WO2018214736A1 - 一类多羟基酞嗪酮化合物、其制备方法及应用 - Google Patents

一类多羟基酞嗪酮化合物、其制备方法及应用 Download PDF

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WO2018214736A1
WO2018214736A1 PCT/CN2018/086244 CN2018086244W WO2018214736A1 WO 2018214736 A1 WO2018214736 A1 WO 2018214736A1 CN 2018086244 W CN2018086244 W CN 2018086244W WO 2018214736 A1 WO2018214736 A1 WO 2018214736A1
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compound
polyhydroxypyridazinone
hydrogen
diseases
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PCT/CN2018/086244
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梁发香
丁燕伶
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上海锐聚恩新药研发有限公司
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Priority to EP18805499.3A priority Critical patent/EP3564215A4/en
Priority to JP2019560453A priority patent/JP6823853B2/ja
Publication of WO2018214736A1 publication Critical patent/WO2018214736A1/zh
Priority to US16/562,436 priority patent/US10640469B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the technical field of biomedicine, and particularly relates to a polyhydroxypyridazinone compound, a preparation method thereof and application thereof.
  • the estrogen receptor belongs to the steroid nuclear receptor and is a receptor for nuclear transcription factors induced by ligands.
  • the estrogen receptor is an important cytoregulatory protein that plays a vital role in numerous physiological processes through endogenous estrogens, including the development and maintenance of secondary sexual characteristics in women, including muscle and bone mass. Wait.
  • Endogenous steroidal estrogens are commonly referred to as female sex hormones, including estradiol.
  • Estradiol is the major steroidal estrogen found in women's serum, which is mainly secreted by the ovaries.
  • the estrogen receptor includes the receptor subtypes ER- ⁇ (estrogen receptor alpha) and ER- ⁇ (estrogen receptor beta). There are also receptors (ERRs) closely related to the structure of the estrogen receptor, such as ERR- ⁇ , ERR- ⁇ and ERR- ⁇ .
  • ERRs receptors closely related to the structure of the estrogen receptor, such as ERR- ⁇ , ERR- ⁇ and ERR- ⁇ .
  • Steroid nuclear receptors play an important role in the physiological functions of the body, including transcriptional homeostasis, growth and development, wound healing, fertility, stress response, immune function and cognitive function in relation to electrolyte and water balance.
  • modulators that modulate i.e., antagonists, agonists, partial antagonists, partial agonists
  • steroid nuclear receptor activity have diseases that treat and prevent steroid receptor activity.
  • the estrogen receptor ER- ⁇ is present in tissues such as the brain, bones, immune system, gastrointestinal tract, lung, ovary, endometrium, prostate, vascular system, genitourinary tract, parotid gland, and the like.
  • tissues such as the brain, bones, immune system, gastrointestinal tract, lung, ovary, endometrium, prostate, vascular system, genitourinary tract, parotid gland, and the like.
  • ER- ⁇ acts as an antagonist to the ER- ⁇ receptor by heterodimerization with the estrogen receptor ER- ⁇ .
  • an ER-beta receptor agonist can prevent the estrogen receptor ER-alpha from promoting the proliferation of tumors in prostate cancer and breast cancer tissues.
  • Estrogen directly affects the diastolic function of various vascular tissues (ie, reduces vasoconstriction or vascular tone), reduces systemic vascular resistance, and improves microvascular circulation. Estrogen also reduces vascular cell proliferation and migration, reduces vascular reactivity, viscosity, and slows fibrosis of blood vessels. ER-beta receptor agonists may have therapeutic effects on hypertension and various other cardiovascular diseases such as atherosclerosis and congestive heart failure.
  • ER-beta receptor agonists also have antioxidant activity.
  • various reactive oxygen radicals unstable molecules such as superoxide (O 2 ⁇ - ) and hydrogen peroxide (H 2 O 2 ) are produced.
  • These reactive oxygen species cause various oxidation reactions with endogenous macromolecules such as DNA, lipids and proteins to impair their function.
  • This accumulation of oxidative damage over time can lead to a variety of age-related conditions.
  • neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, various types of cancer, including vascular diseases such as prostate and colon, stroke, and various Age-related atherosclerosis, etc.
  • Ascorbic acid (vitamin C), tea polyphenols derived from red wine, and phytoestrogens such as genistein and coumestrol derived from soy products have the function of eliminating active oxygen in the body.
  • the ER ⁇ receptor agonist is a polyphenolic compound having antioxidant activity.
  • Many literatures and patents have reported non-steroidal small molecule ER[beta] receptor agonists, but polyhydroxypyridazinone compounds have not been reported as ER[beta] receptor agonists.
