CN113395995A - 作为抗衰老剂的烟酸和烟酰胺单核苷酸和核苷的季铵盐 - Google Patents
作为抗衰老剂的烟酸和烟酰胺单核苷酸和核苷的季铵盐 Download PDFInfo
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- CN113395995A CN113395995A CN201980062525.9A CN201980062525A CN113395995A CN 113395995 A CN113395995 A CN 113395995A CN 201980062525 A CN201980062525 A CN 201980062525A CN 113395995 A CN113395995 A CN 113395995A
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- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
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Abstract
本发明涉及式I的烟酸和烟酰胺的氨基酸盐及其组合物,其可用于治疗与NAD+缺乏相关的病症和疾病:(I)其中A、L、M1、M2、R1、R2和R3如本文所述。
Description
相关申请
本申请要求2018年8月1日提交的美国临时申请号62/713,046的优先权和权益,所述临时申请的全部内容通过引用并入本文。
技术领域
本发明涉及烟酸单核苷酸和烟酰胺单核苷酸的季盐及其组合物,其可用于治疗与衰老有关的病症和疾病。
背景技术
衰老是涉及导致细胞和器官功能障碍的生物、物理和生物化学过程的复杂相互作用的结果,所述功能障碍表现为多种疾病和其他结果。例如,女性生殖力对衰老的影响非常敏感。例如,美国疾病控制中心报道,辅助生殖技术(ART)相关的妊娠百分比和出生百分比在妇女中稳步下降,在三十五六岁时,ART周期的约25%导致单胎活产,到40岁时,此比率为14%(Centers for Disease Control and Prevention,American Society forReproductive Medicine,Society for Assisted ReproductiveTechnology.2011Assisted Reproductive Technology National SummaryReport.Atlanta(GA):US Dept of Health and Human Services;2013)。这一趋势在40岁以上显著增加,CDC报道大于44岁的妇女成功的可能性非常低。在该组中,活产和单胎活产的百分比下降到约1%。通常认为,妇女的年龄是当使用她自己的卵(卵母细胞)时影响活产机会的最重要因素。
可以理解,由于衰老引起的卵母细胞的质量退化是生育力下降的基本因素。例如,据报道,在老年妇女中,卵母细胞容易发生异常染色体分裂、表现出线粒体质量下降、低ATP产量、增加的氧化应激和降低的抗氧化水平(Nelson SM,Telfer EE,Anderson RA.Theageing ovary and uterus:new biological insights.Hum Reprod Update.2013;19:67–83.;Wilding M.Potential long-term risks associated with maternal aging(therole of the mitochondria).Fertil.Steril.2015;103:1397–401;3.Meldrum DR,CasperRF,Diez-Juan A,Simon C,Domar AD,Frydman R.Aging and the environment affectgamete and embryo potential:can we intervene?Fertil.Steril.2016;105:548–59)。
出于所有前述原因,卵母细胞代表了用于评估预期对衰老过程有影响且进一步提供了解决年龄相关不孕症的前景的治疗方式的优良靶组织。
一种用于治疗衰老的可能的治疗方式包括增强NAD+的治疗水平的剂。NAD+是支持各种代谢功能所必需的细胞过程的必需组分。NAD+的经典作用是在许多基本的代谢过程(例如糖酵解、脂肪酸β氧化或三羧酸循环)中催化细胞氧化还原反应并被还原为NADH的辅酶。除了发挥这些作用外,NAD+作为消耗NAD+的酶(例如聚ADP-核糖聚合酶(PARP)、去乙酰化酶和CD38/157外切酶)的底物发挥关键作用。已知这些消耗NAD+的酶介导许多基本的细胞过程。
有五种主要的合成NAD+的前体和中间体:色氨酸、烟酰胺、烟酸(NA)、烟酰胺核苷(NR)和烟酰胺单核苷酸(NMN)。NAD+可以通过经多个酶促步骤将氨基酸色氨酸转化为烟酸单核苷酸(NaMN)从头合成。NaMN通过NMN/NaMN腺苷酰转移酶(NMNAT)转化为烟酸二核苷酸(NaAD+),然后通过NAD+合成酶酰胺化为NAD+。
在哺乳动物中,NAD+生物合成的主要途径是来自烟酰胺的补救途径。烟酰胺通过烟酰胺磷酸核糖基转移酶(NAMPT)(此途径中的限速酶)转化为NAD+的关键中间体NMN。然后,NMNAT将NMN转化为NAD+。NAMPT在调节细胞NAD+水平中起关键作用。另一方面,烟酸通过烟酸磷酸核糖基转移酶(NPT)转化为NaMN。NR需要通过使NR磷酸化的烟酰胺核糖激酶NMRK1和NMRK2(也称为NRK1和NRK2)转化为NMN。维持足够的NAD+生物合成对于细胞存活和功能是至关重要的。脱离正常NAD+稳态基本上不仅影响氧化还原反应所需的NAD+/NADH池,而且影响关键细胞功能的NAD+依赖性酶的活性。
现在已经成为共识,即NAD+水平在衰老过程中在细胞、组织/器官和生物体水平下降。消耗NAD+的酶的活性受这种NAD+下降的影响,从而导致各种年龄相关的病理生理学。
烟酰胺腺嘌呤二核苷酸是与还原-氧化反应和能量代谢相关的几种酶的功能所必需的酶辅因子。(Katrina L.Bogan&Charles Brenner,Nicotinic Acid,Nicotinamide andNicotinamide Riboside:A Molecular Evaluation of NAD+Precursor Vitamins inNutritions,28,Annual Review of Nutrition 115(2008)).NAD+在氨基酸、脂肪酸和碳水化合物的能量代谢中起电子载体的作用(Bogan&Brenner,Annu.Rev.Nutr.2008,28,115–130)。NAD+对于氧化还原反应是关键的,并且在DNA修复、能量代谢、细胞存活和昼夜节律的调节中作为PARP(聚腺苷二磷酸核糖聚合酶)和去乙酰化酶(SIRT1至SIRT7)的信号传导的底物,所有这些都已显示在衰老过程中是关键的(Bronkowski,M.S.&Sinclair,D.,Nat.Rev.Mole.Cell.Bio.,17,679-690,(2016))。升高NAD+浓度会延迟酵母、档案和小鼠中的衰老(Mouchiroud等人Cell 154,464-471,(2014))。最近还证明NAD+直接调节蛋白质-蛋白质相互作用,其调节可防止癌症和辐射暴露以及对衰老有直接影响(Li等人,Science355,1312-1317,2017)。因此,越来越多的证据支持这样的想法,即使用NAD+中间体(例如NMN和NR)进行干预可以通过恢复可用的NAD+来支持系统,并缓解与衰老相关的生理衰退。
尽管NAD+可以从氨基酸色氨酸从头合成,但是该过程并非在所有组织中发生,需要大多数细胞依靠补救途径(如上所述)从其他细胞内中间体再生NAD+,所述中间体主要通过饮食来源获得(Christopher R.Martens,等人,NatCommun.9,1286,(2018)和Bogan,K.L.&Brenner,C.,Annu.Rev.Nutr.28,115–130,(2008))。也可以施用其他NAD前体(如烟酸和烟酰胺)以增强NAD细胞生物利用度。但是,临床相关的烟酸水平与治疗剂量下的不良潮红有关(MacKay,D.,Hathcock,J.&Guarneri,E.,Nutr.Rev.70,357–366(2012))。尽管NAD浓度升高,但烟酰胺不能可靠地激活(甚至可能抑制)去乙酰化酶(Bitterman,K.J.,等人,J.Biol.Chem.277,45099–45107(2002);Guan,X.,等人,PLoS One.9,e107729(2014);和Trammell,S.A.等人Nat.Commun.7,12948(2016))。因此,烟酸或烟酰胺的施用不太可能被广泛用于随衰老维持健康和功能。
与烟酸和烟酰胺相反,施用NAD+代谢物例如烟酰胺单核苷酸(NMN)或烟酰胺核苷(NR)似乎增加NAD+的水平并改善动物模型中的多种生理功能(Yoshino,J.等人,CellMetab.14,528–536(2011);Mills,K.F.等人,Cell Metab.24,795–806(2016);和Frederick,D.W.等人,Cell Metab.24,269–282(2016))。据报道,这些代谢物中的至少一种在人类中具有良好耐受性,导致NAD水平升高和改善生理功能,尽管还需要进一步的研究来证实该探索性研究的发现(Christopher R.Martens等人,Nat.Commun.9,1286,(2018))。此外,最近的一项研究表明,单剂量NR以剂量依赖的方式刺激健康人的血细胞NAD+代谢(Trammell,S.A.等人,Nat.Commun.7,12948(2016)),表明了该代谢物的局限性。然而,许多已知的NAD+代谢物在各种生理环境中是不稳定的,因此不适于向需要这种代谢物的患者施用以提高所述患者的NAD+水平的可行药物。
考虑到NAD+在关键的细胞和生理途径中所起的核心作用,开发具有改善的性质的新颖稳定剂对于改善人类病状是必需的,所述改善的性质可以提高疾病状态中和/或衰老过程中的NAD+水平。
发明内容
本申请的第一方面涉及式(I)的盐:
和其对映异构体、立体异构体和互变异构体,
