CN102452990A - 神经毒性低的高哌嗪乙酰肼类衍生物及其制备方法和用途 - Google Patents
神经毒性低的高哌嗪乙酰肼类衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一种式I所示的高哌嗪乙酰肼类衍生化合物:或其药学可接受的盐、溶剂合物、立体异构体或前体药物,其中各符号如说明书所述。本发明还涉及所述化合物的制备方法,该类化合物在制备用于治疗和/或预防肿瘤和/或癌症的药物中的用途,使用此类化合物治疗和/或预防肿瘤和/或癌症的方法,以及包括治疗和/或预防有效量的此类化合物的药物组合物。本发明所述化合物能够选择性地杀死某些癌细胞,具有很强的抗癌活性,并且神经毒性大大降低,临床应用前景广阔。
Description
技术领域
本发明涉及一类新颖的神经毒性低的高哌嗪乙酰肼类化合物,本发明还涉及制备所述化合物的方法,所述化合物在制备用于治疗和/或预防肿瘤和/或癌症的药物中的用途,以及包含所述化合物的药物组合物。
背景技术
GPQ-Cl(如下)被证实是一种具有明显抗肿瘤活性的分子,并且其对正常细胞毒副作用小,具体可参见本申请人的另一中国专利申请案200910127432.8。因此开发这类化合物具有很重要的实用价值。
GPQ-Cl结构式
但小鼠体内试验表明,高剂量给药后发现GPQ-Cl具有显著的神经毒性症状(主要表现为跳跃、震颤和站立不稳等)。这很有可能是GPQ-Cl能够穿透血脑屏障并与NMDA受体发生相互作用而产生此类症状。因此设计合成GPQ-Cl的衍生物从而减少神经毒性具有很强的应用前景。
发明内容
本发明第一方面的目的是提供一类新颖的神经毒性低的高哌嗪乙酰肼类化合物。本发明的第二方面的目的是提供所述新颖的神经毒性低的高哌嗪乙酰肼类化合物的制备方法。本发明第三方面的目的是提供所述新颖的神经毒性低的高哌嗪乙酰肼类化合物在制药中的用途。此外,本发明第四方面提供包含本发明所述的含神经毒性低的高哌嗪乙酰肼类化合物的药物组合物。本发明人令人惊奇地发现,本发明提供的新颖的神经毒性低的高哌嗪乙酰肼类化合物具有有效的抗癌活性并且低的神经毒性,本发明基于上述发现而得以完成。
概括地说,本发明第一方面提供式I的化合物:
其中,
m、n选自1、2、或3;
A、B、C、D、和E各自独立地为碳原子或氮原子;以及
R、R1、R2、R3、R4和R5各自独立地选自氢原子、羟基、卤素、C2-C6链烯基、C1-C6烷基、C1-C6烷基氧基、硝基、氰基、磺酰胺基、烷基磺酰基、脒基、羧基、氨基、烷基芳基、烷氧羰基、环烷基、烷氨基、二烷氨基、烷氨基烷基,
或其药学可接受的盐、溶剂合物、立体异构体或前体药物。
根据本发明第一方面任一项的化合物,其中:
m、n选自1、2、或3;
A、B、C、D、和E各自独立地为碳原子;以及
R、R1、R2、R3、R4和R5各自独立地选自氢原子、羟基、卤素、C2-C6链烯基、C1-C6烷基、C1-C6烷基氧基、硝基、氰基、磺酰胺基、烷基磺酰基、脒基、羧基、氨基、烷基芳基、烷氧羰基、环烷基、烷氨基、二烷氨基、烷氨基烷基,
或其药学可接受的盐、溶剂合物、立体异构体或前体药物。
根据本发明第一方面任一项的化合物,其中:
m为1;
n选自1、2、或3;
A、B、C、D、和E各自独立地为碳原子;以及
R、R1、R2、R3、R4和R5各自独立地选自氢原子、羟基、卤素、C2-C6链烯基、C1-C6烷基、C1-C6烷基氧基、硝基、氰基、磺酰胺基、烷基磺酰基、脒基、羧基、氨基、烷基芳基、烷氧羰基、环烷基、烷氨基、二烷氨基、烷氨基烷基,
或其药学可接受的盐、溶剂合物、立体异构体或前体药物。
根据本发明第一方面任一项的化合物,其中:
m为1;
n为1;
A、B、C、D、和E各自独立地为碳原子;以及
R、R1、R2、R3、R4和R5各自独立地选自氢原子、羟基、卤素、C2-C6链烯基、C1-C6烷基、C1-C6烷基氧基、硝基、氰基、磺酰胺基、烷基磺酰基、脒基、羧基、氨基、烷基芳基、烷氧羰基、环烷基、烷氨基、二烷氨基、烷氨基烷基,
或其药学可接受的盐、溶剂合物、立体异构体或前体药物。
更进一步地,R、R1、R2、R3、R4和R5各自独立地选自氢原子,羟基,卤素,乙烯基,烯丙基,丙烯基,直链和支链的包含一个或多个双键的并且双键位于任意可行位置的丁烯基、戊烯基和己烯基,甲基,乙基,直链和支链丙基、丁基、戊基和己基,甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,异丁氧基,仲丁氧基,叔丁氧基,硝基,氰基,磺酰胺基,脒基,羧基和氨基。
根据本发明第一方面任一所述的化合物,其为以下化合物:
2-(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼
2-(4-对硝基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼
2-(4-间羧基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼
或其药学可接受的盐、溶剂合物、立体异构体或前体药物。
根据本发明第一方面任一项所述的化合物,其为2-(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼。
本发明第二方面提供制备本发明第一方面式I所述化合物的方法,其包括以下步骤:
