CN103958499A - 苯基吡咯衍生物 - Google Patents
苯基吡咯衍生物 Download PDFInfo
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- CN103958499A CN103958499A CN201280060132.2A CN201280060132A CN103958499A CN 103958499 A CN103958499 A CN 103958499A CN 201280060132 A CN201280060132 A CN 201280060132A CN 103958499 A CN103958499 A CN 103958499A
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- alkyl
- pharmaceutically acceptable
- acceptable salt
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Abstract
提供对于痴呆症、阿尔茨海默氏病、注意力缺陷/多动症、精神分裂症、癫痫、中枢性痉挛、肥胖、糖尿病、高脂血症、嗜睡症、特发性睡眠过度症、行为诱发性睡眠不足综合征、睡眠呼吸暂停综合征、昼夜节律障碍、深眠状态、睡眠相关运动障碍、失眠症、抑郁症、或过敏性鼻炎等疾病的预防或治疗是有用的新的化合物或其药物上可接受的盐。具体地,提供下式(I)所示的苯基吡咯衍生物或其药物上可接受的盐,式(I)[化1][式(I)中,Q表示下式(A)或(B)所示的基团。][化2]
Description
技术领域
本发明涉及新的苯基吡咯衍生物及其药物用途,特别地,涉及组胺H3受体关联疾病的预防或治疗药物。
背景技术
组胺在肥胖细胞、肺、肝、和胃粘膜等中普遍贮存于细胞内的颗粒,受到抗原结合到细胞表面的抗体上等的外部刺激而释放到细胞外。例如肥胖细胞被从外部进入的抗原刺激时,组胺从肥胖细胞释放,通过刺激存在于血管、平滑肌上的组胺H1(H1)受体而引起过敏反应。另外,从胃粘膜上的ECL细胞(enterochromaffin-like cell)释放的组胺刺激壁细胞上的组胺H2(H2)受体,促进胃酸分泌。基于这些事实,作为过敏性疾病治疗药物、或胃溃疡治疗药物,进行H1受体拮抗物质、或H2受体拮抗物质的开发,目前广泛用作药物。
进而,清楚地知道:组胺作为神经递质作用于在中枢神经和末梢神经中存在的组胺受体(组胺H3(H3)受体),发挥各种生理功能。该受体在1999年被克隆,其基因序列和氨基酸序列是清楚的,但与H1受体和H2受体的氨基酸序列同源性分别为22%、和21.4%,是低的(参照非专利文献1)。H3受体存在于突触前膜,其作为控制组胺的合成和游离的自受体而显示功能(参照非专利文献2)。另外,清楚地知道:H3受体控制组胺的释放,同时还控制乙酰胆碱、血清素、多巴胺、去甲肾上腺素这样的其它神经递质的释放(参照非专利文献3)。进而,暗示H3受体在激动剂的不在下具有活性,该活性可以被作为反向激动物质发挥作用的化合物所抑制。这些事实暗示了H3受体拮抗物质、或反向激动物质增大由H3受体控制的神经递质的释放,可成为释放异常相关的各种疾病的治疗药物。
实际上,使用了动物模型的实验结果显示H3受体拮抗物质、或反向激动物质可用作痴呆症、阿尔茨海默氏病(参照非专利文献4和5)、注意力缺陷/多动症(参照非专利文献6)、精神分裂症(参照非专利文献7)、癫痫、中枢性痉挛等的治疗药物的可能性。
另外,H3受体显示与摄食行为相关(参照非专利文献8),作为H3受体拮抗物质、或反向激动物质的适应疾病,还设想有肥胖、糖尿病、高脂血症等的代谢系统疾病。
另外,组胺显示有调节脑内的日周期节律,保持清醒和睡眠的平衡的作用(参照非专利文献9和10),作为H3受体拮抗物质、或反向激动物质的适应疾病,还设想有嗜睡症、特发性睡眠过度症、行为诱发性睡眠不足综合征、睡眠呼吸暂停综合征、昼夜节律障碍、深眠状态(睡眠時随伴症)、睡眠相关运动障碍、失眠症、抑郁症等伴随睡眠障碍的疾病。
进而,报道了H3受体显示存在于鼻粘膜的交感神经中,通过H3受体拮抗物质与H1受体拮抗物质的并用而可显著改善鼻塞(参照非专利文献11)。这表明H3受体拮抗物质、或反向激动物质以单独、或与H1受体拮抗物质并用的方式用于过敏性鼻炎等的治疗的可能性。
对于H3受体拮抗物质、或反向激动物质,在多篇综述中进行了汇总(参照非专利文献12~15)、可以参照它们。初期大量报道了以组胺自身作为先导化合物的咪唑系化合物,但表明有药物代谢酶细胞色素P450(CYP)的抑制作用等的担心,没有达到作为药物开发的阶段。
最近,大量报道了非咪唑系的H3受体拮抗物质或反向激动物质的文献和专利(参照专利文献1~10)。
另外,报道了具有吡唑环等5元芳香环的组胺H3受体拮抗物质(参照专利文献11~14)。进而,在具有芳基氧基哌啶骨架的组胺H3受体拮抗物质中,报道了具有未取代吡咯作为取代基的化合物(参照专利文献15)。但是,没有具有本发明公开的结构的化合物的报道。
【现有技术文献】
【专利文献】
【专利文献1】WO2005097751国际公开公报
【专利文献2】WO2005097778国际公开公报
【专利文献3】WO2005118547国际公开公报
【专利文献4】WO2006014136国际公开公报
【专利文献5】WO2006045416国际公开公报
【专利文献6】WO2006046131国际公开公报
【专利文献7】WO2006059778国际公开公报
【专利文献8】WO2006061193国际公开公报
【专利文献9】WO2006107661国际公开公报
【专利文献10】WO2006103057国际公开公报
