CN101455661A - 3-取代苯酞及其类似物的用途 - Google Patents
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Abstract
本发明涉及一种3-取代苯酞及其类似物用于制备治疗阿尔茨海默症以及其他神经性疾病的药物的用途,其结构式如右式,通过目前集基因技术和生物技术为一体的高效生物模型进行了筛选,发现大部分的化合物都具有一定的缺陷个体恢复学习能力的作用,其中的几个特定化合物表现出了比较好的活性,能够使缺陷个体的学习能力恢复85%以上,并且在多轮实验中均能表现出稳定的治疗作用。
Description
技术领域
本发明涉及一系列3-取代苯酞类化合物及其类似物的用途,尤其是作为制备预防和治疗阿尔茨海默症以及其他神经性疾病的药物的用途。
背景技术
老年痴呆症,又称阿尔茨海默症(Alzheimer’s disease,AD)是发生在老年期及老年前期的一种原发性退行性脑病,指的是一种持续性高级神经功能活动障碍,即在没有意识障碍的状态下,记忆、思维、分析判断、视空间辨认、情绪等方面的障碍。其特征性病理变化为大脑皮层萎缩,并伴有β-淀粉样蛋白(β-amyloid,β-AP)沉积,神经原纤维缠结(neurofibrillary tangles,NFT),大量记忆性神经元数目减少,以及老年斑(senileplaque,SP)的形成。目前尚无特效治疗或逆转疾病进展的治疗药物。
随着社会的发展,人口老龄化速度正在加快。目前,全世界60岁以上人口有5.9亿人,到2020年可能突破10亿人大关。我国60岁以上人口1998年已达1.2亿人,并以年均3.2%的速度递增,大大高于人口增长速度。老年人口的不断增多,使得老年性痴呆症的发病率相对上升。目前,欧洲、日本和美国80岁以上的老年人中有20%以上的人患有此病。全世界65岁以上老年人中有5000多万人患有不同种类的痴呆症。我国近几年该病的发病率也在不断增加。据北京老年病医疗研究中心对北京地区60岁以上老人的调查发现,老年痴呆症的患病率达到75%,其中女性病人的患病率明显高于男性,高龄、低教育水平、居住在农村是老年性痴呆症的高发因素。
因此,抗老年痴呆药物的研究和开发引起了世界各国医药界的高度重视,尤其是近年来随着对老年神经生理、生化、药理等方面研究的不断深入,导致相关药物的开发研究不断取得进展,治疗老年性痴呆症药物的市场销售额也一直在稳步增长。成千上万的老年性痴呆症患者正迫切需要安全、有效、价廉的药物,其市场潜力不可估量,前景看好。
发明内容
本发明的目的是提供3-取代苯酞及其类似物的用途,特别是作为制备治疗阿尔茨海默症以及其他神经性疾病的潜在药物的用途。
本发明所涉及的3-取代苯酞及其类似物具有如下的结构通式:
式(1) 式(2) 式(3)
其中,式(3)表示为消旋体(racemate),即式(1)和式(2)的等比例混合物;
X1或和X2为CH或N;X3可以是O或NH;
R1可以是氢、卤素或C1~20的烃基;
所述的C1~20的烃基推荐R4或CH2R8,其中R8为H或R4,R4代表C1~8的烷基或烯基、C1~8的卤代烷基或烯基、苯基、萘基、蒽基、噻吩基、喹啉基、苯氧基、卤代苯氧基、苯硫基、卤代苯硫基、烯丙基,2-呋喃基、3-吡咯基、3-吲哚基、3-香豆素基、R5或/和R6或/和R7取代的苯基、R5或/和R6或/和R7取代的2-呋喃基、R5或/和R6或/和R7取代的3-吡咯基、R5或/和R6或/和R7取代的3-吲哚基、R5或/和R6或/和R7取代的3-香豆素基,或者R5或/和R6或/和R7取代的苯氧基;R5、R7为H或R6;R6为卤素、C1~4的烷基、C1~4的烷氧基、C1~4的烷硫基或C1~4的卤代烷基;
R2或和R3为氢、卤素、硝基、C1~4的烷基、C1~4的烷氧基、胺基、羧基、亚砜基、砜基、酰胺基或硫酰胺基,或者R2和R3为苯并基或-CH=CH-CH=CH-;
本发明所涉及的3-取代苯酞及其类似物的典型结构式如下:
本发明所涉及的3-取代苯酞及其类似物等通过果蝇(Drosophila)模型测定其生物活性用于治疗阿尔茨海默症(K lijima,H P Liu,A S Chiang,S A Hearn,MKonsolaki,Y Zhong,PNAS,2004,101,6623-6628;X Ge,F Hannan,Z L Xie,C H Feng,T Tully,H M Zhou,Z P Xie,Y Zhong,PNAS,2004,101,10172-10176)。在该模型中,正常的果蝇是具有一定的学习记忆能力的,而通过基因技术培养出的携带阿尔茨海默致病基因的果蝇个体,具有记忆缺陷。通过对突变缺陷果蝇用不同的化合物进行一段时间的给药,考察其记忆学习能力的恢复情况来筛选得到不同化合物的活性。
本发明通过目前集基因技术和生物技术为一体的高效生物模型,经清华大学生命科学院的钟毅教授对一系列的3-取代苯酞及其类似物进行了筛选,发现大部分的化合物都具有一定的缺陷个体恢复学习能力的作用,其中的几个特定化合物表现出了比较好的活性,能够使缺陷个体的学习能力恢复90%以上,并且在多轮实验中均能表现出稳定的治疗作用。基于此,我们认为3-取代苯酞及其类似物对于预防和治疗阿尔茨海默症以及其他神经性疾病具有一定的生物活性,其具有开发成为预防和治疗阿尔茨海默症以及其他神经性疾病的潜在药物分子的价值。
具体实施方法
通过下述实施例将有助于理解本发明,但并不限制本发明的内容。
实施例1 3-取代苯酞类化合物的制备:
