CN1942446A - 用于治疗癌症的吡唑啉衍生物 - Google Patents
用于治疗癌症的吡唑啉衍生物 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
本发明涉及新型取代的吡唑啉化合物、包含所述化合物的药物组合物以及这些化合物用于治疗癌症的用途,所述化合物具体用于治疗脑癌、骨癌、唇癌、口癌、食道癌、胃癌、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌,特别用于治疗结肠癌和/或肠癌和/或前列腺癌。
Description
本发明涉及新型取代的吡唑啉化合物、包含所述化合物的药物组合物以及这些化合物用于治疗癌症的用途,具体用于治疗脑癌、骨癌、唇癌、口癌、食道癌、胃癌、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌,特别用于治疗结肠癌和/或肠癌和/或前列腺癌。
WO 00/76503公开了1-(4-氨基磺酰基芳基)-3-取代的5-芳基-4,5-二氢-吡唑作为环加氧酶-2的抑制剂用于治疗炎症和与炎症相关的疾病以及作为细胞肿瘤变异和肿瘤转移增长的抑制剂。
癌症仍是世间最令人恐惧的疾病之一。寻找有效的治疗方法和治疗用药物为正在进行的研究的目标,对人的预期寿命和健康将会有很大的影响。
因此本发明的目标为提供在治疗癌症中具有改进活性的新型化合物。
令人惊讶地发现式I和式I′的取代的吡唑啉化合物在治疗癌症(特别是结肠和/或前列腺癌)方面具有改进的抗肿瘤活性,虽然这些化合物不抑制环加氧酶-1和/或环加氧酶-2。
因此,本发明的一方面为提供式I和式I′的化合物及其非对映异构体和/或对映异构体或其混合物包括其外消旋物及其药学上可接受的盐:
其中
R1和R2为甲基;
R3和R4相同或不同,为C1-6烷基,其中至少一个被至少一个卤原子取代。
优选式I′化合物,其中R3和R4相同或不同,为C1-3烷基,其中至少一个被至少一个卤原子取代,及其非对映异构体和/或对映异构体或其混合物包括其外消旋物及其药学上可接受的盐。
优选式I′化合物,其中R3和R4为甲基,其中至少一个被至少一个卤原子取代,及其非对映异构体和/或对映异构体或其混合物包括其外消旋物及其药学上可接受的盐。
还优选式I′化合物,其中R3和R4为甲基,其中至少一个被至少一个氟和/或氯原子取代,及其非对映异构体和/或对映异构体或其混合物包括其外消旋物及其药学上可接受的盐。
还更优选式I′化合物,其中R3和R4为甲基,且被至少一个氟和/或氯原子取代,及其非对映异构体和/或对映异构体或其混合物包括其外消旋物及其药学上可接受的盐。
还优选式I′化合物,其中R3和R4为CF3基团,及其非对映异构体和/或对映异构体或其混合物包括其外消旋物及其药学上可接受的盐。
最优选式I化合物为1-(4-氨基磺酰基苯基)-3-三氟甲基-5-(2,5-二甲基苯基)-4,5-二氢-吡唑和式I′化合物为1-(4-氨基磺酰基苯基)-3-三氟甲基-5-[3,5-双-(三氟甲基)-苯基]-4,5-二氢-吡唑及其非对映异构体和/或对映异构体或其混合物包括其各自的外消旋物及其药学上可接受的盐。
本发明的式I化合物可根据以下反应流程通过常规路线制备:
其中R1和R2如上定义。
本发明的式I化合物通过式II化合物(其中R1和R2如上定义)与式III化合物反应制得。
所述反应优选在有机溶剂如醇(甲醇或乙醇)或醚(二烷或四氢呋喃)中进行。所述反应优选在酸性介质中进行。优选加入有机酸(如乙酸)或无机酸(如盐酸)。所述反应还可在碱性介质中进行。优选加入碱如哌啶、哌嗪、氢氧化钠、氢氧化钾、甲醇钠或乙醇钠。反应温度可从室温至有机溶剂的回流温度,反应时间可从数小时至最长达数天。
本发明的式I′化合物可根据以下流程通过常规路线制备:
其中R3和R4如上定义。
本发明的通式I′化合物可通过通式II′化合物(其中R3和R4如上定义)与式III化合物反应制得。
