CN103958513B - 6-羟基嘌呤衍生物盐酸盐 - Google Patents
6-羟基嘌呤衍生物盐酸盐 Download PDFInfo
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- CN103958513B CN103958513B CN201280058152.6A CN201280058152A CN103958513B CN 103958513 B CN103958513 B CN 103958513B CN 201280058152 A CN201280058152 A CN 201280058152A CN 103958513 B CN103958513 B CN 103958513B
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Abstract
6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐,具有Btk选择性抑制活性、代谢稳定性优异,此外,还是针对游离碱基溶解性和吸收性优异、能结晶的化合物,因此所述化合物可作为与B细胞和/或肥大细胞相关的疾病的治疗剂。
Description
技术领域
本发明涉及6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮的盐酸盐(以下,有时简称为本发明化合物)其晶体和其药物组合物,所述盐酸具有Btk选择性抑制活性,可作为自身免疫疾病、癌症等的治疗剂,
背景技术
Bruton型酪氨酸激酶(以下,简称为Btk)属于作为非受体型酪氨酸激酶的Tec家族激酶,选择性表达在B细胞系和骨髓细胞系的细胞中。Btk担负着B细胞的信号传递的重要作用,是有助于B细胞的生存、分化、增殖和活化等的因子。经由B细胞抗原受体(B-cellantigenreceptor;BCR)的B细胞的信号在广泛范围内诱发生物学反应,在其信号传递异常的情况下,引发B细胞的异常活化和/或病原性的自身抗体的形成等。认为Btk担负着向经由该BCR的B细胞的信号传递通路的一部分的作用。因此,已知,由于人Btk基因的缺失,会诱发B细胞的异常分化,使得免疫球蛋白的产生显著降低,由此产生X连锁性无γ-球蛋白血症(XLA)的发病(参照非专利文献1)。作为该疾病的症状,可举出末梢血中的B细胞显著减少、和/或对细菌感染的感受性增加等。另外,还已知Btk涉及肥大细胞的活化和/或血小板的生理功能。因此,具有Btk抑制活性的化合物对与B细胞和/或肥大细胞相关的疾病,例如,变应性疾病、自身免疫疾病、炎性疾病、血栓栓塞性疾病、癌症等的治疗是有用的(参照非专利文献2)。
但是,作为本发明化合物的现有技术,已知有以下的化合物。
作为具有Btk抑制活性的化合物,已知有通式(A)表示的化合物
[化1]
(式中,La A表示CH2、O、NH或S,ArA表示取代或未取代的芳基、或者取代或未取代的杂芳基,YA表示选自烷基、杂烷基、环烷基、杂环烷基、芳基和杂芳基的任意取代基,ZA表示CO、OCO、NHCO、CS,R7-A和R8-A独立地表示H、未取代的C1-C4烷基、取代的C1-C4烷基、未取代的C1-C4杂烷基、取代的C1-C4杂烷基、未取代的C3-C6环烷基、取代的C3-C6环烷基、未取代的C2-C6杂环烷基、和取代的C2-C6杂环烷基,或者R7-A和R8-A一起形成键,R6-A表示H、取代或未取代的C1-C4烷基、取代或未取代的C1-C4杂烷基、C1-C6烷氧基烷基、C1-C8烷基氨基烷基、取代或未取代的C3-C6环烷基、取代或未取代的芳基(其中,各基团的定义是摘选的)。)(参照专利文献1、2和3)。
另一方面,作为具有6-羟基嘌呤骨架的化合物,例如已知有通式(B)表示的化合物
[化2]
(式中,Q1B和Q2B独立地选自CX1B、CX2B和氮,Q3B表示N或CH,X1B和X2B独立地选自氢、(C1-C6)烷基、氰基和卤素等的基团,R1B选自氢和(C1-C6)烷基的基团,yB表示0或1~3的整数,R2B和R3B独立地选自氢和(C1-C6)烷基,R4B选自烷基、杂环基、芳基和杂芳基等,R5B选自烷基、杂环基、和取代的杂环基(其中,各基团的定义是摘选的)。)(参照专利文献4)。
另外,已知有通式(C)表示的化合物
[化3]
(式中,XC选自氮和CR8C,R8C选自氢、卤素、和取代或未取代的烷基等,Q1C选自O、S等,ZC选自氧、硫、和NY5C,Y5C选自氢、和取代或未取代的烷基等,Q2C、Q3C和Q4C独立地选自氢、取代或未取代的烷基、和取代或未取代的芳基等,R2C选自氢和取代或未取代的烷基,nC表示0、1、2、3或4(其中,各基团的定义是摘选的)。)(参照专利文献5)。
进而,专利文献6中公开了作为式20的具有6-羟基嘌呤骨架的化合物(参照段落0028)。
本发明涉及6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮的盐酸盐,其具有Btk的选择性抑制作用、而且代谢稳定性优异、此外针对游离碱基溶解性和吸收性优异,但关于这样的特征,在任何现有技术中均没有记载或暗示。
现有技术文献
专利文献
专利文献1:特表2010-504324号公报
专利文献2:国际公开第2008/121742号小册子
专利文献3:国际公开第2010/009342号小册子
专利文献4:国际公开第2008/060301号小册子
专利文献5:国际公开第2007/142755号小册子
专利文献6:特表2003-509427号公报
非专利文献
非专利文献1:Nature,第361卷,第226-233页,1993年
非专利文献2:AnticancerAgentsinMedicinalChemistry,第7卷,第6号,第624-632页,2007年
发明内容
发明要解决的课题
本发明的课题在于,为了提供安全性优异、与B细胞和/或肥大细胞相关的疾病的治疗剂、开发具有Btk选择性抑制活性、并且代谢稳定性优异、此外针对游离碱基溶解性、吸收性优异的化合物的化合物。此外,期望的是,作为医药品原料药(原薬),稳定性优异、可以长期保存的能结晶的化合物。
【用于解决课题的手段】
本发明人为了前述解决课题,进行深入研究,结果发现,本发明化合物具有Btk选择性抑制活性、代谢稳定性优异,此外还针对游离碱基溶解性和吸收性优异、能结晶,从而完成本发明。
即,本发明涉及
[1]6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐、
[2]6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐的晶体、
