CN117460512A - Idh突变体抑制剂及其用途 - Google Patents
Idh突变体抑制剂及其用途 Download PDFInfo
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- CN117460512A CN117460512A CN202280040684.0A CN202280040684A CN117460512A CN 117460512 A CN117460512 A CN 117460512A CN 202280040684 A CN202280040684 A CN 202280040684A CN 117460512 A CN117460512 A CN 117460512A
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
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- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
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- 230000008929 regeneration Effects 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
一类IDH突变体抑制剂及其用途。具体的,涉及一类如通式(1)所示的化合物及其制备方法,及通式(1)化合物及其各光学异构体、各晶型、药学上可接受的盐作为IDH突变体不可逆抑制剂在抗肿瘤药物制备中的用途。
Description
本申请要求申请日为2021年6月15日的中国申请CN202110661394.5的优先权。本申请引用上述中国申请的全文。
本发明涉及药物化学领域,更具体而言,涉及一类新型IDH突变体抑制剂,及其制备方法和该类化合物的使用方法。
异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)是参与三羧酸循环的重要酶,催化异柠檬酸转化为α-酮戊二酸(α-ketoglutarate,α-KG),此反应是三羧酸循环的限速步骤。人类共有三种不同的异柠檬酸脱氢酶,分别是IDH1、IDH2和IDH3,IDH1主要定位于胞质和过氧化物酶体,IDH2和IDH3主要分布于线粒体中。
在人类癌症基因突变鉴定中,IDH1和IDH2是出现最频繁的代谢基因,IDH突变在低级胶质瘤、二级恶性胶质瘤、黑色素瘤、血管免疫母细胞性T细胞淋巴瘤、骨髓增生性肿瘤、骨髓增生异常综合征(myelodysplastic syndromes,MDS)以及急性骨髓性白血病(acute myelocytic leukemia,AML)中都存在。肿瘤细胞中IDH突变位点为IDH1Arg132(R132),IDH2 Arg172(R172)或IDH2 Arg140(R140)。这些突变会导致IDH蛋白野生型功能缺失,转而获得将α-KG转化为致瘤代谢物D-2-羟戊二酸(D-2-hydroxyglutarate,D-2HG)的能力。致瘤代谢产物2-HG抑制DNA或组蛋白去甲基化酶,从而导致DNA和组蛋白的过度甲基化,进而促进癌症的发生。IDH抑制剂可以通过抑制IDH1/R132,IDH2/R172或IDH2/R140位点突变的蛋白活性,使体内致癌代谢物D-2HG减少,诱导组蛋白H3K9me3去甲基化,达到抑制肿瘤发展的效果。因此,将突变IDH1和IDH2(mIDH1和mIDH2)作为靶标可能是一种有希望的癌症治疗途径。
迄今为止,已经有IDH抑制剂小分子上市,如Agios公司研发的Enasidenib和Ivosidenib,两者为非共价抑制剂。礼来公司在专利WO2017019429、WO2017213910和WO2018111707中报道了IDH的共价抑制剂,相对于野生型IDH1和IDH2,该类共价抑制剂对于突变型的IDH1和IDH2具有更好的选择性。然而还没有IDH共价抑制剂进入临床研究,因此目前有研究和发现活性更好及成药性更佳的共价IDH抑制剂的需要。
发明内容
本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物:
通式(1)中:
L为
其中“*”表示和羰基相连的位点;
X为NH或NMe;
R
1为Me、Et、-CH
2CH
2CH
3、-CH(CH
3)
2、
R
2和R
3独立为H、Me或Et,或者R
2和R
3和它们相连的碳原子形成
R
4和R
5独立为H、Me、Et、-CH
2CH
2CH
3、-CH(CH
3)
2、-CH
2CH(CH
3)
2、
或者R
4和R
5和它们相连的碳原子形成C3-C7环烷基,其中所述C3-C7环烷基可被卤素 或C1-C3烷基取代。
在另一优选例中,其中所述通式(1)中,R
2和R
3独立为H或Me,或者R
2和R
3和它们相连的碳原子形成
在另一优选例中,其中所述通式(1)中,R
4和R
5独立为H、Me、Et、-CH
2CH