本发明说涉及的新型3-取代苯酞类化合物可以按照一下的两个方法进行制备,其中方法一用于制备手性的新型3-取代苯酞类化合物,而方法二用于制备消旋的新型3-取代苯酞类化合物。
方法一:在室温至80℃,底物浓度为0.5~1.25mol/L,在2~5当量还原剂甲酸盐、手性二胺配体与(对甲基异丙基)苯基二氯化钌二聚体的配合物催化剂催化下,底物摩尔数和催化剂摩尔数为100~500:1,反应4~24小时,通过柱层析纯化即以一定的产率和一定的光学纯度得到产物;反应通式如下:
其中,产物的主要构型决定于手性配体的构型,配体上取代基团的不同会影响产物的光学纯度;推荐的手性配体结构如下:R1、R2、R3、R5、R6、R7、X1和X2定义如前。
方法二:在室温下,底物溶解于甲醇中,在2~5当量还原剂如硼氢化钠或钯碳氢气条件下,反应0.5小时,通过柱层析纯化即以一定的产率消旋产物;反应通式如下:
其中,R1、R2、R3、X1和X2定义如前。
实施例中新化合物数据如下表(表1):
表1
编号 | 化合物数据 |
(S)-1 | [α]D 24:-53.6(c1.13,CHCl3)for 98.5%ee.1H NMR(300MHz,CDCl3):δ 1.61-1.76(m,2H),1.78-1.90(m,3H),2.07-2.13(m,1H),3.54(t,J=6.5Hz,2H),5.50(dd,J=3.9,7.5Hz,1H),7.45(d,J=7.5Hz,1H),7.54(t,J=7.4Hz,IH),7.69(t,J=7.2Hz,1H),7.94(d,J=7.5Hz,IH).EI-MS(m/z,%):224(M+,2.77),133(100.00),105(61.36),77(40.43),51(27.16). |
(S)-2 | [α]D 24:-74.9(c0.78,CHCl3)for 99.3%ee.1H NMR(300MHz,CDCl3):δ 3.21(d,J=6.0Hz,2H),5.67(t,J=6.0Hz,1H),7.13(d,J=7.2Hz,2H),7.23-7.28(m,3H),7.51(t,J=7.5Hz,1H),7.64(t,J=7.5Hz,IH),7.84(d,J=7.5Hz,1H).EI-MS(m/z,%):258(M+,8.94),133(100.00),125(12.16),105(14.53),77(14.50). |
(S)-3 | 1H NMR(300MHz,CDCl3):δ 2.43(s,3H),3.09-3.38(m,2H),5.65(t,J=6.3Hz,1H),7.02(d,J=8.1Hz,1H),7.20-7.31(m,5H),7.40(d,J=8.1Hz,IH),7.64(s,1H).HPLC:Chiracel OJ-H Column(250mm);detected at 214nm;n-hexane/i-propanol=95/5;flow=0.7mL/min;Retention time:38.4min(S),51.3min(R). |
(S)-4 | [α]D 24:-56.0(c 0.82,CHCl3)for 98.5%ee.1H NMR(300MHz,CDCl3):δ 3.47(d,J=6.0Hz,2H),5.70(t,J=5.9Hz,IH),6.86(d,J=3.3Hz,1H),6.90-6.93(m,1H),7.15-7.17(m,1H),7.23-7.26(m,1H),7.51(t,J=7.4Hz,1H),7.63(dt,J=1.1,7.5Hz,1H),7.86(d,J=7.8Hz,1H).EI-MS(m/z,%):230(M+,2.13),229(M+-1,12.63),175(7.84),131(100.00),103(30.56),91(57.86),57(36.36),41(24.31). |
(R)-4 | [a]D 24:-54.2(c0.79,CHCl3)for 95%ee. |
(R)-5 | [α]D 24:-172.8(c0.46,CH2Cl2)for 99.3%ee.1H NMR(400MHz,CDCl3):δ 3.43(dd,J=8.2,15.0Hz,1H),3.95(dd,J=3.2,14.8Hz,1H),6.17(dd,J=3.0,7.8Hz,IH),7.35(d,J=8.4Hz,1H),7.44-7.50(m,2H),7.66(t,J=7.4Hz,IH),7.77(d,J=7.6Hz,1H),7.95(d,J=8.4Hz,1H),8.08(d,J=8.4Hz,1H),8.14(d,J=7.6Hz,1H),8.88(d,J=4.0Hz,1H).ESI-MS(M++H):277.2. |
rac-5 | 1H NMR(400MHz,CDCl3):δ 3.43(dd,J=8.2,15.0Hz,IH),3.95(dd,J=3.2,14.8Hz,1H),6.17(dd,J=3.0,7.8Hz,1H),7.35(d,J=8.4Hz,1H),7.44-7.50(m,2H),7.66(t,J=7.4Hz,1H),7.77(d,J=7.6Hz,IH),7.95(d,J=8.4Hz,IH),8.08(d,J=8.4Hz,1H),8.14(d,J=7.6Hz,1H),8.88(d,J=4.0Hz,1H). |
