CN112225703B - 一种治疗或预防与lrrk2激酶或异常lrrk2突变激酶活性相关疾病的药物 - Google Patents
一种治疗或预防与lrrk2激酶或异常lrrk2突变激酶活性相关疾病的药物 Download PDFInfo
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- CN112225703B CN112225703B CN202011046968.XA CN202011046968A CN112225703B CN 112225703 B CN112225703 B CN 112225703B CN 202011046968 A CN202011046968 A CN 202011046968A CN 112225703 B CN112225703 B CN 112225703B
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Abstract
本发明提供了一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物，属于医药领域。本发明药物包括化学式1表示的化合物、其光学异构体、其前体药物、其盐、其水合物、其溶剂化物、其N‑氧化物、其氘化类似物中的至少一种，对LRRK2激酶或异常LRRK2突变激酶具有很好的抑制作用，能用于治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病，例如阿兹海默氏症、L多巴诱发性运动障碍、帕金森氏病、痴呆症、肾癌、乳腺癌、前列腺癌、血癌、乳头状瘤、肺癌、急性骨髓性白血病、多发性骨髓瘤、麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎或强直性脊椎炎。
Description
技术领域
本发明属于医药领域，具体涉及一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物。
背景技术
LRRK2基因编码的蛋白包括一个富含亮氨酸重复(LRR)结构域，激酶结构域，一个DFG样基序，一个RAS域，一个GTP酶域，MLK-域，和WD40结构域。很多遗传和生化证据证明LRRK2激酶活性与帕金森病PD易感性有关，LRRK2基因的致病性突变(特别是最常见的Gly2019Ser突变)会增加细胞和组织中的LRRK2激酶活性和GTP水解速率降低，在某些PD模型中，小分子LRRK2激酶抑制剂会阻断这些活动还可以提供神经保护作用，这一发现使LRRK2已成为治疗帕金森病(PD)疾病最有希望的靶标(Tolosa等，Nature Reviews inNeurology，Vol.16，2020，PP.97-10；Paisan-Ruiz等，J.Parkinson's Disease，Vol.3，2013，pp.85-103；Guo等，Experimental Cell Research，Vol.313(16)，2007，pp.3658-3670；Andrew B.West，Experimental Neurology，Vol.298，2017，pp.236-245)。LRRK2被鉴别为潜在地与升高的对克罗恩氏病的易感性和对麻风病的易感性相关的基因(Zhang等，New England J.Med.，Vol.361，2009，pp.2609-2618；Barrett等,Nature Genetics，Vol.40，2008，pp.955-962)；还与脊椎强直(ankyIosing spondylytis)(Danoy等，PLoSGenetics，Vol 6(12)，2010，pp.1-5)和肌萎缩侧索硬化(Shtilans等，Amyotrophiclateral Sclerosis，2011，pp.1-7)相关。
