharm. Exp. Ther., 2006, 319, 1200) and cancer (WO 200010391) play a therapeutic role in various diseases.
  • the adenosine A2A receptor is mainly distributed in the striatum, regulating the release of GABA in the striatum, which may regulate the function of the medium-sized spiny neurons.
  • A2A receptors are used to treat central nervous system diseases such as Parkinson's disease, Huntington's disease, attention deficit hyperactivity disorder (ADHD), stroke, Alzheimer's disease.
  • ADHD attention deficit hyperactivity disorder
  • A2A receptor antagonists may be helpful in the treatment of neurodegenerative motor diseases such as Parkinson's disease and Huntington's disease (Tuite P., J. Expert Opin. Investig. Drugs 2003, 12: 1335-52; Popoli P., J. Neurosci. 2002, 22: 1967-75), lower limb restless syndrome (Happe S., Neuropsychobiogy 2003, 48: 82-6), and dyskinesias such as those caused by long-term use of tranquillizers and dopamine drugs (Jenner P.
  • A2A antagonists may have therapeutic potential as neuroprotective agents (Stone TW., Drug Dev. Res. 2001, 52: 323-330), as well as for the treatment of sleep disorders (Dunwiddie TV., Ann. Rev. Neurosci. 2001, 24: 31-55).
  • an object of the present invention to provide an aminopyrimidine heterocyclic compound which can be used as an effective antagonist of adenosine receptors and which can be used for the treatment or prevention of disorders caused by abnormal levels of adenosine.
  • R 2 is OR 5 , NR 5 R 6 or a heterocyclic ring, a heteroaromatic ring or an aromatic ring, which is a heterocyclic ring, a heteroaryl ring or an aromatic ring substituted with 0-4 R 5 groups;
  • R4 is halogen, cyano or alkyl
  • R5, R7 are a hydrogen atom, a lower alkyl group, a lower alkoxy group, an alkoxyalkyl group, an oxo group, a cyano group, a halogen group, a hydroxyl group, a -C(O)-alkyl group, a lower alkenyl group, a lower alkynyl group, and an aromatic group.
  • a base, a heteroaryl group, a heteroalkyl group, a heteroarylalkyl group, a heterocyclic ring, a heterocycloalkyl group or a hydrogen atom is exemplified by lower alkyl, halogen, alkoxyalkyl, hydroxy, cyano, aryl, and -C.
  • R6, R8 are a hydrogen atom, a lower alkyl group, a lower alkoxy group or an alkoxyalkyl group;
  • the lower alkenyl group is a linear, branched, cyclic, bicyclic or spirocyclic hydrocarbon group or substituted hydrocarbon group having at least one carbon-carbon double bond composed of 1 to 10 carbon atoms;
  • the lower alkynyl group is a linear, branched, cyclic, bicyclic or spiro cyclic hydrocarbon group or substituted hydrocarbon group having at least one carbon-carbon triple bond composed of 1 to 10 carbon atoms;
  • the halogen is fluorine, chlorine, bromine and iodine
  • heteroatoms in the heteroaryl, heteroalkyl, heteroarylalkyl, heterocycle, heterocycloalkyl are nitrogen, oxygen, sulfur, and various oxidized and quaternary ammonium salts of nitrogen;
  • the heterocyclic ring is a non-aromatic monocyclic, bicyclic, tricyclic or spiro ring substituent comprising one or more of nitrogen, oxygen and sulfur, and cyclic substituents thereof in various oxidation states. ;
  • the heteroaryl group is an aromatic ring composed of 5-14 atoms of one or more atoms of nitrogen, oxygen and sulfur, and cyclic substituents of various oxidation states thereof, or a saturated ring and A derivatized cyclic substituent of a heteroaryl ring.
  • the parent structure of R1 includes:
  • R1 includes:
  • R2 comprises:
  • R3 comprises:
  • R4 includes:
  • aminopyrimidine heterocyclic compounds having adenosine receptor antagonist activity preferred include the following compounds and pharmaceutically acceptable salts thereof, various isotopes, various crystal structures, and various isomers:
  • isotopes include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 32 p, 35 S, 36 Cl.
  • the present invention also provides a combination application composition of an aminopyrimidine heterocyclic compound having an adenosine receptor antagonist activity, which is an aminopyrimidine heterocyclic compound described above, and an L-DOPA, a dopamine agonist, A combination of one or more of a dopamine decarboxylase inhibitor, a catechol-O-methyltransferase inhibitor, and a monoamine oxidase inhibitor is used in combination.
  • the present invention also provides a combination application composition of an aminopyrimidine heterocyclic compound having an adenosine receptor antagonist activity and an aminopyrimidine heterocyclic compound having an adenosine receptor antagonist activity in the preparation of a drug for the anti-adenosine receptor application.
  • the aminopyrimidine heterocyclic compound having adenosine receptor antagonist activity of the present invention has a pathological condition for treating an anti-angiogenic action of an adenosine receptor, particularly an anti-angiogenic action by an A2A adenosine receptor. Or the use of the disease.
  • Improved diseases and conditions through anti-angiogenesis of adenosine receptors including, but not limited to, Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiratory defects, depression, asthma, metamorphosis Reaction and psychoactive substance abuse.
  • the aminopyrimidine heterocyclic compound having the adenosine receptor antagonist activity proposed by the present invention can be used as an effective antagonist of adenosine receptor, and can be used for treating or preventing a disorder caused by abnormal adenosine levels.
  • Figure 1 is a non-linear least squares curve fit of the binding ability of compound A30 to A2A adenosine receptor
  • Figure 2 is a non-linear least squares curve fit of the binding ability of compound A31 to the A2A adenosine receptor.
  • the method of the present invention will now be described by way of specific examples, but the invention is not limited thereto.
  • the experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.
  • the solvent and drug used are analytically pure or chemically pure; the solvent is re-distilled before use; the anhydrous solvent is treated according to standard methods or literature methods.
  • LC-MSD Trap High Performance Liquid Chromatography-Ion Trap Mass Spectrometer
  • DAD diode array detector
  • detection wavelengths 214 nm and 254 nm
  • ESI source ion trap mass spectrometry
  • This example provides an aminopyrimidine heterocyclic compound A1 having an adenosine receptor antagonist activity which is synthesized by the following method:
  • A1-6 80 mg, 0.26 mmol
  • pyrazole 177 mg, 2.60 mmol
  • Cs 2 CO 3 421 mg, 1.30 mmol
  • the mixture was heated to 120 ° C under stirring, and after reacting for 6 h, cooled to room temperature, poured into 10 mL of water, and the resulting solid was filtered and dried to give a yellow solid (10 mg, yield 12%). After mass spectrometry and nuclear magnetic spectroscopy (see Table 1 for the map data), the obtained solid is a compound.
