CN104292210B - 含吡啶的一氧化氮供体类化合物、其制备方法及用途 - Google Patents
含吡啶的一氧化氮供体类化合物、其制备方法及用途 Download PDFInfo
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- CN104292210B CN104292210B CN201310295541.7A CN201310295541A CN104292210B CN 104292210 B CN104292210 B CN 104292210B CN 201310295541 A CN201310295541 A CN 201310295541A CN 104292210 B CN104292210 B CN 104292210B
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- compound
- pharmaceutically acceptable
- acceptable salt
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- alkyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 Nitric oxide donors class compound Chemical class 0.000 title claims description 13
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明公开了具有式Ⅰ结构的一类含吡啶的一氧化氮供体衍生物及其药学上可接受的盐，其中：其中n=1,2或3；R1为C1‑C4烷基、环烷基；R2、R3同时或分别为氢，C1‑C4烷基；R4为氢，C1‑C4烷基。本发明还公开了上述衍生物的制备方法，并同时公开了以该类衍生物或其药学上可接受的盐作为活性有效成分的药物组合物，以及它们在作为抗肿瘤药物，特别是在用于制备治疗乳腺癌、肺癌、胃癌药物方面的应用。
Description
技术领域
本发明属于医药技术领域，更确切地说，是涉及一类具有抗肿瘤作用的化合物及其制备方法、含有它们的药物组合物和作为抗肿瘤药物的用途。
背景技术
一氧化氮（NO）分子中，N原子外层有5个电子，O原子外层有6个电子，形成共价键后，在分子轨道上还有一个不成对电子，化学性质不稳定，半衰期短，脂溶性强，容易弥散通过细胞膜，扩散到邻近组织中，凭其活泼的化学性质，很快与靶物质作用，产生生物学效应。NO与某些药物相连，不仅可以增强药效，增加新的适应性，而且能显著降低不良反应。
生物体的一氧化氮来源包括内源性、外源性两个方面。内源性是指以L-精氨酸作为底物，通过NO合成酶的作用，生成NO和L-瓜氨酸。外源性NO供体是指释放NO性质的不同结构的化合物，它们的化学活性取决于相关氮原子的氧化状态，控制着生理性转化NO的速度和程度。理想的NO供体药物是在体内能自发稳定地释放NO，且释放简单，无需细胞代谢，长时间应用不易产生耐受性，有不同作用时间和不同作用强度的品种供选用。
外源性NO供体的重要来源是NO供体，即在体内释放NO的化合物。化学上根据与NO释放部位相连的原子的不同，将NO供体分为六类：C-NO供体，N-NO供体，O-NO供体，S-NO供体，杂环-NO供体和过渡金属-NO供体。目前研究最多也最深入的是O-NO供体，主要包含有机硝酸酯和有机亚硝酸酯。
癌症目前已成为严重危害人类健康的一大顽症。据统计世界上每年罹患癌症的人有900万，死于癌症的患者为600万，已成为仅次于心血管疾病的第二大杀手。临床上治疗肿瘤，一般采用手术、放疗、化疗三大疗法。化疗方法虽较为快捷，但治愈率很低。同时临床发现许多抗癌药物存在明显的对正常机体的损伤和毒副作用。因此，引入一氧化氮供体，开发疗效好、毒副作用低的新型化合物成为研究的方向之一。
发明内容
本发明的一个目的在于，公开了一类含吡啶的一氧化氮供体衍生物及其药用盐。
本发明的另一个目的在于，公开了以一类含吡啶的一氧化氮供体衍生物及其药用盐为主要活性成分的药物组合物。
本发明的再一个目的在于，公开了含吡啶的一氧化氮供体衍生物及其药用盐的制备方法。