2CH
3、-CH(CH
3)
2、-CH
2CH(CH
3)
2、
或者R
4和R
5和它们相连的碳原子形成
在本发明的另一具体实施方案中,通式(1)化合物具有以下结构之一:
本发明的另一个目的是提供了一种药物组合物,其含有药学上可接受的载体、稀释剂和/或赋形剂,以及本发明通式(1)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
本发明的再一个目的提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与IDH突变体蛋白相关疾病的药物中的应用。
应理解,本发明的前述一般性描述和以下详细描述都是示例性和说明性的,旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明通式(1)化合物的制备方法,但这些具体方法不对本发明构成任何限制。
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外,在此提到的溶剂,温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关 化合物可使用公知的技术和原料来合成,包括发现于March,ADVANCED ORGANIC CHEMISTRY 4
th Ed.,(Wiley 1992);Carey和Sundberg,ADVANCED ORGANIC CHEMISTRY 4
th Ed.,Vols.A和B(Plenum 2000,2001),Green和Wuts,PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3
rd Ed.,(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面,本文所述的化合物根据工艺中公知的方法。然而方法的条件,例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。一方面,本发明还提供了一种所述的通式(1)所示化合物的制备方法,其中通式(1)化合物可采用下列一般反应流程1制备:
一般反应流程1
PG表示胺基的保护基,R
1、R
2、R
3、R
4、R
5和L如上文中所定义。如一般反应流程1所示,原料A1经取代反应得到化合物A2,化合物A2和A3在碱性条件下反应得到化合物A4,化合物A4还原硝基得到A5,化合物A5环合得到化合物A6,化合物A6脱除保护基PG(例如Boc)得到化合物A7,化合物A7和丙烯酰氯反应生成目标化合物A8。
化合物的进一步形式
“药学上可接受”这里指一种物质,如载体或稀释液,不会使化合物的生物活性或性质消失,且相对无毒,如,给予个体某物质,不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式,该形式不会引起对给药有机体的重要的刺激,且不会使化合物的生物活性和性质消失。在某些具体方面,药学上可接受的盐是通过通式(1)化合物与酸反应获得,如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、碳酸等无机酸,甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式,尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂,且是在与药学上可接受溶剂如水,乙醇等,结晶化过程中选择性形成的。当溶剂是水时形成水合物,或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法,很方便的制得或形成。举例说明,通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得,使用的有机溶剂包括但不限于,四氢呋喃、丙酮、乙醇或甲醇。此外,在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之,对于在此提供的化合物和方法为目的,溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中,通式(1)化合物被制备成不同的形式,包括但不限于,无定形,粉碎形和毫微-粒度形式。此外,通式(1)化合物包括结晶型,也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂,结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面,通式(1)化合物可能存在手性中心和/或轴手性,并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体,并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(
3H)、碘-125(
125I)和C-14(
