CN115057855A - 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途 - Google Patents
取代五元并六元杂环类化合物、其制备方法、药物组合及其用途 Download PDFInfo
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- CN115057855A CN115057855A CN202210486406.XA CN202210486406A CN115057855A CN 115057855 A CN115057855 A CN 115057855A CN 202210486406 A CN202210486406 A CN 202210486406A CN 115057855 A CN115057855 A CN 115057855A
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- hydrogen
- alkyl
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- amino
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 102100038028 1-phosphatidylinositol 3-phosphate 5-kinase Human genes 0.000 claims abstract description 33
- 101710145421 1-phosphatidylinositol 3-phosphate 5-kinase Proteins 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 239000012453 solvate Substances 0.000 claims abstract description 21
- 201000010099 disease Diseases 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 17
- 206010027476 Metastases Diseases 0.000 claims abstract description 4
- 230000009401 metastasis Effects 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 178
- 239000001257 hydrogen Substances 0.000 claims description 165
- -1 amino, hydroxy Chemical group 0.000 claims description 144
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 81
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 78
- 150000002431 hydrogen Chemical class 0.000 claims description 72
- 239000011737 fluorine Substances 0.000 claims description 53
- 229910052731 fluorine Inorganic materials 0.000 claims description 53
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 52
- 125000001072 heteroaryl group Chemical group 0.000 claims description 50
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 41
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 37
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 32
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- 229910052801 chlorine Inorganic materials 0.000 claims description 30
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 29
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- 125000003277 amino group Chemical group 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
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- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 20
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 19
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- 125000001424 substituent group Chemical group 0.000 claims description 16
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- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
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- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 7