LRRK2还与以下病症相关:自轻度认知障得到阿兹海默氏症转化(WO2007149798)；L-多巴诱发性运动障碍(Hurley等，Eur.J,Neurosci.，Vol.26，2007，pp.171-177)；与神经母细胞增生和迁移相关联的CNS病症，并且LRRK2的调节可用于缺血性损伤后改良神经效果和神经元损伤(诸如缺血性中风、创伤性脑损伤或脊髓损伤)后刺激CNS官能复原(Milosevic等，Neurodegen.，Vol.4，2009，25；Zhang等，J.Neurosci.Res，Vol.88，2010，pp.3275-3281)。其他疾病：包括糖尿病、肥胖症、运动神经元疾病、癫痫症和一些癌症(Rubinsztein等，Nat.Rev.Drug Discovery，Vol.11，2012，709-730)。癌症如肾癌、乳腺癌、前列腺癌(例如实体肿瘤)、血癌和肺癌以及急性髓性白血病(AML)(WO2011038572)；淋巴瘤和白血病(Ray等，J.Immunolo.，Vol.230，2011，109)；乳头状肾癌和甲状腺癌(Brendan DLooyenga等，Proc Natl Acad Sci U S A，Vol.108(4)，2011，pp.1439-44)；多发性骨髓瘤(Chapman等，Nature，Vol.471，2011，pp.467-472)。免疫系统疾病：包括类风湿性关节炎、全身性红斑性狼疮症、自体免疫溶血性贫血、纯红细胞形成不全、特发性血小板减少性紫癜(ITP)、伊凡氏症候群((Evans syndrome)、血管炎、大疱性皮肤病、I型糖尿病、休格连氏症候群(Sjogren's syndrome)、德维克氏病(Delvic's disease)和炎症性疾病(Nakamura等，DNA Res.，Vol.13(4)，2006，pp.169-183；Engel等，Pharmacol.Rev.，Vol.63，2011，127-156；Homam等，J.Clin.Neuromuscular Disease，Vol.12，2010，pp.91-102)。肺部疾病如慢性阻塞性肺病和特发性肺纤维化(Araya等，Intern.Med.，Vol.52，2013，2295-2303)。作为自噬和吞噬过程的启动子，LRRK2激酶的小分子抑制剂也可用于增加宿主对一系列细胞内细菌感染、寄生虫感染和病毒感染(包括诸如结核病等疾病)的治疗反应(Rubinsztein等，Nat.Rev.，2012，709-730；Araya等，Intern.Med.，Vol.52，2013，95-2303；Gutierrez，Biochemical Society Conference，Leucine rich repeat kinase2:ten years alongthe road to therapeutic intervention,Henley Business School，UK 12July 2016)、HIV、西尼罗病毒和切昆贡亚病毒(Shoji-Kawata等，Nature，Vol.494，2013，pp.201-206)。也用于其他a-突触核蛋白病(Orenstein等，Nature Neurosci.，Vol.16，2013，394-406)、Tau蛋白病(Li等，Neurodegen.Dis.，Vol.7，2010，pp.265-271)、阿尔茨海默氏病和其他神经变性疾病(Nixon，Nat.Med.，Vol.19，2013，pp.983-97)和戈谢病(Westbroek等，Trends.Mol.Med.，Vol.17，2011，485-493)；特征在于Tau的过磷酸化的tau蛋白病，诸如嗜银颗粒病、皮克氏病(Pick's disease)、皮质基底核退化症、进行性核上麻痹以及与染色体17相关联的遗传性额颞叶型痴呆和帕金森氏症(Jakes R等，Biochemicaet BiophysicaActa，Vol.1739,2005，pp.240-250)；小神经胶质促炎性反应(Moehle等，J.Neuroscience，Vol.32，2012，pp.1602-1611)。
因此，有效调节LRRK2活性的化合物可以提供由LRRK2介导的疾病或病状为神经退化疾病，癌症，炎症性疾病，细菌、病毒感染和其它疾病的治疗。
发明内容
本发明的目的在于克服现有技术存在的不足之处而提供一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物。
为实现上述目的，本发明提供了一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物，含有LRRK2抑制剂，所述LRRK2抑制剂包括化学式1表示的化合物、其光学异构体、其前体药物、其盐、其水合物、其溶剂化物、其N-氧化物、其氘化类似物中的至少一种；
[化学式1]
