CN110668992B - Ido/hdac双靶点化合物及其合成方法和应用 - Google Patents
Ido/hdac双靶点化合物及其合成方法和应用 Download PDFInfo
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- CN110668992B CN110668992B CN201810705636.4A CN201810705636A CN110668992B CN 110668992 B CN110668992 B CN 110668992B CN 201810705636 A CN201810705636 A CN 201810705636A CN 110668992 B CN110668992 B CN 110668992B
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- indole
- carboxamide
- benzyl
- hydroxycarbamoyl
- methylenedioxyphenyl
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- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 description 1
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- CFJQBNFFHMBNKQ-UHFFFAOYSA-N methyl 3-bromo-4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C(Br)=C1 CFJQBNFFHMBNKQ-UHFFFAOYSA-N 0.000 description 1
- DCXFLSHDURQRML-UHFFFAOYSA-N methyl 4-(bromomethyl)-2-methoxybenzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1OC DCXFLSHDURQRML-UHFFFAOYSA-N 0.000 description 1
- KQHHSNCXMBIUQF-UHFFFAOYSA-N methyl 4-(bromomethyl)-3,5-dichlorobenzoate Chemical group COC(=O)C1=CC(Cl)=C(CBr)C(Cl)=C1 KQHHSNCXMBIUQF-UHFFFAOYSA-N 0.000 description 1
- CKOPIHBZTQSVJU-UHFFFAOYSA-N methyl 4-(bromomethyl)-3,5-dimethoxybenzoate Chemical group COC(=O)C1=CC(OC)=C(CBr)C(OC)=C1 CKOPIHBZTQSVJU-UHFFFAOYSA-N 0.000 description 1
- XTZCVWDSGCVDFI-UHFFFAOYSA-N methyl 4-(bromomethyl)-3-chlorobenzoate Chemical compound COC(=O)C1=CC=C(CBr)C(Cl)=C1 XTZCVWDSGCVDFI-UHFFFAOYSA-N 0.000 description 1
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- UXSNXOMMJXTFEG-UHFFFAOYSA-N methyl 4-(bromomethyl)-3-methoxybenzoate Chemical compound COC(=O)C1=CC=C(CBr)C(OC)=C1 UXSNXOMMJXTFEG-UHFFFAOYSA-N 0.000 description 1
- RAVVJKCSZXAIQP-UHFFFAOYSA-N methyl 5-bromopentanoate Chemical compound COC(=O)CCCCBr RAVVJKCSZXAIQP-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种IDO/HDAC双靶点化合物,及其药用衍生物、水合物、含有所述化合物的组合物,及其制备方法。本发明还公开了所述化合物作为IDO和HDAC的双靶点抑制剂,用于治疗恶性肿瘤,提高目前IDO和HDAC单靶点小分子抗癌药物的疗效,并减少其毒副作用。本发明还公开了所述化合物用于具有IDO介导的色氨酸代谢途径的病理性特征的疾病,包括自身免疫性疾病、阿尔兹海默症、抑郁症、焦虑症、病毒感染等。
Description
技术领域
本发明属于生物医药领域,涉及一类IDO/HDAC双靶点化合物及其合成方法和用途。
背景技术
表观遗传学的改变,包括组蛋白的修饰和DNA甲基化,在许多疾病(包括癌症等)的发病机理中都扮演着至关重要的作用。组蛋白的修饰是调控表观遗传现象的重要分子机制之一,其乙酰化水平取决于组蛋白乙酰化转移酶(HATs)和组蛋白去乙酰化转移酶(HDACs)(Jaenisch,R.et al.Nat Genet.2003,33 Suppl,245-54)。一般来讲,HATs的功能是在核心组蛋白上乙酰化,导致组蛋白电性中和,呈现更为开放的、可转录的染色质活性结构;而HDACs的功能是去乙酰化和抑制转录。染色质乙酰化与去乙酰化的平衡的移动将导致基因表达模式的改变(Kurdistani,S.K.et al.Nat Rev Mol Cell Biol 2003,4(4),276-84)。大部分组蛋白在肿瘤细胞中的乙酰化状态偏低,染色质致密卷曲,导致一些抑癌基因的有效表达。HDACs在多数肿瘤细胞中异常表达,HDAC抑制剂能使组蛋白乙酰化水平提高,核小体结构松弛,从而使各种转录因子和协同转录因子能与DNA结合位点特异性结合,激活一些抑癌基因的转录,导致肿瘤细胞的凋亡。因此,HDAC已成为抗癌药物中具有潜力的靶点之一。
IDO,吲哚胺2,3-双加氧酶,是细胞内一种含亚铁血红霉素的单体酶,能将色氨酸通过犬尿氨酸的途径进行代谢分解。IDO有三种不同的亚型,分别为IDO1,IDO2和TDO,TDO主要分布于肝脏中,而IDO1广泛分布于除肝脏以外的其他组织中,包括成纤维细胞、上皮细胞、巨噬细胞和树突状细胞。在正常生理状态下IDO1表达水平较低,但在某些特殊或病理状态下,如妊娠、器官移植、慢性感染和肿瘤情况下,IDO1的表达呈明显上调的趋势。
近年来大量研究表明,IDO在肿瘤的免疫逃逸中起重要作用。一方面,IDO的过度表达使人体局部色氨酸衰竭,而色氨酸是T细胞增殖必需氨基酸,T细胞增殖中的G1期中期对色氨酸缺乏非常敏感,在这种环境下,T细胞不能有效增殖,并且容易发生凋亡而被清除。另一方面,IDO催化色氨酸代谢生成犬尿氨酸,这种代谢产物的大量累积也会抑制T细胞的功能,甚至诱导T细胞凋亡。除此之外,IDO还可以诱导Treg细胞的增殖来抑制效应T细胞的活性。用不含色氨酸的培养基培养模拟体内色氨酸缺乏的环境,发现小鼠初始T细胞经刺激活化后能表达早期细胞激活信号(CD25和CD69),但不能表达晚期细胞激活信号(CD71、周期素D3和细胞周期素依赖性蛋白激酶4),T细胞停止在G1期中期,最终不能分化为细胞毒性效应T细胞。此外,IDO可以诱导在肿瘤细胞免疫中发挥主要作用的Th1细胞的凋亡,因此,肿瘤细胞可以通过表达IDO来阻断T细胞周期进展以及诱导Th1细胞凋亡,最终诱导抗原特异性的T细胞免疫耐受。以转染了IDO的细胞系或高表达IDO的转基因小鼠分别进行体外和体内试验,结果显示与IDO转染细胞共培养的T细胞并不增殖,但可以表达活化标志,以转染IDO基因的肿瘤细胞接种小鼠后,其同种T细胞反应能力显著降低(Lee G K.etal.Immunology.2002,107(4),452—460)。IDO表达增加后,其结果会消耗局部色氨酸以及产生犬尿氨酸等代谢产物。Brandacher等研究了140例结直肠癌患者肿瘤细胞中IDO表达和肿瘤局部浸润性T淋巴细胞的情况,发现肿瘤细胞通过消耗局部色氨酸和产生代谢产物诱导局部免疫耐受,同时肿瘤局部浸润性T淋巴细胞明显减少(Brandacher G.etal.ClinCancerRes.2006,12(4),1144-1151)。
综上所述,HDAC和IDO已经成为抗癌药物中非常具有潜力的两个靶点。HDAC抑制剂能抑制肿瘤细胞增殖、阻断细胞周期,促进细胞凋亡。IDO抑制剂能抑制色氨酸的降解,以及扭转树突状细胞对T细胞的抑制,激活T细胞产生免疫反应最终抑制或杀死肿瘤组织。因此,同时具有IDO和HDAC抑制活性的小分子化合物在某种程度上对治疗癌症具有协同性和互补性。除此之外,IDO已被证实与自身免疫性疾病、阿尔兹海默症、抑郁症、焦虑症、病毒感染等多种人类重大疾病密切相关。
发明内容
为了克服上述现有技术的不足,本发明提供了一类结构新颖的可作为IDO和HDAC双靶点抑制剂的小分子化合物。
本发明提供了一种IDO/HDAC双靶点化合物或其水合物或药学上可接受的盐,其结构式如式(I)所示:
其中,X为氮原子或碳原子;
m,n=0-3;
p=0-8;
A选自下列基团中的一个或不存在:-O-、-SO-、-SO2-、-CONR-、-NRCO-、-NR-、-CO-;其中R为氢、C1-8烷基及其异构体、C3-8的环烷基;
U为CR1或N;
V为CR2或N;
W为CR3或N;
Z为CR4或N;
其中,R1,R2,R3,R4独立的选自下列基团中的任意一个,包括氢,C1-8烷基(包括:甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、异戊基、新戊基、正己基)及其异构体,卤素包括(F、Cl、Br、I),硝基,氨基,氰基,二氟甲基,三氟甲基,甲氧基,乙氧基,异丙氧基,二氟甲氧基,三氟甲氧基,羟基;
R9选自下列基团中的任意一个,包括C1-6烷基(包括:甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、异戊基、新戊基、正己基及其异构体);C3-6环烷基(包括:环丙基、环丁基、环戊基、环己基及其同分异构体),其中环烷基上可以包含杂原子(O、N、S、SO、SO2)或是一个或多个卤素取代(F、Cl、Br、I);苯基、含一个或多个杂原子的五元或六元杂环芳香基(包括:异唑基、异噻唑基、吡唑基、吡啶基、恶唑基、噻唑、咪唑、三唑、四唑、呋喃基、三嗪基、噻吩、嘧啶、哒嗪、吡嗪)、取代的苯基及取代的五元或六元杂环芳香基(所述取代的苯基及取代的五元或六元杂环芳香基有一个或多个取代基,包括:F、Cl、Br、I、羟基、甲基、乙基、异丙基、甲氧基、三氟甲基、二氟甲氧基、三氟甲氧基、硝基、-CN、氨基);苯并杂环基,其中,杂环包括C3-6的环烷基,其中环烷基上包含1个或多个杂原子O、N、S、SO、SO2或是一个或多个卤素或羟基取代,包括并不限于下列基团:
其中,
X5为CR5或N;
X6为CR6或N;
X7为CR7或N;
X8为CR8或N;
R5,R6,R7,R8独立的选自下列基团中的任意一个,包括氢,C1-6烷基(包括:甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、异戊基、新戊基、正己基及其异构体),卤素包括(F、Cl、Br、I),硝基,氨基,氰基,二氟甲基,三氟甲基,二氟甲氧基,三氟甲氧基,羟基,-OR11;
其中,R11包括C1-6烷基(包括:甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、异戊基、新戊基、正己基及其异构体);C3-6环烷基(包括:环丙基、环丁基、环戊基、环己基及其同分异构体),其中环烷基上可以包含杂原子(O、N、S、SO、SO2)或是一个或多个卤素取代(F、Cl、Br、I);苯基、含一个或多个杂原子的五元或六元杂环芳香基(包括:异唑基、异噻唑基、吡唑基、吡啶基、恶唑基、噻唑、咪唑、三唑、四唑、呋喃基、三嗪基、噻吩、嘧啶、哒嗪、吡嗪)、取代的苯基及取代的五元或六元杂环芳香基(所述取代的苯基及取代的五元或六元杂环芳香基有一个或多个取代基,包括:F、Cl、Br、I、羟基、甲基、乙基、异丙基、甲氧基、三氟甲基、二氟甲氧基、三氟甲氧基、硝基、-CN、氨基);
本发明还提供了一种IDO/HDAC双靶点化合物或其水合物或药学上可接受的盐,其结构如式(II)所示:
其中,Y为氮原子或碳原子;
m,n=0-3;
p=0-8;
