CN1164575C - 具有抗真菌活性的四氢异喹啉衍生物及其制备方法 - Google Patents

具有抗真菌活性的四氢异喹啉衍生物及其制备方法 Download PDF

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CN1164575C
CN1164575C CNB021453462A CN02145346A CN1164575C CN 1164575 C CN1164575 C CN 1164575C CN B021453462 A CNB021453462 A CN B021453462A CN 02145346 A CN02145346 A CN 02145346A CN 1164575 C CN1164575 C CN 1164575C
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CN1412182A (zh
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周有骏
王金政
蒋庆峰
吕加国
朱驹
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Second Military Medical University SMMU
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Abstract

本发明涉及医药技术领域，是具有抗真菌活性的四氢异喹啉衍生物及其制备方法。本发明化合物的结构通式为：其中R基团分别为-(CH2)2CH3，-(CH2)4CH3，-(CH2)6CH3，-(CH2)7CH3，(CH2)8CH3，-(CH2)9CH3，-(CH2)11CH3，-(CH2)15CH3，经测定上述化合物均有抗真菌活性，本发明为寻求新的抗真菌药物提供了一类新的化合物。

Description

具有抗真菌活性的四氢异喹啉衍生物及其制备方法
技术领域：
本发明涉及医药技术领域，是具有抗真菌活性的四氢异喹啉衍生物及其制备方法。
背景技术：
真菌感染日趋严重，而抗真菌药物种类有限，有的已产生耐药性，目前抗真菌药物主要有抗生素类、唑类(咪唑和三唑)、烯丙胺类、硫代氨基甲酸类、二甲基吗啉类、吡酮类、嘧啶类，而药效较好的为唑类药物。
发明内容：
本发明提供了一类新的抗真菌化合物，其为四氢异喹啉的衍生物，化学结构通式为
Figure C0214534600031
其中R基团分别为-(CH2)2CH3，-(CH2)4CH3，-(CH2)6CH3，-(CH2)7CH3，(CH2)8CH3，-(CH2)9CH3，-(CH2)11CH3，-(CH2)15CH3，
Figure C0214534600032
上述18个化合物均已合成，并经核磁共振氢谱测定，其结构及物理性质见表1。
表1  本发明四氢异喹啉衍生物的化学结构、熔点及核磁共振氢谱
       结构通式
Figure C0214534600041
化合物                                    熔点         H-NMR
           R基团        分子式
编号                                       ℃          δppm
1       -(CH2)2CH3 C14H21NO2·HCl 190～191 0.977～1.014(3H，t，CH3)
                                                  1.793～1.852(2H，m，CH2)
                                                  3.004～3.035(2H，t，CH2)
                                                  3.198～3.218(2H，t，CH2)
                                                  3.475～3.489(2H，t，CH2)
                                                  3.297(3H，s，OCH3)
                                                  3.806(3H，s，OCH3)
                                                  4.314(2H，s，CH2)
                                                  6.783(1H，s，Ar-H)
                                                  6.866(1H，s，Ar-H)
2       -(CH2)4CH3 C16H25NO2·HCl 196～197 0.880～0.914(3H，t，CH3)
                                                  1.353～1.828(6H，m，3×CH2)
                                                  3.086～3.115(2H，t，CH2)
                                                  3.234～3.274(2H，t，CH2)
                                                  3.488～3.505(2H，t，CH2)
                                                  3.821(3H，s，OCH3)
                                                  3.833(3H，s，OCH3)
                                                  4.336(2H，s，CH2)
                                                  6.810(1H，s，Ar-H)
                                                  6.901(1H，s，Ar-H)
3       -(CH2)6CH3 C18H29NO2·HCl 205～206 0.839～0.874(3H，t，CH3)
                                                  1.277～1.841(10H，m，5×CH2)
                                                  3.087～3.115(2H，t，CH2)
                                                  3.230～3.270(2H，t，CH2)
                                                  3.480～3.610(2H，t，CH2)
                                                  4.336(2H，s-CH2)
                                                  6.813，6.903(2H，s，Ar-H)
4       -(CH2)7CH3 C19H31NO2·HCl 210～212 0.832～0.860(3H，t，CH3)
                                                  1.863～1.839(12H，m，6×CH2)
                                                  3.079～3.126(2H，t，CH2)
                                                  3.228～3.268(2H，t，CH2)
                                                  3.350～3.748(2H，t，CH2)
                                                  3.822，3.834(3H，s，OCH3)
                                                  4.445(2H，s，CH2)
                                                  6.815(1H，s，Ar-H)
                                                  6.904(1H，s，Ar-H)
5       -(CH2)8CH3 C20H33NO2·HCl 214～215 0.836～0.853(3H，t，CH3)
                                                  1.266～1.827(14H，m，7×CH2)
                                                  3.090～3.156(2H，t，CH2)
                                                  3.230～3.276(2H，t，CH2)
                                                  3.366～3.374(2H，t，CH2)
                                                  3.840(3H，s，OCH3)
                                                  3.847(3H，s，OCH3)
                                                  4.455(2H，s，CH2)
