CN115232129A - 一种parp1选择性抑制剂及其制备方法和用途 - Google Patents
一种parp1选择性抑制剂及其制备方法和用途 Download PDFInfo
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- CN115232129A CN115232129A CN202210994673.8A CN202210994673A CN115232129A CN 115232129 A CN115232129 A CN 115232129A CN 202210994673 A CN202210994673 A CN 202210994673A CN 115232129 A CN115232129 A CN 115232129A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 title abstract description 21
- 229940124639 Selective inhibitor Drugs 0.000 title description 4
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- 150000001875 compounds Chemical class 0.000 claims abstract description 105
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- -1 methoxy, ethoxy, n-propoxy, isopropoxy Chemical group 0.000 claims description 119
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims description 23
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种以下式(I)表示的化合物及其药学上可接受的盐,及其制备方法和医药用途。同已公开的化合物相比,本发明的化合物出乎意料的显示了更优的PARP1/DNA复合物和PARP2/DNA复合物捕获能力比,显示了更高的PARP1/PARP2抑制选择性;同时环戊基并环喹啉酮化合物的PARP1/PARP2抑制选择性优于同类环己基并环,环己醚并环、环庚基并环、环戊醚基并环化合物。
Description
技术领域
本发明属于医药技术领域,具体而言,涉及一种PARP1选择性抑制剂及其制备方法和用途。
背景技术
聚腺苷二磷酸核糖聚合酶(Poly(addenosine diphosphate[ADP])-ribose)polymerase,PARP)PARP是存在于多数真核细胞中的一个多功能蛋白质翻译后修饰酶。它通过识别结构损伤的DNA单链断裂(single-strand breaks,SSB)或DNA双链断裂(double-strand breaks,DSB)而被激活,被认为是DNA损伤的感受器。它还能对许多核蛋白进行聚腺苷二磷酸核糖基化。同时,PARP又是细胞凋亡核心成员胱天蛋白酶(caspase)的切割底物。因此,它在DNA损伤修复与细胞凋亡中发挥着重要作用。PARP家族蛋白均含有保守的PARP催化结构域,目前已确认18个成员。
DNA单链断裂(SSB)是最常发生的DNA损伤,如果得不到修复,会转成对细胞具有致死性的染色体损伤--DSB。PAPP由DNA单链断裂激活后,通过其N-端锌指结构域结合到SSB,并利用C-端催化结构域催化从底物尼克酰胺腺嘌呤二核苷酸(Nicotinamide adeninedinucleotide,NAD+)上将一个或多个ADP-核糖单位转移至目标蛋白。受它修饰的蛋白质包括组蛋白、RNA聚合酶、DNA聚合酶、DNA连接酶和PARP自身蛋白等。组蛋白的ADP-核糖基化使组蛋白与DNA间的结合变得松散,并最终脱离下来,让位于修复因子,后者被募集到DNA上并完成DNA的损伤修复。同步地,PARP蛋白也会在经ADP-核糖基化后从DNA上解离下来。而当PARP功能受损或被抑制时,单链断裂持续存在,易导致复制的停顿和DNA双链断裂(DSB),于是出现受损的DNA复制物并逐步积累,最终可导致复制崩溃。
因此,PARP在介导DNA修复中的关键作用,为开发PARP抑制剂治疗人类恶性肿瘤提供了理论依据。尤其是双链断裂(DSB)修复缺陷的癌细胞,如BRCA1/2突变细胞,基于“合成致死”的机理,对PARP抑制剂格外敏感。因此,PARP也成为炙手可热的癌症治疗靶点。
目前,已有5个PARP抑制剂上市,并在全球范围有大量的专利申请,应用于卵巢癌,乳腺癌,胰腺癌和前列腺癌等恶性肿瘤的治疗。虽然在临床上得到很好的应用,但均显示了较显著的毒性,主要为血液毒性,如贫血、中性粒细胞减少和血小板减少等。研究发现,PARP2对维持体内造血功能起重要作用(Blood 2013,122,44-54)。此外,有研究发现,BRCA突变引起的合成致死主要是通过PARP1驱动的(Cancer Res.2012,72,5588-5599;Nat.Commun.2018,9,746)。目前已上市药物同时抑制PARP1和PAPR2和PARP家族其他成员,对PARP1的选择性较弱。开发PARP1高选择性抑制剂,有望为恶性肿瘤患者提供安全、高效的小分子靶向药物。
J Med Chem,2021,64,14496-14512报道了一些选择性的三环并环为核心骨架的PARP1抑制剂如化合物F和G:
本发明基于PARP1晶体结构改造其选择性抑制剂。经过对并环部分的结构进行改造后,一些环戊基并环化合物保留了很强PARP1抑制活性,但不可预料的发现,与对应的环己基,和环己醚并环化合物相比,环戊基并环化合物对PARP2的选择性提高了一倍。从而在临床上可以降低潜在副作用。
发明内容
为解决以上技术问题,根据本发明的一个方面,本发明提供了一种以下式(I)表示的化合物及其药学上可接受的盐:
其中,
R1选自C1-C3烷基、氘代C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基;
R2和R3分别选自氢、卤素,C1-C3烷基、氘代C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基;
Y选自CH或N。
进一步优选地,R1选自甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、氘代甲基、氘代乙基、氘代正丙基、氘代异丙基、一氟甲基、二氟甲基、三氟甲基、二氯甲基、三氯甲基、一氟乙基、二氟乙基、三氟乙基、四氟乙基、五氟乙基、二氯乙基、三氯乙基、四氯乙基、五氯乙基、二氟丙基、三氟丙基、四氟丙基、五氟丙基、六氟丙基、全氟丙基、一氯丙基、二氯丙基、三氯丙基、四氯丙基、五氯丙基、六氯丙基、全氯丙基、氘代甲氧基、氘代乙氧基、氘代正丙氧基、氘代异丙氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、二氯甲氧基、三氯甲氧基、一氟乙氧基、二氟乙氧基、三氟乙氧基、四氟乙氧基、五氟乙氧基、二氯乙氧基、三氯乙氧基、四氯乙氧基、五氯乙氧基、二氟丙氧基、三氟丙氧基、四氟丙氧基、五氟丙氧基、六氟丙氧基、全氟丙氧基、一氯丙氧基、二氯丙氧基、三氯丙氧基、四氯丙氧基、五氯丙氧基、六氯丙氧基、全氯丙氧基。
进一步优选地,R1选自甲基、乙基、正丙基、异丙基。
优选地,R2和R3选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、氘代甲基、氘代乙基、氘代正丙基、氘代异丙基、一氟甲基、二氟甲基、三氟甲基、二氯甲基、三氯甲基、一氟乙基、二氟乙基、三氟乙基、四氟乙基、五氟乙基、二氯乙基、三氯乙基、四氯乙基、五氯乙基、二氟丙基、三氟丙基、四氟丙基、五氟丙基、六氟丙基、全氟丙基、一氯丙基、二氯丙基、三氯丙基、四氯丙基、五氯丙基、六氯丙基、全氯丙基、氘代甲氧基、氘代乙氧基、氘代正丙氧基、氘代异丙氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、二氯甲氧基、三氯甲氧基、一氟乙氧基、二氟乙氧基、三氟乙氧基、四氟乙氧基、五氟乙氧基、二氯乙氧基、三氯乙氧基、四氯乙氧基、五氯乙氧基、二氟丙氧基、三氟丙氧基、四氟丙氧基、五氟丙氧基、六氟丙氧基、全氟丙氧基、一氯丙氧基、二氯丙氧基、三氯丙氧基、四氯丙氧基、五氯丙氧基、六氯丙氧基、全氯丙氧基。
进一步优选地,R2选自氢,氟,氯,甲基。
