CN111542513A - 用于预防或治疗急性髓性白血病或转移性乳腺癌的药物组合物 - Google Patents
用于预防或治疗急性髓性白血病或转移性乳腺癌的药物组合物 Download PDFInfo
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- CN111542513A CN111542513A CN201880084849.8A CN201880084849A CN111542513A CN 111542513 A CN111542513 A CN 111542513A CN 201880084849 A CN201880084849 A CN 201880084849A CN 111542513 A CN111542513 A CN 111542513A
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- imino
- ethoxy
- biindolinylidene
- dihydrochloride
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- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims abstract 3
- -1 nitro, carboxyl Chemical group 0.000 claims description 201
- 230000002401 inhibitory effect Effects 0.000 claims description 35
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
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Classifications
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- 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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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
本发明涉及一种用于预防或治疗急性髓性白血病或转移性乳腺癌的药物组合物,其包含靛玉红衍生物作为活性成分。当使用本发明的化合物时,它可有效地抑制FLT3激酶的活性,并可有效地用于预防或治疗急性髓性白血病或转移性乳腺癌。
Description
技术领域
本发明涉及用于预防或治疗急性髓性白血病或转移性乳腺癌的药物组合物,其包含作为活性成分的靛玉红衍生物。
背景技术
FMS-样酪氨酸激酶-3(FLT-3),一种属于III型RTK家族的受体酪氨酸激酶(RTK),在造血细胞的存活和增殖中起重要作用[1]。FLT3的激活通过基质细胞表达的FLT3配体与受体的结合而启动。结果,FLT3受体二聚化和自磷酸化触发下游信号传导途径,其分类为PI3K/AKT、RAS/MAPK和STAT5信号传导途径[2]。FLT3受体在70-100%AML细胞中以高水平表达。FLT3在白血病中的重要性已经得到了充分的研究,FLT3突变的群体据报道在所有AML患者中大约1/3[3]。迄今为止已经鉴定了两种主要类型的FLT3突变:近膜区域中的内部串联重复(ITD)突变和激酶结构域中的点突变[4]。这些突变在化疗失败和复发中具有不利的预后影响[5-8]。另外,最近的研究表明FLT3-ITD突变代表AML进展的驱动突变和AML中的有效治疗靶标[9-10]。因此,许多研究人员和制药公司试图寻找FLT3抑制剂作为AML的潜在治疗剂。
已经报道了靶向FLT3的几种临床候选物,包括来他替尼[11]、米哚妥林[12]、坦度替尼[13]、索拉非尼[14]、KW-2449[15]和奎扎替尼[16]。其中,来他替尼和米哚妥林是吲哚并咔唑衍生物和公知的多靶点酪氨酸激酶抑制剂。作为哌嗪基-喹唑啉化合物的坦度替尼抑制FLT3以及c-kit和PDGFR。这些抑制剂中的大多数通过抑制FLT3-ITD突变而从它们靶向其它激酶的初始目的又重新定向到AML。此外,已经发现作为FLT3抑制剂、用作乳腺癌治疗剂的帕博西尼在治疗AML患者中是有效的,因此可以判断FLT3抑制剂不仅可以用于乳腺癌而且可以用于急性髓性白血病。
除了奎扎替尼之外,似乎大多数现在的FLT3抑制剂不令人信服,主要是因为它们的效力和靶选择性低[17-20]。因此,目前强烈需要开发强效的FLT3激酶抑制剂。
在本说明书中引用了许多论文和专利文献,并且指出了它们的引用。所引用的论文和专利文献的内容通过引用整体并入本文,作为参考,并且将更清楚地描述本发明所属的技术领域的水平和本发明的内容。
[现有技术文献]
[非专利文献]
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公开内容
技术问题
本发明人已进行了大量的努力以发现具有FLT3激酶抑制能力的新化合物。结果是,本发明人已经确认了预定的靛玉红衍生化合物能够有效地抑制FLT3激酶,从而完成本发明。
因此,本发明的一个目的是提供具有FLT3抑制能力的新化合物、其药学上可接受的盐、溶剂化物或水合物。
本发明的另一个目的是提供用于预防或治疗急性髓性白血病的药物组合物。
本发明的再一个目的是提供用于预防或治疗转移性乳腺癌的药物组合物。
本发明的其它目的和优点从详细描述以及所附权利要求和附图中明显显示出来。
技术方案
根据本发明的一个方面,本发明提供了由以下化学式1表示的化合物、其药学上可接受的盐、溶剂化物或水合物:
[化学式1]
本发明人已进行了大量的努力来开发新颖的FLT3激酶抑制剂,且因此,已确认预定的靛玉红衍生化合物能够有效地抑制FLT3激酶。
在本发明的一个具体实施方案中,本发明的R2为C1-C4烷基酯。本发明的一个具体实施方案的C1-C4烷基酯中包含的C1-C4烷基取代基包括直链或支链C1-C4烷基,具体地,其可以是例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。当本发明的R2是化合物的烷基酯取代基而不是化合物的羧基取代基时,它对FLT3激酶具有较小的IC50值,因此可更有效地抑制FLT3激酶。
在本发明的一个具体实施方案中,本发明的R2为卤素。具体地,卤素可以是氟、氯、溴或碘。
在本发明的一个具体实施方案中,本发明的R2为被卤素取代或未取代的C1-C4烷氧基。本发明一个具体实施方案的C1-C4烷氧基中包含的C1-C4烷基取代基包括直链或支链C1-C4烷基,具体地,其可以是例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。具体地,被卤素取代的C1-C4烷氧基可以是C1-C4烷氧基氟化物,更具体地为三氟甲氧基。
在本发明的一个具体实施方案中,本发明的C1-C4烷基酯是甲酯。
在本发明的一个具体实施方案中,由本发明的化学式表示的化合物可以选自以下化合物中的任一个:(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基(biindolinylidene)]-5’-甲酸甲酯二盐酸盐(化合物4)、(2Z,3E)-3-(羟基亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物1)、(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物2)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物3)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐(化合物5)、(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物6)、(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸(化合物8)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸盐酸盐(化合物9)、(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物10)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物11)、(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸酯盐酸盐(化合物12)、(2Z,3E)-5-羟基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物14)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物15)、(2Z,3E)-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物16)、(2Z,3E)-5-氟-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物17)、(2Z,3E)-5-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物18)、(2Z,3E)-5-氟-5’-硝基-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物19)、(2Z,3E)-5-氟-5’-硝基-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物20)、(2Z,3E)-5,5’-二氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物21)、(2Z,3E)-5,5’-二氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物22)、(2Z,3E)-5,5’-二氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物23)、(2Z,3E)-5,5’-二氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物24)、(2Z,3E)-3-((2-(4-氨基哌啶-1-基)乙氧基)亚氨基)-5,5’-二氟-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物25)、(2Z,3E)-5,5’-二氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物26)、(2Z,3E)-5,5’-二氟-3-((2-吗啉代乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物27)、(2Z,3E)-5’-氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物33)、(2Z,3E)-5’-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物34)、(2Z,3E)-5’-氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物35)、(2Z,3E)-5’-氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物36)、(2Z,3E)-5’-氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物37)、(2Z,3E)-5’-氯-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物38)、(2Z,3E)-5’-氯-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物39)、(2Z,3E)-5’-溴-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物40)、(2Z,3E)-5’-溴-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物41)、(2Z,3E)-5’-碘-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物42)、(2Z,3E)-5’-碘-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物43)、(2Z,3E)-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物44)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物45)、(2Z,3E)-5’-甲氧基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物46)和(2Z,3E)-5’-甲氧基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物47)。
