CN104024217B - 用于治疗或预防与内分泌功能障碍相关的症状的三环含氨基化合物 - Google Patents
用于治疗或预防与内分泌功能障碍相关的症状的三环含氨基化合物 Download PDFInfo
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- CN104024217B CN104024217B CN201280066247.2A CN201280066247A CN104024217B CN 104024217 B CN104024217 B CN 104024217B CN 201280066247 A CN201280066247 A CN 201280066247A CN 104024217 B CN104024217 B CN 104024217B
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Abstract
本公开提供了可用于治疗内分泌紊乱的某些症状、特别是与热潮红相关的症状的某些化合物的使用方法。
Description
对相关申请的交叉引用
本申请要求2011年11月7日申请的美国临时申请号61/556,346的优先权,所述申请以其整体通过引用并入本文。
领域
本公开提供了预防或治疗与内分泌紊乱相关的症状(通常为热潮红)的某些三环含氨基化合物的药物组合物和使用方法。
背景
在美国百分之八十五的女性当她们接近绝经时和她们的月经停止后一年或两年经历某种热潮红。20至50%女性继续持续更多年具有热潮红。热潮红的特征在于面部和上身的突然、强烈的发热感。经常,热潮红可以之前存在或伴随快速心跳和出汗、恶心、头晕、焦虑、头痛、乏力、或窒息的感觉。一些女性仅仅在热潮红之前经历一般整体不安的感觉。热潮红随后通常为潮红,使患者发红和流汗。高强度热潮红可以导致患者变得浸泡在汗水中。较低强度的潮红仅仅引起产生湿润上唇。发冷经常在潮红之前发生,但也可以在潮红结束时发生。当夜间发生热潮红时,这些患者无法入睡,导致白天注意力不集中、记忆问题、烦躁和疲惫。
热潮红经常是由于绝经期的激素变化,但也可以受到生活方式和药物治疗的影响。热潮红的确切原因目前还不知道。一些理论表明,热潮红是由于体内被称为雌激素的女性激素水平下降。减少水平的雌激素对下丘脑、脑中负责控制食欲、睡眠周期、性激素和体温的部分具有直接影响。身体通过增加下丘脑的神经递质释放对降低的雌激素水平进行响应,其肾上腺素、去甲肾上腺素、前列腺素和血清素的增加引起心脏跳得更快,皮肤中的血管扩张以及汗腺释放汗水。一些人皮肤温度在热潮红过程中可以上升六摄氏度。皮肤中的血管扩张区域在头部、面部、颈部和胸部的皮肤附近的那些区域特别明显。这种皮肤扩张导致更多血液循环以散发掉热量。汗腺然后释放汗水以使得身体更加冷却。一旦血管回复至正常尺寸,则患者会再次感到发冷。
绝经前后不久的数年期间(其发生在平均约51岁),约85%女性患有热潮红。然而,热潮红可以早在末次月经期之前2-3年开始。热潮红可以持续长达六个月,或者持续长达末次月经期后15年后。平均地,热潮红持续两年。发作的频率差异很大,从一年发作几次,到多达一天20次发作。如果男性的雄性激素睾酮水平突然且急剧下降,则男性也可以具有热潮红。
作为癌症治疗的副作用,男性和女性均可患有热潮红。某些药物诸如用于治疗乳腺癌的他莫昔芬(Nolvadex)以及用于治疗前列腺癌的醋酸亮丙瑞林(Leuprolide)和戈舍瑞林 (Goserelin)均可导致热觉。针对前列腺癌或睾丸癌的双侧睾丸切除术也影响激素系统,从而使得患者随后可患有热潮红。尤其在癌症患者的情况下,通常不建议使用激素替代治疗,因为存在刺激癌症再生长的担忧。
模拟热潮红的症状可以发生在具有下丘脑或脑下垂体的肿瘤的男性和女性,以及已经患有某些严重感染诸如结核或HIV的男性和女性,酗酒的男性和女性或患有甲状腺病症的男性和女性。与热潮红类似的症状也可以是食品添加剂谷氨酸钠(MSG)或某些药物、特别是硝酸甘油、硝苯啶、烟酸、万古霉素和降钙素的副作用。
最通常,激素替代治疗(HRT)被认为是可用来降低热潮红发生的最有效的治疗方法之一。这些激素可以口服施用,静脉内施用,经皮施用和/或局部施用(以膏剂涂用)。然而,HRT已经与心脏疾病的风险增加以及某些种类的癌症相关联。
除了hrt和上面提到的其它药物以外,几种非处方膳食补充剂或草药已经被开发为预防或治疗热潮红的自然方式。已经倡导使用一系列基于草药的“天然”治疗包括黑升麻、植物雌激素、亚麻籽、红三叶草、维生素E (D. L. Barton等人, J. Clin. Oncol.1998, 16: 495-500)、人参和月见草油作为可能的药物治疗(University of WisconsinMedical School, online courses, "Alternatives for Menopausal Symptoms: AReview of the Evidence"; www.cme.wisc.edu/online/menopause)。然而,这些治疗并非全部有效(K. I. Pritchard, The Oncologist, 2001, 6(4), 353-362)。
帮助降低热潮红强度的替代药物包括可乐定、洛非西定、甲基多巴和舍曲林。已经被建议使用的其它药物治疗是选择性5-羟色胺重摄取抑制剂(SSRI)诸如盐酸氟西汀(Prozac; C. Loprinzi; www.medicine-news.com/articles/pharma/misc/hotflash-es.html)和盐酸帕罗西汀(Paxil; V. Stearns等人, Ann. Oncol., 2000, 11:17-22)以及盐酸文拉法辛(Effexor; C. L. Loprinzi等人, J. Clin. Oncol., 1998, 16: 2377-2381),其是5-羟色胺和去甲肾上腺素重摄取抑制剂。
还已显示低剂量的醋酸甲地孕酮降低男性和女性中热潮红的频率(Loprinzi等人, N. Engl. J. Med. 1994, 331:347-351)。慢性肾上腺功能不全和体重增加可以是副作用。经皮可乐定也已被用于降低热潮红的频率和严重度(R. M. Goldberg等人, J.Clin. Onc. 1994, 12:155-158); R. M. Goldberg等人, J. Clin. Oncol. 1994, 12:155-158; L. R. Laufer, Obstet. Gynecol. 1982, 60:583-586)。然而,在一些患者中观察到副作用诸如困倦、疲劳和低血压症状。
已经提出各种解决热潮红的治疗方法。例如,Pharmacia & Upjohn的美国公开号2004/0092519描述了通过施用有效剂量的选自瑞波西汀、S,S-瑞波西汀、其药学上可接受的盐、其衍生物或其前药的化合物而治疗或预防热潮红的方法。Barr Labs的美国专利号6,165,504描述了通过施用醋酸环丙孕酮来治疗热潮红和改善去势前列腺癌患者的生活质量的方法。美国公开号2004/0152733描述了度洛西汀用于治疗热潮红的用途。美国公开号2004/0092519描述了瑞波西汀用于治疗激素改变的症状诸如热潮红的用途。美国专利号6,395,757描述了吡咯糖(glycopyrrolate)类似物用于治疗热潮红的用途。美国公开号2007/0281997描述了使用毒蕈碱受体拮抗剂治疗用雄激素去势管理的具有前列腺病症诸如前列腺癌的对象中热潮红。美国公开号2007/0015786描述了使用选择性去甲肾上腺素再摄取抑制剂(例如,托莫西汀和外消旋瑞波西汀)治疗由于一般医疗状况的热潮红、冲动控制障碍和人格改变。美国公开号2002/0016283描述了使用速激肽受体拮抗剂治疗激素改变的症状(包括热潮红)的方法。美国专利号6,310,098描述了通过施用作为电压门控钙通道的α-2-δ亚单位的配体的化合物治疗激素改变的症状(包括热潮红)的方法。
然而,需要预防或减少与此类内分泌紊乱有关的症状的新型治疗。
概述
令人惊讶地发现,某些三环含氨基化合物有效减少与内分泌紊乱相关的症状,特别是与改变或降低的雌激素和孕激素水平相关的症状。因此提供了通过治疗有需要的宿主来治疗或预防内分泌紊乱,特别是减少内分泌紊乱的症状,诸如与绝经期或化疗相关的热潮红的方法。通常,提供了治疗或预防宿主中与内分泌紊乱相关的症状的方法,包括向宿主施用本文所述的化合物。
在某些实施方案中,本公开涉及治疗或预防热潮红的方法,包括向诊断为激素水平改变、表现出激素水平改变的症状或处于激素水平改变的风险的对象施用包含本文公开的化合物的药物组合物。在进一步实施方案中,对象是绝经期或围绝经期妇女,或者对象正在月经来潮或预期一周月经来潮,或者对象是诊断具有外阴痛的妇女。在某些实施方案中,对象是诊断具有前列腺癌的人。
在某些实施方案中,药物组合物与另一种活性剂联合施用,所述另一种活性剂诸如雌激素受体的激动剂或拮抗剂,或他莫昔芬或抗雄激素或螺内酯、环丙孕酮、氟他胺、尼鲁米特、比卡鲁胺、非那雄胺、或度他雄胺。
在某些实施方案中,所述化合物是MSX-122,即,N-(4-((嘧啶-2-基氨基)甲基)苄基)-嘧啶-2-胺或其药学上可接受的盐。
