CN106432011B - 一类具有辐射防护作用的新化合物、其制备方法及其药物应用 - Google Patents

一类具有辐射防护作用的新化合物、其制备方法及其药物应用 Download PDF

Info

Publication number
CN106432011B
CN106432011B CN201610829269.XA CN201610829269A CN106432011B CN 106432011 B CN106432011 B CN 106432011B CN 201610829269 A CN201610829269 A CN 201610829269A CN 106432011 B CN106432011 B CN 106432011B
Authority
CN
China
Prior art keywords
compound
radiation
injury
hydrogen
purposes
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.)
Active
Application number
CN201610829269.XA
Other languages
English (en)
Other versions
CN106432011A (zh
Inventor
田红旗
朱知梅
张倩如
程瑛
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.)
KECHOW PHARMA Inc
Original Assignee
Institute of Radiation Medicine of CAMMS
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 Institute of Radiation Medicine of CAMMS filed Critical Institute of Radiation Medicine of CAMMS
Priority to CN201610829269.XA priority Critical patent/CN106432011B/zh
Publication of CN106432011A publication Critical patent/CN106432011A/zh
Application granted granted Critical
Publication of CN106432011B publication Critical patent/CN106432011B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C07D213/34—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明提供了一类具有辐射防护作用的新化合物及其药学上可接受的盐、前药和溶剂化物，如式(I)化合物及其药学上可接受的盐、前药和溶剂化物：其中W选自羰基，亚砜基和磺酰基。R1选自取代或未取代的芳族环或芳族杂环:X选自碳和氮；R4选自氢，卤素，氰基，取代或未取代的C1‑3烷基或烷氧基，甲基，三氟甲基，甲氧基，三氟甲氧基；R2选自以下基团：R3选自氢，甲基，乙烯基等。当W选自磺酰基，R1选自4‑氟苯基，4‑氯苯基，4‑碘苯基和4‑三氟甲氧基苯基时，R2不可选取4‑羧酸苯基和4‑羧酸钠苯基，R3不可选取氢；当W选自亚砜基，R1选自4‑氟苯基，4‑氯苯基和4‑碘苯基时，R2不可选取4‑羧酸苯基和4‑羧酸钠苯基，R3不可选取氢。