在本发明的一个具体实施方案中,本发明化学式1表示的化合物对FLT3抑制而言的IC50值可以是100nM或更低。更加尤其是,由化学式1表示的化合物可以具有50nM或更低,甚至更加尤其是40nM或更低,甚至更加尤其是35nM或更低,甚至更加尤其是30nM或更低,甚至更加尤其是25nM或更低,甚至更加尤其是20nM或更低,甚至更加尤其是15nM或更低,并且甚至更加尤其是10nM或更低的对于FLT3抑制而言的IC50值。
根据本发明的另一个方面,本发明提供了用于预防或治疗急性髓性白血病或转移性乳腺癌的药物组合物,其包括:(a)由以下化学式1表示的化合物、其药学上可接受的盐、溶剂化物或水合物;和(b)药学上可接受的载体:
[化学式1]
根据本发明的一个实施方案,由化学式1表示的化合物可以是选自以下化合物中的任一个:(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐(化合物4)、(2Z,3E)-3-(羟基亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物1)、(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物2)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物3)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐(化合物5)、(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物6)、(2Z,3E)-3-(羟基亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸(化合物7)、(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸(化合物8)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸盐酸盐(化合物9)、(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物10)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物11)、(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸酯盐酸盐(化合物12)、(2Z,3E)-5-羟基-3-(羟基亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮(化合物13)、(2Z,3E)-5-羟基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物14)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物15)、(2Z,3E)-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物16)、(2Z,3E)-5-氟-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物17)、(2Z,3E)-5-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物18)、(2Z,3E)-5-氟-5’-硝基-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物19)、(2Z,3E)-5-氟-5’-硝基-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物20)、(2Z,3E)-5,5’-二氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物21)、(2Z,3E)-5,5’-二氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物22)、(2Z,3E)-5,5’-二氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物23)、(2Z,3E)-5,5’-二氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物24)、(2Z,3E)-3-((2-(4-氨基哌啶-1-基)乙氧基)亚氨基)-5,5’-二氟-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物25)、(2Z,3E)-5,5’-二氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物26)、(2Z,3E)-5,5’-二氟-3-((2-吗啉代乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物27)、(2Z,3E)-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物28)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物29)、(2Z,3E)-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物30)、(2Z,3E)-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物31)、(2Z,3E)-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物32)、(2Z,3E)-5’-氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物33)、(2Z,3E)-5’-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物34)、(2Z,3E)-5’-氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物35)、(2Z,3E)-5’-氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物36)、(2Z,3E)-5’-氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物37)、(2Z,3E)-5’-氯-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物38)、(2Z,3E)-5’-氯-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物39)、(2Z,3E)-5’-溴-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物40)、(2Z,3E)-5’-溴-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物41)、(2Z,3E)-5’-碘-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物42)、(2Z,3E)-5’-碘-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物43)、(2Z,3E)-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物44)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物45)、(2Z,3E)-5’-甲氧基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物46),和(2Z,3E)-5’-甲氧基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物47)。
本发明的药物组合物除了活性成分之外还包括药学上可接受的载体。本发明的药物组合物中包含的药学上可接受的载体通常用于制剂中,其实例包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟苯甲酯、羟苯丙酯、滑石、硬脂酸镁和矿物油等,但不限于此。除了上述组分外,本发明的药物组合物还可包括润滑剂、润湿剂、甜味剂、芳香剂、乳化剂、混悬剂和防腐剂等。合适的药学上可接受的载体和制剂在Remington’sPharmaceutical Sciences(第19版,1995)中有详细描述。
可以根据诸如配制方法、施用方法、患者的年龄、体重、性别和病理状况、食物、施用时间、施用途径、排泄速度和反应敏感性等因素而不同地采用本发明的药物组合物的适当剂量。同时,本发明的药物组合物的剂量可以优选为每天1至1000mg/kg(重量)。
本发明的药物组合物可以口服或肠胃外施用,其中在肠胃外施用的情况下,它可以局部施用于皮肤或通过静脉内注射、皮下注射、肌内注射、腹膜内注射、透皮施用等施用。考虑到本发明的药物组合物用于治疗急性髓性白血病,优选通过静脉内注射或口服施用进行施用。
本发明的药物组合物可以使用药学上可接受的载体和/或赋形剂根据本发明所属领域的技术人员容易实施的方法配制,并且可以制备成单位剂型或者可以通过包装在多剂量容器中制备。特别地,制剂可以是油或水溶性介质中的溶液、混悬液或乳液的形式,或者可以是提取物、粉末、颗粒、片剂或胶囊的形式,并且可以进一步含有分散剂或稳定剂。
本发明的药物组合物可以口服施用。口服施用的固体制剂的实例包括片剂、丸剂、粉末、颗粒剂、胶囊剂、锭剂等,所述固体制剂通过将本发明的化合物与淀粉、碳酸钙、蔗糖、乳糖、明胶等赋形剂中的至少一种混合来制备来配置。除简单的赋形剂外,还使用诸如硬脂酸镁和滑石粉的润滑剂。用于口服施用的液体制剂的实例可包括混悬剂、内服用液、乳剂、糖浆剂等。在液体制剂中除了通常使用的单纯的稀释剂如水、液体石蜡以外,还可以包括多种赋形剂,如湿润剂、甜味剂、香料、防腐剂等。