(1)在有机溶剂中,使2-氯乙酸乙酯、3-溴丙酸乙酯和4-溴丁酸乙酯与高哌嗪反应,生成以下式Ia化合物:
(2)在碱性条件下,使Ia化合物与以下式Ib化合物反应,
生成以下式Ic化合物:
(3)在有机溶剂中,使水合肼与式Ic化合物反应,生成以下式Id化合物:
(5)使式I化合物与酸反应,得到式I化合物的相应盐,
其中各符号如本发明第一方面任一项所述。
根据本发明第二方面任一项所述的方法,其中所述步骤(1)是在溶剂中进行的,所述的溶剂可以是有机溶剂,该有机溶剂包括,但不限于甲醇、乙醇、二氯甲烷、甲苯、苯、四氢呋喃、或其任意两种或两种以上的混合物。
根据本发明第二方面任一项所述的方法,其中所述步骤(2)所用的碱包括,但不限于,三乙胺、碳酸钾。
根据本发明第二方面任一项所述的方法,其中所述步骤(3)和(4)是在溶剂中进行的,两个步骤所用的溶剂可以各自独立地是有机溶剂,该有机溶剂可以各个独立地包括但不限于甲醇、乙醇,优选的有机溶剂是乙醇。
根据本发明第二方面任一项所述的方法,其中所述步骤(5)所用酸为富马酸。根据本发明第二方面任一项所述的方法,其中所述步骤(5)在回流加热下进行反应。
根据本发明第二方面任一项所述的方法,其中所述步骤(5)中所得的相应盐为下式所示化合物:
其中各符号如本发明第一方面任一项所述。
根据本发明第二方面任一项所述的方法,其中所述式I的化合物为:2-(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼,或其药学可接受的盐、溶剂合物、立体异构体或前体药物。
本发明第二方面所述方法的一个实施方案中,所述式I化合物的合成路线如下:
根据本发明第二方面任一项所述的方法,其中所述的各原料或者中间体(例如式Ia化合物)是市售可得的,或者本领域技术人员可根据已有知识合成获得。
本发明第三方面提供本发明第一方面任一项所述化合物在制备用于治疗和/或预防肿瘤和/或癌症的药物中的用途。
根据本发明的第三方面的用途,其中所述的肿瘤和/或癌症可以是医学上已知的任何肿瘤和/或癌症。优选地,所述的肿瘤和/或癌症包括但不限于:
恶性肿瘤,包括但不限于膀胱癌、乳腺癌、结肠癌、肾癌肝癌、肺癌(包括小细胞肺、非小细胞癌)、头和颈癌、食管癌、胆囊癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌和皮肤癌(包括鳞状细胞癌);
淋巴系统的造血肿瘤,包括但不限于白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B-细胞淋巴癌、T-细胞淋巴癌、霍奇金淋巴癌、非-霍奇金淋巴癌、毛细胞淋巴癌、外套细胞淋巴瘤、骨髓瘤和Brukett`s氏淋巴癌;
骨髓系统的造血肿瘤,包括但不限于急性和慢性髓细胞性白血病、骨髓增生异常综合征和前髓细胞性白血病;
间质成因的肿瘤,包括但不限于纤维肉瘤和横纹肌肉瘤;
中枢成因的肿瘤,包括但不限于纤维肉瘤和横纹肉瘤;
中枢和周围神经系统的肿瘤,包括星形细胞瘤、成纤维神经瘤、神经胶质瘤和神经鞘瘤;以及
其他肿瘤,包括但不限于黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、外生性色紫颈瘤(xenoderoma pigmentosum)、甲状腺滤囊癌和卡波氏肉瘤。
本发明第四方面提供在有需要的受试者中治疗和/或预防肿瘤和/或癌症的方法,所述方法包括所述受试者施用治疗和/或预防有效量的本发明第一方面任一项所述化合物。
根据本发明的第四方面的方法,其中所述的肿瘤和/或癌症可以是医学上已知的任何肿瘤和/或癌症。优选地,所述的肿瘤和/或癌症包括但不限于:
恶性肿瘤,包括但不限于膀胱癌、乳腺癌、结肠癌、肾癌肝癌、肺癌(包括小细胞肺、非小细胞癌)、头和颈癌、食管癌、胆囊癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌和皮肤癌(包括鳞状细胞癌);
淋巴系统的造血肿瘤,包括但不限于白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B-细胞淋巴癌、T-细胞淋巴癌、霍奇金淋巴癌、非-霍奇金淋巴癌、毛细胞淋巴癌、外套细胞淋巴瘤、骨髓瘤和Brukett`s氏淋巴癌;
骨髓系统的造血肿瘤,包括但不限于急性和慢性髓细胞性白血病、骨髓增生异常综合征和前髓细胞性白血病;
间质成因的肿瘤,包括但不限于纤维肉瘤和横纹肌肉瘤;
中枢成因的肿瘤,包括但不限于纤维肉瘤和横纹肉瘤;
中枢和周围神经系统的肿瘤,包括星形细胞瘤、成纤维神经瘤、神经胶质瘤和神经鞘瘤;以及
其他肿瘤,包括但不限于黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、外生性色紫颈瘤(xenoderoma pigmentosum)、甲状腺滤囊癌和卡波氏肉瘤。
本发明第五方面提供一种药物组合物,其包括治疗和/或预防有效量的本发明第一方面任一项所述化合物以及任选的药学可接受的稀释剂、载体、赋形剂、辅料或媒介物。
根据本发明的第五方面的药物组合物,其可用于治疗和/或预防肿瘤和/或癌症。根据本发明的第五方面的药物组合物,其中所述的肿瘤和/或癌症可以是医学上已知的任何肿瘤和/或癌症。优选地,所述的肿瘤和/或癌症包括但不限于:
恶性肿瘤,包括但不限于膀胱癌、乳腺癌、结肠癌、肾癌肝癌、肺癌(包括小细胞肺、非小细胞癌)、头和颈癌、食管癌、胆囊癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌和皮肤癌(包括鳞状细胞癌);
