CN107056785B - 作为ido和tdo抑制剂的杂环化合物 - Google Patents
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- CN107056785B CN107056785B CN201610893887.0A CN201610893887A CN107056785B CN 107056785 B CN107056785 B CN 107056785B CN 201610893887 A CN201610893887 A CN 201610893887A CN 107056785 B CN107056785 B CN 107056785B
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- 229940124530 sulfonamide Drugs 0.000 description 1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
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Abstract
本发明提供了作为IDO和TDO抑制剂的杂环化合物,具体地本发明提供了一类新型杂环化合物,其合成及作为IDO抑制剂和TDO抑制剂的应用。根据本发明的作为IDO和TDO抑制剂的杂环化合物可以用于治疗与IDO1和/或TDO活性相关疾病。
Description
技术领域
本发明属于医药领域,具体地本发明提供了一类新型杂环化合物,其合成及作为IDO抑制剂和TDO抑制剂的应用。
背景技术
吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)和色氨酸2,3-加氧酶(tryptophan 2,3-dioxygenase TDO)是催化分解色氨酸为犬尿氨酸的含亚铁氧化还原限速酶。吲哚胺2,3-双加氧酶有两种异构体(IDO1,IDO2),广泛高表达于多种细胞中,列如:神经元,星形胶质细胞,小神经胶质细胞,特别是抗原提呈细胞(巨噬细胞以及树状突细胞)。IDO在人体正常细胞中的表达水平较低,但在机体处于感染、炎症时,在脂多糖(LPS)、IFN-γ等细胞因子的作用下其表达可明显增加。IDO在多种肿瘤组织中存在的高表达现象,已经证实IDO与恶性肿瘤的免疫耐受密切相关。IDO可能通过三种机制抑制局部T细胞的免疫反应:1.色氨酸耗竭机制,色氨酸是T细胞活化增生过程中的必需氨基酸,在肿瘤细胞IDO过度表达后会导致色氨酸缺乏,IDO抑制剂可使T细胞增殖抑制得到恢复;2.色氨酸代谢产物的毒性机制,色氨酸的代谢产物(L-犬尿氨酸和吡啶甲酸)可以直接抑制T细胞增殖和可诱导其死亡;3.调节性T细胞(Tregs)可以抑制T细胞增殖生长,过度表达的IDO可通过诱导Tregs的增殖来抑制活化的T细胞,从而为肿瘤细胞的侵袭和转移创造有利条件。因此吲哚胺2,3-双加氧酶在肿瘤免疫领域可能成为一种有效的靶点。色氨酸2,3-加氧酶主要表达于肝脏组织内,主要负责调节系统的色氨酸水平,可以分解食物中过多的色氨酸,在一定范围维持血清色氨酸的浓度并且其活性不受免疫系统的调节。最近的研究结果表明转染TDO的人细胞可以使色氨酸耗竭从而阻止T淋巴细胞增殖,TDO可能与IDO1一样可以调节肿瘤的免疫耐受,因此抑制TDO可能成为一种有效的肿瘤治疗手段。
越来越多的研究表明小分子IDO抑制剂可以用于多种疾病的治疗,列如,病毒引起的传染病,如HIV,HPV,HCV等病毒引起的疾病;神经系统疾病,如抑郁、阿尔茨海默病、多发性硬化症、帕金森综合症、亨廷顿疾病等;各种癌症,肺癌、膀胱癌、乳腺癌、肾癌、胃癌、肝癌、卵巢癌、前列腺癌、宫颈癌、肠癌、上皮细胞癌、多发性骨髓瘤、胰腺癌、淋巴瘤、白血病等,动脉粥样硬化、炎症、疼痛等。
IDO抑制剂不仅可以单独使用,更可以和其他靶向药物,化疗药物或免疫制剂(PD-1,CTLA-4,PD-L1等等)联合用药,具有广阔的应用前景。
发明内容
本发明的目的是提供一类结构新颖的IDO抑制剂和TDO抑制剂,以及它们的制备方法和应用。
本发明的第一方面,提供了一种如式(I)所示的化合物,或其药学上可接受的盐、前药、氘代衍生物、水合物、或溶剂合物:
式(I)中:
环A为5-元芳环,其中各个T和U各自独立地为N或C;各个P、V、和W各自独立地为N或CR3;
环B为5-元或6-元芳环,其中各个D、E、和F各自独立地为CR4=CR5、CR4、N、O、S或NR6;
Z为CR8或N;
R1和R2各自独立地为氢、卤素、C1-4烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、-CN、-OR9或-N(R9)2;
或R1和R2与其相连的碳原子共同形成任选地含有0-2个独立选自N、O或S的杂原子的3-至8-元环;
m和n各自独立地为0、1、2、3或4;
各个R3独立地为氢、卤素或C1-4烷基;
各个R4和R5各自独立地为氢、卤素、C1-4烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、芳基、杂芳基、氰基、硝基、-OR9、-N(R9)2、-SR9、-C(O)OR9、-C(O)N(R9)2、-C(O)R9、-S(O)2R9、-S(O)2N(R9)2、-OC(O)R9、-OC(O)OR9、-OC(O)N(R9)2、-N(R9)C(O)R9或-N(R9)C(O)N(R9)2;
各个R6独立地为氢、C1-4烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、芳基、杂芳基、-C(O)R9、-C(O)OR9、-C(O)N(R9)2或-S(O)2R9;
各个R8独立地为氢、卤素或C1-4烷基;
各个R9各自独立地为氢、C1-4烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、芳基、杂芳基、C3-8环烷基C1-4烷基、3-至8-元杂环基C1-4烷基、芳基C1-4烷基、或杂芳基C1-4烷基;
或者在N(R9)2结构中,两个R9与其相连的氮原子共同形成3-至8-元环,所述3-至8-元环任选地还含有0-2个独立选自N、O或S的杂原子,且所述3-至8-元环可任选地被=O取代;
R为RA、-ORA、-N(RA)(RC)、-C(O)RA、-C(O)N(RA)(RC)、-C(ORB)(RA)(RC)、-C(NHRB)(RA)(RC)、-C(=N-ORC)RA或-N(ORC)(RA),其中,
各个RA独立地为C6-12桥式二环烷基(C6-12Bridged bicycloalkyl)、或C4-11的含1-3个杂原子的6-至12-元桥式二环杂环基(Bridged bicyclic heterocyclyl);各杂原子独立地选自N、O或S,
其中,RA任选地具有1-3个RA1取代基团和/或任选地具有1-2个=RA2取代基团;
各个RA1各自独立地为氢、卤素、C1-4烷基、C2-4烯基、C2-4炔基、芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-至8-元杂环基、氰基、硝基、N-氧化物、-OR9、-N(R9)2、-SR9、-C(O)OR9、-C(O)N(R9)2、-C(O)N(OH)R9、-C(O)R9、-C(NR9)R9、-C(NR9)N(R9)R9、-N(R9)S(O)R9、-S(O)R9、-S(O)OR9、-N(R9)S(O)N(R9)2、-S(O)N(R9)2、-N(R9)S(O)2R9、-S(O)2R9、-S(O)2OR9、-N(R9)S(O)2N(R9)2、-S(O)2N(R9)2、-OC(O)R9、-OC(O)OR9、-OC(O)N(R9)2、-N(R9)C(O)R9、-N(R9)C(O)OR9、-N(R9)C(O)N(R9)2、-O(CH2)2-4OR9、-O(CH2)2-4N(R9)2、-O(CH2)2-4N(R9)S(O)2R9、-O(CH2)2-4N(R9)S(O)2N(R9)2、-N(R9)(CH2)2-4OR9、-N(R9)(CH2)2-4N(R9)2、-N(R9)(CH2)2-4N(R9)S(O)2R9、或-N(R9)(CH2)2-4N(R9)S(O)2N(R9)2;
