CN104703655A - 具有抗-癌活性的6-氧代-1,6-二氢-哒嗪衍生物与mek抑制剂的组合 - Google Patents
具有抗-癌活性的6-氧代-1,6-二氢-哒嗪衍生物与mek抑制剂的组合 Download PDFInfo
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- CN104703655A CN104703655A CN201380053015.8A CN201380053015A CN104703655A CN 104703655 A CN104703655 A CN 104703655A CN 201380053015 A CN201380053015 A CN 201380053015A CN 104703655 A CN104703655 A CN 104703655A
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
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- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nutrition Science (AREA)
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Abstract
一种药用组合物，其包含3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物和N-(S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物。
Description
发明领域
本发明涉及用于癌症疾病的药用组合物，其包含具有抗-癌活性的化合物，即与MEK抑制剂，即N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物组合的3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物。
发明背景
本发明的目的在于发现新的具有有价值性质的药用组合物，特别是那些可用来制备药物的组合物。
此外，本发明的目的是用于预防和治疗恶性肿瘤包括，但不限于，实体瘤癌症、淋巴或血液系统的癌症的新组合物。
已经发现，依据本发明的药用组合物及其药学上可接受的盐和/或溶剂合物具有非常有价值的药用性质，同时是良好耐受的。
靶向疗法选择性地抑制肿瘤中的特定靶标。通过将这些靶向疗法与护理标准(SoC)结合，可以改善SoC的活动。已经发现，通过将3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物与N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物组合，改进了抗癌化合物在异种移植物中的活性。
与单一疗法比较，在NSCLC (非小细胞肺癌)异种移植模型中的功效得到提高。观察到联合组的功效增强而没有增加毒性。
现有技术
在WO 2009/006959 A1中已经描述了3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈。
在WO 2009/007074 A1中已经描述了3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物。
在WO 2012/078832 A1中描述了MEK抑制剂N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺与PI3K抑制剂的组合。
发明简述
本发明涉及一种组合物，其包含3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物。
此外，本发明涉及一种组合物，其包含3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物。
此外，本发明涉及3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物的组合物，其用于治疗选自以下的疾病：头、颈、眼、口、喉咙、食管、支气管、喉、咽、胸、骨、肺、结肠、直肠、胃、前列腺、膀胱、子宫、子宫颈、乳房、卵巢、睾丸或其它生殖器官、皮肤、甲状腺、血、淋巴结、肾、肝、胰腺、脑、中枢神经系统、实体瘤和血生肿瘤的癌症。