在某些实施方案中,本公开涉及本文公开的化合物在制造用于治疗或预防热潮红的药物中的用途。
在具体实施方案中,宿主由于绝经而患有雌激素水平的降低。在其它实施方案中,宿主由于施用药物、特别是由于施用化疗剂而患有内分泌紊乱。在进一步实施方案中,宿主患有内分泌病症诸如自身免疫性内分泌疾病。在具体实施方案中,宿主患有格雷夫斯病。
在一个实施方案中,本公开涉及提供用于治疗或预防与内分泌紊乱相关的症状的方法,特别是治疗或预防热潮红的方法,包括向有需要的宿主施用式I的化合物,或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、V、W、X、Y和Z独立地选自H、R、酰基、F、Cl、Br、I、OH、OR、NH2、NHR、NR2、SR、SR、S2R、S-NHR、S2-NHR、S-NRR'、S2-NRR'、NH酰基、N(酰基)2、CO2H、CO2R,其中R和R'独立地选自直链烷基、支链烷基或环烷基或芳烷基以及芳基和杂芳基;且
R1、R2、R3、R4、R5和R6独立地选自H、直链烷基、支链烷基或环烷基、芳烷基、芳基、杂芳基、酰基(R(O=C)-和亚胺酰基(R(NH=C)-或R(NR'=)C-)基团。
本文提供了式II-VII的额外化合物,其用于治疗或预防与内分泌紊乱相关的症状,特别用于治疗或预防热潮红。
在一个具体实施方案中,提供了用于治疗或预防与内分泌紊乱相关的症状的方法,特别是治疗或预防热潮红的方法,包括向有需要的宿主施用式XVI的化合物,或其药学上可接受的盐、酯或前药:
式XVI。
通常,向处于内分泌紊乱风险的宿主施用所述化合物或组合物。在某些实施方案中,宿主是绝经前或绝经期女性。在其它实施方案中,宿主患有内分泌疾病。在又一其它实施方案中,宿主在接受本文所述的化合物或组合物的10天之内或9天之内,或者8天之内或7天之内,或6天之内,或5天之内或4天之内,或3天之内,或2天之内或一天之内或更少已经接受药物治疗,特别是化疗治疗。
在一些实施方案中,药物组合物或方法包括与至少一种第二活性化合物联合或交替的至少一种式(I)-(XVII)的化合物。第二活性化合物可以是化疗剂,特别是对原发性肿瘤具有活性的药剂。在其它实施方案中,第二药剂是激素替代或激素补充。在进一步实施方案中,第二药剂是雌激素受体激动剂。
在某些实施方案中,本文公开的治疗方法考虑在外科手术之后、之前或过程中向所述对象施用包含本文公开的化合物的药物组合物,所述外科手术选自子宫切除术、卵巢切除术、部分卵巢切除术、单侧输卵管-卵巢切除术、双侧输卵管-卵巢切除术或其组合。
公开详述
提供了用于治疗或预防内分泌紊乱、特别是与改变或降低的雌激素和孕激素水平相关的症状(诸如导致热潮红的症状的那些)的药物组合物和方法。本发明人已经发现本文所述的某些化合物可以预防或减少这些症状。
本文所述的化合物先前被鉴定为趋化因子受体调节剂。趋化因子是通过与G蛋白-偶联受体相互作用诱导几种细胞类型的细胞骨架重排和定向迁移的小细胞因子的超家族。这些分泌的蛋白与细胞表面蛋白以协调方式作用,以便引导细胞的各种子集归巢至特定的解剖部位(Morales,等人 (1999) Proc Natl Acad Sci U S A96: 14470-14475; Homey,B., 等人 (2000) J Immunol 164: 3465-3470; Peled,等人 (1999) Science 283: 845-848; Forster,等人 (1999) Cell 99: 23-33)。
趋化因子被认为是炎症的引发和维持中的主要介质。也已经发现它们在内皮细胞功能(包括损伤后的血管生成和再内皮化过程中的增殖、迁移和分化的)的调节中发挥重要作用(Gupta等人 (1998) J Biol Chem, 7:4282-4287)。
在病毒研究中已知趋化因子受体CXCR4是T细胞系嗜性HIV进入的主要共受体(Feng,等人 (1996) Science 272: 872-877; Davis,等人 (1997) J Exp Med 186:1793-1798; Zaitseva,等人 (1997) Nat Med 3: 1369-1375; Sanchez,等人 (1997) J Biol Chem272: 27529-27531)。源于T基质细胞的因子1(SDF-1)是与CXCR4特异相互作用的趋化因子。当SDF-1与CXCR4结合时,CXCR4活化Gαi-蛋白-介导的信号传导(百日咳毒素-敏感的),包括下游激酶途径,诸如淋巴细胞、巨核细胞和造血干细胞中的Ras/MAP激酶和磷脂酰肌醇3-激酶(PI3K)/Akt (Bleul,等人 (1996) Nature 382: 829-833; Deng,等人(1997) Nature 388: 296-300; Kijowski,等人 (2001) Stem Cells 19: 453-466;Majka,等人 (2001) Folia. Histochem. Cytobiol. 39: 235-244; Sotsios,等人(1999) J. Immunol. 163: 5954-5963; Vlahakis,等人 (2002) J. Immunol. 169:5546-5554)。
已经开发了主要用于治疗HIV的靶向CXCR4的化合物,因为CXCR4是对于T-嗜性HIV感染的主要共受体。已经公开了CXCR4受体的肽拮抗剂。Tamamura等人报道了基于具体肽的CXCR4抑制剂T140的鉴定。在所有CXCR4拮抗剂中,T140是具有抗HIV活性和对T细胞系嗜性HIV-1进入具有拮抗作用的14-残基肽(Tamamura,等人 (1998) Biochem. Biophys. Res. Commun. 253: 877-882)。也已经公开了其它基于肽的拮抗剂。例如,the University OfBritish Columbia的欧洲专利公开号1 286 684和1 061 944包括使用衍生自天然SDF-1配体的修饰肽CXCR4拮抗剂治疗疾病(包括肿瘤转移)的方法。Takeda Chemical Industries,Ltd.的PCT公开号WO 04/020462提供了用于治疗和预防乳腺癌和慢性类风湿关节炎的肽CXCR4拮抗剂。美国卫生与公众服务部(U.S. Dept. of Health & Human Services)的美国专利申请号2004/0132642部分涵盖用多肽CXCR4抑制剂抑制肿瘤细胞的转移或生长的方法。此外,金属螯合的环拉胺(cyclams)和双环拉胺(bicyclams)是有效阻断CXCR4的少数报道的非肽分子中的一种(Onuffer and Horuk (2002) Trends Pharmacol Sci 23: 459-467.36)。这些非肽分子中的一种是AMD3100,作为阻断CXCR4-介导的病毒进入的抗HIV药物,其已经进入了临床试验阶段 (Donzella,等人 (1998) Nat Med 4: 72-77; Hatse,等人 (2002) FEBS Lett 527: 255-262; Fujii,等人 (2003) Expert Opin Investig Drugs 12: 185-195; Schols,等人 (1997) Antiviral Res 35: 147-156)。
其它含氮二环分子已经作为CXCR4拮抗剂进行开发。Kureha Chemical IndustryCo., Ltd的欧洲专利公开号1 431 290和PCT公开号WO 02/094261涵盖了潜在用于治疗多种疾病(包括癌转移疾病)的CXCR4抑制剂。此外,某些化合物在Yamamazi等人的美国专利公开号2004/0254221、全部是AnorMED的PCT公开号WO 00/5672、04/091518、04/093817和04/106493中被描述为CXCR4抑制剂,其将这些化合物描述为CXCR4和/或CCR5受体的抑制剂,且表明,这些作为抗病毒剂,特别是针对人免疫缺陷病毒(HIV)对靶细胞的感染、具有血细胞产生的癌症和某些炎症性状况是活性的。
Shim等人的美国专利公开号2007/0054930提供了某些化合物,所述化合物是用于治疗通过CXCR4受体介导的增殖状况、特别是治疗肿瘤转移的CXCR4抑制剂。
活性化合物及其生理学上可接受的盐和前药
在第一个主要实施方案中,提供了式I的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、V、W、X、Y和Z独立地选自H、R、酰基、F、Cl、Br、I、OH、OR、NH2、NHR、NR2、SR、SR、S2R、S-NHR、S2-NHR、S-NRR'、S2-NRR'、NH酰基、N(酰基)2、CO2H、CO2R,其中R和R'独立地选自直链烷基、支链烷基或环烷基或芳烷基,以及芳基和杂芳基;且
R1、R2、R3、R4、R5和R6独立地选自H、直链烷基、支链烷基或环烷基、芳烷基、芳基、杂芳基、酰基(R(O=C)-和亚胺酰基(R(NH=C)-或R(NR'=)C-)基团。
在式I的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
