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CN102603676B - 一种能避免呕吐反应的磷酸二酯酶4抑制剂 - Google Patents

一种能避免呕吐反应的磷酸二酯酶4抑制剂 Download PDF

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CN102603676B
CN102603676B CN201210037980.3A CN201210037980A CN102603676B CN 102603676 B CN102603676 B CN 102603676B CN 201210037980 A CN201210037980 A CN 201210037980A CN 102603676 B CN102603676 B CN 102603676B
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inhibitor
phosphodiesterase
vomiting
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pde4
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CN102603676A (zh
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徐江平
周中振
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Lanshi Ming Pharmaceutical Technology Guangzhou Co ltd
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Priority to PCT/CN2012/080593 priority patent/WO2013123766A1/zh
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Abstract

本发明涉及一种能避免呕吐反应的磷酸二酯酶4抑制剂，其中，由式(I)为
Figure 2012100379803100004DEST_PATH_IMAGE002
代表的化合物或前药或溶剂化物，R1是独立的甲氧基，溴和取代芳基；X是任意取代的六元杂环；Y是－(CH2)n－，－NH(CH2)n－，－NH(CH2)n－O－，其中，n的值可以为0，1，2，3中的任何一位数；Z是任意取代的芳环或者任意取代的杂芳环。本发明所涉及的一种能避免呕吐反应的磷酸二酯酶4抑制剂为一类新型联苯类PDE4D抑制剂，该抑制剂可用于治疗抑郁症、阿尔茨海默病及改善认知能力，并能够避免呕吐等不良反应。

