CN117402173A - 一种新型异香豆素类衍生物及其制备方法与应用 - Google Patents
一种新型异香豆素类衍生物及其制备方法与应用 Download PDFInfo
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- CN117402173A CN117402173A CN202311158821.3A CN202311158821A CN117402173A CN 117402173 A CN117402173 A CN 117402173A CN 202311158821 A CN202311158821 A CN 202311158821A CN 117402173 A CN117402173 A CN 117402173A
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- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract
本发明涉及一种新型异香豆素类衍生物,或其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或前药,以及包含该化合物的药物组合物。本发明还公开了新型异香豆素类衍生物的制备方法及其在促血管生成药物中的应用。经转基因斑马鱼模型研究发现,本发明提供的异香豆素类衍生物具有很强的促血管生成活性,且具有低毒的特点,具有被开发为促血管生成药物的潜力。
Description
技术领域
本发明涉及一种新型异香豆素类衍生物及其制备方法与应用,并具体涉及新型异香豆素类衍生物及其药物组合物作为药物,尤其是作为促血管生成药物的用途。
背景技术
血管新生是指从原有的血管系统中生长新的毛细血管和血管,涉及内皮细胞增殖、迁移、基底膜降解、血管管腔形成等一系列复杂的生物学过程。这一过程的不平衡可能导致许多疾病的发病机制,如心血管和缺血性疾病、类风湿关节炎、眼科和视网膜病变等(Nature,2005,438:932-936)。利用各种促血管生成或抗血管生成的药物或分子来调节血管生成临床上往往可以有效治疗这些病理性疾病(Eur.J.Med.Res.,2022,27:232)。血管生成不足导致血液循环不畅和组织死亡,促血管生成疗法已被认为是治疗血管功能不全相关疾病(如心力衰竭和缺血性中风)的一种有吸引力和有前途的方法,这些疾病目前仍然是全世界死亡的主要原因(Curr.Opin.Pharmacol.2018,39:60-67)。截止到目前,已经确定了多种诱导治疗性血管生成的方法,包括细胞因子治疗、基因治疗、小分子治疗以及传递祖细胞或干细胞(Curr.Med.Chem.2017,24:3413–3432)。然而,目前所有的治疗方法都存在疗效短暂、毒副作用强、成功率低等缺点(Coronary Artery Dis.2017,28:605–613)。因此,需要大力开发新型促进缺血组织血管生成的治疗药物。
发明内容
本发明的目的在于提供一株真菌Phomopsis prunorum F4-3来源的新型异香豆素类衍生物及其制备方法与作为促血管生成药物的应用,它能满足现有技术的上述需求。菌种保藏信息:保藏单位名称:中国典型培养物保藏中心CCTCC;保藏单位地址:湖北省武汉市武昌区八一路299号武汉大学校内;保藏日期:2023年5月17日;保藏编号:CCTCC No:M2023771;分类命名:Phomopsis prunorum F4-3,见文章(+)-/()-Prunomarin Aand(+)-pestalactone B,three new isocoumarin derivatives from the endophytic fungusPhomopsis prunorum,Tetrahedron Letters 75(2021)153205。
本发明具体涉及一种式I结构的新型异香豆素类衍生物,其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、代谢产物、药学上可接受的盐或它的前药,
其中R1为H,-CH3或-CHO;R2为H,或-CH3。
在一些实施方案中,本发明所述化合物具体包含但不局限于以下之一的结构或以下之一结构的互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、代谢产物、药学上可接受的盐或它的前药:
本发明提供式I化合物的制备方法其特征在于将活化的Phomopsis prunorum F4-3菌株接入真菌发酵培养基中,于室温25-28℃进行发酵培养;待发酵结束,利用有机溶剂对菌体或发酵液进行反复浸泡,将有机相进行合并,经浓缩、萃取、减压浓缩得到粗浸膏,再经正相硅胶柱层析、Sephadex LH-20凝胶柱层析和HPLC高效液相柱分离,获得新型异香豆素类化合物。