Zou等人(Zou,等人 (2003) Acta Cryst. E59: 在线1312-o1313)描述了潜在四配位基配体1,4-二-(吡啶-2-氨甲基)苯的合成。Zou说明了该化合物是金属离子的可能配体。
在一个子实施方案中,提供了式I-1至I-10的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在另一个子实施方案中,提供了式I-11至I-20的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在第二个主要实施方案中,本公开提供了式IIa或IIb的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、V、W、X、Y和Z如上所定义;
A和B是独立地选自-CR=、-CR3R4-、-CR3=、-N=、-O-、-NR3-、-S-、-CR3=CR4-、-CR3R4-CR5R6-、-CR3=N-、-CR3R4-NR5-、-N=CR3-、和-NR3-CR4R5-的一个和两个原子系链;
-D-E-和-G-J-独立地为-NR3-CR4-或-N=C-;且
R1、R2、R3、R4、R5、R6、R7和R8独立地选自H、直链烷基、支链烷基或环烷基、芳烷基、芳基、杂芳基、酰基(R(O=C)-和亚胺酰基(R(NH=C)-或者R(NR'=)C-)基团。
在式II的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
在一个子实施方案中,本公开提供了式II-1至 II-18的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;
A和-D-E-如上所定义;且
R1、R2、R3、R4、R5、R6、R7和R8如上所定义。
在另一个子实施方案中,本公开提供了式II-19至II-30的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;
A、B、-D-E-和-G-J-如上所定义;且
R1、R2、R3、R4、R5、R6、R7和R8如上所定义。
在第三个主要实施方案中,式III化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、V、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在式III的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
Reyes等人(Reyes,等人 (2002) Tetrahedron 58:8573-8579)描述了从吡啶鎓N-aminides开始进行的某些多胺的合成。没有特定功能归因于这些化合物。
在一个子实施方案中,提供了式III-1至III-10的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在另一个子实施方案中,提供了式III-11至III-20的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在第四个主要实施方案中,本公开提供了式IVa或IVb的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义。
在式IVa或IVb的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
在一个子实施方案中,本公开提供了式IV-1至IV-12的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和-D-E-如上所定义。
在另一个子实施方案中,提供了式IV-13至IV-20的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A、B、-D-E-和-G-J-如上所定义。
在第五个主要实施方案中,提供了式Va、Vb或Vc的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在式Va-c的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
在一个子实施方案中,提供了式V-1至V-3的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在另一个子实施方案中,提供了式V-4至V-9的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在第六个主要实施方案中,提供了式VIa或VIb的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义。
在式VIa或VIb的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
在一个子实施方案中,提供了式VI-1至VI-6的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和-D-E-如上所定义。
在另一个子实施方案中,提供了式VI-7至VI-10的化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义。
在第七个主要实施方案中,提供了式VII的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5和R6如上所定义;且
M为O、S或NR3。
在式VII的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
在一个子实施方案中,提供了式VII-1至VII-10的化合物或其药学上可接受的盐、酯或前药:
其中
U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5和R6如上所定义;且
M为O、S或NR3。
在另一个子实施方案中,提供了式VII-11至VII-20的化合物或其药学上可接受的盐、酯或前药:
其中
U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5和R6如上所定义;且
M为O、S或NR3。
在第八个主要实施方案中,本公开提供了式VIIIa或VIIIb的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义;且
M为O、S或NR3。
在式VIIIa或VIIIb的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
在一个子实施方案中,提供了式VIII-1至VIII-12的化合物或其药学上可接受的盐、酯或前药:
其中
M、U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和-D-E-如上所定义。
在另一个子实施方案中,提供了式VIII-13至VIII-20的化合物或其药学上可接受的盐、酯或前药:
其中
M、U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A、B、-D-E-和-G-J-如上所定义。
在第九个主要实施方案中,本公开提供了式IX的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5和R6如上所定义;
A* 独立地选自式a-g:
M为O、S或NR3。
在一个子实施方案中,提供了式IX-1至IX-12的化合物或其药学上可接受的盐、酯或前药:
其中
W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在另一个子实施方案中,提供了式IX-13至IX-24的化合物或其药学上可接受的盐、酯或前药:
其中
M、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在又另一个子实施方案中,提供了式IX-25至IX-36的化合物或其药学上可接受的盐、酯或前药:
其中
M、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在第十个主要实施方案中,本公开提供了式X的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义;且
A*如上所定义;且
M如上所定义。
在一个子实施方案中,提供了式X-1至X-14的化合物或其药学上可接受的盐、酯或前药:
其中
M、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义。
在另一个子实施方案中,提供了式X-15至X-28的化合物或其药学上可接受的盐、酯或前药:
其中
M、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义。
在又另一个子实施方案中,提供了式X-29至X-38的化合物或其药学上可接受的盐、酯或前药:
其中
