CN109153639B - 葫芦巴碱类化合物 - Google Patents
葫芦巴碱类化合物 Download PDFInfo
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- CN109153639B CN109153639B CN201780017508.4A CN201780017508A CN109153639B CN 109153639 B CN109153639 B CN 109153639B CN 201780017508 A CN201780017508 A CN 201780017508A CN 109153639 B CN109153639 B CN 109153639B
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明提供.了新型的化合物,其具有改善的溶解性和改变的药代动力学性质。本发明的化合物可以由式(I)表示。
Description
技术领域
本发明涉及具有改善的溶解度和改变的药代动力学性质的新型化合物和改变化合物的药代动力学特征的方法。
背景技术
许多药学上感兴趣的化合物由于其药代动力学或药效动力学性质以及其差的溶解性而在药物开发过程中面临挑战。
药物物质的分子修饰被设计为(相比于其他方面而言)用于增强特定靶位点的特异性、增加其效力、改善其吸收速率和吸收程度、改变药物在体内变成生物可利用形式的时间跨度等,同时保留药物的功效和毒性值。已知存在有限数量的化学修饰,其可以提高药物物质与pH无关的水溶性,或者可以改变药物的药代动力学性质而不影响其功效和毒性。
值得注意的是,基于分子修饰来提高药用化合物(如紫杉烷类)的溶解度的尝试并未产生任何成功的临床产品。已经制备了某些紫杉醇前药,据称这些前药在体内转化为紫杉醇和一些其他产物。例如,PCT专利公开号WO 1997044063公开了某些前药,但似乎这些化合物仍然不具有所需的药代动力学性质。制药工业主要依赖于新型制剂或赋形剂,以产生生物学上感兴趣的分子的理想溶解度特征,从而对其进行开发以用于临床。
在现有技术中,已知一些具有嘌呤或嘧啶碱基型结构的生物碱用于药物物质的分子修饰,以用于位点特异性药物递送。
例如,EP0110955 B1公开了式[D-DHC]的化合物,其用于将中枢作用药物物质位点特异性/缓释递送至大脑。施用时化合物在体内转化为季铵盐,其中季铵盐仅在大脑内部被锁定,而进入身体其他部位的盐很容易从肝脏和肾脏排出体外。因此,与身体的其他部分相比,在大脑中季铵盐的浓度更高。
仍然需要开发具有改善的溶解度和/或药代动力学性质的更好的前药或经修饰的化合物,以用于有效的药物递送而不损失治疗功效且不增加活性分子或药物的毒性。
发明内容
本发明的目的是通过使用葫芦巴碱作为衍生剂的化学修饰而提供新型化合物,该化合物具有更好的与培养基的pH无关的水溶性以及改善或改变的药代动力学特征。
本发明提供了具有改善的溶解度和改变的药代动力学性质的新型化合物。本发明化合物可由如下式I表示:
其中DX-是活性药物成分(API)或药物物质;以及
X是O或NR;或可官能化的N,其是API或药物物质的一部分。
Z选自Cl-、Br-、I-、甲磺酸根、甲苯磺酸根、四氟硼酸根或磷酸根。
R是H、CH3、低级直链或支链烷基,或者当R与D上的另一个原子之间存在键时,X也可以是3至7元环的一部分。
本发明还公开了制备本发明化合物的方法以及本发明化合物的用途,式I化合物的不是CYP450的底物。
具体实施方式
因此,本发明提供了一种具有改善的溶解性和改变的药代动力学性质的新型化合物,以及一种改变化合物的药代动力学特征的方法。
其中DX-是活性药物成分(API)或药物物质;以及
X是O或NR;或可官能化的N,其是API或药物物质的一部分;
Z选自Cl-、Br-、I-、甲磺酸根、甲苯磺酸根、四氟硼酸根或磷酸根。
R是H、CH3、低级直链或支链烷基,或者当R与D上的另一个原子之间存在键时,X也可以是3至7元环的一部分。