Description

一类具有辐射防护作用的新化合物、其制备方法及其药物 应用
技术领域
本发明涉及医药领域，特别是涉及电离辐射损伤防护方面，具体在于，一类具有辐射防护作用的新化合物。
本发明还涉及该化合物的制备方法。
本发明还涉及该化合物在用于预防和治疗电离辐射造成的相关损伤救治和疾病治疗方面的应用。
背景技术
随着全球核事业的蓬勃发展，核技术已在核电站、航天事业、国防和生物医药等各个领域广泛应用，人类接触电离辐射并导致损伤的机会增加，同时随着世界核安全形势紧张带来的核战争和核恐怖事件隐忧，电离辐射造成的机体损伤(简称为辐射损伤)的防护与救治正在受到越来越多的重视。
另一方面，恶性肿瘤的发病率和患者数量近年来一直呈持续上升的趋势，放射治疗作为主要治疗手段之一，起着不可或缺的作用，但是高剂量辐射照射难免会导致的肿瘤周边正常组织和器官乃至全身的急性辐射损伤，辐射损伤带来的副反应严重地限制了放射治疗在肿瘤治疗中的广泛应用，也明显影响了肿瘤患者放射治疗疗效和治疗后的生活质量。
目前已有的辐射损伤救治相关药物主要有：含硫化合物、激素类、细胞因子类以及中草药等，它们分别存在各自的固有缺陷：比如含硫化合物普遍副作用较大，氨磷汀(又名amifostine)作为此类化合物的代表是目前公认的防护效果最好的化合物，是国际管理机构通过的第一个有选择性的广谱细胞保护剂，但是半衰期极短(7分钟)和价格昂贵(国内医疗市场价格在400-500元/支)限制了它的应用；而激素类药物对辐射损伤的防治主要是对骨髓有核细胞、造血干细胞和祖细胞，此类药物对性器官和生殖系统的影响限制了它的广泛使用；细胞因子类药物例如白介素类、集落刺激因子类药物能够缓解和救治辐射导致的骨髓造血功能系统损伤，但是其辐射防护作用与给药时间密切相关(在用于预防和救治的医疗实践中，此类药物对医护检测水平和关注程度要求高)，存在明显的致炎作用，且价格昂贵，难以常温保存；中草药类抗辐射成分主要有酚类、多糖类、天然黄酮类，具有活性成分不明确、低毒等特点，经多年研究，至今无上市或待上市的同类药物
发明内容
本发明的一个目的是要提供一类具有辐射防护作用的新的化合物。它具有延长亚致死剂量照射后动物的生存期和降低死亡率的作用，可以单独作为辐射损伤防护和救治药物，也可以与放疗联合应用，对放疗引起的不良反应有缓解和防治作用。
本发明的另一目的在于提供制备该化合物的方法。
本发明的再一目的在于该化合物在用于预防和治疗电离辐射造成的相关损伤救治和疾病治疗方面的应用。
根据本发明的一方面，提供具有下列化学结构式的化合物：
其中W选自羰基，亚砜基和磺酰基；
R1选自取代或未取代的芳族环或芳族杂环：
X选自碳和氮；
R4选自氢，卤素，氰基，取代或未取代的C1-3烷基或烷氧基，甲基，三氟甲基，甲氧基，三氟甲氧基；
R2选自以下基团：
R3选自氢，甲基，乙烯基等。
当W选自磺酰基，式I化合物具有以下通式：
其中X，R1、R2、R3、R4如上定义；
当R1选自4-氟苯基，4-氯苯基，4-碘苯基和4-三氟甲氧基苯基时，R2不可选取4-羧酸苯基和4-羧酸钠苯基基团，R3不可选取氢；
当W选自亚砜基时，式I化合物具有以下通式：
其中X，R1、R2、R3、R4如上定义；
当R1选自4-氟苯基，4-氯苯基和4-碘苯基时，R2不可选取4-羧酸苯基和4-羧酸钠苯基，R3不可选取氢。
当W选自亚砜基时，式I化合物具有以下通式：
其中X，R1、R2、R3、R4如上定义；
根据本发明的另一方面，提供本发明化合物(I-1)的制备方法：
化合物(I-2)以及化合物(I-3)的合成方法参照化合物(I-1)的合成方法进行。
根据本发明的再一方面，提供含有本发明化合物的药物组合物及其衍生物与一种或多种药剂学上可接受的媒介载体，辅剂，助剂或稀释剂混合，剂型包括但不限于：注射剂，乳剂，微乳剂，亚微乳剂，纳米颗粒，片剂，胶囊，丸剂，吸入剂，含片，凝胶剂，粉剂，栓剂，悬乳液，乳膏剂，胶冻剂，喷雾剂等。可采取的给药方式包括但不限于：皮下注射，肌肉注射，静脉注射，口服，直肠给药，阴道给药，鼻腔给药，透皮给药，结膜下给药，眼球内给药，眼眶给药，眼球后给药，视网膜给药，脉络膜给药，鞘内注射等。
