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叔丁基苯哌嗪取代硫醚类化合物的合成及其抗变态、抗炎活性
http://www.100md.com 《中国药物化学杂志》 1999年第4期
     作者:王立升 周永红 刘百里 计志忠

    单位:王立升 周永红 广西大学工业测试实验中心,南宁 530004;刘百里 计志忠 沈阳药科大学制药系,沈阳 110015

    关键词:叔丁基苯哌嗪取代硫醚类衍生物;抗变态;抗炎

    中国药物化学杂志 CHINESE JOURNAL OF MEDICINAL CHEMISTRY 1999年 第9卷 第4期 vol摘 要 设计并合成了13个未见文献报道的叔丁基苯哌嗪取代硫醚类目标化合物,并经元素分析、核磁共振氢谱及红外光谱确证其化学结构.对部分目标化合物进行了抗变态和抗炎等生物活性测定.结果表明:W01,W03,W07和W09具有较强的抗变态活性.

    Synthesis and Antiallergic,Antiinflammatory activities
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    of Substituted t-Butylphenylpiperazinylthio-ether Derivatives

    Wang Lisheng,Zhou Yonghong

    (Industrial Testing and Experimental Center,Guangxi University,Nanning 530004)

    Liu Baili,Ji Zhizhong

    (Department of Pharmaceutics,Shenyang Pharmaceutical University,Shengyang 110015)

    Abstract Thirteen substituted t-butylphenylpiperazinylthio-ether derivatives were designed and synthesized which were identified by IR,1H-NMR spectral and elemental analysis and had not been found in literature.Some of them were evaluated from the antiallergic and antiinflammatory tests.The results showed that W01,W03,W07and W09 had stronger antiallergic effects.
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    Key words substituted t-butylphenylpiperazinylthio-ether derivatives;antiallergy;antiinflammation

    1 抗变态反应及抗炎双重活性化合物的设计

    哌嗪类抗组胺药物在抗组胺药物中占有较大的比例〔1〕,其抗组胺作用大都强而持久,较少产生嗜睡,属于强效及长效H1受体拮抗剂.分析哌嗪类抗组胺药物的结构,发现大都具有二苯甲基哌嗪母核结构,故认为二苯甲基哌嗪母核为哌嗪类抗变态反应药物的活性必要部分.

    Mueller,Richard August〔2〕报道了一系列2,6-二叔丁基酚类衍生物能阻断花生四烯酸的5-脂氧酶代谢途径,阻断白三烯的形成,而白三烯是产生过敏性哮喘的炎症介质,因而该类化合物具有抗变态反应及抗炎双重活性.其中化合物(Ⅰ)和(Ⅱ)作用较强.采用与二苯甲基哌嗪并合原理,设计出13个目标化合物(Ⅲ,W01~W13),其结构和分析数据见表1,2.5.1.gif (4182 字节)
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    Tab.1 Structures,physical data of substituted t-butylphenylpiperazinylthio-ether derivatives

    Compd.

    n

    R

    Formular

    Yield/%

    mp/℃

    Elemental analysis/%

    Calcd.(Found)

    C
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    H

    N

    W01

    25.2.gif (306 字节)

    C33H46Cl2N2OS

    34.0

    115~116

    67.22

    (67.21

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    7.92

    4.75

    5.04)

    W02

    25.3.gif (341 字节)

    C33H45Cl3N2OS

    62.5

    140~142

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    (63.60

    7.27

    7.30

    4.49

    4.27)

    W03

    25.4.gif (352 字节)

    C33H45FCl2N2OS

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    112~114

    65.23

    (65.22

    7.46

    7.50

    4.61

    4.88)

    W04

    35.5.gif (326 字节)

    C34H48Cl2N2OS
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    21.6

    144~146

    67.65

    (67.62

    8.01

    8.07

    4.64

    4.69)

    W05

    35.6.gif (335 字节)

    C34H47Cl3N2OS
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    25.1

    138~139

    64.00

    (64.15

    7.42

    7.57

    4.39

    4.42)

