CN105111210B - 用作ido抑制剂的稠合咪唑衍生物 - Google Patents
用作ido抑制剂的稠合咪唑衍生物 Download PDFInfo
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- CN105111210B CN105111210B CN201510262906.5A CN201510262906A CN105111210B CN 105111210 B CN105111210 B CN 105111210B CN 201510262906 A CN201510262906 A CN 201510262906A CN 105111210 B CN105111210 B CN 105111210B
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Abstract
本发明提供IDO抑制剂及其药物组合物,用于调控吲哚胺2,3‑双加氧酶的活性;治疗吲哚胺2,3‑双加氧酶(IDO)介导的免疫抑制;处理从吲哚胺2,3双加氧酶的酶活性抑制获益的医疗条件;增强抗癌症治疗的有效性,包括服用抗癌剂;治疗与癌症有关的肿瘤特异性免疫抑制;治疗与感染性疾病相关的免疫抑制。
Description
本申请是申请日为2012年4月12日、申请号为201280018684.7、发明名称“用作IDO抑制剂的稠合咪唑衍生物”的专利申请的分案申请。
相关应用的交叉引用
本申请要求2011年4月15日提交的美国临时申请序列号61/475,788的申请日收益,特此通过引用将其全部并入。
本发明的背景
本发明的领域
目前披露涉及吲哚胺2,3双加氧酶的化合物和抑制方法;另外,该披露涉及吲哚胺2,3双加氧酶介导的疾病和紊乱的治疗方法。
背景技术综述
色氨酸(Trp)为蛋白质、烟酸和神经递质5-羟色胺(血清素)生物合成所需的一种必需氨基酸。酶吲哚胺2,3双加氧酶(也称作INDO或IDO)催化将L色氨酸降解为N甲酰犬尿氨酸的第一限速步骤。在人体细胞中,IFN-y刺激诱导IDO 的激活,导致色氨酸耗尽,从而阻止刚地弓形虫和沙眼衣原体等色氨酸依赖细胞病原体的增长。IDO的活性还对许多肿瘤细胞具有抗增殖作用,在异体肿瘤的排斥反应过程中,已发现体内IDO诱导,表明这种酶在肿瘤排斥过程中可能发挥的作用。
已观察到用外周血淋巴细胞(PBL细胞)共培养的HeLa细胞,通过IDO活性的上调获得免疫抑制显型。用白细胞介素2(IL-2)处理后,PBL增殖减少,原因可能在于肿瘤细胞释放的IDO对PBL产生的IFN-y分泌物进行反应。用具体IDO 抑制剂1-甲基色氨酸(1MT)处理,逆转了这种效应。有人建议,肿瘤细胞内的 IDO活性可能有助于削弱抗肿瘤反应(Logan等人,2002年,免疫学,105:47887)。
一些证据表明,IDO参与免疫耐受的诱导。哺乳动物妊娠、肿瘤耐药性、慢性感染和自身免疫性疾病的研究表明,表达IDO的细胞能抑制T细胞反应,促进耐受性。在与细胞免疫激活相关的感染、恶性肿瘤、自身免疫性疾病和艾滋病等疾病和紊乱中以及在怀孕期间,发现了加速色氨酸分解代谢。有人建议,IDO 被HIV感染慢性诱导,被机会性感染进一步增强,色氨酸的慢性损失启动了负责恶病质、老年痴呆症和腹泻和可能免疫抑制艾滋病患者的一些机制(Brown等人, 1991,Adv.Exp.,医学生物学,294:42535)。为此,最近已证明,IDO抑制可以增强病毒特异性T细胞的水平,从而,降低HIV老鼠模型中被病毒感染的巨噬细胞的数量(Portula等人,2005,血液,106:238290)。
有人认为,IDO在防止子宫内胎儿排斥反应的免疫过程中发挥作用。40余年前,可以观察到,在怀孕期间,基因完全不同的哺乳动物孕体存活了下来,没有受组织移植免疫学预测情况的影响(Medawar,1953,Symp.Soc.Exp.Biol.7: 320-38)。母体和胎儿的解剖分离以及胎儿的抗原不成熟,不能完全解释胎儿移植存活。最近的注意力都集中在母体的免疫耐受性。由于IDO表达的人合体滋养层细胞和全身色氨酸浓度在正常妊娠期间有所降低,假设在母婴界面的IDO表达对于防止移植胎儿的免疫排斥反应非常必要。为了检验这一假设,将怀孕的老鼠(怀同源或异体胎儿)接触1MT,发现T细胞诱导对所有异体concepti产生快速排斥反应。因此,通过异化色氨酸,哺乳动物孕体似乎抑制T细胞的活性,并防止排斥反应,老鼠怀孕期间阻止色氨酸代谢,可使母体T细胞引起人胎儿移植排斥反应(Munn等,1998年,科学281:11913)。
基于IDO对色氨酸降解的抗肿瘤免疫机制的进一步证据来源于这样的一种观察,即大多数人类肿瘤持续表达IDO,免疫原性老鼠肿瘤细胞对ITO的表达,阻止其被提前免疫老鼠排斥。这种效应伴随着特异性T细胞缺乏在肿瘤部位的积累,在没有明显的毒性时,可以用IDO的抑制剂,通过对老鼠的全身治疗部分恢复。因此,有人认为,同时服用IDO抑制剂(Uyttenhove等,2003年,自然医学,9: 126974)可能提高癌症患者的治疗性疫苗疗效。还表明,IDO抑制剂,即1-MT,可以与化疗药物合用,降低老鼠体内的肿瘤生长,表明IDO抑制也可增强常规细胞毒疗法的抗肿瘤活性(Muller等,2005,自然医学11:3129)。
耐受性宿主APCs表达肿瘤抗原,可能是导致对肿瘤免疫反应迟钝的一个机制。也描述了共表达CD123(IL3RA)和CCR6并抑制T细胞增殖的人类IDO表达抗原呈递细胞(APCs)的一个子集。成熟和不成熟的CD123阳性树突状细胞抑制T细胞的活性,这种IDO抑制活性被1MT阻断(Munn等,2002年,科学297: 186770)。还证明,老鼠肿瘤引流淋巴结(TDLNs)含有不断表达IDO免疫抑制水平的浆细胞样树突状细胞(pDC)的一个子集。尽管体内只含有0.5%的淋巴结细胞,这些pDC有效抑制对pDCs本身呈现的抗原T细胞反应,同时,以显性方式抑制非抑制APC呈现的第三方抗原的T细胞反应。在pDCs的人群内,大多数功能IDO介导的抑制活性用共表达B谱系标记物的pDC新子集分离。因此,有人推测,TDLN内的pDC进行的IDO介导抑制创建一个局部微环境,这个微环境可有效抑制宿主抗肿瘤T细胞反应(Munn等,2004年,J.临床研究,114(2):28090)。
IDO降解色氨酸、5-羟色胺和褪黑激素的吲哚类,启动神经活性和免疫调节代谢产物(统称为犬尿氨酸)的生产。通过局部消耗色氨酸,增加促凋亡犬尿氨酸,树突状细胞(DC)表达的IDO可能极大地影响T细胞的增殖和存活。DC内的IDO 感应可能是调节性T细胞驱动的缺失耐受性的共同机制。因为这种耐受性反应可能在各种病理生理条件下起作用,色氨酸代谢和犬尿氨酸的生产可能代表免疫系统和神经系统之间的一种关键界面(GROHMANN等。趋势免疫学杂志,2003, 24:2428)。
目前正开发IDO的小分子抑制剂来治疗或预防IDO相关的疾病,如上面描述的那些疾病。例如,PCT出版物WO 99/29310报告了改变T细胞介导免疫的方法,包改变局部色氨酸和色氨酸代谢物的胞外浓度,使用1-甲基DL色氨酸、p-(3苯并呋喃基)-DL-丙氨酸、p-[3(b)苯并噻吩基]-DL-丙氨酸与6硝基-L-色氨酸) (Munn,1999年)。WO 03/087347中报告的也作为欧洲专利1501918发表的是生产抗原递呈细胞增强或减少T细胞耐受性的一些方法(Munn,2003年)。WO 2004/094409还进一步报道了具有吲哚胺2,3-双加氧酶(IDO)抑制活性的化合物;美国专利申请第2004/0234623号出版物阐述通过服用吲哚胺2,3双加氧酶抑制剂并结合其它治疗方式治疗癌症或感染患者的方法。
鉴于实验数据指明IDO对免疫抑制、肿瘤耐性和/或排斥反应、慢性感染、HIV 感染、艾滋病(包括恶病质、老年痴呆症和腹泻等表现形式)、自身免疫性疾病或紊乱(例如类风湿关节炎)和免疫耐受性及子宫内胎儿排斥反应的预防,最好采用通过IDO活性抑制色氨酸降解的治疗剂。IDO抑制剂可以用于激活T细胞,因此,当妊娠、恶性肿瘤或HIV等病毒抑制T细胞时,增强T细胞的活性。对于患有神经或神经精神病学疾病或抑郁症等障碍的患者,IDO抑制也可能是重要的治疗策略。此处所述的化合物、组合物和方法帮助满足目前对IDO调控代谢物的需要。
发明概要
在一方面,本发明包括符合结构式(I)的化合物,
其中R1,R2,n和α分别在本文定义。在另一方面,本发明包括符合结构式 (II)的化合物
其中,R1,R3,RC,和n分别在本文定义。
在另一个方面,提供药物组合物,包括药学上可接受的赋形剂、稀释剂或载体以及根据式(I)或(II)的化合物。
在另一方面,规定了相关的方法:(a)用有效量的符合结构式(I)或(II) 的化合物,通过接触吲哚胺2,3-双加氧酶,调控吲哚胺2,3双加氧酶的活性, (b)处理急需受试者中吲哚胺2,3-双加氧酶(IDO)介导的免疫抑制,包括服用有效的吲哚胺2,3双加氧酶抑制量的符合结构式(I)或(II)的化合物,或含有符合结构式(I)或(II)的化合物的药物成分,(c)处理从吲哚胺2,3双加氧酶的酶活性抑制获益的医疗条件,包括服用有效吲哚胺2,3双加氧酶抑制量的符合结构式(I)或(II)的化合物,或含有符合结构式(I)或(II)的化合物的药物成分;(d)增强抗癌症治疗的有效性,包括服用抗癌药物和符合结构式(I)或 (II)的化合物,或包括符合结构式(I)或(II)之化合物的治疗成分;(e)处理与癌症相关的肿瘤特异性免疫抑制,包括服用有效吲哚胺2,3双加氧酶抑制量的符合结构式(I)或(II)的化合物,或含有符合结构式(I)或(II)的化合物的药物成分;与(f)处理与传染性疾病(如HIV-1感染)相关的免疫抑制,包括服用有效吲哚胺2,3双加氧酶抑制量的符合结构式(I)或(II)的化合物,或含有符合结构式(I)或(II)的化合物的药物成分。
附图简述
图1显示用X-射线结晶学证实的化合物1417的HBr盐非对映体的绝对构型。
本发明的具体描述
在一个方面,本发明提供结构式(I)的化合物,
或其药学上可接受的盐,其中
α键是单键或双键;
n为0,1,2,3,或4;
每个R1独立为卤素、氰基、硝基、C1-6烷基,C1-6卤代烷基,-OR,-N(R)2,-SR,-C(O)OR,-C(O)N(R)2,-C(O)R,-S(O)R,-S(O)OR,-S (O)N(R)2,-S(O)2R,-S(O)2OR,-S(O)2N(R)2,-OC(O)R,-OC(O)OR,-OC(O)N(R )2,-N(R)C(O)R,-N(R)C(O)OR,或-N(R)C(O)N(R)2;
当α键是单键时,R2是-C1-4烷基-RA或-C2-4链烯基-R3键;
当α键是双键时,R2为=C(H)RA;
其中,
RA为-CN,-C(O)R3,-C(O)OR3,-C(O)N(R3)(RC), -C(ORB)(R3)(RC),-C(NHRB)(R3)(RC),或-C(=N-ORC)R3,其中
RB为氢,C1-6烷基,C1-6卤代烷基,-C1-6烷基RB1,-C(O)R3,或-S(O)2R3, -C(O)(CH2)1- 4COOR,-C(O)CH(NH2)(RD),--S(O)2OR3,-S(O)2N(R3)2, -CH2-OP(O)2(OR)2,或-P(O)(OR3)2,其中,
RB1是氰基、硝基、C1-6烷基,C1-6卤代烷基,-OR,-N(R)2,-SR,-C(O)OR,-C(O)N(R)2,-C(O)R,-S(O)R,-S(O)OR,-S (O)N(R)2,-S(O)2R,-S(O)2OR,-S(O)2N(R)2,-OC(O)R,-OC(O)OR,-OC(O)N(R )2,-N(R)C(O)R,-N(R)C(O)OR,或-N(R)C(O)N(R)2;
RD为氢、甲基,-CH(CH3)2,-CH2CH(CH3)2,-CH(CH3)(CH2CH3),苄基,4- 羟基苄基,-CH2(3-吲哚基),-CH2SH,-CH2CH2SCH3,-CH2OH,-CH(CH3)OH, -(CH2)4-NH2,-(CH2)3-N(H)C(=NH)NH2,-CH2(4-咪唑基), -CH2COOH,-CH2CH2COOH,-CH2CONH2,-CH2CH2CONH2;
每个R3独立为氢、C1-6烷基、C1-6卤代烷基、芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基、芳基C1-6烷基-、杂芳基C1-6烷基-、C3-8环烷基C1-6烷基-、 C3-8环烯基C1-6烷基-或(3-10元杂环基)C1-6烷基-,
其中
芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基、C3-8环烷基C1-6烷基-、C3-8环烯基C1-6烷基和(3-10元杂环基)C1-6烷基-各被一个=R32基团任选且独立地取代,各被一个、两个、三个或四个R31基团任选且独立地取代;
芳基、杂芳基、芳基C1-6烷基-和杂芳基C1-6烷基-,各被一个、两个、三个或四个R31基团任选取代;
其中
每个R31独立为卤素、氰基、硝基、C1-6烷基,-C1-6烷基-R33,C1-6卤代烷基,-OR,-N(R)2,-SR,-C(O)OR,-C(O)N(R)2,-C(O)R,--S(O)R,-S(O)OR,- S(O)N(R)2,-S(O)2R,-S(O)2OR,-S(O)2N(R)2,-OC(O)R,-OC(O)OR,-OC(O)N( R)2,-N(R)C(O)R,-N(R)C(O)OR,-N(R)C(O)N(R)2,其中
R33是
氰基,-OR,-N(R)2,-SR,-C(O)OR,-C(O)N(R)2,-C(O)R,-S(O)R,-S(O)OR,-S (O)N(R)2,-S(O)2R,-S(O)2OR,-S(O)2N(R)2,-OC(O)R,-OC(O)OR,-OC(O)N(R )2,-N(R)C(O)R,-N(R)C(O)OR,或-N(R)C(O)N(R)2;
R32为=O,=S,=N(R),=N(OR),=C(R34)2,=(螺环-C3-8环烷基),或=螺环-(3-10元杂环基),其中
每个R34独立为氢、卤素、C1-6烷基、C16卤代烷基、C3-8环烷基,或3-10元杂环基;
或两个R34与它们所连接的原子共同构成单环C3-8环烷基或单环3-8元杂环基;
RC是氢或C1-6烷基;和
每个R独立为氢或R10,其中
R10是C1-6烷基、C1-6卤代烷基、芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10 元杂环基、芳基C1-6烷基、杂芳基C1-6烷基-、C3-8环烷基C1-6烷基-、C3-8环烯基 C1-6烷基-,或(3-10元杂环基)C1-6烷基-,每个R10被一个、两个、三个或四个各自独立为下述的基团任选取代:卤素、氰基、硝基、C1-6烷基、C1-6卤代烷基,-OR11,-N(R11)2,-SR11,-C(O)OR11,-C(O)N(R11)2,-C(O)R11,-S(O)R11,-S (O)OR11,-S(O)N(R11)2,-S(O)2R11,-S(O)2OR11,-S(O)2N(R11)2,-OC(O)R11,-OC (O)OR11,-OC(O)N(R11)2,-N(R11)C(O)R11,-N(R11)C(O)OR11,-N(R11)C(O)N(R11)2,其中每个R11独立为氢或C1-6烷基。
在一个实施例中,结构式(I)的化合物还包括那些化合物,
其中,
RB还是-C(O)N(H)R3或-C(O)(CH2)1-4(NR)CO或;
R3还是(杂芳基)-(3-10元杂环基)-,
R31还是-C(O)N(OH)R,-C(N=R11)R,或-C(N=R11)N(R11)R;
R34还是氰基或-C1-6烷基-OR;和/或
R10还被-N(R11)S(O)2R11或-C(O)-(3-10元杂环基)任选取代;
这样的化合物被称为结构式(I′)的化合物。
本发明还包括结构式(I)和结构式(I′)的亚类,其中取代物被选择为一种或多种结构式(I),n,R1,R2,R3,RA,RB,和RC的任何组合(见此处定义),包括但不限于以下:
结构式I为如下(1a)-(1h)中的一种:
从下组(1a)-(1u)中选择n和R1:
(1a)n为1,2,3,或4,各R1按结构式(I)定义。
(1b)n为0,1,2,或3,各R1按结构式(I)定义。
(1c)n为0,1,或2,各R1按结构式(I)定义。
(1d)n为0,1,或2,各R1独立为卤素,-OR,-N(R)2,或-SR。
(1e)n为0,1,或2,各R1独立为卤素,-OR0,-N(R0)2,或-SR0,其中各R0独立为氢或C1-6烷基。
(1f)n为0,1,或2,各R1独立为氟、氯、羟基或甲氧基。
(1g)n为0,1,或2,各R1独立为卤素。
(1h)n为0,1,或2,各R1独立为氟或氯。
(1i)n为0或1,且R1按结构式(I)定义。
(1j)n为0或1,且R1为卤素,-OR,-N(R)2,或-SR。
(1k)n为0或1,且R1为卤素,-OR0,-N(R0)2,或-SR0;其中各R0独立为氢或 C1-6烷基。
(1l)n为0或1,且R1为氟、氯、羟基或甲氧基。
(1m)n为0或1,且R1为卤素。
(1n)n为0或1,且R1为氟或氯。
(1o)n为1,且R1按结构式(I)定义。
(1p)n为1,且R1为卤素,-OR,-N(R)2,或-SR;
(1q)n为1,且R1为卤素,-OR0,-N(R0)2,或-SR0;其中各R0独立为氢或C1-6烷基。
(1r)n为1,且R1为氟、氯、羟基或甲氧基。
(1s)n为1,且R1为卤素。
(1t)n为1,且R1为氟或氯。
(1u)n为0。
R2从下组(2a)-(2l)中选择:
(2a)R2为-C1-4烷基-RA。
(2b)R2为-C1-2烷基-RA。
(2c)R2为-C(H)=C(H)R3。
(2d)R2为-C(H)=C(H)R30,其中R30为被一个、两个、三个或四个R31基团任选取代的苯基。
(2e)R2为-C(H)=C(H)R30,其中R30为被一个或两个R31基团任选取代的苯基。
(2f)R2为-CH2-RA,-CH2CH2-RA,-C(H)(CH3)CH2-RA,或-C(H)=C(H)R3。
(2g)R2为-CH2-RA,-CH2CH2-RA,或-C(H)(CH3)CH2-RA。
(2h)R2为-CH2-RA,-CH2CH2-RA,或-C(H)=C(H)R3。
(2i)R2为-CH2-RA。
(2j)R2为-CH2CH2-RA。
(2k)R2为-C(H)(CH3)CH2-RA。
(2l)R2为-CH2-RA,-CH2CH2-RA,或-C(H)=C(H)R3。
RA从下组(3a)-(3n)中选择:
(3a)RA为-CN,-C(O)OR3,或-C(O)N(R3)(RC)。
(3b)RA为-C(O)R3或-C(ORB)(R3)(RC)。
(3c)RA为-C(NHRB)(R3)(RC),或-C(=N-ORC)R3。
(3d)RA为-C(NHRB)(R3)(RC),其中RB为氢,C1-6烷基,或-C(O)C1-6烷基。
(3e)RA为-C(NH2)(R3)(RC)。
(3f)RA为-C(O)OR3。
(3g)RA为-C(O)N(R3)(RC)。
(3h)RA为-C(O)R3。
(3i)RA为-C(ORB)(R3)(RC)。
(3j)RA为-C(OH)(R3)(RC)。
(3k)RA为-CH(OH)(R3)。
(3l)RA为-CN,-C(O)R3,-C(O)OR3,-C(O)N(R3)(RC), -C(ORB)(R3)(RC),-C(NHRB)(R3)(RC),或-C(=N-ORC)R3。
(3m)RA为-C(O)R3或-C(ORB)(R3)(RC),其中RB为氢,RC为氢或C1-6烷基。
(3n)RA为-C(ORB)(R3)(RC),其中RB为氢,RC为氢或C1-6烷基。
RB从下组(4a)-(4k)中选择:
(4a)RB为氢、C1-6烷基、C1-6卤代烷基、-C1-6烷基-RB1、 -C(O)(CH2)1-4COORB2、-C(O)C(NH2)RD、-P(O3)(RB2)2、-CH2-OP(O)2(OR)2、其中 RD为天然α氨基酸的侧链,-C(O)R3,或-S(O)2R3,其中RB1为氰基,硝基,C1-6烷基,C1-6卤代烷基,-ORB2,-N(RB2)2,-SRB2,-C(O)ORB2,-C(O)N(RB2)2,-C(O)RB2,-S(O)RB2,- S(O)ORB2,-S(O)N(RB2)2,-S(O)2RB2,-S(O)2ORB2,-S(O)2N(RB2)2,-OC(O)RB2,- OC(O)ORB2,-OC(O)N(RB2)2,-N(RB2)C(O)RB2,-N(RB2)C(O)ORB2,或-N(RB2)C(O)N(RB2)2,其中各RB2独立为氢或C1-6烷基。
(4b)RB为氢,C1-6烷基,C1-6卤代烷基,-C1-6烷基-RB1,-C(O)R3,或-S(O)2R3,其中RB1为氰基,硝基,C1-6烷基,C1-6卤代烷基,-ORB2,-N(RB2)2,-SRB2,-C(O)ORB2,-C(O)N(RB2)2,-C(O)RB2,-S(O)RB2,- S(O)ORB2,-S(O)N(RB2)2,-S(O)2RB2,-S(O)2ORB2,-S(O)2N(RB2)2,-OC(O)RB2,-OC(O)ORB2,-OC(O)N(RB2)2,-N(RB2)C(O)RB2,-N(RB2)C(O)ORB2,或-N(RB2)C(O)N(RB2)2,其中各RB2独立为氢或C1-6烷基。
(4c)RB为氢,C1-6烷基,C1-6卤代烷基,或-C1-6烷基-RB1,其中RB1为氰基,硝基,C1-6烷基,C1-6卤代烷基,-ORB2,-N(RB2)2,-SRB2,-C(O)ORB2,-C(O)N(RB2)2,-C(O)RB2,-S(O)RB2,- S(O)ORB2,-S(O)N(RB2)2,-S(O)2RB2,-S(O)2ORB2,-S(O)2N(RB2)2,-OC(O)RB2,- OC(O)ORB2,-OC(O)N(RB2)2,-N(RB2)C(O)RB2,-N(RB2)C(O)ORB2,或-N(RB2)C(O)N(RB2)2,其中各RB2独立为氢或C1-6烷基。
(4d)RB为氢、C1-6烷基、C1-6卤代烷基,或-C1-6烷基-RB1,其中RB1为氰基、-C(O)ORB2、-C(O)N(RB2)2、-C(O)RB2、-S(O)2RB2、-S(O)2ORB2,或-S(O)2N(RB2)2,其中各RB2独立为氢或C1-6烷基。
(4e)RB为-C1-6烷基-RB1,其中RB1为氰基、-C(O)ORB2、-C(O)N(RB2)2、-C(O)RB2、-S(O)2RB2、-S(O)2ORB2,或-S(O)2N(RB2)2,其中各RB2独立为氢或C1-6烷基。
(4f)RB为氢、C1-6烷基、C1-6卤代烷基、-C1-6烷基-RB1、-C(O)RB2,或-S(O)2RB2,其中RB1为-C(O)ORB3、-C(O)N(RB3)2、-S(O)2ORB3,或-S(O)2N(R3)2,RB2为C1-6烷基;RB3为氢或C1-6烷基。
(4g)RB为氢、C1-6烷基,或C1-6卤代烷基。
(4h)RB为氢或C1-6烷基;
(4i)RB为氢。
(4j)RB为C1-6烷基。
(4k)RB为氢、-C(O)RB2、-C(O)(CH2)1-4COORB2、 -C(O)C(NH2)RD、-P(O)(ORB2)2、-CH2-OP(O)2(OR)2、-S(O)2RB2、-C(O)N(RB2)2、- S(O)2ORB2、-S(O)2N(R2)2,其中,RB2为氢或C1-6烷基。
RC从下组(5a)-(5g)中选择:
(5a)RC为氢或C1-4烷基。
(5b)RC为氢或C1-2烷基。
(5c)RC为氢或甲基。
(5d)RC为氢。
(5e)RC为C1-6烷基。
(5f)RC为C1-4烷基。
(5g)RC为甲基。
R3从下组(6a)-(6z)中选择:
(6a)R3为氢、C1-6烷基、芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基、或C3-8环烷基C1-6烷基-,其中C1-6烷基、C3-8环烷基、C3-8环烯基、3-10元杂环基、C3-8环烷基C1-6烷基-,各被一个=R32基团任选取代,各被一个或两个R31基团任选取代;芳基和杂芳基基团各被一个或两个R31基团任选取代。
(6b)R3为芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基,或C3-8环烷基C1-6烷基-,其中C3-8环烷基、C3-8环烯基、3-10元杂环基、C3-8环烷基C1-6烷基-,各被一个=R32基团任选且独立地取代,各被一个或两个R31基团任选且独立地取代;芳基和杂芳基基团各被一个或两个R31基团任选取代。
(6c)R3为苯基、五元或六元杂芳基、单环C5-8环烷基、单环C5-8环烯基、五元或六元单环杂环基,或(单环C5-8环烷基)C1-6烷基-,其中C5-8环烷基、C5-8环烯基、 5-6元杂环基和C5-8环烷基C1-6烷基-,各被一个=R32基团任选且独立地取代,各被一个或两个R31基团任选且独立地取代;苯基和杂芳基基团各被一个或两个R31基团任选取代。
(6d)R3为苯基或五元或六元杂芳基,各被一个或两个R31基团任选取代。
(6e)R3为单环C5-8环烷基、单环C5-8环烯基、五元或六元单环杂环基,或(单环 C5-8环烷基)C1-6烷基-,各被一个=R32基团以及一个或两个R31基团任选取代。
(6f)R3为其中a键为单键或双键;m为0、1或2;p为0或1;其中
当a键为单键时,则Z为-C(R36)2-、-C(=R32)-、-N(R35)-或-O-,其中各R36独立为氢或R21;
R35为氢、C1-6烷基、-C(O)R、-S(O)2R、-C(O)OR、-C(O)N(R)2、-S(O)2OR,或-S(O)2N(R)2;
当a键为双键时,则Z为-C(R36)=或-N=。
(6g)R3为其中a键为单键或双键;m为0、1,或2;p为0或 1;其中
当a键为单键时,则Z为-C(R36)2-、-C(=R32)-、-N(R35)-,或-O-,其中各R36独立为氢或R31;且
R35为氢、C1-6烷基、-C(O)R、-S(O)2R、-C(O)OR、-C(O)N(R)2、-S(O)2OR,或-S(O)2N(R)2;
当a键为双键时,则Z为-C(R36)=或-N=。
(6h)如同组(6g),其中当a键为单键时,则Z为-C(R36)2-或-C(=R32)-;当a键为双键时,则Z为-C(R36)=或-N=。
(6i)如同组(6g),其中m为0;当a键为单键时,则Z为-C(R36)2-或-C(=R32)-;当a键为双键时,则Z为-C(R36)=或-N=。
(6j)如同组(6g),其中a键为单键,Z为-C(R36)2-或-C(=R32)-。
(6k)如同组(6g),其中a键为单键,Z为-C(R36)2-。
(6l)如同组(6g),其中a键为单键,Z为-C(=R32)-。
(6m)如同组(6g),其中m为0;a键为单键,Z为-C(R36)2-或-C(=R32)-。
(6n)如同组(6g),其中m为0;a键为单键,Z为-C(R36)2-。
(6o)如同组(6g),其中m为0;a键为单键,Z为-C(=R32)-。
(6p)如同组(6g),其中a键为单键,Z为-C(R36)2-或-C(=R32)-,其中各R36独立为氢、卤素、C1-6烷基、-C1-6烷基-OH、C1-6卤代烷基,或-OH,其中
R32为=O、=C(R34)2、=(螺环-C3-8环烷基),或=(螺环-(3-8元杂环基)),其中各R34独立为氢、卤素、C1-6烷基、C1-6卤代烷基、C3-8环烷基、或3-8元杂环基。
(6q)如同组(6g),其中m为0;a键为单键,Z为-C(R36)2-或-C(=R32)-,其中各 R36独立为氢、卤素、C1-6烷基、-C1-6烷基-OH、C1-6卤代烷基,或-OH,其中
R32为=O、=C(R34)2、=(螺环-C3-8环烷基),或=(螺环-(3-8元杂环基)),其中各R34独立为氢、卤素、C1-6烷基、C1-6卤代烷基、C3-8环烷基、或3-8元杂环基。
(6r)如同组(6g),其中a键为单键,Z为-N(R35)-或-O-。
(6s)R3为氢、C1-6烷基、芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基,或C3-8环烷基C1-6烷基,其中
C1-6烷基、C3-8环烷基、C3-8环烯基、3-10元杂环基和C3-8环烷基C1-6烷基各被一个=R32基团以及一个或两个R31基团任选取代;
芳基和杂芳基各被一个或两个R31基团任选取代;其中
各R31独立为卤素、氰基、硝基、C1-6烷基、-C1-6烷基-R33,C1-6卤代烷基,-OR,-N(R)2,-SR,-C(O)OR,-C(O)N(R)2,-C(O)R,-S(O)R,-S(O)OR,-S (O)N(R)2,-S(O)2R,-S(O)2OR,-S(O)2N(R)2,-OC(O)R,-OC(O)OR,-OC(O)N(R )2,-N(R)C(O)R,-N(R)C(O)OR,-N(R)C(O)N(R)2,其中R33为-OR、-N(R)2,或-SR;且
R32为氧代、=C(R34)2、=(螺环-C3-8环烷基),或=(螺环-(3-10元杂环基)),其中各R34独立为氢、卤素、C1-6烷基,或C3-8环烷基。
(6t)R3为氢、C1-6烷基、芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基,或C3-8环烷基C1-6烷基-,其中
C1-6烷基、C3-8环烷基、C3-8环烯基、3-10元杂环基和C3-8环烷基C1-6烷基- 各被一个=R32基团任选且独立地取代,以及各被一个或两个R31基团任选且独立地取代;
芳基和杂芳基基团各被一个或两个R31基团任选取代;其中
各R31独立为卤素、氰基、硝基、C1-6烷基、C1-6烷基,-C1-6烷基-R33,C1-6卤代烷基,-OR,-N(R)2,-SR,-C(O)OR,-C(O)N(R)2,-C(O)R,-S(O)R,-S(O)OR,-S (O)N(R)2,-S(O)2R,-S(O)2OR,-S(O)2N(R)2,-OC(O)R,-OC(O)OR,-OC(O)N(R )2,-N(R)C(O)R,-N(R)C(O)OR,-N(R)C(O)N(R)2,其中R33为-OR、-N(R)2,或-SR;
R32为氧代、=C(R34)2、=(螺环-C3-8环烷基),或=(螺环-(3-10元杂环基)),其中各R34独立为氢、卤素、C1-6烷基,或C3-8环烷基.
(6u)R3为芳基、杂芳基、C3-8环烷基、C3-8环烯基、或3-10元杂环基,其中, C3-8环烷基、C3-8环烯基和3-10元杂环基各被一个=R32基团以及一个、两个、三个或四个R31基团任选取代;且
芳基和杂芳基各被一个、两个、三个或四个R31基团任选取代。
(6v)R3为苯基、环戊基、环己基、环己烯基、呋喃基、四氢吡喃基、哌啶基、咪唑基、噻唑基,各被一个、两个、三个或四个R31基团任选取代,其中环戊基、环己基、环己烯基和哌啶基基团各被一个=R32基团任选取代。
(6w)R3为苯基、环戊基、环己基、环己-1-烯-1-基、环己-3烯-1-基、呋喃-2-基、呋喃-3-基、四氢吡喃-3-基、四氢吡喃-4-基、哌啶-3-基、哌啶-4-基、咪唑-2-基、咪唑-4-基、噻唑-2-基、噻唑-4-基、噻唑-5-基,各被一个或两个R31基团任选取代,其中环戊基、环己基、环己烯基和哌啶基基团各被一个=R32基团任选取代。
(6x)任一组(6a)-(6w),其中各R独立为氢、C1-6烷基、C1-6卤代烷基、芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基、芳基C1-6烷基、杂芳基C1-6烷基-、C3-8环烷基C1-6烷基-、C3-8环烯基C1-6烷基-,或(3-10元杂环基)C1-6烷基-。
(6y)任一组(6a)-(6w),其中各R独立为氢、C1-6烷基、C1-6卤代烷基、苯基、 5-或6-元杂芳基、C3-8环烷基、C3-8环烯基、3-8元杂环基、苄基、(5-或6-元杂芳基)C1-6烷基-、C3-8环烷基C1-6烷基-、C3-8环烯基C1-6烷基-,或(3-8元杂环基)C1-6烷基-。
(6z)任一组(6a)-(6w),其中各R独立为氢或C1-6烷基。
本发明这方面的特殊实施例包括(I)、(I’)和(Ia)-(Id)中任何一个结构式化合物,各在下面几行中定义,其中每一条为如上定义的基团编号(例如,(1s)指n为1,各R1为卤素),破折号“-”表示按结构式(I)或(I’)定义的或按照其中任何一个适用的变量定义(1a)-(6z)定义的变量[例如,当RC为破折号时,它可以按照结构式(I)或 (I’)或任何定义(5a)-(5g)定义]:
在一个方面,本发明提供结构式(II)的化合物,
或其药学上可接受的盐,其中
n为0或1;
各R1独立为卤素,-OR,-N(R)2,或-SR;
各R3独立为氢,C1-6烷基,芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基,或C3-8环烷基C1-6烷基-,其中
C1-6烷基,C3-8环烷基、C3-8环烯基、3-10元杂环基和C3-8环烷基C1-6烷基-,各被一个=R32基团任选且独立地取代,各被一个或两个R31基团任选且独立地取代;
芳基和杂芳基各被一个或两个R31基团任选取代;其中
各R31独立为卤素,氰基,硝基,C1-6烷基,-C1-6烷基-R33,C1-6卤代烷基,-OR,-N(R)2,-SR,-C(O)OR,-C(O)N(R)2,-C(O)R,-S(O)R,-S(O)OR,-S (O)N(R)2,-S(O)2R,-S(O)2OR,-S(O)2N(R)2,-OC(O)R,-OC(O)OR,-OC(O)N(R )2,-N(R)C(O)R,-N(R)C(O)OR,-N(R)C(O)N(R)2,其中R33为-OR,-N(R)2,或-SR;
R32为氧代,=C(R34)2,=(螺环-C3-8环烷基),或=(螺环-(3-10元杂环基)),其中各R34独立为氢,卤素,C1-6烷基,或C3-8环烷基;且
RC为氢或C1-6烷基;且
各R独立为氢或R10,其中
R10为C1-6烷基,C1-6卤代烷基,芳基、杂芳基、C3-8环烷基、C3-8环烯基、 3-10元杂环基,芳基C1-6烷基,杂芳基C1-6烷基-,C3-8环烷基C1-6烷基-,C3-8环烯基C1-6烷基-,或(3-10元杂环基)C1-6烷基-,每个R10被一个、两个、三个或四个独立为下述的基团任选取代:卤素、氰基、硝基、C1-6烷基,C1-6卤代烷基,-OR11,-N(R11)2,-SR11,-C(O)OR11,-C(O)N(R11)2,-C(O)R11,-S(O)R11,-S (O)OR11,-S(O)N(R11)2,-S(O)2R11,-S(O)2OR11,-S(O)2N(R11)2,-OC(O)R11,-OC (O)OR11,-OC(O)N(R11)2,-N(R11)C(O)R11,-N(R11)C(O)OR11,-N(R11)C(O)N(R11)2,其中各R11独立为氢或C1-6烷基。
在一个实施例中,结构式(II)的化合物还包括那些化合物,其中
R3还是(杂芳基)-(3-10元杂环基)-;
R31还是-C(O)N(OH)R,-C(N=R11)R,或-C(N=R11)N(R11)R;
R34还是氰基或-C1-6烷基-OR;且/或
R10还被-N(R11)S(O)2R11或-C(O)-(3-10元杂环基)任选取代;
这样的化合物被称为结构式(II’)的化合物。
本发明还包括结构式(II)和结构式(II‘)的亚类,其中取代物被选择为一种或多种结构式(II),n,R1,R3和RC的任何组合(见此处定义),包括但不限于以下:
结构式II为结构式(IIa)-(IId)中的一种:
(IIa):其中,结构式(II)碳-1(C-1)和碳-3(C-3)的立体异构构型分别是(R,R)。
(IIb):其中,碳-1和碳-3的立体异构构型分别属于结构式(II)(R,S)。
(IIc):其中,碳-1和碳-3的立体异构构型分别属于结构式(II)(S,R)。
(IId):其中,碳-1和碳-3的立体异构构型分别属于结构式(II)(S,S)。
结构式II为结构式(IIe)-(IIh)中的一种:
(IIe):其中,结构式(II)碳-1(C-1)和碳-3(C-3)的立体异构构型分别是(R,R)。、
(IIf):其中,碳-1和碳-3的立体异构构型分别属于结构式(II)(R,S)。
(IIg):其中,碳-1和碳-3的立体异构构型分别属于结构式(II)(S,R)。
(IIh):其中,碳-1和碳-3的立体异构构型分别属于结构式(II)(S,S)。
n,R1从下组(7a)-(7i)中选择:
(7a)n为0或1,R1为卤素,-OR0,-N(R0)2,或-SR0;其中各R0独立为氢或C1-6烷基。
(7b)n为0或1,R1为氟、氯、羟基或甲氧基。
(7c)n为0或1,R1为卤素。
(7d)n为0或1,R1为氟或氯。
(7e)n为1,R1为卤素,-OR0,-N(R0)2,或-SR0;其中各R0独立为氢或C1-6烷基。
(7f)n为1,R1为氟、氯、羟基或甲氧基。
(7g)n为1,R1为卤素。
(7h)n为1,R1为氟或氯。
(7i)n为0。
RC从下组(8a)-(8g)中选择:
(8a)RC为氢或C1-4烷基。
(8b)RC为氢或C1-2烷基。
(8c)RC为氢或甲基。
(8d)RC为氢。
(8e)RC为C1-6烷基。
(8f)RC为C1-4烷基。
(8g)RC为甲基。
R3从下组(9a)-(6x)中选择:
(9a)R3为芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基,或C3-8环烷基C1-6烷基-,其中C3-8环烷基、C3-8环烯基、3-10元杂环基和C3-8环烷基C1-6烷基-各被一个=R32基团任选且独立地取代,各被一个或两个R31基团任选且独立地取代;芳基和杂芳基基团各被一个或两个R31基团任选取代。
(9b)R3为苯基、五元或六元杂芳基、单环C5-8环烷基、单环C5-8环烯基、五元或六元单环杂环基,或(单环C5-8环烷基)C1-6烷基-,其中C5-8环烷基、C5-8环烯基、 5-6元杂环基和C5-8环烷基C1-6烷基-各被一个=R32基团任选且独立地取代,各被一个或两个R31基团任选且独立地取代;芳基和杂芳基基团各被一个或两个R31基团任选取代。
(9c)R3为苯基或五元或六元杂芳基,各被一个或两个R31基团任选取代。
(9d)R3为单环C5-8环烷基、单环C5-8环烯基、五元或六元单环杂环基,或(单环 C5-8环烷基)C1-6烷基-,各被一个=R32基团和一个或两个R31基团任选取代。
(9e)R3为其中a键为单键或双键;m为0、1或2;p为0或1;其中
当a键为单键时,则Z为-C(R36)2-、-C(=R32)-、-N(R35)-或-O-,其中各R36独立为氢或R31;
R35为氢、C1-6烷基、-C(O)R、-S(O)2R、-C(O)OR、-C(O)N(R)2、-S(O)2OR,或-S(O)2N(R)2;
当a键为双键时,则Z为-C(R36)=或-N=。
(9f)R3为其中a键为单键或双键;m为0、1,或2;p为0或 1,其中
当a键为单键时,则Z为-C(R36)2-、-C(=R32)-、-N(R35)-,或-O-,其中各R36独立为氢或R31;且
R35为氢、C1-6烷基、-C(O)R、-S(O)2R、-C(O)OR、-C(O)N(R)2、-S(O)2OR,或-S(O)2N(R)2;
当a键为双键时,则Z为-C(R36)=或-N=。
(9g)如同基团(9f),其中当a键为单键时,则Z为-C(R36)2-或-C(=R32)-;当a键为双键时,则Z为-C(R36)=或-N=。
(9h)如果基团(9f),其中m为0;当a键为单键时,则Z为-C(R36)2-或-C(=R32)-;当a键为双键时,则Z为-C(R36)=或-N=。
(9i)如同基团(9f),其中a键为单键,Z为-C(R36)2-或-C(=R32)-。
(9j)如同基团(9f),其中a键为单键,Z为-C(R36)2-。
(9k)如同基团(9f),其中a键为单键,Z为-C(=R32)-.