【专利文献11】WO2006103045国际公开公报
【专利文献12】WO2007094962国际公开公报
【专利文献13】WO2008072724国际公开公报
【专利文献14】WO2009063953国际公开公报
【专利文献15】WO2002012190国际公开公报
【非专利文献】
【非专利文献1】Lovenberg T.W.等,Molecular pharmacology, 55, 1101-1107, 1999
【非专利文献2】Arrang J-M.等,Nature, 302, 832-837, 1983
【非专利文献3】Brown R.E. 等,Progress in Neurobiology, 63, 637-672, 2001
【非专利文献4】Huang Y-W.等,Behavioural Brain Research, 151, 287-293, 2004
【非专利文献5】Komater V.A.等,Behavioural Brain Research, 159, 295-300, 2005
【非专利文献6】Passani M.B.等,Neuroscience and Biobehavioral Reviews, 24, 107-113, 2000
【非专利文献7】Fox G.B.等,J. Pharmacol. Exp. Ther., 313, 176-190, 2005
【非专利文献8】Hancock A.A. 等,Curr. Opin. Investig. Drug, 4, 1190-1197
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【非专利文献10】Babier A.J.等,Br. J. Pharmacol., 143, 649-661, 2004
【非专利文献11】McLeod R.L.等,Am. J. Rhinol., 13, 391-399, 1999
【非专利文献12】Schwartz J.C.等,Trends in Pharmacol. Sci., 7, 24-28, 1986
【非专利文献13】Passani M.B.等,Trends in Pharmacol. Sci., 25, 618-625, 2004
【非专利文献14】Leurs R.等,Nature Drug Discovery, 4, 107-122, 2005
【非专利文献15】Leurs R.等,Drug Discovery Today, 10, 1613-1627, 2005。
发明内容
本发明的目的在于提供新的化合物或其药物上可接受的盐,其对于组胺对组胺H3受体的结合具有强的抑制作用,在起因于组胺H3受体的障碍、例如痴呆症、阿尔茨海默氏病、注意力缺陷/多动症、精神分裂症、癫痫、中枢性痉挛、肥胖、糖尿病、高脂血症、嗜睡症、特发性睡眠过度症、行为诱发性睡眠不足综合征、睡眠呼吸暂停综合征、昼夜节律障碍、深眠状态、睡眠相关运动障碍、失眠症、抑郁症、或过敏性鼻炎等疾病的预防或治疗中是有用的。
本发明人等为了上述目的而进行了努力研究,结果发现吡咯的3位被具有羰基的基团取代了的苯基吡咯衍生物对于组胺对组胺H3受体的结合具有强的抑制活性,从而完成了本发明。
以下详细地说明本发明。本发明的方案(以下将化合物的方案称为“本发明化合物”)如以下所示。
即,本发明是
(1)式(I)所示的化合物、或其药物上可接受的盐,
【化1】
[式(I)中,Q表示下式(A)或(B)所示的基团,
【化2】
R1表示羟基、C1~C6烷氧基或NR1AR1B,
R1A和R1B相同或不同,表示氢原子、C1~C6烷基或C3~C7环烷基,
或R1A和R1B可与相邻的氮原子一起相互键合而形成3~7元的饱和杂环(该饱和杂环可被1或2个C1~C6烷基取代。),
R2表示氢原子、卤素原子或C1~C6烷基,
n表示1或2,
R3表示氢原子、卤素原子或C1~C6烷基,
R4表示C1~C6烷基(该C1~C6烷基可被1或2个C3~C7环烷基取代)或C3~C7环烷基(该C3~C7环烷基可被1或2个C1~C6烷基取代),
R5和R6相同或不同,表示C1~C6烷基或C3~C7环烷基,
或R5和R6可与相邻的氮原子一起相互键合而形成3~7元饱和杂环(该饱和杂环可被1或2个C1~C6烷基取代)。];
(2)根据(1)所述的化合物、或其药物上可接受的盐,其中,Q为式(A)
【化3】
(式中,R4如(1)中那样定义);
(3)根据(1)或(2)所述的化合物、或其药物上可接受的盐,其中,R1为NR1AR1B(式中,R1A和R1B如(1)中那样定义);
(4)根据(1)~(3)中任一项所述的化合物、或其药物上可接受的盐,其中,R2和R3为氢原子;
(5)根据(1)~(4)中任一项所述的化合物、或其药物上可接受的盐,其中,R4为C3~C7环烷基;
(6)药物,其含有(1)~(5)中任一项所述的化合物、或其药物上可接受的盐作为有效成分;
(7)根据(6)所述的药物,其是组胺H3受体拮抗剂或反向激动剂;或
(8)根据(6)或(7)所述的药物,其是痴呆症、阿尔茨海默氏病、注意力缺陷/多动症、精神分裂症、癫痫、中枢性痉挛、肥胖、糖尿病、高脂血症、嗜睡症、特发性睡眠过度症、行为诱发性睡眠不足综合征、睡眠呼吸暂停综合征、昼夜节律障碍、深眠状态、睡眠相关运动障碍、失眠症、抑郁症、或过敏性鼻炎的预防剂或治疗剂。
本发明的化合物具有优异的组胺H3受体拮抗作用。
具体实施方式
本说明书中使用的用语如以下这样定义。
在本发明中,“卤素原子”表示氟原子、氯原子、溴原子或碘原子。
“C1~C6烷基”表示碳原子数为1~6个的直链状或支链状的烷基,例如表示甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基等的基团。