Description

一种能避免呕吐反应的磷酸二酯酶4抑制剂
技术领域
本发明涉及一种具有抑制磷酸二酯酶的化合物的技术领域，尤其是一种联苯类PDE4D抑制剂，具体的说是一种能避免呕吐反应的磷酸二酯酶4抑制剂，这种抑制剂可用于治疗抑郁症、阿尔茨海默病及改善认知能力。
背景技术
磷酸二酯酶4(PDE4)主要分布于炎性细胞(肥大细胞、巨噬细胞、淋巴细胞和上皮细胞)和神经细胞内。PDE4与中枢神经系统和免疫系统的功能有密切的关系，其抑制剂被认为是作用于细胞内靶点的新抗炎药和中枢神经系统候选药物。由于PDE4特异性的催化cAMP的水解，因此对调节细胞内cAMP浓度起关键的作用，抑制PDE4使cAMP在细胞内积聚，产生各种生物学效应，包括抗炎、抗抑郁、增强记忆和改善认知功能等。
第一代PDE4抑制剂如咯利普兰具有很好的抗抑郁效果，导致其不能上市的原因是抑制PDE4所带来的恶心呕吐等副反应。与第一代PDE4抑制剂相比，第二代PDE4抑制剂具有更好的治疗效果，但至今还没有能避免呕吐的PDE4抑制剂上市。所以迫切需要开发一类能够减少甚至避免呕吐，但又具有抗抑郁及改善认知功能的新型PDE4抑制剂。
PDE4可分为PDE4A、PDE4B、PDE4C、PDE4D4个亚型，分别由相互独立的A、B、C、D4个基因编码，每个PDE4基因都有多个转录单位和启动子，大约有20个PDE4同工酶。张汉霆等人通过对PDE4D基因敲出鼠的研究发现PDE4D与抑郁及认知功能密切相关，同时也与呕吐相关，陆续有文献证实了这一推测。
所有的实验结果显示，PDE4抑制剂有可能是一种与cAMP竞争的抑制剂(Houslay，et al. 2005, DDT, 10, 1503 - 2119)。这也就能够解释其治愈率低的原因了。
发明内容
本发明所要解决的技术问题是针对上述现有技术现状，提供一种不与cAMP竞争的能避免呕吐反应的非竞争型磷酸二酯酶4抑制剂。这种化合物具有很高的PDE4及PDE4D亚型抑制活性，在动物身上的实验结果显示，在改善学习记忆方面，具有比抗抑郁药第一代PDE4抑制剂咯利普兰更好的效果。另外，在比格犬的呕吐实验中，也没有观察到明显的致呕反应。因此，此类化合物有望成为第一个能够避免呕吐等不良反应的治疗抑郁症、阿尔茨海默病并改善认知能力的药物。
本发明解决上述技术问题所采用的技术方案为：
一种能避免呕吐反应的磷酸二酯酶4抑制剂，其特征是：由式(I)为
Figure DEST_PATH_IMAGE002
代表的化合物或前药或溶剂化物，
其中：R1是独立的甲氧基，溴和取代芳基；
X是任意取代的六元杂环；
Y 是－(CH2)n－，－NH(CH2)n－，－NH(CH2)n－O－，其中，n的值可以为0，1，2，3中的任何一位数；
Z是任意取代的芳环或者任意取代的杂芳环。
2.根据权利要求1所述的一种能避免呕吐反应的磷酸二酯酶4抑制剂，其特征是：所述的R1是
Figure DEST_PATH_IMAGE004
；
X-Y是
；
Z为任意取代的芳环。
3.根据权利要求1所述的一种能避免呕吐反应的磷酸二酯酶4抑制剂，其特征是：所述的X是
Figure DEST_PATH_IMAGE008
。
与现有技术相比，本发明所涉及的一种能避免呕吐反应的磷酸二酯酶4抑制剂，其中，由式(I)为
Figure 2012100379803100002DEST_PATH_IMAGE002A
代表的化合物或前药或溶剂化物，
R1是独立的甲氧基，溴和取代芳基；
X是任意取代的六元杂环；
Y 是－(CH2)n－，－NH(CH2)n－，－NH(CH2)n－O－，其中，n的值可以为0，1，2，3中的任何一位数；
Z是任意取代的芳环或者任意取代的杂芳环。
本发明所涉及的一种能避免呕吐反应的磷酸二酯酶4抑制剂是一种不与cAMP竞争的非竞争PDE4D抑制剂，对PDE4及PDE4D亚型具有很高的抑制活性，在动物身上的实验结果显示，在改善学习记忆方面，具有比抗抑郁药第一代PDE4抑制剂咯利普兰更好的效果。另外，在比格犬的呕吐实验中，也没有观察到明显的致呕反应。因此，此类化合物有望成为第一个能够避免呕吐等不良反应的治疗抑郁症、阿尔茨海默病并改善认知能力的药物。
具体实施方式
以下结合附图对本发明的实施例作进一步详细描述。
一种能避免呕吐反应的磷酸二酯酶4抑制剂，其中，由式(I)为
代表的化合物或前药或溶剂化物，
R1是独立的甲氧基，溴和取代芳基；
X是任意取代的六元杂环；
Y 是－(CH2)n－，－NH(CH2)n－，－NH(CH2)n－O－，其中，n的值可以为0，1，2，3中的任何一位数；
Z是任意取代的芳环或者任意取代的杂芳环。
上述的由式(II)为
Figure DEST_PATH_IMAGE010
代表的化合物或前药或可药用盐或溶剂化物；
其中：Z为任意取代的芳环。
上述的由式(III)为
代表的化合物或前药或可药用盐或溶剂化物；
其中：R1是独立的甲氧基和取代芳基；
Y 是－(CH2)n－，－NH(CH2)n－，－NH(CH2)n－O－，其中，n的值可以为0，1，2，3中的任何一位数；
Z是任意取代的芳环或者任意取代的杂芳环。
式(II)系列化合物如下所示：