(S)-6 | [a]D 24:-44.7(c 0.65,CHCl3)for 99.3%ee.1H NMR(300MHz,CDCl3):δ 3.10(dd,J=6.3,14.1Hz,1H),3.24(dd,J=6.3,14.4Hz,1H),3.79(s,3H),5.65(t,J=6.6Hz,1H),6.80-6.83(m,2H),7.10-7.13(m,2H),7.18(d,J=8.1Hz,1H),7.49(t,J=7.5Hz,1H),7.60(dt,J=0.8,7.5Hz,1H),7.84(d,J=7.5Hz,1H).EI-MS(m/z,%):254(M+,2.79),133(4.05),121(100.00),77(10.15),51(4.18). |
(S)-7 | 1H NMR(300MHz,CDCl3):δ 2.44(s,3H),3.13-3.26(m,2H),5.63(t,J=6.6Hz,1H),6.99(s,1H),7.20-7.31(m,6H),7.73(d,J=7.8Hz,IH).HPLC:Chiracel OJ-H Column(250mm);detected at 214nm;n-hexane/i-propanol=95/5;flow=0.7mL/min;Retention time:47.7min(S),72.9min(R). |
(S)-8 | [d]D 24:-49.5(c 0.92,CHCl3)for 99.2%ee.1H NMR(300MHz,CDCl3):δ 3.12(dd,J=6.0,14.1Hz,1H),3.25(dd,J=6.3,14.1Hz,IH),3.81(s,3H),3.85(s,3H),5.69(t,J=6.0Hz,1H),6.68-6.79(m,3H),7.20(d,J=7.5 |
Hz,1H),7.49(t,J=7.5Hz,1H),7.60(t,J=7.5Hz,1H),7.83(d,J=7.2Hz,1H).EI-MS(m/z,%):284(M+,6.57),151(100.00),133(5.73),107(6.91),77(7.59),51(4.33). | |
(S)-9 | [a]D 24:-84.4(c 0.71,CHCl3)for 99.1%ee.1H NMR(300MHz,CDCl3):δ 3.15(dd,J=6.6,14.1Hz,1H),3.26(dd,J=5.1,14.4Hz,1H),5.68(t,J=6.2Hz,1H),6.67-6.78(m,3H),7.33(d,J=7.8Hz,1H),7.54(t,J=7.5Hz,1H),7.68(t,J=7.5Hz,1H),7.88(d,J=7.5Hz,1H).EI-MS(m/z,%):260(M+,1.74),133(100.00),105(14.38),77(14.52),51(6.53). |
(S)-10 | [α]D 24:-51.9(c 1.05,CHCl3)for 99.2%ee.1H NMR(300MHz,CDCl3):δ 2.46(s,3H),3.14(dd,J=6.5,14.0Hz,1H),3.23(dd,J=6.5,14.0Hz,1H),5.66(t,J=6.3Hz,1H),7.11-7.23(m,5H),7.49(t,J=7.7Hz,1H),7.61(t,J=7.4Hz,1H),7.84(d,J=7.5Hz,1H).EI-MS(m/z,%):270(M+,7.44),137(100.00),122(10.81),105(5.27),91(6.06),77(10.75). |
(S)-11 | [α]D 24:26.2(c 0.80,CHCl3)for 34.8%ee.1H NMR(400MHz,CDCl3):δ 3.46(dd,J=8.0,14.4Hz,1H),3.53(dd,J=5.6,14.4Hz,1H),6.16(t,J=6.6Hz,1H),7.35(d,J=8.0Hz,2H),7.46-7.53(m,2H),7.58(t,J=7.4Hz,1H),7.67-7.71(m,1H),7.79(d,J=8.0Hz,1H),7.87(d,J=7.6Hz,1H),8.03(d,J=8.4Hz,1H),8.10(d,J=8.4Hz,1H).ESI-MS(M++Na):298.0,(M++H):276.0. |
(R)-12 | [α]D 24:+14.6(c 0.71,CHCl3)for 98.0%ee.1H NMR(300MHz,CDCl3):δ 4.26(dd,J=5.1,9.9Hz,1H),4.34(dd,J=5.6,10.1Hz,1H),5.78(t,J=5.3Hz,1H),6.81-6.84(m,2H),7.22-7.25(m,2H),7.60-7.63(m,2H),7.69-7.75(m,1H),7.96(d,J=7.2Hz,1H).EI-MS(m/z,%):274(M+,39.68),147(30.46),133(100.00),119(26.22),91(25.01),77(18.08). |
(S)-13 | [α]D 24:-69.2(c 0.76,CHCl3)for 92.8%ee.1H NMR(300MHz,CDCl3):δ 3.66(d,J=6.9Hz,2H),5.89(t,J=6.8Hz,1H),7.23(d,J=7.8Hz,1H),7.36(d,J=4.5Hz,1H),7.55(t,J=7.48Hz,1H),7.61-7.65(m,2H),7.76(t,J=7.5Hz,1H),7.91(d,J=7.2Hz,1H),8.08(d,J=8.7Hz,1H),8.17(d,J=8.4Hz,1H),8.88(d,J=4.2Hz,1H).ESI-MS(M++H):276.2. |