淋巴系统的造血肿瘤,包括但不限于白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B-细胞淋巴癌、T-细胞淋巴癌、霍奇金淋巴癌、非-霍奇金淋巴癌、毛细胞淋巴癌、外套细胞淋巴瘤、骨髓瘤和Brukett`s氏淋巴癌;
骨髓系统的造血肿瘤,包括但不限于急性和慢性髓细胞性白血病、骨髓增生异常综合征和前髓细胞性白血病;
间质成因的肿瘤,包括但不限于纤维肉瘤和横纹肌肉瘤;
中枢成因的肿瘤,包括但不限于纤维肉瘤和横纹肉瘤;
中枢和周围神经系统的肿瘤,包括星形细胞瘤、成纤维神经瘤、神经胶质瘤和神经鞘瘤;以及
其他肿瘤,包括但不限于黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、外生性色紫颈瘤(xenoderoma pigmentosum)、甲状腺滤囊癌和卡波氏肉瘤。
下面对本发明的各个方面和特点作进一步的描述。
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。
本文所用的术语“烷基”是指包含指定数目碳原子的直链和支链的饱和烃基,通常例如是甲基、乙基,以及直链和支链丙基、丁基、戊基、己基等。
术语“烷基”也包括环烷基,即环状C3-C6烃基,如环丙基、环丁基、环戊基和环己基。优选地,本文所用的术语“烷基”是指包括指定数目碳原子的直链和支链的链状烷基。
本文所用的术语“烯基”是指包含指定数目碳原子的直链和支链的烯烃基,通常例如是乙烯基、烯丙基、丙烯基,以及直链和支链的包含一个或多个双键的并且双键位于任意可行位置的丁烯基、戊烯基、己烯基等。
本文所用的术语“烷氧基”单独或在组合中指烷基醚基团,其中术语“烷基”同上定义。合适的烷氧基基团的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。
术语“卤素”在本文中定义为包括氟、氯、溴或碘,还可以包括它们的同位素。
反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的,或者是可以通过文献公知的方法制得的,或者是可以通过商业购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。或者,本领域技术人员也可以根据本发明的教导制备本发明方法未能涵盖的其它式I化合物。
本发明式I化合物可以立体异构体形式存在。本发明包括所有可能的立体异构体,即顺或反单一立体异构体、或二者任何所需比例的混合物。本发明考虑了所有这种异构体(例如对映异构体和非对映异构体)的纯化形式和混合形式,包括外消旋混合物。烯醇形式也包括在本发明范围内。
本发明式I化合物即可以其本身也可以其药学可接受的盐或溶剂合物的形式使用。式I化合物的药学可接受的盐包括与药学上可接受的无机酸或有机酸、或者无机碱或者有机碱形成的常规盐。合适的酸加成盐的例子包括与盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。药用盐包括其无机或有机酸盐,其中包括但不限于:氢碘酸盐、硫酸氢盐、磷酸氢盐、丁酸盐、草酸盐、三甲基乙酸盐、己二酸盐、藻酸盐、苦味酸盐、天冬氨酸盐、葡糖酸盐、乙磺酸盐、对甲苯磺酸盐、双羟萘酸盐、丙酮酸盐、乙醇酸盐、三氟乙酸盐、对氨基水杨酸盐、双羟萘酸盐、丙酮酸盐、乙醇酸盐、三氟乙酸盐、对氨基水杨酸盐、扑酸盐和抗坏血酸盐等。合适的碱加成盐的例子包括与钠、锂、钾、镁、铝、钙、锌、N,N`-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形成的盐。本文中涉及到本发明化合物时,包括式I化合物及其药学可接受的盐或溶剂合物。本发明化合物游离碱形式与它们各自的盐形式在某些物理性质(如在极性溶剂中的溶解度)上稍有不同,但对于本发明目的,各酸式盐与它们各自游离碱形式相当。参见例如S.M.Berge,etal.,“Pharmaceutical Salts,”J.Pharm.Sci.,66:1-19(1977),其通过引用并入本文。
本文所用的术语“组合物”意指包括包含指定量的各指定成分的产品,以及直接或间接从指定量的各指定成分的组合产生的任何产品,本领域技术人员根据该解释可类似明了“药物组合物”所具有的含义,并且在某些情况下“组合物”与“药物组合物”可以互换使用。依据给药方式的不同,本发明组合物中可以含有重量比0.1%,或更合适的重量比10-60%的活性组分。但组分中包含单位剂量时,每个单位最好包含1-500毫克活性成分。