(9l)如同基团(9f),其中m为0;a键为单键,Z为-C(R36)2-或-C(=R32)-。
(9m)如同基团(9f),其中m为0;a键为单键,Z为-C(R36)2-。
(9n)如同基团(9f),其中m为0;a键为单键,Z为-C(=R32)-。
(9o)如同基团(9f),其中a键为单键,Z为-C(R36)2-或-C(=R32)-,其中各R36独立为氢、卤素、C1-6烷基、-C1-6烷基-OH、C1-6卤代烷基,或-OH,其中
R32为=O、=C(R34)2、=(螺环-C3-8环烷基),或=(螺环-(3-8元杂环基)),其中各R34独立为氢、卤素、C1-6烷基、C1-6卤代烷基、C3-8环烷基、或3-8元杂环基。
(9p)如同基团(9f),其中m为0;a键为单键,Z为-C(R36)2-或-C(=R32)-,其中各R36独立为氢、卤素、C1-6烷基、-C1-6烷基-OH、C1-6卤代烷基,或-OH,其中
R32为=O、=C(R34)2、=(螺环-C3-8环烷基),或=(螺环-(3-8元杂环基)),其中各R34独立为氢、卤素、C1-6烷基、C1-6卤代烷基、C3-8环烷基、或3-8元杂环基。
(9q)如同基团(9f),其中a键为单键,Z为-N(R35)-或-O-。
(9r)R3为氢、C1-6烷基、芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基,或C3-8环烷基C1-6烷基,其中
C1-6烷基、C3-8环烷基、C3-8环烯基、3-10元杂环基和C3-8环烷基C1-6烷基各被一个=R32基团以及一个或两个R31基团任选取代;
芳基和杂芳基各被一个或两个R31基团任选取代;其中
各R31独立为卤素、氰基、硝基、C1-6烷基、C1-6烷基,-C1-6烷基-R33,C1-6卤代烷基,-OR,-N(R)2,-SR,-C(O)OR,-C(O)N(R)2,-C(O)R,-S(O)R,-S(O)OR,-S (O)N(R)2,-S(O)2R,-S(O)2OR,-S(O)2N(R)2,-OC(O)R,-OC(O)OR,-OC(O)N(R )2,-N(R)C(O)R,-N(R)C(O)OR,-N(R)C(O)N(R)2,其中R33为-OR、-N(R)2,或-SR;且
R32为氧代、=C(R34)2、=(螺环-C3-8环烷基),或=(螺环-(3-10元杂环基)),其中各R34独立为氢、卤素、C1-6烷基,或C3-8环烷基。
(9s)R3为芳基、杂芳基、C3-8环烷基、C3-8环烯基、或3-10元杂环基,其中C3-8环烷基、C3-8环烯基和3-10元杂环基各被一个=R32基团以及一个、两个、三个或四个R31基团任选取代;且
芳基和杂芳基各被一个、两个、三个或四个R31基团任选取代。
(9t)R3为苯基、环戊基、环己基、环己烯基、呋喃基、四氢吡喃基、哌啶基、咪唑基、噻唑基,各被一个、两个、三个或四个R31基团任选取代,其中环戊基、环己基、环己烯基和哌啶基基团各被一个=R32基团任选取代。
(9u)R3为苯基、环戊基、环己基、环己-1-烯-1-基、环己-3-烯-1-基、呋喃-2-基、呋喃-3-基、四氢吡喃-3-基、四氢吡喃-4-基、哌啶-3-基、哌啶-4-基、咪唑-2-基、咪唑-4-基、噻唑-2-基、噻唑-4-基、噻唑-5-基,各被一个或两个R31基团任选取代,其中环戊基、环己基、环己烯基和哌啶基基团各被一个=R32基团任选取代。
(9v)任一组(9a)-(9u),其中各R独立为氢、C1-6烷基、C1-6卤代烷基、芳基、杂芳基、C3-8环烷基、C3-8环烯基、3-10元杂环基、芳基C1-6烷基、杂芳基C1-6烷基-、C3-8环烷基C1-6烷基-、C3-8环烯基C1-6烷基-,或(3-10元杂环基)C1-6烷基-。
(9w)任一组(9a)-(9u),其中各R独立为氢、C1-6烷基、C1-6卤代烷基、苯基、 5-或6-元杂芳基、C3-8环烷基、C3-8环烯基、3-8元杂环基、苄基、(5-或6-元杂芳基)C1-6烷基-、C3-8环烷基C1-6烷基-、C3-8环烯基C1-6烷基-,或(3-8元杂环基)C1-6烷基-。
(9x)任一组(9a)-(9u),其中各R独立为氢或C1-6烷基。
本发明这方面的特殊实施例包括(II)、(II’)和(IIa)-(IId)中任何一个结构式化合物,各在下面几行中定义,其中每一条为如上定义的基团编号(例如,(1s)指n为 1,各R1为卤素),破折号“-”表示按结构式(II)或(II’)定义的或按照其中任何一个适用的变量定义(7a)-(9t)定义的变量[例如,当RC为破折号时,它可以按照结构式 (II)或(II’)或任何定义(8a)-(8g)定义]:
在另一方面,本披露提供如下特点的化合物
在另一方面,本披露提供化合物和药物组合物,包含符合本发明前述各方面或其任何实施例的化合物以及药学上可接受的赋形剂、稀释剂或载体。
在另一方面,本发明提供在所需受试者中吲哚胺2,3-加双氧酶(IDO)介导的免疫治疗的方法,包括服用有效吲哚胺2,3双加氧酶抑制量的符合本发明前述各方面或其任何实施例的化合物或药物组合物。
在一个实施例中,免疫抑制与感染性疾病或癌症相关。
在另一个实施例中,免疫抑制与感染性疾病相关,这种感染性疾病是从包括如下内容的小组中选择出来的病毒感染:丙型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、巨细胞病毒(CMV)、爱泼斯坦病毒(EBV)、脊髓灰质炎病毒、水痘带状疱疹病毒、柯萨奇病毒和人类免疫缺陷病毒(HIV)。
在另一个实施例中,免疫抑制为HIV-1感染相关的免疫抑制。
在另一个实施例中,与癌症相关的免疫抑制。
在实施例中,免疫抑制是与癌症相关的肿瘤特异性免疫抑制。
在另一个实施例中,免疫抑制与癌症相关,其特征在于,所述癌症是结肠、胰腺、乳房、前列腺、肺、脑、卵巢、子宫颈、睾丸、肾、头部或颈部癌或淋巴瘤、白血病或黑色素瘤。
在另一方面,本发明提供上面定义的前述各方面(及其任何实施例)描述的化合物的使用方法,这些化合物用于制备一种药物,处理受益于抑制吲哚胺2,3 双加氧酶酶活性的医疗条件。这方面预期的医疗条件包括本文所述的所有条件。
在另一方面,本发明提供上面定义的前述各方面(及其任何实施例)描述的化合物的使用方法,这些化合物用于制备刺激T细胞增殖或扭转无反应力或免疫抑制免疫状态的一种药物。
在一个实施例中,在无反应力或免疫抑制由酶吲哚胺2,3双加氧酶的表达导致。
在另一方面,本发明提供上面定义的前述各方面(及其任何实施例)描述的化合物的使用方法,这些化合物用于制备用于治疗与癌症、感染性疾病或病毒感染相关的免疫抑制的一种药物。
在一个实施例中,本发明提供上面定义的前述各方面(及其任何实施例)描述的化合物的使用方法,这些化合物用于制备用于治疗与癌症相关的肿瘤特异性免疫抑制的药物。更确切地讲,所述癌症是结肠、胰腺、乳房、前列腺、肺、脑、卵巢、子宫颈、睾丸、肾、或头部和颈部、淋巴瘤、白血病、黑色素瘤等部位的癌症。
在一个实施例中,本发明提供上面定义的前述各方面(及其任何实施例)描述的化合物的使用方法,这些化合物用于制备用于治疗传染性疾病的一种药物,这种情况下,传染性疾病是病毒感染。该病毒传染最好选自包括如下病毒的小组:流感、丙型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、巨细胞病毒(CMV)、爱泼斯坦病毒(EBV)、水痘带状疱疹病毒、脊髓灰质炎病毒、柯萨奇病毒、病毒感染和人类免疫缺陷病毒(HIV)。病毒感染最好是人类免疫缺陷病毒(HIV)。
定义
本文所使用的术语前面和/或后面可以加单破折号,“-”,或双破折号,“=”,表明被命名取代基及其母体类之间键的键序;单破折号表示单键,双破折号表示双键或螺环取代基情况下的一对单键。在没有单破折号或双破折号时,可以认为在取代基及其母体类之间形成单键;此外,取代基的目的是被“从左到右”阅读,除非另有指示。例如,C1-C6烷氧基羰基氧基和-OC(O)C1-C6烷基表示相同的功能;同样,芳基烷基、芳基烷基、烷基芳基表示相同的功能。
此外,此处的某些术语也可用作一价和二价连接基,本领域的成熟技术人员对此很熟悉,通过其表达,在其他两个类之间形成连接。例如,烷基基团可以是一价基或二价基;在后者情况下,本领域的成熟技术人员显然可以看出,从一价烷基消除一个二维氢原子,提供合适的二价类。
本文所用的术语“链烯基”指含有2至10个碳原子(除非另有规定)并含有至少一个碳碳双键的直链或支链烃基。链烯基的代表性实例包括,但不限于,乙烯基、丙烯基、2-甲基丙烯基、丁烯基、戊烯基、己烯基、庚烯基、2-甲基-1-庚烯基、癸烯基、2,6-二甲基辛3,7二烯。
本文所用的术语“烷氧基”指烷基基团,如本文定义,通过氧原子附加到母体分子类。烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、2丙氧基、丁氧基、叔丁氧基、戊氧基和己氧基。
本文所用的术语“烷基”、是指直链或支链烃基、含1至10个碳原子、除非另有规定。烷基的代表性例子包括但不限于、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、三甲基己基、 2,2二甲基戊基、2,3二甲戊基、正庚、正辛基、正壬基和正癸基。当“烷基”基团其他类之间的连接基团时,它也可能是直链或支链,例子包括但不限于-CH2-,-CH2CH2-,-CH2CH2CHC(CH3)-,-CH2CH(CH2CH3)CH2-。
本文所用的术语“芳基”指苯基(即,单环芳基)或者是芳族双环体系中含有至少一个苯环或只含有碳原子的双环体系。双环芳基可以是薁基、萘基、或稠合到单环环烷基、单环环烯基或单环杂环的苯基。双环芳基通过双环体系的苯基部分所含的任何碳原子或带有萘基或薁环的任何碳原子附到母体分子类上。双环芳基的稠合单环环烷基或单环杂环基部分被一个或两个氧代基和/或硫杂基团选择性取代。双环芳基的代表性例子包括但不限于薁基、萘基、二氢茚-1-基、二氢茚-2- 基、二氢茚-3-基、二氢茚-4-基、2,3-二氢吲哚-4-基、2,3-二氢吲哚-5-基、2, 3二氢-6-基、2,3二氢-7-基、茚-1-基、茚-2-基、茚-3-基、茚-4-基、二氢萘-2- 基、二氢萘-3-基、二氢萘-4-基、二氢萘-1-基、5,6,7,8-四氢化萘-1-基、5, 6,7,8-四氢萘-2-基、2,3-二氢苯并呋喃-4-基、2,3-二氢苯并呋喃-5-基、2, 3-二氢苯并呋喃-6-基、2,3-二氢苯并呋喃-7-基、苯并[d][1,3]间二氧杂环戊烯-4- 基、苯并[d][1,3]间二氧杂环戊烯-5-基、2H-苯并吡喃-2-on-5-基、2H苯并吡喃 -2-on-6-基、2H苯并吡喃-2-on-7-基、2H苯并吡喃-2-on-8-基、异吲哚啉-1,3-聚脂-4-基、异吲哚啉-1,3-聚脂-5-基、茚-1-on-4-基、茚-1-on-5-基、茚-1-on-6-基、茚-1-on-7-基、2,3-二氢苯并[b][1,4]二恶烷-5-基、2,3-二氢苯并[b][1,4]二恶烷-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-on-5-基、2H-苯并[b][1,4]杂氧嗪 3(4H)-on-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-on-7-基、2H-苯并[b][1,4]杂氧嗪 3(4H)-on-8-基、苯并[d]杂氧嗪-2(3H)-on-5-基、苯并[d]杂氧嗪-2(3H)-on-6-基、苯并 [d]杂氧嗪-2(3H)-on-7-基、苯并[d]杂氧嗪-2(3H)-on-8-基、喹唑啉-4(3H)-on-5-基、喹唑啉-4(3H)-on-6-基、喹唑啉-4(3H)-on-7-基、喹唑啉-4(3H)-on-8-基、喹恶啉-2(1H)-on-5-基、喹恶啉-2(1H)-on-6-基、喹恶啉-2(1H)-on-7-基、喹恶啉-2(1H)-on-8-基、苯并[d]噻唑-2(3H)-on-4-基、苯并[d]噻唑-2(3H)-on-5-基、苯并[d] 噻唑-2(3H)-on-6-基和苯并[d]噻唑-2(3H)-on-7-基。在某些实施例中,双环芳基是稠合到5元或6元单环环烷基或5元或6元单环环烯基或5元或6元单环杂环基的 (i)萘基或(ii)苯基环,其中稠合的环烷基、环烯基和杂环基被一个或两个基团选择性取代,这些基团是独立的氧代基或硫杂。
如本文所定义,本文所用的术语“芳烷基”、“烷基芳基”和“芳基烷基”通过此处定义的烷基团连接到母体分子类。芳烷基的代表性例子包括但不限于苄基、苯乙基、苯丙基和2萘基-2-乙基。
本文所用的术语“氰基”和“腈”指-CN基团。
本文所用的术语“环烷基”指单环或双环环烷基环系统。单环系统是含3至8 个碳原子的环烃基基团,这些基团可以饱和或不饱和、但不是芳族。在某些实施例中、环烷基基团完全饱和。单环环烷基的实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。双环环烷基环系统是桥接的单环环或稠合的双环环。桥接的单环环中含有单环环烷基环,其中单环环的两个非相邻碳原子被一至三个额外碳原子之间的亚烷基桥连接(即,-(CH2)w-形式的桥接基团,其中w是1、2、或3)。双环体系的代表性例子包括但不限于双环[3.1.1] 庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷和双环 [4.2.1]壬烷。稠合双环环烷基环系统包含稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环环烷基环。桥连或稠合的双环环烷基,通过单环环烷基环内含有的任何碳原子连接到母体分子类。环烷基基团被作为独立氧代基或硫基的一个或两个基团选择性取代。在某些实施例中,稠合双环环烷基是环稠合到苯基环、5元或6元单环环烷基、5元或6元单环环烯基、5元或6元单环杂环基或5元或6元单环杂芳基的5元或6元单环环烷基,其中稠合双环环烷基被作为独立氧代基或硫基的一个或两个基团选择性取代。
单环系统是含3至8个碳原子的环烃基基团,这些基团不饱和(即,含有至少一个环形碳-碳双键)但不是芳族。单环系统的例子包括环戊烯和环己烯基。双环环烯基环是桥接的单环环或稠合的双环环。桥接的单环环中含有单环环烯基环,其中单环环的两个非相邻碳原子被一至三个额外碳原子之间的亚烷基桥连接 (即,-(CH2)w-形式的桥接基团,其中w是1、2、或3)。双环的环烯基的代表性实例包括但不限于降冰片烯基和双环[2.2.2]辛烯基。稠合双环环烯基环系统包含稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环环烯基环。桥连或稠合的双环环烯基,通过单环环烯基环内含有的任何碳原子连接到母体分子类。环烯基基团被作为独立氧代基或硫基的一个或两个基团选择性取代。
本文所用的术语“卤素”或“卤”指氯、Br、I或F。
本文所用的术语“卤代烷基”指通过烷基(见本文定义)附加到母体分子类的至少一个卤(如本文定义)。卤代烷基的代表性例子包括但不限于氯甲基、氟乙基、三氟甲基、五氟乙基、2-氯-3-氟戊基。
本文所用的术语“杂芳基”指含有至少一个杂芳环的单环杂芳基或双环体系。单环杂芳基可以是一个5元或6元环。5元环由两个双键和一个、两个、三个或四个氮原子以及一个氧原子或硫原子组成。6元环由三个双键和一个、两个、三个或四个氮原子组成。5元或6元杂芳基通过杂芳基内含有的任意碳原子或氮原子连接到母体分子类。单环式杂芳基的代表性实例包括但不仅限于呋喃基、咪唑基、异恶唑基、噻唑基、异噻唑基、恶二唑基、恶唑基、异恶唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基和三嗪基。双环杂芳基由稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环杂芳基组成。稠合的双环杂芳基的环烷基或杂环基部分被被作为独立氧代基或硫基的一个或两个基团选择性取代。当双环杂芳基含有稠合的环烷基、环烯基或杂环基环时,则双环杂芳基通过双环体系的单环杂芳基部分含有的任何碳原子或氮原子连接到母体分子类。当双环杂芳基是稠合到苯环或单环杂芳基的单环杂芳基时,双环杂芳基通过双环体系内的任何碳原子或氮原子连接到母体分子类。双环杂芳基的代表性例子包括但不限于苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻吩基、苯并恶二唑基、benzoxathiadiazolyl、苯并噻唑基、噌啉基、5,6二氢喹啉-2-基、5,6二氢异喹啉-1-基、furopyridinyl、吲唑基、吲哚基、异喹啉基、萘啶基、嘌呤基、喹啉基、5,6,7,8四氢喹啉-2-基、5,6, 7,8四氢喹啉基、5,6,7,8四氢喹啉-4-基、5,6,7,8四氢异喹啉-1-基、thienopyridinyl、4,5,6,7四氢并[c][1,2,5]恶二唑和6,7二氢并[c][1,2, 5]恶二唑-4(5H)酮基。在某些实施例中,稠合双环杂芳基是稠合到苯基环、5元或6元单环环烷基、5元或6元单环环烯基、5元或6元单环式杂环基或5元或6 元单环杂芳基的5元或6元单环杂芳环,其中稠合的环烷基、环烯基和杂环基被作为独立氧代基或硫基的一个或两个基团选择性取代。
本文所用术语“杂芳基烷基”和“烷基杂芳基”指通过一个烷基附加到母体分子类的本文所定义的杂芳基。杂芳基烷基的代表性例子包括但不限于3-呋喃甲基、 1H咪唑-2-亚甲基、1H咪唑4-亚甲基、1-(吡啶-4-基)乙基、吡啶亚甲基、吡啶亚甲基、嘧啶亚甲基、2-(嘧啶2基)丙基、噻吩-2-亚甲基和噻吩-3-亚甲基。
本文所用的术语“杂环基”指单环杂环或双环杂环。该单环杂环是3、4、5、6 或7元环,含有从包括O、N、和S的基团中独立选择出来的至少一个杂原子,其中该环为饱和或不饱和,但不是芳族。3元或4元环含有从包括O、N、和S的基团中选择出来的1个杂原子。5元环可以包含零个或一个双键和一个、两个或三个从包括O、N、和S的基团中选择出来的杂原子。6元或7元环含有零个、一个或两个双键和一个、两个或三个从包括O、N、和S的基团中选择出来的杂原子。单环杂环通过单环杂环内含有的任何碳原子或氮原子连接到母体分子类。单环杂环的代表性实例包括但不限于氮杂环丁烷基、氮杂环庚烷基、氮丙啶、二氮杂环庚烷基、1,3-二恶烷基、1,3-二氧戊环基、1,3 dithiolanyl、1,3-二噻烷基、咪唑啉基、咪唑烷基、异噻唑烷基、异噻唑、异恶唑啉基、异恶唑烷基、吗啉基、 oxadiazolinyl、oxadiazolidinyl、恶唑啉基、恶唑烷基、哌嗪基、哌啶基、吡喃基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基、哌啶基、四氢呋喃基、四氢噻吩基、 thiadiazolinyl thiadiazolidinyl、噻唑啉基、噻唑烷基、硫代吗啉基、1,1 dioxidothiomorpholinyl(硫代吗啉基砜)、噻喃和三噻烷基。双环杂环是稠合到苯基、单环环烷基、单环环烯基、单环式杂环或单环杂芳基的单环杂环。通双环体系的单环杂环部分内含有的任何碳原子或任何氮原子,双环杂环连接到母体分子类。双环杂环基的代表性实例包括但不限于2,3-二氢苯并呋喃-2-基、2,3-二氢苯并呋喃基-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚3-基、2,3二氢苯并噻吩-2基、decahydroquinolinyl、decahydroisoquinolinyl、八氢-1H-吲哚基、八氢苯并呋喃基。杂环基被被作为独立氧代基或硫基的一个或两个基团选择性取代。在某些实施例中,双环杂环基是稠合到苯环、5元或6元的单环环烷基、5 元或6元单环环烯基、5元或6元单环杂环基或5元或6元单环杂芳基的5元或 6元单环杂环基环,其特征在于双环杂环基被作为独立氧代基或硫基的一个或两个基团选择性取代。
本文所用的术语“羟基”指一个-OH基团。
本文所用的术语“硝基”指一个-NO2基团。
本文所用的术语“氧代基”指一个=O基团。
本文所用的术语“饱和”指所引用的不包含多个碳碳键的化学结构。例如,本文所定义的饱和环烷基包括环己基、环丙基等。
本文所用的术语“螺环”指被取代的原子和该原子上的两个可用被取代位置形成的环形类。例如,这样的类,式中R是螺环-环烷基=基团团,包括等化合物,式中螺环-环戊基基团是通过两个单键附在父体环己基环上的R基团。同样,如果R为螺杂环基团,这类化合物包括式中,螺环 -1,3-二氧戊环基环是通过两个单键附在父体环己基环上的R基团。
本文所用的术语“硫基”指=S基团。
本文所用的术语“不饱和”指所引用的包含至少一个碳-碳键的化学结构,但不是芳族。例如,如本文所定义的一个不饱和环烷基包括环己烯基、环戊烯基、环己二烯基等。
本文所用的术语“细胞”指体外、离体或体内细胞。在一些实施例中,体外细胞可以是从生物体如哺乳动物的一部分切下的组织样本。在一些实施例中,体外细胞可以是细胞培养中的细胞。在一些实施例中,体内细胞是哺乳动物等有机体中的活细胞。
本文所用的术语“接触”指将指示的类汇聚到体外系统中或体内系统中。例如,IDO酶“接触”化合物包括给具有IDO的个人或患者服用这里所描述的一种化合物,例如,将化合物引入到含有细胞或纯化制剂(含有IDO酶)的样品中。
本文所用的术语“个人”或“患者”可以互换使用,指任何动物,包括哺乳动物,优选老鼠、大鼠、其他啮齿类动物、兔、狗、猫、猪、牛、羊、马、或灵长类动物,最优选人类。
如本文所用,短语“治疗有效量”指引出研究人员、兽医、医生或其他临床医生正寻求之在组织、系统、动物、个人或人类中的生物或医学反应的活性化合物或药剂的量。
在某些实施例中,治疗有效量可以是适合(1)预防疾病的量;例如,对于可能易患疾病、病症或紊乱但尚未经历或显示疾病的病理或症状的个人,防止其出现疾病、病症或紊乱;
(2)抑制疾病;例如,对于正经历或显示疾病、病症或紊乱的病理或症状的个人,抑制其出现疾病、病症或紊乱;或
(3)缓解疾病、例如,对于正在经历或显示疾病、病症或紊乱的病理或症状的个人(即,扭转病理和/或症状),缓解其疾病、病情或紊乱,如降低疾病的严重程度。
如本文所用,术语“治疗”指(i)改善所引用的疾病状态,例如,对于正在经历或显示疾病、病症或紊乱的病理或症状的个人(即,扭转病理和/或症状),缓解其疾病、病情或紊乱,如降低疾病的严重程度,或(ii)引出引用的生物效应(例如,IDO调变或色氨酸降解抑制)。
为证明用潜在IDO介导的免疫抑制改善疾病状况,可能需要伴随服用或连续服用额外的治疗剂,癌症情况下,服用抗肿瘤药物,病毒疾病情况下,服用抗逆转录病毒药物。例如,服用IDO抑制剂治疗癌症,在用作单一药物时,并不总是产生直接的抗肿瘤效果。然而,当结合化疗药物(抗肿瘤)使用时,所观察到的抗肿瘤效果高于单独药物效果的总和。
本文所用的术语“催化口袋”、“催化位”、“活性部位”共同指酶的一种区域,这种酶含有负责底物结合的氨基酸渣(电荷、疏水性、空间位阻)和作为质子给体或受体或负责结合辅银子并参与化学反应催化的催化氨基酸渣。
本文所用的术语“药学上可接受的盐”指药学上可接受的酸和碱加成盐和溶剂化物。这类药学上可接受的盐包括酸的盐,酸包括盐酸、磷酸、氢溴酸、硫酸、亚磺酸、甲酸、对甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷、HOOC-(CH2)n-COOH等乙酸,式中n为0-4等等。无毒药物碱加成盐包括碱的盐,这些碱包括钠、钾、钙、铵等。本领域的成熟技术人员可认出各种各样的无毒药学上可接受的加成盐。
使用方法
本文所描述的化合物和药物组合物可以调节酶吲哚胺2,3-加双氧酶(IDO) 的活性。术语“调节”指降低酶或受体活性的能力。因此,本文所描述的化合物可用于通过将酶与本文所描述的一种或多种化合物接触对IDO进行调节的方法。在一些实施例中,本文所述化合物可以作为氧酶的抑制剂。在进一步的实施例中,本文所述化合物可用于调节IDO在细胞中或需要通过服用本文所述调节(例如,抑制)量的化合物对酶进行调节之个人中的活性。
