CN116322680A - Parp抑制剂的联合用药方案 - Google Patents
Parp抑制剂的联合用药方案 Download PDFInfo
- Publication number
- CN116322680A CN116322680A CN202180058992.1A CN202180058992A CN116322680A CN 116322680 A CN116322680 A CN 116322680A CN 202180058992 A CN202180058992 A CN 202180058992A CN 116322680 A CN116322680 A CN 116322680A
- Authority
- CN
- China
- Prior art keywords
- carbonyl
- dione
- quinazoline
- benzyl
- piperazine
- 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.)
- Pending
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- 239000012661 PARP inhibitor Substances 0.000 title claims abstract description 95
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 title claims abstract description 95
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 60
- 239000003814 drug Substances 0.000 claims abstract description 40
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 38
- 229940079593 drug Drugs 0.000 claims abstract description 27
- 230000005778 DNA damage Effects 0.000 claims abstract description 20
- 231100000277 DNA damage Toxicity 0.000 claims abstract description 20
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 194
- 229960004964 temozolomide Drugs 0.000 claims description 192
- VBTUJTGLLREMNW-UHFFFAOYSA-N 5-fluoro-1-[[4-fluoro-3-(4-pyrimidin-2-ylpiperazine-1-carbonyl)phenyl]methyl]quinazoline-2,4-dione Chemical compound FC1=CC=C(CN2C(NC(=O)C3=C(F)C=CC=C32)=O)C=C1C(=O)N(CC1)CCN1C1=NC=CC=N1 VBTUJTGLLREMNW-UHFFFAOYSA-N 0.000 claims description 143
- 229910052736 halogen Inorganic materials 0.000 claims description 108
- 150000002367 halogens Chemical class 0.000 claims description 108
- 229910052739 hydrogen Inorganic materials 0.000 claims description 103
- 239000001257 hydrogen Substances 0.000 claims description 103
- 125000000217 alkyl group Chemical group 0.000 claims description 97
- 150000002431 hydrogen Chemical group 0.000 claims description 87
- 206010028980 Neoplasm Diseases 0.000 claims description 82
- -1 hydroxy, mercapto Chemical class 0.000 claims description 74
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 54
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 51
- 238000011282 treatment Methods 0.000 claims description 47
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- 201000011510 cancer Diseases 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 32
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 229910052731 fluorine Inorganic materials 0.000 claims description 31
- 239000011737 fluorine Substances 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 239000000460 chlorine Substances 0.000 claims description 22
- 125000004076 pyridyl group Chemical group 0.000 claims description 19
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 125000001188 haloalkyl group Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
- SDQJTWBNWQABLE-UHFFFAOYSA-N 1h-quinazoline-2,4-dione Chemical compound C1=CC=C2C(=O)NC(=O)NC2=C1 SDQJTWBNWQABLE-UHFFFAOYSA-N 0.000 claims description 13
- 125000004423 acyloxy group Chemical group 0.000 claims description 13
- 125000003368 amide group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 13
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
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- 125000005605 benzo group Chemical group 0.000 claims description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 10
- 125000001793 isothiazol-3-yl group Chemical group [H]C1=C([H])C(*)=NS1 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
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- 230000000259 anti-tumor effect Effects 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 8
- 125000005312 heteroarylalkynyl group Chemical group 0.000 claims description 8
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- 239000000651 prodrug Substances 0.000 claims description 8
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- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
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- 238000009472 formulation Methods 0.000 claims description 6
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- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
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- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 5
- 229960002707 bendamustine Drugs 0.000 claims description 5
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 5
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 5
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
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- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 4
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- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 4
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- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 4
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
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- HFKBTQXIIBMLFN-UHFFFAOYSA-N 1-[[3-(4-pyrimidin-2-ylpiperazine-1-carbonyl)phenyl]methyl]quinazoline-2,4-dione Chemical compound C=1C=CC(CN2C(NC(=O)C3=CC=CC=C32)=O)=CC=1C(=O)N(CC1)CCN1C1=NC=CC=N1 HFKBTQXIIBMLFN-UHFFFAOYSA-N 0.000 claims description 3
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- QMKISCQPKPFHRP-UHFFFAOYSA-N 1-[[2-chloro-5-[4-(cyclopentanecarbonyl)piperazine-1-carbonyl]phenyl]methyl]quinazoline-2,4-dione Chemical compound C1=C(CN2C(NC(=O)C3=CC=CC=C32)=O)C(Cl)=CC=C1C(=O)N(CC1)CCN1C(=O)C1CCCC1 QMKISCQPKPFHRP-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明涉及PARP抑制剂的联合用药方案。具体而言,本发明涉及下式I所示的PARP抑制剂与低剂量DNA损伤类抗癌药的联合用药方案。采用本发明的联合用药方案,能减低DNA损伤类抗癌药的日剂量,降低毒性和提高抗癌效果。
Description
技术领域
本发明涉及PARP抑制剂的联合用药方案。
背景技术
多聚(ADP-核糖)聚合酶(PARP)催化由NAD+向目标蛋白分子上添加多聚(ADP-核糖)的细胞内ADP-核糖聚合反应。PARP是一个由17个家族成员组成的蛋白酶家族。PARP1和PARP2是DNA损伤修复途径中的关键分子,也是碱基切除修复(BER)复合物的一部分。激活后,PARP1和PARP2将多聚(ADP-核糖)(PAR)附着在组蛋白或自身的蛋白质上,这种反应称为PARylation。这个过程对保持DNA及染色体的完整和稳定至关重要,是哺乳类细胞存活的重要保障。科学证据表明,具有DNA损伤修复途径缺陷(如同源重组缺陷)的细胞对PARP1抑制敏感。多个PARP抑制剂,已批准上市用于治疗具有BRCA突变或同源重组缺陷的癌症。