本发明的化合物可以以衍生自无机酸或有机酸的药学可接受的盐的形式使用。词语“药学可接受的盐”指在可靠的医学判断范围内,适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等,且与合理的效果/风险比相称的盐。药学可接受的盐是本领域公知的。例如,S.M.Berge,et al.,“Pharmaceutical Salts,”J.Pharm.Sci.,66:1-19(1977),其中对药学可接受的盐进行了详细描述。所述盐可通过本发明化合物的游离碱官能度与合适的有机酸反应,在本发明化合物的最终分离和纯化过程中,原位制备或者单独制备。代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、海藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(异硫代硫酸盐,isothionate)、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。同样,碱性含氮基团可用以下物质季铵化;低级烷基卤化物如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;硫酸二烷基酯如硫酸二甲酯、二乙酯、二丁酯和二戊酯;长链卤化物如癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物;芳基烷基卤化物如苄基溴和苯乙基溴及其他。因此得到可溶于或分散于水或油的产品。可用来形成药学可接受的酸加成盐的酸实例包括无机酸如盐酸、氢溴酸、硫酸和磷酸,以及有机酸如草酸、马来酸、琥珀酸和柠檬酸。
碱加成盐可通过使本发明化合物的含羧酸部分与合适的碱反应,在本发明化合物的最终分离和纯化过程中原位制备,所述的碱例如药学可接受的金属阳离子的氢氧化物,碳酸盐和碳酸氢盐,或者氨或有机伯胺、仲胺或叔胺。
药学可接受的盐包括但不限于基于碱金属或碱土金属的阳离子如锂、钠、钾、钙、镁和铝盐等,以及无毒的季胺和胺阳离子,包括铵、四甲基铵、四乙基铵、甲基铵、二甲基铵、三甲基铵、三乙基铵、二乙基铵和乙基铵等。可用于形成碱加成盐的其他代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶、哌嗪等。
本发明式I化合物或其药学可接受的盐还可以形成溶剂合物,例如水合物、醇合物等。上述化合物还可以是前药或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前衍生物是本领域技术人员公知技术。一般来说,对于本发明的目的,与药学可接受的溶剂如水、乙醇等的溶剂合物形式与非溶剂合物形式相当。
供局部给予本发明化合物的剂量形式包括散剂、喷雾剂、软膏剂和吸入剂。在无菌条件下将活性化合物与药学可接受的载体和任何防腐剂、缓冲剂或推进剂混合。眼用制剂、眼膏剂、散剂和溶液剂也被考虑在本发明范围内。
当用于上述治疗或其他治疗时,治疗有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的盐、酯或前药形式(在存在这些形式的情况下)应用。或者,所述化合物可以以含有该目的化合物与一种或多种药学可接受的赋形剂的药物组合物给药。词语“治疗有效量”的本发明化合物指以适用于任何医学治疗的合理效果/风险比治疗障碍的足够量的化合物。但应认识到,本发明化合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径和排泄率;治疗持续时间;与所采用的具体化合物组合使用或同时使用的药物;及医疗领域公知的类似因素。例如,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到所需的效果。一般说来,本发明化合物用于哺乳动物特别是人的剂量可以介于0.0001~1000mg/kg体重/天,例如介于0.001~100mg/kg体重/天,例如介于0.01~100mg/kg体重/天,例如介于0.01~10mg/kg体重/天。
发明人发现,本发明提供的新颖的式I化合物具有有效的抗肿瘤和/或抗癌活性。在此基础上,本发明提供了一种在有需要的受试者中治疗和/或预防肿瘤和/或癌症的方法,所述方法包括给所述受试者中治疗和/或预防肿瘤和/或癌症的方法,所述方法包括给所述受试者施用治疗有效量的本发明第一方面任一项所述的I化合物或其药学可接受的盐、溶剂合物、立体异构体或前体药物。术语“受试者是指患有或将会罹患或可能罹患本发明所述肿瘤和/或癌症的动物,优选例如脊椎动物,更优选例如哺乳动物,再更优选特别是例如人。术语“治疗有效量”是一种剂量,其施用于该受试者后可产生期望的生理应答,特别是产生针对本发明所述肿瘤和/或癌症有关的生理应答。
本发明还提供包含任选地与一种或多种无毒药学可接受的稀释剂、载体、赋形剂、辅料或媒介物配制在一起的本发明化合物的药物组合物。所述药物组合物可特别专门配制成以固体或液体形式供口服给药、供胃肠外注射或供直肠给药。
本发明的药物组合物可通过口服、直肠、胃肠外、池内、阴道内、腹膜内、局部(如通过散剂、软膏剂或滴剂)、口颊给予人类和其他哺乳动物,或者作为口腔喷雾剂或鼻腔喷雾剂给予。本文所用术语“胃肠外”指包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输液的给药方式。
在另一个方面,本发明提供包括本发明成分和生理可耐受稀释剂的药物组合物。在发明包括一种或多种上述化合物,其与一种或多种无毒生理可耐受或可接受的稀释剂、载体、辅料或媒介物(本文将它们统称为稀释剂)一起配制成组合物,以供胃肠外注射、鼻内传递、以固体或液体形式口服给药、直肠或局部给药等等。
适合于胃肠外注射的组合物可包括生理上可接受的无菌含水或非水溶液剂、分散剂、混悬剂或乳剂,及供重构成无菌可注射溶液剂或分散剂的无菌散剂。合适的含水或非水载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、植物油(如橄榄油)、可注射有机酯如油酸乙酯及它们的合适混合物。