本发明进一步提供抑制色氨酸降解的方法以及防止在组织、生物或细胞培养等含有表达IDO之细胞的系统中产生N formylkynurenine的方法。在一些实施例中,改变(例如,增加)哺乳动物细胞外色氨酸水平的方法包括服用本文提供的有效量的化合物或药物组合物。本技术中经常出现色氨酸水平和色氨酸降解的测量方法。
本发明进一步提供通过给患者服用本文叙述的有效量的化合物或组合物抑制患者中IDO介导的免疫抑制等免疫抑制的方法。IDO介导的免疫抑制一直与癌症、肿瘤生长、转移、感染性疾病(例如,病毒感染)、病毒复制等有关。
本发明进一步提供通过给患者服用本文叙述的有效量的化合物或组合物治疗与患者癌症有关的肿瘤特异性免疫抑制的方法。例如,与癌症有关的肿瘤特异性免疫抑制可用本文描述的方法治疗,包括与结肠、胰腺、乳房、前列腺、肺、脑、卵巢、子宫颈、睾丸、肾、头部和颈部、淋巴瘤、白血病、黑色素瘤等的癌症有关的免疫抑制。
例如,某个患者,如果正在接受或完成了用于治疗癌症等疾病状态的化疗和/ 或放射治疗过程,则可以受益于给患者服用此处叙述的治疗上有效量的化合物或组合物,以抑制疾病状态和/或其治疗阐述的免疫抑制。
本发明进一步提供通过给患者服用本文叙述的有效量的化合物或组合物治疗与患者中的HIV-1传染等传染性疾病相关的免疫抑制的方法。
例如,IDO介导的与病毒感染相关的免疫抑制,与选自该小组的病毒感染有关,该组包括:流感、丙型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、巨细胞病毒(CMV)、爱泼斯坦巴尔病毒感染病毒(EBV)、脊髓灰质炎病毒、柯萨奇病毒、水痘带状疱疹病毒、人类免疫缺陷病毒(HIV)等。
本发明进一步提供通过给需要治疗的个人服用本文描述的治疗上有效数量或剂量的化合物或其药物组合物治疗与个人(例如,患者)内IDO的活性或表达-包括异常活性和/或过度表达有关的疾病的治疗方法。例如,疾病可以包括与IDO酶的表达或活性直接或间接相关的任何疾病、紊乱或病症,如过度表达或异常活性。与IDO相关疾病也可以包括通过调节酶的活性预防、缓解或治愈的任何疾病、紊乱或病症。
IDO相关的疾病包括癌症、艾滋病毒感染等病毒感染、抑郁症、阿尔茨海默氏病和亨廷顿氏病等神经退行性疾病、外伤、年龄相关性白内障、器官移植(例如,器官移植排斥反应)和自身免疫性疾病,包括哮喘、类风湿关节炎、多发性硬化症、炎症性肠疾病、牛皮癣和系统性红斑狼疮erythematosusor。可用本文方法治疗的癌症包括癌症、结肠、胰腺、乳房、前列腺、肺、脑、卵巢、子宫颈、睾丸、肾、头部和颈部、淋巴瘤、白血病、黑色素瘤等。
联合治疗
治疗方法的一个或多个附加药剂,例如,抗病毒剂、化疗药物或其他抗肿瘤剂、免疫促进剂、免疫抑制剂、辐射、抗肿瘤和抗病毒疫苗、细胞因子治疗(例如,IL-2、GM-CSF等)和/或酪氨酸激酶抑制剂,可以结合本文所述的化合物和药物组合物治疗IDO相关的疾病、失调或病症(如上所述)或提高疾病状态或状况(如癌症)的治疗有效性。这些妖姬可以按单一剂型结合本发明化合物使用,或作为单独剂型同时或连续给药。
构成特定癌症类型或传染性疾病护理标准的治疗药物,如结合本发明的IDO 抑制剂使用,可能会取得很好的效果。例如,对于肿瘤,肿瘤最好对化疗药物的细胞毒素作用敏感,以刺激释放出最终介导免疫响应的抗原,通过向联合治疗添加IDO抑制剂,可提高这种免疫响应。该领域的技术人员将知道如何根据临床特征和已知的每种肿瘤对抗肿瘤药的敏感性选择此类化疗药物。
拟结合本文描述的化合物使用的合适抗病毒制剂可以包括核苷和核苷酸类逆转录酶抑制剂(NRTIs)、非核苷类逆转录酶抑制剂(NNRTIs)、蛋白酶抑制剂和其他抗病毒的药物。
合适的NRTIs包括齐多夫定(AZT);去羟肌苷(DDI);扎西他滨(DDC);司他夫定(D4T);拉米夫定(3TC);阿巴卡韦(1592U89);阿德福韦酯[双(POM) PMEA];lobucavir(BMS180194);BCH 10652;emitricitabine[(-)-FTC]、β-L-FD4(也称β-LD4C、名为β-L-2′,3′-dicleoxy-5-fluoro-cytidene);DAPD((-) β-D-2,6,-二氨基嘌呤二氧戊环);lodenosine(FDDA)。典型的合适NNRTIs包括奈韦拉平(BI-RG-587);delaviradine(BHAP,U-90152);依非韦伦(DMP 266); PNU 142721;AG 1549;MKC 442(1-(乙氧亚甲基)-5-(1甲基乙基)-6-(苯基甲基)-(2,4(1H,3H)pyrimid-i nedione);和(+)-calanolide A(NSC 675451)与B。典型的合适蛋白酶抑制剂包括沙奎那韦(Ro 31-8959);利托那韦(ABT 538)、茚地那韦(MK639);nelfnavir(AG 1343);安普那韦(141W94);lasinavir(BMS- 234475);DMP-450;BMS-2322623;ABT-378;和AG-1549。其他抗病毒药物包括羟基脲、利巴韦林、IL-2、IL-12、pentafuside和11607号Yissum项目。
合适的化疗或其他抗肿瘤剂包括烷基化剂(包括但不限于氮芥、氮丙啶衍生物、烷基磺酸酯、亚硝基脲类、三氮烯类),如芥尿嘧啶氮芥、环磷酰胺(环磷酰胺)、异环磷酰胺、马法兰、苯丁酸氮芥、pipobroman、三乙撑蜜胺、 triethylenethiophosphoramine、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、达卡巴嗪和替莫唑胺。
合适的化疗或其他抗肿瘤剂包括抗代谢物(包括但不限于叶酸拮抗剂、嘧啶类似物、嘌呤类似物和腺苷脱氨酶抑制剂),如氨甲喋呤、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-巯基嘌呤、6-硫鸟嘌呤、氟达拉滨磷酸、pentostatine和吉西他滨。
合适的化疗或其他抗肿瘤剂还可以包括某些天然产品及其衍生物(例如,长春花生物碱、抗肿瘤抗生素、酶、淋巴因子和表鬼臼毒素),如长春花碱、长春新碱、长春地辛、博来霉素、放线菌素D、柔红霉素、阿霉素、表柔比星、伊达比星、阿糖胞苷、紫杉醇(泰素TM)、多西他赛、光辉霉素、deoxyco-间型霉素、丝裂霉素C、L天门冬酰胺酶、干扰素(尤其是IFN-a)、依托泊苷和替尼泊苷。
其他细胞毒性药物包括navelbene、CPT-11、anastrazole、letrazole、卡培他滨、reloxafine、环磷酰胺、ifosamide和droloxafine。
细胞毒性药物也合适,如epidophyllotoxin;抗肿瘤药物酶;拓扑异构酶抑制剂;甲基苄肼;米托蒽醌;铂协调联合体,如顺铂和卡铂;生物反应调节剂;生长抑制剂;抗激素治疗剂、亚叶酸钙、替加氟;造血生长因子。
其他抗肿瘤剂包括抗体疗法,如曲妥珠单抗(赫赛汀)、共刺激分子的抗体,如CTLA-4,4-1BB和PD-1、或细胞因子的抗体((IL-10,TGF-β等)。
其他抗癌药物还包括阻碍免疫细胞迁移的药物,如趋化因子受体拮抗剂,包括CCR2、CCR4和CCR6。
其他抗癌剂也包括增强免疫系统的药剂,如佐剂或过继性T细胞转移。
防癌疫苗包括树突状细胞、合成肽、DNA疫苗及重组病毒。
本技术领域内的技术人员已经知道其中多数化疗药物的安全有效的给药方法。此外,其给药在标准文献中描述。例如,许多疗药物的给药在“医师案头参考” (PDR,例如,1996年版,医学经济公司,Montvale,NJ)中描述,其披露被通过引用形式纳入本文内,如完整规定一样。
药剂配方和剂型
本文所述的药物组合物一般包括本文描述的化合物及药学上可接受的载体、稀释剂或赋形剂的组合。此类组合物基本上不含非药学上可接受的成分,即,非药学上可接受成分的含量低于美国监管规定在提交本申请时所允许的数量。在这方面的一些实施例中,如果化合物溶解或悬浮于水,所述组合物还视情况包含额外的药学上可接受的载体、稀释剂或赋形剂。在其它实施例中,本文描述的药物物组合物是固体药物组合物(例如,片剂、胶囊剂等)。
这些组合物可用制药技术中熟知的方式制备,并可以通过各种途径给药,这取决于是否需要局部或全身治疗以及和待处理的区域。给药可以外用(包括滴眼药和通过鼻腔、阴道和直肠等粘膜给药)、肺部(例如,通过吸入或吹入粉末或气溶胶,包括通过喷雾器;气管;鼻腔、表皮和透皮)、眼部、口腔或肠外。眼部可以包括局部用药(眼药水)、结膜下、眼周或玻璃体内注射或通过球囊导管或将眼科手术插管插入到结膜囊内导入。肠外给药包括静脉注射、动脉内、皮下、腹腔或肌肉注射或静滴;或颅内,例如膜内或脑室给药。肠胃外给药可以采用单次剂量的形式,或者可以采用连续灌注泵。用于局部给药的药物组合物和配方可包括贴剂、软膏、洗剂、霜剂、凝胶剂、滴剂、栓剂、喷雾剂、液体和粉末。常规药物载体、水、粉末或油性基质、增稠剂等可能是必要的或可取的。
此外,药物组合物可以含有作为活性成分的一种或多种本文描述的化合物以及一种或多种药学上可接受的载体。在制作本文所描述的组合物时,活性成分通常与赋形剂混合,通过赋形剂稀释或封闭于胶囊、小药囊、纸或其他容器。当用作稀释剂时,赋形剂可以是固体、半固体或液体物质,作为活性成分的媒介物、载体或介质。因此,该组合物可以是片剂、丸剂、粉剂、锭剂、香囊剂、扁囊剂、酏剂、悬浮液、乳状液、溶液、糖浆、气雾剂(作为固体或在液体介质中)、活性化合物含量高达10%(按重量)的软膏、软硬明胶胶囊、栓剂、无菌注射液和无菌包装粉剂。
在制备制剂时,可以研磨活性化合物,以在与其他成分结合之前提供适当的颗粒尺寸。如果活性化合物基本上不能溶解,可以将其研磨至尺寸小于200目的颗粒。如果活性化合物基本上溶解于水,可以通过研磨调整颗粒尺寸,以使制剂分布基本上均匀,例如约40目。
合适的赋形剂包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯树胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。该制剂还可以包括:润滑剂,如滑石、硬脂酸镁和矿物油;润湿剂、乳化剂和悬浮剂;防腐剂,如甲基-和丙基羟基-苯甲酸酯;甜味剂和矫味剂。可以配制本文所描述的组合物,以便在按本领域中所知的程序给患者用药后快速、持续或延迟释放活性成分。
可以按单位剂型配制组成物,每一剂量含有约5-100mg,更常见的是约10- 30mg的活性成分。术语“单位剂型”指适合作为人类受试者或其他哺乳动物的单位剂量的物理分散单位,每单位含有经计算能产生预期治疗效果的预定数量的活性物质和适当的药物赋形剂。
活性化合物可在很宽的剂量范围内有效,一般按药学上有效量给药。然而,可以理解,实际给药的化合物量通常由医生根据相关情况决定,这些情况包括待处理的条件、所选择的给药途径、实际给药的化合物、个别患者的年龄、体重和反应、患者症状的严重程度等等。
在制备片剂等固体组合物时,主要活性成分与药物赋形剂混合,以形成固体预制剂组合物,该组合物包含本文所描述化合物的均匀混合物。为使预制剂组合物达到均匀的程度,活性成分通常均匀地分散在整个组合物内,从而可轻易将该组合物细分成同等有效的单位剂型,如片剂、丸剂和胶囊。然后,将该固体预制剂细分成上述类型的单位剂型,含有(例如)0.1-约500mg本文所述化合物的有效成分。
片剂或丸剂可以涂层或以其他方式复合,形成具有疗效延长优势的剂型。例如,片剂或丸剂可以由内剂量和外剂量成分组成,后者为前者的包络形式。这两种成分可以由肠溶层分开,这种肠溶层的作用是防止在胃内分解,并允许内成分完整进入十二指肠或延迟释放。可用各种材料制作这样的肠溶层或涂层,这样的材料包括许多聚合酸以及聚合酸与虫胶、鲸蜡醇和乙酸纤维素这类材料的混合物。
液体剂型可以装入化合物和组合物,口服或注射使用,包括水溶液、适当调味的糖浆、水或油悬浮液和带有棉籽油、芝麻油、椰子油或花生油等食用油的调味乳液以及酏剂和类似药物载体。
吸入或吹入用的组合物包括药学上可接受的水溶剂或有机溶剂或其混合物和粉末。液体或固体组合物可能含有适当的前面描述的药学上可接受的赋形剂。在一些实施例中,该组合物通过口服或局部或全身作用的鼻呼吸途径给药。组合物可通过使用惰性气体雾化。喷雾溶液可直接从雾化装置吸入,或将该雾化装置可以连接到一个面罩帐篷或间歇正压呼吸机上。溶液、悬浮液或粉末状组合物可经口或鼻从适当输送制剂的装置给药。
给病人所用的化合物或组合物的量取决于给药的内容、给药的目的,例如预防或治疗,患者的状态、给药的方式等。在治疗应用中,给已经患有某种疾病的患者服用组合物,给药量足以治愈或至少部分抑制疾病症状及其并发症。有效剂量取决于正在治疗的疾病状况以及临床医师的判断,视许多因素而定,如疾病的严重程度、患者的年龄、体重和一般状况等。
对患者施用的组合物可采用上述药物组合物的形式。这些组合物可以通过常规的灭菌技术进行灭菌,或者可以进行无菌过滤。水溶液可以包装使用,或者冻干,冻干制剂在给药前与无菌水性载体结合。化合物制剂的pH值通常在3-11之间,5-9之间较好,最好在7-8之间。可以理解,使用前述的某些赋形剂、载体或稳定剂会导致药物盐的形成。
化合物的治疗剂量可能随治疗的特定用途、给药方式、病人的健康和状况以及处方医生的判断发生变化。本文描述的化合物在药物组合物中的比例或浓度可能随一些因素发生变化,包括剂量、化学特性(例如疏水性)以及给药途径。例如,本文所述化合物可用水性生理缓冲液形式提供,含有约0.1%-10%w/v用于肠胃外给药的化合物。某些典型的剂量范围从约1微克/千克至约1克/千克体重/每天。在一些实施例中,剂量范围从约0.01毫克/千克至约100毫克/千克体重/每天。该剂量可能取决于疾病或病症的类型和进展程度、特定患者的整体健康状态、所选择化合物的相对生物功效、赋形剂的形成及其给药途径等变量。可以从体外或动物模型试验系统衍生的剂量-反应曲线推断有效剂量。
本文所描述的化合物也可以结合一种或多种附加活性成分配制,这些活性成分可以包括任何药物,如抗病毒制剂、疫苗、抗体、免疫促进剂、免疫抑制剂、抗炎剂等。
标记化合物和测定方法
另一方面涉及本文所描述化合物的荧光染料、自旋标记、重金属或同位素标记衍生物,它们不仅可用于成像,还可用于体外和体外的检测,定位和定量组织样品(包括人类)中的IDO酶,通过记化合物的结合抑制,识别IDO酶配合基。因此,进一步提供含有这种标记化合物的IDO酶检测。
本发明进一步提供本文描述化合物的同位素-标记化合物。“同位素”或“同位素标记”的化合物是本文所描述的化合物,其中一个或多个原子被一个原子替换或取代,该原子的原子质量或质量数不同于通常在自然界中发现的(即自然发生的) 原子质量或质量数。适用的放射性核素可能包括但不限于2H(氘也写成D)、3H (氚也写成T)、11C、13C、14C、13N、15N、15O、17O、18O、18F、35S、36Cl、82Br、75Br、76Br、77Br、123I、124I、125I和131I。瞬间同位素标记的化合物内包括的放射性核将取决于该同位素标记的化合物的具体应用。例如,对于体外IDO酶标记和竞争试验,包含3H、14C、82Br、125I、131I、35S的化合物通常最有用。对于同位素成像应用,11C、18F、125I、123I、124I、131I、75Br、76Br或77Br一般最有用。
据了解,“同位素标记”或“标记化合物”是一种包含至少一种放射性核素的化合物。在一些实施例中,放射性核素选自由3H、14C、125I、35S和82Br组成的组。
将放射性同位素放入有机化合物的合成方法适用于本文所描述的化合物,在本技术领域众所周知。
可在筛选试验中使用本文描述的同位素标记的化合物,以确定/评估化合物。总体而言,可评价新合成的或确定的化合物(即,试验化合物)是否能够降低本文所述的同位素标记化合物与IDO酶的结合。因此,试验化合物与同位素标记的化合物竞争与IDO结合的能力直接与其结合亲合力相关。
试剂盒
另外,药物试剂还用于治疗或预防IDO相关的疾病或病症、肥胖症、糖尿病和本文提及的其他疾病,其中包括一个或多个含有药物组合物的容器,该组合物包括治疗有效量的本文描述的化合物。这样的试剂盒可以进一步包括(如果需要) 一个或多个各种常规的药物试剂盒成分,例如,带有一种或多种药学上可接受载体的容器、附加容器等,这对本领域的技术人员显而易见。试剂盒中也可以包括作为插件或作为标签的说明书,指示给药的成分数量、给药准则和/或混合各组分的准则。
提供下面的例子,为便于说明,而不是打算以任何方式限制本披露。本技术领域的技术人员将容易识别各种各样的非关键参数,为得到基本上相同的结果,可以改变或修改参数。下面示范化合物被认为是符合本文所述一个或多个试验的 IDO抑制剂。
示范
所有试剂和溶剂购自商业来源。所有商业试剂和溶剂按原样使用,无需进一步纯化。使用带有0.25毫米EM科学硅胶板(60F-254)的分析薄层色谱(TLC) 监测各种反应。通过短波UV光(波长254nm)或通过浸泡在高锰酸钾溶液内,然后在热板上加热,使开发的PLC板形象化。用粒径32-63微米的Selecto科学硅胶进行快速层析。所有反应均在氮气气氛下在火焰或烘箱干燥的玻璃器皿内进行。所有反应均在环境温度下磁力搅拌,除另有说明。用Bruker DRX400、Varian VXR400或VXR3001获得1H NMR光谱。以相对于TMS(0.0)、DMSO-d6(2.50) 或CD3OD(4.80)百万分之一(δ)将1H NMR光谱作为内部参考报告。所有1H NMR光谱采自CDCl3,除非另有说明。按照文献方法制备如下启动原料:(E)- 乙基-3-(2-碘苯基)丙烯酸酯(Synth.Comm.2007,37,2989-2994)、2-氯-6-碘苯甲醛(J.农业食品化学,2008,56,5247-5253)、2-碘-3-甲氧基苯甲醛(Chem. -Eur.J.,2004,10,5233-5242)、二甲基(2-(环己烯-1-en-1-基)-2-酮乙基) 磷酸二乙酯(磷、硫硅Relat.Elem.,1999,155,67-80)、二甲基(2-环己基-2 -氧代基)乙基磷(专利:US5807892 A1,1998年)、乙基1,4-二氧杂螺[4.5]癸烷-8-羧酸乙酯(专利:US2008/306084 A1,2008年)、(反式)-乙基4- ((叔丁基二甲基甲硅烷基)氧基)环己烷羧酸(专利号:US2006/25383 A1, 2006年)、乙基螺[2.5]辛烷-6-羧酸甲酯(生物有机医药化学学报,2008,18, 5280-5284)、乙基4-(环丙基亚苄基氨基)环己烷羧酸(专利:US4584013 A1, 1986),
上述化合物分别被分配化合物标识号86-91和113-115,便于将来在本专利(4.80)中作为内部参考。所有光谱在CDCl3中记录,除非另有说明。
方案1中概括本专利中使用的合成中间体A的各种方法。在钯催化作用下,4 -碘-1-三苯甲基-1H-咪唑与苯硼酸进行铃木交叉耦合,产生2-(1-三苯甲基-1H- 咪唑-4-基)苯甲醛。所得2-(1-三苯甲基-1H-咪唑-4-基)苯甲醛受醇醛缩合或霍纳-沃兹沃思反应的影响,得到中间体A。另外,在碱存在下,令2碘苯甲醛与被取代的甲基酮反应,获得3-(2-碘苯基)丙-2-烯-1-酮,可实现中间体A的合成。所得3-(2-碘苯基)丙-2-烯-1-酮与4-碘-1-三苯甲游基-1H-咪唑的根岸交叉耦合也导致中间体A。将中间体A置于三苯甲游基的脱保护条件下,产生可还原成2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙醇C的2-(5H-咪唑并[5,1-a] 异吲哚-5-基)乙酮B(方案2)。
方案1.(E)-3-(2-(1-三苯甲游基-1H-咪唑-4-基)苯基)丙-2-烯-1-酮的合成(中间物A)
方案2. 2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酮及其相应2-(5H-咪唑并[5,1-a]异吲哚 -5-基)乙醇的合成
范例1通过醇醛缩合合成3-(2-碘苯)prop-2-烯-1-酮的一般程序
在室温下,向适当的市售苯甲醛或无水甲醇(15mL)87(4.31毫摩尔)中加入NaOMe(4.31毫摩尔,0.5M MeOH),搅拌黄色溶液5分钟。逐滴加入适量的甲酮(4.31毫摩尔),制成MeOH溶液(3mL)。搅拌通宵后,在减压条件下除去溶剂,用饱和液稀释粗产物。NH4Cl(20mL).用CH2Cl2(3x 20mL)萃取水层,干燥(MgSO4)复合有机萃取物,减压蒸馏出溶剂,得到粗产物渣。将粗制品用硅胶急骤层析纯化,得到下面的化合物。
# | 化合物 | 名称 | 产率(%) |
范例2通过联芳基碘化物1和2与4-碘代-1-三苯甲游基-1H-咪唑钯催化根岸交叉偶联合成2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酮的一般程序
在室温下,在N2环境下,向搅拌后的4-碘-1-三苯甲基-1H-咪唑(218mg,0.5 毫摩尔)无水THF(4mL)溶液逐滴加入EtMgBr(1.0M THF,0.5毫摩尔,0.5mL)。搅拌合成溶液90分钟,加入无水ZnCl2(0.5毫摩尔,68.2mg)。将所得白色悬浮液搅拌90分钟,加入适当芳基碘1,2或86(0.5毫摩尔)THF(1mL)溶液,然后迅速加入Pd(PPh3)4(56mg,0.05毫摩尔)。在N2环境下,70℃时,搅拌反应混合物12小时。冷却到室温后,用CH2Cl2(20mL)稀释溶液,用EDTA(aq)缓冲液 (pH=9)(2x 5mL)和盐水洗涤有机层。在减压条件下,干燥(Na2SO4)并浓缩有机层。在下一步使用粗产物渣,无需进一步纯化。向上一步产生的粗咪唑溶液中,加入乙酸(1.0毫升)和MeOH(4.0mL)。在90℃,搅拌溶液3小时。令反应混合物冷却到室温,将pH值用饱和溶液调节到~10。K2CO3(aq).用EtOAc(3x 20mL)萃取水相。用盐水洗涤并干燥复合的有机层。在真空中,除去溶剂,获得粗产物渣,在硅胶上,用快速柱层析法纯化,得到下列化合物。
范例3 4-碘代-1-三苯甲游基-1H-咪唑与苯基硼化物的铃木交叉耦联
用氮气吹扫4-碘-1-三苯甲基-1 1H-咪唑悬浮液(6.88毫摩尔)、相应的2- 甲酰基硼酸衍生物(10.31毫摩尔)和K3PO4(20.63毫摩尔)N,N-二甲基甲酰胺 (30mL)和水(6mL)5分钟,加入Pd(PPh3)4,用氮气再吹扫混合物5分钟。N2s环境下,在90℃,搅拌反应混合物16小时。冷却溶液,并通过硅藻土塞过滤。用水(50mL)和EtOAc(25mL)稀释混合物。收集有机层,用EtOAc(2x 25mL)萃取水层。用盐水(2x 25mL)洗涤并干燥(Na2SO4)复合有机萃取物。过滤溶液,在减压条件下,除去溶剂,获得粗产物渣,在硅胶上,用快速柱层析法纯化,得到下列化合物。
范例4 3-甲氧基-2-(1-三苯甲游基-1H-咪唑-4-基)苯甲醛
在80℃,搅拌88(667毫克,2.55毫摩尔)、双(频哪醇)二硼(711毫克, 2.88毫摩尔)、KOAc(749毫克,7.64毫摩尔)、Pd(OAc)2(17毫克,76微摩尔) DMF(10mL)悬浮液16小时。通过硅藻土塞过滤混合物,将滤液倒入水中。用 EtOAc(2x 20mL)萃取水层。用盐水(2x25mL)洗涤、干燥并浓缩复合有机萃取物。使用粗产物,无需进一步纯化。在80℃,将4-碘-1-三苯甲基-1H-咪唑(400毫克, 0.917毫摩尔)、3-甲氧基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2- 基)苯甲醛(288毫克,1.10毫摩尔)、K2CO3(444mg,3.21毫摩尔), Pd(dppf)Cl2·CH2Cl2配合物(150毫克,0.18毫摩尔)DMSO(10mL)悬浮液加热 20小时。通过硅藻土塞过滤溶液,将滤液倒入水中。用乙酸乙酯(2x 20mL)萃取水层。用盐水(2x 10mL)洗涤、干燥并浓缩复合有机萃取物。将粗产物用快速柱层析法纯化,获得白色固体8(78mg,19%)。1HNMR:3.75(s,3H),7.08(d,1H, J=8.0Hz),7.20-7.25(m,7H),7.30-7.36(m,10H),7.52(s,1H),7.55(d, 1H,J=4.0Hz),10.31(s,1H).