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, hydroxy, C 1 ⁇ 3 alkoxy or halogen;
  • R 5 is hydrogen, C 1 ⁇ 4 alkyl, C 1 ⁇ 4 haloalkyl, benzene Or cyano;
  • R 6 is hydrogen or halogen.
  • the halogen is fluorine, chlorine or bromine.
  • R 1, R 2, R 3 is hydroxy
  • R 4 and R 6 is hydrogen
  • R 5 is hydrogen, C 1 ⁇ 4 alkyl group, C 1 ⁇ 4 haloalkyl, phenyl or cyano.
  • R 1 , R 2 , R 3 are hydroxyl groups, R 4 and R 6 are hydrogen; and R 5 is chlorine or bromine.
  • R 1 , R 2 , R 3 are a hydroxyl group;
  • R 4 is hydrogen or halogen;
  • R 5 is hydrogen;
  • R 6 is chlorine or bromine.
  • the halogen is fluorine, chlorine or bromine.
  • a second object of the present invention is to provide a process for preparing a polyhydroxypyridazinone compound, wherein R 1 , R 2 and R 3 are hydroxyl groups, R 4 and R 6 are hydrogen; R 5 is hydrogen, C 1 ⁇ When a 4- alkyl group, a C 1 - 4 haloalkyl group, a phenyl group or a cyano group, the following steps are included:
  • the compound (1) is used as a starting material to react with an alkyl or phenyl format reagent to obtain a corresponding secondary alcohol compound (2); the bromination is compound (3), and the compound (3) is subjected to a carboxylation reaction to obtain a compound (4).
  • Compound (4) is oxidized to form (5); compound (5) and corresponding hydrazine are subjected to condensation reaction to form compound (6); compound (6) is demethylated to obtain target compound (7), and its chemical reaction formula as follows:
  • R 1 , R 2 , R 3 are a hydroxyl group; R 4 is hydrogen or halogen; R 5 is hydrogen; and when R 6 is chlorine or bromine, the following steps are included: compound (12) and brominated succinimide or chlorine The succinimide reacts to form the compound (13); the compound (13) is further subjected to demethylation to obtain the target compound (14), and the chemical reaction formula is as follows:
  • a third object of the present invention is to provide a use of the above polyhydroxypyridazinone compound for the preparation of a medicament for treating and/or preventing estrogen-related diseases.
  • the estrogen-related diseases include prostate diseases, tumors, genitourinary tract diseases, gastrointestinal diseases, inflammation, osteoporosis, peripheral vascular diseases, Alzheimer's disease, Parkinson's disease,
  • a fourth object of the present invention is to provide a composition comprising the above polyhydroxypyridazinone compound or a salt thereof, and a pharmaceutically acceptable adjuvant.
  • the present invention discloses for the first time that a polyhydroxypyridazinone compound has a good ER ⁇ receptor agonistic effect, and it is expected to develop a novel ER ⁇ receptor agonist.
  • Step 1 In a 50 mL round bottom flask, add 1.0 g of the raw material 3,5-dimethoxybenzaldehyde, 20 mL of anhydrous tetrahydrofuran as a solvent, and add 7.2 mmol of methylmagnesium bromide format reagent at -20 ° C, stir. The reaction time is 2.5 to 3.5 hours. The end point of the reaction is determined by a dot chromatography plate. After the reaction is completed, the mixture is hydrolyzed, extracted with ethyl acetate, and concentrated to dryness to give an oil.
  • Step 2 In a 50 mL round bottom flask, add 1.00 g of raw material 3,5-dimethoxyphenylethanol, 1.17 g of bromosuccinimide, 30 mL of anhydrous chloroform as a solvent, stir, reaction time 6 hours, point chromatography The plate was used to determine the end of the reaction. After completion of the reaction, the mixture was hydrolyzed, extracted with ethyl acetate and concentrated to dryness to give an oil. This was separated by silica gel column chromatography (dichlorodiethyl acetate:EtOAc:EtOAc). Mass Spectrum: (ESI, positive) m/z [M+H] + 261.01.
  • Step 3 In a 250 mL round bottom flask, 17.4 g of 2-bromo-3,5-dimethoxyphenylethanol and 100 mL of anhydrous tetrahydrofuran were added as a solvent, and 140 mmol of n-butyllithium was added dropwise at -78 °C. After stirring, the reaction time was 2 hours, and then carbon dioxide was introduced. After completion of the reaction, the mixture was hydrolyzed, extracted with ethyl acetate, and concentrated to dryness to give an oil. This was separated by silica gel column chromatography (dichlorodiethyl acetate:EtOAc:EtOAc) Mass Spectrum: (ESI, positive) m/z [M+H] + 209.09.