其中
A为NRaRb或O–;
M1和M2独立地不存在或为季阳离子,条件为M1或M2中的至少一个为季阳离子;
R1和R2独立地为H、C1-C6烷基、C1-C6卤代烷基、-C(O)C1-C6卤代烷基、(C0-C3亚烷基)C(O)C1–C6烷基、-C(O)ORa、-C(O)NRaRb、-[CH2-CH2-O]k-Ra、-C(O)[CH2-CH2-O]k-Ra、-[CH2-CH2-CH2-O]k-Ra或-C(O)[CH2-CH2-CH2-O]k-Ra,
或R1和R2与它们所连接的原子一起形成5元杂环,该5元杂环任选地被一个或多个选自C1-C6烷基、C2-C6烯基、C2-C6炔基、(C0-C3亚烷基)C3-C8环烷基、(C0-C3亚烷基)杂环烷基、(C0-C3亚烷基)C6-C14芳基、或(C0-C3亚烷基)杂芳基的取代基取代;
R3为负电荷、H或C1-C6烷基;
Ra和Rb在每次出现时独立地为H或C1-C6烷基,其中该烷基任选地被一个或多个选自(C0-C3亚烷基)C3-C8环烷基、(C0-C3亚烷基)杂环烷基、(C0-C3亚烷基)C6-C14芳基或(C0-C3亚烷基)杂芳基的取代基取代;并且
k为1到8的整数,
条件为
a)当L为键时,M1不存在,以及
b)当A为NRaRb时,M2不存在。
本公开的另一方面涉及一种药物组合物,其包含式I的盐或其药学上可接受的盐以及药学上可接受的载体。
本申请的另一方面涉及治疗或预防年龄相关病症的方法,其包括向有此需要的受试者施用有效量的式(I)的盐或其对映异构体、立体异构体或互变异构体。
本申请的另一方面涉及治疗或预防不孕症的方法,其包括向有此需要的受试者施用有效量的式(I)的盐或其对映异构体、立体异构体或互变异构体。
本申请的另一方面涉及式(I)的盐或其对映异构体、立体异构体或互变异构体,其用于治疗年龄相关病症的方法。
本申请的另一方面涉及式(I)的盐或其对映异构体、立体异构体或互变异构体,其用于治疗不孕症的方法。
本申请的另一方面涉及式(I)的盐或其对映异构体、立体异构体或互变异构体在制备用于治疗年龄相关病症的药物中的用途。
本申请的另一方面涉及式(I)的盐或其对映异构体、立体异构体或互变异构体在制备用于治疗不孕症的药物中的用途。
本公开的另一方面涉及改善卵母细胞质量和成熟的方法,其包括向有此需要的受试者施用治疗有效量的式I的盐。
本公开的另一方面涉及式(I)的盐或其对映异构体、立体异构体或互变异构体在制备用于治疗年龄相关病症的药物中的用途。
在另一方面,本发明包括在植入受试者之前用式(I)的盐离体处理卵母细胞,用于治疗年龄相关不孕症。
在另一方面,本发明包括在植入受试者之前用式(I)的盐离体处理囊胚,用于治疗年龄相关不孕症。
在另一方面,本发明包括在植入受试者之前用式(I)的盐离体处理卵母细胞,用于治疗不孕症。
在另一方面,本发明包括在植入受试者之前用式(I)的盐离体处理囊胚,用于治疗不孕症。
在另一方面,提供式(I)的盐作为溶液中的组分,用于离体处理细胞以用于治疗年龄相关病症。在一些实施方案中,年龄相关病症是年龄相关不孕症。在其他方面中,提供式(I)的盐作为溶液中的组分,用于离体处理细胞以用于治疗不孕症。
本公开的另一方面涉及制备式(I)的盐的方法,其包括在有效产生式I的盐的合适条件下,使式II的烟酸单核苷酸衍生物与金属-碱式氢氧化物接触。
本公开还涉及加速从疾病或病症中恢复的方法。该方法包括向有此需要的受试者施用有效量的式(I)的盐与所述疾病的处方治疗的组合。
在另一方面,本公开涉及用于体外受精的细胞培养基,其包含:一种或多种式(I)的盐和培养剂。
具体实施方式
本申请涉及能够治疗或预防年龄相关病症的盐和组合物。该申请的特征在于通过向有此需要的患者施用治疗有效量的式(I)的盐或其对映异构体、立体异构体或互变异构体来治疗、预防或改善与衰老相关的疾病或病症的方法。本申请的方法可用于通过预防或改善衰老和细胞恢复的过程来治疗多种疾病和病症,包括但不限于不孕症、细胞降解。
式(I)的盐是有效的并且在临床上可实现的剂量下是有效的;在多种潜在剂型中是稳定的;具有可接受的溶解度、可接受的pH、是结晶的、具有降低的吸水倾向、显示易于处理,-所有这些与药物开发、制造和使用一致。另外,本文公开的盐对增加的细胞NAD+水平提供增加的生物学活性,增加的稳定性并具有生理上更可接受的pH。
本公开的第一方面涉及式I的盐
其中A、L、M1、M2、R1、R2和R3如本文所述。
在本公开中,冠词“一(a)”和“一(an)”用于指一个或多于一个(即,至少一个)该冠词的语法对象。例如,“一个元件”是指一个元件或多于一个元件。
除非另外指出,否则术语“和/或”在本公开中用于表示“和”或“或”。
术语“任选地被取代的”应理解为是指给定的化学部分(例如烷基)可以(但不要求)键合其他取代基(例如杂原子)。例如,任选地被取代的烷基可以是完全饱和的烷基链(即,纯烃)。或者,相同的任选地被取代的烷基可以具有不同于氢的取代基。例如,它可以在链的任何点上与卤素原子、羟基或本文所述的任何其他取代基键合。因此,术语“任选地被取代”是指给定的化学部分具有包含其他官能团的潜力,但不一定具有任何其他官能团。在所述基团的任选取代中使用的合适的取代基包括但不限于卤素、氧代、-OH、-CN、-COOH、-CH2CN、-O-(C1-C6)烷基、(C1-C6)烷基、C1-C6烷氧基、(C1-C6)卤代烷基、C1-C6卤代烷氧基、-O-(C2-C6)烯基、-O-(C2-C6)炔基、(C2-C6)烯基、(C2-C6)炔基、-OH、-OP(O)(OH)2、-OC(O)(C1-C6)烷基、-C(O)(C1-C6)烷基、-OC(O)O(C1-C6)烷基、-NH2、-NH((C1-C6)烷基)、-N((C1-C6)烷基)2、-NHC(O)(C1-C6)烷基、-C(O)NH(C1-C6)烷基、-S(O)2(C1-C6)烷基、-S(O)NH(C1-C6)烷基和S(O)N((C1-C6)烷基)2。取代基本身可以任选地被取代。如本文所用,“任选地被取代”还指取代的或未取代的,其含义如下文所述。
如本文所用,术语“取代的”是指指定的基团或部分带有一个或多个合适的取代基,其中所述取代基可以在一个或多个位置连接到指定的基团或部分。例如,被环烷基取代的芳基可表示环烷基通过键或通过与芳基稠合并共享两个或更多个共同原子而连接至芳基的一个原子。
如本文所用,术语“未取代的”是指指定的基团不带有取代基。
除非另外具体定义,否则术语“芳基”是指具有1-3个芳环的环状芳族烃基,包括单环或双环基团,例如苯基、联苯基或萘基。在含有两个芳环(双环等)的情况下,芳基的芳环可在单个点处连接(例如联苯基)或稠合(例如萘基)。芳基可在任何连接点处任选地被一个或多个取代基,例如1-5个取代基取代。示例性的取代基包括但不限于-H、-卤素、-O-(C1-C6)烷基、(C1-C6)烷基、-O-(C2-C6)烯基、-O-(C2-C6)炔基、(C2-C6)烯基、(C2-C6)炔基、-OH、-OP(O)(OH)2、-OC(O)(C1-C6)烷基、-C(O)(C1-C6)烷基、-OC(O)O(C1-C6)烷基、NH2、NH((C1-C6)烷基)、N((C1-C6)烷基)2、-S(O)2-(C1-C6)烷基、-S(O)NH(C1-C6)烷基和S(O)N((C1-C6)烷基)2。取代基本身可以任选地被取代。此外,当含有两个稠合环时,本文所定义的芳基可具有与完全饱和的环稠合的不饱和或部分饱和的环。这些芳基的示例性环系统包括但不限于苯基、联苯基、萘基、蒽基、萉基、菲基、茚满基、茚基、四氢萘基、四氢苯并轮烯基等。
除非另外具体定义,否则“杂芳基”是指5至24个环原子的单价单环芳族基团或多环芳族基团,其含有一个或多个选自N、O或S的环杂原子,其余的环原子为C。本文定义的杂芳基还表示双环杂芳族基团,其中杂原子选自N、O或S。芳族基团任选地独立地被一个或多个本文所述的取代基取代。实例包括但不限于呋喃基、噻吩基、吡咯基、吡啶基、吡唑基、嘧啶基、咪唑基、异恶唑基、恶唑基、恶二唑基、吡嗪基、吲哚基、噻吩-2-基、喹啉基、苯并吡喃基、异噻唑基、噻唑基、噻二唑、吲唑、苯并咪唑基、噻吩并[3,2-b]噻吩、三唑基、三嗪基、咪唑并[1,2-b]吡唑基、呋喃并[2,3-c]吡啶基、咪唑并[1,2-a]吡啶基、吲唑基、吡咯并[2,3-c]吡啶基、吡咯并[3,2-c]吡啶基、吡唑并[3,4-c]吡啶基、噻吩并[3,2-c]吡啶基、噻吩并[2,3-c]吡啶基、噻吩并[2,3-b]吡啶基、苯并噻唑基、吲哚基、二氢吲哚基、吲哚酮基、二氢苯并噻吩基、二氢苯并呋喃基、苯并呋喃、苯并二氢吡喃基、硫代苯并二氢吡喃基、四氢喹啉基、二氢苯并噻嗪、二氢苯并氧杂基、喹啉基、异喹啉基、1,6-萘啶基、苯并[de]异喹啉基、吡啶并[4,3-b][1,6]萘啶基、噻吩并[2,3-b]吡嗪基、喹唑啉基、四唑并[1,5-a]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、异吲哚基、吡咯并[2,3-b]吡啶基、吡咯并[3,4-b]吡啶基、吡咯并[3,2-b]吡啶基、咪唑并[5,4-b]吡啶基、吡咯并[1,2-a]嘧啶基、四氢吡咯并[1,2-a]嘧啶基、3,4-二氢-2H-1λ2-吡咯并[2,1-b]嘧啶、二苯并[b,d]噻吩、吡啶-2-酮、呋喃并[3,2-c]吡啶基、呋喃并[2,3-c]吡啶基、1H-吡啶并[3,4-b][1,4]噻嗪基、苯并恶唑基、苯并异恶唑基、呋喃并[2,3-b]吡啶基、苯并噻吩基、1,5-萘啶基、呋喃并[3,2-b]吡啶、[1,2,4]三唑并[1,5-a]吡啶基、苯并[1,2,3]三唑基、咪唑并[1,2-a]嘧啶基、[1,2,4]三唑并[4,3-b]哒嗪基、苯并[c][1,2,5]噻二唑基、苯并[c][1,2,5]恶二唑、1,3-二氢-2H-苯并[d]咪唑-2-酮、3,4-二氢-2H-吡唑并[1,5-b][1,2]恶嗪基、4,5,6,7-四氢吡唑并[1,5-a]吡啶基、噻唑并[5,4-d]噻唑基、咪唑并[2,1-b][1,3,4]噻二唑基、噻吩并[2,3-b]吡咯基、3H-吲哚基及其衍生物。此外,当含有两个稠合环时,本文所定义的芳基可具有与完全饱和的环稠合的不饱和或部分饱和的环。这些杂芳基的示例性环系统包括二氢吲哚基、吲哚酮基、二氢苯并噻吩基、二氢苯并呋喃、苯并二氢吡喃基、硫代苯并二氢吡喃基、四氢喹啉基、二氢苯并噻嗪、3,4-二氢-1H-异喹啉基、2,3-二氢苯并呋喃、二氢吲哚基、吲哚基和二氢苯并氧杂基。