活性药物成分(API)或药物物质可以选自由以下物质构成的组:止痛剂;麻醉剂;抗关节炎剂;呼吸道药物,包括抗哮喘剂;抗癌剂,包括抗肿瘤剂;抗胆碱能药;抗惊厥剂;抗抑郁剂;抗糖尿病剂;止泻剂;驱虫剂;抗组胺剂;抗高血脂剂;抗高血压剂;抗感染剂,如抗生素和抗病毒剂;抗炎剂;抗偏头痛制剂;止吐剂;抗帕金森病药物;止痒剂;退热剂;抗痉挛药;抗结核剂;抗溃疡剂;抗病毒剂;抗焦虑药;食欲抑制剂;注意力缺陷障碍(ADD)和注意力缺陷多动障碍(ADHD)药物;心血管制剂,包括钙通道阻滞剂,CNS剂;β-阻滞剂和抗心律失常剂;α肾上腺素能拮抗剂或激动剂;咳嗽和感冒制剂,包括解充血剂;镇咳剂;利尿剂;胃肠道(GI)运动剂;激素;激素溶解剂(hormonolytics);催眠剂;降血糖剂;免疫抑制剂;白三烯抑制剂;有丝分裂抑制剂;磷酸二酯酶抑制剂;肌肉松弛剂;麻醉拮抗剂;阿片类药物调制剂(opiod modulators);尼古丁;尼古丁/乙酰胆碱(nictone/acetylcholine)拮抗剂或激动剂;精神刺激剂;镇静剂;类固醇;镇定剂;和包括一般冠状动脉、外周和脑的血管扩张剂。
活性药物成分(API)或药物物质可以优选选自由以下物质构成的组:抗癌化合物,如紫杉醇、多西他赛和卡巴他赛;磷酸二酯酶5抑制剂,如他达拉非;血管扩张剂,如多巴胺;麻醉拮抗剂;阿片类药物调制剂;尼古丁;尼古丁/乙酰胆碱拮抗剂或激动剂;最优选地,所述活性药物成分是抗癌化合物。
本发明公开了式II和式III的化合物;
其中所述药物是如上所述的任意活性药物化合物或药物物质。
当通过使用羟基和酸的标准偶联法使活性药物成分或药物物质通过活性药物成分或药物物质的可官能化的氧(例如羟基)而附接至式(IV)的化合物时,可以获得式(II)的化合物。
当通过使用羟基和酸的标准偶联法使活性药物成分或药物物质通过活性药物成分或药物物质的可官能化的氮(例如氨基)而附接至式(IV)的化合物时,可以获得式(III)的化合物。
本发明还包括落入式(I)的化合物的范围内的各种化合物。式(I)的化合物不是CYP450的底物。
在下文表1中列举了式(I)化合物。表1示出了可使用本发明所述方法修饰的现有活性药剂或药物物质的示例性而非限制性列表。
表1:本发明的示例性化合物
本发明的化合物包括但不限于:
i.3-((((1R,2R)-1-苯甲酰氨基-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-二乙酰氧基-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-亚甲基环癸并[3,4]苯并[1,2-b]氧杂环丁二烯-9-基)氧基)-3-氧代-1-苯基丙烷-2-基)氧基)羰基)-1-甲基吡啶-1-碘化鎓;
ii.3-((((1R,2R)-1-苯甲酰氨基-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-二乙酰氧基-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-亚甲基环癸并[3,4]苯并[1,2-b]氧杂环丁二烯-9-基)氧基)-3-氧代-1-苯基丙烷-2-基)氧基)羰基)-1-甲基吡啶-1-甲磺酸鎓;
iii.3-(((1R,2R)-1-苯甲酰氨基-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-二乙酰氧基-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-亚甲基环癸并[3,4]苯并[1,2-b]氧杂环丁二烯-9-基)氧基)-3-氧代-1-苯基丙烷-2-基)氧基)羰基)-1-甲基吡啶-1-四氟硼酸鎓;
iv.3-((((1R,2R)-1-苯甲酰氨基-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-二乙酰氧基-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-亚甲基环癸并[3,4]苯并[1,2-b]氧杂环丁二烯-9-基)氧基)-3-氧代-1-苯基丙烷-2-基)氧基)羰基)-1-甲基吡啶-1-甲苯磺酸鎓;