=RA2为=O、=S、=N(R9)、=N(OR9)、=C(RA3)2、=(C3-6螺环烷基),或=(3-至6-元螺杂环基),其中,各个RA3独立地为氢、卤素、氰基、C1-4烷基、C3-8环烷基、或3-至8-杂环基;或者两个RA3与其相连的原子共同形成C3-6环烷基或3-至6-元杂环基;
各个RB独立地为氢、C1-4烷基、-C(O)R9、-CH2-OP(O)2(OR9)2或-P(O)(OR9)2;
各个RC独立地为氢或C1-4烷基;
各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代:卤素、C1-4烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至12-元杂环基、芳基、杂芳基、-CN、-NO2、-OR9、-SR9、-N(R9)2、-C(O)R9、-C(O)OR9、-C(O)N(R9)2或-S(O)2R9;
除非特别说明,上述的芳基为含有6-12个碳原子的芳基;杂芳基为5-至15-元杂芳基。
在另一优选例中,作为式(I)所示的化合物的一部分的式(II)
其中,
各个R3、R4、R5、和R6各自分别如上所述。
在另一优选例中,式(II)
其中,各个R3、R4、和R5各自分别如上所述。
在另一优选例中,作为式(I)所示的化合物的一部分的式(III)中,
其中,
在另一优选例中,式(III)
其中R如上所述。
在另一优选例中,式(I)所示的化合物如式IV、IV’、IV”、或IV”’所示:
其中,
各个R1、R2、R3、R4、和R各自分别如上所述。
在另一优选例中,式(I)所示的化合物如式V、V’、V”、或V”’所示:
其中,
各个R1、R2、R3、R4、和RA各自分别如上所述。
在另一优选例中,式(I)所示的化合物如式(VI)所示:
其中,
R3为氢、卤素或C1-4烷基;
R4为氢、卤素、C1-4烷基、C3-8环烷基、氰基、OR9;
RA选自:
在另一优选例中,RA具有1-3个(优选为1或2个)RA1取代基团,优选地至少1个所述RA1取代基团取代了RA中叔碳原子上的氢。
在另一优选例中,各个RA独立地为
在另一优选例中,各个RA独立地选自:
其中,RA1如上所述。
在另一优选例中,式(I)所示的化合物如式(VII)所示:
其中,
R4为氢、卤素;
RA选自:
其中,RA1为-OR9、-N(R9)2、-NHC(O)R9、-NHC(O)NHR9、-NHS(O)2R9、或-NHS(O)2NHR9、-C(O)N(R9)2、-O(CH2)2-4OR9,其中,R9为氢、C1-4烷基、C3-8环烷基、3-至8-元杂环基、芳基、杂芳基、C3-8环烷基C1-4烷基、3-至8-元杂环基C1-4烷基、芳基C1-4烷基、或杂芳基C1-4烷基;或者在N(R9)2结构中,两个R9与其相连的氮原子共同形成3-至8-元环,所述3-至8-元环任选地还含有0-2个独立选自N、O或S的杂原子,且所述3-至8-元环可任选地被=O取代;
在另一优选例中,所述的式(I)化合物具有选自下组的结构:
在另一优选例中,所述的式(I)化合物具有选自下组的结构:
本发明的第二方面,提供了本发明第一方面所述的式(I)化合物的用途,用于:
(a)制备治疗与IDO和/或TDO活性或表达相关的疾病的药物;和/或
(b)制备IDO和/或TDO靶向抑制剂;和/或
(c)体外非治疗性地抑制IDO和/或TDO的活性。
在另一优选例中,所述“IDO和/或TDO活性或表达相关的疾病”包括肿瘤(如,肺癌、膀胱癌、乳腺癌、肾癌、胃癌、肝癌、卵巢癌、前列腺癌、宫颈癌、肠癌、上皮细胞癌、多发性骨髓瘤、胰腺癌、淋巴瘤、白血病);感染(如病毒感染、细菌感染);神经系统疾病(如抑郁、阿尔茨海默病、多发性硬化症、帕金森综合症、亨廷顿疾病等);动脉粥样硬化;炎症;疼痛等。
本发明的第三方面,提供了一种药物组合物,其特征在于,所述的药物组合物包括:(i)有效量的本发明第一方面所述的化合物,或其药学上可接受的盐;和(ii)药学上可接受的载体。
本发明的第四方面,提供了一种抑制IDO和/或TDO活性的方法,所述方法包括步骤:对抑制对象施用抑制有效量的如本发明第一方面所述的式(I)化合物或其药学上可接受的盐,或对抑制对象施用抑制有效量的如本发明第三方面所述的药物组合物。
本发明的第五方面,提供了一种如本发明第一方面所述的化合物的制备方法,该方法包括步骤:
(a)在惰性溶剂中,化合物A1和化合物A2反应得到化合物A3
(b)在惰性溶剂中,化合物A3和化合物A4-1或化合物A4-2在碱存在的条件下反应得到化合物A5
(c)在惰性溶剂中,化合物A5和酸反应得到化合物A6
(d)用还原剂还原化合物A6得到化合物A7
其中,环B、R3、R4、R5、RA分别如上所述。
在另一优选例中,RA分选自下组:
具体实施方式
本发明人经过长期而深入的研究,意外地发现了一类具有IDO1和TDO抑制活性的杂环化合物,因此可以用于制备治疗与IDO1和/或TDO活性或表达量相关的疾病的药物组合物。基于上述发现,发明人完成了本发明。
术语
除特别说明之处,本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处,本发明的所有化合物之中,各手性碳原子(手性中心)可以任选地为R构型或S构型,或R构型和S构型的混合物。
如本文所用,在单独或作为其他取代基一部分时,术语“烷基”指具有1~8个碳原子的直链(即,无支链)或支链烷基,或其组合。所述的烷基可以是饱和的,单不饱和或多不饱和的,且可以包括二价或多价的原子团。当烷基前具有碳原子数限定(如C1-10)时,指所述的烷基含有1-10个碳原子,例如,C1-8烷基可以包括具有1-8个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“烯基”是指直链或支链,具有至少1个碳碳双键的碳链。具有一个双键的烯基可以被表示为-CnH2n-1,具有2个双键的烯基可以被表示为-CnH2n-3。当烯基前具有碳原子数限定(如C2-8)时,指所述的烯基含有2-8个碳原子,例如,具有2-8个碳原子的直链或支链烯基,例如乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“炔基”是指具有至少一个碳碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的,或其组合。在一些实施例中,所述的炔基具有2-12(例如,2-8,2-6,或2-4)个碳原子。当炔基前具有碳原子数限定(如C2-8炔基)时,指所述的炔基含有2-8个碳原子,例如,术语“C2-8炔基”指具有2~8个碳原子的直链或支链炔基,例如乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“环烷基”指具有饱和的或部分饱和的单环、二环或三环(包括并环、桥环或螺环)环系。所述的环烷基可以具有3-16个(例如,3-10个,或5-10个)碳原子。当某个环烷基前具有碳原子数限定(如C3-10)时,指所述的环烷基含有3-10个碳原子。在一些优选实施例中,术语“C3-8环烷基”指具有3~8个碳原子的饱和或部分饱和的单环或二环烷基,例如环丙基、环丁基、环戊基、环庚基、或类似基团。在本发明的一个优选的实施方式中,C6-12桥式二环烷基(C6-12Bridged bicycloalkyl)包括但不局限于以下基团:
如本文所用,术语“烷氧基”或“烷基氧基”指通过氧原子相连的烷基(例如,-O-烷基),其中烷基如上所述。特定的烷氧基的例子例如(但并不限于)甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。烷氧基可以被1个或多个取代基取代,所述的取代基例如卤素、氨基、氰基,或羟基。烷氧基可以为直链或支链的。当烷氧基前具有碳原子数限定(如C1-8)时,指所述的环烷基含有1-8个碳原子。