A选自下列基团中的一个或不存在:-O-、-SO-、-SO2-、-CONR-、-NRCO-、-NR-、-CO-;其中R为氢、C1-8烷基及其异构体、C3-8的环烷基;
U为CR1或N;
V为CR2或N;
W为CR3或N;
Z为CR4或N;
其中,R1,R2,R3,R4独立的选自下列基团中的任意一个,包括氢,C1-8烷基(包括:甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、异戊基、新戊基、正己基)及其异构体,卤素包括(F、Cl、Br、I),硝基,氨基,氰基,二氟甲基,三氟甲基,甲氧基,乙氧基,异丙氧基,二氟甲氧基,三氟甲氧基,羟基;
R9选自下列基团中的任意一个,包括C1-6烷基(包括:甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、异戊基、新戊基、正己基及其异构体);C3-6环烷基(包括:环丙基、环丁基、环戊基、环己基及其同分异构体),其中环烷基上可以包含杂原子(O、N、S、SO、SO2)或是一个或多个卤素取代(F、Cl、Br、I);苯基、含一个或多个杂原子的五元或六元杂环芳香基(包括:异唑基、异噻唑基、吡唑基、吡啶基、恶唑基、噻唑、咪唑、三唑、四唑、呋喃基、三嗪基、噻吩、嘧啶、哒嗪、吡嗪)、取代的苯基及取代的五元或六元杂环芳香基(所述取代的苯基及取代的五元或六元杂环芳香基有一个或多个取代基,包括:F、Cl、Br、I、羟基、甲基、乙基、异丙基、甲氧基、三氟甲基、二氟甲氧基、三氟甲氧基、硝基、-CN、氨基);苯并杂环基,其中,杂环包括C3-6的环烷基,其中,环烷基上包含1个或多个杂原子O、N、S、SO、SO2或是一个或多个卤素或羟基取代,包括并不限于下列基团:
其中,
X5为CR5或N;
X6为CR6或N;
X7为CR7或N;
X8为CR8或N;
R5,R6,R7,R8独立的选自下列基团中的任意一个,包括氢,C1-6烷基(包括:甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、异戊基、新戊基、正己基)及其异构体,卤素包括(F、Cl、Br、I),硝基,氨基,氰基,二氟甲基,三氟甲基,二氟甲氧基,三氟甲氧基,羟基,-OR11;
其中,R11包括C1-6烷基(包括:甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、异戊基、新戊基、正己基及其异构体);C3-6环烷基(包括:环丙基、环丁基、环戊基、环己基及其同分异构体),其中环烷基上可以包含杂原子(O、N、S、SO、SO2)或是一个或多个卤素取代(F、Cl、Br、I);苯基、含一个或多个杂原子的五元或六元杂环芳香基(包括:异唑基、异噻唑基、吡唑基、吡啶基、恶唑基、噻唑、咪唑、三唑、四唑、呋喃基、三嗪基、噻吩、嘧啶、哒嗪、吡嗪)、取代的苯基及取代的五元或六元杂环芳香基(所述取代的苯基及取代的五元或六元杂环芳香基有一个或多个取代基,包括:F、Cl、Br、I、羟基、甲基、乙基、异丙基、甲氧基、三氟甲基、二氟甲氧基、三氟甲氧基、硝基、-CN、氨基)。
根据本发明的实施例,本发明所述式(I)-(II)所示的IDO/HDAC双靶点化合物或其水合物或药学上可接受的盐,包括:
4-((1H-吲哚基)甲基))-1-苯甲羟肟酸
4-((1H-苯并咪唑)甲基))-1-苯甲羟肟酸
4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸甲酯
N-(3,4-亚甲二氧基苯基)-1-(4-(甲磺酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-甲酰基苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-((羟胺)亚甲基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(肼基甲酰基)苄基)-1H-吲哚-3-甲酰胺
4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸
N-(3,4-亚甲二氧基苯基)-1-(4-(甲氧基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(甲氧基氨甲基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-氰基苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(羟甲基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(苯丙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(2,4-二甲氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,5-二甲氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3-甲氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(4-氟苯乙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
3-Boc-哌嗪基甲酰基-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚
N-(苯丁基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(2-金刚烷胺基)-1-(4-(羟基氨基甲酰基)苄基)-5-甲氧基-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-5-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-6-甲酰胺
N-(对羟基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-2-甲酰胺
N-(3,4-亚甲二氧基苯乙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苄基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-苯并咪唑-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-5-甲基-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-氟)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-氯)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-溴)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-3-甲氧基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2,6-二氯)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2,6-二甲氧基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-甲氧基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2,6-二氟)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-(3-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
吗啉基甲酰基-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲唑-3-甲酰胺
(7-(3-((3,4-亚甲二氧基苯胺基)甲酰基))-吲哚基)庚酰羟胺
(6-(3-((3,4-亚甲二氧基苯胺基)甲酰基))-吲哚基)己酰羟胺
(5-(3-((3,4-亚甲二氧基苯胺基)甲酰基))-吲哚基)戊酰羟胺
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基乙酰基)苄基)-1H-吲哚-3-甲酰胺
N-(1-苯乙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(2-苯丙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-乙氧基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-(2-甲氧基乙氧基))苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-异丙氧基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-环丙氧基)苄基)-1H-吲哚-3-甲酰胺
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-异丁氧基)苄基)-1H-吲哚-3-甲酰胺。
本发明所述式(I)和式(II)所示的IDO/HDAC双靶点化合物的药学上可接受的盐,包括但不限于所述化合物与下列酸形成的酸加成盐;所述酸包括盐酸、氢溴酸、硫酸、磷酸、乙酸、酒石酸、水杨酸、柠檬酸、苹果酸、甲磺酸、对甲苯磺酸、乳酸、丙酮酸、马来酸、琥珀酸等。
本发明所述式(I)和式(II)所示的IDO/HDAC双靶点化合物的药学上可接受的盐,包括但不限于所述化合物与下列碱形成的碱加成盐,所述碱包括从无机碱(烧碱、氢氧化钾、氢氧化钡、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁、氢氧化锌、纯碱、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾等)衍生的盐;从有机无毒碱(分子中含有氨基的有机化合物)衍生的盐,所述有机无毒碱包括一级、二级和三级胺、取代胺(包括天然取代胺)、环胺、乙醇胺、N-乙基吗啉、N-乙基哌啶、葡萄胺等。
本发明中,式(I)所述化合物可以与放射性、荧光基团或者生物素结合。
本发明还提供了一种药物组合物,所述药物组合物包括式(I)和式(II)所示的化合物或其水合物或药学上可接受的盐,以及药学上可接受的载体。所述药物组合物被配制成可注射流体、气雾剂、乳膏、凝胶剂、丸剂、胶囊剂、糖浆剂、透皮贴剂或赋形剂。
本发明所述药物组合物可单独使用或与其他药物联合使用。
本发明还提供了式(I)和式(II)所示的化合物或其水合物或药学上可接受的盐、或所述的药物组合物在制备IDO/HDAC双靶点抑制剂中的应用。
本发明还提供了式(I)和式(II)所示的化合物或其水合物或药学上可接受的盐、或所述的药物组合物在制备增强人或哺乳动物免疫能力或抗肿瘤药物中的应用;所述抗肿瘤是指抑制肿瘤细胞的增殖、生长、浸润和迁移。
其中,所述肿瘤包括肝癌、肺癌、前列腺癌、皮肤癌、结肠癌、胰腺癌、乳腺癌、白血病、淋巴癌、卵巢癌、胃癌、膀胱癌、肾癌、口腔癌、黑色素瘤、食道癌、宫颈癌等。
本发明还提供了式(I)和式(II)所示的化合物或其水合物或药学上可接受的盐、或所述的药物组合物在治疗恶性肿瘤的药物中的应用,其用于抑制恶性肿瘤的生长、转移,预防恶性肿瘤的复发;其中,所述恶性肿瘤包括但不限于肝癌、肺癌、前列腺癌、皮肤癌、结肠癌、胰腺癌、乳腺癌、白血病、淋巴癌、卵巢癌、胃癌、膀胱癌、肾癌、口腔癌、黑色素瘤、食道癌、淋巴癌、宫颈癌等。
本发明还提供了式(I)和式(II)所示的化合物或其水合物或药学上可接受的盐、或所述的药物组合物,在制备具有IDO介导的色氨酸代谢途径的病理性特征的疾病的药物中的应用;所述疾病包括自身免疫性疾病、阿尔兹海默症、抑郁症、焦虑症、病毒感染等。
本发明还提供了一种制备式(I)-(II)所示的化合物的方法,合成路线如反应式(1)所示:
试剂和条件:(a)ΗATU;DIPEA;DMF;室温;4h;(b)4-溴甲基苯甲酸甲酯;Cs2CO3;MeCN;室温;5h;(c)NH2OH·HCl;KOH;MeOH;室温;5h。
本发明还提供了一种制备式(I)-(II)所示的化合物的方法,合成路线如反应式(2)所示:
试剂和条件:(a)ΗATU;DIPEA;DMF;室温;4h;(b)4-溴甲基苯甲酸甲酯;Cs2CO3;MeCN;室温;5h;(c)NH2OH·HCl;KOH;MeOH;室温;5h。
