CN112912382A - 经取代的吲哚二聚体化合物 - Google Patents
经取代的吲哚二聚体化合物 Download PDFInfo
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- CN112912382A CN112912382A CN201980070010.3A CN201980070010A CN112912382A CN 112912382 A CN112912382 A CN 112912382A CN 201980070010 A CN201980070010 A CN 201980070010A CN 112912382 A CN112912382 A CN 112912382A
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- C07D471/02—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 two hetero rings
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Abstract
公开了式(I)式(I)的化合物、其N‑氧化物或盐,其中G1、G2、L、R1a、R1b、R4、R5、n、m、x和y如本文所定义。还公开了使用此类化合物作为通过Toll样受体7或8或9的信号传导的抑制剂的方法,以及包含此类化合物的药物组合物。这些化合物可用于治疗炎性疾病和自身免疫性疾病。
Description
相关申请的交叉引用
本申请要求2018年10月24日提交的美国临时申请序列号62/749,924的权益,将所述临时申请以其整体并入本文。
说明
本发明总体上涉及经取代的吲哚二聚体化合物,其可用作通过Toll样受体7、8或9(TLR7、TLR8、TLR9)或其组合的信号传导的抑制剂。本文提供了经取代的吲哚二聚体化合物、包含此类化合物的组合物、以及它们的使用方法。本发明进一步涉及含有根据本发明的至少一种化合物的药物组合物,其可用于治疗与TLR调节相关的病症,诸如炎性疾病和自身免疫性疾病;以及抑制哺乳动物的TLR的活性的方法。
Toll/IL-1受体家族成员是炎症和宿主抗性的重要调节因子。Toll样受体家族识别源自传染性生物体(包括细菌、真菌、寄生生物和病毒)的分子模式(综述于Kawai,T.等人,Nature Immunol.,11:373-384(2010))。与受体结合的配体诱导衔接分子的二聚化和募集到被称为Toll/IL-1受体(TIR)的受体(TLR3除外)的结构域中的保守细胞质基序,所有TLR均募集衔接分子MyD88。IL-1受体家族还含有细胞质TIR基序并且在配体结合时募集MyD88(综述于Sims,J.E.等人,Nature Rev.Immunol.,10:89-102(2010))。
Toll样受体(TLR)是参与一线防御的进化上保守的跨膜天然免疫受体的家族。作为模式识别受体,TLR保护抵抗外来分子,由病原体相关分子模式(PAMP)激活,或保护免于受损组织,由危险相关分子模式(DAMP)激活。已经鉴定出总共13个TLR家族成员,其中10个在人类中,这些家族成员跨越细胞表面或内体区室。TLR7-9属于内体定位的并且响应单链RNA(TLR7和TLR8)或含有胞嘧啶-磷酸-鸟嘌呤(CpG)基序的未甲基化单链DNA(TLR9)的集合。
TLR7/8/9的激活可以引发多种炎症反应(细胞因子产生,B细胞激活和IgG产生,I型干扰素反应)。在自身免疫性障碍的情况下,TLR7/8/9的异常持续激活导致疾病状态的恶化。虽然已显示小鼠中TLR7的过表达会加剧自身免疫性疾病,但发现小鼠中TLR7的敲除在易患狼疮的MRL/lpr小鼠中保护抵抗疾病。TLR7和9的双重敲除显示出进一步增强的保护。
由于许多病症可以通过涉及调节细胞因子、IFN产生和B细胞活性的治疗而受益,因此立即显而易见的是,能够调节TLR7和/或TLR8和/或TLR9的新化合物以及使用这些化合物的方法可以为多种多样的患者提供实质性的治疗益处。
本发明涉及一类新的经取代的吲哚二聚体化合物,发现所述化合物是经由TLR7/8/9的信号传导的有效抑制剂。提供的这些化合物可用作药物,所述药物具有希望的稳定性、生物利用度、治疗指数和对其可药用性重要的毒性值。
发明内容
本发明提供了可用作经由Toll样受体7、8或9的信号传导的抑制剂并且可用于治疗增殖性疾病、过敏性疾病、自身免疫性疾病和炎性疾病的式(I)的化合物,或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。
本发明还提供了药物组合物,其包含药学上可接受的载体以及至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。
本发明还提供了一种用于抑制Toll样受体7、8或9的方法,其包括向需要此类治疗的宿主施用治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。
本发明还提供了一种用于治疗增殖性、代谢性、过敏性、自身免疫性和炎性疾病的方法,其包括向需要此类治疗的宿主施用治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。
本发明还提供了一种治疗与Toll样受体7、8或9活性相关的疾病或障碍的方法,所述方法包括向有需要的哺乳动物施用至少一种式(I)的化合物或其盐、溶剂化物和前药。
本发明还提供了用于制造式(I)的化合物(包括其盐、溶剂化物和前药)的方法和中间体。
本发明还提供了至少一种式(I)的化合物或其盐、溶剂化物和前药,其用于疗法。
本发明还提供了至少一种式(I)的化合物或其盐、溶剂化物和前药用于制造治疗或预防Toll样受体7、8或9相关病症(诸如过敏性疾病、自身免疫性疾病、炎性疾病和增殖性疾病)的药剂中的用途。
式(I)的化合物和包含式(I)的化合物的组合物可以用于治疗、预防或治愈各种Toll样受体7、8或9相关病症。包含这些化合物的药物组合物可用于治疗、预防多种治疗领域中的疾病或障碍(诸如过敏性疾病、自身免疫性疾病、炎性疾病和增殖性疾病)、或减缓其进展。
随着本公开文本的继续,本发明的这些和其他特征将以扩展的形式阐述。
具体实施方式
本发明的第一方面提供了至少一种式(I)的化合物:
其N-氧化物或盐,其中:
L是-(CH2)q-或-L1-NRxC(O)-(CH2)t-C(O)NRx-L2-;
L1和L2独立地是-(CH2)1-3-;
q是在10至30范围内的整数;
t是在2至24范围内的整数;
G1和G2独立地是:
(iv)选自以下的9元杂环:
(v)选自以下的10元杂环:
R1a和R1b独立地是H、Cl、-CN、C1-4烷基、C1-3氟烷基、C1-3羟基-氟烷基、C3-6环烷基、-CH2(C3-6环烷基)、-C(O)O(C1-3烷基)、或四氢吡喃基;
每个R2独立地是卤基、-CN、-OH、-NO2、C1-4烷基、C1-2氟烷基、C1-2氰基烷基、C1-3羟烷基、C1-3氨基烷基、-O(CH2)1-2OH、-(CH2)0-4O(C1-4烷基)、C1-3氟烷氧基、-(CH2)1-4O(C1-3烷基)、-O(CH2)1-2OC(O)(C1-3烷基)、-O(CH2)1-2NRxRx、-C(O)O(C1-3烷基)、-(CH2)0-2C(O)NRyRy、-C(O)NRx(C1-5羟烷基)、-C(O)NRx(C2-6烷氧基烷基)、-C(O)NRx(C3-6环烷基)、-NRyRy、-NRy(C1-3氟烷基)、-NRy(C1-4羟烷基)、-NRxCH2(苯基)、-NRxS(O)2(C3-6环烷基)、-NRxC(O)(C1-3烷基)、-NRxCH2(C3-6环烷基)、-(CH2)0-2S(O)2(C1-3烷基)、-(CH2)0-2(C3-6环烷基)、-(CH2)0-2(苯基)、吗啉基、二氧代硫代吗啉基、二甲基吡唑基、甲基哌啶基、甲基哌嗪基、氨基-噁二唑基、咪唑基、三唑基、或-C(O)(噻唑基);
R2a是C1-6烷基、C1-3氟烷基、C1-6羟烷基、C1-3氨基烷基、-(CH2)0-4O(C1-3烷基)、C3-6环烷基、-(CH2)1-3C(O)NRxRx、-CH2(C3-6环烷基)、-CH2(苯基)、四氢呋喃基、四氢吡喃基、或苯基;
每个R2b独立地是H、卤基、-CN、-NRxRx、C1-6烷基、C1-3氟烷基、C1-3羟烷基、C1-3氟烷氧基、-(CH2)0-2O(C1-3烷基)、-(CH2)0-3C(O)NRxRx、-(CH2)1-3(C3-6环烷基)、-C(O)O(C1-3烷基)、-C(O)NRx(C1-3烷基)、-CRx=CRxRx、或-CRx=CH(C3-6环烷基);
R2c是R2a或R2b;
R2d是R2a或R2b;条件是R2c和R2d之一是R2a并且R2c和R2中的另一个是R2b;
每个R4独立地是F、-OH、C1-2烷基、或-OCH3;或附接至同一个碳原子的两个R4形成=O;或其中当m或n是至少2时,各自附接至与哌啶基环中的氮原子相邻的不同碳原子的两个R4可以形成-CH2CH2-桥;
每个R5独立地是F、Cl、-CN、C1-3烷基、C1-2氟烷基、或-OCH3;
每个Rx独立地是H或-CH3;
每个Ry独立地是H或C1-6烷基;
m是0、1、2、3或4;
n是0、1、2、3或4;
每个p独立地是0、1、2、3或4;
x是0、1或2;并且
y是0、1或2。
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2独立地是并且L、R1a、R1b、R2a、R2b、R2c、R2d、R4、R5、m、n、x和y是在第一方面中定义的。此实施方案包括这样的化合物,其中R2a是C1-4烷基、C1-2氟烷基、C1-4羟烷基、-(CH2)1-3OCH3、C3-6环烷基、-CH2C(O)NRxRx、-CH2(C3-6环烷基)、-CH2(苯基)、四氢呋喃基、或苯基;并且每个R2b独立地是H、F、Cl、-CN、-NRxRx、C1-6烷基、C1-2氟烷基、C1-3羟烷基、-(CH2)0-2O(C1-2烷基)、-(CH2)0-2C(O)NRxRx、-(CH2)1-3(环丙基)、-C(O)O(C1-2烷基)、-C(O)NRx(C1-3烷基)、-CRx=CH2、或-CH=CH(C3-6环烷基)。此实施方案还包括这样的化合物,其中R2a是-CH3;并且每个R2b独立地是H、Cl、或-CH3。