如本文所用,在单独或作为其他取代基一部分时,术语“卤素”指F、Cl、Br和I。
如本文所用,术语“烷氧基羰基”指直链或支链的烷基-氧羰基片段(烷氧基-C=O)。烷氧基可具有1-8个碳原子。当烷氧基羰基前具有碳原子数限定(如C1-8)时,指所述的烷氧基羰基的烷基部分含有1-8个碳原子,例如,C1-8烷氧基羰基指具有C1-8烷氧基-C=O-结构的基团,例如甲氧基羰基、乙氧基羰基、叔丁氧基羰基,或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“芳基”指单环,二环或稠环的芳香族碳氢基团。所述的芳基可以是取代或未取代的。当一个芳基前具有碳原子数限定(如C6-12)时,指所述的芳基含有6-12个碳原子。芳基的例子例如(但并不限于):苯基、联苯基、萘基、或类似基团(其中的每个碳原子均可以被任意取代)。所述的芳基可以不含或包含一个或多个相同或不同的(如2、3、4个)杂原子,所述杂原子可以选自N、O或S。
如本文所用,在单独或作为其他取代基一部分时,术语“杂芳基”指单环,二环或稠环的芳香族基团,所述基团具有特定的成环碳原子数(例如,C4-10即具有4-10个成环碳原子),且包括至少一个相同或不同的选自N、O或S的杂原子。每个环上原子可以被任意取代。所述的杂芳基可以是5-至15-元的,具有1-5个各自独立地选自N、O或S的杂原子的芳香环基。杂芳基的例子例如(但并不限于):吡啶、嘧啶、吡咯、吲唑、吲哚、呋喃、苯并呋喃、噻吩,或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“杂环基”指单环或稠环的饱和或部分饱和取代基,所述基团具有特定的成环碳原子数(例如,C3-11即具有3-11个成环碳原子),且包括至少一个相同或不同的选自N、O或S的杂原子。所述的杂环基可以是3-至15-元的,具有1-5个各自独立地选自N、O或S的杂原子的杂环基。杂环基的例子例如(但并不限于):氮杂环基、氧杂环基、硫杂环基、氮氧杂环基、氮硫杂环基、氧硫杂环基等,更优选的为本申请各实施例中所出现的杂环基。本发明中,杂环基可以为单环、二环或三环(包括并环、桥环或螺环)。在本发明的一个优选地实施方式中,所述6-至12-元桥式二环杂环基(Bridged bicyclic heterocyclyl)包括但不局限于以下基团:
如本文所用,术语“任意的”或“任选的”(例如,“被任意取代的”)指所述的部分为取代的或未取代的,且该取代仅发生与化学上可实现的位置。例如,H、共价键或-C(=O)-基团不可以被取代基取代。
如本文所用,“氧”或“氧基”指=O。如本文所用,除非特别说明,术语“药学上可接受的盐”指适合与对象(例如,人)的组织接触,而不会产生不适度的副作用的盐。在一些实施例中,本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如,钾盐,钠盐,镁盐,钙盐)或具有碱性基团的本发明的化合物的盐(例如,硫酸盐,盐酸盐,磷酸盐,硝酸盐,碳酸盐)。
如本文所用,术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。环状取代基,例如杂环烷基,可以与另一个环相连,例如环烷基,从而形成螺二环系,例如,两个环具有一个共用碳原子。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基,芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基。
为了方便以及符合常规理解,术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点,而不包括那些化学上不能实现的取代。
化合物的通用合成方法
本本发明通式I所示化合物可通过如下的方法制得,然而该方法的条件,例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易地进行。
在本发明的制备方法中,各反应通常在惰性溶剂中,反应温度-78℃~150℃(优选20~120℃)下进行。各步反应时间通常为0.5~48h,较佳地为2~12h。
反应式A描述了化合物A7的通用合成方法:
反应式A:
药学上可接受的盐、溶剂合物、立体异构体、互变异构体
如本文所用,术语“药学上可接受的盐”指本发明化合物与药学上可接受的无机酸和有机酸所形成的盐,其中,优选的无机酸包括(但并不限于):盐酸、氢溴酸、磷酸、硝酸、硫酸;优选的有机酸包括(但并不限于):甲酸、乙酸、丙酸、丁二酸、萘二磺酸(1,5)、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸,以及氨基酸。
如本文所用,术语“药学上可接受的溶剂合物”指本发明化合物与药学上可接受的溶剂形成溶剂合物,其中,所述药学上可接受的溶剂包括(但并不限于):水、乙醇、甲醇、异丙醇、四氢呋喃、二氯甲烷。
如本文所用,术语“药学上可接受的立体异构体”指本发明化合物所涉及手性碳原子可以为R构型,也可以为S构型,或其组合。
药物组合物和施用方法
由于本发明化合物具有优异的对IDO1和TDO抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由与IDO1和/或TDO活性或表达量相关的疾病。根据现有技术,本发明化合物可用于治疗以下疾病(但并不限于):各种癌症,列如肺癌、膀胱癌、乳腺癌、肾癌、胃癌、肝癌、卵巢癌、前列腺癌、宫颈癌、肠癌、上皮细胞癌、多发性骨髓瘤、胰腺癌、淋巴瘤、白血病等等;病毒引起的传染病,如HIV,HPV,HCV等病毒引起的疾病;神经系统疾病,如抑郁、阿尔茨海默病、多发性硬化症、帕金森综合症、亨廷顿疾病等;动脉粥样硬化、炎症、疼痛等。本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选5~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的IDO1和/或TDO抑制剂及其制备和应用,所述的抑制剂在极低浓度下即可抑制IDO1和/或TDO的活性。
3.提供了一类治疗与IDO1和/或TDO活性相关疾病的药物组合物。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1:化合物1的制备
在室温搅拌下将碘甲烷(1.5g,10.57mmol)在五分钟内滴加到化合物1a(1.2g,7.05mmol)和碳酸钾(1.5g,10.85mmol)在无水N,N-二甲基甲酰胺(20mL)的溶液中,反应混合物在室温下搅拌16小时,TLC监测反应完成,向反应体系加入20毫升水,然后用乙酸乙酯提取三次(30mL x 3)。合并有机相用饱和食盐水洗涤(30mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到黄色固体化合物1b(1.2g,收率92%),无需进一步纯化,直接用于下一步反应。1H NMR(DMSO-d6,400MHz):δ4.34(s,1H),3.55(s,3H),1.81-1.75(m,6H),1.53-1.48(m,6H)。
将化合物1b(1.2g,6.51mmol)和2,6-二甲基吡啶(2.1g,19.60mmol)溶于干燥的N,N-二甲基甲酰胺(15mL)中,然后在0℃下向其中滴加叔丁基二甲硅基三氟甲磺酸酯(5.2g,19.67mmol),反应体系在室温下搅拌过夜。向体系中加入20mL水淬灭,用乙酸乙酯萃取三遍(30mL x 3)。合并有机相用饱和食盐水洗涤(30mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到残留物。残留物通过硅胶柱层析分离(石油醚/乙酸乙酯=50/1)得到黄色油状化合物1c(1.5g,收率77%)。1H NMR(CDCl3,400MHz):δ3.62(s,3H),1.90-1.85(m,6H),1.68-1.62(m,6H),0.82(s,9H),0.04(s,6H).