本发明还提供了一种制备式(I)-(II)所示的化合物的方法,合成路线如反应式(3)所示:
试剂和条件:(a)R4Br;Cs2CO3;MeCN;室温;5h;(b)NBS;AIBN;CHCl3;回流;16h;(c)Cs2CO3;MeCN;室温;5h;(d)NH2OH·HCl;KOH;MeOH;室温;5h。
本发明还提供了一种制备式(I)-(II)所示的化合物的方法,合成路线如反应式(4)所示:
试剂和条件:(a)MeOH:H2O:THF=2:1:2;室温;2h(b)HATU;DIPEA;DMF;室温;6h;(c)NH2NH2·H2O;MeOH;回流;15h。
本发明还提供了一种制备式(I)-(II)所示的化合物的方法,合成路线如反应式(5)所示:
试剂和条件:(d)Cs2CO3;MeCN;室温;5h;(e)NH2OH·HCl;MeOH;50℃;5h(f)BuOK;BuOH;回流;15h;(g)多聚甲醛;K2CO3;室温;24h。
合成本发明化合物所涉及到的反应包括酰胺反应,水解反应,自由基反应,取代反应。反应路线是现有技术常规采用的方法,反应条件简单,反应步骤少,产率较高,原料价格低廉易得,对小试、中试及放大具有重大的指导价值。反应完毕后一般用冰水淬灭,用乙酸乙酯或二氯甲烷等溶剂萃取,分别用水和饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸馏除去溶剂,经柱层析得到最终产物。得到的产物用核磁共振、质谱、高效液相色谱等方法证明化合物结构和纯度。
本发明的有益效果包括:本发明化合物能够用于治疗恶性肿瘤的生长、转移和复发等疾病,作为IDO/HDAC双靶点的小分子抑制剂用于治疗恶性肿瘤,提高目前IDO和HDAC单靶点小分子抗癌药物的疗效,以及用于具有IDO介导的色氨酸代谢途径的病理性特征的疾病。上述制备方法为合成专利化合物的成熟路线,反应路线简单,反应步骤少,产率较高,原料价格低廉易得,对小试、中试及放大具有重大的指导价值。
附图说明
图1为本发明化合物BE014的抑制类型图。
图2为本发明化合物BE014对血浆中犬尿氨酸浓度的影响图。
具体实施方式
结合以下具体实施例和附图,对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
1H-NMR用Bruker 500MHz型仪和Bruker 400MHz型仪测定;MS用Bruker MicroTOF-Q LCMS型仪测定,除注明外均为ESI方式;所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得;除特别说明外,所有反应均是在氩气保护下进行并用TLC跟踪,后处理时均经饱和食盐水洗和无水硫酸镁干燥过程;产品的纯化除特别说明外均使用硅胶(200-300目)的柱色谱法;所使用的硅胶,包括200-300目和GF254为青岛海洋化工厂或烟台缘博硅胶公司生产。
实施例1-1、化合物4-((1H-吲哚基)甲基))-1-苯甲羟肟酸(BE001)的制备
取吲哚(352mg,3.0mmol)于乙腈(10ml)中,加入碳酸铯(1955mg,6.0mmol)和4-溴甲基苯甲酸甲酯(825mg,3.6mmol),在室温下搅拌12h。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体4-((1H-吲哚基)甲基))-1-苯甲酸甲酯(557mg,2.1mmol)。
40℃时在盐酸羟胺(1.96g,28.0mmol)的甲醇(20ml)溶液中加入KOH(1.58g,28.0mmol)并保持10min,然后将反应体系冷却至0℃后过滤,再将上述酯加入到滤液中,随后加入KOH(158mg,2.8mmol),反应体系在室温下保持30min。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规后处理后过硅胶柱,得产物BE001(145mg,45%)。1H NMR(500MHz,DMSO)δ11.13(s,1H),8.99(s,1H),7.67(d,J=8.2Hz,2H),7.56(d,J=7.8Hz,1H),7.52(d,J=3.1Hz,1H),7.42(d,J=8.2Hz,1H),7.23(d,J=8.2Hz,2H),7.09(dd,J=7.6,7.1Hz,1H),7.02(dd,J=12.9,5.6Hz,1H),6.50(d,J=3.0Hz,1H),5.48(s,2H)。
实施例1-2、表1所示BE系列化合物的制备(具体过程见下文)
表1
实施例1-3、化合物4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸甲酯(BE003)的制备
取3-吲哚甲酸(483mg,3.0mmol),3,4-亚甲二氧基苯胺(411mg,3.0mmol),HATU(1369mg,3.6mmol),DIPEA(1.3ml,7.5mmol)于N,N-二甲基甲酰胺(5ml)中反应6h。反应结束后,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体N-(3,4-亚甲二氧基苯基)-1H-吲哚-3-甲酰胺(505mg,1.8mmol)。
取中间体N-(3,4-亚甲二氧基苯基)-1H-吲哚-3-甲酰胺(505mg,1.8mmol)于乙腈(20ml)中,加入碳酸铯(1759mg,5.4mmol)和4-溴甲基苯甲酸甲酯(495mg,2.2mmol),在室温下搅拌12h。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE003(622mg,1.4mmol)。1H NMR(500MHz,DMSO)δ8.13(d,J=8.2Hz,1H),7.86(d,J=8.0Hz,2H),7.46(d,J=8.0Hz,3H),7.16(s,1H),7.11(d,J=8.1Hz,2H),6.81(s,1H),6.72(d,J=8.2Hz,1H),6.63(s,1H),6.53(d,J=8.1Hz,1H),5.37(s,2H),5.09(s,2H),3.83(s,3H).
实施例1-3至1-6、表2所示BE系列化合物的制备(具体过程见下文)
表2
实施例1-7、化合物N-(3,4-亚甲二氧基苯基)-1-(4-((羟胺)亚甲基)苄基)-1H-吲哚-3-甲酰胺(BE007)的制备
取中间体N-(3,4-亚甲二氧基苯基)-1-(4-甲酰基苄基)-1H-吲哚-3-甲酰胺(413mg,1.0mmol)溶于甲醇(20ml),加入盐酸羟胺(209mg,3.0mmol),在40℃条件下反应4h。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE007(265mg)。1H NMR(500MHz,DMSO)δ11.22(s,1H),9.71(s,1H),8.34(s,1H),8.20(d,J=8.6Hz,1H),8.10(s,1H),7.62–7.44(m,4H),7.31–7.11(m,5H),6.88(d,J=8.2Hz,1H),5.99(s,2H),5.53(s,2H).
实施例1-8、化合物N-(3,4-亚甲二氧基苯基)-1-(4-肼基甲酰基苄基)-1H-吲哚-3-甲酰胺(BE008)的制备
取中间体4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸甲酯(50mg)溶于甲醇(15ml)中,加入一水合肼(10ml),回流72h。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE008(21mg)。1H NMR(500MHz,DMSO)δ9.72(s,2H),8.36(s,1H),8.20(d,J=7.2Hz,1H),7.78(d,J=8.3Hz,2H),7.54(d,J=7.4Hz,1H),7.46(s,1H),7.31(d,J=8.3Hz,2H),7.22–7.12(m,3H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.57(s,2H),4.46(s,2H).
实施例1-9、化合物4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸(BE009)的制备
取中间体4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸甲酯(311mg,0.7mmol)溶于混合溶剂四氢呋喃(4ml)、甲醇(4ml)和水(2ml)中,加入氢氧化锂一水合物(147mg,3.5mmol)。室温下反应3h。反应结束后,减压除去溶剂,用3N HCl的酸化后,用乙酸乙酯和水萃取后得到粗产物BE009(301mg,0.7mmol)。1H NMR(500MHz,DMSO)δ10.04(s,1H),8.15(d,J=8.0Hz,1H),7.90(d,J=8.7Hz,2H),7.48(d,J=8.5Hz,3H),7.22(s,1H),7.11(d,J=8.3Hz,2H),6.81(s,1H),6.78(d,J=8.5Hz,1H),6.63(s,1H),6.53(d,J=8.1Hz,1H),5.37(s,2H),5.09(s,2H).
实施例1-10、化合物N-(3,4-亚甲二氧基苯基)-1-((4-甲氧基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE010)的制备
取4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸(301mg,0.7mmol),甲氧基胺盐酸盐(59mg,0.7mmol),HATU(304mg,0.8mmol),DIPEA(0.3ml,1.7mmol)于N,N-二甲基甲酰胺(5ml)中反应6h。反应结束后,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE010。1H NMR(500MHz,DMSO)δ11.70(s,1H),9.72(s,1H),8.35(s,1H),8.20(d,J=7.9Hz,1H),7.71(d,J=7.8Hz,2H),7.51(d,J=7.7Hz,1H),7.46(s,1H),7.33(d,J=8.0Hz,2H),7.22–7.16(m,2H),7.13(d,J=8.4Hz,1H),6.89(d,J=8.3Hz,1H),6.00(s,2H),5.59(s,2H),3.68(s,3H)。
实施例1-11、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(甲氧基氨甲基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE011)的制备
将甲氧基胺盐酸盐置换成N-甲基-N-甲氧基胺盐酸盐,按制备化合物BE010的方法制备。1H NMR(500MHz,DMSO)δ9.72(s,1H),8.36(s,1H),8.20(d,J=7.6Hz,1H),7.60–7.52(m,3H),7.46(s,1H),7.29(d,J=7.6Hz,2H),7.23–7.15(m,2H),7.13(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),5.99(s,2H),5.58(s,2H),3.51(s,3H),3.22(s,3H)。
实施例1-12、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE012)的制备
取中间体N-(3,4-亚甲二氧基苯基)-1-(4-氰基苄基)-1H-吲哚-3-甲酰胺(421mg,1.1mmol)溶于正叔丁醇(10ml)中,加入叔丁醇钾(357mg,3.2mmol),反应回流过夜。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE012(112mg)。1HNMR(500MHz,DMSO)δ9.73(s,1H),8.36(s,1H),8.20(d,J=7.1Hz,1H),7.93(s,1H),7.83(d,J=8.3Hz,2H),7.53(d,J=7.5Hz,1H),7.46(s,1H),7.35(s,1H),7.32(d,J=8.2Hz,2H),7.23–7.15(m,2H),7.13(d,J=8.4Hz,1H),6.89(d,J=8.4Hz,1H),6.00(s,2H),5.58(s,2H).