上述制备方法中真菌发酵培养基含有大米1.0%–80.0%(重量百分比,下同)、葡萄糖0.01%–5%、氯化钠0.01%–5%、乙酸钠0.01%–5%、丙酸钠0.01%–5%、蛋氨酸0.01%–5%、莽草酸0.01%–5%、其余为水,培养时间优选为20–100天。
所述的正相硅胶柱层析采用的固定相优选200-300目硅胶,流动相优选体积比为30%-100%的乙酸乙酯-石油醚混合溶剂;Sephadex LH-20凝胶柱层析采用的流动相优选体积比为氯仿:甲醇=1:1的混合溶剂;所述HPLC高效液相制备色谱中采用的半制备色谱柱:ODS C18柱,优选为Cosmosil 4.6×250mm,5μm,流速优选为1.0–5.0mL/min,流动相优选体积比为30%–70%的乙腈-水混合溶剂。
本发明涉及本发明化合物及其药学上可接受的盐的应用,用于生产医药产品治疗或减轻人类或动物由血管功能不足引起的疾病。
本发明包含药物组合物,该药物组合物包括本发明所述化合物与至少一种药学上可接受的载体,赋形剂,稀释剂,辅剂,媒介物的结合所需的有效治疗量。
另一方面,本发明涉及一种使用本发明化合物或其药物组合物在治疗由血管生成不足引起的各种疾病的方法用途,该用途包含使用本发明的化合物或其药物组合物的药学上可接受的有效治疗量对人类或动物进行给药。
本发明同样包含治疗或减轻由血管生成不足等引起的疾病,或对此病症敏感的方法,该方法包含使用本发明所述化合物的治疗有效量对患者进行治疗。
前面所述内容只概述了本发明的某些方面,但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。
附图说明
图1为斑马鱼体节间血管数的荧光图。
具体实施方式
定义和一般术语
本发明将会把确定的具体化的内容所对应的文献详细列出,实施例都伴随有结构式和化学式的解释说明。本发明有预期地涵盖所有的选择余地、变体和同等物,这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质,这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明申请相区别或抵触,其中包括但绝不限于术语的定义,术语的用法,描述的技术,或像本发明申请所控制的范围。
本发明将应用以下定义除非其他方面表明。根据本发明的目的,化学元素根据元素周期表,CAS版本和化学药品手册,75,thEd,1994来定义。另外,有机化学一般原理见“Organic Chemistry,”Thomas Sorrell,University Science Books,Sausalito:1999,and“March's Advanced Organic Chemistry,”by Michael B.Smith and Jerry March,John.Wiley&Sons,New York:2007,因此所有的内容都融合了参考文献。
除非其他方面表明,本发明所描述的结构式包括所有的同分异构形式(如对映异构,非对映异构,和几何异构(或构象异构)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体,和(Z)、(E)的构象异构体。因此,本发明的化合物的单个立体化学异构体或其对映异构体,非对映异构体,或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明所使用的术语“前药”,代表一个化合物在体内转化为本发明所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1-C24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献:T.Higuchi and V.Stella,Pro-drugs as Novel DeliverySystems,Vol.14of the A.C.S.Symposium Series;Edward B.Roche,ed.,BioreversibleCarriers in Drug Design,American Pharmaceutical Association and PergamonPress,1987;J.Rautio et al,Prodrugs:Design and Clinical Applications,NatureReview Drug Discovery,2008,7,255-270;and S.J.Hecker et al,Prodrugs ofPhosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345.