在化学式1中，L1、L2、L3均独立地为C或N；L4为C、N、O或S；
R1独立地为无取代基或酰胺基，
R2独立地为无取代基、-H、-NHAr、-CH＝CHPh、
或未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基，
或者L3为N，L1、L2、R1和R2共同形成
或-ArRbRd，其中，X为卤素；
R3为无取代基、-H、卤素、C1-10烃基、或-NHRa；
R4独立地为-H、-NHAr、-CH＝CHPh、-NHRa、取代或未取代的含有N、O、S中至少一种杂原子的5至8元环杂环基乙烯基、C1-5直链或支链烷基氨基磺酰基C6-10芳基氨基、二(C1-5直链或支链烷基)磷酸基C6-10芳基氨基、
未取代或被第二取代基取代的含N、O中至少一种杂原子的5至8元环杂环基、或5至8元环杂环基氨基，
R5独立地为
或者L1为N，R4和R5共同形成
其中，L5为-O-、-S-、或-NH-，
Y1为未取代或被第三取代基取代的C1-10直链或支链烷基，
Y环为苯环、或未取代或被第四取代基取代的含N、O中至少一种杂原子的4至8元环杂环烷基或杂环芳基；
R6为无取代基或-H；
R7为-H、C1-10烃基、-(CH2)nOH、-ORc、-O(CH2)nRa、卤素、或未取代或被第三取代基取代的含N、O中至少一种杂原子的4至8元环杂环烷基或杂环芳基；
R8、R9、R10、R11均独立地为-H、C1-10烃基、-(CH2)nOH、-O(CH2)nRa、-C(O)ORa、卤素、-CF3或-OCF3；
每个Ra均独立地为-H、C1-10烃基、C1-10环烃基、芳基、或未取代或被第五取代基取代的含N、O中至少一种杂原子的5至8元环杂环烷基或杂环芳基；
每个Rb均独立地为-H、C1-10烃基、-O(CH2)nRa、-NRaRc、或未取代或被第六取代基取代的含N、O中至少一种杂原子的3至8元环杂环基；
每个Rc均独立地为-H、C1-10烃基、-(CH2)nOH、芳基、或未取代或被第三取代基取代的含N、O中至少一种杂原子的4至8元环杂环烷基或杂环芳基；
每个Rd均独立地为-H或-O(CH2)nRa；
所述第一取代基、第二取代基、第四取代基、第五取代基、第六取代基各自独立地为-OH、卤素、-CN、硝基、-NH2、C1-10烃基、取代或未取代的C3-10环烷基、取代或未取代的含N、O中至少一种杂原子的3至8元环杂环烷基中的至少一种；
每个n均独立地选自0至4任意整数。
优选地，所述化学式1表示的化合物的结构式如下所示：
所述R3为卤素或C1-10烃基；所述R4为C1-5直链或支链烷基氨基磺酰基C6-10芳基氨基、二(C1-5直链或支链烷基)磷酸基C6-10芳基氨基、
或未取代或被第二取代基取代的含N、O中至少一种杂原子的5至8元环杂环基；所述R7为
Rb为C1-10烃基、-NRaRc、或被C1-10烃基取代的含N、O中至少一种杂原子的3至8元环杂环基，Ra为C1-10烃基，Rc为-(CH2)nOH；所述R10、R11均独立地为-H、-O(CH2)nRa、C1-10烃基或卤素。
进一步优选地，所述R3为-F、-Cl或-CH3；所述R4为
所述R7为
所述R10、R11均独立地为-H、-OCH3、-CH3或-F。
优选地，所述化学式1表示的化合物的结构式如下所示：
所述L4为N、S或O；所述R5为
或被-O(CH2)nRa、卤素中至少一种取代的苯基；Rb为-O(CH2)nRa；Ra为-H、或未取代或被第五取代基取代的含N、O中至少一种杂原子的5至8元环杂环烷基或杂环芳基；Rd为-H或-O(CH2)nRa。
进一步优选地，所述L4为N、S或O；所述R5为
所述Rb为
Rd为-H或-OCH3。
优选地，所述化学式1表示的化合物的结构式如下所示：
所述R4为被C1-10烃基取代的5至8元环杂环基氨基；所述L4为N、S或O；所述R7为O(CH2)nRa，Ra为芳基、或未取代或被第五取代基取代的含N、O中至少一种杂原子的5至8元环杂环烷基或杂环芳基。
优选地，所述化学式1表示的化合物的结构式如下所示：
所述R2为未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基；所述L4为N；所述R4为-CH＝CHPh、或取代或未取代的含有N、O、S中至少一种杂原子的4至8元环杂环基乙烯基；所述R5为
优选地，所述化学式1表示的化合物的结构式如下所示：