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- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 238000001727 in vivo Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 claims description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
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- 239000011668 ascorbic acid Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical group [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
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- 229940001468 citrate Drugs 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 235000015097 nutrients Nutrition 0.000 claims description 2
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- 229940086735 succinate Drugs 0.000 claims description 2
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 10
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
本发明涉及药物化学领域,取代五元并六元杂环化合物、其制备方法、药用组合物及其应用。具体地,涉及一类具有PIKfyve激酶选择性抑制活性的化合物及其药学上可接受的盐或药学上可接受的溶剂合物,其制备方法、包含该化合物的药物组合物,以及这些化合物在制备用于预防或治疗与生物体内PIKfyve相关疾病的药物中的用途,尤其是在制备用于预防或治疗肿瘤生长与转移的药物中的用途。
Description
技术领域
本发明涉及药物化学领域,具体地,涉及一类具有PIKfyve激酶选择性抑制活性的化合物及其药学上可接受的盐或药学上可接受的溶剂合物,其制备方法、包含该化合物的药物组合物,以及这些化合物在制备用于预防或治疗与生物体内PIKfyve相关疾病的药物中的用途,尤其是在制备用于预防或治疗肿瘤生长与转移的药物中的用途。
背景技术
肿瘤严重威胁着人类的健康与生命,据世界卫生组织2003年公布的数据,2000年全球共有恶性肿瘤患者1000万,因恶性肿瘤死亡者高达620万,占总死亡人数的12%~25%。预期到2020年,全球每年新发病例将达1500万。近年来靶向治疗药物imatinib、crizotinib、osimertinib等先后上市,造福了一大批患者。该类药物针对肿瘤细胞生长、增殖过程中的关键蛋白分子进行选择性抑制,如BCR-ABL、ALK、EGFR等,因此具有疗效高、副作用小等优点。
PIKfyve是一种可将磷脂酰肌醇-3-磷酸进行进一步磷酸化生成磷脂酰肌醇-3,5-二磷酸的磷脂激酶,在体内行使多项调控功能,如调控外体的释放、内吞途径等。当PIKfyve激酶活性受到抑制时,细胞会表现出明显的空泡化现象(EMBO Reports 2008,9,164-174)。近年来,越来越多的研究表明,PIKfyve在促进肿瘤的生长与转移方面也发挥了重要作用。如PIKfyve参与了肿瘤细胞的侵袭和迁移(J Biol.Chem.2011;286,32105-32114;Biochem.J.2014,461,383-390);在过表达K-RasG12D的小鼠胚胎成纤维细胞中,抑制PIKfyve能抑制血清蛋白依赖性的细胞增殖(Dev.Cell 2016,38,536-547);同时抑制PIKfyve与细胞表面营养物质转运蛋白,可杀伤LS180、SW480、MDA-MB-231等多种肿瘤细胞(J.Clin.Invest.2016,126,4088-4102);在非霍奇金淋巴瘤细胞中,以小分子抑制剂作用于PIKfyve可有效杀死多种该类细胞,并且在动物模型上表现出良好的治疗效果(Blood2017,129,1768-1778);抑制PIKfyve可诱导肿瘤细胞产生巨泡式死亡(ACS Omega 2018,3,6097-6103),有望应用于目前尚无靶向药物(如三阴性乳腺癌)或耐药的难治性肿瘤的治疗。因此,PIKfyve已成为一个肿瘤治疗的新靶点,发展新型PIKfyve抑制剂,可用于PIKfyve介导的癌症或其他相关疾病,以及难治性肿瘤的治疗,具有良好的应用价值。
发明内容
本发明发明人经过广泛深入的研究,设计、合成了一系列结构新颖、安全性高、对激酶PIKfyve具有较高的活性的取代五元并六元杂环化合物,并且研究了这一类新型衍生物的抗肿瘤活性。
本发明提供了以下通式化合物:
其中,X1,X2,X3,X4,X5,X6可包含以下几种组合:
或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
其中取代基和符号的定义下面详细说明。
本发明的一个目的是提供一类具有抑制PIKfyve活性的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
本发明的另一个目的是提供上述化合物的制备方法。
本发明的另一个目的是提供包含上述化合物的药物组合物。
本发明的另一个目的是提供上述化合物及包含上述化合物的药物组合物在制备用于PIKfyve介导的癌症或其他疾病,以及难治性肿瘤的预防与治疗的药物中的用途。
本发明的另一个目的是提供一种治疗癌症的方法,所述方法包括向受试者施用有效量的本发明化合物或组合物。
附图说明
图1.化合物抑制PIKfyve导致细胞产生空泡化。
a、V-c-19(1μmol/L)诱导MDA-MB-231细胞产生空泡化,具有良好的时间依耐性。
b、V-c-19(1μmol/L)诱导MDA-MB-231细胞产生空泡化,具有良好的浓度依耐性。
图2、化合物与PIKfyve的解离平衡常数Kd值的测定(replicate 1和replicate 2代表每个化合物测2个重复)。