用于胃肠外施用的制剂包括灭菌水溶液、非水溶剂、混悬溶剂、乳剂、冷冻干燥剂、栓剂等。作为非水溶剂和混悬溶剂,可以使用丙二醇、聚乙二醇、植物油如橄榄油、可注射的酯如油酸乙酯等。作为栓剂的基质,可以使用witepsol、聚乙二醇、吐温61、可可脂、月桂精油、甘油、明胶等。
考虑到本发明的药物组合物是用于预防或治疗急性髓性白血病或转移性乳腺癌的组合物,其可以优选通过胃肠外施用,例如,通过静脉内施用、腹膜内施用、肌内施用、皮下施用、局部施用等。
本发明的靛玉红衍生物可以以药学上可接受的盐的形式使用,并且作为盐,可以使用由药学上可接受的游离酸形成的酸加成盐。酸加成盐从以下获得:无机酸,如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸或亚磷酸;无毒有机酸,如脂族单和二羧酸酯、苯基取代的链烷酸酯、羟基链烷酸酯和链烷二酸酯、芳族酸、以及脂族和芳族磺酸;或有机酸,如乙酸、苯甲酸、柠檬酸、乳酸、马来酸、葡糖酸、甲磺酸、4-甲苯磺酸、酒石酸和富马酸。药学非毒性盐的实例包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、苹果酸盐、丁炔-1,4-二酸盐、己烷-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸、柠檬酸盐、乳酸盐、β-羟基丁酸盐、羟基乙酸盐、苹果酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等,但并不限定于这些。
本发明的酸加成盐可通过常规方法制备。例如,酸加成盐可以通过将化学式1的靛玉红衍生物溶解在有机溶剂如甲醇、乙醇、丙酮、二氯甲烷、乙腈等中,向其中加入有机酸或无机酸以产生沉淀,然后过滤并干燥所产生的沉淀来制备,或者可以通过在减压下蒸馏溶剂和过量的酸,然后在有机溶剂中干燥或结晶来制备。
另外,药学上可接受的金属盐可以通过使用碱来制备。例如,通过将化合物溶解在过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤不溶的化合物盐,然后蒸发并干燥滤液,获得碱金属或碱土金属盐。特别地,作为金属盐,从药学方面来看,钠、钾或钙盐是适合制备的。另外,相应的银盐通过使碱金属或碱土金属盐与合适的银盐(例如硝酸银)反应而获得。此外,本发明不仅包括由化学式1所表示的靛玉红衍生物及其药学上可接受的盐,而且包括可由其制备的溶剂化物、水合物、立体异构体等。
根据本发明的另一个方面,本发明提供了一种预防或治疗急性髓性白血病或转移性乳腺癌的方法,包括:(a)向个体施用包含由以下化学式1表示的化合物、其药学上可接受的盐、溶剂化物或水合物的组合物:
[化学式1]
本文所用的术语如上所述。待施用根据本发明的制剂的个体可以指任何动物,包括人。动物可以包括需要治疗类似症状的人以及哺乳动物,例如牛、马、绵羊、猪、山羊、骆驼、羚羊、狗、猫等,但不限于此。
本文使用的术语"施用"是指通过任何适当的方法将本发明的药物组合物引入患者,并且本发明的施用途径可以包括各种途径,例如口服或肠胃外施用,只要它可以到达靶组织即可。本发明的制剂可以根据所需的施用方法制备成各种形式。
根据本发明的再一方面,本发明提供了由以下化学式1表示的化合物、其药学上可接受的盐、溶剂化物或水合物在制备用于预防或治疗急性髓性白血病或转移性乳腺癌的药物组合物中的用途:
[化学式1]
有益效果
本发明的特征和优点总结如下:
(a)本发明提供了抑制FLT3的新组合物。
(b)本发明提供了用于预防或治疗急性髓性白血病或转移性乳腺癌的药物组合物。
(c)当使用本发明的组合物时,它可有效抑制FLT3激酶的活性,并可有效地用于预防或治疗急性髓性白血病或转移性乳腺癌。
附图简述
图1显示LDD1937(化合物4)的结构和对FLT3激酶活性的抑制作用。(A)显示LDD1937的化学结构,(B)显示LDD1937在体外对FLT3激酶活性的影响。通过HTRF分析测定重组FLT3激酶活性的抑制。用1%DMSO作为阴性对照计算激酶的抑制。数据是三个独立实验的平均值±SEM。
图2显示LDD1937(化合物4)的体内抗肿瘤效力。将MV-4-11细胞皮下接种到BALB/cnu/nu小鼠中。当肿瘤达到平均体积100mm3时,每天在尾静脉中给小鼠注射5mg/kg或10mg/kg的LDD1937或PBS(对照),持续21天。(A)显示了测量肿瘤大小和计算肿瘤体积的结果。(B)显示了在药物施用后第21天处死小鼠测量肿瘤重量的结果。拍摄从对照组和5mg/kg组解剖的肿瘤块的代表性图像(Inset)。数据表示平均值±SEM。与对照组相比,分别为**P<0.01,***P<0.001。
图3显示LDD1937的施用期间的体重变化。测定从实验开始21天施用5mg/kg或10mg/kg LDD1937或PBS(对照)的小鼠的体重。
图4显示了在施用四种化合物4周后肝、肾和癌组织重量的变化。LDD-2614代表化合物21,LDD-2633代表化合物28,LDD-2634代表化合物34,LDD-2635代表化合物33。
图5显示了在施用四种化合物4周后癌组织体积的变化。LDD-2614代表化合物21,LDD-2633代表化合物28,LDD-2634代表化合物34,LDD-2635代表化合物33。
图6显示了在施用四种化合物4周后癌组织大小的图像。LDD-2614代表化合物21,LDD-2633代表化合物28,LDD-2634代表化合物34,LDD-2635代表化合物33。
实施方案详述
以下,通过实施例进一步详细说明本发明。然而,提供这些实施例仅仅是为了具体解释本发明,并且对于本领域技术人员显而易见的是,根据本发明的主旨,本发明的范围不限于这些实施例。
实施例1:细胞培养
MV4;从美国模式培养物保藏所(ATCC,Rockville,MD,美国,CRL-9591)购买11份人急性髓性白血病细胞,并在补充有10%胎牛血清、1%青霉素/链霉素和4mM L-谷氨酰胺(Life Technology,Grand Island,NY)的IMDM培养基(Sigma公司,St.Louis,MO,美国)中培养细胞。将MDA-MB-231(转移性乳腺癌,ATCC HTB-26)、Jurkat(人急性T淋巴细胞白血病,ATCC TIB-152)和K-562(人慢性髓性白血病,ATCC CCL-243)细胞在RPMI-1640(Sigma公司)中培养。在补充了10%胎牛血清和1%青霉素/链霉素的DMEM(Sigma公司)培养基中培养MCF7(人乳腺癌,ATCC HTB-22)和PC-3(人前列腺腺癌,ATCC CRL-1435)细胞。将培养的细胞在3℃用5%CO2孵育。
使用EZ-Cytox细胞生存力测定试剂盒(DaeilLab,韩国),通过基于四唑的测定来评估细胞生存力。简言之,将2,000至15,000个细胞在100μl培养基中接种于96孔板中。第二天,用化合物以及作为阴性对照的二甲亚砜(DMSO)处理这些细胞。在药物加入后三天(72小时),将15μl EZ-Cytox试剂盒试剂加入96孔板的每个孔中,然后在37℃在加湿的CO2培养箱中培养4小时。孵育后,使用Victor Multilabel读数器(Perkin Elmer,Waltham,MA,美国)在450nm波长测定光密度(OD)。通过非线性回归使用Prism5.01版(GraphPad,La Jolla,CA,美国)计算IC50。
实施例2:化合物的合成和储存
设计并合成化合物1至化合物47。
2-1.合成流程1
试剂和反应条件:(a)水合氯醛,H2NOH·HCl,Na2SO4,水,H2SO4,100℃,过夜(on);(b)浓H2SO4,90℃,25分钟;(c)H2SO4,60℃,1小时。
将4-氨基苯甲酸乙酯在水合氯醛和Na2SO4水溶液中加热1小时。随后,使所得产物与盐酸羟胺反应,然后冷却,得到固体产物,用乙醚过滤,得到产物2,在高浓度硫酸条件下将所得产物加热到90℃,得到产物,将其用1N NaOH水溶液中和。然后,用EA萃取所得产物并通过旋转蒸发浓缩。用乙醚和DCM的混合物使所得混合物沉淀,然后过滤,得到产物3,使该产物与硫酸和甲醇反应,得到沉淀物(产物4a和4b)。
2-2.合成流程2
试剂和反应条件:(a)Na2CO3,甲醇:水(2:1),室温,3小时(b)盐酸羟胺,吡啶,回流,6小时
将溶解在MeOH中的靛红(isatin)类似物6a-i加入吲哚酚N,O-二乙酸酯4a-b或吲哚酚乙酸酯5中,并将该混合物搅拌5分钟。然后,向其中加入无水Na2CO3(2.5当量),并在室温搅拌3小时。随后,通过加水过滤所得产物,并用冷水洗涤几次,以沉淀物的形式得到产物7a、8a-i和9a-b,其中5,5’位被取代。然后,将这样得到的产物溶解在吡啶(0.1M)中,加入盐酸羟胺(5当量),回流6小时。然后,冷却混合物,用1N HCl酸化,得到沉淀,过滤沉淀,用水洗涤数次。最后,通过使用DCM和己烷固化来纯化由此获得的沉淀物,得到最终产物10a、11a-i和12a-b。
2-3.合成流程3
试剂和反应条件:(a)2-(Boc-氨基)乙基溴,K2CO3,DMF,室温,过夜;(b)4N HCl,在1,4-二噁烷中,DCM,室温,3小时;(c)1N NaOH,1,4-二噁烷,40℃,过夜;(d)1,2-二溴乙烷,Et3N,DMF,室温,过夜;(e)胺i-vi,DMF,50℃,过夜;(f)4N HCl,在1,4-二噁烷中,DCM或THF,0℃,30分钟或TFA,0℃,30分钟
由合成流程3所获得的靛玉红衍生物的代表性合成方法如下:
3-1)靛玉红-3’-肟衍生物的烷基氨基化
由合成流程3所得的靛玉红-3’-肟衍生物的烷基氨基化的代表性合成方法如下:
将靛玉红-3’-肟衍生物溶于DMF(1ml至4ml)中,加入2-(Boc-氨基)乙基溴(1.2当量)和K2CO3(2当量至3当量),然后在室温搅拌过夜。确认反应结束后,旋转蒸发浓缩DMF,然后加入水以产生沉淀,通过过滤获得沉淀。将沉淀物经柱色谱纯化,得到靛玉红衍生物产物13、14a及14b。接着,将由此获得的靛玉红衍生物溶解于DCM(1ml)中,在0℃添加二噁烷中的4N HCl(6当量至18当量),并在室温搅拌3小时。在确认反应完成后,通过过滤用DCM洗涤所得沉淀几次并干燥,得到纯净固体。靛玉红衍生物以盐的形式获得(产物15、16a和16b)。
3-2)靛玉红-3’-肟衍生物的烷基化
由合成流程3所获得的靛玉红-3’-肟衍生物的烷基化的代表性合成方法如下:
将靛玉红-3’-肟衍生物溶解在DMF(15ml)中,加入1,2-二溴乙烷(10当量)和TEA(3当量至10当量),然后在室温搅拌过夜。在确认反应完成后,加入水以产生沉淀,将其通过过滤用水洗涤几次,并干燥,得到作为清洁固体的产物(产物17a、18a-i和19a-b)。接着,将如此获得的靛玉红衍生物溶解于DMF中,添加哌嗪、吗啉、吡咯烷和哌啶试剂(10当量至30当量),然后在50℃搅拌过夜。在确认反应完成后,将水加入到混合溶液中以产生固体,其通过过滤获得,并用水洗涤几次。然后,用丙酮和MeOH洗涤剩余的杂质,得到所需产物(产物20a-c、21a、22a-e、23a-e、24a-c、25a-d、26a-g、27a-b、28a-b、29a-b、30a-b和31a-b)。接着,将由此得到的产物溶解在DCM或THF中,在0℃加入4N HCl的二噁烷溶液,然后搅拌30分钟。反应后,通过过滤用DCM洗涤所得固体,得到所需的盐形式的产物(产物20as-cs、21as、22as-es、23as-es、24as-cs、25as-ds、26as-fs、27as-bs、28as-bs、29as-bs、30as-bs和31as-bs)。此外,使用TFA以相同的方式得到化合物26gs的盐形式。