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是选自以下的9元杂环:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是选自以下的10元杂环:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有两个氮杂原子的9元杂环,选自:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有两个氮杂原子并且被=O取代的9元杂环,选自:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有三个氮杂原子的9元杂环,选自:
并且L、R1a、R1b、R2、R4、R5、m、n、p、x和y是在第一方面中定义的。
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有三个氮杂原子并且被=O取代的9元杂环,选自:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有四个氮杂原子的9元杂环,选自:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有四个氮杂原子并且被=O取代的9元杂环,选自: 并且L、R1a、R1b、R2、R4、R5、m、n、p、x和y是在第一方面中定义的。
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有一个或两个氧杂原子并且任选地被=O取代的9元杂环,选自:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有一个或两个氮杂原子和一个氧杂原子并且任选地被=O取代的9元杂环,选自:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有一个或两个氮杂原子和一个硫杂原子的9元杂环,选自:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有两个氮杂原子和一个氧杂原子并且被=O取代的9元杂环,选自:并且L、R1a、R1b、R2、R4、R5、m、n、p、x和y是在第一方面中定义的。
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有一个氮杂原子的10元杂环,选自:
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自独立地是具有一个或两个氮杂原子和一个氧杂原子并且任选地被=O取代的10元杂环,选自:
一个实施方案提供了一种式(I)的化合物、其N-氧化物或盐,其中G1和G2各自独立地是:
(iv)并且L、R1a、R1b、R2a、R2b、R2、R4、R5、m、n、p、x和y是在第一方面中定义的。此实施方案包括这样的化合物,其中R1a和R1b独立地是-CH2CH3或-CH(CH3)2;每个R2独立地是-CH3或-OCH3;每个R2a是-CH3;每个R2b独立地是H、Cl、或-CH3;每个R4独立地是F、-CH3、或-OCH3;并且每个R5独立地是F、Cl、-CN、-CH3、-CF3、或-OCH3。
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自是并且L、R1a、R1b、R2、R4、R5、m、n、p、x和y是在第一方面中定义的。此实施方案包括这样的化合物,其中每个R2独立地是-CH3或-OCH3。此实施方案还包括这样的化合物,其中每个R2是-OCH3。
一个实施方案提供了一种式(I)的化合物或其盐,其中G1和G2各自是并且L、R1a、R1b、R4、R5、m、n、x和y是在第一方面中定义的。此实施方案包括这样的化合物,其中R1a和R1b独立地是H、Cl、-CN、C1-4烷基、或C1-2氟烷基。此实施方案还包括这样的化合物,其中R1a和R1b独立地是-CH2CH3或-CH(CH3)2。
一个实施方案提供了一种式(I)的化合物、其N-氧化物或盐,其中:L是-(CH2)q-或-L1-NRxC(O)-(CH2)t-C(O)NRx-L2-;q是在8至26范围内的整数;t是在2至16范围内的整数;并且G1、G2、L1、L2、R1a、R1b、R1b、R2a、R2b、R2c、R2d、R4、R5、Rx、m、n、x、p和y是在第一方面中定义的。此实施方案包括这样的化合物,其中q是在从10至24范围内的整数;并且t是在2至16范围内的整数。此实施方案还包括这样的化合物,其中q是在从16至20范围内的整数;并且t是在2至12范围内的整数。另外,此实施方案包括这样的化合物,其中q是16、17或18;并且t是在2至12范围内的整数。
一个实施方案提供了一种式(I)的化合物、其N-氧化物或盐,其中:L是-(CH2)q-;q是在8至26范围内的整数;并且G1、G2、R1a、R1b、R1b、R2a、R2b、R2c、R2d、R4、R5、m、n、x和y是在第一方面中定义的。此实施方案包括这样的化合物,其中q是在10至24范围内的整数。还包括其中q是在16至20范围内的整数的化合物。另外,此实施方案包括这样的化合物,其中q是16、17或18。
一个实施方案提供了一种式(I)的化合物、其N-氧化物或盐,其中:L是-L1-NRxC(O)-(CH2)t-C(O)NRx-L2-;t是在2至16范围内的整数;并且G1、G2、L1、L2、R1a、R1b、R2a、R2b、R2c、R2d、R4、R5、Rx、m、n、p、x和y是在第一方面中定义的。此实施方案包括这样的化合物,其中t是在2至16范围内的整数。此实施方案还包括这样的化合物,其中t是在2至12围内的整数。另外,此实施方案包括这样的化合物,其中t是在2至12范围内的整数;并且L1和L2各自是-(CH2)2-。
一个实施方案提供了一种式(I)的化合物、其N-氧化物或盐,其中:R1a和R1b独立地是H、Cl、-CN、C1-4烷基、C1-3氟烷基、C1-3羟基-氟烷基、C3-6环烷基、-CH2(C3-6环烷基)、-C(O)O(C1-3烷基)、或四氢吡喃基;每个R2独立地是卤基、-CN、-OH、-NO2、C1-3烷基、C1-2氟烷基、C1-3羟烷基、C1-3氨基烷基、-(CH2)0-4O(C1-3烷基)、C1-3氟烷氧基、C2-4烷氧基烷氧基、-O(CH2)1- 2NRxRx、-C(O)O(C1-3烷基)、-C(O)NRyRy、-NRyRy、-NRxC(O)(C1-3烷基)、-NRx(CH2-环丙基)、C3-6环烷基、甲基哌啶基、甲基哌嗪基、氨基-噁二唑基、咪唑基、三唑基、或-C(O)(噻唑基);每个R4独立地是F、-OH、C1-2烷基、或-OCH3;或附接至同一个碳原子的两个R4形成=O;每个R5独立地是F、Cl、-CN、C1-2烷基、C1-2氟烷基、或-OCH3;并且G1、G2、L、R2a、R2b、R2c、R2d、Rx、Ry、m、n、p、x和y是在第一方面中定义的。此实施方案包括这样的化合物,其中m是0、1或2;n是0、1或2;p是0、1或2;x是0或1;并且y是0或1。
一个实施方案提供了一种式(I)的化合物、其N-氧化物或盐,其中:R1a和R1b独立地是H、Cl、-CN、C1-4烷基、或C1-2氟烷基;每个R2独立地是F、Cl、-CN、-OH、C1-3烷基、C1-2氟烷基、C1-2氰基烷基、C1-3羟烷基、C1-3氨基烷基、-O(CH2)1-2OH、-O(C1-4烷基)、C1-2氟烷氧基、-(CH2)1- 4O(C1-3烷基)、-O(CH2)1-2OC(O)(C1-3烷基)、-O(CH2)1-2NRxRx、-C(O)O(C1-3烷基)、-C(O)NRyRy、-NRyRy、-NRy(C1-3氟烷基)、-NRy(C1-4羟烷基)、-NRxCH2(苯基)、-NRxS(O)2(C3-6环烷基)、-NRxC(O)(C1-3烷基)、-NRx(CH2-环丙基)、C3-6环烷基、吗啉基、二氧代硫代吗啉基、甲基哌啶基、甲基哌嗪基、氨基-噁二唑基、咪唑基、三唑基、或-C(O)(噻唑基);R5是F、Cl、-CN、C1-2烷基、或-OCH3;m是0;n是0;并且G1、G2、L、R2b、R2c、R2d、R4、Rx、Ry、x和y是在第一方面中定义的。
一个实施方案提供了一种式(I)的化合物、其N-氧化物或盐,其中m是0、1或2;n是0、1或2;并且G1、G2、L、R1b、R2a、R2b、R2c、R2d、R4、R5、Rx、Ry、x和y是在第一方面中定义的。
一个实施方案提供了一种式(I)的化合物、其N-氧化物或盐,其中:G1和G2各自是R1a和R1b各自是-CH(CH3)2;每个R2是-OCH3;L是-(CH2)18-或-L1-NRxC(O)-(CH2)t-C(O)NRx-L2-;L1和L2各自是-(CH2)2-;t是在2至12范围内的整数;m是0;n是0;每个p是1;x是0;并且y是0。此实施方案包括这样的化合物,其中G1和G2各自是
一个实施方案提供了一种式(I)的化合物或其盐,其中所述化合物是:
N1,N13-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十三烷二酰胺(1);
N1,N14-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十四烷二酰胺(2);
N1,N12-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十二烷二酰胺(3);