图3、代表性化合物V-c-17抑制PIKfyve引起溶酶体功能紊乱。在V-c-17或对照化合物apilimod作用下,未成熟的组织蛋白酶A与D逐渐增多,具有良好的剂量依耐性。
图4、代表性化合物I-a-1在三阴性乳腺癌细胞(MDA-MB-231)的异种转移模型中能有效抑制肿瘤的生长。在构建的MDA-MB-231异种移植小鼠模型中,每天给予5mg/kg、20mg/kg的剂量,经尾静脉给药。a)给药组能有效抑制肿瘤体积增长,且呈良好的剂量依赖性;b)给药组最后的肿瘤重量明显小于对照组,且呈良好的剂量依赖性。
图5、代表性化合物V-c-17在非霍奇金淋巴瘤细胞(JeKo-1)的异种转移模型中能有效抑制肿瘤的生长。在构建的JeKo-1异种移植小鼠模型中,给予25mg/kg一天一次或一天2次的剂量,经尾静脉给药。a)给药组能有效抑制肿瘤体积增长,且呈良好的剂量依赖性;b)给药组最后的肿瘤重量明显小于对照组,且呈良好的剂量依赖性。
发明详述
本文描述了各种具体实施方案、方式和实施例,包括为了理解所要求保护的本发明而采用的示例性实施方式和定义。尽管以下详细描述给出了具体的优选实施方案,但是本领域技术人员将理解,这些实施方式仅是示例性的,并且本发明可以以其他方式实践。为了确定侵权的目的,本发明的范围将涉及所附权利要求中的任何一个或多个,包括其等同物,以及等同于所述的那些的要素或限制。
本发明是通过下面的技术方案实现的。
一方面,本方案提供了下面通式表示的化合物:
其中,X1,X2,X3,X4,X5,X6可包含以下几种组合:
R1、R2选自:
1)取代或未被取代的C6-C10芳基、杂芳基,取代基选自:卤素原子、C6-C10芳基、杂芳基、杂环基、C1-C6烷基,C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基,其中所述取代基直接或任选地通过NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH或CO与C6-C10芳基、杂芳基相连接;
2)取代或未被取代的C6-C10芳胺基、杂芳胺基、C1-C6烷基氨基、C3-C7环烷基氨基、C1-C6含氧烷基氨基、C3-C7含氧环烷基氨基,取代基选自:卤素原子、C6-C10芳基、杂芳基、杂环基、C1-C6烷基,C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基,其中所述取代基任选地通过NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH与C6-C10芳胺基、杂芳胺基、C1-C6烷基氨基、C3-C7环烷基氨基、C1-C6含氧烷基氨基、C3-C7含氧环烷基氨基相连接;
优选R1、R2选自:
1)取代或未被取代的苯、吡啶、呋喃、噻吩、苯并呋喃、苯并噻吩、苯并二噁茂、咪唑、吡唑、噻唑、噁唑、嘧啶、吲哚、喹啉,取代基选自卤素原子、C1-C6烷基,C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基;
L1选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH,
R4选自氢、取代或未被取代的C6-C10芳基、杂芳基、杂环基、C1-C6烷基、C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基C3-C7环烷基;
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH、CO,
R5选自取代或未被取代的C6-C10芳基、杂芳基、杂环基、C1-C6烷基、C1-C6烷氧基、C1-C6含氧烷基,C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基C3-C7环烷基;
n=0、1或2;
Y1、Y2、Y3之一选自N;
R6选自氢、卤素原子、C1-C6烷基;
5)甲胺基、乙胺基、丙氨基、环丙基氨基、环丁基氨基、四氢吡咯基、哌啶基、吗啉基、4-氨基哌啶基、4-N,N-二甲基氨基哌啶基、3,5-二甲基吗啉基、N-甲基哌嗪基;
R3选自氢、卤素、取代或未被取代的烷基、环烷基,取代基选自卤素、氨基、羟基、烷硅氧基;
优选,药学上可接受的盐为:无机酸盐,选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐;或有机酸盐,选自甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐;优选地,所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐;所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐等。
第一方面,按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或其药学上可接受的盐或药学上可接受的溶剂合物具有以下结构:
其中,
R1选自:
2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基;
氢、氟,氯,溴,氨基,羟基、C1-C3烷基;
其中,
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L2为NHCO、CONH;最优选L2为NHCO;
R5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;
氢、卤素,氨基,羟基、C1-C3含氟烷基;
R7选自H、C1-C6烷基;优选R7为甲基;
R2选自:
2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基;
氢、氟,氯,溴,氨基,羟基、C1-C3烷基、C1-C3烷氧基;
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH、CO;优选NHCO、CONH、NHCONH、NHCSNH、CO;
R5选自取代或未被取代的C6-C10芳基、杂芳基、任选被取代的杂环基、C1-C6烷基、氨基取代的C1-C6烷基、C1-C6烷氧基、C1-C6含氟烷基、C1-C6含氟烷氧基、硝基、氰基、氨基、羟基C3-C7环烷基;
