CN111655256B - 包含adam9抑制剂化合物的组合物 - Google Patents
包含adam9抑制剂化合物的组合物 Download PDFInfo
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- CN111655256B CN111655256B CN201880070735.8A CN201880070735A CN111655256B CN 111655256 B CN111655256 B CN 111655256B CN 201880070735 A CN201880070735 A CN 201880070735A CN 111655256 B CN111655256 B CN 111655256B
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明是关于式(I)的ADAM9抑制剂化合物,包含其盐,其组合物及其使用方法。包含使用有效量的所述化合物或组合物治疗有需要的人,并检测其结果以改善人的健康或状况。
Description
背景技术
ADAM9(含有去整合素和金属蛋白酶结构域的蛋白质9(Disintegrin andmetalloproteinase domain-containing protein 9)在许多肿瘤中过度表达,例如胰腺癌、乳腺癌、***癌和肺癌,且ADAM9高表现量与癌症病人预后差有关,可当作预测标记。因ADAM9表达可帮助肿瘤细胞适应不利的环境,使ADAM9被认为可促进肿瘤发展,并且被认为是比其他与癌症相关的金属蛋白酶更好的治疗靶点。ADAM9因具有切割和释放许多参与癌症进展相关分子的能力而参与肿瘤发生,由于其能够切割和释放参与癌症进展的许多分子而参与肿瘤发生,并且肿瘤周围的基质细胞所分泌的ADAM9可藉由新血管形成促进肿瘤发展。
我们先前发表的结果显示,抑制ADAM9表达及其下游信号传导可显著延长肺肿瘤小鼠的存活时间。而从肺癌和乳腺癌的临床样本明显可见,肿瘤标本中ADAM9表现水平低的患者存活时间长于ADAM9表现水平高的患者。此外,由于ADAM9缺陷鼠并无明显表型,代表以ADAM9当标靶蛋白可能有良好的药物耐受性。
在本发明中我们公开了小分子化合物的设计,并确认其可作为ADAM9抑制剂来阻断ADAM9蛋白酶的活性。
发明内容
本发明的一态样是在提供一种组合物,包含式I化合物,或其医药上可接受的盐类,以及共同配制的不同的抗癌化合物,其中所述的式I化合物如下所示:
其中所述的式I化合物选自:
及
在实施例中
-所述的式I化合物为
-所述的式I化合物为
本发明包括本文所述的特定实施方式的所有组合。
具体实施方式
以下对于特定实施方式和实施例的描述仅用于说明而非为限制,本领域技术人员而言可依据其所进行各种修改或改变各种非关键参数以产生基本相似结果。本发明提供多种实施方式。
除非另有说明,本文中及本说明书所述之「一」及「一个」意指文章中的文法对象为一或多个(即至少一个),「或」意指「及/或」,以及多核酸序列应理解为包含了正股之序列和反股之序列和本文所述的可替代的骨架。此外,类别为包含于该类别的所有成员的缩写;例如,C1-C3的烷基为对所有C1-C3的烷基的缩写,举例而言,C1-C3的烷基包含甲基、乙基、丙基及其异构体。
下列用语、片语和符号通常旨在具有以下阐述的含义,除非使用它们的上下文中另有说明。以下缩写词和术语具有指示的含义。
本说明书所述之「烷基」是指选自碳原子数为1-18个、1-12个或1-6个的直链和支链饱和的烃基。烷基的实例包含甲基、乙基、1-丙基或正丙基("n-Pr")、2-丙基或异丙基("i-Pr")、1-丁基或正丁基("n-Bu")、2-甲基-1-丙基或异丁基("i-Bu")、1-甲基丙基或仲丁基("s-Bu")和1,1-二甲基乙基或叔丁基("t-Bu")。烷基的其他实例包含但不限于1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基和3,3-二甲基-2-丁基。
而低碳数烷基是指碳原子数为1-8个,较佳地为1-6个,更佳地为1-4个的烷基。低碳数烯基或炔基是指碳原子数为2-8个、2-6个或2-4个的烯基或炔基。
本说明书所述之「烯基」是指选自包含至少一个C=C双键和碳原子数为2-18个、2-12个或2-6个的直链和支链的烃基。烯基的实例可选自但不限于乙烯基或乙烯基、丙-1-烯基、丙-2-烯基、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和六-1,3-二烯基团。
本说明书所述之「炔基」是指选自直链和支链烃基,其包含至少一个C≡C三键和2-18个、2-12个或2-6个碳原子。炔基的实例包含但不限于乙炔基、1-丙炔基、2-丙炔基(炔丙基)、1-丁炔基、2-丁炔基和3-丁炔基。
本说明书所述之「环烷基」是指选自饱和及部分不饱和的环状烃基,包含单环和多环(例如双环和三环)基团。例如,环烷基可以是碳原子数为3-12个、3-8个或3-6个的环状烃基。进一步可举例,环烷基可以是碳原子数为3-12个、3-8个或3-6个的单环基团。单环环烷基的实例包含但不限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己基-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基和环十二烷基。双环环烷基的实例包含但不限于具有7-12个环原子且其双环排列为选自[4,4]、[4,5]、[5,5]、[5,6]和[6,6]的环***,或选自双环[2.2.1]庚烷、双环[2.2.2]辛烷和双环[3.2.2]壬烷的桥键联双环。环可以是饱和的或具有至少一个双键(即部分不饱和的),但不是完全共轭的,并且不是芳族的。具有芳基的芳族在本说明书中另有定义。
本说明书所述之「芳基」是指选自以下的基团:5-和6-元碳环芳环,例如苯基、双环***和三环***。其中所述之双环***可为7-12元双环***,其中至少一个环是碳环和芳香环,其选自但不限于萘、二氢化茚和1,2,3,4-四氢喹啉。所述之三环***可为10-15元三环***,其中至少一个环是碳环和芳香环,例如芴。
举例而言,芳基选自与任选地包含至少一个选自氮、氧和硫的杂原子的5-至7-元环烷基或杂环稠合的5-和6-元碳环芳环。当碳环芳环与杂环稠合时,连接点在碳环芳环上,当碳环芳环与环烷基稠合时,连接点可以在碳环芳环或环烷基上。由取代的苯衍生物形成并在环原子上具有自由价的二价基团被称为取代的亚苯基基团。藉由从具有自由价的碳原子移除一个氢原子而源于名称以“-基(-idene)”结尾的单价多环烃基团的二价基团通过添加“-亚基(-yl)”至相应单价基团的名称中来命名,例如具有两个连接点的萘基被称为亚萘基。然而,芳基不包含杂芳基或与杂芳基重迭,本说明书下文分别定义。因此,如果一个或多个碳环芳环与杂环芳环稠合,则所得的环***是杂芳基,而非本说明书所定义的芳基。