将甲基膦酸二甲酯(209mg,1.68mmol)溶于无水四氢呋喃(6mL)中并冷却至-78℃,向其中缓慢滴加正丁基锂(2.5M正己烷溶液,0.84mL,2.10mmol),反应体系在-78℃搅拌40分钟。然后将化合物1c(250mg,0.84mmol)的无水四氢呋喃溶液(1.0mL)缓慢滴加至上述反应体系中,在-78℃搅拌反应2小时。将反应体系缓慢加入到冰的氯化铵水溶液中(10mL),用乙酸乙酯萃取三遍(20mL x 3),合并的有机相用饱和食盐水洗涤(20mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到黄色油状化合物1d(300mg,收率92%),无需进一步纯化,直接用于下一步反应。1H NMR(CDCl3,400MHz):δ3.79(s,3H),3.77(s,3H),3.14(s,1H),3.08(s,1H),1.87-1.81(m,6H),1.71-1.65(m,6H),0.83(s,9H),0.04(s,6H).
将氢化钠(60%,62mg,1.55mmol)加入到冰浴冷却的化合物1d(300mg,0.77mmol)的无水四氢呋喃(6mL)中,反应体系室温下搅拌20分钟后,再次将反应体系置于冰水浴中冷至0℃,将化合物1e(332mg,0.77mmol)缓慢(5分钟内)加入到反应体系中,该反应体系在室温下搅拌16小时。将反应体系缓慢加入到冰的氯化铵水溶液中(20mL),用乙酸乙酯萃取三遍(25mL x 3),合并的有机相用饱和食盐水洗涤(20mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到残留物。残留物通过硅胶柱层析分离(石油醚/乙酸乙酯=8/1)得到黄色固体化合物1f(400mg,收率74%)。1H NMR(CDCl3,400MHz):δ7.72(d,J=12.0Hz,1H),7.57(d,J=8.0Hz,1H),7.50(s,1H),7.39-7.26(m,10H),7.20-7.16(m,6H),7.10-6.97(m,2H),6.88(s,1H).1.84-1.78(m,6H),1.71-1.65(m,6H),0.83(s,9H),0.06(s,6H)。
将化合物1f(400mg,0.57mmol)溶于甲醇/乙酸(10mL/2.5mL)中,然后反应体系加热至60℃搅拌反应2小时。LCMS监测反应完毕,将该反应体系减压浓缩,向其中加入碳酸钠水溶液(30mL),用乙酸乙酯萃取三遍(30mL x 3)。合并的有机相用饱和食盐水洗涤(30mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到残留物。残留物通过硅胶柱层析分离(石油醚/乙酸乙酯=8/1)得到黄色固体化合物1g(220mg,收率84%)。MS 455.2[M+H]+.
将化合物1g(172mg,0.375mmol)溶于二氯甲烷/三氟乙酸(4mL/1mL)中,该反应体系在室温下搅拌反应16小时。反应体系减压浓缩,然后向其中加入饱和碳酸钠水溶液(20mL),用乙酸乙酯萃取三遍(20mL x 3)。合并有机相用饱和食盐水洗涤(20mL),无水硫酸钠干燥、过滤,浓缩后得到的残留物。残留物用制备薄板层析(CH2Cl2/MeOH=15/1)纯化得到黄色固体化合物1h(75mg,收率59%)。1H NMR(CDCl3,400MHz):δ7.55(s,1H),7.40-7.28(m,2H),7.18(s,1H),6.94(dd,J=9.2Hz,8.4Hz,1H),5.74(d,J=9.6Hz,1H),3.49(s,1H),3.43(dd,J=18.8Hz,2.0Hz,1H),2.80(dd,J=18.4Hz,10.4Hz,1H),1.91-1.82(m,6H),1.72-1.66(m,6H);MS 341.2[M+H]+.
将硼氢化钠(16mg,0.423mmol)搅拌下加入到冰浴冷却的化合物1h(46mg,0.135mmol)的甲醇(3mL)溶液中,然后该反应混合物在冰浴冷却下继续搅拌反应8分钟。然后反应液用冰冷的饱和氯化铵溶液淬灭(10mL),乙酸乙酯萃取三次(10mL x 3)。合并有机相用饱和食盐水(10mL)洗涤、无水硫酸钠干燥、过滤,滤液浓缩后的粗品通过用制备薄板层析(CH2Cl2:MeOH=10:1)纯化得到白色固体化合物1(34mg,收率73%)。1H NMR(非对映体异构体的混合物,DMSO-d6,400MHz):δ7.97and 7.95(two s,1H),7.47-7.37(m,2H),7.21and7.17(two s,1H),7.13-7.04(m,1H),5.63-5.57and 5.55-5.50(two m,1H),4.95and 4.51(two d,J=6.4Hz,6.4Hz,1H),4.17(s,1H),3.18-3.08(m,1H),2.35-2.20(m,1H),1.83-1.73(m,1H),1.50-1.31(m,12H);MS 343.2[M+H]+。
化合物1的四个对映异构体1-1,1-2,1-3和1-4经Waters手性制备色谱SFC-80进行拆分而得。手性制备柱条件:CHIRALCEL OJ柱,Daicel,30x 250mm,5μm;流动相:溶剂A是二氧化碳,共溶剂是B 15%乙醇含0.1%DEA;检测波长:272nm;柱温:35℃。手性分析柱条件:CHIRALCEL OJ柱,Daicel,4.6x 100mm,3μm;流动相:溶剂A是二氧化碳,共溶剂B是20%乙醇含0.1%DEA;检测波长:273nm;柱温:35℃。
化合物1-1:1H NMR(CDCl3,400MHz):δ7.82(s,1H),7.38-7.29(m,2H),7.20(s,1H),6.95-6.90(m,1H),5.61(d,J=8.8Hz,1H),3.53(d,J=10.8Hz,1H),2.43-2.33(m,1H),2.10-1.97(m,1H),1.74-1.45(m,12H);MS 343.2[M+H]+;RT=2.16min.
化合物1-2:1H NMR(CDCl3,400MHz):δ7.83(s,1H),7.37-7.29(m,2H),7.18(s,1H),6.96-6.90(m,1H),5.44(t,J=4.8Hz,1H),3.41(d,J=10.4Hz,1H),2.35-2.27(m,1H),2.06-1.97(m,1H),1.74-1.43(m,12H);MS 343.2[M+H]+;RT=2.89min.