卤素或“卤基”是指氟、氯、溴或碘。
“烷基”是指含有1-12个碳原子的直链或支链饱和烃。(C1-C6)烷基的实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、新戊基和异己基。
“烷氧基”是指在链中含有末端“O”的含有1-12个碳原子的直链或支链饱和烃,即-O(烷基)。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、叔丁氧基或戊氧基。
“烯基”是指含有2-12个碳原子的直链或支链不饱和烃。“烯基”在链中含有至少一个双键。烯基的双键可以是非缀合的或与另一个不饱和基团缀合。烯基的实例包括乙烯基、丙烯基、正丁烯基、异丁烯基、戊烯基或己烯基。烯基可以是未取代的或取代的。如本文所定义,烯基可以是直链或支链的。
“炔基”是指含有2-12个碳原子的直链或支链不饱和烃。“炔基”在链中含有至少一个三键。烯基的实例包括乙炔基、炔丙基、正丁炔基、异丁炔基、戊炔基或己炔基。炔基可以是未取代的或取代的。
术语“亚烷基”或“亚烷基”是指二价烷基。上述单价烷基中的任一个可以通过从烷基中提取第二个氢原子而为亚烷基。如本文所定义,亚烷基还可以是C1-C6亚烷基。亚烷基可进一步是C1-C4亚烷基。典型的亚烷基包括但不限于-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-等。
“环烷基”是指含有3至18个碳原子(例如,C3-C10)的单环或多环饱和碳环(例如,稠合、桥接或螺环)。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片基、降冰片烯基、双环[2.2.2]辛基或双环[2.2.2]辛烯基。
“杂环基”或“杂环烷基”是指单环或多环(例如,稠合、桥接或螺环),其含有碳和取自氧、氮或硫的杂原子,并且其中在环碳或杂原子之间不共享离域的电子(芳香性)。杂环烷基可以是3-、4-、5-、6-、7-、8-、9-、10-、11-或12元环。杂环烷基环结构可以被一个或多个取代基取代。取代基本身可以任选地被取代。杂环基环的实例包括但不限于:氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、吡咯烷基、恶唑啉基、恶唑烷基、噻唑啉基、四氢噻唑基、吡喃基、硫代吡喃基、四氢吡喃基、二恶唑啉基、哌啶基、吗啉基、硫代吗啉基、硫代吗啉基S-氧化物、硫代吗啉基S-二氧化物、哌嗪基、氮杂卓基、氧杂环庚烷基、二氮杂卓基、托烷基、恶唑烷酮基和高托烷基。根据本申请,3至10元杂环基是指包含3至10个原子的饱和或部分饱和的非芳族环结构,其中存在至少一个选自N、O或S的杂原子。
术语“羟烷基”是指如上所定义的烷基,其中烷基被一个或多个-OH基团取代。羟烷基的实例包括HO-CH2-、HO-CH2-CH2-和CH3-CH(OH)-。
如本文所用,术语“卤代烷基”是指被一个或多个卤素取代的如本文所定义的烷基。卤代烷基的实例包括但不限于三氟甲基、二氟甲基、五氟乙基、三氯甲基等。
如本文所用,术语“卤代烷氧基”是指被一个或多个卤素取代的如本文所定义的烷氧基。卤代烷基的实例包括但不限于三氟甲氧基、二氟甲氧基、五氟乙氧基、三氯甲氧基等。
如本文所用,术语“氰基”是指具有通过三键与氮原子连接的碳原子的取代基,即C≡N。
如本文所用,术语“胺”是指伯胺(R-NH2,R≠H)、仲胺(R2-NH,R2≠H)和叔胺(R3-N,R≠H)。取代的胺是指其中至少一个氢原子被取代基取代的胺。
如本文所用,术语“氨基”是指含有至少一个氮原子的取代基。具体地,术语“氨基”中包括NH2、-NH(烷基)或烷基氨基、-N(烷基)2或二烷基氨基、酰胺-、碳酰胺-、脲和磺酰胺取代基。
如本文所用,术语“氧代”是指“=O”基团。
术语“季阳离子”是指在其氮或磷原子上具有四个可以相同或不同的取代基的季铵或鏻离子。所述季阳离子的具体实例包括三甲基甘氨酸、肉碱、胆碱等。
术语“异构体”是指具有相同组成和分子量但物理和/或化学性质不同的盐和/或化合物。结构差异可能在构造上(几何异构体)或在旋转偏振光平面的能力上(立体异构体)。关于立体异构体,式(I)的盐可以具有一个或多个不对称碳原子,并且可以作为外消旋体、外消旋混合物以及作为单独的对映异构体或非对映异构体存在。
本公开还包括药物组合物,其包含有效量的所公开的盐和药学上可接受的载体。代表性的“药学上可接受的盐”包括例如水溶性和水不溶性盐,例如乙酸盐、氨芪磺酸盐(4,4-二氨基-2,2-二磺酸盐)、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、钙盐、依地酸钙、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、克拉维酸盐、二盐酸盐、乙二胺四乙酸盐、乙二磺酸盐、雌酚盐、乙磺酸盐、富马酸盐、fiunarate、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、对羟乙酰氨基苯胂酸盐(glycollylarsanilate)、六氟磷酸盐、己基间苯二酚盐(hexylresorcinate)、海巴盐(hydrabamine)、氢溴酸盐、盐酸盐、羟萘甲酸盐、碘化物、异硫羟酸盐、乳酸盐、乳糖酸盐、月桂酸盐、镁盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴、甲基硝酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡糖胺铵盐、3-羟基-2-萘甲酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐(1,1-亚甲基-双-2-羟基3-萘甲酸盐、依伯酸盐(einbonate))、泛酸盐、磷酸盐/二磷酸盐、苦味酸盐、聚半乳糖醛酸盐、丙酸盐、对甲苯磺酸盐、水杨酸盐、硬脂酸盐、次乙酸盐、琥珀酸盐、硫酸盐、磺基水杨酸盐、苏拉明酸盐(suramate)、鞣酸盐、酒石酸盐、茶氯酸盐(teoclate)、甲苯磺酸盐、三乙基碘盐和戊酸盐。
“患者”或“受试者”是哺乳动物,例如人、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪或非人灵长类动物,例如猴子、黑猩猩、狒狒或恒河猴。
当与盐或药物组合物结合使用时,“有效量”是有效治疗或预防如本文所述的受试者的疾病的量。
在本公开中使用的术语“载体”包括载体、赋形剂和稀释剂,并且是指参与将药剂从受试者的一个器官或身体的一部分携带或运输至另一个器官或身体的一部分的材料、组合物或媒介物,如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。
关于受试者的术语“治疗”是指改善受试者病症的至少一种症状。治疗包括治愈、改善或至少部分改善病症。
除非另有说明,否则术语“病症”在本公开中用于表示术语疾病、病状或疾患,并且可以与之互换使用。
在本公开中使用的术语“施用”是指直接向受试者施用所公开的盐或组合物,或向受试者施用盐或组合物的前药衍生物或类似物,其可以在受试者体内形成等量的活性盐。
本申请的盐
本申请涉及能够治疗或预防年龄相关病症的盐或其对映异构体、立体异构体或互变异构体,其可用于治疗与衰老和细胞恢复有关的疾病和病症。
在式I的盐的一个实施方案中,A为O–。在另一个实施方案中,A为NRaRb。
在本发明的一些实施方案中,Ra在每次出现时独立地为H或C1–C6烷基。在其他实施方案中,Ra为H。在其他实施方案中,Ra为C1-C6烷基。在其他实施方案中,Ra为被一个或多个选自C1–C6烷基、C2–C6烯基、C2–C6炔基、(C0–C3亚烷基)C3–C8环烷基、(C0–C3亚烷基)杂环烷基、(C0–C3亚烷基)C6–C14芳基或(C0–C3亚烷基)杂芳基的取代基取代的C1–C6烷基。在其他实施方案中,Ra为被一个或多个选自C1–C6烷基的取代基取代的C1–C6烷基。在其他实施方案中,Ra为被一个或C2–C6烯基取代的C1–C6烷基。在其他实施方案中,Ra为被一个或多个C2–C6炔基取代的C1–C6烷基。在其他实施方案中,Ra为被一个或多个(C0–C3亚烷基)C3–C8环烷基取代的C1–C6烷基。在其他实施方案中,Ra为被一个或多个(C0–C3亚烷基)杂环烷基取代的C1–C6烷基。在其他实施方案中,Ra为被一个或多个(C0–C3亚烷基)C6–C14芳基取代的C1–C6烷基。在其他实施方案中,Ra为被一个或多个(C0–C3亚烷基)杂芳基取代的C1–C6烷基。在其他实施方案中,Ra为甲基。在另一个实施方案中,Ra为被一个或多个选自C1–C6烷基、C2–C6烯基、C2–C6炔基、(C0–C3亚烷基)C3–C8环烷基、(C0–C3亚烷基)杂环烷基、(C0–C3亚烷基)C6–C14芳基或(C0–C3亚烷基)杂芳基的取代基取代的甲基。
在本发明的一些实施方案中,Rb在每次出现时独立地为H或C1-C6烷基。在其他实施方案中,Rb为H。在其他实施方案中,Rb为C1-C6烷基。在其它实施方案中,Rb为被一个或多个选自C1–C6烷基、C2–C6烯基、C2–C6炔基、(C0–C3亚烷基)C3–C8环烷基、(C0–C3亚烷基)杂环烷基、(C0–C3亚烷基)C6–C14芳基或(C0–C3亚烷基)杂芳基的取代基取代的C1–C6烷基。在其它实施方案中,Rb为被一个或多个选自C1–C6烷基的取代基取代的C1–C6烷基。在其他实施方案中,Rb为被一个或C2–C6烯基取代的C1–C6烷基。在其他实施方案中,Rb为被一个或多个C2–C6炔基取代的C1–C6烷基。在其他实施方案中,Rb为被一个或多个(C0–C3亚烷基)C3–C8环烷基取代的C1–C6烷基。在其他实施方案中,Rb为被一个或多个(C0–C3亚烷基)杂环烷基取代的C1–C6烷基。在其他实施方案中,Rb为被一个或多个(C0–C3亚烷基)C6–C14芳基取代的C1–C6烷基。在其他实施方案中,Rb为被一个或多个(C0–C3亚烷基)杂芳基取代的C1–C6烷基。在其他实施方案中,Rb为甲基。在另一个实施方案中,Rb为被一个或多个选自C1–C6烷基、C2–C6烯基、C2–C6炔基、(C0–C3亚烷基)C3–C8环烷基、(C0–C3亚烷基)杂环烷基、(C0–C3亚烷基)C6–C14芳基或(C0–C3亚烷基)杂芳基的取代基取代的甲基。