实施例1-13、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟甲基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE013)的制备
取中间体N-(3,4-亚甲二氧基苯基)-1-(4-(氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(60mg,0.2mmol)于水中,加入碳酸钾(783mg,5.7mmol)和40%的福尔马林溶液(0.5ml),反应回流过夜。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE013(18mg)。1H NMR(500MHz,DMSO)δ9.73(s,1H),9.10(s,1H),8.36(s,1H),8.21(d,J=7.3Hz,1H),7.89–7.79(m,2H),7.53(d,J=7.6Hz,1H),7.47(s,1H),7.37–7.30(m,2H),7.23–7.16(m,2H),7.14(d,J=6.8Hz,1H),6.89(d,J=8.4Hz,1H),6.00(s,2H),5.59(s,2H),4.76–4.60(m,2H).
实施例1-14、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE014)的制备
在40℃时在盐酸羟胺(3.33g,50.7mmol)的甲醇(10ml)溶液中加入KOH(2.83g,50.7mmol),反应10min后将反应体系置于冰浴中,30min后抽滤得滤液,再将化合物4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸甲酯(118mg,0.27mmol)加入到滤液中,并在此体系中补加KOH(333mg,5.07mmol),在室温下反应2个小时后萃取过柱得产物BE014(65mg,55%)。1H NMR(500MHz,DMSO)δ11.17(s,1H),9.72(s,1H),9.01(s,1H),8.36(s,1H),8.20(d,J=7.3Hz,1H),7.77–7.67(m,2H),7.53(d,J=7.7Hz,1H),7.46(s,1H),7.32(d,J=8.1Hz,2H),7.22–7.10(m,3H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.57(s,2H)。
实施例1-14至1-47、表3所示BE系列化合物的制备(具体过程见下文)
表3
实施例1-48、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-乙氧基)苄基)-1H-吲哚-3-甲酰胺(BE048)的制备
将4-甲基-3-羟基苯甲酸甲酯(315mg,1.9mmol)溶于N,N-二甲基甲酰胺(5ml)中,冰浴条件下缓慢加入NaH(152mg,3.8mmol),至无气泡产生后加入溴乙烷(248mg,2.3mmol),在室温条件下反应1h。反应结束后,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体4-甲基-3-羟乙基苯甲酸甲酯(200mg,1.0mmol)。
取中间体4-甲基-3-羟乙基苯甲酸甲酯(200mg,1.0mmol)溶于三氯甲烷(15ml),加入N-溴代琥珀酰亚胺(214mg,1.2mmol)和催化量的偶氮二异丁腈(10mg)。在80℃条件下回流过夜。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体4-溴甲基-3-羟乙基苯甲酸甲酯(252mg,0.9mmol)。
取N-(3,4-亚甲二氧基苯基)-1H-吲哚-3-甲酰胺(280mg,1.0mmol)溶于乙腈(20ml),加入4-溴甲基-3-羟乙基苯甲酸甲酯(252mg,0.9mmol)和碳酸铯(815mg,2.5mmol),室温下反应过夜。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体N-(3,4-亚甲二氧基苯基)-1-(4-甲氧基甲酰基-2-乙氧基)苄基-1H-吲哚-3-甲酰胺(180mg)。
在40摄氏度时在盐酸羟胺(3.33g,50.7mmol)的甲醇(10ml)溶液中加入KOH(2.83g,50.7mmol),反应10min后将反应体系置于冰浴中,30min后抽滤得滤液,再将上述酯(180mg)加入到滤液中,并在此体系中补加KOH(333mg,5.07mmol),在室温下反应2个小时后萃取过柱得产物BE048。1H NMR(500MHz,DMSO)δ11.19(s,1H),9.69(s,1H),9.03(s,1H),8.29(s,1H),8.19(d,J=7.9Hz,1H),7.55(d,J=8.0Hz,1H),7.45(s,1H),7.38(s,1H),7.29(d,J=7.8Hz,1H),7.23–7.05(m,4H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.46(s,2H),4.22–4.10(m,2H),1.37(t,J=6.9Hz,3H)。
实施例1-48至1-52、表4所示BE系列化合物的制备(具体过程见下文)
表4
实施例2、本发明部分化合物对IDO1抑制活性检测
本发明中含人IDO1基因的质粒构建,在大肠杆菌中的扩增表达,以及提取纯化均按照Christopher等报道的方法进行(Austin,C.J.,et al.(2004).Protein Expr Purif37(2):392-398.)。本发明合成的化合物按照如下的方法检测:在96孔板中加入50mM的磷酸钾缓冲液(PH 6.5),10mM抗坏血酸钠,10μM亚甲基蓝,100μg/ml过氧化氢酶,200μM L-色氨酸,以及不同浓度的抑制剂。抑制剂的浓度设置为3.2805,10.935,36.45,121.5,405,1350,4500,15000,50000nM。37℃孵育5min后加入IDO1酶,37℃反应30min。之后加入30%(w/v)三氯乙酸终止反应,65℃放置15min,水解N-甲酰犬尿氨酸变成犬尿酸,然后2500rpm离心10min。每孔取100μL上清转移到新的96孔板内,加入100μL 2%(w/v)对二甲基氨基苯甲醛的乙酸溶液,最后在490nm下检测吸光值。
表5为本发明化合物对人IDO1蛋白的抑制率IC50。由表5可知,本发明实施例制备的大部分化合物对人IDO1蛋白具有较好的抑制率。
表5
*A:<100nM;B:100-1000nM;C:>1000nM;“-”代表活性未测试。
实施例3、本发明部分化合物对HDAC1和HDAC6酶活性的抑制
将MDA-MB231细胞接种在6厘米的细胞培养皿中,当细胞长到80%的密度时,分别加入本发明化合物和SAHA,作为对照组,细胞处理24小时后,去培养基,加入预冷的PBS,然后吸取PBS,加入细胞裂解液,刮下细胞至1.5毫升的离心管中,把离心管放在冰上,每五分钟一次涡旋离心管,共涡旋5次后,在4度离心机12000转离心15分钟,吸取上清至新的预冷离心管中,BCA法测蛋白浓度,含有40微克蛋白的loading缓冲液,在8%-12%的SDS蛋白分离胶上跑胶,待溴酚蓝跑出胶板后停止,在100伏电压下转膜1小时,在4度摇床孵育对应HDAC1和HDAC6的一抗过夜,用TBST每次10分钟洗三次,然后孵育对应二抗1小时,用TBST每次10分钟洗三次,用ECL试剂盒,曝光显示各目的条带。
表5为本发明化合物对HDAC1和HDAC6的抑制率IC50。由表5可知,本发明实施例制备的大部分化合物对HDAC1和HDAC6具有较好的抑制率。
实施例4、IDO1抑制剂类型的判断
在96孔板中加入50mM的磷酸钾缓冲液(PH 6.5),10mM抗坏血酸钠,10μM亚甲基蓝,100μg/ml过氧化氢酶,分别加入50、150、200、250μM L-色氨酸,在每一个底物浓度下,加入不同浓度的化合物,37℃孵育5min后加入IDO1酶,37℃反应30min。之后加入30%(w/v)三氯乙酸终止反应,65℃放置15min,水解N-甲酰犬尿氨酸变成犬尿酸,然后2500rpm离心10min。每孔取100μL上清转移到新的96孔板内,加入100μL 2%(w/v)对二甲基氨基苯甲醛的乙酸溶液,最后用酶标仪检测在490nm下吸光值。以双倒数作图法将1/V对1/[S]作图判定本发明化合物的抑制剂类型。
从图1可知,本发明化合物BE014是非竞争性IDO1抑制剂。
实施例5、细胞水平半数有效抑制浓度IC50的测定
细胞水平抑制活性测定采用的Hela细胞培养基为EMEM,含50U/ml青霉素,50U/ml链霉素,10%FBS,5%CO2培养。将Hela细胞以5000个/孔的密度接种于96孔板,24h后加入10ng/μL的IFN-γ及不同浓度的待测化合物,48h后每孔取140μL上清转移到新的96孔板内,加入10μL 100%(w/v)三氯乙酸终止反应。65℃放置15min,水解N-甲酰犬尿氨酸变成犬尿酸,然后2500rpm离心10min。每孔取100μL上清转移到新的96孔板内,加入100μL 2%(w/v)对二甲基氨基苯甲醛的乙酸溶液,最后用酶标仪检测在490nm下吸光值。
表5为本发明化合物在Hela细胞水平上对IDO1的半数有效抑制浓度IC50。由表5可知,本发明实施例制备的大部分化合物在细胞水平上具有较好的抑制率。
实施例6、血浆中犬尿氨酸含量测定
对IDO1的抑制活性通过血浆中犬尿氨酸的含量确定。体内模型选用8周大的C57雌鼠,给药处理前禁食过夜。给药方式为口服,给药剂量为50mg/kg,每组设置三个重复。给药后分别在0h,1h,4h,8h对小鼠进行眼球取血,并将血置于已加肝素的EP管中。4℃,8000rpm离心15min,取上清(血浆)保存于-20℃。之后利用液相色谱-串联质谱法对犬尿氨酸的含量进行检测。
通过图2可知,本发明化合物BE014能有效降低血浆中犬尿氨酸的浓度。
实施例1-1、化合物4-((1H-吲哚基)甲基))-1-苯甲羟肟酸(BE001)的制备
取吲哚(352mg,3.0mmol)于乙腈(10ml)中,加入碳酸铯(1955mg,6.0mmol)和4-溴甲基苯甲酸甲酯(825mg,3.6mmol),在室温下搅拌12h。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体4-((1H-吲哚基)甲基))-1-苯甲酸甲酯(557mg,2.1mmol)。
40℃时在盐酸羟胺(1.96g,28.0mmol)的甲醇(20ml)溶液中加入KOH(1.58g,28.0mmol)并保持10min,然后将反应体系冷却至0℃后过滤,再将上述酯加入到滤液中,随后加入KOH(158mg,2.8mmol),反应体系在室温下保持30min。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规后处理后过硅胶柱,得产物BE001(145mg,45%)。1H NMR(500MHz,DMSO)δ11.13(s,1H),8.99(s,1H),7.67(d,J=8.2Hz,2H),7.56(d,J=7.8Hz,1H),7.52(d,J=3.1Hz,1H),7.42(d,J=8.2Hz,1H),7.23(d,J=8.2Hz,2H),7.09(dd,J=7.6,7.1Hz,1H),7.02(dd,J=12.9,5.6Hz,1H),6.50(d,J=3.0Hz,1H),5.48(s,2H)。
实施例1-2、化合物4-((1H-苯并咪唑)甲基))-1-苯甲羟肟酸(BE002)的制备
将吲哚置换成苯并咪唑,按制备化合物BE001的方法制备。1H NMR(500MHz,DMSO)δ11.16(s,1H),9.02(s,1H),8.43(s,1H),7.75–7.64(m,3H),7.54–7.46(m,1H),7.36(d,J=8.3Hz,2H),7.25–7.14(m,2H),5.56(s,2H)。
实施例1-3、化合物4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸甲酯(BE003)的制备
取3-吲哚甲酸(483mg,3.0mmol),3,4-亚甲二氧基苯胺(411mg,3.0mmol),HATU(1369mg,3.6mmol),DIPEA(1.3ml,7.5mmol)于N,N-二甲基甲酰胺(5ml)中反应6h。反应结束后,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体N-(3,4-亚甲二氧基苯基)-1H-吲哚-3-甲酰胺(505mg,1.8mmol)。
取中间体N-(3,4-亚甲二氧基苯基)-1H-吲哚-3-甲酰胺(505mg,1.8mmol)于乙腈(20ml)中,加入碳酸铯(1759mg,5.4mmol)和4-溴甲基苯甲酸甲酯(495mg,2.2mmol),在室温下搅拌12h。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE003(622mg,1.4mmol)。1H NMR(500MHz,DMSO)δ8.13(d,J=8.2Hz,1H),7.86(d,J=8.0Hz,2H),7.46(d,J=8.0Hz,3H),7.16(s,1H),7.11(d,J=8.1Hz,2H),6.81(s,1H),6.72(d,J=8.2Hz,1H),6.63(s,1H),6.53(d,J=8.1Hz,1H),5.37(s,2H),5.09(s,2H),3.83(s,3H).