根据本发明的再一方面，提供本发明所述的化合物及其药物组合物用于治疗或预防辐射损伤和化疗药损伤的用途本发明所述电离辐射损伤包括但不限于由X、α、β、γ射线以及质子引起的致死剂量照射、亚致死剂量和低剂量照射损伤，也包括肿瘤放射治疗所产生的包括辐射损伤。本发明的化合物可单独作为辐射损伤防护和救治药物，也可与放射治疗或者化疗联合应用来治疗肿瘤，从而降低放疗对周边组织和器官乃至全身引起的不良反应，对放疗引起的不良反应有缓解和防治作用。
本发明提供了一种新的稳定的化合物，其具有降低电离辐射引起的生物损伤的作用，同时该化合物还具有延长动物生存期和存活率的作用，对放疗副作用具有明显的缓解作用，且该化合物毒性较低。本发明开辟了电离辐射损伤防护与救治的新途径，其中辐射损伤包括辐射引起的直接损伤和间接损伤；包括辐射引起的哺乳动物外周血白细胞、血小板和红细胞减少。化疗药物指作用于DNA、RNA和微管蛋白等与细胞生死攸关的抗肿瘤药物。本发明提供的化合物及其衍生物也可以与已知辐射防护剂联用。
根据下文结合附图对本发明具体实施例的详细描述，本领域技术人员将会更加明了本发明的上述以及其他目的、优点和特征。根据下文结合附图对本发明具体实施例的详细描述，本领域技术人员将会更加明了本发明的上述以及其他目的、优点和特征。
附图说明
后文将参照附图以示例性而非限制性的方式详细描述本发明的一些具体实施例。
图1是化合物1、化合物2、化合物3和化合物4体外辐射保护作用的相关情况。
具体实施方式
根据本发明，本发明中所述用语“辐射损伤”是指电磁波谱中各种射线造成的损害，如微波、红外线、可见光、紫外线、X射线、β射线、γ射线等。中子或质子束照射也能引起这类损伤。
术语“药学上可接受的盐”，除非另有说明，包括可存在于本发明化合物中的酸性基团的盐(例如，但不限于，钾盐、钠盐、镁盐、钙盐等)或碱性基团的盐(例如，但不限于，硫酸盐、盐酸盐、磷酸盐、硝酸盐、碳酸盐等)。
术语“溶剂化物”是指在溶液中，溶质分子或离子通过库伦力、范德瓦尔斯力、电荷传递力、氢键等分子间力吸引相邻的溶剂分子形成的复合分子化合物。在一个实施方案中，溶剂为水，即本发明化合物形成水合物。
所述烷基、烯基、炔基、环烷基部分可各自独立地被一个或多个选自以下的基团任选取代：羟基、氧代、卤素、氰基、硝基、三氟甲基、叠氮基、氨基、羧基、巯基。
饱和或不饱和烃基，例如烷基、烷二基或烯基，包括与杂原子的结合，例如烷氧基，均可以分别是直链或带有支链的。
依据取代基的不同，式(I)化合物可以旋光异构体或不同组成的异构体混合物形式存在，所述混合物如果合适可通过常规方式分离。本发明提供了纯异构体和异构体混合物，及其制备方法和用途，以及包括它们的组合物。为简便起见，下文中将其称为式(I)化合物，其既指纯的旋光异构体，如果合适也指不同比例的异构体混合物。
在本发明的一些实施方案中，提供式(I)的化合物及其药学上可接受的盐、前药和溶剂化物。
其中W选自羰基，亚砜基和磺酰基。
R1选自取代或未取代的芳族环或芳族杂环:
X选自碳和氮；
R4选自氢，卤素，氰基，取代或未取代的C1-3烷基或烷氧基(例如：甲基，三氟甲基，甲氧基，三氟甲氧基等)；
R2选自以下基团：
R3选自氢，甲基，乙烯基等。
当W选自磺酰基，式I化合物具有以下通式：
其中X，R1、R2、R3、R4如上定义；
当R1选自4-氟苯基，4-氯苯基，4-碘苯基和4-三氟甲氧基苯基时，R2不可选取4-羧酸苯基和4-羧酸钠苯基基团，R3不可选取氢；
当W选自亚砜基时，式I化合物具有以下通式：
其中X，R1、R2、R3、R4如上定义；
当R1选自4-氟苯基，4-氯苯基和4-碘苯基时，R2不可选取4-羧酸苯基和4-羧酸钠苯基，R3不可选取氢。