N1,N11-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十一烷二酰胺(4);
N1,N9-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)壬烷二酰胺(5);
N1,N8-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)辛烷二酰胺(6);
N1,N10-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)癸烷二酰胺(7);
N1,N7-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)庚烷二酰胺(8);
N1,N6-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)己二酰二胺(9);
N1,N12-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十二烷二酰胺(10);
N1,N4-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)琥珀酰胺(11);或
1,18-双(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)十八烷(12)。
本发明可以在不脱离其精神或本质属性的情况下以其他特定形式实施。本发明涵盖本文所述的本发明的方面和/或实施方案的所有组合。应当理解,本发明的任何和所有实施方案可以与任何一个或多个其他实施方案结合来描述另外的实施方案。还应理解,所述实施方案中的每个单独要素意在与来自任何实施方案中的任何和所有其他要素组合来描述另外的实施方案。
定义
在阅读下面详细描述时,本领域普通技术人员可以更容易地理解本发明的特征和优点。应当理解,出于清楚的原因,在单独的实施方案的上下文中所述的本发明的某些特征也可以组合以形成单个实施方案。相反,出于简洁的原因,在单个实施方案的上下文中所述的本发明的各种特征也可以被组合以形成其子组合。本文中确定为示例性或优选的实施方案旨在是说明性的而非限制性的。
除非本文另有明确说明,否则以单数形式作出的引用也可以包括复数形式。例如,“一个”和“一种”可以指代一个/一种、或者一个/一种或多个/多种。
如本文所用,短语“化合物”是指至少一种化合物。例如,式(I)的化合物包括一种式(I)的化合物以及两种或更多种式(I)的化合物。
除非另有指示,否则具有不饱和化合价的任何杂原子被假定为具有足以满足所述化合价的氢原子。
本文阐述的定义优先于通过引用并入本文的任何专利、专利申请和/或专利申请出版物中阐述的定义。
下文列出了用于描述本发明的各种术语的定义。这些定义适用于在整个说明书中单独使用或者作为较大基团的一部分使用时的术语(除非它们在特定情况下另有限制)。
在整个说明书中,本领域技术人员可以选择基团及其取代基以提供稳定的部分和化合物。
根据本领域中使用的惯例,在本文的结构式中使用
用于本文的结构式中以描绘作为部分或取代基的与核心或骨架结构附接的点的键。
如本文所用的术语“卤基”和“卤素”是指F、Cl、Br和I。
术语“氰基”是指基团-CN。
术语“氨基”是指基团-NH2。
术语“氧代基”是指基团=O。
如本文所用的术语“烷基”是指含有例如从1至12个碳原子、从1至6个碳原子和从1至4个碳原子的支链和直链饱和脂族烃基两者。烷基的例子包括但不限于甲基(Me)、乙基(Et)、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、异丁基、仲丁基、和叔丁基)、和戊基(例如,正戊基、异戊基、新戊基)、正己基、2-甲基戊基、2-乙基丁基、3-甲基戊基、和4-甲基戊基。当数字出现在符号“C”之后的下标中时,所述下标更具体地定义了特定基团可能含有的碳原子的数目。例如,“C1-6烷基”表示具有1至6个碳原子的直链和支链烷基。
如本文所用的术语“氟烷基”旨在包括被一个或多个氟原子取代的支链和直链饱和脂族烃基两者。例如,“C1-4氟烷基”旨在包括被一个或多个氟原子取代的C1、C2、C3、和C4烷基。氟烷基的代表性例子包括但不限于-CF3和-CH2CF3。
术语“氰基烷基”包括被一个或多个氰基取代的支链和直链饱和烷基两者。例如,“氰基烷基”包括-CH2CN、-CH2CH2CN、和C1-4氰基烷基。
术语“氨基烷基”包括被一个或多个胺基团取代的支链和直链饱和烷基两者。例如,“氨基烷基”包括-CH2NH2、-CH2CH2NH2、和C1-4氨基烷基。
术语“羟烷基”包括被一个或多个羟基取代的支链和直链饱和烷基两者。例如,“羟烷基”包括-CH2OH、-CH2CH2OH、和C1-4羟烷基。
术语“羟基-氟烷基”包括被一个或多个羟基和一个或多个氟原子取代的支链和直链饱和烷基两者。例如,“羟基-氟烷基”包括-CHFCH2OH、-CH2CHFC(CH3)2OH、和C1-4羟基-氟烷基。
如本文所用的术语“环烷基”是指通过从饱和环碳原子上除去一个氢原子而衍生自非芳族单环或多环烃分子的基团。环烷基的代表性例子包括但不限于环丙基、环戊基和环己基。当数字出现在符号“C”之后的下标中时,下标更具体地定义了特定环烷基可能包含的碳原子的数目。例如,“C3-C6环烷基”表示具有3至6个碳原子的环烷基。
如本文所用的术语“烷氧基”是指通过氧原子与母体分子部分附接的烷基,例如甲氧基(-OCH3)。例如,“C1-3烷氧基”表示具有1至3个碳原子的烷氧基。
如本文所用的术语“烷氧基烷基”是指经由其氧原子与烷基附接的烷氧基,所述烷基与母体分子部分附接,例如甲氧基甲基(-CH2OCH3)。例如,“C2-4烷氧基烷基”表示具有2至4个碳原子的烷氧基烷基,诸如-CH2OCH3、-CH2CH2OCH3、-CH2OCH2CH3和-CH2CH2OCH2CH3。
短语“药学上可接受的”在本文中用于指在合理的医学判断范围内,适合用于与人类或动物的组织接触,而不产生过多毒性、刺激、过敏反应或者其他问题或并发症,与合理的效益/风险比相称的那些化合物、材料、组合物和/或剂型。
式(I)的化合物可以提供呈无定形固体或结晶固体。可以使用冻干来提供呈无定形固体的式(I)的化合物。
还应当理解,式(I)的化合物的溶剂化物(例如,水合物)也在本发明的范围内。术语“溶剂化物”意指式(I)的化合物与一个或多个溶剂分子(无论是有机的还是无机的)的物理缔合物。这种物理缔合物包括氢键。在某些情况下,溶剂化物将能够分离,例如当一个或多个溶剂分子掺入结晶固体的晶格中时。“溶剂化物”涵盖溶液相和可分离溶剂化物两者。示例性溶剂化物包括水合物、乙醇化物、甲醇化物、异丙醇化物、乙腈溶剂化物和乙酸乙酯溶剂化物。溶剂化方法是本领域已知的。
各种形式的前药是本领域熟知的,并且描述于:
a)The Practice of Medicinal Chemistry,Camille G.Wermuth等人,Ch 31,(Academic Press,1996);
b)Design of Prodrugs,由H.Bundgaard编辑(Elsevier,1985);
c)A Textbook of Drug Design and Development,P.Krogsgaard–Larson和H.Bundgaard编辑Ch 5,第113-191页(Harwood Academic Publishers,1991);和
d)Hydrolysis in Drug and Prodrug Metabolism,Bernard Testa和JoachimM.Mayer,(Wiley-VCH,2003)。
前药的制备是本领域熟知的,并且描述于例如,King,F.D.编辑,MedicinalChemistry:Principles and Practice,The Royal Society of Chemistry,剑桥,英国(1994);Testa,B.等人,Hydrolysis in Drug and Prodrug Metabolism.Chemistry,Biochemistry and Enzymology,VCHA和Wiley-VCH,苏黎世,瑞士(2003);Wermuth,C.G.编辑,The Practice of Medicinal Chemistry,Academic Press,圣地亚哥,加利福尼亚州(1999);Rautio,J.等人,Nature Review Drug Discovery,17,559-587,(2018)。
此外,可以在式(I)的化合物制备之后将其分离并且纯化以获得含有按重量计等于或大于99%的量的式(I)的化合物(“基本上纯的”)的组合物,然后如本文所述使用或配制所述组合物。此类“基本上纯的”式(I)的化合物在本文中也被考虑作为是本发明的一部分。
“稳定的化合物”和“稳定的结构”意在指示化合物足够稳健以经受住从反应混合物中分离至有用程度的纯度并且配制成有效的治疗剂。本发明旨在实施稳定的化合物。
“治疗有效量”旨在包括单独的本发明化合物的量、或所要求保护的化合物的组合的量、或本发明化合物与其他活性成分的组合的量,它们有效充当TLR7/8/9抑制剂或有效治疗或预防自身免疫性疾病状态和/或炎性疾病状态,诸如SLE、IBD、多发性硬化(MS)和肖格伦综合征和类风湿性关节炎。
如本文所用的,“治疗(treating或treatment)”涵盖哺乳动物(特别是人)的疾病状态的治疗,并且包括:(a)防止所述疾病状态在哺乳动物中发生,特别是当这种哺乳动物易患所述疾病状态,但尚未被诊断为患有所述疾病状态时;(b)抑制所述疾病状态,即阻止其发展;和/或(c)缓解所述疾病状态,即引起所述疾病状态的消退。