此外，本发明涉及3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物在制备用于治疗癌症的药物中的用途，所述癌症选自结肠直肠、肺、乳房、肾和胶质母细胞瘤，其中所述药物与N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物组合使用。
此外，本发明涉及3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物在制备用于治疗癌症的药物中的用途，所述癌症选自结肠直肠、肺、乳房、肾和胶质母细胞瘤，其中所述药物与N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物组合使用。
此外，本发明涉及3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物在制备用于治疗癌症的药物中的用途，所述癌症选自小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、头和颈的鳞状细胞癌(SCCHN)，其中所述药物与N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物组合使用。
此外，本发明涉及如上所述的用途，其中3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物或3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物以每周250 mg-12500 mg的量，优选以每周800 mg-8000 mg的量，特别优选以每周500 mg-2000 mg的量给予患者。
依据本发明，治疗活性组合物也可通过药剂盒提供，所述药剂盒包含含有在单一包装中或在分开的容器中的3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物的包装。
采用这些组合的疗法可任选地包括用放射进一步治疗。本发明还涉及一种新的疗法形式，其包括在放射疗法之前开始给予3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物。
在包括在放射疗法之前开始给予3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物的这种新的疗法形式中，优选的特点是，在给予其它癌症共治疗剂(cotherapeutic agent)之前和/或期间，优选至少在治疗方案的重要部分期间，给予3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物。在本上下文中，依据本发明，辐射或放射治疗，优选要理解为一种癌症共治疗剂。
本发明还涉及这些化合物的任选的活性形式(立体异构体)、对映体、外消旋体、非对映体和水合物和溶剂合物。
本发明还涉及所述化合物的盐的溶剂合物，例如盐酸盐的一水合物或二水合物。
术语化合物的溶剂合物用以指内收惰性溶剂分子到化合物上，其由于它们的相互吸引力而形成。溶剂合物例如为单或二水合物或醇化物。
表述“有效量”表示在组织、系统、动物或人类中引起例如由研究人员或医师所探求或希望的生物学或医学反应的药物或药学活性成分的量。
另外，表述“治疗有效量”表示与没有接收该量的相应受试者相比较具有以下结果的量：
治疗改善、痊愈、预防或消除疾病、综合征、病况、症状、病症或副作用或者还有降低疾病、症状或病症的进展。
表述“治疗有效量”还涵盖有效增加正常生理功能的量。
药用盐和其它形式
根据本发明的所述化合物可以其最终非盐形式使用。另一方面，本发明还涵盖以其药学上可接受的盐的形式的这些化合物的用途，所述药学上可接受的盐可通过本领域已知的方法得自各种有机和无机的酸和碱。3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺的药学上可接受的盐形式大部分通过常规方法制备。