M、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义。
在第十一个主要实施方案中,本公开提供了式XI的化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、V、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在式XI的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
在一个子实施方案中,提供了式XI-1至XI-6化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;且
R1、R2、R3、R4、R5和R6如上所定义。
在第十二个主要实施方案中,本公开提供了式XII化合物或其药学上可接受的盐、酯或前药:
其中
每个K独立地为N或CH;
Q、T、U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义。
在式XII的一个子实施方案中,Y和Z各自为氢。或者,W和X各自为氢。在又另一个子实施方案中,W、X、Y和Z均为氢。
在一个子实施方案中,提供了式XII-1至XII-5化合物或其药学上可接受的盐、酯或前药:
其中
Q、T、U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5、R6、R7和R8如上所定义;且
A和B以及-D-E-和-G-J-如上所定义。
在第十三个主要实施方案中,式XIII化合物或其药学上可接受的盐、酯或前药:
其中
K、Q、T、U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5和R6如上所定义;且
“间隔团”独立地为一个键、直链或者支链的C1-C5烷基、C2-C5烯基、C2-C5炔基、C1-C5烷氧基、C2-C5烯氧基和C2-C5炔氧基,其中烷基可以被杂原子(诸如N、O或S)取代,例如-CH2-OCH2-、-CH2CH2-OCH2-、-CH2CH2-OCH2CH2-、-CH2-OCH2CH2-、-CH2CH2-OCH2CH2CH2-、-CH2CH2CH2-OCH2-、-CH2CH2CH2-OCH2CH2-、-CH2CH2-OCH2CH2CH2-、-(CH2)n-OH(CH3)-(CH2)n-、CH2-OH(CH3)-O-CH2、-(CH2)n-、-(CH2)n-CO-、-(CH2)n-N-、-(CH2)n-O-、-(CH2)n-S-、-(CH2O)-、-(OCH2)-、-(SCH2)-、-(CH2S-)、-(芳基-O)-、-(O-芳基)-、-(烷基-O)-、-(O-烷基)- ,其中n独立地为0、1、2、3、4、5、6、7、8、9或10。
在第十四个主要实施方案中,式XIVa或XIVb的化合物或其药学上可接受的盐、酯或前药:
其中
K、Q、T、U、V、W、X、Y和Z如上所定义;
R1、R2、R3、R4、R5和R6如上所定义;
“间隔团”如上所定义;且
“杂环”和“杂芳基”如本文中所定义。
在一个具体实施方案中,式XV的化合物或其药学上可接受的盐、酯或前药:
在一个具体的子实施方案中,所述化合物为式XV的化合物的盐,特别是氯化物盐。
在另一个具体实施方案中,式XVI的化合物或其药学上可接受的盐、酯或前药:
。
在另一个具体实施方案中,式XVII的化合物或其药学上可接受的盐、酯或前药:
。
在某些具体实施方案中,所述化合物选自:
定义
除非另有说明,本文使用的术语烷基包括但不限于通常为C1 - C10的饱和直链、支链或环状的伯、仲或叔烃基,并且具体包括甲基、三氟甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、叔丁基、戊基、环戊基、异戊基、新戊基、己基、异己基、环己基、环己基甲基、3-甲基戊基、2,2-二甲基丁基和2,3-二甲基丁基。该术语任选包括取代烷基。可以取代烷基的基团选自羟基、氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸、硫酸基、膦酸、磷酸基或膦酸基,如本领域技术人员已知,例如,如Greene,等人, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991(其通过引用并入本文)中所教导,它们未进行保护或根据需要进行保护。
无论何时,术语“C1-C5烷基”、“C2-C5烯基”、“C1-C5烷氧基”、“C2-C5烯氧基”、“C2-C5炔基”和“C2-C5炔氧基”在使用时,应当认为它们独立地包括组中的各个成员,从而使得,例如,C1-C5烷基包括直链、支链和适当情况下的环状C1、C2、C3、C4和C5烷基官能团;C2-C5烯基包括直链、支链和适当情况下的环状C2、C3、C4和C5烯基官能团;C1-C5烷氧基包括直链、支链和适当情况下的环状C1、C2、C3、C4和C5烷氧基官能团;C2-C5烯氧基包括直链、支链和适当情况下的环状C2、C3、C4和C5烯氧基官能团;C2-C5炔基包括直链、支链和适当情况下的环状C1、C2、C3、C4和C5炔基官能团;和C2-C5炔氧基包括直链、支链和适当情况下的环状C2、C3、C4和C5炔氧基官能团。
除非另有说明,本文使用的术语低级烷基,包括C1 - C4饱和直链、支链和适当时的环状(例如,环丙基)烷基,任选包括其取代形式。在本申请中除非另有明确说明,当烷基是合适的基团时,优选低级烷基。类似地,当烷基或低级烷基是合适的基团时,优选未被取代的烷基或低级烷基。
术语烷基氨基或芳基氨基是指分别具有一个或两个烷基或芳基取代基的氨基。
除非另有说明,本文使用的术语“保护”是指加入到氧、氮或磷原子上防止其进一步发生反应或用于其它目的的基团。多种氧和氮保护基是有机合成的本领域技术人员已知的。
除非另有说明,本文使用的术语芳基是指苯基、联苯基或萘基,并且优选苯基。该术语包括取代和未被取代的部分。所述芳基可以被任何期望的不会不利地影响其关键生物学性质的取代基取代,包括但不限于选自以下的基团:羟基、硫醇、氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸、卤素(F、Cl、I、Br)、羧基、酯、酰基、烷基、烯基、炔基、硫酸基、磷酸、膦酸、磷酸基或膦酸基,如本领域技术人员已知,例如,如Greene,等人,Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition,1991中所教导,它们根据需要未进行保护或进行保护。
术语烷芳基或烷基芳基是指具有芳基取代基的烷基。术语芳烷基或芳基烷基是指具有烷基取代基的芳基。
本文使用的术语卤素包括氯、溴、碘和氟。
术语酰基是指酯基的非羰基部分选自以下基团的羧酸酯:直链、支链或环状烷基或低级烷基、烷氧基烷基(包括甲氧基甲基)、芳烷基(包括苄基)、芳氧基烷基(诸如苯氧基甲基)、芳基(包括任选被卤素、C1-C4烷基或C1-C4烷氧基取代的苯基)、磺酸酯(诸如烷基或芳烷基磺酰基,包括甲磺酰基)、单、二或三磷酸酯、三苯甲基或单甲氧基三苯甲基、取代苄基、三烷基甲硅烷基(例如,二甲基叔丁基甲硅烷基)或二苯基甲基甲硅烷基。优选酯中的芳基包括苯基。术语“低级酰基”是指其中非羰基部分为低级烷基的酰基。
在整个说明书中使用术语“药学上可接受的盐、酯或前药”是指化合物的任何药学上可接受的形式(诸如酯、磷酸酯、酯的盐或相关基团),在将其施用至患者之后,其提供在本申请中所描述的化合物。药学上可接受的盐包括由药学上可接受的无机或有机碱和酸衍生的盐,所述酸诸如盐酸、氢溴酸、硫酸、硝酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸、苹果酸、马来酸、琥珀酸、酒石酸和柠檬酸等。合适的盐包括由碱金属(诸如钾和钠)、碱土金属(诸如钙和镁)、本领域众所周知的多种其它酸衍生的盐。药学上可接受的“前药”是指在宿主中新陈代谢(例如水解或氧化)形成本公开的化合物的化合物。前药的一般实例包括在活性化合物的官能部分具有生物学上不稳定的保护基的化合物。所述前药包括可以氧化、还原、胺化、去氨基化、羟基化、去羟基化、水解、脱水、烷基化、去烷基化、酰基化、去酰基化、磷酸化、去磷酸化而产生活性化合物的化合物。