“C3~C7环烷基”表示环丙基、环丁基、环戊基、环己基或环庚基的基团。
“C1~C6烷氧基”表示碳原子数为1~6个的直链状或支链状的烷氧基,例如表示甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊基氧基、异戊基氧基、新戊基氧基或正己基氧基等基团。
“与相邻的氮原子一起相互键合而形成3~7元饱和杂环”中的“3~7元饱和杂环”表示含有上述氮原子,进而可含有选自O、N和S中的1个杂原子的、由3~7个成环原子构成的饱和的单环或螺环,可以列举例如1-吖丙啶基、1-氮杂环丁烷基、1-吡咯烷基、哌啶子基、1-氮杂环庚烷基、吗啉代或2-氧杂-6-氮杂螺[3,3]庚-6-基等的基团。
本发明化合物的优选方案示于以下。
本发明式(I)的化合物的优选方案之一是Q为式(A)。
【化4】
(式中,R4表示C1~C6烷基(该C1~C6烷基可被1或2个C3~C7环烷基取代)或C3~C7环烷基(该C3~C7环烷基可被1或2个C1~C6烷基取代))
式(A)中的R4优选为C3~C7环烷基,进而优选是环丁基。
本发明式(I)的化合物的优选的一个方案是R1为NR1AR1B(式中,R1A和R1B相同或不同,表示氢原子、C1~C6烷基或C3~C7环烷基,或R1A和R1B可与相邻的氮原子一起相互键合而形成3~7元饱和杂环(该饱和杂环可被1或2个C1~C6烷基取代))。
本发明式(I)的化合物的优选的一个方案是R2和R3为氢原子,n为1。
作为本发明的化合物的优选特征,可以列举药效优异、体内药动学性质优异(口服吸收性好/在特定的组织不具有蓄积性)、作为药物显示优异的物性、低毒性等。本发明优选的化合物作为控制药物的脑转移性的外流性转运蛋白、即P-糖蛋白质的底物的识别性低,因此可以期待具有优异的脑内转移性。
在本发明中,药物上可接受的盐包含例如与硫酸、盐酸、氢溴酸、磷酸、硝酸等无机酸的盐、与醋酸、草酸、琥珀酸、乳酸、酒石酸、富马酸、马来酸、柠檬酸、苯磺酸、甲磺酸、对甲苯磺酸、苯甲酸、樟脑磺酸、乙磺酸、葡庚糖酸、葡萄糖酸、谷氨酸、羟基乙酸、苹果酸、丙二酸、扁桃酸、粘酸、萘-2-磺酸等有机酸的盐、与锂离子、钠离子、钾离子、钙离子、镁离子、锌离子、铝离子等的1种或多种金属离子的盐、与氨、精氨酸、赖氨酸、哌嗪、胆碱、二乙胺、4-苯基环己基胺、2-氨基乙醇、苄星青霉素等胺的盐。
本发明的化合物也可作为各种溶剂化物存在。另外,从作为药物的适用性的方面来说,也有水合物的情况。
本发明的化合物包含对映异构体、非对映体、平衡化合物、它们的任意比例的混合物、外消旋体等所有的方式。各个异构体可以利用公知的方法、例如光学活性的起始物质或中间体的使用、中间体或最终产物的制造中的光学选择性反应或非对映选择性反应、或中间体或最终产物的制造中使用了层析的分离等来得到。
在本发明的化合物中,还包含一个以上的氢原子、碳原子、氮原子、氧原子、硫原子被放射性同位素、稳定同位素置换了的化合物。这些标记化合物例如在代谢或药动学研究中、作为受体的配体在生物学的分析等中是有用的。
本发明的化合物、或其药物上可接受的盐可以与一种或二种以上的药物上可接受的载体、赋形剂或稀释剂组合而形成药物制剂。作为上述载体、赋形剂和稀释剂,包含例如水、乳糖、右旋糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、淀粉、橡胶、明胶、海藻酸盐、硅酸钙、磷酸钙、纤维素、糖水、甲基纤维素、聚乙烯基吡咯烷酮、对羟基苯山梨酸烷基酯(アルキルパラヒドロキシベンゾソルベート)、滑石、硬脂酸镁、硬脂酸、甘油、芝麻油、橄榄油、大豆油等的各种油等。
另外,可根据需要在上述载体、赋形剂或稀释剂中混合一般使用的增量剂、粘合剂、崩解剂、pH调节剂、溶解剂等的添加剂,利用常用的制剂技术作为片剂、丸剂、胶囊剂、颗粒剂、粉剂、液剂、乳剂、悬浮剂、软膏剂、注射剂、皮肤贴剂等的口服或非口服用药物制备。对于成人患者,本发明的化合物能够以口服或非口服的方式将作为1次的给予量的0.001~500mg、1天1次或分为数次来给予。应予说明,该给予量可根据治疗对象的疾病的种类、患者的年龄、体重、症状等适当增减。
含有本发明的化合物、或其药物上可接受的盐作为有效成分的药物作为组胺H3受体拮抗剂或反向激动剂是有用的。
另外,含有本发明的化合物、或其药物上可接受的盐作为有效成分的药物作为痴呆症、阿尔茨海默氏病、注意力缺陷/多动症、精神分裂症、癫痫、中枢性痉挛、肥胖、糖尿病、高脂血症、嗜睡症、特发性睡眠过度症、行为诱发性睡眠不足综合征、睡眠呼吸暂停综合征、昼夜节律障碍、深眠状态、睡眠相关运动障碍、失眠症、抑郁症、或过敏性鼻炎的预防剂或治疗剂是有用的。
本发明的化合物可以利用公知的有机化学的方法来制造。采用了以下反应式的方法为本发明化合物的制造方法的列举,并不限于此。在下述反应式1~4中,R1、R2、R3、R4、R5、R6和n与上述同义。另外,X、Y1和Y2相同或不同,表示氯原子、溴原子、碘原子等的卤素原子或甲烷磺酰基氧基、苯磺酰基氧基、对甲苯磺酰基氧基、三氟甲烷磺酰基氧基等的有机磺酰基氧基等的离去基团。
以下对于反应式1所示的本发明化合物的制造方法进行说明。该制造步骤是用于由化合物(1)制造本发明的化合物(IA)的步骤。
(反应式1)
【化5】
(步骤1a)
步骤1a是用于利用偶联反应将化合物(1)和化合物(2)缩合而得到化合物(3)的步骤。化合物(1)和(2)是公知化合物、或是可由公知化合物容易地合成的化合物。