除非其他方面表明,本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外,除非其他方面表明,本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化,还原,水解,酰氨化,脱酰氨作用,酯化,脱脂作用,酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明的化合物可以包含不对称中心或手性中心,因此存在不同的立体异构体。本发明的化合物所有的立体异构形式,包括但绝不限于,非对映体,对映异构体,阻转异构体,和它们的混合物,如外消旋混合物,组成了本发明的一部分。很多有机化合物都以光学活性形式存在,即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时,前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀D、L或(+)、(-)用来命名化合物平面偏振光旋转的符号,(-)或L是指化合物是左旋的,前缀(+)或D是指化合物是右旋的。这些立体异构体的化学结构是相同的,但是它们的立体结构不一样。特定的立体异构体可以是对映体,异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体,这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物,缺乏光学活性。
术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变,如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,describepharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括,但并不限于,与氨基基团反应形成的无机酸盐有盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐,和有机酸盐,如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括:己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过适当的碱得到的盐包括碱金属,碱土金属,铵和N+(C1-C4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-C8磺酸化物和芳香磺酸化物。
本发明所述的的部分化合物的盐可以如下所示的具体化合物的盐来说明,但并不限定本发明。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸,氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明的部分化合物的溶剂化物或其盐的溶剂化物可以用如下列出的具体化合物的盐来说明,但不限定于本发明:
本发明的化合物的盐还包括用于制备或纯化本发明所示化合物的中间体或本发明所示化合物分离的对映异构体的盐,但不一定是药学上可接受的盐。
如果本发明的化合物是碱性的,则想得到的盐可以通过文献上提供的任何合适的方法制备得到,例如,使用无机酸,如盐酸,氢溴酸,硫酸,硝酸和磷酸等等。或者使用有机酸,如乙酸,马来酸,琥珀酸,扁桃酸,富马酸,丙二酸,丙酮酸,草酸,羟乙酸和水杨酸;吡喃糖酸,如葡萄糖醛酸和半乳糖醛酸;α-羟酸,如柠檬酸和酒石酸;氨基酸,如天门冬氨酸和谷氨酸;芳香族酸,如苯甲酸和肉桂酸;磺酸,如对甲苯磺酸,乙磺酸,等等。
如果本发明的化合物是酸性的,则想得到的盐可以通过合适的方法制备得到,如使用无机碱或有机碱,如氨(伯氨,仲氨,叔氨),碱金属氢氧化物或碱土金属氢氧化物,等等。合适的盐包括但并不限于,从氨基酸得到的有机盐,如甘氨酸和精氨酸,氨,如伯氨、仲氨和叔氨,和环状氨,如哌啶,吗啉和哌嗪等,和从钠,钙,钾,镁,锰,铁,铜,锌,铝和锂得到无机盐。
根据另一方面,本发明的药物组合物的特点包括本发明所示化合物,或实施例所示的化合物,和药学上可接受的载体,辅剂,或赋形剂。本发明的组合物中化合物的量能有效地可探测地治疗或减轻患者由血管生成不足引起的疾病。
本发明的化合物存在自由形态,或合适的、作为药学上可接受的衍生物。根据本发明,药学上可接受的衍生物包括但并不限于,药学上可接受的前药,盐,酯,酯类的盐,或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物,本发明其他方面所描述的化合物,其代谢产物或他的残留物。
