CN1259867A - 双－1,2,4－三唑在制备癌症治疗药物中的用途 - Google Patents
双－1,2,4－三唑在制备癌症治疗药物中的用途 Download PDFInfo
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Abstract
本发明揭示了一种能抑制哺乳动物中肿瘤和癌症的生长的药物组合物,它包括杀真菌剂。所用的具体的杀真菌剂是1,3－双—三唑基－2－丙醇衍生物。这些组合物对病毒感染也有效。
Description
技术背景
本发明涉及抑制哺乳动物，特别是人和温血动物中癌症和肿瘤生长的药物组合物。该组合物含1，3-双-三唑基-2-丙醇衍生物。
发明背景
癌症是动物和人体死亡的主要原因。确切的癌症成因尚属未知，但与诸如吸烟或暴露于致癌物质的某些活动有联系，许多研究者已报道了某些癌症和肿瘤的发生率。
已知许多类型的化疗剂对癌症和肿瘤细胞是有效的，但不是所有类型的癌症和肿瘤对这些药物都有反应。不幸的是，这些药物中的许多种也会损伤正常细胞。也未全部了解这些化疗剂的确切作用机制。
尽管癌症治疗领域有了发展，但到目前为止其主要疗法是手术、放射和化疗。化疗据说能对抗转移的癌症或特别有侵袭性的癌症。这类杀细胞剂或细胞抑制剂对生长系数大，即细胞分裂迅速的癌症最能发挥作用。到目前为止，激素，特别是雌激素、孕激素和睾酮和一些由各种微生物产生的抗生素、烷化剂和抗代谢药构成了肿瘤学家们可利用的许多疗法。很需要对癌症和肿瘤细胞有特异性、但对正常细胞没有影响的理想的细胞毒剂。不幸的是，现尚未发现这类细胞毒剂，然而在使用以快速分裂的细胞(肿瘤细胞和正常细胞)为靶的药物。
很清楚，由于其对肿瘤细胞具有某种独特的特异性而以肿瘤细胞为靶的物质的开发将是一个突破。可替换的是，也需要对肿瘤细胞有细胞毒性但对正常细胞仅有轻度作用的材料。因此本发明的一个目的是提供一种药物组合物，它能有效地抑制哺乳动物的肿瘤和癌症生长，而对正常细胞作用轻微或没有作用。
更具体的是，本发明的一个目的是提供抗癌组合物，它包括药物载体和本文定义的1，3-双-三唑基-2-丙醇衍生物，以及治疗这类癌症的方法。
本发明的这些和其它目的将从本发明的下列详细叙述中得以了解。
发明综述
一种治疗哺乳动物，特别是温血动物和人体的药物组合物，包括药物载体和有效量的选自下组的抗癌化合物。及其盐和金属复合物和醚或酯，和无毒的药学上可接受的与有机酸和无机酸反应的酸加成盐：
其中R1是任意取代的烷基、环烷基(如，环戊基或环己基)、芳基或卤代芳基(如苯基或2，4-二氯苯基)或芳烷基(如苄基)。具体的是，本发明要求了这类诸如2-(2，4-二氯苯基)-1，3-双(1H-1，2，4-三唑-1-基)丙-2-醇和它的相应的2-和4-氯苯基类似物和2，4-二氟苯基类似物的双三唑衍生物类。
这些组合物可通过将有效剂量口服、直肠给药、局部给药或非胃肠道给药、静脉给药或通过注入肿瘤来抑制人体或动物的癌症、白血病和其它肿瘤的生长。与对健康细胞有有害作用的阿霉素相比，这些组合物对健康细胞没有明显的影响。
这些组合物对病毒也是有效的。因此，本发明的一个目的是提供对HIV、疱疹、流感、鼻病毒等有效的组合物。
发明详述
A.定义：
本文所用的术语“包括”表示各种组份可在本发明的药物组合物中结合使用。因此术语“基本由…构成”和“由…构成”是术语“包括”的具体化。
本文使用的“药学上可接受的”组份适用于人体和/或动物体但没有过度的不良副作用(如毒性、刺激性和过敏反应)，具有合理的效益/风险比。
本文使用的术语“安全有效量”是指以本发明方法使用时，某一组份的量足以取得所需的治疗反应而没有过度的不良副作用(如毒性、刺激性或过敏反应)，具有合理的效益/风险比。特定的“安全有效量”显然依诸如治疗的特定疾病、病人的身体状态、被治疗的哺乳动物的类型、治疗的持续时间、同时进行的治疗(如果使用)的性质和所用的特定配方以及化合物或其衍生物的结构而异。
本文使用的“药物加成盐”是抗癌化合物与有机酸或无机酸形成的盐。较好的酸加成盐是氯化物、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、抗坏血酸盐等等。
本文的“药物载体”是药学上可接受的溶剂、悬浮剂或将抗癌剂释放到动物或人体的赋形剂。载体可为液体或固体，根据谋划中的给药的方法选择。
本文使用的“癌症”是指哺乳动物中发现的所有类型的癌或赘生物或恶性肿瘤，包括白血病。
本文使用的“抗癌化合物”是1，3-双-三唑基-2-丙醇和它们的盐。确切的1，3-双-三唑基-2-丙醇类的细节如下所述。较好的材料是商品名为“氟康唑”(fluconazole)的Pfzer出售的产品。
本文使用的“病毒”包括导致人体和其他温血动物疾病(病毒感染)的病毒，如HIV病毒、疱疹、流感和鼻病毒。
B.抗-癌化合物
抗癌化合物是1，3-双-三唑基-2-丙醇衍生物，已知它们具有抗真菌活性。它们是用来预防和根除真菌的有全身作用的杀真菌剂。化合物具有下列结构：
其中R1是任意取代的烷基、环烷基(如环戊基或环己基)，芳基或卤代芳基(如苯基或2，4-二氯苯基)或芳基烷基(如苄基)；及其盐、金属复合物及其醚或酯，及其与有机酸和无机酸形成的无毒的药学上可接受的酸加成盐。具体的是，本文使用了这类双三唑衍生物如2-(2，4-二氯苯基)-1，3-双(1H-1，2，4-三唑-1-基)丙-2-醇及其相应的2-和4-氯苯基类似物和2，4-二氟苯基类似物。较好的组合物是2-(2，4-二氟苯基)-1，3-双(1H-1，2，4-三唑-1-基)丙-2-醇及其与有机酸和无机酸的药学上可接受的酸加成盐。