当W选自亚砜基时，式I化合物具有以下通式：
其中X，R1、R2、R3、R4如上定义；
根据本发明，通式(I)的化合物可以存在顺/反异构体，本发明涉及順式形式和反式形式以及这些形式的混合物。如果需要，单一立体异构体的制备可根据常规方法拆分混合物，或通过例如立体选择合成制备。如果存在机动的氢原子，本发明也涉及(I)化合物的互变异构形式。
根据本发明，(I)化合物及其立体异构体在用于改善造血功能，升高血液白细胞水平、预防或治疗放射性损伤及肿瘤辅助治疗中显示优良效果。因此可以作为改善造血功能、预防或治疗辐射损伤，及肿瘤辅助治疗等的药物用于动物，优先哺乳动物，特别是人。
在一些优选实施方案中，式(I)中R1优选以下基团：
X优选碳和氮；
R2优选以下基团：
R3优选氢，甲基，乙烯基；
R4优选氢，卤素，氰基，取代或未取代的C1-3烷基或烷氧基(例如：甲基，三氟甲基，甲氧基，三氟甲氧基等)；
在一些优选实施方式中，式I化合物优选自但不仅限于以下化合物：
合成反应
有机反应中常用的合适溶剂均可在以下本发明制备方法的各步反应中使用，例如，但不限于脂肪族和芳香族的、任选烃或者卤化的烃(例如戊烷、己烷、庚烷、环己烷、石油醚、汽油、挥发油、苯、甲苯、二甲苯、二氯甲烷、二氯乙烷、氯仿、四氯化碳、氯苯和邻二氯苯)、脂肪族和芳香族的、任选的醇类(例如甲醇、乙醇、丙醇、异丙醇、叔丁醇、乙二醇等)、醚(例如乙醚和二丁醚，乙二醇二甲醚和二甘醇二甲醚、四氢呋喃和二噁烷等)、酯(例如乙酸甲酯或乙酸乙酯等)、腈(例如乙腈或丙腈等)、酮(例如丙酮、丁酮等)、酰胺(例如二甲基甲酰胺、二甲基乙酰胺和N-甲基吡咯烷酮等)、以及二甲基亚砜、四亚甲基砜和六甲基磷酰三胺和N,N-二甲基丙撑脲(DMPU)等。
合成实施例：
本发明可以通过下例实施例得到进一步说明，但这些实施例子不意味着对本发明的任何限制。
通式(I)化合物的制备方法：
化合物(II)、(III)化合物的制备方法参照化合物(I)的合成方法进行。
实施例1：4-(2–(((5-氯吡啶-2-基)甲基)磺酰基)乙烯基苯甲酸(化合物1)的合成
步骤1：2–(((5-氯吡啶-2-基)甲基)硫代)乙酸的制备
将计算好的NaOH固体(2.7g，66.9mmol，易吸潮，需注意)投入到圆底烧瓶中，加入水，搅拌溶解后冷却至室温，搅拌下慢慢加入巯基乙酸(3.1g，33.4mmol)，反应数分钟后加入对5-氯-2-(氯甲基)吡啶(5.0g，31.1mmol)，50℃反应，油层逐渐消失溶液变为均相，TLC监测反应，大概2h后停止反应，冰浴冷却下，用盐酸调酸，PH值为3左右。加入适量的碎冰，有白色固体析出，抽滤，冷水洗涤两次，晾置，得白色固体。收率为：73.58％。1H NMR(400MHz,CDCl3):δ13.05(s,1H),8.84(s,1H),7.75(d,J＝8.8Hz,1H),7.38(d,J＝9.2Hz 1H),3.85(s,2H),3.09(s,2H).
步骤2：2–(((5-氯吡啶-2-基)甲基)磺酰基)乙酸的制备
将圆底烧瓶中加入冰醋酸(3.5mL)，加入原料(1g，4.2mmol)，搅拌溶解，冰浴下慢慢滴加过氧化氢(1.4g，42.3mmol)，控制内温不高于40℃，加完后室温反应1h，在于内温45℃下反应5h。TLC检测反应的完成。加入冰水，有白色固体析出，抽滤，固体用冷水洗涤两次，晾置，得到白色固体。收率为：73.68％。1H NMR(400MHz,CDCl3):δ13.25(s,1H),8.88(s,1H),7.92(d,J＝8.8Hz,1H),7.38(d,J＝9.2Hz 1H),4.35(s,2H),3.89(s,2H).
步骤3：(E)-4-(2–(((5-氯吡啶-2-基)甲基)磺酰基)乙烯基苯甲酸(化合物1)的合成