[3]在粉末X射线衍射光谱中,前述[2]记载的晶体具有在如下2θ的峰:选自约8.11、8.43、11.57、12.73、13.85、14.20、14.67、14.91、15.94、16.64、18.06、19.74、20.42、21.05、22.57、23.21、23.85、和24.70度的至少2个以上的2θ、
[4]在粉末X射线衍射光谱中,前述[2]或[3]记载的晶体具有在如下2θ的峰:约8.11、8.43、14.20、14.67、14.91和23.21度2θ、
[5]在粉末X射线衍射光谱中,前述[2]至[4]中任一项中记载的晶体具有在如下2θ的峰:约8.11、8.43、11.57、12.73、13.85、14.20、14.67、14.91、15.94、16.64、18.06、19.74、20.42、21.05、22.57、23.21、23.85、和24.70度2θ、
[6]前述[2]至[5]中任一项中记载的晶体,其特征为图3中所示的粉末X射线衍射光谱图、
[7]前述[2]至[6]中任一项中记载的晶体在差示扫描量热法中,具有峰温度为约216℃的吸热峰、
[8]前述[2]至[7]中任一项中记载的晶体,其特征为图4中所示的差示扫描量热法图、
[9]药物组合物,含有6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐。
[10]前述[9]所述的药物组合物,其为Btk抑制剂。
[11]前述[10]所述的药物组合物,其为与Btk相关的疾病的预防和/或治疗剂。
[12]前述[11]所述的药物组合物,其中,与Btk相关的疾病为变应性疾病、自身免疫疾病、炎性疾病、血栓栓塞性疾病、骨相关疾病或癌症。
[13]前述[12]所述的药物组合物,其中,癌症为非霍奇金淋巴瘤。
发明效果
本发明化合物除了具有Btk选择性抑制活性、代谢稳定性优异以外,还是针对游离碱基溶解性、吸收性优异的化合物,因此可用作安全性优异、与非霍奇金淋巴瘤等B细胞和/或肥大细胞相关的疾病的治疗剂。
【附图简述】
图1表示6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮的晶体的粉末X射线衍射光谱图。(图1中,纵轴表示强度(计数)、横轴表示2θ(度)。)
图2表示6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮的晶体的差示扫描量热法(DSC)图。
图3表示6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐的晶体的粉末X射线衍射光谱图。(图3中,纵轴表示强度(计数)、横轴表示2θ(度)。)
图4表示6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐的晶体的差示扫描量热法(DSC)图。
具体实施方式
以下,详细地说明本发明。
本发明中,“具有Btk选择性抑制活性”是指对Btk以外的酪氨酸激酶,特别是对Lck、Fyn、LynA具有Btk选择性抑制活性。由该特性,可避免由抑制其他酪氨酸激酶而产生的不期望的副作用。
在本发明中、6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮(以下、简写为化合物A)意指以下的结构式所示的化合物
【化学式4】
式中,符号
【化学式5】
表示β构型。
[化合物A的酸加成盐的研究]
使用下述实施例8中制备的化合物A与多种酸性平衡物质(カウソタ-)、采用以下的方法,进行化合物A的酸加成盐的平衡物质筛选。将化合物A的摩尔用量与相同量的多种酸性平衡物质混合,得到无定形的粉末,向所述粉末中,作为步骤(1),添加甲基叔丁基醚(MTBE),之后,用微型スパ-テル(miroSpatel)研磨,作为步骤(2),在前述步骤(1)中晶体没有析出的情况下添加甲醇,自然干燥。采用这种筛选,得到晶体的情况下,在下述条件下测量物理性质数据。此外,针对之前的化合物A的晶体,在下述条件下得到物理性质数据,与通过前述筛选得到的晶体的物理性质数据进行比较。
[1]粉末X射线衍射光谱
<测量条件>
装置:BRUKERaxs制BRUKERD8DISCOVER,其具有GADDS、
靶:Cu、
过滤器:无、
电压:40kV、
电流:40mA、
暴露时间:3min。
[2]差示扫描量热法(DSC)
<测量条件>
装置:METTLERTOLEDO制DSC822e、
样品量:1~2mg、
样品池:铝平锅40μL、
氮气体流量:40mL/min、
升温速度:10℃/min(25~240℃)。
化合物A的晶体的粉末X射线衍射光谱显示在图1中,差示扫描量热法(DSC)图显示在图2。另外,粉末X射线衍射光谱中的衍射角2θ和相对强度在以下的表1中显示。
【表1】
另外,化合物A的晶体显示对应于约169℃的起始温度和约172℃的峰温度所示的融解的吸热峰,如图2中所显示。
如以下的表2中所显示、使用18种酸性平衡物质,进行前述筛选。
【表2】
酸性平衡物质 | 步骤(1) | 步骤(2) |
盐酸 | 无定形 | 油状 |
硫酸 | 无定形 | 油状 |
乙酸 | 无定形 | 晶体 |
柠檬酸 | 无定形 | 晶体 |
(+)-酒石酸 | 油状 | 晶体 |
磷酸 | 无定形 | 晶体 |
富马酸 | 无定形 | 晶体 |
乳酸 | 油状 | 晶体 |
琥珀酸 | 油状 | 晶体 |
甲磺酸 | 无定形 | 油状 |
对甲苯磺酸 | 无定形 | 油状 |
苯磺酸 | 无定形 | 油状 |
(-)-樟脑磺酸 | 无定形 | 油状 |
(+)-樟脑磺酸 | 无定形 | 油状 |
2-萘磺酸 | 油状 | 油状 |
1-羟基-2-苯甲酸(ナフト酸) | 油状 | 晶体 |
苯甲酸 | 油状 | 晶体 |
和烟酸 | 和烟酸的晶体 | 晶体 |
结果,明确的是,没有从步骤(1)析出任何晶体,步骤(2)中,采用10种酸性平衡物质(乙酸、柠檬酸、(+)-酒石酸、磷酸、富马酸、乳酸、琥珀酸、1-羟基-2-苯甲酸(ナフト酸)、苯甲酸、和烟酸)得到晶体物质,但是,这些晶体粉末X射线衍射光谱图全部与化合物A粉末X射线衍射光谱图一致,因此,没有形成盐。一方面,采用其余8种酸性平衡物质(盐酸、硫酸、甲磺酸、对甲苯磺酸、苯磺酸、(-)-樟脑磺酸、(+)-樟脑磺酸、2-萘磺酸),没有得到晶体性的粉末,没有析出化合物A的晶体,因此,认为形成盐。因此,针对这8种酸性平衡物质,进一步进行以下结晶研究。
[化合物A的盐的结晶研究]
采用硫酸、甲磺酸、苯磺酸、对甲苯磺酸作为酸性平衡物质,采用甲醇、2-丙醇、丙酮、甲苯、乙酸乙酯、乙腈、MTBE、正庚烷作为溶剂,使用自动结晶装置(Freeslate制CoreModule(X)),研究化合物A的盐的结晶。作为结晶方法,设定成浆法(50℃~室温自然放冷)、冷却法(50℃~10℃、-10℃/h)、沉淀法(50℃溶解、室温析出)、蒸发浓缩法(50℃溶解、室温蒸发)的4种条件,组合溶剂和结晶方法,针对各种盐,设定72种结晶条件。结果,采用任何一种盐,均没有得到晶体性的粉末。