本发明的化合物旨在包括在本发明化合物中存在的原子的所有同位素。同位素包括那些原子数相同但质量数不同的原子。通过一般举例而非限制的方式,氢的同位素包括氘(D)和氚(T)。碳的同位素包括13C和14C。本发明的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与本文所述那些类似的方法,使用适当的同位素标记的试剂代替原本采用的未经标记的试剂来制备。例如,甲基(-CH3)还包括氘代甲基,诸如-CD3。
效用
人类免疫系统已经进化为保卫身体免受可能导致感染、疾病或死亡的微生物、病毒和寄生生物的侵害。复杂的调节机制确保免疫系统的各种细胞组分靶向外来物质或生物体,同时不对个体造成永久性或显著损害。虽然此时尚未充分理解起始事件,但在自身免疫性疾病状态中,免疫系统将针对受折磨的个体的靶器官指导其炎症反应。不同的自身免疫性疾病的特征典型地在于受影响的主要或初始靶器官或组织;诸如在类风湿性关节炎的情况下的关节、在桥本氏甲状腺炎的情况下的甲状腺、在多发性硬化的情况下的中枢神经系统、在I型糖尿病的情况下的胰腺、和在炎症性肠病的情况下的肠。
本发明化合物抑制经由Toll样受体7或8或9(TLR7、TLR8、TLR9)或其组合的信号传导。因此,式(I)的化合物具有治疗与经由TLR7、TLR8或TLR9中的一种或多种的信号传导的抑制相关的病症的效用。此类病症包括TLR7、TLR8、或TLR9受体相关疾病,其中细胞因子水平因细胞内信号传导而被调节。
如本文所用,术语“治疗”(“treating”或“treatment”)涵盖对哺乳动物、特别是人类中的疾病状态的治疗,并且包括:(a)预防或延迟哺乳动物中疾病状态的发生,特别是当此类哺乳动物易患所述疾病状态但尚未被诊断为患有所述疾病状态时;(b)抑制疾病状态,即,阻止其发展;和/或(c)实现症状或疾病状态的完全或部分减少和/或缓解、改善、减轻或治愈所述疾病或障碍和/或其症状。
鉴于它们作为TLR7、TLR8或TLR9的选择性抑制剂的活性,式(I)的化合物可用于治疗TLR7、TLR8或TLR9家族受体相关疾病,但不限于炎性疾病,诸如克罗恩病、溃疡性结肠炎、哮喘、移植物抗宿主病、同种异体移植排斥、慢性阻塞性肺病;自身免疫性疾病,诸如格雷夫斯病、类风湿性关节炎、系统性红斑狼疮、狼疮性肾炎、皮肤狼疮、银屑病;自身炎性疾病,包括冷吡啉蛋白相关周期性综合征(CAPS)、TNF受体相关周期性综合征(TRAPS)、家族性地中海热(FMF)、成人发作性斯蒂尔氏病、全身发作性幼年特发性关节炎、痛风、痛风性关节炎;代谢性疾病,包括2型糖尿病、动脉粥样硬化、心肌梗塞;破坏性骨障碍,诸如,诸如骨吸收疾病、骨关节炎、骨质疏松症、多发性骨髓瘤相关骨障碍;增殖性障碍,诸如急性骨髓性白血病、慢性骨髓性白血病;血管生成障碍,诸如血管生成障碍,包括实体瘤、眼部新生血管、和婴儿血管瘤;传染性疾病,诸如败血症、败血性休克和志贺氏菌病;神经变性疾病,诸如阿尔茨海默病、帕金森病、脑缺血或由创伤性损伤引起的神经变性疾病;肿瘤疾病和病毒性疾病,分别诸如转移性黑色素瘤、卡波济氏肉瘤、多发性骨髓瘤以及HIV感染和CMV视网膜炎、AIDS。
更具体地,可以用本发明化合物治疗的具体病症或疾病包括但不限于胰腺炎(急性或慢性)、哮喘、过敏症、成人呼吸窘迫综合征、慢性阻塞性肺病、肾小球性肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性嗜中性粒细胞减少症、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化、炎性肠病、溃疡性结肠炎、克罗恩病、银屑病、移植物抗宿主病、由内毒素诱导的炎症反应、结核、动脉粥样硬化、肌肉变性、恶病质、银屑病性关节炎、莱特尔综合征、痛风、创伤性关节炎、风疹性关节炎、急性滑膜炎、胰腺β细胞疾病;以大量嗜中性白细胞浸润为特征的疾病;类风湿性脊柱炎、痛风性关节炎和其他关节炎性病症、脑型疟疾、慢性肺部炎性疾病、矽肺、肺结节病、骨吸收疾病、同种异体移植物排斥、由于感染所致的发热和肌痛、继发于感染的恶病质、瘢痕疙瘩形成、瘢痕组织形成、溃疡性结肠炎、热病、流感、骨质疏松症、骨关节炎、急性骨髓性白血病、慢性骨髓性白血病、转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤、败血症、败血性休克和志贺氏菌病;阿尔茨海默病、帕金森病、脑缺血或由创伤性损伤引起的神经变性疾病;血管生成障碍,包括实体瘤、眼部新生血管和婴儿血管瘤;病毒性疾病,包括急性肝炎感染(包括甲型肝炎、乙型肝炎和丙型肝炎)、HIV感染和CMV视网膜炎、AIDS、ARC或恶性病和疱疹;中风、心肌缺血、中风心脏病发作中的缺血、器官缺氧、血管增生、心肌和肾脏再灌注损伤、血栓形成、心肌肥大、凝血酶诱导的血小板聚集、内毒素血症和/或中毒性休克综合征、与前列腺素内过氧化酶合酶-2相关的病症、和寻常型天疱疮。此实施方案中包括其中病症选自以下的治疗方法:狼疮,包括狼疮性肾炎和系统性红斑狼疮(SLE)、克罗恩病、溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、银屑病、强直性脊柱炎、银屑病性关节炎、和寻常型天疱疮。还包括其中病症选自以下的治疗方法:缺血再灌注损伤,包括由中风引起的脑缺血再灌注损伤和由心肌梗塞引起的心肌缺血再灌注损伤。另一种治疗方法是其中病症是多发性骨髓瘤的方法。
在一个实施方案中,式(I)的化合物可用于治疗癌症,包括瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom’s Macroglobulinemia,WM)、弥漫性大B细胞淋巴瘤(DLBCL)、慢性淋巴细胞白血病(CLL)、皮肤弥漫性大B细胞淋巴瘤、和原发性CNS淋巴瘤。
另外,本发明的TLR7、TLR8或TLR9抑制剂会抑制诱导型促炎蛋白的表达,所述诱导型促炎蛋白诸如前列腺素内过氧化物合酶-2(PGHS-2)(也称为环氧合酶-2(COX-2))、IL-1、IL-6、IL-18、趋化因子。因此,另外的TLR7/8/9相关病症包括水肿、镇痛、发热和疼痛(诸如神经肌肉疼痛、头痛、由癌症引起的疼痛、牙痛和关节炎疼痛)。本发明化合物还可以用于治疗兽医病毒感染,诸如慢病毒感染,包括但不限于马传染性贫血病毒;或逆转录病毒感染,包括猫免疫缺陷病毒、牛免疫缺陷病毒和犬免疫缺陷病毒。
因此,本发明提供了用于治疗此类病症的方法,其包括向有需要的受试者施用治疗有效量的至少一种式(I)的化合物或其盐。“治疗有效量”旨在包括当单独或组合施用时有效抑制自身免疫性疾病或慢性炎性疾病的本发明化合物的量。
治疗TLR7、TLR8或TLR9相关病症的方法可以包括单独或彼此组合和/或与可用于治疗此类病症的其他合适治疗剂组合施用式(I)的化合物。因此,“治疗有效量”还旨在包括有效抑制TLR7、TLR8或TLR9和/或治疗与TLR7、TLR8或TLR9相关的疾病的所要求保护的化合物的组合的量。
此类其他治疗剂的例子包括皮质类固醇、咯利普兰、卡弗他丁、细胞因子抑制性消炎药(CSAID)、白介素-10、糖皮质激素、水杨酸盐、一氧化氮和其他免疫抑制剂;核转位抑制剂,诸如脱氧精胍菌素(DSG);非类固醇消炎药(NSAID),诸如布洛芬、塞来昔布和罗非昔布;类固醇,诸如泼尼松或地塞米松;抗病毒剂,诸如阿巴卡韦;抗增殖剂,诸如甲氨蝶呤、来氟米特、FK506(他克莫司,);抗疟疾药,诸如羟氯喹;细胞毒性药物,诸如硫唑嘌呤和环磷酰胺;TNF-α抑制剂,诸如替尼达普、抗TNF抗体或可溶性TNF受体、和雷帕霉素(西罗莫司或)或其衍生物。
以上其他治疗剂在与本发明的化合物组合使用时可以例如以医师案头参考(Physicians’Desk Reference,PDR)中所指示或者如本领域普通技术人员以其他方式确定的那些量来使用。在本发明的方法中,此类一种或多种其他治疗剂可以在施用本发明的化合物之前、同时或之后施用。本发明还提供了能够治疗TLR7/8/9受体相关病症的药物组合物,所述病症包括如上所述的IL-1家族受体介导的疾病。
本发明的组合物可以含有如上所述的其他治疗剂,并且可以例如通过采用常规的固体或液体媒介物或稀释剂以及适于所希望的施用方式的类型的药物添加剂(例如,赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)根据诸如药物配制领域熟知的那些的技术来配制。
因此,本发明进一步包括含有一种或多种式(I)的化合物和药学上可接受的载体的组合物。
“药学上可接受的载体”是指本领域通常接受用于将生物活性剂递送至动物、特别是哺乳动物的介质。药学上可接受的载体是根据本领域普通技术人员认知范围内的许多因素来配制。它们包括但不限于所配制的活性剂的类型和性质;待施用含有所述药剂的组合物的受试者;所述组合物的预期施用途径;以及目标治疗适应症。药学上可接受的载体包括水性和非水性液体介质两者,以及多种固体和半固体剂型。此类载体还可以包括除活性剂之外的许多不同的成分和添加剂,此类另外的成分出于本领域普通技术人员熟知的多种原因(例如,活性剂、粘结剂等的稳定化)被包含在配制品中。合适的药学上可接受的载体及其选择中涉及的因素的描述在多种可容易获得的来源(例如像Remington's PharmaceuticalSciences,第17版(1985))中找到,将其通过方式以其整体并入本文。
根据式(I)的化合物可以通过适合于待治疗病症的任何方式施用,这可以取决于对部位特异性治疗的需要或待递送的式(I)化合物的量。
本发明中还包括一类药物组合物,其包含式(I)的化合物和一种或多种无毒的药学上可接受的载体和/或稀释剂和/或佐剂(在本文中统称为“载体”材料)以及(如果希望)其他活性成分。式(I)的化合物可以通过任何合适的途径、优选以适于此类途径的药物组合物的形式,并且以对于预期治疗有效的剂量施用。本发明的化合物和组合物可以例如在含有常规药学上可接受的载体、佐剂和媒介物的剂量单位配制品中口服、粘膜、或非肠道(包括血管内、静脉内、腹膜内、皮下、肌内、和胸骨内)施用。例如,药物载体可以含有甘露醇或乳糖和微晶纤维素的混合物。所述混合物可以含有另外的组分,诸如润滑剂(例如,硬脂酸镁)和崩解剂(诸如交聚维酮)。载体混合物可以填充到明胶胶囊中或压缩成片剂。例如,药物组合物可以作为口服剂型或输注剂施用。