目前批准的所有PARP抑制剂对PARP1和PARP2没有选择性。例如,Olaparib对PARP1和PARP2抑制活力相当。PARP抑制剂在癌症治疗中的应用主要有两种,单独使用或与其他抗癌药物联合使用。其一,对有DNA修复缺陷的癌症,比如BRCA1或BRCA2缺失的三重阴性乳腺癌,PARP抑制剂能独立地作为抗癌药物,通过合成致死机制直接杀死这些癌细胞。据统计大约10-15%的乳腺癌都有家族史遗传的因素,其中由于BRCA1或BRCA2基因突变而引起的乳腺癌又占所有遗传性乳腺癌的15-20%。其二,癌细胞的DNA突变率通常比正常细胞高得多,导致染色体不稳定的程度更高。这些癌细胞对引起DNA损伤的药物敏感,如DNA烷基化/甲基化剂和拓扑异构酶I抑制剂。然而,由于DNA修复通路的存在,这些药物的治疗效果并不能完全实现。抑制DNA修复机制,如PARP抑制剂,可以显著增强DNA损伤类抗癌药物如替莫唑胺(TMZ)的药效。在临床前药理模型中,已观察到PARP抑制剂与TMZ联合使用的协同作用,这些治疗一般采用高剂量的TMZ与低剂量的PARP抑制剂联合用药。例如,在一项药效研究中,低剂量的Olaparib(10mg/kg每天,Olaparib(AZD2281)在BRCA突变的动物模型研究中的单药有效剂量为50-100mg/kg每天)与高剂量的TMZ(50mg/kg每天)在人结肠癌SW620异种移植瘤模型中联合使用(Keith A.Menear等人,2008,JMC 51:6581)。在临床试验中,高剂量化疗抗癌药物也通常与低剂量PARP抑制剂联合使用。例如,在一项针对复发性胶质母细胞瘤患者的Olaparib联合TMZ的I期临床试验中,发现Olaparib会加剧TMZ相关的血液学毒性,需要间歇给药。在36例评估疗效的患者中,14例患者(39%)6个月疾病无进展。II期推荐剂量(RP2D)为Olaparib 150mg 3天/周(Olaparib作为单一药物的批准剂量为400mg每天两次(BID),连续给药)和TMZ 75mg/m2每天给药连续42天(TMZ 75mg/m2,基于60kg成人体表面积1.62m2换算,相当于121.5mg每天一次(QD))(Catherine Hanna等人,2020,Neuro Oncol.1-11)。TMZ的这些剂量与TMZ联合放疗治疗新诊断的多形性胶质母细胞瘤的日剂量相似,即75mg/m2,接近TMZ的最低推荐剂量。作为单药治疗,即100mg/m2(相当于162mg)。
PARP抑制剂杀伤癌细胞的作用机制已经被广泛接受,这超出了PARP抑制剂抑制DNA修复的最初假设。PARP抑制剂可以使PARP-DNA复合物稳定在单链DNA断裂位点,称为“捕获”(trapping)。捕获被认为比抑制单链断裂修复造成更大的细胞毒性,因此被认为与治疗效果密切相关(Murai和Pommier 2019Annu Rev Cancer Biol 3:7.1-7.20)。因此,PARP抑制剂与DNA损伤烷基化剂(如TMZ)的联合应用有两种途径。一种方法是使用TMZ作为DNA损伤的主要原因,PARP抑制剂通过阻断DNA修复机制作为增强剂。其机制是在PARP抑制剂存在的情况下,TMZ可引起更多的DNA损伤。另一种方法是依靠PARP抑制剂的捕获活性,其中TMZ作为引发剂诱导DNA损伤,PARP抑制剂作为捕获剂产生DNA-PARP复合物。由于捕获会对癌细胞产生更严重的细胞毒性,因此被认为是一种更合理的方法(Murai J.等人,2014,JPharmacol Exp Ther 349:408)。这两种方法的主要区别在于剂量选择和给药方案。使用这种新的组合策略,TMZ可以在大大降低剂量的情况下有效,且使其毒性最小化,PARP抑制剂可以在接近其最大耐受剂量的水平上使用,以产生最大的捕获和抗肿瘤疗效(Shen Y.等人,2015,J Pharmacol Exp Ther 353:446)。这种组合方法的另一个优点是它不依赖于特定的突变,如BRCA突变的疗效,并且可用于不同瘤种患者的治疗。
已报道有具有强PARP捕获活性的高剂量PARP抑制剂与低剂量TMZ的联合应用。据报道,在一项人小细胞肺癌(SCLC)NCI-H209异种移植模型的临床前疗效研究中,高剂量Talazoparib(0.25mg/kg,在BRCA突变模型中Talazoparib的单药有效剂量为0.33mg/kg)与低剂量TMZ(3mg/kg,TMZ在人结肠癌SW620异种移植模型中的单药有效剂量为50mg/kg;Keith A.Menear等人,2008,JMC 51:6581)采用间断的每日给药方案(D1-4,D17-20和D28-31)联用,具有良好的协同疗效,但有一定的毒性(第一次给药后观察到体重减轻约10%)(Feng等人,EORTC2014,Ab#242)。在临床中,报道了一项Talazoparib和TMZ的I/II期联合临床研究(Wainberg等人,AACR2016,CT011)。在该研究中,起始剂量和方案为Talazoparib0.5mg(D1-28每天一次(QD),Talazoparib批准的单药剂量为1mg QD,连续给药)和TMZ25mg/m2(D1-5,QD),为期28天。最大耐受剂量(MTD)确定为Talazoparib 1mg(D1-28,QD)和TMZ 37.5mg/m2(D1-5,QD,37.5mg/m2等于65.6mg),28天一周期。在非BRCA突变的卵巢癌患者中观察到2例PR(部分缓解)和2例SD,5例黑色素瘤、胆管癌和卵巢癌患者观察到超过200天的研究治疗天数。
据报道,Olaparib联合TMZ治疗小细胞肺癌(SCLC)的I/ll期联合临床研究,RP2D为Olaparib 200mg BID(Olaparib作为单一药物的批准剂量为300或400mg BID)和TMZ 75mg/m2 QD(相当于121.5mg QD),均在21天周期的第1-7天给药(Farago等人,2019,CancerDiscov 9:1372)。确诊的总有效率为41.7%(20/48可评估);中位无进展生存期为4.2个月,中位总生存期为8.5个月。此外,临床试验中患者的PDX模型用于探索Olaparib联合TMZ的多剂量和给药方案,包括间歇、连续、顺序和交替给药。Olaparib剂量分别为25mg/kg和12.5mg/kg BID;TMZ的剂量分别为12.5mg/kg、6.25mg/kg、3.13mg/kg和1.56mg/kg。PDX模型研究结果表明,连续Olaparib联合间歇TMZ是一种良好的人体研究给药方案。正在进行的I/II期临床试验中增加了一个新的持续Olaparib和间歇TMZ队列,其中起始剂量和给药方案为Olaparib 50mg BID连续用D1-21,TMZ 50mg/m2(相当于87.5mg)QD连续D1-7,每21天一周期(Drapkin等人,AACR 2019,摘要4736)。
为了在联合治疗中达到良好的疗效和耐受性,需要更多的研究来确定具有良好捕获活性的PARP抑制剂的合适剂量和给药方案,并联合TMZ等DNA损伤抗癌药物的合适剂量和给药方案来治疗癌症。
发明内容
本发明涉及一种或多种PARP抑制剂,尤其是PCT/CN2012/073362(对应于U.S.9,290,460)所公开的化合物,与DNA损伤类抗癌药物(如TMZ)联合用药,用于治疗癌症。
具体而言,本发明涉及本文式I、II或III所示的一种或多种PARP抑制剂与DNA损伤类抗癌药物,尤其是TMZ的联合用药方案,包括在制备治疗或预防PARP介导的疾病或受益于DNA损伤的疾病的药物中的应用。
本发明还提供一种治疗肿瘤的方法,该方法包括给予需要的对象有效剂量的一剂或多剂本文所述的具有良好PARP捕获活性的PARP抑制剂和一剂或多剂低剂量的DNA损伤类抗癌药,如TMZ。
本发明还提供一剂或多剂具有良好PARP捕获活性的PARP抑制剂与一剂或多剂DNA损伤类抗癌药(如TMZ)的组合,用于治疗癌症。
还提供一种药盒,其含有本文式I、II或III所示的PARP抑制剂的药物制剂与DNA损伤类抗癌药物的药物制剂,尤其是TMZ的药物制剂。在一些实施方案中,药盒中,所述PARP抑制剂的药物制剂中,PARP抑制剂的含量满足所述PARP抑制剂的单用有效日剂量;所述DNA损伤类抗癌药的药物制剂中,所述DNA损伤类抗癌药的含量能提供为该DNA损伤类抗癌药单用或与其它药物或疗法联用时的日剂量的约1/12到约1/5的日剂量。该药盒可含有1剂或多剂所述PARP抑制剂的药物制剂与1剂或多剂所述DNA损伤类抗癌药物的药物制剂,以满足给予患者1天或多天药物,进行1天以上的治疗。应理解,所述1剂可以是1片或多片药片或其它形式的药物制剂,只要该1片药片或多片药片中各活性成分(即PARP抑制剂或DNA损伤类抗癌药物)的总量满足给药剂量要求即可。
在一些实施方案中,所述的药盒含有独立包装的5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮(IMP4297)的药物制剂和替莫唑胺的药物制剂;其中所述5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮的药物制剂中,5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮的含量满足20-120mg的日剂量要求;所述替莫唑胺的药物制剂中,替莫唑胺的含量满足10-30mg的日剂量要求。
本发明还提供一种复方制剂,其含有一剂或多剂本文式I、II或III所示的PARP抑制剂与一剂或多剂DNA损伤类抗癌药物。该复方制剂中所述PARP抑制剂和DNA损伤类抗癌药物的含量如前述药盒方案中所限定。
在一些实施方案中,所述复方制剂含有5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮和替莫唑胺;其中,所述复方制剂中5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮的含量满足20-120mg的日剂量要求,替莫唑胺的含量满足10-30mg的日剂量要求。
还提供5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮和替莫唑胺,或含有这两者的复方制剂,在制备治疗癌症的药物中的应用。
在一个或多个实施方案中,本发明提供了5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1羰基)苄基)喹唑啉-2,4(1H,3H)-二酮(senaparib)和TMZ用于治疗癌症的剂量和给药方案。senaparib的剂量为20-100mg,每天1次,连续28天,TMZ的剂量为10-30mg,每天1次,该28天的周期中连续给予21天。
在一个或多个实施方案中,本发明所述的肿瘤或癌症包括肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、非小细胞肺癌、小细胞肺癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖系统肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和前列腺癌。
具体实施方式
应理解,在本发明范围中,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,从而构成优选的技术方案。
本发明公开了低剂量DNA损伤抗癌药物,如烷基化剂抗癌药物,如TMZ,可诱导DNA损伤,并通过与有效的具有强PARP捕获活性的高剂量PARP抑制剂,如5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮(IMP4297,senaparib)联合形成PARP-DNA复合物。这两种药物的联合具有高的抗癌功效和低毒性。因此,本发明提供了一种治疗癌症的联合用药方法,包括给予有效剂量的一种或多种具有强效PARP捕获活性的PARP抑制剂(特别是IMP4297)和低剂量的一种或多种DNA损伤抗癌药物(如TMZ)。本发明发现,在SCLC的异种移植模型中,连续给予低剂量的TMZ(3mg/kg,每天一次,第1到第21天,据报道TMZ在人类结肠癌SW620异种移植模型中的单用有效剂量是50mg/kg;Keith A.Menear etal.2008,JMC 51:6581)联合IMP4297有效剂量(5mg/kg或10mg/kg,每天一次,第1到第21天,IMP4297在BRCA突变动物模型中的单用有效剂量是2.5-20mg/kg每天,8倍治疗窗口)显示出极强的协同作用,所有药物治疗组体重减轻不超过5%,血液生理学无明显变化。这种低剂量TMZ与有效高剂量IMP4297的联合,每天给药(即连续给药),具有良好的疗效和良好的体内耐受性。相比之下,在采用高剂量Talazoparib联合低剂量TMZ的疗效研究中,在同一SCLC异种移植模型中,采用间歇给药方案(D1-4、D17-20和D28-31),第一次QD4给药后,观察到约10%的体重减轻(Feng等人,EORTC2014,Ab#242)。
基于IMP4297的动物模型研究结果和单药治疗癌症患者的临床研究结果,其显示IMP4297单药治疗癌症患者的临床有效剂量为20-120mg(6倍治疗窗口)QD连续给药(Xu B等,2020ESMO,摘要#1317;Souza P等,2020ESMO,摘要#1338),启动了一项有效高剂量IMP4297与低剂量TMZ的I/II期联合临床研究(ClinicalTrials.gov标识符:NCT04434482),并正在进行中(队列0:IMP4297 40mg+TMZ 10mg;队列1:IMP4297 40mg+TMZ 20mg;队列2:IMP4297 60mg+TMZ 20mg;队列3:IMP4297 80mg+TMZ 20mg;队列4:IMP4297 80mg+TMZ30mg,IMP4297单药的RP2D为100mg QD连续给药)。给药方案为IMP4297 QD连续给药1-28天,TMZ QD连续给药28天周期中的1-21天。初步临床数据表明,不同类型晚期实体瘤患者均有良好的耐受性和疗效。IMP4297联合TMZ的临床研究中,TMZ的剂量和给药方案不同于Olaparib联合TMZ的临床研究,也不同于Talazoparib联合TMZ的临床研究,Olaparib联合TMZ和Talazoparib联合TMZ的临床研究均采用了相对高剂量的TMZ,并采用间歇给药方案。
具有强大的PARP捕获活性、同时具有大的治疗窗口(2.5-20mg/kg QD,在小鼠上有8倍的治疗窗口,20-120mg QD,在人上有6倍的治疗窗口)的有效的高剂量IMP4297(20-100mg QD)与低剂量TMZ(10-30mg QD)的联合,采用IMP4297 QD连续给药1-28天、TMZ QD连续给药28天周期中的1-21天的给药方案,对不同类型晚期实体瘤患者均有良好的耐受性和疗效。在一些实施例中,TMZ的剂量为10-30mg QD,IMP4297的剂量为20-100mg QD,IMP4297的给药方案为QD给药连续28天,TMZ为28天周期中的21天QD连续给药。在一些实施例中,TMZ的剂量为20-30mg QD,IMP4297的剂量为40-100mg QD。在另一个实施例中,TMZ的剂量为20mg QD,IMP4297的剂量为40、60或80mg QD。在另一个实施例中,TMZ的剂量为30mg QD,IMP4297的剂量为80mg QD。在另一个实施例中,TMZ的剂量为10mg QD,IMP4297的剂量为40mg QD。在另一个实施例中,TMZ的剂量为10mg QD,IMP4297的剂量为20mg QD。
由于这种联合方法不依赖于特定的突变才有效,如癌症中的BRCA突变,这种联合的一个优点是它可以用于治疗不同类型的癌症患者。