  • A2-2 (2.04 g, 6.34 mmol) and 2-aminopyrazine (725 mg, 7.63 mmol) were dissolved in 10 mL of anhydrous tetrahydrofuran, and sodium hydride (380 mg, 12.7 mmol) was slowly added to mineral oil under ice bath. 80 wt% of the suspension was formed. After the addition, the mixture was stirred at room temperature for 12 h, poured into 150 mL of water, and the resulting solid was filtered, washed with a small amount of water and petroleum ether to give a pale brown solid (2.14 g, The rate is 89%).
  • This example provides an aminopyrimidine heterocyclic compound A3 having an adenosine receptor antagonist activity which is synthesized by the following method:
  • A3-2 (400 mg, 2.54 mmol) was dissolved in 14 mL of ethanol, and 2 mL of 28% sodium methoxide in methanol was added with stirring in an ice bath. The mixture was stirred for 15 minutes in an ice bath, and diethyl 2-fluoro-malonate was added. (1.81 g, 10.2 mmol), stirred at room temperature for one hour and then refluxed for 4 hours. After cooling to room temperature, concentrated hydrochloric acid was added with stirring in an ice bath to adjust the pH to 2. Part of the ethanol was distilled off and filtered, and the obtained solid was washed with ethanol and diethyl ether to give one. Yellow solid (260 mg, yield 49%).
  • A3-3 (1.70 g, 8.14 mmol) was dissolved in 20 mL of toluene, and triethylamine (3.30 g, 32.6 mmol) and phosphorus oxychloride (12.5 g, 81.4 mmol) were added sequentially in an ice bath. It was refluxed at ° C for 2 hours. The mixture was decanted under reduced pressure to remove toluene and phosphorus oxychloride, and ice water and a saturated aqueous solution of sodium hydrogencarbonate were slowly added to the solute until no more bubbles appeared. Ethyl acetate (200 mL) was added, and the organic layer was washed with brine (40 mL). 1) A white solid (1.0 g, yield: 65%) was obtained.
  • This example provides an aminopyrimidine heterocyclic compound A7 having an adenosine receptor antagonist activity which is synthesized by the following method:
  • A8-1 (3.19 g, 19.63 mmol) was dissolved in 100 mL of water, and dimethyl sulfate (2.73 g, 21.67 mmol) was added in an ice bath. After stirring at room temperature for 12 h, the pH was adjusted to 1 with 6N diluted hydrochloric acid. The resulting solid was washed with a small portion of petroleum ether to give a white solid (2.73 g, yield 67%).
  • A8-3 (1.5 g, 7.04 mmol), 2-aminopyrazine (1.2 g, 12.63 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran, and sodium hydride (400 mg, 13.3 mmol, dispersed) was slowly added in an ice bath.
  • An 80 wt% suspension was formed in mineral oil, and stirred at room temperature for 12 h. Further, 200 mL of water was poured into the system, and the precipitated solid was filtered and washed with a small amount of petroleum ether to give a pale yellow solid (1.7 g, yield: 89%).
  • A8-4 (1.1 g, 4.049 mmol) was dissolved in 10 mL of tetrahydrofuran, and m-chloroperoxybenzoic acid (2.04 g, purity 75%, 8.869 mmol) was slowly added in an ice bath, stirred at room temperature for 6 h, and then transferred to the system. 200mL was poured into aqueous saturated NaHCO 3 and NaS 2 O 3, the solid was filtered, the solid was rinsed with a small amount of petroleum ether to give a white solid (890 mg of, 73% yield).
  • This example provides an aminopyrimidine heterocyclic compound A9 having an adenosine receptor antagonist activity which is synthesized by the following method:
  • A9-1 (40 mg, 0.14 mmol) and tetrahydropyrrole (35 mg, 0.49 mmol) were dissolved in 1 mL of tetrahydrofuran, heated to 45 ° C, and reacted for 2 h, then the solvent was evaporated and the solute was purified by column chromatography (mobile phase 0.5% methanol / dichloromethane) gave a white solid (17 mg, yield 38%). After mass spectrometry and nuclear magnetic spectroscopy (see Table 1 for the map data), the obtained solid was compound A9.
  • This example provides an aminopyrimidine heterocyclic compound A17 having an adenosine receptor antagonist activity which is synthesized by the following method:
  • This example provides an aminopyrimidine heterocyclic compound A19 having an adenosine receptor antagonist activity which is synthesized by the following method:
  • This example provides an aminopyrimidine heterocyclic compound A25 having an adenosine receptor antagonist activity which is synthesized by the following method:
  • A25-1 (1.0 g, 3.43 mmol) was dissolved in 10 mL of tetrahydrofuran / water (10:1), and potassium hydrogen persulfate (2.7 g, 8.88 mmol) was slowly added in an ice bath, stirred at room temperature for 12 h, then dried. The solvent and the solute were extracted with ethyl acetate/water.
  • A25-2 (1.2 g, 3.70 mmol) and 3,5-dimethylpyrazole (350 mg, 3.65 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran, and sodium hydride (140 mg, 80%) was slowly added in an ice bath. Dispersed in mineral oil, 4.67 mmol). After the addition, stirring at room temperature for 6 h, pour 20 mL of water to quench the reaction with ethyl acetate (50 The extract was extracted with EtOAc (3 mL).
  • This example provides an aminopyrimidine heterocyclic compound A30 having an adenosine receptor antagonist activity which is synthesized by the following method:
  • a white solid (750 mg, crude) was obtained from A30-1 (650 mg, 3.35 mmol).
  • a white solid (271 mg, yield 51%) was obtained from A30-2 (500 mg, 2.21 mmol).
  • A30-3 (120 mg, 0.50 mmol) was dissolved in 5 mL of EtOAc. The mixture was cooled to room temperature, EtOAc (EtOAc m.
  • a white solid (22 mg, yield 35%) was obtained from A30-4 (50 mg, 0.18 mmol). After mass spectrometry and nuclear magnetic spectroscopy analysis (see Table 1 for the map data), the obtained solid is compound A30.
  • This example provides an aminopyrimidine heterocyclic compound A32 having an adenosine receptor antagonist activity which is synthesized by the following method:
  • A32-2 (650 mg, 3.35 mmol) was dissolved in 10 mL of tetrahydrofuran/water (10:1), and potassium hydrogensulfate (2.7 g, 8.88 mmol) was slowly added in an ice bath, stirred at room temperature for 12 h, then the solvent was evaporated. The solute was extracted with EtOAc / EtOAc (EtOAc)EtOAc.
  • A32-3 500 mg, 2.21 mmol
  • 3,5-dimethylpyrazole 208 mg, 2.17 mmol
  • sodium hydride 83 mg, 80% dispersion
  • mineral oil 2.77 mmol
  • the mixture was stirred at room temperature for 6 h, then poured into 20 mL of water to quench the reaction, which was extracted with ethyl acetate (50 mL ⁇ 3 ⁇ ), the organic phase was dried and purified by column chromatography (0.5% methanol / dichloromethane) (271 mg, yield 51%).