本说明书所述之「卤素」是指氟、氯、溴或碘。
本说明书所述之「杂烷基」是指包含至少一个杂原子的烷基。
本说明书所述之「杂芳基」是指选自以下的基团:
5-至7-元芳族单环,包含1、2、3或4个选自氮、氧和硫的杂原子,其余的环原子为碳;
包含1、2、3或4个选自氮、氧和硫的杂原子的8-至12-元双环,其余环原子为碳,并且其中至少一个环为芳族且至少一个杂原子存在于芳香环。
例如,杂芳基包含与5-至7-元环烷基环稠合的5-至7-元杂环芳环。前述稠合的双环杂芳基环***,其中仅一个环包含至少一个杂原子,连接点可以在杂芳环或环烷基环上。
当杂芳基中硫和氧原子的总数超过1时,该些杂原子彼此不相邻。在一些实施方案中,杂芳基中硫和氧原子的总数不大于2,在另一些实施方案中,芳族杂环中硫和氧原子的总数不大于1。
杂芳基的实例包含但不限于(从分配优先级1的链接位置开始编号)吡啶基(如2-吡啶基、3-吡啶基或4-吡啶基)、喹啉基、吡嗪基、2,4-嘧啶基、3,5-嘧啶基、2,4-咪唑基、咪唑并吡啶基、异恶唑基、恶唑基、噻唑基、异噻唑基、噻二唑基、四唑基、噻吩基、三嗪基、苯并噻吩基、呋喃基、苯并呋喃基、苯并咪唑基、吲哚基、异吲哚基、二氢吲哚基、酞嗪基、吡嗪基、哒嗪基、吡咯基、***基、喹啉基、异喹啉基、吡唑基、吡咯并吡啶基(如1H-吡咯并[2,3-b]吡啶-5-基)、吡唑并吡啶基(如1H-吡唑并[3,4-b]吡啶-5-基)、苯并恶唑基(如苯并[d]恶唑-6-基)、哌啶基、嘌呤基、1-氧杂-2,3-二唑基、1-氧杂-2,4-二唑基、1-氧杂-2,5-二唑基、1-氧杂-3,4-二唑基、1-噻吩-2,3-二唑基、1-噻吩-2,4-二唑基、1-噻吩-2,5-二唑基、1-噻吩-3,4-二唑基、呋喃基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并恶唑基、喹唑啉基、喹喔啉基、萘啶基、呋喃并吡啶基、苯并噻唑基(如苯并[d]噻唑-6-基)、吲唑基(如1H-吲唑-5-基)和5,6,7,8-四氢异喹啉。
本说明书所述之「杂环」或「杂环基」是指选自4-至12-元的单环、双环和三环以及饱和及部分不饱和环。所述饱和及部分不饱和环除了包含1、2、3或4个选自氧、硫和氮的杂原子外,还含有至少一个碳原子。「杂环」还指包含至少1个选自氮、氧和硫的杂原子的5-至7-元杂环,所述杂原子与5-、6-和/或7-元环烷基、碳环芳族或杂芳族环稠合,条件是当杂环与碳环芳香环或杂芳环稠合时,连接点在杂环上,并且当杂环与环烷基稠合时,连接点可以在环烷基或杂环上。
「杂环」还指包含至少一个选自氮、氧和硫的杂原子的脂族螺环,条件是连接点在杂环上。环可以是饱和的或具有至少一个双键(即部分不饱和的)。杂环可以被氧代取代。杂环中的附着点可以是碳或杂原子。杂环基不是本说明书所定义的杂芳基。
杂环的实例包含但不限于(从分配优先级1的链接位置开始编号)1-吡咯烷基、2-吡咯烷基、2,4-咪唑烷基、2,3-吡唑烷基、1-哌啶基、2-哌啶基、3-哌啶基、4-哌啶基、2,5-哌嗪基、吡喃基、2-吗啉基、3-吗啉基、环氧乙烷基、氮丙啶基、硫杂环丁基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、1,2-二噻烷基、1,3-二噻烷基、二氢吡啶基、四氢吡啶基、硫代吗啉基、噻吩基、哌嗪基、高哌嗪基、高哌啶基、氮杂环庚烷基、氧杂环庚烷基、噻吩基、1,4-氧杂硫杂环戊烷、1,4-二氧杂环庚烷基、1,4-氧杂硫杂环戊烷、1,4-氧杂氮杂环庚烷基、1,4-二噻吩基、1,4-硫杂环庚烷、1,4-二氮杂环庚烷、1,4-二噻烷基、1,4-氮杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、二氢噻吩基、二氢吡喃基、二氢呋喃基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、二氢-吡喃基、四氢-吡喃基、1,4-二恶烷基、1,3-二氧戊环基、吡唑啉基、吡唑烷基、二硫醇基、二硫杂环戊基、吡唑烷基咪唑啉基、嘧啶酮基、1,1-二氧代-硫代吗啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基和氮杂双环[2.2.2]己基。取代的杂环还包含被一个或多个被氧取代部分的环系,例如哌啶基N-氧化物、吗啉基-N-氧化物、1-氧代-1-硫代吗啉基和1,1-二氧代-1-硫代吗啉基。
取代基选自:卤素、-R'、-OR'、=O、-NR'、=N-OR'、=NR'R"、-SR'、-SiR'R"R'"、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R'"、-NR'SO2NR'"、-NR"CO2R'、-NH-C(NH2)=NH、-NR'C(NH2)=NH、-NH-C(NH2)=NR'、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R、-CN和-NO2、-N3、-CH(Ph)2、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,其数量范围为0至3,较佳地为具有0、1或2个取代基的基团。R'、R"和R'"各自独立地表示为氢、未取代的(C1-C8)烷基和杂烷基、未取代的芳基、被1至3个卤素取代的芳基、未取代的烷基、烷氧基或硫代烷氧基、或芳基-(C1-C4)烷基。当R'和R"与相同的氮原子连接时,可以与氮原子结合形成5-、6-或7-元环。因此-NR'R"包含1-吡咯烷基和4-吗啉基,「烷基」包含三卤代烷基的基团(例如-CF3和-CH2CF3),且当芳基是1,2,3,4-四氢化萘时,可以被取代或未取代的(C3-C7)螺环烷基取代。而(C3-C7)螺环烷基可以本说明书中对「环烷基」所定义的相同方式被取代。
优选的取代基选自:卤素、-R'、-OR'、=O、-NR'R"、-SR'、-SiR'R"R'"、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-SO2NR"R'"、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R、-CN和-NO2、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,其中R'和R"的定义如上所述。