对于口服施用,所述药物组合物可以呈例如片剂、胶囊、液体胶囊、悬浮液或液体的形式。所述药物组合物优选地以含有特定量活性成分的剂量单位的形式制造。例如,所述药物组合物可以提供呈片剂或胶囊剂,其包含在从约0.1至1000mg、优选从约0.25至250mg并且更优选从约0.5至100mg范围内的量的活性成分。对于人或其他哺乳动物的合适日剂量可以根据患者的状况和其他因素而广泛地变化,但是可以使用常规方法确定。
本文中考虑的任何药物组合物可以例如经由任何可接受且合适的口服制剂口服递送。示例性的口服制剂包括但不限于例如片剂、锭剂、糖锭剂、水性和油性悬浮液、可分散粉末或颗粒、乳液、硬和软胶囊、液体胶囊、糖浆和酏剂。旨在用于口服施用的药物组合物可以根据本领域已知用于制造旨在用于口服施用的药物组合物的任何方法来制备。为了提供药学上可口的制剂,根据本发明的药物组合物可以含有至少一种选自甜味剂、调味剂、着色剂、缓和剂、抗氧化剂、和防腐剂的试剂。
片剂可以例如通过将至少一种式(I)的化合物与适合于制造片剂的至少一种无毒的药学上可接受的赋形剂混合来制备。示例性的赋形剂包括但不限于例如惰性稀释剂,例如像碳酸钙、碳酸钠、乳糖、磷酸钙和磷酸钠;制粒剂和崩解剂,例如像微晶纤维素、交联羧甲基纤维素钠、玉米淀粉和海藻酸;粘合剂,例如像淀粉、明胶、聚乙烯吡咯烷酮和阿拉伯胶;以及润滑剂,例如像硬脂酸镁、硬脂酸和滑石。另外,片剂可以是未包衣的,或通过已知技术包衣以掩蔽令人不快的味道的药物的不良味道或延迟胃肠道中活性成分的崩解和吸收从而维持所述活性成分的作用持续较长时间段的。示例性的水溶性味道掩蔽材料包括但不限于羟丙基甲基纤维素和羟丙基纤维素。示例性的延时材料包括但不限于乙基纤维素和乙酸丁酸纤维素。
硬明胶胶囊可以例如通过将至少一种式(I)的化合物与至少一种惰性固体稀释剂(例如像碳酸钙、磷酸钙和高岭土)混合来制备。
软明胶胶囊可以例如通过将至少一种式(I)的化合物与至少一种水溶性载体(例如像聚乙二醇)和至少一种油介质(例如像花生油、液体石蜡和橄榄油)混合来制备。
水性悬浮液可以例如通过将至少一种式(I)的化合物与适合于生产水性悬浮液的至少一种赋形剂混合来制备。适合于制造水性悬浮液的示例性赋形剂包括但不限于例如悬浮剂,例如像羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、海藻酸、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂,例如像天然存在的磷脂,例如卵磷脂;环氧烷与脂肪酸的缩合产物,例如像聚氧乙烯硬脂酸酯;环氧乙烷与长链脂族醇的缩合产物,例如像十七烷乙烯-氧基鲸蜡醇;环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,例如像聚氧乙烯山梨糖醇单油酸酯;以及环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物,例如像聚乙烯脱水山梨糖醇单油酸酯。水性悬浮液还可以含有至少一种防腐剂,例如像对羟基苯甲酸乙酯和对羟基苯甲酸正丙酯;至少一种着色剂;至少一种调味剂;和/或至少一种甜味剂,包括但不限于例如蔗糖、糖精和阿斯巴甜。
油性悬浮液可以例如通过将至少一种式(I)的化合物悬浮在植物油(例如像花生油、橄榄油、芝麻油和椰子油)或者悬浮在矿物油(例如像液体石蜡)中来制备。油性悬浮液还可以含有至少一种增稠剂,例如像蜂蜡、硬石蜡和鲸蜡醇。为了提供可口的油性悬浮液,可以将以上已经描述的至少一种甜味剂和/或至少一种调味剂添加到油性悬浮液中。油性悬浮液可以进一步含有至少一种防腐剂,包括但不限于例如抗氧化剂,例如像丁基化羟基茴香醚和α-生育酚。
可分散粉末和颗粒可以例如通过将至少一种式(I)的化合物与至少一种分散剂和/或润湿剂、至少一种悬浮剂和/或至少一种防腐剂混合来制备。合适的分散剂、润湿剂和悬浮剂已如上文所述。示例性的防腐剂包括但不限于例如抗氧化剂,例如抗坏血酸。此外,可分散粉末和颗粒还可以含有至少一种赋形剂,包括但不限于例如甜味剂、调味剂和着色剂。
至少一种式(I)的化合物的乳液可以例如制备呈水包油乳液。包含式(I)的化合物的乳剂的油相可以以已知方式由已知成分构成。油相可以通过但不限于例如植物油(例如像橄榄油和花生油)、矿物油(例如像液体石蜡)及其混合物来提供。虽然所述相可以仅包含乳化剂,但是它可以包含至少一种乳化剂与脂肪或油或与脂肪和油两者的混合物。合适的乳化剂包括但不限于例如天然存在的磷脂,例如大豆卵磷脂;衍生自脂肪酸和己糖醇酐的酯或偏酯,例如像脱水山梨糖醇单油酸酯;以及偏酯与环氧乙烷的缩合产物,例如像聚氧乙烯脱水山梨糖醇单油酸酯。优选地,亲水性乳化剂与亲脂性乳化剂一起被包括,所述亲脂性乳化剂充当稳定剂。还优选的是包含油和脂肪两者。一种或多种乳化剂与或不与一种或多种稳定剂一起构成所谓的乳化蜡,并且蜡与油和脂肪一起构成所谓的乳化软膏基质,其形成乳膏配制品的油性分散相。乳液还可以含有甜味剂、调味剂、防腐剂和/或抗氧化剂。适用于本发明配制品的乳化剂和乳液稳定剂包括Tween 60、Span 80、鲸蜡硬脂醇、肉豆蔻醇、单硬脂酸甘油酯、十二烷基硫酸钠、单独或与蜡一起的二硬脂酸甘油酯、或本领域熟知的其他材料。
式(I)的化合物还可以例如通过任何药学上可接受的且合适的可注射形式静脉内、皮下和/或肌内递送。示例性的可注射形式包括但不限于例如无菌水溶液,其包含可接受的媒介物和溶剂,例如像水、林格氏溶液和等渗氯化钠溶液;无菌水包油微乳液;以及水性或油性悬浮液。
用于肠胃外施用的配制品可以呈水性或非水性等渗无菌注射溶液或悬浮液的形式。这些溶液和悬浮液可以使用提及用于在供口服施用的配制品中使用的一种或多种载体或稀释剂或者通过使用其他合适的分散剂或润湿剂和悬浮剂由无菌粉末或颗粒制备。可以将化合物溶解在水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苯甲醇、氯化钠、黄蓍胶和/或各种缓冲剂中。其他佐剂和施用方式是制药领域中熟知且众所周知的。活性成分也可以通过作为与合适的载体(包括盐水、右旋糖或水)或与环糊精(即Captisol)、共溶剂增溶(即丙二醇)或胶束增溶(即Tween 80)的组合物注射来施用。
无菌可注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为在1,3-丁二醇中的溶液。可以使用的可接受的媒介物和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,常规地将无菌的固定油用作溶剂或悬浮介质。为此目的,可以采用任何温和的非挥发性油,包括合成的单甘油酯或二甘油酯。此外,脂肪酸(诸如油酸)可用于制备注射剂。
无菌可注射的水包油微乳液可以例如通过以下方式制备:1)将至少一种式(I)的化合物溶解在油相(例如像大豆油和卵磷脂的混合物)中;2)将含有式(I)的油相与水和甘油混合物组合;以及3)处理所述组合以形成微乳液。
可以根据本领域已知的方法制备无菌水性或油性悬浮液。例如,可以用无毒的肠胃外可接受的稀释剂或溶剂(例如像1,3-丁二醇)制备无菌水溶液或悬浮液;并且可以用无菌无毒可接受溶剂或悬浮介质(例如像无菌固定油,例如合成的甘油单酯或甘油二酯;和脂肪酸,例如像油酸)制备无菌油性悬浮液。
可用于本发明的药物组合物的药学上可接受的载体、佐剂和媒介物包括但不限于离子交换剂,氧化铝,硬脂酸铝,卵磷脂,自乳化药物递送系统(SEDDS)(诸如d-α-生育酚聚乙二醇1000琥珀酸酯),用于药物剂型的表面活性剂(诸如Tween),聚乙氧基化蓖麻油(诸如CREMOPHOR表面活性剂(BASF)),或其他类似的聚合物递送基质,血清蛋白(诸如人血清白蛋白),缓冲物质(诸如磷酸盐),甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的偏甘油酯混合物,水、盐或电解质(诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐),胶体二氧化硅,三硅酸镁,聚乙烯吡咯烷酮,基于纤维素的物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜡,聚乙烯-聚氧丙烯嵌段聚合物,聚乙二醇和羊毛脂。诸如α-、β-和γ-环糊精的环糊精或诸如羟烷基环糊精(包括2-和3-羟丙基-环糊精)的化学改性的衍生物或其他溶解的衍生物也可以有利地用于增强本文所述的式的化合物的递送。
可以根据常规药学方法加工本发明的药物活性化合物,以产生用于施用于患者(包括人类和其他哺乳动物)的药剂。所述药物组合物可以经受诸如灭菌的常规制药操作和/或可以含有常规佐剂,诸如防腐剂、稳定剂、润湿剂、乳化剂、缓冲剂等。片剂和丸剂可以另外用肠溶衣制备。此类组合物还可以包含佐剂,诸如润湿剂、甜味剂、调味剂和芳香剂。
所施用的化合物的量和用于用本发明的化合物和/或组合物治疗病状的剂量方案取决于多种因素,包括受试者的年龄、重量、性别、医学状况,疾病类型,疾病的严重程度,施用的途径和频率,以及所采用的具体化合物。因此,剂量方案可以广泛变化,但是可以使用标准方法常规确定。约0.001至100mg/kg体重、优选在约0.0025与约50mg/kg体重之间、并且最优选在约0.005至10mg/kg体重之间的日剂量可能是适当的。日剂量可以以1至4剂/天施用。其他给药方案包括一剂/周和一剂/两天周期。
出于治疗目的,本发明的活性化合物通常与适合于所指示的施用途径的一种或多种佐剂组合。如果口服施用,可以将化合物与乳糖、蔗糖、淀粉、烷酸的纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐和钙盐、明胶、阿拉伯胶、海藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇混合,并且然后压片或胶囊化以方便施用。此类胶囊或片剂可以含有控释配制品,其可以在活性化合物在羟丙基甲基纤维素中的分散体中提供。