范例5通过2-(1-三苯甲游基-1H-咪唑-4-基)苯甲醛与甲基酮醇醛缩合及环化合成2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酮的一般程序
在室温下,将NaOEt(1.25毫摩尔,21wt%EtOH溶液)加入相应的醛3-8(0.97 毫摩尔)和酮(0.97毫摩尔)无水THF(5mL)溶液中,在室温下,搅拌黄色溶液3小时。蒸馏出溶剂,用饱和NH4Cl(10mL)稀释粗产物,用二氯甲烷(3×20mL) 萃取水层。用盐水洗涤复合有机萃取物,用Na2SO4干燥,在减压条件下,蒸发溶剂,得到粗制品。向上一步产生的粗咪唑中,加入乙酸(1.0mL)和MeOH(4.0mL)。在90℃,搅拌溶液3-10小时。令反应混合物冷却到室温,将pH值用饱和溶液调节到~10。K2CO3(aq).用EtOAc(3x 20mL)萃取水相。用盐水洗涤并干燥复合的有机层。在真空中,除去溶剂,获得粗产物渣,在硅胶上,用快速柱层析法纯化,得到下列化合物。
范例6乙烷基4-亚甲基环己烷羧酸盐
在-10℃时,向甲基三苯基溴化鏻(1.57克,4.41毫摩尔)THF(9mL)悬浮液,逐滴加入n-BuLi(己烷2.5M中,1.65mL,4.11毫摩尔),搅拌溶液1小时。加入4-氧代环己烷羧酸乙酯(0.47mL,2.94毫摩尔),将反应加热到室温3小时。加入丙酮(3ml),在减压条件下出去溶剂。将残渣悬浮在二氯甲烷和乙醚(1∶1) 中,并过滤与浓缩。将粗产物用快速柱层析法纯化,获得透明油状物(419mg, 85%)。1H NMR:1.25(t,3H),1.50-1.70(m,2H),1.90-2.16(m,4H),2.30-2.50 (m,3H),4.12(q,2H),4.65(s,2H).
范例7乙烷基础4-(碘代亚甲基)环己烷羧酸
-23℃时,缓慢向甲基三苯基碘化磷(1.95克,3.67毫摩尔)THF(10mL)悬浮液中加入六甲基二硅氮烷钾(20%甲苯,7.34mL,3.67毫摩尔)溶液,将所得溶液搅拌15分钟。加入乙烷基4-氧代环己烷羧酸乙酯(500毫克,2.94毫摩尔)。除去冷浴,在室温下搅拌溶液2天。将反应混合物用水(20mL)稀释,并用乙醚 (3×20mL)萃取。复合有机层在无水MgSO4上方干燥,并浓缩,获得粗制品。粗残余物通过柱层析法纯化,以获得浅粉色油状物20(207mg,24%)。1H NMR:1.21-1.52(m,2H),1.93-2.13(m,4H),2.30-2.50(m,4H),2.49-2.70(m,4H),4.12(q,2H),4.60(s,1H)
范例8乙烷基4-(亚丙-2-基)环己烷羧酸
在0℃,向异丙基三苯基碘化磷(3.81克,8.81毫摩尔)无水THF(20mL) 悬浮液中加入t-BuOK(1.19g,10.58毫摩尔)THF(15mL)溶液。将反应混合物加热到室温,搅拌1小时。将所得混合物冷却到0℃,在5分钟时间内加入4-氧代基-环己烷羧酸乙酯(1.0克,5.88毫摩尔)。缓慢将溶液加热到室温,搅拌2小时。在50℃时,搅拌溶液一整晚。减压蒸馏出溶剂,在CH2Cl2(50mL)和饱和液之间分割粗产物。NH4Cl(30mL).收集有机层,用CH2Cl2(2x 30mL)萃取水层。用盐水洗涤有机层、干燥(Na2SO4)并减压浓缩,获得粗制品。将粗产物在硅胶上用柱层析法纯化,获得透明油状物21(280mg,24%)。1H NMR:1.24(t,3H,J=6.0Hz), 1.43-1.50(m,2H),1.63(s,6H),1.74-1.83(m,2H),1.92-1.98(m,2H), 2.39-2.47(m,1H),2.58-2.69(m,2H).
范例9乙烷基4-(环丙基亚甲基)环己烷羧酸
在0℃,向环丙基三苯基碘化磷(3.5克,8.81毫摩尔)无水THF(20mL)悬浮液中加入t-BuOK(1.19g,10.58毫摩尔)THF(15mL)溶液。将反应混合物加热到室温,搅拌1小时。将所得混合物冷却到0℃,在5分钟时间内加入4-氧代基 -环己烷羧酸乙酯(1.0克,5.88毫摩尔)。缓慢将溶液加热到室温,搅拌2小时。在50℃时,搅拌溶液一整晚。减压蒸馏出溶剂,在CH2Cl2(50mL)和饱和液之间分割粗产物。NH4Cl(30mL).收集有机层,用CH2Cl2(2x 30mL)萃取水层。用盐水洗涤有机层、干燥(Na2SO4)并减压浓缩,获得粗制品。将粗产物在硅胶上用柱层析法纯化,获得无色油状物22(800mg,65%)。1H NMR:CDCl3 0.22-0.26(m,2H), 0.62-0.68(m,2H),1.22(t,3H,J=7.2Hz),1.39-1.47(m,3H),1.75-2.04 (m,4H),2.14-2.20(m,1H),2.37-2.46(m,1H),2.67-2.75(m,1H),4.10 (q,2H,J=7.2Hz),4.49(d,1H,J=9.3Hz).
范例10乙烷基-4-(三苯甲氧基)环己烷羧酸
向三苯甲基氯(0.97克,3.48毫摩尔)二氯甲烷溶液(10mL)溶液加入DBU (0.61mL,4.06毫摩尔)和4-羟基-环己烷甲酸乙酯(500mg,2.90毫摩尔),并将该混合物回流24小时。冷却反应混合物,加入冷水(40mL)。收集有机层,用二氯甲烷(2×30mL)萃取水层。减压干燥(Na2SO4)并浓缩复合有机层。将粗产物用快速柱层析法纯化,获得无色油状物23(714mg,59%)。1HNMR:(顺式和反式异构体的混合物(1∶1.4))1.06(t,2H,J=12.4Hz),1.16-1.26(m,14H),1.32-1.35 (m,2H),1.54-1.58(m,2H),1.76-1.79(m,3H),1.95-2.04(m,2H),2.11-2.22 (m,2H),3.35-3.41(m,1.4H),3.72-3.76(m,1H),4.04(q,2.8H,J=7.2 Hz),4.14(q,2H,J=6.8Hz),7.22-7.27(m,24H,与CHCl3重叠),7.49-7.51 (m,13H).
范例11甲基顺式-4-氨基环己烷羧酸甲酯盐酸盐
将顺式-4-氨基环己烷甲酸(1.04克,7.26毫摩尔)10mL甲醇溶液冷却到0℃,加入亚硫酰氯(1.58mL,21.79毫摩尔)。将反应混合物加温到室温,搅拌18小时。浓缩反应溶液,用乙醚洗涤残渣,获得无色晶体115(1.3g,92%)。1H NMR (CD3OD):1.73-1.77(m,4H),1.92-1.96(m,2H),2.16-2.73(m,2H),2.70-2.73 (m,1H),3.19-3.24(m,1H),3.74(s,3H).
范例12顺式-4-苯甲酰氨基环己烷甲酸甲酯
在0℃,向甲基顺式-4-氨基环己烷羧酸甲酯盐酸盐(0.63克,3.26毫摩尔) CH2Cl2(10mL)悬浮液加入二异丙基乙基胺(1.71mL,9.79毫摩尔),并将该悬浮液搅拌10分钟。逐滴加入苯甲酰氯(0.45mL,3.92毫摩尔),将透明溶液加温至室温并搅拌一晚上。用水(15mL)和CH2Cl2(15mL)稀释反应混合物,收集有机层,用CH2Cl2(2x 25mL)萃取水层。在Na2SO4上方干燥复合有机萃取物,减压浓缩,获得透明硅胶116(850mg,100%)。1H NMR:1.70-1.73(m,2H),1.76-1.90 (m,4H),1.95-2.06(m,2H),2.55-2.61(m,1H),3.72(s,3H),4.14-4.20 (m,1H),6.14(d,1H,J=6.0Hz),7.43-7.47(m,2H),7.49-7.51(m,1H), 7.76-7.78(m,2H).
范例13反式-4-氨基环己烷甲酸甲酯盐酸盐
将反式-4-氨基环己烷甲酸(1.24克,8.66毫摩尔)12mL甲醇溶液冷却到0℃,加入亚硫酰氯(1.89mL,25.98毫摩尔)。将反应混合物加温到室温,搅拌18小时。浓缩反应溶液,用乙醚洗涤残渣,获得无色晶体117(1.61g,95%)。1H NMR (CD3OD):1.43-1.61(m,4H),2.11-2.15(m,4H),2.39(dt,1H,J=2.8,11.8 Hz),3.12(dt,1H,J=3.2,8.0Hz),3.70(s,3H).
范例14反式-4-苯甲酰氨基环己烷甲酸甲酯
向甲基反式4-氨基环己烷羧酸甲酯盐酸盐的悬浮液中,9.79毫摩尔),将悬浮液搅拌10分钟。逐滴加入苯甲酰氯(0.45mL,3.92毫摩尔),将透明溶液加温至室温并搅拌一晚上。用水(15mL)和CH2Cl2(15mL)稀释反应混合物,分离有机层,用CH2Cl2(2x 25mL)萃取水层。用Na2SO4干燥复合有机萃取物,减压浓缩,获得白色固体118(200mg,24%)。1H NMR(CD3OD):1.46(q,2H,J=11.5 Hz),1.60(q,2H,J=12.0Hz),2.09(d,4H,J=11.2Hz),2.37(t,1H, J=12.0Hz),3.71(s,3H),3.90(t,1H,J=11.4Hz),7.46-7.57(m,3H), 7.83(d,2H,J=7.1Hz).
范例15 1-叔丁基-3-甲基氮杂环丁烷-1,3-二羧酸二乙酯
将1-(叔丁氧基羰基)氮杂环丁烷-3-羧酸(2.03克,10.09毫摩尔)溶于甲醇(10mL)和DCM(10mL)中,然后冷却至0℃。然后,逐滴加入三甲基硅烷化重氮甲烷乙醚2M溶液(7.57ml,15.1毫摩尔),持续5分钟。将溶液在0℃搅拌10分钟,然后在30分钟内加温至室温。减压浓缩溶液,消除挥发物,获得粗产物119,在下一步骤中直接使用粗产物,无需进一步纯化。1H NMR:1.44(s,9H), 3.35(m,1H),3.75(s,3H),4.10(d,4H,J=7.6Hz).
范例16甲基顺式-4-羟基环己甲酸
室温下,向顺式-4-羟基环己烷羧酸(5.0克,34.7毫摩尔)无水甲醇(40mL) 溶液加入浓H2SO4(0.2mL,3.47毫摩尔),在65℃搅拌16小时。蒸馏出溶剂,将粗产物溶于EtOAc(40ml)中,并用饱和NaHCO3溶液(25mL)洗涤溶液。分离有机层,用EtOAc(2x 20mL)萃取水层。用H2SO4干燥复合有机萃取物,减压浓缩,获得120(4.90g,89%)。1.62-2.01(m,8H),2.34-2.38(m,1H),3.64 (s,3H),3.82-3.88(m,1H).
范例17甲基顺式-4-(苄氧基)环己烷羧酸
向甲基顺式-4-羟基环己烷甲酸乙酯(4.80克,30.3毫摩尔)己烷/CHCl3 2∶1(60mL)溶液中,在23℃加入苄基三氯乙酰亚胺酯(9.19克,36.4毫摩尔)和三氟甲磺酸(683mg,4.55毫摩尔)。将反应混合物搅拌18小时,用EtOAc(300mL) 稀释。用饱和水状NaHCO3和盐水洗涤混合物。在无水Na2SO4上干燥并减压浓缩有机层。将粗产物在硅胶上用柱层析法纯化,获得121(4.60g,18.5毫摩尔)。1H NMR:1.55-1.98(m,8H),2.36-2.41(s,1H),3.56-3.66(,1H),3.67(s,3H), 4.51(s,2H),7.28-7.35(m,5H).
范例18甲基哌啶-4-羧酸乙酯盐酸盐与酰氯反应的一般程序
在0℃,向甲基哌啶-4-羧酸乙酯盐酸盐的悬浮液(5.6毫摩尔)CH2Cl2(20mL) 悬浮液加入二异丙基乙基胺(16.7mL,9.79毫摩尔),并将该悬浮液搅拌10分钟。逐滴加入酰基氨(8.4毫摩尔),将溶液加温至室温并搅拌一晚上。用水(15mL)和 CH2Cl2(15mL)稀释反应混合物。收集有机层,用CH2Cl2(2x 20mL)萃取水层。干燥(Na2SO4)并减压浓缩复合有机萃取物,得到如下化合物。
范例19甲基2-溴-3-氟苯甲酸乙酯
室温下,向2-溴-3-氟苯甲酸(300mg,1.37毫摩尔)甲醇(10mL)悬浮液加入SOCl2的(0.11mL,1.51毫摩尔),并在室温下搅拌混合物18小时。减压蒸馏出溶剂。加入饱和的NaHCO3水溶液,用EtOAc(3×25ml)萃取水层。在Na2SO4上干燥、过滤并浓缩复合有机层。在下一步使用粗制品,无需进一步纯化。
范例20甲基3-氟-2-(1-三苯甲游基-1H-咪唑-4-基)苯甲酸甲酯
在室温下,在N2环境下,向搅拌后的4-碘-1-三苯甲基-1H-咪唑(436mg,1.0 毫摩尔)的无水THF(6mL)溶液中逐滴加入EtMgBr(THF中3.0M,1.20毫摩尔,0.40mL)。搅拌合成溶液90分钟,加入ZnCl2(0.5M THF,1.20毫摩尔)。将所得白色悬浮液搅拌90分钟,加入适当甲基2-溴-3-氟苯甲酸乙酯(280mg,1.20毫摩尔)THF(1mL)溶液,然后迅速加入Pd(PPh3)4(58mg,0.05毫摩尔)。在N2环境下,90℃时,搅拌反应混合物18小时。冷却到室温后,用CH2Cl2(20mL)稀释溶液,用EDTA(aq)缓冲液(pH=9)(2x 5mL)和盐水洗涤有机层。在减压条件下,干燥(Na2SO4)并浓缩有机层。将粗产物渣用快速柱层析法纯化,获得所需的黄色油状物(190mg,41%)。1H NMR:3.93(s,3H),7.12-7.59(m,18H),7.56(s, 1H),7.73-7.75(m,1H).
范例21 3-氟-2-(1-三苯甲游基-1H-咪唑-4-基)苯甲醛
在-78℃,向甲基-3-氟-2-(1-三苯甲基-1H-咪唑-4-基)苯甲酸甲酯(62mg, 0.134毫摩尔)甲苯(4mL)溶液中,逐滴加入溶液DIBAH(1M,0.161mL,0.161 毫摩尔),继续搅拌10分钟。在此温度下,加入无水甲醇。将混合物倒入饱和 NH4Cl(5mL)水(5mL)内,用水EtOAc(15ml)稀释,剧烈振摇3分钟,加入盐水(5mL),再次摇动,分离相位,在Na2SO4上干燥、过滤并蒸发有机层,得到所需的醛,使用时无需进一步纯化。
范例22二甲基(2-氧代)磷酸盐合成的一般程序
-78℃时,向甲基磷酸二甲酯(3.14克,25.3毫摩尔)20mL无水四氢呋喃的搅拌溶液,N2气氛下,滴加入正丁基锂溶液(10.13mL,25.3毫摩尔,己烷中2.5M),并搅拌混合物30分钟。逐滴向该反应混合物加入适当的市售甲基或乙基酯基或19-26、91或115-121(12.7毫摩尔)溶液,作为THF(5mL)溶液。搅拌30 分钟后,将反应混合物加温至0℃,搅拌1小时。蒸馏除去溶剂,用饱和NH4Cl(10 mL)和10ml水稀释粗产物。用乙酸乙酯(2×40mL)萃取混合物。用水(1×20mL) 和盐水(1×20ml)洗涤复合乙酸乙酯层,在无水硫酸钠水上干燥。减压过滤与浓缩溶液,得到粗制品。用柱层析法纯化粗产物,得到如下化合物。
范例23通过霍纳尔-沃兹沃思-埃蒙斯反应及环化合成2-(5H-咪唑并 [5,1-a]异吲哚-5-基)乙酰基的一般程序。
0℃时,向95%NaH(17.4mg,0.7毫摩尔)THF(3mL)悬浮液,加入适当的磷酸盐试剂27-46、89、90或122-135(0.75毫摩尔),作为THF(2毫升)溶液,将混合物搅拌40分钟。在3分钟时间内,逐滴加入相应的2-(1-三苯甲基-1H-咪唑-4 -基)苯甲醛,作为THF溶液(3mL)。将反应物温热至室温并搅拌一晚上。减压消除溶剂,用饱和的NH4Cl(10mL)和水(10mL)稀释粗产物。用CH2Cl2(2x 20mL) 萃取水层,用盐水(15mL)洗涤、用Na2SO4干燥并减压浓缩复合有机馏分,得到粗制品。向粗产物残渣加入AcOH(1mL)和MeOH(3mL),在90℃搅拌溶液2小时。冷却至室温后,蒸馏消除溶剂,在饱和K2CO3(5mL)和EtOAc(5mL)的混合物中搅拌粗产物。分离有机层,用EtOAc(2x 10mL)萃取水层。用水、盐水洗涤并干燥(Na2SO4)复合有机层,减压蒸发溶剂。用柱层析法在硅胶上纯化粗产物渣,得到如下化合物。
范例24 1-(环己烯-3-烯基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酮
71(270毫克,0.86毫摩尔)溶解于苯(7毫升)内,加入对甲苯磺酸(444 毫克,2.58毫摩尔)。在100℃下,搅拌反应混合物48小时,然后浓缩。用碳酸钾水溶液(5毫升)碱化残渣。用乙酸乙酯(2x 20mL)萃取水溶液。用水、盐水洗涤、干燥(Na2SO4)并浓缩复合有机层。将残渣用快速柱层析法纯化,获得标题化合物黄色硅胶155(218mg,86%)。1H NMR:1.35-1.71(m,1H),1.88-2.40(m, 5H),2.62-2.67(m,1H),2.74-2.87(m,1H),3.47-3.58(m,1H),5.66-5.75 (m,3H),6.91(t,1H,J=8.9Hz),7.15(s,1H),7.26-7.35(m,2H),7.62 (d,1H,J=9.8Hz).