(S)-14 | [α]D 24:-73.6(c 0.61,CHCl3)for 98.3%ee.1H NMR(300MHz,CDCl3):δ 3.12(dd,J=6.6,14.1Hz,1H),3.31(dd,J=6.3,14.1Hz,1H),5.65(t,J=6.3Hz,1H),7.18-7.21(m,3H),7.29-7.36(m,3H),7.91(s,1H).EI-MS(m/z,%):292(M+,8.38),201(47.11),145(8.92),109(9.44),91(100.00),65(15.14). |
rac-14 | 1H NMR(300MHz,CDCl3):δ 3.12(dd,J=6.6,14.1Hz,1H),3.31(dd,J=6.3,14.1Hz,1H),5.65(t,J=6.3Hz,1H),7.18-7.21(m,3H),7.29-7.36(m,3H),7.91(s,1H). |
(S)-15 | [α]D 24:-121.8(c 0.75,CHCl3)for 97.7%ee.1H NMR(300MHz,CDCl3):δ 3.24(dd,J=6.0,14.1Hz,1H),3.37(dd,J=6.5,14.0Hz,1H),5.86(t,J=6.6Hz,1H),7.26-7.33(m,5H),7.57-7.67(m,3H),7.87(d,J=8.1Hz,1H),8.01(d,J=7.8Hz,1H),8.43(s,1H).EI-MS(m/z,%):274(M+,8.66),183(100.00),155(11.97),127(22.32). |
(R)-16 | [α]D 24:+14.7(c 0.93,CHCl3)for 97.8%ee.1H NMR(300MHz,CDCl3):δ 3.37(dd,J=6.0,14.1Hz,1H),3.50(dd,J=5.0,14.0Hz,1H),5.60(t,J=5.4Hz,1H),7.21-7.30(m,4H),7.52-7.65(m,3H),7.90(d,J=7.2Hz,1H)EI-MS(m/z,%):290(M+,35.86),157(100.00),133(75.89),105(15.56),77(21.64),51(9.59). |
(S)-17 | [α]D 24:-45.0(c 0.68,CHCl3)for 99.0%ee.1H NMR(300MHz,CDCl3):δ 2.32(s,3H),3.10(dd,J=6.4,14.3Hz,1H),3.25(dd,J=6.6,14.1Hz,1H),5.66(t,J=6.5Hz,1H),7.09(s,4H),7.16(d,J=8.4Hz,1H),7.48(t,J=7.5Hz,1H),7.59(t,J=7.6Hz,1H),7.84(d,J=7.8Hz,1H).EI-MS(m/z,%):238(M+,9.09),133(36.56),105(100.00),77(21.10),51(8.51). |
(S)-18 | [α]D 24:-28.1(c 0.78,CHCl3)for 99.2%ee.1H NMR(300MHz,CDCl3):δ 3.46(dd,J=7.2,14.4Hz,1H),3.75(dd,J=7.2,14.4Hz,1H),5.82(t,J=6.8Hz,1H),6.96(d,J=7.2Hz,1H),7.34(d,J=6.6Hz,1H),7.43(t,J=7.7Hz,1H),7.48-7.62(m,4H),7.81(d,J=8.4Hz,1H),7.88(d,J=6.9Hz,2H),8.07(d,J=8.4Hz,1H).EI-MS(m/z,%):274(M+,13.80),141(100.00),133(20.29),115(12..22),105(5.33),77(6.38). |
(S)-19 | [α]D 24:-79.2(c 0.89,CHCl3)for 98.5%ee.1H NMR(300MHz,CDCl3):δ 3.24(dd,J=6.9,13.8Hz,1H),3.35(dd,J=5.4,14.1Hz,1H),5.72(t,J=6.2Hz,1H),7.30-7.36(m,3H),7.50-7.55(m,3H),7.64-7.69(m,1H),7.85(d,J=7.8Hz,1H).EI-MS(m/z,%):292(M+,0.76),273(1.13),133(100.00),105(13.61),77(16.01),51(8.34). |
rac-19 | 1H NMR(300MHz,CDCl3):δ 3.24(dd,J=6.9,13.8Hz,1H),3.35(dd,J=5.4,14.1Hz,1H),5.72(t,J=6.2Hz,1H),7.30-7.36(m,3H),7.50-7.55(m,3H),7.64-7.69(m,1H),7.85(d,J=7.8Hz,1H). |
(S)-20 | [α]D 20+24.59(c 1.14,CHCl3)(for 69%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.37-7.23(m,5H,Ph),6.98(d,J=1.8Hz,1H,Ph),6.65(d,J=1.8Hz,1H,Ph),6.34(s,1H,CH),3.87(s,3H,OMe),3.70(s,3H,OMe);ESI-MS(m/z,%):271.2(M++H),293.1(M++Na); |