如果化合物含有羧基，则其合适盐中的一种可通过使所述化合物与合适的碱反应得到相应的碱加成盐来形成。所述碱例如为碱金属氢氧化物，包括氢氧化钾、氢氧化钠和氢氧化锂；碱土金属氢氧化物，诸如氢氧化钡和氢氧化钙；碱金属醇盐，例如乙醇钾和丙醇钠；和各种有机碱，诸如哌啶、二乙醇胺和N-甲基谷氨酰胺。同样包括所述化合物的铝盐。在某些化合物的情况下，酸加成盐可通过用以下药学上可接受的有机和无机酸处理这些化合物来形成：例如卤化氢，诸如氯化氢、溴化氢或碘化氢；其它无机酸及其相应盐，诸如硫酸盐、硝酸盐或磷酸盐等；和烷基和单芳基磺酸盐，诸如乙烷磺酸盐、甲苯磺酸盐和苯磺酸盐；及其它有机酸及其相应盐，诸如乙酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此，所述化合物的药学上可接受的酸加成盐包括以下：乙酸盐、已二酸盐、海藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(benzenesulfonate)(苯磺酸盐(besylate))、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡萄糖酸盐、二氢磷酸盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、半乳糖二酸盐(由粘酸得到)、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙烷磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲烷磺酸盐、甲基苯甲酸盐、单氢磷酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、棕榈酸盐(palmoate)、果胶酸盐、过硫酸盐、苯乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐，但这不代表限制。
另外，根据本发明的化合物的碱式盐包括铝、铵、钙、铜、铁(III)、铁(II)、锂、镁、锰(III)、锰(II)、钾、钠及锌盐，但这并非意欲代表限制。在上述盐之中，优选铵、碱金属钠和钾盐及碱土金属钙和镁盐。得自药学上可接受的有机无毒碱的化合物的盐包括以下的盐：伯、仲和叔胺；被取代的胺，还包括天然存在的被取代的胺；环胺；和碱离子交换树脂，例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、N,N'-二苄基乙二胺(苄星青霉素)、二环己胺、二乙醇胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺、葡糖胺、组氨酸、哈胺(hydrabamine)、异丙胺、利多卡因(lidocaine)、赖氨酸、葡甲胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟甲基)甲胺(缓血酸胺)，但这并非意欲代表限制。
含有碱性含氮基团的本发明化合物可使用例如以下试剂季胺化：(C1-C4)烷基卤化物，例如甲基、乙基、异丙基和叔丁基氯化物、溴化物和碘化物；硫酸二(C1-C4)烷基酯，例如硫酸二甲酯、硫酸二乙酯和硫酸二戊酯；(C10-C18)烷基卤化物，例如癸基、十二烷基、月桂基、肉豆寇基和十八烷基氯化物、溴化物和碘化物；和芳基(C1-C4)烷基卤化物，例如苄基氯和苯乙基溴。根据本发明的水溶性和油溶性化合物两者都可使用这样的盐制备。
优选的上述药学上的盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙基磺酸盐、扁桃酸盐、葡甲胺、硝酸盐、油酸盐、膦酸盐、新戊酸盐、磷酸钠、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和缓血酸胺，但这并非意欲代表限制。
特别优选盐酸盐、二盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、磷酸盐、硫酸盐和琥珀酸盐。
所述碱性化合物的酸加成盐通过使游离碱形式与足够量的所需酸接触，促使以常规形式形成所述盐来制备。所述游离碱可通过使所述盐形式与碱接触并以常规方式分离所述游离碱而再生。所述游离碱形式在某方面关于某些物理性质如在极性溶剂中的溶解性而与其相应盐形式不同；然而，对于本发明的目的，所述盐在其它方面与其相应游离碱形式一致。
如所提到的，所述化合物的药学上可接受的碱加成盐用金属或胺如碱金属和碱土金属或有机胺形成。优选的金属有钠、钾、镁和钙。优选的有机胺有N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