Y1为卤素原子或有机磺酰基氧基等的离去基团时,该偶联反应可以利用在碱的存在下或不存在下、在溶剂中或在无溶剂下进行苯酚的羟基的烷基化的一般方法来实施。另外,根据需要,可以例如添加碘化钾、溴化钠等的添加物。作为在本反应中使用的碱,可以列举例如吡啶、三乙胺、二异丙基乙胺等的有机碱类;叔丁醇钾、碳酸钾、碳酸铯、碳酸氢钠、氢氧化钠、氢氧化钾、氢化钠等的无机碱类。作为在本反应中使用的溶剂,可以列举例如甲醇、乙醇、异丙醇等的醇类;四氢呋喃、1,2-二甲氧基乙烷、1,4-二噁烷等的醚类;甲苯、苯等的烃类;氯仿、二氯甲烷等的卤代烃类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮等的酰胺类;丙酮、2-丁酮等的酮类;二甲基亚砜;乙腈;水或它们的混合溶剂。本反应的反应温度通常为0℃~200℃,优选为15℃~150℃,反应时间通常为1~48小时,优选为1~16小时。
Y1为氢氧基时,该偶联反应可以列举光延反应,例如可以列举在将三苯基膦、三丁基膦等的有机磷化合物和偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、偶氮二甲酸二叔丁酯等的偶氮化合物组合的试剂、或氰基甲基三丁基正膦等磷叶立德试剂的存在下、在溶剂中进行的方法。作为在本反应中使用的溶剂,可以列举例如四氢呋喃、1,2-二甲氧基乙烷、1,4-二噁烷等的醚类;甲苯、苯等的烃类;氯仿、二氯甲烷等的卤代烃类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮等的酰胺类;丙酮、2-丁酮等的酮类;二甲基亚砜;乙腈或它们的混合溶剂。本反应中的反应温度通常为0℃~150℃,优选为15℃~100℃,反应时间通常为1~48小时,优选为1~16小时。
(步骤2a)
步骤2a是用于利用交叉偶联反应将化合物(3)和化合物(4)缩合而得到本发明的化合物(IA)的步骤。化合物(4)是公知化合物、或可由公知化合物容易地合成的化合物。该交叉偶联反应可以利用在催化剂和其配体的存在下、在溶剂中进行反应的一般方法来实施,例如可以按照Kunz等,Synlett,2003年,15卷,2428-2439页中记载的方法或依照其的方法来实施。另外,本反应优选在碱的存在下进行。作为在本反应中使用的催化剂,可以列举铜、镍或钯等的一般在交叉偶联反应中使用的过渡金属催化剂,更具体地,可以列举铜(0)、碘化铜(I)、氯化铜(I)、氧化铜(I)、溴化铜(I)三(三苯基膦)配位化合物、三氟甲磺酸铜(I)苯配位化合物、硫酸铜(II)、醋酸钯(II)、四(三苯基膦)钯(0)、双(三苯基膦)氯化钯(II)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)、三(二亚苄基丙酮)二钯(0)、双(乙酰基乙酰丙酮)合镍(II)等。作为在本反应中使用的配体,可以列举一般在使用金属催化剂的缩合反应中使用的配体,可以列举例如N,N’-二甲基乙二胺、N,N’-二甲基环己烷-1,2-二胺、2-氨基吡啶、1,10-菲咯啉、3,4,7,8-四甲基-1,10-菲咯啉、2-羟基苯甲醛肟、乙二醇、三苯基膦、三叔丁基膦等。作为在本反应中使用的碱,可以列举例如碳酸钾、磷酸钾、氢氧化钾、叔丁醇钾、叔丁醇钠、碳酸铯、碳酸钠、碳酸氢钠、醋酸钠、甲醇钠、四丁基氢氧化铵等。作为在本反应中使用的溶剂,可以列举例如甲醇、乙醇、异丙醇等的醇类;四氢呋喃、1,2-二甲氧基乙烷、1,4-二噁烷等的醚类;甲苯、苯等的烃类;氯仿、二氯甲烷等的卤代烃类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮等的酰胺类;丙酮、2-丁酮等的酮类;二甲基亚砜;乙腈;水或它们的混合溶剂。本反应中的反应温度通常为0℃~200℃,优选为40℃~150℃,反应时间通常为1~48小时,优选为1~16小时。
另外,化合物(IA)也可以根据反应式2所示的方法来制造。
(反应式2)
【化6】
(步骤3a)
步骤3a是用于利用水解将本发明的化合物(IA)中R1=甲氧基的化合物(5)的甲氧基羰基转换为羧酸,而得到R1=羟基的本发明化合物(6)的步骤。该水解反应可以利用一般的酯的水解反应来实施,例如可以根据在强酸存在下、在溶剂中或无溶剂下进行反应的方法、在碱存在下、在溶剂中进行反应的方法等、在T.W.Greene and P.G.M.Wuts著 Protective Groups in Organic Synthesis、第4版、John Wiley and Sons公司中记载的方法或依照其的方法来实施。本反应中的反应温度通常为0℃~120℃,优选为15℃~80℃,反应时间通常为1~48小时,优选为1~12小时。
(步骤4a)
步骤4a是用于利用偶联反应将化合物(6)和胺衍生物(7)缩合而得到本发明的化合物(IA)的步骤。胺衍生物(7)是公知化合物,或是可由公知化合物容易地合成的化合物。该偶联反应可以利用一般的羧酸的酰胺化的方法来实施,可以列举例如将羧酸引入酰氯(カルボン酸クロリド)、酰溴等的酰卤化物后使其与胺反应的方法、使由羧酸和氯碳酸酯等得到的混合酸酐与胺反应的方法、将羧酸引入1-苯并三唑基酯、琥珀酰亚胺酯等的活性酯后使其与胺反应的方法、使羧酸在脱水缩合剂存在下与胺反应的方法等。这些反应全部可以在碱的存在下或不存在下、在溶剂中进行。作为在本反应中使用的脱水缩合剂,可以列举例如3-(3-二甲基氨基丙基)-1-乙基碳化二亚胺盐酸盐、二环己基碳化二亚胺、二苯基磷酰叠氮化物、羰基二咪唑等,根据需要可以使用1-羟基苯并三唑、羟基琥珀酰亚胺等的活化剂。作为在本反应中使用的碱,可以列举例如吡啶、三乙胺、二异丙基乙胺、碳酸钾、碳酸钠、碳酸氢钠等。作为在本反应中使用的溶剂,可以列举例如四氢呋喃、1,4-二噁烷等的醚类;甲苯、苯等的烃类;氯仿、二氯甲烷等的卤代烃类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮等的酰胺类;丙酮、2-丁酮等的酮类;二甲基亚砜;乙腈;水或它们的混合溶剂,其中,优选是甲苯、四氢呋喃或N,N-二甲基甲酰胺。本反应中的反应温度通常为0℃~120℃,优选为15℃~40℃,反应时间通常为1~48小时,优选为1~12小时。