所述R1为酰胺基；所述R3为C1-10烃基；所述R4为5至8元环杂环基氨基；所述R7为
所述Rb为未取代或被第六取代基取代的含N、O中至少一种杂原子的3至8元环杂环基；所述R9为-O(CH2)nRa。
优选地，所述化学式1表示的化合物的结构式如下所示：
优选地，所述化学式1表示的化合物为以下化合物中的任意一种：
(1)(1S，2S，3R，4R)-3-[[5-氟-2-[3-甲基-4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]双环[2.2.1]庚-5-烯-2-甲酰胺；
(2)N-叔丁基-3-[[5-甲基-2-[4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]苯磺酰胺；
(3)2-[[1-[2-氟-4-[[5-甲基-4-(1-丙-2-基吡唑-4-基)嘧啶-2-基]氨基]苯基]哌啶-4-基]-甲基氨基]乙醇；
(4)5-氯-4-N-(2-二甲基磷酰苯基)-2-N-[2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基]嘧啶-2,4-二胺；
(5)1-(4-甲基苯基)-3-[5-[7-(3-吗啉-4-基丙氧基)喹唑啉-4-基]磺酰基-1,3,4-噻二唑-2-基]脲；
(6)N-(2-氯-5-甲氧基苯基)-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹唑啉-4-胺；
(7)8-溴-2-[(1-甲基哌啶-4-基)氨基]-4-(4-苯氧基苯胺)-6H-吡啶[4,3-d]嘧啶-5-酮；
(8)6-(4-甲基哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)-2-[((E)-2-苯基乙烯基]嘧啶-4-胺；
(9)6-乙基-3-[3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯胺基]-5-(氧烷-4-基氨基)吡嗪-2-羧酰胺；
(10)(16E)-11-(2-吡咯烷-1-乙氧基)-14,19-二恶英-5,7,27-三氮四环[19.3.1.12,6.18,12]庚-1(24)，2(27)，3,5,8(26)，9,11,16,21(25)，22-癸烯。
优选地，所述疾病包括神经退化性疾病、癌前病状和癌症、自身免疫性病、炎症中的至少一种。
优选地，所述疾病包括阿兹海默氏症、L-多巴诱发性运动障得、帕金森氏病、增强认知记忆、中枢神经系统病症、痴呆症、肌萎缩侧索硬化症、肾癌、乳腺癌、前列腺癌、血癌、乳头状癌、肺癌、急性骨髓性白血病、多发性骨髓瘤、麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎或强直性脊椎炎中的至少一种。
另外需要说明的是，以上烃基均包括烷基以及不饱和烃基，如烯基；以上卤素均包括F、Cl、Br等；Ar表示芳基，如苯基、萘基等；Ph表示苯基；未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基是指构成5至8元环的原子除碳原子外，还含有N、O中至少一种杂原子，且该5至8元环未被取代或被第一取代基取代，其他类似描述所表达的意思同理；二(C1-5直链或支链烷基)磷酸基C6-10芳基氨基中，磷酸基上的取代基烷基可以相同，也可以不同，如
等；被C1-10烃基取代的5至8元环杂环基氨基指的是5至8元环杂环基氨基中的5至8元环杂环基被C1-10烃基取代；R2独立地为无取代基、-H、-NHAr、-CH＝CHPh、
或未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基，指的是R2独立地为无取代基、-H、-NHAr、-CH＝CHPh、
无取代基的含N、O中至少一种杂原子的5至8元环杂环基、或者被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基，其他类似描述同理。