  • Step 5 In a 50 mL round bottom flask, add 2.0 g of the starting material 3-hydroxy-5,7-dimethoxy-3-methyl-isophenylfuranone, 1.1 molar equivalents of 4-methoxyphenylhydrazine hydrochloride.
  • Step 6 Add 5,8-dimethoxy-2-(4-methoxyphenyl)-4-methylpyridazinone 500 mg, 5 molar equivalents of boron tribromide in a 50 mL round bottom flask. 30 mL of 1,2-dichloroethane was used as a solvent, stirred, and refluxed for 24 hours. Hydrolysis was carried out by adding methanol and water, extraction by dichloroethane, and concentrated to give an oil.
  • the compound was reacted according to the synthesis method of Example 1 to give a white powder.
  • the compound was reacted with 3,5-dimethoxybenzyl alcohol as a starting material according to the synthesis method of Example 1 to give a white powder.
  • the compound was reacted according to the synthesis method of Example 1 to give the corresponding white powder material.
  • the compound was reacted with 3,5-dimethoxybenzaldehyde and a phenyl format reagent according to the synthesis method of Example 1 to obtain a white powdery substance.
  • Step 2 Add the raw material 6,8-dimethoxy-2-(4-methoxy-phenyl)-2,3-dihydro-pyridazine-1,4-dione 500 into a 50 mL round bottom flask.
  • Mg 2 molar equivalents of phosphorus oxybromide, 30 mL of 1,2-dichloroethane as solvent, stirring, refluxing reaction time 24 hours, adding water hydrolysis, sodium bicarbonate neutralization, dichloroethane extraction, concentration and drying An oil is obtained.
  • Step 3 Add the starting material 4-bromo-6,8-dimethoxy-2-(4-methoxy-phenyl)-2,3-dihydro-pyridazine-1,4 to a 50 mL round bottom flask. - 500 mg of diketone, 5 equivalents of boron tribromide, 30 mL of 1,2-dichloroethane as a solvent, stirring, refluxing for 24 hours, adding methanol and water for hydrolysis, dichloroethane extraction, concentration and drying to obtain Oily.
  • the compound was reacted according to the synthetic method of Example 6 to give a white powder.
  • the compound was reacted according to the synthetic method of Example 6 to give a white powder.