  • A32-5 (50 mg, 0.16 mmol) was dissolved in dichloromethane (5 mL), and the mixture was added dropwise to chlorosulfonic acid isocyanate (100 mg, 0.71 mmol) in 1 mL of dichloromethane.
  • A32-5 200 mg, 0.64 mmol
  • carbonyl imidazole compound A33-1 88 mg, 0.70 mmol
  • sodium hydride 95 mg, 80% disperse in mineral oil 3.19 mmol
  • the mixture was stirred at room temperature for 12 hours, and the mixture was poured into 50 mL of water to quench the reaction, and the mixture was allowed to stand for 2h, filtered, and the filter cake was washed with water and dried to give a gray solid (180 mg, yield 76%).
  • mass spectrometry and nuclear magnetic spectroscopy see Table 1 for the map data
  • the obtained solid was compound A33.
  • Table 1 lists the analytical structures and spectral data of the compounds obtained in Examples 1-12 and the compounds A1-A33 obtained in a similar manner.
  • This example measures the binding ability of the compounds listed in Table 1 to the A2A adenosine receptor, and includes the following steps:
  • the collected HEK293 (G418-resistant) cells stably expressing adenosine A2A were dissolved in lysis buffer (5 mM Tris base, pH 7.4, EDTA ⁇ Na 25 mM, EGTA 5 mM, PMSF 1:1000) for 30 min on ice, and the needle was passed on an ice bath. (1 mL needle) 15 times, the crude membrane of HEK293/A2A cells was obtained by high-speed centrifugation (40000r/min, 4°C, 20min), and the obtained crude membrane was dissolved in reaction buffer (50mM Tris, pH 7.4, 2mM MgCl 2 ).
  • the needle (1 mL needle) was passed through the bath 15 times, and the membrane protein of HEK293/A2A was obtained by high-speed centrifugation (40000 r/min, 4 ° C, 20 min), and dissolved in 500 ⁇ L of reaction buffer Reaction buffer under ice bath (1 mL needle) 10 Times.
  • the protein concentration was measured by the BCA method and stored in a -80 ° C refrigerator.
  • Non-specific binding was determined by adding 1 U/mL adenosine deaminase to the membrane protein solution in the presence of NECA (10 ⁇ M).
  • Membrane proteins 50 ⁇ g
  • 0.1 nM of [3H]ZM241385 50.00 Ci/mmol
  • the reaction was stopped in an ice water bath.
  • vacuum-filtered, bound ligand and free ligand were separated into GF/B glass fiber filter paper, then rinsed three times with ice-cold 50 mM Tris-HCL, and the film was removed and dried.
  • the K i value is very small, and the aminopyrimidine heterocyclic compound of the example, as an effective antagonist of the adenosine receptor, can strongly bind to the receptor and effectively block the adenosine receptor, and can be used. For the treatment or prevention of disorders caused by abnormal levels of adenosine.
  • the present invention has various embodiments, and all technical solutions formed by equivalent transformation or equivalent transformation are within the scope of the present invention.

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Abstract

本发明提出一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，包括该化合物及其药学上可接受的盐、各种同位素、各种异构体和各种晶型结构，具有通式I所示的结构。本发明的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，能够作为腺苷受体的有效拮抗剂，能够用于治疗或预防因腺苷水平失常引起的病症。

Description

一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物 技术领域
本发明涉及医药技术领域，尤其涉及一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物。
背景技术
腺苷是多种生理活动中普遍存在的调节剂，特别是在心血管和神经系统中，通过与特异性细胞表面受体的相互作用，调控多种生理功能。已知的腺苷受体分为A1、A2A、A2B和A3受体，属于G蛋白偶联受体家族。其中，A1和A3受体通过与G蛋白结合抑制腺苷酸环化酶，引起细胞cAMP水平降低，而A2A和A2B受体则通过与G蛋白结合激活腺苷酸环化酶，引起细胞cAMP水平升高。