相比现有技术，本发明的有益效果在于：本发明药物包含特定的LRRK2抑制剂，能有效治疗或预防与LRRK2激酶或其任意突变体(如LRRK2突变体G2019S)活性相关疾病，如可用于预防和治疗神经变性疾病，诸如帕金森病和其它雷维小体型疾病，包括弥散性雷维小体疾病、阿尔茨海默氏病的雷维小体变型、复合的帕金森病和阿尔茨海默氏病、多系统萎缩和痴呆伴雷维小体等；也可用于预防和治疗癌症，诸如肾癌、乳腺癌、前列腺癌、血癌、乳头状瘤、肺癌、急性骨髓性白血病、多发性骨髓瘤、黑素瘤等；还可用于预防和治疗自身免疫疾病和炎症，诸如麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎或强直性脊椎炎。
附图说明
图1是实施例1化合物通过实验实施例11测定的LRRK2 WT和LRRK2G2019S的激酶生物活性Kd曲线；
图2是实施例2化合物通过实验实施例11测定的LRRK2 WT和LRRK2G2019S的激酶生物活性Kd曲线；
图3是实施例4化合物通过实验实施例11测定的LRRK2 WT和LRRK2G2019S的激酶生物活性Kd曲线；
图4是实施例7化合物通过实验实施例11测定的LRRK2 WT和LRRK2G2019S的激酶生物活性Kd曲线；
图5是实施例9化合物通过实验实施例11测定的LRRK2 WT和LRRK2G2019S的激酶生物活性Kd曲线。
具体实施方式
为更好的说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。
本发明涉及一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物，含有LRRK2抑制剂，该LRRK2抑制剂包括化学式1表示的化合物、其光学异构体、其前体药物、其药学上可接受的盐、其水合物、其溶剂化物、其N-氧化物、其氘化类似物中的至少一种。
根据本发明，化学式1表示的化合物可用于预防和治疗LRRK2或异常LRRK2突变引起的相关的病症，例如阿兹海默氏症、L多巴诱发性运动障碍、帕金森氏病、痴呆症、肌肉萎缩性侧索硬化、肾癌、乳腺癌、前列腺癌、血癌、乳头状瘤、肺癌、急性骨髓性白血病、多发性骨髓瘤、麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎、强直性脊椎炎等。
根据本发明，化学式1表示的化合物可用于预防和治疗至少部分由LRRK2或异常LRRK2突变介导的疾病或病状为神经退化疾病，例如，中枢神经系统(CNS)病症(诸如帕金森氏病(PD)、阿兹海默氏病(AD))、痴呆症(包括路易体性痴呆和血管性痴呆)、肌肉萎缩性侧索硬化(ALS)、年龄相关记忆功能障得、轻度认知障碍(例如，包括自轻度认知障碍转变至阿兹海默氏症)、嗜银颗粒病、溶嗨体病(例如，C型尼曼一皮克病、高歇病)、皮质基底核退化症、进行性核上麻痹、与染色体17相关联的遗传性额题叶型痴呆和帕金森氏症(FTDP-17)、与药物成瘾相关联的停药症状/复发、L-多巴诱发性运动障得、亨廷顿氏病(HD)和HIV关联性痴呆症(HAD)。病症为包括(但不限于)大脑、心脏、肾脏和肝脏的器官的缺血性疾病。
在一些实施方案中，化学式1表示的化合物用于治疗至少部分由LRRK2或异常LRRK2突变介导的疾病或病状为癌症，如甲状腺癌、肾癌(包括乳头状肾癌)、乳腺癌、肺癌、血癌和前列腺癌(例如实体肿瘤)、白血病(包括急性骨髓性白血病(AML)或淋巴瘤。
在另一些实施方案中，化学式1表示的化合物用于治疗至少部分由LRRK2或异常LRRK2突变介导的疾病或病状为炎症性病症。炎症性病症为炎症性肠疾病，诸如克罗恩氏病或溃疡性结肠炎(两者一般一起称为炎症性肠病)。炎症性疾病为麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎或强直性脊椎炎。
在其它实施方案中，化学式1表示的化合物用于治疗至少部分由LRRK2或异常LRRK2突变介导的其它疾病：多发性硬化症、全身性红斑狼疮症、自体免疫溶血性贫血、纯红细胞形成不全、特发性血小板减少性紫癜(ITP)、伊凡氏症候群、血管炎、大疱性皮肤病、1型糖尿病、休格连氏症候群、德维克氏病和炎症性肌病。