  • Step 2 In a 50 mL round bottom flask, add the raw material 5-bromo-6,8-dimethoxy-2-(4-methoxyphenyl)pyridazinone 500 mg, 5 molar equivalents of boron tribromide, 30 mL of 1,2-dichloroethane was used as a solvent, stirred, and refluxed for 24 hours. Hydrolysis was carried out by adding methanol and water, extracted with dichloroethane, and concentrated to give an oil.
  • the activity of the compound was obtained as follows: The compound was first dissolved in DMSO to prepare a solution of 6-8 concentration gradients. The estrogen receptor and radiolabeled estradiol ([ 3 H]-estradiol, 100 nM) were added to the buffer and mixed to prepare a reaction solution. The compound concentration gradient dilutions were separately added to the reaction solution, mixed, and incubated overnight at 4 ° C to fully react the compound and estradiol with the estrogen receptor. Then, the TopCount NXT liquid scintillation instrument (Perkin Elmer) was subjected to radioactivity intensity measurement by GF/B filtration. Data processing was performed according to the values of the detected concentrations to obtain the estrogen receptor affinity constant of the compound, as shown in the following table:

Abstract

本发明提供了一类多羟基酞嗪酮化合物、其制备方法及应用，所述多羟基酞嗪酮化合物的化学结构通式如式(I)所示。本发明公开的多羟基酞嗪酮化合物具有良好的ERβ受体激动效果，有望开发出新型的ERβ受体激动剂。

Description

一类多羟基酞嗪酮化合物、其制备方法及应用 技术领域
本发明属于生物医药技术领域，具体涉及一类多羟基酞嗪酮化合物、其制备方法及应用。
背景技术
雌激素受体属于类固醇核受体，是由配体诱导的核转录因子的受体。雌激素受体是一种重要的细胞调节蛋白，它通过内源性雌激素在众多的生理过程中起着至关重要的作用，包括女性第二性征发育和维护，包括肌肉和骨骼的质量等。内源性甾体雌激素一般被称为女性性激素，包括雌二醇。雌二醇是在女性血清中发现的主要的甾体雌激素，它主要由卵巢分泌的。
雌激素受体(ER)包括受体亚型ER-α(雌激素受体α)和ER-β(雌激素受体β)。此外还有与雌激素受体结构密切相关的受体(ERRs)，如ERR-α，ERR-β和ERR-γ。类固醇类核受体在身体生理功能中起着重要作用，其中包括有关电解质和水平衡的转录动态平衡、生长发育、伤口愈合、生育、应激反应、免疫功能和认知功能。因此，化合物具有调节(即拮抗剂，激动剂，部分拮抗剂，部分激动剂)类固醇核受体活动的调节剂都具有治疗和预防受类固醇核受体活动影响的疾病。例如，雌激素受体ER-β存在于脑、骨骼、免疫系统、胃肠道、肺、卵巢、子宫内膜、前列腺、血管系统、泌尿生殖道、涎腺等组织中。因此，有关这些组织的病症可通过ER-β受体选择性配体调节剂来治疗。ER-β可通过与雌激素受体ER-α异二聚而对ER-α受体起到拮抗剂的作用。例如，ER-β受体激动剂可以阻止雌激素受体ER-α在前列腺癌和乳腺癌组织中促进肿瘤的增生的作用。
众所周知，内源性雌激素对绝经前妇女的血管系统的影响巨大，对心肌也具有保护作用。雌激素直接影响各种血管组织舒张功能(即降低血管收缩或血管张力)，降低全身血管阻力，改善微血管循环。雌激素还减少血管细胞增殖和迁移，降低血管反应性、粘性，减缓血管的纤维化。ER-β受体激动剂可能对高血压和各种其他心血管疾病如动脉粥样硬化和充血性心力衰竭有治疗效用。
