CN117658983A - 选择性parp1抑制剂 - Google Patents
选择性parp1抑制剂 Download PDFInfo
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- CN117658983A CN117658983A CN202211067317.8A CN202211067317A CN117658983A CN 117658983 A CN117658983 A CN 117658983A CN 202211067317 A CN202211067317 A CN 202211067317A CN 117658983 A CN117658983 A CN 117658983A
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
-
- 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
- C07D401/14—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 three or more hetero rings
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
本发明提供了选择性PARP1抑制剂。具体地,本发明提供了一种化合物或其药学上可接受的盐或溶剂化物,所述的化合物如式A所示,其中各基团如本文中定义;以及,该化合物的制备方法和用途。
Description
技术领域
本发明属于医药领域,具体涉及一种选择性的聚(ADP-核糖)聚合酶1(PARP1)抑制剂,以及在预防或治疗PARP1相关的疾病中的用途。.
背景技术
聚腺苷酸二磷酸核糖聚合酶(PARP)是一种单体蛋白酶,在多数真核细胞核内广泛存在。在聚ADP糖基化过程中,PARP酶参与某些进程,如调节细胞死亡、细胞周期进程、基因转录、细胞内DNA修复等。目前研究发现,PARP家族至少有18个成员,成员间具有一定的同源性。PARP1、PARP2是PARP家族中主要的两类酶,其中PARP1发挥着90%以上的功能,两者的底物选择性不同。与其他市场上的PARP1/2抑制剂相比,改善PARPl的选择性可能具有改进的功效,并且毒性降低。而且可以进入大脑,对脑转移病人有极大应用价值。并且可用于除了肿瘤以外的疾病,扩大应该范围。因此,对于有效且安全的PARP抑制剂存在未满足的医疗需求,特别是高选择性和脑渗透功能的PARP1抑制剂。本文所述的选择性PARP1抑制剂,具有惊人的高选择性,如PARP2。
综上所述,本领域迫切需要开发一种新的PARP1选择性抑制剂。
发明内容
本发明的目的就是提供了一种高选择性的聚(ADP-核糖)聚合酶1(PARP1)抑制剂。本发明的另一个目的是提供所述抑制剂在预防或治疗和PARP1相关的疾病中的用途。
在本发明的第一方面中,提供了一种化合物或其药学上可接受的盐或溶剂化物,其中,所述的化合物如式A所示;
其中,
X1为如式M1或式M2所示的二价基团:
(i)
其中,W3和W4各自独立地为-(CH2)-、-(CH2)2-或-(CH2)3-;
(ii)
其中,W1和W2各自独立地为-(CH2)-或-(CH2)2-;
R6选自下组:H、取代或未取代的C1-3烷基;
R1选自下组:取代或未取代的C1-6烷基、取代或未取代的C3-6环烷基;
R2选自下组:H、卤素、取代或未取代的C1-3烷基、取代或未取代的C3-6环烷基;
R3选自下组:H、取代或未取代的C1-3烷基;
R4和R5各自独立地选择下组:H、卤素;
Ra1、Ra2、Ra3、Rc1和Rc2各自独立地选自下组:H、取代或未取代的C1-4烷基;
除非特别说明,所述取代是指基团中一个或多个(如1、2或3个)氢被选自下组的取代基所述取代:氘(D)、卤素、C1-4烷基、C1-4卤代烷基。
在另一优选例中,所述化合物如式A1或式A2所示
其中,R1、R2、R3、R4、R5、R6、Ra1、Ra2、Ra3、Rc1、Rc2、W1、W2、W3和W4如前定义。
在另一优选例中,所述化合物如式A2所示。
在另一优选例中,Ra1、Ra2、Ra3、Rc1和Rc2均为H。
在另一优选例中,R5为H。
在另一优选例中,所述化合物如式B所示
其中,R1、R2、R3和R4如式A中定义。
在另一优选例中,R1为取代或未取代的C1-6烷基。
在另一优选例中,R1为取代或未取代的C1-4烷基。
在另一优选例中,R1选自下组:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基;较佳地,R1选自下组:甲基、乙基、正丙基。
在另一优选例中,R1为甲基或乙基。
在另一优选例中,R2选自下组:H、卤素、取代或未取代的C1-3烷基。
在另一优选例中,R2选自下组:H、卤素;较佳地,R2选自下组:H、F、Cl。
在另一优选例中,R2为H或F。
在另一优选例中,R3为取代或未取代的C1-3烷基。
在另一优选例中,R3为C1-3烷基或氘代C1-3烷基。
在另一优选例中,R3为甲基。
在另一优选例中,R4为卤素。
在另一优选例中,R4选自下组:F、Cl、Br。
在另一优选例中,R4为F。
在另一优选例中,X1为如式M1所示的二价基团。
在另一优选例中,W3和W4之一为-(CH2)-,另一个为-(CH2)-、-(CH2)2-或-(CH2)3-;或,W3和W4之一为-(CH2)2-,另一个为-(CH2)-或-(CH2)2-。
在另一优选例中,W3和W4均为-(CH2)2-。
在另一优选例中,如式M1所示的二价基团为
在另一优选例中,X1为如式M2所示的二价基团。
在另一优选例中,W1和W2之一为-(CH2)2-,另一个为-(CH2)-;或W1和W2均为-(CH2)-。
在另一优选例中,W1和W2均为-(CH2)-。
在另一优选例中,R6选自下组:H、甲基、乙基。
在另一优选例中,R6为H。
在另一优选例中,如式M2所示的二价基团为
在另一优选例中,所述化合物如式C1或式C2所示
其中,R1、R2、R3和R4如式A中定义。
在另一优选例中,所述化合物为如是C1所示。
在另一优选例中,R1、R2、R3、R4、R5、R6、Ra1、Ra2、Ra3、Rc1、Rc2、W1、W2、W3和W4各自独立地为实施例中具体化合物(如表A中所示的化合物)中对应的基团。
在另一优选例中,所述化合物为选自表A的化合物:
表A
在本发明的第二方面中,提供了一种如第一方面所述的化合物的制备方法,包括步骤:(a)使式I中间体与式II中间体反应,从而得到式A所示的化合物;
各式中,
X2为如式M3或式M4所示的基团