像本发明所描述的,本发明药学上可接受的组合物进一步包含药学上可接受的载体,辅剂,或赋形剂,这些像本发明所应用的,包括任何溶剂,稀释剂,或其他液体赋形剂,分散剂或悬浮剂,表面活性剂,等渗剂,增稠剂,乳化剂,防腐剂,固体粘合剂或润滑剂等等,适合于特有的目标剂型。如以下文献所描述的:In Remington:The Science and Practiceof Pharmacy,21st edition,2005;ed.D.B.Troy,Lippincott Williams Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick andJ.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容,表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围,例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用,它们的用途也是本发明所考虑的范围。
可作为药学上可接受载体的物质包括但并不限于,离子交换剂,铝,硬脂酸铝,卵磷脂,血清蛋白,如人血清蛋白,缓冲物质如磷酸盐,甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶体硅,三硅酸镁,聚乙烯吡咯烷酮,聚丙烯酸脂,蜡,聚乙烯-聚氧丙烯-阻断聚合体,羊毛脂,糖,如乳糖,葡萄糖和蔗糖;淀粉如玉米淀粉和土豆淀粉;纤维素和它的衍生物如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;树胶粉;麦芽;明胶;滑石粉;辅料如可可豆脂和栓剂蜡状物;油如花生油,棉子油,红花油,麻油,橄榄油,玉米油和豆油;二醇类化合物,如丙二醇和聚乙二醇;酯类如乙基油酸酯和乙基月桂酸酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗盐;林格(氏)溶液;乙醇,磷酸缓冲溶液,和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁,着色剂,释放剂,包衣衣料,甜味剂,调味剂和香料,防腐剂和抗氧化剂。
本发明的药物组合物可以是口服给药,注射给药,喷雾吸入法,局部给药,经直肠给药,经鼻给药,含服给药,阴道给药或通过植入性药盒给药。可以是胶囊,片剂,丸剂,粉剂、粒剂和水制悬浮液或溶液。口服给药可以用如下形式:片剂、丸剂、胶囊、可分散的粉末、颗粒或悬浮液、糖浆、和酏剂,或以外用方式给药:软膏剂、凝胶、含药胶布等,或者以无菌可注射溶液或悬浮液形式进行非肠胃给药。本发明化合物也可肠胃外或腹腔内给药。也可在适当混合有表面活性剂(如羟丙基纤维素、聚乙烯吡咯烷酮)的水中制备这些活性化合物(作为游离碱或药学上可接受的盐)的溶液或悬浮液。还可在甘油、液体、聚乙二醇及其在油中的混合物中制备分散液。在常规储存和使用条件下,这些制剂中含有防腐剂以防止微生物生长。
适于注射的药物形式包括:无菌水溶液或分散液和无菌粉(用于临时制备无菌注射溶液或分散液)。在所有情况下,这些形式必须是无菌的且必须是流体以易于注射器排出流体。在制造和储存条件下必须是稳定的,且必须能防止微生物(如细菌和真菌)的污染影响。载体可以是溶剂或分散介质,其中含有如水、醇(如甘油、丙二醇和液态聚乙二醇)、它们的适当混合物和植物油。
化合物可以以局部方式施用,而不以系统方式施用。例如通常以稀释制剂或持续释放制剂的形式将化合物直接注射至器官内。此外,含有本发明化合物的药物组合物可以在靶向药物传递系统中使用,例如在用器官特异性抗体包衣的脂质体中递送。所述脂质体将靶向所述器官并被该器官选择性摄取。此外,含有本发明化合物的组合物可以以快速释放制剂、延时释放制剂或即时释放制剂的形式提供。
对于吸入施用,本发明的化合物可以是气溶胶、气雾剂或粉末形式。本发明化合物的药物组合物可以方便地以气溶胶喷雾剂形式递送,所述气溶胶喷雾剂可以装在压力容器或雾化器中,使用合适的抛射剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。在压力气溶胶的情况下,剂量单位可以通过阀门进行确定以递送计量量。例如,以胶囊剂和药筒为例,用于吸入器或吹药器的明胶可以制备为含有所述化合物与适当粉末基质例如乳糖或淀粉的粉末混合物。
本发明化合物还可以制备为直肠组合物例如灌肠剂、直肠凝胶剂、直肠泡沫剂、直肠气溶胶、栓剂、凝胶栓剂(gel suppository)或保留灌肠剂(retention enema),其中含有常规的栓剂基质例如可可脂或其他甘油酯以及合成聚合物例如聚乙烯吡咯烷酮、PEG等。在组合物的栓剂形式中,低熔点蜡例如但不限于脂肪酸甘油酯任选与可可脂的混合物首先被熔化。
此外,本发明化合物还可与促血管生成药物联用。具体包括但不限于,丹红注射液、阿魏酸、丹参等。
可以根据常规方式用一种或多种生理学可接受的载体制备药物组合物,其中包括可帮助将活性化合物加工为可药用制剂的赋形剂和辅剂。所选择的施用途径决定适当的剂型。任何熟知的技术、载体和赋形剂都可以根据现有技术中的理解适当的使用。含有本发明化合物的药物组合物可以根据常规方法制备,例如通过常规的混合、溶解、制粒、制锭、研磨、乳化、包囊、包封或压制过程制备。