在圆底烧瓶中加入2–(((5-氯吡啶-2-基)甲基)磺酰基)乙酸(0.5g，2.0mmol)，再加入相对应量对羧基苯甲醛(0.3g，2.2mmol)，冰醋酸(2.5mL)，搅拌，再慢慢加入苄胺(40.6uL)，加热回流6h(温度设为120℃)，有不溶固体析出，冷却后抽滤，固体用冷甲醇充分洗涤两次，晾置，得白色固体。收率为：69.24％。HMNR(400MHz，DMSO-d6)：δ13.18(s,1H),9.28(d,1H),8.30(d,J＝8.4Hz,2H)，7.94(d,J＝8.4Hz 2H),7.84(dd,J＝8.6,2.2Hz,2H),7.69(d,J＝8.8Hz,1H),7.59(d,J＝15.4Hz 1H),5.21(s,2H).MS(ESI)m/z[M+H]:338.81.
实施例2：4-(2–(((5-氯吡啶-2-基)甲基)磺酰基)乙烯基苯甲酸(化合物2)的合成
步骤1：2–((4-氯苄基-2-基)巯基))乙酸的制备
将计算好的NaOH固体(2.7g，66.9mmol，易吸潮，需注意)投入到圆底烧瓶中，加入水，搅拌溶解后冷却至室温，搅拌下慢慢加入巯基乙酸(3.1g，33.4mmol)，反应数分钟后加入对对氯氯苄(5.0g，31.1mmol)，50℃反应，油层逐渐消失溶液变为均相，TLC监测反应，大概2.5h后停止反应，冰浴冷却下，用盐酸调酸，PH值为3左右。加入适量的碎冰，有白色固体析出，抽滤，冷水洗涤两次，晾置，得白色固体。收率为：73.4％。1H NMR(400MHz,CDCl3):δ13.05(s,1H),7.32(d,J＝8.8Hz,2H),7.28(d,J＝8.8Hz,2H),3.85(s,2H),3.09(s,2H).
步骤2：2–((4-氯苄基)磺酰基))乙酸的制备
将圆底烧瓶中加入冰醋酸(3.5mL)，加入原料(1.0g，4.2mmol)，搅拌溶解，冰浴下慢慢滴加过氧化氢(1.4g，42.3mmol)，控制内温不高于40℃，加完后室温反应1.5h，在于内温45℃下反应5.5h。TLC检测反应的完成。加入冰水，有白色固体析出，抽滤，固体用冷水洗涤两次，晾置，得到白色固体。收率为：72.38％。1H NMR(400MHz,CDCl3):δ13.54(s,1H),7.49(d,J＝8.8Hz,2H),7.41(d,J＝8.8Hz,2H),4.65(s,2H),4.19(s,2H).
步骤3：(E)-6-(2–((4-氯苄基)磺酰基)乙烯基)烟酸(化合物2)的合成
在圆底烧瓶中加入2–((4-氯苄基)磺酰基))乙酸(0.5g，2.0mmol)，再加入相对应量6-甲酰基烟酸(0.33g，2.2mmol)，冰醋酸(2.5mL)，搅拌，再慢慢加入苄胺(40.6uL)，加热回流6h(温度设为120℃)，有不溶固体析出，冷却后抽滤，固体用冷甲醇充分洗涤两次，晾置，得白色固体。收率为：58.24％。HMNR(400MHz，DMSO-d6)：δ13.38(s,1H),9.18(d,1H),8.23(d,J＝8.4Hz,2H)，7.95(d,J＝8.4Hz 2H),7.82(dd,J＝8.6,2.2Hz,2H),7.64(d,J＝8.8Hz,1H),7.53(d,J＝15.4Hz 1H),5.22(s,2H).MS(ESI)m/z[M+H]:338.78.
生物学活性实施例：
实施例3：体外细胞毒性测定
以Ex-Rad为阳性对照，检测4个化合物在HFL-1中的细胞毒性，计算其IC50值，结果见表1。由表1可知，四个化合物中化合物2及化合物4的细胞毒性较小，同Ex-Rad类似，浓度为100μM时未见细胞毒性，化合物结构见表2。
表1
表2
实例4：建立体外HFL-1辐射模型，研究已经获得的Ex-Rad含氮杂环类似物的体外辐射保护作用。
采用10Gy铯137辐射HLF-1细胞建立HFL-1模型，研究XH-001～XH-004的体外辐射保护作用，方法见图1，结果可见(图1(b))，已经合成的化合物中XH-002体外辐射保护效果明显，GI50值为5μM，明显优于阳性对照Ex-Rad。