    W06

    35.7.gif (334 字节)

    C34H47FCl2N2OS
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    33.8

    142~143

    65.69

    (65.65

    7.62

    7.68

    4.51

    4.55)

    W07

    45.8.gif (300 字节)

    C35H50Cl2N2OS
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    8.1

    110~111

    68.06

    (67.97

    8.16

    7.80

    4.54

    4.41)

    W08

    45.9.gif (334 字节)

    C35H49Cl3N2OS
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    21.9

    96~97

    64.46

    (64.43

    7.57

    7.67

    4.30

    4.55)

    W09

    45.10.gif (335 字节)

    C36H49FCl2N2S
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    18.9

    117~119

    66.13

    (66.19

    7.77

    7.82

    4.41

    4.46)

    W10

    25.11.gif (380 字节)

    C36H60Cl2N2O2S2
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    28.3

    215~217

    (dec.)

    62.87

    (62.81

    8.79

    8.96

    4.07

    4.17)

    W11

    35.12.gif (433 字节)
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    C38H64Cl2N2O2S2

    32.7

    212~213

    (dec.)

    63.76

    (63.69

    9.01

    9.11

    3.91

    4.01)

    W12
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    45.13.gif (418 字节)

    C40H68Cl2N2O2S2

    23.6

    209~210

    (dec.)

    64.58

    (64.49

    9.21

    9.40
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    3.77

    3.48)

    W13

    65.14.gif (436 字节)

    C44H76Cl2N2O2S2

    9.8

    194~195

    (dec.)

    66.06
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    (66.10

    9.58

    9.55

    3.50

    3.47)

    Tab.2 Spectral data of substituted t-butylphenylpiperazinylthio-ether derivatives

    Compd.

    IR(KBr)1.1.gif (853 字节)/cm-1
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    1H-NMR δ

    W01

    3618(O—H),2958(CH3∶C—H),2361(N+—H)

    1.37(s,18H),2.80(br s,2H),3.20~3.80(m,10H),4.50(s,1H),7.13(s,2H),7.30(m,6H),7.44(br s,4H),10.40(s,1H),2.50(d,H—DMSO-d5)

    W02

    3616(O—H),2961(CH3∶C—H),2412(N+—H),1493(Ar∶ CC ),1310(C—O),1233(O—H)
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    1.43(s,18H),3.26(br s,4H),3.48(br s,4H),3.94(br s,2H),4.31(br s,2H),5.06(s,1H),5.36(s,1H),7.25(s,2H),7.42(m,5H),7.85(br s,4H),13.60(s,1H),7.26(s,HCCl3)

    W03

    3620(O—H),2959(CH3∶C—H),2361(N+—H),1606,1511(Ar∶ CC ),1307(C—O),1235(O—H)

    1.41(s,18H),3.23(s,4H),3.44(br s,4H),3.89(br s,2H),4.25(br s,2H),5.00(s,1H),5.33(d,1H),7.10(m,2H),7.22(s,2H),7.40(m,3H),7.83(m,4H),13.43(s,1H),13.95(s,1H),7.24(d,HCCl3)
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    W04

    3619(O—H),2954(CH3∶C—H),2422(N+—H),1307(C—O),1238(O—H)

    1.40(s,18H),2.13(m,2H),2.93(t,2H),3.25(brs,2H),3.47(m,4H),4.00(m,2H),4.35(br s,2H),5.09(s,1H),5.27(s,1H),7.21(s,2H),7.40(m,6H),7.88(d,4H),13.35(s,1H),13.97(s,1H),7.26(s,HCCl3)

    W05

    3618(O—H),2956(CH3∶C—H),2535,2418(N+—H),1489(Ar∶ CC ),1306(C—O),1231(O—H)
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    1.42(s,18H),2.17(m,2H),2.85~2.93(m,8H),3.39(m,2H),3.74(br s,2H),4.37(s,1H),5.27(s,1H),7.21(s,2H),7.32(m,5H),7.47(br s,4H),12.94(s,1H),7.27(s,HCCl3)