以下对于反应式3所示的本发明化合物的制造方法进行说明。该制造步骤是用于由化合物(1)制造本发明的化合物(IB)的步骤。
(反应式3)
【化7】
(步骤1b)
步骤1b是用于利用化合物(1)与化合物(8)的偶联反应而得到化合物(9)的步骤。化合物(8)是公知化合物,或是可由公知化合物容易地合成的化合物。该偶联反应可以利用与步骤1a同样的方法来实施。
(步骤2b)
步骤2b是用于利用交叉偶联反应将化合物(9)和化合物(4)缩合而得到本发明的化合物(IB)的步骤。该偶联反应可以利用与步骤2a同样的方法实施。
另外,化合物(IB)也可以根据反应式4所示的方法来制造。
(反应式4)
【化8】
(步骤3b)
步骤3b是用于利用水解将本发明的化合物(IB)中R1=甲氧基的化合物(9)的甲氧基羰基转换为羧酸,而得到R1=羟基的本发明的化合物(10)的步骤。该水解反应可以利用与步骤3a同样的方法来实施。
(步骤4b)
步骤4b是用于利用偶联反应将化合物(10)和胺衍生物(7)缩合而得到本发明的化合物(IB)的步骤。该偶联反应可以利用与步骤4a同样的方法实施。
实施例
以下示出实施例和试验例,具体地说明本发明,但本发明不限于这些例子。
实施例中记载的各仪器数据用以下的测定仪器测定。
MS光谱:micromass Platform LC或micromass GCT
NMR光谱:[1H-NMR]600MHz:JNM-ECA600(日本电子)。
(实施例1)
1-{4-[(1-环丁基哌啶-4-基)氧基]苯基}-1H-吡咯-3-甲酸甲酯(化合物编号1)的制造
【化9】
将1-环丁基-4-(4-碘代苯氧基)哌啶(3g,可以按照WO2008072703中记载的方法合成)、1H-吡咯-3-甲酸甲酯(1.75g)、N,N’-二甲基乙二胺(0.592g)、碘化铜(0.32g)和碳酸铯(2.32g)的甲苯(8.4mL)悬浮液在110℃搅拌4小时。将反应混合物放冷至室温,加入氯仿,用セライト(注册商标)过滤。将滤液在减压下浓缩,将所得的残渣利用硅胶柱层析法(NH型硅胶,洗脱溶剂:正己烷/乙酸乙酯=88/12~0/100)纯化,得到无色固体的标题化合物(1.42g)。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.61 - 1.74 (m, 2 H) 1.78 - 1.92 (m, 4 H) 1.95 - 2.08 (m, 4 H) 2.10 - 2.27 (m, 2 H) 2.62 (br. s., 2 H) 2.73 (t, J=8.05 Hz, 1 H) 3.82 (s, 3 H) 4.32 (br. s., 1 H) 6.71 (dd, J=2.89, 1.65 Hz, 1 H) 6.88 - 6.92 (m, 1 H) 6.93 - 6.99 (m, 2 H) 7.26 - 7.31 (m, 2 H) 7.58 (t, J=1.86 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 355。
(实施例2)
1-{4-[(1-环丁基哌啶-4-基)氧基]苯基}-1H-吡咯-3-甲酸(化合物编号2)的制造
【化10】
在实施例1合成的1-{4-[(1-环丁基哌啶-4-基)氧基]苯基}-1H-吡咯-3-甲酸甲酯(1.4g)的乙醇(8mL)溶液中加入6N 氢氧化钠水溶液(1.32mL),在60℃搅拌4小时。将反应混合物放冷至室温,加入水,用氯仿萃取。将水层用盐酸中和,用氯仿萃取。将有机层合并,用硫酸镁干燥,在减压下浓缩,得到无色非晶质的标题化合物(1.22g)。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.52 - 3.32 (m, 15 H) 4.13 - 4.87 (m, 1 H) 6.76 (dd, J=2.89, 1.65 Hz, 1 H) 6.86 - 7.03 (m, 3 H) 7.31 (d, J=8.67 Hz, 2 H) 7.58 - 7.68 (m, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 341。
(实施例3)
杂氮环丁烷-1-基(1-{4-[(1-环丁基哌啶-4-基)氧基]苯基}-1H-吡咯-3-基)甲酮(化合物编号3)的制造
【化11】
将实施例2合成的1-{4-[(1-环丁基哌啶-4-基)氧基]苯基}-1H-吡咯-3-甲酸(0.1g)、1-{3-(二甲基氨基)丙基}-3-乙基碳化二亚胺盐酸盐(0.085g)、1-羟基苯并三唑水合物(0.067g)和氮丙环(0.034g)加入到N,N-二甲基甲酰胺(0.1ml)中,形成悬浮液,在室温下搅拌16小时。在反应混合物中加入水,用氯仿萃取。将有机层在减压下浓缩,将所得的残渣利用硅胶柱层析法(NH型硅胶,洗脱溶剂:正己烷/乙酸乙酯=88/12~0/100)纯化,得到无色固体的标题化合物(0.056g)。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.60 - 1.73 (m, 2 H) 1.76 - 1.93 (m, 4 H) 1.95 - 2.08 (m, 4 H) 2.10 - 2.22 (m, 2 H) 2.34 (t, J=7.64 Hz, 2 H) 2.54 - 2.68 (m, 2 H) 2.70 - 2.82 (m, 1 H) 4.11 - 4.23 (m, 2 H) 4.28 - 4.35 (m, 1 H) 4.37 - 4.55 (m, 2 H) 6.53 (dd, J=2.89, 1.65 Hz, 1 H) 6.83 - 7.00 (m, 3 H) 7.25 - 7.33 (m, 2 H) 7.44 (t, J=1.86 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 380。