Claims (7)

1.式(I)的化合物及其药学上可接受的盐：
其中：R4选自卤素，R3选自氢或甲基。
2.权利要求1所述化合物及其药学上可接受的盐，其特征在于，所述化合物选自：
3.权利要求1或2所述化合物或其药物组合物用于制备治疗或预防辐射损伤和化疗药损伤的药物的用途。
4.权利要求3所述用途，其中所述辐射包括电离辐射、非电离辐射或共同发生的情况，其中所述电离辐射包括α射线、β射线、γ射线、X射线和中子辐射。
5.如权利要求3所述用途，其中所述辐射损伤包括辐射引起的直接损伤和间接损伤。
6.如权利要求3所述用途，其中所述辐射损伤包括辐射引起的哺乳动物外周血白细胞、血小板和红细胞减少。
7.如权利要求3所述用途，其中所述化疗药物指作用于DNA、RNA和微管蛋白的抗肿瘤药物。
CN201610829269.XA 2016-09-18 2016-09-18 一类具有辐射防护作用的新化合物、其制备方法及其药物应用 Active CN106432011B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610829269.XA CN106432011B (zh) 2016-09-18 2016-09-18 一类具有辐射防护作用的新化合物、其制备方法及其药物应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610829269.XA CN106432011B (zh) 2016-09-18 2016-09-18 一类具有辐射防护作用的新化合物、其制备方法及其药物应用