化合物可含有不对称中心,因此可作为镜像异构物存在。当化合物具有两个或更多个不对称中心时,可另外作为非镜像异构物存在。镜像异构物和非镜像异构物属于更广泛的立体异构体类别。所有可能的立体异构体包含如实质上纯的可分离的镜像异构物、其外消旋混合物以及非镜像异构物的混合物。化合物的所有立体异构体和/或其药学上可接受的盐皆被包含在适用的情况下。除非另有说明,否则提及的异构体适用于任何可能的异构体。而当异构体组合物未指定时,包含所有可能的异构体。
本说明书所述之「实质上纯的」是指目标立体异构体以重量计算含有其他任何立体异构体的量不超过35%,例如不超过30%,较佳地不超过25%,更佳地不超过20%。在一些实施方案中,「实质上纯的」是指目标立体异构体以重量计算含有其他任何立体异构体的量不超过10%,较佳地不超过5%,更佳地不超过1%。
当化合物含有烯烃双键时,除非另有说明,否则双键表示化合物包含E和Z几何异构体。
一些化合物可能存在氢的不同连接点而称为互变异构体。例如,包含羰基-CH2C(O)-基团(酮形式)的化合物可以经互变异构而形成羟基-CH=C(OH)-基团(烯醇形式)。酮和烯醇两者单独形成以及同时含有酮和烯醇的混合物也包含在适用的情况下。
将反应产物彼此分离和/或与原料分离是有利的。可藉由本领域常用的技术将每个步骤或一系列步骤的所需产物分离和/或纯化(下文中称为分离)至所需的均匀度。通常前述分离涉及多相萃取、从溶剂或溶剂混合物中结晶、蒸馏、升华或层析法。层析法可包含反相层析法、正相层析法、尺寸大小排除层析法、离子交换层析法、高、中、低压液相层析法和装置、小规模分析层析法、模拟移动床层析法("SMB")和制备薄层层析法或厚层层析法,以及小规模薄层和快速层析法。本领域技术人员将应用最适合的技术达到所需的分离效果。
非镜像异构物混合物可以藉由本领域技术人员熟知的方法,例如基于非镜像异构物间的物理化学差异藉由层析法和/或分级结晶而分离。藉由与适当的光学活性化合物(例如,手性助剂如手性醇或Mosher酰氯化物)反应,将镜像异构物混合物转化为非镜像异构物混合物,分离非镜像异构物并将各个非镜像异构物转化(例如水解)成相应的纯镜像异构物。镜像异构物也可以使用手性HPLC柱分离。
单一立体异构体,例如实质上纯的镜像异构物,可以藉由使用光学活性分离剂取得(可参考Eliel,E.and Wilen,S.Stereochemistry of Organic Compounds.New York:John Wiley&Sons,Inc.,1994;Lochmuller,C.H.,et al."Chromatographic resolutionof enantiomers:Selective review."J.Chromatogr.,113(3)(1975):pp.283-302)。本发明的对掌性异构物的外消旋混合物可藉由任何合适的方法分离和纯化,所述方法包含:(1)将对掌性异构物形成离子型非镜像异构物盐,并藉由分级结晶或其他方法分离;(2)用手性衍生化试剂形成非镜像异构物后,分离非镜像异构物,再转化为纯立体异构体;以及(3)在手性条件下直接分离实质上纯的或富含的立体异构体。可参考:Wainer,Irving W.,Ed.Drug Stereochemistry:Analytical Methods and Pharmacology.New York:MarcelDekker,Inc.,1993。
本说明书所述之「药学上可接受的盐」包含但不限于与无机酸形成的盐以及与有机酸形成的盐。与无机酸形成的盐可选自例如盐酸盐、磷酸盐、二磷酸盐、氢溴酸盐、硫酸盐、亚磺酸盐和硝酸盐。与有机酸形成的盐可选自例如苹果酸、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟乙基磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐、链烷酸盐(例如乙酸盐)以及与HOOC-(CH2)n-COOH形成的盐,其中n为0至4。药学上可接受的阳离子的实例包含但不限于钠、钾、钙、铝、锂和铵。
此外,若化合物是作为酸加成盐,则可以藉由碱化酸式盐的溶液来获得游离碱。相反,如果产物是游离碱,则可以通过将游离碱溶解在合适的有机溶剂中并以酸处理所述溶液,再依照碱化合物制备酸加成盐的常规方法来制备加成盐(例如药学上可接受的加成盐)。本领域技术人员可在没有过度实验的情况下使用的各种合成方法来制备无毒的药学上可接受的加成盐。
本说明书所述之「治疗(treating)」、「治疗(treat)」或「治疗(treatment)」是指将至少一种化合物和/或至少一种立体异构体和/或至少一种其药学上可接受的盐施用予有需要的受试者,例如癌症患者。
本说明书所述之「有效量」是指有效「治疗」受试者的疾病或病症的至少一种化合物和/或其至少一种立体异构体和/或至少一种其药学上可接受的盐的量。有效量与所施用的组织、***、动物或人的生物或医学反应有一定程度上的相关性,例如当施用时其足以在一定程度上防止一种或多种疾病或病症的发展或减轻一种或多种所治疗的病症或病症的症状。治疗有效量将根据化合物、疾病及其严重程度以及待治疗的哺乳动物的年龄和体重等而变化。
本说明书所述之「至少一个取代基」包含但不限于1至4个取代基、1至3个取代基、1或2个取代基。例如所述「至少一个取代基L-R4」在本说明书中包含1至4个、1至3个、1或2个选自本说明书所述的L-R4列表的取代基。
本发明之化合物、其立体异构体及其药学上可接受的盐可单独使用或与至少一种其它治疗剂合并使用进行治疗。在一些实施方案中,化合物、其立体异构体及其药学上可接受的盐可以与至少一种另外的治疗剂合并使用。所述至少一种另外的治疗剂可以选自抗过度增殖剂、抗癌剂和化学治疗剂。本说明书揭示的化合物和/或一种药学上可接受的盐可以与单一剂型中的至少一种其他治疗剂一起施用,或作为单独剂型施用。当作为单独剂型施用时,可以在施用本说明书揭示的化合物和/或一种药学上可接受的盐之前,同时或之后施用至少一种其他治疗剂。
本说明书所述之「化学治疗剂」是指用于治疗癌症的化学化合物而不论其作用机理。化学治疗剂包含用于「靶向治疗」和常规化疗的化合物。合适的化学治疗剂,举例来说,可以选自:诱导细胞雕亡试剂、多核苷酸(例如核酶)、多肽(例如酶)、药物、生物模拟物、生物碱、烷化剂、抗肿瘤抗生素、抗代谢药物、激素、铂化合物、与抗癌药物、毒素和/或放射性核素结合的单株抗体、生物反应调节剂(例如IFN-α等干扰素和IL-2等白细胞介素)、过继免疫治疗剂、造血生长因子、诱导肿瘤细胞分化的药剂(例如全反式维甲酸)、基因治疗试剂、反义治疗试剂和核苷酸、肿瘤疫苗以及血管生成抑制剂。