范例252-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酰基,2-(5H-咪唑并[5,1-a] 异吲哚-5-基)乙醇还原的一般程序。
在0℃时,向适当的酮(9-18,47-72,136-153,155,1256,1287,1300, 1306,1326,1328,1334,1348或1353)(0.25毫摩尔)的MeOH(2mL)溶液加入NaBH4(0.75毫摩尔),搅拌溶液1小时。减压消除溶剂,向粗产物加入2M HCl (2mL)。搅拌溶液10分钟,用饱和的K2CO3溶液碱化。用CH2Cl2(3x 5mL)萃取水层。用盐水洗涤、干燥(Na2SO4)并减压浓缩复合有机萃取物,得到粗产物渣。 1-10%MeOH:DCM梯度通过柱层析法纯化粗产物,得到如下化合物。
范例261469-1472的制备
利用制备手性超临界流体色谱(SFC)技术,使用甲醇∶CO2(24∶76)中的AD-H 柱(Regis Technologies,Inc.),从1363的外消旋混合物获得纯非对映异构体。
范例27保护基团消除的一般程序
向适当的Boc保护的胺1363,1469,1470,1471,1472或1460(1.13毫摩尔) 的二氯甲烷(10mL)溶液中,加入三氟乙酸(33.8毫摩尔)。在室温下,搅拌所得溶液 2小时,然后浓缩。将粗产物溶解于甲醇(4mL)中,加入氯化氢(4M二恶烷)(3.39 毫摩尔)。浓缩混合物,并在高度真空下干燥,得到所需产物二盐酸盐,在下一步骤中,无需进一步纯化直接使用。
范例28用HATC偶联合成1423,1424,1425,1437,1439,1448,1450, 1458,1480,1481,1490,1493,1500和1511的一般程序。
向装有从范例27(0.25毫摩尔)获得的相应铵盐的DMF(4mL)小瓶加入对应的羧酸(0.26毫摩尔)、DIPEA(1.5毫摩尔)和HATU(0.28毫摩尔)。将反应混合物在室温下搅拌18小时,倒入水(10mL)中,用二氯甲烷(2×20mL)萃取水层。用盐水(2 x 10mL)洗涤、干燥(Na2SO4)并浓缩复合有机层。通过快速柱层析法纯化粗制品,获得1423,1424,1425,1437,1439,1448,1450,1458,1480,1481,1490, 1493或1500。
范例291449,1459,1476,1477,1478和1479合成的一般程序。
向装有从范例19(0.25毫摩尔)获得的相应铵盐的二氯甲烷(4mL)小瓶加入对应的DIPEA(1.0毫摩尔)和异氰酸苯酯(0.25毫摩尔)。在室温下,搅拌反应混合物30分钟,然后浓缩。将残余物溶解在二氯甲烷(30ml)内,用水(3×10mL)洗涤。用Na2SO4干燥有机层,并浓缩。通过快速柱层析法纯化粗制品,获得脲类1449,1459, 1476,1477,1478和1479。
范例301495,1496,1497,1503,1504,1507和1512合成的一般程序。
在0℃和N2气氛下,向相应的胺(0.3毫摩尔)CH2Cl2(3mL)溶液中加入羰基二咪唑(0.35毫摩尔)和乙基二异丙基胺(2.0毫摩尔),将该混合物搅拌1小时。加入从范例19(0.25毫摩尔)中得到的相应胺盐,并搅拌该混合物一晚上。用水用分液漏斗分割溶液,收集有机层。用二氯甲烷(3×10mL)萃取水层,干燥(Na2SO4)复合有机馏分。通过快速柱层析法纯化粗制品,获得脲类1495,1496,1497,1503,1504 或1507。
范例31 1-(1-(苄基磺酰基)哌啶-4-基)-2-(5H-咪唑并[5,1-a]异吲哚-5 -基)乙醇
向装有2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(哌啶-4-基)乙醇二盐酸盐(0.12克,0.34毫摩尔)CH2Cl2(3mL)溶液的小瓶中,加入乙基二异丙基胺(0.35mL,2.0 毫摩尔)和苄基磺酰氯(67mg,0.35毫摩尔)。在室温下,搅拌反应混合物18分钟,然后浓缩。将残渣溶解在二氯甲烷(30ml)内,用水(3×10mL)洗涤。用Na2SO4干燥有机层,并浓缩。将粗制品用快速柱层析法纯化,获得白色固体1442(85mg,58%)。
范例32 2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸
室温下,向1256(0.41毫摩尔)四氢呋喃(2mL)溶液,加入LiOH·H2O(0.45毫摩尔)和水(0.5mL),搅拌溶液一晚上。蒸馏除去溶剂,粗产物溶解于甲醇(1.5mL) 中,然后加入乙酸乙酯(2.5mL),过滤析出的白色固体,用乙酸乙酯洗涤,减压干燥,得到1258(68mg,75%)。
范例33 2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙醇
室温下,向1256(3.51毫摩尔)THF∶EtOH(24mL)1∶2的混合物溶液加入 NaBH4(12.28毫摩尔)和LiCl(12.28毫摩尔)。搅拌一晚上后,蒸馏除去溶剂,用饱和液稀释粗产物。NH4Cl(20mL).CH2Cl2(3x 40mL)萃取水层。用MgSO4干燥符合有机萃取物,减压蒸馏出溶剂,获得粗产物渣。用硅胶急骤层析纯化粗制品,获得1254(638mg,91%)。1H NMR:2.04-2.08(m,1H),2.36-2.40(m,1H), 3.84(t,2H,J=6.3Hz),5.37-5.41(m,1H),7.17(s,1H),7.25-7.28(m, 1H),7.35(d,1H,J=6.90Hz),7.38(d,1H,J=7.2Hz),7.54(d,1H, J=7.5Hz),7.76(s,1H).
范例34 2-(5H-咪唑并[5,1-a]异吲哚-5-基)-N-甲基乙酰胺
室温下,向1256(0.124毫摩尔)四氢呋喃(1.5mL)溶液,加入甲胺溶液(1.24毫摩尔,0.62mL,THF内2M),60℃时搅拌溶液一晚上。冷却至室温后,减压蒸除溶剂,用柱层析法纯化粗产物,得到1259(21mg,75%)。1H NMR:2.43(dd,1H, J=20.0Hz,12.8Hz),2.91(d,3H,J=4.8Hz),2.94(dd,1H,J=20.0Hz, 6.0Hz)5.69(dd,1H,J=12.8Hz,5.60Hz),5.81(brs,1H),7.13(s,1H), 7.22-7.26(m,1H),7.33(d,1H,J=8.4Hz),7.38(d,1H,J=7.2Hz),7.53 (d,1H,J=7.80Hz),7.67(s,1H).
范例35 2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙醛
0℃时,向1254(0.5毫摩尔)二氯甲烷(5ml)溶液中加入氯铬酸吡啶(0.6毫摩尔),将该溶液温热至室温。搅拌4小时后,减压蒸除溶剂,用柱层析法纯化粗产物,得到74(63mg,64%)。1H NMR:2.99(dd,1H,J=7.5Hz,6.0Hz),3.28(dd, 1H,J=12.0Hz),5.61-5.65(m,1H),7.18(s,1H),7.26-7.30(m,1H), 7.32(d,1H,J=6.0Hz),7.39(t,1H,J=6.0Hz),7.55(d,1H,J=6.0 Hz),7.68(s,1H),9.80(s,1H).
范例36 (E)-5-(2-溴苯乙烯基)-5H-咪唑并[5,1-a]异吲哚
-20℃时,向74(1.21毫摩尔)四氢呋喃(4mL)溶液,逐滴加入iPrMgCl·LiCl (1.21毫摩尔,1.3M THF)。搅拌1小时后,加入-20℃的-(5H-咪唑并[5,1-a] 异吲哚-5-基)乙醛,作为四氢呋喃(2mL)中的溶液,将反应物温热至-10℃。在-10℃搅拌2小时后,加入饱和NH4Cl溶液(2mL)和水(2mL),将反应物骤冷。用EtOAc (3x 15mL)萃取水层。干燥(Na2SO4)并减压浓缩复合有机萃取物,得到粗产物渣。 EtOAc∶MeOH(98∶2)对粗产物进行层析纯化,得到1273(42mg,21%)。1H NMR 5.77(d,1H,J=6.0Hz),6.26(dd,1H,J=15.0Hz,Hz,6.0Hz),6.97 (d,1H,J=15.0Hz),7.13-7.17(m,2H),7.26-7.33(m,2H),7.47-7.65(m, 5H).
范例37 2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基2-(((1R,2R,5S)-2-异丙基 -5-甲基环己烷)氧化酶)乙酸
0℃时,向1254(110mg,0.55毫摩尔)CH2Cl2溶液中,加入二异丙基乙基胺 (110mg,0.824毫摩尔)。搅拌混合物5分钟,加入,2-(((1S,2S,5R)-2-异丙基-5- 甲基环己基)氧)亚氨基乙酰氯(129mg,0.55毫摩尔)。将该溶液温热至室温并搅拌4 小时。将反应混合物用水(10mL)稀释,并收集有机层。CH2Cl2(3x 15mL)萃取水层。干燥(Na2SO4)并减压浓缩复合有机萃取物,得到粗制品。用急骤层析纯化粗产物渣,获得1288(200mg,92%)。1H NMR:0.77(d,3H,J=3.0Hz),0.75-1.25 (m,7H)1.23-1.31(m,2H),1.54-1.72(m,3H),1.98-2.03(m,1H),2.20-2.28 (m,2H),2.50-2.54(m,1H),3.09-3.14(m,1H),3.97-4.15(m,2H),4.27 (t,2H,J=4.5Hz),5.26-5.31(m,1H),7.19(s,1H),7.26-7.30(m,1H), 7.35(d,1H,J=6.0Hz),7.39(d,1H,J=6.0Hz),7.55(d,1H,J=6.0 Hz),7.75(s,1H).
范例38 1-环己基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙胺和(E)-5-(2--环己基乙烯基)-5H-咪唑并[5,1-a]异吲哚
0℃时,向三苯基磷(255mg,0.97毫摩尔)THF(10mL)溶液中,加入邻苯二甲酰亚胺(143mg,0.97毫摩尔)和1304(250mg,0.885毫摩尔),然后逐滴加入 DEAD(0.44mL,0.97毫摩尔)。将反应混合物温热至室温并搅拌一晚上。减压蒸除溶剂,用CH2Cl2(30mL)稀释,依次用10%NaOH水溶液(2×15mL)、水和盐水洗涤。干燥(Na2SO4)有机层,减压蒸发溶剂,得到灰白色固体。将固体溶于EtOH(5ml) 中,加入肼一水合物(0.09mL,1.77毫摩尔)。将混合物在80℃加热一晚上。将溶液冷却至室温并减压蒸馏除去溶剂。用CH2Cl2(20mL)稀释粗产物,用水(10mL) 洗涤有机相。干燥(Na2SO4)有机层,减压蒸发溶剂,得到粗产物渣,通过柱层析法纯化,得到白色固体(50mg,14%)和消除的副产物1412 1388 1388(30mg)。13881H NMR:0.97-1.24(m,7H),1.62-1.71(m,6H),2.0(m,1H),2.89(m,1H), 5.34(dd,1H,J=8.4Hz,15.6Hz),5.38和5.49(2m,1H),7.15(s,1H), 7.24(m,1H),7.31-7.52(m,3H),7.77和7.81(2s,1H).14121H NMR:1.11-1.28 (m,5H),1.55-1.75(m,5H),2.01-2.11(m,1H),5.47(d,1H,J=8.0Hz), 6.01(dd,1H,J=6.8Hz,15.0Hz),7.18(s,1H),7.26(m,2H),7.36(m, 1H),7.52(d,1H,J=7.6Hz),7.64(s,1H).
范例39 4-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟乙基)环己酮
向1378(186mg,0.52毫摩尔)THF(5mL)溶液中加入2M盐酸(5mL),并将溶液在室温下搅拌一晚上。在真空下除去溶剂,用2M NaOH水溶液(6mL)碱化剩余的溶液,使pH值>8.0。用二氯甲烷(2×50mL)萃取水溶液,干燥(Na2SO4)复合有机层,并在真空下浓缩,得到白色固体1379(155mg,95%)。
1H NMR:(CD3OD)1.23-2.51(m,11H),3.53-3.77(m,2H),5.60-5.75(m, 1H),7.03-7.08(m,1H),7.26-7.27(m,1H),7.43-7.44(m,1H),8.13和 8.21(2s,1H).
范例40 1-(4-(羟甲基)环己基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙醇(1383)
0℃时,向1386(121mg,0.41毫摩尔)无水THF(10mL)溶液加入BH3·SMe2 (0.05mL,0.53毫摩尔)。将反应混合物温热至室温并在N2气氛下搅拌一晚上。用水(10mL)稀释该溶液,冷却至0℃。依次加入3M NaOH(0.55mL,1.64毫摩尔)和 30%(重量/重量)过氧化氢溶液(0.19mL,1.64毫摩尔)。在室温下,将反应混合物搅拌一晚上。CH2Cl2(3x 40mL)萃取水层。干燥(Na2SO4)并减压浓缩复合有机层。将粗产物渣用快速柱层析法纯化,获得白色固体1383(45mg,35%)。1H NMR MeOH-d4:1.20-1.78(m,11H),2.02-2.22(m,2H),3.46-3.51(m,2H),3.78-3.88 (m,2H),5.38-5.44(m,1H),7.12和7.14(2s,1H),7.27-7.46(m,2H),7.52-7.61(m,2H),7.92和7.95(2s,1H).
范例41 1-(5H-咪唑并[5,1-a]异吲哚-5-基)-2-叔丁醇
0℃时,向1256(48mg,0.20毫摩尔)THF搅拌溶液中逐滴加入MeMgBr 1.0 M THF(0.4mL,)。将所得的溶液在室温下搅拌2小时。小心向反应混合物加入甲醇,骤冷反应物。浓缩粗混合物,用硅胶吸收,并通过柱层析法纯化,得到 1335(24mg,52%)。1H NMR 1.43(s,3H),1.49(s,3H),2.05-2.30(m,2H), 5.30-5.35(m,1H),7.14(s,1H),7.20-7.40(m,3H),7.52(d,1H,J=9.6 Hz),8.02(s,1H).
范例42 4-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟基乙基)环己醇
℃时,向1379(38mg,0.12毫摩尔)无水甲醇混合物中加入硼氢化钠(0.36毫摩尔),并将该溶液在室温下搅拌2小时。减压蒸馏出溶剂,在CH2Cl2(15mL)和饱和液之间分割残渣。NH4Cl(5mL).收集有机层,用CH2Cl2(2x 10mL)萃取水层。盐水洗涤复合有机萃取物、干燥(Na2SO4),然后蒸发溶剂。用柱层析(EtOAc中25 %MeOH)纯化粗产物,得到1371(29mg,76%)。1H NMR MeOH-d4(非对映体混合物):1.00-1.40(m,5H),1.40-2.10(m,5H),2.37-2.47(m,1H),3.39-3.57 (m,2H),5.54和5.72(2m,1H),6.98-7.06(m,1H),7.15-7.18(m,1H),7.37-7.42(m,2H),7.93-7.99(m,1H).
范例43 1-环己基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酮肟
室温下,向86(186mg,0.57毫摩尔)EtOH(3mL)溶液中加入50%NH2OH水溶液(1.71毫摩尔),并将溶液在室温下搅拌一晚上。冷却至室温后,减压蒸除溶剂,用快速柱层析法纯化粗产物,得到1360(120mg,71%)。1H NMR 0.99-1.15(m, 5H),1.45-1.72(m,6H),2.43和2.58(2m,1H),2.70和2.91(m,1H), 4.69(m,1H),7.23-7.29(m,3H),7.40和7.46(2m,1H),7.53和7.58(2 m,1H),7.75和7.76(2s,1H),10.34和10.41(2s,1H).
范例44 1-环己基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙胺
向1360(100mg,0.34毫摩尔)的1∶1 EtOH/AcOH(4mL)溶液中加入锌粉(67mg, 1.0毫摩尔),并将该混合物在室温下搅拌一晚上。减压消除溶剂,将混合物悬浮在 1∶1 MeOH/DCM(10mL)内,并过滤。收集滤液,并减压浓缩。用离子交换层析纯化粗产物,将水和NH4OH作为洗脱剂,得到1364(25mg,26%)。1H NMR(非对映体混合物)0.89-1.75(m,11H),2.24和2.42(2m,1H),2.62(m,1H),4.52 (m,1H),7.09(t,1H,J=9.2Hz),7.29(m,2H),7.38(m,1H),7.47 (m,1H),7.60(d,1H,J=9.2Hz).
范例45从取代的苯胺和胺中去除BOC保护基团的一般程序
向17,1300,1328或1363(66.0微摩尔)二氯甲烷(2mL)溶液中加入三氟乙酸(0.2mL,2.66毫摩尔),并将该混合物在室温下搅拌2小时。减压蒸除溶剂,用饱和液碱化溶液。NaHCO3.用EtOAc(3x 15mL)萃取水层。用水、盐水洗涤并干燥 (Na2SO4)复合有机层。过滤溶液,减压消除溶剂。用柱层析法纯化粗产物渣,得到如下化合物。
范例46 5-(2-环己基-2-羟基乙基)-5H-咪唑并[5,1-a]异吲哚-9-羟基
0℃时,向1372(28mg,0.09毫摩尔)DCM(3ml)溶液中,逐滴加入BBr3(1M in DCM,0.27mL,0.27毫摩尔),在0℃时,搅拌混合物2小时。加入饱和NaHCO3水溶液,用DCM(2x10mL)萃取水层。减压干燥(Na2SO4)并浓缩复合有机层。用急骤层析纯化残渣,获得1373(15mg,56%)。
方案3.(S)-1-环己基-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙醇(1417)和((R)-1- 环己基-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙醇(1418)的对映体选择性合成
范例47环己基-3-羟基-1-(2-碘苯基)丙烷-1-酮
0℃时,在N2气氛下,向二异丙基胺(1.6mL,11.1毫摩尔)THF(38mL)溶液,加入n-BuLi(4.1mL,10.2毫摩尔)。30分钟后,将溶液冷却至~℃,逐滴向混合物中加入1-(2-碘苯基)乙酮(2.27克,9.23毫摩尔)THF(6mL)溶液,在-30℃时搅拌45分钟。将混合物冷却至-78℃,逐滴加入环己基甲醛(1.2mL,9.69毫摩尔),在2小时内将混合物温热至-40℃。通过加入饱和NH4Cl水溶液骤冷反应物。用 EtOAc(2x 50mL)萃取水层。用盐水洗涤、干燥(Na2SO4)并浓缩复合有机层。将残渣用快速柱层析法纯化,获得标题化合物黄色油状物(2.56g,78%)。1H NMR:1.02-1.27(m,4H),1.41-1.49(m,1H),1.66-1.76(m,4H),1.89(d, 1H,J=12.4Hz),2.88(d,1H,J=3.2Hz),2.98(dd,1H,J=9.2Hz,17.2 Hz),3.13(dd,1H,J=2.0Hz,17.2Hz),3.99-4.01(m,1H),7.11-7.15(m, 1H),7.42(d,2H,J=4.4Hz),7.93(d,1H,J=8.0Hz).
范例48 3-(叔丁基二甲基甲硅烷氧基)-3-环己基-1-(2-碘苯)丙烷-1 -酮
向3-环己基-3-羟基-1-(2-碘苯基)丙烷-1-酮(2.56克,7.15毫摩尔)和 DMAP(1.05克,8.58毫摩尔)的DMF(40mL)溶液加入TBSCl(1.62,10.7)。在室温下将反应混合物搅拌18小时,然后倒入水(40mL)中。用EtOAc(2×50mL)萃取水层,用水(2×20mL)、盐水(10mL)洗涤、干燥(Na2SO4)、过滤并浓缩复合有机层。将粗产物用快速柱层析法纯化,获得透明油状物106(3.15g,93%)。1H NMR:0.01(s, 3H),0.08(s,3H),0.86(s,9H),1.12-1.24(m,6H),1.43-1.52(dt,1H, J=3.6Hz,15.2Hz),1.65-1.76(m,4H),2.91(dd,1H,J=6.8Hz,22.0Hz), 3.1(dd,1H,J=9.4Hz,22.0Hz),4.19-4.24(m,1H),7.11(dt,1H,J= 2.4Hz,10.0Hz),7.40(t,1H,J=9.6Hz),7.48(dd,1H,J=2.4Hz,10.4 Hz),7.92(d,1H,J=10.4Hz).