Figure 2012100379803100002DEST_PATH_IMAGE010A
Compd. Z
II-1 2-methoxyphenyl
II-2 2-chlorophenyl
式(III)系列化合物如下所示：
Figure DEST_PATH_IMAGE012A
Compd. R1 R2 R3 Y Z
III-1 3-chlorophenyl Cl Cl H \
III-2 3-chlorophenyl H H -N(CH2CH2)2-N- 2-chlorophenyl
III-3 3-chlorophenyl H H -NHCH2CH2O- 2-methoxyphenyl
III-4 Br H H -NH CH2CH2O- 2-methoxyphenyl
III-5 MeO H H -NH CH2CH2O- 2-methoxyphenyl
式(I)和式(II)代表的本发明的化合物可通过化学文献中描述的众所周知的方法合成，下面总结可用于本发明的方法，如Scheme 1所示。
Figure DEST_PATH_IMAGE014
Scheme 1
取3－取代－4－甲氧基甲苯（2mmol）于50ml二颈圆底烧瓶中后，加入0.356g （2mmol）N－溴代丁二酰亚胺（NBS）和20ml无水四氯化碳，加热至回流，薄层层析监测反应进程。反应完成后，过滤，减压除去溶剂即得到3－取代－4－甲氧基溴甲基苯粗品，不用分离直接进入下面的反应。
将2mmol杂环胺加入25ml二颈圆底烧瓶中，加入10ml无水DMF后，再加入0.417g无水碳酸钾（3mmol），常温搅拌1h，加入上一步得到的溴甲基3－取代－4－甲氧基溴甲基苯粗品，常温搅拌反应12h，薄层层析监测反应进程。反应完成后，过滤，减压除去DMF后，得粗品。进行柱层析分离得到目标化合物。
目标化合的谱图数据：
Compound II-1 (ZX-I01)：Yield: 65%；ESI–MS: m/z 424.0 ([M+H]+), 446.0 ([M+Na]+)；1H NMR (400MHz, CDCl3): 2.65 ~ 2.70 (m, 4H), 3.05 ~ 3.15 (m, 4H), 3.81 (s, 3H, MeO), 3.85 (s, 3H, MeO), 3.89 (s, 2H, CH2), 6.84 ~ 7.01 (m, 5H), 7.27 ~ 7.36 (m, 4H), 7.41(s, 1H), 7.53(s, 1H)；
Figure DEST_PATH_IMAGE018
Compound II-2 (ZX-I02)：Yield: 63%；ESI–MS: m/z 427.5(M+), 428.5([M+1]+), 429.5 ([M+2]+)；1H NMR (400MHz, CDCl3): 2.63 ~ 2.70 (m ,4H), 3.09 ~ 3.12 (m, 4H), 3.82 (s, 3H, MeO), 3.89 (s, 2H, CH2), 6.94 ~ 6.98 (m, 2H), 7.03 (d, J = 8.0Hz, 1H),7.21 (t, J = 7.6Hz, 1H),7.28 ~ 7.40 (m, 5H),7.43 (s, 1H),7.55 (s, 1H)；
Figure DEST_PATH_IMAGE020
Compound III-1 (ZX-I03)：Yield: 43%；ESI–MS: m/z 395.6(M+), 396.5 ([M+1]+), 397.5 ([M+2]+)；1H NMR(400MHz, CDCl3): 3.80 (s, 3H, MeO), 5.29 (s, 2H, CH2), 6.92 (d, J = 7.6Hz, 1H), 7.29 ~ 7.39 (m, 3H), 7.45 ~ 7.48 (m, 2H) ,7.64 (d, J = 2.0Hz, 1H), 7.77 ~ 7.8 (m, 2H)；
Figure DEST_PATH_IMAGE022
Compound III-2 (ZX-I06)：Yield: 33%；ESI–MS: m/z521.5(M+), 522.5([M+1]+), 523.5 ([M+2]+)；1H NMR (400MHz, CDCl3): 3.20 ~ 3.30(m, 4H), 3.50 ~ 3.60(m, 4H), 3.82 (s, 3H, MeO), 5.14 (s, 2H, CH2), 6.86 ~ 7.00 (m, 2H), 7.08 (t, J = 8.0Hz, 1H), 7.15 (d, J = 9.6Hz, 1H), 7.28 ~ 7.34 (m, 4H), 7.39 ~ 7.44 (m, 3H), 7.46 (d, J = 8.4Hz, 1H), 7.51(s, 1H), 7.68 (d, J = 1.6Hz, 1H)；