化学治疗剂的实例包含但不限于厄洛替尼(Erlotinib)(Genentech/OSI Pharm.);硼替佐米(Bortezomib)(/>Millennium Pharm.);氟维司群(Fulvestrant)(/>AstraZeneca);舒尼替尼(Sunitinib)(/>辉瑞);来曲唑(Letrozole)(/>诺华);甲磺酸伊马替尼(Imatinib mesylate)(诺华);PTK787/ZK 222584(诺华);奥沙利铂(Oxaliplatin)(/>Sanofi);5-FU(5-氟尿嘧啶);亚叶酸钙(Leucovorin);雷帕霉素(Rapamycin)(西罗莫司,Wyeth);拉帕替尼(Lapatinib)(/>GSK572016,Glaxo SmithKline);洛那法尼(Lonafarnib)(SCH 66336);索拉非尼(Sorafenib)(/>拜耳);伊立替康(Irinotecan)(/>辉瑞)和吉非替尼(Gefitinib)(阿斯特捷利康);AG1478、AG1571(SU 5271,Sugen);烷基化剂,例如噻替哌(thiotepa)和环磷酰胺(/>cyclosphosphamide);烷基磺酸盐,例如白消安(busulfan)、英丙舒凡(improsulfan)和呱泊舒凡(piposulfan);氮杂环庚烷,例如苯并二氮(benzodopa)、碳喹啉(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙烯亚胺和甲基蜜胺类,例如六甲蜜胺(altretamine)、三亚乙基蜜胺(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫代磷酰胺(triethylenethiophosphoramide)和三羟甲基蜜胺(trimethylomelamine);乙酰生合成物(acetogenins)(例如布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));喜树碱(camptothecin)(例如合成类似物托泊替康(topotecan));苔藓抑素(bryostatin);海绵多烯酮(callystatin)、CC-1065及其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物;隐藻素(cryptophycins)(例如隐藻素1和隐藻素8);多拉司他汀(dolastatin);倍癌霉素(duocarmycin)及其合成类似物,例如KW-2189和CB1-TM1;艾槽素(eleutherobin);水鬼蕉碱(pancratistatin);sarcodictyin;海绵抑素(spongistatin);氮芥类(nitrogen mustards)例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlomaphazine)、胆磷酰胺(chlorophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxidehydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶芥末(uracil mustard);亚硝基脲类,例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimnustine);抗生素类,例如烯二炔类抗生素(enediyne)(例如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1(可参见AgnewChem.Intl.Ed.Engl.(1994)33:183-186);蒽环类抗生素(dynemicin),包括dynemicin A;二膦酸盐类(bisphosphonates),例如氯膦酸盐(clodronate);埃斯波霉素(esperamicin);以及新制癌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团、阿克拉霉素(aclacinomysins)、放线菌素(actinomycin)、氨茴霉素(authramycin)、偶氮丝氨酸(azaserine)、博来霉素(bleomycins)、放线菌素C(cactinomycin)、卡拉比辛(carabicin)、洋红霉素(caminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycinis)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-二氮-5-氧-L-正亮氨酸、/>多柔比星(doxorubicin)、吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯代多柔比星和去氧多柔比星),表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类(mitomycins)例如丝裂霉素C、霉酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(porfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物类,例如甲氨蝶呤(methotrexate)和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸(denopterin)、甲氨蝶呤(methotrexate)、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,例如氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,例如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素类,例如卡鲁睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、表硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺类,例如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,例如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸(aminol evulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);***-氯芥苯丁酸复合物(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);伊尔福尼辛(elformithine);依利醋铵(elliptinium acetate);埃坡霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱类(maytansinoids),例如美登素(maytansine)和安丝菌素(ansamitocins);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫呱达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基酰肼(2-ethylhydrazide);丙卡巴肼(procarbazine);/>多糖复合物(JHS NaturalProducts,Eugene,Oreg.);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofuran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2”-三氯三乙胺;单端孢菌素类(trichothecenes)(尤其是T-2毒素、疣孢菌素(verracurin)A、杆孢菌素(roridin)A和蛇行菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);呱泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺(cyclophosphamide);塞替派(thiotepa);类紫杉醇类(taxoids),例如/>帕利他塞(paclitaxel,Bristol-Myers Squibb Oncology,Princeton,N.J.)、/>不含克列莫佛(Cremophor-free)、清蛋白改造纳米颗粒剂型帕利他塞(American Pharmaceutical Partners,Schaumberg,Ill.)和/>多西他塞(doxetaxel;Rhone-Poulenc Rorer,Antony,France);苯丁酸氮芥(chloranmbucil);/>吉西他滨(gemcitabine);6-硫鸟嘌呤(6-thioguanine);巯基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂类似物,例如顺铂(cisplatin)和卡铂(carboplatin);长春碱(vinblastine);依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine);/>长春瑞滨(vinorelbine);能灭瘤(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);卡培他滨(capecitabine)(/>);伊本膦酸盐(ibandronate);抗癌妥(CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类维生素A(例如维甲酸);以及上述任一种药学上可接受的盐、酸和衍生物。
「化学治疗剂」还可以选自:(i)用来调节或抑制激素对肿瘤的作用的抗激素药,例如抗***(anti-estrogens)和选择性***受体调节剂(selective estrogenreceptor modulators,SERMs),包含他莫昔芬(tamoxifen)(包括他莫昔芬柠檬酸盐(tamoxifen citrate))、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羟基他莫昔芬(4-hydroxytamoxifen)、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和/>(toremifine citrate);(ii)抑制调节肾上腺中的***生成的芳香酶的芳香酶抑制剂,例如4(5)-咪唑、氨鲁米特(aminoglutethimide)、/>(醋酸甲地孕酮)、/>(依西美坦;辉瑞)、福美坦(formestanie)、法罗唑(fadrozole)、/>(伏罗唑)、/>(来曲唑;诺华)和/>(阿那罗唑;阿斯特捷利康);(iii)抗雄激素类,例如氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);以及曲沙他滨(troxacitabine)(1,3-二氧戊环胞嘧啶核苷类似物);(iv)蛋白激酶抑制剂;(v)脂质激酶抑制剂;(vi)反义寡核苷酸,特别是抑制与异常的细胞增殖相关的信号转导途径中的基因例如PKC-α、Ralf和H-Ras;(vii)核酶,例如VEGF表达抑制剂(例如/>)和HER2表达抑制剂;(viii)疫苗,例如基因治疗疫苗,例如/>和/> rlL-2;拓扑异构酶1抑制剂,例如/> rmRH;(ix)抗血管生成剂,例如贝伐珠单抗(/>Genentech);以及(x)上述任一种的药学可接受的盐、酸和衍生物。
「化学治疗剂」也可以选自治疗性抗体,例如阿仑珠单株抗体(Campath)、贝伐珠单株抗体(Genentech);西妥昔单株抗体(/>Imclone);帕木单株抗体(/>Amgen)、利妥昔单株抗体(/>Genentech/Biogen Idec)、帕妥珠单株抗体(/>2C4,Genentech)、曲司珠单株抗体(/>Genentech)、托西莫单株抗体(Bexxar,Corixia),以及抗体药物偶联物,吉妥珠单株抗体奥加米星(/>Wyeth)。