优选R5选自以下:
当L2为NHCO、CONH、NHCONH、NHCSNH时,R5为其中Z1,Z2,Z3,Z4,Z5中的1个或2个独立地选自以下,其余为氢:氢、C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基、氰基、经任选被取代的杂环基所取代的C1-C6烷基;
当L2为NHCO时,R5还为氨基取代的C1-C6烷基,其中优选C1-C6烷基为甲基、乙基、丙基,更优选C1-C6烷基为甲基;或者
R7选自
1)H、卤素、任选被取代的杂环基;
2)取代或未取代的C1-C6烷基,取代基为任选被取代的杂环基、双C1-C3烷基取代的氨基;
3)双取代的氨基,取代基选自C1-C3烷基、双C1-C3烷氨基取代的C1-C3烷基;
R9选自H、C1-C6烷氧基;优选R9为氢、甲氧基;
其中,R7和R9都为非氢基团时,它们不同时存在;
R3选自:-H,C1-C6烷基;优选选自:-H,-CH3。
第二方面,按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或其药学上可接受的盐或药学上可接受的溶剂合物具有以下结构:
其中,
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L2为NHCO、CONH;
R5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;
R7选自H、C1-C6烷基;优选R7为甲基;
R3选自:-H,C1-C6烷基;优选选自:-H,-CH3。
第三方面,按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或其药学上可接受的盐或药学上可接受的溶剂合物具有以下结构:
其中,
R1选自:
2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基、氰基;
氢、氟,氯,溴,氨基,羟基;
L1选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;L1优选为NHCONH、NHCSNH,
R4选自氢、取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L2为NHCO、CONH;最优选L2为CONH;
R5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;
氢、卤素、氨基、羟基、C1-C3含氟烷基;
R7选自H、C1-C6烷基;优选R7为甲基;
R2选自:
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L2为NHCO、CONH;
R5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;
R7选自H、C1-C6烷基;优选R7为甲基;
2)任选被杂芳基-C1-C6烷基取代的氨基;优选为被吡啶基-甲基取代的氨基;最优选为
R3选自:-H,C1-C6烷基;优选选自:-H,-CH3。
第四方面,按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或其药学上可接受的盐或药学上可接受的溶剂合物具有以下结构:
其中,
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L2为NHCO、CONH;
R5选自取代或未被取代的C6-C10芳基,优选取代或未被取代的苯基;
R7选自H、C1-C6烷基;优选R7为甲基;
R3选自:-H,C1-C6烷基;优选选自:-H,-CH3。
第五方面,按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或其药学上可接受的盐或药学上可接受的溶剂合物具有以下结构:
其中,
R1选自:
2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基、HOOC-、C1-C6烷氧基甲酰基;
优选为其中Z1,Z2,Z3,Z4,Z5中的1个选自以下,其余为氢:氢、C1-C6烷基、C1-C3烷氧基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、HOOC-、C1-C6烷氧基甲酰基;
氢、氟,氯,氨基,羟基、C1-C3烷基、HOOC-、乙氧基甲酰基(EtOOC-);
L1选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L1为NHCO、CONH、NHCONH、NHCSNH;
R4选自氢、取代或未被取代的的C6-C10芳基、优选取代或未被取代的苯基,或取代或未被取代的的杂芳基、优选取代或未被取代的吡啶基;
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;
优选L2选自NHCO、CONH、NHSO2、NHCONH、NHCSNH;
R5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;
R5优选为其中Z1,Z2,Z3,Z4,Z5中的1个或2个独立地选自以下,其余为氢:氢、卤素,氨基,羟基、C1-C3含氟烷基、C1-C3烷氧基、C1-C6酰胺基、C1-C6烷基磺酰胺基、C1-C3含氟烷氧基、硝基、氰基、经任选被取代的杂环基所取代的C1-C6烷基、任选被取代的杂芳基;
最优选R5为其中,Z2或Z4为氢或-OCF3,或Z3为氢、-NO2、-CN或-OMe,或Z2或Z4、Z3中的一个为氢、-CF3或-NHAc,或Z1或Z5、Z2或Z4、Z3中的一个为氢、-NH2或-NHMs;或Z2与Z4独立地选自-CF3、或Z2与Z3独立地选自-CF3、或Z1与Z4独立地选自-CF3、-OMe、-F、-Cl;其余为氢;
R7选自
1)H、任选被取代的杂环基、C1-C6烷氧基;
2)取代或未取代的C1-C6烷基,取代基为任选被取代的杂环基、双C1-C3烷基取代的氨基;
3)双取代的氨基,取代基选自C1-C3烷基、双C1-C3烷氨基取代的C1-C3烷基;
5)经任选被取代的苯基取代的氨基,
优选为未取代的苯基或被以下取代的苯基取代的氨基:被甲磺酰氨基单取代的苯基,被杂环基双取代的苯基;
R2选自:
1)任选被取代的杂芳基,
2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基、C1-C6烷基磺酰基;
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L2为NHCO、CONH、NHSO2、NHCONH、NHCSNH;
R5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;
R5优选为其中Z1,Z2,Z3,Z4,Z5中的1个或2个独立地选自以下,其余为氢:氢、卤素,氨基,双C1-C3烷基取代的氨基、羟基、C1-C3烷基、C1-C3烷氧基、C1-C3含氟烷基、C1-C3含氟烷氧基、任选被取代的杂芳基、经任选被取代的杂环基所取代的C1-C6烷基;
R5更优选为其中Z1,Z2,Z3,Z4,Z5中的1个或2个独立地选自以下,其余为氢:氢、氟、氯、溴、氨基、双C1-C3烷基取代的氨基、羟基、三氟甲基、三氟甲氧基、C1-C6烷基取代的经任选被C1-C6烷基取代的杂环基所取代的C1-C6烷基、C1-C3烷基、C1-C3烷氧基;
R7选自H、C1-C6烷基;优选R7为H、甲基;
4)经任选被C3-C7环烷基、任选被取代的杂芳基或任选被杂芳基取代的C1-C6烷基取代的氨基;
优选选自被以下取代的氨基:C3-C6环烷基,任选经C1-C6烷基取代的杂芳基或任选经杂芳基取代的C1-C6烷基;
最优选选自以下取代的氨基:
5)任选被取代的杂环基,
优选选自经二(C1-C6烷基)氨基、C1-C6烷基取代的杂芳基取代的杂环基,
R3选自:-H,C1-C6烷基;优选选自:-H,-CH3。
第六方面,按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或其药学上可接受的盐或药学上可接受的溶剂合物具有以下结构:
其中,
R2选自:
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L2为NHCO、CONH;
R5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;
R5优选为其中Z1,Z2,Z3,Z4,Z5中的1个或2个独立地选自以下,其余为氢:氢、卤素,氨基,羟基、C1-C3含氟烷基、C1-C3含氟烷氧基、任选被取代的杂芳基、经任选被取代的杂环基所取代的C1-C6烷基;
R5更优选为其中Z1,Z2,Z3,Z4,Z5中的1个或2个独立地选自以下,其余为氢:氢、氟、氯、氨基,羟基、三氟甲基、三氟甲氧基、C1-C6烷基取代的经任选被C1-C6烷基取代的杂环基所取代的C1-C6烷基、;
R7选自H、C1-C6烷基;优选R7为甲基;
第七方面,按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或其药学上可接受的盐或药学上可接受的溶剂合物具有以下结构:
其中,
L1选自NHCO、CONH;L1优选为NHCO;
R4选自氢、取代或未被取代的的C6-C10芳基、优选取代或未被取代的苯基,或取代或未被取代的的杂芳基、优选取代或未被取代的吡啶基;
R4优选为其中Z1,Z2,Z3,Z4,Z5中的1个选自以下,其余为氢:氢、卤素,氨基,羟基、C1-C3含氟烷基;更优选R4为其中Z2或Z4选自以下,其余为氢:氢、氯,氨基,羟基、三氟甲基;最优选R4为其中Z2或Z4为三氟甲基,其余为氢;或
R2选自:
1)任选被C3-C7环烷基取代的氨基、经任选被取代的杂芳基取代的氨基;
优选选自被环丙基取代的氨基、经任选被C1-C6烷基取代的杂芳基取代的氨基;
2)任选被取代的杂环基,
优选选自经二(C1-C6烷基)氨基、C1-C6烷基取代的杂环基,
第八方面,按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或其药学上可接受的盐或药学上可接受的溶剂合物具有以下结构:
其中,
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L2为NHCO、CONH;
R5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;
R7选自H、C1-C6烷基;优选R7为H、甲基;
除非特殊说明,上述基团和取代基具有药物化学领域的普通含义。
需要说明的是,C1-C6含氧烷基是指是指C1-C6烷基骨架被一个或多个C1-C6烷氧基取代所成的基团,例如,甲氧基乙基,甲氧基乙氧基甲基等。类似地,C1-C3含氧烷基是指是指C1-C3烷基骨架被一个或多个C1-C6烷氧基取代所成的基团。
术语"芳基"或“C6-C10芳基”是指C6-10的单-、二-或多-碳环烃,其具有任选地进一步通过单键彼此稠合或连接的1至2个环系统,其中所述碳环中至少一个是“芳族的”,其中术语“芳族的”是指完全共轭的π-电子键系统。芳基环可以任选地进一步稠合或连接于芳族的和非芳族的碳环和杂环的环。所述芳基的非限制性的实例是苯基、α-或β-萘基。
术语"杂芳基"是指芳族的杂环,通常为具有1至3个选自N、O或S的杂原子的5-至8-元的杂环;杂芳基环可以任选地进一步稠合或连接于芳族和非芳族的碳环和杂环。所述杂芳基的非限制性的实例为例如吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、咪唑基、噻唑基、异噻唑基、噻噁唑基、吡咯基、苯基-吡咯基、呋喃基、苯基-呋喃基、噁唑基、异噁唑基、吡唑基、噻吩基、苯并呋喃基、苯并噻吩基、苯并1,3-二氧戊环(苯并二噁茂)、异二氢吲哚基、苯并咪唑基、吲唑基、喹啉基、异喹啉基、1,2,3-三唑基、1-苯基-1,2,3-三唑基、2,3-二氢吲哚基、2,3-二氢苯并呋喃基、2,3-二氢苯并噻吩基、苯并吡喃基、2,3-二氢苯并噁嗪基、2,3-二氢喹喔啉基等。
术语“C6-C10芳胺基”是指-NH-或含氮基团连接到上述定义的"芳基"或“C6-C10芳基”上所成的基团,该基团与化合物的其它部分的连接位置在-NH-或含氮基团上。
类似地,术语“杂芳胺基”是指-NH-或含氮基团连接到上述定义的"杂芳基"上所成的基团,该基团与化合物的其它部分的连接位置在-NH-或含氮基团上。