3-3)靛玉红-3’-肟羧酸衍生物
由合成流程3所获得的靛玉红-3’-肟羧酸衍生物的代表性合成方法如下:
将靛玉红-3’-肟衍生物(产物11d、14b、18d和24a-24c)溶解在1,4-二噁烷中,加入1N NaOH,然后在40℃搅拌过夜。在确认反应完成后,将所得产物在室温冷却,并通过加入1NHCl酸化。然后,将水浓缩,浓缩后将剩余的NaCl用MeOH过滤除去,得到所需的固体产物(产物32、33、35和31as-cs(盐))。然后,将由此得到的产物33溶解在DCM中,在0℃下加入在二噁烷中的4N HCl,然后搅拌10分钟。反应后,通过过滤用DCM洗涤所得固体,得到所需的盐形式的产物34。
化合物合成的确认
产物11d:(2Z,3E)-3-(羟基亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物1)
1H NMR(400MHz,DMSO-d6)δppm11.76-11.80(m,1H),11.05-11.10(m,1H),9.17-9.21(m,1H),8.24(d,J=8.01Hz,1H),7.73-7.78(m,1H),7.36-7.42(m,2H),7.00-7.06(m,1H),6.92-6.98(m,1H),3.79-3.86(m,3H)。
产物18d:(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物2)
1H NMR(400MHz,DMSO-d6)δppm11.68(s,1H),11.18(s,1H),9.36(d,J=1.6Hz,1H),8.23(d,J=7.6Hz,1H),7.83(dd,J=8.0,1.6Hz,1H),7.48(m,2H),7.10(m,1H),7.01(d,J=8.0Hz,1H),4.98(t,J=5.6Hz,2H),4.06(t,J=5.6Hz,2H),3.86(s,3H)。
产物16b:(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物3)
1H NMR(400MHz,DMSO-d6)δppm11.66(s,1H),11.18(s,1H),9.30(d,J=1.60Hz,1H),8.24(d,J=7.78Hz,1H),8.17(brs,2H),7.80(dd,J=8.13,1.72Hz,1H),7.41-7.48(m,2H),7.04(ddd,J=7.90,5.72,2.63Hz,1H),6.98(d,J=8.01Hz,1H),4.78-4.85(m,2H),3.79-3.86(m,3H),3.47(d,J=4.81Hz,2H)。
产物24as:(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐(化合物4,LDD1937)
1H NMR(400MHz,DMSO-d6)δppm11.70(s,1H),11.23(s,1H),9.36(s,1H),8.27(d,J=7.6Hz,1H),7.84(d,J=8.4Hz,1H),7.48(m,2H),7.07(m,1H),7.02(d,J=8.8Hz,1H),5.03(m,2H),3.88(s,3H),3.30(m,10H,与DMSO峰交盖)。
产物24bs:(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐(化合物5)
1H NMR(400MHz,DMSO-d6)δppm11.71(s,1H),11.22(s,1H),9.38(d,J=1.6Hz,1H),8.24(d,J=7.6Hz,1H),7.84(dd,J=8.4,1.6Hz,1H),7.48(m,2H),7.08(m,1H),7.02(d,J=8.4Hz,1H),4.96(m,2H),3.87(s,3H),3.30(m,10H,与水峰交盖)。
产物24cs:(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物6)
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),11.22(s,1H),10.94(brs,1H,吗啉N+-H),9.36(s,1H),8.26(d,J=7.6Hz,1H),7.84(dd,J=8.0,2.0Hz,1H),7.49(m,2H),7.09(m,1H),7.02(d,J=8.0Hz,1H),5.08(brs,2H),3.97(m,2H),3.80(s,3H),3.81(m,4H),3.56(m,2H),3.18(m,2H,与水峰部分交盖)。
产物32:(2Z,3E)-3-(羟基亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸(化合物7)
1H NMR(400MHz,DMSO-d6)δppm11.68(s,1H),11.23(s,1H),8.73-8.78(m,1H),8.18(s,1H),8.01(d,J=5.04Hz,1H),7.49(m,2H),6.95(d,J=8.0Hz,1H)。
产物35:(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸(化合物8)
1H NMR(400MHz,DMSO-d6)δppm11.66(s,1H),11.11(s,1H),9.34(s,1H),8.22(d,J=7.6Hz,1H),7.80(d,J=8.0Hz,1H),7.63(m,2H),7.08(m,1H),6.97(d,J=8.4Hz,1H),4.96(t,J=5.6Hz,2H),4.03(t,J=5.6Hz,2H)。
产物34:(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸盐酸盐(化合物9)
1H NMR(400MHz,DMSO-d6)δppm11.68(s,1H),11.18(s,1H),9.35(d,J=1.2Hz,1H),8.26(d,J=7.6Hz,1H),8.17(s,3H,H+),7.82(dd,J=8.0,1.6Hz,1H),7.48(m,2H),7.08(m,1H),7.00(d,J=8.4Hz,1H),4.83(t,J=5.2Hz,2H),3.45(t,J=5.2Hz,2H)。
产物36as:(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物10,LDD1940)
1H NMR(400MHz,DMSO-d6)δppm11.69(s,1H),11.17(s,1H),9.37(s,1H),8.91(brs,2H,哌嗪N+-H),8.23(d,J=7.6Hz,1H),7.82(d,J=8.4Hz,1H),7.47(m,2H),7.07(m,1H),7.00(d,J=8.4Hz,1H),4.92(brs,2H),3.05(m,10H,与水峰交盖)。
产物36bs:(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物11)
1H NMR(400MHz,DMSO-d6)δppm11.68(s,1H),11.16(s,1H),9.36(s,1H),8.23(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),7.47(m,2H),7.07(m,1H),6.99(d,J=8.0Hz,1H),4.93(brs,2H),3.17(m,10H,与水峰交盖),2.77(s,3H)。
产物36cs:(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸盐酸盐(化合物12)
1H NMR(400MHz,DMSO-d6)δppm11.67(s,1H),11.27(brs,1H,吗啉N+-H),11.18(s,1H),9.34(s,1H),8.25(d,J=7.6Hz,1H),7.82(d,J=8.4Hz,1H),7.48(m,2H),7.08(m,1H),6.99(d,J=8.0Hz,1H),5.06(brs,2H),3.96(m,2H),3.80(m,4H),3.53(m,2H),3.24(m,2H,与水峰部分交盖)。
产物10a:(2Z,3E)-5-羟基-3-(羟基亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮(化合物13)
1H NMR(300MHz,DMSO-d6)δ13.87(1H,s,NOH),11.78(1H,s,NH),11.35(1H,s,N-H),9.41(1H,d,J=2.8Hz),9.32(1H,s,O-H),8.05(1H,dd,J=11.6,2.8Hz),7.76(1H,d,J=3.2Hz),7.29(1H,d,J=11.6Hz),7.04(1H,d,J=11.2Hz)6.86(1H,dd,J=11.2,3.2Hz)
产物20bs:(2Z,3E)-5-羟基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物14)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.66(s,1H),11.46(s,1H),9.56(d,J=2.4Hz,1H),9.51(brs,1H),8.10(dd,J=8.8,2.4Hz,1H),7.75(s,1H),7.32(d,J=8.8Hz,1H),7.08(d,J=8.8Hz,1H)6.93(dd,J=8.8,2.4Hz,1H),5.01(brs,2H),3.27(m,10H,与水峰部分交盖),2.8(s,3H)。
产物16a:(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物15)
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H)11.18(s,1H)9.30(d,J=1.60Hz,1H)8.24(d,J=7.78Hz,1H)8.17(br.s.,2H)7.80(dd,J=8.13,1.72Hz,1H)7.41-7.48(m,2H)7.04(ddd,J=7.90,5.72,2.63Hz,1H)6.98(d,J=8.01Hz,1H)4.78-4.85(m,2H)3.79-3.86(m,3H)3.47(d,J=4.81Hz,2H)
产物21as:(2Z,3E)-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物16)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.70(s,1H),11.25(s,1H),9.45(d,J=2.4Hz,1H),8.23(d,J=8.4Hz,2H),8.03(m,1H),7.50(d,J=2.4Hz,1H),7.43(m,1H),7.04(m,2H),4.82(m,2H)3.81(m,3H)3.42(m,2H)
产物15as:(2Z,3E)-5-氟-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物17)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.66(s,1H),11.47(s,1H),9.51(d,J=2.4Hz,1H),9.48(s,1H),8.24(brs,3H),8.09(dd,J=8.4,2.4Hz,1H),7.78(d,J=2.4Hz,1H),7.30(d,J=8.4Hz,1H),7.07(d,J=8.8Hz,1H),6.95(dd,J=8.4,2.4Hz,1H),4.87(t,J=4.4Hz,2H),3.49(t,J=4.4Hz,2H).