一方面,采用盐酸作为酸性平衡物质,进行同样的结晶研究,当采用1,2-二甲氧基乙烷(DME)作为溶剂时,得到晶体性的粉末,所述条件下进行粉末X射线衍射测量,峰形状与化合物A的晶体峰形状不同,根据1H-NMR和元素分析结果,明确了,得到晶体性的粉末是化合物A的盐酸盐的晶体。另外,采用下述实施例9的方法,粉末X射线衍射光谱图一致,因此,明确了,得到化合物A的盐酸盐的晶体。实施例9中制备的化合物的晶体粉末X射线衍射光谱显示在图3中,差示扫描量热法(DSC)图显示在图4。另外,粉末X射线衍射光谱中的衍射角2θ和相对强度在以下的表3中显示。特别是,在8.11、8.43、14.20、14.67、14.91和23.21度的衍射角2θ显示特征峰。
【表3】
另外,实施例9中制备的化合物的晶体显示对应于约201℃的起始温度和约216℃的峰温度所示的融解的吸热峰,如图4中所显示。
[异构体]
另外,本发明中的光学异构体不仅包括100%纯的光学异构体,而且包括小于50%的其他光学异构体。
本发明中,只要没有特殊说明,如本领域技术人员所熟知的,符号
[化学式6]
表示键合至纸面的观察者眼前侧(即β构型),
[化学式7]
表示α构型、β构型或它们的任意比例的混合物。
本发明化合物也可以转变为溶剂合物。溶剂合物优选为低毒性且水溶性的。作为适当的溶剂合物,例如可举出水、醇类的溶剂(例如,乙醇等)的溶剂合物。
另外,本发明化合物的前药是指能够在生物体内通过酶和/或胃酸等发生反应,由此转变成本发明化合物的化合物。作为本发明化合物的前药,在本发明化合物具有氨基时,可举出该氨基被酰化、烷基化、磷酰化的化合物(例如,本发明化合物的氨基被二十烷酰化(エイコサノイル化)、丙氨酰化、戊基氨基羰基化、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲氧基羰基化、四氢呋喃基化、吡咯烷基甲基化、特戊酰氧基甲基化、乙酰氧基甲基化、叔丁基化的化合物等);等。这些化合物可以通过公知的方法制备。另外,本发明化合物的前药可以为水合物和非水合物的任一种。另外,本发明化合物的前药,也可以如“广川书店,1990年刊,“医药品的开发”,第7卷,“分子设计”,第163~198页”中所述的那样,在生理学条件下转变为本发明化合物。进而,本发明化合物也可以用同位素(例如,2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、35S、18F、36Cl、123I、125I等)等标记。
[毒性]
本发明化合物的毒性足够低,可作为药物有效成分安全使用。
[在药品中的用途]
本发明化合物由于具有选择性的Btk抑制作用,因此有效用作与Btk相关的疾病,即与B细胞和/或肥大细胞相关的疾病、例如,变应性疾病、自身免疫疾病、炎性疾病、血栓栓塞性疾病、骨相关疾病、癌症、移植物抗宿主病等的预防和/或治疗剂。另外,本发明化合物还具有选择性抑制B细胞活化的作用,因此有效用作B细胞活化抑制剂。
本发明中,作为变应性疾病,例如可举出过敏、过敏性反应、过敏性结膜炎、过敏性鼻炎、特应性皮炎。
本发明中,作为自身免疫疾病,例如可举出炎性肠病、关节炎、狼疮、风湿、干癣性关节炎、变形性关节炎、斯蒂尔病、青少年性关节炎(若年性关节炎)、I型糖尿病、重症肌无力症、桥本甲状腺炎、ord’s 氏甲状腺炎(オ-ド甲状腺炎)、巴塞多氏病、舍格林氏综合征、多发性硬化症、吉兰-巴雷综合征、急性流行性脑脊髓炎、艾迪生病、斜视性眼阵挛综合征(オプソクロ-ヌス-ミオクロ-ヌス症候群)、强直性脊椎炎、抗磷脂抗体综合征、再生不良性贫血、自身免疫性肝炎、腹腔病、肺出血肾综合征、特发性血小板减少性紫癜病、视神经炎、硬皮症、原发性胆汁性肝硬化、赖特尔病、高安动脉炎、颞动脉炎、温抗体型自身免疫性溶血性贫血、韦氏肉芽肿病、干癣、全身性脱毛症、Behcet氏病、慢性疲劳综合征、自律神经失调、子宫内膜疾病、间质性膀胱炎、肌强直、外阴部痛、系统性红斑狼疮。
本发明中,作为炎性疾病,例如可举出哮喘、阑尾炎、眼睑炎、细支气管炎、支气管炎、滑液包炎、宫颈炎、胆管炎、胆囊炎、大肠炎、结膜炎、膀胱炎、泪腺炎、皮炎、皮肌炎、脑炎、心内膜炎、子宫内膜炎、肠炎、上髁炎(上顆炎)、附睾炎(精巣上体炎)、肌膜炎、结缔组织炎、胃炎、胃肠炎、肝炎、汗腺脓肿、喉炎、乳腺炎、髓膜炎、脊髓炎、心肌炎、肌炎、肾炎、卵巢炎、睾丸炎、骨炎、胰腺炎、腮腺炎、心膜炎、腹膜炎、咽炎、胸膜炎、静脉炎、肺炎、直肠炎、前列腺炎、肾盂肾炎、鼻炎、耳咽管炎、鼻窦炎、口腔炎、滑膜炎、腱炎、扁桃体炎、葡萄膜炎、阴道炎、血管炎、外阴炎。
本发明中,作为血栓栓塞性疾病,例如可举出心肌梗塞、心绞痛、血管形成术后的再闭塞、血管形成术后的再狭窄、大动脉冠状动脉旁路术后的再闭塞、大动脉冠状动脉旁路术后的再狭窄、脑梗塞、一时性缺血(一過性虚血)、末梢血管阻塞、肺栓塞、深静脉血栓症。
在本发明中,作为骨相关疾病,可以举出,例如,骨质疏松症、牙周炎、癌的骨转移、变形性关节病、高钙血症、骨折、贝塞病等。
本发明中,作为癌症,包括非霍奇金淋巴瘤,其中优选B细胞性非霍奇金淋巴瘤,例如可举出伯基特淋巴瘤、AIDS相关性淋巴瘤、边缘区B细胞淋巴瘤(结边缘区B细胞淋巴瘤、结外边缘区B细胞淋巴瘤、脾边缘区B细胞淋巴瘤)、弥漫性大细胞型B细胞淋巴瘤、原发性渗出性淋巴瘤、淋巴瘤样肉芽肿病、滤泡性淋巴瘤、B细胞慢性淋巴性白血病、B细胞前淋巴性白血病、淋巴浆细胞性白血病/瓦尔登斯特伦巨球蛋白血症、浆细胞瘤、外套细胞淋巴瘤、纵膈大细胞型B细胞淋巴瘤、血管内大细胞型B细胞淋巴瘤、毛细胞白血病。另外,作为本发明中的癌症,作为非霍奇金淋巴瘤以外的癌症,包括胰腺内分泌肿瘤,多发性骨髓瘤。作为胰腺内分泌肿瘤,例如可举出胰岛素瘤、胃泌素瘤、胰高血糖素瘤、生长激素瘤、VIP产生肿瘤(VIPoma)、PP产生肿瘤(PPoma)、GRF产生肿瘤。
为了
1)本发明化合物的预防和/或治疗效果的补充和/或增强、
2)本发明化合物的动态吸收改善、给予量的降低、和/或
3)本发明化合物的副作用的减轻,
本发明化合物也可以与其他药物组合,作为联合药物给予。
本发明化合物与其他药物的联合药物可以以在1个制剂中配合两种成分的配伍剂的形式给予,也可以制成在各自的制剂中给予的形式。在以该各自的制剂给予的情况下,包括同时给予和间隔时间差来给予的情况。另外,间隔时间差的给予既可以先给予本发明化合物、后给予其他药物,也可以先给予其他药物、后给予本发明化合物。它们各自的给予方法可以相同或不同。
对由前述联合药物发挥预防和/或治疗效果的疾病没有特殊限定,只要是能够补充和/或增强本发明化合物的预防和/或治疗效果的疾病即可。