根据本发明，化学式1表示的化合物可以以其药学上可接受的盐的形式使用。这里，药学上可接受的盐可为药学上可接受的游离酸形成的酸加成盐。酸加成盐可获自无机酸(例如盐酸、硝酸、磷酸、硫酸、溴酸、氢碘酸、亚硝酸、亚磷酸等)、无毒有机酸(例如脂肪族单一和二羧酸酯、苯基取代的链烷酸酯、羟基链烷酸酯和链烷酸酯、芳香酸、脂肪族和芳香族磺酸等)或有机酸(例如乙酸、苯甲酸、柠檬酸、乳酸、马来酸葡萄糖酸、甲磺酸、4-甲苯磺酸、酒石酸、富马酸等)。酸加成盐可获自药学上无毒的盐，包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐(decanoate)、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐(caprate)、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二油酸盐、己烷-1,6油酸盐、苯甲酸盐、氯苯甲酸盐、苯甲酸甲酯、二硝基苯甲酸盐、羟苤酸盐、甲苯基苯甲酸盐邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐，β-羟基丁酸盐、乙醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、禁-2-磺酸盐、扁桃酸盐等。
根据本发明，酸加成盐可以通过常规方法制备，例如，通过将化学式1表示的化合物或其衍生物溶解在有机溶剂如甲醇、乙醇、丙酮、二氯甲烷或乙腈中，并向其中加入有机酸或无机酸以获得沉淀物，然后将沉淀物过滤并干燥，或者将溶剂和过量的酸进行真空蒸馏、干燥然后在有机溶剂存在下结晶。
另外，根据本发明，化学式1表示的化合物可以以其药学上可接受的金属盐的形式制备和使用。具体地，碱金属或碱土金属盐可通过以下方法获得：例如将化合物溶解在过量的碱金属氢氧化物或碱土金属氢氧化物溶液中，过滤未溶解的化合物盐，并将滤液蒸发至干。这里，钠盐、钾盐或钙盐作为金属盐是药学上合适的。此外，相应的盐可通过使碱金属或碱土金属盐与合适的银盐(例如硝酸银)反应来获得。
根据本发明，化学式1表示的化合物可以以其药学上可接受的氘化类似物、前药、立体异构体、其盐、其水合物、其溶剂化物、其N-氧化物中的至少一种的形式制备和使用。
在根据本发明的药物中，化学式1表示的化合物、其光学异构体或其药学上可接受的盐可在临床给药时以单一剂量或多剂量形式施用。本发明药物可利用各种方法施用，所述方法包括例如经直肠、肺部、口服、口腔、鼻内和经皮途径。在某些实施方案中，药物可通过动脉内注射、静脉内、腹膜内、经肠、非经肠、肌肉内、皮下、经口、局部或以吸入剂形式施用。
本发明药物制剂制备时可使用常用的稀释剂或赋形剂，如填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等。
本发明药物用作口服给药制剂的实例包括片剂、丸剂、硬/软胶囊、液体、悬浮液、乳液、糖浆、颗粒、酏剂、锭剂等。除了活性成分外，这些制剂可含有稀释剂(如乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素和/或甘氨酸)或润滑剂(如二氧化硅、滑石、硬脂酸及其镁盐或钙盐和/或聚乙二醇)。片剂可含有粘合剂，例如硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和聚乙烯叱咯烷等，并且可任选地含有崩解剂(例如淀粉、琼脂、海藻酸或其钠盐、或沸腾混合物)吸收剂、着色剂、调味剂、甜味剂等。
本发明药物的一种施用模式为非经肠，例如通过注射，可将其制成水性或油性悬浮液或乳液，含有芝麻油、玉米油、棉籽油、花生油中的一种以及酏剂、甘露糖醇和右旋糖，或无菌水溶液和类似医药媒剂。
本发明药物以吸入或吹入方式使用时，可包括溶液和悬浮液的药学上可接受的水性溶剂或有机溶剂或其混合物以及散剂。液体或固体药物可含有如本文中所描述的适合的药学可接受的赋形剂。在一些实施方案中，针对局部或全身性作用，通过经口或经鼻呼吸道途径施用药物。在其它实施方案中，药学上可接受的溶剂中的药物可通过使用惰性气体进行雾化。雾化溶液可直接自雾化装置吸入或雾化装置可连接到面罩托或间歇性正压呼吸机。可以是适合递送装置施用(优选经口或经鼻)的溶液、悬浮液或粉末组合物。
此外，本发明涉及一种用于预防或治疗LRRK2或异常LRRK2突变引起的相关病症的药物试剂盒，试剂盒包括化学式1表示的化合物或其药学上可接受的盐、氘化类似物、互变异构体、立体异构体、立体异构体的混合物、前药或氘化类似物，和使用所述化合物治疗适应症(包括本文所述的疾病或病状)的标签和/或说明。包括处于适合容器中的本文中所描述的化合物或其药学上可接受的盐、氘化类似物、互变异构体、立体异构体、立体异构体混合物、前药或氘化类似物。容器可为小瓶、广口瓶、安瓿、预装载注射器和静脉内袋。