根据本发明,术语“低剂量”是指由美国食品和药物管理局(FDA)、欧洲药品管理局(EMA)、国家药品监督管理局(NMPA)和制药和医疗器械管理局(PMDA)批准或将批准的DNA损伤药物(如TMZ)的最低推荐剂量的约1/12至约1/5的剂量,如下表所示。
注:*按60公斤成人体表面积1.62平方米换算。
“约”是指所述量的±10%。例如,大约10的意思是9-11,包括9-11。
PARP抑制剂
本发明所述的PARP抑制剂特别包括PCT/CN2012/073362(对应于U.S.9,290,460)所公开的PARP抑制剂,本文将其全文以引用的方式纳入本文。本发明的PARP抑制剂也特别包括授权公告文本CN 103097361 B、授权公告文本CN 104230827 B以及授权公告文本EP 2709 990 B1中获得专利授权的那些化合物,本文将其全文以引用的方式纳入本文。
具体而言,本发明的PARP抑制剂选自下式I所述的化合物,或其药学上可接受的盐、溶剂合物或前药:
式中,
Ar为任选取代的芳基或任选取代的杂芳基;
R1-R6各自独立为氢、卤素、任选取代的氨基、任选取代的烷氧基、任选取代的C1-10烷基(如卤代烷基、羟基烷基、氨基烷基、羧基烷基)、链烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基、羟基酰氨基或任选取代的烷硫基。
优选的式I化合物中Ar为可任选地被取代的苯基、吡啶基或呋喃基。更为优选的Ar为间位有取代羰基或甲基,特别为有取代羰基的苯基、吡啶基或呋喃基。优选的式I化合物中R5和R6都为氢。
在式I化合物的一些优选实施方案中,Ar为间位有取代羰基的苯基、吡啶基或呋喃基,优选为间位有取代羰基的苯基;R1为卤素、NH2、C1-6烷基、硝基或羟基,R2-R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R2为卤素、NH2、C1-6烷基、硝基或羟基,R1、R3-R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R3为卤素、NH2、C1-6烷基、硝基或羟基,R1、R2和R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R4为卤素、NH2、C1-6烷基、硝基或羟基,R1-R3各自独立为氢、卤素、NH2、C1-6烷氧基、C1-6烷基、卤代C1-6烷基、硝基或羟基;R5和R6分别为氢;其中,所述取代羰基为被1个选自以下的取代基取代的羰基:哌嗪基或哌啶基,任选地被1个选自以下的取代基取代:吡啶基,嘧啶基,C3-8环烷基,任选地被1个C3-8环烷基取代的C1-6烷基,任选地被1个或多个选自卤素和C1-6烷氧基取代的苯甲酰基,任选地被1个选自C3-8环烷基、噻吩基、吡啶基、呋喃基和四氢呋喃基的取代基取代的羰基,C1-6烷基磺酰基,苯基,吡嗪基,苯并[d]异噻唑-3-基,任选地被1个或多个卤素取代的苯并异噁唑基,噻唑基,哌啶基和苯氧基。
在一些实施方案中,本发明PARP抑制剂选自下式II所述的化合物,或其药学上可接受的盐、溶剂合物或前药:
式中,
R1-R4各自独立为氢、卤素、任选取代的氨基、任选取代的烷氧基、任选取代的C1-10烷基(如卤代烷基、羟基烷基、氨基烷基、羧基烷基)、链烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基、羟基酰氨基或任选取代的烷硫基;
R7-R10各自独立为氢、卤素、任选取代的氨基、烷氧基、C1-10烷基、卤代烷基、芳基、杂芳基、碳环基、杂环基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、羟基烷氧基、氨基烷基、氨基烷氧基、羧基烷基、羧基烷氧基、硝基、氰基、酰氨基、氨基羰基、羟基、巯基、酰氧基、叠氮基、羧基、羟基酰氨基、烷基磺酰基、氨基磺酰基、二取代烷基氨基磺酰基、烷基亚磺酰基、烷硫基或取代的羰基;
R11为任选取代的氨基、肼基、烷氧基、C1-10烷基、卤代烷基、芳基、杂芳基、碳环基、杂环基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、羟基烷氧基、氨基烷基、氨基烷氧基、羧基烷基、羧基烷氧基、酰氨基、羟基、巯基、酰氧基、羟基酰氨基或烷硫基。
在式II化合物的一些实施方案中,R7、R8、R9和R10各自独立是氢或卤素,特别是氟。优选地或进一步的,式II化合物中,R1和R2各自独立是氢、氟、氯、溴或甲基。优选地或进一步的,式Ⅱ化合物中,R4是氢、氟、甲基、甲氧基或羟基。优选地或进一步的,式II化合物中,R11是取代的氨基,更优选的是取代的哌嗪或哌啶。
在式II化合物的一些优选实施方案中,R1为卤素、NH2、C1-6烷基、硝基或羟基,R2-R4独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R2为卤素、NH2、C1-6烷基、硝基或羟基,R1、R3-R4独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R3为卤素、NH2、C1-6烷基、硝基或羟基,R1、R2和R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R4为卤素、NH2、C1-6烷基、硝基或羟基,R1-R3各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;R7-R10独立为氢、卤素、NH2、C1-6烷氧基、C1-6烷基、卤代C1-6烷基和硝基;R11选自:哌嗪基或哌啶基,任选地被1个选自以下的取代基取代:吡啶基,嘧啶基,C3-8环烷基,任选地被1个C3-8环烷基取代的C1-6烷基,任选地被1个或多个选自卤素和C1-6烷氧基取代的苯甲酰基,任选地被1个选自C3-8环烷基、噻吩基、吡啶基、呋喃基和四氢呋喃基的取代基取代的羰基,C1-6烷基磺酰基,苯基,吡嗪基,苯并[d]异噻唑-3-基,任选地被1个或多个卤素取代的苯并异噁唑基,噻唑基,哌啶基,和苯氧基。
在一些实施方案中,本发明PARP抑制剂选自下式III所述的化合物,或其药学上可接受的盐、溶剂合物或前药:
式中,
R1-R4独立为氢、卤素、任选取代的氨基、任选取代的烷氧基、任选取代的C1-10烷基(如卤代烷基、羟基烷基、氨基烷基、羧基烷基)、链烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基、羟基酰氨基或任选取代的烷硫基;
R7-R10独立为氢、卤素、任选取代的氨基、烷氧基、C1-10烷基、卤代烷基、芳基、杂芳基、碳环基、杂环基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、羟基烷氧基、氨基烷基、氨基烷氧基、羧基烷基、羧基烷氧基、硝基、氰基、酰氨基、氨基羰基、羟基、巯基、酰氧基、叠氮基、羧基、羟基酰氨基、烷基磺酰基、氨基磺酰基、二取代烷基氨基磺酰基、烷基亚磺酰基、烷硫基或取代的羰基;
R12为任选取代的C1-10烷基、卤代烷基、环烷基、芳基、杂芳基、碳环基、杂环基、链烯基、炔基、酰基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、氨基烷基、羧基烷基、烷基羰基、环烷基羰基、芳基羰基、杂芳基羰基、杂环基羰基、氨基羰基、烷基磺酰基、环烷基磺酰基或氨基磺酰基。
在式III化合物的一些实施方案中,R1和R2各自独立选自H、卤素、C1-6烷基和C1-6烷氧基;R3为H;R4选自H、卤素、C1-6烷基、C1-6烷氧基和羟基;R7、R8、R9和R10各自独立是氢或卤素;R12是任选取代的环烷基、芳基、杂芳基、碳环基、杂环基、芳基烷基、杂芳基烷基、碳环烷基、杂环烷基、烷基羰基、环烷基羰基、芳基羰基、杂芳基羰基或杂环基羰基。优选地,R12是任选取代的C3-8环烷基、吡啶基、嘧啶基、苯甲酰基、苯基、哌啶基、噻吩基羰基、呋喃基羰基、哌嗪基或噻唑基。
在式III化合物的一些实施方案中,R12是任选取代的环烷基、芳基、杂芳基、碳环基、杂环基、芳基烷基、杂芳基烷基、碳环烷基、杂环烷基、烷基羰基、环烷基羰基、芳基羰基、杂芳基羰基或杂环基羰基。优选的或进一步的,式III化合物中,R1和R2各自独立选自氢、氟、氯、溴和甲基;R4是氢、氟、甲氧基或羟基;R7、R8、R9和R10各自独立是氢或卤素,特别是氟。优选地,R12是任选取代的C3-8环烷基、吡啶基、嘧啶基、苯甲酰基、苯基、哌啶基、噻吩基羰基、呋喃基羰基、哌嗪基或噻唑基。
在式III化合物的一些优选实施方案中,R1为卤素、NH2、C1-6烷基、硝基或羟基,R2-R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R2为卤素、NH2、C1-6烷基、硝基或羟基,R1、R3-R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R3为卤素、NH2、C1-6烷基、硝基或羟基,R1、R2和R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R4为卤素、NH2、C1-6烷基、硝基或羟基,R1-R3各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;R7-R10各自独立为氢、卤素、C1-6烷氧基或硝基;R12为吡啶基,嘧啶基,C3-8环烷基,任选地被1个C3-8环烷基取代的C1-6烷基,任选地被1个或多个选自卤素和C1-6烷氧基取代的苯甲酰基,任选地被1个选自C3-8环烷基、噻吩基、吡啶基、呋喃基和四氢呋喃基的取代基取代的羰基,C1-6烷基磺酰基,苯基,吡嗪基,苯并[d]异噻唑-3-基,任选地被1个或多个卤素取代的苯并异噁唑基,和噻唑基。优选的,在这些优选实施方案中,R1或R2是氟、氯、溴或甲基;R3是氢、氟、甲基或甲氧基;R4是氢、氟、甲基、甲氧基或羟基;R7,R8、R9或R10是氢或氟。优选的或进一步的,在这些实施方案中,R12是C3-8环烷基、苯基、吡啶基、嘧啶基、或任选地被1个选自C3-8环烷基、噻吩基、吡啶基、呋喃基和四氢呋喃基的取代基取代的羰基。
在式III化合物的一些优选实施方案中,R1为卤素或C1-6烷基,R2为氢、卤素、-NH2或C1-6烷基,R3为氢、卤素、C1-6烷氧基或C1-6烷基,和R4为氢、卤素、羟基、C1-6烷氧基或C1-6烷基;或R1为氢、卤素或C1-6烷基,R2为卤素、-NH2或C1-6烷基,R3为氢、卤素、C1-6烷氧基或C1-6烷基,和R4为氢、卤素、羟基、C1-6烷氧基或C1-6烷基;或R1为氢、卤素或C1-6烷基,R2为氢、卤素、-NH2或C1-6烷基,R3为卤素、C1-6烷氧基或C1-6烷基,和R4为氢、卤素、羟基、C1-6烷氧基或C1-6烷基;或R1为氢、卤素或C1-6烷基,R2为氢、卤素、-NH2或C1-6烷基,R3为氢、卤素、C1-6烷氧基或C1-6烷基,和R4为卤素、羟基、C1-6烷氧基或C1-6烷基;R7-R10独立为氢、卤素、或C1-6烷基;R12为任选地被1、2、3或4个选自卤素和C1-6烷基的取代基取代的C3-8环烷基、C3-8环烷基羰基、吡啶基、嘧啶基、苯甲酰基、苯基、哌啶基、噻吩基羰基、呋喃基或吡嗪基。优选地,在这些优选实施方案中,R1是氟、氯、溴或甲基,R2是氢、氟、氯、溴或甲基,R3是氢、氟、氯或甲基,R4是氢、氟、氯、甲氧基或甲基,R7、R8、R9和R10各自独立是氢或氟;或R2是氟、氯、溴或甲基,R1是氢、氟、氯、溴或甲基,R3是氢、氟、氯或甲基,R4是氢、氟、甲氧基或羟基,R7、R8、R9和R10各自独立是氢或氟;或R4是氟、甲氧基或羟基,R1是氢,氟、氯、溴或甲基,R2是氢、氟、氯、溴或甲基,R3是氢、氟、氯或甲基,R7、R8、R9和R10各自独立是氢或氟。
在式III化合物的一些优选实施方案中,R1为卤素;R2为氢、卤素或C1-6烷基;R3为氢、卤素或C1-6烷基;R4为氢、卤素或C1-6烷基;R7-R10各自独立为氢或卤素;R12为嘧啶基。
本文所述的各基团如烷基、芳基、杂芳基、杂环基、氨基、烷氧基、卤代烷基、链烯基、炔基、酰氨基、酰氧基等的定义以及各基团上的取代基如PCT/CN2012/073362(对应于U.S.9,290,460)所述。
PARP抑制剂包括但不限于:
1-(3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-环己基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-([1,2,4]三唑并[4,3-b]哒嗪-6-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-乙基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(4-氟苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(4-氯苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(4-溴苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(4-甲氧基苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(四氢-2H-吡喃-4-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(乙基磺酰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-乙酰基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-苯基哌啶-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-苯基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡嗪-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-甲氧基羰基苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-羰基-4-氟苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(哌啶-1-基)哌啶-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡啶-4-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(6-氟苯并[d]异恶唑-3-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(呋喃-3-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(噻吩-3-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡啶-3-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡啶-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡啶-4-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-苯氧基哌啶-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(吡嗪-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氯-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮
1-(6-氯-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氯-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氯-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-氯-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-氯-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(5-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(5-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氯-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氯-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(环戊基羰基)哌嗪-1-羰基)呋喃-5-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(苯并[d]异噻唑-3-基)哌嗪-1-羰基)呋喃-5-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(环戊基羰基)哌嗪-1-羰基)吡啶-6-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(吡啶-2-基)哌嗪-1-羰基)吡啶-6-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(嘧啶-2-基)哌嗪-1-羰基)吡啶-6-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(噻唑-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环己基甲基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环戊基甲基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环己基磺酰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-氟-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-氟-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-甲基-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-溴-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-溴-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-溴-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-硝基-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-硝基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-硝基-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(4-甲氧基苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(4-氟苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(4-溴苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-氟-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-甲基-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-氯-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-氯-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(5-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(5-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-环戊基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(5-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氯-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(噻唑-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(噻唑-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(噻唑-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环己基氨基甲酰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮盐酸盐;
5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮盐酸盐;
1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮盐酸盐;
1-(3-((4-(吡啶-2-基)哌嗪-1-基)甲基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(萘-2-基)乙酰氨基苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(3,4-二甲氧基苯基)乙酰氨基苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-([1,2,4]三唑[4,3-a]吡啶-6-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-((2-(4-(嘧啶-2-基)哌嗪-1-羰基)吡啶-6-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-甲氧基苄基氨基甲酰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(3-氯苄基氨基甲酰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(苄基氨基甲酰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-甲氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(5-溴嘧啶-2-氨基甲酰氨基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-三氟甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6,7-亚乙基二氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-甲氧基-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-甲氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(四氢呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-硝基-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-环己基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-苯基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-苯基哌啶-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-溴-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6,7-亚甲基二氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环己基甲基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-氟-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氨基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-氯-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-甲氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-羟基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
或其药学上可接受的盐、溶剂合物或前药。
特别优选的PARP抑制剂是5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮(本文也称为“IMP4297”和“senaparib”)及其药学上可接受的盐、溶剂合物和前药。
本发明中,化合物的药学上可接受的盐的例子包括但不限于无机和有机酸盐,例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐;以及与碱例如钠羟基、三(羟基甲基)氨基甲烷(TRIS,胺丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。
本发明中,化合物的前药的实施例包括含有羧酸的化合物的简单酯(例如依据本领域已知方法通过与C1-4醇缩合而获得的酯);含有羟基的化合物的酯(例如依据本领域已知方法通过与C1-4羧酸、C3-6二酸或其酸酐例如琥珀酸酐和富马酸酐缩合而获得的酯);含有氨基的化合物的亚胺(例如依据本领域已知方法通过与C1-4醛或酮缩合而获得的亚胺);含有氨基的化合物的氨基甲酸酯,例如Leu等人(J.Med.Chem.,42:3623-3628(1999))和Greenwald等人(J.Med.Chem.,42:3657-3667(1999))描述的那些酯;含有醇的化合物的醛缩醇或酮缩醇(例如依据本领域已知方法通过与氯甲基甲基醚或氯甲基乙基醚缩合而获得的那些缩醇)。
可使用本发明PARP抑制剂的溶剂合物,包括但不限于水合物,如二水合物。
DNA损伤类抗癌药物
本发明中,DNA损伤类抗癌药物在一些实施例中为烷化剂类抗癌药。烷化剂的例子包括但不局限于:氮芥N-氧化物、环磷酰胺、异环磷酰胺、硫替派、雷莫司汀(ranimustine)、嘧啶亚硝脲、替莫唑胺、六甲蜜胺、apaziquone、brostallicin、苯达莫司汀、卡莫司汀、雌莫司汀、福莫司汀、葡膦酰胺、马磷酰胺(mafosfamide)、苯达莫司汀(bendamustin)和二溴卫矛醇;铂配位的烷基化化合物,包括但不局限于:顺铂、卡铂、依他铂、乐铂、奈达铂、奥沙利铂和沙铂。
在一些实施方案中,所述烷化剂为具有抗肿瘤活性的咪唑并四嗪类烷化剂,更具体而言,为替莫唑胺(TMZ)。替莫唑胺在体内可自发和很快地降解产生活性代谢物MTIC,从而产生抗肿瘤作用。
已知替莫唑胺可用于治疗神经胶质瘤(如多形性胶质母细胞瘤、间变性星形细胞瘤)、黑色素瘤和淋巴瘤、乳腺癌、肺癌(包括非小细胞肺癌)、难治性垂体腺瘤、胃癌等。
癌症
可采用本发明的方法或组合物或药物制剂治疗的癌症是本领域周知的可用PARP抑制剂治疗以及可用DNA损伤类抗癌药如TMZ治疗的各种癌症,或者可以用PARP抑制剂和DNA损伤抗癌药物如TMZ联合治疗的各种癌症。这些癌症包括但不限于肝癌、黑素瘤(如恶性黑素瘤)、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、原发性脑癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖系统肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌、前列腺癌、神经胶质瘤(如多形性胶质母细胞瘤、间变性星形细胞瘤)和难治性垂体腺瘤等。
在一些实施例中,可以用本发明的方法或组合物或药物制剂治疗的癌症特别包括可用TMZ治疗的癌症,其包括胶质瘤(如多形性胶质母细胞瘤、间变性星形细胞瘤)、黑色素瘤和淋巴瘤、乳腺癌、肺癌(包括非小细胞肺癌)、难治性垂体腺瘤、胃癌等。
在一些实施例中,用本发明的方法或组合物或药物制剂治疗的癌症包括但不限于胰腺癌、子宫内膜癌、卵巢癌、间皮瘤癌、小细胞肺癌、直肠癌和周围神经鞘癌。
治疗方法