作为用于补充和/或增强本发明化合物对变应性疾病的预防和/或治疗效果的其他药物,例如可举出抗组胺药、白三烯拮抗药、抗过敏药、血栓烷A2受体拮抗剂、血栓烷合成酶抑制剂、甾体等。
作为用于补充和/或增强本发明化合物对自身免疫疾病的预防和/或治疗效果的其他药物,例如可举出免疫抑制剂、甾体、疾病修饰型抗风湿病药物、弹性硬蛋白酶抑制剂、大麻素-2受体刺激药、前列腺素、前列腺素合成酶抑制剂、磷酸二酯酶抑制剂、金属蛋白酶抑制剂、粘附分子抑制剂、抗TNF-α制剂、抗IL-1制剂、抗IL-6制剂等抗细胞因子蛋白制剂、细胞因子抑制剂、非甾体类抗炎药、抗CD20抗体等。
作为用于补充和/或增强本发明化合物对炎性疾病的预防和/或治疗效果的其他药物,例如可举出甾体、弹性硬蛋白酶抑制剂、大麻素-2受体刺激药、前列腺素、前列腺素合成酶抑制剂、磷酸二酯酶抑制剂、金属蛋白酶抑制剂、粘附分子抑制剂、抗白三烯药、抗胆碱药、血栓烷A2受体拮抗剂、血栓烷合成酶抑制剂、黄嘌呤衍生物、祛痰药、抗菌药、抗组胺药、抗细胞因子蛋白制剂、细胞因子抑制剂、弗司扣林制剂(フォルスコリン制剤)、介质游离抑制剂(メディェ-タ-遊離抑制薬)、非甾体类抗炎药等。
作为用于补充和/或增强本发明化合物对血栓栓塞性疾病的预防和/或治疗效果的其他药物,例如可举出溶栓药物、肝素、肝素类似物、低分子量肝素、华法林(ヮ-ファリン)、凝血酶抑制剂、因子Xa抑制剂、ADP受体拮抗剂、环氧合酶抑制剂等。
作为用于补充和/或增强本发明化合物针对骨相关疾病的预防和/或治疗効果的其他药物,可以举出,例如,二碳磷酸盐(酯)(ビスホスホネ-ト)制剂、前列腺素类、维生素D制剂、钙制剂、雌激素制剂、降钙素制剂、依普黄酮(ィプリフテボン)制剂、蛋白质同化类固醇药、维生素K制剂、组织蛋白酶K抑制剂、副甲状腺激素、生长因子、胱天蛋白酶-1抑制剂、PTHrP衍生物、金属蛋白酶抑制剂、ファルソネィドX受体激动剂、抗雄激素药、选择性雌激素受体调节剂(SERMs)、孕酮激动剂、钙受体拮抗剂(calcylitics)、锶制剂、α-降钙素基因相关肽制剂、骨形成蛋白制剂、抗RANKL抗体、抗TNF-α抗体、抗IL-6抗体等。
作为用于补充和/或增强本发明化合物对非霍奇金淋巴瘤的预防和/或治疗效果的其他药物,例如可举出烷基化剂、代谢拮抗剂、抗癌性抗生素、植物性质生物碱药、激素药、铂化合物、抗CD20抗体、其他抗癌剂等。
作为抗组胺药的例子,例如可举出盐酸氮卓斯汀(盐酸ァゼラスチン)、依巴斯汀、盐酸依匹斯汀、富马酸依美斯汀、金诺芬、奥沙米特、盐酸奥洛他定、dl-马来酸氯苯那敏、富马酸氯马斯汀、富马酸酮替芬、西咪替丁、茶苯海明、盐酸苯海拉明、盐酸赛庚啶、盐酸西替利嗪、地氯雷他定、特非那定、法莫替丁、盐酸非索非那定、贝他斯汀、苯磺酸贝他斯汀、咪唑斯汀、美喹他嗪、糠酸莫米松、雷尼替丁、盐酸雷尼替丁、氯雷他定、盐酸异丙嗪、盐酸高氯环嗪等。
作为白三烯拮抗药的例子,例如可举出普仑司特水合物、孟鲁司特钠、扎鲁司特、阿鲁司特、泊比司特、硫鲁司特、伊拉司特钠(イラルカストナトリゥム)、维鲁司特、利托司特、西那司特、吡咯司特、托鲁司特、多夸司特等。
作为抗过敏药的例子,例如可举出氨来呫诺、盐酸氮卓斯汀、伊拉帕泛、异丁司特、咪曲司特钠、依巴斯汀、盐酸依匹斯汀、富马酸依美斯汀、奥沙米特、盐酸奥扎格雷、盐酸奥洛他定、色甘酸、色甘酸钠、富马酸酮替芬、塞曲司特、盐酸西替利嗪、甲磺司特、他扎司特、特非那定、多米曲班钙水合物、曲尼司特、奈多罗米、非索非那定、盐酸非索非那定、吡嘧司特钾、美喹他嗪、雷马曲班、瑞吡司特、氯雷他定等。
作为血栓烷A2受体抑制剂的例子,例如可举出塞曲司特、多米曲班钙水合物、雷马曲班等。
作为血栓烷合成酶抑制剂的例子,例如可举出咪曲司特钠、盐酸奥扎格雷等。
作为甾体的例子,例如可举出安西奈德、氢化可的松琥珀酸钠、泼尼松龙琥珀酸钠、甲泼尼龙琥珀酸钠、环索奈德、二氟泼尼酯、丙酸倍他米松、地塞米松、地夫可特、曲安西龙、曲安奈德、氯氟舒松、棕榈酸地塞米松、氢化可的松、氟米松新戊酸酯、丁乙酸泼尼松龙、布地奈德、硫酸普拉睾酮、糠酸莫米松、醋酸氟轻松、氟轻松、氟氢缩松、氟尼缩松、泼尼松龙、丙酸阿氯米松、丙酸氯倍他索、丙酸地塞米松、丙酸地泼罗酮、丙酸氟替卡松、丙酸倍氯米松、倍他米松、甲泼尼龙、磺庚甲泼尼龙、甲泼尼龙琥珀酸钠、磷酸地塞米松钠、氢化可的松磷酸钠、泼尼松龙磷酸钠、戊酸二氟可龙、戊酸地塞米松、戊酸倍他米松、泼尼松龙醋酸戊酸酯、醋酸可的松、双醋二氟拉松、醋酸地塞米松、醋酸曲安西龙、醋酸帕拉米松、醋酸卤泼尼松、醋酸氟氢可的松、泼尼松龙醋酸酯、甲泼尼龙醋酸酯、丁酸氯倍他松、丁酸氢化可的松、丁酸丙酸氢化可的松、丁酸丙酸倍他米松等。
作为免疫抑制剂的例子,例如可举出硫唑嘌呤、子囊霉素、依维莫司、柳氮磺吡啶、环孢素、环磷酰胺、西罗莫司、他罗利姆、布西拉明、甲氨蝶呤、来氟米特等。
作为疾病修饰型抗风湿病药物的例子,例如可举出D-青霉胺、阿克他利、金诺芬、柳氮磺吡啶、羟氯喹、布西拉明、甲氨蝶呤、来氟米特、氯苯扎利二钠(ロベンザリットナトリゥム)、金硫葡糖、硫代苹果酸金钠(マレィン酸ォ-ロチォナトリゥム)等。
作为弹性硬蛋白酶抑制剂的例子,例如可举出ONO-5046、ONO-6818、MR-889、PBI-1101、EPI-HNE-4、R-665、ZD-0892、ZD-8321、GW-311616、DMP-777、L-659286、L-680833、L-683845、AE-3763等。
作为前列腺素类(以下,简称为PG),例如可举出PGE1制剂(例如:前列地尔α-环糊精包合物、前列地尔等)、PGI2制剂(例如:贝前列素钠等)、PG受体激动剂、PG受体拮抗剂等。作为PG受体,可举出PGE受体(EP1、EP2、EP3、EP4)、PGD受体(DP、CRTH2)、PGF受体(FP)、PGI2受体(IP)、TX受体(TP)等。
作为前列腺素合成酶抑制剂的例子,例如可举出柳氮磺吡啶、美沙拉嗪、奥沙拉秦、4-氨基水杨酸、JTE-522、金诺芬、卡洛芬、联苯吡胺、氟诺洛芬、氟比洛芬、吲哚美辛、酮洛芬、氯诺昔康、洛索洛芬、美洛昔康、奥沙普秦、帕沙米特、哌普生、吡罗昔康、肉桂酸吡罗昔康(ピロキシカムシンナメ-ト)、扎托洛芬、普拉洛芬等。
作为磷酸二酯酶抑制剂的例子,例如可举出咯利普兰、西洛司特、Bay19-8004、NIK-616、罗氟司特(BY-217)、西潘茶碱(BRL-61063)、atizoram(ァチゾラム)(CP-80633)、ONO-6126、SCH-351591、YM-976、V-11294A、PD-168787、D-4396、IC-485等。
作为粘附分子抑制剂的例子,例如可举出α4-整联蛋白拮抗剂等。