药物组合物将包含至少一种可药用载体、稀释剂或赋形剂和游离酸、游离碱或可药用盐形式的本发明的化合物作为活性成分。此外,药物组合物还可包括其它医学或药学活性剂、载体、辅剂、例如防腐剂、稳定剂、湿润剂或乳化剂、溶解促进剂、调节渗透压的盐或缓冲剂。此外,药物组合物还可含有其它有治疗价值的物质。
含有本文所述化合物的组合物的制备方法包括将化合物与一种或多种惰性的可药用赋形剂或载体一起制备为固体、半固体或液体形式。固体组合物包括但不限于散剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。液体组合物包括其中溶解有化合物的溶液剂、含有化合物的乳剂、含有包含本文公开化合物的脂质体、胶团或纳米粒子的溶液剂。半固体组合物包括但不限于凝胶剂、混悬剂和乳膏剂。组合物可以是液体溶液剂或混悬剂形式、适合于在使用前溶解或悬浮在液体中的固体形式或乳剂形式。这些组合物还可以含有少量无毒的辅剂,例如湿润剂或乳化剂、pH缓冲剂等。
本发明的化合物优选地按制剂配方制备成剂量单位型以减轻给药量和剂量的均匀性。术语“剂量单位型”在此处是指患者得到适当治疗所需药物的物理分散单位。然而,应了解本发明的化合物或组合物每日总的用法将通过主治医生根据可靠的医学范围判断来确定。具体的有效剂量水平对于任何一个特殊的患者或有机体将取决于许多因素包括被治疗的病症和病症的严重性,具体化合物的活性,所用的具体组合物,患者的年龄、体重、健康状况、性别和饮食习惯,给药时间,给药途径和所用具体化合物的排泄速率,治疗的持续时间,药物应用于联合用药或与有特效的化合物联用,以及其他一些药学领域公知的因素。
可以将本发明化合物通过附加适宜的官能团进行修饰以提高选择性生物特性。这样的修饰是本领域己知的并且包括向生物腔隙(例如血液、淋巴系统、中枢神经系统)渗透、提高口服有效性、提高溶解性以便可以通过注射给药、改变代谢和改变排泄的修饰。可以将本发明化合物通过附加适宜的官能团进行修饰以提高选择性生物特性。这样的修饰是本领域己知的并且包括向生物腔隙(例如血液、淋巴系统、中枢神经系统)渗透、提高口服有效性、提高溶解性以便可以通过注射给药、改变代谢和改变排泄的修饰。
一般的,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,下面的实施例用将进一步举例说明本发明的内容。
为了便于对本发明的进一步理解,下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则,本发明的实施方式不限于以下内容。
实施例1
真菌Phomopsis prunorum F4-3的菌种发酵、提取分离
发酵培养所用的培养基含有大米60.0%(重量百分比,下同)、葡萄糖2.4%、氯化钠2.5%、乙酸钠1.3%、丙酸钠2.0%、蛋氨酸4.8%、莽草酸1.2%、6-氟莽草酸3.0%、分支酸1.6%、其余为水,真菌菌株于25–28℃发酵培养40天。
将发酵所得菌体用乙酸乙酯或氯仿-甲醇混合液(1:1)浸提3次减压浓缩后,用乙酸乙酯萃取3次得粗浸膏;乙酸乙酯相粗浸膏浓缩后分别进行正相硅胶柱层析(流动相为80%的乙酸乙酯-石油醚混合溶剂,体积比)、Sephadex LH-20凝胶柱层析(流动相为氯仿:甲醇=1:1的混合溶剂,体积比)后,再经HPLC高效液相制备色谱(ODS C18柱,流动相为60%的乙腈-水混合溶剂,体积比),将所得洗脱液浓缩,可分别获得新型异香豆素类化合物1-4。
实施例2
对实施例1中的化合物进行结构分析测试,得到以下理化性质数据:
化合物1:白色无定型粉末;[α]25 D+20.0(c 0.05,MeCN);UV(MeCN)λmax(logε)248(5.16),280(0.48),334(1.81)nm;CD(MeCN)λmax(Δε)209(-5.71),239(+24.41),286(-1.53),330(-1.00)nm;HR-ESI-MS m/z 445.1130[M+H]+(calcd for C23H23O10,445.1129);1HNMR(DMSO-d6,400MHz)δ:6.49(s,1H),6.45(t,J=2.3Hz,1H),4.38(br s,1H),4.30(dd,J=10.8,8.0Hz,1H),4.19(td,J=10.0,6.2Hz,1H),3.08(d,J=17.9Hz,1H),2.97(d,J=17.9Hz,1H),2.65(dd,J=17.5,6.0Hz,1H),2.56(m,2H),2.25(m,1H),2.14(m,1H),2.10(m,1H),2.01(s,3H);13C NMR(100MHz)δ:170.7(C),167.6(C),165.6(C),164.5(C),160.4(C),147.3(C),137.6(CH),135.8(C),128.8(C),109.7(C),108.7(C),99.0(CH),97.4(C),84.5(CH),76.0(C),68.9(CH),66.0(CH),33.9(CH2),31.0(CH2),29.0(CH2),18.6(CH2),8.0(CH3).