    W06

    3619(O—H),2954(CH3∶C—H),2420(N+—H),1307(C—O),1236(O—H)

    1.39(s,18H),1.95(m,2H),2.91(t,2H),3.21~4.00(m,10H),5.42(s,1H),7.10(s,2H),7.38(m,5H),7.80(d,4H),11.62(s,1H),2.50(s,H—DMSO-d5)
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    W07

    3620(O—H),2954(CH3∶C—H),2438(N+—H),1309(C—O),1236(O—H)

    1.41(s,18H),1.61(br s,2H),2.00(br s,2H),2.82(t,2H),3.05(br s,2H),3.44(m,4H),3.94(br s,2H),4.35(br s,2H),4.92(s,1H),5.22(s,1H),7.19(s,2H),7.42(m,6H),7.83(br s,4H),13.37(s,1H),13.95(s,1H),7.25(s,HCCl3)

    W08

    3624(O—H),2956(CH3∶C—H),2436(N+—H),1310(C—O),1234(O—H)
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    1.42(s,18H),1.63(br s,2H),2.00(br s,2H),2.83(t,2H),3.06(br s,2H),3.45(m,4H),3.96(br s,2H),4.32(br s,2H),4.94(s,1H),5.23(s,1H),7.20(s,2H),7.44(m,5H),7.84(br s,4H),13.36(s,1H),13.97(s,1H),7.26(s,HCCl3)

    W09

    3617(O—H),2958(CH3∶C—H),2428(N+—H),1606,1513(Ar∶ CC ),1308(C—O),1235(O—H)

    1.42(s,18H),1.70(m,2H),2.00(s,2H),2.84(t,2H),3.12(br s,2H),3.49(br s,4H),3.95(br s,2H),4.24(br s,2H),5.20(s,1H),5.23(s,1H),7.12(m,2H),7.19(s,2H),7.42(m,3H),7.99(br s,4H),13.23(s,1H),14.24(s,1H)
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    W10

    3634(O—H),2958(CH3∶C—H),2396(N+—H),1316(C—O),1234(O—H)

    1.43(s,36H),3.26(br s,8H),3.60(m,4H),4.00(br s,4H),5.37(s,2H),7.25(s,4H),13.72(s,1H),7.28(s,HCCl3)

    W11

    3633(O—H),2958(CH3∶C—H),2362(N+—H),1312(C—O),1233(O—H)

    1.42(s,36H),2.14(m,4H),2.93(t,4H),3.42(t,4H),3.52(m,4H),4.02(m,4H),5.27(s,2H),7.21(s,4H),3.58(s,1H),7.26(s,HCCl3)
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    W12

    3635(O—H),2955(CH3∶C—H),2364(N+—H),1314(C—O),1233(O—H)

    1.37(s,36H),1.58(m,4H),1.77(br s,4H),2.87(t,4H),3.11(br s,4H),3.30(br s,4H),3.58(m,4H),7.08(s,4H),11.30(s,1H),2.50(H—DMSO-d5)

    W13

    3639(O—H),2954(CH3∶C—H),2331(N+—H),1312(C—O),1232(O—H)

    1.36(s,36H),1.49~1.68(m,16H),2.83(t,4H),3.08(br s,4H),3.45(br s,4H),3.68(br s,4H),7.07(d,4H),11.62(s,1H),2.50(t,H—DMSO-d5)
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    2 合成实验

    熔点用毛细管法测定,温度未经校正.红外光谱采用Bruker IFS 55 型仪器测定,溴化钾压片.核磁共振氢谱采用Bruker AC(E)-250 NMR仪和Bruker ARX-300 NMR仪测定,TMS为内标.元素分析采用Carlo Erba-1106型元素分析仪测定.

    2.1 1-〔2-(3,5-二叔丁基-4-羟基苯基)硫〕乙基-4-二苯甲基哌嗪盐酸盐(W01)的制备

    参考文献〔5〕制备2,6-二叔丁基-4-巯基苯酚,收率:90.5%,mp 86~88℃.