所述反应可在有机溶剂如醇(例如甲醇或乙醇)或醚(例如二烷或四氢呋喃)中进行。所述反应可在酸性介质中进行。优选加入有机酸(如乙酸)或无机酸(如盐酸)。所述反应还可在碱性介质中进行。因此优选加入碱如哌啶、哌嗪、氢氧化钠、氢氧化钾、甲醇钠或乙醇钠。反应温度可从室温至最高达有机溶剂的回流温度,反应时间可从数小时至最长达数天。
式II化合物为得到本发明的式I化合物的合成路线中的中间体,可通过公知的路线制备:在膦酸二烷基酯(如甲基膦酸二乙酯(diethylmethylphosphonate))和强碱(优选有机碱,如LDA)存在下,将式IV的取代的苯甲醛(其中R1和R2如上定义)
与N-苯基-1-氯-三氟乙亚胺反应,或者通过Wittig反应与单-、二-或三氟乙酰基甲叉三苯膦烷和碱(如碳酸钠或碳酸钾)反应。所述反应可在溶剂如二氯甲烷、氯仿或醚(如四氢呋喃、乙醚、二甲氧基乙烷或二烷)中进行。反应温度可从-70℃至有机溶剂的回流温度。反应时间可从数分钟至最长达几小时。
式II化合物还可通过通式IV的醛(其中R1和R2如上定义)与1,1,1-三氟丙酮的羟醛缩合反应制备。所述反应可在无机碱(例如碱金属(如锂、钠)的氢氧化物或氢氧化钾)或有机碱(例如哌啶)存在下,在有机溶剂(如四氢呋喃、二甲氧基乙烷、二甲基亚砜、二甲基甲酰胺、甲醇、乙醇),任选在水存在下进行。所述缩合反应的反应温度可从-20℃至室温,反应时间可从数小时至最长达数天。
式II′化合物可通过常规路线制备:在膦酸二烷基酯(如甲基膦酸二乙酯)和强碱(优选有机碱,如LDA)存在下,将式IV′的取代的苯甲醛(其中R3和R4如上定义)
与N-苯基-1-氯-三氟乙亚胺反应,或者通过Wittig反应与单-、二-或三氟乙酰基甲叉三苯基膦烷和碱(如碳酸钠或碳酸钾)反应。所述反应可在有机溶剂如二氯甲烷、氯仿或醚(如四氢呋喃、乙醚、二甲氧基乙烷或二烷)中进行。反应温度可从-70℃至有机溶剂的回流温度。反应时间可从数分钟至最长达几小时。
式II化合物还可通过通式IV的醛(其中R3和R4如上定义)与1,1,1-三氟丙酮的羟醛缩合反应制备。所述反应可在无机碱(例如碱金属(如锂、钠)的氢氧化物或氢氧化钾)或有机碱(例如哌啶)存在下,在溶剂(如四氢呋喃、二甲氧基乙烷、二甲基亚砜、二甲基甲酰胺、甲醇、乙醇),任选在水存在下进行。所述缩合反应的反应温度可从-20℃至室温,反应时间可从数小时至最长达数天。
本发明的式I和I′化合物可以其碱形式或其任何药学上可接受的盐形式分离。
本发明还涉及至少一种通式I和/或式I′的取代的吡唑啉化合物用于制备治疗癌症用药物的用途,具体用于治疗脑癌、骨癌、唇癌、口癌、食道癌、胃癌、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌、肠癌、结肠癌和/或前列腺癌,特别用于治疗结肠癌、肠癌和/或前列腺癌。
本发明还涉及一种包含至少一种通式I和/或式I′化合物的药物组合物,所述药物组合物用于对人或动物(优选人,包括婴儿、儿童和成人)给药。本发明的组合物可通过本领域的技术人员已知的标准方法制备。根据给药的方式,可通过加入公知的助剂来改变药物的组成。
本发明的药物组合物可例如与常规的可注射的液体载体(例如水或合适的醇)胃肠道外给药。常规的注射用药物赋形剂(例如稳定剂、增溶剂和缓冲剂)可包括在这些可注射的组合物中。这些药物组合物可优选肌内、腹膜内或静脉内注射。
本发明的药物制剂还可配制成包含一种或多种固体或液体形式的生理学上相容的载体或赋形剂的口服给药制剂。这些制剂可包含常规的组分,例如粘合剂、填料、润滑剂和可接受的湿润剂。所述制剂可采用任何方便的形式,例如片剂、丸剂、胶囊剂、锭剂、水溶液或油性溶液、混悬液、乳剂或适用于在使用之前与水或其他合适的液体介质再构成用于瞬间释放或缓释的干燥的粉末形式。本发明的组合物还可更具体地进行配制。
口服给药用液体组合物还可包含某些添加剂,例如增甜剂、矫味剂、防腐剂和乳化剂。还可配制包含食用油的口服给药用非含水的液体组合物。这些液体组合物可方便地以单位剂量包封在例如胶囊中。