RP为H或氨基保护基(如Boc);
RH为活性反应基团(如-CH2Cl、-C(O)H);
R1、R2、R3、R4、R5、R6、Ra1、Ra2、Ra3、Rc1、Rc2、W1、W2、W3和W4如式A中定义。
在本发明的第三方面中,提供了一种药物组合物,包括:
(i)如第一方面所述的化合物或其药学上可接受的盐,和(ii)药学上可接受的载体或赋形剂。
在另一优选例中,所述的药物组合物还包括另外的抗肿瘤药物。
在本发明的第四方面中,提供了一种如第一方面所述的化合物在制备(i)用于治疗、改善或预防与PARP1相关的疾病和/或由PARP1介导的疾病的药物;和/或(ii)PARP1抑制剂;和/或(iii)抗肿瘤药物;和/或(iv)肿瘤药物增敏剂中的用途。
在另一优选例中,所述化合物通过选择性抑制PARP1来治疗、改善或预防与PARP1相关的疾病和/或由PARP1介导的疾病。
在另一优选例中,所述与PARP1相关的疾病和/或由PARP1介导的疾病包括:心血管疾病、炎症疾病、纤维化疾病(如疤痕等)、脑神经疾病、骨质疏松症、眼疾、病毒。
在另一优选例中,所述与PARP1相关的疾病和/或由PARP1介导的疾病包括:肿瘤(如癌症)。
在另一优选例中,所述与PARP1相关的疾病和/或由PARP1介导的疾病包括:乳腺癌、卵巢癌、胰腺癌、前列腺癌、血癌、脑瘤、肉瘤、胃肠道癌(如胃癌和结直肠癌)或肺癌或其组合。
在另一优选例中,所述PARP1抑制剂为选择性PARP1抑制剂。
在另一优选例中,所述肿瘤为癌症;较佳地,包括:乳腺癌、卵巢癌、胰腺癌、前列腺癌、血癌、胃肠道癌(如胃癌和结直肠癌)或肺癌或其组合
在另一优选例中,所述胃肠道癌包括:胃癌、结直肠癌。
在另一优选例中,所述肿瘤药物增敏剂与至少一种另外的抗肿瘤药物联合应用。
在本发明的第五方面中,提供了一种药物组合,包括:
(a)如第一方面所述的化合物或其药学上可接受的盐或溶剂化物,或者如权利要求;以及
(b)至少一种另外的抗肿瘤药物。
在本发明的第六方面中,提供了一种选择性抑制PARP1的方法,所述方法包括:
使对象与如第一方面所述的化合物接触,从而抑制对象中PARP1活性。
在另一优选例中,所述对象为细胞或PARP1酶。
在另一优选例中,所述抑制是对PARP1的选择性抑制。
在另一优选例中,所述的方法是体外非治疗性的。
在本发明的第七方面中,提供了一种治疗、改善或预防(i)与PARP1相关的疾病和/或由PARP1介导的疾病或者(ii)肿瘤的方法,包括步骤:
向有需要的对象施用治疗有效量的如第一方面的化合物或如第四方面所述的药物组合物,从而治疗、改善或预防(i)与PARP1相关的疾病和/或由PARP1介导的疾病或者(ii)肿瘤。
在另一优选例中,所述对象为哺乳动物,较佳地,为人。
在另一优选例中,所述化合物通过选择性抑制PARP1来治疗、改善或预防与PARP1相关的疾病和/或由PARP1介导的疾病。
在另一优选例中,所述与PARP1相关的疾病和/或由PARP1介导的疾病包括:肿瘤(如癌症)。
在另一优选例中,所述与PARP1相关的疾病和/或由PARP1介导的疾病包括:乳腺癌、卵巢癌、胰腺癌、前列腺癌、血癌、胃肠道癌(如胃癌和结直肠癌)或肺癌或其组合。
在另一优选例中,所述胃肠道癌包括:胃癌、结直肠癌。
在另一优选例中,所述方法还包括向需要的对象施用治疗有效量的另外的抗肿瘤药物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
发明人经过广泛而深入地研究,发现一类具有新颖结构的化合物具有显著更优异的PARP1抑制活性和具有惊人的对PARP1高选择性,例如,这类化合物在对PARP1抑制活性显著高于其他PARP家族成员如PARP2,从而使得这类化合物具有有利的低PARP2活性、更低毒性。基于此,发明人完成了本发明。
术语
除非另有说明,基团中以虚线表示的单键代表与分子其他部分连接的位置。
如本文所述,术语“卤素”是指F、Cl、Br或I。相应地,“卤代”是指基团中的氢原子被F、Cl、Br或I取代。
除非另有表述,术语“烷基”本身或作为另一取代基的一部分是指具有指定碳原子数的直链或支链烃基(即,C1-6表示1-6个碳)。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基等。
术语“环烷基”是指具有指定环原子数(例如,C3-6环烷基具有3-6个环原子)并且完全饱和的烃环。“环烷基”也指双环和多环烃环,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。
烷基(包括通常称为亚烷基,烯基,炔基和环烷基的那些基团)的取代基可以是选自下组的各种基团:卤素、烷基(如C1-4烷基)、卤代烷基(如C1-4卤代烷基)。
对于本文提供的化合物,从取代基(通常为R基团)到环的中心的键将被理解为是指连接至环的任何可用顶点的键。
如本文所用,术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此,术语“主要由...组成”和“由...组成”包含在术语“含有”中。
如本文所用,术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应),即有合理的效益/风险比的物质。
除非特别说明,本发明中,所有出现的化合物均意在包括所有可能的光学异构体,如单一手性的化合物,或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中,各手性碳原子可以任选地为R构型或S构型,或R构型和S构型的混合物。
如本文所用,术语“杂原子”意在包括氧(O)、氮(N)、硫(S)。
本发明的某些化合物拥有不对称碳原子(光学中心)或双键;消旋体、非对映体、几何异构体、区域异构体和单独的异构体(例如,分离的对映体)均应包括在本发明范围内。当本文提供的化合物具有确定的立体化学(表示为R或S,或具有虚线或楔形键指明)时,被本领域技术人员将理解那些化合物为基本上不含其他异构体(例如至少80%,90%,95%,98%,99%和至多100%不含其他异构体)。
本发明化合物还可在构成此类化合物的一个或多个同位素原子处含有非天然比例的原子同位素。某同位素的非天然比例可以定义为从所讨论原子的天然发现的量到100%该原子的量。例如,化合物可以掺入放射性同位素,例如氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,例如氘(2H)或碳-13(13C)。除了本申请所述的那些用途,此类同位素变体可提供额外的用途。例如,本发明化合物的同位素变体可以有额外的用途,包括但不限于作为诊断的和/或成像试剂,或作为细胞毒性/放射毒性治疗剂。另外,本发明化合物的同位素变体可具有改变的药代动力学和药效学特征,从而有助于增加治疗期间的安全性、耐受性或疗效。无论是否有放射性,本发明化合物的所有同位素变体均应包括在本发明范围内。