利用与实施例3所示的方法同样的方法制造下表1-1和1-2所示的化合物(化合物编号4~13)。
【化12】
【表1-1】
(实施例4)
1-{4-[(1-环丁基哌啶-4-基)氧基]苯基}-2,5-二甲基-1H-吡咯-3-甲酸甲酯(化合物编号14)的制造
【化13】
利用与实施例1同样的方法,使用2,5-二甲基-1H-吡咯-3-甲酸甲酯代替1H-吡咯-3-甲酸甲酯而得到无色非晶质的标题化合物。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.60 - 1.73 (m, 2 H) 1.77 - 1.90 (m, 4 H) 1.93 (s, 3 H) 1.97 - 2.07 (m, 4 H) 2.08 - 2.20 (m, 2 H) 2.25 (s, 3 H) 2.53 - 2.78 (m, 3 H) 3.77 (s, 3 H) 4.33 (br. s., 1 H) 6.30 (d, J=1.24 Hz, 1 H) 6.88 - 6.96 (m, 2 H) 7.00 - 7.08 (m, 2 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 383。
(实施例5)
(1-{4-[(1-环丁基哌啶-4-基)氧基]苯基}-2,5-二甲基-1H-吡咯-3-基)(吡咯烷-1-基)甲酮(化合物编号15)的制造
【化14】
将实施例4合成的1-{4-[(1-环丁基哌啶-4-基)氧基]苯基}-2,5-二甲基-1H-吡咯-3-甲酸甲酯(0.06g)和吡咯烷(0.112g)的混合物在密封管中、100℃下搅拌16小时。将反应混合物放冷至室温,在减压下浓缩,将残渣利用硅胶柱层析法(NH型制备硅胶板、0.5mm厚、洗脱溶剂:正己烷/乙酸乙酯=50/50)纯化,得到无色固体的标题化合物。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.59 - 1.93 (m, 12 H) 1.95 (s, 3 H) 1.98 - 2.09 (m, 4 H) 2.17 (s, 3 H) 2.64 (br. s., 2 H) 2.74 (t, J=8.05 Hz, 1 H) 3.62 (d, J=9.91 Hz, 4 H) 4.34 (br. s., 1 H) 6.06 (s, 1 H) 6.88 - 6.98 (m, 2 H) 7.02 - 7.11 (m, 2 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 422。
(实施例6)
[1-(4-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}苯基)-1H-吡咯-3-基](吡咯烷-1-基)甲酮(化合物编号16)的制造
【化15】
利用与实施例1同样的方法,分别使用(2R)-1-[3-(4-碘代苯氧基)丙基]-2-甲基吡咯烷(可按照WO2009063953中记载的方法来合成)代替1-环丁基-4-(4-碘代苯氧基)哌啶,使用3-(吡咯烷-1-基羰基)-1H-吡咯代替1H-吡咯-3-甲酸甲酯来得到无色非晶质的标题化合物。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.08 (d, J=5.78 Hz, 3 H) 1.35 - 1.48 (m, 1 H) 1.63 - 1.83 (m, 2 H) 1.85 - 2.04 (m, 3 H) 2.11 (d, J=9.08 Hz, 1 H) 2.16 - 2.23 (m, 1 H) 2.25 - 2.33 (m, 1 H) 2.92 - 2.99 (m, 1 H) 3.17 (d, J=2.48 Hz, 1 H) 3.65 (br. s., 4 H) 3.73 (br. s., 4 H) 3.96 - 4.15 (m, 2 H) 6.63 (dd, J=3.10, 1.86 Hz, 1 H) 6.89 - 6.97 (m, 3 H) 7.27 - 7.32 (m, 2 H) 7.45 - 7.49 (m, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 382。
(实施例7)
(1-{4-[(1-异丙基哌啶-4-基)氧基]苯基}-1H-吡咯-3-基)(吡咯烷-1-基)甲酮(化合物编号17)的制造
【化16】
利用与实施例1同样的方法,使用(1H-吡咯-3-基)(吡咯烷-1-基)甲酮代替1H-吡咯-3-甲酸甲酯,使用4-(4-碘代苯氧基)-1-异丙基哌啶(可以按照WO2004089373中记载的方法合成)代替1-环丁基-4-(4-碘代苯氧基)哌啶来得到无色非晶质的标题化合物。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.05 (d, J=6.61 Hz, 6 H) 1.74 - 2.07 (m, 8 H) 2.39 (br. s., 2 H) 2.66 - 2.84 (m, 3 H) 3.60 - 3.81 (m, 4 H) 4.24 - 4.34 (m, 1 H) 6.63 (dd, J=3.10, 1.86 Hz, 1 H) 6.87 - 7.00 (m, 3 H) 7.22 - 7.32 (m, 2 H) 7.47 (t, J=2.06 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 382。