在正常的生理条件下，A1腺苷受体水平是恒定的。然而，在应激条件下，如局部贫血或炎症条件下，A1腺苷受体水平会被上调。例如在人类哮喘患者的气道上皮细胞和支气管平滑肌中，A1腺苷受体被上调激活，诱导导致气道高反应性(airway hyperreactivity)、炎症和气道重构(airway remodelling)的介质和细胞因子的释放，并导致支气管组织发生支气管狭窄。因此，A1腺苷受体拈抗剂可以在炎症病症和哮喘病起到潜在的治疗效果。另外，在例如高血压、充血性心力衰竭的病症中A1腺苷受体拈抗剂也具有治疗潜能。
A2B腺苷受体亚型(参见Feoktistov，I.，Biaggioni，I.，Pharmacol.Rev.1997，49，381-402)已在多种人和鼠科动物组织中鉴定出并调节多种生理活性。例如，腺苷和A2B受体的结合会促进内皮细胞的生长，从而刺激血管生成。但是内皮细胞的高增生会促进糖尿病性视网膜病，而在瘤形成中血管会发生不希望的增加。因此，腺苷A2B受体拈抗剂可以缓和或预防血管过多，因而预防视网膜病并抑制肿瘤形成。在胃肠和代谢系统中，A2B腺苷受体亚型似乎与调节肝脏葡萄糖生成、调节肠运动和小肠分泌有关。因此A2B拈抗剂可能有助于治疗II型糖尿病和肥胖症。此外，通过与肥大细胞的A2B受体结合可刺激I型超敏反应病症，如哮喘、枯草热、以及特应性湿疹。因此，阻滞这些腺苷受体会对这样的病症提供治疗益处。
研究发现，A3受体的激活能引发肥大细胞脱颗粒状态、并促进释放缩血管物质，导致脱敏作用和低血压应答，同时与运动的衰退、受体的脱敏有关。因此，A3受体拈抗剂已经被推荐作为抗哮喘药物开发(Fishman和Bar-Yehuda，2003；Nadeem和Mustafa，2006)。也有研究显示A3腺苷受体拈抗剂在包括心肌保护(Vasc. Pharmacol.，2005，42，271；J.Pharm.Exp.Ther.，2006，319，1200)和癌症(WO200010391)的各种疾病中起到治疗作用。
腺苷A2A受体主要分布于纹状体中，调节纹状体中GABA的释放，从而可能调节中型多棘神经元的功能。对基因改性小鼠的研究和药理学分析表明，A2A受体是治疗中枢神经系统疾病，例如帕金森症、亨廷顿舞蹈病、注意力缺陷多动障碍(ADHD)、中风、阿尔茨海默病(Fredholm，Annu.Rev.Pharmacol.Toxicol.2005，45：385-412；Behav.Brain Res.2007，185：32-42；Dall’Igna，Exp.Neurol.2007，203(1)：24l-5，Arendash，Neuroscience 2006，142：941-52)以及各种有机源精神病(Weiss，Neurology，2003，61：S88-93)的有希望的治疗靶标。因此，A2A受体拈抗剂可能有助于治疗神经变性运动疾病如帕金森病和亨廷顿舞蹈病(Tuite P.，J.Expert Opin.Investig.Drugs 2003，12：1335-52；Popoli P.，J.Neurosci.2002，22：1967-75)、下肢不宁综合症(Happe S.，Neuropsychobiogy 2003，48：82-6)、以及运动障碍例如由长期服用安定药和多巴胺药物引起的疾病(Jenner P. J.Neurol.2000，247Supp12：II43-50)。另外，A2A拈抗剂可能具有用作神经保护剂的治疗潜力(Stone TW.，Drug Dev.Res.2001，52：323-330)，以及用于治疗睡眠障碍(Dunwiddie TV.，Ann.Rev.Neurosci.2001，24：31-55)。
由上可见，要改善因上述腺苷水平失常引起的的病症，就需要提出有效的腺苷受体拈抗剂。
发明内容
鉴于上述现有技术存在的缺陷，本发明的目的是提出一种氨基嘧啶杂环化合物，能够作为腺苷受体的有效拈抗剂，能够用于治疗或预防因腺苷水平失常引起的病症。
本发明的目的将通过以下技术方案得以实现：
一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物，包括该化合物、其药学上可接受的盐、各种同位素、各种异构体或各种晶型结构，具有通式I所示的结构：
Figure PCTCN2014093397-appb-000001
其中，R1为被包括低级烷基、低级烷氧基、卤素和氰基中的一个或多个取代基取代的杂环；
R2为OR5、NR5R6或杂环，杂芳环或芳环，所述杂环、杂芳环或芳环为被0-4个R5基团取代的杂环、杂芳环或芳环；
R3为氢原子、烷基、COR7、CONR7R8、SO2R7、SO2NR7R8；或至少含有一个氮原子的杂芳环，所述杂芳环被0-4个R5基团取代；
R4为卤素、氰基或烷基；
R5、R7为氢原子、低级烷基、低级烷氧基、烷氧基烷基、氧代、氰基、卤素、羟基、-C(O)-烷基、低级烯基、低级炔基、芳基、杂芳基、杂烷基、杂芳烷基、杂环、杂环烷基或氢原子被包括低级烷基、卤素、烷氧基烷基、羟基、氰基、芳基、和-C(O)-烷基中的一个或多个取代基取代的低级烷基、低级烷氧基、烷氧基烷基、芳基、杂芳基、杂烷基、杂芳烷基、杂环或杂环烷基；
R6、R8为氢原子、低级烷基、低级烷氧基或烷氧基烷基；
R5、R6为独立取代，或者连接成环，R7、R8为独立取代，或者连接成环。
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的：
所述低级烷基为1-10个碳原子组成的饱和的直链、支链、环状、双环状或螺环状的烃基或取代烃基；
所述低级烯基为1-10个碳原子组成的含有至少一个碳碳双键的直链、支链、环状、双环状或螺环状的烃基或取代烃基；
所述低级炔基为1-10个碳原子组成的含有至少一个碳碳三键的直链、支链、环状、双环状或螺环状的烃基或取代烃基；
所述卤素为氟，氯，溴和碘；
所述杂芳基、杂烷基、杂芳烷基、杂环、杂环烷基中的杂原子为氮，氧，硫，及其各种氧化态和氮的季铵盐；
所述芳基为苯环、萘环、联苯环及其取代衍生物，或者为饱和环与芳环的衍生环状取代基；
所述杂环为非芳香性的包含氮、氧和硫中一个原子或多个原子的组合的单环、双环、三环或螺环取代基，及它们的各种氧化态的环状取代基；
所述杂芳基为包含氮、氧和硫中的一个原子或多个原子的组合的5-14个原子组成的芳香环及其各种氧化态形式的环状取代基，或者为饱和环与杂芳环的衍生环状取代基。
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的，R1为被0-4个 R5取代的五元或六元的杂芳基。
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的，R1的母体结构包括：
Figure PCTCN2014093397-appb-000002
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的，R1包括：
Figure PCTCN2014093397-appb-000003
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的，R2包括：
Figure PCTCN2014093397-appb-000004
Figure PCTCN2014093397-appb-000005
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的，R3包括：
Figure PCTCN2014093397-appb-000006
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的，R4包括：
Figure PCTCN2014093397-appb-000007
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的，其包括下列化合物及其药学上可接受的盐、各种同位素、各种晶型结构和各种异构体：
Figure PCTCN2014093397-appb-000008
Figure PCTCN2014093397-appb-000009
Figure PCTCN2014093397-appb-000010
Figure PCTCN2014093397-appb-000011
Figure PCTCN2014093397-appb-000012
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的，同位素包括但不只限于2H，3H，11C，13C，14C，15N，17O，18O，18F，32p，35S，36Cl。