产物25bs:(2Z,3E)-5-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物18)
1H NMR(400MHz,DMSO-d6)δ(ppm);9.58(1H,d,J=2.1Hz),8.14(1H,m),7.97(1H,dd,J=8.9,2.4Hz),7.57(1H,m),7.41(1H,m),7.08(1H,m),4.87(2H,m),2.96(2H,m),2.38(4H,m),2.15(3H,m).
产物25ds:(2Z,3E)-5-氟-5’-硝基-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物19)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.80(m,1H),10.79(s,1H),8.46(dd,J=11.3,2.4Hz,1H),8.19(m,1H),7.48(m,2H),7.08(m,1H),7.01(m,1H),6.90(m,1H),4.69(t,J=6.1Hz,2H),2.90(m,2H),2.24(s,2H),1.94(m,1H),1.58(m,3H),1.40(m,2H)
产物25cs:(2Z,3E)-5-氟-5’-硝基-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物20)
1H NMR(400MHz,DMSO-d6)δ(ppm);9.56(s,1H),8.07d,J=8.8Hz,1H),7.88(d,J=8.8Hz,1H),7.48(s,1H),7.34(s,1H),7.03(d,J=9.6Hz,1H),4.84(m,2H),4.12(m,2H)。
产物26as:(2Z,3E)-5,5’-二氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物21)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.80(m,1H),10.83(m,1H),8.44(m,1H),8.01(m,1H),7.49(m,1H),7.38(m,1H),7.01(m,1H),6.87(dd,J=4.9Hz,1H),4.75(m,2H),2.90(m,2H),2.74(m,3H),2.47(m,3H)。
产物26bs:(2Z,3E)-5,5’-二氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物22)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.77(m,1H),10.81(m,1H),8.44(m,1H),7.99(dd,J=8.9,2.8Hz,1H),7.47(dd,J=8.9,4.6Hz,1H),7.34(td,J=9.0,2.8Hz,1H),6.98(td,J=8.9,2.8Hz,1H),6.89(m,1H),4.74(m,2H),2.92(m,2H),2.38(m,3H),2.15(m,3H)。
产物26es:(2Z,3E)-5,5’-二氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物23)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.78(m,1H),10.79(brs,1H),8.41(dd,J=11.3,2.8Hz,1H),7.97(dd,J=8.7,2.6Hz,1H),7.47(dd,J=8.7,4.4Hz,1H),7.38(m,1H),7.01(m,1H),6.89(m,1H),4.69(t,J=6.0Hz,2H),2.85(t,J=6.1Hz,2H),1.51(q,J=5.5Hz,4H),1.42(m,2H)。
产物26ds:(2Z,3E)-5,5’-二氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物24)
1H NMR(400MHz,DMSO-d6)δ(ppm);10.86(m,1H),8.41(dd,J=11.3,2.8Hz,1H),7.92(dd,J=8.6,2.8Hz,1H),7.47(dd,J=8.9,4.6Hz,1H),7.34(td,J=9.1,2.6Hz,1H),6.97(td,J=8.8,2.6Hz,1H),6.89(m,1H),4.70(t,J=6.0Hz,1H),3.00(t,J=6.0Hz,2H),2.60(m,4H),1.69(dt,J=6.6,3.1Hz,4H)。
产物26gs:(2Z,3E)-3-((2-(4-氨基哌啶-1-基)乙氧基)亚氨基)-5,5’-二氟-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物25)
1H NMR(400MHz,DMSO-d6)δ(ppm);8.32(dd,J=11.1,2.6Hz,1H),8.01(dd,J=8.7,2.6Hz,1H),7.48(d,J=8.9,4.6Hz,1H),7.40(m,1H),7.04(m,1H),6.88(dd,J=8.6,4.9Hz,1H),5.01(m,2H),3.37(m,4H),2.96(dd,J=11.6Hz,2H),2.15(m,4H),1.73(m,1H)。
产物26fs:(2Z,3E)-5,5’-二氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物26)
1H NMR(400MHz,DMSO-d6)δ(ppm);8.41(dd,J=11.3,2.8Hz,1H),7.96(dd,J=8.7,2.6Hz,1H),7.47(dd,J=8.9,4.3Hz,1H),7.38(1H,m),6.97(dd,J=9.2,2.8Hz,1H),6.86(dd,J=8.6,4.9Hz,1H),4.69(t,J=6.0Hz,2H),2.93(m,4H),2.15(m,2H),1.72(m,2H),1.33(m,2H)。
产物26cs:(2Z,3E)-5,5’-二氟-3-((2-吗啉代乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物27)
1H NMR(400MHz,DMSO-d6)δ(ppm);9.59(d,J=2.4Hz,1H),8.13(m,1H),7.97(d,J=6.1Hz,1H),7.51(s,1H),7.37(s,1H),7.07(d,J=8.6Hz,1H),4.83(t,J=5.8Hz,1H),3.17(s,2H),2.94(m,4H),1.53(m,5H),1.38(dd,J=5.3,0.8Hz,3H).