这些组合物也可含有辅料,如防腐剂、湿润剂、乳化剂和分散剂。通过各种抗细菌剂和抗真菌剂,如尼泊金酯类、三氯叔丁醇、苯酚、山梨酸等,可确定防止微生物的作用。还期望包括等渗剂,例如糖类、氯化钠等。通过使用能延迟吸收的物质,例如单硬脂酸铝和明胶,可达到可注射药物形式的延长吸收。
混悬剂中除活性化合物外还可含有悬浮剂,例如乙氧基化异十八醇、聚氧乙烯山梨醇和聚氧乙烯失水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄著胶或者这些物质的混合物等。
在一些情况下,为延长药物的作用时间,期望减慢皮下或肌肉注射药物的吸收。这可通过使用水溶性差的晶体或无定形物质的液体混悬剂来实现。这样,药物的吸收速度取决于其溶解速度,而溶解速度又可取决于晶体大小和晶型。或者,胃肠外给药的药物形式的延迟吸收通过将该药物溶解于或悬浮于油媒介物中来实现。
可注射贮库制剂可通过在生物可降解聚合物如聚丙交酯-聚乙交酯(polylatide-polyglycolide)中形成药物的微胶囊基质来制备。可根据药物与聚合物之比和所采用的具体聚合物的性质,对药物释放速度加以控制。其他生物可降解聚合物的实例也包括聚原酸酯类(poly(orthoesters))和聚酐类(poly(anhydrides))。可注射贮库制剂也可通过将药物包埋于能与身体组织相容的脂质体或微乳中来制备。
可注射剂可例如通过用滤菌滤菌器过滤或通过掺入无菌固体组合物形式的灭菌剂来灭菌,所述固体组合物可在临用前溶解或分散于无菌水或其他无菌可注射介质。
供可服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中,活性化合物可与至少一种惰性的药学可接受的赋形剂或载体如柠檬酸钠或磷酸二钙和/或以下物质混合:a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅胶;b)粘合剂如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯树胶;c)保温剂如甘油;d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶液阻滞剂如石蜡;f)吸收加速剂如季胺化合物;g)湿润剂如鲸蜡醇和甘油单硬脂酸酯;h)吸附剂如高岭土和膨润土以及i)润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠和它们的混合物。在胶囊剂、片剂和丸剂的情况下,所述剂型也可包含缓冲剂。
相似类型的固体组合物使用赋形剂例如乳糖及高分子量聚乙二醇等,也可用作软胶囊和硬胶囊中的填充物。
片剂、糖衣丸剂(dragees)、胶囊剂、丸剂和颗粒剂的固体剂型可与包及和壳料如肠溶衣材和医药制剂公知的其他衣材一起制备。这些固体剂型可任选含有遮光剂,且其组成可使其只是或优先地在肠道的某个部位任选以延迟方式释放活性成分。可以使用的包埋组合物的实例包括高分子物质和蜡类。如果适合,活性化合物也可与一种或多种上述赋形剂配成微囊形式。
供口服给药的液体剂型包括药学可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。液体剂型除含有活性化合物外还可含有本领域常用的惰性稀释剂,例如水或其他溶液,增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酯乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇(tetrahydrofurfuryl alcochol)、聚乙二醇和胶水山梨醇的脂及酸酯及它们的混合物。口服组合物除包括惰性稀释剂外还可包含辅料,例如湿润剂、乳化剂和悬浮剂、甜味剂、矫味剂和香味剂。
供直肠或阴道给药的组合物优选是栓剂。栓剂可通过将本发明化合物与合适的非刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合来制备,它们在室温下为固体,但在体温下则为液体,因此可直肠腔或阴道内熔化而释放出活性化合物。
本发明化合物也可以脂质体形式给药。本领域所公知,脂质体通常用磷脂或其他脂类物质制得。脂质体由分散于含水介质中的单层或多层水液晶所形成。任何能够形成脂质体的无毒、生理上可接受和可代谢的脂质均可使用。脂质体形式的本发明组合物除含有本发明化合物外,还可含有稳定剂、防腐剂、赋形剂等。优选的脂类是天然和合成的磷脂和磷脂酰胆碱(卵磷脂),它们可单独或者一起使用。形成脂质体的方法是本领域公知的。参见例如Prescott,Ed.,Methods in Cell Biology,Volume XIV,Academic Press,New York,N.Y.(1976),p.33。
本文所用的术语“药学可接受的前盐”代表本发明化合物的前药,其在可靠的医学判断范围内适合用于人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等,与合理的效果/风险比相称且对其预定用途有效,在可能的情况下还代表本发明化合物的两性离子形式。本发明的前药可例如通过在血液中水解而在体内快速转化成上述的母体化合物。充分讨论提供于T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,V.14of the A.C.S.Symposium Series以及Edward B.Roche,ed.,Bioreversible Carriers in Drug Design.American PharmaceuticalAssociation and Pergamon Press(1987),其通过引用并入本文。