14C)。又例如,可用重氢取代氢原子形成氘代化合物,氘与碳构成的键比普通氢和碳构成的键更坚固,相比于未氘代药物,通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗 效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包含在本发明的范围之内。
术语
如果无另外说明,用于本发明申请,包括说明书和权利要求书中的术语,定义如下。必须注意,在说明书和所附的权利要求书中,如果文中无另外清楚指示,单数形式“一个”包括复数意义。如果无另外说明,使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中,如果无另外说明,使用“或”或“和”指“和/或”。
除非另有规定,“烷基”指饱和的脂肪烃基团,包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基,例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用,“烷基”包括未取代和取代的烷基,尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH
3、CH
3CH
2、CF
3、CHF
2、CF
3CH
2、CF
3(CH
3)CH、
iPr、
nPr、
iBu、
nBu或
tBu。
除非另有规定,“环烷基”是指非芳香族烃环***(单环、双环或多环),如果碳环含有至少一个双键,那么部分不饱和环烷基可被称为“环烯基”,或如果碳环含有至少一个三键,那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中,环烷基为单环的。在一些实施方案中,环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫离子基。环烷基还包括亚环烷基。在一些实施方案中,环烷基含有0、1或2个双键。在一些实施方案中,环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中,环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中,环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中,环烷基可以与芳基和杂环烷基稠合。一些实施方案中,环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。
除非另有规定,“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代,也就是说,以任意组合的方式被F,Cl,Br或I取代,优选被F或Cl取代。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
取代基“-O-CH
2-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的 碳原子连接,比如:
当一个连接基团的数量为0时,比如-(CH
2)
0-,表示该连接基团为单键。
当其中一个变量选自化学键时,表示其连接的两个基团直接相连,比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如,环己基、吡啶基、吡喃基、噻喃基是六元环,环戊基、吡咯基、呋喃基和噻吩基是五元环。
术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。
除非另有说明,用楔形实线键
和楔形虚线键
表示一个立体中心的绝对构型,用直形实线键
和直形虚线键
表示立体中心的相对构型,用波浪线
表示楔形实线键
或楔形虚线键
或用波浪线
表示直形实线键
或直形虚线键
除非另有说明,用
表示单键或双键。
特定药学及医学术语
术语“可接受的”,如本文所用,指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用,包括缓和、抑制或改善疾病的症状或状况;抑制并发症的产生;改善或预防潜在代谢综合症;抑制疾病或症状的产生,如控制疾病或情况的发展;减轻疾病或症状;使疾病或症状减退;减轻由疾病或症状引起的并发症,或预防或治疗由疾病或症状引起的征兆。如本文所用,某一化合物或药物组合物,给药后,可以使某一疾病、症状或情况得到改善,尤指其严重度得到改善,延迟发病,减缓病情进展,或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药,可以归因于或与给药有关的情况。