进一步优选地,R3选自氢,氟,氯,甲基,乙基,正丙基,异丙基。
优选地,式(I)表示的化合物及其药学上可接受的盐为以下化合物中的一种:
根据本发明的另一个方面,本发明的另一个目的在于提供一类由化学式(I)表示的化合物的制备方法,所述方法包括如下步骤:
1)商品化原料I-a与硼酸化合物B1偶联关环得到通式化合物I-b;
2)得到的通式化合物I-b用铝锂氢还原酯基成醇,得到通式化合物I-c;
3)通式化合物I-c与二氯亚砜反应,将醇转化成氯代物,得到通式化合物I-d;
4)得到的通式化合物I-d,在碱性条件下,与中间体B2进行SN2反应,得到通式(I)表示的化合物。
其中,通式化合物I-b也可以通过硼酯类通式化合物I-e与化合物B3偶联关环得到。
根据本发明的另一个方面,本发明提供了一种药物组合物,所述药物组合物包括治疗有效量的根据本发明的通式(I)表示的化合物及其药学上可接受的盐作为活性成分,以及药学上可接受的辅料。
根据本发明的另一个方面,本发明提供了所述化合物及其药学上可接受的盐在制备PARP相关疾病治疗药物中的用途。
优选地,所述PARP相关疾病为肿瘤。
优选地,所述肿瘤为卵巢癌、前列腺癌、乳腺癌、肝癌、黑色素瘤、结肠癌或胃癌的实体瘤。
根据本发明的另一个方面,本发明提供了一种治疗PARP相关疾病的方法,所述方法包括向受试者施用有效量的根据本发明的所述通式(I)表示的化合物或包含所述化合物及其药学上可接受的盐作为活性成分的药物组合物。
根据本发明的另一个方面,本发明提供了一种用于治疗PARP相关疾病的试剂盒,其包括:
根据本发明所述通式(I)表示的化合物或其药学上可接受的盐,或者根据本发明的包含所述通式(I)表示的化合物及其药学上可接受的盐作为活性成分的药物组合物;和使用所述化合物或所述药物组合物的用法说明。
本文所述的试剂盒可以包含单剂量或多剂量的化合物或药物组合物。所述试剂盒可以用于本公开的方法。在某些实施方式中,所述试剂盒进一步包括用于使用所述化合物或药物组合物的用法说明。
有益效果
与现有技术相比,本发明的优势在于:同已公开的对比化合物F和G相比,本发明的化合物出乎意料的显示了更高的PARP1/PARP2选择性;同时环戊基并环喹啉酮化合物的PARP1/PARP2选择性优于类似的环己基并环,环己醚并环、环庚基并环、环戊醚基并环喹啉酮化合物。临床上,可以潜在降低PARP抑制剂使用时产生的血液毒性。
具体实施方式
以下,将详细地描述本发明。在进行描述之前,应当理解的是,在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义,而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上,根据与本发明的技术方面相应的含义和概念进行解释。因此,这里提出的描述仅仅是出于举例说明目的的优选实例,并非意图限制本发明的范围,从而应当理解的是,在不偏离本发明的精神和范围的情况下,可以由其获得其他等价方式或改进方式。
定义
在本文中,用语“包含”、“包括”、“具有”、“含有”或其他任何类似用语均属于开放性连接词(open-ended transitional phrase),其意欲涵盖非排他性的包括物。举例而言,含有复数要素的一组合物或制品并不仅限于本文所列出的这些要素而已,而是还可包括未明确列出但却是该组合物或制品通常固有的其他要素。除此之外,除非有相反的明确说明,否则用语“或”是指涵盖性的“或”,而不是指排他性的“或”。例如,以下任何一种情况均满足条件“A或B”:A为真(或存在)且B为伪(或不存在)、A为伪(或不存在)且B为真(或存在)、A和B均为真(或存在)。此外,在本文中,用语“包含”、“包括”、“具有”、“含有”的解读应视为已具体公开并同时涵盖“由…所组成”及“实质上由…所组成”等封闭式或半封闭式连接词。
在本文中,所有以数值范围或百分比范围形式界定的特征或条件仅是为了简洁及方便。据此,数值范围或百分比范围的描述应视为已涵盖且具体公开所有可能的次级范围及范围内的个别数值,特别是整数数值。举例而言,“1至8”的范围描述应视为已经具体公开如1至7、2至8、2至6、3至6、4至8、3至8等等所有次级范围,特别是由所有整数数值所界定的次级范围,且应视为已经具体公开范围内如1、2、3、4、5、6、7、8等个别数值。除非另有指明,否则前述解释方法适用于本发明全文的所有内容,不论范围广泛与否。当列出一系列值时,意图涵盖该范围内的每个值和子范围。例如,“C1–6”意图涵盖C1、C2、C3、C4、C5、C6、C1–6、C1–5、C1–4、C1–3、C1–2、C2–6、C2–5、C2–4、C2–3、C3–6、C3–5、C3–4、C4–6、C4–5和C5–6。
若数量或其他数值或参数是以范围、较佳范围或一系列上限与下限表示,则其应理解成是本文已特定公开了由任一对该范围的上限或较佳值与该范围的下限或较佳值构成的所有范围,不论这些范围是否有分别公开。此外,本文中若提到数值的范围时,除非另有说明,否则该范围应包括其端点以及范围内的所有整数与分数。
在本文中,在可实现发明目的的前提下,数值应理解成具有该数值有效位数的精确度。举例来说,数字40.0则应理解成涵盖从39.50至40.49的范围。
在本文中,对于使用马库什群组(Markush group)或选项式用语以描述本发明特征或实例的情形,本领域技术人员应了解马库什群组或选项列表内所有要素的次级群组或任何个别要素亦可用于描述本发明。举例而言,若X描述成“选自于由X1、X2及X3所组成的群组”,亦表示已经完全描述出X为X1的主张与X为X1及/或X2的主张。再者,对于使用马库什群组或选项式用语以描述本发明的特征或实例的情况,本领域技术人员应了解马库什群组或选项列表内所有要素的次级群组或个别要素的任何组合亦可用于描述本发明。据此,举例而言,若X描述成“选自于由X1、X2及X3所组成的群组”,且Y描述成“选自于由Y1、Y2及Y3所组成的群组”,则表示已经完全描述出X为X1或X2或X3而Y为Y1或Y2或Y3的主张。
术语“烷基”是指具有1至6个碳原子的直链或支链饱和烃基的基团(“C1–6烷基”)。在一些实施方案中,烷基具有1至6个碳原子(“C1-6烷基”)。在一些实施方案中,烷基具有1至5个碳原子(“C1-5烷基”)。在一些实施方案中,烷基具有1至4个碳原子(“C1-4烷基”)。在一些实施方案中,烷基具有1至3个碳原子(“C1-3烷基”)。在一些实施方案中,烷基具有1至2个碳原子(“C1-2烷基”)。在一些实施方案中,烷基具有1个碳原子(“C1烷基”)。在一些实施方案中,烷基具有2至6个碳原子(“C2-6烷基”)。C1–6烷基的实例包括甲基(C1),乙基(C2),丙基(C3)(例如,正丙基、异丙基),丁基(C4)(例如正丁基、叔丁基、仲丁基、异丁基),戊基(C5)(例如,正戊基、3-戊基、新戊基、3-甲基-2-丁基、叔戊基)和己基(C6)(例如,正己基)。除非另有说明,烷基的每个实例独立地未被取代(“未取代的烷基”)或被一个或多个取代基(例如,卤素,如F)所取代(“取代的烷基”)。在某些实施方案中,烷基是未取代的C1-10烷基(例如未取代的C1-6烷基,如-CH3)。在某些实施方案中,烷基为取代的C1-10烷基(例如取代的C1-6烷基,如-CF3)。
“环烷基”是指非芳族环系中具有3至9个环碳原子(“C3-9碳环基团”)和零个杂原子的非芳族环烃基的基团。在一些实施方案中,碳环基团具有3至6个环碳原子(“C3-6环烷基”)。示例性的C3-6环烷基团包括但不限于环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环己二烯基(C6)等。在某些实施方案中,环烷基团为单环(“单环环烷基团”)或含有稠环、桥环或螺环系,如双环系(“双环环烷基团”)并且可以是饱和的或可以是部分不饱和的。
“烷氧基”表示单价-O-烷基,其中所述烷基部分具有指定数目的碳原子。本公开中烷氧基通常含有1-6个碳原子(“C1-6烷氧基”),例如包括甲氧基、乙氧基、异丙氧基、叔丁基氧基等。除非另有说明,烷氧基的每个实例独立地任选被取代,即未取代(“未取代的烷氧基”)或被一个或多个取代基所取代(“取代的烷氧基”)。在某些实施方案中,烷氧基是未取代的C16烷氧基。在某些实施方案中,烷氧基是取代的C16烷氧基。