根据本发明的酸性化合物的碱加成盐通过使所述游离酸形式与足够量的所需要的碱接触，促使以常规方式形成所述盐来制备。所述游离酸可通过使所述盐形式与酸接触并以常规方式分离所述游离酸而再生。所述游离酸形式在某方面关于某些物理性质如在极性溶剂中的溶解性而与其相应盐形式不同；然而，对于本发明的目的，所述盐在其它方面与其相应游离酸形式一致。
如果根据本发明的化合物含有多于一个能够形成该类型的药学上可接受的盐的基团，本发明则还涵盖多重盐。典型的多重盐形式例如包括酒石酸氢盐、二乙酸盐、富马酸氢盐、二葡甲胺、磷酸氢盐、二钠和三盐酸盐，但这并非意欲代表限制。
关于上文所述，可见在本上下文中的表述“药学上可接受的盐”用以指活性成分，其包含以其盐中的一种的形式的化合物，特别是如果与活性成分的游离形式或先前使用的活性成分的任何其它盐形式相比较，该盐形式赋予活性成分改善的药代动力学性质。所述活性成分的药学上可接受的盐形式还可首次提供给该活性成分先前没有的所要的药代动力学性质，且关于其在体内的治疗功效，甚至可以对该活性成分的药效学具有有利的影响。
本发明另外涉及药物，所述药物包含至少一种化合物和/或其药学上可接受的盐、溶剂合物、互变异构体和立体异构体，包括其以所有比率的混合物，及任选的赋形剂和/或助剂。
药物制剂可以包含预定量的活性成分/剂量单位的剂量单位形式施用。所述单位可根据所治疗的病况、施用方法及患者的年龄、体重和病况而包含例如0.5mg-1g、优选1mg-700mg、特别优选5mg-100mg的本发明化合物，或者药物制剂可以包含预定量的活性成分/剂量单位的剂量单位形式施用。优选的剂量单位制剂为包含如上指出的日剂量或份剂量或其相应分数的活性成分的那些。另外，该类型的药物制剂可使用在制药领域中通常已知的方法制备。
药物制剂可适合经由任何需要的合适方法，例如经口(包括颊或舌下)、直肠、鼻、局部(包括颊、舌下或经皮)、阴道或肠胃外(包括皮下、肌肉内、静脉内或皮内)方法施用。所述制剂可使用制药领域中已知的所有方法通过例如将活性成分与赋形剂或助剂组合来制备。
适合口服的药物制剂可作为独立单位如胶囊或片剂；粉剂或颗粒剂；在水性或非水性液体中的溶液剂或混悬剂；可食用泡沫或泡沫食品；或水包油液体乳剂或油包水液体乳剂来施用。
因此，例如，在以片剂或胶囊形式口服的情况下，可将活性成分组分与经口、无毒且药学上可接受的惰性赋形剂如乙醇、甘油、水等组合。粉剂通过将化合物粉碎成合适的小尺寸并将其与以类似方式粉碎的药用赋形剂如可食用的碳水化合物如淀粉或甘露糖醇混合来制备。同样可存在矫味剂、防腐剂、分散剂和染料。
胶囊通过制备如上所述的粉末混合物并用其填充成型的明胶壳来生成。在填充操作之前可将诸如以固体形式的高度分散的硅酸、滑石粉、硬脂酸镁、硬脂酸钙或聚乙二醇等助流剂和润滑剂加到所述粉末混合物中。同样可加入诸如琼脂、碳酸钙或碳酸钠等崩解剂或增溶剂以改善服用胶囊之后药物的利用度。
另外，如果需要或必需，则同样可将合适的粘合剂、润滑剂和崩解剂以及染料掺入所述混合物中。合适的粘合剂包括淀粉、明胶、天然糖如葡萄糖或β-乳糖、由玉米制造的甜味剂、天然和合成橡胶如阿拉伯胶、黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。在这些剂型中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。所述崩解剂包括(而不受此限制)淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。所述片剂通过例如制备粉末混合物、造粒或压干所述混合物、加入润滑剂和崩解剂并压制全部混合物以给出片剂来配制。粉末混合物通过混合以合适方式粉碎的化合物与如上所述的稀释剂或基质和任选粘合剂如羧甲基纤维素、海藻酸盐、明胶或聚乙烯吡咯烷酮；溶解延缓剂如石蜡；吸收加速剂如季盐；和/或吸收剂如膨润土、高岭土或磷酸二钙来制备。所述粉末混合物可通过用粘合剂如糖浆、淀粉糊、阿卡迪亚胶浆或纤维素或聚合物材料的溶液将其润湿并挤压穿过筛网来造粒。作为造粒的替代，可使所述粉末混合物穿过制片机，给出不均匀形状的结块，将其破碎以形成颗粒剂。所述颗粒剂可通过加入硬脂酸、硬脂酸盐、滑石粉或矿物油润滑以免粘住片剂铸模模具。随后将润滑的混合物压制以给出片剂。根据本发明的化合物还可与自由流动的惰性赋形剂组合且随后直接压制给出片剂而不进行造粒或压干步骤。可存在由虫胶封闭层、糖或聚合物材料的层和蜡的光泽层组成的透明或不透明的保护层。可将染料加到这些涂层中以能够区分开不同的剂量单位。