本发明的治疗方法包括先后或同时给予需要的治疗对象有效剂量的本发明所述的具有“捕获”功能的PARP抑制剂与非毒性低剂量的DNA损伤类抗癌药如TMZ。先后给药时,对PARP抑制剂和DNA损伤类抗癌药的给药顺序无特殊限制,可先给予PARP抑制剂、间隔一段时间后再给予DNA损伤类抗癌药,也可先给予DNA损伤类抗癌药、间隔一段时间后再给予PARP抑制剂。同时给药包括将同时服用或给予两种药物,或给予其中一种药物后立即给予另一种药物。
本发明中,PARP制剂的有效剂量是指能实现其预期目的的剂量,所述预期目的包括但不限于作为抗癌药自身起到抑制肿瘤生长和/或杀灭癌细胞的作用,以及作为捕获剂捕获TMZ产生的DNA病变,形成DNA-PARP复合物,有效杀死癌细胞来增强TMZ等DNA损伤抗癌药物的抗癌功效。。虽然每个人的需求各不相同,本领域技术人员可确定本发明所用的PARP抑制剂的有效剂量或最佳剂量。一般情况下,对哺乳动物每天口服给药而言,本发明的PARP抑制剂的药量可为约0.0025到50毫克/公斤体重,在一些实施例中,PARP抑制剂的药量为约0.01到20毫克/公斤体重。在一些实施例中,本发明的PARP抑制剂IMP4297单独使用时的临床有效日剂量为20-120mg。在一些实施例中,IMP4297的临床有效日剂量为20-100mg。在一些实施例中,IMP4297的临床有效日剂量为40-80mg,例如40mg、60mg和80mg。在一些实施例中,IMP4297的给药方案为28天周期中的第1-28天QD连续给药。
本文中,DNA损伤类抗癌药如TMZ的“低剂量”通常指日剂量为已知的DNA损伤类抗癌药单用或与其它药物联用时的日剂量的约1/12到约1/5。已知现有的替莫唑胺药物在与放疗联合治疗新诊断的多形性胶质母细胞瘤时,日剂量为75mg/m2(相当于121.5mg),和TMZ在单药治疗中的最低推荐剂量为100mg/m2(相当于162mg)。因此,本发明中,TMZ的“低剂量”通常可在约10mg到约35mg(日剂量)的范围内。在一些实施例中,本发明的DNA损伤抗癌药物TMZ的“低剂量”(每日剂量)为10-30mg。在一些实施例中,TMZ的日剂量为20-30mg。在一些实施例中,TMZ的日剂量为20mg。在一些实施例中,TMZ的日剂量为10mg。在一些实施例中,TMZ的给药方案为28天周期中的第1-21天连续每天一次。在一些实施例中,低剂量为无毒剂量。
在一些实施例中,IMP4297的日剂量为40mg,TMZ的日剂量为20mg。在一些实施例中,IMP4297的日剂量为60mg,TMZ的日剂量为20mg。在一些实施例中,IMP4297的日剂量为80mg,TMZ的日剂量为20mg。在一些实施例中,IMP4297的日剂量为80mg,TMZ的日剂量为30mg。在一些实施例中,IMP4297的日剂量为40mg,TMZ的日剂量为10mg。在一些实施例中,IMP4297的日剂量为20mg,TMZ的日剂量为10mg。
在本发明的用于治疗癌症的方法的一些实施方案中,该方法包括以20-120mg,如20-100mg,如40mg、60mg、80mg或100mg的日剂量口服给予需要的受试者连续28天IMP4297,以及以10-30mg,如10mg、20mg或30mg的日剂量口服给予该受试者连续21天TMZ,以28天为一个周期。在一些实施例中,TMZ在28天周期的第1天至第21天给药。
药盒和复方制剂
本发明的试剂盒包含本文所述的PARP抑制剂的一剂或多剂药物制剂和本文所述的DNA损伤抗癌药物的一剂或多剂药物制剂。在一些实施方案中,本发明的试剂盒包含一剂或多剂IMP4297的药物制剂和一剂或多剂TMZ的药物制剂。在一些实施方案中,本发明的试剂盒包含PARP抑制剂的药物制剂和DNA损伤抗癌药物的药物制剂,其量足以在本文所述的任何给药方案中施用。
本发明的方法或试剂盒中使用的PARP抑制剂和DNA损伤抗癌药物如TMZ可以配制成单独的药物制剂,用于顺序或同时给药。单独使用时,PARP抑制剂的药物制剂应能满足PARP抑制剂有效日剂量的剂量要求。在一些实施方案中,IMP4297的药物制剂应能满足20-120mg/天的剂量要求,TMZ的药物制剂应满足10-30mg/天的剂量要求。换句话说,药物制剂可以配制成多剂(如2个或2个以上胶囊或片剂),但PARP抑制剂或TMZ在其各自的所有药物制剂中的总量应分别满足上述日剂量要求。
本发明的试剂盒能够提供每日40mg剂量的IMP4297和每日20mg剂量的TMZ,或每日60mg剂量的IMP4297和剂量每日20mg的TMZ,或每日80mg剂量的IMP4297和每日20mg剂量的TMZ,或每日80mg剂量的IMP4297和每日30mg剂量的TMZ,或每日40mg剂量的IMP4297和每日10mg剂量的TMZ,或每日20mg剂量的IMP4297和每日10mg剂量的TMZ,或提供IMP4297的日剂量为20-120mg,如20-100mg或40-80mg,和TMZ的日剂量为10-30mg,如10-20mg或20-30mg。在一些实施例中,试剂盒中的一种或多种IMP4297药物制剂和一种或多种TMZ药物制剂的量足以提供IMP4297和TMZ用于至少连续7天,例如至少连续14天或至少连续21天或28天的上述每日剂量中的任何一种。在一些实施例中,试剂盒中一种或多种IMP4297药物制剂和一种或多种TMZ药物制剂的量足以提供IMP4297和TMZ用于至少一个周期,例如2-8个周期,其中一个周期包括连续28天,IMP4297全部28天给药,TMZ连续21天给药。
本发明的药物制剂也可以是同时含有本发明所述有效剂量的具有“捕获”功能的PARP抑制剂与所述非毒性低剂量的DNA损伤类抗癌药的复方制剂。
本发明的药物制剂可以是口服的剂型,如片剂、锭剂和胶囊,以及适合于注射或口服的溶液,包含约0.01%到99%,最好从约0.25%到75%的活性化合物以及辅料。
本发明的药物制剂可通过任何合适的途径给药以达到其预期目的。例如,可以通过肠外、皮下、静脉、肌肉、腹腔内、透皮、口腔、鞘内、颅内、鼻腔或外用途径给药。作为替代或并行地,可以通过口服给药。给药剂量将根据病人的年龄、健康与体重、并行治疗的种类、治疗的频率、以及所需治疗效益来决定。
本发明的药物制剂可用已知的方式制造。例如,由传统的混合、制粒、制锭、溶解、或冷冻干燥过程制造。制造口服制剂时,可结合固体辅料和活性化合物,选择性研磨混合物。如果需要或必要时加入适量助剂后,加工颗粒混合物,获得片剂或锭剂芯。
合适的辅料特别是填料,例如糖类如乳糖或蔗糖、甘露醇或山梨醇;纤维素制剂和/或钙磷酸盐,例如磷酸三钙或磷酸氢钙;以及粘结剂,例如淀粉糊,包括玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如果需要,可增加崩解剂,比如上面提到的淀粉,以及羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或褐藻酸或其盐,如海藻酸钠。辅助剂特别是流动调节剂和润滑剂,例如,硅石、滑石、硬脂酸或其盐,如硬脂酸镁或硬脂酸钙和/或聚乙二醇。如果需要,可以给锭剂核芯提供可以抵抗胃液的合适包衣。为此,可以应用浓缩糖类溶液。这个溶液可以含有阿拉伯树胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛,漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣,可使用适当的纤维素溶液,例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如,用于识别或为了表征活性成分剂量的组合。
其他可口服的药物制剂包括明胶制成的压接式胶囊,以及用明胶和甘油或山梨醇等增塑剂制成的密封软胶囊。该压接式胶囊可含有颗粒形式的活性化合物,与填料例如乳糖;粘结剂例如淀粉;和/或润滑剂例如滑石粉或硬脂酸镁,以及稳定剂混合而成。在软胶囊,活性化合物最好是溶解或悬浮在适当的液体例如油脂或液体石蜡中,其中可加入稳定剂。
合适于肠外给药的制剂包括活性化合物的水溶液,如水溶性盐的溶液和碱性溶液。此外,可施用适当的活性化合物的油性注射悬浮液。合适的亲脂性溶剂或载体包括油脂例如香油,合成脂肪酸酯例如油酸乙酯,或甘油三酯,或聚乙二醇400,或氢化蓖麻油,或环糊精。水性注射悬浮液可含有增加悬浮液黏度的物质,例如羧甲基纤维素钠、山梨醇和/或葡聚糖。也可以含有悬浮稳定剂。
在一些实施方案中,本发明所述PARP抑制剂的药物制剂可以是固体分散体的形式。优选地,本发明的PARP抑制剂的固体分散剂含有无定形5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮和聚合物,其中所述聚合物是羟丙基甲基纤维素乙酸琥珀酸酯或羟丙基甲基纤维素邻苯二甲酸酯,所述聚合物存在的量为50重量%至80重量%,且其中,5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮中少于10重量%为结晶形式。更优选地,本发明的PARP抑制剂的固体分散剂含有无定形5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮和羟丙基甲基纤维素邻苯二甲酸酯(优选为HP-55),所述羟丙基甲基纤维素邻苯二甲酸酯存在的量为50重量%至80重量%、优选71重量%到79重量%,且其中,5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮中少于10重量%为结晶形式。
在进一步的实施方案中,本发明的PARP抑制剂的药物制剂选自:
(1)药物组合物,包含:5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮和羟丙基甲基纤维素邻苯二甲酸酯(优选为HP-55)的无定形固体分散体粉末,其中所述5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮构成所述药物组合物的20~40%wt/wt,所述羟丙基甲基纤维素邻苯二甲酸酯构成所述药物组合物的60~80%wt/wt,其中所述药物组合物是通过喷雾干燥获得的固体分散体;
(2)药物组合物,包含:5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮和羟丙基甲基纤维素邻苯二甲酸酯HP-55的无定形固体分散体粉末,其中,所述5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮构成所述药物组合物的25%wt/wt,所述羟丙基甲基纤维素邻苯二甲酸酯HP-55构成所述药物组合物的75%wt/wt;
(3)药物组合物,包含:5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮和羟丙基甲基纤维素邻苯二甲酸酯HP-55的无定形固体分散体粉末,其中,所述5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮构成所述药物组合物的33%wt/wt,所述聚合物是羟丙基甲基纤维素邻苯二甲酸酯HP-55,构成所述药物组合物的67%wt/wt;和
(4)药物组合物,包含:5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮、羟丙基甲基纤维素邻苯二甲酸酯HP-55和泊洛沙姆,其中所述5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮占药物组合物25%wt/wt,所述羟丙基甲基纤维素邻苯二甲酸酯HP-55构成所述药物组合物的70%wt/wt,和所述泊洛沙姆构成所述药物组合物的5%wt/wt。
适用于本发明的PARP抑制剂的药物制剂,尤其是固体分散剂的更多内容可参见PCT/CN2016/078262,本文将其全部内容以引入的方式纳入本文。
在本发明的一些实施方案中,PARP抑制剂为IMP4297,DNA损伤类抗癌药为TMZ。在一些实施方案中,IMP4297的日剂量为20-120mg,TMZ的日剂量为10-30mg。在一些实施方案中,通过口服的方式先后或同时给予IMP4297和TMZ。两者可分别制备成独立的制剂,或者可制备成同时含有两者的复方制剂。制剂可以含有1剂或多剂药物,只要1剂或多剂药物中的PARP抑制剂和TMZ的含量分别满足本文所述的日剂量要求即可。
在一些实施例中,IMP4297以每天40-80mg的剂量给药,从D1到D28连续给药28天(一个周期),DNA损伤抗癌药物TMZ以每天10-30mg的剂量给药,从D1到D21连续给药21天,而在D22到D28不给药。在一些实施例中,给药周期为28天。
本发明的药物制剂可以给予任何哺乳动物,只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类和兽医动物,虽然本发明不打算如此受限。
用途
在一些实施方案中,提供了一种或多种本文所述的PARP抑制剂,特别是IMP4297,以及一种或多种本文所述的DNA损伤抗癌药物,特别是TMZ,在治疗本文所述的一种或多种癌症的方法中的应用,其中所述方法如本文任一实施方案所述。在一些实施方案中,所述方法包括以20-120mg,如20-100mg,如40mg、60mg、80mg或100mg的日剂量口服给予需要的受试者连续28天IMP4297,以及以10-30mg,如10mg、20mg或30mg的日剂量口服给予该受试者连续21天TMZ,以28天为一个周期。在一些实施例中,TMZ在28天周期的第1天至第21天每天连续施用。
还提供了一种或多种本文所述的PARP抑制剂(特别是IMP4297)和一种或多种本文所述的DNA损伤抗癌药物(特别是TMZ)在制备用于治疗或预防本文所述癌症的药物或试剂盒中的应用。优选地,所述试剂盒如本文任一试剂盒实施方案所述。
优选地,该药物或试剂盒包含PARP抑制剂(特别是IMP4297)的一剂或多剂药物组合物以及DNA损伤抗癌药物(特别是TMZ)的一剂或多剂药物组合物,用于以20-120mg(如20-100mg或40-80mg)的日剂量给予PARP抑制剂(特别是IMP4297)和以约为DNA损伤类抗癌药物单独使用或与其他药物或疗法联合使用时日剂量的约1/12至约1/5的日剂量(例如10-30mg的TMZ)给予DNA损伤抗癌药物(特别是TMZ)。
优选地,所述药物或药盒包含PARP抑制剂尤其是IMP4297的一剂或多剂药物组合物,和DNA损伤抗癌药物特别是TMZ的一剂或多剂药物组合物,用于以20-120mg、如20-100mg或40-80mg的日剂量给予所述PARP抑制剂(尤其是IMP4297)和以10-30mg、如10mg、20mg或30mg的日剂量给予所述DNA损伤类抗癌药(尤其是TMZ)至少连续7天;优选地,给予至少一个周期,其中,一个周期包括连续28天给予所述PARP抑制剂(尤其是IMP4297)和连续21天给予所述DNA损伤类抗癌药(尤其是TMZ)。