在另一个实施方案中,R3为负电荷、H或C1-C6烷基。在一个实施方案中,R3代表负电荷。在另一个实施方案中,R3为H。在另一个实施方案中,R3为C1-C6烷基。
在另一个实施方案中,R1独立地为H、C1-C6烷基、C1-C6卤代烷基、-C(O)C1-C6卤代烷基、(C0-C3亚烷基)C(O)C1-C6烷基、-C(O)ORa、-C(O)NRaRb、-[CH2-CH2-O]k-Ra、-C(O)[CH2-CH2-O]k-Ra、-[CH2-CH2-CH2-O]k-Ra或-C(O)[CH2-CH2-CH2-O]k-Ra。在另一个实施方案中,R1为H。在另一个实施方案中,R1为C1-C6烷基。在另一个实施方案中,R1为C1-C6卤代烷基。在另一个实施方案中,R1为(C0-C3亚烷基)C(O)C1-C6烷基。在另一个实施方案中,R1为-C(O)ORa。在另一个实施方案中,R1为-[CH2-CH2-O]k-Ra。在另一个实施方案中,R1为C(O)C1-C6烷基。在另一个实施方案中,R1为-C(O)C1-C6卤代烷基。在另一个实施方案中,R1为-C(O)[CH2-CH2-O]k-Ra。在另一个实施方案中,R1为-[CH2-CH2-CH2-O]k-Ra。在另一个实施方案中,R1为-C(O)[CH2-CH2-CH2-O]k-Ra。
在一个实施方案中,R2独立地为H、C1-C6烷基、C1-C6卤代烷基、-C(O)C1-C6卤代烷基、(C0-C3亚烷基)C(O)C1–C6烷基、-C(O)ORa、-C(O)NRaRb、-[CH2-CH2-O]k-Ra、-C(O)[CH2-CH2-O]k-Ra、-[CH2-CH2-CH2-O]k-Ra或-C(O)[CH2-CH2-CH2-O]k-Ra。在另一个实施方案中,R2为H。在另一个实施方案中,R2为C1-C6烷基。在另一个实施方案中,R2为C1-C6卤代烷基。在另一个实施方案中,R2为(C0-C3亚烷基)C(O)C1-C6烷基。在另一个实施方案中,R2为-C(O)ORa。在另一个实施方案中,R2为-[CH2-CH2-O]k-Ra。在另一个实施方案中,R2为C(O)C1-C6烷基。在另一个实施方案中,R2为-C(O)C1-C6卤代烷基。在另一个实施方案中,R2为-C(O)[CH2-CH2-O]k-Ra。在另一个实施方案中,R2为-[CH2-CH2-CH2-O]k-Ra。在另一个实施方案中,R2为-C(O)[CH2-CH2-CH2-O]k-Ra。
在式I的盐的另一个实施方案中,R1和R2与它们所连接的原子一起可以形成5元杂环。在式I的盐的另一个实施方案中,R1和R2与它们所连接的原子一起可以形成6元杂环。在式I的盐的又另一个实施方案中,R1和R2与它们所连接的原子一起可以形成被一个或多个选自C1–C6烷基、C2–C6烯基、C2–C6炔基、(C0–C3亚烷基)C3–C8环烷基、(C0–C3亚烷基)杂环烷基、(C0–C3亚烷基)C6–C14芳基和(C0–C3亚烷基)杂芳基的取代基取代的5元杂环。在式I的盐的又另一个实施方案中,R1和R2与它们所连接的原子一起可以形成被一个或多个选自C1–C6烷基、C2–C6烯基、C2–C6炔基、(C0–C3亚烷基)C3–C8环烷基、(C0–C3亚烷基)杂环烷基、(C0–C3亚烷基)C6–C14芳基和(C0–C3亚烷基)杂芳基的取代基取代的6元杂环。
在式I的盐的一个实施方案中,M1不存在。在式I的盐的一个实施方案中,M1为季阳离子。在另一个实施方案中,M1为式II、式III或式IV的季阳离子:
在式I的盐的一个实施方案中,M2不存在。在式I的盐的一个实施方案中,M2为季阳离子。在另一个实施方案中,M2为式II、式III或式IV的季阳离子:
在式I的盐的一个实施方案中,M1不存在,并且M2为季阳离子。在另一个实施方案中,M1不存在且M2为式II、式III或式IV的季阳离子:
在式I的盐的一个实施方案中,M2不存在,并且M1为季阳离子。在另一个实施方案中,M2不存在且M1为式II、式III或式IV的季阳离子:
在式I的盐的一个实施方案中,M1和M2各自为季阳离子。在另一个实施方案中,M1和M2各自独立地为式II、式III或式IV的季阳离子:
在式I的盐的一个实施方案中,M1为式IIa的季阳离子:
在式I的盐的一个实施方案中,M2为式IIa的季阳离子:
在式I的盐的一个实施方案中,R4为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、(C0-C3亚烷基)C3-C8环烷基、(C0-C3亚烷基)杂环烷基、(C0-C3亚烷基)C6-C14芳基或(C0-C3亚烷基)杂芳基。在另一个实施方案中,R4为H。在另一个实施方案中,R4为C1-C6烷基。在另一个实施方案中,R4为C2-C6烯基。在另一个实施方案中,R4为C2-C6炔基。在另一个实施方案中,R4为(C0-C3亚烷基)C3-C8环烷基。在另一个实施方案中,R4为(C0-C3亚烷基)杂环烷基。在另一个实施方案中,R4为(C0-C3亚烷基)C6-C14芳基。在另一个实施方案中,R4为(C0-C3亚烷基)杂芳基。在另一个实施方案中,R4为被一个或多个(C0-C3亚烷基)SRc取代的C1-C4烷基。
在另一个实施方案中,R4为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的C1–C6烷基。在另一个实施方案中,R4为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的C2–C6烯基。在另一个实施方案中,R4为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的C2–C6炔基。在另一个实施方案中,R4为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的(C0-C3亚烷基)C3–C8环烷基。在另一个实施方案中,R4为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的(C0–C3亚烷基)杂环烷基。在另一个实施方案中,R4为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的(C0–C3亚烷基)C6–C14芳基。在另一个实施方案中,R4为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的(C0–C3亚烷基)杂芳基。
在式I的盐的一个实施方案中,R5为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、(C0-C3亚烷基)C3-C8环烷基、(C0-C3亚烷基)杂环烷基、(C0-C3亚烷基)C6-C14芳基或(C0-C3亚烷基)杂芳基。在另一个实施方案中,R5为H。在另一个实施方案中,R5为C1-C6烷基。在另一个实施方案中,R5为C2-C6烯基。在另一个实施方案中,R5为C2-C6炔基。在另一个实施方案中,R5为(C0-C3亚烷基)C3-C8环烷基。在另一个实施方案中,R5为(C0-C3亚烷基)杂环烷基。在另一个实施方案中,R5为(C0-C3亚烷基)C6-C14芳基。在另一个实施方案中,R5为(C0-C3亚烷基)杂芳基。
在另一个实施方案中,R5为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的C1–C6烷基。在另一个实施方案中,R5为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的C2–C6烯基。在另一个实施方案中,R5为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的C2–C6炔基。在另一个实施方案中,R5为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的(C0-C3亚烷基)C3–C8环烷基。在另一个实施方案中,R5为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的(C0–C3亚烷基)杂环烷基。在另一个实施方案中,R5为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的(C0–C3亚烷基)C6–C14芳基。在另一个实施方案中,R5为被一个或多个选自氰基、卤基、SeH、(C0–C3亚烷基)NRcRd、(C0–C3亚烷基)ORc、(C0–C3亚烷基)OC(O)Rc、(C0–C3亚烷基)C(O)ORc、(C0–C3亚烷基)SRc、(C0–C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0–C3亚烷基)C(NRc)NRcRd、(C0–C3亚烷基)NRcC(NRc)NRcRd、(C0–C3亚烷基)P(O)OnRcRd、(C0–C3亚烷基)S(O)mNRcRd、(C0–C3亚烷基)S(O)mORc、或(C0–C3亚烷基)BOpRcRd的取代基取代的(C0–C3亚烷基)杂芳基。
在另一个实施方案中,R6为H或C1-C6烷基。在另一个实施方案中,R6为H。在另一个实施方案中,R6为C1-C6烷基。在另一个实施方案中,R6为被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0-C3亚烷基)ORc的取代基取代的C1-C6烷基。
在另一个实施方案中,R7为H或C1-C6烷基。在另一个实施方案中,R7为H。在另一个实施方案中,R7为C1-C6烷基。在另一个实施方案中,R7为被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0–C3亚烷基)ORc的取代基取代的C1-C6烷基。
在另一个实施方案中,R8为H或C1-C6烷基。在另一个实施方案中,R8为H。在另一个实施方案中,R8为C1-C6烷基。在另一个实施方案中,R8为被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0-C3亚烷基)ORc的取代基取代的C1-C6烷基。
