CN109574950A - 1,2,5-噁二唑类衍生物及其用途 - Google Patents
1,2,5-噁二唑类衍生物及其用途 Download PDFInfo
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- CN109574950A CN109574950A CN201710895800.8A CN201710895800A CN109574950A CN 109574950 A CN109574950 A CN 109574950A CN 201710895800 A CN201710895800 A CN 201710895800A CN 109574950 A CN109574950 A CN 109574950A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
- C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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Abstract
本发明公开了一种具有下述通式(I)的化合物,其中,K选自:环烷烃基 本发明还公开了包含上述化合物的吲哚胺‑2,3‑双加氧酶抑制剂及该化合物在制备治疗癌症的药物中的应用。本发明的化合物,能有效抑制细胞增殖,对多种疾病如癌症具有良好的治疗效果,对乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、I V期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌等均具有显著的治疗效果,应用前景非常广阔。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种作为吲哚胺-2,3-双加氧酶抑制剂的1,2,5-噁二唑类衍生物及其用途。
背景技术
吲哚胺-2,3-双加氧酶(Indoleamine-2,3-dioxygenase,ID0)由Hayaishi小组1967年首次在细胞内发现,是一种含有亚铁血红素的单体酶,cDNA编码蛋白由403个氨基酸组成,包括IDO1,IDO2,TDO(tryptophan 2,3-dioxygenase)。Munn and Mellor 1998年在Science上首次提出IDO1扮演从母体免疫系统分离的婴儿的免疫调节保护作用。此后,人类对IDO的研究快速深入,发现它是色氨酸-犬尿氨酸途径分解代谢的限速酶,并且在多种哺乳动物的组织中具有广泛的表达。在肿瘤患者的细胞中,ID0常作为诱导肿瘤微环境免疫耐受产生重要的生理作用,其介导的色氨酸(Tryptophan,Trp)-犬尿氨酸(Kynurenine,Kyn)代谢途径参与了肿瘤免疫逃逸,而ID0作为诱导肿瘤微环境免疫耐受也产生重要的作用。
IDO与干扰素(interferon,IFN)、白细胞介素(interleukin,IL)、肿瘤坏死因子等多种细胞因子关系密切,它们在一定条件下可激活IDO。而T-细胞的细胞周期中存在一个对色氨酸水平非常敏感的调节点,一方面,IDO使局部色氨酸耗竭,致使T-细胞停滞于G1期中期,从而抑制了T细胞的增殖,也抑制了T细胞的免疫应答,而T细胞一旦停止增殖,可能就不会再被刺激作用,这是IDO在体内免疫作用机制;另一方面,IDO催化色氨酸代谢产生的主要产物犬尿素由氧自由基介导引起细胞内氧化剂和抗氧化剂改变而诱导T-细胞凋亡,这是存在于机体的固有的免疫抑制机制。
目前大量研究表明IDO在白血病细胞中较高表达,使局部T细胞增殖受抑,抑制T-细胞介导的免疫反应,使T-细胞活化信号转导受阻,从而介导肿瘤细胞逃逸免疫系统的攻击。已经发现大多数人类肿瘤组成性地表达IDO。因此,IDO是一个具潜力的癌症免疫治疗的靶标。
因此,生物医疗技术领域急需IDO抑制剂,尤其是小分子化合物的IDO抑制剂。
发明内容
本发明要解决目前缺乏高效的IDO抑制剂的技术问题,提供一种新型的1,2,5-噁二唑类衍生物,该化合物作为吲哚胺-2,3-双加氧酶抑制剂,能有效抑制癌细胞的增殖,使临床癌症治疗取得更好效果。
为了解决上述技术问题,本发明通过如下技术方案实现:
在本发明的一个方面,提供了一种具有通式(I)的化合物,或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,
式(I)中,
K选自下述基团:环烷烃基 b、d为数字1、2、3、4或5;E、F为氢、卤素、羟基、烷氧基、羟基烷基、烷胺基、胺烷基,且当b是3或4,或b加d等于3或4时,E、F不同时为氢;a、c分别表示数字0、1、2、或3;
R1、R2各自独立地选自氢原子、烷基、氰基、氨基、卤素、烯基、炔基、羟基、硝基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;
X为N(R3)CO-、N(R3)O(R4)、N(R3)O、C(R4R5)CO-、C(R4R5)SO2-、N(R3)N(R4R5)、N(R3)N(R4)、或为空;
Y为O、S、N-R6、O-N-R6、N(R6)-N(R6)中的一种或为空;
A为N(R7R8)、N(R7)N(R7R8)、N(R3)O(R4)、N(R3)O、取代或非取代的胍基、取代或非取代的双胍基;
B为SO2、PO、PON(R3)、或AB或ABEF形成
G为H、OH、MeO、EtO、或C1-C6的烷基或环烷基,或G与E、F成环;
R3、R4、R5、R6、R7、R8各自独立地选自氢原子、烷烃基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代,或为空;
选自顺式异构体、反式异构体或顺反异构体的混合物。
优选的,所述R1、R2各自独立地选自卤素。
优选的,所述通式(I)化合物包括下述具体结构的化合物:
在本发明的另一方面,还提供了一种药物组合物,其含有治疗有效量的上述通式(I)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
上述可接受的载体是无毒的、能辅助施用并且对化合物的治疗效果没有不利影响。此类载体可以是本领域的技术人员通常能得到的任何固体赋形剂、液体赋形剂、半固体赋形剂或者在气雾剂组合物中的气体赋形剂。固体药物赋形剂包括淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻米、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、甘油硬脂酰酯、氯化钠、无水脱脂乳等。液体和半固体赋形剂可以选自甘油、丙二醇、水、乙醇和各种油,包括那些源于石油、动物、植物或人工合成的油,例如,花生油、豆油、矿物油、芝麻油等、优选的液体载体,特别是用于可注射溶液的,包括水、盐水、葡萄糖水溶液和甘醇。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明的化合物以治疗上的有效量施用,其施用方式可以是口服、全身施用(例如,透过皮肤的、鼻吸入的或者用栓剂)或肠胃外施用(例如,肌肉内、静脉内或皮下)。优选的施用方式是口服,它可根据疾病程度调节。