根据授予Richardson(1983，9，13)的U.S.4,404,216和英国专利申请2,078,719A(1982，1，13公开)和欧洲专利申请44,605(1982，1，27公开)(两者都转让给Imperial Chemical Industries Ltd)揭示的方法来制备这些化合物。
据信这些特定的杀真菌剂能明显地缩小肿瘤或减少其生长，因为它们能抑制甾醇的合成。
C.剂量
在本发明的方法中可给予任何合适的剂量。化合物和载体的类型和用量可根据温血动物或人的种类、体重、被治疗的肿瘤、病毒、癌症或疾病而定。一般剂量在2毫克/公斤体重和约400毫克/公斤体重之间。较好的是15毫克到约150毫克/公斤体重。一般来说，人体的剂量低于小的温血动物如小鼠的剂量。剂量单位可包括单个化合物或它们与其它化合物或其它抑制癌症的化合物的混合物。剂量单位也可包括稀释剂、增量剂、载体等。剂型可为固体或凝胶形式，如丸剂、片剂、胶囊剂等，或为适合口服、直肠给药、局部给药、静注或非胃肠道给药或注入肿瘤或其周围的液体形式。
D.给药剂型
典型地是将抗癌化合物与药学上可接受的载体混合。该载体可为固体或液体，其类型一般根据所使用的给药类型来选择。活性物质可以片剂或胶囊剂的形式、作为附的粉末或以液体形式共同给药。合适的固体载体的例子包括乳糖、蔗糖、明胶和琼脂。可容易地制成胶囊和片剂，这样可方便地吞咽或咀嚼；其它的固体剂型包括颗粒剂和原粉。片剂可含合适的粘合剂、润滑剂、稀释剂、崩解剂、着色剂、调味剂、助流剂和助熔剂。合适液体剂型的例子包括在水、药学上可接受的脂肪和油、醇或包括酯的其它有机溶剂中的溶液剂或悬浮剂、乳剂、糖浆剂或酏剂、悬浮剂、由非泡腾颗粒再生的溶液剂和/或悬浮剂和由泡腾颗粒再生的泡腾制剂。这类液体剂型可含，例如合适的溶剂、防腐剂、乳化剂、悬浮剂、稀释剂、甜味剂、增稠剂和助熔剂。口服剂型任意地含有调味剂和着色剂。非胃肠道剂型和静注剂型也包括无机物和其它材料以使它们能与注射剂或选择的给药系统类型配伍。
可用来配制本发明口服剂型的药学上可接受的载体和赋形剂的具体例子如US专利3,903,297(授予Robert，1975.9.2颁布)所述。用来制备用于本发明的剂型的技术和组合物在下列参考文献中述及：7现代制药学(ModernPharmaceutics)，第9和10章(Banker & Rhodes编辑，1979)；Lieberman等，药剂：片剂(Pharmaceutical Dosage Forms：Tablets)(1981)；和Ansel，药剂导论(Introduction to Pharmaceutical Dosage Forms)第2版(1976)。
E.治疗方法
治疗方法可为治疗特定类型的癌或肿瘤或病毒有效的任何适当方法。治疗可为口服、直肠给药、局部给药、非胃肠道给药或静脉注射给药或注射入肿瘤等等。给予有效量的方法也随被治疗的肿瘤而改变。据信静注、皮下或肌注给予以合适的载体、其他抑制癌症的化合物或方便使用的稀释剂配制的1，3-双-三唑基-2-丙醇化合物的非胃肠道治疗是对温血动物给予化合物的较好的方法。
Claims (10)
1.一种治疗癌症、肿瘤、病毒的药物组合物，包括安全有效量的下式化合物，其盐和金属复合物及其醚或酯，以及无毒的药学上可接受的与有机酸和无机酸的酸加成盐：
其中R1是任意取代的烷基、环烷基(如，环戊基或环己基)、芳基或卤代芳基(如苯基或2，4-二氯苯基)或芳烷基(如苄基)。
2.根据权利要求1所述的药物组合物，包括药学上可接受的载体和安全有效量的1，3-双-三唑基-2-丙醇，它选自2-(2，4-二氯苯基)-1，3-双(1H-1，2，4-三唑-1-基)丙-2-醇和它的相应的2-和4-氯苯基类似物和2，4-二氟苯基类似物和2-(2，4-二氟苯基)-1，3-双-(1H-1，2，4-三唑-1-基)丙-2-醇，及其药学上可接受的与有机酸和无机酸反应的酸加成盐。
3.根据权利要求1或2所述的药物组合物，它用于抑制肿瘤的生长和治疗白血病。
4.根据权利要求1、2或3所述的药物组合物，其中所述的药学上可接受的酸加成盐选自氯化物、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、抗坏血酸盐及其混合物。
5.治疗温血哺乳动物的癌症和病毒感染的方法，包括以2毫克/kg体重到400毫克/kg体重的量给予权利要求1、2或4所述的1，3-双-三唑基-2-丙醇。
6.根据权利要求5所述的方法，其中所述的1，3-双-三唑基-2-丙醇以口服或肠道给药、静注给药、非胃肠道给药或注入肿瘤给药。
7.根据权利要求6所述的方法，其中所述1，3-双-三唑基-2-丙醇以固体剂型给予，其中所述的固体剂型包括选自乳糖、蔗糖、明胶和琼脂的载体。
8.根据权利要求6所述的方法，其中所述的1，3-双-三唑基-2-丙醇以液体剂型给药，其中所述的液体剂型选自水溶液剂、醇溶液剂、乳剂、悬浮剂和以非泡腾和泡腾制剂再生的悬浮剂和在药学上可接受的脂肪或油中的悬浮剂。
9.根据权利要求6、7或8所述的方法，其中所述的药学上可接受的酸加成盐选自氯化物、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、抗坏血酸盐及其混合物。
10.一种治疗动物或人体的病毒感染和癌症的单位剂量组合物，包括如权利要求1或2所述的1，3-双-三唑基-2-丙醇。
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| CN100334084C (zh) * | 2005-04-26 | 2007-08-29 | 武汉大学 | 联三唑化合物及其制备方法和用途 |