Publications (2)

Publication Number Publication Date
CN106432011A CN106432011A (zh) 2017-02-22
CN106432011B true CN106432011B (zh) 2018-11-02

Family

ID=58168605

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610829269.XA Active CN106432011B (zh) 2016-09-18 2016-09-18 一类具有辐射防护作用的新化合物、其制备方法及其药物应用

Country Status (1)

Country Link
CN (1) CN106432011B (zh)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6767926B1 (en) * 1999-10-12 2004-07-27 Temple University - Of The Commonwealth System Of Higher Education Method for protecting normal cells from cytotoxicity of chemotherapeutic agents
CA2439288C (en) * 2001-02-28 2011-08-09 Temple University Of The Commonwealth System Of Higher Education Method for protecting cells and tissues from ionizing radiation toxicity with .alpha.,.beta. unsaturated aryl sulfones
WO2005044181A2 (en) * 2003-09-09 2005-05-19 Temple University-Of The Commonwealth System Of Higher Education Protection of tissues and cells from cytotoxic effects of ionizing radiation by abl inhibitors
JP5196787B2 (ja) * 2003-11-14 2013-05-15 テンプル・ユニバーシティ−オブ・ザ・コモンウェルス・システム・オブ・ハイアー・エデュケイション 増殖性疾患を治療するためのα，β−不飽和スルホキシド
US20110028504A1 (en) * 2005-07-29 2011-02-03 Onconova Therapeutics, Inc. Formulation of radioprotective alpha beta unsaturated aryl sulfones
JP5275985B2 (ja) * 2006-07-28 2013-08-28 オンコノバ・セラピューティックス・インコーポレーテッド 放射線保護α，β不飽和アリールスルホン類の処方
CA2792913C (en) * 2010-03-26 2020-01-21 Onconova Therapeutics, Inc. Improved stable aqueous formulation of (e)-4-carboxystyryl-4-chlorobenzyl sulfone
CN104817488B (zh) * 2015-02-04 2018-04-24 中国人民解放军第四军医大学 砜类氮氧自由基作为辐射防护剂的应用

Also Published As

Publication number Publication date
CN106432011A (zh) 2017-02-22

Similar Documents

Publication Publication Date Title
US11504346B2 (en) Redox-activated pro-chelators
ES2774330T3 (es) Polímero de suministro de fármaco y usos del mismo
RU2448096C2 (ru) Диарилгидантоины
EP2044938B1 (en) Radioprotectors
AU2004224070A1 (en) Bioreductively-activated prodrugs
JP2001515516A (ja) 血管損傷剤としてのコルヒノール誘導体の使用
EA010834B1 (ru) Пиридилзамещённые порфириновые соединения и способы их применения
US11787816B2 (en) Chlorin compound, and preparation and use thereof
CN107848985A (zh) 制备取代的3‑(2‑苯胺基‑1‑环己基‑1h‑苯并咪唑‑5‑基)丙酸衍生物的方法
CN107021961B (zh) 一类具有辐射防护作用的新化合物、其制备方法及其药物应用
CN103992236B (zh) 一种新型靶向性抗肿瘤药物及其制备方法与应用
CN108586443B (zh) 一种防治支气管肺癌的药物及其制备方法
CN102627685B (zh) 一氧化氮供体型谷胱甘肽类化合物、其制备方法及医药用途
CN106432011B (zh) 一类具有辐射防护作用的新化合物、其制备方法及其药物应用
RU2345086C2 (ru) Способ получения цис-диаммонийдихлордигидроксоплатины (iv) и ее применение
JP5583680B2 (ja) アンサマイシンヒドロキノン組成物
EP0281463A2 (en) Platinum complex, process for its preparation and pharmaceutical composition including such a complex
EP1685134B1 (de) Neue chelidonin-derivate, verfahren zu ihrer herstellung und ihre verwendung zur herstellung von pharmazeutischen wirkstoffen
CN103304573A (zh) 石蒜碱类化合物在制备抗肿瘤药物的应用
US20160102066A1 (en) Benzothiazole derivative and anti-tumor use thereof
JP7105465B2 (ja) キニーネ塩懸濁液を含む抗癌治療のための局所投与用注射剤組成物及び懸濁液注射剤の製造方法
EP3805225A1 (en) SELECTIVE A2a RECEPTOR ANTAGONIST
CN111960978A (zh) 一种具有神经保护活性的s-烯丙基-l-半胱氨酸取代酪醇衍生物合成方法及其应用
CN105153238B (zh) 一种米铂的制备方法
CN113766952B (zh) 放射性药品的制造方法及放射性药品

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20220527

Address after: 201203 block m, 3 / F, 780 Cailun Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai

Patentee after: KECHOW PHARMA, Inc.

Address before: 300192, 238 Bai Causeway Road, Tianjin, Nankai District

Patentee before: INST OF RADIATION MEDICINE CHINESE ACAD OF MEDICAL SCIENCES

TR01 Transfer of patent right