化合物1-3:1H NMR(CDCl3,400MHz):δ7.86(s,1H),7.39-7.29(m,2H),7.18(s,1H),6.95-6.90(m,1H),5.44(t,J=4.8Hz,1H),3.42(d,J=9.6Hz,1H),2.35-2.27(m,1H),2.06-1.97(m,1H),1.76-1.43(m,12H);MS 343.2[M+H]+;RT=3.31min.
化合物1-4:1H NMR(CDCl3,400MHz):δ7.82(s,1H),7.39-7.30(m,2H),7.20(s,1H),6.94(dd,J=9.2Hz,8.4Hz,1H),5.61(d,J=8.4Hz,1H),3.53(d,J=10.8Hz,1H),2.43-2.33(m,1H),2.10-1.97(m,1H),1.73-1.46(m,12H);MS 343.2[M+H]+;RT=4.46min.
实施例2:化合物2的制备
将甲基磷酸二甲酯(811mg,6.54mmol)溶于无水四氢呋喃中(5mL),然后冷却至-78℃,在搅拌的状态下向反应液中缓慢滴加n-BuLi(2.5M正己烷溶液,2.62mL,6.54mmol)。该反应液在-78℃搅拌反应1小时后,在保持-78℃和搅拌的状态下向反应体系中滴加2a(300mg,1.64mmol)的无水四氢呋喃(2mL)溶液。该反应液在-78℃搅拌反应3小时,LCMS检测反应完毕,加入饱和氯化铵水溶液(5mL)淬灭,再将反应液用2M HCl调至pH=1,加入乙酸乙酯(20mL)搅拌、分液。水相用饱和碳酸钠水溶液调至pH=9-10,加入二氯甲烷(10mL X 4)萃取四次。合并后的有机相用饱和食盐水(5mL)洗涤,无水硫酸钠干燥、过滤,滤液减压浓缩后得到浅黄色浅黄色油状物2b(220mg,收率49%),无需进一步纯化,直接用于下一步反应。1HNMR(DMSO-d6,400MHz,):δ3.80(s,3H),3.77(s,3H),3.15(s,1H),3.10(s,1H),1.85-1.53(m,14H);MS 276.3[M+H]+。
将氢化钠(60%,116mg,2.91mmol)加入到冰浴冷却的化合物2b(200mg,0.73mmol)的无水四氢呋喃(5mL)中,反应体系0℃下搅拌反应1小时后,将化合物1e(315mg,0.73mmol)缓慢加入到反应体系中。该反应体系在室温下搅拌3小时。将反应体系缓慢加入到冰的饱和氯化铵溶液中(10mL),用乙酸乙酯萃取三遍(25mL x 3)。合并的有机相用饱和食盐水洗涤(20mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后的粗品通过硅胶柱层析(二氯甲烷/甲醇=5/1混合溶剂淋洗)分离纯化得到的浅黄色固体化合物2c(90mg,收率21%)。582.3[M+H]+。
将化合物2c(90mg,0.15mmol)溶于甲醇/乙酸(4mL/1mL)中,然后该反应液加热至60℃搅拌反应2小时。LCMS监测反应完毕,将该反应液减压浓缩,向其中加入饱和碳酸氢钠水溶液(5mL),用乙酸乙酯萃取三遍(10mL x 3)。合并的有机相用饱和食盐水洗涤(10mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到残留物。残留物通过用制备薄板层析(CH2Cl2:MeOH=5:1)纯化得到浅黄色固体化合物2d(33mg,收率63%)。MS 340.2[M+H]+。
将化合物2d(30mg,0.088mmol)溶于甲醇(1mL)中,然后在0℃搅拌的状态下,向该溶液中加入硼氢化钠(17mg,0.45mmol)。该反应液在0℃下搅拌反应15分钟。LCMS监测反应完毕,将反应液用饱和氯化铵水溶液(3mL)淬灭后直接旋干,固体用适量的甲醇打浆、过滤,滤液浓缩得到浅黄色固体产物2(30mg,产率99%)。MS 342.2[M+H]+。
实施例3:化合物3的制备
将化合物2(27mg,0.079mmol),磺酰胺(51mg,0.53mmol)和二异丙基乙胺(68mg,0.53mmol)溶于1,4-二氧六环(1mL)中。该反应液在100℃下搅拌反应6小时后减压浓缩得到残留物,通过制备薄板层析(石油醚/乙酸乙酯=7/1)纯化得到白色固体化合物3(2.74mg,收率8.2%)。1H NMR(非对映体异构体的混合物,DMSO-d6,400MHz):δ7.93and 7.91(two s,1H),7.46-7.37(m,2H),7.19and 7.14(two s,1H),7.12-7.03(m,1H),6.39(s,2H),6.23(s,1H),5.62-5.57and 5.55-5.51(two m,1H),4.96and 4.51(two d,J=6.4Hz,6.4Hz,1H),3.15-3.04(m,1H),2.34-2.20(m,1H),1.83-1.65(m,7H),1.46-1.28(m,6H);MS 421.2[M+H]+。
实施例4:化合物4的制备
将化合物2b(110mg,0.40mmol)和三乙胺(121mg,1.20mmol)加入二氯甲烷(5mL)中,然后在室温搅拌的状态下加入MsCl(69mg,0.60mmol)。该反应体系在室温下搅拌反应16小时后,向反应体系中加入二氯甲烷(15mL)和饱和食盐水(10mL),搅拌后分离出有机相,有机相用饱和食盐水(5mL)洗涤,无水硫酸钠干燥、过滤,滤液减压浓缩后得到浅黄色浅黄色油状物4a(63mg,收率45%),无需进一步纯化,直接用于下一步反应。MS 354.2[M+H]+。
将氢化钠(60%,36mg,0.89mmol)加入到冰浴冷却的化合物4a(63mg,0.18mmol)的无水四氢呋喃(5mL)中,反应体系室温下搅拌60分钟后,再次将反应体系置于冰水浴中冷至0℃,将化合物1e(77mg,0.18mmol)加入到反应体系中。反应体系在室温下搅拌3小时,将反应体系缓慢加入到冰的饱和氯化铵溶液中(10mL),用乙酸乙酯萃取三遍(10mL x 3)。合并的有机相用饱和食盐水洗涤(10mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到残留物。残留物通过制备薄板层析(石油醚/乙酸乙酯=3/2)纯化得到浅黄色固体化合物4b(15mg,收率13%)。1H NMR(DMSO-d6,400MHz,):δ7.61-7.54(m,3H),7.45-7.36(m,10H),7.24-7.05(m,8H),6.96(s,1H),6.90(s,1H),2.93(s,3H),1.83-1.64(m,12H)。
将化合物4b(15mg,0.02mmol)溶于甲醇/乙酸(4mL/1mL)中,然后该反应液加热至60℃搅拌反应1小时。LCMS监测反应完毕,将该反应液减压浓缩,向其中加入饱和碳酸氢钠水溶液(10mL),用乙酸乙酯萃取三遍(10mL x 3)。合并的有机相用饱和食盐水洗涤(10mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到残留物。残留物通过制备薄板层析(乙酸乙酯)纯化得到浅黄色固体化合物4c(7.5mg,收率79%)。MS 418.2[M+H]+.