| CN100451007C (zh) * | 2006-10-12 | 2009-01-14 | 杭州宇龙化工有限公司 | 含芳醚双三氮唑类化合物及其用途 |
| CN102321036A (zh) * | 2011-07-13 | 2012-01-18 | 王健祥 | 一种氟康唑可溶性盐的制备方法 |
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| KR100396278B1 (ko) * | 1994-03-21 | 2003-11-28 | 톰슨 존 브라운 | 피부질환의치료및피부의살균용겔 |
| US6177460B1 (en) | 1995-04-12 | 2001-01-23 | The Procter & Gamble Company | Method of treatment for cancer or viral infections |
| US6262093B1 (en) | 1995-04-12 | 2001-07-17 | The Proctor & Gamble Company | Methods of treating cancer with benzimidazoles |
| US6479526B1 (en) | 1995-04-12 | 2002-11-12 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of viruses and cancers |
| US5770616A (en) * | 1995-06-07 | 1998-06-23 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of cancers |
| US6265427B1 (en) | 1995-06-07 | 2001-07-24 | The Proctor & Gamble Company | Pharmaceutical composition for the method of treating leukemia |
| US6686391B2 (en) | 1995-08-04 | 2004-02-03 | University Of Arizona Foundation | N-chlorophenylcarbamate and N-chlorophenylthiocarbamate compositions |
| MX9800998A (es) * | 1995-08-04 | 1998-04-30 | Procter & Gamble | Uso de fluconazol para inhibir el crecimiento de canceres. |
| US5900429A (en) | 1997-01-28 | 1999-05-04 | The Procter & Gamble Company | Method for inhibiting the growth of cancers |
| US6506783B1 (en) | 1997-05-16 | 2003-01-14 | The Procter & Gamble Company | Cancer treatments and pharmaceutical compositions therefor |
| US6245789B1 (en) | 1998-05-19 | 2001-06-12 | The Procter & Gamble Company | HIV and viral treatment |
| US6136835A (en) * | 1999-05-17 | 2000-10-24 | The Procter & Gamble Company | Methods of treatment for viral infections |
| US6423734B1 (en) * | 1999-08-13 | 2002-07-23 | The Procter & Gamble Company | Method of preventing cancer |
| US6407105B1 (en) | 2000-09-26 | 2002-06-18 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6608096B1 (en) * | 2000-09-26 | 2003-08-19 | University Of Arizona Foundation | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6380232B1 (en) | 2000-09-26 | 2002-04-30 | The Procter & Gamble Company | Benzimidazole urea derivatives, and pharmaceutical compositions and unit dosages thereof |
| US6462062B1 (en) | 2000-09-26 | 2002-10-08 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6515074B2 (en) * | 2001-01-22 | 2003-02-04 | Delphi Technologies, Inc. | Thermoplastic polymer alloy compositions and process for manufacture thereof |