作为抗TNF-α制剂的例子,例如可举出抗TNF-α抗体、可溶性TNF-α受体、抗TNF-α受体抗体、可溶性TNF-α结合蛋白质,特别是可举出英夫利西单抗、依那西普等。
作为抗IL-1制剂的例子,可举出抗IL-1抗体、可溶性IL-1受体、抗IL-1Ra和/或IL-1受体抗体,特别是可举出阿那白滞素等。
作为抗IL-6制剂的例子,可举出抗IL-6抗体、可溶性IL-6受体、抗IL-6受体抗体,特别是可举出托珠单抗等。
作为细胞因子抑制剂的例子,例如可举出甲磺司特、T-614、SR-31747、sonatimod(ソナチモド)等。
作为抗胆碱药的例子,例如可举出苯海索、盐酸苯海索、比哌立登、盐酸比哌立登等。
作为黄嘌呤衍生物,例如可举出氨茶碱、茶碱、多索茶碱、西潘茶碱、二羟丙茶碱等。
作为祛痰药,可举出氨茴香精(アンモニア·ウイキョウ精)、碳酸氢钠、盐酸溴己新、羧甲司坦、盐酸氨溴索、盐酸甲基半胱氨酸、乙酰基半胱氨酸、L-盐酸乙基半胱氨酸、泰洛沙泊等。
作为抗菌药的例子,例如可举出头孢呋辛钠、美罗培南三水合物、硫酸奈替米星、硫酸西梭霉素、头孢布烯、PA-1806、IB-367、妥布霉素、PA-1420、多柔比星、硫酸阿司米星、盐酸头孢他美酯等。
作为介质(mediator)游离抑制剂(キディェ-タ-遊離抑制药)的例子,例如可举出曲尼司特、色甘酸钠、氨来呫诺、瑞吡司特、异丁司特、他扎司特、吡嘧司特钾等。
作为溶栓药物的例子,例如可举出阿替普酶、尿激酶、替来激酶、那沙普酶、那替普酶、t-PA、帕米普酶、孟替普酶、蛋白激酶、链激酶等。
作为肝素类似物的例子,例如可举出磺达肝素等。
作为低分子量肝素的例子,例如可举出达那肝素钠、依诺肝素(钠)、纳屈肝素钙、贝米肝素(钠)、瑞肝素(钠)、亭扎肝素(钠)等。
作为凝血酶抑制剂的例子,例如可举出阿加曲班、希美加群、美拉加群、达比加群、比伐卢定、来匹卢定、水蛭素、地西卢定等。
作为ADP受体拮抗剂的例子,例如可举出盐酸噻氯匹定、硫酸氯吡格雷等。
作为环氧合酶抑制剂的例子,例如可举出阿司匹林等。
作为二碳磷酸盐(酯)制剂,可以举出例如,阿仑膦酸钠水合物、伊班膦酸、英卡膦酸二钠、依替膦酸二钠、奥帕膦酸盐(酯)、氯屈膦酸钠水合物、唑来膦酸、替鲁膦酸二钠、奈立膦酸盐(酯)、帕米膦酸二钠、吡膦酸盐(酯)、米诺膦酸水合物、利塞膦酸钠水合物、YM175等。
作为维生素D制剂,可以举出,例如,阿法骨化醇、氟骨化三醇、骨化三醇、1α,25-二羟基胆骨化醇、二氢速甾醇、ST-630、KDR、ED-71、罗盖全、他卡西醇、马沙骨化醇等。
作为钙制剂,可以举出,例如,盐化钙、葡糖酸钙、甘油磷酸钙、乳酸钙、L-天冬氨酸钙、磷酸氢钙等。
作为雌激素制剂,可以举出,例如,雌二醇、苯甲酸雌二醇、雌二醇环比酸酯、雌二醇二丙酸酯、雌二醇庚酸酯、雌二醇六氢苯甲酸酯、雌二醇苯基丙酸酯、雌二醇十一酸酯、吉草酸雌二醇、雌酮、乙炔雌二醇、美雌醇等。
作为降钙素制剂,可以举出,例如,降钙素、鲑降钙素、鸡(ニヮトリ)降钙素、司骨化醇、降钙素、TJN-135等。
作为依普黄酮制剂,可以举出,例如,依普黄酮等。
作为蛋白质同化类固醇药,可以举出,例如,羟甲烯龙、司坦唑醇、癸酸诺龙(ナンドロロン)、苯基丙酸诺龙、环己基丙酸诺龙、乙酸美替诺龙、美雄诺龙、乙雌烯醇、卡芦睾酮等。
作为维生素K制剂,可以举出,例如,四烯甲萘醌、四烯甲萘醌。
作为组织蛋白酶K抑制剂,可以举出,例如,ONO-5334、AAE581、SB462795、奥当卡替等。
作为副甲状腺激素(PTH),可以举出,例如,乾燥甲状腺、左甲状腺素钠、碘塞罗宁钠、丙硫氧嘧啶、甲巯咪唑、乙酸特立帕肽等。
作为生长因子,可以举出,例如,成纤维细胞生长因子(FGF)、血管内皮生长因子(VEGF)、肝细胞生长因子(HGF)、胰岛素样生长因子(IGF)等。
作为胱天蛋白酶-1抑制剂,可以举出,例如,硝基氟吡洛芬、普那卡生等。
作为PTHrP衍生物,可以举出,例如,hPTHrP、RS-66271等。
作为类法尼醇X受体激动剂,可以举出,例如,SR-45023A等。
作为抗雄激素药,可以举出,例如,乙酸奥沙特龙等。
作为选择性雌激素受体调节剂(SERMs),可以举出,例如,TSE-424、WJ-713/MPA、酒石酸拉索昔芬、盐酸雷洛昔芬、柠檬酸他莫昔芬等。
作为孕酮激动剂,可以举出,例如,曲美孕酮等。
作为钙受体拮抗剂(calcylitics),可以举出,例如,NPS-423557等。
作为锶制剂,可以举出,雷奈酸锶等。
作为抗RANKL抗体,可以举出,例如,地舒单抗等。
作为骨形成蛋白制剂,可以举出,例如,YM484等。
作为烷化剂的例子,可以举出,例如,盐酸氮芥-N氧化物、环磷酰胺、异环磷酰胺、美法仑、噻替派、卡波醌、白消安、盐酸尼莫司汀、达卡巴嗪、雷莫司汀等。
作为代谢拮抗剂的例子,例如可举出甲氨蝶呤、巯嘌呤、6-巯嘌呤苷、氟尿嘧啶、替加氟、替加氟-尿嘧啶、卡莫氟、去氧氟尿苷、阿糖胞苷、依诺他滨、替加氟·吉美斯特·氧嗪酸钾、盐酸吉西他滨、阿糖胞苷(シタテビンオクホスファ-ト)、盐酸丙卡巴肼、羟基脲等。
作为抗癌性抗生素的例子,例如可举出放线菌素D、丝裂菌素C、盐酸柔红霉素、盐酸多柔比星、盐酸阿柔比星、新制癌菌素、盐酸吡柔比星、(盐酸)表柔比星、盐酸伊达比星、色霉素A3、(盐酸)博来霉素、硫酸培洛霉素、吡柔比星(テラルビシン)、净司他丁斯酯(ヅノスタチン·スチマラマ-)等。
作为植物性质制剂的例子,例如可举出硫酸长春碱、硫酸长春新碱、硫酸长春地辛、盐酸伊立替康、依托泊苷、氟他胺、酒石酸长春瑞滨、多西他赛水合物、紫杉醇等。
作为激素剂的例子,例如可举出雌莫司汀磷酸钠、美雄烷、环硫雄醇、醋酸戈舍瑞林、磷雌酚(二磷酸己烯雌酚)、枸橼酸他莫昔芬、枸橼酸托瑞米芬、盐酸法倔唑水合物、醋酸甲羟孕酮、比卡鲁胺、醋酸亮丙瑞林、阿那曲唑、依西美坦等。
作为铂化合物的例子,例如可举出卡铂、顺铂、奈达铂等。
作为抗CD20抗体的例子,例如可举出利妥昔单抗、替伊莫单抗、奥瑞珠单抗等。
作为其他抗癌剂的例子,例如可举出L-天冬酰胺酶、醋酸奥曲肽、卟菲尔钠、醋酸米托蒽醌等。
另外,作为与本发明化合物组合的联合药物,不仅包括迄今为止已经出现的药物,还包括今后将会出现的药物。
本发明化合物通常作为药物有效成分以口服或非口服的形式全身或局部给予。作为口服剂,例如可举出内服用液体制剂(例如,酏剂、糖浆剂、药剂学可接受的水剂、混悬剂、乳剂)、内服用固体制剂(例如,片剂(包括舌下片、口腔崩解片)、丸剂、胶囊剂(包括硬胶囊、软胶囊、明胶胶囊、微囊)、散剂、颗粒剂、糖锭剂)等。作为非口服剂,例如可举出液体制剂(例如,注射剂(皮下注射剂、静脉内注射剂、肌内注射剂、腹腔内注射剂、滴注剂等)、滴眼剂(例如,水性滴眼剂(水性滴眼液、水性混悬滴眼液、粘性滴眼液、可溶性滴眼液等)、非水性滴眼剂(非水性滴眼液、非水性混悬滴眼液等))等)、外用剂(例如,软膏(眼膏等))、滴耳剂等。这些制剂也可以是速释制剂、缓释制剂等释放控制剂。这些制剂可以通过公知方法例如日本药典中所述的方法等来制备。