在另一个实施方案中,R4和R6与它们连接的原子一起可以形成5元环。在另一个实施方案中,R4和R6与它们连接的原子一起可以形成被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0-C3亚烷基)ORc的取代基取代的5元环。在另一个实施方案中,R4和R6与它们连接的原子一起可以形成6元环。在另一个实施方案中,R4和R6与它们连接的原子一起可以形成被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0-C3亚烷基)ORc的取代基取代的6元环。
在另一个实施方案中,R7和R8与它们连接的原子一起可以形成5元环。在另一个实施方案中,R7和R8与它们连接的原子一起可以形成被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0-C3亚烷基)ORc的取代基取代的5元环。在另一个实施方案中,R7和R8与它们连接的原子一起可以形成6元环。在另一个实施方案中,R7和R8与它们连接的原子一起可以形成被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0-C3亚烷基)ORc的取代基取代的6元环。
在另一个实施方案中,Rd在每次出现时独立地为H或C1-C6烷基。在另一个实施方案中,Rd为H。在另一个实施方案中,Rd为C1-C6烷基。在另一个实施方案中,Rd为被一个或多个选自(C0-C3亚烷基)C3-C8环烷基、(C0-C3亚烷基)杂环烷基、(C0-C3亚烷基)C6-C14芳基或(C0-C3亚烷基)杂芳基的取代基取代的C1-C6烷基。
在另一个实施方案中,Rc在每次出现时独立地为H或C1-C6烷基。在另一个实施方案中,Rc为H。在另一个实施方案中,Rc为C1-C6烷基。在另一个实施方案中,Rc为被一个或多个选自(C0-C3亚烷基)C3-C8环烷基、(C0-C3亚烷基)杂环烷基、(C0-C3亚烷基)C6-C14芳基或(C0-C3亚烷基)杂芳基的取代基取代的C1-C6烷基。
在另一个实施方案中,k在每次出现时为1、2、3、4、5、6、7或8。在另一个实施方案中,k为1。在另一个实施方案中,k为2。在另一个实施方案中,k为3。在另一个实施方案中,k为4。在另一个实施方案中,k为5。在另一个实施方案中,k为6。在另一个实施方案中,k为7。在另一个实施方案中,k为8。
在一个实施方案中,m为0、1或2。在另一个实施方案中,m为0。在另一个实施方案中,m为1。在另一个实施方案中,m为2。
在一个实施方案中,n为0、1或2。在另一个实施方案中,n为0。在另一个实施方案中,n为1。在另一个实施方案中,n为2。
在一个实施方案中,p为0、1或2。在另一个实施方案中,p为0。在另一个实施方案中,p为1。在另一个实施方案中,p为2。
在一个实施方案中,q为0、1、2、3、4或5。在另一个实施方案中,q为0。在另一个实施方案中,q为1。在另一个实施方案中,q为2。在另一个实施方案中,q为3。在另一个实施方案中,q为4。在另一个实施方案中,q为5。
在一个实施方案中,r为0或1。在另一个实施方案中,r为0。在另一个实施方案中,r为1。
在一些实施方案中,式I的盐具有式(Ia)的结构:
在一些实施方案中,式I的盐具有式Ib的结构:
在一些实施方案中,式I的盐具有式Ic的结构:
在一些实施方案中,式I的盐具有式Id的结构:
在一些实施方案中,式I的盐具有式Ie的结构:
在一些实施方案中,式I的盐具有式If的结构:
在一些实施方案中,式I的盐具有式Ig的结构:
在一些实施方案中,式I的盐具有式Ik的结构:
在一些实施方案中,式I的盐具有式Il的结构:
在一些实施方案中,式I的盐具有式Im的结构:
在一些实施方案中,式I的盐具有式In的结构:
在一些实施方案中,式I的盐具有式Io的结构:
在一些实施方案中,式I的盐具有式Ip的结构:
在一些实施方案中,式I的盐具有式Iq的结构:
在一些实施方案中,式I的盐具有式Ir的结构:
在一些实施方案中,式I的盐具有式Is的结构:
在另一个实施方案中,合适的盐包括但不限于:
盐的制备方法
本申请的盐可以通过多种方法制备,包括标准化学方法。合适的合成路线在以下给出的方案中描述。
式(I)的盐可以通过有机合成领域中已知的方法制备,如以下合成方案部分所述。在以下描述的方案中,应充分理解,根据一般原理或化学,在必要时使用敏感或反应性基团的保护基。根据有机合成的标准方法操纵保护基(T.W.Greene和P.G.M.Wuts,“ProtectiveGroups in Organic Synthesis”,第三版,Wiley,New York 1999)。使用本领域技术人员显而易见的方法在盐合成的适宜阶段除去这些基团。选择方法以及反应条件和其执行顺序应与式(I)的盐的制备一致。
本领域技术人员将认识到式(I)的盐中是否存在立体中心。因此,本申请包括可能的立体异构体(除非在合成中另有说明),并且不仅包括外消旋盐,还包括单独的对映异构体和/或非对映异构体。当期望化合物或盐作为单一对映异构体或非对映异构体时,其可以通过立体特异性合成或通过拆分最终产物或任何方便的中间体来获得。最终产物、中间体或起始材料的拆分可通过本领域已知的任何合适方法来实现。参见例如E.L.Eliel、S.H.Wilen和L.N.Mander的”Stereochemistry of Organic Compounds”(Wiley-lnterscience,1994)。
本文所述的盐和化合物可以由可商购的起始材料制备或使用已知的有机、无机和/或酶促方法合成。
本申请的盐可以以有机合成领域的技术人员众所周知的多种方式制备。例如,本申请的盐可以使用以下描述的方法,以及合成有机化学领域中已知的合成方法,或者如本领域技术人员所理解的其变化形式来合成。这些方法包括但不限于以下描述的那些方法。本申请的盐可以通过遵循一般方案1和2中概述的步骤来合成,所述步骤包括组装各种中间体的不同顺序。起始材料是可商购的或通过报道的文献中或如说明的已知程序制备。
方案1
方案2
由上述方法得到的对映异构体、非对映异构体、顺式/反式异构体的混合物可根据分离的性质通过手性盐技术,使用正相、反相或手性柱的色谱法分离成其单一组分。
应当理解,在以上所示的描述和式中,除非另有说明,否则方案中的基团R表示R4和R5,其他变量如上所定义。此外,出于合成目的,一般方案1和2的盐仅代表选定基团以说明如本文所定义的式(I)的盐的一般合成方法。
还应理解,本文公开的盐具有中性电荷,并且式I的结构仅代表属,如果需要,其可以用抗衡离子平衡以使盐呈现中性电荷。这样的抗衡离子可包括但不限于溴、氯和三氟甲磺酸根。在一个实施方案中,本发明的盐可以原位产生而无需从溶液中分离。在一些实施方案中,本文公开的盐可以是离散的1:1或1:2盐。在一些实施方案中,盐也可以以其他比例存在,例如1:1.5、1:5和1:10。
公开盐的使用方法
本公开的另一方面涉及一种治疗或预防与衰老、细胞降解和/或细胞恢复相关的疾病或病症的方法。此类疾病和病症的非限制性实例包括不孕症、年龄相关不孕症、年龄相关的眼功能丧失、骨密度降低、肥胖症和胰岛素不敏感性。在一个实施方案中,式(I)的盐可用于治疗年龄相关不孕症。在另一个实施方案中,式(I)的盐可用于治疗生育力。
本公开的另一方面涉及一种治疗或预防年龄相关疾病或病症的方法。该方法包括向有此需要的受试者施用治疗有效量的式I的盐的药物组合物。
本公开的另一方面涉及改善卵母细胞或囊胚质量和成熟的方法。该方法包括使卵母细胞或囊胚与包含式(I)的盐的IVF培养基接触一段有效时间。
在另一方面,本公开提供了包含式(I)的盐的培养基。式(I)的盐在溶液中显示出令人惊讶和出乎意料的长期稳定性,因此可在植入患有不孕症或年龄相关不孕症的受试者之前用于使卵子、卵母细胞和/或囊胚暴露的培养基中持续增强NAD+产生所需的时间段。在一些实施方案中,提供了包含式(I)的盐的培养基。在一些实施方案中,取决于卵子、卵母细胞或囊胚处于哪个成熟和发育阶段,培养基包含卵子、卵母细胞或囊胚必需的各种试剂和因子。例如,培养基可以包含下表1中列出的可用于IVF培养基的任何试剂或因子:
表1
还提供了一种用于体外受精的细胞培养基,其包含:一种或多种式(I)的盐和培养剂。
在一个实施方案中,所述培养剂是无机盐、能量基质、氨基酸、螯合剂、pH指示剂、抗生素、血清、维生素、生长因子或其任何组合。在一个实施方案中,无机盐是氯化钙、氯化镁、硫酸镁、氯化钾、碳酸氢钠、氯化钠、磷酸一钠、磷酸二钠或其任何组合。
在一个实施方案中,能量基质是葡萄糖、丙酮酸盐、乳酸盐、丙酮酸盐或其任何组合。
在一个实施方案中,氨基酸是必需氨基酸。在一个实施方案中,必需氨基酸是精氨酸、半胱氨酸、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸或其任何组合。
在一个实施方案中,氨基酸是非必需氨基酸。
在一个实施方案中,非必需氨基酸为丙氨酸、天冬酰胺、天冬氨酸、谷氨酸、脯氨酸、丝氨酸或其任何组合。
在一个实施方案中,螯合剂为笼状螯合物、乙酰丙酮、氨基多羧酸、ATMP、BAPTA、BDTH2、柠檬酸、穴醚、地拉罗司(deferasirox)、2,3-二氢苯甲酸、2,3-二巯基-1-丙烷磺酸、二巯基琥珀酸、DOTA、DTPMP、EDDHA、EDDS、EDTMP、依替膦酸、fura-2、葡萄糖酸、高柠檬酸、亚氨基二乙酸、Indo-1、腈三乙酸、喷替酸(DTPA)、膦酸盐、植物螯合肽、聚天冬氨酸、聚天冬氨酸钠、柠檬酸三钠、转铁蛋白、EDTA、EGTA或其任何组合。
在一个实施方案中,pH指示剂是酚红、溴百里酚蓝、茜素红、9-氨基吖啶或其任何组合。
在一个实施方案中,抗生素是放线菌素D、氨苄青霉素、羧苄青霉素、头孢噻肟、膦胺霉素、庆大霉素、卡那霉素、新霉素、青霉素、多粘菌素B、链霉素或其任何组合。
在一个实施方案中,血清是人血清白蛋白、牛血清白蛋白、胎牛血清、合成血清或其任何组合。
在一个实施方案中,维生素是抗坏血酸、生物素、甲萘醌亚硫酸氢钠、丝裂霉素C、吡哆胺二盐酸盐、乙酸视黄酯、(-)-核黄素、(+)-L-抗坏血酸钠、(+)-α-生育酚、维生素B12、盐酸硫胺、异肌醇、盐酸吡哆醛、烟酰胺、叶酸、D-泛酸钙、氯化胆碱或其任何组合。