术语“杂环基”(也称作“杂环烷基”)指的是3-、4-、5-、6-和7-元饱和或部分不饱和碳环,其中一个或多个碳原子被杂原子例如氮、氧和硫替代。杂环基的非限制性实例是,例如吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、噻唑啉、噻唑烷、二氢呋喃、四氢呋喃、1,3-二氧戊环、哌啶、哌嗪、吗啉、吗啡啉基、四氢吡咯基、硫吗啉基等。
术语“任选被取代的杂环基”指的是上述“杂环基”被一个或多个“C1-C6烷基”、“C1-C3烷基”、“C3-C6环烷基”等取代。
术语“C1-C6烷基”指的是任意的含有1-6个碳原子的直链或支链基团,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基等。
术语“C1-C3烷基”指的是任意的含有1-3个碳原子的直链或支链基团,例如甲基、乙基、正丙基、异丙基等。
除非另有提供,术语“C3-C7环烷基”是指具有饱和环的3-7元单环系统的烃,C3-C7环烷基可以为环丙基、环丁基、环戊基、环己基、环庚基。
类似地,术语“C3-C6环烷基”是指具有饱和环的3-6元单环系统的烃,C3-C7环烷基可以为环丙基、环丁基、环戊基、环己基。
术语“C1-C6含氟烷基”是指C1-C6烷基骨架被一个或多个氟基取代所成的基团,例如,四氟化碳,单氟甲基,二氟乙基,三氟甲基等。
类似地,术语“C1-C3含氟烷基”是指C1-C3烷基骨架被一个或多个氟基取代所成的基团,例如,四氟化碳,单氟甲基,二氟乙基,三氟甲基等。
术语“C1-C6酰基”指的是-C(=O)-H和-C(=O)-C1-C5烷基,例如甲酰基、乙酰基、丙酰基、丁酰基等。
术语“C1-C6酰胺基”指的是-C(=O)-NH2和NH2-C(=O)-C1-C5烷基-,例如甲酰胺基、乙酰胺基、丙酰胺基、丁酰胺基等。
术语“C1-C6烷基磺酰氨基”指的是和NH2-S(=O)2-C1-C6烷基,例如甲磺酰氨基、乙磺酰氨基、丙磺酰氨基、丁磺酰氨基等。
术语“烷氧基”、“环基氧基”及其衍生物指的是任意上述烷基(例如C1-C6烷基、C1-C3烷基等)、环烷基(例如C3-C6环烷基),其通过氧原子(-O-)连接到分子的其余部分。
从所有上述描述中,对本领域技术人员显而易见的是,其名称是复合名称的任意基团,例如“含氟含氧烷基”,应该指的是常规地从其衍生的部分例如从被氟基取代的含氧烷基来构建,其中烷基如上文所定义。类似地,还有“含氟烷氧基”。又例如,“芳基氨基”,应该指的是常规地从其衍生的部分例如从被芳基取代的氨基来构建,其中芳基如上文所定义。类似地,可以理解“杂芳氨基”的含义。
同样,任意术语例如烷基氨基、二烷基氨基、烷氧基羰基、烷氧基羰基氨基、杂环基羰基、杂环基羰基氨基、环烷基氧基羰基、烷氧基甲酰基等包括基团,其中烷基、烷氧基、芳基、C3-C7环烷基和杂环基部分如上文所定义。
根据本发明和除非另有提供,任意上述基团可以任选地在其任意自由位置上被一个或多个基团取代,例如被1-6个基团取代,该基团独立地选自:卤素原子、硝基、氧代(=O)、氰基、C1-C6烷基、多氟化烷基、多氟化烷氧基、烯基、炔基、羟基烷基、羟基烷基氨基、羟基杂环基、芳基、芳基-烷基、杂芳基、杂芳基-烷基、杂环基、杂环基-烷基、C3-C7环烷基、环烷基-烷基、烷基-芳基、烷基-杂芳基、烷基-杂环基、烷基-环烷基、烷基-芳基-烷基、烷基-杂芳基-烷基、烷基-杂环基-烷基、烷基-环烷基-烷基、烷基-杂环基-杂环基、杂环基-杂环基、杂环基-烷基-杂环基、杂环基-烷基氨基、烷基-杂环基-烷基-氨基、羟基、烷氧基、芳氧基、杂环基氧基、烷基-杂环基氧基、亚甲二氧基、烷基羰基氧基、芳基羰基氧基、环烯基氧基、杂环基羰基氧基、亚烷基氨基氧基、羧基、烷氧基羰基、芳氧基羰基、环烷基氧基羰基、杂环基氧基羰基、氨基、脲基、烷基氨基、氨基-烷基氨基、二烷基氨基、二烷基氨基-杂环基、二烷基氨基-烷基氨基、芳基氨基、芳基烷基氨基、二芳基氨基、杂环基氨基、烷基-杂环基氨基、烷基-杂环基羰基、甲酰基氨基、烷基羰基氨基、芳基羰基氨基、杂环基羰基氨基、烷基-杂环基羰基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、芳基氨基羰基、杂环基氨基羰基、烷氧基羰基氨基、烷氧基羰基氨基-烷基氨基、烷氧基羰基杂环基-烷基氨基、烷氧基-芳基-烷基、羟基氨基-羰基、烷氧基亚氨基、烷基磺酰基氨基、芳基磺酰基氨基、杂环基磺酰基氨基、甲酰基、烷基羰基、芳基羰基、环烷基羰基、杂环基羰基、烷基磺酰基、芳基磺酰基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、芳基氨基磺酰基、杂环基氨基磺酰基、芳硫基、烷硫基、膦酸酯基和烷基膦酸酯基。
进而,如果适合,上述取代基各自可以进一步被一个或多个上述举出的基团取代。
在这方面,术语“卤原子”指的是氟、氯、溴或碘原子。
术语“氰基”指的是-CN残基。
术语“硝基”指的是-NO2基团。
如本文所使用,除非另外说明,术语“前药”是指可以在生物学条件(体外或体内)下水解、氧化或进行其他反应以提供本发明的化合物的衍生物。前药仅在生物学条件下经过该反应成为活性化合物,或者它们在它们不反应的形式中具有活性。通常可以使用公知的方法制备前药,例如1Burger's Medicinal Chemistry and Drug Discovery(1995)172-178,949-982(Manfred E.Wolff编,第5版)中描述的那些方法。
药学上可以接受的盐可使用本领域熟知的标准程序获得,例如,通过将足量的碱性化合物和提供药学上可以接受的阴离子的合适的酸反应。
本文使用的术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状,可以是预防性的;和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用,可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗,包括:(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状;(b)抑制疾病的症状,即阻止其发展;或(c)缓解疾病的症状,即,导致疾病或症状退化。
按照本发明的一种具体技术方案所述化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物,其中所述化合物为下面实施例中所述化合物之一。
