CN1224005A - 新型抗癌药缩胺硫脲类化合物及其制造方法 - Google Patents
新型抗癌药缩胺硫脲类化合物及其制造方法 Download PDFInfo
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- -1 thiosemicarbazides compounds Chemical class 0.000 title claims abstract description 22
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- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 150000003583 thiosemicarbazides Chemical class 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 abstract description 3
- KYJSIOGIVBTKSX-UHFFFAOYSA-N NC(CNC=S)C1=NC=CC=C1 Chemical compound NC(CNC=S)C1=NC=CC=C1 KYJSIOGIVBTKSX-UHFFFAOYSA-N 0.000 abstract 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 abstract 1
- 229940042396 direct acting antivirals thiosemicarbazones Drugs 0.000 abstract 1
- 150000007857 hydrazones Chemical class 0.000 abstract 1
- ILAXBOIRSPXAMM-UHFFFAOYSA-N methyl n-aminocarbamodithioate Chemical compound CSC(=S)NN ILAXBOIRSPXAMM-UHFFFAOYSA-N 0.000 abstract 1
- 238000003556 assay Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
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- 238000005406 washing Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 229910000474 mercury oxide Inorganic materials 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 1
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical compound CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229940046892 lead acetate Drugs 0.000 description 1
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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Abstract
一种新型抗癌药缩胺硫脲类化合物及其制造方法,其特征是该化合物的分子结构式示于附图,采用水合肼与二硫化碳、硫酸二甲酯反应,生成肼基二硫代甲酸甲酯,它与酮反应生成相应的腙,再与1－(2－吡啶基)哌嗪反应,制得缩胺硫脲类化合物[4－(2－吡啶基)哌嗪－1]硫代甲酰[1－(2吡啶基)乙撑]肼。它是一种抗癌药物,具有明显的抗癌活性。
Description
本发明涉及一种含硫、氮杂原子的环杂原子的杂环化合物，特别涉及一种新型抗癌药缩胺硫脲类化合物及其制造方法。
缩胺硫脲类化合物的一种重要原料是肼基二硫代甲酸甲酯，《有机化学杂志》Audrieth,L.F.et.al.J.Org.Chem.1954,19,733曾作过报导，该原料采用肼与二硫化碳、碘甲烷反应制成。其缺陷是所用的碘甲烷价格昂贵，生产成本较高。
本发明的目的是提供一种新型抗癌药缩胺硫脲类化合物及其制造方法，该药物具有明显的抗癌活性，是一种新型的抗癌药物。
以下详细叙述本发明的具体内容：
一种新型抗癌药缩胺硫脲类化合物，其特征在于该化合物的分子结构式为
式中R1为H，或者烃基、苯基、杂环基中的一种，R2为杂环基，如R2为2-嘧啶基，或者2-噻唑基，或者吡啶基等。
制备上述化合物采用以下三个工艺步骤：
1)等摩尔的水合肼与二硫化碳、硫酸二甲酯在异丙醇和氢氧化钾存在下，于10～15℃反应，生成肼基二硫代甲酸甲酯，其反应式为
2)肼基二硫代甲酸甲酯与等摩尔的酮在异丙醇溶剂中，于常温下反应5～24小时，生成相应的酮腙，其反应式为
3)以步骤2生成的酮腙与等摩尔的1-(2-吡啶基)哌嗪在溶剂中回流反应24～28小时，制得缩胺硫脲类化合物[4-(2-吡啶基)哌嗪-1]硫代甲酰[1-(2-吡啶基)乙撑]肼，溶剂为低碳醇，如乙醇、丙醇、异丙醇等，其反应式为
本发明的突出优点是提供一种新的具有明显的抗癌活性的新型抗癌药物。
摘要附图为本发明化合物的分子结构式图。
实施例1：
·肼基二硫代甲酸甲酯的制备。在500ml三颈瓶中加入60ml水和50ml异丙醇，水浴冷却下，分批加入49.5g(0.75mol)氢氧化钾，搅拌使全溶，在≤20℃下慢慢加入39g(0.75mol)85％的单水合肼，在10分钟加完，撤去水浴换冰浴，在10℃下于100分钟内滴加冰冷的57.5g(0.75mol)二硫化碳，加毕搅拌2小时，然后升温至15℃，于2.5小时内滴加冰冷的94.5g(0.75mol)硫酸二甲酯，加完后，再继续搅拌1小时。将生成的白色沉淀物过滤，用少量冰水淋洗，真空干燥，用二氯甲烷重结晶得到无色片状晶体55g，产率为60％,mp.81～82℃。