rac-21 | 1H NMR(300MHz,CDCl3)δ(ppm)7.42(d,J=7.8Hz,1H,Ph),7.27(t,J=8.1Hz,1H,Ph),7.14(t,J=7.5Hz,1H,Ph),6.98(d,J=1.8Hz,1H,Ph),6.86(dd,J1=7.8Hz,J2=1.5Hz1H,Ph),6.80(s,1H,CH),6.66(d,J=1.8Hz,1H,Ph),3.87(s,3H,OMe),3.69(s,3H,OMe); |
(S)-22 | [α]D 20+22.66(c 1.65 CHCl3)(for 73%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.30(d,J=8.7Hz,2H,Ph),7.19(d,J=8.4Hz,2H,Ph),6.96(d,J=2.1Hz,1H,Ph),6.65(d,J=1.5Hz,1H,Ph),6.30(s,1H,CH),3.87(s,3H,OMe),3.71(s,3H,OMe);ESI-MS(m/z,%):305(M++H),327(M++Na); |
(S)-23 | [α]D 20+9.14(c 2.73,CHCl3)(for 80%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.40(d,J=8.7Hz,1H,Ph),7.34(d,J=1.8Hz,1H,Ph),7.12(dd,J1=8.1Hz,J2=2.1Hz,1H,Ph),6.96(d,J=1.8Hz,1H,Ph),6.66(d,J=1.5Hz,1H,Ph),6.26(s,1H,Ph),3.87(s,3H,OMe),3.73(s,3H,OMe);ESI-MS(m/z,%):339(M++H),361(M++Na); |
(S)-24 | [α]D 20+32.67(c 0.84,CHCl3)(for 78%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.43(s,1H,Ph),7.12(d,J=8.1Hz,1H,Ph),6.96(s,1H,Ph),6.79(d,J=8.4Hz,1H,Ph),6.71(s,1H,Ph),6.67(s,1H,Ph),3.86(s,3H,OMe),3.70(s,3H,OMe);ESI-MS(m/z,%):339(M++H),361(M++Na); |
(S)-25 | [α]D 20+23.82(c 1.9,CHCl3)(for 74%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.28-7.21(m,2H,Ph),7.04-6.97(m,3H,Ph),6.66(d,J=2.1Hz,1H,Ph),6.31(s,1H,CH),3.87(s,3H,OMe),3.71(s,3H,OMe);ESI-MS(m/z,%):289(M++H),311(M++Na); |
(S)-26 | [α]D 20+18.72(c 2.05,CHCl3)(for 80%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.15-7.00(m,3H,Ph),6.93(d,J=2.1Hz,1H,Ph),6.65(d,J=1.8Hz,1H,Ph),6.25(s,1H,CH),3.84(s,3H,OMe),3.71(s,3H,OMe);ESI-MS(m/z,%):307(M++H),329(M++Na); |
(S)-27 | [α]D 20+64.96(c 1.05 CHCl3)(for 76%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.23-7.22(m,2H,Ph),7.11-7.05(m,1H,Ph),7.00(d,J=1.8Hz,1H,Ph),6.79(d,J=7.2Hz,1H,Ph),6.60(s,1H,CH)3.89(s,3H,OMe),3.70(s,3H,OMe),2.54(s,3H,Me);ESI-MS(m/z,%):285(M++H),307(M++Na); |
rac-27 | 1H NMR(300MHz,CDCl3)δ(ppm)7.23-7.22(m,2H,Ph),7.11-7.05(m,1H,Ph),7.00(d,J=1.8Hz,1H,Ph),6.79(d,J=7.2Hz,1H,Ph),6.60(s,1H,CH)3.89(s,3H,OMe),3.70(s,3H,OMe),2.54(s,3H,Me) |
(S)-28 | [α]D 20+26.22(c 1.01CHCl3)(for 67%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.13(s,4H,Ph),6.97(s,1H,Ph),6.65(s,1H,Ph),6.31(s,1H,CH),3.87(s,3H,OMe),3.70(s,3H,OMe);ESI-MS(m/z,%):285(M++H),307(M++Na); |
(S)-29 | [α]D 20+114.20(c 0.7C HCl3)(for 76%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.14(d,J=7.2Hz,1H,Ph),6.99-6.94(m,2H,Ph),6.70(d,J=1.5Hz,1H,Ph),6.68(s,1H,Ph),6.62(d,J=7.5Hz,1H,CH),3.88(s,3H,OMe),3.71(s,3H,OMe),2.46(s,3H,Me),2.34(s,3H,Me);ESI-MS(m/z,%):299(M++H),321(M++Na); |