v.3-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基-1,4-二氧代-1,2,3,4,6,7,12,12a-八氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-7-羰基)-1-甲基吡啶-1-碘化鎓;
vi.3-((4-((1E,4Z,6E)-5-羟基-7-(4-羟基-3-甲氧基苯基)-3-氧代庚-1,4,6-三烯-1-基)-2-甲氧基苯氧基)羰基)-1-甲基吡啶-1-碘化鎓;
vii 3,3'-(((((1E,3Z,6E)-3-羟基-5-氧代庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-亚苯基))双(氧基))双(羰基))双(1-甲基吡啶-1-鎓)碘化物;
viii.3-((((2R,3S)-1-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-12-(苯甲酰氧基)-4,6,11三羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-亚甲基环癸并[3,4]苯并[1,2-b]氧杂环丁二烯-9-基)氧基)-3-((叔丁氧基羰基)氨基)-1-氧代-3-苯基丙烷-2-基)氧基)羰基)-1-甲基吡啶-1-碘化鎓;
ix.3-((1-((2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)-2-氧代-1,2-二氢嘧啶-4-基)氨基甲酰基)-1-甲基吡啶-1-碘化鎓;
x.3-((((2R,3R,5R)-5-(4-氨基-2-氧代嘧啶-1(2H)-基)-4,4-二氟-2-(羟甲基)四氢呋喃-3-基)氧基)羰基)-1-甲基吡啶-1-碘化鎓;
xi.3-((R)-2-((S)-(2,8-双(三氟甲基)喹啉-4-基)(羟基)甲基)哌啶-1-羰基)-1-甲基吡啶-1-鎓;
xii.(R)-3-(((1-(4-((2-(5-氯-2-氟苯基)-5-异丙基嘧啶-4-基)氨基)烟酰胺基)丙烷-2-基)氧基)羰基)-1-甲基吡啶-1-鎓;
xiii.(S)-3-(((1-(4-((2-(5-氯-2-氟苯基)-5-异丙基嘧啶-4-基)氨基)烟酰胺基)丙烷-2-基)氧基)羰基)-1-甲基吡啶-1-碘化鎓。
在一个方面中,本发明包括式I的化合物,其可以由式V表示;
其中R1选自环状或非环状或支链烷基,芳基,如甲基、丙基、异丙基、正丁基、叔丁基,或芳烷基,如苄基,氢,叔丁氧基羰基氨基或N-苯基氨基甲酰基;R2选自氢、羟基、非环状,环状或支链烷基,芳基或芳烷基;R3和R4独立地选自由以下基团构成的组:氢、羟基、低级烷基、低级烷氧基、乙酰基或苄基。
本发明还公开了制备式(I)化合物的方法。式(I)的化合物可通过以下描述的一般方案来制备。
制备式(I)化合物的方法可以基于活性药物成分或药物物质的官能团。
例如,对于含有羟基作为官能团的活性药物成分或药物物质,可以按照如下所述的合成方案1或2来制备:
具有-OH作为官能团之一的药物或生物学感兴趣的分子的修饰的一般合成方案。
方案1
方案2
其中Y选自由以下基团构成的组:OH、Cl、F、Br或酸的任何活化形式,如酸酐;
其中药物可以是如上所述的任意活性药物化合物或药物物质。
本发明还公开了合成式(I)化合物的方法,其中活性成分的官能团是-NH-。
例如,含有氨基作为官能团的化合物可以由如下文所述的合成方案3或4来制备:
具有-NH-作为官能团之一的药物或生物学目的分子的修饰的一般合成方案。
方案3
方案4
其中Y选自由以下基团构成的组:OH、Cl、F、Br或酸的任何活化形式,如酸酐;
其中药物可以是如上所述的任意活性药物化合物或药物物质。
式I的化合物的合成可以包括以下步骤:
步骤1:
其中Y选自卤素(如F、Cl或Br)和OH;X选自O、N,并且根据X的允许价态,n=0至2。将活性药物成分溶解在溶剂中,并在0℃至60℃范围内的温度下,在碱以及任选的催化剂和/或脱水剂存在下用烟酸或烟酸的活化形式(如烟酰氯或相应的酸酐)处理。