产物23as:(2Z,3E)-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物28)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.84(1H,m,N-H),10.78(1H,s,N-H),8.62(1H,d,J=7.9Hz),8.17(1H,d,J=7.6Hz),7.46(2H,m),7.15(1H,td,J=7.6,1.2Hz),7.03(1H,m),6.99(1H,m),6.90(1H,d,J=7.6Hz),4.69(2H,t,J=6.0Hz),3.46(4H,m),2.84(2H,t,J=6.1Hz),2.69(2H,t,J=4.7Hz),2.45(2H,m)。
产物23bs:(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物29)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.70(1H,m,N-H),10.78(1H,s),8.64(1H,m),8.17(1H,d,J=7.9Hz),7.42(1H,d,J=1.2Hz),7.16(1H,td,J=7.6,1.2Hz),7.06(1H,m),7.00(1H,m),6.93(1H,m),4.69(2H,t,J=6.1Hz),2.96(2H,m),2.54(4H,m),2.39(4H,m),2.14(3H,s)。
产物23ds:(2Z,3E)-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物30)
1H NMR(400MHz,DMSO-d6)δ(ppm);8.61(1H,d,J=6.0Hz),8.16(1H,d,J=6.0Hz),7.43(1H,m),7.15(1H,m),7.03(1H,s),6.97(1H,m),6.89(1H,d,J=6.0Hz),4.69(2H,m),2.86(2H,m),2.08(4H,s),1.52(3H,m),1.43(2H,m)。
产物23cs:(2Z,3E)-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物31)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.69(1H,s,br),10.76(1H,s),8.66(1H,m),8.18(1H,m),7.46(2H,m),7.18(1H,m),7.06(1H,m),6.98(1H,td,J=7.7,1.1Hz),6.91(1H,dd,J=7.7,0.6Hz),4.69(2H,t,J=6.0Hz),2.99(2H,t,J=6.0Hz),2.59(4H,m),1.69(4H,dt,J=6.9,3.2Hz)。
产物23es:(2Z,3E)-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物32)
1H NMR(400MHz,DMSO-d6)δ(ppm);8.62(1H,d,J=7.6Hz),8.17(1H,d,J=7.7Hz),7.46(2H,m),7.15(1H,td,J=7.56,1.2Hz),7.03(1H,td,J=7.2,1.6Hz),7.01(1H,m),6.91(1H,d,J=7.7Hz),4.68(2H,t,J=6.1Hz),2.92(4H,m),2.17(2H,m)。
产物22as:(2Z,3E)-5’-氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物33)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.83(1H,m,N-H),10.84(1H,m,N-H),8.45(1H,dd,J=11.3,2.8Hz),8.21(1H,m),7.47(2H,m),7.09(1H,m),6.99(1H,m),6.87(1H,dd,J=8.4,5.0Hz),4.76(3H,m),2.91(2H,m),2.70(4H,m),2.47(3H,m)。
产物22bs:(2Z,3E)-5’-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物34)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.84(1H,m,N-H),10.81(1H,m,N-H),8.47(1H,dd,J=11.3,2.7Hz),8.20(1H,m),7.46(2H,m),7.13(1H,m),6.99(1H,m),6.85(1H,dd,J=8.4,5.0Hz),4.74(3H,m),2.90(2H,m),2.72(4H,m),2.45(3H,m),2.14(3H,m)。
产物22ds:(2Z,3E)-5’-氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物35)
1H NMR(400MHz,DMSO-d6)δ(ppm);11.80(m,1H),10.79(s,1H),8.46(dd,J=11.3,2.4Hz,1H),8.19(m,1H),7.48(m,2H),7.08(m,1H),7.01(m,1H),6.90(m,1H),4.69(t,J=6.1Hz,2H),2.90(m,2H),2.24(s,2H),1.94(m,1H),1.58(m,3H),1.40(m,2H)。
产物22cs:(2Z,3E)-5’-氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物36)
1H NMR(400MHz,DMSO-d6)δ(ppm);10.78(1H,s,br),8.46(1H,dd,J=11.1,2.6Hz),8.18(1H,m),7.47(2H,m),7.09(1H,m),6.96(1H,dd,J=9.0,2.6Hz),6.87(1H,dd,J=8.4,5.0Hz),4.69(2H,t,J=6.1Hz),3.01(2H,t,J=6.0Hz),2.61(4H,m),1.68(4H,dt,J=7.0,3.2Hz)。
产物22es:(2Z,3E)-5’-氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物37)
1H NMR(400MHz,DMSO-d6)δ(ppm);8.48(1H,m),8.17(1H,dd,J=7.6,0.9Hz),7.46(2H,m),6.98(1H,d,J=2.8Hz),6.89(1H,m),4.68(2H,t,J=6.1Hz),2.93(4H,m),2.15(2H,m)。
产物27a:(2Z,3E)-5’-氯-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物38)
1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),10.84(s,1H),8.60(s,1H),8.24(d,J=7.6Hz,1H),7.45(m,2H),7.14(m,2H),6.88(d,J=7.9Hz,1H),4.69(t,J=6.0Hz,2H),3.46(m,4H),2.84(t,J=6.1Hz,2H),2.69(t,J=4.7Hz,2H),2.45(m,2H)。
产物27b:(2Z,3E)-5’-氯-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物39)
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),10.82(s,1H),8.59(s,1H),8.19(d,J=7.6Hz,1H),7.65(m,2H),7.14(m,2H),6.90(d,J=7.9Hz,1H),4.74(m,2H),2.91(m,2H),2.40(m,3H),2.15(m,3H)。
产物28a:(2Z,3E)-5’-溴-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物40)
1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),10.76(s,1H),8.65(s,1H),8.19(d,J=8.0Hz,1H),7.45(m,2H),7.28(d,J=8.2Hz,1H),7.08(m,1H),6.88(d,J=8.0Hz,1H)4.72(m,3H),2.87(m,2H),2.70(m,4H),2.47(m,3H)。
产物28b:(2Z,3E)-5’-溴-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物41)
1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),10.77(s,1H),8.65(s,1H),8.19(d,J=8.0Hz,1H),7.45(m,2H),7.28(d,J=8.2Hz,1H),7.08(m,1H),6.88(d,J=8.0Hz,1H),4.74(m,3H),2.93(m,2H),2.75(m,4H),2.45(m,3H),2.17(m,3H)。
产物29a:(2Z,3E)-5’-碘-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物42)
1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),10.80(s,1H),8.85(s,1H),8.20(d,J=8.0Hz,1H),7.45(m,3H),7.06(m,1H),6.75(d,J=8.0Hz,1H)4.75(m,3H),2.85(m,2H),2.71(m,4H),2.45(m,3H)。
产物29b:(2Z,3E)-5’-碘-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物43)
1H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),10.77(s,1H),8.66(s,1H),8.21(d,J=8.0Hz,1H),7.46(m,3H),7.08(m,1H),6.74(d,J=8.0Hz,1H),4.75(m,3H),2.90(m,2H),2.72(m,4H),2.42(m,3H),2.17(m,3H,)。
产物30a:(2Z,3E)-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物44)
1H NMR(400MHz,DMSO-d6)δ(ppm)11.73(s,1H),10.79(s,1H),8.57(s,1H),8.27(d,J=7.5Hz,1H),7.41(m,2H),6.99(m,2H),6.94(d,J=8.4Hz,1H)4.73(m,2H),2.87(m,2H),2.76(m,3H),2.45(m,3H)。
产物30b:(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物45)
1H NMR(400MHz,DMSO-d6)δ(ppm)11.68(s,1H)10.88(s,1H),8.60(s,1H),8.24(1H,d,J=7.5Hz),7.40(2H,m),7.01(2H,m),6.94(1H,d,J=8.4Hz)4.82(2H,m),2.98(2H,m),2.41(4H,m),2.18(3H,m)。
产物31a:(2Z,3E)-5’-甲氧基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物46)
1H NMR(400MHz,DMSO-d6)δ(ppm)11.74(s,1H),10.49(s,1H),8.35(d,J=2.2Hz,1H),8.22(d,J=7.4Hz,1H),7.40(m,2H),7.02(m,1H),6.75(d,J=8.3Hz,1H),6.70(dd,J=7.6Hz,2.4Hz,,1H),4.75(m,2H),3.72(s,3H),2.90(m,2H),2.74(m,3H),2.47(m,3H)。
产物31b:(2Z,3E)-5’-甲氧基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物47)
1H NMR(400MHz,DMSO-d6)δ(ppm)11.76(s,1H),10.51(s,1H),8.38(d,J=2.1Hz,1H),8.23(d,J=7.4Hz,1H),7.42(m,2H),7.02(m,1H),6.75(d,J=8.3Hz,1H),6.72(m,1H),4.75(m,2H),3.72(s,3H),2.94(m,2H),2.36(m,3H),2.17(m,3H)。
将由此得到的化合物以10mmol/L的浓度溶解于DMSO(Fisher,Waltham,MA,美国)中,并储存于-20℃。
实施例3:体外激酶分析