具有作为化学治疗剂的治疗潜力的人源化单株抗体,与其目标化合物、其立体异构体及其药学上可接受的盐可以选自:阿仑珠单抗(alemtuzumab)、阿泊珠单株抗体(apolizumab)、阿塞珠单株抗体(aselizumab)、阿利珠单株抗体(atlizumab)、巴匹珠单株抗体(bapineuzumab)、贝伐单株抗体(bevacizumab)、比伐珠单株抗体美登素(bivatuzumabmertansine)、美坎珠单株抗体美登素(cantuzumab mertansine)、西利珠单株抗体(cedelizumab)、赛妥珠单株抗体(certolizumab pegol)、西福珠单抗(cidfusituzumab)、西土珠单抗(cidtuzumab)、达珠单株抗体(daclizumab)、依库珠单株抗体(eculizumab)、依法利珠单株抗体(efalizumab)、依帕珠单株抗体(epratuzumab)、厄利珠单株抗体(erlizumab)、泛维珠单株抗体(felvizumab)、芳妥珠单株抗体(fontolizumab)、吉妥珠单株抗体奥佐米星(gemtuzumab ozogamicin)、伊珠单株抗体奥佐米星(inotuzumabozogamicin)、伊匹木单株抗体(ipilimumab)、拉贝珠单株抗体(labetuzumab)、林妥珠单抗(lintuzumab)、马妥珠单株抗体(matuzumab)、美泊利单株抗体(mepolizumab)、莫维珠单株抗体(motavizumab)、莫妥珠单抗(motovizumab)、那他珠单株抗体(natalizumab)、尼妥珠单抗(nimotuzumab)、诺罗珠单抗(nolovizumab)、努玛珠单抗(numavizumab)、奥瑞珠单株抗体(ocrelizumab)、奥马珠单株抗体(omalizumab)、帕利珠单株抗体(palivizumab)、帕考珠单株抗体(pascolizumab)、帕西珠单抗(pecfusituzumab)、培妥珠单抗(pectuzumab)、帕妥珠单株抗体(pertuzumab)、培克珠单株抗体(pexelizumab)、拉利珠单抗(ralivizumab)、雷珠单株抗体(ranibizumab)、瑞利珠单株抗体(reslivizumab)、瑞利珠单株抗体(reslizumab)、瑞维珠单抗(resyvizumab)、罗维珠单株抗体(rovelizumab)、卢利珠单株抗体(ruplizumab)、西罗珠单株抗体(sibrotuzumab)、西利珠单株抗体(siplizumab)、松妥珠单株抗体(sontuzumab)、他珠单株抗体替塞坦(tacatuzumab tetraxetan)、他度珠单株抗体(tadocizumab)、他利珠单株抗体(talizumab)、替非珠单株抗体(tefibazumab)、托珠单株抗体(tocilizumab)、托利珠单株抗体(toralizumab)、曲妥珠单株抗体(trastuzumab)、西莫白介素单株抗体(tucotuzumab celmoleukin)、突西珠单抗(tucusituzumab)、乌玛珠单抗(umavizumab)、乌珠单株抗体(urtoxazumab)和维西珠单株抗体(visilizumab)。
本发明另提供了包含目标化合物、其立体异构体及其药学上可接受的盐和至少一种药学上可接受的载体的组合物。
包含目标化合物、其立体异构体的组合物及其药学上可接受的盐可以用各种已知方式给药,例如口服、局部、直肠、肠胃外、藉由吸入喷雾,或藉由植入式贮存器。任何给定情况下最合适的途径将取决于特定宿主,以及给予活性成分的性质和严重程度。本说明书所述之「肠胃外」包含皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内和颅内注射或输注技术。本说明书揭示的组合物可以方便地以单位剂型提供,并藉由本领域熟知的任何方法制备。
本发明化合物及其立体异构体及其药学上可接受的盐可以固体剂型口服给药,例如胶囊、片剂、锭剂、糖衣丸、颗粒和粉末;或以液体剂型口服给药,例如酏剂、糖浆、乳剂、分散剂和悬浮液。本说明书揭示的目标化合物、其立体异构体及其药学上可接受的盐还可以于肠胃外施用以无菌液体剂型,例如分散体、悬浮液或溶液。其它剂量形式也可用于施用本发明之目标化合物、其立体异构体及其药学上可接受的盐,例如作为软膏、乳膏、滴剂、经皮贴剂或粉末用于局部给药;作为眼用溶液或悬浮液形式,即用于眼部给药的滴眼剂;用于吸入或鼻内给药的气溶胶喷雾剂或粉末组合物;或用于直肠或***给药的乳膏剂、软膏剂、喷雾剂或栓剂。
此外,本说明书揭示的化合物和/或其至少一种药学上可接受的盐和粉末状载体亦可被包覆于明胶胶囊中,所述粉末状载体可举例但不限于乳糖、淀粉、纤维素衍生物、硬脂酸镁和硬脂酸。类似的稀释剂可用于制备压缩片剂。片剂和胶囊均可制成持续释放产品,以在一段时间内连续释放药物。压缩片剂可以是涂覆糖衣或薄膜包衣的,以掩盖任何令人不快的味道并保护片剂不受大气影响,或为肠溶包衣以在胃肠道中选择性崩解。
用于口服给药的液体剂型可进一步包含至少一种选自着色剂和调味剂的药剂,以增加患者的接受度。
通常,水、合适的油、盐水、葡萄糖水溶液(葡萄糖)和相关的糖溶液和乙二醇,例如丙二醇或聚乙二醇可以是用于肠胃外溶液的合适载体的实例。用于肠胃外给药的溶液可包含至少一种本说明书所述化合物的水溶性盐、至少一种合适的稳定剂,以及如果需要的话至少一种缓冲物质。单独或组合的抗氧化剂,例如亚硫酸氢钠、亚硫酸钠或抗坏血酸,可以是合适的稳定剂的实例。柠檬酸及其盐和乙二胺四乙酸钠也可用作合适稳定剂的实例。此外,肠胃外溶液可进一步包含至少一种防腐剂,例如选自苯扎氯铵、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和氯丁醇。
本说明书所述之「药学上可接受的载体」可选自与组合物的活性成分相容的载体(并且在一些实施方案中能够稳定活性成分)并且对待治疗的受试者无害。举例而言,增溶剂,例如环糊精(其可与本说明书揭示的至少一种化合物和/或至少一种药学上可接受的盐形成特定更可溶的复合物)可用作药物赋形剂以递送活性成分。其他载体的实例包含胶体二氧化硅、硬脂酸镁、纤维素、十二烷基硫酸钠和颜料,例如D&C Yellow#10。合适的药学上可接受的载体可参照Remington's Pharmaceutical Sciences,A.Osol,其为本领域的标准参考文献。
本发明揭示的目标化合物、其立体异构体及其药学上可接受的盐可以藉由体内(in vivo)试验进一步验证其治疗ADAM9相关疾病(ADAM9活性在一种或多种细胞类型中过表达并且是致病性的病症)的功效。例如,本说明书揭示的化合物和/或其至少一种其药学上可接受的盐可以施用于患有ADAM9相关疾病的动物(例如小鼠模型),并且可以获得治疗效果。在一个或多个测试中的阳性结果足以证明所测试的化合物和/或盐的实际效用。并且可基于试验结果确定动物(例如人)的合适剂量范围和给药途径。