本发明还有一个目的在于，公开了含吡啶的一氧化氮供体衍生物及其药用盐作为抗肿瘤药物方面的应用。
现结合本发明目的，对本发明内容进行详细阐述。
本发明具体涉及式I结构的化合物及其药学上可接受的盐：
其中：
n=1,2或3；
R1为C1-C4烷基、环烷基；
R2、R3同时或分别为氢，C1-C4烷基；
R4为氢，C1-C4烷基。
更可优选以下化合物及其药学上可接受的盐：
Ⅰ-1）3-(环丙基氨基甲酰基)-2-（（4-（1-氧代-2-硝酸酯）乙基）-3-甲基哌嗪-1-基)吡啶；
Ⅰ-2）3-(环丙基氨基甲酰基)-2-（（4-（1-氧代-3-硝酸酯）乙基）哌嗪-1-基)吡啶；
Ⅰ-3）3-(环丙基氨基甲酰基)-2-（（4-（1-氧代-3-硝酸酯）乙基）-3，3-二甲基哌嗪-1-基)吡啶；
Ⅰ-4）3-(环丙基氨基甲酰基)-2-（（4-（1-氧代-2-硝酸酯）丁基）哌嗪-1-基)吡啶；
Ⅰ-5）3-(环丙基氨基甲酰基)-2-（（4-（1-氧代-5-硝酸酯）戊基）哌嗪-1-基)吡啶；
本发明的具有式Ⅰ结构的化合物，其药学上可接受的盐系指：本发明化合物与无机酸、有机酸成盐。其中特别优选的盐是：盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、丙酸盐、丁酸盐、乳酸盐、甲磺酸盐，对甲苯磺酸盐、马来酸盐，苯甲酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、富马酸盐、牛磺酸盐、氨基酸盐、葡萄糖酸盐，等等。
式Ⅰ化合物的制备路线如下：
X为氯、溴；n、R1、R2、R3、R4定义如前所述。
将1-（3-取代基吡啶-2-基）哌嗪(Ⅱ)溶于二氯甲烷，三氯甲烷，乙腈，四氢呋喃，丙酮,乙酸乙酯，甲醇，乙醇或DMF等溶剂中，在三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠或氢氧化钾等缚酸剂的催化下，控制温度在-10℃～30℃，与卤酰卤反应得中间体Ⅲ，中间体Ⅲ与硝酸银在二氯甲烷、三氯甲烷、乙腈或甲苯等溶剂中，30～120℃避光反应最终制得化合物Ⅰ。其中各取代基的定义同前。
将反应制得各种中间体或所得产物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种，滴加无机酸或有机酸，制成药学上可接受的盐。
具体是将各种化合物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种，于冰水浴下滴加盐酸乙醚至pH=2，制成盐酸盐；或将各种化合物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种，加入等摩尔葡萄糖酸，加热搅拌得其葡萄糖酸盐；抑或将各种化合物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种，于冰水浴下滴加浓硫酸至pH=3，制成硫酸盐，等等。
此类化合物在治疗人类肿瘤疾病方面是有效的。尽管本发明的化合物可以不经任何配置直接给药，但所述的各种化合物优选以药物制剂的形式使用，给药途径可以是非肠道途径(如静脉、肌肉给药)及口服给药。
本发明化合物的药物组合物制备方法如下：使用标准和常规的技术，使本发明化合物与制剂学上可接受的固体或液体载体结合，以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成微粒或微球。固体剂型包括片剂、分散颗粒、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质，其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖、果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。液体剂型包括溶剂、悬浮液例如注射剂、粉剂等等。
药物组合物以及单元剂型中含有的活性成份(本发明化合物)的量可以根据患者的病情、医生诊断的情况特定地加以应用，所用的化合物的量或浓度在一个较宽的范围内调节。通常，活性化合物的量范围为组合物的0.5％～90％(重量)，另一优选的范围为0.5%～70%。