活性成分
如本文所用,术语“本发明化合物”或“本发明化合物”指本文中式(A)、式(A1)、式(A2)、式(B)、式(C1)或式(C1)所示的化合物。该术语还包括及式(A)或者式(A1)、式(A2)、式(B)、式(C1)或式(C1)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
其中,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外,本发明化合物还包括式(A)、式(A1)、式(A2)、式(B)、式(C1)或式(C1)所示的化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成式(A)、式(A1)、式(A2)、式(B)、式(C1)或式(C1)的一类化合物,或式(A)、式(A1)、式(A2)、式(B)、式(C1)或式(C1)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
本文中具体地描述本发明式(A)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
药物组合物和施用方法
由于本发明化合物具有优异的对PARP1的选择抑制活性和抗肿瘤活性,因此,本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及改善与PARP1相关或者由PARP1介导的疾病或者治疗、预防以及改善肿瘤。根据现有技术,本发明化合物可用于治疗以下疾病:癌症、心血管疾病、炎症疾病、纤维化疾病(如疤痕等)、脑神经疾病、骨质疏松症、眼疾、病毒。所述的癌症可以是乳腺癌、卵巢癌、胰腺癌、前列腺癌、血癌、脑瘤、肉瘤、胃肠道癌(如胃癌和结直肠癌)或肺癌。
在本文中,术语“选择性”是指对指定靶标(如PARP1)的活性或效力(如抑制活性)高于对其他靶标(如PARP2)的活性或效力(如抑制活性);例如,对指定靶标(如PARP1)的活性或效力(如抑制活性)是对其他靶标(如PARP2)的活性或效力(如抑制活性)至少10倍。例如,以IC50值来定量酶学抑制活性时,IC50其他/IC50PARP1>10(>20、>50),其中,IC50PARP1是指本发明化合物对PARP1的酶学抑制活性IC50(例如以本文测试例1方法测得的IC50值),IC50其他是指本发明的化合物对下述一种或多种酶的抑制活性IC50(nM):PARP2。
本发明的药物组合物包含安全有效量或治疗有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有0.01-100mg本发明化合物/剂,更佳地,含有0.01-50mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。例如,本发明的化合物可作为抗肿瘤药物的增敏剂与至少一种另外的抗肿瘤药物联合给药。另外的抗肿瘤药物可以是靶向药物或化疗和放射治疗的药物(如卡铂、紫杉醇、替莫唑胺等),和质子治疗。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为0.01~100mg,优选0.01~50mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
1.本发明的化合物具有优异的选择性。相比于PARP2,本发明的化合物具有更优异的对PARP1的抑制活性。因此,本发明的化合物具有更低的毒性和更优异的安全性。
2.本发明的化合物在具有优异的选择性的同时具有优异的抑制活性。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
A.制备实施例
实施例1:化合物1的合成
步骤A:
将化合物1a(3g,12.80mmol),三丁基锡甲醇(4.93g,15.36mmol)和XPhos Pd G2(1.01g,1.28mmol)依次溶于1,4-二氧六环(100mL)中,氮气保护,80℃搅拌4小时。LCMS监控,反应完成后,减压浓缩,残留物加乙酸乙酯稀释(100mL),用水洗涤(50mL×2),饱和氯化铵洗涤(50mL),无水硫酸钠干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯1/1),得到黄色固体化合物1b(2g,84.2%)。1H NMR(400MHz,DMSO-d6):δppm 7.42–7.24(m,1H),6.88(s,2H),6.74(dd,J=8.8,1.4Hz,1H),5.15(t,J=5.7Hz,1H),4.37(dd,J=5.7,1.6Hz,2H).LCMS:169.1[M-16]+.
步骤B:
将化合物1b(2g,10.7mmol)溶于乙腈(110mL)中,加入溴化铜(3.25g,14.55mmol),冰浴搅拌下滴加亚硝酸叔丁酯(3g,29.10mmol),氮气保护,室温搅拌1小时。LCMS监控,反应完成后减压浓缩,残留物加乙酸乙酯稀释(100mL),用水洗涤(50mL x 2),饱和食盐水洗涤(50mL),无水硫酸钠干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯3/1),得到黄色固体化合物1c(2.18g,75.7%)。1H NMR(400MHz,DMSO-d6):δppm 7.78–7.75(m,1H),7.70–7.66(m,1H),5.62(s,1H),4.59(s,2H).
步骤C:
将化合物1c(2.0g,8.03mmol),铁粉(2.35g,42mmol)和氯化铵(2.25g,42mmol)依次加入到乙醇和水的混合溶液中(40mL:10mL),70℃搅拌5小时。LCMS监控,反应完成后过滤,减压浓缩,残留物加乙酸乙酯稀释(50mL),用水洗涤(30mL×2),饱和氯化铵洗涤(30mL),无水硫酸钠干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯3/1),得到黄色固体化合物1d(1.7g,96.25%)。1H NMR(400MHz,DMSO-d6):δppm 7.19–7.16(m,1H),6.61-6.57(m,1H),5.21-5.18(m,3H),4.45(d,J=4.8Hz,2H).LCMS:219.9,221.9[M+1]+.
