CN1091102C - 7－氯－4－氧代－喹啉的制备方法及在治疗肿瘤中的应用 - Google Patents
7－氯－4－氧代－喹啉的制备方法及在治疗肿瘤中的应用 Download PDFInfo
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Abstract
本发明公开了一种化合物的制备方法和医药用途，既7-氯-4-氧代-喹啉(氯氧喹)及其制备方法和医药新用途。氯氧喹可用作制备抗癌药品，它是从喹啉酸高温脱羧制得粗品。
Description
本发明涉及一种化合物的制备方法和医药用途，即7-氯-4-氧代-喹啉的制备方法及在治疗肿瘤中的应用。
癌症是当今常见的恶性肿瘤之一，死亡率较高。现今对治疗癌症的药物较多，如中药楼莲胶囊，西药环磷酰胺，5-氟尿嘧啶等等，药效各有千秋。
本发明目的之一是提供一种7-氯-4-氧代-喹啉的制备方法；
本发明目的之二是提供一种7-氯-4-氧代-喹啉在制备抗癌药中的应用。
本发明是这样实现的：(1)7-氯-4-氧代-喹啉的化学结构式为：
其分子式为C9H6CLNO，分子量179.6，熔点为282-285℃。7-氯-4-氧代-喹啉为其化学名称，正式名称氯氧喹，商品名称为安体舒。性状为白色或类白色粉末。该化合物具有互变异构性，其互变异构体为7-氯-4-羟基-喹啉。
(2)7-氯-4-氧代-喹啉的制备方法是以二苯醚或液体石蜡或白油为导热介质，从7-氯-4-羟基-喹啉-3-羧酸高温脱羧制得粗品。将制得的粗品再用冰醋酸、活性炭经两次重结晶得到白色或类白色晶体粉末成品。其化学反应方程式为：
(3)7-氯-4-氧代-喹啉具有抗癌(镇痛)作用。可制成各种剂型如胶囊剂、片剂(其它途径—注射)。在临床可单独使用或配合化疗、放疗、手术进行控制治疗各种恶性肿瘤，如乳腺癌、原发性肝癌、肺癌，毒副作用小。并有明显的镇痛作用。
通过试验研究发现，该化合物对小鼠移植性S-180及艾氏腹水癌、实体型肿瘤均具有显著的抑瘤作用(P＜0.01或0.001)；对腹水型者可明显延长荷瘤鼠生存时间(P＜0.01)；对人成骨肉瘤细胞体外抗肿瘤试验IC50＜10μg/ml。临床试验对232例乳腺癌、96例原发性肝癌及82例肺癌(共416例)的有效率(完全缓解和部分缓解)分别为40.1、39.6及30.5％，显著高于各自对照组的有效率(P＜0.05或0.01)。从实验和临床研究均证实其抗癌活性。另外本品兼有镇痛作用，对造血及免疫功能无明显损害，因而，可明显改善患者生活质量，为其重要特点。
对该化合物的活性实验，氯氧喹75、150、300mg/kg(ig)对小鼠肉瘤180(S-180)及艾氏癌实体型(EC)肿瘤的抑制率均大于30％，且P＜0.05，三批试验结果基本一致；对三批S-180腹水型及EAC小鼠的生命延长率均＞50％，与对照组比较有明显差异(P＜0.01)。对人成骨肉瘤细胞外抗肿瘤试验，作用24小时的IC50为9.32±0.84μg/ml，48小时者为2.44±0.28μg/ml，72小时者为1.74±0.18μg/ml，均＜10μg/ml。上述抗肿瘤试验证明氯氧喹对整体小鼠S-180实体型或腹水型、EC或EAC，及体外人成骨肉瘤细胞具有明显的抗肿瘤作用。此外，还证实氯氧喹对荷瘤动物(小鼠S-180实体型)的化疗(环磷酰胺、5-氟尿嘧啶)具有明显的增效作用。有关其抗肿瘤作用机理的试验表明：氯氟喹明显减少小鼠S-180腹水癌细胞DNA量(P＜0.05)，并明显抑制荷瘤(S-180)小鼠腹水癌细胞3H-TdR的掺入，在1～10μg/ml范围内显示一定的量效关系。由此初步证实，氯氧喹对肿瘤细胞的DNA的合成具有抑制作用，并证实其作用方式属损伤DNA模板型。对人成骨肉瘤细胞体外杀伤作用的细胞生物学观察，发现氯氧喹可使其溶酶体体积增大、数目增多，这一变化可能在抗肿瘤作用中发挥一定作用。整体试验证实小鼠灌胃给予300mg/kg氯氧喹24小时后，肝微粒P-含量即有明显增加(P＜0.01)。氯氧喹与环磷酰胺和5-氟尿嘧啶合用的抗癌作用增强可能部分与此有关。
