CN1186433A - 苯并咪唑类在制备白血病治疗药物上的应用 - Google Patents
苯并咪唑类在制备白血病治疗药物上的应用 Download PDFInfo
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Abstract
本发明公开了治疗哺乳动物白血病的药物组合物。所用的此杀真菌剂是式(Ⅰ)所示苯并咪唑衍生物,其中X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基;n为小于4的正整数;Y为氢、氯、硝基、甲基或乙基;R为氢或1—8个碳原子的烷基;R2为4－噻唑基、NHCOOR1,其中R1为少于7个碳原子的脂族烃,或其药学上可接受的无机或酸加成盐。
Description
技术领域
本发明是治疗白血病(特别是人和温血动物)有用的药物组合物。本组合物包含苯并咪唑衍生物。
发明背景
癌症(包括白血病)是动物和人死亡的主要原因。白血病的确切病因尚不明确，但某些活动如吸烟或暴露于致癌物和某些类型白血病及肿瘤的发生率之间的联系已被一些研究者证明。
已证明很多类型的化疗剂对白血病有效，但并非所有类型的白血病和肿瘤细胞对这些化疗剂起反应。不幸的是，这些化疗剂中很多还损害正常细胞。这些化疗剂的确切机制并不总是明了的。
尽管癌症和白血病治疗有所进展，迄今主要的治疗方法是放射治疗和化学治疗及骨髓移植。据说化学治疗法攻击特别有侵袭性的癌症。这样的杀细胞剂或细胞生长抑制剂对生长指数大的癌症即细胞快速分裂的癌症作用最好。迄今，激素(特别是雌激素、孕酮和睾酮)、各种微生物产生的某些抗生素、烷化剂和抗代谢物构成了肿瘤学家可采用的治疗主体。对白血病、癌症和肿瘤细胞具有特异性而不影响正常细胞的理想的细胞毒剂是特别合乎需要的。不幸的是，没有发现一种这样的药物，故使用特别针对快速分裂细胞(有病变的细胞和正常细胞)的替代药物。
显然，开发由于对白血病细胞有某种独特的特异性而攻击这些细胞的物质将是一个突破点。或者，对白血病细胞具有细胞毒而对正常细胞仅有轻度作用的物质将是合乎人意的。因此，本发明的目的是提供治疗白血病有效而对正常血细胞仅有轻度作用或无作用的药物组合物。
更具体地说，本发明的目的是提供包含药物载体和本文所定义的并咪唑衍生物的组合物及治疗白血病的方法。
发明概述
治疗罹患白血病的哺乳动物(特别是温血动物和人)的药物组合物，包含药物载体和有效量的选自下组的化合物：
其中X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基、NHCOOR1，其中R1为少于7个碳原子的脂族烃，较佳为少于7个碳原子的烷基。较佳的组合物为其中R为1-8个碳原子的烷基；R2选自4-噻唑基、NHCOOR1，其中R1为甲基、乙基或异丙基，以及与有机或无机酸形成的药学上可接受的无毒的酸加成盐。最佳的化合物为2-(4-噻唑基)苯并咪唑、(丁基氨基甲酰基)-2-苯并咪唑氨基甲酸甲酯和2-甲氧基羰基氨基-苯并咪唑，以及Y为氯的那些化合物。
这些组合物可通过口服、直肠给予、局部给予或胃肠外给予或静脉给予有效量而用来抑制人或动物白血病细胞的生长。这些组合物不明显影响健康细胞。
发明的详述
A.定义
本文所用的术语“包含”指合用于本发明的药物组合物的各种成分，术语“基本上由…组成”和“由…组成”包含在术语“包含”中。
本文所用的术语“药学上可接受的”成分是适用于人和/或动物而无过度不良副作用(如毒性、刺激性和变态反应)相当于有合理的利益/风险比的成分。
本文所用的术语“安全有效量”指按本发明的方法使用时足以产生希望的治疗反应而无过度不良副作用(如毒性、刺激性和变态反应)相当于有合理的利益/风险比的成分的量。具体的“安全有效量”显然随各种因素而异，如所治疗的特定病情、患者的身体状况、受治疗的哺乳动物的种类、疗程、同时进行的治疗(如果有的话)和具体使用的制剂及化合物或其衍生物的结构。
本文所用的“药物加成盐”是抗白血病化合物和有机或无机酸的盐。较佳的这些酸加成盐为氯化物、溴化物、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲酸盐、酒石酸盐、马来酸盐、苹果酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。