术语“杂环”是指可以是部分或完全饱和的并且在环中存在至少一个杂原子(诸如氧、硫、氮或磷)的非芳香环基团。在此使用的术语杂芳基或杂芳香基是指在芳环中包括至少一个硫、氧、氮或磷的芳基。杂环和杂芳基的非限制性实例为吡咯烷基、四氢呋喃基、哌嗪基、哌啶基、吗啉代、硫代吗啉代、四氢吡喃基、咪唑基、吡咯啉基、吡唑啉基、二氢吲哚基、二氧戊环基或1,4 –二噁烷基、氮杂环丙烯基、呋喃基、呋喃基、吡啶基、嘧啶基、苯并噁唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,3,4-噻二唑、吲唑基、1,3,5-三嗪基、噻吩基、四唑基、苯并呋喃基、喹啉基、异喹啉基、苯并噻吩基、异苯并呋喃基、吲哚基、异氮杂茚基、苯并咪唑基、嘌呤、咔唑基、噁唑基、噻唑基、苯并噻唑基、异噻唑基、1,2,4-噻二唑基、异噁唑基、吡咯基、喹唑啉基、噌啉基、酞嗪基、黄嘌呤基、次黄嘌呤基、吡唑、1,2,3-三唑、1,2,4-三唑、1,2,3-噁二唑、噻嗪、哒嗪、苯并噻吩基、异吡咯、噻吩、吡嗪、或喋啶基,其中所述杂芳基或杂环基可以任选被一个或多个选自以下的取代基取代:卤素、卤代烷基、烷基、烷氧基、羟基、羧基衍生物、酰氨基、羟基、酰基、氨基、烷基氨基、二烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸、硫酸基、膦酸、磷酸基或膦酸基,如本领域技术人员已知,例如,如Greene,等人, “Protective Groups in Organic Synthesis,” John Wiley and Sons, SecondEdition, 1991(其通过引用并入本文)中所教导,它们根据需要未进行保护或进行保护。杂环和杂芳基包括嘌呤和嘧啶。
根据需要或期望,可以对杂芳基基团上的官能氧和氮基团进行保护。合适的保护基是本领域技术人员众所周知的,并且包括三甲基甲硅烷基、二甲基己基甲硅烷基、叔丁基二甲基甲硅烷基和叔丁基二苯基甲硅烷基、三苯甲基或取代的三苯甲基、烷基、酰基(诸如乙酰基和丙酰基)、甲磺酰基和对甲苯磺酰基。
术语嘌呤或嘧啶包括但不限于,腺嘌呤、N6-烷基嘌呤、N6-酰基嘌呤(其中酰基为C(O)(烷基、芳基、烷基芳基或芳基烷基))、N6-苄基嘌呤、N6-卤代嘌呤、N6-乙烯基嘌呤、N6-乙炔基嘌呤、N6-酰基嘌呤、N6-羟烷基嘌呤、N6-硫烷基嘌呤、N2-烷基嘌呤、N2-烷基-6-硫代嘌呤、胸腺嘧啶、胞嘧啶、5-氟胞嘧啶、5-甲基胞嘧啶、6-氮杂嘧啶(包括6-氮杂胞嘧啶、2-和/或4-巯基嘧啶)、尿嘧啶、5-卤代尿嘧啶(包括5-氟尿嘧啶)、C5-烷基嘧啶、C5-苄基嘧啶、C5-卤代嘧啶、C5-乙烯基嘧啶、C5-乙炔基嘧啶、C5-酰基嘧啶、C5-羟烷基嘌呤、C5-酰胺基嘧啶、C5-氰基嘧啶、C5-硝基嘧啶、C5-氨基嘧啶、N2-烷基嘌呤、N2-烷基-6-硫代嘌呤、5-氮杂胞嘧啶基、5-氮杂尿嘧啶基、三偶氮吡啶基、咪唑并吡啶基、吡咯并嘧啶基和吡唑并嘧啶基。嘌呤碱基包括但不限于鸟嘌呤、腺嘌呤、次黄嘌呤、2,6-二氨基嘌呤和6-氯嘌呤。
制备活性化合物的方法
一般方法。1H NMR或13C NMR光谱在400 MHz或100 MHz INOVA光谱仪或600 MHz或150 MHz INOVA光谱仪上进行记录。所得光谱以残留溶剂峰作为参考。它们在氘代氯仿、二甲亚砜-d6、重水或丙酮-d6中进行记录。熔点采用Thomas Hoover毛细管法熔点装置进行测定并且未进行校正。低分辩率EI质谱在JEOL光谱仪上进行记录。元素分析由AtlanticMircolab (Norcross, GA)进行。快速柱色谱法使用Scientific Absorbent IncorporatedSilica Gel 60进行。分析薄层色谱法(TLC)在Scientific Adsorbents Incorporated (硅胶60 F254)的预涂覆玻璃背板上进行。使用紫外线或碘蒸汽或磷钼酸(PMA)对板进行观察。
使用六种不同的方法制备本公开的化合物并且表征数据列于表1中。
方法A:胺和氰化胺之间的亲核加成。该方法根据改进的文献程序(Braun,等人(1938) J. Am. Chem. Soc. 3: 146-149)进行。在回流下,在无水乙醇中将1.0当量的二氢卤化二胺和3.0当量的氰化胺一起搅拌数小时。在减压下将溶剂除去,从而得到粗盐,然后在甲醇中通过重结晶对其进行纯化。
方法B:胺和甲基巯基衍生物之间的加成消去反应。该方法差不多类似于文献程序(Linton,等人 (2001) J. Org. Chem. 66(22): 7313-7319)。将1.0当量的二胺和2.0当量的甲基巯基氢卤化物衍生物溶于甲醇中。连接在顶部装配有NaOH分液器的冷凝器。回流数小时之后,在减压下将溶液浓缩至最低体积。将乙醚加入其中,从而产生白色沉淀。在热甲醇中对其进行重结晶,从而得到纯产物。
方法C:醛/酮和氨基胍之间进行缩合反应,从而得到脒基腙衍生物。该方法是文献程序(Murdock,等人 (1982) J. Med. Chem. 25:505-518)的改进方法。在乙醇中,将1.0当量的二醛/酮和2.0当量的氨基胍氢卤化物的混合物回流下加热数小时。将所述混合物冷却至室温并且对其进行过滤,从而得到脒基腙氢卤化物。
方法D:醛/酮和胺之间的还原胺化作用(Abdel-Magid,等人 (1996) J. Org. Chem. 61:3849-3862)。将1.0当量二醛或酮和2.0当量胺混合在1, 2-二氯乙烷中,然后用3.0当量的三乙酰氧基硼氢化钠进行处理(还可以将1.0-2.0摩尔当量的乙酸加入酮的反应中)。在氩气或氮气气氛下,将混合物在室温下搅拌数小时,直至在TLC板上反应物消失为止。通过加入1 N NaOH将反应混合物猝灭,用乙醚对产物进行萃取、用盐水洗涤并且用无水MgSO4对其进行干燥。将溶剂蒸发,从而得到粗游离碱,该游离碱可以通过色谱法进行纯化。将游离碱溶于乙醇盐酸盐或酒石酸中,从而得到盐,通常可以在MeOH/Et2O中对其进行重结晶。
方法E:酰胺的还原(Micovic and Mihailovic (1953) J. Org. Chem. 18:1190)。酰胺可以由相应的羧酸或酰氯(carboxylic chlorides)进行制备。在具有顶部装配有NaOH分液器的冷凝器的无水系统中,将羧酸和亚硫酰氯的混合物回流数小时。在减压下将过量亚硫酰氯除去,从而得到酰氯。加入2.0当量的胺和3当量的吡啶之后,将酰氯溶于二氯甲烷中。在室温下,将混合物搅拌,直至在TLC板上反应物消失为止。在减压下将溶剂除去,从而得到粗酰胺,该酰胺可以通过色谱法进行纯化。
对1当量的酰胺和1.9当量的LiAlH4的THF混合物进行回流,直至TLC板中酰胺消失为止。然后,如文献5所述,通过加入水和15% NaOH水溶液将所述溶液猝灭,用乙醚萃取并且用MgSO4进行干燥。将溶剂除去,从而得到游离胺产物,该游离胺产物可以通过色谱法进行纯化。将游离碱溶于乙醇盐酸或酒石酸中,从而得到盐,通常可以在MeOH/Et2O中对其进行重结晶。
方法F:卤化物与胺的亲核取代反应。将1.0当量的卤化物、2.0当量的胺和3当量的吡啶的乙醇混合物回流数小时,直至反应物消失为止。对所述溶液进行浓缩并且用乙醚萃取、用盐水洗涤、用MgSO4进行干燥。将溶剂除去,从而得到游离胺产物,该游离胺可以通过色谱法进行纯化。将游离碱溶于乙醇盐酸或酒石酸中,从而得到盐,通常可以在MeOH/Et2O中对其进行重结晶。
制备额外化合物并在细胞试验中测试以测定病毒抑制:
制剂
在化合物具有形成稳定无毒酸或碱盐的充分碱性或酸性的情形中,施用作为药学上可接受的盐的化合物可以是适当的。药学上可接受的盐的实例是与形成生理学上可接受的阴离子的酸形成的有机酸加成盐,所述阴离子例如甲苯磺酸根、甲磺酸根、乙酸根、柠檬酸根、丙二酸根、酒石酸根、琥珀酸根、苯甲酸根、抗坏血酸根、α-酮戊二酸根和α-甘油磷酸根。还可以形成合适的无机盐,包括硫酸盐、硝酸盐、碳酸氢盐和碳酸盐。
药学上可接受的盐可以使用本领域众所周知的标准程序得到,例如,通过使充分碱性的化合物(诸如胺)与提供生理学上可接受的阴离子的合适酸反应。还可以制备羧酸的碱金属(例如,钠、钾或锂)或碱土金属(例如钙)盐。
还可以将活性化合物作为在体内转化为生物学活性形式的前药提供。前药可以通过多种机制转化成母体药物,包括酶方法和新陈代谢水解。Harper, N.J. (1962) inJucker, ed. Progress in Drug Research, 4:221-294; Morozowich等人 (1977) in E.B. Roche ed. Design of Biopharmaceutical Properties through Prodrugs and Analogs, APhA (Acad. Pharm. Sci.); E. B. Roche, ed. (1977) Bioreversible Carriers in Drug in Drug Design, Theory and Application, APhA; H. Bundgaard,ed. (1985) Design of Prodrugs, Elsevier; Wang等人 (1999) Curr. Pharm. Design.5(4):265-287; Pauletti等人 (1997) Adv. Drug. Delivery Rev. 27:235-256; Mizen 等人 (1998) Pharm. Biotech. 11:345-365; Gaignault等人 (1996) Pract. Med. Chem. 671-696; M. Asghamejad (2000) in G. L. Amidon, P. I. Lee and E. M.Topp, Eds., Transport Proc. Pharm. Sys., Marcell Dekker, p. 185-218; Balant等人 (1990) Eur. J. Drug Metab. Pharmacokinet., 15(2): 143-53; Balimane andSinko (1999) Adv. Drug Deliv.Rev., 39(1-3):183-209; Browne (1997). Clin. Neuropharm. 