本发明的具有式Ⅰ结构的化合物及其药学上可接受的盐，在抗肿瘤方面有明显的效果。
下面通过药效学实验进一步说明本发明化合物的抗肿瘤作用。
体外的抗肿瘤作用
（1）实验方法：
采用经典的细胞毒活性体外检测法MTT法，检测发明化合物对体外培养的人肿瘤细胞的细胞增殖毒性。
（2）实验材料：
实验样品：式Ⅰ化合物由发明人自制提供。实验时样品以DMSO助溶，无血清DMEM培养基稀释到所需浓度，部分样品溶液呈悬浮状。
主要试剂：MTT，Amresco公司分装，批号：04M0904；完全DMEM培养基，Gibco公司产品，批号：1290007；小牛血清，兰州民海生物，批号：20060509；胰蛋白酶，Amresco公司分装，批号：016B0604；氟尿嘧啶注射液，0.25g/10ml(支)，批号：0512022，天津金耀氨基酸有限公司。
实验仪器：超净工作台，苏州净化设备厂；CO2培养箱，Thermo公司，型号：HERACell150；倒置显微镜，Carl Zeiss公司，型号：Axiovert200；酶联免疫检测仪，TECAN公司，型号：Sunrise；离心机，Kerdro公司，型号：Heraeus。
细胞株：SPCA1人肺腺癌细胞株、MCF7人乳腺癌细胞、SGC-7901人胃癌细胞，均购自中国科学院上海细胞研究所。
（3）实验步骤：
细胞培养：肿瘤细胞接种在含10%小牛血清，100IU/ml青霉素G钠盐及100μg/ml硫酸链霉素的DMEM培养液中，置于37℃、100%相对湿度、含5%CO2的培养箱中，传代3次后备用。
MTT法测定：取对数生长期的细胞，经0.25%胰蛋白酶消化后（悬浮细胞无须消化），悬浮于含10%小牛血清的DMEM培养液中，用玻璃滴管轻轻吹打成单细胞悬液，显微镜下用血细胞记数板记数活细胞。96孔培养板每孔接种细胞悬液90μL（细胞浓度调整为6～10×104个/ml），在37℃、100%相对湿度、含5%CO2、95%空气的培养箱培养24h后，每孔加10μL药液（终浓度设为：40μg/ml、20μg/ml、10μg/ml、5μg/ml和2.5μg/ml五个浓度）。另外，每个浓度设阴性对照（等浓度DMSO）及空白本底（不加细胞），各组均设6个复孔。再连续培养24h，然后每孔加入5mg/ml的MTT溶液10μL，继续培养4h后，仔细吸去上清液（悬浮细胞，需要先离心，再吸去上清）。每孔加入100μL DMSO，置微量振荡器震荡5min以使结晶完全溶解，酶标仪492nm单波长比色，测定OD值。以下述方法计算细胞生长抑制率作为评价指标。
抑制率(%)=[1-（实验组OD均值-空白组OD均值）/（对照组OD均值-空白组OD均值）]×100%。根据细胞生长抑制率，以直线回归方法计算IC50值。
（4）实验结果：
表1对体外培养的肿瘤细胞的IC50(μg/ml)
（5）结论：
根据上述体外试验结果，我们可以看出具有式Ⅰ结构的化合物对上述3种人类肿瘤细胞具有比较强的抑制作用。
具体实施方式
下面结合实例对本发明做进一步地说明。实例仅为解释性的，决不意味着它以任何方式限制本发明的范围。
参考实施例1：
中间体Ⅲ-1
在装有搅拌、冷凝器、温度计的反应瓶中加入2.60g（0.01mol）N-环丙基-2-(3-甲基哌嗪-1-基)烟酰胺，用10mL DMF将其溶解，加入三乙胺2.5g，控制温度在-10℃～2℃下，滴加氯乙酰氯1.70g（0.15mol），滴完后维持温度反应6h，自然升至室温后将反应液倒入30mL蒸馏水中，搅拌，过滤固体，真空干燥，即得中间体Ⅲ-1（HPLC：84.5%）。HRMS(m/z)：337.1426。
参照参考实施例1的方法即可方便制备化合物：中间体Ⅲ-2～Ⅲ-5。
表2中间体Ⅲ-2～Ⅲ-5
实施例1：
3-(环丙基氨基甲酰基)-2-（（4-（1-氧代-2-硝酸酯）乙基）-3-甲基哌嗪-1-基)吡啶（化合物Ⅰ-1）
在装有搅拌、冷凝器、温度计的反应瓶中加入中间体Ⅲ-1(3.2g，0.01mo1)，无水乙腈(20m1)溶解，加入硝酸银(2.0g，0.012mo1)的无水乙腈溶液(10m1)，避光搅拌下回流5h，TLC显示反应完全后冷却至室温，减压蒸干溶剂。剩余物中加入二氯甲烷(20m1)，搅拌10min，过滤，滤液减压蒸干溶剂。加入无水乙醇(30m1)，经活性炭脱色后减压蒸干，室温减压干燥过夜，得到淡黄色透明油状物Ⅰ-1(3.1g，收率90%)，纯度98.9%(HPLC法)。HRMS（m/z）：364.1615。