术语“药学上可接受的盐”是指在合理的医学判断范围内适合用于与人和低等动物的组织接触而没有不适当的毒性、刺激、过敏反应等并且与合理的利益/风险比相称的那些盐。药学上可接受的盐在本领域中是公知的。本文所述的化合物的药学上可接受的盐包括衍生自合适的无机酸和有机酸和碱的那些盐。药学上可接受的无毒酸加成盐的实例为用无机酸(如盐酸、氢溴酸、磷酸、硫酸和高氯酸)或用有机酸(如乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、琥珀酸或丙二酸)或通过使用本领域已知的其他方法(如离子交换)形成的氨基盐。其他药学上可接受的盐包括己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘化物、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月硅酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、三甲基乙酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐等。由合适的碱衍生的盐包括碱金属、碱土金属、铵和N+(C1-4烷基)4-盐。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。合适时,其他药学上可接受的盐包括使用抗衡离子形成的无毒铵、季铵和胺阳离子,所述抗衡离子如卤离子、氢氧根离子、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
术语“抑制”或“抑制剂”是指相对于载体而言化合物降低、减慢、阻止或防止细胞中特定生物过程的活性的能力。
术语“施用”是指将本文所述的化合物或其组合物植入、吸收、摄取、注射、吸入或以其他方式引入受试者中或受试者上。
术语“治疗”是指逆转、减轻、延迟本文所述疾病的发作或抑制本文所述疾病的发展。在一些实施方案中,可以在疾病的一种或多种体征或症状已发展或已被观察到之后施用治疗。在其他实施方案中,可以在没有疾病的体征或症状的情况下施用治疗。例如,可以在症状发作之前对易感受试者施用治疗(例如,根据症状的历史和/或根据暴露于病原体的情况)以延迟或预防疾病发生。症状消退后,也可以继续进行治疗,例如,为延迟或预防复发。
本文所述化合物的“有效量”或“治疗有效量”是指足以引起所需生物反应(即治疗病症)的量。如本领域普通技术人员将理解的,本文描述的化合物的有效量可以根据诸如期望的生物学终点,化合物的药代动力学,被治疗的病症,给药方式和受试者的年龄和健康状况等因素而有所变化。在某些实施方案中,有效量是治疗有效量。在某些实施方案中,有效量是预防性治疗。在某些实施方案中,有效量是本文描述的化合物在单剂量中的量。在某些实施方案中,有效量是本文所述的化合物在多剂量中的组合量。
本文所述的药物组合物可以通过药理学领域已知的任意方法来制备。一般而言,这种制备方法包括使本文所述的化合物(即,“活性成分”)与载体或赋形剂联合,和/或一种或多种其它助剂接触,然后,如有必要和/或需要,使产品成型和/或包装成所需的单-或多-剂量单元。
药物组合物可以以整批、作为单单位剂量和/或多个单单元剂量的方式制备、包装和/或售卖。在本文所述的药物组合物中的活性成分、药学上可接受的赋形剂和/或任意的额外的成分的相对量将根据本身、尺寸和/或待治疗的受试者的条件而变化,以及还根据待施用的组合物的途径而变化。所述组合物可以包含0.1%至100%(w/w)的活性成分。
在所提供的药物组合物的制备过程中使用的药学上可接受的赋形剂包括惰性稀释剂、分散剂和/或成粒剂、表面活性剂和/或乳化剂、崩解剂、粘合剂、防腐剂、缓冲剂、润滑剂和/或油。赋形剂,例如可可油和栓剂蜡、着色剂、涂布剂、甜味剂、调味品和香料也可以存在于所述组合物中。
用于口服和肠胃外给药的液体剂型包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除了活性成分之外,液体剂型可以包含在本领域内通常使用的惰性稀释剂,例如,水或其它溶剂,增溶剂和乳化剂,如乙醇,异丙醇,碳酸乙酯,乙酸乙酯,苯甲醇,苯甲酸苄酯,丙二醇,1,3-丁二醇,二甲基甲酰胺,油(如,棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油),甘油,四氢糠醇,丙二醇和脱水山梨糖醇的脂肪酸酯,以及它们的混合物。除了惰性稀释剂之外,口服组合物可以包括佐药,例如润湿剂、乳化和悬浮剂、甜味剂、调味品和香料。在肠胃外给药的某些实施方式中,本文所述的结合物与增溶剂(如醇、油、改性油、二醇、聚山梨醇酯、环糊精、聚合物和它们的混合物)混合。
可注射制剂,例如,无菌的可注射的水性或油质的悬浮液可以使用合适的分散剂或润湿剂和悬浮剂根据已知的技术来配制。无菌的可注射制剂可以为在无毒的非肠道可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮液或乳液,例如,1,3-丁二醇的溶液。可以使用的可接受的载体和溶剂为水、林格氏液、U.S.P.和生理盐溶液。此外,无菌的、固定油通常被用作溶剂或悬浮介质。基于该目的,可以采用的任意的温和的固定油包括合成的单甘油酯或二甘油酯。此外,脂肪酸(如油酸)被用于可注射制剂的制备。
为了延长药物的效果,通常合意的是降低来自皮下注射或肌内注射的吸收。这可以通过使用具有差的水溶性的晶体或无定型材料的液体悬浮液来实现。药物的吸收速率则依赖于溶解速率,而溶解速率反过来依赖晶体尺寸和晶型。或者,非肠道给药的药物形式的延迟吸收可以通过将药物溶解或悬浮在油性载体中来实现。
用于口服施用的固体剂型包括胶囊、药片、药丸、粉末和颗粒。在这种固体剂型中,活性成分与至少一种惰性、药学上可接受的如下的混合:赋形剂或载体,如柠檬酸钠或磷酸二钙和/或(a)填料或增量剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸,(b)粘合剂,如,例如,羧甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶,(c)保湿剂,如甘油,(d)崩解剂,如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠,(e)溶液阻凝剂,如凡士林,(f)吸收促进剂,如季铵化合物,(g)润湿剂,如,例如,鲸蜡醇和单硬脂酸甘油酯,(h)吸收剂,如高岭土和膨润土,和(i)润滑剂,如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠和它们的混合物。在胶囊、药片或药丸的情况下,剂型可以包含缓冲剂。
所述活性成分可以以具有一种或多种以上所述的赋形剂的微胶囊。固体制剂形式的药片、糖衣药丸、胶囊、药丸和颗粒可以利用包衣和壳(如肠溶衣、释放控制剂包衣和药物制剂领域已知的其它包衣)来制备。在这种固体制剂中,所述活性成分可以与至少一种惰性稀释剂(例如蔗糖、乳糖或淀粉)混合。按照惯例,这种剂型可以包含除了惰性稀释剂之外的其它物质,例如,压片润滑剂和其它压片助剂,如硬脂酸镁和微晶纤维素。在胶囊、药片或药丸的情况下,剂型可以包含缓冲剂。它们可以任选地包含遮光剂,并且可以为具有如下性能的组合物:它们仅,或优选地,在肠道的某些部分,任选地以延迟的方式,释放活性成分。可以使用的封装剂的实例包括聚合物和蜡。
尽管本文提供的药物组合物的描述主要针对适合于施用于人的药物组合物,但是这种组合物通常适合于施用给所有类型的动物。对适合于施用给人的药物组合物的改性以使得组合物适合于施用于多种动物是容易理解的,并且本领域的技术人员可以设计和/或利用常规的实验进行这种改性。
本文所提供的化合物通常配制为剂量单元的形式以便于施用和剂量的均一。然而,可以理解的是本文所述的组合物的全部日常使用将由内科医生在合理的医疗判断范围内确定。用于任何特定的受试者或生物体的具体的治疗有效剂量水平取决于包括如下的一系列因素:待治疗的疾病和病症的严重程度;所使用的特定的活性成分的活性;所使用的特定的组合物;受试者的年龄、体重、健康状况、性别和饮食;特定活性成分的施用的时间、施用的途径和排泄率;治疗的持续时间;与所使用的特定的活性成分的组合或一致的药物;医疗领域已知的其它因素。
此外,本公开还涵盖了试剂盒(例如制药包装)。提供的试剂盒可以包含本文所述的药物组合物或化合物和容器(例如,药瓶、安瓿、瓶子、注射器和/或分装包装或其它合适的容器)。在一些实施方式中,提供的试剂盒可以任选地进一步包括第二容器,其包含用于稀释或悬浮本文所述的药物组合物或化合物的药用赋形剂。在一些实施方式中,设置在第一容器和第二容器中的本文所述的药物组合物或化合物组合形成一个单元剂量形式。
本文提供的化合物和组合物可以通过常规途径施用,包括肠道(例如,口服)施用、肠胃外施用、静脉内施用、肌内施用、动脉内施用、髓内施用、囊内施用、皮下施用、心室内施用、经皮施用、皮下施用、直肠施用、阴道内施用、腹膜内施用、局部施用(例如通过粉末、药膏、乳脂和/或液滴)。特别预期的途径为口服施用、静脉内施用(例如,全身静脉注射)、通过血液和/或淋巴供给的局部施用和/或直接施用至预定部位。一般而言,最合适的施用途径将取决于一系列因素,包括:药剂的性质(例如,在胃肠道环境内的稳定性)和/或受试者的状况(例如,是否能够容许口服施用)。