本发明的药物组合物包含至少一种式(I)的化合物和任选地选自任何药学上可接受的载体、佐剂和媒介物的另外药剂。本发明的替代组合物包含本文所述的式(I)的化合物或其前药以及药学上可接受的载体、佐剂或媒介物。
本发明还涵盖制品。如本文所用,制品旨在包括但不限于试剂盒和包装。本发明的制品包含:(a)第一容器;(b)位于第一容器内的药物组合物,其中所述组合物包含:第一治疗剂,其包含本发明的化合物或其药学上可接受的盐形式;和(c)包装插页,其说明所述药物组合物可以用于治疗炎性障碍和/或自身免疫性疾病(如先前所定义的)。在另一个实施方案中,所述包装插页说明所述药物组合物可以与用于治疗炎性障碍和/或自身免疫性疾病的第二治疗剂组合(如先前所定义)使用。所述制品还可以包含:(d)第二容器,其中组分(a)和(b)位于第二容器内,并且组分(c)位于第二容器内或外。位于第一容器和第二容器内意指相应的容器将物品保持在其边界内。
第一容器是用于保持药物组合物的接收容器。此容器可以用于制造、储存、运输和/或单独/批量销售。第一容器旨在涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如,用于乳膏制剂),或用于制造、保持、储存或分配药物产品的任何其他容器。
第二容器是用于保持第一容器和任选地包装插页的容器。第二容器的例子包括但不限于盒(例如,纸板或塑料)、板条箱、纸箱、袋(例如,纸或塑料袋)、小袋和包。所述包装插页可以通过胶带、胶水、订书钉或其他附接方法物理地附接到第一容器的外侧,或者它可以静置在第二容器内侧而无需与第一容器附接的任何物理装置。可替代地,所述包装插页位于第二容器的外侧。当位于第二容器外侧时,优选的是,所述包装插页通过胶带、胶水、订书钉或其他附接方法物理地附接。可替代地,它可以与第二容器外侧相邻或接触,而不是物理附接。
所述包装插页是标签、签条、标记等,其列举了与位于第一容器内的药物组合物有关的信息。所列举的信息将通常由管理其中销售制品的地区的管理机构(例如,美国食品和药物管理局(United States Food and Drug Administration))来确定。在一个实施方案中,所述包装插页具体列举了已被批准药物组合物所针对的适应症。所述包装插页可以由人可以阅读其中或其上所含信息的任何材料制成。例如,所述包装插页是可印刷材料(例如,纸、塑料、硬纸板、箔、背胶纸或塑料等),在其上已形成(例如,印刷或施加)所希望的信息。
制备方法
本发明的化合物可以通过有机合成领域的技术人员熟知的多种方式制备。本发明的化合物可以使以下所述的方法,连同合成有机化学领域中已知的合成方法、或如本领域技术人员所理解的其变化来合成。优选的方法包括但不限于以下所述的那些。将本文列举的所有参考文献通过引用以其整体并入本文。
可以使用本部分中所述的反应和技术来制备本发明的化合物。所述反应在适合于所用试剂和材料的溶剂中进行,并且适用于所进行的转化。此外,在以下所述的合成方法的描述中,应当理解,所有提出的反应条件(包括溶剂的选择、反应气氛、反应温度、实验的持续时间和后处理程序)被选择为对于所述反应为标准的条件,本领域技术人员应该容易认识到这一点。有机合成领域的技术人员应理解,分子的各部分上存在的官能团必须与所提出的试剂和反应相容。对于与反应条件相容的取代基的此类限制将对于本领域技术人员而言是显而易见的,并且于是必须使用替代方法。有时,这将需要判断以修改合成步骤的顺序或选择一种而不是另一种特定的过程方案,以便获得所希望的本发明化合物。还将认识到,在此领域的任何合成途径的规划中的另一个主要考虑因素是明智地选择用于保护本发明中所述化合物中存在的反应性官能团的保护基团。为受过培训的从业者描述许多替代方案的权威解释是Greene和Wuts(Protective Groups In Organic Synthesis,第三版,Wileyand Sons,1999)。
实施例
式(I)的化合物和用于制备式(I)的化合物的中间体的制备可以使用以下实施例中示出的程序和有关程序来制备。在这些实施例中使用的方法和条件以及在这些实施例中制备的实际化合物不意在限制,而意在证明如何可以制备式(I)的化合物。当不通过本文所述的方法程序时,这些实施例中使用的起始材料和试剂通常是可商购的,或者报道在化学文献中,或者可以通过使用化学文献中所述的程序制备。
缩写
Ac 乙酰基
ACN 乙腈
AcOH 乙酸
anhyd. 无水的
aq. 水性
Bn 苄基
Bu 丁基
Boc 叔丁氧基羰基
CV 柱体积
DCE 二氯乙烷
DCM 二氯甲烷
DMAP 二甲基氨基吡啶
DMF 二甲基甲酰胺
DMSO 二甲亚砜
EDC 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐
EtOAc 乙酸乙酯
Et 乙基
EtOH 乙醇
H或H2 氢
h、hr或hrs 小时
HCTU O-(6-氯苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐
hex 己烷
i 异
IPA 异丙醇
HOAc 乙酸
HCl 盐酸
HPLC 高压液相色谱法
LC 液相色谱法
M 摩尔
mM 毫摩尔
Me 甲基
MeOH 甲醇
MHz 兆赫
min. 分钟
min 分钟
M+1 (M+H)+
MS 质谱法
n或N 正
NBS n-溴琥珀酰亚胺
nm 纳米
nM 纳摩尔
NMP N-甲基吡咯烷
Pd/C 钯碳
PdCl2(dppf)2 [1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)
Pd(PPh3)4 四(三苯基膦)钯
Ph 苯基
PPh3 三苯基膦
Pr 丙基
PSI 磅/平方英寸
PyBOP 溴三吡咯烷基鏻六氟磷酸盐
Ret Time 保留时间
sat. 饱和的
SFC 超临界流体色谱法
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
分析型和制备型HPLC条件:
QC-ACN-AA-XB:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7μm颗粒;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B下保持0.75分钟;流量:1.0mL/min;检测:在220nm下的UV。
QC-ACN-TFA-XB:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7μm颗粒;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B下保持0.75分钟;流量:1.0mL/min;检测:在220nm下的UV。
(TS):柱:Waters Acquity UPLC BEH C18(2.1x50mm),1.7微米;溶剂A=含0.05%TFA的100%水;溶剂B=含0.05%TFA的100%乙腈;梯度=经1分钟2%-98%B,然后在98%B下保持0.5分钟;流速:0.8mL/min;检测:在254nm下的UV。
实施例1
N1,N13-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十三烷二酰胺
中间体1A:2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙-1-胺
向20ml闪烁小瓶中添加4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-甲酸叔丁酯(200mg,0.408mmol)、DCM(3mL)和TFA(3mL)。将反应在室温搅拌30分钟,此时LCMS表明Boc脱保护完成。将小瓶在N2流下浓缩,并且用乙醚研制若干次,此时形成固体。将产物溶解在DMF(5mL)中,并且添加DIEA(0.214mL,1.225mmol),然后添加(2-氧代乙基)氨基甲酸叔丁酯(195mg,1.225mmol)。30分钟后,添加三乙酰氧基硼氢化钠(260mg,1.225mmol)。将反应混合物搅拌2小时。将反应混合物用乙酸乙酯稀释并且用饱和NaCl洗涤。将有机层用MgSO4干燥,过滤并且浓缩。将粗产物在硅胶上纯化(DCM/MeOH0-15%)以得到(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)氨基甲酸叔丁酯,将其立即用TFA/DCM处理30分钟。LCMS显示除去了Boc基团。在真空中蒸发溶剂。将材料用乙酸乙酯稀释并且用饱和NaHCO3洗涤。将有机层用MgSO4干燥,过滤并且浓缩以得到2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙-1-胺(72mg,0.166mmol,40.7%产率)。LCMS保留时间0.6min[TS]。MS(E+)m/z:433.3(M+H)。
实施例1:
向十三烷二酸(6.78mg,0.028mmol)和DIEA(0.015mL,0.083mmol)在DMF(2mL)中的混合物中添加HATU(21.10mg,0.055mmol)。30分钟后,添加2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙-1-胺(24mg,0.055mmol)。将反应混合物搅拌一小时。将反应混合物过滤并且通过HPLC纯化以得到N1,N13-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十三烷二酰胺(12.4mg,0.011mmol,40.8%产率)。LCMS保留时间0.77min[TS]。MS(E+)m/z:1073.8(M+H)。1H NMR(500MHz,DMSO-d6)δ11.25(s,2H),8.61-8.55(m,2H),8.53-8.49(m,2H),8.22-8.12(m,2H),7.62-7.55(m,2H),7.37(d,J=8.2Hz,2H),7.16(s,2H),7.04(br d,J=8.5Hz,2H),4.11-4.04(m,6H),3.66(br d,J=11.0Hz,2H),3.23-3.09(m,6H),2.98-2.78(m,2H),2.54-2.48(m,9H),2.21-1.90(m,12H),1.57-1.48(m,4H),1.48-1.42(m,12H),1.34-1.17(m,15H)。