步骤D:
将化合物1d(1.3g,5.91mmol),咪唑(0.6g,8.86mmol)依次加入到N,N-二甲基甲酰胺(40ml)中,0℃加入叔丁基二甲基氯硅烷(1.07g,7.09mmol),室温搅拌1小时。LCMS监控,反应完成后加水(100mL)稀释,乙酸乙酯萃取(3x 50mL),有机相用水洗涤(30mL×3),饱和氯化铵洗涤(30mL),无水硫酸钠干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯20/1),得到白色固体化合物1e(2g,95.24%)。LCMS:333.9,335.9[M+1]+.
步骤E:
化合物1e(2g,6mmol)溶于吡啶(20ml)中,0℃下滴加甲基丙烯酰氯(0.69g,6.6mmol),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,残留物加乙酸乙酯稀释(50mL),用1N稀盐酸洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯20/1),得到白色固体化合物1f(1.5g,65.80%)。1H NMR(400MHz,DMSO-d6):δppm 9.68(s,1H),7.61–7.58(m,1H),7.38(t,J=7.6Hz,1H),5.96(s,1H),5.61(s,1H),4.76(s,2H),1.99(s,3H),0.95–0.94(m.9H),0.14(s.6H).LCMS:401.9,403.9[M+1]+.
步骤F:
将化合物1f(1.5g,3.7mmol),N,N-二异丙基乙胺(1.43g,11.1mmol),三苯基膦(0.1g,0.37mmol)和醋酸钯(0.04g,0.19mmol)依次溶于N,N-二甲基甲酰胺(30ml)中,氮气保护,100℃反应2小时。LCMS监控,反应完成后加水(100mL)稀释,乙酸乙酯萃取(3×50mL),有机相用水洗涤(30mL×3),饱和氯化铵洗涤(30mL),无水硫酸钠干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯10/1),得到白色固体化合物1g(740mg,62.16%)。1H NMR(400MHz,DMSO-d6):δppm 11.58(s,1H),7.55(d,J=8.4Hz,1H),7.26–7.22(m,1H),6.44(s,1H),4.85(s,2H),2.5-2.4(s,3H)0.91(s,9H),0.10(s,6H)。LCMS:322.0[M+1]+.
步骤G:
将化合物1g(700mg,2.18mmol)依次溶于四氢呋喃(10ml)中,加入四丁基氟化铵(854mg,3.27mmol),氮气保护,室温搅拌2小时。LCMS监控,反应完成减压浓缩,残留物用乙醚打浆,过滤得到类白色固体粗品化合物1h(350mg),无需纯化,直接用于下一步反应。1HNMR(400MHz,DMSO-d6):δppm 11.58(s,1H),7.54–7.52(d,J=8.0Hz,1H),7.29–7.25(s,1H),6.41(d,J=1.2Hz,1H),5.42(s,1H),4.64(s,2H),2.40(s,3H).LCMS:208.0[M+1]+.
步骤H:
将化合物1h(300mg,1.45mmol)溶于二氯甲烷(10ml)中,随后加入三溴化磷(588mg,2.18mmol),氮气保护,室温反应2小时。LCMS监控,反应完成减压浓缩,残留物用乙醚打浆,过滤得到类白色固体粗品化合物1i(350mg),无需纯化,直接用于下一步反应。LCMS:269.9,271.9[M+1]+.
步骤I:
将化合物1i(200mg,0.74mmol)溶于乙腈(10ml)中,加入化合物1j(196mg,0.89mmol)和N,N-二异丙基乙胺(287mg,2.22mmol),氮气保护,70℃反应12小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,21mm直径,150mm长度),水(0.1%FA)和MeCN作为洗脱剂(5-40%)],得到白色固体化合物1(38mg,12.5%)。1H NMR(400MHz,DMSO-d6)δppm 11.57(s,1H),8.41–8.38(m,1H),8.26(d,J=2.7Hz,1H),7.82(d,J=8.8Hz,1H),7.53(d,J=8.3Hz,1H),7.38(dd,J=8.8,2.8Hz,1H),7.27–7.21(m,1H),6.45(s,1H),3.69(s,2H),3.45-3.35(s,4H),2.78(d,J=4.8Hz,3H),2.59–2.55(m,4H),2.43(s,3H).LCMS:410.0[M+1]+.
实施例2:化合物2的合成
步骤A:
将化合物2a(5g,13.1mmol),二氟化银(11.8g,80.6mmol)依次加入到含有100mL乙腈的圆底烧瓶内,氮气保护,避光室温搅拌20小时。LCMS监测,反应完成后,过滤,滤液浓缩。加入200mL乙酸乙酯,水(100mL)洗涤,有机相用无水硫酸钠干燥,减压浓缩,柱层析分离,(洗脱液:乙酸乙酯/石油醚,1/10,v/v),得到白色固体化合物2b(3.6g,59.7%)。1H NMR(400MHz,CDCl3):δppm 8.12(t,J=8.1Hz,1H),7.90(dd,J=7.9,1.3Hz,1H),3.98(s,3H).LCMS:233.9,235.9[M+H]+.
步骤B:
将化合物2b(1g,4.32mmol),化合物2c(0.83g,4.8mmol),1,1'-联萘-2,2'-双二苯膦(0.3g,0.48mmol),三(二亚苄基丙酮)二钯(0.44g,0.48mmol),碳酸铯(1.88g,5.76mmol)依次加入到含有1,4-二氧六环(30mL)的圆底烧瓶内,氮气保护,100℃搅拌16小时。LCMS监测,反应完成后,减压浓缩,加水稀释(100mL),乙酸乙酯萃取(80mL×3),合并萃取液,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,柱层析分离,(洗脱液:石油醚/乙酸乙酯,5/1,v/v),得到白色的固体化合物2d(0.9g,54.2%)。LCMS:326.1
[M+H]+.