(S)-30 | [α]D 20-88.59(c 0.72 CHCl3)(for 86%ee)1H NMR(300MHz,CDCl3)δ(ppm)8.51-848(m,2H,Ph),8.03(d,J=8.4Hz,1H,Ph),7.94(d,J=8.1Hz,1H,Ph),7.83(s,1H,Ph),7.58(t,J=7.2Hz,1H,Ph),7.49(t,J=7.8Hz,1H,Ph),7.38-7.30(m,2H,Ph),7.19-7.14(m,2H,Ph),7.57(d,J=1.5Hz,1H,CH),3.91(s,3H,OMe),3.28(s,3H,OMe);ESI-MS(m/z,%):371(M++H),393(M++Na); |
(S)-31 | [α]D 20+248.07(c 0.95CHCl3)(for 78%ee)1H NMR(300MHz,CDCl3)δ(ppm)8.33(d,J=8.4Hz,1H,Ph),7.88(t,J=9.6Hz,2H,Ph),7.64-7.52(m,2H,Ph),7.34(t,J=7.2Hz,1H,Ph),7.15(s,1H,Ph),7.05(d,J=1.8Hz,1H,Ph),7.02(s,1H,Ph),6.75(d,J=1.8Hz,1H,CH),3.91(s,3H,OMe),3.68(s,3H,OMe);ESI-MS(m/z,%):321(M++H),343(M++Na); |
(S)-32 | [α]D 20-11.63(c 0.80 CHCl3)(for 75%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.83-7.77(m,5H,Ph),7.50-7.47(m,2H,Ph),7.27-7.24(m,1H,Ph),7.02(d,J=1.5Hz,1H,Ph),6.65(d,J=1.8Hz,1H,Ph),6.50(s,1H,CH), |
3.88(s,3H,OMe),3.64(s,3H,OMe);ESI-MS(m/z,%):321(M++H),343(M++Na); | |
rac-32 | 1H NMR(300MHz,CDCl3)δ(ppm)7.83-7.77(m,5H,Ph),7.50-7.47(m,2H,Ph),7.27-7.24(m,1H,Ph),7.02(d,J=1.5Hz,1H,Ph),6.65(d,J=1.8Hz,1H,Ph),6.50(s,1H,CH),3.88(s,3H,OMe),3.64(s,3H,OMe) |
(S)-33 | [α]D 20+15.37(c 2.5CHCl3)(for 76%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.29-7.22(m,1H,Ph),6.97(d,J=2.1Hz,1H,Ph),6.89-6.84(m,2H,Ph),6.79(s,1H,Ph),6.65(d,J=1.5Hz,1H,Ph),6.31(s,1H,CH),3.87(s,3H,OMe),3.77(s,3H,OMe),3.71(s,3H,OMe);ESI-MS(m/z,%):301.2(M++H),323.2(M++Na); |
(S)-34 | [α]D 20+35.41(c 0.25CHCl3)(for 67%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.15(d,J=9Hz,2H,Ph),6.97(d,J=1.2Hz,1H,Ph),6.85(d,J=8.4Hz,2H,Ph),6.97(d,J=1.5Hz,1H,Ph),6.30(s,1H,CH),3.87(s,3H,OMe),3.79(s,3H,OMe),3.70(s,3H,OMe);ESI-MS(m/z,%):301(M++H),323(M++Na); |
(S)-35 | [α]D 20+25.02(c 0.63CHCl3)(for 82%ee)1H NMR(300MHz,CDCl3)δ(ppm)6.98(s,1H,Ph),6.68(s,1H,Ph),6.49(s,2H,Ph),6.29(s,1H,CH),3.89(s,3H,OMe),3.84(s,3H,OMe),3.81(s,3H,OMe),3.76(s,3H,OMe);ESI-MS(m/z,%):361(M++H),383(M++Na); |
(S)-36 | [α]D 20+49.70(c 0.73 CHCl3)(for 74%ee)1H NMR(300MHz,CDCl3)δ(ppm)6.94(s,1H,Ph),6.76(dd,J1=12.6Hz,J1=8.1Hz,2H,Ph),6.65(s,1H,Ph),6.59(s,1H,Ph),6.23(s,1H,CH),3.85(s,3H,OMe),3.71(s,3H,OMe);ESI-MS(m/z,%):315(M++H),337(M++Na); |
(R)-37 | [α]D 20+75.05(c 2.75 CHCl3)(for 60%ee)1H NMR(300MHz,CDCl3)δppm7.19-7.13(m,5H,Ph),6.77(d,J=1.8Hz,1H,Ph),6.66(d,J=1.8Hz,1H,Ph),5.65(dd,J1=6.6Hz,J2=3.3Hz,1H,CH),3.92(s,3H,OMe),3.79(s,3H,OMe),3.53(dd,J1=14.1Hz,J2=3.6Hz,1H,CH),3.06(dd,J1=14.1Hz,J2=6.3Hz,1H,CH);ESI-MS(m/z,%):285.0(M++H),307.0(M++Na); |