实现有效量所需的化合物的准确量将根据受试者不同而不同,取决于,例如受试者的人种、年龄和一般状况,副作用或病症的严重程度、特定化合物的确认、施用的模式等。在单剂量(例如,单口服剂量)或多剂量(例如,多口服剂量)中可以包括有效的量。在某些实施方式中,当将多剂量施用给受试者或应用至生物样品、组织或细胞时,多剂量的任意两个剂量包含不同或基本相同的本文所述的化合物。在某些实施方式中,当将多剂量施用给受试者或应用至生物样品、组织或细胞时,将多剂量施用至受试者或将多剂量应用至组织或细胞的频率为每天三剂量、每天两剂量、每天一剂量、每两天一剂量、每三天一剂量或每周一剂量。在某些实施方式中,将多剂量施用至受试者或将多剂量应用至组织或细胞的频率每天一剂量。在某些实施方式中,将多剂量施用至受试者或将多剂量应用至组织或细胞的频率每天两剂量。在某些实施方式中,当将多剂量施用给受试者或应用至生物样品、组织或细胞时,多剂量的第一剂量与最后剂量之间的持续时间为一天,两天,四天,一周,两周,三周,一个月,两个月,三个月,四个月,六个月,九个月,一年,两年,三年,四年,五年,七年,十年,十五年,二十年或受试者、生物样品、组织或细胞的生命期。在某些实施方式中,多剂量的第一剂量和最后剂量之间的持续时间为三个月、六个月或一年。在某些实施方式中,多剂量的第一剂量和最后剂量之间的持续时间为受试者、生物样品、组织或细胞的生命期。在某些实施方式中,本文所述的剂量(例如,单剂量或多剂量的任意剂量)独立地包含内含1mg至3mg、3mg至10mg、10mg至30mg、30mg至100mg、100mg至300mg、300mg至1,000mg或1g至10g的本文所述的化合物。在某些实施方式中,本文所述的剂量独立地包含内含3mg至10mg的本文所述的化合物。在某些实施方式中,本文所述的剂量独立地包含内含10mg至30mg的本文所述的化合物。在某些实施方式中,本文所述的剂量独立地包含内含30mg至100mg的本文所述的化合物。在某些实施方式中,本文所述的剂量独立地包含内含100mg至300mg的本文所述的化合物。在某些实施方式中,本文所述的剂量独立地包含内含300mg至1000mg的本文所述的化合物。
以下实施例仅是作为本发明的实施方案的例子列举,并不对本发明构成任何限制,本领域技术人员可以理解在不偏离本发明的实质和构思的范围内的修改均落入本发明的保护范围。除非特别说明,以下实施例中使用的试剂和仪器均为市售可得产品。
以下实施例中化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定使用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号:Finnigan LCQadvantage MAX)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.2mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例中无特殊说明,反应的温度为室温,为20摄氏度-30摄氏度。
实施例中的反应进程的检测采用薄层色谱法(TLC),所使用的展开剂体系,以及纯化化合物采用的柱层析的洗脱机体系包括有:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:石油醚和乙酸乙酯体系,D:丙酮和石油醚体系,溶剂的体积比例根据化合物的极性不同而进行调节。
实施例
实施例1:N-甲基-5-(4-((4-氧-2,3,4,5-四氢-1氢-环戊环基并喹诺林-7-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺(化合物1)的制备:
第一步:2-(((三氟甲基)磺酸基)氧基)环戊烯-1-甲酸甲酯(1b)的合成:
冰浴下,将1a(2.5g,17.6mmol),慢慢滴加到NaH(2.11g,87.9mmol)悬浮于无水乙醚(35ml)的溶液中,滴完后保持冰浴搅拌反应0.5h。慢慢滴加三氟甲磺酸酐(9.924g,35.2mmol),保持冰浴搅拌反应1h。
TLC显示反应完全,缓慢加水淬灭,加入二氯甲烷萃取,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。柱层析(PE:EA=100:1~50:1)得产品1b(3.905g)淡黄色油状物。
1H NMR(400MHz,CDCl3):3.79(s,3H),2.76(m,4H),2.05-1.98(m,2H).
第二步:4-氧基-2,3,4,5-四氢-1氢-环戊基并喹诺林-7-甲酸甲酯(1c)的合成:
将1b(1.185g,4.32mmol),2-氨基-4(甲氧羰基)苯基-硼酸(1g,4.32mmol),碳酸钾(1.493g,10.8mmol)溶于1,4-二氧六环(6ml)和水(1..5ml)中,加入Pd(dppf)Cl2(0.158g,0.216mmol)。氮气保护下,升温至80℃搅拌反应3h。
TLC显示反应完全,加入乙酸乙酯稀释,加水淬灭反应。分液,水相加入乙酸乙酯萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩。柱层析(PE:EA=4:1~DCM:MeOH=100:1)得产品1c(0.496mg)类白色粉末。
1H NMR(400MHz,CDCl3):10.72(s,1H),8.00(m,1H),7.86-7.84(m,1H),7.52-7.50(m,1H),3.97(s,3H),3.11(m,2H),3.00(m,2H),2.24-2.17(m,2H).
MS m/z(ESI):243.95[M+1].
第三步:7-(羟甲基)-1,2,3,5-四氢-环戊基并喹诺林-4-酮(1d)的合成:
冰浴下,将LiAlH4(168mg,4.4mmol)慢慢加入将1c(268mg,1.1mmol)的四氢呋喃(20ml)溶液中,加完后保持冰浴搅拌反应0.5h。
TLC显示反应完全后,加入依次滴入3滴水,3滴15%的氢氧化钠水溶液溶液,9滴水。加入无水硫酸钠干燥,过滤,乙酸乙酯洗涤,浓缩得1d(200mg)粗品。
MS m/z(ESI):215.95[M+1]
第四步:7-(氯甲基)-1,2,3,5-四氢-环戊基并喹诺林-4-酮(1e)的合成:
分别将1滴DMF,和SOCl2(1.1g,9.3mmol)滴加到1d(200mg,0.93mmol)的无水DCM(10ml)溶液中,室温搅拌反应过夜。
TLC显示反应完全后,浓缩,加入饱和碳酸氢钠水溶液调节pH至8,乙酸乙酯萃取3次,合并有机相,并用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析(PE:EA=3:1~1:1)得A5(62mg)白色粉末。
取样HNMR:1H NMR(400MHz,DMSO-d6):11.65(s,1H),7.54-7.52(m,1H),7.37(s,H),7.23-7.21(m,1H),4.82(s,2H),3.09-3.05(m,2H),2.77-2.74(m,2H),2.13-2.05(m,2H).
第五步:N-甲基-5-(4-((4-氧-2,3,4,5-四氢-1氢-环戊环基并喹诺林-7-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺(化合物1)的合成;
将1e(62mg,0.265mmol)、B2(85mg,0.291mmol)、二异丙基乙基胺(171mg,1.32mmol)加入乙腈(3ml)中,升温至70℃搅拌反应2h。
TLC显示反应完全后,加入水,用乙酸乙酯萃取3次,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。薄层硅胶板(DCM:MeOH=10:1)制备得化合物1(97mg)白色粉末。
1H NMR(400MHz,DMSO-d6):11.53(s,1H),8.39-8.38(m,1H),8.26(m,1H),7.84-7.81(m,1H),7.51-7.49(m,1H),7.40(m,1H),7.33(m,1H),7.18-7.16(m,1H),3.59(m,2H),3.32(m,4H),3.08-3.06(m,2H),2.77-2.74(m,5H),2.54-2.50(m,4H),2.12-2.08(m,2H).