| WO2008079973A2 (en) | 2006-12-21 | 2008-07-03 | Centocor, Inc. | Egfr binding peptides and uses thereof |
| US8278415B2 (en) | 2006-12-21 | 2012-10-02 | Centocor, Inc. | Dimeric high affinity EGFR constructs and uses thereof |
| WO2008079982A2 (en) | 2006-12-21 | 2008-07-03 | Centocor, Inc. | Liposome composition for targeting egfr receptor |
| KR100980328B1 (ko) * | 2007-12-14 | 2010-09-06 | 한국생명공학연구원 | 단백질 포스파타제의 활성을 억제하는트리아졸릴-티오-에타논 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암 예방 및 치료용조성물 |
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| US4079062A (en) * | 1974-11-18 | 1978-03-14 | Janssen Pharmaceutica N.V. | Triazole derivatives |
| US4160838A (en) * | 1977-06-02 | 1979-07-10 | Janssen Pharmaceutica N.V. | Antimicrobial and plant-growth-regulating triazole derivatives |
| GB2078719B (en) * | 1980-06-02 | 1984-04-26 | Ici Ltd | Heterocyclic compounds |
| DE3262386D1 (en) * | 1981-06-06 | 1985-03-28 | Pfizer Ltd | Antifungal agents, processes for their preparation, and pharmaceutical compositions containing them |
| DE3837463A1 (de) * | 1988-11-04 | 1990-05-10 | Bayer Ag | Substituierte bisazole, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100334084C (zh) * | 2005-04-26 | 2007-08-29 | 武汉大学 | 联三唑化合物及其制备方法和用途 |
| CN100451007C (zh) * | 2006-10-12 | 2009-01-14 | 杭州宇龙化工有限公司 | 含芳醚双三氮唑类化合物及其用途 |
| CN102321036A (zh) * | 2011-07-13 | 2012-01-18 | 王健祥 | 一种氟康唑可溶性盐的制备方法 |
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| NO975661L (no) | 1998-02-09 |
| TR199701535T1 (xx) | 1998-03-21 |
| JPH11506733A (ja) | 1999-06-15 |
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| AU717201B2 (en) | 2000-03-23 |
| NZ308393A (en) | 2001-04-27 |
| TW466113B (en) | 2001-12-01 |
| EP0831815A1 (en) | 1998-04-01 |
| HUP9802629A2 (hu) | 1999-04-28 |
| AR003430A1 (es) | 1998-08-05 |
| AU5802196A (en) | 1996-12-30 |
| BR9609093A (pt) | 1999-06-29 |
| PL324078A1 (en) | 1998-05-11 |
| HUP9802629A3 (en) | 2000-01-28 |
| KR19990022618A (ko) | 1999-03-25 |
| WO1996040120A1 (en) | 1996-12-19 |
| USRE37003E (en) | 2000-12-26 |
| SK168797A3 (en) | 1998-12-02 |
| CZ391897A3 (cs) | 1998-05-13 |
| CA2223803A1 (en) | 1996-12-19 |
| US5840742A (en) | 1998-11-24 |
| IL118426A0 (en) | 1996-09-12 |
| TR200102287T2 (tr) | 2002-06-21 |
| NO975661D0 (no) | 1997-12-05 |
| US5665751A (en) | 1997-09-09 |
| IL118426A (en) | 2001-03-19 |
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