FLT3激酶活性的抑制使用均相时间分辨荧光(HTRF)测定来测定。含有FLT3激酶结构域的重组蛋白购自Carna Biosciences(日本)。根据制造商的说明书,使用HTRF KinEASE试剂盒(Cisbio,法国)确定最佳的酶、ATP和底物浓度。FLT3酶依次与稀释的化合物和肽底物在激酶反应缓冲液((50mM HEPES(pH7.0),500μM ATP,0.1mM原钒酸钠,5mM MgCl2,1mMDTT,0.01%牛血清白蛋白(BSA)和0.02%NaN3)中混合。加入检测试剂后,使用Victor多标记读数器(Perkin Elmer,Waltham,MA,美国)测定TR-FRET信号。使用Prism5.01版(GraphPad)通过非线性回归计算IC50。还使用HTRF测定进行了JAK2、JAK3、cMET和RET体外激酶测定。
IRAK4的体外激酶分析使用LANCE Ultra激酶活性试验(Perkin Elmer)进行,包括ULight-p70S6K(Thr389)肽(磷酸化基序FLGFTYVAP)。该试验由与依次稀释的化合物、50nMULight-p70S6K(Thr389)肽和500μM ATP混合的酶组成,将其在激酶缓冲液(50mM HEPES(pH7.5),10mM MgCl2,1mM EGTA,2mM DTT和0.01%Tween20)中预稀释。激酶反应在25℃孵育90分钟,并通过加入10mM EDTA终止。为了检测磷酸底物,加入用检测缓冲液稀释的Eu-抗-磷酸-p70S6K(Thr389)抗体至终浓度为2nM,将反应产物在25℃孵育1小时。用EnVision多标记读数器测定信号。
实施例4:小鼠肿瘤异种移植物(异种移植物MV4;11)
在雌性BALB/c nu/nu(无胸腺裸鼠)小鼠的胁腹皮下接种MV4;11细胞(5×106个细胞/小鼠)。当肿瘤达到平均体积100mm3时(接种后约14天),将小鼠随机分成3组(对照组n=10,5mg/kg或10mg/kg组n=6),并在尾静脉中注射20ml/kg在PBS中的5mg/kg或10mg/kg的LDD1937,或纯PBS(对照)。每天注射药物或对照PBS,持续21天。每周两次测量肿瘤大小,持续21天,并用以下等式计算肿瘤体积:V(体积)=X(长度)x D(宽度)2/2。21天后,处死小鼠,测量肿瘤重量。
实施例5:小鼠肿瘤异种移植物(异种移植物MDA-MB-231)
6周龄Balb/c nu/nu小鼠(雌性)购自Central Lab.Animal Inc.,备用。MDA-MB-231细胞系购自ATCC,备用。为制备荷瘤小鼠模型,每只小鼠接种1x107个细胞,并使用100μLCorning Matrigel/PBS混合溶液作为溶剂。当肿瘤体积达到200mm3-300mm3时开始施用药物(原则上,每天测量肿瘤体积,并通过以下公式计算体积:V(体积)=X(长度)×D(宽度)2/2)。
候选物质LDD-2614(化合物21)、2633(化合物28)、2634(化合物34)、2635(化合物33)以20mg/kg/p.o/天施用,作为对照的多柔比星以5mg/kg/i.p施用(每周一次)4周。
实验结果
1.作为FLT3激酶活性抑制剂的LDD1937
表1显示了对FLT3和MV4;11的抑制活性。
[表1]
表2显示化合物13至37对FLT3、MV4;11和MDA-MB-231的抑制活性。
[表2]
每种化合物的活性测试了3次。
本发明人先前已报导一系列5-取代靛玉红衍生物为强效的FLT3抑制剂,其有效地抑制急性髓性白血病细胞的生长[21]。虽然靛玉红具有强效的激酶抑制作用,但其在水中的差溶解度会造成一些生理问题。为了解决这些靛玉红衍生物的溶解度问题,本发明人已设计并合成了分子上具有亲水性官能基的新颖类似物。
最近,本发明人发现5-羧基靛玉红衍生物7强烈抑制FLT3激酶(IC50=8nM),对人白血病细胞系MV4;11缺乏抗增殖活性,其表达FLT3-ITD(参见表1)。有趣的是,相应的5-羧基酯类似物1显示了针对MV4;11细胞的有效抗增殖活性(IC50=41nM),尽管其FLT3抑制活性非常弱。因此,本发明人试图通过在靛玉红骨架的3’位置进行进一步衍生化来优化以提高FLT3激酶和MV4;11的生长抑制活性。
据报道,针对其它激酶的3’-烷基取代的靛玉红肟衍生物具有诸如更高的效力和水溶性的优点。虽然没有有关于具有5-羧酸或酯基团的3’-烷基取代的靛玉红肟衍生物作为FLT3抑制剂的报道,但本发明人合成了这些类似物以获得在3’肟位置烷基取代的优点。3’-取代靛玉红类似物的抑制效果描述于表1中。总体而言,烷基取代的化合物相比于化合物1和7对FLT3和MV4;11都显示出增加的抑制活性。5-酯取代的化合物1的类似物显示出对FLT3激酶以及MV4;11细胞的强效抑制活性。但是,尽管对FLT3激酶有强的抑制活性,5-羧基衍生物(9-12)显示的抑制活性略低于5-酯类似物(3-6)。对FLT3和MV4;11的抑制作用依赖于R位置的取代基。对FLT3的抑制活性按吗啉、乙基溴<N-甲基哌嗪<胺、哌嗪的顺序增加,而对MV4;11的抑制活性以以下顺序增加:吗啉、乙基溴<胺、N-甲基哌嗪<哌嗪。R位的乙基溴和吗啉取代(化合物2、6、8和12)对FLT3和MV4;11的抑制能力没有关键影响。在每个系列中,乙基哌嗪化合物4和10显示对FLT3(IC50=3nM)和MV4;11(IC50=1nM和40nM)最强效的抑制活性。此外,化合物4比CEP-701(一种众所周知的FLT3抑制剂)更强效地抑制MV4;11细胞的生长。令人惊奇的是,5-甲酯化合物1的所有烷基取代系列对FLT3激酶显示显著增加的抑制活性。乙基哌嗪取代的化合物4对FLT3(IC50=3nM)和MV4;11(IC50=1nM)显示最强效的活性,其活性与起始化合物1相比分别增加1000倍和40倍,另外,在5-羧酸靛玉红7的3’-肟位置引入烷基取代基显著改善了对MV4;11的抑制作用。类似于5-甲酯家族,哌嗪取代的化合物10对FLT3和MV4;11均显示出出最强效的抑制作用。然而,化合物10仅对MV4;11显示中等抑制活性,尽管其具有针对FLT3激酶的强抑制活性。本发明人预测5-羧酸衍生物的极性太强而不能通过细胞膜。
在确定受体酪氨酸激酶抑制剂的过程中,合成了数种靛玉红类似物,并研究其结构活性关系(表1)。在12种化合物中,选择化合物4(LDD1937,图1A)、(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐,并进一步表征。如图1B所示,化合物4(LDD1937)对FLT3激酶活性的IC50是3nM。还测定了化合物4对其它激酶活性的IC50值(表3)。FLT3和其它激酶之间的IC50至少有170倍的差异。
[表3]
2.MV4;11细胞增殖的抑制和LDD1937的选择性凋亡性细胞死亡的诱导
MV4;11细胞是具有受体酪氨酸激酶FLT3突变的白血病细胞。MV4;11细胞具有在近膜结构域中带有内部串联重复(ITD)的FLT3突变(FLT3-ITD),其引起FLT3活性的组成型活化[3]。MV4;11细胞生长和存活已知依赖于FLT3活性[23]。测定LDD1937的细胞毒性并示于表4中。永生化的T淋巴细胞Jurkat细胞、前列腺癌PC-3细胞、乳腺癌MCF-7细胞和红细胞生成K562细胞也用于细胞毒性试验。MV4;11细胞与其它细胞系相比,对LDD1937处理表现出高灵敏度(GI50=1nM)。根据GI50值,LDD1937在MV4;11细胞中的效力比其它细胞系强1000至2000倍。
[表4]
3.LDD1937的体内肿瘤生长抑制
为了检验LDD1937在体内的功效,进行MV4;11异种移植研究。将MV4;11细胞皮下注射到BALB/c nu/nu小鼠中,使肿瘤生长到约100mm3大小。另外,将LDD1937或PBS对照静脉内施用3周。如图2A所示,LDD1937组的肿瘤尺寸明显小于对照组的肿瘤尺寸。特别是,在10mg/kg组中,肿瘤从第3天消失,其基于测定的肿瘤体积(图2A)。肿瘤注射部位的解剖证实了10mg/kg组中肿瘤质的完全消失。因此,肿瘤重量只能在对照组和5mg/kg组中测定,并且在LDD1937的5mg/kg组中肿瘤重量有显著降低(图2B)。此外,在施用期间各组之间的体重没有显著差异(图3)。
4.4种化合物的体内抗癌作用
为了检验四种靛玉红衍生物的体内功效,进行MDA-MB-231异种移植物研究。使培养的细胞在BALB/c nu/nu(雌性)小鼠中生长至肿瘤大小约为200mm3至300mm3。此外,将四种靛玉红衍生物,LDD-2614(化合物21)、2633(化合物28)、2634(化合物34)及2635(化合物33)各以20mg/kg施用。作为对照组,将多柔比星以5mg/kg施用4周。如图4所示,在施用四种化合物后,肝和肾的重量没有显著差异,但癌组织的重量有一些差异。在相同的时间内,证实了癌组织的体积减少到与对照组相似的水平(图5)。肿瘤注射部位的解剖证实2633(化合物28)、2634(化合物34)和2635(化合物33)三种化合物显示出与对照组相似的抗癌作用(图6)。
FMS样受体酪氨酸激酶-3(FLT3)属于受体酪氨酸激酶(RTK)家族,在1/3的急性髓性白血病(AML)患者中观察到FLT3突变。如上所述,本发明人已确认一种强效的FLT3抑制剂LDD1937,其包括靛玉红骨架。用体外激酶试验显示了LDD1937对FLT3的有效抑制活性(IC50=3nM)。LDD1937化合物选择性抑制MV4;11细胞(GI50=1nM))的生长,并诱导凋亡性细胞死亡。LDD1937引起细胞周期在G2/M期停滞,并在亚-G1期增加细胞群体。LDD1937以剂量依赖性方式显著降低了作为FLT3下游信号传导的STAT5的磷酸化。在小鼠中研究LDD1937的药代动力学性质。另外,使用MV4;11异种移植物评估体内抗肿瘤效果。在Nu/Nu小鼠中静脉内施用5mg/kg和10mg/kg,肿瘤体积和重量与对照组相比显著降低。
尽管已经详细描述了本发明的具体部分,但是对于本领域技术人员来说显然的是,这些具体技术仅仅是优选实施方案,并且本发明的范围不限于此。因此,本发明的实质范围将由所附权利要求及其等同内容限定。
Claims (13)
5.权利要求1至4中任一项的化合物、其药学上可接受的盐、溶剂化物或水合物,其中R2是C1-C4烷基酯。
6.权利要求5的化合物、其药学上可接受的盐、溶剂化物或水合物,其中C1-C4烷基酯是甲酯。
8.权利要求1的化合物、其药学上可接受的盐、溶剂化物或水合物,其中由化学式1表示的化合物是选自以下化合物的任一种:(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐(化合物4)、(2Z,3E)-3-(羟基亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物1)、(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物2)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物3)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐(化合物5)、(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物6)、(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸(化合物8)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸盐酸盐(化合物9)、(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物10)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物11)、(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸酯盐酸盐(化合物12)、(2Z,3E)-5-羟基-3-(羟基亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮(化合物13)、(2Z,3E)-5-羟基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物14)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物15)、(2Z,3E)-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物16)、(2Z,3E)-5-氟-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物17)、(2Z,3E)-5-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物18)、(2Z,3E)-5-氟-5’-硝基-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物19)、(2Z,3E)-5-氟-5’-硝基-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物20)、(2Z,3E)-5,5’-二氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物21)、(2Z,3E)-5,5’-二氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