下文将以具体实施例的方式阐述本发明。应理解,这些实施例仅仅是阐述性的,并非意图限制本发明的范围。实施例中所用到的材料和方法,除非另有说明,否则为本领域常规的材料和方法。
实施例
实施例1:IMP4297联合TMZ对人小细胞肺癌细胞NCI-H209生长的抑制效应
本实施例采用CCK-8检测法测定IMP4297联合TMZ对人小细胞肺癌细胞NCI-H209增长的抑制作用。将复苏好的人小细胞肺癌细胞NCI-H209接种到培养皿,加入实验培养基(RPMI1640+20%FBS),置于37℃、5% CO2培养箱静置培养。取生长状态良好,汇合度合适的细胞用于实验,800rpm离心5min,弃上清,用新鲜培基重悬,以合适细胞密度接种至96孔细胞培养板,每孔接种190μL细胞悬液。受试化合物(包括IMP4297,TMZ和参考化合物AZD2281)母液用DMSO按1:3和1:10比例分别进行连续系列稀释至10个浓度(最后一个浓度为DMSO阴性对照),每个浓度取5μL加入到120μL培基(25倍稀释),振荡混匀。单独用药:分别加入5μL稀释好的含相应浓度化合物的培基和5μL培基;联合用药:分别加入5μL稀释好的含相应浓度化合物的培基和5μL含终浓度为50μM TMZ的培基。DMSO终浓度为2‰。随后将培养板置于37℃、5% CO2培养箱培养5天。每孔加20μL CCK-8检测试剂,继续培养2小时后,震荡10分钟置于多功能读数仪读取450/650nm波长的吸光值(OD值)。用软件Graph Pad Prism 6.0分析数据,化合物对细胞增殖的抑制活性以细胞存活率和化合物浓度为坐标绘图。细胞存活率%=OD化合物/ODDMSO×100。IC50值以S形剂量反应曲线方程拟合,曲线方程为:Y=100/(1+10^(LogC-LogIC50)),C是化合物浓度。联合用药指数使用CalcuSyn软件计算。
表1汇总了化合物对人小细胞肺癌细胞NCI-H209增长的抑制作用数据(IC50)。表2列出了IMP4297和TMZ联合用药指数(CI)。CI<0.1表示药物联合用极强的协同效应;0.1<CI<1表示药物联合有协同效应,CI>1表示没有协同效应。
表1:化合物对人小细胞肺癌细胞NCI-H209增长的抑制作用数据(IC50)
化合物 | IC50(nM) |
TMZ | >100000 |
IMP4297 | 113.2 |
50μM TMZ+IMP4297 | 6.847 |
AZD2281 | 2176 |
50μM TMZ+AZD2281 | 199.1 |
表2:IMP4297和TMZ联合用药指数(CI)
CIMP4297(nM) | CTMZ(nM) | 细胞存活率% | CI |
0.1 | 50000 | 0.841 | 5.045 |
0.33 | 50000 | 0.8599 | 6.996 |
1 | 50000 | 0.8661 | 7.916 |
10 | 50000 | 0.2685 | 0.062 |
33 | 50000 | 0.139 | 0.065 |
100 | 50000 | 0.1382 | 0.191 |
333 | 50000 | 0.1238 | 0.548 |
因此,经CCK-8检测法测定,结果显示IMP4297与TMZ联用对抑制人小细胞肺癌细胞NCI-H209的增殖有极强的协同效应。
实施例2:IMP4297对MMS处理的DU145细胞中PARP1的捕获作用
使用人前列腺癌DU145细胞进行实验。第一天,将细胞接种到10cm的细胞培养皿中,并在培养箱中保存一夜。次日,在每个培养皿中分别加入溶媒(0.5% DMSO)和含有0.01% MMS的10μM、1μM、0.1μM、0.01μM和0μM的IMP4297或奥拉帕尼。值得注意的是,10%的MMS是由99%的MMS的磷酸盐缓冲盐水(PBS)溶液新鲜制备得到,然后在培养基中稀释至最终浓度(0.01%)。将培养皿振荡混匀,细胞在37℃,5% CO2的培养箱中保存4小时。共制备并测试了12个样品。孵育后,根据亚细胞蛋白分离试剂盒说明书提取核染色体组分。用Pierce(R)BCA Protein Assay Kit(Thermo)检测蛋白浓度,准备蛋白进行western blot检测。螺栓凝胶每孔加载10μg蛋白,然后进行湿转移,用抗PARP抗体(Santa CruzBiotechnology)分别用1:500稀释和1:25000稀释的抗H3抗体在4℃孵育过夜。第二天用TBST冲洗3次,5分钟/次,然后用山羊抗兔IgG-HRP(Santa Cruz Biotechnology)以1:4000的比例稀释,稀释液在室温下孵育1小时。使用ECL Prime Western Blotting Det kit(GE)在膜上显影。利用ImageJ对PARP1波段的灰色密度值进行分析,结果汇总于表3。
表3:IMP4297和Olaparib在DU145细胞中的PARP1捕获作用
本研究在MMS处理的DU145细胞中检测了IMP4297对PARP1核染色体的诱捕作用,并以PARP抑制剂Olaparib作为阳性对照。结果表明,Olaparib对核染色体PARP1的诱捕作用与文献报道一致。IMP4297在0.01~10μM的浓度条件下在核染色体上表现出良好的PARP1诱捕作用。此外,数据显示,在相同浓度和条件下,IMP4297在核染色体上的PARP1诱捕能力出乎意料地强于Olaparib。
实施例3:IMP4297对TMZ处理的HCT116细胞中PARP1的捕获作用
使用大肠癌HCT116细胞进行实验。将指数生长期的细胞胰酶化,以10-20%的密度接种到10cm的细胞培养板上。两天后,当细胞密度达到70-80%时,有含有或不含有1mm TMZ的条件下,将细胞培养基替换为含有溶媒、0.1μM或10μM的IMP4297的新鲜培养基。处理细胞4小时。根据“亚细胞蛋白分离试剂盒培养细胞(Thermo,LOT78840)”方案提取染色质结合蛋白。
采用SDS-PAGE电泳和Western blot检测PARP捕获。提取的染色质结合蛋白样品与5×SDS-PAGE溶液混合,在100℃下加热5min。等量(25-30μg)的蛋白质加载到预先制备的SDS-PAGE凝胶(Genscript SurePAGETM,Bis-Tris,4-20%,15孔M00657)的每个通道上。抗PARP1抗体(ABCAM ab227244)按1:1000稀释,抗组蛋白H3抗体(ABCAM ab1791)按1:5000稀释,抗兔IgG HRP-linked antibody(CST 7074s)按1:2000稀释。用标准Western blot方法检测条带。
利用ImageJ对PARP1波段的灰色密度值进行分析,结果汇总于表4。
表4:IMP4297对TMZ处理的HCT116细胞的PARP1捕获作用
本研究检测了IMP4297对TMZ处理的HCT116细胞核染色体上PARP1的诱捕作用。在TMZ存在的HCT116细胞中,IMP4297在0.1-10μM的核染色体上表现出良好的PARP1捕获作用。
实施例4:IMP4297联合TMZ在NCI-H209人小细胞肺癌裸鼠异种移植瘤模型中的体内药效学研究
评价化合物IMP4297联合TMZ在NCI-H209人小细胞肺癌裸鼠异种移植瘤模型中的抗肿瘤活性。为此目的,将人小细胞肺癌细胞NCI-H209接种于裸鼠右侧腋窝皮下乳腺区。细胞接种量为2×106个对数生长期细胞,接种形成移植瘤后使用。将生长旺盛的肿瘤组织切成1×1×1mm3的小块,接种于每只BALB/c裸鼠的右侧腋窝处乳腺区皮下。当肿瘤平均体积达到约124.08(57.16-280.79)mm3时,根据瘤体积随机分组并开始给药,分组及给药方案见表5。
表5:IMP4297联合TMZ体内药效实验动物分组及给药方案
组别 | N | 化合物治疗 | 剂量(mg/kg) | 给药容积(μL/g) | 给药途径 | 给药方案 |
1 | 10 | 溶媒 | -- | 20 | p.o | QD x21D |
2 | 10 | TMZ | 3mg/kg | 20 | p.o | QD x 21D |
3 | 10 | IMP4297 | 10mg/kg | 20 | p.o | QD x 21D |
4 | 10 | IMP4297+TMZ | 5+3mg/kg | 20 | p.o | QD x 21D |
5 | 10 | IMP4297+TMZ | 10+3mg/kg | 20 | p.o | QD x 21D |
注1:根据裸鼠体重20μL/g给药。
注2:N为动物数,每组10只荷瘤裸鼠;p.o.为口服给药;QD为每天一次;持续服用21天。
注3:溶媒,成分为10% DMSO in 10%HP-β-CD PBS。
注4:溶媒对照组根据体重灌胃给予20μL/g溶媒;TMZ和IMP4297单独给药组先灌胃给予10μL/g的溶媒,然后再灌胃给药10μL/g的药物;联合给药组先灌胃给予10μL/g的TMZ,30min后再灌胃给予10μL/g相应浓度的IMP4297。
分组给药后,裸鼠体重每周称量2次,并记录,体重变化(%)=(Wt-W1)/W1×100%,其中W1为分组给药时(即D1)测量所得体重,Wt为记录当天体重。体重变化(%)是治疗相关毒性的量度(平均体重下降超过15%,治疗停止或方案调整,直至恢复;平均体重下降超过20%,实验终止)。每周用游标卡尺测量2次肿瘤直径(长和宽),计算肿瘤体积(长×宽2/2),及相对肿瘤体积RTV=Vt/V1,其中V1为分组给药时(即D1)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标表示为相对肿瘤增殖率T/C(%)和肿瘤生长抑制率TGI(%)。T/C(%)=TRTV/CRTV×100%,其中TRTV为治疗组RTV,具有低于50的T/C(%)的化合物被定义为有活性(有效);CRTV为溶媒对照组RTV;TGI(%)=[(CVt-CV1)-(TVt-TV1)]/(CVt-CV1)×100%,其中CVt为溶媒对照组记录当天的肿瘤体积,CV1为溶媒对照组分组给药时的肿瘤体积,TVt为给药组记录当天的肿瘤体积,TV1为给药组分组给药时的肿瘤体积。
实验结束后,每组随机选取3只裸鼠,眼眶采集300μL全血到BD K2 EDTA抗凝管(REF367841)中,进行血常规检测。
采用Graph-Pad Prism 6.0软件two-way ANOVA进行各组间肿瘤体积均值及相对肿瘤体积均值的比较。与对照组(溶媒)相比,*p<0.05(有统计学差异),**p<0.01(有显著性统计学差异),***p<0.001(有极显著性统计学差异);与TMZ组相比,#p<0.05(有统计学差异),##p<0.01(有显著性统计学差异),###p<0.001(有极显著性统计学差异);与IMP4297组相比,+p<0.05(有统计学差异),++p<0.01(有显著性统计学差异),+++p<0.001(有极显著性统计学差异)。
实验结果
1、体重
给药期间,与溶媒对照组相比,TMZ单独给药组小鼠体重变化无差异;IMP4297单独给药组在给药后期体重增长稍缓;联合给药组(IMP4297 5mg/kg+TMZ 3mg/kg)给药期间,体重没有增加;联合给药组(IMP4297 10mg/kg+TMZ 3mg/kg)给药期间,平均体重略有下降,但没有超过5%。
2、肿瘤体积
与溶媒对照组相比,TMZ 3mg/kg和IMP4297 10mg/kg单独给药组对肿瘤的增殖没有明显的抑制作用,而联合给药对肿瘤增殖具有极显著的抑制作用(p<0.0001);与单独给药组相比,两个联合给药组都显示了TMZ和IMP4297联用有显著的协同作用(p<0.0001)。IMP4297 10mg/kg和TMZ 3mg/kg联合给药组肿瘤体积与0天相比有下降。
3、抗肿瘤活性的评价指标
实验期间各组相对肿瘤增殖率[T/C(%)]和肿瘤生长抑制率[TGI(%)]如下表6所示。
表6:抗肿瘤活性的评价指标
注1:与对照组(vehicle)相比,*p<0.05,**p<0.01,***p<0.001,****p<0.0001;
与TMZ组相比,#p<0.05,##p<0.01,###p<0.001,####p<0.0001;
与IMP4297组相比,+p<0.05,++p<0.01,+++p<0.001,++++p<0.0001。
注2:平均体重变化(%):与治疗开始时的初始体重相比的各组裸鼠的体重变化(%)平均值。
4、血常规检测结果
实验结束时,每组取3只小鼠进行血常规检测。所有药物组的红细胞没有明显减少,在正常范围内;血小板变化不大,联合用药组略有升高。所有给药组都出现了白细胞的减少。联合药物组的减少较明显,但还是在合理范围内,对动物的毒性影响有限。
综上所述,IMP4297联合TMZ每天给药一次,连续给药21天,对NCI-H209人小细胞肺癌裸鼠异种移植瘤模型表现出极显著的抗肿瘤效果,且具有明显的协同作用,同时高剂量联合给药组体重仅有轻微下降,没有观察到明显的血液学生理变化。
实施例5:IMP4297联合替莫唑胺治疗晚期实体瘤的Ib/II期临床试验
方法:
晚期实体瘤患者采用IMP4297(连续1-28天QD给药)联合TMZ(28天周期中连续1-21天QD给药,第22-28天停药)治疗(ClinicalTrials.gov Identifier:NCT04434482)。
结果:
7例患者被纳入3个队列(队列1:IMP4297 40mg+TMZ 20mg,1例患者;队列2:IMP4297 60mg+TMZ 20mg,3例患者;队列3:IMP4297 80mg+TMZ 20mg,3例患者),包括胰腺癌(1例)、子宫内膜癌(1例)、卵巢癌(1例)、间皮瘤(1例)、小细胞肺癌(1例)、直肠癌(1例)和周围神经鞘癌(1例)。在这7例患者中未报道剂量限制性毒性(DLT)。临床试验正在进行中,IMP4297联合替莫唑胺的最大耐受剂量(MTD)和II期推荐剂量(RP2D)尚未确定。
所有7例患者均可进行肿瘤评估。队列1中有1例患者出现部分缓解(PR);队列2中3例患者疾病稳定(SD)(1例患者因非治疗相关原因在一次肿瘤评估后退出研究);在队列3中,1例患者PR,1例患者SD和1例患者进展性疾病(PD,新病变,退出研究)。结果如下:
·在队列1中纳入的胰腺癌患者中确诊了1例PR。该患者在一线治疗后出现PR,但不能耐受治疗。目标病灶开始消退,非目标病灶在治疗2个周期后消失。6个治疗周期后观察到PR,8个治疗周期后观察到确定的PR(目标疾病减少43.3%)。该患者目前正在接受治疗,第12周期持续响应。
·在队列2中纳入的晚期子宫内膜癌患者中观察到1例SD。该患者接受了大量的预处理,并接受了至少4线化疗和/或免疫治疗。目标病灶在2个周期治疗后开始消退,8个周期治疗后减少28.8%。病人现在正在第10周期的治疗中。
·在队列2中纳入的晚期卵巢癌患者中观察到1例SD。该患者既往至少接受过3次化疗。4个周期治疗后,目标病灶减少20%。病人现在正在第9周期的治疗中。
·在队列3中纳入的小细胞肺癌患者中观察到1例PR。2个治疗周期后,目标病灶开始消退(减少27%),4个治疗周期后,目标病变开始消退(减少38.5%)。病人现在正在第5周期的治疗中。