另一方面,本发明提供了药物组合物其包含上述任一技术方案所述的化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物,和药学上可接受的载体、稀释剂或赋形剂。
制备各种含有一定量的活性成分的药物组合物的方法是已知的,或根据本发明的公开内容对于本领域技术人员是显而易见的。如REMINGTON’S PHARMACEUTICAL SCIENCES,Martin,E.W.,ed.,Mack Publishing Company,19th ed.(1995)所述,制备所述药物组合物的方法包括掺入适当的药学赋形剂、载体、稀释剂等。
以已知的方法制造本发明的药物制剂,包括常规的混合、溶解或冻干方法。本发明的化合物可以制成药物组合物,并向患者以适于选定的施用方式的各种途径施用,例如,口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。
因此,本发明的化合物结合药学上可以接受的载体(如惰性稀释剂或可同化的可食用的载体)可以全身施用,例如,口服。它们可以封闭在硬或软壳的明胶胶囊中,可以压为片剂。对于口服治疗施用,活性化合物可以结合一种或多种赋形剂,并以可吞咽的片剂、颊含片剂、含片、胶囊剂、酏剂、悬浮剂、糖浆、圆片等的形式使用。这种组合物和制剂应该包含至少0.1%的活性化合物。这种组合物和制剂的比例当然可以变化,可以占给定的单位剂型重量的大约1%至大约99%。在这种治疗有用的组合物中,活性化合物的量使得能够获得有效剂量水平。
片剂、含片、丸剂、胶囊剂等也可以包含:粘合剂,如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,如磷酸氢二钙;崩解剂,如玉米淀粉、马铃薯淀粉、藻酸等;润滑剂,如硬脂酸镁;和甜味剂,如蔗糖、果糖、乳糖或阿司帕坦;或调味剂,如薄荷、冬青油或樱桃香味。当单位剂型是胶囊时,除了上面类型的材料,它还可以包含液体载体,如植物油或聚乙二醇。各种其他材料可以存在,作为包衣,或以其他方式改变固体单位剂型的物理形式。例如,片剂、丸剂或胶囊剂可以用明胶、蜡、虫胶或糖等包衣。糖浆或酏剂可以包含活性化合物,蔗糖或果糖作为甜味剂,对羟苯甲酸甲酯或对羟苯甲酸丙酯作为防腐剂,染料和调味剂(如樱桃香料或桔子香料)。当然,用于制备任何单位剂型的任何材料应该是药学上可以接受的且以应用的量基本上无毒。此外,活性化合物可以掺入缓释制剂和缓释装置中。
活性化合物也可以通过输注或注射来静脉内或腹膜内施用。可以制备活性化合物或其盐的水溶液,任选地混和无毒的表面活性剂。也可以制备在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散剂。在普通的储存和使用条件下,这些制剂包含防腐剂以防止微生物生长。
适于注射或输注的药物剂型可以包括包含适于无菌的可注射或可输注的溶液或分散剂的即时制剂的活性成分(任选封装在脂质体中)的无菌水溶液或分散剂或无菌粉末。在所有情况下,最终的剂型在生产和储存条件下必须是无菌的、液体的和稳定的。液体载体可以是溶剂或液体分散介质,包括,例如水、乙醇、多元醇(例如,甘油、丙二醇、液体聚乙二醇等)、植物油、无毒的甘油酯及其合适的混合物。可以维持合适的流动性,例如,通过脂质体的形成,通过在分散剂的情况下维持所需的粒子大小,或通过表面活性剂的使用。可以通过各种抗细菌剂和抗真菌剂(如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)产生预防微生物的作用。在许多情况下,优选包括等渗剂,如糖、缓冲剂或氯化钠。通过使用延缓吸收剂的组合物(例如,单硬脂酸铝和明胶)可以产生可注射的组合物的延长吸收。
通过将合适的溶剂中的需要量的活性化合物与需要的上面列举的各种其他成分结合,然后进行过滤灭菌,制备无菌可注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥技术,这会产生活性成分加上任何另外需要的以前无菌过滤溶液中存在的成分的粉末。
有用的固体载体包括粉碎的固体(如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等)。有用的液体载体包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物,本发明的化合物可以任选在无毒的表面活性剂的帮助下以有效含量溶解或分散在其中。可以加入佐剂(如香味)和另外的抗微生物剂来优化对于给定用途的性质。
增稠剂(如合成的聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性无机材料)也可和液体载体用于形成可涂覆的糊剂、凝胶、软膏、肥皂等,直接用于使用者的皮肤上。
如本文所使用,术语“受试者”可以指患者或者其它接受本发明化合物或药物组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物,特别是哺乳动物,例如人、狗、猴、牛、马等。
如本文所使用,术语“有效量”或“需要量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。
化合物或其活性盐或衍生物的治疗需要量,不仅取决于选择的特定的盐,而且取决于施药方式、待治疗的疾病的本质和患者的年龄和状态,最终取决于在场医师或临床医生的决定。
上述制剂可以以单位剂型存在,该单位剂型是含有单位剂量的物理分散单元,适于向人体和其它哺乳动物体给药。单位剂型可以是胶囊或片剂,或是很多胶囊或片剂。根据所涉及的具体治疗,活性成分的单位剂量的量可以在大约0.1到大约1000毫克或更多之间进行变化或调整。
此外,还包括各种药物新剂型如乳脂质体、微球和纳米球的应用,如使用微粒分散体系包括聚合物胶束(polymeric micelles)、纳米乳(nanoemulsion)、亚微乳(submicroemuls微囊(microcapsule)、微球(microsphere)、脂质体(liposomes)和类脂囊泡(niosomes)(又称非离子表面活性剂囊泡)等制备的药剂。
反应条件:(a)金属钯催化的杂芳基氯代物与硼酸或硼酸酯的碳碳键形成偶联反应,或金属钯催化的杂芳基氯代物与胺类化合物的碳氮键形成的偶联反应,或碱性条件下胺类化合物对杂芳基氯代物的亲核取代反应,或酸性条件下胺类化合物对杂芳基氯代物的亲核取代反应;(b)金属钯催化的杂芳基氯代物与硼酸或硼酸酯的碳碳键形成偶联反应,或金属钯催化的杂芳基氯代物与胺类化合物的碳氮键形成的偶联反应,或酸性条件下胺类化合物对杂芳基氯代物的亲核取代反应。