本文所用的“药物载体”是释放抗白血病药给动物或人的药学上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体，是根据计划的给药方式而选择的。
本文所用的“癌症”或“白血病”指攻击正常健康血细胞或骨髓(它产生在哺乳动物中发现的血细胞)的各种类型的癌症或赘生物或恶性肿瘤。
本文所用的“抗白血病化合物”是苯并咪唑类化合物及其盐。确切的苯并咪唑化合物在下面作详细描述。较佳的物质是BASF和Hoechst，DuPont和MSD-AgVet销售的名为“thiabendazole(噻苯达唑)”、“benomyl”和“carbendazim”的产品。
B.抗白血病化合物
抗白血病化合物是以其抗真菌作用而为人所知的苯并咪唑衍生物。它们是用于预防和根除真菌的全身杀真菌剂。这些化合物具有如下结构：其中X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基、NHCOOR1，其中R1为少于7个碳原子的脂族烃，较佳为少于7个碳原子的烷基。较佳的组合物为其中R为1-8个碳原子的烷基；R2选自4-噻唑基、NHCOOR1，其中R1为甲基、乙基或异丙基，以及与有机或无机酸形成的药学上可接受的无毒的酸加成盐。
最佳的化合物为2-(4-噻唑基)苯并咪唑、(丁基氨基甲酰基)-2-苯并咪唑氨基甲酸甲酯和2-甲氧基羰基氨基-苯并咪唑，以及Y为氯、X为氢的那些化合物。
这些化合物按1973年6月12日授予Adams等的美国专利3,738,995所述方法进行制备。噻唑基衍生物按照Brown et al.，J.Am.Chem.Soc.83，1764(1961)和Grenda et al.，J.Org.Chem.，30，259(1965)所述方法进行制备。
C.剂量
本发明的方法中可给予任何合适的剂量。根据温血动物或人的种类、体重和受治疗的白血病的类型，化合物和载体的种类和数量会有很大变化。通常，在约2mg/kg体重和约400 mg/kg体重之间的剂量是合适的，以使用15-150mg/kg体重为宜。通常，人的剂量低于小的温血动物如小鼠。剂量单位可包括单一的化合物或与其它化合物或其它抑制癌症的化合物的混合物。剂量单位还可包括稀释剂、填充剂、载体等。剂量单位可以是适合于口服、直肠给药、局部给药、静脉注射或胃肠外给药或注射到骨髓或骨髓周围的固体剂型或凝胶剂型，如丸剂、片剂、胶囊剂等，或者液体剂型。
D.给药剂型
抗白血病化合物典型地与药学上可接受的载体混合。载体可以是固体或液体，其类型一般根据所用的给药剂型而进行选择。活性剂可作为附聚的粉末以片剂或胶囊剂剂型或以液体剂型共同给予(coadministered)。合适的固体载体的例子包括乳糖、蔗糖、明胶和琼脂。胶囊剂和片剂可容易地加以配制，可容易地吞服或嚼服；其它固体剂型包括颗粒剂和疏松粉末。片剂可包含合适的粘合剂、润滑剂、稀释剂、崩解剂、着色剂、调味剂、助流剂和熔化剂。合适的液体剂型的例子包括在水中、药学上可接受的脂肪和油、醇类或其它有机溶剂中的溶液或悬浮液，包括酯类、乳剂、糖浆剂或酏剂、悬浮液、溶液和/或从非泡腾颗粒重配的悬浮液和从泡腾颗粒重配的泡腾制剂。这样的液体剂型可包括例如合适的溶剂、防腐剂、乳化剂、悬浮剂、稀释剂、甜味剂、增稠剂和熔化剂。口服剂型任选地包含矫味剂和着色剂。胃肠外和静脉剂型还包括无机物和其它物质以使其与所选择的注射或给药系统相适应。
可用于配制本发明的口服剂型的药学上可接受的载体和赋形剂的具体例子在1975年9月2日授予Robert的美国专利No.3,903,297中作了描述。用于制备本发明的剂型的技术和组合物在下面的文献中作了描述：7 ModernPharmaceutics，Chapters 9 and 10(Banker&Rhodes，Editors，1979)；Lieberman et al.，Pharmaceutical Dosage Forms：Tablets(1981)；和Ansel，Introduction toPharmaceutical Dosage forms 2nd Edition(1976)。
E.治疗方法
治疗方法可以是在接受治疗的特定白血病类型的治疗上有效的任何合适的方法。治疗可以是口服、直肠给药、局部给药、静脉注射或胃肠外给药或注射到骨髓中。施用有效量的方法也因受治疗的白血病而异。据信，与合适的载体、另外的一种或几种抑制癌症化合物或稀释剂一起配制的苯并咪唑化合物的经静脉、皮下或肌肉给药的胃肠外治疗将是对温血动物投与这些化合物的较佳的方法。