本发明的药物组合物的各种制剂还可局部或通过栓剂给药。
人和动物的日剂量可基于各自的种类或其他因素(例如年龄、性别、体重或疾病程度等)而变。优选人的日剂量可为1-2000,优选1-1500,更优选1-1000mg待给药的活性物质,每天一次或几次给药。
实施例
表1中概述了各实施例的化合物,表2中概述了它们的物理和光谱数据。
实施例1
制备4-[5-(2,5-二甲基-苯基)-3-三氟甲基-4,5-二氢吡唑-1-基]-苯磺酰胺
步骤1
制备(E)-4-(2,5-二甲基-苯基)-1,1,1-三氟-丁-3-烯-2-酮
在圆底烧瓶中,将5g(37mmol)2,5-二甲基苯甲醛、3ml(53mmol)冰醋酸和3.6ml(37.3mmol)哌啶与70ml THF混合。将该溶液冷却至5-10℃,随后向该溶液中鼓泡加入4.7g(41.4mmol)CF3COCH3。在2小时内搅拌下将反应混合物升至室温。加入另一份2.1g(19mmol)CF3COCH3,随后将该混合物搅拌2小时。最后加入第三份2gCF3COCH3,随后搅拌2小时。接着,加入13ml 20%的氯化铵溶液,减压除去溶剂。加入水,随后该混合物用二氯甲烷萃取。有机相经水、5%的H2SO4、水洗涤,并经无水硫酸钠干燥。过滤混合物,除去溶剂。得到8.5g粗产物,经硅胶柱层析纯化,用石油醚洗脱。得到2.1g油状形式的4-(2,5-二甲基苯基)-1,1,1-三氟-3-丁烯-2-酮。
IR(薄膜,cm-1):1718,1595,7,1200,7,1145,8,1058,4
1H-NMR(CDCl3,δ):2,36(s,3H),2,45(s,3H),6,94(d,J=15,8Hz,1H),7,15(m,2H),7,49(s,1H),8,28(d,J=15,8Hz,1H).
步骤2
制备4-[5-(2,5-二甲基-苯基)-3-三氟甲基-4,5-二氢-吡唑-1-基]-苯磺酰胺
在惰性气氛下,在100ml圆底烧瓶中,将1.47g(6.48mmol)(E)-4-(2,5-二甲基苯基)-1,1,1-三氟-3-丁烯-2-酮、1.49g(7.13mmol)4-氨基磺酰基苯基盐酸肼和0.77ml哌啶在40ml无水乙醇中混合,搅拌回流20小时。减压除去溶剂,向残余物中加入水,将烧瓶搅动数分钟,过滤混合物,收集固体。得到2.6g粗制的固体物质,用乙醇重结晶,得到1.75g 1-(4-氨基磺酰基)-4,5-二氢-5-(2,5-二甲基苯基)-3-三氟甲基-1H-吡唑,熔点200-202℃。
IR(KBr,cm-1):3385,5,3274,7,1594,3,1327,8,1149,1
1H-NMR(d6-DMSO,δ):2,1(s,3H),2,3(s,3H),2,84(dd,J=6,8y 12,8Hz,1H),3,9(dd,12,8y 13,2Hz,1H),5,8(dd,J=6,8y 13,2Hz,1H),6,7(s,1H),6,9(m,3H),7,1(m,1H),7,6(d,J=8,9Hz)
实施例2
制备4-[5-(3,5-双-三氟甲基-苯基)-3-三氟甲基-4,5-二氢吡唑-1-基]-苯磺酰胺
步骤1
制备(E)-4-(3,5-双-三氟甲基-苯基)-1,1,1-三氟-丁-3-烯-2-酮
在惰性气氛下,在圆底烧瓶中,将20ml不含水的THF冷却至-70℃。加入8ml(16mmol)2M的LDA的THF/己烷溶液和溶解于5ml THF中的1.17ml(8mmol)甲基膦酸二乙酯,并搅拌30分钟。滴加1.66g(8mmol)N-苯基-1-氯-三氟乙亚胺(根据Tamura,K.;Mizukami,H.等人;J.Org.Chem.,1993,58,32-35制备),并继续搅拌1小时。加入1.93g(8mmol)3,5-双(三氟甲基)苯甲醛,随后将反应混合物升至室温,并搅拌16小时。加入20ml 2N的HCl,再继续搅拌4小时。旋转蒸发除去THF,残余物用乙醚(3×30ml)萃取,合并的有机相经碳酸氢钠溶液(5%)和饱和氯化钠溶液(pH约6)洗涤。经无水硫酸钠干燥,蒸发溶剂后,得到2.66g粗制的油状产物,该粗产物立即固化,无需进一步纯化即可用于下一步骤。