(R)-38 | [α]D 20+20.92(c 0.55 CHCl3)(for 43%ee)1H NMR(300MHz,CDCl3)δ(ppm)7.30-7.17(m,5H,Ph),6.91(s,1H,Ph),6.63(d,J=1.2Hz,1H,Ph),5.45(dd,J1=8.1Hz,J2=2.7Hz,1H,CH),3.85(s,3H,OMe),3.82(s,3H,OMe),2.76(m,2H,CH2),2.6(m,2H,CH2);ESI-MS(m/z,%):298.1(M++H),321.1(M++Na); |
(S)-39 | [α]D 20+76.48(c 0.35 CHCl3)(for 71%ee)1H NMR(300MHz,CDCl3)δ(ppm)8.03-7.92(m,3H,Ph),7.65-7.42(m,3H,Ph),7.39-7.25(m,5H,Ph),6.69(s,1H,CH);ESI-MS(n/z,%):261(M++H),283(M++Na); |
rac-40 | 1H NMR(300MHz,CDCl3)δ(ppm)6.89(d,J=2.1Hz,1H,Ph),6.66(d,J=2.1Hz,1H,Ph),5.38(d,J=2.1Hz,1H,CH),3.85(s,6H,OCH3),0.70(s,9H,CH3); |
rac-41 | 1H NMR(300MHz,CDCl3)δ(ppm)6.89(d,J=2.1Hz,1H,Ph),6.66(d,J=2.1Hz,1H,Ph),5.38(d,J=2.1Hz,1H,CH),3.85(s,6H,OCH3),2.53(m,1H,CH),1.20(d,J=6.9Hz,3H,CH3),0.55(d,J=6.9Hz,3H,CH3); |
rac-42 | 1H NMR(500MHz,Acetorne-D6):δ.8.03(d,J=7.5Hz,1H),7.36(t,J1=7.7Hz,J2=7.7Hz,1H),7.08(s,1H),6.92-7.06(m,2H),6.92(d,J=7.8Hz,1H),6.64(d,J=7.8Hz,1H),6.11(s,2H); |
rac-43 | 1H NMR(500MHz,Acetone-D6):δ.7.95(d,J=8.3Hz,1H),7.68(d,J=7.5Hz,1H),7.47(t,J1=7.3Hz,J2=7.1Hz,1H),7.37(t,J1=7.4Hz,J2=7.4Hz,1H),7.20(d,J=7.3Hz,1H),7.14(s,1H),6.60(d,J=8.6Hz,1H),6.51(s,1H); |
rac-44 | 1H NMR(400MHz,Acetone-D6):δ.7.75(d,J=7.3Hz,1H),7.57(m,1H),7.42-7.45(m,2H),7.29(d,J=7.3Hz,1H),7.06-7.10(m,2H),6.96(s,1H),3.72(s,3H). |
rac-45 | 1H NMR(400MHz,Acetone-D6):δ.7.75(t,J1=7.4Hz,J2=11.0Hz,2H),7.59(t,J1=7.8Hz,J2=7.3Hz,1H),7.47(t,J1=7.4Hz,J2=7.8Hz,1H),7.22-7.25(m,2H),7.03(t,J1=7.8Hz,J2=8.2Hz,2H),2.29(s,3H); |
rac-46 | 1H NMR(400MHz,CDCl3):δ.7.74(d,J=7.3Hz,1H),7.45-7.53(m,3H),7.39-7.41(m,2H),7.23-7.25(m,2H),7.05-7.18(m,3H),6.37(s,1H); |
rac-47 | 1H NMR(400MHz,Acetone-D6):δ.8.11(d,J=8.3Hz,1H),7.86(d,J=8.3Hz,1H),7.67-7.73(m,2H),7.53-7.59(m,2H),7.44(t,J1=7.3Hz,J2=8.3Hz,1H),7.36(d,J=8.2Hz,1H),6.95(s,1H). |
rac-48 | 1H NMR(500MHz,Acetone-D6):δ.8.37(d,J=8.0Hz,1H),8.20(d,J=8.7Hz,1H),7.95(d,J=7.9Hz,1H),7.76(d,J=7.6Hz,1H),7.71(d,J=8.7Hz,1H),7.60-7.66(m,2H),7.51-7.53(m,1H),7.45(t,J1=7.5Hz,J2=7.4Hz,1H),7·40(d,J=7.5Hz,1H),7.17(s,1H); |
rac-49 | 1H NMR(500MHz,Acetone-D6):δ.10.17(d,J=8.6Hz,1H),7.81(d,J=8.9Hz,1H),7.75(d,J=8.0Hz,1H),7.67(d,J=7.4Hz,1H),7.41(t,J1=7.5Hz,J2=7.6Hz,1H),7.20-7.33(m,4H),7.13(d,J=8.9Hz,1H),7.08(d,J=7.2Hz,1H); |