口服液体如溶液、糖浆和酏剂可以剂量单位形式制备，以使得给定的量包含预定量的所述化合物。糖浆可通过将所述混合物溶解于具有合适矫味剂的水溶液中来制备，而酏剂使用无毒醇媒剂制备。混悬剂可通过将所述化合物分散在无毒媒剂中来配制。同样可加入增溶剂和乳化剂，诸如乙氧化异十八醇和聚氧乙烯山梨糖醇醚；防腐剂；调味添加剂，诸如薄荷油；或天然甜味剂或糖精；或其他人工甜味剂等。
如果需要，可将用于口服的剂量单位制剂封装在微囊中。所述制剂还可以延迟释放或阻释的方式来制备，例如通过将微粒材料涂布或包埋在聚合物、蜡等中。
所述化合物及其盐、溶剂合物、互变异构体和立体异构体还可以脂质体传送系统如小单层囊泡、大单层囊泡和多层囊泡的形式施用。脂质体可由各种磷脂诸如胆固醇、十八胺或磷脂酰胆碱形成。
所述化合物及其盐、溶剂合物、互变异构体和立体异构体还可使用单克隆抗体作为化合物分子与其偶联的单独的载体来递送。所述化合物也可偶联到作为靶向药物载体的可溶性聚合物。所述聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基丙基甲基丙烯酰胺基苯酚、聚羟基乙基天冬酰胺基苯酚或被棕榈酰基取代的聚环氧乙烷聚赖氨酸。所述化合物可另外偶联到一类可生物降解的聚合物，所述可生物降解的聚合物适合用于实现药物的受控释放，例如聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲的嵌段共聚物。
适合经皮施用的药物制剂可作为独立膏剂施用以便与接受者的表皮扩展地紧密接触。因此，例如，活性成分可通过离子电渗从膏剂中递送，如在Pharmaceutical Research, 3(6), 318 (1986)的一般术语中所述。
可将适合局部施用的药物化合物配制为软膏、乳膏、混悬剂、洗液、粉剂、溶液剂、糊剂、凝胶剂、喷剂、气溶胶或油剂。
为了治疗眼睛或其它外部组织如口和皮肤，所述制剂优选作为局部软膏或乳膏施用。在产生软膏的制剂的情况下，活性成分可与石蜡或水混溶的膏基一起使用。或者，活性成分可用水包油膏基或油包水基质一起配制以产生乳膏。
适合局部施用到眼睛的药物制剂包括滴眼剂，其中活性成分溶解或悬浮在合适载体、特别是水性溶剂中。
适合在口中局部施用的药物制剂包括锭剂、软锭剂和漱口剂。
适合直肠施用的药物制剂可以栓剂或灌肠剂的形式施用。
其中载体物质为固体的适合经鼻施用的药物制剂包括具有例如在20-500微米范围内的粒度的粗粉剂，其以采用嗅剂的方式，即通过从保持靠近鼻的含有粉剂的容器经鼻道迅速吸入来施用。用于作为具有液体作为载体物质的鼻喷剂或滴鼻剂施用的合适制剂包括在水或油中的活性成分溶液。
适合通过吸入施用的药物制剂包括细微粒粉尘或烟雾，其可通过各种类型的具有气溶胶的加压分配器、喷雾器或吹入器产生。
适合阴道施用的药物制剂可作为子宫托、棉塞、乳膏、凝胶剂、糊剂、泡沫或喷雾制剂施用。
适合肠胃外施用的药物制剂包括水性和非水性无菌注射液，其包含抗氧化剂、缓冲剂、抑菌剂和溶质，借助于所述无菌注射液使所述制剂与欲治疗的接受者的血液等渗；和水性和非水性无菌混悬液，其可包含悬浮介质和增稠剂。所述制剂可在单剂量或多剂量容器如密封安瓿和小瓶中施用并以冷冻干燥(冻干)状态储存，以使得仅需要紧接在使用之前加入无菌载液，例如用于注射目的的水。根据该配方制备的注射溶液和混悬液可由无菌粉末、颗粒剂和片剂制备。
不用说，关于特定制剂类型，除了以上特别提到的成分之外，所述制剂还可包含本领域中常用的其他试剂；因此，例如，适合口服的制剂可包含矫味剂。
化合物的治疗有效量取决于许多因素，例如包括动物的年龄和体重、需要治疗的精确病况及其严重性、制剂的性质和施用方法，且其最终由治疗医师或兽医确定。然而，根据本发明的化合物的有效量通常在0.1-100 mg/kg接受者(哺乳动物)体重/日的范围内且特别典型地在1-10 mg/kg体重/日的范围内。因此，对于体重为70 kg的成年哺乳动物每日的实际量通常为70-700 mg，其中该量可以每日单一剂量或通常以每日一系列多份剂量(诸如2、3、4、5或6份)施用，以使得日总剂量相同。其盐、溶剂合物、互变异构体及立体异构体的有效量可确定为本发明的化合物的有效量本身的分数。可以假定类似的剂量适合用于治疗上述其他病况。
该类型的组合疗法可借助于同时、连续或单独分配该治疗的单独组分来实现。该类型的组合茶品采用根据本发明的化合物。
本文定义的抗-癌治疗可作为单一疗法施用或除了本发明的组合物外，还可包括常规手术或放射疗法。