作为口服剂的内服用液体制剂例如可通过将本发明化合物在通常使用的稀释剂(例如,纯化水、乙醇或它们的混合液等)中溶解、混悬或乳化来制备。进而,该液体制剂还可以含有湿润剂、助悬剂、乳化剂、甜味剂、风味剂、芳香剂、防腐剂(保存剤)、缓冲剂等。
作为口服剂的内服用固体制剂例如可通过将本发明化合物与赋形剂(例如,乳糖、甘露醇、葡萄糖、微晶纤维素、淀粉等)、粘合剂(例如,羟丙基纤维素、聚乙烯吡咯烷酮、偏硅酸铝酸镁等)、崩解剂(例如,纤维素葡糖酸钙等)、润滑剂(例如,硬脂酸镁等)、稳定剂、助溶剂(谷氨酸、抗坏血酸等)等混合,根据常规方法来制剂化。另外,根据需要还可以用包衣剂(例如,白糖、明胶、羟丙基纤维素、羟丙甲基纤维素酞酸酯等)包覆,并且可以用2个以上的层来包覆。
作为非口服剂的外用剂可以通过公知的方法或通常使用的配方来制备。例如,软膏剂可以通过将本发明化合物在基剂中研磨或熔融来制备。软膏基剂可以是公知的或者选自通常使用的基剂。例如,可以将选自高级脂肪酸或高级脂肪酸酯(例如,己二酸、肉豆蔻酸、棕榈酸、硬脂酸、油酸、己二酸酯、肉豆蔻酸酯、棕榈酸酯、硬脂酸酯、油酸酯等)、蜡类(例如,蜜蜡、鲸蜡、地蜡(セレシン)等)、表面活性剂(例如,聚氧乙烯烷基醚磷酸酯等)、高级醇(例如,鲸蜡醇、硬脂醇、十六十八醇等)、硅油(例如,二甲基聚硅氧烷等)、烃类(例如,亲水凡士林、白色凡士林、纯化羊毛脂、液体石蜡等)、二醇类(例如,乙二醇、二甘醇、丙二醇、聚乙二醇(木°リエチレングリコ-ル)、聚乙二醇(マクロゴ-ル)等)、植物油(例如,蓖麻油、橄榄油、芝麻油、松节油等)、动物油(例如,貂油、蛋黄油、角鲨烷、角鲨烯等)、水、吸收促进剂、和抗肿剂中的任一物质单独或2种以上混合使用。进而,还可以含有保湿剂、防腐剂、稳定剂、抗氧化剂、增香剂等。
作为非口服剂的注射剂包括溶解或混悬在溶液、混悬液、乳浊液和用时溶剂(用時溶剤)中使用的固态的注射剂。注射剂例如可以使用将本发明化合物在溶剂中溶解、混悬或乳化而成的注射剂。作为溶剂,例如可使用注射用蒸馏水、生理盐水、植物油、丙二醇、聚乙二醇、乙醇之类的醇类等及它们的组合。进而,该注射剂还可以含有稳定剂、助溶剂(例如,谷氨酸、抗坏血酸、聚山梨酯80(注册商标)等)、助悬剂、乳化剂、无痛化剂、缓冲剂、防腐剂等。它们可以在最终工序中通过灭菌或无菌操作法来制备。另外,还可以制备无菌的固体制剂,例如冻干品,可以在使用前将其溶解在无菌化或无菌的注射用蒸馏水或其他溶剂中来使用。
本发明化合物的给予量可以根据症状、年龄、剂型等来适宜选择,如果是口服剂,优选每日1次~数次(例如,1~3次)给予1~100mg,更优选5~30mg。此外,可以以每次50μg~500mg的范围、每日1次~数次非口服给予,或者以一日1小时至24小时的范围静脉内持续给予。
当然,如上所述,给予量可以根据各种条件而变化,因此,既存在以比前述给予量更少的量给予就足够的情况,也存在必须超出前述范围的情况。
[实施例]
以下,通过实施例详述本发明,但本发明并不限定于这些实施例。
通过色谱的分离的部分和TLC中表示的括号内的溶剂表示所使用的洗脱溶剂或展开溶剂,比例表示体积比。
NMR数据只要没有特殊说明,为1H-NMR的数据。
NMR的部分所示的括号内表示用于测定的溶剂。
本说明书中使用的化合物的名称,一般采用基于IUPAC法则进行命名的计算机程序——AdvancedChemistryDevelopment公司的ACD/Name(注册商标),或者根据IUPAC命名法来命名。
实施例1:N,N-二苄基-6-氯-5-硝基嘧啶-4-胺
在冰浴下,向4,6-二氯-5-硝基嘧啶(10g)的二氯甲烷(70mL)溶液中滴入在二氯甲烷(30mL)溶液中的二苄胺(10.2g),然后加入三乙胺(14.4mL),搅拌1小时。向反应混合物中加入水后,用饱和盐水洗涤有机层,用无水硫酸钠干燥,通过减压浓缩溶剂,得到具有下述物理性质值的标题化合物(19.2g)。
TLC:Rf0.50(己烷:乙酸乙酯=7:1)。
实施例2:(3R)-3-{[6-(二苄基氨基)-5-硝基嘧啶-4-基]氨基}氮杂环丁烷-1-甲酸叔丁酯
将实施例1制备的化合物(19g)和(3R)-3-氨基氮杂环丁烷-1-甲酸叔丁酯(10.5g)溶解在二噁烷(58mL)中,加入三乙胺(8.1mL)后,在50℃下搅拌5小时。将反应混合物恢复到室温后,蒸馏除去溶剂,加入水,用乙酸乙酯萃取。将有机层用饱和盐水洗涤后,用无水硫酸钠干燥,蒸馏除去溶剂。用硅胶柱色谱法纯化残渣,得到具有下述物理性质值的标题化合物(27.0g)。
TLC:Rf0.29(己烷:乙酸乙酯=4:1)。
实施例3:(3R)-3-{[5-氨基-6-(二苄基氨基)嘧啶-4-基]氨基}氮杂环丁烷-1-甲酸叔丁酯
在冰浴下,向锌(23.3g)和3.0M氯化铵水溶液(11.4g)的混合液中滴入在乙酸乙酯(360mL)溶液中的实施例2制备的化合物(17.5g),立即升温至室温。搅拌2小时后,用硅藻土(セラィト)(商品名)过滤反应混合物,蒸馏除去溶剂。用硅胶柱色谱法纯化残渣,得到具有下述物理性质值的标题化合物(12.4g)。
TLC:Rf0.69(己烷:乙酸乙酯=1:1)。
实施例4:(3R)-3-[6-(二苄基氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基]氮杂环丁烷-1-甲酸叔丁酯
将实施例3制备的化合物(8.4g)和1,1’-羰基二咪唑(5.9g)溶解在四氢呋喃(120mL)中后,在60℃下搅拌15小时。蒸馏除去反应混合物的溶剂后,加入水,用乙酸乙酯萃取。将有机层用饱和盐水洗涤后,用无水硫酸钠干燥,蒸馏除去溶剂。将残渣用硅胶柱色谱法纯化,得到具有下述物理性质值的标题化合物(7.8g)。
TLC:Rf0.28(己烷:乙酸乙酯=2:1)。
实施例5:(3R)-3-(6-氨基-8-氧代-7,8-二氢-9H-嘌呤-9-基)氮杂环丁烷-1-甲酸叔丁酯
将实施例4制备的化合物(7.8g)溶解在甲醇(240mL)和乙酸乙酯(50mL)中后,加入20%的Perlman(パ一ルマン)催化剂(Pd(OH)2/C)(8.0g、100wt%),用氢气置换,在60℃下搅拌7.5小时。用硅藻土(Celite,商品名)过滤反应混合物,通过蒸馏除去溶剂,得到具有下述物理性质值的标题化合物(5.0g)。
TLC:Rf0.50(乙酸乙酯)。
实施例6:(3R)-3-[6-氨基-8-氧代-7-(4-苯氧基苯基)-7,8-二氢-9H-嘌呤-9-基]氮杂环丁烷-1-甲酸叔丁酯
在室温下,向实施例5制备的化合物(2.5g)的二氯甲烷(200mL)混悬液中加入对苯氧基苯基硼酸(2.1g)和乙酸铜(II)(1.48g)、分子筛4A(2.5g)、吡啶(0.82mL),然后搅拌21小时。用硅藻土(商品名)过滤反应液,将残渣用硅胶柱色谱法纯化,得到具有下述物理性质值的标题化合物(1.3g)。