Compound III-3 (ZX-I07): Yield: 45%；ESI–MS: m/z 492.6(M+), 493.6([M+1]+), 494.6 ([M+2]+), 514.6([M+Na]+), 530.6([M+K]+)；1H NMR (400MHz, CDCl3): 3.64(t, J = 4.8Hz, 2H), 3.79(s, 3H, MeO), 3.84(s, 3H, MeO), 4.13((t,J = 4.8Hz, 2H), 5.16 (s, 2H, CH2), 6.78(d, J = 9.6Hz, 1H), 6.85 ~ 6.98 (m, 6H), 7.28 ~ 7.44(m, 4H), 7.505(s, 1H), 8.02(s, 1H)；
Figure DEST_PATH_IMAGE026
Compound III-4 (ZX-I11): Yield: 42%；ESI–MS: m/z 482.4 ([(M-1)+Na]+), 484.4 ([(M+1)+Na]+)；1H NMR(400MHz, CDCl3): 3.64(t, J = 4.8Hz, 2H), 3.85(s, 3H, MeO), 3.96(s, 3H, MeO), 4.18((t, J = 4.8Hz, 2H), 5.08 (s, 2H, CH2),6.73 ~ 6.99(m, 5H), 7.36(d, J = 7.2Hz, 1H), 7.53 ~ 7.55(m, 1H), 7.65(d, J = 1.2Hz, 1H),7.72 ~ 7.74(m, 1H)；
Compound III-5 (ZX-I12): Yield: 28%；ESI–MS: m/z 412.7([M+1]+), 434.7([M+Na]+), 450.7([M+K]+); 1H NMR (400MHz, CDCl3): 3.79(s, 3H, MeO), 3.81(s, 3H, MeO), 3.85 ~ 3.87(m, 5H, MeO, CH2), 4.19(t, J = 5.2Hz, 2H), 4.68(s, 2H, CH2), 6.76 ~ 6.94(m, 7H), 7.00 (d, J = 10Hz, 1H), 7.34(d, J = 10Hz, 1H);
磷酸二酯酶4抑制活性实验
1、实验方法
PDE4抑制活性的测定采用的是IMAP技术，该方法能精确而稳定测得化合物对PDE4的抑制活性。
2、实验结果
表1新型PDE4抑制剂II-1，II-2，III-1～III-3对PDE4、PDE4D4及PDE4D5的抑制活性
Figure DEST_PATH_IMAGE030
表2新型PDE4抑制剂ZX-111和ZX-112对PDE4的抑制活性
Figure DEST_PATH_IMAGE032
动物实验
1．新型PDE4抑制剂III-3对东莨菪碱所致学习记忆获得性障碍小鼠学习记忆的影响
1.1方法
将60只昆明小鼠随机分为6组，每组10只，即空白组、模型组、咯利普兰对照组、III-3低、中、高剂量组，连续给药1周后采用Morris水迷宫进行行为学测试，测试前20分钟，除空白腹腔注射生理盐水外，其余各组均注射东莨菪碱注射液，连续训练4天，第5天进行空间探索实验，记录各组小鼠第一次穿越目标区时间、穿越目标区次数及目标象限停留时间。
表3新型PDE4抑制剂III-3对学习记忆障碍性小鼠Morris水迷宫测试的影响(
Figure DEST_PATH_IMAGE034
±S)
Figure DEST_PATH_IMAGE036
注：与模型组相比，*P<0.05，**P<0.01
2.新型PDE4抑制剂III-3致呕吐反应的初步研究
2.1方法
将6条比格犬随机分为2组，即咯利普兰0.5 mg/kg对照组(0.5 mg/ml，1ml/kg)和溶剂对照组(5% DMSO，1ml/kg)，以灌胃的方式给药。连续观察120分钟，观察动物有无呕吐反应，观察指标为动物出现恶心干呕、大量流涎及呕吐，记录潜伏期。一周后，将6条比格犬重新随机分成2组，即咯利普兰对照组和III-3给药组，以灌胃的方式给予高剂量咯利普兰0.5 mg/kg(药液浓度为0.5 mg/ml，给药容积1 ml/kg)，以同样的方式连续观察120分钟。
1.2实验结果
表4给予新型PDE4抑制剂III-3后狗的呕吐反应情况
Figure DEST_PATH_IMAGE038
本发明的最佳实施例已阐明，由本领域普通技术人员做出的各种变化或改型都不会脱离本发明的范围。

Claims (1)

1.一种能避免呕吐反应的磷酸二酯酶4抑制剂，其特征是：其选自III-1、III-2、III-3、III-4、III-5，其中：
III-1为：“                                               
Figure DEST_PATH_IMAGE002A
”；
III-2为：“
Figure DEST_PATH_IMAGE004A
”；
III-3为：“
Figure DEST_PATH_IMAGE006A
”；
III-4为：“
Figure DEST_PATH_IMAGE008A
”；
III-5为：“
Figure DEST_PATH_IMAGE010A
”。
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