ER-β受体激动剂也具有抗氧化活性。在体内氧化磷酸化的过程中，会产生各种活性氧自由基，超氧(O 2· -)和过氧化氢(H 2O 2)等不稳定分子。这些活性氧与内源性大分子如DNA、脂类和蛋白质产生各种氧化反应而损害其功能。随着时间的推移这氧化损伤积累会导致各种与年龄有关的病症。例如，神经退行性疾病包括老年痴呆症、帕金森病、亨廷顿氏病，多发性硬化症，肌萎缩性侧索硬化症，多种类型的癌症，包括前列腺和结肠、中风等血管疾病和各种年龄相关的动脉粥样硬化等。抗坏血酸(维生素C)，来自红酒的茶多酚和源自大豆产品的染料木黄酮与香豆雌酚等植物雌激素分子具有消除体内活性氧的功能。ERβ受体激动剂是多酚类化合物，具有抗氧化活性。很多文献与专利报道了非甾体类小分子ERβ受体激动剂，但多羟基酞嗪酮化合物作为ERβ受体激动剂还没有报道。
发明内容
为了克服现有技术中所存在的问题，本发明的目的在于提供一类新的多羟基酞嗪酮化合物。
为了实现上述目的以及其他相关目的，本发明采用如下技术方案：
一类多羟基酞嗪酮化合物，其化学结构通式如式(I)所示：
Figure PCTCN2018086244-appb-000001
Figure PCTCN2018086244-appb-000002
其中R 1、R 2、R 3、R 4各自独立的为氢、羟基、C 1～ 3烷氧基或卤素；R 5为氢、C 1～ 4烷基、C 1～ 4卤代烷基、苯基或氰基；R 6为氢或卤素。所述卤素为氟、氯或溴。
优选的，所述R 1、R 2、R 3为羟基，R 4和R 6为氢；R 5为氢、C 1～ 4烷基、C 1～ 4卤代烷基、苯基或氰基。
优选的，所述R 1、R 2、R 3为羟基，R 4和R 6为氢；R 5为氯或溴。
优选的，所述R 1、R 2、R 3为羟基；R 4为氢或卤素；R 5为氢；R 6为氯或溴。所述卤素为氟、氯或溴。
本发明的第二目的在于提供一类多羟基酞嗪酮化合物的制备方法，当所述R 1、R 2、R 3为羟基，R 4和R 6为氢；R 5为氢、C 1～ 4烷基、C 1～ 4卤代烷基、苯基或氰基时，包括如下步骤：
以化合物(1)为起始原料与烷基或苯基格式试剂反应得到相应的二级醇化合物(2)；再溴化为化合物(3)，化合物(3)经羧基化反应得到化合物(4)；化合物(4)经氧化生成(5)；化合物(5)和相应的肼经过缩合反应生成化合物(6)；化合物(6)经脱甲基反应得到目标化合物(7)，其化学反应式如下：
Figure PCTCN2018086244-appb-000003
当R 1、R 2、R 3为羟基，R 4和R 6为氢；R 5为氯或溴时，包括如下步骤：化合物(8)与肼缩合生成化合物(9)；化合物(9)再经过卤化反应得到中间 体(10)；化合物(10)通过脱甲基反应得到目标化合物(11)，其化学反应式如下：
Figure PCTCN2018086244-appb-000004
当所述R 1、R 2、R 3为羟基；R 4为氢或卤素；R 5为氢；R 6为氯或溴时，包括如下步骤：化合物(12)与溴代琥珀亚酰胺或氯代琥珀亚酰胺反应生成化合物(13)；化合物(13)再经过脱甲基化反应得到目标化合物(14)，其化学反应式如下：
Figure PCTCN2018086244-appb-000005
本发明的第三目的在于提供上述多羟基酞嗪酮化合物在制备治疗和/或预防与雌激素相关的疾病中的应用。
优选地，所述与雌激素相关的疾病包括前列腺疾病、肿瘤、泌尿生殖道疾病、胃肠疾病、炎症、骨质疏松症、周围血管疾病、阿兹海默症、帕金森病、
中风、眼疾病、关节炎、更年期潮热、心血管疾病、肥胖及脂肪肝。
本发明的第四目的在于提供一种组合物，包含上述多羟基酞嗪酮化合物或其盐，以及药学上可接受的辅料。
与现有技术相比，本发明首次公开了多羟基酞嗪酮化合物具有良好的ERβ受体激动效果，有望开发出新型的ERβ受体激动剂。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
实施例1
6,8-二羟基-2-(4-羟基苯基)-4-甲基酞嗪酮，(C 15H 12N 2O 4)
Figure PCTCN2018086244-appb-000006
步骤1.在50mL圆底烧瓶中加入原料3，5-二甲氧基苯甲醛1.0克，无水四氢呋喃20mL作为溶剂，在-20℃下滴加7.2毫摩尔甲基溴化镁格式试剂，搅拌，反应时间2.5～3.5小时，点层析板确定反应终点，反应完成后，水解，乙酸乙酯萃取，浓缩抽干，得到油状物。硅胶柱层析(二氯甲烷:乙酸乙酯＝9：1)分离， 纯化，得到白色粉末物质，烘干，称重，得1.0克3,5-二甲氧基苯乙醇，产率约为92％。质谱：(ESI,positive)m/z[M+H] +183.09。
步骤2.在50mL圆底烧瓶中加入原料3，5-二甲氧基苯乙醇1.00克，溴代琥珀酰亚胺1.17克，无水氯仿30mL作为溶剂，搅拌，反应时间6小时，点层析板确定反应终点，反应完成后，水解，乙酸乙酯萃取，浓缩抽干，得到油状物。硅胶柱层析(二氯甲烷:乙酸乙酯＝9：1)分离，纯化，得到黄色粉末物质，烘干，称重，得1.3克产物，产率约为91％。质谱：(ESI,positive)m/z[M+H] +261.01。