MS m/z(ESI):447.1[M+1]
实施例2:N-甲基-5-(4-((6-氧基-6,7,8,9-四氢-5氢-环戊基[1,5]并萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺(化合物2)的制备:
第一步:2-(4,4,5,5-四甲基-1,3,2-二氧硼-2基)环戊基-1-烯-1-甲酸甲酯(2a)的合成:
将化合物1b(4.4g,16mmol),PdCl2(PPh3)2(337mg,0.48mmol),PPh3(252mg,0.96mmol),(Bpin)2(4.47g,17.6mmol),K2CO3(3.31g,24mmol)加入到二氧六环(96ml)中,氮气氛围下,80℃搅拌反应过夜。
TLC检测反应结束后,冷却至室温,缓慢加入稀盐酸调节pH至5,用乙酸乙酯(100ml*3)萃取,合并有机相,饱和食盐水(100ml)洗涤,无水硫酸钠干燥,浓缩,柱层析得化合物2a(3.5g)淡黄色油,为硼酸和硼酯的混合物。
取样LCMS:硼酯:MS m/z(ESI):253.00[M+1],硼酸:MS m/z(ESI):170.95[M+1]。
第二步:6-氧-6,7,8,9-四氢-5氢-环戊基并[1,5]萘啶-3-甲酸甲酯(2b)的合成:
将第一步反应得到的粗品(1.26g),甲基5-氨基-6-溴尼古丁酯(1.15g,5mmol),碳酸钾(1.40g),PdCl2(dppf)(0.18g)加入二氧六环(20ml)和水(5ml)的混合溶剂中,氮气氛围下80℃搅拌反应过夜。
TLC监测反应结束后,加入水(20ml)淬灭,用乙酸乙酯(20ml*3)萃取,合并有机相,饱和食盐水(20ml)洗涤,无水硫酸钠干燥,浓缩。柱层析得化合物2b(200mg)棕色固体。
1H NMR(400MHz,DMSO-d6):11.93(s,1H),8.90(m,1H),8.18(m,1H),3.91(s,3H),3.20-3.16(m,2H),2.85-2.81(m,2H),2.16-2.10(m,2H).
MS m/z(ESI):244.95[M+1]
第三步:3-(羟甲基)-5,7,8,9-四氢-6-氢-环戊基并[1,5]萘啶-6-酮(2c)的合成:
冰浴下,将LiAlH4(120mg,3.148mmol)慢慢加入到化合物2b(192mg,0.787mmol)的四氢呋喃(20ml)溶液中,保持冰浴搅拌反应0.5h。
TLC检测反应结束后,依次加入4滴水,4滴10%的氢氧化钠水溶液溶液,12滴水,用乙酸乙酯(10ml*3)萃取,合并有机相,饱和食盐水(10ml)洗涤,无水硫酸钠干燥,浓缩得化合物2c粗品(215mg)。
取样LCMS:MS m/z(ESI):216.95[M+1]
第四步:3-(氯甲基)-5,7,8,9-四氢-6-氢-环戊基并[1,5]萘啶-6-酮(2d)的合成:
将化合物2c(215mg,1mmol)溶于二氯甲烷(10ml)中,依次加入1滴DMF,SOCl2(1.19g,10mmol),室温搅拌反应过夜。
TLC监测反应结束后,加入饱和碳酸氢钠溶液调节pH至8,乙酸乙酯(10ml*3)萃取,合并有机相,饱和食盐水(10ml)洗涤,无水硫酸钠干燥,浓缩,薄层硅胶板制备得化合物2d(16mg)黄色固体。
取样LCMS:MS m/z(ESI):234.90[M+1]
第五步:N-甲基-5-(4-((6-氧基-6,7,8,9-四氢-5氢-环戊基[1,5]并萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺(化合物2)的合成:
将化合物2d(20mg,0.085mmol),化合物B2(28mg,0.094mmol),二异丙基乙基胺(55mg,0.425mmol)加入乙腈(2ml)中,70℃搅拌反应2h。
TLC监测反应结束后,浓缩,薄层硅胶板制备得化合物3(28mg)白色固体。
1H NMR(400MHz,DMSO-d6):11.68(s,1H),8.41(m,2H),8.25(m,1H),7.80(m,1H),7.65(m,1H),7.39-7.36(m,1H),3.65(m,2H),3.30(m,2H),3.18-3.07(m,4H),2.77-2.74(m,5H),2.56-2.53(m,4H),2.14-2.06(m,2H).
MS m/z(ESI):419.3[M+1]
实施例3:6-氟-5-(4-((6-氟-4-氧-2,3,4,5-四氢-1H-环戊基并喹诺林-7-基)甲基)哌嗪-1-基)-吡啶-2-甲酰胺(化合物3)的制备:
第一步:6-氟-5-(4-((6-氟-4-氧-2,3,4,5-四氢-1H-环戊基并喹诺林-7-基)甲基)哌嗪-1-基)-吡啶-2-甲酰胺(化合物3)的合成:
将化合物2d(16mg,0.068mmol),化合物B3(23mg,0.075mmol),二异丙基乙基胺(44mg,0.34mmol)加入乙腈(2ml)中,70℃搅拌反应2h。
TLC监测反应结束后,浓缩,薄层硅胶板制备得化合物3(15mg)白色固体。
1H NMR(400MHz,DMSO-d6):11.68(s,1H),8.40-8.37(m,2H),7.84-7.82(m,1H),7.64(m,1H),7.57-7.53(m,1H),3.65(s,2H),3.16-3.15(m,6H),2.87-2.74(m,5H),2.62(m,4H),2.13-2.06(m,2H).
MS m/z(ESI):437.10[M+1]
实施例4:6-氟-5-(4-((6-氟-4-氧-2,3,4,5-四氢-1H-环戊基并喹诺林-7-基)甲基)哌嗪-1-基)-吡啶-2-甲酰胺(化合物4)的制备:
第一步:3-氨基-2-氟苯甲酸甲酯(4a)的合成:
将10%的Pd/C(1g)加入2-氟-3-硝基苯甲酸甲酯(5g,25mmol)溶于乙醇(50ml)的溶液中,一个大气压氢气氛围下常温搅拌反应过夜。
TLC监测反应完全后,过滤,浓缩得红色油状物4a粗品(4.17g)。
MS m/z(ESI):169.95[M+1]
第二步:3-氨基-4-溴-2-氟苯甲酸甲酯(4b)的合成:
将化合物4a粗品(3.08g,18.22mmol)溶于1,2二氯乙烷(45ml),加入NBS(3.244g,18.22mmol),室温搅拌反应过夜。
TLC监测反应完全后,加水(45ml),二氯甲烷(45ml*3)萃取,合并有机相,用饱和食盐水(45ml)洗涤,无水硫酸钠干燥,浓缩,柱层析得化合物4b(500mg)淡黄色粉末。
1H NMR(400MHz,CDCl3):7.27-7.24(m,1H),7.17-7.13(m,1H),4.26(s,2H),3.91(s,3H),.
MS m/z(ESI):247.85[M+1]
第三步:6-氟-4-氧-2,3,4,5-四氢-1氢-环戊基并喹诺林-7-甲酸甲酯(4c)的合成:
将化合物4b(416mg,1.68mmol),化合物2a(423mg,1.68mmol),碳酸钾(811mg,5.87mmol),PdCl2(dppf)(61mg,0.0839mmol)加入二氧六环(4ml)和水(1ml)的混合溶剂中,氮气氛围下80℃搅拌反应过夜。
TLC监测反应结束后,加入水(20ml)淬灭反应,用乙酸乙酯(20ml*3)萃取,合并有机相,饱和食盐水(20ml)洗涤,无水硫酸钠干燥,浓缩。柱层析得化合物4c(39mg)黄色固体。
1H NMR(400MHz,CDCl3):9.28(s,1H),7.73-7.70(m,1H),7.33-7.31(m,1H),3.98(s,3H),3.17-3.13(m,2H),3.04-3.00(m,2H),2.30-2.22(m,2H).