范例49 (1R,3R)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基-1-(2-碘苯)丙烷-1-羟基和(1R,3S)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基-1-(2 -碘苯)丙烷-1-羟基
在室温下,搅拌106(3.15克,6.67毫摩尔)、BH3·SMe2(0.63mL,6.67毫摩尔) 和S-2-甲基-CBS-恶唑硼烷(370mg,1.33毫摩尔)THF(50ml)混合物16小时。加入6M 盐酸水溶液(4mL),搅拌混合物5分钟。将混合物倒入水(20mL)中,用EtOAc(2x 40 mL)萃取水层。用盐水洗涤、干燥(Na2SO4)、过滤并浓缩复合有机层。用急骤层析(3%-6%EtOAc/己烷梯度法)纯化残渣。以这种方式分离两种非对映体107和108。将正相硅胶TLC板靠在108的可靠样品上,配制107和108,确认立体化学。用方案4中描述的醛醇缩合反应,独立制备108的可靠样品。1HNMR:(1R,3S):0.15(s, 3H),0.18(s,3H),0.87(s,9H),1.08-1.27(m,5H),1.52-1.68(m,4H), 1.75-1.89(m,4H),4.02-4.10(m,1H),4.91(d,1H,J=9.6Hz),6.95(t, 1H,J=6.8Hz),7.37(t,1H,J=7.4Hz),7.61(d,1H,J=6.8Hz),7.78 (d,1H,J=7.2Hz).1H NMR:(1R,3R):0.12(s,3H),0.16(s,3H),0.88-0.93 (m,2H),0.97(s,9H),1.12-1.17(m,1H),1.27-1.31(m,2H),1.57-1.79 (m,5H),1.91-2.07(m,3H),3.70-3.72(m,1H),4.19(s,1H),5.20(d, 1H,J=10.4Hz),6.94(t,1H,J=6.8Hz),7.38(t,1H,J=7.4Hz),7.60 (d,1H,J=7.2Hz),7.77(d,1H,J=7.2Hz).
范例50 (1R,3S)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基-1-(2-碘苯)丙烷基4-甲基苯磺酸酯
向107或108(300mg,0.63毫摩尔)二氯甲烷(5ml)溶液中加入三乙胺(0.18mL,1.26毫摩尔)和DMAP(85mg,0.70毫摩尔)。将反应混合物在室温下搅拌5分钟,加入对甲苯磺酰氯(145mg,0.76毫摩尔)。将反应混合物回流18小时。减压消除溶剂。将残渣溶于EtOAc(30ml)中,用水(10mL)、饱和NaHCO3水溶液(15ml)和盐水洗涤有机层。用Na2SO4干燥有机层,并浓缩。在下一步使用标题化合物,无需进一步纯化。
范例51 (1R,3R)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基-1-(2- 碘苯)丙烷基4-甲基苯磺酸酯
按上述程序中的描述制备(1R,3R)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基-1-(2-碘苯)丙烷基4-甲基苯磺酸酯。下一步直接使用标题化合物,无需进一步纯化。
范例52 1-((1S,3S)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基-1-(2-碘苯)丙烷基)-1H-咪唑
向NaH(55mg,2.17毫摩尔)无水DMF(4mL)悬浮液中加入咪唑(148mg,2.17 毫摩尔)。将溶液搅拌2小时,然后加入(1R,3S)-3(叔丁基二甲基甲硅烷氧基)-3- 环己基-1-(2-碘苯基)丙基4-甲基苯磺酸酯(341mg,0.54毫摩尔)DMF(2mL)溶液。将反应混合物在60℃下搅拌14小时,倒入水(10mL)中,用EtOAc(2x 20mL) 萃取水层。用水(2x 10mL)、盐水(10mL)洗涤、干燥并浓缩复合有机萃取物。将残渣用快速柱层析法纯化,获得透明硅胶109(130mg,46%)。1H NMR:(1S,3S) 0.03(s,3H),0.05(s,3H),0.97(s,9H),1.11-1.31(m,5H),1.53-1.59(m, 2H),1.68-1.79(m,4H),2.20-2.23(m,2H),3.59-3.62(m,1H),5.75-5.79 (m,1H),7.01-7.13(m,3H),7.17(s,1H),7.34-7.37(m,1H),7.73(s, 1H),7.93(d,1H,J=7.8Hz).
范例53 1-((1S,3R)-3-(叔丁基二甲基甲硅烷氧基)-3-环己基-1-(2-碘苯)丙烷基)-1H-咪唑e(78)
按上述步骤中对化合物109的描述,制备化合物111。将111隔离成透明硅胶(42%,分2步)。1H NMR:(1S,3R)0.05(s,3H),0.07(s,3H),0.97(s, 9H),1.12-1.29(m,5H),1.47-1.50(m,1H),1.69-1.77(m,3H),1.82-1.85 (m,2H),2.20-2.28(m,1H),2.39-2.47(m,1H),3.56-3.60(m,1H),5.63 (t,1H,J=7.4Hz),6.97-6.98(m,1H),7.04-7.11(m,2H),7.31-7.34(m, 2H),7.45(dt,1H,J=1.0Hz,7.6Hz),7.64(s,1H),7.96(dd,1H,J= 1.2Hz,8.0Hz).
范例54 (S)-5-((S)-2-(叔丁基二甲基甲硅烷氧基)-2-环己基)-5H-咪唑并[5,1-a]异吲哚
向含有109(65mg,0.12毫摩尔)的小瓶中加入二环己基甲胺(0.04mL,0.19毫摩尔)、PPh3(13mg,0.05毫摩尔)和DMF(4mL)。将混合物脱气10分钟,加入Pd(OAc)2(6mg,25μmol)。将该混合物在95℃加热5小时,冷却至室温后,用乙酸乙酯(15mL)稀释混合物,通过硅藻土垫。用乙酸乙酯洗涤滤饼。用水(3x 10 mL)、盐水(10mL)洗涤、干燥(Na2SO4)并浓缩复合有机萃取物。粗产物渣在下一步直接使用。
范例55 (S)-5-((R)-2-((叔丁基二甲基甲硅烷基)氧基)-2-环己基乙基)-5H-咪唑并[5,1-a〕异吲哚
按上述程序的描述制备化合物111a,下一步中直接使用粗产物渣。
范例56 (S)-1-环己基-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙醇(1417)
向含有粗产物109a(60mg,0.15毫摩尔)的小瓶加入1%HCl乙醇(2mL)。将反应混合物在50℃加热3小时,然后倒入饱和NaHCO3水溶液(5mL)中。用二氯甲烷(2×15mL)萃取水层。干燥(Na2SO4)、过滤并浓缩复合有机层。将残渣用快速柱层析法纯化,获得白色固体1417(17mg,47%,分2步)。1H NMR:(1S,2S) 1.02-1.28(m,5H),1.40-1.42(m,1H),1.67-1.83(m,4H),1.91(d,1H, J=12.4Hz),2.22-2.30(m,1H),2.82(br s,1H),3.80-3.83(m,1H),5.52(dd,1H,J=3.0Hz,10.8Hz),7.20(s,1H),7.25-7.29(m,1H),7.36-7.40 (m,2H),7.56(d,1H,J=7.6Hz),7.84(s,1H).通过HBr:1417盐晶体的 X-射线结晶确认了本非对映体的绝对构型(图1)。
范例57 (R)-1-环己基-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙醇(1418)
按上述步骤中对化合物111a的描述,制备化合物1418。将1418隔离成透明硅胶(42%,分2步)。1H NMR:(1S,2R)0.97-1.26(m,5H),1.32-1.39(m,1H), 1.63-1.67(m,2H),1.71-1.80(m,3H),2.00-2.06(m,1H),2.10-2.18(m,1H), 2.55(br s,1H),3.70-3.74(m,1H),5.35(t,1H,J=7.6Hz),7.14(s,1H), 7.19-7.23(m,1H),7.34(t,1H,J=7.6Hz),7.42(d,1H,J=7.4Hz),7.52 (d,1H,J=7.4Hz),7.78(s,1H).
范例58 (反式)-1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基)环己烷羧酸(1436)
向1426(268mg,0.79毫摩尔)THF∶水3∶1(4mL)溶液中加入氢氧化锂一水合物(99mg,2.36毫摩尔)。搅拌溶液18小时。减压清除THF,用1M HCl将溶液中和到pH=5。减压浓缩溶液,向剩余残渣中加入20%MeOH/DCM。将残渣用硅胶塞过滤,并用200mL 20%MeOH/DCM洗脱。将溶液浓缩,获得浅黄色固体193mg (75%)NLG-1436。1H NMR(DMSO-d6):0.83-0.85(m,1H),1.05-1.25(m,4H), 1.41-1.45(m,2H),1.85-1.88(m,3H),2.03-2.21(m,2H),3.61-3.64(m,1H), 5.35-5.42(m,1H),7.11和7.13(2s,1H),7.27(t,1H,J=7.0Hz),7.37 (t,1H,J=7.4Hz),7.49和7.56(2d,1H,J=7.5Hz),7.59(d,1H,J =7.5Hz),7.88和7.92(2s,1H),11.98(br s,1H).
范例59 1-((反式)-4-(羟基甲基)环己基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙醇(NLG-1430)
向1426(100mg,0.30毫摩尔)THF∶EtOH(3mL,1∶2比例)的混合物溶液加入NaBH4(48.1mg,1.27毫摩尔)和LiCl(53.9mg,1.27毫摩尔)。搅拌反应混合物一晚上。减压消除溶剂,用饱和的NH4Cl(20mL)稀释粗产物渣。用EtOAc (3x 10mL)萃取产物。用Na2SO4干燥复合有机萃取物,减压消除溶剂。用硅胶急骤层析纯化粗制品,获得1430(78mg,85%)。1H NMR(非对映异构混合物)0.94-1.13(m,4H),1.14-2.18(m,10H),3.45(d,J=6.3Hz,2H),3.73-3.78 (m,1H),5.30-5.38(m,1H),7.17(s,1H),7.22-7.27(m,1H,与CHCl3 重叠),7.33-7.44(m,2H),7.54(d,J=7.6Hz,1H),7.83(d,J=10.4Hz, 1H).
范例60 (反式)-1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基)-N-(2-((甲基亚磺酰氨基)乙基)环己烷甲酰胺(1432)
向含有N-(2-氨基乙基)甲磺酰胺二盐酸盐(56.4mg,0.27毫摩尔)DMF(4mL)的小瓶中加入1436(83mg,0.25毫摩尔)、DIPEA(197mg,1.53毫摩尔)和HATU(106mg, 0.28毫摩尔)。在室温下,搅拌反应混合物18分钟,然后浓缩。用己烷/乙酸乙酯 10%->60%梯度,将残余物在硅胶上通过柱层析法纯化。将化合物隔离成浅黄色固体72mg(64%)。1H NMR:(CD3OD)1.04-1.14(m,2H),1.38-1.46(m,3H), 1.73-1.96(m,4H),2.11-217(m,2H),2.32-2.38(m,1H),2.93和2.97(2 s,3H),3.15(t,1.7H,J=6.4Hz),3.29-3.31(m overlap with,1H),3.54-3.58 和3.78-3.80(2m,1H),5.57-5.66(t和dd,1H,J=6.3和J=2.6,9.2H), 7.33-7.47(m,3H),7.52和7.60(2d,1H,J=7.6Hz),7.68-7.71(m,0.8H), 7.91(s,0.4H),8.21(dd,0.6H,J=1.1,8.4Hz),8.44(s,0.4H),8.53-8.57 (m,1H).
范例61 (顺式)-4-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟基乙基)环己醇
向-78℃氮气气氛下的NLG-1379(60mg(0.19毫摩尔)无水THF(5mL)溶液,加入三戊基硼氢化锂溶液(1.0M THF溶液)(0.38mL,0.38毫摩尔)。在-78℃下,剧烈搅拌所得混合物3小时,然后温热到室温(1小时)。用1∶1 H2O/EtOH(4mL)骤冷反应混合物。6N HCl用酸化反应物,然后用饱和K2CO3溶液碱化。用二氯甲烷 (5×15mL)萃取水层。干燥(Na2SO4)、过滤并减压浓缩复合有机萃取物,得到粗产物渣。用柱层析法纯化残渣,获得1465(35mg,58%)。非对映体混合物1H NMR:1.45-2.15(m,10H),2.35-2.51(m,1H),3.66-3.79(2m,1H),4.03(br s,1H),5.48(t,1H,J=5.1Hz,isomer),5.67(dd,1H,J=10.6,2.8 Hz),6.91-6.95(m,1H),7.19(d,1H,J=5.4Hz),7.25-7.39(m,2H),7.88 (2,s,1H).
通过制备型手性超临界流体色谱法(SFC)分离四个非对映异构体的混合物(1465),得到纯非对映体1482-1485.在异丙醇/CO2:0.2%DEA内的RegisPack 5 柱上进行SFC。
1482和14841H NMR(CD3OD)δ1.16(d,J=6.1Hz,1H),1.23(d,J= 17.8Hz,2H),1.28(s,1H),1.37-1.65(m,6H),1.73(s,2H),1.90- 2.14(m,1H),2.48(d,J=15.2Hz,1H),3.55(s,1H),3.90(s,1H), 5.58(s,1H),6.91-7.08(m,1H),7.16(s,1H),7.41(s,2H),7.96 (d,J=28.8Hz,1H).
1483和14851H NMR:(CD3OD)δ1.15(d,J=6.4Hz,1H),1.26(d,J= 24.4Hz,2H)1.41-1.79(m,8H)2.35-2.50(m,1H),3.65(d,J=7.8Hz, 1H),3.90(s,1H),5.69(dd,J=10.1,2.4Hz,1H),6.93-7.08(m, 1H),7.18(s,1H),7.41(dd,J=5.2,3.5Hz,2H),7.94(s,1H).
范例62 2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-((反式)-4-羟基环己基)乙酮
在-10℃,向NaH(1.11g,46.2毫摩尔)THF(150mL)溶液逐滴加入126 (18.5g,50.8毫摩尔)THF(75mL)溶液,在0℃搅拌混合物45分钟。在15分钟时间内,以THF(120mL)溶液形式,逐滴加入乙醛4(20.0克,46.4毫摩尔)。在0℃搅拌1小时后,将反应混合物温热至室温并搅拌一晚上。减压蒸除溶剂,用饱和的NH4Cl(80mL)、水(100mL)和EtOAc(100mL)稀释粗产物。用分液漏斗分割溶液,收集有机层。用EtOAc(3x 150mL)萃取水层,用盐水洗涤并干燥(Na2SO4) 复合有机馏分。减压过滤与浓缩溶液,得到粗制品。在90℃,在乙酸(20mL)和甲醇(170mL)的混合物中搅拌粗产物1.5小时。冷却至50℃后,用6N HCl(20mL) 处理反应混合物,并搅拌30分钟。冷却至室温后,蒸除溶剂,向残渣中加入饱和的NaHCO3(200mL),然后加入CH2Cl2(200mL)。分离有机层,用CH2Cl2(2x 100 mL)萃取水层。用Na2SO4干燥复合有机层,减压蒸发溶剂,得到粗产物,用快速硅胶柱层析法纯化粗产物,得到154(13.8克,95%)。
范例63 (反式)-4-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟基乙基)环己醇(1475)
在-10至0℃,向154(13.8克,43.9毫摩尔)MeOH(150mL)溶液少量加入NaBH4(4.98g,131.71毫摩尔),将溶液搅拌4小时。减压蒸馏除去溶剂,加入饱和NH4Cl 溶液(200mL)和二氯甲烷(200mL),稀释混合物,将该混合物搅拌25分钟。分离有机层,用5%2,2,2-三氟乙醇CH2Cl2(5x 75mL)混合物萃取水层。用盐水洗涤、干燥(Na2SO4)并减压浓缩复合有机萃取物,得到粗制品。用柱层析进行纯化,得到白色固体(13.24g,95%)1475。1H NMR(非对映异构混合物):1.07-2.52(m, 11H),3.48-3.68(2m,2H),5.45(t,1H,J=6.0Hz),5.65(dd,1H,J= 9.0,3.0Hz),6.89-6.96(m,1H),7.16(s,1H),7.29-7.38(m,2H),7.80 和7.88(2s,1H).
通过制备手性超临界流体层析,分离四个非对映体的混合物,得到纯非对映体1486-1489。通过AD-H柱(Regis Technologies,Inc.),用第一通道,进行SFC 分离,以分离化合物1487,1486+1488和1489。峰值包括1486+1488的混合物,用Whelk-O1柱(RegisTechnologies,Inc)内的SFC分离。在异丙醇∶CO2(10∶90)+ DEA 0.1%中执行所有分离操作。
NLG-1486和NLG-14891H NMR:1.03-1.26(m,6H),1.43-1.47(m,2H), 1.93-1.96(m,2H),2.45-2.50(m,3H),3.48(s,1H),3.61(s,1H), 5.62(d,J=8.9Hz,1H),6.91(t,J=8.6Hz,1H),7.12(s,1H), 7.26-7.30(m,2H,与CHCl3重叠),7.79(s,1H).
NLG-1487和NLG-14881HNMR:0.95-1.33(m,6H),1.61-1.64(m,1H), 1.79-1.82(m,1H),1.91-2.04(m,4H),2.28(d,J=14.4Hz,1H), 3.42-3.45(m,1H),3.62(s,1H),5.37(t,J=4.9Hz,1H),6.88(t,J= 8.9Hz),7.05(s,1H),7.24-7.31(m,2H,与CHCl3重叠),7.84(s,1H).
1304的前体药物合成
范例64 1-环己基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基磷酸钠(1434)
在0℃,向1304(150mg,0.53毫摩尔)和吡啶(85.7μL,1.1毫摩尔)的二氯甲烷(4ml)溶液中加入POCl3(99.3μL,1.06毫摩尔),将该溶液温热至室温。搅拌一晚上后,用NaHCO3骤冷反应物,搅拌15分钟。减压蒸发溶剂,用THF(2x 15mL) 洗涤固体。减压除去溶剂,得到粗产物渣。将残渣溶解于DCM(5mL),并经过 Na2SO4塞,除去水分。减压蒸发溶剂,得到1434.
(33%).1H NMR(非对映异构混合物):(CD3OD)1.15-1.41(m,6H), 1.59-1.82(m,5H),1.98-2.04(m,1H),2.56-2.86(2m,1H),3.57-3.58和 4.08-4.11(2m,1H),5.29-5.54(2m,1H),7.11和7.16(2s,1H), 7.25-7.47(m,3H),7.53-7.60(m,1H),7.83和7.95(2s,1H).
范例65 1-环己基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基乙酸
在室温下,用乙酸酐(32μL,0.34毫摩尔)处理1304(80mg,0.28毫摩尔)和 4-二甲基氨基吡啶(1.04mg,8.5微摩尔)的吡啶(3ml)溶液中,将反应物搅拌一晚上。在真空中浓缩溶液,将残渣溶解于二氯甲烷中(10ml)中,依次用水(3x 10ml)洗涤,并用Na2SO4干燥。浓缩溶液,将粗产物渣用快速柱层析法纯化,获得所需的黄色硅胶产物(75mg,82%)。1H NMR(非对映体的混合物):0.76-1.25(m,5H), 1.30-1.75(m,6H),1.78-2.20(m,4H),2.26-2.40(m,1H),4.96-5.12(m,2H), 7.17-7.39(m,4H),7.51-7.53(m,1H),7.71和8.00(2s,1H).
范例66 4-(1-环己基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙氧基)-4-氧代丁酸(1428)
在室温下,用琥珀酸酐(19mg,0.19毫摩尔)和DIPEA(33微升,0.19毫摩尔) 处理1304(48mg,0.28毫摩尔)和4-二甲基氨基吡啶(0.83mg,6.8微摩尔)的二氯甲烷(3ml)溶液,将反应物搅拌一晚上。将溶液倒入饱和的NH4Cl(10mL)内,用二氯甲烷(3×10ml)萃取。在Na2SO4上干燥并浓缩复合有机层。将粗产物从乙醇/ 氯仿(1∶4)中结晶,得到白色固体(62mg,95%)。1H NMR(非对映异构混合物):0.93-1.65(m,11H),1.90-2.32(m,1H),2.50-2.90(m,3H),2.92-3.05(m, 1H),3.57和3.73(m,1H),5.20-5.22(m,1H),5.29-5.33(m,1H),6.41-6.78 (m,1H),7.16-8.00(m,5H),12.20-12.80(br s,1H).
范例67 1-环己基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)苯甲酸乙酯(1431)
在室温下,用苯甲酸酐(73mg,0.32毫摩尔)处理1304(76mg,0.27毫摩尔) 和4-二甲基氨基吡啶(1.0mg,8.1微摩尔)的吡啶(3ml)溶液,将反应物搅拌一晚上。在真空中浓缩溶液,将残渣溶解于二氯甲烷中(10ml)中,依次用饱和的NaHCO3(10 mL)洗涤,并用Na2SO4干燥。浓缩溶液,用快速柱层析法纯化粗产物,得到1431 (25mg,23%)。1H NMR(非对映异构混合物):0.88-1.25(m,7H),1.62-1.90(m, 4H),2.15-2.25(m,1H),2.49-2.58(m,1H),5.19-5.21(m,1H),5.34-5.37 (m,1H),7.16-7.28(m,4H),7.40-7.64(m,4H),7.80(s,1H),8.00-8.02 (d,J=6.3Hz,1H),8.12-8.14(d,J=5.7Hz,1H).
范例68 1-环己基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基苯基氨基甲酸酯(1427)
向1304(40mg,0.14毫摩尔)的THF(5mL)溶液中,加入三乙胺(43微升, 0.31毫摩尔),然后加入异氰酸苯酯(17微升,0.16毫摩尔)。在室温下,搅拌反应混合物18分钟,然后浓缩。用快速柱层析(4∶1 EtOAc∶MeOH)纯化粗制品,得到无色硅胶(19mg,34%)1427.1HNMR(非对映异构混合物):1.02-1.04(m,5H), 1.56-1.70(m,6H),2.10-2.14(m,1H),2.31-2.40(m,1H),5.02-5.10(m,1H), 5.18-5.24(m,1H),7.04-7.08(m,1H),7.18-7.35(m,6H),7.39-7.41(m,2H), 7.50(d,J=4Hz,1H),7.65(d,J=8Hz,1H),7.74(s,1H).