“活性成分”指通式(1)所示化合物,以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性),并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心,取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体,并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用,且都是指当施用于个体(人类或动物)时,能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物,或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值,此处已尽可能精确地呈现具体实施例中的相关数值。然而,任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处,“约”通常是指实际数值在一特定数值或范围的正负10%、5%、1%或0.5%之内。或者是,“约”一词代表实际数值落在平均值的可接受标准误差之内,视本领域技术人员的考虑而定。除了实验例之外,或除非另有明确的说明,当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此,除非另有相反的说明,本说明书与附随权利要求书所揭示的数值参数皆为约略的数值,且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义,此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外,在不和上下文冲突的情形下,本说明书所用的单数名词涵盖该名词的复数型;而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明通式(1)化合物或药物组合物治疗疾病的方法,包括但不限于涉及IDH突变体蛋白相关的病况(例如癌症)。
在一些实施例中,提供了用于癌症治疗的方法,该方法包括给予有需要的个体有效量的任何前述的包括结构通式(1)化合物的药物组合物。在一些实施例中,癌症由IDH突变体蛋白相关介导。在其它实施例中,该癌症是血液癌和实体瘤,包括但不限于白血病、乳腺癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、***癌、肝癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂,其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。化合 物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时,可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势,使本发明的内容变得十分明了。在此应理解,下述的详细说明及实例描述了具体的实施例,仅用于参考。在阅读了本发明的说明内容后,本领域的技术人员可对本发明作各种改动或修改,这些等价形势同样落于本申请所限定的范围。
所有实施例中,
1H-NMR用Varian Mercury 400核磁共振仪记录,化学位移以δ(ppm)表示;分离用硅胶未说明均为200-300目,洗脱液的配比均为体积比。
本发明采用下述缩略词:CDCl
3代表氘代氯仿;DCM代表二氯甲烷;Dioxane代表1,4-二氧六环;DIPEA代表二异丙基乙基胺;DMSO代表二甲基亚风;EA代表乙酸乙酯;EtOH代表乙醇;h代表小时;H
2代表氢气;KOH代表氢氧化钾;LC-MS代表液相-质谱;min代表分钟;mL代表毫升;MS代表质谱;n-BuLi代表正丁基铝;NaBH(OAc)
3代表三乙酰氧基硼氢化钠;NH
4Cl代表氯化铵;NMR代表核磁共振;Pd/C代表钯碳;PE代表 石油醚;THF代表四氢呋喃;Ti(O
i-Pr)
4代表四异丙醇钛。
制备例1 2-氯-N-乙基-5-硝基嘧啶-4-胺
将2,4-二氯-5-硝基嘧啶(2g,10.31mmol)溶于THF(30mL)中,氩气保护,-70℃下滴加乙胺水溶液(1.33g,70%),滴毕,移至室温反应约0.5h。LC-MS检测反应完全后,加入水(50mL),EA(30mL*2)萃取两次,合并有机相浓缩,残留物经柱层析纯化得黄色固体产物A2-1(1.763g,收率84%),ESI-MS m/z:203[M+H]
+。
利用不同原料,采用中间体A2-1的合成方法得到目标中间体A2-2至A2-6。
表1中间体A-2至A-6结构式
制备例2 4-(1-(4-((S)-1-氨基乙基)苯基)-2-环丙乙基)哌嗪-1-甲酸叔丁酯(A3-1)的合成
(S)-N-(1-(4-(2-环丙基乙酰基)苯基)乙基)-2,2,2-三氟乙酰胺的合成
将(S)-N-(1-(4-溴苯基)乙基)-2,2,2-三氟乙酰胺(10.7g,36.2mmol)溶于干燥THF(100mL)中,氩气保护下,-78℃下滴加n-BuLi(2.5M,30mL,72.3mmol),滴毕,保温在-78℃至-60℃下反应约1h,后缓慢滴加2-环丙基-N-甲氧基-N-甲基乙酰胺(5.7g,39.8mmol)的干燥THF(50mL)溶液,滴毕,继续保温反应0.5h。LC-MS检测反应完全后,加饱和NH
4Cl水溶液(100mL)淬灭反应,以EA(50mL*2)萃取两次,有机相浓缩,残留物柱层析纯化得白色固体产物(6.06g,收率56%),ESI-MS m/z:300[M+H]