在一个实施方案中,生长因子是肾上腺髓质素、血管生成素、骨形态发生蛋白、巨噬细胞集落刺激因子(M-CSF)、粒细胞集落刺激因子(G-CSF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、表皮生长因子、肝配蛋白、促红细胞生成素、成纤维细胞生长因子、生长分化因子-9、肝细胞生长因子、胰岛素、胰岛素样生长因子、白介素、角质形成细胞生长因子、迁移刺激因子、巨噬细胞刺激蛋白、肌生长抑制素、神经营养蛋白、t细胞生长因子、血小板生成素、转化生长因子、肿瘤坏死因子-α、血管内皮生长因子或其任何组合。
在一个实施方案中,细胞培养基还包含卵母细胞、合子、囊胚或其任何组合。
还提供了用于IVF培养基的试剂盒,其包含各种剂,以及卵母细胞或囊胚成熟所需的因子,包括一种或多种式(I)的盐。在用于暴露卵母细胞或囊胚之前不久,可以将这些剂和辅因子溶解在溶液中以产生IVF培养基,然后植入需要治疗不孕症或年龄相关不孕症的患者。
本发明还涉及式I的盐及其对映异构体、立体异构体和互变异构体在制备用于治疗衰老、细胞恢复、细胞降解或不孕症的药物中的用途。在某些实施方案中,治疗的不孕症是年龄相关不孕症。
本发明的另一方面是药物组合物,其包含式I的盐和药学上可接受的载体。
本发明的另一方面是包含式I的盐和药学上可接受的载体的药物组合物,其包含治疗有效量的一种或多种另外的治疗剂。
在一些实施方案中,式(I)的盐或包含本发明的盐和药学上可接受的载体的药物组合物的施用诱导细胞周期或细胞生存力的改变。
在一些实施方案中,式(I)的盐或包含本发明的盐和药学上可接受的载体的药物组合物的施用诱导与衰老相关的病症或疾病的预防性变化。
所公开的盐的施用可以通过用于治疗剂的任何施用方式来实现。这些方式包括全身或局部施用,例如口服、鼻腔、肠胃外、透皮、皮下、阴道、颊、直肠或局部施用方式。
取决于预期的施用方式,所公开的组合物可以是固体、半固体或液体剂型,例如注射剂、片剂、栓剂、丸剂、延时释放胶囊、酏剂、酊剂、乳剂、糖浆剂、粉剂、液体、悬浮液等,有时以单位剂量使用,并且与常规药物实践一致。同样,它们也可以以静脉内(推注和输注)、腹膜内、皮下或肌内形式施用、以及药学领域技术人员熟知的所有使用形式。
药物组合物可以分别根据常规的混合、制粒或包衣方法制备,并且本发明的药物组合物可以含有按重量或体积计约0.1%至约99%,约5%至约90%或约1%至约20%的所公开的盐。
在一个实施方案中,本发明涉及一种通过混合至少一种本发明的药学上可接受的盐,以及任选地一种或多种药学上可接受的载体、添加剂或赋形剂来制备本发明的药物组合物的方法。
在另一个实施方案中,本发明涉及一种通过将至少一种本发明的药学上可接受的盐与一种或多种其他治疗剂混合来制备本发明的药物组合物的方法。
当用于所述方法时,式(I)的盐的有效剂量在治疗病状所需的约0.5mg至约5000mg的所公开的盐的范围内。用于体内或体外使用的组合物可包含约0.5、5、20、50、75、100、150、250、500、750、1000、1250、2500、3500、或5000mg所公开的盐或在剂量列表中的一个量至另一个量的范围内。在一个实施方案中,组合物为可刻痕的片剂形式。
根据多种因素选择使用所公开的盐的给药方案,所述因素包括患者的类型、物种、年龄、体重、性别和医学状况;待治疗病状的严重程度;施用途径;患者的肾或肝功能;以及所使用的具体公开的盐。本领域普通医师或兽医可容易地确定和开出预防、对抗或阻止病状进展所需的药物的有效量。
说明性的药物组合物是片剂和明胶胶囊,其包含本发明的盐和药学上可接受的载体,例如a)稀释剂,例如纯净水、甘油三酸酯油,例如氢化或部分氢化的植物油或其混合物、玉米油、橄榄油、葵花籽油、红花油、鱼油(例如EPA或DHA)或其酯或甘油三酸酯或其混合物、ω-3脂肪酸或其衍生物、乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素、钠、糖精、葡萄糖和/或甘氨酸;b)润滑剂,例如二氧化硅、滑石、硬脂酸、其镁盐或钙盐、油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠和/或聚乙二醇;也用于片剂;c)粘合剂,例如硅酸铝镁、淀粉糊、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠、碳酸镁、天然糖(例如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶(例如阿拉伯胶、黄芪胶或海藻酸钠)、蜡和/或聚乙烯吡咯烷酮,如果需要;d)崩解剂,例如淀粉、琼脂、甲基纤维素、膨润土、黄原胶、海藻酸或其钠盐或泡腾混合物;e)吸收剂、着色剂、调味剂和甜味剂;f)乳化剂或分散剂,例如Tween 80、Labrasol、HPMC、DOSS、己酰基909、labrafac、labrafil、peceol、transcutol、capmul MCM、capmul PG-12、captex 355、gelucire、维生素E TGPS或其他可接受的乳化剂;和/或g)增强盐吸收的剂,例如环糊精、羟丙基-环糊精、PEG400和/或PEG200。
为了由式(I)的盐制备药物组合物,惰性的药学上可接受的载体可以是固体或液体。固体形式的制剂包括粉剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。粉剂和片剂可包含约5%至约95%的活性成分。合适的固体载体是本领域已知的,例如碳酸镁、硬脂酸镁、滑石、糖或乳糖。片剂、粉剂、扁囊剂和胶囊剂可用作适合口服的固体剂型。用于各种组合物的药学上可接受的载体和制造方法的实例可以在A.Gennaro(编辑),Remington’sPharmaceutical Sciences,第18版,(1990),Mack Publishing Co.,Easton,Pa中找到。
液体形式的制剂包括溶液、悬浮液和乳剂。例如,水或水-丙二醇溶液用于肠胃外注射,或添加甜味剂和遮光剂用于口服溶液、悬浮液和乳剂。液体形式的制剂还可以包括用于鼻内施用的溶液。
液体,特别是可注射的组合物可以例如通过溶解、分散等来制备。例如,将所公开的盐溶解在药学上可接受的溶剂中,或与之混合,所述药学上可接受的溶剂例如水、盐水、右旋糖水溶液、甘油、乙醇等,从而形成可注射的等渗溶液或悬浮液。蛋白质如白蛋白、乳糜微粒颗粒或血清蛋白可用于溶解所公开的化合物。
可胃肠外注射施用通常用于皮下、肌内或静脉内注射和输注。注射剂可以以常规形式制备,作为液体溶液或悬浮液或适于在注射前溶解在液体中的固体形式。
适于吸入的气溶胶制剂可包括溶液和粉末形式的固体,其可与药学上可接受的载体如惰性压缩气体如氮气组合。
还包括在使用前不久转化成用于口服或肠胃外施用的液体形式制剂的固体形式制剂。这样的液体形式包括溶液、悬浮液和乳液。
实施例
通过以下实施例和合成方案进一步说明本公开,这些实施例和合成方案不应被解释为将本发明的范围或精神限制于本文所述的具体程序。应该理解的是,提供这些实施例以说明某些实施方案,并且不意图限制本公开的范围。还应理解的是,在不脱离本公开的精神和/或所附权利要求的范围的情况下,可以采取本领域技术人员可以想到的各种其他实施方案、修改及其等同物。
使用一般合成方法制备本文公开的以下盐,所述方法包括但不限于例如缬氨酸、亮氨酸、丙氨酸、异亮氨酸、蛋氨酸、苯丙氨酸、色氨酸和酪氨酸的试剂。也使用合适的溶剂,例如甲醇、乙醇、水、乙酸、乙二醇、异丙醇。
以下实施例和本文其他地方使用的缩写是:
AcOH 醋酸
anh. 无水
atm 气氛
aq. 水性
br 宽
Boc 叔丁氧羰基
盐水 饱和氯化钠水溶液
n-BuLi 正-丁基锂
n-BuOH 正-丁醇
Calc’d 计算值
CDCl3 氘代氯仿
CDI 羰基二咪唑
氯仿-d 氘代氯仿
d 二重峰
dd 双二重峰
dt 双三重峰
D2O 氘化水(氧化氘)
DCE 二氯乙烷
DCM 二氯甲烷
DIAD 偶氮二甲酸二异丙酯
DIPEA N,N-二异丙基乙胺
DMAc N,N-二甲基乙酰胺
DMAP N,N-二甲基吡啶-4-胺
DME 1,2-二甲氧基乙烷
DMEDA N,N’-二甲基乙二胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DMSO-d6 氘代二甲亚砜
EDA 乙二胺
EDC 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺
Et2O 乙醚
EtOAc 乙酸乙酯
EtOH 乙醇
ESI 电喷雾电离
g 克
h 小时
H 氢
1H NMR 核磁共振(质子核)
HATU [双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5- b]吡啶鎓3-氧化物六氟磷酸盐
HBTU 3-[双(二甲氨基)亚甲基]-3H-苯并三唑-1-氧 化物六氟磷酸盐
HOBt 羟基苯并三唑
HPLC 高压(或性能)液相色谱
Hz 赫兹
J 耦合常数
KHCO3 碳酸氢钾
KHMDS 六甲基二硅氮化钾
KOAc 醋酸钾
LCMS 液相色谱质谱
LHMDS 六甲基二硅氮化锂
[#]M 摩尔浓度
m 多重峰
[M+H]+ 分子离子加氢
[M-tBu+H]+ 分子离子减去叔丁基加氢
mCPBA 间氯过氧苯甲酸
Me2NH 二甲胺
Me4NBr 四甲基溴化铵
MeCN 乙腈
MeNH2 甲胺
MeOH 甲醇
甲醇-d4 氘代甲醇
2-MeTHF 2-甲基四氢呋喃
mg 毫克
MHz 兆赫
min 分钟
mmol 毫摩尔
mL 毫升
MS 质谱
MS ES 质谱电喷雾
Ms2O 甲磺酸酐
MTBE 甲基叔丁基醚
MW 微波
m/z 质荷比
μL 微升
N2 氮气
NaHCO3 碳酸氢钠
NaMN 烟酸单核苷酸
NIS N-碘代琥珀酰亚胺
NMP N-甲基-2-吡咯烷酮
NMR 核磁共振
PEPPSI-iPr [1,3-双(2,6-二异丙基苯基)咪唑-2-亚基](3- 氯吡啶基)二氯化钯(II)
PdCl2(Amphos) 双(二叔丁基(4-二甲基氨基苯基)膦)二氯钯 (II)
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
Pd(OAc)2 乙酸钯(II)
PdCl2(dppf) [1,1’-双(二苯基膦基)二茂铁]二氯钯(II)
PdCl2(MeCN)2 双(乙腈)二氯钯(II)
PdCl2(PPh3)2 双(三苯基膦二氯化钯(II)
Pd(P(Cy)3)2Cl2 二氯双(三环己基膦)钯(II)