20(l): 1-12; Bundgaard (1979) Arch. Pharm. Chemi. 86(l): 1-39; H.Bundgaard, ed. (1985) Design of Prodrugs, New York: Elsevier; Fleisher等人(1996) Adv. Drug Delivery Rev, 19(2): 115-130; Fleisher等人 (1985) Methods Enzymol. 112: 360-81; Farquhar D,等人 (1983) J. Pharm. Sci., 72(3): 324-325;Han, H.K.等人 (2000) AAPS Pharm Sci., 2(1): E6; Sadzuka Y. (2000) Curr. Drug Metab., 1:31-48; D.M. Lambert (2000) Eur. J. Pharm. Sci., 11 Suppl 2:S1 5-27;Wang, W.等人 (1999) Curr. Pharm. Des., 5(4):265。
还可以将活性化合物提供为脂质前药。公开了可以共价并入化合物或亲脂制剂中的合适的亲脂取代基的美国专利的非限制性实例包括美国专利号5,149,794 (Sep. 22,1992, Yatvin等人);5,194,654 (Mar. 16, 1993, Hostetler等人, 5,223,263 (June29, 1993, Hostetler等人);5,256,641 (Oct. 26, 1993, Yatvin等人);5,411,947 (May2, 1995, Hostetler等人);5,463,092 (Oct. 31, 1995, Hostetler等人);5,543,389(Aug. 6, 1996, Yatvin等人);5,543,390 (Aug. 6, 1996, Yatvin等人);5,543,391(Aug. 6, 1996, Yatvin等人);和5,554,728 (Sep. 10, 1996; Basava等人)。
治疗方法
本文所述的化合物特别可用于治疗或预防与内分泌紊乱相关的症状。待治疗的宿主是任何哺乳动物,优选人患者,并且可以是女性或男性,尽管热潮红的最终原因对于两组可能显著不同。例如,在女性患者中,热潮红通常为绝经期激素改变导致的主要症状。然而,热潮红也可以是抗雌激素化合物(例如他莫昔芬,醋酸亮丙瑞林等)药物诱导的,或雌激素产生组织去除(例如,经腹全子宫切除术、双侧输卵管-卵巢切除术等)外科手术诱导的。在男性患者中,热潮红通常作为转移性前列腺癌的雄激素依赖性治疗的副作用出现。它们可以是外科手术诱导的(例如,双侧睾丸切除术)或药物诱导的(例如,用促性腺激素释放激素激动剂,醋酸亮丙瑞林等治疗)。
在某些实施方案中,宿主是绝经期或绝经前(也称为围绝经期)女性。绝经期是女性生命中持续1年没有月经期的点。对于大多数女性,绝经发生在50岁左右,但每个女人的身体有其自己的时间表。一些女性在其45岁左右停经。其他很好地持续到50多岁。前绝经期或绝经前期是导致绝经期的变化过程。它可以早在30多岁晚期或迟至50多岁早期开始。绝经前期持续多久不同,但通常持续2至8年。与绝经前期相关的症状包括月经周期的改变,热潮红,盗汗,阴道干涩,睡眠问题,情绪改变(情绪波动,悲伤或易怒),性交时疼痛,更多尿路感染,尿失禁,对性交不感兴趣,围绕腰部的身体脂肪增加和注意力和记忆力的问题。
绝经期最众所周知的效果是“热潮红(hot flash)”或“热潮红(hot flush)”,体温突然暂时性增加:“热潮红”的“潮红”感觉作为几乎瞬间的体温峰值出现,并且开始慢得多回复到正常状态。热潮红可以变得如此强烈,以至于它们可以在非常短的时期内使体温升高多度,并引起患者感到虚弱和大量出汗的爆发。尽管使人不舒服,但医生不认为热潮红是有害的。
宿主可以被诊断为由于患有至少一种与内分泌紊乱诸如绝经相关的症状而需要治疗。具体地,如果宿主已经患有至少一种热潮红,特别是治疗前六个月内患有至少一种热潮红,则宿主需要治疗。更具体地,宿主在治疗前三个月内,或两个月内,或一个月内已经患有至少一种热潮红。
在一些实施方案中,宿主患有内分泌紊乱或处于患有内分泌紊乱的风险。内分泌病症包括,但不限于,肾上腺病症,包括肾上腺不足,诸如艾迪生病,先天性肾上腺增生(肾上腺性综合征)和盐皮质激素缺乏症,康恩综合征和库欣综合征,肾上腺性综合征,包括嗜铬细胞瘤,肾上腺皮质癌和gra/糖皮质激素可补救性醛固酮增多症;葡萄糖稳态病症诸如糖尿病,低血糖(特发性低血糖和胰岛素瘤);代谢性骨骼疾病,包括骨质疏松症,变形性骨炎(骨骼佩吉特氏病),佝偻病和骨软化症;脑垂体病症,包括尿崩症,垂体功能低下(或全垂体机能减退),垂体肿瘤(垂体腺瘤,泌乳素瘤(或高泌乳素血症),肢端肥大症,巨人症和库欣病);甲状旁腺病症,包括原发性甲状旁腺功能亢进症,继发性甲状旁腺功能亢进,三发性甲状旁腺功能亢进和甲状旁腺功能减退症(包括假性甲状旁腺功能减退症);性激素病症,包括性发育病症或双性病症,雌雄同体性,性腺发育不全和雄激素不敏感综合征;性腺功能低下症,包括促性腺激素缺乏症,卡尔曼综合征,Klinefelter综合征,卵巢衰竭,睾丸衰竭和特纳综合征;性别认同病症;延迟或性早熟;月经功能或生育能力障病症,包括闭经和多囊卵巢综合征;甲状腺病症,包括甲状腺肿,甲状腺功能亢进和格雷夫斯-眼球突出性甲状腺肿病(Graves- basedow disease),甲状腺功能减退症,甲状腺炎和甲状腺癌;内分泌腺肿瘤,诸如多发性内分泌肿瘤类型1、2a和2b;和自身免疫性多内分泌腺病综合征。某些潜在疾病,诸如HIV或下面描述的某些癌症,在患有所述紊乱的宿主中可以引起导致症状(包括热潮红)的内分泌紊乱。在某些实施方案中,提供了治疗患有导致内分泌病症的症状的病症诸如HIV或下面描述的某些癌症的患者的方法,包括施用本文所述的化合物。
在一个实施方案中,提供了治疗或预防与内分泌紊乱相关症状的方法,其包括向有需要的宿主施用有效量的至少一种式(I)-(XVII)化合物。在某些实施方案中,宿主患有绝经前或绝经期症状。在其它实施方案中,宿主患有内分泌病症。
在其它实施方案中,宿主正在用药物治疗,特别是正在用化疗剂治疗。在某些实施方案中,症状包括热潮红。具有癌症,特别是由性激素雌激素和雄激素刺激的癌症,诸如乳腺癌、子宫癌和睾丸癌的女性和男性可以得到热潮红,因为化疗降低了这些身体水平。在具体实施方案中,向处于化疗治疗风险或接受化疗治疗的宿主施用所述化合物。在具体实施方案中,宿主在接受所述化合物或组合物的10天之内或9天之内,或者8天之内或7天之内,或6天之内,或5天之内或4天之内,或3天之内,或2天之内或一天之内或更少处于化疗治疗风险或接受化疗治疗。
在一些实施方案中,在化疗治疗后施用所述化合物。在具体实施方案中,在化疗治疗之后至少一小时、或之后至少两小时、或之后至少三小时、或之后至少四小时、或之后至少五小时、或之后至少六小时、或之后至少七小时、或之后至少八小时、至少之后十二小时或之后至少一天施用所述化合物。
在一些实施方案中,在化疗治疗之前或同时施用所述化合物。在具体实施方案中,在化疗治疗之前至少一小时、或之前至少两小时、或之前至少三小时、或之前至少四小时、或之前至少五小时、或之前至少六小时、或之前至少七小时、或之前至少八小时、至少之前十二小时或之前至少一天施用所述化合物。
活性物质可以通过任何适当的途径施用,例如,以液体或固体形式口服、肠胃外、静脉内、皮内、皮下或局部施用。然而,所述化合物特别适于口服递送。
化合物的剂量的非限制性实例范围为约1-50 mg/kg体重/天,优选1-20 mg/kg体重/天,更一般为0.1-约100 mg/千克受体体重/天。药学上可接受的盐和前药的有效剂量范围可以基于待递送的母体化合物的重量进行计算。如果所述盐、酯或前药自身表现活性,则有效剂量可以如上所述,使用所述盐、酯或前药的重量进行估计或通过本领域技术人员已知的其它方式进行估计。
在一个具体实施方案中,提供了治疗或预防内分泌病症的症状的方法,包括向有需要的宿主施用式XVI的化合物,或其药学上可接受的盐、酯或前药:
式XVI。
在一个具体子实施方案中,所述化合物为式XVI化合物的盐,特别是氯化物盐。在典型实施方案中,所述症状是热潮红。在最具体实施方案中,宿主患有复发性热潮红或处于患有复发性热潮红的风险。
药物组合物
在一个实施方案中,提供了用于预防或治疗内分泌病症的症状的药物组合物,包括至少一种式(I)-(XVII)中任一种的化合物和药学上可接受的载体。在某些实施方案中,至少一种第二活性化合物包括在组合物中。第二活性化合物可以是化疗剂,特别是对原发性肿瘤具有活性的药剂。
所述化合物方便地以任何合适的剂型进行施用,包括但不限于在每个单位剂型中含有7-3000 mg,优选70-1400活性成分的剂型。50-1000 mg的口服剂量通常是方便的。理想地,应当施用活性成分,从而获得约1uM -100mM或0.2-700 uM或约1.0-10 uM的活性化合物的峰值血浆浓度。