+。
叔丁基4-(2-环丙基-1-(4-((S)-1-(2,2,2-三氟乙酰氨基)乙基)苯基)乙基)哌嗪-1-羧酸酯的合成
将(S)-N-(1-(4-(2-环丙基乙酰基)苯基)乙基)-2,2,2-三氟乙酰胺(3.068g,10.25mmol)、哌嗪-1-羧酸叔丁酯(3.82g,20.5mmol)溶于干燥THF(50mL),氩气保护下滴加Ti(i-PrO)
4(15mL,51.25mmol),混合液60℃反应过夜后冷却至室温,加入MeOH(20mL),NaBH(OAc)
3(1.288g,20.5mmol),混合物室温反应10h,LC-MS检测剩余少量原料。加水(100mL)淬灭,EA(50mL*2)萃取,有机相浓缩,残留物柱层析纯化得白色固体产物(957mg,收率20%),同时回收未反应原料(2.2g),ESI-MS m/z:470[M+H]
+。
叔丁基4-(1-(4-((S)-1-氨基乙基)苯基)-2-环丙基乙基)哌嗪-1-羧酸酯(A3-1)的合成
将叔丁基4-(2-环丙基-1-(4-((S)-1-(2,2,2-三氟乙酰氨基)乙基)苯基)乙基)哌嗪-1-羧酸酯(3.74g,7.97mmol)溶于EtOH/H
2O(100mL/20mL)中,冰浴冷却下,分批加KOH(2.24g,39.87mmol),后氩气保护下升温至50℃反应3h。LC-MS检测反应完全,减压浓缩至剩余约30mL,加水(50mL)稀释,DCM(50mL*2)萃取,合并有机相,饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得目标化合物A3-1(3.854g,收率100%),ESI-MS m/z:374[M+H]
+。
利用不同原料,采用中间体A3-1的合成方法得到目标中间体A3-2至A3-20。
表2中间体A3-2至A3-20结构式
实施例1 2-(((1S)-1-(4-(1-(4-丙烯酰哌嗪-1-基)-2-环丙基乙基)苯基)乙基)氨基)-9-乙基-7,9-二氢-8H-嘌呤-8-酮(化合物1)的合成
步骤1:化合物A4-1的合成
将化合物A3-1(200mg,0.535mmol)和化合物A2-1(130mg,0.642mmol)溶于DMSO(5mL)中,加入DIPEA(207mg,1.605mmol),80℃反应约3h。LC-MS检测反应完全后,加入水(30mL),EA(20mL*2)萃取,合并有机相,浓缩,残留物经柱层析纯化得黄色固体产物A4-1(290mg,收率91%),ESI-MS m/z:540[M+H]
+。
步骤2:化合物A5-1的合成
将化合物A4-1(290mg,0.537mmol)溶于MeOH(10mL)中,加入Pd/C(40mg,10%),氢气置换后室温反应过夜。LC-MS检测反应完全后,过滤,浓缩得紫色固体A5-1(236mg,收率86%),ESI-MS m/z:510[M+H]
+。
步骤3:化合物A6-1的合成
将化合物A5-1(236mg,0.463mmol)溶于DCM(10mL)中,加入CDI(150mg,0.926mmol),室温反应过夜。LC-MS检测反应完全后,减压浓缩,残留物经Flash纯化得紫黑 色固体A6-1(151mg,收率61%),ESI-MS m/z:536[M+H]
+。
步骤4:化合物A7-1的合成
将化合物A6-1(151mg,0.282mmol)溶于DCM(5mL)中,加入4M HCl/Diox(1mL,4mmol),室温搅拌反应约3h。LC-MS检测反应完全后,减压浓缩得黄色固体产物A7-1(170mg,收率100%),ESI-MS m/z:436[M+H]
+。
步骤5:化合物1的合成
将化合物A7-1(170mg,0.282mmol)和DIPEA(183mg,1.41mmol)溶于DCM(5mL)中,氩气保护,冰浴冷却至0℃,滴加丙烯酰氯(23mg,0.254mmol)的DCM(3mL)溶液,冰浴下反应约10min。LC-MS检测反应完全后,加水(10mL)搅拌,分液,水相再用DCM(10mL)萃取,合并有机相。浓缩残留物经pre-TLC纯化得淡黄色固体产物(100mg,收率72%)。
1H NMR(400MHz,CDCl
3)δ:7.81(s,1H),7.32(d,J=7.9Hz,2H),7.18(d,J=8.0Hz,2H),6.49(dd,J=16.9,10.5Hz,1H),6.23(dd,J=16.8,1.9Hz,1H),5.64(dd,J=10.5,1.9Hz,1H),5.26(s,1H),5.10(p,J=6.9Hz,1H),3.86(q,J=7.2Hz,2H),3.63(m,2H),3.49(m,2H),3.44-3.36(m,1H),2.38(m,4H),1.89-1.79(m,1H),1.65(m,2H),1.55(d,J=6.8Hz,3H),1.29-1.25(m,3H),0.40(q,J=6.4,4.8Hz,1H),0.36-0.24(m,2H),-0.01-0.09(m,2H);ESI-MS m/z:490[M+H]
+.