TLC:Rf0.18(己烷:乙酸乙酯=1:1)。
实施例7:(3R)-6-氨基-9-氮杂环丁烷-3-基-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮二盐酸盐
在室温下,向实施例6制备的化合物(1.3g,2.76mmol,1.0当量)的甲醇(13mL)混悬液中加入4N盐酸/二噁烷(13mL),搅拌1小时。通过蒸馏除去溶剂,得到具有下述物理性质值的标题化合物(1.5g)。
TLC:Rf0.50(二氯甲烷:甲醇:28%氨水=9:1:0.1)。
实施例8:6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮(化合物A)
[化8]
向实施例7制备的化合物(100mg)的二甲基甲酰胺(3mL)溶液中加入2-丁酸(34mg)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺·盐酸盐(EDC)(78mg)、1-羟基苯并三唑(HOBt)(62mg)、三乙胺(114μL),然后在室温下搅拌3小时。向反应混合物中加入水,用乙酸乙酯萃取。将有机层用饱和碳酸氢钠水溶液、饱和盐水洗涤后,用无水硫酸钠干燥,蒸馏除去溶剂。将残渣通过薄层色谱(二氯甲烷:甲醇:28%氨水=90:10:1)纯化,得到具有以下物理性质值的标题化合物(75mg)。
TLC:Rf0.68(乙酸乙酯:甲醇=9:1);
1H-NMR(CDCl3):δ1.94-2.03,2.23-2.39,2.80-3.01,3.50-3.63,3.67-3.80,3.86-4.02,4.03-4.18,4.23-4.33,4.42-4.51,5.11-5.25,7.04-7.23,7.34-7.45,8.20-8.23。
实施例9:6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐
【化9】
在300mL的3颈茄形烧瓶中,加入实施例8中制备的化合物(3.0g),添加乙酸乙酯(30mL)和1-丙醇(4.5mL),之后,使外温达到70℃(内温61℃)。确认实施例8中制备的化合物完全溶解后,加入10%盐酸/甲醇(3.5mL),确认晶体析出后,在外温70℃熟化30分钟,外温60℃熟化30分钟,外温50℃熟化60分钟,外温40℃熟化30分钟、在室温熟化30分钟、在冰浴下熟化30分钟,从而熟化晶体。过滤得到的晶体,用乙酸乙酯(6mL)洗涤后,在50℃减压干燥,得到具有下述物理性质值的标题化合物(2.76g),所述化合物为白色晶体。
TLC:Rf0.55(二氯甲烷:甲醇=9:1);
1H-NMR(CD3OD):δ1.97-2.07,2.38-2.52,2.63-2.80,3.51-3.63,3.77-3.94,4.00-4.19,4.27-4.35,5.26-5.38,7.08-7.23,7.38-7.52,8.44-8.47。
[药理实验例]
生物学实施例1:Btk抑制活性和对Btk选择性的测定(体外试验)
Btk酶抑制活性的测定使用含有以下试剂(Tyr-1肽、Thy-1磷肽、5×激酶缓冲剂、ATP、显色试剂B、显色缓冲剂、和反应终止试剂)的Z’-LYTETM激酶测量试剂盒-Tyr1肽(Invitrogen公司)和Btk(Invitrogen公司),基于所附的说明书实施。
将受试化合物在二甲亚砜(DMSO)中稀释的溶液、或DMSO分别以5μL/孔添加到96孔测量板中,并且将底物/酶混合溶液以10μL/孔添加到96孔测量板中,在30℃下反应20分钟。将底物/酶混合溶液用激酶缓冲剂(DL-二硫苏糖醇(DTT;2.7mM)、1.33×激酶缓冲剂)稀释至Tyr-1肽的终浓度为4μM、且BtK的终浓度为5nM而制成。接着,以5μL/孔添加三磷腺苷(ATP;终浓度36μM),在30℃下反应1小时。反应终止后,用显色缓冲剂将显色试剂B稀释至128倍而制成显色溶液,添加10μL的显色溶液,再在30℃下反应1小时。然后,添加10μL的反应终止液,使酶反应停止。使用荧光板读数器、融合通用酶标仪(FusionUniversalMicroplateAnalyzer)(PerkinElmer公司),测定各孔在445nm和520nm处的荧光强度。磷酸化的比例根据试剂盒所附的说明书,通过445nm(香豆素显色)处相对于520nm(荧光素显色)处的显色比例来确定。
受试化合物的抑制率(%)使用以下公式计算:
[数1]
磷酸化抑制率(%)=1-{(Ac-Ax)/(Ac-AB)}×100
AX:添加受试化合物时的磷酸化率
AB:未添加ATP时(空白)的磷酸化率
AC:只添加DMSO时(对照)的磷酸化率
由基于受试化合物的各浓度下的抑制率的抑制曲线,计算受试化合物的50%抑制率的值(IC50值)。
其他激酶(例如,Lck、Fyn、LynA(均为Invitrogen公司的)的抑制活性的测定使用各种激酶代替Btk,与前述方法同样操作。
结果,实施例9中制备的化合物的IC50值为0.0021μM。
另外,实施例9中制备的合物对其他激酶,特别是对Lck、Fyn、LynA的Btk选择性抑制活性之比基于各种激酶的IC50值而计算,如下表4所示。
[表4]
Lck[IC50]/Btk[IC50] | Fyn[IC50]/Btk[IC50] | LynA[IC50]/Btk[IC50] | |
实施例9 | 375 | 1057 | 1662 |
由该结果可知,本发明化合物不仅具有Btk抑制活性,而且对其他激酶具有Btk选择性抑制活性。
生物学实施例2:犬血中动态
使用禁食的雄性比格犬,评价化合物A和其盐(实施例9中制备的化合物)的血中动态特性。针对实施例8中制备的化合物A,进行静脉内给药、经口溶液给药和经口悬浮给药,针对实施例9中制备的化合物,进行经口胶囊给药。在静脉内给药和经口溶液给药的情况下,采用可溶化液,所述可溶化液通过将化合物A溶解在加热至60℃的wellsolve(株式会社セレステ)中得到。采用所述可溶化液,采用1mg/1mL/kg的用量,通过注射器,进行经由前肢桡侧皮静脉的快速静脉内给药,采用1mg/5mL/kg的用量,使用导管(カテ-テル),进行管饲法给药。针对静脉内给药,在给药前,给药2、5、15和30分钟后,给药1、2、4、6、8和24小时后,经由颈静脉每次采血约300μL,针对经口给药,在给药前,给药5、15和30分钟后,在给药1、2、4、6、8和24小时后,经由颈静脉每次采血约300μL。得到的血液在采用冰浴的情况下,使用12,000rpm离心3分钟,分离后,分取血浆。使用LC/MS/MS(UPLC/Xevo、Waters),测量血浆中的化合物A的浓度。根据得到的血浆中浓度,计算出曲线下面积(AUC、ng·h/mL)、最高血中浓度(Cmax、μg/mL)和清除率(CL、mL/hr/kg)。另外,根据经口给药AUC和静脉内给药AUC,计算出化合物A的生物学利用度(BA)。结果,使用可溶化液计算出的化合物A的BA是114.6%。