将硼氢化钠(3.4mg,0.09mmol)搅拌下加入到冰浴冷却的化合物4c(7.5mg,0.02mmol)的甲醇(3mL)溶液中,反应混合物在冰浴冷却下继续搅拌反应15分钟。然后用冰冷的饱和氯化铵溶液淬灭(5mL)后直接旋干,固体用适量的甲醇打浆、过滤,滤液减压浓缩,粗品经过制备博板层析(二氯甲烷/甲醇=5/1)分离纯化,得到白色固体化合物4(6.51mg,收率86%)。1H NMR(非对映体异构体的混合物,DMSO-d6,400MHz):δ7.93and 7.91(two s,1H),7.46-7.37(m,2H),7.19and 7.15(two s,1H),7.12-7.03(m,1H),6.75(s,1H),5.63-5.57and 5.55-5.50(two m,1H),5.00and 4.56(two d,J=6.4Hz,6.4Hz,1H),3.17-3.08(m,1H),2.89(s,3H),2.35-2.20(m,1H),1.83-1.75(m,1H),1.75-1.65(m,6H),1.49-1.31(m,6H);MS 420.2[M+H]+.
实施例5:化合物5的制备
将4-碘-5-甲基-咪唑(1.0g,4.80mmol)和N,N-二异丙基乙胺(1.2g,9.29mmol)溶于干燥的N,N-二甲基甲酰胺(20mL)中,在搅拌状态下向反应液中加入三苯基氯甲烷(1.4g,5.02mmol),反应体系在室温下搅拌反应16小时。将反应溶液倒入水(40mL)中,搅拌、固体析出,抽滤,固体用水和乙醚分别洗涤两遍,将固体真空干燥得到白色固体化合物5b(1.3g,收率60%)。该化合物无需进一步纯化,直接用于下一步反应。
将化合物5b(1.2g,2.67mmol),化合物5c(500mg,2.94mmol)和七水磷酸钾(1.8g,5.32mmol)溶于1,4-二氧六环/水(12mL/2mL)混合溶剂中,再加入Pd(PPh3)4(154mg,0.134mmol)。反应体系用氩气置换3次,将反应体系加热到90℃搅拌5小时。反应液冷却至室温,然后将其倒入水(20mL)中,用乙酸乙酯萃取三遍(20mL x 3)。合并的有机层用饱和食盐水洗涤,然后无水硫酸钠干燥,过滤,滤液减压浓缩后得到的粗品通过柱层析分离(石油醚/乙酸乙酯=5/1)纯化得到黄色固体化合物5d(440mg,收率37%)。1H NMR(DMSO-d6,400MHz,):δ9.84(s,1H),7.67-7.61(m,1H),7.50-7.39(m,9H),7.30-7.25(m,3H),7.19-7.12(m,6H),1.46(s,3H).
将化合物1d(150mg,0.385mmol)溶于无水四氢呋喃(5mL)中,将体系置于冰水浴中冷至0℃,向体系中加入氢化钠(60%,46mg,1.15mmol),室温下搅拌30分钟。再次将反应体系置于冰水浴中冷至0℃,将化合物5d(172mg,0.386mmol)分三批加入到反应体系中。反应体系在室温下搅拌2小时后,将反应体系缓慢倒入到饱和氯化铵溶液中(20mL),用乙酸乙酯萃取三遍(20mL x3)。合并的有机相用饱和食盐水洗涤(20mL),无水硫酸钠干燥,过滤,滤液浓缩后得到黄色固体化合物5e。该化合物没有进一步纯化,直接用于下一步反应。
将上述所得的化合物5e溶于甲醇/乙酸(4mL/1mL)中,然后该反应液加热至60℃搅拌反应2小时。LCMS监测反应完毕,将该反应液减压浓缩,向其中加入饱和碳酸氢钠水溶液(10mL),用乙酸乙酯萃取三遍(10mL x 3)。合并的有机相用饱和食盐水洗涤(10mL),然后无水硫酸钠干燥,过滤,滤液浓缩后得到的粗品通过制备层析薄板(石油醚/乙酸乙酯=2/1混合溶剂淋洗)纯化得到黄色固体化合物5f(48mg,两步收率27%)。MS 469.3[M+H]+。
将化合物5f(48mg,0.103mmol)溶于二氯甲烷/三氟乙酸(2mL/0.5mL)中,该反应体系在室温下搅拌反应5小时。TLC监测反应完毕,将该反应液减压浓缩,向其中加入饱和碳酸氢钠水溶液(10mL),用乙酸乙酯萃取三遍(10mL x 3)。合并的有机相用饱和食盐水洗涤(10mL),然后无水硫酸钠干燥,过滤,滤液浓缩后得到的粗品通过制备层析薄板(二氯甲烷/甲醇=25/1)纯化得到黄色固体化合物5g(35mg,收率96%)。MS 355.2[M+H]+。
将化合物5g(34mg,0.096mmol)溶于甲醇(1mL)中,然后在0℃搅拌状态下加入硼氢化钠(11mg,0.289mmol)。该反应体系在0℃下搅拌反应10分钟。TLC监测反应完毕,将反应液用饱和氯化铵水溶液(5mL)淬灭,用乙酸乙酯萃取三遍(5mL x 3)。合并的有机相用饱和食盐水洗涤,然后无水硫酸钠干燥,过滤,滤液浓缩后得到的粗品通过制备层析薄板(二氯甲烷/甲醇=15/1)纯化得到白色固体化合物5(32mg,收率94%)。1H NMR(非对映体异构体的混合物,DMSO-d6,400MHz):δ7.78(s,1H),7.45-7.35(m,2H),7.08-6.97(m,1H),5.55-5.51and 5.50-5.41(two m,1H),4.92and 4.48(two d,J=6.4Hz,6.4Hz,1H),4.15(s,1H),3.16-3.07(m,1H),2.33(s,3H),2.28-2.17(m,1H),1.79-1.69(m,1H),1.50-1.31(m,12H);MS 357.2[M+H]+。
实施例6:化合物6的制备
将化合物6a(1.5g,6.25mmol)溶于甲醇/水(15mL/3mL)中,然后向其中加入氢氧化钾(350mg,6.24mmol),反应体系在室温下搅拌反应过夜。反应体系减压浓缩除去甲醇,加入水(15mL),用乙酸乙酯萃取两遍(15mL x 2)。水层用稀盐酸中和至pH为3,然后用乙酸乙酯萃取三遍(15mL x 3)。合并的有机相用饱和食盐水洗涤(20mL),然后无水硫酸钠干燥,过滤,滤液浓缩后得到黄色固体化合物6b(1.0g,收率71%)。该化合物无需进一步纯化,直接用于下一步反应。1H NMR(DMSO-d6,400MHz):δ12.04(s,1H),3.57(m,3H),1.83-1.62(m,14H)。
将化合物6b(1.5g,6.25mmol)溶于丙酮(12mL)中,然后向其中加入1N氢氧化钠(4.42mL,4.42mmol)水溶液,反应体系在室温下搅拌10分钟,然后将硝酸银(790mg,4.65mmol)水溶液缓慢滴加至反应体系中。反应体系在室温下搅拌20分钟,抽滤,固体用水、丙酮、乙醚依次洗涤,将固体真空干燥得到白色固体化合物6c(1.2g,收率75%)。
将化合物6c(1.2g,3.60mmol)分散于石油醚(12mL)中,然后将溴素(596mg,3.73mmol)缓慢滴加至体系中,在室温下搅拌20分钟,然后加热至80℃搅拌反应30分钟。将反应体系过滤,用石油醚洗涤固体,合并滤液,滤液用1N氢氧化钠溶液洗涤(10mL),有机层用无水硫酸钠干燥,过滤,滤液浓缩后得到黄色油状化合物6d(225mg,收率24%)。该化合物没有进一步纯化,直接用于下一步反应。1H NMR(DMSO-d6,400MHz):δ3.58(s,3H),2.44-2.37(m,6H),1.98-1.60(m,8H);MS 261.0[M+H]+,263.0[M+H]+。
将化合物6d(225mg,0.86mmol)溶于1%的氢氧化钠(23mL)中,反应体系加热至100℃搅拌16小时。将反应液冷却到室温,用稀盐酸中和至体系pH值为3,用乙酸乙酯萃取七遍(20mL x 7)。合并的有机相用无水硫酸钠干燥,过滤,滤液浓缩后得到黄色固体化合物6e(144mg,收率90%)。该化合物无需进一步纯化,直接用于下一步反应。1H NMR(DMSO-d6,400MHz):δ11.96(s,1H),4.21(s,1H),1.82-1.45(m,14H).