关于吸入给药,本发明之化合物、其立体异构体及其药学上可接受的盐可以加压包装或喷雾器的气溶胶喷雾形式方便地递送。本发明之化合物、其立体异构体及其药学上可接受的盐也可以粉末形式递送,其可以被配制并且粉末组合物可以藉助于吹入粉末吸入器装置吸入。用于吸入的一种示例性递送***可以是计量吸入(MDI)气溶胶,其可以配制成本发明揭示的目标化合物、其立体异构体的悬浮液或溶液,以及其在至少一种合适的推进剂,例如碳氟化合物和碳氢化合物中的药学上可接受的盐。
关于眼部给药,眼科制剂可以用适当重量百分比的目标化合物、其立体异构体的溶液或悬浮液及其药学上可接受的盐配制在合适的眼科载体中,使得本发明化合物、其立体异构体及其至少一种药学上可接受的盐与眼表面保持足够的时间以使化合物渗透眼睛的角膜和内部区域。
用于施用本发明之化合物、其立体异构体及其药学上可接受的盐的有用药物剂型包含但不限于硬和软明胶胶囊、片剂、肠胃外注射剂和口服悬液剂。
施用的剂量的取决因素包含受试者的年龄、受试者的健康和体重、疾病的程度、同时治疗的类型(如果有的话)、治疗频率和所需效果的性质。通常活性成分的每日剂量可以为非定量,例如每天0.1至2000mg。例如,每天一次或多次10-500mg可有效获得所需结果。
在一些实施方案中,可以藉由填充标准的两片式硬明胶胶囊来制备大量单位胶囊,所述胶囊各自具有例如100mg本发明之化合物、其立体异构体及其药学上可接受的盐粉末,和其它药学上可接受的赋形剂,例如乳糖、纤维素和硬脂酸镁。
在一些实施方案中,制备含有本发明之化合物、其立体异构体和其药学上可接受的盐的混合物至可消化的油,例如大豆油、棉籽油或橄榄油中,并通过正位移泵注入明胶中以形成软明胶胶囊,其中所含有的活性成分为100mg,再将胶囊洗涤并干燥。
在一些实施方案中,可以藉由常规方法制备大量片剂,使得剂量单位包含例如100mg本发明之化合物、其立体异构体和其药学上可接受的盐,以及其他药学上可接受的赋形剂,例如胶体、二氧化硅、硬脂酸镁、微晶纤维素、淀粉和乳糖。并可以加上适当的涂层以增加适口性或延迟吸收。
在一些实施方案中,适合于藉由注射给药的肠胃外组合物可以藉由在10体积百分比的丙二醇中搅拌1.5重量百分比的本发明之化合物和/或至少其镜像异构体、非镜像异构体或药学上可接受的盐来制备。并以注射用水使溶液达到预期体积和灭菌。
在一些实施方案中,可以制备含水悬浮液用于口服给药。例如,每5毫升的水悬浮液含有100mg微细分散的化合物、其立体异构体和药学上可接受的盐,以及其它药学上可接受的赋形剂,例如羧甲基纤维素钠、苯甲酸钠、山梨糖醇溶液、U.S.P.和香草醛。
当本发明之化合物、其立体异构体和其药学上可接受的盐逐步给药或与至少一种其它治疗剂联合给药时,通常可以使用相同的剂型。当药物以物理组合给药时,应根据组合药物的相容性选择剂型和给药途径。因此,本说明书所述之共同给药应理解为包含伴随或顺序给予至少两种药剂,或者作为至少两种活性组分的固定剂量组合。
本说明书揭示的化合物、其立体异构体和药学上可接受的盐可以作为单一的活性成分或与至少一种第二活性成分组合施用,所述第二活性成分选自例如已知可用于治疗ADAM9相关疾病患者的其他活性成分。
实施例
研发ADAM9抑制剂的合理设计策略
为了研发ADAM9抑制剂,采用分子对接方法来实际筛选可以适合ADAM9的金属蛋白酶结构域的催化位点的化合物结构。我们之前的研究中(Cancer Res 2014,74:5229),我们发现将ADAM9基因剔除可藉由纤溶酶原的激活途径降低CDCP1表达和CDCP1切割。最初,预计有11个前1%会靶向ADAM9的催化位点的化合物,再藉由研究他们于调节CDCP1和PAI-1表现中的作用。我们证实代表性的化合物310可以在结构上占据所述位点,抑制CDCP1裂解并增加Bm7肺癌细胞中PAI-1的表现。我们还证明,藉由使用CCD摄影机(AxioCam MRm,蔡司,耶拿,德国)和Image J软体(美国国立卫生研究院,贝塞斯达,马里兰州,美国)的跟踪点(Track Point)功能确认Bm7肺癌细胞减少的细胞移行距离。
我们选择化合物310作为核心结构,并选择其衍生物进行进一步研究(参见表一)。代表性的衍生物可以减少CDCP1表现。我们进行细胞毒性测定,以测量这些衍生物在肺癌细胞系中的IC50值(参见表二)。与原始化合物310,例如12W-0271和6X-0214相比,优选的衍生物大大降低了悬浮培养中肺癌细胞的细胞毒性的IC50值。
我们以Autodock v.4.2计算潜在的ADAM9抑制剂,例如MMP抑制剂CGS27023A和两个310衍生物的Ki(抑制常数)。我们发现,这两个310衍生物均比MMP抑制剂具有更低的Ki值,其可支持我们的论点-较低浓度的ADAM9抑制剂可达到与较高浓度的MMP抑制剂相同的抑制效果。
ADAM9抑制剂的特异性
为了测量ADAM9抑制剂抑制ADAM9酵素活性的功效,我们建立了使用重组人类ADAM9和萤光肽底物的ELISA***(R&D***)。包括广效型金属蛋白酶抑制剂BB-94作为正对照。ADAM9抑制剂组的前导化合物(12W-0271和6X-0214)以剂量依赖的方式将ADAM9活性降低至相似的程度。但它们对于ADAM17没有抑制效果。为了评估ADAM9抑制剂的特异性,我们在处理25μM的每种化合物的情况下,于对照(shGFP)和ADAM9基因剔除(shADAM9)的肺癌细胞中进行迁移抑制测定。代表性化合物显著降低了Bm7-shGFP对照细胞的迁移能力。为了确保所述化合物在阻断癌细胞的抗失巢雕亡能力的通用性,我们确定了代表性化合物在无贴附培养条件下对癌细胞系和白血球中失巢凋亡(无贴附诱导的细胞雕亡)的IC50值。这些结果显示,代表性化合物可以在无贴附培养条件下诱导细胞死亡,并在乳腺癌脑转移细胞系(MDA-231brm)中具有良好的治疗效果。结果亦显示以20μM的ADAM9抑制剂处理的Bm7和以10μM的ADAM9抑制剂处理的TC1细胞的种植效率。对照和ADAM9基因剔除(KO)TC1的细胞分别以ADAM9抑制剂处理24小时,再利用Annexin V和PI染色。雕亡细胞(Annexin V阳性细胞)的百分比为3次独立实验的统计结果,具有平均值±SD。细胞群落形成试验的数据显示,与ADAM9静默细胞相比,ADAM9抑制剂可显著降低对照肺癌细胞的生长并诱导细胞雕亡。
此外,我们检测ADAM9抑制剂对于胰腺癌细胞的IC50值,其显示ADAM9抑制剂可以降低胰腺癌细胞的生长。
我们另发现ADAM9抑制剂治疗组的形成癌细胞球体显著低于载体治疗组,与我们发现ADAM9基因剔除降低了肺癌细胞的癌细胞球体数量的结果一致,显示这些ADAM9抑制剂可以抑制癌细胞球体的形成(*表示P<0.05,**表示P<0.01)。
减少癌症动物模型中癌症转移的功效:ADAM9抑制剂作为肺癌和乳癌的抗肿瘤药。