本发明的化合物的实际施用量(即活性组分)依赖于许多因素,如待治疗疾病的严重性、治疗对象的年龄和相对健康程度、所使用的化合物的效能、施用途径和形式,以及其他因素。
本发明药物组合物的各种剂型可以按照药学领域的常规方法制备。例如使该化合物与一种或者多种载体混合,然后将其制成所需的剂型,如片剂、药丸、胶囊、半固体、粉末、缓释剂型、溶液、混悬液、配剂、气雾剂等等。
在本发明的另一方面,还提供了一种包含上述化合物的吲哚胺-2,3-双加氧酶抑制剂。
在本发明的另一方面,还提供了上述通式(I)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,或上述药物组合物在制备预防和/或治疗吲哚胺-2,3-双加氧酶介导的疾病的药物中的用途。
所述吲哚胺-2,3-双加氧酶介导的疾病包括癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。
所述癌症包含乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
由于吲哚胺-2,3-双加氧酶抑制剂是目前效果明显的抗肿瘤药物靶点,而本发明的化合物具有显著的吲哚胺-2,3-双加氧酶抑制活性,通过实验证实这些化合物对各种癌细胞增殖具有抑制作用,因此本发明化合物适用于治疗各种癌症。尤其是对于肺癌、胃癌、卵巢癌、结肠癌、恶性胶质瘤具有较好的治疗效果。
本发明的吲哚胺-2,3-双加氧酶抑制剂,能有效抑制细胞增殖,对多种疾病如癌症具有良好的治疗效果,尤其是对肺癌、胃癌、卵巢癌、恶性胶质瘤等具有显著的治疗效果,应用前景非常广阔。
具体实施方式
实施例1中间体7合成:4-(3-溴-4-氟苯基)-3-(4-硝基-1,2,5-噁二唑-3-)-1,2,4-噁二唑-5-酮
步骤1:
将化合物1(32g,485mmol)溶于500mL水中,加热45℃至完全溶解。冰水浴冷却下,加入亚硝酸钠(38g,533mmol)和6N盐酸(5.5mL)。在冰浴下反应0.5小时后,升温至室温反应1.5小时。将反应液继续冰浴冷却,将50%盐酸羟胺水溶液(99g,1500mmol)滴加入反应液,搅拌半小时后,升至室温反应1小时。加热回流反应2小时,反应完后,冰浴下,用80mL 6N盐酸调节pH至7.0。过滤沉淀,用水洗一次,干燥,得到白色固体化合物2(69.3g,92%)。
步骤2:
将化合物2(30g,210mmol)溶于213mL乙酸、420mL水和105mL 6N盐酸中,加热至45℃至完全溶解再加入氯化钠(36.7g,629mmol)。冰浴下,缓慢滴加溶于50mL水的亚硝酸钠(14.2g,206mmol),保持零度反应1.5小时后,升温至室温反应2小时。反应结束后,过滤沉淀,滤饼用水洗,抽干后,用乙酸乙酯溶解,无水硫酸钠干燥,过滤,浓缩滤液,得到类白色固体化合物3(17.1g,51%)。
步骤3:
将化合物3(5g,30.9mmol)溶于50mL水中,加热至65℃。再将化合物4(6.5g,34.0mmol)加入,然后滴加饱和碳酸氢钠溶液(50mL)。反应1小时后,加乙酸乙酯萃取,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(4:1)过柱,得白色固体化合物5(9g,92%)。
步骤4:
将化合物5(9g,28.5mmol)和N,N′-羰基二咪唑(6.9g,42.7mmol)溶于60mL乙酸乙酯中,加热至60℃反应2小时。冷却至室温,加水洗两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(5:1)过柱,得白色固体化合物6(9g,92%)。
步骤5:
在冰浴下将98%浓硫酸(120mL)慢慢滴加入30%过氧化氢(120mL)中,然后将化合物6(9g,26.3mmol)分三次加入混合液中,将温度升至55℃反应5小时。在冰浴下加入水(500mL),乙酸乙酯萃取,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(5:1)过柱,得白色固体化合物7(8g,81%)。
LC-MS:372[M+H]+
实施例2化合物A合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰氨基环丁甲胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物8(96mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物9(190mg,97%)。
步骤2:
将化合物9(190mg,0.40mmol)溶于2mL二氧六环中,加入盐酸二氧六环(3mL)在常温下反应1小时。反应完后,将反应液旋干,得白色固体化合物10(163mg,98%)。
步骤3:
将化合物10(160mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物11(130mg,76%)。
步骤4:
将化合物11(130mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物A(50mg,39%)。
LC-MS:478[M+H]+
实施例3化合物B合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酸基环丁甲胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物12(85mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物13(180mg,87%)。
步骤2:
将化合物13(180mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物14(120mg,72%)。
步骤3:
将化合物14(110mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物B(50mg,37%)。
LC-MS:479[M+H]+
实施例4化合物C合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰胺巯基乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物15(73mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物16(170mg,88%)。
步骤2:
将化合物16(170mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物17(110mg,68%)。
步骤3:
将化合物17(110mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物C(50mg,38%)。
LC-MS:455[M+H]+
实施例5化合物D合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰胍胺基乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物18(97mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物19(180mg,87%)。