本发明式I化合物,当然还包括由它们形成的药物组合物,在抗肿瘤和/或癌症方面是有用的。
本发明人对本发明提供的新颖的式I化合物进行了抗肿瘤/抗癌活性试验的研究,结果表明,本发明的I化合物能够选择性地杀死某些癌细胞,具有很强的抗癌活性,并且能够抑制肿瘤的生长,神经毒性低的特点。与其它的抗癌药物相比,显示出具有高效、选择性和副作用较小等优点。
具体实施方式
下面通过具体的实施例和/或试验例进一步说明本发明,但是,应当理解为,这些实施例和/或试验例仅仅是用于更详细具体地说明之用,而不应理解为以任何形式限制本发明。
本发明对试验中使用到的材料及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的,但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚,在下文中,如果未特别说明,本发明所用材料和操作方法是本领域公知的。
实施例1、2-(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼富马酸的制备
反应流程如下:
步骤1.室温下,电磁搅拌的条件下,向装有10g(100mmol)高哌嗪、20ml甲醇的反应瓶中逐滴加入2.45g(20mmol)2-氯乙酸乙酯和20ml甲醇的混合溶液。半小时内滴加完毕,室温下搅拌5小时,反应结束以后,过滤,滤饼用少量丙酮洗涤,合并滤液,浓缩去除甲醇,残液中加入水,乙酸乙酯萃取二次,合并,无水MgS04干燥,浓缩,残液硅胶柱分离,得到产物([1,4]二氮杂环庚烷-1-基)乙酸乙酯1.86g,产率50%。质谱:187(M+1)。
步骤2.室温下,电磁搅拌的条件下,向反应瓶中加入10ml丙酮、1.86g(10mmol)的([1,4]二氮杂环庚烷-1-基)乙酸乙酯和1.01g(10mmol)的三乙胺,搅拌均匀,然后分批加入2.5g(10mmol)的对磺酰胺基苄基溴,室温反应6小时,检测反应结束以后,停止反应。过滤,滤饼用少量丙酮洗涤,合并滤液,浓缩,残渣硅胶柱纯化,得到类白色固体产物(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)乙酸乙酯3g,产率84.5%。质谱:356(M+1)。
步骤3.室温下,电磁搅拌的条件下,向反应瓶中加入5ml甲醇和1.77g(5mmol)的(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)乙酸乙酯,搅拌均匀,然后,缓慢滴加0.88g(15mmol)的85%的水合肼。加热回流反应3小时,检测反应结束以后,停止反应。110℃高真空抽干浓缩得到产物(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)乙酰肼1.6g,产率94%,质谱:342(M+1)。
步骤4.室温下,电磁搅拌的条件下,向反应瓶中加入10ml甲醇和1.36g(4mmol)的(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)乙酰肼,搅拌均匀,然后加热到60℃,滴加648mg(4mmol)的2-羟基-3-烯丙基苯甲醛,随着反应进行有大量固体析出,继续搅拌反应1小时,然后检测反应结束以后,停止反应,冷却到室温析晶,固体通过过滤收集,红外烘干得到白色固体产物2-(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼1.8g,产率92.7%。氢谱(400MHz,DMSO):11.93(s,1H);11.48(s,1H);8.49(s,1H);7.78(d,2H);7.51(d,2H);7.1-7.3(m,4H);6.8(m,1H);6.0(m,1H);5.0(m,2H);3.62(s,2H);3.36(m,4H);2.4-2.65(m,8H);1.75(t,2H)。质谱:486(M+1)。
步骤5.室温下,电磁搅拌的条件下,向反应瓶中加入5ml甲醇、1.36g(4mmol)的(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)乙酰肼和464mg(4mmol)的富马酸,搅拌均匀,然后加热回流反应1小时,检测反应结束以后,停止反应。降温析出大量白色固体,过滤干燥得到2-(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼富马酸。
实施例2、2-(4-对硝基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼的制备
反应流程如下:
步骤1.室温下,电磁搅拌的条件下,向反应瓶中加入10ml丙酮、1.86g(10mmol)的([1,4]二氮杂环庚烷-1-基)乙酸乙酯和1.01g(10mmol)的三乙胺,搅拌均匀,然后分批加入2.16g(10mmol)的对硝基苄基溴,室温反应6小时,检测反应结束以后,停止反应。过滤,滤饼用少量丙酮洗涤,合并滤液,浓缩,残渣硅胶柱纯化,得到类白色固体产物(4-对硝基苄基-[1,4]二氮杂环庚烷-1-基)乙酸乙酯3g,产率93.4%。质谱:322(M+1)。