上述的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物中，优选的，各种异构体包括但不局限于立体异构体，顺反异构体，互变异构体。
本发明还提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物的联合应用组合物，该联合应用组合物是上所述的氨基嘧啶杂环化合物与L-DOPA、多巴胺激动剂、多巴胺脱羧酶抑制剂、儿茶酚-O-甲基转移酶抑制剂和单胺氧化酶抑制剂中的一种或几种的组合进行联合应用得到的组合物。
本发明还提供具有腺苷受体拈抗活性的氨基嘧啶杂环化合物、具有腺苷受体拈抗活性的氨基嘧啶杂环化合物的联合应用组合物在制备拈抗腺苷受体的药物中的应用。
本发明的具有腺苷受体拈抗剂活性的氨基嘧啶杂环化合物具有用于治疗可被腺苷受体的拈抗作用(特别是被A2A腺苷受体的拈抗作用)改善的病理病况或疾病的用途。通过腺苷受体的拈抗作用而得到改善的疾病和病症，包括但不限于阿尔茨海默病、帕金森病、神经保护、精神分裂症、焦虑、疼痛、呼吸缺陷、抑郁、哮喘、变态反应和精神作用物质滥用。
本发明的突出效果为：
本发明提出的具有腺苷受体拈抗活性的氨基嘧啶杂环化合物，能够作为腺苷受体的有效拈抗剂，能够用于治疗或预防因腺苷水平失常引起的病症。
以下便结合实施例附图，对本发明的具体实施方式作进一步的详述，以使本发明技术方案更易于理解、掌握。
附图说明
图1是化合物A30与A2A腺苷受体的结合能力的非线性最小二乘法曲线拟合图；
图2是化合物A31与A2A腺苷受体的结合能力的非线性最小二乘法曲线拟合图。
具体实施方式
下面通过具体实施例对本发明的方法进行说明，但本发明并不局限于此。下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。所用溶剂和药品均为分析纯或化学纯；溶剂在使用前均经 过重新蒸馏；无水溶剂均按照标准方法或文献方法进行处理。柱层析硅胶(100-200目)和薄层层析硅胶(GF254)为青岛海洋化工厂和烟台化工厂产品；如未特别说明，均采用石油醚(60-90℃)/乙酸乙酯(v/v)作为洗脱剂；显色剂用碘或磷钼酸的乙醇溶液；所有萃取溶剂未经说明均用无水Na2SO4干燥。1H NMR用Bruck-400型核磁共振仪记录，TMS为内标。LC-MS用美国Agilent公司1100型高效液相色谱-离子阱质谱联用仪(LC-MSD Trap)记录，二极管阵列检测器(DAD)，检测波长214nm和254nm，离子阱质谱(ESI源)。HPLC柱为Agela Durashell C18(4.6×50mm，3.5μm)；流动相为0.1％NH4HCO3水溶液：乙腈(5分钟内从5∶95到95∶5)；流速为1.8mL/min。
实施例1
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A1，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000013
1)中间体A1-2的合成：
将A1-1(500mg，2.27mmol)和2-氨基吡嗪(432mg，4.54mmol)溶于5mL无水四氢呋喃，在冰浴条件下，缓慢加入氢化钠(136mg，4.54mmol，分散于矿物油中形成80wt％的混悬液)，加毕，升至常温搅拌12h，倒入150mL水中，将生成的固体抽滤，用少量水和石油醚淋洗，得一黄色固体(520mg，得率82％)。
2)中间体A1-3的合成：
将A1-5(278mg，1.00mmol)溶于0℃的5mL四氢呋喃中，边搅拌边缓慢加入间氯过氧苯甲酸(459mg，纯度75％，2.00mmol)，常温搅拌12h后，旋干，用柱层析精制(流动相为石油醚/乙酸乙酯＝2∶1～1∶1)，得一黄色固体(80mg，得率26％)。
3)产物A1的合成：
分别将A1-6(80mg，0.26mmol)，吡唑(177mg，2.60mmol)和Cs2CO3(421 mg，1.30mmol)溶于1mL N，N-二甲基甲酰胺中。搅拌加热至120℃，反应6h后，冷至室温，倒入10mL水，将生成的固体过滤，干燥得一黄色固体(10mg，得率12％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物
Figure PCTCN2014093397-appb-000014
实施例2
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A2，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000015
1)中间体A2-2的合成：
在100mL的三颈瓶内，加入4，6-二氯-2-(甲硫基)嘧啶(4g，20mmol)，用40mL无水四氢呋喃溶解，并用氮气置换三次。在-78℃条件下，边搅拌边滴加二异丙基氨基锂(15.1mL，2mol/L，30.2mmol)，加毕升温至-50℃，反应2h后，移至常温，滴加溶有碘单质(7.66g，30.2mmol)的无水四氢呋喃40mL。搅拌1h后，加入饱和NaS2O3水溶液20mL，搅拌至有机层不在褪色后，用乙酸乙酯萃取(50mL×3次)，有机相用无水硫酸钠干燥后旋干，得黄色固体(6g，得率93％)。
2)中间体A2-3的合成：
将A2-2(2.04g，6.34mmol)和2-氨基吡嗪(725mg，7.63mmol)溶于10mL无水四氢呋喃，在冰浴条件下，缓慢加入氢化钠(380mg，12.7mmol，分散于矿物油中形成80wt％的混悬液)，加毕，升至常温搅拌12h后，倒入150mL水，将生成的固体过滤，用少量水和石油醚淋洗，得一浅棕色固体(2.14g，得率89％)。
3)中间体A2-4的合成：
将A2-3(2.14g，5.63mmol)溶于0℃的150mL四氢呋喃中后，边搅拌边缓慢加入间氯过氧苯甲酸(纯度75％，2.7g，11.739mmol)，常温搅拌12h后，加入 NaHCO3和NaS2O3的饱和水溶液250mL，常温搅拌10min，将生成的固体过滤，用少量水和PE淋洗，得以浅棕色固体(1.57g，得率68％)。
4)产物A2的合成：
分别将A2-4(780mg，1.898mmol)，吡唑(1033mg，15.19mmol)和Cs2CO3(2780mg，8.533mmol)溶于5mL N，N-二甲基甲酰胺中。搅拌加热至120℃，反应6h后，冷至室温，倒入250mL水，将固体过滤，用柱层析精制(流动相为1％甲醇/二氯甲烷)得一白色固体(250mg，得率30％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A2
Figure PCTCN2014093397-appb-000016
实施例3
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A3，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000017
1)中间体A3-2的合成：
将A3-1(1.0g，9.6mmol)溶于甲醇14mL中，加入甲醇钠(25mg，0.44mmol)，氮气保护。此混合液在常温下搅拌过夜，加入氯化铵(535mg，10mmol)，常温搅拌5小时。过滤，用50mL异丙醇/乙酸乙酯＝1/10的混合溶剂洗涤，得到白色固体(1.5g，得率96％)。
2)中间体A3-3的合成：
将A3-2(400mg，2.54mmol)溶解于14mL乙醇中，冰浴搅拌下加入2mL 28％甲醇钠的甲醇溶液，此混合物冰浴下搅拌15分钟，加入2-氟-丙二酸二乙酯(1.81g，10.2mmol)，先常温搅拌一小时，再回流4小时。冷却到室温，在冰浴搅拌下加入浓盐酸，调节PH至2。旋蒸出部分乙醇，过滤，所得固体依次用乙醇和乙醚洗涤，得一 黄色固体(260mg，得率49％)。
3)中间体A3-4的合成：
将A3-3(1.70g，8.14mmol)溶解于20mL甲苯中，在冰浴下依次加入三乙胺(3.30g，32.6mmol)和三氯氧磷(12.5g，81.4mmol)，此混合物在110℃下回流2小时。减压旋蒸，除去甲苯和三氯氧磷，向溶质中缓慢加入冰水和饱和碳酸氢钠水溶液，至不再有气泡冒出。加入乙酸乙酯(200mL)，有机相用饱和食盐水(40mL)洗，无水硫酸钠干燥，过滤后旋去溶剂，溶质经柱层析精制(流动相为石油醚∶乙酸乙酯＝5∶1)得到白色固体(1.0g，得率65％)。