本文使用的活性药物成分可选自紫杉醇、多西他赛、卡巴他赛、他达拉非、姜黄素。碱可选自任何碱,例如DIPEA(N,N-二异丙基乙胺)、三乙胺或吡啶,或无机碱,如NaH(氢化钠)或钠或钾的碳酸盐。溶剂可以选自二氯甲烷、四氢呋喃、乙腈、乙酸乙酯、二甲基甲酰胺等。脱水剂可以是有或没有任何助催化剂(如二甲基氨基吡啶)的N,N'-二环己基碳二亚胺或EDCI等。
步骤2:式I化合物的合成。
在合适的溶剂中,向步骤1的产物中加入化学计量或过量的烷基卤化物,如MeI。然后将反应在0℃至回流范围内的温度下搅拌一段时间直至最大量消耗原料。真空去除溶剂,并将得到的残余物用溶剂洗涤或结晶来纯化,以得到纯化的化合物。溶剂可以选自乙腈、乙醚、正戊烷、四氢呋喃。
在另一实施方案中,本发明的方法可任选地包含助催化剂,如四丁基氯化铵,或其他相转移催化剂,例如季铵盐、季鏻盐、聚乙二醇、冠醚、烷基硫酸盐和烷基磺酸盐,可以示例的两性表面活性剂等,通常为四丁基硫酸氢铵、四丁基溴化铵、四丁基氯化铵、等分试样336(aliquots 336)、氢三辛基甲基铵硫酸铵、18-冠-6、四丁基氯化鏻、十二烷基硫酸钠、月桂基二甲基氨基乙酸甜菜碱等。此外,也可以使用其两种或多种的混合物。
步骤3:任选地,使式D-XHn的活性药物成分(API)与3,3'-(氧基双(羰基))双(1-甲基吡啶-1-鎓)碘化物反应,以得到化合物(300);
步骤4:任选地,通过加入催化剂和适当的抗衡离子将化合物(300)的碘抗衡离子转化为另一种抗衡离子,以得到化合物(400);
与活性药物成分相比,本发明的经修饰的药物化合物具有增强的药代动力学性质。经修饰的药物在宽pH范围内具有更高的溶解度。本发明的经修饰的化合物具有所需的安全性和毒性特征。本发明的经修饰的化合物在体内解离成药物化合物和式IV的化合物。
式IV化合物通常称为葫芦巴碱。葫芦巴碱(N-甲基烟酸内酯)是一种化学式为C7H7NO2的吡啶生物碱,其主要来自豆科植物。葫芦巴碱通常存在于植物的种子中,葫芦巴(Trigonella foenum-graecum)也称为胡芦巴(Fenugreek)或葫芦巴(Methi)。葫芦巴碱是由烟酸(维生素B3)的氮原子的甲基化形成的两性离子。葫芦巴碱是一种降胆固醇剂并且具有营养益处和降低葡萄糖的活性。
葫芦巴碱具有由FDA认可的GRAS(通常认为是安全的)资格。由于葫芦巴碱是在植物中发现的天然存在的代谢物,因此认为机体能够更好地将新分子处理回至活性、母体药物中。
本发明的经修饰的化合物在保持所需的安全性和毒性特征的同时,适合用作具有改善的药代动力学性质的药物和/或药剂。本发明还提供了改变化合物的药代动力学特征以使化合物在盐水中和/或在生物学上有用的pH下更易溶解的方法。
本发明的新型化合物可以用于药物和营养保健的目的。本发明的化合物用于治疗不同类型的癌症,包括头颈部、乳房、食道、肺、胃、膀胱、前列腺、卵巢的淋巴瘤和癌症,黑色素瘤和其他类型的实体瘤,卡波济氏肉瘤;用于治疗炎症性疾病,例如皮肤病:寻常痤疮、肺动脉高血压、焦虑症、阿尔茨海默病、细胞凋亡;勃起功能障碍;严重低血压、心动过缓(心率缓慢)、循环性休克或心脏骤停。
本发明包括在其范围内的盐、溶剂化物和异构体。式I和式VI的化合物的溶剂化物优选为水合物或任何其他药学上可接受的溶剂化物。
本发明化合物的所有立体异构体(例如由于活性药物成分或药物物质上的不对称碳而可能存在的那些,包括对映体和非对映体形式)都包括在本发明的范围内。本发明化合物的单个立体异构体可以(例如)基本上不含其他异构体,或者可以(例如)作为外消旋体或与所有其他选择的立体异构体混合。本发明的手性中心可具有S或R构型。
本发明还在其范围内设想了选择合适的抗衡离子的效果。可以通过选择在所述pH范围内能够电离的药物的解离常数来选择本发明化合物的抗衡离子。抗衡阴离子选自卤离子、甲磺酸根、甲苯磺酸根、硼酸根、碳酸根、磷酸根等。
因此,本发明还提供了如本文所定义的修饰实体在人类医学或兽医学中的用途。用作药物的化合物可以呈现为药物制剂。
因此,在另一方面中,本发明提供了一种药物制剂,其包含本发明的经修饰的化合物及其药学上可接受的载体和任选的其他治疗和/或预防成分。载体必须在与配方的其他成分相容并且对其接受者无害的意义上是“可接受的”。合适的药物制剂将是合适的单位剂型。