化合物2:白色无定型粉末;[α]25 D-38.0(c 0.1,MeCN);UV(MeCN)λmax(logε)248(5.16),280(0.48),334(1.81)nm;CD(MeCN)λmax(Δε)215(4.11),241(-25.2),286(1.62),331(1.37)nm;HR-ESI-MS m/z 459.1277[M+H]+(calcd for C23H23O10,459.1286);1H NMR(DMSO-d6,400MHz)δ:6.55(t,J=2.3Hz,1H),6.47(s,1H),4.45(br s,1H),4.34(dd,J=10.8,8.0Hz,1H),4.16(td,J=10.0,6.2Hz,1H),3.67(s,3H),3.18(d,J=17.9Hz,1H),2.80(d,J=17.9Hz,1H),2.75(dd,J=17.5,6.0Hz,1H),2.60(m,1H),2.50(m,2H),2.15(m,1H),1.93(m,1H),2.02(s,3H);13C NMR(100MHz)δ:170.2(C),165.5(C),165.5(C),163.9(C),160.5(C),147.1(C),139.7(CH),135.8(C),126.5(C),109.7(C),108.8(C),98.9(CH),97.6(C),84.0(CH),76.0(C),68.4(CH),65.1(CH),52.0(CH3),36.6(CH2),29.3(CH2),26.7(CH2),18.3(CH2),7.9(CH3).化合物3:白色无定型粉末;[α]25 D-156.0(c 0.1,MeCN);UV(MeCN)λmax(logε)226(4.08),272(5.42),328(1.78)nm;CD(MeCN)λmax(Δε)215(+8.33),230(-14.4),265(-30.8),332(-8.0)nm;HR-ESI-MS m/z 509.1067[M+Na]+(calcd forC24H22O11Na,509.1060);1H NMR(DMSO-d6,400MHz)δ:10.42(s,1H),6.58(t,J=2.3Hz,1H),4.49(br s,1H),4.38(dd,J=10.8,8.0Hz,1H),4.18(td,J=10.0,6.2Hz,1H),3.70(s,3H),3.27(d,J=16.8Hz,1H),3.07(m,1H),2.94(d,J=16.8Hz,1H),2.99(dd,J=17.2,6.0Hz,1H),2.61(m,1H),2.54(m,1H),2.18(m,1H),2.02(s,3H),1.74(m,1H);13C NMR(100MHz)δ:195.6(C),170.0(C),168.9(C),165.6(C),165.1(C),164.4(C),152.0(C),142.0(C),139.9(CH),126.6(C),110.5(C),110.2(C),109.3(CH),99.7(C),84.2(CH),75.4(C),68.4(CH),65.1(CH),52.0(CH3),37.6(CH2),29.2(CH2),28.2(CH2),24.5(CH2),7.3(CH3).
化合物4:白色无定型粉末;[α]25 D+148.0(c 0.1,MeCN);UV(MeCN)λmax(logε)226(4.08),272(5.42),328(1.78)nm;CD(MeCN)λmax(Δε)212(-7.63),229(+16.1),265(+17.8),333(+7.09)nm;HR-ESI-MS m/z 473.1074[M+H]+(calcd for C23H21O11,473.1078);1HNMR(DMSO-d6,400MHz)δ:10.31(s,1H),6.56(t,J=2.3Hz,1H),4.42(br s,1H),4.32(dd,J=10.8,8.0Hz,1H),4.32(td,J=10.0,6.2Hz,1H),3.22(d,J=16.8Hz,1H),3.03(m,1H),2.91(d,J=16.8Hz,1H),2.78(dd,J=16.7,6.2Hz,1H),2.68(m,1H),2.27(m,1H),2.25(m,1H),1.98(s,3H),1.94(m,1H);13C NMR(100MHz)δ:195.1(C),170.3(C),168.6(C),165.5(C),165.1(C),164.4(C),152.4(C),141.7(C),137.6(CH),128.5(C),110.5(C),110.1(C),109.1(CH),99.6(C),83.7(CH),75.3(C),68.5(CH),65.5(CH),35.3(CH2),32.2(CH2),29.5(CH2),25.0(CH2),7.2(CH3).