活性化合物在药物组合物中的浓度将取决于药物的吸收、失活和排泄速率以及本领域技术人员已知的其它因素。应当注意,剂量值还随待缓解的状况的严重程度而变化。此外,应当理解,对于任何具体对象,具体施用方案应该随时间推移根据个体需要以及施用或指导施用组合物的人的专业判断进行调整,并且本文所述的浓度范围仅仅是示例性的,并不意图限制权利要求的组合物的范围或实施。所述活性成分可以一次施用,或可以分成多个较小剂量在不同的时间间隔时施用。
优选活性化合物的施用模式是口服。口服组合物通常将包括惰性稀释剂或可食用载体。可以将它们封装入胶囊中或压缩成片剂。为了口服治疗施用的目的,可以将活性化合物与赋形剂合并并且以片剂、药片或胶囊的形式来使用。可以将药学上相容的粘合剂和/或添加剂物质作为组合物的部分包含入组合物中。
片剂、丸剂、胶囊和药片等可以含有以下任何成分或具有类似性质的化合物:粘合剂,诸如微晶纤维素、黄蓍树胶或凝胶;赋形剂,诸如淀粉或乳糖;崩解剂,诸如藻酸、Primogel或玉米淀粉;润滑剂,诸如硬脂酸镁或Sterotes;助流剂,诸如胶体二氧化硅;甜味剂,诸如蔗糖或糖精;或增香剂,诸如胡椒薄荷、水杨酸甲酯或橘子香精(orangeflavoring)。当剂量单位形式为胶囊时,除了上述类型的物质之外,它还可以含有液体载体,诸如脂肪油。此外,所述剂量单位形式可以含有多种其它改变剂量单位外形的物质,例如,蔗糖包衣、虫胶包衣或其它肠内吸收药包衣。
所述化合物可以作为酏剂、混悬剂、糖浆剂、板片或口香糖等的组分施用。除了活性化合物之外,糖浆剂还可以含有作为甜味剂的蔗糖和某些防腐剂、染料和着色剂和香料。
所述化合物或其药学上可接受的前药或盐还可以与其它不会削弱期望活性的活性化合物混合,或与补充期望作用的物质(诸如抗生素、抗真菌剂、抗炎药或抗病毒化合物)或与其它化学治疗剂混合。用于肠胃外、真皮内、皮下或局部应用的溶液剂或混悬剂可以包含以下组分:无菌稀释剂,诸如注射用水、盐水溶液、固定油类、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗细菌剂,诸如苄醇或羟苯甲酸甲酯;抗氧化剂,诸如抗坏血酸或亚硫酸氢钠;螯合剂,诸如乙二胺四乙酸;缓冲剂,诸如乙酸盐、柠檬酸盐或磷酸盐和调节张力的试剂,诸如氯化钠或葡萄糖。可以将母体制剂封装在安瓿、一次性注射器或由玻璃或塑料制成的多剂量管形瓶中。
在典型的实施方案中,将活性化合物与防止化合物从体内迅速消除的载体一起制备,诸如,控释制剂,包括植入物和微囊密封递送系统。可以使用可生物降解的、生物相容的聚合物,诸如乙烯-乙酸乙烯酯共聚物、聚酐聚乙醇酸、胶原蛋白、聚原酸酯和聚乳酸。制备此类制剂的方法对于本领域技术人员而言将是显而易见的。所述物质还可以商业得自AlzaCorporation。如果静脉内施用,优选载体为生理盐水或磷酸盐缓冲盐水(PBS)。
还优选将脂质体混悬剂(包括靶向受感染细胞的脂质体与病毒抗原的单克隆抗体)作为药学上可接受的载体。它们可以根据本领域技术人员已知的方法进行制备,例如,如美国专利号4,522,811 (其通过引用并入本文) 中所述。例如,脂质体制剂可以通过以下方式进行制备,将适当的脂质(诸如硬脂酰磷脂酰乙醇胺、硬脂酰磷脂酰胆碱、花生酰磷脂酰胆碱和胆固醇)溶解在无机溶剂中,然后对其进行蒸发,在容器的表面上留下干燥脂质的薄膜。然后,将活性化合物或其单磷酸盐、磷酸氢盐和/或三磷酸盐衍生物的水溶液引入到容器中。然后,用手涡旋所述容器,从而使得脂质物质从容器的侧壁上分离下来并分散脂质聚集体,从而形成脂质体混悬剂。
联合和交替治疗
在一个实施方案中,本文所述的化合物与另一种活性化合物联合或交替施用。
在一个实施方案中,所述化合物与激素替代治疗联合或交替施用。在某些实施方案中,所述化合物与雌激素和/或孕激素或孕酮联合或交替施用。
在一个实施方案中,所述活性化合物是用作化疗剂的化合物。联合或交替中提供的化合物,例如,可以选自下表:
13-顺-维甲酸 | 2-氨基-6-巯基嘌呤 | 2-CdA | 2-氯脱氧腺苷 |
5-氟尿嘧啶 | 5-FU | 6 - TG | 6 -硫鸟嘌呤 |
6-巯基嘌呤 | 6-MP | 异维甲酸 | 放线菌素-D |
阿霉素 | Adrucil | Agrylin | Ala-Cort |
阿地白介素 | 阿仑单抗 | 阿利维A酸 | Alkaban-AQ |
Alkeran | 全反式维甲酸 | α干扰素 | 六甲蜜胺 |
氨甲喋呤 | 氨磷汀 | 氨鲁米特 | 阿那格雷 |
Anandron | 阿那曲唑 | 阿糖胞苷 | Ara-C |
Aranesp | 阿可达 | 瑞宁得 | 阿诺新 |
三氧化二砷 | 天冬酰胺酶 | ATRA | 阿瓦斯汀 |
BCG | BCNU | 贝伐单抗 | 蓓萨罗丁 |
比卡鲁胺 | BiCNU | 博莱霉素 | 争光霉素 |
硼替佐米 | 白消安 | 白舒非 | C225 |
亚叶酸钙 | Campath | Camptosar | 喜树碱-11 |
卡培他滨 | Carac | 卡铂 | 卡莫司汀 |
卡莫司汀薄片 | 康士得 | CCNU | CDDP |
CeeNU | Cerubidine | 西妥昔单抗 | 苯丁酸氮芥 |
顺铂 | 亚叶酸因子 | 克拉屈滨 | 可的松 |
可美净 | CPT-11 | 环磷酰胺 | Cytadren |
阿糖胞苷 | 阿糖胞苷脂质体 | Cytosar-U | Cytoxan |
达卡巴嗪 | 更生霉素 | 达依泊汀α | 道诺霉素 |
正定霉素 | 正定霉素盐酸盐 | 正定霉素脂质体 | DaunoXome |
Decadron | Delta-Cortef | Deltasone | Denileukin diftitox |
DepoCyt | 氟美松 | 氟美松醋酸盐 | 氟美松磷酸钠 |
塞米松 | 右丙亚胺 | DHAD | DIC |
Diodex | 多西他赛 | Doxil | 多柔比星 |
多柔比星脂质体 | Droxia | DTIC | DTIC-Dome |
Duralone | Efudex | Eligard | Ellence |
乐沙定 | Elspar | Emcyt | 表柔比星 |
依泊汀α | 爱必妥 | 欧文氏菌L-门冬酰胺酶 | 雌氮芥 |
Ethyol | Etopophos | 依托泊苷 | 磷酸依托泊苷 |
Eulexin | Evista | 依西美坦 | 法乐通 |
Faslodex | Femara | 非格司亭 | 氟尿苷 |
Fludara | 氟达拉滨 | Fluoroplex | 氟尿嘧啶 |
氟尿嘧啶(膏剂) | 氟甲睾酮 | 氟他米特 | 亚叶酸 |
FUDR | 氟维司群 | G-CSF | 吉非替尼 |
吉西他滨 | 吉妥单抗奥佐米星 | 健择 | 格列卫 |
Gliadel薄片 | 格列卫 | GM-CSF | 戈舍瑞林 |
粒细胞集落刺激因子 | 粒细胞巨噬细胞集落刺激因子 | Halotestin | 赫赛汀 |
Hexadrol | Hexalen | 六甲嘧胺 | HMM |
Hycamtin | Hydrea | Hydrocort Acetate | 氢化可的松 |
氢化可的松磷酸钠 | 氢化可的松琥珀酸钠 | 磷酸氢化可的松 | 羟基脲 |
替伊莫单抗 | 替伊莫单抗Tiuxetan | Idamycin | 伊达比星 |
Ifex | IFN-α | 异环磷酰胺 | IL - 2 |
IL-11 | 甲磺酸伊马替尼 | 咪唑甲酰胺 | 干扰素α |
干扰素α-2b (PEG缀合物) | 白介素- 2 | 白介素-11 | 内含子A (干扰素α-2b) |
易瑞沙 | 伊立替康 | 异维甲酸 | Kidrolase |
Lanacort | L-门冬酰胺酶 | LCR | 来曲唑 |
亚叶酸 | 瘤可宁 | Leukine | 亮丙瑞林 |
长春新碱 | Leustatin | 脂质体Ara-C | 液体Pred |
罗氮芥 | L-PAM | L-溶肉瘤素 | Lupron |
Lupron Depot | Matulane | Maxidex | 氮芥 |
氮芥盐酸盐 | Medralone | Medrol | Megace |
甲地孕酮 | 醋酸甲地孕酮 | 美法仑 | 巯基嘌呤 |
美司钠 | Mesnex | 甲氨蝶呤 | 甲氨蝶呤钠 |
甲泼尼龙 | Meticorten | 丝裂霉素 | 丝裂霉素-C |
米托蒽醌 | M-Prednisol | MTC | MTX |
Mustargen | Mustine | Mutamycin | 马利兰 |
Mylocel | Mylotarg | 诺维本 | |
Neosar | Neulasta | Neumega | 优保津 |
Nilandron | |||
尼鲁米特 | 氮芥 | Novaldex | Novantrone |
奥曲肽 | 醋酸奥曲肽 | Oncospar | Oncovin |
Ontak | Onxal | Oprevelkin | Orapred |
Orasone | 奥沙利铂 | 紫杉醇 | 帕米膦酸盐 |