步骤3.在250mL圆底烧瓶中加入原料2-溴-3,5-二甲氧基苯乙醇17.4克，无水四氢呋喃100mL作为溶剂，在-78℃下滴加140毫摩尔正丁基锂，搅拌，反应时间2小时，然后通入二氧化碳，反应完成后，水解，乙酸乙酯萃取，浓缩抽干，得到油状物。硅胶柱层析(二氯甲烷:乙酸乙酯＝9：2)分离，纯化，得到白色粉末物质，烘干，称重，得10.0克产物，产率约为72％。质谱：(ESI,positive)m/z[M+H] +209.09。
步骤4.在50mL圆底烧瓶中加入原料5，7-二甲氧基-3-甲基-异苯基呋喃酮500毫克，2摩尔当量的硝酸锰，5摩尔当量的高锰酸钾和水20mL，在70-80℃下搅拌，反应时间2小时，乙酸乙酯萃取，浓缩抽干，得到油状物。硅胶柱层析(二氯甲烷:甲醇＝19：1)分离，纯化，得到白色粉末物质，烘干，称重，得250毫克产物，产率约为46％。质谱：(ESI,positive)m/z[M+H] +225.08。
步骤5.在50mL圆底烧瓶中加入原料3-羟基-5，7-二甲氧基-3-甲基-异苯基呋喃酮2.0克，1.1摩尔当量的4-甲氧基苯肼盐酸盐，1.2摩尔当量的醋酸钠和醋酸20mL作为溶剂，搅拌，回流反应时间24小时，浓缩抽干，乙酸乙酯萃取，抽干得到油状物。硅胶柱层析(二氯甲烷:甲醇＝19：1)分离，纯化，得到白色粉末物质，烘干，称重，得1.3克产物，产率约为45％。质谱：(ESI,positive)m/z[M+H] +327.14。
步骤6.在50mL圆底烧瓶中加入原料6，8-二甲氧基-2-(4-甲氧基苯基)-4-甲基酞嗪酮500毫克，5摩尔当量的三溴化硼，30mL 1,2-二氯乙烷作为溶剂，搅拌，回流反应时间24小时，加入甲醇和水水解，二氯乙烷萃取，浓缩抽干得到油状物。硅胶柱层析(二氯甲烷:甲醇＝9：1)分离，纯化，得到白色粉末物质，烘干，称重，得300毫克目标产物6,8-二羟基-2-(4-羟基苯基)-4-甲基酞嗪酮，产率约为70％。
核磁共振谱： 1H NMR(400MHz,DMSO-d6)δ12.70(s,1H,OH)10.88(s,1H,OH),9.74(s,1H,OH),7.33(d,J＝8.8Hz,2H,ArH),6.87(d,J＝8.8Hz,2H,ArH),6.68(s,1H,ArH),6.61(s,1H,ArH),3.35(s,3H,CH 3)；质谱：(ESI,negative)m/e[M-H] -283.23。
实施例2
4-乙基-6,8-二羟基-2-(4-羟基苯基)-酞嗪酮，(C 16H 14N 2O 4)
Figure PCTCN2018086244-appb-000007
化合物按照实例1的合成方法反应得到白色粉末物质。
核磁共振谱： 1H NMR(400MHz,DMSO-d6)δ12.75(s,1H,OH)10.87(s,1H,OH),9.74(s,1H,OH),7.36(d,J＝8.8Hz,2H,ArH),6.86(d,J＝8.8Hz,2H,ArH),6.73(d,J＝2.0Hz，1H,ArH),6.60(d,J＝2.0Hz，1H,ArH),2.86(q,J＝7.2Hz，2H,CH2)；1.24(t,J＝7.2Hz，3H,CH 3)；质谱：(ESI,negative)m/e[M-H] -297.18。
实施例3
6,8-二羟基-2-(4-羟基苯基)-酞嗪酮，(C 14H 10N 2O 4)
Figure PCTCN2018086244-appb-000008
化合物以3，5-二甲氧基苯甲醇为原料按照实例1的合成方法反应得到白色粉末物质。
核磁共振谱： 1H NMR(400MHz,DMSO-d6)δ12.73(s,1H,OH)10.88(s,1H,OH),9.76(s,1H,OH),8.07(s，1H，CH＝N)，7.35(d,J＝8.8Hz,2H,ArH),6.87(d,J＝8.8Hz,2H,ArH),6.71(d,J＝2.0Hz，1H,ArH),6.63(d,J＝2.0Hz，1H,ArH)；质谱：(ESI,negative)m/e[M-H] -269.04。
实施例4
2-(3-氟-4-羟基苯基)-6,8-二羟基-4甲基酞嗪酮，(C 15H 11FN 2O 4)
Figure PCTCN2018086244-appb-000009
化合物按照实例1的合成方法反应得到相应白色粉末物质。
核磁共振谱： 1H NMR(400MHz,DMSO-d6)δ12.73(s,1H,OH)10.87(s,1H,OH),10.25(s,1H,OH),7.45(dd，1H，J＝11.7，2.4Hz，ArH)，7.17-7.03(m，2H，ArH)，6.67(s,1H,ArH),6.62(s,1H,ArH),3.36(s,3H,CH 3)；质谱：(ESI,negative)m/e[M-H] -301.06。