步骤C:
化合物2d(800mg,2.45mmol)加入到含甲醇(3mL)和四氢呋喃(4mL)的圆底烧瓶内,搅拌下加入2N氢氧化钠水溶液(30mL),室温搅拌16小时。LCMS监测,反应完成后,浓缩反应液,加10mL水稀释,并用3M的HCl调pH=4。乙酸乙酯萃取(100mL×3),合并萃取液,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得到白色的固体化合物2e(750mg,88.17%)。1H NMR(400MHz,CD3OD):δppm 7.88(dd,J=8.1,1.2Hz,1H),6.97(dd,J=10.2,8.2Hz,1H),4.46–4.17(m,3H),3.85(dd,J=7.9,3.8Hz,2H),1.42(s,9H).LCMS:256.0[M-56]+.
步骤D:
将化合物2e(750mg,2.4mmol),甲氨盐酸盐(194.6mg,2.88mmol),HATU(1.09g,2.88mmol),N,N-二异丙基乙胺(620.7mg,4.80mmol)依次加入到含有N,N-二甲基甲酰胺(30mL)的圆底烧瓶内,70℃搅拌16小时。LCMS监测,反应完成后,加水稀释(50mL),乙酸乙酯萃取(80mL×3),合并萃取液,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,2/3,v/v),得到白色的固体化合物2f(800mg,92.1%)。LCMS:325.1[M+H]+.
步骤E:
将化合物2f(800mg,2.46mmol)加入到含有20mL二氯甲烷的圆底烧瓶内,室温搅拌下加入三氟乙酸(3mL),室温搅拌16小时。LCMS监测,反应完成后,减压浓缩,得到淡黄色的固体化合物2g(600mg,97.9%)。LCMS:225.1[M+H]+.
步骤F:
将化合物1i(100mg,0.37mmol)溶于乙腈(10ml)中,加入化合物2g(124mg,0.56mmol)和N,N-二异丙基乙胺(191mg,1.48mmol),氮气保护,70℃反应12小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,21mm直径,150mm长度),水(0.1%FA)和MeCN作为洗脱剂(5-40%)],得到白色固体化合物2(37mg,甲酸盐的形式,24.2%)。1H NMR(400MHz,DMSO-d6)δppm 11.67(s,1H),8.26–8.17(m,1H),7.72(d,J=8.0Hz,1H),7.54(d,J=8.3Hz,1H),7.28–7.17(m,1H),7.10(dd,J=10.4,8.3Hz,1H),6.94(d,J=5.9Hz,1H),6.47(s,1H),4.27–4.17(m,1H),4.05–3.85(m,4H),3.32–3.20(m,2H),2.74(d,J=4.8Hz,3H),2.42(s,3H).LCMS:414.2[M+1]+.
实施例3:化合物3的合成
步骤A:
将化合物1i(200mg,0.74mmol)溶于乙腈(10mL)中,加入化合物3a(212mg,0.89mmol)和N,N-二异丙基乙胺(287mg,2.22mmol),氮气保护,70℃反应12小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,21mm直径,150mm长度),水(0.1%FA)和MeCN作为洗脱剂(5-40%)],得到白色固体化合物3(34mg,10.7%)。1H NMR(400MHz,DMSO-d6)δppm 11.57(s,1H),8.40(d,J=4.9Hz,1H),7.84(d,J=8.0Hz,1H),7.59–7.50(m,2H),7.28–7.21(m,1H),6.45(s,1H),3.70(s,2H),3.19–3.14(m,4H),2.76(d,J=4.8Hz,3H),2.61–2.56(m,4H),2.43(s,3H).LCMS:428.0[M+1]+.
实施例4:化合物4的合成
步骤A:
将化合物2a(1.25g,5.8mmol),化合物2c(1g,5.8mmol),1,1'-联萘-2,2'-双二苯膦(0.36g,5.8mmol),三(二亚苄基丙酮)二钯(0.53g,0.58mmol),碳酸铯(2.27g,6.96mmol)依次加入到含有100mL 1,4-二氧六环的圆底烧瓶内,氮气保护,100℃搅拌16小时。LCMS监测,反应完成后,冷却至室温。加水稀释(100mL),乙酸乙酯萃取(200mL×3),合并萃取液,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,柱层析分离,(洗脱液:石油醚/乙酸乙酯,2/3,v/v),得到淡黄色的固体化合物4a(0.9g,44.83%)。LCMS:308.1[M+H]+.
步骤B:
化合物4a(400mg,1.30mmol)加入到含有甲醇(3mL)和四氢呋喃(4mL)的圆底烧瓶内,搅拌下加入2N氢氧化钠水溶液(3mL),室温搅拌16小时。LCMS监测,反应完成后,浓缩反应液,加10mL水稀释,并用3M的HCl调pH=4。乙酸乙酯萃取(50mL×3),合并萃取液,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得到淡黄色的固体化合物4b(350mg,82.50%)。LCMS:294.1[M+H]+.
步骤C:
将化合物4b(400mg,1.36mmol),甲氨盐酸盐(110.11mg,1.63mmol),HATU(620.08mg,1.63mmol),N,N-二异丙基乙胺(351.27mg,2.72mmol)依次加入到含有20mL N,N-二甲基甲酰胺的圆底烧瓶内,温室搅拌16小时。LCMS监测,反应完成后,加入40mL水稀释,乙酸乙酯萃取(30mL×3),合并萃取液,无水硫酸钠干燥,柱层析分离,(洗脱液:石油醚/乙酸乙酯,1/5,v/v),得到白色固体化合4c(400mg,86.2%)。LCMS:307.2[M+H]+.
步骤D:
将化合物4c(400mg,1.30mmol)加入到含有20mL二氯甲烷的圆底烧瓶内,室温搅拌下加入三氟乙酸(4mL),室温搅拌16小时。LCMS监测,反应完成后,减压浓缩,得到黄色的油状物化合物4d(270mg,90.5%)。LCMS:207.2[M+H]+.