4)中间体A3-5的合成：
将A3-4(1.0g，4.1mmol)，2-氨基吡嗪(584mg，6.15mmol)溶解于50mL四氢呋喃中，冰浴搅拌下加入氢化钠(300mg，10.0mmol，分散于矿物油中形成80wt％的混悬液)，此混合液在常温下搅拌过夜。减压旋蒸，除去四氢呋喃，溶质中搅拌下缓慢加入40mL水和300mL乙酸乙酯，有机层用饱和氯化钠水洗(40mL)，无水硫酸钠干燥过滤后，旋去溶剂，溶质经柱层析精制(流动相为甲醇∶二氯甲烷＝1∶60)得到黄色固体(700mg，得率53％)。
5)化合物A3的合成：
将A3-5(20mg，0.063mmol)溶解在1mL四氢呋喃中，加入四氢吡咯(12.3mg，0.173mmol)，此混合液在60℃下反应8个小时。冷却，减压旋蒸，除去四氢呋喃和四氢吡咯。溶质经柱层析(二氯甲烷∶甲醇＝150∶1)得到一白色固体(12mg，得率60％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A3
Figure PCTCN2014093397-appb-000018
实施例4
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A7，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000019
将A3-5(40mg，0.13mmol)溶于1.5mL乙醇中，加入无水肼(13mg，0.26mmol)。加热到90℃回流22小时。将反应液冷却到0℃，缓慢加入乙酰丙酮(26mg，0.26mmol)，再加热到90℃回流2小时。减压旋蒸，除去乙醇。粗产品溶于10mL二氯甲烷，用水洗两次，盐水洗一次，有机层用硫酸钠干燥，减压旋蒸，溶质经柱层析精制(流动相为石油醚∶乙酸乙酯＝1∶1)得一白色固体(25mg，得率52％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A7
Figure PCTCN2014093397-appb-000020
实施例5
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A8，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000021
1)中间体A8-1的合成：
将硫脲(2.2g，28.9mmol)，2-氟-丙二酸二乙酯(5g，26.4mmol)和甲醇钠(1.6g，29.6mmol)分别溶于50mL甲醇中，加热至回流，反应5h后，冷至室温，抽滤，固体用少量石油醚淋洗，得一白色固体(3.19g，得率68％)。
2)中间体A8-2的合成：
将A8-1(3.19g，19.63mmol)溶于100mL水中，在冰浴下加入硫酸二甲酯(2.73g，21.67mmol)，加毕常温搅拌12h后，用6N稀盐酸调节PH至1，过滤生成的固体，固体用少量石油醚淋洗，得一白色固体(2.73g，得率67％)。
3)中间体A8-3的合成：
将A8-2(2.37g，13.49mmol)常温下加入10mL三氯氧磷中，加热至95℃，反应12h后，冷至室温，旋干溶剂，溶质用石油醚/水萃取，有机相旋干，得一黄色粗产物(2.33g，81％)。
4)中间体A8-4的合成：
分别将A8-3(1.5g，7.04mmol)，2-氨基吡嗪(1.2g，12.63mmol)溶于20mL无水四氢呋喃中，在冰浴条件下，缓慢加入氢化钠(400mg，13.3mmol，分散于矿物油中形成80wt％的混悬液)，加毕常温搅拌12h。再向体系中倒入200mL水，将析出的固体过滤，用少量石油醚淋洗，得一浅黄色固体(1.7g，得率89％)。
5)中间体A8-5的合成：
将A8-4(1.1g，4.049mmol)溶于10mL四氢呋喃中，在冰浴条件下缓慢加入间氯过氧苯甲酸(2.04g，纯度75％，8.869mmol)，常温搅拌6h后，向体系中倒入200mL饱和NaHCO3和NaS2O3的水溶液，过滤固体，固体用少量石油醚淋洗，得一白色固体(890mg，得率73％)。
6)产物A8的合成：
分别将A8-5(50mg，0.1646mmol)，吡唑(90mg，1.3235mmol)和Cs2CO3(241mg，0.7397mmol)溶于1mL N，N-二甲基甲酰胺中，加热至95℃，反应12h后，倒入150mL乙酸乙酯中，用水(3×50mL)萃取，有机相旋干，用柱层析精制(流动相为0.5％甲醇/二氯甲烷)，得一白色固体(10mg，得率19％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A8
Figure PCTCN2014093397-appb-000022
实施例6
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A9，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000023
1)中间体A9-1的合成：
分别将A8-5(500mg，1.65mmol)和吡唑(200mg，2.94mmol)溶于20mL无水四氢呋喃中，在冰浴条件下缓慢加入氢化钠(140mg，4.67mmol，分散于矿物油 中形成80wt％的混悬液)。加毕，常温搅拌6h后，向体系中倒入200mL水，过滤固体，固体用少量石油醚淋洗，得一白色固体(310mg，得率63％)。
2)产物A9的合成：
分别将A9-1(40mg，0.14mmol)和四氢吡咯(35mg，0.49mmol)溶于1mL四氢呋喃中，加热至45℃，反应2h后，旋干溶剂，溶质用柱层析精制(流动相为0.5％甲醇/二氯甲烷)，得一白色固体(17mg，得率38％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A9
Figure PCTCN2014093397-appb-000024
实施例7
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A17，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000025
在0℃下，向环戊醇(2mL)中加入氢化钠(8mg，0.2667mmol，分散于矿物油中形成80wt％的混悬液)，搅拌10min后，加入A9-1(60mg，0.2058mmol)，加毕升温至120℃，反应12h后，加水(50mL)淬灭反应，并用乙酸乙酯(50mL×3次)萃取，有机相合并旋干，溶质用柱层析精制(流动相为0.5％甲醇/二氯甲烷)，得一白色固体(7mg，得率10％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A17
Figure PCTCN2014093397-appb-000026
实施例8
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A19，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000027
在25mL的三颈瓶内，分别加入A9-1(60mg，0.21mmol)，5-甲氧基吡啶-3-硼酸 (38mg，0.25mmol)，Na2CO3(63mg，0.62mmol)，1，1′-双(二苯基膦)二茂铁二氯化钯(15mg，0.021mmol)和乙二醇二甲醚/水(体积比5∶1，10mL)并用氮气置换三次后，加热至90℃，反应12h，冷至室温，过滤，滤液旋干，并用柱层析精制(流动相为1％甲醇/二氯甲烷)，得一白色固体(14mg，得率18％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A19
Figure PCTCN2014093397-appb-000028
实施例9