步骤2.室温下,电磁搅拌的条件下,向反应瓶中加入5ml甲醇和1.61g(5mmol)的(4-对硝基苄基-[1,4]二氮杂环庚烷-1-基)乙酸乙酯,搅拌均匀,然后,缓慢滴加0.88g(15mmol)的85%的水合肼。加热回流反应3小时,检测反应结束以后,停止反应。110℃高真空抽干浓缩得到产物(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)乙酰肼1.7g,产率94.4%。质谱:308(M+1)。
步骤3.室温下,电磁搅拌的条件下,向反应瓶中加入5ml甲醇和1.23g(4mmol)的(4-对硝基苄基-[1,4]二氮杂环庚烷-1-基)乙酰肼,加热到℃搅拌使固体逐渐溶解,然后缓慢滴加648mg(4mmol)的2-羟基-3-烯丙基苯甲醛。恒温反应1小时,检测反应结束以后,停止反应。冷却到室温析晶,固体通过过滤收集,红外烘干得到白色固体产物2-(4-对硝基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼1.7g,产率94.4%。氢谱(400MHz,DMSO):11.83(s,1H);11.38(s,1H);8.44(s,1H);7.68(d,2H);7.51(d,2H);7.1-7.35(m,2H);6.82(m,1H);6.10(m,1H);5.05(m,2H);3.52(s,2H);3.36(m,4H);2.4-2.65(m,8H);1.83(t,2H)。质谱:452(M+1)。
实施例3、2-(4-间羧基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼的制备
反应流程如下:
步骤1.室温下,电磁搅拌的条件下,向反应瓶中加入10ml丙酮、1.86g(10mmol)的([1,4]二氮杂环庚烷-1-基)乙酸乙酯和2.02g(20mmol)的三乙胺,搅拌均匀,然后分批加入1.70g(10mmol)的间氯甲基苯甲酸,室温反应6小时,检测反应结束以后,停止反应。过滤,滤饼用少量丙酮洗涤,合并滤液,浓缩,残渣硅胶柱纯化,得到类白色固体产物(4-间羧基苄基-[1,4]二氮杂环庚烷-1-基)乙酸乙酯2.4g,产率75%。质谱:321(M+1)。
步骤2.室温下,电磁搅拌的条件下,向反应瓶中加入5ml甲醇和1.61g(5mmol)的(4-间羧基苄基-[1,4]二氮杂环庚烷-1-基)乙酸乙酯,搅拌均匀,然后,缓慢滴加0.88g(15mmol)的85%的水合肼。加热回流反应3小时,检测反应结束以后,停止反应。110℃高真空抽干浓缩得到产物(4-间羧基苄基-[1,4]二氮杂环庚烷-1-基)乙酰肼1.7g,产率94.4%。质谱:307(M+1)。
步骤3.室温下,电磁搅拌的条件下,向反应瓶中加入5ml甲醇和1.23g(4mmol)的(4-间羧基苄基-[1,4]二氮杂环庚烷-1-基)乙酰肼,加热到℃搅拌使固体逐渐溶解,然后缓慢滴加648mg(4mmol)的2-羟基-3-烯丙基苯甲醛。恒温反应1小时,检测反应结束以后,停止反应。冷却到室温析晶,固体通过过滤收集,红外烘干得到白色固体产物2-(4-对硝基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼1.7g,产率94.4%。氢谱(400MHz,DMSO):11.95(s,1H);11.83(s,1H);11.38(s,1H);8.44(s,1H);7.68(d,2H);7.51(d,2H);7.1-7.35(m,2H);6.82(m,1H);6.10(m,1H);5.05(m,2H);3.52(s,2H);3.36(m,4H);2.4-2.65(m,8H);1.83(t,2H)。质谱:451(M+1)。
实验例1、生物学试验
体外活性筛选采用MTT法检测SM-5(实施例1的化合物)对人结肠癌细胞HCT-116、人大细胞肺癌细胞NCI-H460、人原髓细胞白血病细胞HL-60、人黑色素瘤细胞A375、人结肠癌细胞SW480、人慢性髓原白血病细胞K562、人神经母细胞瘤细胞SK、人前列腺癌细胞DU-145、人肝癌细胞Hep-G2、人口腔上皮癌细胞KB、人脑胶质母细胞癌细胞SW038-C2、人非小细胞肺腺癌细胞A549、人胃癌细胞MGC-803、人宫颈癌细胞Hela、人卵巢癌细胞OVCAR-3、人鼻咽癌细胞CNE-2、人乳腺腺癌细胞MCF-7、人胰腺癌细胞SW1990十八种肿瘤细胞和人脐静脉血管内皮细胞HuEVC的生长抑制作用。具体方法为:取对数生长期的肿瘤细胞,常规消化后计数,以3000个/孔的密度接种于96孔板,贴壁生长过夜。分别加入1、10、20、40、60、80μM的SM-5(母液溶于DMSO中),每个浓度设置3个复孔,以最高剂量的DMSO作为阴性对照,以20μM、40μM、60μM的顺铂为阳性对照。分别处理24、48、72小时后,每孔加入10μl MTT(5mg/ml),继续培养2~4个小时。吸弃培养液,于每孔中加入100μl的DMSO,震荡溶解5分钟,用酶标仪检测570nm处的吸光值,根据各个浓度的吸光值与对照吸光值之比,计算各浓度的生长抑制率;生长抑制率计算公式如下:
抑制率(%)=(1-受试孔0D值/阴性对照孔0D值)×100%;