步骤E:
将化合物1i(100mg,0.37mmol)溶于乙腈(10ml)中,加入化合物4d(115mg,0.56mmol)和N,N-二异丙基乙胺(191mg,1.48mmol),氮气保护,70℃反应12小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,21mm直径,150mm长度),水(0.1%FA)和MeCN作为洗脱剂(5-40%)],得到白色固体化合物4(35mg,甲酸盐的形式,23.8%)。1H NMR(400MHz,DMSO-d6)δppm 11.61(s,1H),8.30(q,J=4.6Hz,1H),7.89(d,J=2.6Hz,1H),7.73(d,J=8.6Hz,1H),7.51(d,J=8.2Hz,1H),7.19(dd,J=8.1,6.8Hz,1H),7.01–6.87(m,2H),6.45(d,J=1.1Hz,1H),4.18–
4.03(m,1H),3.78(s,2H),3.73(t,J=6.8Hz,2H),3.02(t,J=6.4Hz,2H),2.76(d,J=4.8Hz,3H),2.42(s,3H).LCMS:396.0[M+1]+.
实施例5:化合物5的合成
步骤A:
将化合物1e(1.5g,4.49mmol)溶于吡啶(25mL)中,0℃下滴加乙基丙烯酰氯(0.80g,6.7mmol),氮气保护,室温搅拌12小时。LCMS监控,反应完成后减压浓缩,残留物加乙酸乙酯稀释(50mL),用1N稀盐酸洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯20/1),得到白色固体化合物5a(1.8g,98.21%)。LCMS:415.9,418.0[M+H]+.
步骤B:
将化合物5a(1.8g,4.32mmol),N,N-二异丙基乙胺(1.68g,12.97mmol),三苯基膦(0.113g,0.432mmol)和醋酸钯(0.04g,0.22mmol)依次溶于N,N-二甲基甲酰胺(30mL)中,氮气保护,100℃反应36小时。LCMS监控,反应完成后加水(50mL)稀释,乙酸乙酯萃取(3×50mL),有机相用水洗涤(30mL×3),饱和氯化铵洗涤(30mL),无水硫酸钠干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯10/1),得到白色固体化合物5b(490mg,33.79%)。1HNMR(400MHz,DMSO-d6):δppm 11.59(s,1H),7.61(d,J=8.4Hz,1H),7.26–7.22(m,1H),6.40(s,1H),4.85(s,2H),2.83(q,J=7.6Hz,2H),1.23(t,J=7.4Hz,3H),0.91(s,9H),0.10(s,6H).LCMS:336.0[M+H]+.
步骤C:
将化合物5b(690mg,2.06mmol)溶于四氢呋喃(10mL)中,加入四丁基氟化铵(1M inTHF,2.47mL,2.47mmol),氮气保护,室温搅拌2小时。LCMS监控,反应完成减压浓缩,残留物用乙醚打浆,过滤得到类白色固体粗品化合物5c(390mg),无需纯化,直接用于下一步反应。1H NMR(400MHz,DMSO-d6):δppm 11.57(s,1H),7.76–7.71(m,1H),7.59–7.57(m,1H),7.29–7.25(m,1H),6.39(s,1H),4.64–4.63(m,2H),3-2.8(m,2H),1.23(t,J=7.4Hz,3H).LCMS:222[M+H]+.
步骤D:
将化合物5c(390mg,1.88mmol)溶于二氯甲烷(10mL)中,随后加入三溴化磷(764.2mg,2.82mmol),氮气保护,室温反应2小时。LCMS监控,反应完成减压浓缩,残留物用乙醚打浆,过滤得到类白色固体粗品化合物5d(460mg),无需纯化,直接用于下一步反应。LCMS:284.0,286.0[M+H]+.
步骤E:
将化合物5d(50mg,0.177mmol)溶于乙腈(10ml)中,加入化合物1j(46mg,0.21mmol)和N,N-二异丙基乙胺(45mg,0.35mmol),氮气保护,70℃反应12小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,21mm直径,150mm长度),水(0.1%FA)和MeCN作为洗脱剂(5-40%)],得到白色固体化合物5(22mg,29.3%)。1H NMR(400MHz,DMSO-d6)δppm 11.57(br.s,1H),8.37–8.34(m,1H),8.21(s,1H),7.77(d,J=8.8Hz,1H),7.53(d,J=8.4Hz,1H),7.35–7.32(m,1H),7.19(t,J=7.2Hz,1H),6.37(s,1H),3.64(s,2H),3.29–3.27(m,4H),2.80–2.76(m,2H),2.74–2.73(m,3H),2.54–2.51(m,4H),1.20(t,J=7.6Hz,3H).LCMS:424.1[M+H]+.
实施例6:化合物6的合成
将化合物5d(50mg,0.177mmol)溶于乙腈(10mL)中,加入化合物2g(47mg,0.21mmol)和N,N-二异丙基乙胺(45mg,0.35mmol),氮气保护,70℃反应12小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,21mm直径,150mm长度),水(0.1%FA)和MeCN作为洗脱剂(5-40%)],得到白色固体化合物6(12.2mg,16.1%)。1H NMR(400MHz,CD3OD)δppm 7.77(d,J=8.0Hz,1H),7.64(d,J=7.6Hz,1H),7.27(t,J=7.2Hz,1H),7.03–6.98(m,1H),6.52(s,1H),4.27–4.20(m,1H),3.98(s,2H),3.95–3.92(s,2H),3.38–3.35(m,2H),2.93–2.87(m,2H),2.86(s,3H),1.31(t,J=7.2Hz,3H).LCMS:428.1[M+H]+.