根据以上实施例中所述的通用程序制备以下实施例。
表1
实施例12
1,18-双(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)十八烷
向6-(3-异丙基-5-(哌啶-4-基)-1H-吲哚-2-基)-8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶(21.73mg,0.056mmol)和碳酸钾(15.42mg,0.112mmol)在DMF(2mL)中的混合物中添加1,18-二溴十八烷(11.5mg,0.028mmol)。将反应混合物在室温搅拌1小时,加热至70℃,并且搅拌过夜。将反应混合物冷却、过滤并且通过HPLC纯化以得到1,18-双(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)十八烷(8mg,7.62μmol,27.3%产率)。LCMS保留时间2.65min[QC-ACN-AA-XB]。MS(E+)m/z:1030.07(M+H)。1H NMR(500MHz,DMSO-d6)δ11.24(s,2H),8.53(s,2H),8.50(s,2H),7.58(s,2H),7.37(d,J=8.5Hz,2H),7.13(s,2H),7.04(br d,J=8.2Hz,2H),4.06(s,6H),3.32(dt,J=14.0,7.0Hz,2H),3.06(br d,J=7.0Hz,6H),2.92(br s,2H),2.52-2.49(m,6H),2.14-1.88(m,7H),1.68(br s,4H),1.45(br d,J=7.0Hz,11H),1.38-1.17(m,30H)。
比较化合物C1
1,18-双(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)十八烷-1,18-二酮
向十八烷二酸(8.88mg,0.028mmol)和DIEA(0.015mL,0.085mmol)在DMF(2mL)中的混合物中添加HATU(21.48mg,0.056mmol)。30分钟后,添加6-(3-异丙基-5-(哌啶-4-基)-1H-吲哚-2-基)-8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶(22mg,0.056mmol)。将反应混合物搅拌2小时,并且然后过滤并且通过HPLC纯化以得到1,18-双(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)十八烷-1,18-二酮(10.6mg,10.02μmol,35.5%产率)。LCMS保留时间3.02min[QC-ACN-AA-XB]。MS(E+)m/z:1057.94(M+H)。1H NMR(500MHz,DMSO-d6)δ11.15(s,2H),8.56(s,2H),8.51(s,2H),7.57(s,2H),7.32(d,J=8.2Hz,2H),7.15(s,2H),7.03(br d,J=8.5Hz,2H),4.59(br d,J=11.9Hz,2H),4.08(s,6H),3.12(br t,J=11.9Hz,2H),2.85(br t,J=12.2Hz,2H),2.61(brt,J=11.6Hz,2H),2.46-2.18(m,5H),1.85(br t,J=15.3Hz,4H),1.70-1.57(m,2H),1.56-1.48(m,6H),1.46(br d,J=7.0Hz,12H),1.36-1.20(m,27H)。
根据以上化合物中所述的通用程序制备以下化合物。
表2
比较化合物C4
2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙-1-胺
比较化合物C4的制备描述在中间体1A中。
比较化合物C5
N-(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)乙酰胺
向2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙-1-胺、2TFA(20mg,0.030mmol)和TEA(0.013mL,0.091mmol)在DCM(1mL)中的混合物中添加乙酸酐(2.86μL,0.030mmol)。将反应混合物搅拌一小时,然后在真空中除去溶剂,并且将粗材料通过HPLC纯化以得到N-(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)乙酰胺(12.6mg,0.026mmol,87%产率)。LCMS保留时间1.16min[QC-ACN-AA-XB]。MS(E+)m/z:475.1(M+H)。1H NMR(500MHz,DMSO-d6)δ11.14(s,1H),8.56(s,1H),8.52(s,1H),7.81(br s,1H),7.58(s,1H),7.33(d,J=8.2Hz,1H),7.16(s,1H),7.05(br d,J=8.9Hz,1H),4.09(s,3H),3.27-3.17(m,1H),3.03(br d,J=10.7Hz,1H),2.65-2.56(m,2H),2.48-2.36(m,2H),2.14(br t,J=8.2Hz,2H),1.92(s,3H),1.87-1.69(m,6H),1.47(d,J=7.0Hz,6H)。
生物测定
本发明化合物的药理特性可以通过许多生物测定来确认。已经用本发明的化合物进行以下示例的生物测定。
TLR7/8/9抑制报告测定
使用过表达人TLR7、TLR8或TLR9受体的HEK-BlueTM-细胞(Invivogen)来使用诱导型SEAP(分泌胚胎碱性磷酸酶)报告基因在融合至5个NF-κB和AP-1结合位点的IFN-β最小启动子的控制下筛选这些受体的抑制剂。简言之,将细胞接种到Greiner 384孔板中(对于TLR7每孔15000个细胞,对于TLR8每孔20,000个细胞,并且对于TLR9每孔25,000个细胞),并且然后用在DMSO中的测试化合物处理以产生0.05nM-50μM的最终剂量反应浓度范围。在室温下进行30分钟的化合物预处理后,然后用TLR7配体(gardiquimod,最终浓度为7.5μM)、TLR8配体(R848,最终浓度为15.9μM)或TLR9配体(ODN2006,最终浓度为5nM)刺激细胞以激活诱导产生SEAP的NF-κB和AP-1。在37℃、5%CO2下孵育22小时后,根据制造商的说明书通过添加HEK-BlueTM检测试剂(Invivogen)(允许检测SEAP的细胞培养基)来确定SEAP水平。百分比抑制被确定为与用已知抑制剂处理的孔相比,在用单独的激动剂加DMSO处理的孔中存在的HEK-Blue信号的降低%。
表2
TLR7/8/9报告测定数据
Claims (11)
1.一种式(I)的化合物
其N-氧化物或盐,其中:
L是-(CH2)q-或-L1-NRxC(O)-(CH2)t-C(O)NRx-L2-;
L1和L2独立地是-(CH2)1-3-;
q是在10至30范围内的整数;
t是在2至24范围内的整数;
G1和G2独立地是:
(iv)选自以下的9元杂环:
(v)选自以下的10元杂环:
R1a和R1b独立地是H、Cl、-CN、C1-4烷基、C1-3氟烷基、C1-3羟烷基、C1-3羟基-氟烷基、C3-6环烷基、-CH2(C3-6环烷基)、-C(O)O(C1-3烷基)、或四氢吡喃基;
每个R2独立地是卤基、-CN、-OH、-NO2、C1-4烷基、C1-2氟烷基、C1-2氰基烷基、C1-3羟烷基、C1-3氨基烷基、-O(CH2)1-2OH、-(CH2)0-4O(C1-4烷基)、C1-3氟烷氧基、-(CH2)1-4O(C1-3烷基)、-O(CH2)1-2OC(O)(C1-3烷基)、-O(CH2)1-2NRxRx、-C(O)O(C1-3烷基)、-(CH2)0-2C(O)NRyRy、-C(O)NRx(C1-5羟烷基)、-C(O)NRx(C2-6烷氧基烷基)、-C(O)NRx(C3-6环烷基)、-NRyRy、-NRy(C1-3氟烷基)、-NRy(C1-4羟烷基)、-NRxCH2(苯基)、-NRxS(O)2(C3-6环烷基)、-NRxC(O)(C1-3烷基)、-NRxCH2(C3-6环烷基)、-(CH2)0-2S(O)2(C1-3烷基)、-(CH2)0-2(C3-6环烷基)、-(CH2)0-2(苯基)、吗啉基、二氧代硫代吗啉基、二甲基吡唑基、甲基哌啶基、甲基哌嗪基、氨基-噁二唑基、咪唑基、三唑基、或-C(O)(噻唑基);
R2a是C1-6烷基、C1-3氟烷基、C1-6羟烷基、C1-3氨基烷基、-(CH2)0-4O(C1-3烷基)、C3-6环烷基、-(CH2)1-3C(O)NRxRx、-CH2(C3-6环烷基)、-CH2(苯基)、四氢呋喃基、四氢吡喃基、或苯基;
每个R2b独立地是H、卤基、-CN、-NRxRx、C1-6烷基、C1-3氟烷基、C1-3羟烷基、C1-3氟烷氧基、-(CH2)0-2O(C1-3烷基)、-(CH2)0-3C(O)NRxRx、-(CH2)1-3(C3-6环烷基)、-C(O)O(C1-3烷基)、-C(O)NRx(C1-3烷基)、-CRx=CRxRx、或-CRx=CH(C3-6环烷基);
R2c是R2a或R2b;
R2d是R2a或R2b;条件是R2c和R2d之一是R2a并且R2c和R2中的另一个是R2b;