实例2：
·3-[1-(2-吡啶基)乙撑]肼基二硫代甲酸甲酯(Hu-la)的合成：
将2.4g(20mmol)的2-乙酰吡啶和2.44g(20mmol)肼基二硫代甲酸甲酯溶于8ml异丙醇中，于室温下搅拌24小时，将生成的黄色沉淀物过滤，用少量异丙醇淋洗，用95％乙醇重结晶得到4.7g黄色晶体，产率为85％,m.p.126-128℃。用相似方法制备如下化合物列于表1：
表1
实施例3：
[4-(2-吡啶基)哌嗪-1]硫代甲酰[1-(2-吡啶基)乙撑]肼(Hu-1b)的合成：
将2.25g(10mmol)的3-[1-(2-吡啶基)乙撑]肼基-二硫代甲酸甲酯溶于50ml乙醇，加入1.63g(10mmol)的1-(2-吡啶基)哌嗪搅拌回流48小时，用醋酸铅试纸检测已几乎无CH3SH放出。自然冷至室温，将黄色沉淀物过滤，用少量乙醇淋洗后，用乙腈重结晶得到2.5g黄色针状晶体，mp.174～176℃，产率为73.5％。
IR3438,1600,1490,1471,1368,1231,1090。
HNMR(CDCl3)δ.ppm,8.68-6.58(m；8H),4.20(d,4H),3.75(t,4H),2.44(s,3H)
U.V.(乙醇),250,0(15899)304,5(3881)399,5(10571)
元素分析，按C17H20N6S(MW340.44)计算，计算值：C为59.97％,H为5.92％,N为24.69％。实测值：C为60.28％,H为5.89％,N为25.18％。
用类似方法制备的化合物列于表2：
表2
*括号内数据为计算值
该类化合物经体外检测有明显的抗癌活性。筛选方法采用四氮唑盐还原法(MTT法)和磺酰罗丹明β-蛋白染色法(SRB法)，细胞株为P-388鼠白血病，SGC-7901人胃癌，HO89019人卵巢癌和SPC-A459人肺癌，剂量为10-5-10-7mol/l。部分结果如下：
| 计量mol/l | 10-5 10-6 10-7 | 10-5 10-6 10-7 | 10-5 10-6 10-7 | 10-5 10-6 10-7 |
| 细胞株Hu-1Hu-2Hu-3 | P388(MTT法)100 12.8 13.894.5 74.3 73.596.5 89.4 28.3 | SGC-7901(SRB法)/90.00 90.0 81.792.5 60.8 14.3 | H089019(SRB法)/88.1 79.3 22.292.6 20.0 4.4 | SPC-A459(SRB法)100 19.7 24.613.6 21.5 15.679.3 18.5 12.6 |
Claims (5)
1．一种新型抗癌药缩胺硫脲类化合物，其特征在于该化合物的分子结构式为
2．根据权利要求1的化合物，其特征在于：结构式中的R1为甲基，R2为2-嘧啶基。
3．根据权利要求1的化合物，其特征在于：结构式中的R1为甲基，R2为噻唑基。
4．根据权利要求1的化合物，其特征在于：结构式中的R1为甲基，R2为2-吡啶基。
5．一种制造权利要求1所述化合物的方法，其特征在于：等摩尔的水合肼与二硫化碳、硫酸二甲酯在异丙醇和氢氧化钾存在下，于10～15℃反应，生成肼基二硫代甲酸甲酯，它与等摩尔的酮在异丙醇溶剂中，于常温反应5～24小时，生成相应的酮腙，再与等摩尔的1-(2-吡啶基)哌嗪在乙醇溶剂中回流反应24～28小时，获得缩胺硫脲类化合物[4-(2-吡啶基)哌嗪-1]硫代甲酰[1-(2-吡啶基)乙撑]肼。
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| CN 98121914 CN1224005A (zh) | 1998-09-26 | 1998-09-26 | 新型抗癌药缩胺硫脲类化合物及其制造方法 |
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| CN 98121914 CN1224005A (zh) | 1998-09-26 | 1998-09-26 | 新型抗癌药缩胺硫脲类化合物及其制造方法 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102757425A (zh) * | 2012-07-30 | 2012-10-31 | 台州职业技术学院 | 一种新型的硫辛酰肼衍生物其及制备方法和应用 |
| US9624220B2 (en) | 2010-04-01 | 2017-04-18 | Critical Outcome Technologies Inc. | Compounds and method for treatment of HIV |
| CN113277969A (zh) * | 2021-05-17 | 2021-08-20 | 山东京博生物科技有限公司 | 一种肼基二硫代甲酸甲酯的制备方法 |
-
1998
- 1998-09-26 CN CN 98121914 patent/CN1224005A/zh active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9624220B2 (en) | 2010-04-01 | 2017-04-18 | Critical Outcome Technologies Inc. | Compounds and method for treatment of HIV |
| CN102757425A (zh) * | 2012-07-30 | 2012-10-31 | 台州职业技术学院 | 一种新型的硫辛酰肼衍生物其及制备方法和应用 |
| CN102757425B (zh) * | 2012-07-30 | 2015-01-07 | 台州职业技术学院 | 一种硫辛酰肼衍生物其及制备方法和应用 |
| CN113277969A (zh) * | 2021-05-17 | 2021-08-20 | 山东京博生物科技有限公司 | 一种肼基二硫代甲酸甲酯的制备方法 |
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