IR(KBr,cm-1):1731,1614,1382,1280,1135,1056
1H-RMN(CDCl3,δ):7,1(d,J=16Hz,1H);7,9(m,4H).
步骤2
制备4-[5-(3,5-双-三氟甲基-苯基)-3-三氟甲基-4,5-二氢-吡唑-1-基]-苯磺酰胺
在惰性气氛下,在圆底烧瓶中,将0.336g(1mmol)(E)-4-(3,5-双-三氟甲基苯基)-1,1,1-三氟-3-丁烯-2-酮、0.25g(1.1mmol)4-(氨基磺酰基苯基)-盐酸肼和0.12ml(1.2mmol)哌啶溶解于10ml乙醇中。将该混合物回流12小时。旋转蒸发除去溶剂后,向残余物中加入水,过滤收集固体。粗制固体用乙醇/水混合物重结晶。得到0.37g(收率73%)白色固体状的4-[5-(3,5-双-三氟甲基苯基)-3-三氟甲基-4,5-二氢-吡唑-1-基]-苯磺酰胺,熔点195-197℃。
IR(KBr,cm-1):3362,3264,1597,1509,1334,1279,1136,903.
1H-RMN(CDCl3,δ):1,8(bs,2H),3,0(dd,J=7,1y 17,8Hz,1H),3,8(dd,J=12,9y17,8Hz,1H),5,5(dd,J=7,1y 12,7Hz,1H),6,95(d,J=8,8Hz,2H),7,65(s,2H),7,7(d,J=8,8Hz,2H),7,8(s,1H).
表1
实施例 | R1 | R2 | R3 | R4 |
1 | CH3 | CH3 | - | - |
2 | - | - | CF3 | CF3 |
表2
实施例 | 熔点(℃) | IR(KBr,cm-1) | ′H-RMN(CDCl3,δ) |
1 | 200-202 | 3385,5,3274,7,1594,3,1327,8,1149,1 | 2,1(s,3H),2,3(s,3H),2,84(dd,J=6,8y 12,8Hz,1H),3,9(dd,12,8y 13,2Hz,1H),5,8(dd,J=6,8y 13,2Hz,1H),6,7(s,1H),6,9(m,3H),7,1(m,1H),7,6(d,J=8,9Hz) |
2 | 195-197 | 3362,3264,1597,1509,1334,1279,1136,903. | 1,8(bs,2H),3,0(dd,J=7,1y17,8Hz,1H),3,8(dd,J=12,9y 17,8Hz,1H),5,5(dd,J=7,1y 12,7Hz,1H),6,95(d,J=8,8Hz,2H),7,65(s,2H),7,7(d,J=8,8Hz,2H),7,8(s,1H) |
化合物名称:
4-[5-(2,5-二甲基-苯基)-3-三氟甲基-4,5-二氢-吡唑-1-基]-苯磺酰胺
4-[5-(3,5-双-三氟甲基-苯基)-3-三氟甲基-4,5-二氢-吡唑-1-基]-苯磺酰胺
生物学评价
抗肿瘤活性
使用XTT试剂盒,采用厂商(Roche Diagnostics)的建议,通过测定细胞代谢能力(生存能力)来评价本发明化合物的抗肿瘤活性。测定至少进行5次,参照物包含未暴露的细胞、含有溶媒的细胞(cell withvehicle)或者介质加上化合物。将各细胞接种在96-孔的板上,在100μl介质中温育24小时。随后以不同的浓度组合(1μM-80μM)加入本发明的化合物4小时(短时XTT)或60小时(长时间XTT)。温育过程结束后,向各孔中加入50μl包含XTT和电子耦合试剂的混合物。于37℃下温育4小时后,观察490nm处的吸光率。与未处理的参照物相比,减去空白的吸光率得到各化合物的生长抑制活性,用细胞生长抑制百分比表示。使用Sigmaplot 5.0软件,采用Hill sigmoidal方程式(三个参数),由化合物浓度与细胞生存能力百分比关系的剂量-反应曲线确定50%抑制时的浓度(IC50)。