为了进一步评估ADAM9抑制剂在体内的抗肿瘤作用,我们将小鼠肺癌细胞TC1(8x105)以静脉注射至具正常免疫功能的C57BL/6小鼠作为肺转移模型,并藉由皮下注射处理代表性的ADAM9抑制剂(10mg/kg)。从第15天到第36天,每天注射1次ADAM9抑制剂,持续3周。并在第39天取出全肺以测量肺肿瘤的重量。我们发现,与DMSO组相比,这些化合物可以大幅降低代表转移性肺肿瘤的全肺重量。此外,我们将小鼠肺癌TC1细胞(1x106)以皮下注射到具有正常免疫功能的小鼠中,并藉由皮下注射处理10mg/kg的ADAM9抑制剂。从第15天到第26天,每天注射1次ADAM9抑制剂,持续3周。我们观察到治疗组的肿瘤尺寸比DMSO治疗(负对照组)小,与ADAM9基因剔除TC1肿瘤动物模型中的观察结果一致。我们还藉由将4T1-luc乳癌细胞移植至乳腺脂肪垫中建立同基因原位乳腺肿瘤动物模型,5×104的4T1-luc细胞以乳腺脂肪垫注射至Balb/c小鼠(每组N=10)。从第14天到第35天,藉由皮下注射每天注射1次剂量为10mg/kg的ADAM9抑制剂,持续3周。与第34天的ADAM9抑制剂治疗组相比,我们发现DMSO组的肿瘤转移信号很强,尽管利用IVIS成像***侦测,3组实验组在第13天的肿瘤信号相似。此外,生存曲线显示,与对照组相比,我们的抑制剂治疗显著地延长生存时间。综上所述,我们的结果显示我们的ADAM9抑制剂在减少肺癌和乳腺癌转移具有抗肿瘤作用。
为了模拟用于临床应用的早期癌症患者的手术药物的新辅助治疗,我们在原位乳腺肿瘤模型中进一步评估了ADAM9抑制剂在去除原发性乳腺肿瘤中的抗肿瘤作用。我们将4T1乳腺细胞(5×104)移植到乳腺脂肪垫中,并使用IVIS成像***监控肿瘤大小,其图像在肿瘤中检测到的光通量与肿瘤大小成比例(每组N=5)。我们在手术前藉由皮下注射以10mg/kg的ADAM9抑制剂对小鼠进行了预处理,并在手术后连续注射ADAM9抑制剂。在癌细胞移植后第21天移除原发性乳腺肿瘤,结果显示两组的肿瘤大小相似。然而,虽然移除了原发性乳腺肿瘤,但我们藉由IVIS检测信号在未处理药物的负对照组(NC)中发现肿瘤复发。值得注意的是,图像检测的结果显示,仅处理手术的对照组与合并手术和ADAM9抑制剂治疗可以大幅减少了肺转移。肺样本的组织学评估亦证实合并治疗可以减少肺转移。两组小鼠体重稳定,显示药物治疗后无严重毒性。为了进一步评估所述化合物在动物治疗中的毒性,收集了两组实验组在不同时间点的血液样本,测量血清中肝脏天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)和血尿素氮(BUN)的含量以监测肝肾功能。治疗组中3个因子的含量皆在正常范围内,显示没有肝或肾毒性。上述结果可以证明我们的ADAM9抑制剂对ADAM9活性的抑制具有抗肿瘤的效果,其包含减少术后复发。
为了比较抑制剂对化疗药物阿霉素的治疗效果,在原发性乳腺肿瘤手术后,我们使用12W-0271或阿霉素作为小鼠的辅助治疗。Balb/c小鼠以乳腺脂肪垫注射5×104个4T1-luc细胞。藉由皮下注射ADAM9抑制剂,每次剂量10mg/kg,每天1次,每周5次,共12次。阿霉素以腹膜内注射,每次剂量1mg/kg,每天1次,每周5次,共12次。3组实验组的手术切除的肿瘤具有相似的大小。手术后一天的IVIS图像未侦测到任何信号显示手术成功切除了原发肿瘤,而此乳腺肿瘤动物模型为预后较差的三阴性乳腺癌,具有临床上的意义。在阿霉素治疗中,只有1只小鼠(12.5%)具有完全反应且没有复发。在第140天测定处理阿霉素和处理12W-0271组中存活的小鼠的体重。虚线表示正常小鼠的平均体重。值得注意的是,3只小鼠(37.5%)在接受12W-0271治疗后333天没有复发,其健康状况良好且体型较阿霉素治疗组的存活小鼠更大,显示化合物12W-0271对于长期治疗是安全的。
为了研究化疗药物和ADAM9抑制剂的协同作用,我们藉由MTT测定了TC1细胞中分别处理顺铂(cisplatin)、化合物12W-0271或合并处理顺铂和化合物12W-0271 3天后的细胞毒性。合并指数(CI)曲线分析的分析值<1显示顺铂和12W-0271合并治疗具有协同作用。在静脉注射TC1肺癌细胞的转移性肺肿瘤动物模型中,我们发现单独处理顺铂可以显著延长了存活时间,但单独处理ADAM9抑制剂无效。将ADAM9抑制剂(4mg/kg)以静脉注射,每周处理2次,持续4周。并且将顺铂(1.5mg/kg)以腹膜内注射,每周2次,持续4周。值得注意的是,与顺铂治疗组相比,合并处理顺铂和ADAM9抑制剂的组别显著降低了肺癌的转移,并延长了小鼠的存活时间,显示在小鼠体内对顺铂和ADAM9抑制剂的组合具有协同作用。
应当理解,本文中描述的实施方式和实施例仅用于说明目的,对于本领域技术人员而言可依据其所进行各种修改或改变都包括在本发明的精神和范围内以及依附其申请专利范围内。本文引用的所有出版物、专利和专利申请,包括其中的引文,以作为参考的目的整体并入本文。
表一、ADAM9抑制剂
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表二、在癌细胞中的抑制活性;+表示藉由IC50确认具有显著抑制剂活性;13W化合物的活性为由外推而得。
合成例的示意图
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Claims (3)
1.一种组合物,其特征在于,包含:
式I化合物,或其医药上可接受的盐类;以及
共同配制的不同的抗癌化合物;
其中所述的式I化合物如下所示:
其中所述的式I化合物选自:
及
2.如权利要求1所述的组合物,其特征在于,所述的式I化合物为
3.如权利要求1所述的组合物,其特征在于,所述的式I化合物为
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US5037834A (en) * | 1987-12-18 | 1991-08-06 | Pfizer Inc. | Heterocycylic-substituted quinoline-carboxylic acids |
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WO2015172196A1 (en) * | 2014-05-13 | 2015-11-19 | Monash University | Heterocyclic compounds and use of same |
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