本文使用的“治疗”是指完全或部分地减轻与疾病或病症相关的症状，或减慢或中止那些症状的进一步进展或恶化，或防止或预防处于发展该疾病或病症的危险之中的受试者的疾病或病症。
结合化合物的术语“有效量”可以指能够完全或部分地减轻与疾病或病症相关的症状，或减慢或中止那些症状的进一步进展或恶化，或防止或预防具有本文公开的疾病或处于发展本文公开的疾病的危险之中的受试者的疾病或病症的量，所述疾病例如癌症。
术语“治疗有效的”或“治疗有效量”指有效治疗哺乳动物的疾病或病症的药物的量。在癌症的情况下，药物的治疗有效量可减少癌细胞的数量；减小肿瘤大小；抑制(即，延缓至某种程度和最好是停止)癌细胞浸润进入周围器官；抑制(即，延缓至某种程度和最好是停止)肿瘤转移；抑制(至某种程度)肿瘤生长；和/或将癌症相关的一种或多种症状缓解至某种程度。在药物可防止生长和/或杀灭已存在的癌细胞的程度上，其可以是抑制细胞生长的和/或细胞毒性的。对于癌症治疗，效果可例如通过评估至疾病进展的时间(TTP)和/或确定响应率(RR)来测量。
优选地，厄洛替尼(erlotinib)、西妥昔单抗、阿柏西普(aflibercept)、贝伐单抗一周施用一次，优选为静脉内输注。优选初始剂量为100-1000 mg/m2体表面积，特别优选200-600 mg/m2体表面积。后续剂量为50-600 mg/m2体表面积，特别优选100-400 mg/m2体表面积。
用途
本发明化合物适合作为对于哺乳动物、特别是对于人类而言在治疗免疫调节和应激反应激酶诱发的疾病中的药物活性成分。这些疾病包括恶性肿瘤，包括，但不限于，实体瘤癌症、淋巴或血液系统的癌症、瘤细胞增殖、促使实体瘤生长的病理性新血管形成(或血管生成)、神经退行性疾病(阿尔茨海默氏病、脱髓鞘核心疾病多发性硬化症等)、免疫相关病症如关节炎、银屑病、狼疮，或其它自身免疫性疾病以及慢性感染。
本发明包括所述化合物和/或其生理学上可接受的盐和溶剂合物在制备用于治疗或预防癌症的药物中的用途。为治疗的优选癌起源于以下一组癌症：脑癌、泌尿生殖道癌、淋巴系统癌、胃癌、喉癌和肺癌。另一组优选形式的癌症为单核细胞白血病、肺腺癌、小细胞肺癌、胰腺癌、胶质母细胞瘤、黑素瘤和乳腺癌。另一组优选形式的癌症包括，但不限于，子宫颈癌、神经母细胞瘤、睾丸癌、巨球蛋白血症和肉瘤。
本发明特别涉及化合物及其药学上可接受的盐、溶剂合物、互变异构体和立体异构体，包括其以所有比率的混合物，其用于治疗恶性肿瘤(实体瘤癌症、淋巴或血液系统的癌症等)、神经退行性疾病、免疫相关病症如关节炎、银屑病、狼疮、多发性硬化或其它自身免疫性疾病以及慢性感染。
特别优选的是治疗其中疾病是恶性肿瘤的疾病中的用途。
恶性肿瘤优选选自肺、鳞状上皮、膀胱、胃、肾、头和颈、食管、子宫颈、甲状腺、肠、肝、脑、前列腺、泌尿生殖道、淋巴系统、胃和/或喉的癌症。
恶性肿瘤还优选选自肺腺癌、小细胞肺癌、胰腺癌、胶质母细胞瘤、结肠癌和乳腺癌。
进一步给出的优选是用于治疗血和免疫系统的恶性肿瘤，优选用于治疗选自急性髓细胞性白血病、慢性髓细胞性白血病、急性淋巴性白血病和/或慢性淋巴性白血病的肿瘤中的用途。
化合物可用于治疗或预防的代表性癌症包括，但不限于头、颈、眼、口、喉咙、食管、支气管、喉、咽、胸、骨、肺、结肠、直肠、胃、前列腺、膀胱、子宫、子宫颈、乳房、卵巢、睾丸或其它生殖器官、皮肤、甲状腺、血、淋巴结、肾、肝、胰腺、脑、中枢神经系统、实体瘤和血生肿瘤的癌症。
此外，本发明特别涉及用于治疗和/或预防癌症的化合物，其中要治疗的癌症是实体瘤或血和免疫系统的癌症。
此外，本发明特别涉及用于治疗和/或预防癌症的化合物，其中肿瘤源于急性髓细胞性白血病、慢性髓细胞性白血病、急性淋巴性白血病和/或慢性淋巴性白血病。
此外，本发明特别涉及用于治疗和/或预防癌症的化合物，其中实体瘤源自上皮细胞、膀胱、胃、肾、头和颈、食管、子宫颈、甲状腺、肠、肝、脑、前列腺、泌尿生殖道、淋巴系统、胃、喉、骨(包括软骨肉瘤和尤文氏肉瘤)、生殖细胞(包括胚胎组织肿瘤)和/或肺的肿瘤，选自单核细胞白血病、肺腺癌、小细胞肺癌、胰腺癌、胶质母细胞瘤、纤维神经瘤、血管肉瘤、乳腺癌和/或恶性黑素瘤。
所公开的化合物可与包括抗癌剂的其它已知治疗剂组合施用。如在此使用的，术语“抗癌剂”涉及为治疗癌症的目的施用到具有癌症的患者的任何药剂。
在人KP-4胰腺瘤模型中与MEK抑制剂N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺的组合：