实施例7:化合物7的合成
步骤A:
将化合物5d(300mg,1.05mmol)溶于乙腈(20mL)中,加入化合物3a(302mg,1.27mmol)和N,N-二异丙基乙胺(273mg,2.1mmol),氮气保护,70℃反应12小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,21mm直径,150mm长度),水(0.1%FA)和MeCN作为洗脱剂(5-40%)],得到白色固体化合物7(220mg,47.5%)。1H NMR(400MHz,CD3OD)δppm 7.86–7.85(m,1H),7.64-7.62(m,1H),7.48–7.45(m,1H),7.36–7.33(m,1H),6.51(s,1H),3.77(s,2H),3.24–3.22(m,4H),2.94–2.91(m,2H),2.88(s,3H),2.70–2.67(m,4H),1.32(t,J=7.6Hz,3H).LCMS:442.0[M+H]+.
实施例8:化合物8的合成
步骤A:
将化合物5d(50mg,0.177mmol)溶于乙腈(10ml)中,加入化合物4d(44mg,0.21mmol)和N,N-二异丙基乙胺(45mg,0.35mmol),氮气保护,70℃反应12小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,21mm直径,150mm长度),水(0.1%FA)和MeCN作为洗脱剂(5-40%)],得到白色固体化合物8(16.6mg,22.9%)。1H NMR(400MHz,CD3OD)δppm 7.97(d,J=2.8Hz,1H),7.86(d,J=8.8Hz,1H),7.74(dd,J=8.4Hz,6.8Hz,1H),7.36–7.32(m,1H),7.02–6.99(m,1H),6.58(s,1H),4.67(s,2H),4.64–4.56(m,3H),4.18–4.16(m,2H),2.95–2.89(m,5H),1.32(t,J=7.6Hz,3H).LCMS:410.2[M+H]+.
B.测试实施例
测试例1:对PARP酶的抑制活性测试
实验材料:
HT通用化学发光PARP分析试剂盒购自TREVIGEN。PBS购自维森特。Triton X-100购自麦克林。Envision多标记分析仪(珀金埃尔默)。
HT通用化学发光PARP分析试剂盒成分表
实验方法:
试剂配制:
1.洗涤液:1X PBS中加入Triton X-100,Triton X-100的终浓度为0.1%。
2.1X PARP缓冲液:取试剂盒中的20X PARP缓冲液,用水稀释20倍,配制成1X PARP缓冲液。此缓冲液用来配制化合物,酶溶液,底物溶液。
3.1X链球菌稀释液溶液:用水将试剂盒中的10X链球菌稀释液稀释10倍,配制成1X链球菌稀释液溶液。
待测化合物配制:
将待测化合物用排枪进行5倍稀释至第8个浓度,即从200μM稀释至2.56nM,DMSO浓度为100%。取2ul抑制剂各浓度梯度到化合物中间板,加入38ul 1X PARP缓冲液混匀备用,此时DMSO浓度为5%。
实验步骤:
1.取每孔50ul 1X PARP缓冲液到测试板中,25度孵育30分钟。
2.结束孵育后,弃掉测试板中的液体,从化合物中间板中取出各浓度梯度的化合物10ul每孔,到测试板中。设置双复孔实验。
3.向测试板中加入每孔15ul酶溶液(0.5Unit)。化合物和酶在25度共同孵育10分钟。
4.结束孵育后向测试板每孔加入25ul 1X PARP Cocktail,25ul 1X PARP混合物包括2.5ul 10X PARP混合物,2.5ul 10X活化DNA,20ul 1X PARP缓冲液。测试板在25度孵育1小时。化合物终浓度为2uM至0.0256nM,DMSO浓度为1%。
5.结束孵育后,使用每孔200ul洗涤液对测试板洗涤2次,再用PBS每孔200ul洗涤2次。
6.将试剂盒中的链球菌-HRP使用1X链球菌稀释液溶液稀释500倍,每孔50ul加入到测试板中,25度孵育1小时。
7.结束孵育后,使用每孔200ul洗涤液对测试板洗涤2次,再用PBS每孔200ul洗涤2次。
8.按照1:1混合试剂盒中的PeroxyGlowA和B,向测试板中加入每孔100ul混合液,并且马上使用PerkinElmer Envision多标记分析仪读数化学发光,积分时间0.5秒。
数据分析:
利用方程式(Sample-Min)/(Max-Min)*100%将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(抑制剂)vs.响应--Variableslope模式得出)。测试结果如表1所示,表1提供了本发明的化合物对PARP的酶学抑制活性。
测试例2:对DLD1-BRCA2 KO细胞的抑制活性测试
实验材料:
DLD-1细胞购自南京科佰;DLD1-BRCA2 KO细胞由武汉合研生物医药科技有限公司自行构建;1640培养基购自Biological Industries;胎牛血清购自Biosera,细胞活率化学发光检测试剂购自Promega公司。
实验方法:
细胞抗增殖实验:
将DLD1或DLD1 BRCA2 KO细胞种于白色96孔板中,80μL细胞悬液每孔,其中包含1000个DLD1或DLD1 BRCA2 KO细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进5倍稀释至第8个浓度,即从2mM稀释至0.0256μM,设置双复孔实验。向中间板中加入78μL培养基,再按照对应位置,转移2μL每孔的梯度稀释化合物至中间板,混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.128nM。细胞板置于二氧化碳培养箱中培养7天。另准备一块细胞板,在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂,室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。加入化合物的细胞板结束孵育后,向细胞板中加入每孔25μL的细胞活率化学发光检测试剂,室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
数据分析:
利用方程式(Sample-Min)/(Max-Min)*100%将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。测试结果如表1所示,表1提供了本发明的化合物对DLD-1BRCA2 KO细胞抑制活性。
表1
化合物编号 | PARP1(nM) | PARP2(nM) | BRCA2 DLD-1(nM) |
1 | 60.8 | 1463 | |
2 | 309 | 6110 | |
3 | 13.4 | 2483 | |
4 | 260 | 2510 | |
5 | 8.7 | 542 | |
6 | 48.0 | 1550 | |
7 | 5.0 | 692 | |
8 | 56.0 | 2983 |
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种化合物或其药学上可接受的盐或溶剂化物,其特征在于,所述的化合物如式A所示;