实施例1-4、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(甲磺酰基)苄基)-1H-吲哚-3-甲酰胺(BE004)的制备
将4-溴甲基苯甲酸甲酯置换成对甲磺酰基苄溴,按制备化合物BE003的方法制备。1HNMR(500MHz,DMSO)δ9.74(s,1H),8.37(s,1H),8.21(d,J=8.4Hz,1H),7.96–7.89(m,2H),7.55(d,J=7.5Hz,1H),7.53–7.41(m,3H),7.26–7.16(m,2H),7.16–7.10(m,1H),6.89(d,J=8.4Hz,1H),6.00(s,2H),5.67(s,2H),3.18(s,3H).
实施例1-5、化合物N-(3,4-亚甲二氧基苯基)-1-(4-甲酰基苄基)-1H-吲哚-3-甲酰胺(BE005)的制备
将4-溴甲基苯甲酸甲酯置换成对甲酰基苄溴,按制备化合物BE003的方法制备。1HNMR(500MHz,CDCl3)δ9.99(s,1H),8.10(d,J=7.8Hz,1H),7.92–7.79(m,3H),7.73(s,1H),7.41–7.25(m,6H),6.94(d,J=8.3Hz,1H),6.80(d,J=8.3Hz,1H),5.98(s,2H),5.44(s,2H).
实施例1-6、化合物N-(3,4-亚甲二氧基苯基)-1-(4-氰基苄基)-1H-吲哚-3-甲酰胺(BE006)的制备
将4-溴甲基苯甲酸甲酯置换成对氰基苄溴,按制备化合物BE003的方法制备。1HNMR(500MHz,CDCl3)δ8.18(d,J=7.6Hz,1H),7.95–7.83(m,3H),7.78(s,1H),7.46–7.29(m,6H),6.98(d,J=8.7Hz,1H),6.92(d,J=7.5Hz,1H),5.83(s,2H),5.38(s,2H).
实施例1-7、化合物N-(3,4-亚甲二氧基苯基)-1-(4-((羟胺)亚甲基)苄基)-1H-吲哚-3-甲酰胺(BE007)的制备
取中间体N-(3,4-亚甲二氧基苯基)-1-(4-甲酰基苄基)-1H-吲哚-3-甲酰胺(413mg,1.0mmol)溶于甲醇(20ml),加入盐酸羟胺(209mg,3.0mmol),在40℃条件下反应4h。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE006(265mg)。1H NMR(500MHz,DMSO)δ11.22(s,1H),9.71(s,1H),8.34(s,1H),8.20(d,J=8.6Hz,1H),8.10(s,1H),7.62–7.44(m,4H),7.31–7.11(m,5H),6.88(d,J=8.2Hz,1H),5.99(s,2H),5.53(s,2H).
实施例1-8、化合物N-(3,4-亚甲二氧基苯基)-1-(4-肼基甲酰基苄基)-1H-吲哚-3-甲酰胺(BE008)的制备
取中间体4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸甲酯(50mg)溶于甲醇(15ml)中,加入一水合肼(10ml),回流72h。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE008(21mg)。1H NMR(500MHz,DMSO)δ9.72(s,2H),8.36(s,1H),8.20(d,J=7.2Hz,1H),7.78(d,J=8.3Hz,2H),7.54(d,J=7.4Hz,1H),7.46(s,1H),7.31(d,J=8.3Hz,2H),7.22–7.12(m,3H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.57(s,2H),4.46(s,2H).
实施例1-9、化合物4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸(BE009)的制备
取中间体4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸甲酯(311mg,0.7mmol)溶于混合溶剂四氢呋喃(4ml)、甲醇(4ml)和水(2ml)中,加入氢氧化锂一水合物(147mg,3.5mmol)。室温下反应3h。反应结束后,减压除去溶剂,用3N HCl的酸化后,用乙酸乙酯和水萃取后得到粗产物BE009(301mg,0.7mmol)。1H NMR(500MHz,DMSO)δ10.04(s,1H),8.15(d,J=8.0Hz,1H),7.90(d,J=8.7Hz,2H),7.48(d,J=8.5Hz,3H),7.22(s,1H),7.11(d,J=8.3Hz,2H),6.81(s,1H),6.78(d,J=8.5Hz,1H),6.63(s,1H),6.53(d,J=8.1Hz,1H),5.37(s,2H),5.09(s,2H).
实施例1-10、化合物N-(3,4-亚甲二氧基苯基)-1-((4-甲氧基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE010)的制备
取4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸(301mg,0.7mmol),甲氧基胺盐酸盐(59mg,0.7mmol),HATU(304mg,0.8mmol),DIPEA(0.3ml,1.7mmol)于N,N-二甲基甲酰胺(5ml)中反应6h。反应结束后,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE010。1H NMR(500MHz,DMSO)δ11.70(s,1H),9.72(s,1H),8.35(s,1H),8.20(d,J=7.9Hz,1H),7.71(d,J=7.8Hz,2H),7.51(d,J=7.7Hz,1H),7.46(s,1H),7.33(d,J=8.0Hz,2H),7.22–7.16(m,2H),7.13(d,J=8.4Hz,1H),6.89(d,J=8.3Hz,1H),6.00(s,2H),5.59(s,2H),3.68(s,3H)。
实施例1-11、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(甲氧基氨甲基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE011)的制备
将甲氧基胺盐酸盐置换成N-甲基-N-甲氧基胺盐酸盐,按制备化合物BE010的方法制备。1H NMR(500MHz,DMSO)δ9.72(s,1H),8.36(s,1H),8.20(d,J=7.6Hz,1H),7.60–7.52(m,3H),7.46(s,1H),7.29(d,J=7.6Hz,2H),7.23–7.15(m,2H),7.13(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),5.99(s,2H),5.58(s,2H),3.51(s,3H),3.22(s,3H)。
实施例1-12、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE012)的制备
取中间体N-(3,4-亚甲二氧基苯基)-1-(4-氰基苄基)-1H-吲哚-3-甲酰胺(421mg,1.1mmol)溶于正叔丁醇(10ml)中,加入叔丁醇钾(357mg,3.2mmol),反应回流过夜。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE012(112mg)。1HNMR(500MHz,DMSO)δ9.73(s,1H),8.36(s,1H),8.20(d,J=7.1Hz,1H),7.93(s,1H),7.83(d,J=8.3Hz,2H),7.53(d,J=7.5Hz,1H),7.46(s,1H),7.35(s,1H),7.32(d,J=8.2Hz,2H),7.23–7.15(m,2H),7.13(d,J=8.4Hz,1H),6.89(d,J=8.4Hz,1H),6.00(s,2H),5.58(s,2H).
实施例1-13、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟甲基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE013)的制备
取中间体N-(3,4-亚甲二氧基苯基)-1-(4-(氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(60mg,0.2mmol)于水中,加入碳酸钾(783mg,5.7mmol)和40%的福尔马林溶液(0.5ml),反应回流过夜。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得产物BE013(18mg)。1H NMR(500MHz,DMSO)δ9.73(s,1H),9.10(s,1H),8.36(s,1H),8.21(d,J=7.3Hz,1H),7.89–7.79(m,2H),7.53(d,J=7.6Hz,1H),7.47(s,1H),7.37–7.30(m,2H),7.23–7.16(m,2H),7.14(d,J=6.8Hz,1H),6.89(d,J=8.4Hz,1H),6.00(s,2H),5.59(s,2H),4.76–4.60(m,2H).