Panretin | Paraplatin | Pediapred | PEG干扰素 |
培门冬酶 | 培非司亭 | PEG-INTRON | PEG-L-门冬酰胺酶 |
苯丙氨酸氮芥 | Platinol | Platinol-AQ | 泼尼松龙 |
Prednisone | Prelone | 丙卡巴肼 | PROCRIT |
Proleukin | 具有卡莫司汀植入物的Prolifeprospan 20 | Purinethol | 雷洛昔芬 |
Rheumatrex | 利妥昔 | 利妥昔单抗 | Roveron-A (干扰素α-2a) |
Rubex | 红比霉素盐酸盐 | 善得定 | 善得定LAR |
沙格司亭 | Solu-Cortef | Solu-Medrol | STI-571 |
链佐星 | 他莫昔芬 | 贝沙罗汀 | 紫杉醇 |
泰索帝 | 替莫唑胺 | 替莫唑胺 | 替尼泊苷 |
TESPA | 沙利度胺 | 沙利度胺 | TheraCys |
硫鸟嘌呤 | 硫鸟嘌呤Tabloid | 硫代磷酰胺 | Thioplex |
塞替派 | TICE | Toposar | 拓扑替康 |
托瑞米芬 | 曲妥珠单抗 | Tretinoin | Trexall |
Trisenox | TSPA | VCR | Velban |
万珂 | VePesid | Vesanoid | Viadur |
长春花碱 | 磷酸长春花碱 | Vincasar Pfs | 长春新碱 |
长春瑞滨 | 酒石酸长春瑞滨 | VLB | VM-26 |
VP-16 | Vumon | 希罗达 | Zanosar |
Zevalin | Zinecard | 诺雷德 | 唑来膦酸 |
择泰 |
在一个实施方案中,本公开化合物与另一种活性剂联合施用。所述化合物还可以与另一种活性剂同时施用。在这种情况下,所述化合物可以在相同制剂或在分离制剂中施用。不需要化合物以相同方式进行施用。例如,第二活性剂可以经静脉内注射进行施用,但是本公开化合物可以口服施用。在另一个实施方案中,本公开化合物与至少一种其它活性化合物交替施用。在单独的实施方案中,本公开化合物在用化疗剂(诸如,例如为上述列举的试剂)治疗期间进行施用,并且在停止施用其它活性化合物之后,继续施用本公开化合物。可以持续至少一个月、至少两个月、至少四个、六个、七个、八个、九个、十个、十一个、十二个月或以上施用化合物,以减少肿瘤转移的发生率。
本公开化合物可以在另一种活性化合物停止施用之前或之后施用。在某些情况下,可以在开始原发性肿瘤的疗程之前施用所述化合物,例如,以预防与内分泌病症相关的症状,诸如热潮红。在一个独立实施方案中,可以在化疗疗程之后施用所述化合物,以减少内分泌病症的症状。
实施例
实施例1:使用针对生物素标记的TN14003的竞争性结合测定法筛选小分子化合物。
先前报道了合成的14聚体肽TN14003通过与其配体SDF-1竞争性结合来高特异性阻断体外SDF-1/CXCR4介导的侵袭和体内肿瘤转移。开发了使用生物素标记的TN14003和链霉亲和素缀合的若丹明的竞争结合测定法来测定新化学实体与CXCR4的SDF-1结合结构域的结合效率。与高亲和力化合物孵育的细胞仅显示蓝色的核染色,而具有低亲和力的化合物导致染色CXCR4(红色;罗丹明)以及核(蓝色;cytox蓝色)。鉴定某些化合物的有效浓度(EC50),和MSX-122和AMD3100的EC50分别为0.6和26 nM。
实施例2:cAMP测定
因为CXCR4/SDF-1的主要信号转导途径涉及百日咳毒素敏感的G蛋白Gi,所以关于它们是否抑制SDF-1/CXCR4介导的cAMP降低,对本文所述的化合物进行了测试。通过改变SDF-1的浓度(0 – 200 ng/ml)测定665 nm处的吸光度增加,测定EC80为150 ng/ml。利用MSX-122或AMD3100的预处理,SDF-1对cAMP降低的效果以剂量依赖性的方式得到显著阻断。尽管MSX-122在低至10 nM的浓度有效抵消SDF-1功能,但AMD3100需要几乎1000 nM来显著阻断SDF-1功能。
实施例3:MSX-122的药代动力学
针对某些化合物在多个物种中一致观察口服生物利用度和持续血浆暴露。在小鼠中的初步药代动力学研究中,当腹腔内(IP)和口服施用时,MSX-122均产生持续的血液水平。在大鼠中的药代动力学研究中,当以10 mg/kg施用时,口服吸收似乎非常快速发生,初始Tmax为~30 min,且血浆水平保持在高于100 ng/ml(342 nM),持续10小时。在非未处理的雌性食蟹猴中进行的药代动力学/药效动力学研究中,MSX-122以1、5和10 mg/kg口服施用,并且导致持续的药代动力学,血浆水平是相对剂量成比例的。5和10 mg/kg剂量都产生微摩尔血浆浓度,半衰期支持每天一次给药。
实施例4:体外基因毒性和安全性
在体外Ames试验(BioReliance Corp., Rockville, MD)和使用用MSX-122处理的CHO细胞的体外染色体畸变筛选试验(BioReliance Corp., Rockville, MD)中测试MSX-122的基因毒性,所述体外Ames试验表明没有诱变的证据,所述体外染色体畸变筛选试验显示在高达2 mM的最高剂量的任何剂量水平,结构或数量染色体畸变没有任何统计学显著性增加。在S9存在的情况下,4小时处理可得充分可得分的细胞,在S9不存在的情况下,20小时处理可得充分可得分的细胞。最后,测试MSX-122通过心脏钾通道hERG干扰人心室中快速延迟整流电流(IKr)的潜能,因为IKr的抑制已经被报道为非强心药的心脏动作电位延长的最常见原因。所得数据表明,MSX-122和类似物没有对hERG通道电流施加显著抑制作用(1 μMMSX-122 (WZ40-MS) – 0.2%抑制)。
实施例5:在大鼠和猴中的毒理学研究
在初始研究中,每天一次用0、250和600 mg/kg MSX-122口服给药三组大鼠(每组5只雄性和5只雌性),持续28天。药代动力学数据显示,在第1天之后的研究期间始终维持微摩尔浓度的MSX-122,Cmax值范围为2 – 4 μg/ml (6.8 – 13.6 μM)。在研究过程中在任何动物中都没有观察到任何毒性迹象或症状,并且从血清化学或总体尸检终止之后没有观察到任何毒性。在持续5天每天一次分别口服给药1,000和2,000 mg/kg的两只非未处理食蟹猴(1只雄性和1只雌性)和两只未处理食蟹猴(1只雄性和1只雌性)中进行5天重复剂量研究。没有观察到任何药物相关迹象或毒性症状,并且所得血清化学物没有任何异常。以2000mg/kg给药的动物的总体尸检也没有揭示任何异常或毒性迹象。唯一观察是一个子集动物中的松散和水样粪便,这可能是由制剂中的赋形剂引起的。数据显示,在研究期间始终维持微摩尔浓度的MSX-122,Cmax范围为5.1 μM (1.5 μg/ml)至12 μM (3.5 μg/ml)。
实施例6:热潮红的治疗
用MSX-122 50mg/天口服治疗之前用VEGF捕获物和多西他赛、卡铂和紫杉醇和阿霉素脂质体治疗之后的具有在其右侧输卵管的侵入性高级浆液性癌、全子宫切除术和双侧卵巢切除术历史的约70 kg 56岁大的女性。该女性患有格雷夫斯病并具有热潮红病史。她用MSX-122第三次治疗之后,她注意到,她过去的热潮红病史从开始试验以来已经大为改善。
Claims (13)
1.式I的化合物、或其药学上可接受的盐在制造用于治疗或预防热潮红的药物中的用途,
其中
每个K独立地为N或CH;
Q、T、U和V独立地选自H和R;
W、X、Y和Z独立地选自H、R、F、Cl、OR、CO2H;
每个R独立地选自C1-C10烷基;且
R1、R2、R3、R4、R5和R6独立地选自H和C1-C10烷基。
2.下述结构的化合物在制造用于治疗或预防热潮红的药物中的用途,
。
3.权利要求1或2的用途,其中所述药物用于治疗或预防绝经期或围绝经期妇女的热潮红。
4.权利要求1或2的用途,其中所述药物用于治疗或预防正在月经来潮或预期一周月经来潮的妇女的热潮红。
5.权利要求1或2的用途,其中所述药物用于治疗或预防诊断具有外阴痛的妇女的热潮红。
6.权利要求1或2的用途,其中所述药物与另一种活性剂联合施用。
7.权利要求1或2的用途,其中所述药物与雌激素受体的激动剂或拮抗剂联合施用。
8.权利要求1或2的用途,其中所述药物与他莫昔芬联合施用。
9.权利要求1或2的用途,其中所述药物与抗雄激素联合施用。
10.权利要求1或2的用途,其中所述药物用于治疗或预防诊断具有前列腺癌的人的热潮红。
11.权利要求1或2的用途,其中所述药物与螺内酯、环丙孕酮、氟他胺、尼鲁米特、比卡鲁胺、非那雄胺或度他雄胺联合施用。
12.权利要求1的用途,其中所述化合物是N-(4-((嘧啶-2-基氨基)甲基)苄基)-嘧啶-2-胺或其药学上可接受的盐。
13.权利要求1或2的用途,其中所述药物在外科手术之后、之前或过程中向对象施用,所述外科手术选自子宫切除术、卵巢切除术、部分卵巢切除术、单侧输卵管-卵巢切除术、双侧输卵管-卵巢切除术或其组合。
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