MS m/z(ESI):262.00[M+1]
第四步:6-氟-7-(羟甲基)-1,2,3,5-四氢-4氢-环戊基并喹诺林-4-酮(4d)的合成:
冰浴下,将LiAlH4(64mg,1.68mmol)慢慢加入化合物4c(110mg,0.42mmol)的THF(11ml)溶液中,保持冰浴入搅拌反应0.5h。
TLC检测反应结束后,依次加入4滴水,4滴10%的氢氧化钠水溶液,12滴水,搅拌2小时后用乙酸乙酯(10ml*3)萃取,合并有机相,饱和食盐水(10ml)洗涤,无水硫酸钠干燥,浓缩得化合物6粗品(100mg)。
取样LCMS:MS m/z(ESI):234.00[M+1]
第五步:7-(氯甲基)-6-氟-1,2,3,5-四氢-4氢-环戊基并喹诺林-4-酮(4e)的合成:
将化合物4d(100mg,0.42mmol)溶于二氯甲烷(10ml)中,依次加入1滴DMF,SOCl2(1.09g,9mmol),室温搅拌反应过夜。
TLC监测反应结束后,加入饱和碳酸氢钠溶液调节pH至8,乙酸乙酯(10ml*3)萃取,合并有机相,饱和食盐水(10ml)洗涤,无水硫酸钠干燥,浓缩,薄层硅胶板制备得化合物4e(17mg)黄色固体。
第六步:6-氟-5-(4-((6-氟-4-氧-2,3,4,5-四氢-1H-环戊基并喹诺林-7-基)甲基)哌嗪-1-基)-吡啶-2-甲酰胺(化合物4)的合成:
将化合物4e(17mg,0.068mmol),化合物B3(23mg,0.075mmol),二异丙基乙基胺(44mg,0.34mmol)加入乙腈(2ml)中,70℃搅拌反应2h。
TLC监测反应结束后,浓缩,薄层硅胶板制备得化合物4(30mg)白色固体。
1H NMR(400MHz,CDCl3):9.29(s,1H),7.97(d,J=8Hz,1H),7.48(m,1H),7.31-7.23(m,2H),3.76(s,2H),3.23(s,4H),3.13(m,2H),3.02-2.98(m,5H),2.70(s,4H),2.26-2.22(m,2H).
MS m/z(ESI):454.1[M+1]
实施例5:5-(4-((6-氟-4-氧-2,3,4,5-四氢-1氢-环戊基并喹诺林-7-基)甲基)哌嗪-1-基)-吡啶-2-甲酰胺(化合物5)的制备:
第一步:将化合物4e(17mg,0.068mmol),化合物B2(26mg,0.087mmol),二异丙基乙基胺(51mg,0.398mmol)加入乙腈(2ml)中,70℃搅拌反应2h。
TLC监测反应结束后,浓缩,薄层硅胶板制备得化合物5(20mg)白色固体。
1H NMR(400MHz,DMSO-d6):11.55(s,1H),8.36-8.35(m,1H),8.25-8.24(m,1H),7.82-7.80(m,1H),7.38-7.33(m,2H),7.24-7.20(m,1H),3.68(s,2H),3.32-3.30(m,5H),3.07(m,2H),2.77(m,5H),2.50(s,4H),2.14-2.07(m,2H).
MS m/z(ESI):436.15[M+1]
对比化合物A:N-甲基-5-(4-((6-氧-5,6,7,8,9,10-六氢菲啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺(对比化合物A)的制备:
第一步,2-(((三氟甲磺酸基)氧基)环己基-1-烯基-1-甲酸甲酯(Ab)的制备:
冰浴条件下,将Aa(1g,6.4mmol)缓慢滴加到钠氢(0.768g,60%煤油中)和无水乙醚(15ml)的混合物中,滴完后保持冰浴并搅拌0.5小时。保持冰浴,向反应体系慢慢滴加三氟甲磺酸酐(3.613g,12.8mmol),滴完后保持冰浴,并搅拌1小时。
TLC点板显示原料消失,缓慢加水淬灭,加入二氯甲烷萃取。有机相用饱和氯化钠水溶液洗涤一次后,用无水硫酸钠干燥,浓缩。柱层析(PE:EA=100:1~50:1)得淡黄色油状物中间体Ab(1.226g)。
1H NMR(400MHz,CDCl3):3.81(s,3H),2.49(m,2H),2.39(m,2H),1.82(m,2H),1.64(m,2H).
第二步,6-氧基-5,6,7,8,9,10-六氢菲啶-3-甲酸甲酯(Ac)的制备:
将Ab(3.3g,11.4mmol),2-氨基-4(甲氧羰基)苯基-硼酸(2.65g,11.4mmol),碳酸钾(3.955g,28.6mmol)溶于1,4-二氧六环(16ml)和水(4ml)中,向体系加入Pd(dppf)Cl2(0.419g,0.572mmol)。氮气保护下,升温至80℃搅拌3h。降温后向体系加入乙酸乙酯稀释,加水淬灭反应,分液,水相加入乙酸乙酯萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,浓缩。柱层析(PE:EA=4:1~DCM:MeOH=100:1)得白色粉末状中间体Ac(145mg)。
1H NMR(400MHz,CDCl3):10.07(s,1H),7.88-7.84(m,2H),7.73-7.71(m,1H),3.97(s,3H),2.90(m,2H),2.71(m,2H),1.91-1.84(m,4H).
第三步,3-羟甲基-7,8,9,10-四氢菲啶-6(5氢)-酮(Ad)的制备:
冰浴条件下将锂铝氢(53mg,1.39mmol)慢慢加入到Ac(119mg,0.46mmol)的无水四氢呋喃(20ml)溶液中,加完后保持冰浴继续搅拌0.5小时。
依次滴入3滴水,3滴15%的NaOH溶液,9滴水。加入无水硫酸钠干燥,过滤,用乙酸乙酯洗涤,浓缩得粗品中间体Ad(137mg)。
第四步,3-氯甲基-7,8,9,10-四氢菲啶-6(5氢)-酮(Ae)的制备:
依次将N,N-二甲基甲酰胺(0.05ml),和二氯亚砜(714mg,6mmol)滴加到Ad(137mg,0.6mmol)的无水二氯甲烷(5ml)溶液中,保持室温搅拌过夜。
浓缩干溶剂后,加入饱和碳酸氢钠水溶液调节pH至8,用乙酸乙酯萃取3次,合并有机相后用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析(PE:EA=3:1~1:1)得白色粉末Ae(64mg)。
1H NMR(400MHz,DMSO-d6):11.66(s,1H),7.67(m,1H),7.31(s,1H),7.22(m,1H),4.81(s,2H),2.80(m,2H),2.45(m,2H),1.77-1.70(m,4H).
MS m/z(ESI):248.0[M+1]
第五步,N-甲基-5-(4-((6-氧-5,6,7,8,9,10-六氢菲啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺(对比化合物A)的制备
将Ae(60mg,0.24mmol)、B2(71mg,0.24mmol)、二异丙基乙基胺(155mg,1.2mmol)加入无水乙腈(3ml)中,升温至70℃搅拌2小时。
冷却,向反应体系加入水,用乙酸乙酯萃取3次,合并有机相,用无水硫酸钠干燥,浓缩。薄层硅胶板(DCM:MeOH=10:1)制备得白色粉末对比化合物A(67mg)。
1H NMR(400MHz,DMSO-d6):11.55(s,1H),8.38(m,1H),8.25(m,1H),7.82-7.80(m,1H),7.62(m,1H),7.39-7.36(m,1H),7.26(m,1H),7.15-7.13(m,1H),3.57(s,2H),2.80-2.76(m,5H),2.59-2.39(m,10H),1.78-1.69(m,4H).
MS m/z(ESI):432.1[M+1]
对比化合物B:N-甲基-5-(4-((6-氧-6,7,8,9,10,11-六氢-5氢-环庚环基并喹诺林-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺(对比化合物B)的制备:
与对比化合物A的合成路线类似,将起始原料2-氧环己烷羧酸甲酯(Aa)替换成2-氧环庚烷羧酸甲酯(Ba),可以得到对比化合物B。
1H NMR(400MHz,DMSO-d6):11.58(s,1H),8.40(m,1H),8.25(m,1H),7.82-7.78(m,2H),7.39-7.36(m,1H),7.27(m,1H),7.15-7.13(m,1H),3.57(s,2H),3.16(m,1H),2.99(m,2H),2.87-2.85(m,2H),2.77-2.76(m,3H),2.60-2.51(m,7H),1.78(m,2H),1.55(m,2H),1.45(m,2H).