范例69 1304前药合成的通用步骤
向装有1304(0.5毫摩尔)的二氯甲烷(5mL)小瓶加入对应的羧酸(1.1毫摩尔)、二异丙基乙基胺(3.0毫摩尔)和HATU(1.3毫摩尔)。将反应混合物在室温下搅拌48 小时,倒入饱和NaHCO3(10mL)水溶液中,用二氯甲烷(2×20mL)萃取水层。在 Na2SO4上干燥并浓缩复合有机层。将粗制品溶解于二氯甲烷(6mL)中,并加入 TFA(2mL)。在室温下,搅拌反应混合物2分钟,然后浓缩。将残渣溶解于水中,加入固体K2CO3,直至液体呈碱性。用二氯甲烷(2×20mL)萃取水溶液。用Na2SO4干燥、过滤并浓缩复合有机层,得到1433,1440,1442和1443。
生物实施例1 人类IDO蛋白的克隆、表达和纯化
通过扩大存在于带有引物5’-ggagcatgctaATGGCACACGCTATGGAAAAC-3’和5’-gagagatctACCTTCCTTCAAAAGGGATTTC-3’的载体phIDO6His cDNA的顺序的1219bp片段,将SphI-BglII 1213bp片段克隆到pQE70(Qiagen)内产生载体 pQE70-hIDO,制备人类吲哚胺2,3-双加氧酶(IDO)蛋白质的表达载体。这种结构向人类自然IDO蛋白质的C-末端加入2个额外的氨基酸和1个6-组氨酸标签,完好保存自然起始密码子和N-末端氨基酸序列。人类IDO的扩大等位基因表示存放在SwissProt数据库的加入文件P14902之序列的两个多态性。这些多态性导致 P110S和E119G氨基酸的变化。
质粒pQE70-hIDO被转化成M15(pREP4)细胞(Qiagen),在LB琼脂平板上选择克隆,补充50μg/mL的羧苄青霉素和卡那霉素30μg/mL。执行蛋白表达时,在 100mL LB内种植M15pREP4/pQE70-hIDO克隆的隔夜培养物,补充100μg/mL羧苄青霉素、5050μg/mL卡那霉素和50μg/mL的L-色氨酸(LBCKT介质)。将这种培养物按1∶10比例稀释到LBCKT介质内,在37℃时,再培养2小时,直至OD600 高于0.8。在这一点上,将培养物接种与氯化血红素7μM和L-色氨酸为75微克/mL,在37℃下孵育2小时。在这一点,用血晶素将培养物接种到7μM,将L-色氨酸接种到75μg/mL,并在37C孵化2小时。补充培养物,使IPTG达到1mM、PMSF 达到200μM、EDTA达到1mM,L-色氨酸达到50μg/mL,诱导蛋白表达。在25℃时,继续孵化额外的16小时。通过离心过滤,收集细胞,用PBS缓冲液洗涤细胞团块,补充200μM PMSF和1mM EDTA,并贮存于-80℃,直至蛋白纯化。
在一个批次的纯化中,处理16L培养物的当量。细胞团块被解冻后,重新悬浮于50mM磷酸钾缓冲液pH7.0,200μMPMSF,1mMEDTA,1mg/mL溶菌酶达到每升细菌培养物达到10mL,并在冰上孵化30分钟。然后通过超声处理裂解细胞。细胞裂解物以20000×g离心20分钟,将上清液通过0.45μm的过滤器过滤。将过滤后的上清液加载到一个60mL的磷酸纤维素柱上,用50mM磷酸钾缓冲液 pH6.5(KPB),按1-3mL/min的速度使之平衡。用3倍体积的50mMKPB,3倍体积的100mMKPB,洗涤该柱,用15倍体积的线性梯度的100-500mMKPB,洗提蛋白。收集馏分,通过测量犬尿氨酸产量,进行IDO活性测定。要达到这个目的,将50μL的各馏分与100μL的反应混合物混合,制得最终浓度为50mMKPB的缓冲液、20mM的抗坏血酸,20000μg/mL的过氧化氢酶、20μM的亚甲基蓝和400μM 的L-色氨酸。把证明IDO活性的馏分加载到Ni-NTA纯化柱(15mL)上。这种亲和纯化柱用10倍体积的250mM KPB、150mM氯化钠、50mM咪唑pH值8,并用含有250mM KPB、150mM氯化钠和50-250mM咪唑线性梯度的10倍体积的缓冲液洗提。用上述IDO酶法测定,测定收集的馏分,通过超滤汇集和浓缩正馏分,并用含有250mMKPB、50%甘油的缓冲液透析。此过程产生8-10mg的比活性为170 微摩尔/小时/mg的纯蛋白质(>98%)。
生物范例2 酶IDO化验对IDO抑制化合物的检测
通过测试IDO在含有pH 6.5的50mM磷酸钾的混合物中的活性,确定每种化合物的IC50值;70nM p纯化人类IDO蛋白、200μM L-色氨酸、20mM抗坏血酸、20μM亚甲基蓝、0.1%DMSO。抑制剂最初在DMSO中以100mM稀释,并在50mM磷酸钾内稀释,以1mM至5nM的最终浓度加入到反应混合物中,25℃下,用酶预培养5分钟。向200μM加入L-色氨酸,开始反应,并在37℃下孵化 15分钟。加入0.5体积的30%三氯乙酸使反应停止,并在60℃下孵化30分钟,以将N-甲酰犬尿氨酸水解成犬尿酸。将反应物在3400g下离心分离5分钟,以除去沉淀的蛋白质,将上清液与乙酸内的2%(重量/体积)对-二甲基氨基苯甲醛反应。将反应物在25℃下孵化10分钟,用分光光度计在480nm处读取。将没有IDO抑制剂或没有IDO酶或有参考抑制剂1-甲基-色氨酸(200μM)和甲萘醌(1.2μM)的对照样品作为对照,以设置各化合物的IC50的测定所需的非线性回归参数。用GraphPad 棱镜4软件,执行IC50值的非线性回归和测定。IC50低于500μM的化合物被认为是该测定中的活性抑制剂。
生物范例3 基于细胞的IDO/犬尿氨酸法中IDO抑制活性和毒性的测定
293-T-RExTM细胞(Invitrogen)持续表达一种四环素运算符绑定的阻遏蛋白,并在37℃下保持在DMEM、10%FBS、1X青霉素+链霉素、22mM L-谷氨酰胺、 5μg/mL杀稻瘟素中,空气气氛中有5%CO2,通常在汇合之前分裂。细胞传递的手段是分裂培养物1/10-通过抽吸除去介质、用PBS洗涤1X、用0.25%胰蛋白酶 /EDTA孵化直到细胞分离,向新鲜生长培养基分配细胞,在新鲜生长培养基中放置膜片。为便于长期低温储藏,从上述孔板上分离细胞,通过离心收集,再悬浮于冷冻介质(生长培养基,10%DMSO)内,存储在1.8mL低温储藏小瓶(-2-5×106 细胞/每小瓶),小瓶置于液氮蒸气储罐内。
在多西环素-诱导CMV-tet促进剂的控制下,通过稳定转染质粒 pcDNA-tetO-IDO表达人类IDO或老鼠IDO,产生IDO1-表达293-T-RexTM细胞株。
在37℃下,在DBZ培养基(DMEM、10%FBS、1X青霉素+链霉素、2mM L- 谷氨酰胺、5μg/mL杀稻瘟素和25μg/mL博莱霉素)内选择转染的细胞,空气气氛中有5%CO2。通过限制从这些群体中稀释克隆,隔离单个克隆。化验这些克隆的 IDO活性,显示出多西环素氧酶可诱导的最高IDO活性的克隆,用于随后以细胞为基础的IDO检测分析。
要设置基于IDO细胞的活性检测分析,收获IDO-293-T-Rex细胞,以106细胞/mL再悬浮于DBZ培养基内,按每孔10万分裂到涂覆聚-D-赖氨酸的96-孔板中。向细胞中加入100μL的中性培养基(DBZ培养基,200μM L-色氨酸)或诱导介质(中性培养基用5μM多西环素补充),在37℃下孵化28小时。IDO诱导期后,移除培养基,用含有不同浓度抑制剂(1mM-0.5nM)的诱导或中性培养基替换。中性培养基中孵化的细胞用作检测的阴性对照。在诱导培养基中孵化的没有抑制剂的细胞用作检测的阳性对照。在37℃下,在细胞培养孵化器内孵化16小时。将200μL 的培养基转移到含25μL的30%TCA的U型底聚丙烯96-孔板中,在60℃下孵化30分钟,并按3400克离心5分钟。将150μL的上清液转移到乙酸中含有50μL的4%(重量/体积)对-二甲基氨基苯甲醛的聚苯乙烯96-孔板,孵化10分钟。通过在 480nm处测量吸光度,测定犬尿氨酸浓度。
要在用细胞孵化后16小时测量各化合物的毒性,按照制造商的指示,通过 WST-1化验(Roche)测量胞生存力。简单地说,在用各化合物培养后,培养基被吸出,用100mL的WST-1试剂更换,在37℃下孵化30分钟。540nm处的吸光度与活细胞数相关。使用GraphPadPrism软件,通过非线性回归分析,测定IC50(犬尿氨酸检测)或LD50(WST-1检测)。
生物范例4IDO抑制剂逆转IDO-介导的T-细胞增殖抑制。
通过大血容量从周围外周血单核细胞收集人单核细胞,以106个细胞/孔,在 RPMI1640培养基内的培养液96-孔板上培养过夜,该培养基用10%小牛血清和 2mM L-谷氨酰胺补充。保留贴壁细胞,用200ng/ml IL-4,100ng/ml GM-CSF培养7天。用含有TNF-α,IL-1β,IL-6和PGE2的细胞因子鸡尾酒使细胞成熟2 天,再成熟2天诱导树枝状细胞成熟。成熟结束后,通过轻吸,分离松散的贴壁细胞,以5000个细胞/孔,覆盖在V型平底96孔板内。这些细胞>80%IDO+树突状细胞。将采自正常供体的人同种异体T细胞(3x105)重新悬浮于用100-200U/ml IL-2和100ng/mL抗-CD3抗体补充的RPMI 1640内,加入到孔内。加入溶解于无酚红RPMI的连续稀释的IDO化合物,以达到500与1μM之间的IDOi最终浓度。孵化2-4天后,用BrdU标记混合物(罗氏分子生物化学),在隔夜脉冲后,通过BrdU 掺入法测定T细胞增殖。脉冲结束后,按照制造商的指示,将细胞固定用100μL/ 孔抗BrdU-POD抗体孵化。用酶标仪读取孔板。
或者,按照程序,测试T细胞增殖IDO介导抑制的体外老鼠模型的IDO抑制剂。在右侧,用1x106B78H1-GMCSF肿瘤细胞给C57BL6接种。10-12天后,收集肿瘤引流淋巴结,用抗-CD11C和抗-B220单克隆抗体给细胞染色。通过高速荧光激活细胞分选,拣选细胞,按2000个细胞/孔,在96孔V型底板内收集和接种 CD11C+/B220+浆细胞树突状细胞。通过尼龙毛富集,从BM3转基因老鼠(CBA背景下)收集脾细胞。用200μL的RPMI,10%FCS,50μMβ-巯基乙醇,向每个孔加入BM3T细胞(105细胞/孔)。或者,从OT-I转基因老鼠的脾脏中获得T细胞,然后结合OVA缩氨酸加入到培养基内。加入IDO抑制剂,溶解于RPMI中,终浓度在1mM-10nM之间。经过3天的刺激,用BrdU或3H-胸腺嘧啶脱氧核苷跳动细胞16小时。按照BrdU标记试剂盒制造商(Roche Diagnostics)的说明,收集、固定并测试细胞的BrdU掺入。如果用3H-胸腺嘧啶脱氧核苷测量T细胞增殖,收获细胞,按照本领域内广为人知的程序,用闪烁计数器测量dpm数量。从对侧淋巴结采集的对照CD11c+细胞或从TDLN采集的CD11c+/B220-细胞(IDO-人群)用作增殖的阳性对照。
生物范例5药理学价值
下表中包括报告按照前述一个或多个范例测试之化合物的药学价值,包括,
人类IDO IC50:这是化合物的浓度,在这个浓度,我们在其中一个范例内描述的检测条件下用重组细胞人类IDO,可观察到50%的酶活性;
IC50值报告的范围:A:<1μM,B:1-10μM,C:10-100μM;D:>100 μM.
生物范例6结合化疗药物对抗肿瘤活性的IDO抑制剂的体内测试
可用改良的肿瘤移植协议测试体内抗-肿瘤的疗效。例如,文献中描述,IDO 抑制可与免疫活性老鼠的细胞毒素化疗协调作用。由于不同的肿瘤细胞株对化疗药物和免疫介导的排斥反应有不同的敏感性,每种IDO抑制剂单独测试,并结合 4种不同动物肿瘤模型中的2种不同化疗药物测试,每种IDO抑制剂由4种不同的老鼠肿瘤细胞系代表,采自不同的组织来源(大肠癌、膀胱、乳腺和肺癌),皮下植入老鼠同源菌株。按照来源组织以及引发免疫反应的能力,根据已知的对化疗药物的易感性、作为单剂对IDO抑制剂的部分响应以及IDO表达的假定模式,选择这些细胞系。
对于每一种动物肿瘤模型,按照如下列表,在不同的老鼠群内,测试2种不同的化疗药物:1]LLC肿瘤:环磷酰胺和紫杉醇;2]EMT6肿瘤:环磷酰胺和紫杉醇;3]CT26肿瘤:环磷酰胺和多柔比星;4]MB49肿瘤:环磷酰胺和吉西他滨。
按指示的剂量,使用以下化疗药物。老鼠中以下化疗药物的最大耐受剂量取决于配方、浓度、给药频率、给药途径和剂量数。与每种IDO抑制剂药物结合使用的化疗药物是:1]紫杉醇:20mg/公斤/天,腹腔注射,每4天一次,4次(q4dx4)(聚氧乙烯蓖麻油);2]多柔比星:5mg/公斤,一周一次,3周(q7dx3);3]环磷酰胺(CTX):100mg/公斤,腹腔注射,每4天一次,4次(q4dx4);4]吉西他滨:80mg/ 公斤,每4天一次,4次,腹腔注射(q4dx4)。
所有动物第1天皮下注射活肿瘤细胞(50000-1000000细胞)的肿瘤形成剂量,肿瘤细胞悬浮于0.1mL的PBS或生理盐水内。皮下注射形成一个可随时间监测肿瘤生长的局部肿瘤。
要模仿IDO抑制剂药物作为治疗组合物的效果,在肿瘤接种后的第5-8天,开始服用IDO抑制剂药物。剂量、给药途径、给药频率取决于每种药物的毒性和药代动力学类型。治疗的持续时间为2周。最优选的做法是,通过口头强喂或溶解于饮水连续给药。另外,通过外科手术,将含有100mg每种药物的皮下缓释颗粒或渗透泵植入皮肤。按最大耐受剂量或与LD50对应的浓度,服用IDO抑制剂药物。
为测试化合物1357和1304的抗肿瘤活性,在第0天,将20万LLC老鼠肿瘤细胞皮下注射到同源C57BL6老鼠内。每个治疗组由10只老鼠组成。在第7天,一旦肿瘤建立,在肿瘤引流淋巴结处,将IDO表达诱导到浆细胞样树突状细胞内,一组10只老鼠手术植入(皮下,肿瘤对侧),渗透泵装有200uL的30mg/mL化合物1357或1304的cremaphor∶EtOH∶盐水(10∶10∶80)溶液。这些泵每小时释放1uL 的溶液,为期8天,达到0.5-3微摩尔的稳态血药浓度。从第15至第24天,每天两次皮下注射,每次剂量1mg,连续服用化合物。在化合物1304的情况中,在肿瘤接种后的第9、13和15天,通过腹腔注射,用环磷酰胺100mg/公斤,单剂或结合化合物1304,选择性治疗3-4只老鼠。这些试验结果表明,无论作为单剂或与化疗结合给药,化合物1357和1304有着显著的抗肿瘤作用。观察发现,治疗效果是降低肿瘤生长速度,这对中位生存期和总存活率有影响。
研究了两组老鼠(每组10只)随时间的平均肿瘤体积。用载体治疗对照组,治疗组接受渗透泵及如上所述化合物1357。将肿瘤体积代入指数增长方程,使用 GraphPad软件比较拟合参数。数据表明两条曲线之间的差异有统计学意义 (p<0.0001)。
紧接上面生成所述的相同老鼠组的生存曲线。对数秩检验表明,在用化合物 1357作为单剂治疗动物,中位生存期的差异有统计学意义。
研究了四组老鼠(每组10只)随时间的平均肿瘤体积。用载体治疗对照组,治疗组接受环磷酰胺化疗、渗透泵及化合物1034或环磷酰胺及化合物1304的联合治疗。数据显示,这种肿瘤对化合物1304作为单剂或与化疗结合的治疗效果非常敏感。
紧接上面生成所述的相同老鼠组的生存曲线。对数秩检验表明,在用化合物 1304作为单剂或结合环磷酰胺治疗动物时,中位生存期差异有统计学意义。用1304 治疗观察到的长期存活率非常高,70-80%的老鼠在60天后肿瘤消失。
Claims (24)
1.一种化合物,其为4-((R)-1-羟基-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙基)-N-苯基哌啶-1-甲酰胺,或其药学上可接受的盐。
2.一种化合物,其为1-(4-((R)-1-羟基-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙基)哌啶-1-基)-2-苯基乙酮,或其药学上可接受的盐。
3.一种化合物,其为1-(4-((S)-1-羟基-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙基)哌啶-1-基)-2-苯基乙酮,或其药学上可接受的盐。
4.一种化合物,其为(S)-1-环己基-2-((S)-5H-咪唑并[5,1-a]异吲哚-5-基)乙醇,或其药学上可接受的盐。
5.一种化合物,其为(1R,4r)-4-((R)-2-((S)-6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟基乙基)环己醇,或其药学上可接受的盐。
6.一种药物组合物,含有根据权利要求1-5中任何一项的化合物和药学上可接受的稀释剂、赋形剂或载体。
7.根据权利要求1-5中任何一项的化合物或根据权利要求6的药物组合物在制备用于治疗受试者中吲哚胺2,3-双加氧酶(IDO)介导的免疫抑制的药物中的用途。
8.如权利要求7的用途,其中,所述免疫抑制与传染性疾病或癌症有关。
9.如权利要求8的用途,其中,所述传染性疾病是选自下列的病毒感染:流感、丙型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、巨细胞病毒(CMV)、爱泼斯坦-巴尔病毒(EBV)、脊髓灰质炎病毒、水痘-带状疱疹病毒、柯萨奇病毒、人类免疫缺陷病毒(HIV)。
10.如权利要求8的用途,其中,所述免疫抑制与癌症相关。
11.如权利要求10的用途,其中,所述癌症是结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌,或淋巴瘤、白血病或黑素瘤。
12.式(Ia)的化合物
或其药学上可接受的盐,其中
n是0、1或2,且各R1独立为卤素、-OR0、-N(R0)2或-SR0,其中各R0独立为氢或C1-6烷基;
R2是-C1-2烷基-RA;
RA是-C(O)R3,
R3是苯基、咪唑基、噻唑基、吡啶基、环己基、环戊基、环己烯基、氮杂环丁烷基、哌啶基、吡喃基、呋喃基或环己基甲基,其中环烷基、环烯基、杂环基和环烷基烷基-各自任选且独立地被一个=R32基团取代,且各自任选且独立被一个或两个R31基团取代;所述苯基和杂芳基基团各自任选被一个或两个R31基团取代,
其中各R31独立为卤素、氰基、硝基、C1-6烷基、-C1-6烷基-R33、C1-6卤代烷基、-OR、-N(R)2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)N(OH)R、-C(O)R、-C(NR11)R、-C(NR11)N(R11)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR、-N(R)C(O)N(R)2,
其中R33为氰基、-OR、-N(R)2、-SR、-C(O)OR、-C(O)N(R)2、-C(O)R、-S(O)R、-S(O)OR、-S(O)N(R)2、-S(O)2R、-S(O)2OR、-S(O)2N(R)2、-OC(O)R、-OC(O)OR、-OC(O)N(R)2、-N(R)C(O)R、-N(R)C(O)OR或-N(R)C(O)N(R)2,
其中=R32为=O、=S、=N(R)、=N(OR)、=C(R34)2、=(螺环-环丙基)或=(螺环-1,4-二氧戊环基),其中各R34独立为氢、卤素、氰基、C1-6烷基、-C1-6烷基-OR、C1-6卤代烷基或环丙基;
R独立为氢、C1-6烷基、C1-6卤代烷基、单环部分或(单环部分)-CH2-,其中单环部分是苯基、噻吩基、吡啶基、咪唑基、噻唑基、环丙基、环戊基、环己基或吡喃基,各基团任选被卤素、氰基、硝基、C1-6烷基、C1-6卤代烷基、-OR11、-N(R11)2、-SR11、-C(O)OR11、-C(O)N(R11)2、-C(O)R11、-S(O)R11、-S(O)OR11、-S(O)N(R11)2、-S(O)2R11、-S(O)2OR11、-S(O)2N(R11)2、-OC(O)R11、-OC(O)OR11、-OC(O)N(R11)2、-N(R11)C(O)R11、-N(R11)C(O)OR11、-N(R11)C(O)N(R11)2取代,其中各R11独立为氢或C1-6烷基。
13.如权利要求12所述的化合物,其中
R3是其中键a为单键或双键;
m是0、1或2;
当键a是单键时,则(i)p是0或1且Z是–C(R36)2-或-C(=R32)-,(ii)p是1且Z是-N(R35)-,或(iii)p是0且Z是–O-;和
R35为氢、C1-6烷基、-C(O)R、-S(O)2R、-C(O)OR、-C(O)N(R)2、-S(O)2OR或–S(O)2N(R)2;
以及当键a是双键时,则p是1且Z为–C(R36)=,
其中各R36独立为氢或R31。
14.如权利要求13所述的化合物,其中键a是单键且Z为–C(R36)2-。
15.如权利要求13所述的化合物,其中键a是单键且Z为–N(R35)-或–O-。
16.如权利要求12-15任一项所述的化合物,其中n是0或1且R1是卤素。
17.如权利要求12-15任一项所述的化合物,其中n是1且R1是卤素。
18.如权利要求12-15任一项所述的化合物,其中n是0。
19.如权利要求12-15任一项所述的化合物,其中R2是–CH2-RA。
20.如权利要求12所述的化合物,其为2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-((反式)-4-羟基环己基)乙酮。
21.如权利要求12所述的化合物,其为1-环己基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酮。
22.如权利要求12所述的化合物,其为1-(4-(2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酰基)哌啶-1-基)-2-苯基乙酮。
23.一种化合物,其为2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(哌啶-4-基)乙醇。
24.根据权利要求20-23任一项所述的化合物的药学上可接受的盐。
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