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A25，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000029
1)中间体A25-1的合成：
分别将A8-3(800mg，3.76mmol)，A15-2(860mg，5.63mmol)和三乙胺(910mg，9.0mmol)溶于1，4-二氧六环(20mL)中，加热至50℃，反应12h后，旋干溶剂，溶质用柱层析精制(流动相为石油醚∶乙酸乙酯＝5∶1)，得一白色固体(1g，得率91％)。
2)中间体A25-2的合成：
将A25-1(1.0g，3.43mmol)溶于10mL四氢呋喃/水(10∶1)中，在冰浴条件下缓慢加入过硫酸氢钾(2.7g，8.88mmol)，常温搅拌12h后，旋干溶剂，溶质用乙酸乙酯/水萃取，有机相旋干，得一无色油状物(1.2g，粗品)。
3)中间体A25-3的合成：
分别将A25-2(1.2g，3.70mmol)和3，5-二甲基吡唑(350mg，3.65mmol)溶于20mL无水四氢呋喃中，在冰浴条件下缓慢加入氢化钠(140mg，80％分散于矿物油中，4.67mmol)。加毕，常温搅拌6h后，倒入20mL水淬灭反应，用乙酸乙酯(50 mL×3次)萃取，有机相旋干，柱层析精制(0.5％甲醇/二氯甲烷)(890mg，得率71％)。
4)产物A25的合成：
在25mL的三颈瓶内，分别加入A25-2(60mg，0.18mmol)，2-氨基吡啶(30mg，0.32mmol)，叔丁醇钠(36mg，0.37mmol)，二(二亚苄基丙酮)钯(25mg，0.043mmol)，2-二环己基磷-2′，4′，6′-三异丙基联苯(45mg，0.094mmol)和甲苯(10mL)并用氮气置换三次后，加热至110℃，反应12h，冷至室温，过滤，滤液旋干，并用柱层析精制(流动相为1％甲醇/二氯甲烷)，得一黄色油状物(50mg，得率71％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的油状物为化合物A25
Figure PCTCN2014093397-appb-000030
实施例10
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A30，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000031
1)中间体A30-1的合成：
A8-3(800mg，3.76mmol)，溶于1，4-二氧六环(5mL)和氨水(5mL)中，加热至100℃，反应12h后，倒入30mL水中，乙酸乙酯萃取，有机相干燥浓缩，溶质用柱层析精制(流动相为石油醚∶乙酸乙酯＝5∶1)，得一白色固体(662mg，得率91％)。
2)中间体A30-2的合成：
参照A25-2的合成步骤，由A30-1(650mg，3.35mmol)得一白色固体(750mg，粗品)。
3)中间体A30-3的合成：
参照A25-3的合成步骤，由A30-2(500mg，2.21mmol)得到一白色固体(271mg，得率51％)。
4)中间体A30-4的合成：
A30-3(120mg，0.50mmol)溶于醋酸5mL中，加入醋酸酐(510mg，5.0mmol)，加热回流6h。冷却到常温，乙酸乙酯稀释，饱和碳酸氢钠(5mL)洗，干燥浓缩，得一白色固体(132mg，得率93％)。
5)产物A30的合成：
参照A25-1的合成步骤，由A30-4(50mg，0.18mmol)得到一白色固体(22mg，得率35％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A30
Figure PCTCN2014093397-appb-000032
实施例11
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A32，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000033
1)中间体A32-2的合成：
A32-1(800mg，3.76mmol)，溶于1，4-二氧六环(5mL)和氨水(5mL)中，加热至100℃，反应12h后，倒入30mL水中，乙酸乙酯萃取，有机相干燥浓缩，溶质用柱层析精制(流动相为石油醚∶乙酸乙酯＝5∶1)，得一白色固体(662mg，得率91％)。
2)中间体A32-3的合成：
将A32-2(650mg，3.35mmol)溶于10mL四氢呋喃/水(10∶1)中，在冰浴条件下缓慢加入过硫酸氢钾(2.7g，8.88mmol)，常温搅拌12h后，旋干溶剂，溶质用乙酸乙酯/水萃取，有机相旋干，得一白色固体(750mg，粗品)。
3)中间体A32-4的合成：
分别将A32-3(500mg，2.21mmol)和3，5-二甲基吡唑(208mg，2.17mmol)溶于15mL无水四氢呋喃中，在冰浴条件下缓慢加入氢化钠(83mg，80％分散于矿物油中，2.77mmol)。加毕，常温搅拌6h后，倒入20mL水淬灭反应，用乙酸乙酯(50mL×3次)萃取，有机相旋干，柱层析精制(0.5％甲醇/二氯甲烷)得一白色固体(271mg，得率51％)。
4)中间体A32-5的合成：
A32-4(855mg，3.53mmol)和3-甲氧基吡啶硼试剂溶于1，4-二氧六环25mL和5mL水中，加入碳酸钾(1.95g，14.13mmol)和四三苯基膦钯(408mg，0.35mmol)，加热回流12h。冷却到常温，倒入50mL水中，乙酸乙酯(50mL×3次)萃取，饱和食盐水(50mL×3次)洗，干燥浓缩，柱层析精制(2％甲醇/二氯甲烷)得一黄色固体(500mg，得率45％)。
5)产物A32的合成：
A32-5(50mg，0.16mmol)溶于5mL二氯甲烷，常温滴加到氯磺酸异氰酸酯(100mg，0.71mmol)的1mL二氯甲烷溶液中，常温搅拌12h。减压浓缩除去溶剂，加入3mL二氧六环和2mL 6N盐酸，加热回流20分钟。待冷却后，用饱和碳酸钠调PH＝7，乙酸乙酯萃取4次，有机相干燥浓缩，所得固体用2mL二氯甲烷洗3次，得一淡黄色固体(20mg，得率35％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A32
Figure PCTCN2014093397-appb-000034
实施例12
本实施例提供一种具有腺苷受体拈抗活性的氨基嘧啶杂环化合物A33，其是由如下方法合成的：
Figure PCTCN2014093397-appb-000035
1)产物A33的合成：
A32-5(200mg，0.64mmol)和羰基咪唑化合物A33-1(88mg，0.70mmol)溶于干燥的DMF 10mL中，在冰浴条件下缓慢加入氢化钠(95mg，80％分散于矿物油中，3.19mmol)。加毕，常温搅拌12h后，倒入50mL水淬灭反应，静置2h，抽滤，滤饼用水洗，干燥，得一灰色固体(180mg，得率76％)。经过质谱和核磁图谱解析(图谱数据见表1)，所得到的固体为化合物A33
Figure PCTCN2014093397-appb-000036
表1列出了实施例1-12获得的化合物以及按照类似步骤获得的化合物A1-A33的解析结构和波谱数据。
表1
Figure PCTCN2014093397-appb-000037
Figure PCTCN2014093397-appb-000038
Figure PCTCN2014093397-appb-000039
Figure PCTCN2014093397-appb-000040
实施例13
本实施例对表1所列的化合物与A2A腺苷受体的结合能力进行测定，包括如下步骤：
1.膜制备
将收集的稳定表达腺苷A2A的HEK293(G418抗性)细胞溶于lysis buffer(5mMTris base，PH 7.4，EDTA·Na 25mM，EGTA 5mM，PMSF 1∶1000)冰上裂解30min，冰浴上过针头(1mL针头)15次，通过高速离心(40000r/min，4℃，20min)得到HEK293/A2A细胞粗品膜，将所得粗品膜溶于反应缓冲液Reaction buffer(50mMTris，PH 7.4，2mM MgCl2)冰浴下过针头(1mL针头)15次，将高速离心(40000r/min，4℃，20min)得到HEK293/A2A的膜蛋白，溶于500μL反应缓冲液Reaction buffer冰浴下过针头(1mL针头)10次。通过BCA法测得蛋白浓度，储存在-80℃冰箱。