每个R4独立地是F、-OH、C1-2烷基、或-OCH3;或附接至同一个碳原子的两个R4形成=O;或其中当m或n是至少2时,各自附接至与哌啶基环中的氮原子相邻的不同碳原子的两个R4可以形成-CH2CH2-桥;
每个R5独立地是F、Cl、-CN、C1-3烷基、C1-2氟烷基、或-OCH3;
每个Rx独立地是H或-CH3;
每个Ry独立地是H或C1-6烷基;
m是0、1、2、3或4;
n是0、1、2、3或4;
每个p独立地是0、1、2、3或4;
x是0、1或2;并且
y是0、1或2。
3.根据权利要求1或2所述的化合物或其N-氧化物或盐,其中:
q是在12至24范围内的整数;并且
t是在2至20范围内的整数。
4.根据权利要求1至3中任一项所述的化合物或其N-氧化物或盐,其中:
R1a和R1b独立地是H、Cl、-CN、C1-4烷基、C1-2氟烷基、C1-2羟烷基、或-C(O)O(C1-2烷基);
每个R2独立地是F、Cl、-CN、-OH、C1-4烷基、C1-2氟烷基、C1-2氰基烷基、C1-3羟烷基、C1-3氨基烷基、C1-4烷氧基、-NRyRy、-C(O)NRyRy、-C(O)NRx(C1-4羟烷基)、-C(O)NRx(C2-4烷氧基烷基)、-C(O)NRx(C3-6环烷基)、-S(O)2(C1-3烷基)、C3-6环烷基、吗啉基、苯基、或二甲基吡唑基;
每个R4独立地是F、-CH3、或-OCH3;
每个R5独立地是F、Cl、-CN、C1-2烷基、或-OCH3;
m是0、1或2;
n是0、1或2;
p是0、1或2;
x是0或1;并且
y是0或1。
5.根据权利要求1至4中任一项所述的化合物或其N-氧化物或盐,其中:
R1a和R1b独立地是-CH2CH3或-CH(CH3)2;
每个R2独立地是-CH3或-OCH3;
每个R2a是-CH3;
每个R2b独立地是H、Cl、或-CH3;
每个R4独立地是F、-CH3、或-OCH3;并且
每个R5独立地是F、Cl、-CN、-CH3、-CF3、或-OCH3。
7.根据权利要求1所述的化合物或其盐,其中所述化合物是:
N1,N13-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十三烷二酰胺(1);
N1,N14-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十四烷二酰胺(2);
N1,N12-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十二烷二酰胺(3);
N1,N11-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十一烷二酰胺(4);
N1,N9-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)壬烷二酰胺(5);
N1,N8-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)辛烷二酰胺(6);
N1,N10-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)癸烷二酰胺(7);
N1,N7-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)庚烷二酰胺(8);
N1,N6-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)己二酰二胺(9);
N1,N12-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)十二烷二酰胺(10);
N1,N4-双(2-(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)乙基)琥珀酰胺(11);或
1,18-双(4-(3-异丙基-2-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)哌啶-1-基)十八烷(12)。
8.一种药物组合物,其包含根据权利要求1-7中任一项所述的化合物或其药学上可接受的盐;和药学上可接受的载体。
9.根据权利要求1-7中任一项所述的化合物或其药学上可接受的盐或根据权利要求8所述的组合物,其用于疗法。
10.根据权利要求1-7中任一项所述的化合物或其药学上可接受的盐,其用于在疗法中治疗自身免疫性疾病或慢性炎性疾病。
11.根据权利要求10所述的用于所述用途的化合物或其药学上可接受的盐,其中所述自身免疫性疾病或慢性炎性疾病选自系统性红斑狼疮(SLE)、类风湿性关节炎、多发性硬化(MS)、和肖格伦综合征。
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EP (1) | EP3870589B1 (zh) |
JP (1) | JP2022505827A (zh) |
KR (1) | KR20210080462A (zh) |
CN (1) | CN112912382A (zh) |
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WO (1) | WO2020086505A1 (zh) |
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IL307203A (en) | 2021-04-16 | 2023-11-01 | Gilead Sciences Inc | THIENOPYRROLE COMPOUNDS |
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US20180000790A1 (en) * | 2016-06-29 | 2018-01-04 | Bristol-Myers Squibb Company | [1,2,4]TRIAZOLO[1,5-a]PYRIDINYL SUBSTITUTED INDOLE COMPOUNDS |
WO2018026620A1 (en) * | 2016-07-30 | 2018-02-08 | Bristol-Myers Squibb Company | Dimethoxyphenyl substituted indole compounds as tlr7, tlr8 or tlr9 inhibitors |
WO2018049089A1 (en) * | 2016-09-09 | 2018-03-15 | Bristol-Myers Squibb Company | Pyridyl substituted indole compounds |
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SG11202005696YA (en) * | 2017-12-19 | 2020-07-29 | Bristol Myers Squibb Co | Substituted indole compounds useful as tlr inhibitors |
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- 2019-10-22 EP EP19798498.2A patent/EP3870589B1/en active Active
- 2019-10-22 CN CN201980070010.3A patent/CN112912382A/zh active Pending
- 2019-10-22 JP JP2021522502A patent/JP2022505827A/ja active Pending
- 2019-10-22 ES ES19798498T patent/ES2963696T3/es active Active
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Patent Citations (3)
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US20180000790A1 (en) * | 2016-06-29 | 2018-01-04 | Bristol-Myers Squibb Company | [1,2,4]TRIAZOLO[1,5-a]PYRIDINYL SUBSTITUTED INDOLE COMPOUNDS |
WO2018026620A1 (en) * | 2016-07-30 | 2018-02-08 | Bristol-Myers Squibb Company | Dimethoxyphenyl substituted indole compounds as tlr7, tlr8 or tlr9 inhibitors |
WO2018049089A1 (en) * | 2016-09-09 | 2018-03-15 | Bristol-Myers Squibb Company | Pyridyl substituted indole compounds |
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EP3870589A1 (en) | 2021-09-01 |
US20210393608A1 (en) | 2021-12-23 |
EP3870589B1 (en) | 2023-09-06 |
ES2963696T3 (es) | 2024-04-01 |
JP2022505827A (ja) | 2022-01-14 |
WO2020086505A1 (en) | 2020-04-30 |
KR20210080462A (ko) | 2021-06-30 |
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