将化合物6e(140mg,0.76mmol)和碳酸钾(157mg,1.14mmol)溶于干燥的N,N-二甲基甲酰胺(2mL)中,然后向其中滴加碘甲烷(324mg,2.25mmol),反应体系在室温下搅拌16小时。向体系中加入10mL水淬灭反应,用乙酸乙酯萃取三遍(10mL x 3)。合并的有机相用饱和食盐水洗涤(10mL),然后用无水硫酸钠干燥,过滤,滤液减压浓缩后得到的粗品通过柱层析分离(石油醚/乙酸乙酯=3/1混合溶剂淋洗)纯化得到黄色固体化合物6f(139mg,收率92%)。1H NMR(DMSO-d6,400MHz):δ4.22(s,1H),3.56(s,3H),1.83-1.50(m,14H);MS 199.2[M+H]+。
将化合物6f(137mg,0.69mmol)和2,6-二甲基吡啶(227mg,2.12mmol)溶于干燥的N,N-二甲基甲酰胺(2mL)中,然后在0℃下向其中滴加叔丁基二甲硅基三氟甲磺酸酯(559mg,2.12mmol),反应体系在室温下搅拌过夜。向体系中加入10mL水淬灭,用乙酸乙酯萃取三遍(10mL x 3)。合并有机相用饱和食盐水洗涤(10mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到残留物。残留物通过柱层析分离(石油醚/乙酸乙酯=50/1混合溶剂淋洗)纯化得到黄色固体化合物6g(60mg,收率28%)。1H NMR(CDCl3,400MHz):δ3.65(s,3H),1.93-1.60(m,14H),0.83(s,9H),0.07(s,6H)。
将甲基膦酸二甲酯(72mg,0.58mmol)溶于无水四氢呋喃(1.5mL)中并冷却至-78℃,向其中缓慢滴加正丁基锂(2.5M正己烷溶液,0.31mL,0.78mmol),反应体系在-78℃搅拌30分钟。然后将化合物6g(60mg,0.19mmol)的无水四氢呋喃溶液(0.3mL)缓慢滴加至上述反应体系中,在-78℃搅拌反应2小时。将反应体系缓慢加入到冰的饱和氯化铵溶液中(10mL),用乙酸乙酯萃取三遍(10mL x 3),合并的有机相用饱和食盐水洗涤(10mL),并用无水硫酸钠干燥、过滤,滤液浓缩后得到的粗品通过柱层析分离(乙酸乙酯淋洗)纯化得到黄色固体化合物6h(60mg,收率77%)。1H NMR(CDCl3,400MHz):δ3.80-3.76(m,6H),3.13(s,1H),3.07(s,1H),1.91-1.58(m,14H),0.84and 0.83(two s,9H),0.07and 0.05(two s,6H);MS405.2[M+H]+。
将氢化钠(60%,17mg,0.43mmol)加入到冰浴冷却的化合物6h(60mg,0.14mmol)的无水四氢呋喃(1.5mL)中,反应体系室温下搅拌30分钟后,再次将反应体系置于冰水浴中冷至0℃,将化合物1e(78mg,0.18mmol)缓慢加入到反应体系中,该反应体系在室温下搅拌2小时。将反应体系缓慢加入到冰的饱和氯化铵溶液中(10mL),用乙酸乙酯萃取三遍(10mL x3),合并的有机相用饱和食盐水洗涤(10mL),并用无水硫酸钠干燥、过滤,滤液减压浓缩后得到残留物。残留物通过制备层析薄板(石油醚/乙酸乙酯=4/1)纯化得到黄色固体化合物6i(20mg,收率20%)。
将化合物6i(20mg,0.028mmol)溶于甲醇/乙酸(2mL/0.5mL)中,然后该反应液加热至60℃搅拌反应2小时。LCMS监测反应完毕,将反应液减压浓缩,向其中加入饱和碳酸氢钠水溶液(10mL),用乙酸乙酯萃取三遍(10mLx3)。合并的有机相用饱和食盐水洗涤(10mL),然后用无水硫酸钠干燥,过滤,滤液浓缩后得到的粗品通过制备层析薄板(二氯甲烷/甲醇=30/1)纯化得到黄色固体化合物6j(10mg,收率76%)。MS 469.3[M+H]+。
将化合物6j(10mg,0.021mmol)溶于二氯甲烷/三氟乙酸(1mL/0.25mL)中,反应体系在室温下搅拌反应5小时。TLC监测反应完毕,将该反应液浓缩,向其中加入饱和碳酸氢钠水溶液(5mL),用乙酸乙酯萃取三遍(10mL x 3)。将合并的有机相用饱和食盐水洗涤(10mL),然后用无水硫酸钠干燥,过滤,滤液浓缩后得到的粗品通过制备层析薄板(二氯甲烷/甲醇=20/1)纯化得到黄色固体化合物6k(6mg,收率79%)。MS 355.2[M+H]+。
将化合物6k(6mg,0.017mmol)溶于甲醇(0.5mL)中,然后在0℃搅拌状态下,向该体系中加入硼氢化钠(2mg,0.053mmol)。该反应液在0℃下搅拌反应10分钟。TLC监测反应完毕,将反应液用饱和氯化铵水溶液(5mL)淬灭,用乙酸乙酯萃取三遍(5mL x 3)。将合并的有机相用饱和食盐水洗涤(5mL),然后用无水硫酸钠干燥,过滤,滤液减压浓缩后得到的粗品通过制备层析薄板(二氯甲烷/甲醇=12/1)纯化得到白色固体化合物6(5.3mg,收率88%)。1H NMR(非对映体异构体的混合物,DMSO-d6,400MHz):δ7.93(s,1H),7.48-7.36(m,2H),7.19and 7.16(two s,1H),7.11-7.02(m,1H),5.62-5.55and 5.53-5.49(two m,1H),5.04and 4.64(two d,J=6.0Hz,6.0Hz,1H),4.06(s,1H),3.11-3.04(m,1H),2.33-2.22(m,1H),1.83-1.72(m,1H),1.68-1.27(m,14H);MS 357.2[M+H]+。
实施例7:化合物7的制备
化合物7采用类似于化合物1的制备方法而得。1H NMR(非对映体异构体的混合物,DMSO-d6,400MHz):δ7.95and 7.91(two s,1H),7.46-7.38(m,2H),7.19and 7.16(two s,1H),7.14-7.04(m,1H),5.67-5.61and 5.60-5.55(two m,1H),5.04-4.99and 4.59-4.55(two m,1H),4.47-4.43and 4.22-4.18(two m,1H),3.77-3.73and 3.31-3.20(two m,1H),3.61-3.52and 3.42-3.34(two m,1H),2.37-2.22(m,1H),1.93-1.74(m,3H),1.67-0.94(m,7H);MS 317.2[M+H]+。
实施例8:化合物8的制备
化合物8采用类似于化合物1的制备方法而得。1H NMR(非对映体异构体的混合物,DMSO-d6,400MHz):δ7.95(s,1H),7.44-7.38(m,2H),7.15(s,1H),7.10-7.04(m,1H),5.55(t,J=4.8Hz,1H),4.54(d,J=6.4Hz,1H),3.04-2.98(m,,1H),2.38-2.31(m,1H),1.91(s,3H),1.87-1.77(m,1H),1.68-1.40(m,12H);MS 353.2[M+H]+.