此外，在本公开的另一方面中，化学式1表示的化合物可与其它药剂组合施用，所述药剂包括(但不限于)：为细胞凋亡抑制剂的化合物、PARP聚(ADP-核糖)聚合酶抑制剂、Src抑制剂、用于治疗血管疾病、高血压、高胆固醇血症和ⅡⅠ型糖尿病的药剂、抗炎症剂药剂、抗栓塞剂、纤维蛋溶解剂、抗血小板药剂、降脂剂、直接凝血酶抑制剂、糖蛋白IIb/IIla受体抑制剂、钙离子通道阻断剂、B肾上腺素激导性受体阻断剂、环加氧酶(例如，COX-1和COX-2)抑制剂、血管紧张素系统抑制剂(例如，血管收缩素转化酶(ACE)抑制剂)、肾素抑制剂，和/或与细胞粘着分子结合并抑制白血细胞与此类分子连接的能力的药剂(例如，多肽抗体、多克隆抗体和单克隆抗体)。另外，本公开的化合物可与具有治疗神经退化疾病的活性的额外药剂组合施用。举例来说，在一些实施方案中，化合物可与适用于治疗帕金森氏病的一或多种额外治疗剂组合施用。在一些实施方案中，额外治疗剂为L-多巴(例如，sinemetCR)、多巴胺激导性促效剂(例如，罗宾奈索(Ropinerol)或普拉克索(Pramipexole))、儿茶酚-0-甲基转移酶(COMT)抑制剂(例如恩他卡朋(Entacapone))、L-单胺氧化酵素(MAO)抑制剂(例如，司来吉兰(selegiline)或雷沙吉兰(rasagiline))或增加多巴胺释放的药剂(例如，唑尼沙胺(Zonisamide))。
实施例1
参考专利WO2006055561A3制备(1S，2S，3R，4R)-3-[[5-氟-2-[3-甲基-4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]双环[2.2.1]庚-5-烯-2-甲酰胺，其结构式如下：
实施例2
参考专利WO2016022460A1制备N-叔丁基-3-[[5-甲基-2-[4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]苯磺酰胺，其结构式如下：
实施例3
参考药物化学杂志(Journal of Medicinal Chemistry,(2019),62(22),10305-10320)制备2-[[1-[2-氟-4-[[5-甲基-4-(1-丙-2-基吡唑-4-基)嘧啶-2-基]氨基]苯基]哌啶-4-基]-甲基氨基]乙醇，其结构式如下：
实施例4
参考专利WO2009143389制备5-氯-4-N-(2-二甲基磷酰苯基)-2-N-[2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基]嘧啶-2,4-二胺，其结构式如下：
实施例5
参考药物化学杂志(Journal of Medicinal Chemistry,(2012),55(8),3852-3866)制备1-(4-甲基苯基)-3-[5-[7-(3-吗啉-4-基丙氧基)喹唑啉-4-基]磺酰基-1,3,4-噻二唑-2-基]脲，其结构式如下：
实施例6
参考专利WO02092577A1制备N-(2-氯-5-甲氧基苯基)-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹唑啉-4-胺，其结构式如下：
实施例7
参考专利WO 2013142382 A1制备8-溴-2-[(1-甲基哌啶-4-基)氨基]-4-(4-苯氧基苯胺)-6H-吡啶[4,3-d]嘧啶-5-酮，其结构式如下：
实施例8
参考专利WO2007041358A2制备6-(4-甲基哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)-2-[((E)-2-苯基乙烯基]嘧啶-4-胺，其结构式如下：
实施例9
参考专利WO2010128659 A1制备6-乙基-3-[3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯胺基]-5-(氧烷-4-基氨基)吡嗪-2-羧酰胺，其结构式如下：
实施例10
参考专利WO2007058627 A1制备(16E)-11-(2-吡咯烷-1-乙氧基)-14,19-二恶英-5,7,27-三氮四环[19.3.1.12,6.18,12]庚-1(24)，2(27)，3,5,8(26)，9,11,16,21(25)，22-癸烯，其结构式如下：
对比例