2.结合测定
膜蛋白溶液加入1U/mL腺苷脱氨酶，在NECA(10μM)存在下测定非特异结合。在不同浓度的竞争性配体存在下，膜蛋白(50μg)和0.1nM的[3H]ZM241385(50.00Ci/mmol)在37℃水浴锅中孵育30min。冰水浴终止反应。使用12孔Millipore细胞样品收集器，通过真空过滤，结合配体和游离配体被分离至GF/B玻璃纤维滤纸，然后用冰冷的50mM Tris-HCL冲洗三遍，将膜取下烘干放入EP管中加入540μL闪烁液。使用Beckman LS-6500型多功能液体闪烁计数仪测定结合的放射性配体。计算每个化合物100umol/L浓度对同位素与蛋白受体结合的竞争抑制率，其中cpm为实验所得的放射性配体读数值：抑制率(I％)＝(总结合管cpm--化合物cpm)/(总结合管cpm--非特异结合管cpm)×100％。使用GraphPad Prism，通过非线性最小二乘法曲线拟合算法分析结合数据测得IC50和Ki值。以化合物举A30、A31为例，如图1、图2所示，Data1和Data2是在相同实验条件下两次重复数据，两次数据越接近，两条曲线越重合，说明实验误差越小，实验重复性越好。IC50可以直接从曲线中读出。根据公式Ki＝IC50/(1+L/Kd)可以求得Ki值，Ki值越小，结合越好，其中L为实际同位素浓度，Kd是所用同位素的结合常数，是一个固定值，可由文献和数据库中查到。
上述实施例1-12中所合成的化合物的A2A结合能力测定结果如表2所示：
表2
Figure PCTCN2014093397-appb-000041
Figure PCTCN2014093397-appb-000042
Figure PCTCN2014093397-appb-000043
Figure PCTCN2014093397-appb-000044
Figure PCTCN2014093397-appb-000045
由上可见，Ki值都很小，实施例的氨基嘧啶杂环化合物，作为腺苷受体的有效拈抗剂，能够与受体较强地结合，有效阻断腺苷受体，能够用于治疗或预防因腺苷水平失常引起的病症。
本发明尚有多种实施方式，凡采用等同变换或者等效变换而形成的所有技术方案，均落在本发明的保护范围之内。

Claims (12)

  1. 一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，包括该化合物、其药学上可接受的盐、各种同位素、各种异构体或各种晶型结构，具有通式I所示的结构：
    Figure PCTCN2014093397-appb-100001
    其中，R1为被包括低级烷基、低级烷氧基、卤素和氰基中的一个或多个取代基取代的杂环；
    R2为OR5、NR5R6或杂环，杂芳环或芳环，所述杂环、杂芳环或芳环为被0-4个R5基团取代的杂环、杂芳环或芳环；
    R3为氢原子、烷基、COR7、CONR7R8、SO2R7、SO2NR7R8；或至少含有一个氮原子的杂芳环，所述杂芳环被0-4个R5基团取代；
    R4为卤素、氰基或烷基；
    R5、R7为氢原子、低级烷基、低级烷氧基、烷氧基烷基、氧代、氰基、卤素、羟基、-C(O)-烷基、低级烯基、低级炔基、芳基、杂芳基、杂烷基、杂芳烷基、杂环、杂环烷基或氢原子被包括低级烷基、卤素、烷氧基烷基、羟基、氰基、芳基、和-C(O)-烷基中的一个或多个取代基取代的低级烷基、低级烷氧基、烷氧基烷基、芳基、杂芳基、杂烷基、杂芳烷基、杂环或杂环烷基；
    R6、R8为氢原子、低级烷基、低级烷氧基或烷氧基烷基；
    R5、R6为独立取代，或者连接成环，R7、R8为独立取代，或者连接成环。
  2. 根据权利要求1所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，其特征在于：
    所述低级烷基为1-10个碳原子组成的饱和的直链、支链、环状、双环状或螺环状的烃基或取代烃基；
    所述低级烯基为1-10个碳原子组成的含有至少一个碳碳双键的直链、支链、环状、双环状或螺环状的烃基或取代烃基；
    所述低级炔基为1-10个碳原子组成的含有至少一个碳碳三键的直链、支链、环状、双环状或螺环状的烃基或取代烃基；
    所述卤素为氟，氯，溴和碘；
    所述杂芳基、杂烷基、杂芳烷基、杂环、杂环烷基中的杂原子为氮，氧，硫，及 其各种氧化态和氮的季铵盐；
    所述芳基为苯环、萘环、联苯环及其取代衍生物，或者为饱和环与芳环的衍生环状取代基；
    所述杂环为非芳香性的包含氮、氧和硫中一个原子或多个原子的组合的单环、双环、三环或螺环取代基，及它们的各种氧化态的环状取代基；
    所述杂芳基为包含氮、氧和硫中的一个原子或多个原子的组合的5-14个原子组成的芳香环及其各种氧化态形式的环状取代基，或者为饱和环与杂芳环的衍生环状取代基。
  3. 根据权利要求1或2所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，其特征在于：R1为被0-4个R5取代的五元或六元的杂芳基。
  4. 根据权利要求3所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，其特征在于：R1的母体结构包括：
    Figure PCTCN2014093397-appb-100002
  5. 根据权利要求1-5中任意一项所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，其特征在于R1包括：
    Figure PCTCN2014093397-appb-100003
  6. 根据权利要求1-6中任意一项所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，其特征在于R2包括：
    Figure PCTCN2014093397-appb-100004
  7. 根据权利要求1-7中任意一项所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，其特征在于R3包括：
    Figure PCTCN2014093397-appb-100005
  8. 根据权利要求1-8中任意一项所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，其特征在于R4包括：
    Figure PCTCN2014093397-appb-100006
  9. 根据权利要求1-9任一项所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物，其包括下列化合物及其药学上可接受的盐、各种同位素、各种晶型结构和各种异构体：
    Figure PCTCN2014093397-appb-100007
    Figure PCTCN2014093397-appb-100008
    Figure PCTCN2014093397-appb-100009
    Figure PCTCN2014093397-appb-100010
  10. 一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物的联合应用组合物，该联合应用组合物是权利要求1-10任一项所述的具有腺苷受体拮抗活性的氨基嘧啶杂环化合物与L-DOPA、多巴胺激动剂、多巴胺脱羧酶抑制剂、儿茶酚-O-甲基转移酶抑制剂和单胺氧化酶抑制剂中的一种或几种的组合进行联合应用得到的组合物。
  11. 根据权利要求1-10任一项所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物在制备拮抗腺苷受体的药物中的应用。
  12. 根据权利要求11所述的一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物的联合应用组合物在制备拮抗腺苷受体的药物中的应用。
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