方法：对雌性BalB/c裸鼠(6-8周龄)皮下注射人KP-4胰腺瘤细胞并在产生肿瘤后将其分配到各治疗组(一组10只动物)。对各组口服3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物(100 mg/kg)或N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺(50 mg/kg)，在单一疗法或组合治疗中持续给药5天和停药2天。在治疗结束后计算T/C值并观察肿瘤再生长。统计分析用单因素方差分析(one way ANOVA)进行。结果：3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺显示出抗-肿瘤活性，其T/C值分别为35%和42%。两种药物的组合导致抗-肿瘤活性的显著增加，其T/C为14% (P<0.05)。所有治疗都是良好耐受的。
在10个患者来源的胰腺瘤模型中，与MEK抑制剂N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺的组合：
方法：雌性NMRI裸鼠(6-8周龄)皮下植入患者来源的胰腺瘤片段。在产生肿瘤后将动物分配到各治疗组(一组10只动物)。对各组口服3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物(100 mg/kg)或N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺(100 mg/kg, MTD)，在单一疗法或组合治疗中持续给药5天和停药2天。在治疗结束后计算T/C值并观察肿瘤再生长。统计分析已用单因素方差分析(one way ANOVA)进行。结果：3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物在2/10模型中显示出抗-肿瘤活性，其T/C值为43%和50%，而N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺在所有10个模型中显示出抗-肿瘤活性(T/C值< 55%)。两种药物的组合在所有模型中显示出抗-肿瘤活性的增加，其中3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物单一疗法对比组合疗法在10/10个模型中是有统计学意义的(P<0.01)和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺单一疗法对比组合在2/10个模型中是有统计学意义的(P<0.05)。所有治疗都是良好耐受的。
Claims (7)
1. 一种组合物，其包含3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物。
2. 一种组合物，其包含3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物。
3. 依据权利要求1或2的组合物，其还包含药学上可接受的赋形剂和/或助剂。
4. 3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物和N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物的组合物，其用于治疗选自以下的疾病：头、颈、眼、口、喉咙、食管、支气管、喉、咽、胸、骨、肺、结肠、直肠、胃、前列腺、膀胱、子宫、子宫颈、乳房、卵巢、睾丸或其它生殖器官、皮肤、甲状腺、血、淋巴结、肾、肝、胰腺、脑、中枢神经系统、实体瘤和血生肿瘤的癌症。
5. 3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物在制备用于治疗癌症的药物中的用途，所述癌症选自结肠直肠、肺、乳房、肾和胶质母细胞瘤，其中所述药物与N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物组合使用。
6. 3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物在制备用于治疗癌症的药物中的用途，所述癌症选自结肠直肠、肺、乳房、肾和胶质母细胞瘤，其中所述药物与N-((S)-2,3-二羟基-丙基)-3-(2-氟-4-碘-苯基氨基)-异烟酰胺或其药学上可接受的盐和/或溶剂合物组合使用。