rac-50 | 1H NMR(400MHz,CDCl3):δ.7.82(d,J=8.3Hz,1H),7.71(d,J=7.3,1H),7.53-7.61(m,4H),7.47(t,J1=7.3,J2=7.4,1H),7.34-7.37(m,2H),7.21(t,J1=8.3Hz,J2=7.3Hz,1H),7.10(d,J=7.3Hz,1H),6.91(d,J=8.2Hz,1H),6.38(s,1H); |
rac-51 | 1H NMR(400MHz,CDCl3):δ.7.83(d,J=7.3Hz,IH),7.53-7.61(m,2H),7.49(t,J1=7.4Hz,J2=7.8Hz,1H),7.27-7.35(m,3H),7.13-7.22(m,2H),7.03-7.05(m,2H),6.91(d,J=7.8Hz,1H),6.41(s,IH),4.61-4.63(m,1H),1.38-1.41(m,6H); |
rac-52 | 1H NMR(400MHz,CDCl3):δ.7.79(d,J=7.3Hz,1H),7.55-7.63(m,2H),7.50(t,J1=8.2Hz,J2=7.4Hz,1H),7.39-7.42(m,1H),7.36(d,J=8.3Hz,2H),7.24-7.28(m,1H),7.22(t,J1=7.4Hz,J2=7.3Hz,1H),7.00-7.07(m,3H),6.40(s,1H); |
rac-53 | δ.7.95(d,J=7.3Hz,1H),7.69(d,J=1.8Hz,1H),7.66(t,J1=7.3Hz,J2=7.4Hz,1H),7.56-7.60(m,2H),7.49-7.54(m,2H),7.27-7.36(m,1H),6.84(d,J=3.6Hz,1H),6.66-6.67(m,1H),6.48(s,1H); |
rac-54 | 1H NMR(400MHz,CDCl3):δ.7.78(d,J=7.3Hz,1H),7.52-7.61(m,3H),7.41-7.47(m,2H),7.32-7.35(m,3H),7.21(t,J1=8.2Hz,J2=7.4Hz,1H),7.11(d,J=7.3Hz,2H),6.37(s,1H),1.37(s,9H); |
实施例2 生物测试
1.嗅觉短期记忆缺陷测试的果蝇训练及学习指数测定操作:
约100只果蝇置于自动训练仪接受训练,训练时先后通入两种气体1.5‰辛醇和1‰甲基环己醇,一种伴随电击CS+而另一种不伴随电击CS-,1个周期训练结束后立即检测其记忆。检测时将果蝇置于相对而吹的两种气味中央,任其自由选择120秒,根据选择每种气味的果蝇数目计算出学习指数。
2.嗅觉长期记忆缺陷测试的果蝇训练及学习指数测定操作:
约100只果蝇置于自动训练仪接受训练,训练时先后通入两种气体1.5‰辛醇和1‰甲基环己醇,一种伴随电击CS+而另一种不伴随电击CS-,10个周期训练结束后暗置24小时,检测其记忆。检测时将果蝇置于相对而吹的两种气味中央,任其自由选择120秒,根据选择每种气味的果蝇数目计算出学习指数。记忆指数低于野生型果蝇50%的突变体被保留下来,接受嗅觉敏感度和电击反应性实验。
指数PI计算模式:(总-选错/总×100%);
果蝇嗅敏度测定:将果蝇置于相对而吹的新鲜空气和气味中央,任其自由选择,根据选择结果计算出嗅觉敏感度指数。
电击反应性实验测定:T形迷宫的两臂分别连接管壁铺有导电铜网的塑料管,只在一侧给以电击,任果蝇自由选择2分钟,然后根据选择结果计算出电击反应性指数。
突变体确认:嗅觉敏感度和电击反应性正常,且记忆指数低于野生型果蝇50%的突变体确认为有记忆缺陷的突变体。
3.嗅觉长期记忆增强测试的果蝇训练及学习指数测定:
约125只果蝇置于自动训练仪接受训练,训练时先后通入两种气体1.5‰辛醇和1‰甲基环己醇,一种伴随电击CS+而另一种不伴随电击CS-,5个周期训练结束后暗置24小时检测其记忆,检测时将果蝇置于相对而吹的两种气味中央,任其自由选择120秒,根据选择每种气味的果蝇数目计算出学习指数。记忆指数高于野生型果蝇50%的突变体确认为有记忆缺陷的突变体。
4.实验参照:
2N是系统的对照,用的是出生3天的健康果蝇,不喂任何化学物质,用来检测系统是否稳定,一般应该在70以上;阴性对照是患有老年痴呆症而仅仅给予DMSO的9天果蝇;阳性对照是仅喂DMSO的9天健康果蝇。
具体的筛选得到的结果如下:(表2,图1、2、3、4、5、6)
表2
附图说明
图1是表2中第1~7项的化合物生测数据及系统、阳性和阴性对照;
图2是表2中第8~20项的化合物生测数据及系统、阳性和阴性对照;
图3是表2中第21~32项的化合物生测数据及系统、阳性和阴性对照;
图4是表2中第33~50项的化合物生测数据及系统、阳性和阴性对照;
图5是表2中第51~70项的化合物生测数据及系统、阳性和阴性对照;
图6是表2中第71~83项生测数据及系统、阳性和阴性对照,以及部分随机选择的表2中的若干项化合物的重复实验结果。
Claims (3)
2.如权利要求1所述的用途,其特征是所述的C1~20的烃基为R4或CH2R8,其中R8为H或R4,R4代表C1~8的烷基或烯基、C1~8的卤代烷基或烯基、苯基、萘基、蒽基、噻吩基、喹啉基、苯氧基、卤代苯氧基、苯硫基、卤代苯硫基、烯丙基,2-呋喃基、3-吡咯基、3-吲哚基、3-香豆素基、R5或/和R6或/和R7取代的苯基、2-呋喃基、3-吡咯基、3-吲哚基、3-香豆素基,或者R5或/和R6或/和R7取代的苯氧基;R5、R7为H或R6;R6为卤素、C1~4的烷基、C1~4的烷氧基、C1~4的烷硫基或C1~4的卤代烷基。
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