其中,
X1为如式M1或式M2所示的二价基团:
(i)
其中,W3和W4各自独立地为-(CH2)-、-(CH2)2-或-(CH2)3-;
(ii)
其中,W1和W2各自独立地为-(CH2)-或-(CH2)2-;
R6选自下组:H、取代或未取代的C1-3烷基;
R1选自下组:取代或未取代的C1-6烷基、取代或未取代的C3-6环烷基;
R2选自下组:H、卤素、取代或未取代的C1-3烷基、取代或未取代的C3-6环烷基;
R3选自下组:H、取代或未取代的C1-3烷基;
R4和R5各自独立地选择下组:H、卤素;
Ra1、Ra2、Ra3、Rc1和Rc2各自独立地选自下组:H、取代或未取代的C1-4烷基;
除非特别说明,所述取代是指基团中一个或多个(如1、2或3个)氢被选自下组的取代基所述取代:氘(D)、卤素、C1-4烷基、C1-4卤代烷基。
2.如权利要求1所述的化合物,其特征在于,所述化合物如式B所示
其中,R1、R2、R3和R4如式A中定义。
3.如权利要求1所述的化合物,其特征在于,所述的化合物具有下述一个或多个特征:
(a)R1为取代或未取代的C1-6烷基;
(b)R2选自下组:H、卤素、取代或未取代的C1-3烷基;
(c)R3为取代或未取代的C1-3烷基;
(d)R4为卤素。
4.如权利要求1所述的化合物,其特征在于,所述的化合物具有下述一个或多个特征:
(a)R1为取代或未取代的C1-4烷基;
(b)R2选自下组:H、卤素;较佳地,R2选自下组:H、F、Cl;
(c)R3为C1-3烷基或氘代C1-3烷基;
(d)R4选自下组:F、Cl、Br。
5.如权利要求1所述的化合物,其特征在于,所述的化合物具有下述一个或多个特征:
(a)R1为甲基或乙基;
(b)R2为H或F;
(c)R3为甲基;
(d)R4为F。
6.如权利要求1所述的化合物,其特征在于,所述化合物如式C1或式C2所示
其中,R1、R2、R3和R4如式A中定义。
7.如权利要求1所述的化合物,其特征在于,所述化合物为选自表A的化合物:
表A
8.一种如权利要求1所述的化合物的制备方法,其特征在于,包括步骤:
(a)使式I中间体与式II中间体反应,从而得到式A所示的化合物;
各式中,
X2为如式M3或式M4所示的基团
RP为H或氨基保护基;
RH为活性反应基团;
R1、R2、R3、R4、R5、R6、Ra1、Ra2、Ra3、Rc1、Rc2、W1、W2、W3和W4如式A中定义。
9.一种药物组合物,包括:
(i)如权利要求1所述的化合物或其药学上可接受的盐,和(ii)药学上可接受的载体或赋形剂。
10.一种如权利要1所述的化合物在制备(i)用于治疗、改善或预防与PARP1相关的疾病和/或由PARP1介导的疾病的药物;和/或(ii)PARP1抑制剂;和/或(iii)抗肿瘤药物;和/或(iv)肿瘤药物增敏剂中的用途。
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Application Number | Priority Date | Filing Date | Title |
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CN202211067317.8A CN117658983A (zh) | 2022-09-01 | 2022-09-01 | 选择性parp1抑制剂 |
PCT/CN2023/115820 WO2024046366A1 (zh) | 2022-09-01 | 2023-08-30 | 选择性parp1抑制剂 |
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ES2448870T3 (es) * | 2007-10-26 | 2014-03-17 | Janssen Pharmaceutica, N.V. | Derivados de quinolina como inhibidores de PARP |
JP2022537349A (ja) * | 2019-06-19 | 2022-08-25 | ライボン・セラピューティクス・インコーポレイテッド | 療法に使用するためのparp14の標的タンパク質分解 |
MX2022000711A (es) * | 2019-07-19 | 2022-02-23 | Astrazeneca Ab | Inhibidores de parp1. |
US11795158B2 (en) * | 2020-06-25 | 2023-10-24 | Astrazeneca Ab | Chemical compounds |
CN117279916A (zh) * | 2021-04-22 | 2023-12-22 | 微境生物医药科技(上海)有限公司 | 含哌嗪结构的parp抑制剂、其制备方法及医药用途 |
TW202309026A (zh) * | 2021-04-23 | 2023-03-01 | 大陸商上海翰森生物醫藥科技有限公司 | 雜環類衍生物抑制劑、其製備方法和應用 |
WO2022222966A1 (zh) * | 2021-04-23 | 2022-10-27 | 成都百裕制药股份有限公司 | 一种选择性parp1抑制剂及其应用 |
TW202304911A (zh) * | 2021-04-23 | 2023-02-01 | 大陸商南京明德新藥研發有限公司 | 吡啶醯胺類化合物 |
WO2022228387A1 (en) * | 2021-04-26 | 2022-11-03 | Fochon Biosciences, Ltd. | Compounds as parp inhibitors |
CN115677688A (zh) * | 2021-07-23 | 2023-02-03 | 南京明德新药研发有限公司 | 1,5-萘啶酮类化合物 |
CN116143776A (zh) * | 2021-11-22 | 2023-05-23 | 南京圣和药业股份有限公司 | Parp1抑制剂及其应用 |
CA3241338A1 (en) * | 2021-12-17 | 2023-06-22 | Yongqi Deng | Parp inhibitor, pharmaceutical composition comprising same, and use thereof |
WO2023138541A1 (zh) * | 2022-01-20 | 2023-07-27 | 微境生物医药科技(上海)有限公司 | 吡啶酰胺类parp抑制剂、及其制备方法和医药用途 |
CN116535401A (zh) * | 2022-01-25 | 2023-08-04 | 南京圣和药业股份有限公司 | 新的parp1抑制剂及其应用 |
CN116496271A (zh) * | 2022-01-26 | 2023-07-28 | 正大天晴药业集团股份有限公司 | 含有哌嗪基的化合物 |
WO2023146957A1 (en) * | 2022-01-27 | 2023-08-03 | Xinthera, Inc. | Parp1 inhibitors and uses thereof |
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