·队列3中纳入的直肠癌患者中观察到1例SD。患者目前正在第五个治疗周期中,患者疾病稳定。
7例患者共报告23例不良事件(AEs),其中16例为治疗紧急不良事件(TEAEs)。16个TEAEs中有5个被判定与研究药物有关。最常见的TAEA为血液学毒性,包括1例贫血(3级),1例全血细胞减少(2级)。
结论:
结果表明,在具有不同晚期实体瘤患者中,高剂量IMP4297联合低剂量替莫唑胺采用连续给药方案有很好的耐受性(长时间的治疗以及响应时间,7例患者中,一个病人已经接受了11个周期治疗,1个已经接受了9周期治疗和1个已经接受了8周期治疗,2个已经接受了4周期治疗)和良好的药效(7例患者中,有2例PR,及3例SD伴随肿瘤消退)。结果证实这是一个有潜力的联合治疗方案,在各种癌症患者中这种联合的进一步研究正在进行中。
Claims (15)
2.如权利要求1所述的应用,其特征在于,所述PARP抑制剂选自下式II所述的化合物,或其药学上可接受的盐、溶剂合物或前药:
式中,
R1-R4各自独立为氢、卤素、任选取代的氨基、任选取代的烷氧基、任选取代的C1-10烷基(如卤代烷基、羟基烷基、氨基烷基、羧基烷基)、链烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基、羟基酰氨基或任选取代的烷硫基;
R7-R10各自独立为氢、卤素、任选取代的氨基、烷氧基、C1-10烷基、卤代烷基、芳基、杂芳基、碳环基、杂环基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、羟基烷氧基、氨基烷基、氨基烷氧基、羧基烷基、羧基烷氧基、硝基、氰基、酰氨基、氨基羰基、羟基、巯基、酰氧基、叠氮基、羧基、羟基酰氨基、烷基磺酰基、氨基磺酰基、二取代烷基氨基磺酰基、烷基亚磺酰基、烷硫基或取代的羰基;
R11为任选取代的氨基、肼基、烷氧基、C1-10烷基、卤代烷基、芳基、杂芳基、碳环基、杂环基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、羟基烷氧基、氨基烷基、氨基烷氧基、羧基烷基、羧基烷氧基、酰氨基、羟基、巯基、酰氧基、羟基酰氨基或烷硫基。
3.如权利要求1所述的应用,其特征在于,所述PARP抑制剂选自下式III所述的化合物,或其药学上可接受的盐、溶剂合物或前药:
式中,
R1-R4独立为氢、卤素、任选取代的氨基、任选取代的烷氧基、任选取代的C1-10烷基(如卤代烷基、羟基烷基、氨基烷基、羧基烷基)、链烯基、炔基、硝基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、羧基、亚乙基二氧基、羟基酰氨基或任选取代的烷硫基;
R7-R10独立为氢、卤素、任选取代的氨基、烷氧基、C1-10烷基、卤代烷基、芳基、杂芳基、碳环基、杂环基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、羟基烷氧基、氨基烷基、氨基烷氧基、羧基烷基、羧基烷氧基、硝基、氰基、酰氨基、氨基羰基、羟基、巯基、酰氧基、叠氮基、羧基、羟基酰氨基、烷基磺酰基、氨基磺酰基、二取代烷基氨基磺酰基、烷基亚磺酰基、烷硫基或取代的羰基;
R12为任选取代的C1-10烷基(如卤代烷基、芳基烷基、杂芳基烷基、碳环烷基、杂环烷基、羟基烷基、氨基烷基、羧基烷基)、环烷基、芳基、杂芳基、碳环基、杂环基、链烯基、炔基、酰基、芳基链烯基、芳基炔基、杂芳基链烯基、杂芳基炔基、烷基羰基、环烷基羰基、芳基羰基、杂芳基羰基、杂环基羰基、氨基羰基、烷基磺酰基、环烷基磺酰基或氨基磺酰基。
4.如权利要求3所述的应用,其特征在于,
所述式III中,R1和R2各自独立选自H、卤素、C1-6烷基和C1-6烷氧基;R3为H;R4选自H、卤素、C1-6烷基、C1-6烷氧基和羟基;R7、R8、R9和R10各自独立是氢或卤素;R12是任选取代的环烷基、芳基、杂芳基、碳环基、杂环基、芳基烷基、杂芳基烷基、碳环烷基、杂环烷基、烷基羰基、环烷基羰基、芳基羰基、杂芳基羰基或杂环基羰基;优选地,R12是任选取代的C3-8环烷基、吡啶基、嘧啶基、苯甲酰基、苯基、哌啶基、噻吩基羰基、呋喃基羰基、哌嗪基或噻唑基;或
所述式III中,R1和R2各自独立选自氢、氟、氯、溴和甲基;R4是氢、氟、甲氧基或羟基;R7、R8、R9和R10各自独立是氢或卤素;R12是任选取代的C3-8环烷基、吡啶基、嘧啶基、苯甲酰基、苯基、哌啶基、噻吩基羰基、呋喃基羰基、哌嗪基或噻唑基;或
所述式III中,R1为卤素、NH2、C1-6烷基、硝基或羟基,R2-R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R2为卤素、NH2、C1-6烷基、硝基或羟基,R1、R3-R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R3为卤素、NH2、C1-6烷基、硝基或羟基,R1、R2和R4各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;或R4为卤素、NH2、C1-6烷基、硝基或羟基,R1-R3各自独立为氢、卤素、NH2、C1-6烷基、硝基或羟基;R7-R10各自独立为氢、卤素、C1-6烷氧基或硝基;R12为吡啶基,嘧啶基,C3-8环烷基,任选地被1个C3-8环烷基取代的C1-6烷基,任选地被1个或多个选自卤素和C1-6烷氧基取代的苯甲酰基,任选地被1个选自C3-8环烷基、噻吩基、吡啶基、呋喃基和四氢呋喃基的取代基取代的羰基,C1-6烷基磺酰基,苯基,吡嗪基,苯并[d]异噻唑-3-基,任选地被1个或多个卤素取代的苯并异噁唑基,和噻唑基;或
所述式III中,R1为卤素或C1-6烷基,R2为氢、卤素、-NH2或C1-6烷基,R3为氢、卤素、C1-6烷氧基或C1-6烷基,和R4为氢、卤素、羟基、C1-6烷氧基或C1-6烷基;或R1为氢、卤素或C1-6烷基,R2为卤素、-NH2或C1-6烷基,R3为氢、卤素、C1-6烷氧基或C1-6烷基,和R4为氢、卤素、羟基、C1-6烷氧基或C1-6烷基;或R1为氢、卤素或C1-6烷基,R2为氢、卤素、-NH2或C1-6烷基,R3为卤素、C1-6烷氧基或C1-6烷基,和R4为氢、卤素、羟基、C1-6烷氧基或C1-6烷基;或R1为氢、卤素或C1-6烷基,R2为氢、卤素、-NH2或C1-6烷基,R3为氢、卤素、C1-6烷氧基或C1-6烷基,和R4为卤素、羟基、C1-6烷氧基或C1-6烷基;R7-R10独立为氢、卤素、或C1-6烷基;R12为任选地被1、2、3或4个选自卤素和C1-6烷基的取代基取代的C3-8环烷基、C3-8环烷基羰基、吡啶基、嘧啶基、苯甲酰基、苯基、哌啶基、噻吩基羰基、呋喃基或吡嗪基;或
所述式III中,R1为卤素;R2为氢、卤素或C1-6烷基;R3为氢、卤素或C1-6烷基;R4为氢、卤素或C1-6烷基;R7-R10各自独立为氢或卤素;R12为嘧啶基;或
所述式III中,R1是氟、氯、溴或甲基,R2是氢、氟、氯、溴或甲基,R3是氢、氟、氯或甲基,R4是氢、氟、氯、甲氧基或甲基,R7、R8、R9和R10各自独立是氢或氟;或
所述式III中,R2是氟、氯、溴或甲基,R1是氢、氟、氯、溴或甲基,R3是氢、氟、氯或甲基,R4是氢、氟、甲氧基或羟基,R7、R8、R9和R10各自独立是氢或氟;或
所述式III中,R4是氟、甲氧基或羟基,R1是氢,氟、氯、溴或甲基,R2是氢、氟、氯、溴或甲基,R3是氢、氟、氯或甲基,R7、R8、R9和R10各自独立是氢或氟。
5.如权利要求1所述的应用,其特征在于,所述PARP抑制剂选自:
1-(3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-环己基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-([1,2,4]三唑并[4,3-b]哒嗪-6-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-乙基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(4-氟苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(4-氯苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(4-溴苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(4-甲氧基苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(四氢-2H-吡喃-4-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(乙基磺酰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-乙酰基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-苯基哌啶-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-苯基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡嗪-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-甲氧基羰基苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-羰基-4-氟苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(哌啶-1-基)哌啶-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡啶-4-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(6-氟苯并[d]异恶唑-3-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(呋喃-3-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(噻吩-3-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡啶-3-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡啶-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(吡啶-4-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-苯氧基哌啶-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(吡嗪-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氯-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮
1-(6-氯-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氯-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(6-氯-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-氯-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-氯-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(5-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(5-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氯-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氯-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(环戊基羰基)哌嗪-1-羰基)呋喃-5-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(苯并[d]异噻唑-3-基)哌嗪-1-羰基)呋喃-5-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(环戊基羰基)哌嗪-1-羰基)吡啶-6-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(吡啶-2-基)哌嗪-1-羰基)吡啶-6-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-((2-(4-(嘧啶-2-基)哌嗪-1-羰基)吡啶-6-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(噻唑-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环己基甲基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环戊基甲基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环己基磺酰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-氟-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-氟-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-甲基-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲基-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-溴-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-溴-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-溴-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-硝基-