                                                  6.829(1H，s，Ar-H)
                                                  6.918(1H，s，Ar-H)
化合物                                       熔点           H-NMR
           R基团                分子式
编号                                         ℃            δppm
6        -(CH2)9CH3     C21H35NO2·HCl  215～217    0.832～0.866(3H，t，CH3)
                                                           1.272～1.844(16H，m，8×CH2)
                                                           3.090～3.144(2H，t，CH2)
                                                           3.236～3.276(2H，t，CH2)
                                                           3.377～3.394(2H，t，CH2)
                                                           3.834(3H，s，OCH3)
                                                           3.847(3H，s，OCH3)
                                                           4.455(2H，s，CH2)
                                                           6.830(1H，s，Ar-H)
                                                           6.921(1H，s，Ar-H)
7        -(CH2)11CH3    C23H39NO2·HCl  207～209    0.985～1.015(3H，t，CH3)
                                                           1.412～1.974(20H，m，10×CH2)
                                                           3.248～3.276(2H，t，CH2)
                                                           3.374～3.414(2H，t，CH2)
                                                           3.986～4.004(2H，t，CH2)
                                                           6.985(3H，s，CH3)
                                                           7.073(3H，s，CH3)
                                                           4.395(2H，s，CH2)
                                                           6.985(1H，s，Ar-H)
                                                           7.073(1H，s，Ar-H)
8        -(CH2)15CH3    C17H47NO2·HCl  210～211    1.152～1.187(3H，t，CH3)
                                                           1.247～3.650(34H，m，17×CH2)
                                                           3.834(3H，t，OCH3)
                                                           3.848(3H，s，OCH3)
                                                           4.257(2H，s，CH2)
                                                           6.851(1H，s，Ar-H)
                                                           6.915(1H，s，Ar-H)
9    
Figure C0214534600051
        C18H21NO2·HCl  210～211     2.899～2.988(2H，t，CH2)
                                                           3.355～3.445(2H，t，CH2)
                                                           3.658(3H，s，OCH3)
                                                           3.698(3H，s，OCH3)
                                                           4.131(2H，s，CH2)
                                                           4.313(2H，s，CH2)
                                                           6.594(1H，s，Ar-H)
                                                           6.752(1H，s，Ar-H)
                                                           7.407～7.444(5H，m，Ar-H)
10    
Figure C0214534600052
   C22H29NO2·HCl               1.194(9H，s，CH3)
                                                           2.964～2.977(2H，t，CH2)
                                                           3.665～3.699(2H，t，CH2)
                                                           3.665(3H，s，OCH3)
                                                           3.699(3H，s，OCH3)
                                                           4.138(2H，s，CH2)
                                                           4.303(2H，s，CH2)
                                                           6.613(1H，s，Ar-H)
                                                           6.768(1H，s，Ar-H)
                                                           7.336，7.357(4H，d，Ar-H)
                                                           7.480，7.501(2H，d，Ar-H)
化合物                                                熔点       H-NMR
             R基团               分子式
编号                                                  ℃        δppm
11  
Figure C0214534600061
         C19H33NO2·HCl   201～202   2.247(2H，s，CH3)
                                                                2.944～2.975(2H，t，CH2)
                                                                3.357～3.425(2H，t，CH2)
                                                                3.663(3H，s，OCH3)
                                                                3.698(3H，s，OCH3)