实施例1-14、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE014)的制备
在40℃时在盐酸羟胺(3.33g,50.7mmol)的甲醇(10ml)溶液中加入KOH(2.83g,50.7mmol),反应10min后将反应体系置于冰浴中,30min后抽滤得滤液,再将化合物4-((3-((3,4-亚甲二氧基苯基)氨甲酰基)-1H-吲哚基)甲基)苯甲酸甲酯(118mg,0.27mmol)加入到滤液中,并在此体系中补加KOH(333mg,5.07mmol),在室温下反应2个小时后萃取过柱得产物BE014(65mg,55%)。1H NMR(500MHz,DMSO)δ11.17(s,1H),9.72(s,1H),9.01(s,1H),8.36(s,1H),8.20(d,J=7.3Hz,1H),7.77–7.67(m,2H),7.53(d,J=7.7Hz,1H),7.46(s,1H),7.32(d,J=8.1Hz,2H),7.22–7.10(m,3H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.57(s,2H)。
实施例1-15、化合物N-(苯丙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE015)的制备
将3,4-亚甲二氧基苯胺置换成苯基-3-丙胺,按制备化合物BE014的方法制备。1HNMR(500MHz,DMSO)δ11.16(s,1H),9.00(s,1H),8.15(d,J=7.4Hz,1H),8.12(s,1H),7.94(t,J=5.3Hz,1H),7.70(d,J=8.1Hz,2H),7.49(d,J=7.8Hz,1H),7.39–7.20(m,6H),7.21–7.08(m,3H),5.52(s,2H),3.30–3.23(m,2H),2.66(t,J=7.6Hz,2H),1.89–1.78(m,2H)。
实施例1-16、化合物N-(2,4-二甲氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE016)的制备
将3,4-亚甲二氧基苯胺置换成2,4-二甲氧基苯胺,按制备化合物BE014的方法制备。1H NMR(500MHz,DMSO)δ11.16(s,1H),9.01(s,1H),8.83(s,1H),8.39(s,1H),8.16–8.11(m,1H),7.75–7.65(m,3H),7.54(d,J=7.0Hz,1H),7.37–7.30(m,2H),7.22–7.17(m,2H),6.66(s,1H),6.54(d,J=8.7Hz,1H),5.56(s,2H),3.85(s,3H),3.78(s,3H)。
实施例1-17、化合物N-(3,5-二甲氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE017)的制备
将3,4-亚甲二氧基苯胺置换成3,5-二甲氧基苯胺,按制备化合物BE014的方法制备。1H NMR(500MHz,DMSO)δ11.17(s,1H),9.73(s,1H),9.02(s,1H),8.41(s,1H),8.22(d,J=7.2Hz,1H),7.79–7.66(m,2H),7.54(d,J=7.2Hz,1H),7.38–7.28(m,2H),7.25–7.15(m,2H),7.14–6.99(m,2H),6.27–6.17(m,1H),5.58(s,2H),3.75(s,6H)。
实施例1-18、化合物N-(3-甲氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE018)的制备
将3,4-亚甲二氧基苯胺置换成3-甲氧基苯胺,按制备化合物BE014的方法制备。1HNMR(500MHz,DMSO)δ11.16(s,1H),9.77(s,1H),9.01(s,1H),8.41(s,1H),8.21(d,J=7.1Hz,1H),7.71(d,J=8.1Hz,2H),7.53(d,J=7.6Hz,1H),7.46(s,1H),7.39–7.27(m,3H),7.25–7.09(m,3H),6.62(d,J=8.2Hz,1H),5.57(s,2H),3.76(s,3H)。
实施例1-19、化合物N-(4-氟苯乙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE019)的制备
将3,4-亚甲二氧基苯胺置换成4-氟苯乙胺,按制备化合物BE014的方法制备。1HNMR(500MHz,DMSO)δ11.16(s,1H),9.01(s,1H),8.12(d,J=7.2Hz,1H),8.08(s,1H),8.00(t,J=5.7Hz,1H),7.70(d,J=8.2Hz,2H),7.49(d,J=8.0Hz,1H),7.34–7.24(m,4H),7.20–7.07(m,4H),5.51(s,2H),3.49–3.42(m,2H),2.84(t,J=7.5Hz,2H).
实施例1-20、化合物3-Boc-哌嗪基甲酰基-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚(BE020)的制备
将3,4-亚甲二氧基苯胺置换成1-Boc-哌嗪,按制备化合物BE014的方法制备。1HNMR(500MHz,DMSO)δ11.15(s,1H),9.00(s,1H),7.99(s,1H),7.83–7.62(m,3H),7.48(s,1H),7.39–7.24(m,2H),7.25–7.03(m,2H),5.54(s,2H),3.65(s,4H),3.42(s,4H),1.46(s,9H)。
实施例1-21、化合物N-(苯丁基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE021)的制备
将3,4-亚甲二氧基苯胺置换成苯基-4-丁胺,按制备化合物BE014的方法制备。1HNMR(500MHz,DMSO)δ9.04(s,1H),8.15(d,J=7.6Hz,1H),8.10(s,1H),7.93(s,1H),7.70(d,J=8.0Hz,2H),7.49(d,J=7.9Hz,1H),7.36–7.24(m,4H),7.23–7.04(m,5H),5.51(s,2H),3.30–3.22(m,2H),2.62(t,J=7.5Hz,2H),1.67–1.50(m,4H).
实施例1-22、化合物N-(2-金刚烷胺基)-1-(4-(羟基氨基甲酰基)苄基)-5-甲氧基-1H-吲哚-3-甲酰胺(BE022)的制备
将3,4-亚甲二氧基苯胺置换成2-金刚烷胺,将吲哚-3-羧酸置换成5-甲氧基-3-吲哚羧酸,按制备化合物BE014的方法制备。1H NMR(500MHz,DMSO)δ11.15(s,1H),9.00(s,1H),8.36(s,1H),7.69(d,J=8.3Hz,2H),7.65(s,1H),7.35(d,J=8.6Hz,2H),7.27(d,J=8.2Hz,2H),6.78(d,J=8.9Hz,1H),5.47(s,2H),4.09(d,J=5.2Hz,1H),3.75(s,3H),2.17–2.10(m,2H),2.01–1.94(m,2H),1.89–1.72(m,8H),1.60–1.49(m,2H)。
实施例1-23、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-5-甲酰胺(BE023)的制备
将3-吲哚羧酸置换成5-吲哚羧酸,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.24(s,1H),10.05(s,1H),9.18(s,1H),8.20(s,1H),7.92–7.65(m,5H),7.55(s,1H),7.32(dd,J=14.0,6.8Hz,2H),7.20(d,J=8.0Hz,1H),6.85(d,J=8.0Hz,1H),6.58(s,1H),6.09(s,2H),5.75(s,2H)。
实施例1-24、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-6-甲酰胺(BE024)的制备
将3-吲哚羧酸置换成6-吲哚羧酸,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.14(s,1H),10.01(s,1H),9.01(s,1H),8.09(s,1H),7.82–7.62(m,5H),7.45(s,1H),7.25(dd,J=14.5,7.3Hz,2H),7.18(d,J=8.4Hz,1H),6.89(d,J=8.4Hz,1H),6.61(s,1H),6.01(s,2H),5.59(s,2H)。
实施例1-25、化合物N-(对羟基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE025)的制备
将3,4-亚甲二氧基苯胺置换成对羟基苯胺,按制备化合物BE014的方法制备。1HNMR(500MHz,DMSO)δ11.17(s,1H),9.58(s,1H),9.14(s,1H),9.01(s,1H),8.34(s,1H),8.20(d,J=7.8Hz,1H),7.72(d,J=8.2Hz,2H),7.52(dd,J=11.2,8.5Hz,2H),7.32(d,J=8.2Hz,2H),7.26–7.10(m,2H),6.73(d,J=8.8Hz,2H),5.56(s,2H).
实施例1-26、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-2-甲酰胺(BE026)的制备
将3-吲哚羧酸置换成2-吲哚羧酸,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.11(s,1H),10.33(s,1H),8.99(s,1H),7.74(d,J=7.9Hz,1H),7.62(d,J=8.2Hz,2H),7.53(d,J=8.4Hz,1H),7.40(d,J=1.9Hz,1H),7.39(s,1H),7.27(dd,J=7.7Hz,J=7.5Hz,1H),7.22–7.07(m,4H),6.89(d,J=8.4Hz,1H),6.01(s,2H),5.90(s,2H).
实施例1-27、化合物N-(3,4-亚甲二氧基苯乙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE027)的制备
将3,4-亚甲二氧基苯胺置换成胡椒乙胺,按制备化合物BE014的方法制备。1H NMR(500MHz,DMSO)δ11.19(s,1H),8.25–8.08(m,2H),8.01(s,1H),7.70(d,J=8.1Hz,2H),7.50(d,J=8.0Hz,1H),7.28(d,J=8.2Hz,2H),7.19–7.09(m,2H),7.06–6.89(m,1H),6.86–6.80(m,2H),6.71(d,J=7.9Hz,1H),5.97(s,2H),5.52(s,2H),3.48–3.38(m,2H),2.82–2.71(m,2H).
实施例1-28、化合物N-(3,4-亚甲二氧基苄基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE028)的制备
将3,4-亚甲二氧基苯胺置换成3,4-亚甲二氧基苄胺,按制备化合物BE014的方法制备。1H NMR(500MHz,DMSO)δ11.15(s,1H),9.00(s,1H),8.42(dd,J=6.0,6.0Hz,1H),8.26–8.06(m,2H),7.70(d,J=8.2Hz,2H),7.51(d,J=7.7Hz,1H),7.29(d,J=8.2Hz,2H),7.21–7.10(m,2H),6.96–6.76(m,3H),5.98(s,2H),5.52(s,2H),4.37(d,J=5.9Hz,2H)。
实施例1-29、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-苯并咪唑-3-甲酰胺(BE029)的制备
将3-吲哚羧酸置换成苯并咪唑-3-羧酸,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.13(s,1H),10.90(s,1H),10.43(s,1H),7.96–7.79(m,2H),7.69(dd,J=12.9,5.6Hz,2H),7.52(d,J=5.3Hz,1H),7.47–7.36(m,3H),7.32–7.24(m,2H),6.91(d,J=8.4Hz,1H),6.14–5.99(m,4H)。
实施例1-30、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-5-甲基-1H-吲哚-3-甲酰胺(BE030)的制备
将3-吲哚羧酸置换成5-甲基-吲哚-3-羧酸,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.16(s,1H),9.68(s,1H),8.31(s,1H),8.00(s,1H),7.70(d,J=7.9Hz,3H),7.47(s,1H),7.40(d,J=8.4Hz,1H),7.28(d,J=8.1Hz,2H),7.13(d,J=8.4Hz,1H),7.02(d,J=8.3Hz,1H),6.87(d,J=8.4Hz,1H),5.99(s,2H),5.53(s,2H),2.39(s,3H).