MS m/z(ESI):446.2[M+1]
对比化合物C,N-甲基-5-(4-((5-氧基-1,4,5,6-四氢-2氢吡喃并喹诺林-8-基)甲基)哌嗪-1-基)吡啶酰胺(对比化合物C)的制备:
与对比化合物A的合成路线类似,将起始原料2-氧环己烷羧酸甲酯(Aa)替换成4-氧代四氢-2氢-吡喃-3-羧酸甲酯(Ca),可以得到对比化合物C。
1H NMR(400MHz,DMSO-d6):11.72(s,1H),8.40-8.38(m,1H),8.25(s,1H),7.82-7.80(m,1H),7.62(m,1H),7.39-7.36(m,1H),7.30(s,1H),7.21-7.19(m,1H),4.44(s,2H),3.92-3.90(m,2H),3.59(s,2H),2.86(s,2H),2.77-2.76(m,3H),2.53(m,6H).
MS m/z(ESI):434.05[M+1]
对比化合物D:N-甲基-5-(4-((4-氧-1,3,4,5-四氢呋喃[3,4]并喹诺林-7-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺(对比化合物D)的制备:
与对比化合物A的合成路线类似,将起始原料2-氧环己烷羧酸甲酯(Aa)替换成4-氧代四氢呋喃-3-羧酸甲酯(Da),可以得到对比化合物D。
1H NMR(400MHz,DMSO-d6):11.80(s,1H),8.38-8.37(m,1H),8.26(m,1H),7.84-7.81(m,1H),7.44-7.37(m,3H),7.21-7.19(m,1H),5.29(s,2H),4.96(s,2H),3.61(s,2H),3.31(m,4H),2.78-2.77(m,3H),2.54-2.50(m,4H).
MS m/z(ESI):420.1[M+1]
对比化合物E:N-甲基-5-(4-((3-甲基-5-氧基-1,2,3,4,5,6-六氢苯并[2,7]萘啶-8-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺(对比化合物E)的制备:
与对比化合物A的合成路线类似,将起始原料2-氧环己烷羧酸甲酯(Aa)替换成1-甲基-4-哌啶酮-3-羧酸甲酯(Ea),可以得到对比化合物E。
1H NMR(400MHz,DMSO-d6):11.69(s,1H),8.41-8.40(m,1H),8.27(m,1H),7.82(m,1H),7.62(m,1H),7.40-7.37(m,1H),7.31(m,1H),7.20-7.18(m,1H),3.59(s,2H),3.50-3.20(m,6H),2.93(m,2H),2.79-2.78(m,3H),2.70(m,2H),2.60-2.51(m,4H),2.42(s,3H).
MS m/z(ESI):447.1[M+1]
测试实施例1:PAPR1 DNA捕获实验:
PARP1(购自BPS)和anti GST-Tb cryptate单克隆抗体(购自Cisbio)混合后取4μl加入至384微孔板(购自PerkinElmer)中,然后加入4μl DSB-DNA探针1(购自Generay),并分别加入4μl 4倍稀释的实施例1至5中制备的化合物以及对比化合物A至E(起始浓度1000nM,3倍稀释,共10个浓度点)。室温孵育1小时。然后加入4μl PARP酶底物NAD(购自Sigma),室温孵育10分钟后在Envision 2105(购自PerkinElmer)上读数。数据通过Graphpad 5.0作图,并计算IC50,测试数据见下表1。
测试实施例2:PARP2 DNA捕获实验
PARP2(购自BPS)和anti GST-Tb cryptate单克隆抗体(购自Cisbio)混合后取4μl加入至384微孔板中,然后加入4μl PARP2探针2((购自Generay),并分别加入4μl 3倍稀释的实施例1至5中制备的化合物以及对比化合物A至E(起始浓度5000nM,3倍稀释,共10个浓度点)。室温孵育1小时。然后加入4μl PARP酶底物NAD(购自Sigma),室温孵育10分钟后在Envision 2105(购自PerkinElmer)上读数。数据通过Graphpad 5.0作图,并计算IC50,测试数据见下表1。
测试实施例3:细胞增殖抑制实验
DLD-1BRCA2(-/-)细胞系购自ATCC,并在含10%胎牛血清(Fetal Bovine Serum,FBS)和1×青霉素-链霉素的RPMI 1640中培养(三者均购自Gibco)。分别加入40nL的4倍稀释实施例1至5中制备的化合物以及对比化合物A至E(起始浓度10000nM,3倍稀释,共10个浓度点)至384白微孔板(购自PerkinElmer),同时加入40μl共600个DLD-1BRCA2(-/-)细胞,37℃,5%CO2条件下培养7天。7天后,取出培养板在室温放置30分钟,然后加入20μlCelltiter Glo试剂(购自Promega),室温孵育30分钟。利用Envision 2105(购自PerkinElmer)读取荧光值。数据通过Graphpad 5.0作图,并计算IC50,测试数据见下表1。
表1
现有技术(Cancer Res;72(21);5588–99)中报道了,与烷基化试剂共同孵育,Parp1-/-敲除的细胞相比,野生型的细胞加PARP抑制剂后,对烷基化试剂更敏感。原因是PARP抑制剂可以捕获PARP-DNA复合物。富集PARP-DNA复合物能力对于PARP抑制剂抗癌活性的发挥,重要性甚至超过了抑制PARP的催化活性。
结论:
本发明的大多数化合物显示了很好的同时捕获PARP1/DNA复合物和PARP2/DNA复合物的活性,且捕获PARP1/DNA复合物的能力更高,显示了很好的PARP1/PARP2抑制选择性;但是意外的发现,环戊基并环的喹啉酮化合物1-5与类似的环己基并环A,环庚基并环B,环己醚并环C、环戊醚基并环D的喹啉酮化合物相比,具有更高的PARP1/DNA复合物PARP2/DNA复合物捕获能力比,显示了更高的PARP1/PARP2抑制选择性。
以上所述仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应所述以权利要求的保护范围为准。
Claims (9)
2.根据权利要求1所述的式(I)表示的化合物及其药学上可接受的盐,其特征在于,R1选自甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、氘代甲基、氘代乙基、氘代正丙基、氘代异丙基、一氟甲基、二氟甲基、三氟甲基、二氯甲基、三氯甲基、一氟乙基、二氟乙基、三氟乙基、四氟乙基、五氟乙基、二氯乙基、三氯乙基、四氯乙基、五氯乙基、二氟丙基、三氟丙基、四氟丙基、五氟丙基、六氟丙基、全氟丙基、一氯丙基、二氯丙基、三氯丙基、四氯丙基、五氯丙基、六氯丙基、全氯丙基、氘代甲氧基、氘代乙氧基、氘代正丙氧基、氘代异丙氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、二氯甲氧基、三氯甲氧基、一氟乙氧基、二氟乙氧基、三氟乙氧基、四氟乙氧基、五氟乙氧基、二氯乙氧基、三氯乙氧基、四氯乙氧基、五氯乙氧基、二氟丙氧基、三氟丙氧基、四氟丙氧基、五氟丙氧基、六氟丙氧基、全氟丙氧基、一氯丙氧基、二氯丙氧基、三氯丙氧基、四氯丙氧基、五氯丙氧基、六氯丙氧基、全氯丙氧基;
进一步优选地,R1选自甲基、乙基、正丙基、异丙基。
3.根据权利要求1所述的式(I)表示的化合物及其药学上可接受的盐,其特征在于,R2和R3选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、氘代甲基、氘代乙基、氘代正丙基、氘代异丙基、一氟甲基、二氟甲基、三氟甲基、二氯甲基、三氯甲基、一氟乙基、二氟乙基、三氟乙基、四氟乙基、五氟乙基、二氯乙基、三氯乙基、四氯乙基、五氯乙基、二氟丙基、三氟丙基、四氟丙基、五氟丙基、六氟丙基、全氟丙基、一氯丙基、二氯丙基、三氯丙基、四氯丙基、五氯丙基、六氯丙基、全氯丙基、氘代甲氧基、氘代乙氧基、氘代正丙氧基、氘代异丙氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、二氯甲氧基、三氯甲氧基、一氟乙氧基、二氟乙氧基、三氟乙氧基、四氟乙氧基、五氟乙氧基、二氯乙氧基、三氯乙氧基、四氯乙氧基、五氯乙氧基、二氟丙氧基、三氟丙氧基、四氟丙氧基、五氟丙氧基、六氟丙氧基、全氟丙氧基、一氯丙氧基、二氯丙氧基、三氯丙氧基、四氯丙氧基、五氯丙氧基、六氯丙氧基、全氯丙氧基;
进一步优选地,R2选自氢,氟,氯,甲基;
进一步优选地,R3选自氢,氟,氯,甲基,乙基,正丙基,异丙基。
6.一种药物组合物,所述药物组合物包括治疗有效量的根据权利要求1至4的任意一项所述的式(I)表示的化合物及其药学上可接受的盐作为活性成分,以及药学上可接受的辅料。
7.根据权利要求1至4的任意一项所述的式(I)表示的化合物及其药学上可接受的盐在制备PARP相关疾病的治疗药物中的用途;
优选地,所述PARP相关疾病为肿瘤;
优选地,所述肿瘤为卵巢癌、前列腺癌、乳腺癌、肝癌、黑色素瘤、结肠癌或胃癌的实体瘤。
8.一种治疗PARP相关疾病的方法,所述方法包括向受试者施用有效量的根据权利要求1至4的任意一项所述的式(I)表示的化合物及其药学上可接受的盐或根据权利要求6所述的药物组合物。
9.一种用于治疗PARP相关疾病的试剂盒,其包括:
有效量的根据权利要求1至4的任意一项所述的式(I)表示的化合物及其药学上可接受的盐或根据权利要求6所述的药物组合物;和使用所述化合物及其药学上可接受的盐或所述药物组合物的用法说明。
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11591331B2 (en) | 2021-04-19 | 2023-02-28 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
US11795173B1 (en) | 2022-04-28 | 2023-10-24 | Xinthera, Inc. | Substituted pyridines as PARP1 inhibitors |
US11802128B2 (en) | 2021-10-01 | 2023-10-31 | Xinthera, Inc. | Azetidine and pyrrolidine PARP1 inhibitors and uses thereof |
US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
EP4379038A2 (en) | 2022-12-02 | 2024-06-05 | Horia Hulubei National Institute for R & D in Physics and Nuclear Engineering (IFIN-HH) | Method and device for porating and loading cells, especially immunocompetent cells |