参考专利WO2011151360制备[4-[[5-氯-4-(甲基氨基)嘧啶-2-基]氨基]-3-甲氧基苯基]吗啉-4-基甲酮，其结构式如下：
实施例1至10中制备的化合物的结构示于表1中。
表1
实施例11：化合物的生物活性测定
(1)材料
LRRK2G2019S酶、底物(LRRK肽)、ATP、TR-FRET稀释液缓冲液、pLRRK肽抗体、384孔测定培养盘以及DMSO。
(2)酶反应条件：50mM Tris pH7.5、10mM MgCl2、1mM EGTA、0.01％Brij-35、2mMDTT，5nM LRRK2，134μM ATP，60分钟反应时间，23℃反应温度，10μL总反应体积。
侦测反应条件：1×稀释液缓冲液，10mM EDTA，2nM抗体，23℃反应温度10μL总反应体积。
(3)实验步骤
用100％DMSO溶解稀释测试化合物得到10mM或100μM的储备原液)，以比例为原液体积：缓冲液体积＝1:3.16(20μL+43.2μL)稀释得到最高测试浓度100μM或1μM的待测液。将5μL待测液转移至测定板，未处理的空白对照孔含有5μL DMSO和对照组5μL已知抑制剂比较例的DMSO溶液相继添加到源培养盘(384孔测定培养盘，Labcyte)。将培养盘在2500rpm下离心1分钟并用箔片密封。使用反应缓冲液进行3倍连续稀释以得到11个测试点，并将稀释后100nL的测试化合物溶液、已知抑制剂比较例化合物溶液、DMSO溶液空白组转移至测定培养盘，每个浓度2个复孔。将测定培养盘在2500rpm下离心1分钟,并用箔片密封。
为进行酶反应，将5μL的含5nM LRRK2酶的50mM Tris pH7.5、10mM MgCl2、1mMEGTA、0.01％Brij-35、2mM DTT缓冲液添加到测定培养盘的所有孔。离心培养盘，以将混合物浓缩在孔的底部。在23℃下孵育测定培养盘20分钟。孵育之后，将5μL的1X的激酶反应缓冲液配制2x LRRKtide Substrate和ATP添加到各孔，并离心培养盘以将混合物浓缩在孔的底部。在23℃下孵育培养盘60分钟。
为进行反应的侦测，将10μL包含抗体试剂和10mM EDTA的TR-FRET稀释缓冲液侦测试剂添加到测定培养盘的各孔的所有孔，并离心培养盘以将混合物浓缩在孔的底部。随后，在23℃下孵育培养盘60分钟。使用340m激发滤波器、520nm荧光发射滤波器和490或495nm铽发射滤波器，在TR-FRET模式下的Perkin elmer envision 2104仪器上读取培养盘。变体G2019S LRRK2的抑制作用以完全相同的方法测量。底物ATP和酶的所有最终浓度均相同。
用Graphpad软件进行数据分析，计算得到Kd活性值。
本文中所公开的若干化合物根据上文方法来测试，每个测试浓度为复孔，求平均值，在表2中提供了LRRK2和LRRK2 G2019S相应的Kd活性值。
表2
在本说明书和实施例中认定的所有专利和其他出版物明确地为所有目的通过用并入本文。提供这些出版物仅仅是因为它们的公开早于本申请的提交日期。就此而言，绝不应该被解释为承认本发明人无权凭借先有发明或出于任何其他原因在时间上早于这些公开。对于日期的所有陈述或对于这些文件内容的表述是基于本申请人可以获得的信息并且不对所述日期或这些文件的内容的正确性构成任何承认。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (1)
1.一种化合物在制备治疗因LRRK2激酶或LRRK2突变激酶活性提高而导致的疾病药物中的应用，其特征在于，所述化合物为以下化合物中的任意一种：
（1）（1S，2S，3R，4R）-3-[[5-氟-2-[3-甲基-4-（4-甲基哌嗪-1-基）苯胺基]嘧啶-4-基]氨基]双环[2.2.1]庚-5-烯-2-甲酰胺；
（2）2-[[1-[2-氟-4-[[5-甲基-4-（1-丙-2-基吡唑-4-基）嘧啶-2-基]氨基]苯基]哌啶-4-基]-甲基氨基]乙醇；
（3）5-氯-4-N-（2-二甲基磷酰苯基）-2-N-[2-甲氧基-4-[4-（4-甲基哌嗪-1-基）哌啶-1-基]苯基]嘧啶-2,4-二胺；
（4）6-乙基-3- [3-甲氧基-4- [4-（4-甲基哌嗪-1-基）哌啶-1-基]苯胺基] -5-（氧烷-4-基氨基）吡嗪-2-羧酰胺；
所述疾病为克罗恩氏病。
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