药物制剂可以是任何制剂,并且包括适合口服、鼻内、眼内或肠胃外(包括肌肉内和静脉内)施用的制剂。在适当的情况下,制剂可以方便地以离散剂量单位存在,并且可以通过药学领域熟知的任何方法制备。所有方法包括使活性化合物与液体载体或细碎的固体载体或液体载体和细碎的固体载体这两者结合的步骤,然后,如果需要,将产物成型为所需的制剂。
不受理论的限制,本发明的化合物可能不是细胞色素P450酶(例如CYP3A4)的合适底物或抑制剂,该酶能够减少活性药物成分或药物物质的剂量并提高安全性和功效。
为了这些目的,本发明化合物可以以含有常规无毒的药学上可接受的载体、佐剂和赋形剂的剂量单位制剂口服、局部、鼻内、眼内、胃肠外、通过吸入喷雾或直肠给药。本文所用的术语肠胃外包括皮下注射、静脉内、肌肉内、腔内(intrasteral)注射或输注技术。除了治疗温血动物,如小鼠、大鼠、马、狗、猫等外;本发明化合物在治疗人类方面也是有效的。
实施例
以下实施例是本公开的代表,并提供详细的制备本公开化合物的方法,包括详细的制备中间体化合物的方法。在以下实施例中详细描述了实施方案的具体化合物的制备,但技术人员将认识到所述化学反应可以容易地适用于制备各种实施方案的许多其他试剂。例如,可以通过本领域技术人员显而易见的修饰(例如,通过适当保护干扰基团,通过改变为本领域已知的其它合适试剂,或通过对反应条件进行常规修饰)成功地进行非示例性化合物的合成。
如本文所用,这些方法、方案和实施例中使用的符号和惯例,无论是否对特定缩写进行具体定义,都与当代科学文献(例如Journal of American Chemical Society或Journal of Biological Chemistry)中使用的符号和惯例一致。
实施例1:1001的合成
紫杉醇的2'-烟酸酯的合成:
步骤-1:
在0℃下,在氮气氛下向紫杉醇[1.0g,1.1709mmol,1.0摩尔当量(mol eq)]的25ml无水DCM溶液中加入DIPEA[0.755g,d=0.756,5.8527mmol,5.0当量],并在相同温度下搅拌反应物15分钟。向上述反应中一次性加入烟酰氯盐酸盐[0.625g,3.0当量],同时将温度保持在0℃。在0℃下将反应搅拌另外30分钟并在室温下搅拌24小时。通过每次用20ml的5%HCl水溶液处理反应物料2次,然后每次用20ml水处理2次,用无水Na2SO4干燥并在真空下除去溶剂来处理反应,以得到所需产物。产率:89%。
MS:m/z 959和960。
步骤-2:
葫芦巴碱酯的合成:
在室温下,向紫杉醇的2'-烟酸酯[0.03g,0.03125mmol]的5ml无水ACN溶液中加入大大过量的碘甲烷[0.5ml]。在室温下将反应搅拌24小时。在真空下除去ACN,将黄色残余物用5ml 1:1的戊烷/乙醚混合物处理并研磨,以得到自由流动的黄棕色晶体。该方法得到最终产物1001且产率为~60%。
实施例2至4:利用上述合成方案1的方法进行1002、1003和1004的合成。
MS:m/z 974,975和976
通过在室温下加入甲磺酸银(I)(1.0当量)从而将碘化物抗衡离子转化为甲磺酸根离子。在室温下将反应混合物搅拌2小时。过滤反应物以除去碘化银。在真空下浓缩滤液,将其用无水乙醚(2×5ml)研磨,通过倾析除去乙醚,并在真空下干燥产物,以得到所需产物甲磺酸盐。该方法得到最终产物[1002]、[1003]、[1004]甲磺酸盐作为所需产物甲磺酸盐。
上述方法用于合成如下姜黄素化合物(1006)和化合物(1007)、多西他赛(1008)和吉西他滨(1009)和化合物(1010)的衍生物:
实施例5:3-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基-1,4-二氧代-1,2,3,4,6,7,12,12a-八氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-7-羰基)-1-甲基吡啶-1-碘化鎓化合物(1005)的合成
步骤1:(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基-7-烟酰基-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮
在0℃下,向他达拉非[0.05g,0.128mmol]的无水THF溶液中加入NaH[0.020g,0.257mmol,2.0当量],并搅拌反应直至变为黄色;加入另一部分NaH[0.020g,0.257mmol,2.0当量],然后在0℃下加入烟酰氯盐酸盐[0.045g,0.257mmol,2.0当量]。在0℃下将反应再搅拌1小时,然后在30℃下搅拌30分钟,然后加入催化量的18-冠-6。将反应加热至55℃(外部)并将反应搅拌36小时。将反应混合物倒入水中,用乙酸乙酯10ml×2次萃取,干燥,并在真空下除去乙酸乙酯,以得到黄色产物。产量38mg。m/z在494。
步骤2:3-((6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基-1,4-二氧代-1,2,3,4,6,7,12,12a-八氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-7-羰基)-1-甲基吡啶-1-碘化鎓的合成
在30℃下,向(6R,12aR)-6-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基-7-烟酰基-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮[0.038g]的无水ACN溶液中加入MeI[0.5ml]。在给定温度下将反应搅拌24小时。在真空下除去ACN,加入1:1的乙醚:正戊烷并研磨,以得到黄色沉淀物,通过抽滤分离,干燥。该方法得到最终产物1005,产量为10mg。m/z在509。
实施例6:33-((R)-2-((S)-(2,8-双(三氟甲基)喹啉-4-基)(羟基)甲基)哌啶-1-羰基)-1-甲基吡啶-1-碘化鎓(1011)的合成
步骤1:((R)-2-((S)-(2,8-双(三氟甲基)喹啉-4-基)(羟基)甲基)哌啶-1-基)(吡啶-3-基)甲酮的合成
向甲氟喹[0.150g,0.39mmol,1当量]的2ml DMF溶液中加入EDC[0.090g,0.47mmol,1.2当量]和HOBt[0.069g,0.51mmol,1.3当量],然后在室温下搅拌20分钟。然后在室温下将NMM[0.1ml,0.79mmol,2当量]和烟酸[0.058g,0.47mmol,1.2当量]搅拌24小时。将冰冷的水缓慢加入反应物料中,过滤所形成的固体并用冷水洗涤,真空干燥,以得到((R)-2-((S)-(2,8-双(三氟甲基)喹啉-4-基)(羟基)甲基)哌啶-1-基)(吡啶-3-基)甲酮(产率:0.100g,67%)。m/z在484。
步骤2:33-((R)-2-((S)-(2,8-双(三氟甲基)喹啉-4-基)(羟基)甲基)哌啶-1-羰基)-1-甲基吡啶-1-碘化鎓的合成
向((R)-2-((S)-(2,8-双(三氟甲基)喹啉-4-基)(羟基)甲基)哌啶-1-基)(吡啶-3-基)甲酮[0.050g]的溶液中加入MeI[0.1ml]。在给定温度下将反应搅拌24小时。真空蒸发反应物料,加入1:1的乙醚:正戊烷并研磨,以得到棕色固体33-((R)-2-((S)-(2,8-双(三氟甲基)喹啉-4-基)(羟基)甲基)哌啶-1-羰基)-1-甲基吡啶-1-碘化鎓。该方法得到最终产物1011并且产量为0.035g,产率为70%。m/z在498。
实施例7:本发明化合物的溶解度特征的评价。
分别将1mg/ml和2mg/ml甲氟喹和他达拉非的溶液和相当重量的本发明的经葫芦巴碱修饰的化合物(1011)和化合物(1005)溶于miliQ水中,涡旋,离心3分钟,过滤并装载在HPLC柱上(Zorbax Eclipse C18;流动相:A:0.1%TFA,B:ACN;运行时间15分钟,Waters2996HPLC型)。测定各自的曲线下面积,并基于该面积确定溶解度的增加倍数。结果在下面的表2中给出。
表2:本发明化合物的溶解度特征
如上表2中所示,相对于母体药物,本发明的经修饰的化合物(1011)和化合物(1005)均显示出水溶性显著增加。