表3
化合物 | 人体肿瘤细胞线(line) | ||||
结肠IC50(μM) | 前列腺IC50(μM) | ||||
TD20 | NC59 | HCA7 | HT29 | PC3 | |
Celecoxib | 37.5±3.5 | 18.17 | 26.49 | 21.53 | 30.6±3.2 |
实施例1 | 20.5±2.5 | 16.3±4.0 | 10.53±9.1 | 14.88±6.0 | 12.33±1.4 |
实施例2 | 12.9±1.0 | - | - | - | 10.6±0.5 |
实施例1和2的化合物不具有酶COX-1和COX-2的抑制活性。
Claims (12)
1.一种式I和式I′的化合物及其非对映异构体和/或对映异构体或其混合物包括其外消旋物,或其药学上可接受的盐:
其中
R1和R2为甲基;
R3和R4相同或不同,为C1-6烷基,其中至少一个被至少一个卤原子取代。
2.权利要求1的式I′化合物,其中R3和R4相同或不同,为C1-3烷基,其中至少一个被至少一个卤原子取代。
3.权利要求1的式I′化合物,其中R3和R4相同或不同,为甲基,其中至少一个被至少一个卤原子取代。
4.权利要求1的式I′化合物,其中R3和R4为甲基,其中至少一个被至少一个氟和/或氯原子取代。
5.权利要求1的式I′化合物,其中R3和R4为被至少一个氟和/或氯原子取代的甲基。
6.权利要求1的式I′化合物,其中R3和R4为CF3基团。
7.权利要求1的式I化合物,所述化合物为1-(4-氨基磺酰基苯基)-3-三氟甲基-5-(2,5-二甲基苯基)-4,5-二氢-吡唑。
8.权利要求6的式I′化合物,所述化合物为1-(4-氨基磺酰基苯基)-3-三氟甲基-5-[3,5-双-(三氟甲基)-苯基]-4,5-二氢-吡唑。
9.一种药物组合物,所述组合物包含药学上可接受的载体和至少一种权利要求1-8中任一项的化合物。
10.至少一种权利要求1-8中任一项的式I和/或I′的化合物在制备治疗癌症的药物组合物中的用途。
11.至少一种权利要求10的式I和/或I′的化合物在制备治疗以下癌症的药物组合物中的用途:脑癌、骨癌、唇癌、口癌、食道癌、胃癌、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌和/或前列腺癌。
12.至少一种权利要求10的式I和/或I′的化合物在制备治疗结肠癌、肠癌和/或前列腺癌的药物组合物中的用途。
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- 2004-03-19 US US10/804,695 patent/US20050182119A1/en not_active Abandoned
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Cited By (1)
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CN104230904A (zh) * | 2014-08-29 | 2014-12-24 | 南京大学 | 一类含萘环骨架的二氢吡唑磺胺衍生物的合成及在抗癌药物中的应用 |
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ES2238923A1 (es) | 2005-09-01 |
IL177455A0 (en) | 2006-12-10 |
US20070066651A1 (en) | 2007-03-22 |
ES2238923B1 (es) | 2006-11-01 |
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