就临床作用与观察结果表明，按I期临床试验推荐的给药方案(每次400mg，3次/日，每周服5日，疗程4～6周)进行II期临床试验。对232例乳腺癌、96例原发性肝癌及82例肺癌(共416例)的有效率(CR+PR)分别为40.1、39.6及30.5％，显著高于各自对照组的有效率(P＜0.05或0.01)。基本证实氯氧喹的临床抗癌活性。疗效出现于药后2～4周。试验组全部病例均能很好耐受，416例中仅35例(8.4％)胃部不适，3例(0，7％)恶心，均未见其他不良反应，血、尿常规及肝、肾功能化验检查均无异常。且在取得疗效的同时，能改善病人生活质量。证明氯氧喹上述的剂量和给药方案是有效的。
就药理、毒理研究，本品经白求恩医科大学所作的抗肿瘤判定，在多种小鼠实体瘤和腹水瘤模型及体外瘤细胞株均证实具有显著的抑瘤作用。其抗肿瘤作用是抑制肿瘤细胞的DNA合成，其作用方式属损伤DNA模板型。本品对荷瘤鼠的化疗(环磷酰胺、5-氟尿嘧啶)有显著的增效作用。此与其增加肝微粒体P-450含量有关。在麻醉猫十二指肠给药1g/kg，对心率、血压、心电图及呼吸的频率、幅度均无明显影响；在小鼠100、300、500mg/kg灌胃，均明显抑制其自主活动。
小鼠灌胃给药LD50及其95％可信限为1.035-1.625g/kg。犬及猕猴的长毒试验，连续口服给药三个月，血液学化验、肝肾生化学检查及各脏器肉眼和镜下病理学检查均未见明显改变。本品无致突变作用及生殖毒性。
吸收、分布、消除：大鼠灌胃给药的药动学符合一级吸收、二室开放模型。胃肠吸收较快，且较完全，达峰时间0.71±0.05小时；血浆蛋白结合率37.5±2.4％；分布较广泛Vc1.9±0.4L/kg，V816.7±14.2L/kg，比较均匀，无特殊分布部位；体内代谢，主要以代谢物或原型药经尿排泄，消除半衰期53.9±5.1小时。绝对生物利用度71％。
健康志愿者的药动学符合口服给药、二室开放模型。胃肠吸收快，1.25小时血药浓度达峰值；体内分布也较快，t1/2α2.094±0.958小时，t1/2β为20.283±1.491小时。
适应症：用于乳腺癌、肺癌、原发性肝癌等癌肿治疗；或与环磷酰胺、5-氟尿嘧啶合用，以增强其抗癌作用。
用法与用量：每日20-30mg/kg，分三次服；或400mg/次，3次/日。儿童酌减。每周服药6日，连服6周为一疗程。
本发明的优点在于：(1)从实验和临床研究均证实其抗癌活性；(2)有镇痛作用，对造血及免疫功能无明显损害；(3)可明显改善患者生活质量。
Claims (5)
1、一种制备7-氯-4-氧代-喹啉的方法，其特征在于以二苯醚或液体石蜡或白油为导热介质，从7-氯-4-羟基-喹啉-3-羧酸高温脱羧制得。
2、按照权利要求1的制备方法，其特征在于所制得的产品用冰醋酸、活性碳经两次重结晶呈白色或类白色晶体粉末成品。
3、7-氯-4-氧代-喹啉用于制备抗癌药品。
4、一种抗癌药品，其特征在于含有7-氯-4-氧代-喹啉和赋形剂或载体。
5、如权利要求3的抗癌药品，其特征在于该药品是胶囊剂、片剂、散剂、冲剂及针剂等剂型。
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| CN 98114407 CN1091102C (zh) | 1998-10-21 | 1998-10-21 | 7－氯－4－氧代－喹啉的制备方法及在治疗肿瘤中的应用 |
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| CN 98114407 CN1091102C (zh) | 1998-10-21 | 1998-10-21 | 7－氯－4－氧代－喹啉的制备方法及在治疗肿瘤中的应用 |
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| CN1091102C true CN1091102C (zh) | 2002-09-18 |
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| CN105017145B (zh) * | 2012-12-12 | 2017-12-05 | 王子厚 | 具有抗肿瘤活性的氯氧喹衍生物 |
| CN103408491B (zh) * | 2013-08-22 | 2015-09-30 | 通化茂祥制药有限公司 | 氯氧喹制备方法 |
| CN104353056B (zh) * | 2014-10-22 | 2017-04-12 | 徐向志 | 一种治疗肝癌的西药组合物 |
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