采用SPSS软件,进一步计算药物的IC50值,结果见表1。
另外,取BALB/C小鼠30只,按体重、性别随机分为6组,每组5只。禁食12小时后,按等比稀释法配制不同浓度的GPQ-C1和SM-5溶液,分别按体重尾静脉给予小鼠25mg/kg、37.5mg/kg和50mg/kg不同剂量的药液。4-5秒内匀速注入。注射后观察动物反映:观察24小时。记录动物反应情况和动物死亡情况,结果见表2。
实验结果表明,SM-5对十八种肿瘤细胞的抑制作用明显,在作用72小时后,药物对NCI-H460细胞、HCT-116细胞、HL-60细胞和SW038-C2细胞最为显著。
阴性对照结果表明,溶解药物的DMSO(母液溶液)对细胞生长无影响,与空白对照相比,细胞生长速率相同。
阳性对照结果表明,顺铂对肿瘤细胞有明显的抑制作用,且呈明显的量效和实效关系;对不同肿瘤细胞株其抑制率有所不同。
表1:SM-1A对各种细胞的IC50值
小鼠静脉注射给药实验结果表明(表2):同时都给25mg/kg的GPQ-Cl和SM-5药物,小鼠反应正常,没有毒性反应和小鼠死亡现象。给药剂量增加到37.5mg/kg时,GPQ-Cl组出现了所有小鼠都出现跳跃、震颤和站立不稳现像,且有一只死亡,而SM-5组所有小鼠都正常,没有毒性反应和死亡现象。当给药剂量增加到50mg/kg时,GPQ-Cl组有四只小鼠立刻死亡,而SM-5组小鼠仍然没有毒性反应和死亡现象。
表2GPQ-Cl和SM-5静脉注射给药对小鼠的影响(单位:mg/kg)
GPQ-Cl(mg/kg) | 神经毒性 | SM-5(mg/kg) | 神经毒性 |
25 | 无 | 25 | 无 |
37.5 | 有 | 37.5 | 无 |
50 | 有 | 50 | 无 |
发明人还发现,本发明涉及的其它化合物特别是其它几个实施例的化合物也具有与上述实施例1化合物相同或相类似的结果。
Claims (10)
2.权利要求1的化合物,其中:
m、n选自1、2、或3;
A、B、C、D、和E各自独立地为碳原子;以及
R、R1、R2、R3、R4和R5各自独立地选自氢原子、羟基、卤素、C2-C6链烯基、C1-C6烷基、C1-C6烷基氧基、硝基、氰基、磺酰胺基、烷基磺酰基、脒基、羧基、氨基、烷基芳基、烷氧羰基、环烷基、烷氨基、二烷氨基、烷氨基烷基,
或其药学可接受的盐、溶剂合物、立体异构体或前体药物。
3.权利要求1的化合物,其中:
m为1;
n选自1、2、或3;
A、B、C、D、和E各自独立地为碳原子;以及
R、R1、R2、R3、R4和R5各自独立地选自氢原子、羟基、卤素、C2-C6链烯基、C1-C6烷基、C1-C6烷基氧基、硝基、氰基、磺酰胺基、烷基磺酰基、脒基、羧基、氨基、烷基芳基、烷氧羰基、环烷基、烷氨基、二烷氨基、烷氨基烷基,
或其药学可接受的盐、溶剂合物、立体异构体或前体药物。
4.权利要求1的化合物,其中:
m为1;
n为1;
A、B、C、D、和E各自独立地为碳原子;以及
R、R1、R2、R3、R4和R5各自独立地选自氢原子、羟基、卤素、C2-C6链烯基、C1-C6烷基、C1-C6烷基氧基、硝基、氰基、磺酰胺基、烷基磺酰基、脒基、羧基、氨基、烷基芳基、烷氧羰基、环烷基、烷氨基、二烷氨基、烷氨基烷基,
或其药学可接受的盐、溶剂合物、立体异构体或前体药物。
6.权利要求1的化合物,其为2-(4-对磺酰氨基苄基-[1,4]二氮杂环庚烷-1-基)-乙酰(3-烯丙基-2-羟基-亚甲基苯)肼富马酸盐。
8.权利要求1-6任一项的化合物在制备用于治疗和/或预防肿瘤和/或癌症的药物中的用途。
9.权利要求8的用途,其中所述的肿瘤和/或癌症包括但不限于:
恶性肿瘤,包括但不限于膀胱癌、乳腺癌、结肠癌、肾癌肝癌、肺癌(包括小细胞肺、非小细胞癌)、头和颈癌、食管癌、胆囊癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌和皮肤癌(包括鳞状细胞癌);
淋巴系统的造血肿瘤,包括但不限于白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B-细胞淋巴癌、T-细胞淋巴癌、霍奇金淋巴癌、非-霍奇金淋巴癌、毛细胞淋巴癌、外套细胞淋巴瘤、骨髓瘤和Brukett`s氏淋巴癌;
骨髓系统的造血肿瘤,包括但不限于急性和慢性髓细胞性白血病、骨髓增生异常综合征和前髓细胞性白血病;
间质成因的肿瘤,包括但不限于纤维肉瘤和横纹肌肉瘤;
中枢成因的肿瘤,包括但不限于纤维肉瘤和横纹肉瘤;
中枢和周围神经系统的肿瘤,包括星形细胞瘤、成纤维神经瘤、神经胶质瘤和神经鞘瘤;以及
其他肿瘤,包括但不限于黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、外生性色紫颈瘤(xenoderoma pigmentosum)、甲状腺滤囊癌和卡波氏肉瘤。
10.一种药物组合物,其包括治疗和/或预防有效量的权利要求1-6任一项的化合物以及任选的药学可接受的稀释剂、载体、赋形剂、辅料或媒介物。
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CN105085421B (zh) * | 2015-07-24 | 2017-12-26 | 深圳市湘雅生物医药研究院 | 奥比特嗪‑富马酸盐、水合物、晶型及其制备方法 |
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