                                                                4.157(2H，s，CH2)
                                                                4.269(2H，s，CH2)
                                                                6.608(1H，s，Ar-H)
                                                                6.764(1H，s，Ar-H)
                                                                7.225～7.289(4H，m，Ar-H)
12              C18H19NO2Cl2·HCl 214～215  2.991～3.022(2H，s，CH2)
                                                                 3.672(3H，s，OCH3)
                                                                 3.702(3H，s，OCH3)
                                                                 4.234(2H，s，CH2)
                                                                 6.630(1H，s，Ar-H)
                                                                 6.775(1H，s，Ar-H)
                                                                 4.353(2H，s，CH2)
                                                                 7.354～7.567(3H，m，Ar-H)
13  
Figure C0214534600063
           C18H20NO2Cl·HCl   237～238  2.955～2.987(2H，t，CH2)
                                                                 3.410～3.440(2H，t，CH2)
                                                                 3.662(3H，s，OCH3)
                                                                 3.695(3H，s，OCH3)
                                                                 4.139(2H，s，CH2)
                                                                 4.310(2H，s，CH2)
                                                                 6.606(1H，s，Ar-H)
                                                                 6.762(1H，s，Ar-H)
                                                                 7.357～7.427(4H，m，Ar-H)
14                C18H20NO2Cl·HCl   226～227 3.088～3.119(2H，t，CH2)
                                                                  3.580～3.620(2H，t，CH2)
                                                                  3.790(3H，s，OCH3)
                                                                  3.825(3H，s，OCH3)
                                                                  4.270(2H，s，CH2)
                                                                  4.445(2H，s，CH2)
                                                                  6.729(1H，s，Ar-H)
                                                                  6.992(1H，s，Ar-H)
                                                                  7.445～7.559(4H，m，Ar-H)
15                C18H20NO2Br·HCl   228～229 2.997～3.028(2H，t，CH2)
                                                                  3.420～3.580(2H，t，CH2)
                                                                  3.707(3H，s，OCH3)
                                                                  3.739(3H，s，OCH3)
                                                                  4.182(2H，s，CH2)
                                                                  4.338(2H，s，CH2)
                                                                  6.653(1H，s，Ar-H)
                                                                  6.808(1H，s，Ar-H)
                                                                  7.333～7.354(2H，d，Ar-H)
                                                                  7.607～7.629(2H，d，Ar-H)
16  
Figure C0214534600066
              C18H20NO2Br·HCl    218～219 2.961～2.993(2H，t，CH2)
                                                                   3.400～3.480(2H，t，CH2)
                                                                   3.666(3H，s，OCH3)
                                                                   3.699(3H，s，OCH3)
                                                                   4.141(2H，s，CH2)
                                                                   4.073(2H，s，CH2)
                                                                   6.609(1H，s，Ar-H)
                                                                   6.769(1H，s，Ar-H)
                                                                   7.293，7.602(4H，m，Ar-H)
化合物                                          熔点        H-NMR
            R基团         分子式
编号                                             ℃        δppm
17  
Figure C0214534600071
  C19H19NO3Cl2·HCl 187～188  3.098～3.129(2H，t，CH2)
                                                           3.590～3.615(2H，t，CH2)