另外,在经口悬浮给药的情况下,微粉碎化合物A后,使用采用0.5%甲基纤维素水溶液悬浮制成的溶液,使用3和10mg/kg的用量,与前述同样地,进行管饲法给药。针对实施例9的化合物,将所述化合物与D-甘露醇以1:1的比混合,以达到3mg/kg的用量,装入4号胶囊(クォリカプス株式会社),采用3mg/1胶囊,将胶囊放置在喉深处,使得不被咬碎,使口关闭后,通过牙的间隙,使饮用50mL的注射用水,进行经口胶囊给药。各给药方法的血浆的采取时间和化合物A的血浆中浓度的测量,通过与采用前述可溶化液的化合物A的经口给药同样的方法进行。对于各给药方法和各浓度计算出BA,采用可溶化液的化合物A的BA作为100%,计算出相对的BA。其结果在以下的表5中显示。
【表5】
结果,随着给药量的增加,化合物A的微粉碎悬浮液的相对的BA降低。一方面,与相同用量的化合物A的微粉碎悬浮液相比,实施例9中制备的化合物的相对的BA更高。因此,证明了,本发明化合物与化合物A相比,吸收性提高了。
生物学实施例3:溶解度的测量
针对各个化合物A(采用JetMill粉碎机微粉碎化)与实施例9中制备的化合物,将0.5mg~2.5mg放入37℃的各溶剂(药典崩解试验第I液、药典溶出试验第II液、低浓度McIlvaine缓冲液(pH4.0、pH7.4)、精制水、人工肠液(FaSSIF、FeSSIF))2.5mL,在采用磁搅拌器以700转/分钟搅拌的同时,在试验开始30分后,和在24小时后,从试验悬浮液采样约1mL,通过孔径0.2μm的过滤器过滤后,在下述条件下,采用高效液相色谱法,测量化合物A的溶解度。下述表6中,显示化合物A与实施例9中制备的化合物的溶解度的比较。
<HPLC测量条件>
装置:Agilent制HPLC1100series、
柱:YMC-PackODS-AMAM-302(4.6mm内径×150mm长)、
柱温度:25℃、
流动相成分:20mM磷酸二氢钾水溶液(pH3.0)/乙腈(60:40、固定组成)、
UV:210nm
流速:1.0mL/分、
样品支架温度:25℃、
样品注入量:10μL、
测量时间:12分钟、
保持时间:8.9分。
【表6】
根据上文所述,证明了,本发明化合物与化合物A相比,在任何一种溶剂中,溶解性均更加优异。
生物学的实施例4:大鼠和人肝微粒体中的稳定性评价
(1)受试化合物溶液的制备
用50%乙腈水溶液(195μL)稀释受试化合物(10mmol/LDMSO溶液,5μL),制作0.25mmol/L的溶液。
(2)反应0分钟的样品制备
向预先温热到37℃的反应容器中添加含有0.5mg/mL大鼠和人肝微粒体(Xenotech公司)和NADPH-Co-factor(BDBiosciences公司)的0.1mol/L磷酸缓冲液(pH7.4)245μL,预孵育5分钟后,加入先前的受试化合物溶液(5μL),开始反应。在反应刚开始时即刻采集20μL,添加到含有内标物(华法林)的180μL乙腈中,停止反应。将该溶液20μL放置在带有除蛋白用过滤器的板上与50%乙腈水溶液180μL一起搅拌后,抽吸过滤,将滤液作为标准样品。
(3)反应15分钟的样品制备
将先前的反应溶液在37℃下孵育15分钟后,将20μL添加到冷的乙腈(含有内标物华法林)180μL中,终止反应。将该溶液20μL放置在带有除蛋白用过滤器的板上与50%乙腈水溶液180μL一起搅拌后,抽吸过滤,将滤液作为标准样品。
(4)评价方法和结果
残留率(%)通过向LC-MS/MS中注入1μL试样溶液,将反应样品的峰面积比(受试化合物的峰面积/内标物的峰面积)除以标准样品的峰面积比得到的值乘以100而计算。
[制剂例]
制剂例1
通过常规方法将以下各成分混合后压片,得到每片含有10mg活性成分的片剂1万片。
·6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐
…100g
·羧甲基纤维素钙(崩解剂)…20g
·硬脂酸镁(润滑剂)…10g
·微晶纤维素…870g
制剂例2
采用常规方法混合以下的各成分后,通过除尘过滤器过滤,充填入5ml的各个安瓿,通过高压釜加热灭菌,得到1万个安瓿,所述安瓿的1个安瓿中含有20mg的活性成分。
·6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐
…200g
·甘露醇…20g
·蒸馏水…50L
产业实用性
本发明化合物除了具有Btk选择性抑制活性以外,还是代谢稳定性优异、针对游离碱基溶解性和吸收性优异、能结晶的化合物,因此可用作非霍奇金淋巴瘤等的与B细胞和/或肥大细胞相关的疾病的治疗剂。
Claims (11)
1.6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐,其由下式表示
2.6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐的晶体,所述盐由下式表示所述晶体在粉末X射线衍射光谱中,在如下的2θ角具有峰:约8.11、8.43、14.20、14.67、14.91和23.21度。
3.权利要求2中记载的晶体,所述晶体在粉末X射线衍射光谱中,在如下的2θ角具有峰:约8.11、8.43、11.57、12.73、13.85、14.20、14.67、14.91、15.94、16.64、18.06、19.74、20.42、21.05、22.57、23.21、23.85、和24.70度。
4.权利要求2至3中任一项中记载的晶体,其特征为图3中所示的粉末X射线衍射光谱图。
5.权利要求2中记载的晶体,所述晶体在差示扫描量热法中,具有峰温度为216℃的吸热峰。
6.权利要求5中记载的晶体,其特征为图4中所示的差示扫描量热法图。
7.药物组合物,其含有6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮盐酸盐,所述盐由下式表示
8.权利要求7所述的药物组合物,其为Btk抑制剂。
9.权利要求8所述的药物组合物,其为与Btk相关的疾病的预防和/或治疗剂。
10.权利要求9所述的药物组合物,其中,与Btk相关的疾病为变应性疾病、自身免疫疾病、炎性疾病、血栓栓塞性疾病、骨相关疾病或癌症。
11.权利要求10所述的药物组合物,其中,癌症为非霍奇金淋巴瘤。
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