实施例1-31、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-氟)苄基)-1H-吲哚-3-甲酰胺(BE031)的制备
将4-溴甲基苯甲酸甲酯置换成3-氟-4-溴甲基苯甲酸甲酯,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.29(s,1H),9.73(s,1H),9.15(s,1H),8.32(s,1H),8.22(d,J=7.5Hz,1H),7.73–7.43(m,4H),7.31–7.04(m,4H),6.88(d,J=8.0Hz,1H),6.00(s,2H),5.62(s,2H)。
实施例1-32、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-氯)苄基)-1H-吲哚-3-甲酰胺(BE032)的制备
将4-溴甲基苯甲酸甲酯置换成3-氯-4-溴甲基苯甲酸甲酯,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.33(s,1H),9.73(s,1H),9.17(s,1H),8.28(s,1H),8.24(d,J=7.4Hz,1H),7.88(s,1H),7.65(d,J=8.5Hz,1H),7.50(d,J=7.4Hz,1H),7.45(s,1H),7.26–7.17(m,2H),7.12(d,J=8.8Hz,1H),6.95(d,J=8.0Hz,1H),6.88(d,J=8.5Hz,1H),6.00(s,2H),5.65(s,2H)。
实施例1-33、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-溴)苄基)-1H-吲哚-3-甲酰胺(BE033)的制备
将4-溴甲基苯甲酸甲酯置换成3-溴-4-溴甲基苯甲酸甲酯,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.33(s,1H),9.73(s,1H),9.16(s,1H),8.27(s,1H),8.24(d,J=7.9Hz,1H),8.06(s,1H),7.68(d,J=8.0Hz,1H),7.53–7.41(m,2H),7.30–7.16(m,2H),7.12(d,J=8.4Hz,1H),6.86(dd,J=15.8,8.2Hz,2H),6.00(s,2H),5.62(s,2H)。
实施例1-34、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-3-甲氧基)苄基)-1H-吲哚-3-甲酰胺(BE034)的制备
将4-溴甲基苯甲酸甲酯置换成2-甲氧基-4-溴甲基苯甲酸甲酯,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ10.57(s,1H),9.72(s,1H),9.05(s,1H),8.36(s,1H),8.20(d,J=7.5Hz,1H),7.57(d,J=8.0Hz,1H),7.53–7.41(m,2H),7.29–7.04(m,4H),6.88(d,J=8.4Hz,1H),6.76(d,J=7.9Hz,1H),6.00(s,2H),5.54(s,2H),3.81(s,3H)。
实施例1-35、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2,6-二氯)苄基)-1H-吲哚-3-甲酰胺(BE035)的制备
将4-溴甲基苯甲酸甲酯置换成3,5-二氯-4-溴甲基苯甲酸甲酯,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.54(s,1H),9.62(s,1H),9.36(s,1H),8.24(d,J=7.8Hz,1H),8.02–7.93(m,2H),7.91(s,1H),7.69(d,J=8.2Hz,1H),7.37(s,1H),7.31–7.26(m,1H),7.21(t,J=7.5Hz,1H),7.03(d,J=8.2Hz,1H),6.86(d,J=8.4Hz,1H),5.99(s,2H),5.66(s,2H)。
实施例1-36、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2,6-二甲氧基)苄基)-1H-吲哚-3-甲酰胺(BE036)的制备
将4-溴甲基苯甲酸甲酯置换成3,5-二甲氧基-4-溴甲基苯甲酸甲酯,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.29(s,1H),9.67(s,1H),9.12(s,1H),8.24–8.11(m,2H),7.67(d,J=8.3Hz,1H),7.44(s,1H),7.30–7.07(m,5H),6.87(d,J=8.4Hz,1H),5.99(s,2H),5.35(s,2H),3.91(s,6H).
实施例1-37、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-甲氧基)苄基)-1H-吲哚-3-甲酰胺(BE037)的制备
将4-溴甲基苯甲酸甲酯置换成3-甲氧基-4-溴甲基苯甲酸甲酯,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.22(s,1H),9.71(s,1H),9.07(s,1H),8.30(s,1H),8.20(d,J=7.4Hz,1H),7.52(d,J=8.0Hz,1H),7.46(s,1H),7.42(s,1H),7.28(d,J=7.8Hz,1H),7.19(dt,J=15.5,6.6Hz,2H),7.13(d,J=8.4Hz,1H),6.95(d,J=7.9Hz,1H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.47(s,2H),3.92(s,3H).
实施例1-38、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2,6-二氟)苄基)-1H-吲哚-3-甲酰胺(BE038)的制备
将4-溴甲基苯甲酸甲酯置换成3,5-二氟-4-溴甲基苯甲酸甲酯,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.42(s,1H),9.72(s,1H),9.30(s,1H),8.27(s,1H),8.21(d,J=7.8Hz,1H),7.60(d,J=8.3Hz,1H),7.55(d,J=8.1Hz,2H),7.43(d,J=2.0Hz,1H),7.30–7.26(m,1H),7.22–7.17(m,1H),7.11(dd,J=8.4,8.0Hz,1H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.58(s,2H).
实施例1-39、化合物N-(3,4-亚甲二氧基苯基)-1-(3-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE039)的制备
将4-溴甲基苯甲酸甲酯置换成3-溴甲基苯甲酸甲酯,按制备化合物BE014制备。1HNMR(500MHz,DMSO)δ11.22(s,1H),9.73(s,1H),9.02(s,1H),8.36(s,1H),8.20(d,J=7.6Hz,1H),7.72(s,1H),7.64(d,J=7.6Hz,1H),7.55(d,J=7.9Hz,1H),7.46(s,1H),7.45–7.35(m,2H),7.24–7.15(m,2H),7.13(d,J=9.3Hz,1H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.56(s,2H)。
实施例1-40、化合物吗啉基甲酰基-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚(BE040)的制备
将3,4-亚甲二氧基苯胺置换成吗啉,按制备化合物BE014的方法制备。1H NMR(500MHz,DMSO)δ11.15(s,1H),9.01(s,1H),7.98(s,1H),7.73(d,J=7.6Hz,1H),7.69(d,J=8.0Hz,2H),7.48(d,J=7.9Hz,1H),7.31(d,J=8.0Hz,2H),7.23–7.07(m,2H),5.52(s,2H),3.65(s,4H),3.33(s,4H)。
实施例1-41、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲唑-3-甲酰胺(BE041)的制备
将吲哚-3-羧酸置换成吲唑-3-羧酸,按制备化合物BE014制备。1H NMR(500MHz,DMSO)δ11.16(s,1H),10.30(s,1H),9.02(s,1H),8.25(d,J=8.6Hz,1H),7.91(d,J=7.7Hz,1H),7.80(d,J=8.3Hz,1H),7.78–7.61(m,2H),7.55(s,1H),7.52–7.45(m,1H),7.39–7.29(m,3H),6.91(d,J=8.4Hz,1H),6.02(s,2H),5.88(s,2H)。
实施例1-42、化合物(7-(3-((3,4-亚甲二氧基苯胺基)甲酰基))-吲哚基)庚酰羟胺(BE042)的制备
将4-溴甲基苯甲酸甲酯置换成7-溴庚酸甲酯,按制备化合物BE014制备。1H NMR(400MHz,DMSO)δ10.34(s,1H),9.65(s,1H),8.67(s,1H),8.26(s,1H),8.19(d,J=7.6Hz,1H),7.57(d,J=7.9Hz,1H),7.48(s,1H),7.28–7.10(m,3H),6.88(d,J=8.3Hz,1H),6.00(s,2H),4.23(s,2H),1.93(t,J=6.8Hz,2H),1.35–1.20(m,8H)。
实施例1-43、化合物(6-(3-((3,4-亚甲二氧基苯胺基)甲酰基))-吲哚基)己酰羟胺(BE043)的制备
将4-溴甲基苯甲酸甲酯置换成6-溴己酸甲酯,按制备化合物BE014制备。1H NMR(400MHz,DMSO)δ10.36(s,1H),9.68(s,1H),8.69(s,1H),8.26(s,1H),8.18(d,J=7.8Hz,1H),7.56(d,J=8.1Hz,1H),7.48(s,1H),7.27–7.08(m,3H),6.88(d,J=8.3Hz,1H),5.99(s,2H),4.23(t,J=6.8Hz,2H),2.00–1.88(m,2H),1.85–1.74(m,2H),1.62–1.48(m,2H),1.28–1.20(m,2H)。
实施例1-44、化合物(5-(3-((3,4-亚甲二氧基苯胺基)甲酰基))-吲哚基)戊酰羟胺(BE044)的制备
将4-溴甲基苯甲酸甲酯置换成5-溴戊酸甲酯,按制备化合物BE014制备。1H NMR(400MHz,DMSO)δ10.36(s,1H),9.65(s,1H),8.67(s,1H),8.24(s,1H),8.18(d,J=7.8Hz,1H),7.57(d,J=8.1Hz,1H),7.46(s,1H),7.30–7.08(m,3H),6.88(d,J=8.4Hz,1H),5.99(s,2H),4.25(t,J=6.8Hz,2H),1.99(t,J=7.1Hz,2H),1.85–1.72(m,2H),1.61–1.44(m,2H)。
实施例1-45、化合物N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基乙酰基)苄基)-1H-吲哚-3-甲酰胺(BE045)的制备
将4-溴甲基苯甲酸甲酯置换成4-溴甲基苯乙酸甲酯,按制备化合物BE014制备。1HNMR(500MHz,DMSO)δ10.62(s,1H),9.71(s,1H),8.77(s,1H),8.33(s,1H),8.19(d,J=7.5Hz,1H),7.55(d,J=7.9Hz,1H),7.46(s,1H),7.24–7.11(m,7H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.48(s,2H),3.24(s,2H).