实施例5
6,8-二羟基-2-(4-羟基苯基)-4-苯基酞嗪酮，(C 20H 14N 2O 4)
Figure PCTCN2018086244-appb-000010
化合物以3，5-二甲氧基苯甲醛和苯基格式试剂为原料按照实例1的合成方法反应得到白色粉末物质。
核磁共振谱： 1H NMR(400MHz,DMSO-d6)δ12.70(s,1H,OH)10.86(s,1H,OH),9.73(s,1H,OH),7.53-7.38(m，5H，ArH)，7.33(d,J＝8.8Hz,2H,ArH),6.86(d,J＝8.8Hz,2H,ArH),6.72(d,J＝2.0Hz，1H,ArH),6.62(d,J＝2.0Hz，1H,ArH)；质谱：(ESI,negative)m/e[M-H] -345.11。
实施例6
4-溴-6，8-二羟基-2(4—羟基苯基)酞嗪酮，(C 14H 9BrN 2O 4)
Figure PCTCN2018086244-appb-000011
步骤1.在50mL圆底烧瓶中加入原料4,6-二甲氧基-异苯并呋喃-1,3-二酮1.00克，1.1摩尔当量的4-甲氧基苯肼盐酸盐，1.2摩尔当量的醋酸钠和醋酸20mL作为溶剂，搅拌，回流反应时间24小时，浓缩抽干，乙酸乙酯萃取，抽干得到油状物。硅胶柱层析(二氯甲烷:甲醇＝19：1)分离，纯化，得到白色粉末物质，烘干，称重，得0.89克产物，产率约为56％。质谱：(ESI,positive)m/z[M+H] +329.14。
步骤2.在50mL圆底烧瓶中加入原料6,8-二甲氧基-2-(4-甲氧基-苯基)-2,3-二氢-酞嗪-1,4-二酮500毫克，2摩尔当量的三溴氧磷，30mL 1，2-二氯乙烷作为溶剂，搅拌，回流反应时间24小时，加入水水解，碳酸氢钠中和，二氯乙烷萃取，浓缩抽干得到油状物。硅胶柱层析(乙酸乙酯:己烷＝4：1)分离，纯化，得到白色粉末物质，烘干，称重，得270毫克目标产物4-溴-6,8-二甲氧基-2-(4-甲氧基-苯基)-2,3-二氢-酞嗪-1,4-二酮，产率约为45％。(ESI,positive)m/z[M+H] +391.04。
步骤3.在50mL圆底烧瓶中加入原料4-溴-6,8-二甲氧基-2-(4-甲氧基-苯基)-2,3-二氢-酞嗪-1,4-二酮500毫克，5当量的三溴化硼，30mL 1，2-二氯乙烷作为溶剂，搅拌，回流反应时间24小时，加入甲醇和水水解，二氯乙烷萃取，浓缩抽干得到油状物。硅胶柱层析(二氯甲烷:甲醇＝9：1)分离，纯化，得到白色粉末物质，烘干，称重，得340毫克目标产物4-溴-6,8-二羟基-2-(4-羟基苯基)酞嗪酮，产率约为76％。
核磁共振谱： 1H NMR(400MHz,DMSO-d6)δ12.78(s,1H,OH)10.87(s,1H,OH),9.74(s,1H,OH),7.32(d,J＝8.8Hz,2H,ArH),6.86(d,J＝8.8Hz,2H,ArH),6.70(d,J＝2.0Hz，1H,ArH),6.61(d,J＝2.0Hz，1H,ArH)；质谱：(ESI,negative)m/e[M-H] -348.13。
实施例7
4-氯-6,8-二羟基-2-(4-羟基苯基)酞嗪酮，(C 14H 9ClN 2O 4)
Figure PCTCN2018086244-appb-000012
化合物按照实例6的合成方法反应得到白色粉末物质。
核磁共振谱： 1H NMR(400MHz,DMSO-d6)δ12.75(s,1H,OH)10.86(s,1H,OH),9.77(s,1H,OH),7.33(d,J＝8.8Hz,2H,ArH),6.88(d,J＝8.8Hz,2H,ArH),6.72(d,J＝2.0Hz，1H,ArH),6.61(d,J＝2.0Hz，1H,ArH)；质谱：(ESI,negative)m/e[M-H] -303.04。
实施例8
4-溴-2-(3-氟-4-羟基苯基)-6,8-二羟基酞嗪酮，(C 14H 8BrFN 2O 4)
Figure PCTCN2018086244-appb-000013
化合物按照实例6的合成方法反应得到白色粉末物质。
核磁共振谱： 1H NMR(400MHz,DMSO-d6)δ12.78(s,1H,OH)10.88(s,1H,OH),10.28(s,1H,OH),7.42(dd,J＝11.7，2.4Hz,1H,ArH),7.17-7.04(m，2H，ArH)，6.71(d,J＝2.0Hz，1H,ArH)；6.62(d,J＝2.0Hz，1H,ArH)；质谱：(ESI,negative)m/e[M-H] -364.98。
实施例9
5-溴-2-(4-羟基苯基)-6,8-二羟基酞嗪酮，(C 14H 9BrN 2O 4)
Figure PCTCN2018086244-appb-000014