步骤2:
将化合物19(180mg,0.40mmol)溶于2mL二氧六环中,加入盐酸二氧六环(3mL)在常温下反应1小时。反应完后,将反应液旋干,得白色固体化合物20(165mg,98%)。
步骤3:
将化合物20(160mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氯磺酸(45mg,0.35mmol)和盐酸胍(15mg,0.35mmol)加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物21。
步骤4:
将化合物21(55mg,0.125mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物D(13mg,20%)。
LC-MS:480[M+H]+
实施例6化合物E合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰胺羰基乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物22(73mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物23(170mg,88%)。
步骤2:
将化合物23(170mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰异氰酸酯(43mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物24(60mg,34%)。
步骤3:
将化合物24(110mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物E(25mg,18%)。
LC-MS:482[M+H]+
实施例7化合物F合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰胺羰基乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物20(150mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物25(120mg,68%)。
步骤2:
将化合物25(120mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物26。
步骤3:
将化合物26(55mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物F(25mg,33%)。
LC-MS:517[M+H]+
实施例8化合物G合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰胺肼乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物27(71mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物28(85mg,41%)。
步骤2:
将化合物28(170mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物29(124mg,67%)。
步骤3:
将化合物29(40mg,0.40mmol)溶于2mL二氧六环中,加入盐酸二氧六环(3mL)在常温下反应1小时。反应完后,将反应液旋干,得白色固体化合物30(34mg,98%)。
步骤4:
将化合物30(30mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物G(15mg,50%)。
LC-MS:453[M+H]+
实施例9化合物H-1和H-2合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰胺羟胺乙基胺基)-1,2,5-噁二唑-3-胍和(E)-N-(3-溴-4-氟苯基)-N′-胺基-4-(3-磺酰胺羟胺乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(300mg,0.4mmol)和化合物31(61mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物32(170mg,42%)。
步骤2:
将化合物32(170mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物33-1(45mg,21%)和化合物33-2(27mg,13%)。
步骤3:
将化合物33-1(45mg,0.09mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物H-1(18mg,42%)。
LC-MS:454[M+H]+
将化合物33-2(27mg,0.056mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物H-2(10mg,39%)。
LC-MS:454[M+H]+
实施例10化合物I合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰脲丙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物34(71mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物35(162mg,81%)。
步骤2:
将化合物35(160mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物I(25mg,18%)。
LC-MS:450[M+H]+
实施例11化合物J合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-[二-(3-氨基磺酰胺甲基)胺基]-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物36(136mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物37(168mg,74%)。
步骤2:
将化合物37(160mg,0.40mmol)溶于2mL二氧六环中,加入盐酸二氧六环(3mL)在常温下反应1小时。反应完后,将反应液旋干,得白色固体化合物38(102mg,94%)。
步骤3:
将化合物38(100mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(80mg,0.7mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物39(34mg,15%)。
步骤4:
将化合物39(30mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物J(12mg,42%)。
LC-MS:546[M+H]+