实施例9:IDO1蛋白酶学实验方法
IDO1的体外酶学实验是在以下反应体系中进行:50mM,pH 6.5的MES缓冲液,200nM人源IDO1蛋白酶,150uM的L-色氨酸,2250units/mL过氧化氢酶,20mM的维生素C和和10uM亚甲基蓝。将待测化合物用100%DMSO配制成10mM的储存液,再使用MES缓冲液将其配制成所需浓度。取25uL稀释完毕的化合物加入96孔板中,而后加入25uL 33.68ng/uL的IDO1蛋白,离心1min混匀后室温孵育30min。化合物孵育后,向反应体系中加入50uL的50mM,pH 6.5的MES缓冲液配制的300uM L-色氨酸,4500unites/mL的过氧化氢酶,20uM亚甲基蓝和40mM的维生素C。25℃下反应40min。用50uL 30%(w/v)的三氯乙酸终止反应并于60℃下孵育30min,而后2000rpm离心5min,取上清与等量的2%的4-(二甲基氨基)苯甲醛(溶解于乙酸中),室温孵育10min后于490nm处测定OD值。
化合物的抑制百分比通过以下公式计算:
化合物的抑制百分比=100-(Sample signal-low control)/(High control-lowcontrol)×100。
其中High control为不添加化合物组,Low control为不添加酶也不添加化合物组,其他同样本相同。
化合物IC50值数据应用XLfit4.3.1统计软件分析,通过抑制率百分比数据相对于化合物浓度的非线性回归拟合曲线。
代表性化合物的活性如表1所示。IC50值:A:1-50nM;B:51-100nM;C:101-500nM;D:>501nM。
表1 IDO1活性抑制
化合物 | IDO1抑制IC<sub>50</sub>值 |
1 | 30nM |
1-1 | D |
1-2 | A |
1-3 | D |
1-4 | B |
3 | A |
4 | A |
6 | 22nM |
7 | 204nM |
8 | 91nM |
实施例10:HEK293T细胞中检测抑制IDO1活性的实验方法
将5X106的HEK293T细胞分别种到2个T75的培养瓶里置于37℃,5%CO2的培养箱内孵育过夜。将0.6ul含有1.5ug hIDO1质粒与300ul的opti-MEM制成混和液A;18ul的脂质体fugene6与300ul的opti-MEM制成混和液B,并在室温下放置5分钟。混液A和混液B混匀,在室温下放置20分钟后,加到种有HEK293T的培养瓶里,另外一瓶作为对照,置于37℃,5%CO2的培养箱内孵育过夜。将已瞬时转染hIDO1的HEK293T以20000细胞每孔的密度种于96孔板,每孔80ul。加入10ul 10倍的色氨酸于细胞中,阴性对照孔不加色氨酸。使用完全培养基配制成10倍的化合物溶液(DMSO浓度为2%),加入10ul的化合物溶液于细胞中。细胞板置于37℃,5%CO2的培养箱内孵育16小时。将80ul上清转到另外一个96孔板,加入10ul的6.1N三氟乙酸,50℃孵育30分钟。2800rpm离心10分钟,转移70ul上清至一96孔UV板中。加入70ul 2%(w/v)对二甲胺苯基甲醛。混匀后测量480nM处的吸光值。细胞板中加入100ul CTG试剂,混匀15分钟后检测化学发光值。代表性化合物的活性如表2所示。IC50值:A:≤120nM;B:121-400nM;C:401-1000nM;D:>1000nM。
表2 HEK293T细胞活性抑制
实施例11:TDO2蛋白酶学实验方法
TDO2的体外酶学实验是在以下反应体系中进行:50mM,pH 6.5的磷酸钾缓冲液,200nM人源TDO2蛋白酶,300uM的L-色氨酸,0.2mg/mL过氧化氢酶,20mM的维生素C和20uM亚甲基蓝。将待测100X的化合物用100%DMSO配制成1mM的起始液,然后三倍稀释,共配制8个浓度。取2uL稀释完毕的化合物加入96孔板中,随后在每个孔中加入100μL 400nM TDO2和0.4mg/ml过氧化氢酶。离心1min混匀后室温孵育10min。化合物孵育后,向反应体系中加入50mM,pH6.5的磷酸钾缓冲液配制的100uL 600uM L-色氨酸,40uM亚甲基蓝和40mM的维生素C。反应液混匀30秒后立即在SpectraMax 384仪器上实时读取OD321的数据,常温下读数时长为20分钟。从软件上导出斜率的数据,再根据斜率转换成化合物的抑制率。
抑制率=(最大值-孔值)/(最大值-最小值)*100.最大值是指有酶有底物的孔值,最小值为没有酶仅有底物的孔值。
将化合物浓度和抑制率代入公式,用GraphPad Prism5.0软件拟合化合物的IC50值,具体公式为:Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope).
代表性化合物的活性如表3所示。IC50值:A:1-50nM;B:51-100nM;C:101-500nM;D:>501nM。
表3 TDO2活性抑制
Compound | TDO2抑制IC<sub>50</sub>值 |
1 | C |
Claims (7)
1.一种如式A7所示的化合物,或其药学上可接受的盐:
其中式A7所示的化合物如式(VI)所示:
其中,
R3为氢、卤素或C1-4烷基;
R4为氢、卤素、C1-4烷基、C3-8环烷基、氰基、OR9;
RA选自:
其中,
各个RA1各自独立地为氢、卤素、C1-4烷基、-OR9、-N(R9)2、-N(R9)C(O)R9、-N(R9)C(O)OR9、-N(R9)S(O)2R9、-N(R9)S(O)2N(R9)2;
q=0、1、2或3;
各个上述的烷基、环烷基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代:卤素、C1-4烷基、C2-4 烯基、C2-4炔基、C3-8 环烷基、-CN、-NO2、-OR9、-SR9、-N(R9)2、-C(O)R9、-C(O)OR9、-C(O)N(R9)2或-S(O)2R9;
各个R9各自独立地为氢、C1-4烷基;
5.权利要求1所述的式A7化合物的用途,其特征在于,用于:
(a) 制备治疗与IDO和/或TDO活性或表达相关的疾病的药物;和/或
(b) 制备IDO和/或TDO靶向抑制剂。
6.一种药物组合物,其特征在于,所述的药物组合物包括:(i) 有效量的权利要求1所述的化合物,或其药学上可接受的盐;和(ii) 药学上可接受的载体。
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