    将2.4 g(0.01 mol)2,6-二叔丁基-4-巯基苯酚加入10 mL1,2-二溴乙烷中,加入2 mL三乙胺及0.1 g碘化钾,室温搅拌8 h,水洗一次,稀盐酸洗,再水洗两次,干燥,蒸出过量1,2-二溴乙烷,残留物备用.
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    取2.0 g(0.008 mol)二苯甲基哌嗪加入上述残留物中,加入2 mL三乙胺、0.1 g碘化钾及15 mL甲苯,回流14 h,用盐酸处理后,乙醇-水重结晶,得2.0 g白色晶体,收率:34.0%,mp 115~116℃.

    W02~W13参考W01的制备方法制备,其收率及熔点见表1.

    3 药理实验

    3.1 抗变态反应药理实验结果与讨论

    选定DNCB诱导的小鼠接触性皮炎药理模型〔3〕,对8个化合物进行了抗变态活性测定,结果见表3.

    Tab.3 Effects of W-compounds on the delayed-type hypersensitivity responses to DNCB in mice
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    Treatment

    Dose/mg.kg-1

    Animal number

    Ear swelling

    (x±s)

    Inhibition/%

    P

    control

    -

    10

    33.2±6.1

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    -

    hydrocortisone

    20×5

    10

    13.4±8.6

    59.7

    <0.01

    W01

    100×5

    8

    16.4±7.2

    48.8
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    <0.01

    W02

    100×5

    8

    26.0±6.3

    6.9

    >0.05

    W03

    100×5

    8

    15.4±9.5

    53.4

    <0.01
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    W04

    100×5

    8

    28.5±9.0

    10.6

    >0.05

    W05

    100×5

    8

    29.6±7.7

    7.1

    >0.05

    W06
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    100×5

    8

    27.9±8.3

    15.9

    >0.05

    W07

    100×5

    7

    25.4±9.2

    23.3

    <0.05

    W09

    100×5
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    7

    14.2±4.9

    57.1

    <0.01

    与空白组对照,其中W01,W03,W07及W09的抑制率具有显著性.W01,W03和W09的抑制率较高,P<0.01,与氢化可的松活性相当.分析其结构,说明在该类化合物中,碳链为两个碳和四个碳时活性较高,并且含有氟原子的化合物活性较强.

    3.2 抗炎药理实验结果及讨论

    抗炎药理实验选用巴豆油致小鼠耳廓肿胀法〔4〕,结果见表4.Tab.4 Influences on crotonoil-induced ear swelling

    Treatment
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    Dose/mg.kg-1

    Animal number

    Footpad swelling

    (x±s)

    Inhibition/%

    P

    control

    -

    8

    24.19±3.44

    -

    W03
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    150

    8

    24.06±3.99

    0.54

    >0.05

    W10

    150

    8

    27.55±5.43

    0

    >0.05

    indometacin

    20
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    8

    16.56±2.82

    31.5

    <0.01

    ibuprofen

    100

    8

    22.69±4.75

    6.2

    >0.05

    抗炎药理实验结果表明W03和W10没有抗炎活性.

    作者简介:王立升 通讯联系人
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    参考文献

    1 王泽民,康葵,冯梅.当代结构药物全集.北京:北京科学技术出版社,1993.1977~2040

    2 Mueller RA.Novel heterocyclic amides.EP 190685.1986-08-13

    3 戴岳,杭秉茜,孟庆玉,等.齐墩果酸对变态反应的抑制作用.中国药理学报,1988,9(6):562~565

    4 徐叔云,卞如濂,陈修.药理实验方法学.第二版.北京:人民卫生出版社,1994.719

    5 Fuzisawa T,Hata K,Kojima T.The sulfurization of sterically hindered phenol with sulfur.A convenient synthesis of 4,4′-thio-bis-〔2,6-dialkylphenols〕and 2,6-dialkyl-4-mercaptophenols.Synthesis,1973,1:38~39

    收稿日期:1999-08-09, http://www.100md.com