实施例12化合物K合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-二甲胺磷酰乙胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物40(116mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物41(70mg,36%)。
步骤2:
将化合物41(130mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物K(50mg,41%)。
LC-MS:450[M+H]+
实施例13化合物L合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(1-磺酰胺基吖啶甲胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物42(91mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物43(192mg,95%)。
步骤2:
将化合物43(190mg,0.40mmol)溶于2mL二氧六环中,加入盐酸二氧六环(3mL)在常温下反应1小时。反应完后,将反应液旋干,得白色固体化合物44(161mg,97%)。
步骤3:
将化合物44(160mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物45(123mg,71%)。
步骤4:
将化合物45(110mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物L(50mg,37%)。
LC-MS:464[M+H]+
实施例14化合物M合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰胺甲基吖啶-1)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物46(91mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物47(38mg,19%)。
步骤2:
将化合物47(38mg,0.08mmol)溶于2mL二氧六环中,加入盐酸二氧六环(3mL)在常温下反应1小时。反应完后,将反应液旋干,得白色固体化合物48(30mg,95%)。
步骤3:
将化合物48(30mg)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物49(20mg)。
步骤4:
将化合物49(20mg)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物M(8mg,35%)。
LC-MS:464[M+H]+
实施例15化合物N合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-甲氧基(2-磺酰胺乙胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物50(66mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物51(35mg,16%)。
步骤2:
将化合物51(170mg,0.40mmol)溶于2mL二氧六环中,加入盐酸二氧六环(3mL)在常温下反应1小时。反应完后,将反应液旋干,得白色固体化合物52(156mg,97%)。
步骤3:
将化合物52(150mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(40mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物53(66mg,36%)。
步骤4:
将化合物53(130mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物N(50mg,44%)。
LC-MS:468[M+H]+
实施例16化合物O合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰氨基丙酰胺基环丁甲胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物10(150mg,0.4mmol)和胺磺酰基丙酸(96mg,0.6mmol)溶于2mL二氯甲烷中,加入HATU(760mg,2.0mmol),三乙胺(202mg,2.0mmol)在常温下反应5小时,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物54(170mg,75%)。
步骤2:
将化合物54(160mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物O(50mg,33%)。
LC-MS:534[M+H]+
实施例18化合物P合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰胺羰基胺乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物20(170mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰异氰酸酯(43mg,0.35mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物55(62mg,33%)。
步骤2:
将化合物55(120mg,0.25mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物P(50mg,41%)。
LC-MS:481[M+H]+
实施例17化合物Q合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-[二-(3-氨基磺酰胺甲基)胺基]-1,2,5-噁二唑-3-胍
步骤1:
将化合物38(150mg,0.36mmol)溶于2mL二氯甲烷中,滴加三乙胺(202mg,2.0mmol)和氯磺酰氯(1mL)在冰浴下反应1小时,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物56(70mg,41%)。
步骤2:
将化合物56(70mg,0.15mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物Q(20mg,30%)。
LC-MS:450[M+H]+
实施例20化合物R合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-[二-(3-氨基磺酰胺甲基)胺基]-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物57(98mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物58(69mg,35%)。
步骤2:
将化合物58(65mg,0.12mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物R(20mg,36%)。