(实施例8)
1-{4-[(1-异丙基哌啶-4-基)氧基]苯基}-N-甲基-1H-吡咯-3-甲酰胺(化合物编号18)的制造
【化17】
利用与实施例1同样的方法,使用N-甲基-1H-吡咯-3-甲酰胺代替1H-吡咯-3-甲酸甲酯,使用4-(4-碘代苯氧基)-1-异丙基哌啶代替1-环丁基-4-(4-碘代苯氧基)哌啶来得到无色结晶的标题化合物。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.06 (d, J=6.61 Hz, 6 H) 1.82 (d, J=9.08 Hz, 2 H) 1.95 - 2.09 (m, 2 H) 2.39 (br. s., 2 H) 2.79 (br. s., 3 H) 2.96 (d, J=4.95 Hz, 3 H) 4.19 - 4.39 (m, 1 H) 5.59 - 5.86 (m, 1 H) 6.45 (dd, J=2.89, 1.65 Hz, 1 H) 6.84 - 6.99 (m, 2 H) 7.17 - 7.32 (m, 2 H) 7.52 (t, J=2.06 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 342。
(实施例9)
(1-{4-[(1-叔丁基哌啶-4-基)氧基]苯基}-1H-吡咯-3-基)(吡咯烷-1-基)甲酮(化合物编号19)的制造
【化18】
利用与实施例1同样的方法,使用(1H-吡咯-3-基)(吡咯烷-1-基)甲酮代替1H-吡咯-3-甲酸甲酯,使用1-叔丁基-4-(4-碘代苯氧基)哌啶(可以按照WO2008072724中记载的方法来合成)代替1-环丁基-4-(4-碘代苯氧基)哌啶来得到无色结晶的标题化合物。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.09 (s, 9 H) 1.81 (dd, J=8.46, 3.92 Hz, 2 H) 1.86 - 2.06 (m, 6 H) 2.41 (br. s., 2 H) 2.87 (br. s., 2 H) 3.56 - 3.80 (m, 4 H) 4.22 - 4.32 (m, 1 H) 6.63 (dd, J=3.10, 1.86 Hz, 1 H) 6.85 - 6.99 (m, 3 H) 7.23 - 7.31 (m, 2 H) 7.41 - 7.50 (m, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 396。
(实施例10)
1-{4-[(1-叔丁基哌啶-4-基)氧基]苯基}-N-甲基-1H-吡咯-3-甲酰胺(化合物编号20)的制造
【化19】
利用与实施例1同样的方法,使用N-甲基-1H-吡咯-3-甲酰胺代替1H-吡咯-3-甲酸甲酯,使用1-叔丁基-4-(4-碘代苯氧基)哌啶代替1-环丁基-4-(4-碘代苯氧基)哌啶来得到无色结晶的标题化合物。
1H NMR (600 MHz, 氯仿-d) δ ppm 1.09 (s, 9 H) 1.81 (dd, J=8.46, 3.92 Hz, 2 H) 1.96 - 2.06 (m, 2 H) 2.41 (br. s., 2 H) 2.87 (br. s., 2 H) 2.96 (d, J=4.95 Hz, 3 H) 4.27 (br. s., 1 H) 5.69 - 5.82 (m, 1 H) 6.38 - 6.50 (m, 1 H) 6.86 - 7.00 (m, 3 H) 7.21 - 7.31 (m, 2 H) 7.52 (t, J=1.86 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 356。
(试验例1:大鼠H3受体结合试验)
使用Teflon均质器,将从大鼠摘出的额皮质在含有蛋白质分解酶抑制剂(Complete EDTA-free,Roche Diagnostics)和5mM EDTA的50mM Tris-HCl缓冲液(pH7.4)中匀浆化。将该匀浆物以48000×g离心15分钟。除去上清,将颗粒物悬浮在含有5mM EDTA的50mM Tris-HCl缓冲液(pH7.4)中,进而以48000×g离心15分钟。除去该上清,将颗粒物悬浮在含有5mM EDTA的50mM Tris-HCl缓冲液(pH7.4)中,形成膜级分。将膜级分(最终反应液中的蛋白质量75μg)、N-α-甲基[3H]组胺(PerkinElmer,终浓度0.75nM)、和试验药物混合,使其在室温下反应1小时。反应结束后,将反应混合物在用0.3%聚乙烯亚胺处理过的96孔 GF/C滤板上抽滤,将过滤器用含有5mM EDTA的50mM Tris-HCl缓冲液(pH7.4)洗涤5次。洗涤后,将过滤器干燥,添加闪烁体,用TopCount(PerkinElmer)测定过滤器上的残留放射活性。
将在存在10μM噻普酰胺(チオペラミド)的情况下的残留放射活性作为非特异性结合,将与不存在噻普酰胺下的残留放射活性的差异作为特异性结合。试验药物利用DMSO溶解和稀释,由在各浓度存在下的残留放射活性得到用量反应曲线,由该用量反应曲线求得特异性结合被抑制50%的试验药物浓度(IC50)。实施例化合物的IC50值示于表2。
【表2】
(试验例2:[35S]GTP―γ―S结合试验)