                                                           3.717(3H，s，OCH3)
                                                           3.780(3H，s，OCH3)
                                                           4.415(2H，s，CH2)
                                                           4.894(2H，s，CH2CO)
                                                           6.719(1H，s，Ar-H)
                                                           6.839(1H，s，Ar-H)
                                                           7.413～7.730(3H，m，Ar-H)
18     C19H20N2O5·HCl   176～178  3.126～3.157(3H，t，CH2)
                                                           3.610～3.640(2H，t，CH2)
                                                           3.717(3H，s，OCH3)
                                                           3.755(3H，s，OCH3)
                                                           4.450(2H，s，CH2)
                                                           5.045(2H，s，CH2CO)
                                                           6.727(1H，s，Ar-H)
                                                           6.852(1H，s，Ar-H)
                                                           7.734～8.700(4H，m，Ar-H)
本发明化合物的合成路线如下：
Figure C0214534600073
其中RX的R为表1中所列的R基团，X为卤素Cl或Br。
具体实施方式：
本发明化合物的具体合成步骤为：
1、制备6，7-二甲氧基-1，2，3，4-四氢异喹啉盐酸盐(II)
将3，4-二甲氧基-苯乙胺(I)20ml与多聚甲醛3.60g在无水乙醇中室温下反应，至多聚甲醛完全反应，约2小时后，用盐酸调整pH至2左右，加热回流4小时冷却，析出6，7-二甲氧基-1，2，3，4-四氢异喹啉盐酸盐(II)白色晶体，过滤，
2、制备6，7-二甲氧基-1，2，3，4-四氢异喹啉(III)
将化合物(II)7.5g加入10％NaOH溶液100ml，再加CH2Cl2 100ml，振摇，分离CH2Cl2层，用无水K2CO3干燥，过滤，减压除去溶剂，得6，7-二甲氧基-1，2，3，4-四氢异喹啉(III)，干燥得淡黄色固体。
3、制备本发明化合物(IV)
(1)制备6，7-二甲氧基-2-丙基-1，2，3，4-四氢异喹啉盐酸盐(表1中化合物1)
取化合物(III)0.5g，CH3CH2CH2Br 0.24ml，K2CO3 0.5g溶于10ml乙醇中，回流4小时，过滤，蒸去乙醇，加入20％盐酸乙醇液，放置24小时析出沉淀，沉淀分离，乙醇重结晶，过滤，干燥即得表1中化合物1。
表1中化合物2～16按此法制备。原料RX分别为CH3(CH2)4Br，CH3(CH2)6Br；CH3(CH2)7Br，CH3(CH2)8Br，CH3(CH2)9Br，CH3(CH2)11Br，CH3(CH2)15Br，
Figure C0214534600081
(2)制备6，7-二甲氧基-2-[2，4-二氯苯乙酮]-1，2，3，4-四氢异喹啉盐酸盐(表1中化合物17)
取化合物(III)1g
Figure C0214534600082
1.2g，K2CO3 0.6g加入20ml乙醚中，室温反应1小时，60℃回流半小时，过滤，滤液通入氯化氢干燥气体，沉淀过滤，乙醇重结晶，干燥即得。
表1中化合物18的制备按此法，原料RX为
抗真菌活性测定
采用体外抑菌实验方法
实验菌株：本实验选用了8种常见的人体致病真菌作为筛选对象，其为白色念珠菌，光滑念珠菌，热带念珠菌，近平滑念珠菌，红色毛癣菌，烟曲霉菌，须发毛癣菌，絮状表皮癣菌。前四种菌为球菌，后四种菌为丝菌。
实验方法：
菌液制备：球菌在YEPD液体培养基35℃培养16小时，活化两次，用血细胞计数板计数，以RPMI1640液体培养基调整至1×103～1×105个/ml；丝菌接种至SDA斜面，35℃，培养一周，活化两次，使菌落覆盖SDA斜面，加适量RPMI1640培养液，用吸管吹打菌落，使孢子游离于RPMI1640培养液中，然后经四层无菌纱布过滤。培养液经血细胞计数板计数后，加RPMI1640培养液调整孢子浓度至1×103～1×105个/ml。
药液制备：受试药物分别用DMSO配成6.4mg/ml
接种：无菌96孔板，于每排1号孔加RPMI1640培养液100μl作空白对照，2-6号孔药物浓度分别为64，32，16，8，4μg/ml，7号孔不含药物，作阳性对照。
培养及检测：念珠菌属真菌培养24小时测定结果。丝状真菌培养7天后测定结果，用酶标分析仪于620nm测各孔OD值，与阳性对照孔比，以OD值下降80％以上的最低浓度孔中的浓度为MIC80.结果见表2。
表2化合物的抗真菌活性(MIC80μg/ml)
化合物    白念    光滑    热带    近平滑  红毛    须癣    烟曲    絮表
1         ＞64    ＞64    ＞64    ＞64    ＞64      64    ＞64    ＞64
2           64    ＞64    ＞64    ＞64    ＞64    ＞64    ＞64      16
3           64    ＞64    ＞64      4     ＞64      64    ＞64      16
4           16    ＞64      32    ＞64    ＞64      64    ＞64      16
5           16    ＞64      4     ＞64    ＞64      64    ＞64      4
6           8     ＞64      4     ＞64    ＞64      16    ＞64      4
7           4       64      4       4     ＞64      64    ＞64      4
8           4     ＞64      32    ＞64    ＞64    ＞64    ＞64      64
9         ＞64    ＞64    ＞64    ＞64      64    ＞64    ＞64    ＞64
10          64      64      64      64    ＞64    ＞64    ＞64      32
11          64    ＞64    ＞64    ＞64    ＞64    ＞64    ＞64      32
12        ＞64    ＞64    ＞64      64    ＞64      64    ＞64    ＞64
13        ＞64    ＞64    ＞64      64    ＞64      64    ＞64    ＞64
14        ＞64    ＞64    ＞64      64    ＞64    ＞64    ＞64      64
15          64    ＞64    ＞64      64      64    ＞64    ＞64    ＞64
16          64    ＞64    ＞64      64    ＞64      64    ＞64    ＞64
17        ＞64    ＞64    ＞64    ＞64    ＞64      64    ＞64      64
18        ＞64    ＞64    ＞64    ＞64    ＞64      64    ＞64    ＞64
伊曲康唑    32      16      32      4       4       4       4       4
特比萘芬    64      32      64      4       32      4       4       4
从表2可以看出，所合成的18个化合物均有不同程度的抗真菌活性，尤其是化合物7具有较好的体外抗真菌活性。
优点和积极效果
目前临床所用的抗真菌药物主要集中在唑类药物上，本发明找到了新一类抗真菌化合物，初步的体外活性试验表明，所合成的化合物具有不同程度的抗真菌活性本发明为寻求新的抗真菌药物提供了一种新的化合物。

Claims (2)

1、四氢异喹啉衍生物用于制备抗真菌药物的用途，所述的四氢异喹啉衍生物是指：
化学结构通式为：
Figure C021453460002C1
其中R基团分别为-(CH2)2CH3，-(CH2)4CH3，-(CH2)6CH3，-(CH2)7CH3，-(CH2)8CH3，-(CH2)9CH3，-(CH2)11CH3，-(CH2)15CH，
2、四氢异喹啉衍生物，化学结构通式如权利要求1所示：
其特征在于R基团分别为：-(CH2)6CH3，-(CH2)7CH3，-(CH2)8CH3，-(CH2)9CH3，-(CH2)11CH3，-(CH2)15CH3，
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