Pd(PPh3)4 四(三苯基膦)钯(0)
Pd(t-Bu3P)2 双(三-叔丁基膦)钯(0)
pH 氢势
PMB 4-甲氧基苄基
PMBCl 4-甲氧基苄基氯
ppm 百万分率
prep 制备型
py 吡啶
q 四重峰
qd 四双重峰
quant. 定量
quin. 五重峰
quind 五个双重峰
RBF 圆底烧瓶
Rt 保留时间
rt 室温
s 单峰
sat. 饱和的
sat.aq. 饱和水溶液
SEMCl 2-(三甲基甲硅烷基)乙氧基甲基氯
t 三重峰
t-BuLi 叔丁基锂
td 三个双重峰
TMS 三甲基甲硅烷基
TMSCl 三甲基甲硅烷基氯
tt 三个三重峰
T3P 聚膦酸酐
TBAB 四丁基溴化铵
TEA 三乙胺
TFA 三氟乙酸
TFAA 三氟乙酸酐
THF 四氢呋喃
TLC 薄层色谱法
TPPO 三苯基氧化膦
XantPhos 4,5-双(二苯基膦基)-9,9-二甲基呫吨
XPhos 2-二环己基膦基-2’,4’,6’-三异丙基联苯
实施例1.1-((2R,3R,4S,5R)-5-(((氢膦酸基)氧基)甲基)-3,4-二羟基四氢呋喃-2-基)吡啶-1-鎓-3-甲酸2-羟基-N,N,N-三甲基乙铵的合成
向装有水冷凝器、橡胶隔垫和内部温度计的50mL 3N RBF中加入NAMN(0.200g,5.97mmol,1当量)和15ml蒸馏去离子水,混合以形成溶液。使用冰/水浴将该溶液冷却以使内部温度低于5℃。然后通过注射器向该溶液中缓慢滴加5.67ml 0.1M氢氧化胆碱溶液,以防止温度升高。将所得溶液搅拌10分钟。加入后,pH为4.2-4.8。然后移出烧瓶,并将溶液转移至100ml 1N RBF中。然后在旋转的同时使用液氮将溶液冷冻,以确保冷冻溶液覆盖整个RBF内部。冷冻时,将烧瓶连接至冷冻干燥器,并使其蒸发过夜。干燥后,产物呈现为黄色固体。
产量:253mg(97%)
分析数据。1H-NMR(400MHz,D2O)δ=9.32(s,1H),9.25(d,1H),8.96(d,1H),8.24(t,1H),6.21(d,1H),4.64(p,1H),4.575(t,1H),4.48(m,1H),4.32(m,1H),4.18(dq,1H),4.08(m,2H),3.53(m,2H),3.22(s,9H)ppm
实施例2. 1-((2R,3R,4S,5R)-5-(((氢膦酸基)氧基)甲基)-3,4-二羟基四氢呋喃-2-基)吡啶-1-鎓-3-甲酸(R)-3-羧基-2-羟基-N,N,N-三甲基丙-1-铵的合成
向装有水冷凝器和内部温度计的100mL 3N RBF中加入NaMN(0.300g,0.894mmol,1当量)和30ml蒸馏去离子水并混合形成溶液,稀悬浮液也是可接受的。使用冰/水浴将该溶液冷却以使内部温度低于10℃。然后向该溶液中缓慢滴加8.77ml 0.1M L-肉碱在蒸馏去离子水中的溶液(0.98当量),以防止温度升高,所有悬浮液进入溶液。将所得溶液搅拌10分钟。加完后pH为约3.2。然后移出烧瓶,将无色溶液倒入100ml 1N RBF中,并用液氮冷冻。将烧瓶冷冻后,将其连接至冷冻干燥器。干燥后,产物呈现为无色至淡黄色固体。
产量:0.321.2g(72%)
熔点:92℃(降解,经校正)146℃脱气
分析数据。1H-NMR(400MHz,D2O)δ=9.36(s,1H),9.26(d,1H),8.98(d,1H),8.26(dd,1H),6.24(d,1H),4.65(m,1H),4.56(t,1H),4.47(dd,1H),4.33(dq,1H),4.19(dq,1H),3.50(m,2H),3.25(s,9H),2.60-2.70(m,2H)ppm
实施例3. 1-((2R,3R,4S,5R)-5-(((氢膦酸基)甲基)-3,4-二羟基四氢呋喃-2-基)吡啶-1-鎓-3-甲酸1-羧基-N,N,N-三甲基甲铵的合成
向装有水冷凝器和内部温度计的50mL 3NRBF中加入NaMN(0.100g,0.298mmol,1当量)和10ml蒸馏去离子水,混合以形成溶液。使用冰/水浴将该溶液冷却以使内部温度低于10℃。然后向该溶液中缓慢滴加2.92ml 0.1M甜菜碱在蒸馏去离子水中的溶液(0.98当量),以防止温度升高,所有悬浮液进入溶液中。将所得溶液搅拌10分钟。添加后,pH为约1.8-2.3。然后移出烧瓶,将无色溶液倒入50ml 1N RBF中,并用液氮冷冻。将烧瓶冷冻后,将其连接至冷冻干燥器。干燥后,产物呈现为无色至淡黄色固体。
产量:140.2mg(定量产量)
熔点:122-133℃(降解,经校正)
分析数据。1H-NMR(400MHz,D2O)δ=9.45(s,1H),9.30(d,1H),9.05(d,1H),8.28(dd,1H),6.25(d,1H),4.66(p,1H),4.57(t,1H),4.47(dd,1H),4.33(dq,1H),4.19(dq,1H),4.04(s,2H),3.30(s,9H)ppm
实施例4.((2R,3S,4R,5R)-5-(3-氨基甲酰基吡啶-1-鎓-1-基)-3,4-二羟基四氢呋喃-2-基)甲基磷酸(R)-3-羧基-2-羟基-N,N,N-三甲基丙-1-铵的合成
向装有水冷凝器和内部温度计的50mL 3N RBF中装入NMN(0.250g,0.748mmol,1当量)和25ml蒸馏去离子水,混合以形成溶液。使用冰/水浴将该溶液冷却以使内部温度低于10℃。然后向该溶液中缓慢滴加7.33ml 0.1M L-肉碱在蒸馏去离子水中的溶液(0.98当量),以防止温度升高,所有悬浮液进入溶液。将所得溶液搅拌10分钟。加入后pH为约4.4。然后移出烧瓶,将无色溶液倒入100ml 1N RBF中,并用液氮冷冻。将烧瓶冷冻后,将其连接至冷冻干燥器。干燥后,产物呈现为无色至淡黄色固体。
产量:249.4mg(67%)
熔点:68-99℃(降解,经校正)在136℃下脱气
分析数据。1H-NMR(400MHz,D2O)δ=9.50(s,1H),9.31(d,1H),9.02(d,1H),8.33(dd,1H),6.25(d,1H),4.68(p,1H),4.60(m,2H),4.48(dd,1H),4.33(dq,1H),4.18(dq,1H),3.45(m,2H),3.25(s,9H),2.48(m,2H)ppm
实施例5.((2R,3S,4R,5R)-5-(3-氨基甲酰基吡啶-1-鎓-1-基)-3,4-二羟基四氢呋喃-2-基)甲基磷酸1-羧基-N,N,N-三甲基甲铵的合成
向装有水冷凝器和内部温度计的50mL 3N RBF中加入NMN(0.100g,0.299mmol,1当量)和5ml蒸馏去离子水并混合形成溶液,稀悬浮液也是可以接受的。使用冰/水浴将该溶液冷却以使内部温度低于10℃。然后向该溶液中缓慢滴加2.93ml 0.1M甜菜碱在蒸馏去离子水中的溶液(0.98当量),以防止温度升高,所有悬浮液进入溶液中。将所得溶液搅拌10分钟。加入后,pH为约3.8-4.2。然后移出烧瓶,将无色溶液倒入50ml 1N RBF中,并用液氮冷冻。将烧瓶冷冻后,将其连接至冷冻干燥器。干燥后,产物呈现为无色至淡黄色固体。
产量:129.5mg(97%)
熔点:105℃(熔化)129℃(降解,经校正)
分析数据。1H-NMR(400MHz,D2O)δ=9.50(s,1H),9.31(d,1H),9.02(d,1H),8.33(dd,1H),6.25(d,1H),4.68(m,1H),4.60(t,1H),4.47(dd,1H),4.33(dq,1H),4.18(dq,1H),3.92(s,2H),3.28(s,9H)ppm
实施例6. 1-((2R,3R,4S,5R)-3,4-二羟基-5-((膦酸基氧基)甲基)四氢呋喃-2-基)吡啶-1-鎓-3-羧酸(R)-3-羧基-2-羟基-N,N,N-三甲基丙-1-铵的合成
向装有水冷凝器和内部温度计的100mL 3N RBF中加入NaMN(0.250g,0.298mmol,1当量)和25ml蒸馏去离子水,混合形成溶液,稀悬浮液也可以。使用冰/水浴将该溶液冷却以使内部温度低于10℃。然后向该溶液中缓慢滴加14.76ml 0.1M L-肉碱在蒸馏去离子水中的溶液(1.98当量),以防止温度升高,所有悬浮液进入溶液。将所得溶液搅拌10分钟。在添加后,pH为约3.3-3.9。然后移出烧瓶,将无色溶液倒入100ml 1N RBF中,并用液氮冷冻。将烧瓶冷冻后,将其连接至冷冻干燥器。干燥后,产物呈现为无色至淡黄色固体。
产量:238.9mg(转移后49%)
分析数据。1H-NMR(400MHz,D2O)δ=9.35(s,1H),9.25(d,1H),8.95(d,1H),8.25(dd,1H),6.23(d,1H),4.65(m,3H),4.55(t,1H),4.48(d7,1H),4.33(dq,1H),4.18(dq,1H),3.48(m,4H),3.24(s,18H),2.56(d,4H)ppm
实施例7. 1-((2R,3R,4S,5R)-3,4-二羟基-5-((膦酸基氧基)甲基)四氢呋喃-2-基)吡啶-1-鎓-3-甲酸1-羧基-N,N,N-三甲基甲铵的合成
向装有水冷凝器和内部温度计的50mL 3N RBF中装入NaMN(0.100g,0.298mmol,1当量)和10ml蒸馏去离子水,混合以形成溶液。使用冰/水浴将该溶液冷却以使内部温度低于10℃。然后向该溶液中缓慢滴加5.85ml 0.1M甜菜碱在蒸馏去离子水中的溶液(1.98当量),以防止温度升高,所有悬浮液进入溶液中。将所得溶液搅拌10分钟。添加后,pH为约2.8-2.3。然后移出烧瓶,将无色溶液倒入50ml 1N RBF中,并用液氮冷冻。将烧瓶冷冻后,将其连接至冷冻干燥器。干燥后,产物呈现为无色至淡黄色固体。
产量:167.0mg(49.5%)
熔点:82-102℃(完全熔化)150℃(降解,经校正)
分析数据。1H-NMR(400MHz,D2O)δ=9.42(s,1H),9.30(d,1H),9.02(d,1H),8.28(dd,1H),6.24(d,1H),4.65(m,1H),4.58(t,1H),4.47(dd,1H),4.33(dq,1H),4.19(dq,1H),4.01(s,4H),3.28(s,18H)ppm
实施例10.NAD细胞测定