使用Teflon均质器将由大鼠摘出的额皮质在含有2.5mM 氯化钙二水合物的30mM Tris-HCl缓冲液(pH7.4)中匀浆化。将该匀浆物以48000×g进行15分钟的离心分离。除去上清,将颗粒物悬浮在含有2.5mM 氯化钙二水合物的30mM Tris-HCl缓冲液(pH7.4)中,进而以48000×g进行15分钟的离心分离。除去上清,将颗粒物悬浮在含有2.5mM 氯化钙二水合物的30mM Tris-HCl缓冲液(pH7.4)中,在37℃孵育30分钟后,以48000×g离心分离15分钟。除去该上清,将颗粒物悬浮在含有100mM 氯化钠、10mM 氯化镁的20mM HEPES缓冲液(pH7.4)中,形成膜级分。将膜级分(最终反应液中的蛋白质量20μg)、GDP(终浓度300μM)、腺苷脱氨酶(终浓度1U/mL)、R(-)―α―甲基组胺(终浓度300nM)、和试验化合物混合,在30℃使其反应20分钟。反应结束后,进而添加[35S]GTP-γ-S(终浓度0.3nM),紧接着持续反应90分钟。反应结束后,将反应混合物在96孔 GF/C滤板上抽滤,将过滤器用含有100mM 氯化钠、10mM 氯化镁的20mM HEPES缓冲液(pH7.4)洗涤3次。洗涤后,将过滤器干燥,添加闪烁体,用TopCount (PerkinElmer)测定过滤器上的残留放射活性。
将不存在R(-)-α―甲基组胺的情况下的残留放射活性作为非特异性结合,将与存在R(-)-α―甲基组胺下的残留放射活性的差异作为特异性结合。试验药物用DMSO溶解和稀释,由在各浓度存在下的残留放射活性得到用量反应曲线,由该用量反应曲线求得特异性结合被抑制50%的试验药物浓度(IC50)。其结果是本发明的化合物3和7显示IC50为100nM以下的活性。
(试验例3:大鼠体内药代动力学试验)
使用SD大鼠,以3mg/kg单次口服化合物3、4和化合物7,确认服用1小时后的在血浆/脑/脑脊液中的组织分布。定量使用高效液相色谱/串联质谱仪API4000(LC-MS/MS、AB Sciex)。其结果是化合物3、4和化合物7的脑/血浆转移比良好,分别为4.5、2.9和2.2,此时的脑内浓度分别为78.2ng/g、7.06ng/g和408ng/g。另外,化合物3和化合物7这两种化合物的脑脊液/血浆转移比都为0.3,此时的脑脊液浓度分别为5.75ng/mL和50.5ng/mL。
(试验例4:P-糖蛋白底物识别性试验)
在Transwell上培养LLC-GA5-COL300细胞(源于来自猪肾的培养肾上皮细胞株LLC-PK1的Human MDR1 表达体系)。在刚要试验之前,置换为Hank平衡盐溶液(HBSS)供于试验。将最终浓度调整为10μM的评价化合物溶液添加到LLC-GA5-COL300细胞的Donor侧,一定时间后,从Acceptor侧采集一定量。样品中化合物浓度利用LC-MS/MS测定。由化合物向Acceptor侧的蓄积透过量,算出Apical→Basal和Basal→Apical各自的膜透过系数(×10-6 cm/sec),由其比例(外排率)评价P-糖蛋白底物识别性。实施例化合物的外排率值示于表3。
【表3】
产业上的可利用性
根据本发明,可以提供药物,其具有对组胺H3受体的强的结合抑制作用,在源于组胺H3受体的障碍、例如痴呆症、阿尔茨海默氏病、注意力缺陷/多动症、精神分裂症、癫痫、中枢性痉挛、肥胖、糖尿病、高脂血症、嗜睡症、特发性睡眠过度症、行为诱发性睡眠不足综合征、睡眠呼吸暂停综合征、昼夜节律障碍、深眠状态、睡眠相关运动障碍、失眠症、抑郁症、或过敏性鼻炎等疾病的预防或治疗中是有用的,认为大大有助于药物产业的发展。
Claims (8)
1.式(I)所示的化合物、或其药物上可接受的盐,
[化1]
[在式(I)中,Q表示下式(A)或(B)所示的基团,
[化2]
R1表示羟基、C1~C6烷氧基或NR1AR1B,
R1A和R1B相同或不同,表示氢原子、C1~C6烷基或C3~C7环烷基,
或者R1A和R1B可与相邻的氮原子一起相互键合而形成3~7元饱和杂环(该饱和杂环可被1或2个C1~C6烷基取代),
R2表示氢原子、卤素原子或C1~C6烷基,
n表示1或2,
R3表示氢原子、卤素原子或C1~C6烷基,
R4表示C1~C6烷基(该C1~C6烷基可被1或2个C3~C7环烷基取代)或C3~C7环烷基(该C3~C7环烷基可被1或2个C1~C6烷基取代),
R5和R6相同或不同,表示C1~C6烷基或C3~C7环烷基,
或者R5和R6可与相邻的氮原子一起相互键合而形成3~7元饱和杂环(该饱和杂环可被1或2个C1~C6烷基取代)]。
2.根据权利要求1所述的化合物、或其药物上可接受的盐,其中,
Q为式(A)
[化3]
(式中,R4如权利要求1中那样定义)。
3.根据权利要求1或2所述的化合物、或其药物上可接受的盐,其中,R1为NR1AR1B(式中,R1A和R1B如权利要求1中那样定义)。
4.根据权利要求1~3中任一项所述的化合物、或其药物上可接受的盐,其中,R2和R3为氢原子,n为1。
5.根据权利要求1~4中任一项所述的化合物、或其药物上可接受的盐,其中,R4为C3~C7环烷基。
6.药物,其含有权利要求1~5中任一项所述的化合物、或其药物上可接受的盐作为有效成分。
7.根据权利要求6所述的药物,其是组胺H3受体拮抗剂或反向激动剂。
8.根据权利要求6或7所述的药物,其是痴呆症、阿尔茨海默氏病、注意力缺陷/多动症、精神分裂症、癫痫、中枢性痉挛、肥胖、糖尿病、高脂血症、嗜睡症、特发性睡眠过度症、行为诱发性睡眠不足综合征、睡眠呼吸暂停综合征、昼夜节律障碍、深眠状态、睡眠相关运动障碍、失眠症、抑郁症、或过敏性鼻炎的预防剂或治疗剂。
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