7. 权利要求5或6的用途，其中3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈或其药学上可接受的盐和/或溶剂合物或3-(1-{3-[5-(1-甲基-哌啶-4-基甲氧基)-嘧啶-2-基]-苄基}-6-氧代-1,6-二氢-哒嗪-3-基)-苄腈盐酸盐水合物以每周250 mg-12500 mg的量给予患者。
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| PCT/EP2013/002747 WO2014056566A1 (en) | 2012-10-11 | 2013-09-13 | Combination of a 6-oxo-1,6-dihydro-pyridazine derivative having anti-cancer activity with a mek inhibitor |
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| US10532052B2 (en) * | 2014-12-12 | 2020-01-14 | Merck Patent Gmbh | Combination of a 6-oxo-1,6-dihydro-pyridazine derivative having anti-cancer activity with an EGFR inhibitor |
| JP6719679B2 (ja) * | 2016-10-27 | 2020-07-08 | フーチェン コサンテール ファーマスーティカル カンパニー リミテッド | ｃ−ＭＥＴ阻害剤としてのピリドン系化合物 |
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| WO2012078832A1 (en) * | 2010-12-09 | 2012-06-14 | Sanofi | Compositions comprising a pi3k inhibitor and a mek inhibitor and their use for treating cancer |
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| HK1211255A1 (zh) | 2016-05-20 |
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| BR112015007870B1 (pt) | 2021-12-07 |
| RU2015117550A (ru) | 2016-12-10 |
| JP2015536910A (ja) | 2015-12-24 |
| AU2013329865A1 (en) | 2015-05-21 |
| WO2014056566A1 (en) | 2014-04-17 |
| ZA201503186B (en) | 2021-09-29 |
| RU2684407C2 (ru) | 2019-04-09 |
| KR102157501B1 (ko) | 2020-09-18 |
| IL238061B (en) | 2019-10-31 |
| CA2887628C (en) | 2020-09-08 |
| BR112015007870A2 (pt) | 2017-07-04 |
| MX359110B (es) | 2018-09-14 |
| SG11201502628SA (en) | 2015-05-28 |
| US20150297594A1 (en) | 2015-10-22 |
| EP2906294B1 (en) | 2018-04-18 |
| AU2013329865B2 (en) | 2018-04-26 |
| EP2906294A1 (en) | 2015-08-19 |
| MX2015004428A (es) | 2015-06-24 |
| CA2887628A1 (en) | 2014-04-17 |
| AR092991A1 (es) | 2015-05-13 |
| KR20150067343A (ko) | 2015-06-17 |
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