基于Zhu和Rand,PLoS One(2012)的NAD循环方法来测定NAD水平,该文献通过引用并入本文。将COV434细胞维持在6孔板中,并以200uM的浓度用所示化合物处理4小时。除去培养基,将板在冷PBS中洗涤,并将细胞在含有10mM烟酰胺、50mM Tris HCl、0.1%TritonX-100的NAD提取缓冲液中刮下。通过超声处理将细胞均质化5秒,并且将样品在4℃下以7,000g离心5分钟。取等分试样用于以后的蛋白质测定,然后使样品在4度下以14,000g通过10kDa amicon过滤器30分钟,以从样品中去除蛋白质。每个样品均一式三份进行测量,将25μL样品添加到100μL ADH循环混合物(0.2mg/ml醇脱氢酶,2%乙醇,100mM Tris pH 8.5)中。使样品在室温下循环10分钟,然后添加50μL MTT/PMS溶液(0.1mM吩嗪硫酸甲酯,0.8mM3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物),100mM Tris-HCl pH 8.5)。然后将板孵育15分钟,并在570nM下测量吸光度。从标准曲线外推NAD浓度,并标准化为BCA蛋白测定法测定的蛋白浓度。
上述测定的结果示于表2(下文)中。在摩尔/摩尔上通过直接比较所比较的盐与其母体对应物来获得倍数增加。
表2
等效物
仅使用常规实验,本领域技术人员将认识到或能够确定本文具体描述的具体实施方案的许多等效物。这些等效物包括在以下权利要求的范围内。
Claims (42)
1.一种式(I)的盐:
或其对映异构体、立体异构体或互变异构体,
其中
A为NRaRb或O–;
M1和M2独立地不存在或为季阳离子,条件为M1或M2中的至少一个为季阳离子;
R1和R2独立地为H、C1–C6烷基、C1–C6卤代烷基、-C(O)C1–C6卤代烷基、(C0–C3亚烷基)C(O)C1–C6烷基、-C(O)ORa、-C(O)NRaRb、-[CH2-CH2-O]k-Ra、-C(O)[CH2-CH2-O]k-Ra、-[CH2-CH2-CH2-O]k-Ra或-C(O)[CH2-CH2-CH2-O]k-Ra,
或R1和R2与它们所连接的原子一起形成5元杂环,所述5元杂环任选地被一个或多个选自C1–C6烷基、C2–C6烯基、C2–C6炔基、(C0–C3亚烷基)C3–C8环烷基、(C0–C3亚烷基)杂环烷基、(C0–C3亚烷基)C6–C14芳基、或(C0–C3亚烷基)杂芳基的取代基取代;
R3为负电荷、H或C1–C6烷基;
Ra和Rb在每次出现时独立地为H或C1–C6烷基,其中所述烷基任选地被一个或多个选自(C0–C3亚烷基)C3–C8环烷基、(C0–C3亚烷基)杂环烷基、(C0–C3亚烷基)C6–C14芳基或(C0–C3亚烷基)杂芳基的取代基取代;并且
k为1到8的整数,
条件为
a)当L为键时,M1不存在,以及
b)当A为NRaRb时,M2不存在。
2.如权利要求1所述的盐,其中A为O–。
3.如权利要求1所述的盐,其中A为NRaRb。
4.如权利要求3所述的盐,其中Ra为H。
5.如权利要求3所述的盐,其中Ra为甲基。
6.如权利要求1至5中任一项所述的盐,其中M1和M2独立地不存在或为式(II)、式(III)或式(IV)的季阳离子:
其中
E为任选地被一个或多个选自以下的取代基取代的C1-C6烷基:R4、R5、G-OR9或(C0-C3亚烷基)OR11;
R4和R5每次出现时独立地为H或C1-C6烷基、C2-C6烯基、C2-C6炔基、(C0-C3亚烷基)C3-C8环烷基、(C0-C3亚烷基)杂环烷基、(C0-C3亚烷基)C6-C14芳基或(C0-C3亚烷基)杂芳基,其中所述烷基、烯基、炔基、亚烷基、环烷基、杂环烷基、芳基或杂芳基任选地被一个或多个选自氰基、卤基、SeH、(C0-C3亚烷基)NRcRd、(C0-C3亚烷基)ORc、(C0-C3亚烷基)OC(O)Rc、(C0-C3亚烷基)C(O)ORc、(C0-C3亚烷基)SRc、(C0-C3亚烷基)C(O)SRc、(C0–C3亚烷基)SC(O)Rc、(C0–C3亚烷基)C(O)NRcRd、(C0–C3亚烷基)NC(O)NRcRd、(C0-C3亚烷基)C(NRc)NRcRd、(C0-C3亚烷基)NRcC(NRc)NRcRd、(C0-C3亚烷基)P(O)OnRcRd、(C0-C3亚烷基)S(O)mNRcRd、(C0-C3亚烷基)S(O)mORc或(C0-C3亚烷基)BOpRcRd的取代基取代;
R6、R7、R8和R10独立地为H或C1-C6烷基,其中所述烷基任选地被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0-C3亚烷基)ORc的取代基取代,
或R4和R6与它们所连接的原子一起形成5至6元环,所述5至6元环任选地被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0-C3亚烷基)ORc的取代基取代,
或R7和R8与它们所连接的原子一起形成5至6元环,所述5至6元环任选地被一个或多个选自氰基、卤基、(C0-C3亚烷基)NRcRd或(C0-C3亚烷基)ORc的取代基取代;
Rc和Rd在每次出现时独立地为H或C1-C6烷基,其中所述烷基任选地被一个或多个选自(C0-C3亚烷基)C3-C8环烷基、(C0-C3亚烷基)杂环烷基、(C0-C3亚烷基)C6-C14芳基或(C0-C3亚烷基)杂芳基的取代基取代;
R9为负电荷、H或C1-C6烷基;
R11为H、C1-C6烷基或C(O)C1-C6烷基,其中所述C1-C6烷基或C(O)C1-C6烷基任选地被一个或多个选自(C0-C3亚烷基)NRcRd、(C0-C3亚烷基)ORc、(C0-C3亚烷基)C3-C8环烷基、(C0-C3亚烷基)杂环烷基、(C0-C3亚烷基)C6-C14芳基或(C0-C3亚烷基)杂芳基的取代基取代;
G为CH2或C(O);
m、n和p在每次出现时独立地为为0、1或2;并且
q为0至5的整数。
8.如权利要求6或7所述的盐,其中R5为H。
9.如权利要求6至8中任一项所述的盐,其中R6为H。
10.如权利要求6至9中任一项所述的盐,其中R4为H。
11.如权利要求6至9中任一项所述的盐,其中R4为C1-C4烷基、(C0-C3亚烷基)C6-C14芳基或(C0-C3亚烷基)杂芳基或被一个或多个(C0-C3亚烷基)SRc取代的C1–C4烷基。
14.如权利要求1至13中任一项所述的盐,其中R1为H。
15.如权利要求1至13中任一项所述的盐,其中R1为C(O)C1-C3烷基。
16.如权利要求1至13中任一项所述的盐,其中R1为C1-C3烷基。
17.如权利要求1至16中任一项所述的盐,其中R2为H。
18.如权利要求1至16中任一项所述的盐,其中R2为C(O)C1–C3烷基。
19.如权利要求1至16中任一项所述的盐,其中R2为C1-C3烷基。
20.如权利要求1至19中任一项所述的盐,其中R3为H或甲基。
22.一种药物组合物,其包含如权利要求1至21中任一项所述的盐和药学上可接受的载体。
23.一种治疗或预防年龄相关不孕症的方法,其包括向有此需要的受试者施用有效量的如权利要求1至21中任一项所述的盐或如权利要求22所述的组合物。
24.一种治疗或预防不孕症的方法,其包括向有此需要的受试者施用有效量的如权利要求1至21中任一项所述的盐或如权利要求22所述的组合物。
25.一种改善卵母细胞或囊胚质量的方法,其包括在植入需要治疗年龄相关不孕症的受试者之前,使所述卵母细胞或囊胚与有效量的如权利要求1至21中任一项所述的盐或如权利要求22所述的组合物接触。
26.一种改善卵母细胞或囊胚成熟的方法,其包括在植入需要治疗年龄相关不孕症的受试者之前,使所述卵母细胞或囊胚与有效量的如权利要求1至21中任一项所述的盐或如权利要求22所述的组合物接触。
27.如权利要求25或26所述的方法,其中所述卵母细胞或囊胚在包含所述盐的IVF培养基中培养。
28.如权利要求1至21中任一项所述的盐在制备用于治疗年龄相关病症的药物中的用途。
29.如权利要求1至21中任一项所述的盐在制备用于治疗不孕症的药物中的用途。
30.如权利要求1至21中任一项所述的盐在制备用于治疗年龄相关不孕症的药物中的用途。
31.一种用于体外受精的细胞培养基,其包含:
选自权利要求1至21中任一项的化合物;和
培养剂。
32.如权利要求31所述的细胞培养基,其中所述培养剂为无机盐、能量基质、氨基酸、螯合剂、pH指示剂、抗生素、血清、维生素、生长因子或其任何组合。
33.如权利要求32所述的细胞培养基,其中所述无机盐为氯化钙、氯化镁、硫酸镁、氯化钾、碳酸氢钠、氯化钠、磷酸一钠、磷酸二钠或其任何组合。
34.如权利要求32所述的细胞培养基,其中所述能量基质为葡萄糖、丙酮酸盐、乳酸盐、丙酮酸盐或其任何组合。
35.如权利要求32所述的细胞培养基,其中所述氨基酸为必需氨基酸。
36.如权利要求35所述的细胞培养基,其中所述必需氨基酸为精氨酸、半胱氨酸、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸或其任何组合。
37.如权利要求32所述的细胞培养基,其中所述氨基酸为非必需氨基酸。
38.如权利要求37所述的细胞培养基,其中所述非必需氨基酸为丙氨酸、天冬酰胺、天冬氨酸、谷氨酸、脯氨酸、丝氨酸或其任何组合。
39.如权利要求32所述的细胞培养基,其中所述螯合剂为笼状螯合物、乙酰丙酮、氨基多羧酸、ATMP、BAPTA、BDTH2、柠檬酸、穴醚、地拉罗司、2,3-二氢苯甲酸、2,3-二巯基-1-丙烷磺酸、二巯基琥珀酸、DOTA、DTPMP、EDDHA、EDDS、EDTMP、依替膦酸、fura-2、葡萄糖酸、高柠檬酸、亚氨基二乙酸、Indo-1、腈三乙酸、喷替酸(DTPA)、膦酸盐、植物螯合肽、聚天冬氨酸、聚天冬氨酸钠、柠檬酸三钠、转铁蛋白、EDTA、EGTA或其任何组合。
40.如权利要求32所述的细胞培养基,其中所述pH指示剂为酚红、溴百里酚蓝、茜素红、9-氨基吖啶或其任何组合。
41.如权利要求32所述的细胞培养基,其中所述抗生素为放线菌素D、氨苄青霉素、羧苄青霉素、头孢噻肟、膦胺霉素、庆大霉素、卡那霉素、新霉素、青霉素、多粘菌素B、链霉素或其任何组合。
42.如权利要求32所述的细胞培养基,其中所述血清为人血清白蛋白、牛血清白蛋白、胎牛血清、合成血清或其任何组合。
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