实施例8:紫杉醇经修饰的药物的溶解度:
对紫杉醇修饰的葫芦巴碱药物(1001)的水溶性进行评价。在不同的溶剂系统中检查溶解度。仅选择这样的溶剂,其中该溶剂被发现将经修饰的药物以所需浓度溶解并保持分子的稳定性。发现经修饰的药物在所选溶剂中是稳定的。
在生理盐水,5%DMA的生理盐水,9%NMP的生理盐水和5%DMSO的生理盐水评价经修饰的药物(1001)的溶解度。
将本发明中呈现的紫杉醇和化合物(1001)溶于上述不同的溶剂系统中,涡旋,离心3分钟,过滤并加载到HPLC柱(Zorbax Eclipse C18;Waters 2996HPLC型)上。测定各个曲线下的面积,并基于该面积确定溶解度的增加倍数。结果在下文表3中给出。
表3:紫杉醇和化合物1001的溶解度结果
·溶解度的增加倍数:
·在生理盐水中:>5000X
·在包含5%二甲基乙酰胺的生理盐水中:>10,000X
·在包含5%二甲基亚砜的生理盐水中:>12,000X
·在包含9%N-甲基吡咯烷酮的生理盐水中:>15,000X
从上表3中可以看出,本发明的化合物(1001)显示出增加的溶解度。
实施例9:紫杉醇修饰的药物(1001)与母体药物紫杉醇的比较PK特征
进行药代动力学研究以评价静脉内施用(IV)时SD大鼠中紫杉醇的经修饰的药物的血浆暴露量。将结果与使用相同剂量载体的紫杉醇的暴露量进行比较。在该研究中使用的给药载体是固定组成的PEG400和生理盐水。据发现本发明化合物(1001)是稳定的并可溶于给定溶剂中。
如在溶解度数据中所报道的,(1001)显示出更好的水溶性。这使得在经修饰的药物的情况下更容易IV给药。对经修饰的药物进行3mpk和1mpk IV给药,对紫杉醇母体药物进行3mpk IV。IV给药后,在肝素化管中,在不同时间点通过连续出血收集经修饰的药物血液。在4℃下,将血液样品以10,000rpm离心5分钟,以获得血浆,将血浆吸入单独的标记管中并在-80℃下储存。将萃取溶剂加入到血浆中,涡旋并在振荡器上振荡10分钟,在4℃下以10,000rpm离心10分钟。保留上清液用于分析。
创建乙腈和血浆校准曲线并确定从血浆中回收药物的百分比。通过液相色谱串联质谱仪(API3000LC-MS/MS)进行定量分析。使用Graph Pad PRISM 5.04版计算Cmax、Tmax、AUC和t1/2,结果如表4所示。
表4:本发明化合物的药代动力学特征(紫杉醇)
*3mpk 1001=2.1mpk递送的紫杉醇
*1mpk 1001=0.71mpk递送的紫杉醇
从表4中可以看出,本发明的经修饰的化合物(1001)的Cmax增加超过80倍,且AUC增加超过10倍。因此,与API化合物相比,本发明的化合物(1001)具有更高的药代动力学和溶解度。
实施例10:本发明化合物(1008)的药代动力学特征(多西他赛)
进行药代动力学研究以评价静脉内给药(IV)时SD大鼠中经多西他赛(1008)修饰的药物的血浆暴露量。将结果与使用相同剂量载体的多西他赛(10mpk)的暴露量进行比较。在该研究中使用的给药载体是固定组成的PEG400和生理盐水。据发现经多西他赛修饰的药物在给定溶剂中是稳定的且可溶的。
如表中所示,与母体药物相比,发现经多西他赛修饰的药物(1008)具有显著更高的暴露量。
如在溶解度数据中所报道的,经多西他赛的修饰的药物(1008)显示出更好的水溶性。对经修饰的药物(1008)进行3mpk IV给药,对多西他赛母体药物进行10mpk IV。IV给药后,在肝素化管中,在不同时间点通过连续出血收集经修饰的药物血液。在4℃下,将血液样品以10,000rpm离心5分钟,以获得血浆,将血浆吸入单独的标记管中并在-80℃下储存。将萃取溶剂加入到血浆中,涡旋并在振荡器上振荡10分钟,在4℃下以10,000rpm离心10分钟。保留上清液用于分析。
创建乙腈和血浆校准曲线并确定从血浆中回收药物的百分比。通过液相色谱串联质谱仪(API3000LC-MS/MS)进行定量分析。使用Graph Pad PRISM 5.04版计算Cmax、Tmax、AUC和t1/2,结果如表5所示。
表5:本发明化合物(1008)的药代动力学特征