参照实施例1的方法即可方便制备化合物：化合物Ⅰ-2～Ⅰ-5。
表3化合物Ⅰ-2～Ⅰ-5
实施例2：
化合物Ⅰ-3成盐酸盐：取化合物Ⅰ-3淡黄色油状产物2.0g，溶于10mL无水乙醚。冰水浴冷却至0℃，滴加25%盐酸乙醚溶液至pH为2，继续于冰水浴下搅拌约1h。过滤，得白色固体。
实施例3：
化合物Ⅰ-4成葡萄糖酸盐：取化合物Ⅰ-4黄色油状产物2.0g，溶于10mL无水乙醇。加热至回流后加入等摩尔葡萄糖酸，继续于回流下搅拌反应约2h。反应完毕，于室温下静置24h。过滤，得浅黄色固体。
实施例4：
化合物Ⅰ-5成硫酸盐：取化合物Ⅰ-5淡黄色油状产物2.0g，溶于10mL无水甲醇。冰水浴冷却至5℃，滴加浓硫酸溶液至pH为3，继续于冰水浴下搅拌约0.5h。过滤，得浅黄色固体。
为了更充分地说明本发明的一氧化氮供体类化合物的药物组合物，下面提供下列制剂实施例，所述实施例仅用于说明，而不是用于限制本发明的范围。所述制剂可以使用本发明化合物中的任何活性化合物，优选使用实施1-4中所描述的化合物。
实施例5：
用下述成分制备硬明胶胶囊：
将上述成分混合后，以460mg填充入硬明胶胶囊中。
实施例6：
用下述成分制备片剂：
将原辅料预先干燥，过100目筛备用。先将处方量的辅料充分混匀。将原料药以递增稀释法加到辅料中，每次加时充分混匀2－3次，保证药与辅料充分混匀，过20目筛，在55℃通风烘箱中干燥2h，干颗粒过16目筛整粒，测定中间体含量，混合均匀，在压片机上压片。
实施例7：
注射液的制备：
取活性成分加入到已溶解山梨醇和丙二醇的注射用水中，加入药用碱调节pH值至4－8使其溶解。加入活性炭，搅拌吸附30分钟，除炭、精滤、灌封、灭菌。
实施例8：
注射用冻干粉的制备：
化合物Ⅰ-4的葡萄糖酸盐 100mg
药用碱 0.1-7%
甘露醇 55－85%
取活性成分加入注射用水，用药用碱调节pH值至4-8使其溶解。再加入甘露醇，按注射剂的要求进行高压灭菌，加入活性炭，采用微孔滤膜过滤，滤液进行分装，采用冷冻干燥法，制得疏松块状物，封口，即得。
Claims (9)
1.具有式Ⅰ结构的化合物或其药学上可接受的盐：
其中n＝1,2或3；
R1为C1-C4烷基，环烷基；
R2、R3同时或分别为氢，C1-C4烷基；
R4为氢，C1-C4烷基。
2.具有式Ⅰ结构的化合物或其药学上可接受的盐：
选自：
Ⅰ-1)
Ⅰ-2)
Ⅰ-3)
Ⅰ-4)
Ⅰ-5)
3.如权利要求1或2所述的式Ⅰ化合物或其药学上可接受的盐，其药学上可接受的盐为：式I化合物与无机酸、有机酸成的盐。
4.如权利要求3所述的式Ⅰ化合物或其药学上可接受的盐,其药学上可接受的盐为：盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、丙酸盐、丁酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、马来酸盐、苯甲酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、富马酸盐、牛磺酸盐、氨基酸盐、葡萄糖酸盐。
5.如权利要求1所述的具有式Ⅰ结构的化合物的制备方法，其特征在于：
式Ⅱ所示1-(3-取代基吡啶-2-基)哌嗪在缚酸剂存在下，与卤代烷酰卤反应得中间体Ⅲ；中间体Ⅲ与硝酸银在30～120℃避光反应，制得式Ⅰ化合物，用反应式表示如下：
X为氯、溴；n、R1、R2、R3、R4定义如权利要求1所述。
6.如权利要求5所述的制备方法，其特征在于：所述缚酸剂为三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠或氢氧化钾。
7.一种药物组合物，它包含治疗有效量的如权利要求1～2中任一项所述的具有式Ⅰ结构的化合物或其药学上可接受的盐及一种或多种药用载体。
8.如权利要求1～2中任一项所述的具有式Ⅰ结构的化合物或其药学上可接受的盐在用于制备抗肿瘤药物方面的应用。
9.如权利要求8所述的应用，在用于制备治疗乳腺癌、肺癌、胃癌药物方面的应用。
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