步骤1.在50mL圆底烧瓶中加入原料6,8-二甲氧基-2-(4-甲氧基苯基)酞嗪酮500毫克，1.2当量的溴代琥珀亚酰胺，无水四氢呋喃30mL作为溶剂，搅拌，回流反应时间4小时，，浓缩抽干，乙酸乙酯萃取，抽干得到油状物。硅胶柱层析(二氯甲烷:甲醇＝19：1)分离，纯化，得到白色粉末物质，烘干，称重，得0.51克产物，产率约为81％。质谱：(ESI,positive)m/Z[M+H] +391.04。
步骤2.在50mL圆底烧瓶中加入原料5-溴-6,8-二甲氧基-2-(4-甲氧基苯基)酞嗪酮500毫克，5摩尔当量的三溴化硼，30mL 1,2-二氯乙烷作为溶剂，搅拌，回流反应时间24小时，加入甲醇和水水解，二氯乙烷萃取，浓缩抽干得到油状物。硅胶柱层析(二氯甲烷:甲醇＝9：1)分离，纯化，得到白色粉末物质，烘干，称重，得355毫克目标产物5-溴-6,8-二羟基-2-(4-羟基苯基)酞嗪酮，产率约为79％。
核磁共振谱： 1H NMR(400MHz,DMSO-d6)δ12.88(s,1H,OH)，11.38(s,1H,OH),9.78(s,1H,OH),8.06(s，1H，CH＝N)，7.36(d,J＝8.8Hz,2H,ArH),6.86(d,J＝8.8Hz,2H,ArH),6.53(s，1H，ArH)；质谱：(ESI,negative)m/e[M-H] -346.96。
实施例10
化合物的活性按下述方法得到：先将化合物溶于DMSO中，配成6-8个浓度梯度的溶液。将雌激素受体和带有放射性标记的雌二醇([ 3H]-estradiol，100nM)加入到缓冲液中，混匀，配制成反应液。将各化合物浓度梯度稀释液分别加入到反应液中，混匀，4℃下孵育过夜，使化合物及雌二醇与雌激素受体充分反应。然后，通过GF/B过滤，TopCount NXT液闪仪(Perkin Elmer)进行放射性强度检测。根据检测到的各浓度的数值进行数据处理，得到化合物的雌激素受体亲合常数，见下表：
Figure PCTCN2018086244-appb-000015
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一类多羟基酞嗪酮化合物，其特征在于，其化学结构通式如式(I)所示：
    Figure PCTCN2018086244-appb-100001
    其中R 1、R 2、R 3、R 4各自独立的为氢、羟基、C 1～ 3烷氧基或卤素；R 5为氢、C 1～ 4烷基、C 1～ 4卤代烷基、苯基或氰基；R 6为氢或卤素。
  2. 如权利要求1所述的多羟基酞嗪酮化合物，其特征在于，所述R 1、R 2、R 3为羟基，R 4和R 6为氢；R 5为氢、C 1～ 4烷基、C 1～ 4卤代烷基、苯基或氰基。
  3. 如权利要求1所述的多羟基酞嗪酮化合物，其特征在于，所述R 1、R 2、R 3为羟基，R 4和R 6为氢；R 5为氯或溴。
  4. 如权利要求1所述的多羟基酞嗪酮化合物，其特征在于，所述R 1、R 2、R 3为羟基；R 4为氢或卤素；R 5为氢；R 6为氯或溴。
  5. 一种制备如权利要求2所述多羟基酞嗪酮化合物的方法，其特征在于，包括如下步骤：
    以化合物(1)为起始原料与烷基或苯基格式试剂反应得到相应的二级醇化合物(2)；再溴化为化合物(3)，化合物(3)经羧基化反应得到化合物(4)；化合物(4)经氧化生成(5)；化合物(5)和相应的肼经过缩合反应生成化合物(6)；化合物(6)经脱甲基反应得到目标化合物(7)，其化学反应式如下：
    Figure PCTCN2018086244-appb-100002
  6. 一种制备如权利要求3所述多羟基酞嗪酮化合物的方法，其特征在于，包括如下步骤：化合物(8)与肼缩合生成化合物(9)；化合物(9)再经过卤化反应得到中间体(10)；化合物(10)通过脱甲基反应得到目标化合物(11)，其化学反应式如下：
    Figure PCTCN2018086244-appb-100003
  7. 一种制备如权利要求4所述多羟基酞嗪酮化合物的方法，其特征在于，包括如下步骤：化合物(12)与溴代琥珀亚酰胺或氯代琥珀亚酰胺反应生成化合物(13)；化合物(13)再经过脱甲基化反应得到目标化合物(14)，其化学反应式如下：
    Figure PCTCN2018086244-appb-100004
  8. 如权利要求1～4任一项所述的多羟基酞嗪酮化合物在制备治疗和/或预防与雌激素相关的疾病中的应用。
  9. 如权利要求8所述的应用，其特征在于，所述与雌激素相关的疾病包括前列腺疾病、肿瘤、泌尿生殖道疾病、胃肠疾病、炎症、骨质疏松症、周围血管疾病、阿兹海默症、帕金森病、中风、眼疾病、关节炎、更年期潮热、心血管疾病、肥胖及脂肪肝。
  10. 一种药物组合物，其特征在于包含如权利要求1～4任一项所述的多羟基酞嗪酮化合物或其盐，以及药学上可接受的辅料。
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