LC-MS:462[M+H]+
实施例21化合物S合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰羟胺基乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物20(160mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氯磺酸(45mg,0.35mmol)和盐酸羟胺(24mg,0.35mmol)加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物59(60mg,36%)。
步骤2:
将化合物59(60mg,0.12mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物S(20mg,35%)。
LC-MS:454[M+H]+
实施例22化合物T合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰肼胺基乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物20(160mg,0.35mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氯磺酸(45mg,0.35mmol)和盐酸肼(24mg,0.35mmol)加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物60(60mg,36%)。
步骤2:
将化合物60(60mg,0.12mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物T(20mg,35%)。
LC-MS:453[M+H]+
实施例23化合物U合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰肼胺基乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物8(106mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物62(95mg,48%)。
步骤2:
将化合物62(95mg,0.40mmol)溶于2mL二氧六环中,加入盐酸二氧六环(3mL)在常温下反应1小时。反应完后,将反应液旋干,得白色固体化合物63(82mg,96%)。
步骤3:
将化合物10(80mg,0.2mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(30mg,0.2mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物64(56mg,58%)。
步骤4:
将化合物11(56mg,0.12mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物U(18mg,33%)。
LC-MS:454[M+H]+
实施例24化合物V合成:(E)-N-(3-溴-4-氟苯基)-N′-羟基-4-(3-磺酰环丁基乙基胺基)-1,2,5-噁二唑-3-胍
步骤1:
将化合物7(150mg,0.4mmol)和化合物65(52mg,0.6mmol)溶于2mL四氢呋喃中,滴加三乙胺(202mg,2.0mmol)在常温下反应5分钟,加水(10mL),乙酸乙酯萃取两遍,无水硫酸钠干燥,浓缩,石油醚比乙酸乙酯(8:1)过柱,得白色固体化合物66(95mg,58%)。
步骤2:
将化合物66(82mg,0.2mmol)溶于无水二氯甲烷中,加三乙胺(80mg,0.7mmol),冰浴搅拌几分钟,取氨基磺酰氯(30mg,0.2mmol)滴加进去,继续搅拌半小时。反应完后,将反应液旋干,得白色固体化合物67(56mg,57%)。
步骤3:
将化合物11(56mg,0.11mmol)溶于甲醇中,加1N氢氧化钠溶液(0.5mL,0.5mmol),搅拌半小时。反应完后,将反应液旋干,制备得白色固体化合物V(27mg,50%)。
LC-MS:464[M+H]+
以上所述实施例仅表达了本发明的实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (8)
1.具有通式(I)的化合物,或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,
式(I)中,
K选自下述基团:环烷烃基 b、d为数字1、2、3、4或5;E、F为氢、卤素、羟基、烷氧基、羟基烷基、烷胺基、胺烷基,且当b是3或4,或b加d等于3或4时,E、F不同时为氢;a、c分别表示数字0、1、2、或3;
R1、R2各自独立地选自氢原子、烷基、氰基、氨基、卤素、烯基、炔基、羟基、硝基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;
X为N(R3)CO-、N(R3)O(R4)、N(R3)O、C(R4R5)CO-、C(R4R5)SO2-、N(R3)N(R4R5)、N(R3)N(R4)、或为空;
Y为O、S、N-R6、O-N-R6、N(R6)-N(R6)中的一种或为空;
A为N(R7R8)、N(R7)N(R7R8)、N(R3)O(R4)、N(R3)O、取代或非取代的胍基、取代或非取代的双胍基;
B为SO2、PO、PON(R3)、或AB或ABEF形成
G为H、OH、MeO、EtO、或C1-C6的烷基或环烷基,或G与E、F成环;
R3、R4、R5、R6、R7、R8各自独立地选自氢原子、烷烃基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代,或为空;
选自顺式异构体、反式异构体或顺反异构体的混合物。
2.根据权利要求1所述的化合物,其特征在于,所述R1、R2各自独立地选自卤素。
3.根据权利要求1所述的化合物,其特征在于,所述通式(I)化合物包括:
。
4.一种药物组合物,其含有治疗有效量的权利要求1~3任意一项所述的通式(I)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
5.权利要求1~3任意一项所述的通式(I)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,或权利要求4所述的药物组合物在制备预防和/或治疗吲哚胺-2,3-双加氧酶介导的疾病的药物中的用途。
6.根据权利要求5所述的用途,其特征在于,所述吲哚胺-2,3-双加氧酶介导的疾病包括癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。
7.根据权利要求6所述的用途,其特征在于,所述癌症包含乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
8.一种吲哚胺-2,3-双加氧酶抑制剂,其包含权利要求1~3任意一项所述的通式(I)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐。
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