下面的实施例是阐述性的，并不意味着对本发明的限制。
随机选择小鼠并分成用于治疗的组。5组感染白血病。患病小鼠给5天剂量，停2天，再给药5天，然后停3天，再给药5天，停2天。这种以不规则形式给、停剂量不是理想的治疗方案，但CarbendazimTM确实显示了正效应。一组小鼠用Cytoxan(环磷酰胺)TM(2-〔双(2-氯乙基)-氨基-1-氧代-2-氮杂-5-氧杂磷杂环己烷)处理，对照组给予canola油，三组用各种水平的CarbendazimTM((丁基氨基甲酰基)-2-苯并咪唑氨基甲酸甲酯)处理。还用一组不处理的对照组。CarbendazimTM给三个水平的剂量，4000mg/kg，2500mg/kg和1000mg/kg。CytoxanTM的剂量为125mg/kg。8天后，不处理组失去1只小鼠，第10天，8只小鼠死亡，第11天，全部10只小鼠均死亡。CytoxanTM组小鼠存活了21天以上。较高剂量组CarbendazimTM有1只小鼠在第14天死亡，第15、16和17天各有2只死亡，第20、21和22天各有1只死亡。此组的平均天数为17.3。中等剂量组第14天有2只小鼠死亡，第15天死4只，第16天1只，第19天2只，第21天1只。此组的平均天数为16.5天。最低剂量组第12、13、14和15天各死亡2只小鼠，第16和17天各死亡1只。平均天数为14.1。
Claims (10)
1.治疗白血病的药物组合物，包含安全有效量的其中X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基、NHCOOR1，其中R1为少于7个碳原子的脂族烃，或其药学上可接受的无机或酸加成盐。
2.如权利要求1所述的药物组合物，包含药学上可接受的载体和安全有效量的选自下组的苯并咪唑
其中R为氢或1-8个碳原子的烷基；R2选自4-噻唑基、NHCOOR1，其中R1为甲基、乙基或异丙基，及其药学上可接受的有机或无机酸加成盐。
3.如权利要求2所述的药物组合物，其中所述苯并咪唑化合物选自2-(4-噻唑基)苯并咪唑、(丁基氨基甲酰基)-2-苯并咪唑氨基甲酸甲酯和2-甲氧基羰基氨基-苯并咪唑。
4.如权利要求1、2或3所述的药物组合物，其中所述药学上可接受的酸加成盐为氯化物、溴化物、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲酸盐、酒石酸盐、马来酸盐、苹果酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐或其混合物。
5治疗温血动物白血病的方法，其特征在于：给予2mg/kg体重-400mg/kg体重的包含权利要求1、2、3或4所述苯并咪唑的药物组合物。
6.如权利要求5所述的方法，其中所述苯并咪唑是经口或肠道、静脉、腹腔或注射到骨髓中给药的。
7.如权利要求5或6所述的方法，其中所述苯并咪唑是以液体剂型给药的，其中所述的液体剂型选自水溶液、醇溶液、乳剂、悬浮液、从非泡腾和泡腾制剂重配的悬浮液及在药学上可接受的脂肪或油中的悬浮液。
8.治疗动物或人白血病感染的单位剂量组合物，包含权利要求1、2、3或4所述的苯并咪唑。
9.如权利要求8所述的单位剂量组合物，其中所述苯并咪唑以固体剂型给药，其中所述固体剂型包括选自乳糖、蔗糖、明胶和琼脂的载体。
10.如权利要求9所述的单位剂量组合物，其中所述苯并咪唑以液体剂型给药，其中所述液体剂型选自水溶液、乳剂、悬浮液和从非泡腾和泡腾制剂重配的悬浮液。
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| CZ391197A3 (cs) | 1998-05-13 |
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| ZA964373B (en) | 1996-09-02 |
| HUP9802634A3 (en) | 1999-05-28 |
| BR9608730A (pt) | 1999-06-29 |
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