实施例1-46、化合物N-(1-苯乙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE046)的制备
将3,4-亚甲二氧基苯胺置换成1-苯乙胺,按制备化合物BE014的方法制备。1H NMR(500MHz,DMSO)δ11.17(s,1H),9.03(s,1H),8.30(d,J=8.1Hz,1H),8.27(s,1H),8.13(d,J=7.7Hz,1H),7.70(d,J=8.2Hz,2H),7.49(d,J=8.2Hz,1H),7.41(d,J=7.5Hz,2H),7.36–7.25(m,4H),7.24–7.10(m,3H),5.53(s,2H),5.23–5.16(m,1H),1.47(d,J=7.1Hz,3H).
实施例1-47、化合物N-(2-苯丙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺(BE047)的制备
将3,4-亚甲二氧基苯胺置换成2-苯丙胺,按制备化合物BE014的方法制备。1H NMR(500MHz,DMSO)δ11.17(s,1H),9.03(s,1H),8.15–8.06(m,2H),7.96(s,1H),7.70(d,J=8.2Hz,2H),7.49(d,J=8.1Hz,1H),7.39–7.24(m,6H),7.22–7.10(m,3H),5.51(s,2H),3.46–3.36(m,2H),3.09–3.02(m,1H),1.25(d,J=7.0Hz,3H).
实施例1-48、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-乙氧基)苄基)-1H-吲哚-3-甲酰胺(BE048)的制备
将4-甲基-3-羟基苯甲酸甲酯(315mg,1.9mmol)溶于N,N-二甲基甲酰胺(5ml)中,冰浴条件下缓慢加入NaH(152mg,3.8mmol),至无气泡产生后加入溴乙烷(248mg,2.3mmol),在室温条件下反应1h。反应结束后,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体4-甲基-3-羟乙基苯甲酸甲酯(200mg,1.0mmol)。
取中间体4-甲基-3-羟乙基苯甲酸甲酯(200mg,1.0mmol)溶于三氯甲烷(15ml),加入N-溴代琥珀酰亚胺(214mg,1.2mmol)和催化量的偶氮二异丁腈(10mg)。在80℃条件下回流过夜。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体4-溴甲基-3-羟乙基苯甲酸甲酯(252mg,0.9mmol)。
取N-(3,4-亚甲二氧基苯基)-1H-吲哚-3-甲酰胺(280mg,1.0mmol)溶于乙腈(20ml),加入4-溴甲基-3-羟乙基苯甲酸甲酯(252mg,0.9mmol)和碳酸铯(815mg,2.5mmol),室温下反应过夜。反应结束后,减压除去溶剂,用乙酸乙酯和水萃取,常规处理后过硅胶柱,得中间体N-(3,4-亚甲二氧基苯基)-1-(4-甲氧基甲酰基-2-乙氧基)苄基-1H-吲哚-3-甲酰胺(180mg)。
在40摄氏度时在盐酸羟胺(3.33g,50.7mmol)的甲醇(10ml)溶液中加入KOH(2.83g,50.7mmol),反应10min后将反应体系置于冰浴中,30min后抽滤得滤液,再将上述酯(180mg)加入到滤液中,并在此体系中补加KOH(333mg,5.07mmol),在室温下反应2个小时后萃取过柱得产物BE048。1H NMR(500MHz,DMSO)δ11.19(s,1H),9.69(s,1H),9.03(s,1H),8.29(s,1H),8.19(d,J=7.9Hz,1H),7.55(d,J=8.0Hz,1H),7.45(s,1H),7.38(s,1H),7.29(d,J=7.8Hz,1H),7.23–7.05(m,4H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.46(s,2H),4.22–4.10(m,2H),1.37(t,J=6.9Hz,3H)。
实施例1-49、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-(2-甲氧基乙氧基))苄基)-1H-吲哚-3-甲酰胺(BE049)的制备
将溴乙基置换成2-溴乙基甲基醚,按制备化合物BE048的方法制备。1H NMR(500MHz,DMSO)δ11.19(s,1H),9.67(s,1H),9.05(s,1H),8.30(s,1H),8.17(d,J=7.8Hz,1H),7.57(d,J=8.0Hz,1H),7.45(s,1H),7.40(s,1H),7.30(d,J=7.8Hz,1H),7.21–7.10(m,4H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.46(s,2H),4.28–4.20(m,2H),3.75–3.70(m,2H)。
实施例1-50、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-异丙氧基)苄基)-1H-吲哚-3-甲酰胺(BE050)的制备
将溴乙基置换成2-溴丙基,按制备化合物BE048的方法制备。1H NMR(500MHz,DMSO)δ11.19(s,1H),9.68(s,1H),9.03(s,1H),8.28(s,1H),8.19(d,J=7.4Hz,1H),7.54(d,J=8.0Hz,1H),7.45(s,1H),7.38(s,1H),7.27(d,J=7.8Hz,1H),7.22–7.11(m,4H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.43(s,2H),4.77–4.71(m,1H),1.26(d,J=6.0Hz,6H)。
实施例1-51、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-环丙氧基)苄基)-1H-吲哚-3-甲酰胺(BE051)的制备
将溴乙基置换成溴甲基环丙基,按制备化合物BE048的方法制备。1H NMR(500MHz,DMSO)δ11.18(s,1H),9.70(s,1H),9.04(s,1H),8.32(s,1H),8.18(d,J=7.7Hz,1H),7.60(d,J=8.1Hz,1H),7.45(s,1H),7.36(s,1H),7.29(d,J=7.6Hz,1H),7.25–7.10(m,4H),6.88(d,J=13.3Hz,1H),6.00(s,2H),5.48(s,2H),3.95(d,J=7.0Hz,2H),1.18(t,J=7.1Hz,1H),0.66–0.54(m,2H),0.38–0.28(m,2H)。
实施例1-52、化合物N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-异丁氧基)苄基)-1H-吲哚-3-甲酰胺(BE052)的制备
将溴乙基置换成溴代异丁烷,按制备化合物BE048的方法制备。1H NMR(500MHz,DMSO)δ11.20(s,1H),9.68(s,1H),9.05(s,1H),8.25(s,1H),8.20(d,J=7.2Hz,1H),7.52(d,J=7.6Hz,1H),7.44(s,1H),7.39(s,1H),7.29(d,J=9.0Hz,1H),7.23–7.15(m,2H),7.11(dd,J=8.4,2.0Hz,1H),7.02(d,J=7.9Hz,1H),6.88(d,J=8.4Hz,1H),6.00(s,2H),5.48(s,2H),3.87(d,J=6.4Hz,2H),2.12–2.03(m,1H),0.98(d,J=6.7Hz,6H)。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (9)
2.一种IDO/HDAC双靶点化合物或药学上可接受的盐,其特征在于,其选自:
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺;
N-(苯丙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺;
N-(苯丁基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺;
N-(2-金刚烷胺基)-1-(4-(羟基氨基甲酰基)苄基)-5-甲氧基-1H-吲哚-3-甲酰胺;
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-6-甲酰胺;
N-(3,4-亚甲二氧基苄基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺;
N-(3,4-亚甲二氧基苯基)-1-(4-(羟基氨基甲酰基)苄基)-5-甲基-1H-吲哚-3-甲酰胺;
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-氟)苄基)-1H-吲哚-3-甲酰胺;
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-氯)苄基)-1H-吲哚-3-甲酰胺;
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-溴)苄基)-1H-吲哚-3-甲酰胺;
N-(3,4-亚甲二氧基苯基)-1-((4-(羟基氨基甲酰基)-2-甲氧基)苄基)-1H-吲哚-3-甲酰胺;
N-(3,4-亚甲二氧基苯基)-1-(3-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺;
N-(1-苯乙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺;
N-(2-苯丙基)-1-(4-(羟基氨基甲酰基)苄基)-1H-吲哚-3-甲酰胺。
3.一种根据权利要求1或2所述的IDO/HDAC双靶点化合物或药学上可接受的盐,其特征在于,所述化合物与酸形成的酸加成盐,或所述化合物与碱形成的碱加成盐;其中,所述酸选自盐酸、氢溴酸、硫酸、磷酸、乙酸、酒石酸、水杨酸、柠檬酸、苹果酸、甲磺酸、对甲苯磺酸、乳酸、丙酮酸、马来酸、琥珀酸;所述碱选自无机碱衍生的盐,所述无机碱为烧碱、氢氧化钾、氢氧化钡、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁、氢氧化锌、纯碱、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾;有机无毒碱衍生的盐,所述有机无毒碱选自一级、二级和三级胺、取代胺、环胺、乙醇胺、N-乙基吗啉、N-乙基哌啶、葡萄胺。
4.一种药物组合物,其特征在于,其含有权利要求1或2所述的IDO/HDAC双靶点化合物或药学上可接受的盐,以及药学上可接受的载体;所述药物组合物被配制成可注射流体、气雾剂、乳膏、凝胶剂、丸剂、胶囊剂、糖浆剂、透皮贴剂或赋形剂。
5.一种如权利要求1或2所述的IDO/HDAC双靶点化合物或药学上可接受的盐、或根据权利要求4所述的药物组合物在制备IDO/HDAC抑制剂双靶点抑制剂中的用途。
6.一种根据权利要求1或2所述的IDO/HDAC双靶点化合物或药学上可接受的盐、或根据权利要求4所述的药物组合物在制备增强人或哺乳动物免疫能力或抗肿瘤药物中的应用。
7.如权利要求6所述的应用,其特征在于,所述抗肿瘤是指抑制肿瘤细胞的增殖、生长、浸润和迁移。
8.如权利要求6或7所述的应用,其特征在于,所述肿瘤选自肝癌、肺癌、前列腺癌、皮肤癌、结肠癌、胰腺癌、乳腺癌、白血病、淋巴癌、卵巢癌、胃癌、膀胱癌、肾癌、口腔癌、黑色素瘤、食道癌、宫颈癌。
9.一种根据权利要求1或2所述的IDO/HDAC双靶点化合物或药学上可接受的盐、或根据权利要求4所述的药物组合物在制备具有IDO介导的色氨酸代谢途径的病理性特征的疾病的药物中的应用;所述疾病选自自身免疫性疾病、阿尔兹海默症、抑郁症、焦虑症、病毒感染。
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