物22)、(2Z,3E)-5,5’-二氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物23)、(2Z,3E)-5,5’-二氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物24)、(2Z,3E)-3-((2-(4-氨基哌啶-1-基)乙氧基)亚氨基)-5,5’-二氟-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物25)、(2Z,3E)-5,5’-二氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物26)、(2Z,3E)-5,5’-二氟-3-((2-吗啉代乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物27)、(2Z,3E)-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物28)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物29)、(2Z,3E)-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物30)、(2Z,3E)-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物31)、(2Z,3E)-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物32)、(2Z,3E)-5’-氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物33)、(2Z,3E)-5’-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物34)、(2Z,3E)-5’-氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物35)、(2Z,3E)-5’-氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物36)、(2Z,3E)-5’-氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物37)、(2Z,3E)-5’-氯-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物38)、(2Z,3E)-5’-氯-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物39)、(2Z,3E)-5’-溴-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物40)、(2Z,3E)-5’-溴-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物41)、(2Z,3E)-5’-碘-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物42)、(2Z,3E)-5’-碘-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物43)、(2Z,3E)-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物44)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物45)、(2Z,3E)-5’-甲氧基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物46),和(2Z,3E)-5’-甲氧基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物47)。
9.权利要求1至8中任一项的化合物、其药学上可接受的盐、溶剂化物或水合物,其中由化学式1表示的化合物具有100nM或更小的FLT3抑制IC50值。
10.权利要求1至8中任一项的化合物、其药学上可接受的盐、溶剂化物或水合物,其中由化学式1表示的化合物具有20nM或更小的FLT3抑制IC50值。
13.权利要求11的药物组合物,其中由化学式1表示的化合物是选自以下化合物的任一种:(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐(化合物4)、(2Z,3E)-3-(羟基亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物1)、(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯(化合物2)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物3)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯二盐酸盐(化合物5)、(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸甲酯盐酸盐(化合物6)、(2Z,3E)-3-(羟基亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸(化合物7)、(2Z,3E)-3-((2-溴乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸(化合物8)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸盐酸盐(化合物9)、(2Z,3E)-2’-氧代-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物10)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸二盐酸盐(化合物11)、(2Z,3E)-3-((2-吗啉代乙氧基)亚氨基)-2’-氧代-[2,3’-联吲哚啉亚基]-5’-甲酸酯盐酸盐(化合物12)、(2Z,3E)-5-羟基-3-(羟基亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮(化合物13)、(2Z,3E)-5-羟基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物14)、(2Z,3E)-3-((2-氨基乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物15)、(2Z,3E)-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物16)、(2Z,3E)-5-氟-5’-硝基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物17)、(2Z,3E)-5-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-硝基-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物18)、(2Z,3E)-5-氟-5’-硝基-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物19)、(2Z,3E)-5-氟-5’-硝基-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物20)、(2Z,3E)-5,5’-二氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物21)、(2Z,3E)-5,5’-二氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物22)、(2Z,3E)-5,5’-二氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物23)、(2Z,3E)-5,5’-二氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物24)、(2Z,3E)-3-((2-(4-氨基哌啶-1-基)乙氧基)亚氨基)-5,5’-二氟-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物25)、(2Z,3E)-5,5’-二氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物26)、(2Z,3E)-5,5’-二氟-3-((2-吗啉代乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物27)、(2Z,3E)-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物28)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物29)、(2Z,3E)-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物30)、(2Z,3E)-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物31)、(2Z,3E)-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物32)、(2Z,3E)-5’-氟-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物33)、(2Z,3E)-5’-氟-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物34)、(2Z,3E)-5’-氟-3-((2-(哌啶-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物35)、(2Z,3E)-5’-氟-3-((2-(吡咯烷-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮盐酸盐(化合物36)、(2Z,3E)-5’-氟-3-((2-(哌啶-4-基氨基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物37)、(2Z,3E)-5’-氯-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物38)、(2Z,3E)-5’-氯-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物39)、(2Z,3E)-5’-溴-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物40)、(2Z,3E)-5’-溴-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物41)、(2Z,3E)-5’-碘-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物42)、(2Z,3E)-5’-碘-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物43)、(2Z,3E)-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物44)、(2Z,3E)-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-5’-(三氟甲氧基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物45)、(2Z,3E)-5’-甲氧基-3-((2-(哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物46),和(2Z,3E)-5’-甲氧基-3-((2-(4-甲基哌嗪-1-基)乙氧基)亚氨基)-[2,3’-联吲哚啉亚基]-2’-酮二盐酸盐(化合物47)。
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WO2021090172A1 (en) * | 2019-11-04 | 2021-05-14 | Ck Biotechnology Co. | Compositions and methods for suppressing and/or treating neurodegenerative diseases and/or a clinical condition thereof |
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