从上表5中可以看出,与原始化合物相比,本发明的化合物(1008)具有增强的药代动力学。
Claims (8)
4.根据权利要求2所述的方法,其中步骤(i)中使用的所述碱选自由以下物质构成的组:N,N-二异丙基乙胺、三乙胺或吡啶、无机碱,并且步骤(i)中使用的所述溶剂选自由以下物质构成的组:二氯甲烷、四氢呋喃、乙腈以及乙酸乙酯。
5.根据权利要求2所述的方法,其中所述卤素为F、Cl或Br。
6.根据权利要求4所述的方法,其中所述无机碱为氢化钠、或钠的碳酸盐、或钾的碳酸盐。
7.根据权利要求2所述的方法,其中步骤(i)中使用的所述催化剂选自由以下物质构成的组:4-二甲基氨基吡啶、乙酸叔丁酯,并且步骤(i)中使用的所述脱水剂选自由以下物质构成的组:N,N'-二环己基碳二亚胺或1-乙基-3-(3-二甲氨基丙基)碳二亚胺。
8.根据权利要求3所述的方法,其中步骤(ii)中使用的所述催化剂选自甲磺酸银。
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US5411984A (en) | 1992-10-16 | 1995-05-02 | Virginia Tech Intellectual Properties, Inc. | Water soluble analogs and prodrugs of taxol |
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US8992977B2 (en) * | 2007-06-27 | 2015-03-31 | Samos Pharmaceuticals, Llc | Multi-day delivery of biologically active substances |
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US9119780B2 (en) * | 2013-10-30 | 2015-09-01 | Kimberly-Clark Worldwide, Inc. | Triggerable compositions for two-stage, controlled release of proactive chemistry |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1983003968A1 (en) * | 1982-05-18 | 1983-11-24 | University Of Florida | Brain-specific drug delivery |
Non-Patent Citations (3)
Title |
---|
Improved brain delivery of antiviral agents through the use of redox targeting;M.E. Brewster et al.;《Advanced Drug Delivery Reviews》;19941231;第14卷;第180页第1段-第181页左栏第1段,第181页右栏第2段-第182页左栏第1段,第181页方案II,第185页方案III,第187页方案IV,第191页方案VII,第193页方案VIII * |
Synthesis of trigonelline and nicotinamide linked prodrugs of 5-aminosalicylic acid(5-ASA) with analgesic and anti-inflammatory effects;H. H. M. Abdu-Allah et al.;《Bull. Pharm. Sci.》;20051231;第28卷;第238页方案1,第240页左栏最后1段-右栏第3段 * |
先导化合物结构优化策略(三)——通过化学修饰改善水溶性;栗增等.;《药学学报》;20141231;第49卷(第9期);第1238-1247页 * |
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