EP4379051A2 (en) | 2022-12-02 | 2024-06-05 | Horia Hulubei National Institute for R & D in Physics and Nuclear Engineering (IFIN-HH) | Method and device for porating and loading cells, especially immunocompetent cells |
DE102022132082A1 (de) | 2022-12-02 | 2024-06-13 | Horia Hulubei National Institute for R & D in Physics and Nuclear Engineering (IFIN-HH) | Verfahren zur Herstellung von genetisch transfizierten und mit Nanopartikeln und/oder einem zytotoxischen Stoff beladenen immunokompetenten Zellen sowie immunokompetente Zellen und medizinische Zusammensetzung. |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107849040A (zh) * | 2015-06-09 | 2018-03-27 | 第药品株式会社 | 三环衍生化合物、其制备方法、和含有其的药物组合物 |
WO2021013735A1 (en) * | 2019-07-19 | 2021-01-28 | Astrazeneca Ab | Parp1 inhibitors |
WO2022225934A1 (en) * | 2021-04-19 | 2022-10-27 | Xinthera, Inc. | Parp1 inhibitors and uses thereof |
WO2023025307A1 (en) * | 2021-08-27 | 2023-03-02 | Impact Therapeutics (Shanghai) , Inc | Substituted tricyclic compounds as parp inhibitors and use thereof |
WO2023061406A1 (zh) * | 2021-10-12 | 2023-04-20 | 微境生物医药科技(上海)有限公司 | 含三并环结构的parp抑制剂、及其制备方法和医药用途 |
WO2023122140A1 (en) * | 2021-12-22 | 2023-06-29 | Synnovation Therapeutics, Inc. | Parp1 inhibitors |
WO2023133413A1 (en) * | 2022-01-07 | 2023-07-13 | Slap Pharmaceuticals Llc | Multicyclic compounds |
WO2023134647A1 (zh) * | 2022-01-13 | 2023-07-20 | 优领医药科技(香港)有限公司 | 含哌嗪并环类衍生物、其药学上可接受的盐及其制备方法和应用 |
-
2022
- 2022-08-18 CN CN202210994673.8A patent/CN115232129B/zh active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107849040A (zh) * | 2015-06-09 | 2018-03-27 | 第药品株式会社 | 三环衍生化合物、其制备方法、和含有其的药物组合物 |
AU2016276806B2 (en) * | 2015-06-09 | 2019-02-14 | Onconic Therapeutics Inc. | Tricyclic derivative compound, method for preparing same, and pharmaceutical composition comprising same |
WO2021013735A1 (en) * | 2019-07-19 | 2021-01-28 | Astrazeneca Ab | Parp1 inhibitors |
WO2022225934A1 (en) * | 2021-04-19 | 2022-10-27 | Xinthera, Inc. | Parp1 inhibitors and uses thereof |
WO2023025307A1 (en) * | 2021-08-27 | 2023-03-02 | Impact Therapeutics (Shanghai) , Inc | Substituted tricyclic compounds as parp inhibitors and use thereof |
WO2023061406A1 (zh) * | 2021-10-12 | 2023-04-20 | 微境生物医药科技(上海)有限公司 | 含三并环结构的parp抑制剂、及其制备方法和医药用途 |
WO2023122140A1 (en) * | 2021-12-22 | 2023-06-29 | Synnovation Therapeutics, Inc. | Parp1 inhibitors |
WO2023133413A1 (en) * | 2022-01-07 | 2023-07-13 | Slap Pharmaceuticals Llc | Multicyclic compounds |
WO2023134647A1 (zh) * | 2022-01-13 | 2023-07-20 | 优领医药科技(香港)有限公司 | 含哌嗪并环类衍生物、其药学上可接受的盐及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
CHUNYONG DING ET AL.: ""Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties"", 《J. MED. CHEM.》, vol. 61, pages 760 - 776 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11591331B2 (en) | 2021-04-19 | 2023-02-28 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
US11802128B2 (en) | 2021-10-01 | 2023-10-31 | Xinthera, Inc. | Azetidine and pyrrolidine PARP1 inhibitors and uses thereof |
US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
US11795173B1 (en) | 2022-04-28 | 2023-10-24 | Xinthera, Inc. | Substituted pyridines as PARP1 inhibitors |
US12006322B2 (en) | 2022-04-28 | 2024-06-11 | Xin Thera, Inc. | Substituted pyridines as PARP1 inhibitors |
EP4379038A2 (en) | 2022-12-02 | 2024-06-05 | Horia Hulubei National Institute for R & D in Physics and Nuclear Engineering (IFIN-HH) | Method and device for porating and loading cells, especially immunocompetent cells |
EP4379051A2 (en) | 2022-12-02 | 2024-06-05 | Horia Hulubei National Institute for R & D in Physics and Nuclear Engineering (IFIN-HH) | Method and device for porating and loading cells, especially immunocompetent cells |
DE102022132084A1 (de) | 2022-12-02 | 2024-06-13 | Horia Hulubei National Institute for R & D in Physics and Nuclear Engineering (IFIN-HH) | Vorrichtung zum Porieren und zum Beladen von Zellen sowie Verfahren hierfür |
DE102022132082A1 (de) | 2022-12-02 | 2024-06-13 | Horia Hulubei National Institute for R & D in Physics and Nuclear Engineering (IFIN-HH) | Verfahren zur Herstellung von genetisch transfizierten und mit Nanopartikeln und/oder einem zytotoxischen Stoff beladenen immunokompetenten Zellen sowie immunokompetente Zellen und medizinische Zusammensetzung. |
DE102022132083A1 (de) | 2022-12-02 | 2024-06-13 | Horia Hulubei National Institute for R & D in Physics and Nuclear Engineering (IFIN-HH) | Vorrichtung zum Porieren und zum Beladen von Zellen sowie Verfahren hierfür |
EP4385526A1 (en) | 2022-12-02 | 2024-06-19 | Horia Hulubei National Institute for R & D in Physics and Nuclear Engineering (IFIN-HH) | Method for loading immunocompetent cells with nanoparticles and/or a cytotoxic substance and immunocompetent cells for use in theranostic treatment |
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