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-硝基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-硝基-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(4-甲氧基苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(4-氟苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(4-溴苯甲酰)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-氟-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(环己基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-甲基-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-氯-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-氯-1-(3-(4-(环戊基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(噻吩-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氯-1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(6-氟-3-(4-(吡啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氯-1-(5-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(5-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-环戊基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(环丙基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-苯甲酰哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氟-3-(4-(环丁基羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(5-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(6-氯-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-(4-氟-3-(4-(噻唑-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(噻唑-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(噻唑-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(4-(环己基氨基甲酰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮盐酸盐;
5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮盐酸盐;
1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮盐酸盐;
1-(3-((4-(吡啶-2-基)哌嗪-1-基)甲基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(萘-2-基)乙酰氨基苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-(3,4-二甲氧基苯基)乙酰氨基苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(3-([1,2,4]三唑[4,3-a]吡啶-6-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氟-1-((2-(4-(嘧啶-2-基)哌嗪-1-羰基)吡啶-6-基)甲基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-甲氧基苄基氨基甲酰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(3-氯苄基氨基甲酰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(苄基氨基甲酰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-甲氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-甲氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(5-溴嘧啶-2-氨基甲酰氨基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-三氟甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6,7-亚乙基二氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(6-甲氧基-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
7-甲氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(四氢呋喃-2-羰基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-硝基-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-环己基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-苯基哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-苯基哌啶-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-溴-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6,7-亚甲基二氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
5-氟-1-(4-氟-3-(4-(环己基甲基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-氟-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
6-氨基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
1-(2-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-氯-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-甲基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-甲氧基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
8-羟基-1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮;
或其药学上可接受的盐、溶剂合物或前药。
6.如权利要求1所述的应用,其特征在于,所述DNA损伤类抗癌药为烷化剂类抗癌药,优选选自:氮芥N-氧化物、环磷酰胺、异环磷酰胺、硫替派、雷莫司汀、嘧啶亚硝脲、替莫唑胺、六甲蜜胺、apaziquone、brostallicin、苯达莫司汀、卡莫司汀、雌莫司汀、福莫司汀、葡膦酰胺、马磷酰胺、苯达莫司汀、二溴卫矛醇、顺铂、卡铂、依他铂、乐铂、奈达铂、奥沙利铂和沙铂;优选地,所述烷化剂为具有抗肿瘤活性的咪唑并四嗪类烷化剂,更优选为替莫唑胺。
7.如权利要求1所述的应用,其特征在于,所述药物或试剂盒包含所述PARP抑制剂(尤其是5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮,IMP4297,senaparib)的一剂或多剂药物组合物和所述DNA损伤类抗癌药(尤其是TMZ)的一剂或多剂药物组合物,用于以20-120mg、如20-100mg或40-80mg的日剂量给予所述PARP抑制剂,尤其是IMP4297,以及用于以单独使用或与其他药物或疗法联合使用时的日剂量的约1/12到约1/5的日剂量给予所述DNA损伤类抗癌药(尤其是TMZ),如10-30mg的TMZ。
8.如权利要求1-7中任一项所述的应用,其特征在于,所述药物或试剂盒包含所述PARP抑制剂(尤其IMP4297)的一剂或多剂药物组合物和所述DNA损伤类抗癌药(尤其是TMZ)的一剂或多剂药物组合物,用于以20-120mg、如20-100mg或40-80mg或20mg、40mg、60mg、80mg或100mg的日剂量给予所述PARP抑制剂(尤其是IMP4297)和以10-30mg、如10mg、20mg或30mg的日剂量给予所述DNA损伤类抗癌药(尤其是TMZ)至少连续7天;优选地,给予至少一个周期,其中,一个周期包括连续28天给予所述PARP抑制剂(尤其是IMP4297)和连续21天给予所述DNA损伤类抗癌药(尤其是TMZ)。
9.如权利要求7所述的应用,其特征在于,所述治疗包括每天给予IMP4297一次,日剂量为20、40、60或80mg,连续28天,和每天给予TMZ一次,日剂量为10、20或30mg,连续21天,为期28天,为一个周期。
10.如权利要求1-9中任一项所述的应用,其特征在于,所述癌症选自:肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、非小细胞肺癌、小细胞肺癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖系统肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和前列腺癌。
11.一种药盒,其含有一剂或多剂PARP抑制剂的药物制剂和一剂或多剂DNA损伤类抗癌药的药物制剂;其中,所述PARP抑制剂的药物制剂和DNA损伤类抗癌药的药物制剂为独立包装,其中,所述PARP抑制剂的药物制剂中,PARP抑制剂的含量能提供所述PARP抑制剂的单用有效日剂量;所述DNA损伤类抗癌药的药物制剂中,所述DNA损伤类抗癌药的含量能提供为该DNA损伤类抗癌药单用或与其它药物或疗法联用时的日剂量的约1/12到约1/5的日剂量;优选地,所述PARP抑制剂如权利要求1-5中任一项所述,所述DNA损伤类抗癌药如权利要求6所述;更优选地,所述PARP抑制剂为5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮(IMP4297,senaparib),和所述DNA损伤类抗癌药为替莫唑胺(TMZ)。
12.如权利要求11所述的药盒,其特征在于,其含有5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮的一剂或多剂药物制剂和替莫唑胺的一剂或多剂药物制剂;其中所述5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮的药物制剂中,5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮的含量满足20-120mg、如20-100mg或40-80mg的日剂量要求;所述替莫唑胺的药物制剂中,替莫唑胺的含量满足10-30mg的日剂量要求。
13.如权利要求10-12中任一项所述的药盒,其特征在于,所述药盒含有IMP4297的一剂或多剂药物制剂和TMZ的一剂或多剂药物制剂,以提供日剂量为40mg的IMP4297和日剂量为20mg的TMZ,或日剂量为60mg的IMP4297和日剂量为20mg的TMZ,或日剂量为80mg的IMP4297和日剂量为20mg的TMZ,或日剂量为80mg的IMP4297和日剂量为30mg的TMZ,或日剂量为40mg的IMP4297和日剂量为10mg的TMZ,或日剂量为20mg的IMP4297和日剂量为10mg的TMZ;或提供日剂量为20-120mg,如20-100mg或40-80mg的IMP4297,和日剂量为10-30mg,如10-20mg或20-30mg的TMZ;优选地,药盒中IMP4297的一剂或多剂药物制剂和TMZ的一剂或多剂药物制剂的量足够提供IMP4297和TMZ至少连续7天,如至少连续14天,至少连续21天,或28天;更优选地,药盒中IMP4297的一剂或多剂药物制剂和TMZ的一剂或多剂药物制剂的数量足够提供至少一个周期,如2-8个周期的IMP4297和TMZ的给药,其中一个周期包括连续28天,其中,IMP4297给药全部28天,TMZ连续给药21天。
14.一种复方制剂,其含有5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮和替莫唑胺;其中,所述复方制剂中5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2,4(1H,3H)-二酮的含量满足20-120mg的日剂量要求,替莫唑胺的含量满足10-30mg的日剂量要求。
15.如权利要求11-13中任一项所述药盒或权利要求14所述的复方制剂在制备治疗癌症的药物中的应用;优选地,所述癌症选自:肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、非小细胞肺癌、小细胞肺癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖系统肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和前列腺癌。
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