实施例2-40化合物2-40的合成
类似于化合物1的合成,采用不同中间体为原料,可以得到表3中目标化合物2-40。
表3化合物2-40
实施例41本发明化合物的手性异构体制备
本发明化合物含有一个或多个手性中心,采用光学纯的中间体作为原料,可以制得 本发明化合物的各个光学纯异构体。或者采用手性HPLC或非手性HPLC也可以制备本发明化合物的各光学纯异构体。
本发明化合物1可以采用上述方法得到化合物1的两个光学纯异构体1-1和1-2:
采用相同的合成或者制备方法,对化合物3、4、5、12、29、30、33和34进行手性拆分,各自分别得到其两个手性异构体3-1/3-2、4-1/4-2、5-1/5-2、12-1/12-2、29-1/29-2、30-1/30-2、33-1/33-2和34-1/34-2:
本发明其它化合物也可以采用类似的合成或者制备方法得到其相应的手性异构体。
表4本发明部分化合物的核磁数据
实施例42 U87-IDH1 R132H细胞上清中2-HG的检测
过表达mIDH1 R132H突变的U87MG细胞或者携带IDH1 R132C的HT1080细胞分别按照50000/孔和10000/孔种于48和96孔板中,过夜贴壁后,去除上清。加入含有梯度稀释化合物的细胞培养液,孵育72小时。72小时后,收取培养液,以水稀释10和20倍后,加入乙腈提取代谢产物。用LC-MS-MS分析培养液中2-HG含量,与对照组相比,计算化合物抑制上清中2-HG的抑制百分比和IC
50。
表5本发明部分化合物对U87-IDH R132H细胞上清中2-HG抑制率
A表示抑制率大于90%
B表示抑制率大于60%,但小于或等于至90%
C表示抑制率大于30%,但小于或等于至60%
D表示抑制率小于或等于30%
表6本发明部分化合物对HT1080细胞上清中2-HG抑制率
化合物 | IC 50(nM) | 化合物 | IC 50(nM) | 化合物 | IC 50(nM) |
LY-3410738 | 1.90 | 1 | 4.48 | 1-1 | 2.24 |
3 | 2.06 | 3-1 | 1.22 | 3-2 | 2.36 |
4-1 | 11.5 | 5-1 | 2.63 | 6-1 | 3.22 |
实施例43人肝微粒和小鼠肝微粒体稳定性试验
将1μM化合物分别和500μg/ml的人或小鼠肝微粒体以及NADPH再生***在37度孵育不同时间后,用LC-MS-MS分析化合物的剩余量,计算T
1/2。
表7本发明部分化合物的肝微粒体稳定性
实施例44肿瘤组织中2-HG的检测
裸鼠皮下接种1*10
6HT1080细胞,待肿瘤体积长至100-150mm
3后随机分组给药溶剂对照组,20mg/kg化合物1、3、29、33或LY-3410738。连续给药三天和七天后收取肿瘤,称重瘤重,裂解液裂解匀浆后,用LC-MS-MS测定肿瘤组织中2-HG的水平。与对照组相比,计算化合物抑制肿瘤组织中2-HG的百分比。
表8化合物抑制HT1080肿瘤组织中2-HG的抑制率
化合物 | 1 | 3 | 29 | 33 | LY-3410738 |
3天 | 49±18% | 58±3% | 45±38% | 57±1.8% | 43±11% |
7天 | 94±0.5% | 97±1% | 92±4% | 96±0.4% | 85±12% |
从表5-表8的活性数据可知,本发明通式(1)化合物活性和已经上市的IDH抑制剂Ivosidenib相比,这些化合物更强的抑制了U87-IDH R132H细胞上清以及HT1080细胞上清中和肿瘤组织中2-HG的水平,提示其具有更强的抑制IDH1 R132H和IDH1 R132C突变蛋白的能力。同时,和LY-3410738(专利WO2018111707中化合物2)相比,这些化合物也有类似或更强的活性。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。
Claims (6)
- 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物:通式(1)中:L为 其中“*”表示和羰基相连的位点;X为NH或NMe;R 1为Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、R 2和R 3各自独立为H、Me或Et,或者R 2和R 3和它们相连的碳原子形成R 4和R 5各自独立为H、Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH(CH 3) 2、 或者R 4和R 5和它们相连的碳原子形成C3-C7环烷基,其中所述C3-C7环烷基可被卤素或C1-C3烷基取代。
- 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物,其中所述通式(1)中,R 2和R 3独立为H或Me,或者R 2和R 3和它们相连的碳原子形成
- 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物,其中所述通式(1)中,R 4和R 5独立为H、Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH(CH 3) 2、 或者R 4和R 5和它们相连的碳原子形成
- 如权利要求1-3中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物,其中所述化合物具有以下结构之一:
- 一种药物组合物,其特征在于,其含有药学上可接受的赋形剂或载体,以及如权利要求1-4中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
- 一种如权利要求1-4中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求5所述的药物组合物在制备治疗由IDH突变蛋白介导的相关疾病药物中的应用。
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