实施例3
基于斑马鱼模型促血管生成活性测试
转基因TG(VEGFR2:GFP)系斑马鱼和AB系野生型斑马鱼由山东省科学院生物研究所药物筛选研究室提供。斑马鱼饲养于斑马鱼养殖系统,照明14h/黑暗10h、28℃标准条件下饲养。
斑马鱼胚胎培养:斑马鱼在照明14h/黑暗10h,水温28℃,pH 7.2-7.5标准条件下饲养,定时喂以人工颗粒状饵料和刚孵出的卤虫无节幼体。采卵时,取健康性成熟的斑马鱼,按雌雄1/1或1/2的比例放入交配缸内,次日9~10时获得受精卵。对受精卵进行消毒和清洗后,移入斑马鱼胚胎培养水中于28℃进行控光培养。
斑马鱼体节间血管数的测定:在受精卵发育24h时,使用1.0mg/mL链酶蛋白酶E溶液脱去卵膜。在体视显微镜下挑选正常的斑马鱼胚胎,移入24孔培养板中,每孔10枚。设正常对照组、PTK787模型组、阳性对照组和给药治疗组(选用阿魏酸FA作为阳性对照,样品浓度设置为80μM),置于光照培养箱(28℃)让胚胎继续发育。在药物作用48h后,用荧光显微镜观察荧光血管生长情况并记录有血流的斑马鱼体节间血管(intersegmental vesvessels,ISVs)数。如图1所示,结果表明:空白对照组节间血管生长正常,模型组节间血管生长明显收到抑制(##p<0.01),显示造模成功;与模型组比较,受试化合物在80μM浓度下均能显著增加斑马鱼具有血流的节间血管数量(**p<0.01),具有明显的促血管生成活性;同时,化合物1在40μM浓度下也能显著增加斑马鱼具有血流的节间血管数量(**p<0.01),与阳性药阿魏酸相当。此外,受试化合物在80μM浓度下对斑马鱼未表现出明显毒性,具有低毒的特点,具有被开发为促血管生成药物的潜力。
Claims (9)
1.一种式I结构的新型异香豆素类衍生物,其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或其盐的溶剂化物,其特征在于,式I化合物具有如下结构:
其中R1为H,-CH3或-CHO;R2为H,或-CH3。
2.根据权利要求1所述的新型异香豆素类衍生物,其特征在于,具有以下其中之一的结构或其药学上可接受的盐:
3.根据权利要求1或2所述的新型异香豆素类衍生物的制备方法,其特征在于,包括如下步骤:
(1)将活化的Phomopsis prunorum F4-3菌株接入真菌发酵培养基中,于室温下进行发酵培养;
(2)待发酵结束,利用有机溶剂对菌体或发酵液进行反复浸泡,将有机相进行合并,经浓缩、萃取、减压浓缩得到粗浸膏,再经正相硅胶柱层析、Sephadex LH-20凝胶柱层析、HPLC高效液相制备色谱,将所得洗脱液浓缩,获得新型异香豆素类衍生物;
其中,所述真菌Phomopsis prunorum F4-3的保藏单位为中国典型培养物保藏中心CCTCC,保藏号为CCTCC No:M2023771;保藏日期为2023年5月17日。
4.如权利要求3所述的制备方法,特征在于,所述发酵培养基含有大米1.0wt%–80.0wt%、葡萄糖0.01wt%–5wt%、氯化钠0.01wt%–5wt%、乙酸钠0.01wt%–5wt%、丙酸钠0.01wt%–5wt%、蛋氨酸0.01wt%–5wt%、莽草酸0.01wt%–5wt%、其余为水,培养时间为20–100天。
5.如权利要求3所述的制备方法,其特征在于,所述的正相硅胶柱层析采用的固定相为200–300目硅胶,流动相为体积比为30%–100%的乙酸乙酯-石油醚混合溶剂;所述Sephadex LH-20凝胶柱层析采用的流动相为体积比为氯仿:甲醇=1:1的混合溶剂;所述HPLC高效液相制备色谱中采用的色谱柱为ODS C18柱,流速为1.0–5.0mL/min,流动相为体积比20%–70%的乙腈-水混合溶剂。
6.一种促血管生成药物,其特征在于,含有权利要求1或2所述的新型异香豆素类衍生物、其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或其盐的溶剂化物中的任一种或几种作为有效成分。
7.一种药物组合物,其包含根据要求1或2所述的一种化合物或几种化合物或其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或其盐的溶剂化物中的任意一种或几种作为有效成分;该药物组合物还包含至少一种药学上可接受的载体、稀释剂或赋形剂。
8.权利要求7所述的药物组合物,其特征在于,该药物组合物还包含至少一种其他促血管生成药物;该药物组合物优选注射剂、口服制剂、冻干粉针剂、悬浮剂等。
9.权利要求1或2所述的化合物或其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或其盐的溶剂化物在促血管生成药物先导化合物中的应用。
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