其中,其中,所述杂芳基氯代物包含以下类型:
所述硼酸或硼酸酯选自取代或未被取代的C6-C10芳基、杂芳基硼酸或硼酸酯;所述胺类化合物选自取代或未被取代的C6-C10芳胺、杂芳胺、C1-C6烷基氨、C3-C7环烷基氨、C1-C6含氧烷基氨、C3-C7含氧环烷基氨。详见之前所述。
所述金属钯催化剂选自醋酸钯、四(三苯基膦)钯、双三苯基磷二氯化钯、1,1'-双(二苯基膦)二茂铁]二氯化钯、三(二亚苄基丙酮)二钯;所述碱性条件指以下任意物质存在的条件下:三乙胺、二异丙基乙基胺、吡啶、碳酸氢钠、碳酸钠、碳酸钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、氢化钠、氢化钾;所述酸性条件指以下任意物质存在的条件下:乙酸、三氟乙酸、盐酸、甲磺酸、对甲苯磺酸、樟脑磺酸。
另一方面,本发明还提供了上述任一技术方案所述化合物其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物及包含该化合物的药物组合物在制备用于PIKfyve介导的癌症及其他疾病的预防与治疗的药物的用途。
实验部分
就如下涉及的实施例而言,使用本文所述的方法或本领域众所周知的其他方法合成本发明的化合物。
通用纯化和分析方法
在硅胶GF254预涂覆板(青岛海洋化工厂)上进行薄层色谱。在中压下经硅胶(300-400目,烟台芝黄务硅胶开发试剂厂)进行柱色谱分离或通过使用ISCO Combiflash Rf200快速纯化系统用预装的硅胶筒(ISCO或Welch)进行柱色谱分离。成分通过UV光(λ:254nm)和通过碘蒸气显影。当必要时,将化合物通过制备型HPLC制备经Waters Symmetry C18(19x50mm,5μm)柱或经Waters X Terra RP 18(30x 150mm,5μm)柱纯化,使用装配有996WatersPDA检测器的Waters制备型HPLC 600和Micromass mod.ZMD单四级质谱(电喷雾离子化,阳离子模式)。方法1:相A:0.1%TFA/MeOH 95/5;相B:MeOH/H2O 95/5。梯度:10至90%B进行8min,保持90%B 2min;流速20mL/min。方法2:相A:0.05%NH4OH/MeOH 95/5;相B:MeOH/H2O95/5。梯度:10至100%B进行8min,保持100%B 2min。流速20mL/min。
将1H-NMR谱在600MHz操作的Bruker Avance 600谱仪(对于1H而言)进行记录。化学位移(δ)以百万分率(ppm)进行报道且偶合常数(J)以Hz计。将四甲基硅烷信号用作参比(δ=0ppm)。以下缩写用于峰裂分:s=单;br.s.=宽信号;d=双;t=三;m=多重;dd=双双。
电喷雾(ESI)质谱经Finnigan LCQ离子阱获得。
除非另外说明,所有最终化合物均是均质的(纯度不低于95%),由高效液相色谱(HPLC)所确定。用于评价化合物纯度的HPLC-UV-MS分析通过组合离子阱MS设备与HPLC系统SSP4000(Thermo Separation Products)来进行,所述HPLC系统装配有自动进样器LC Pal(CTC Analytics)和UV6000LP二极管阵列检测器(UV检测215-400nm)。用Xcalibur 1.2软件(Finnigan)进行设备控制、数据采集和处理。HPLC色谱法在室温和1mL/min流速下进行,其使用Waters X Terra RP 18柱(4.6x 50mm;3.5μm)。流动相A是乙酸铵5mM缓冲液(采用乙酸得到pH 5.5):乙腈90:10,流动相B乙酸铵5mM缓冲液(采用乙酸得到pH 5.5):乙腈10:90;梯度为0至100%B进行7分钟,然后在再平衡前保持100%B达2分钟。
试剂纯化参考Purification of Laboratory Chemicals(Perrin,D.D.,Armarego,W.L.F.and Perrins Eds,D.R.;Pergamon Press:Oxford,1980)一书进行。石油醚是60-90℃馏分、乙酸乙酯、甲醇、二氯甲烷均为分析纯。
具体实施方式
合成过程中涉及到的部分原料及中间体描述如下:
以下中间体经过类似方法获得:
所涉及原料为:对三氟甲基苯甲酰氯(CAS:329-15-7,安耐吉,上海),3-甲基-4-硝基苯胺(CAS:611-05-2,安耐吉,上海),间硝基苯胺(CAS:99-09-2,安耐吉,上海),对乙酰氨基苯甲酰氯(CAS:16331-48-9,安耐吉,上海),对氰基苯甲酰氯(CAS:6068-72-0,安耐吉,上海),对硝基苯甲酰氯(CAS:122-04-3,安耐吉,上海),间三氟甲基苯磺酰氯(CAS:777-44-6,安耐吉,上海)。
以下中间体经类似方法获得:
所涉及原料为:间硝基苯甲酸(CAS:121-92-6,安耐吉,上海),间二(三氟甲基)苯胺(CAS:328-74-5,安耐吉,上海),间甲氧基苯胺(CAS:536-90-3,安耐吉,上海),间三氟甲氧基苯胺(CAS:1535-73-5,安耐吉,上海),间甲苯胺(CAS:108-44-1,安耐吉,上海),3-甲磺酰氨基苯胺(CAS:37045-73-1,韶远,上海),间氯苯胺(CAS:108-42-9,安耐吉,上海),3-氨基-4-氯三氟甲苯(CAS:121-50-6,安耐吉,上海),2-氟-5-三氟甲基苯胺(CAS:535-52-4,安耐吉,上海),2-甲氧基-5-三氟甲基苯胺(CAS:349-65-5,安耐吉,上海),间氟苯胺(CAS:372-19-0,安耐吉,上海),4-甲氧基-3-硝基苯甲酸(CAS:89-41-8,毕得医药,上海),2-甲氧基-5-硝基苯甲酸(CAS:40751-89-1,书亚,上海),4-氟-3-硝基苯甲酸(CAS:453-71-4,书亚,上海),5-氨基-1,3-二甲基吡唑(CAS:3524-32-1,百灵威,北京),吗啉(CAS:110-91-8,阿拉丁,上海),N-甲基哌嗪(CAS:109-01-3,安耐吉,上海),3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯胺(CAS:641571-11-1,毕得医药,上海),(CAS:853296-94-3,岚启,上海),(CAS:694499-26-8,岚启,上海);
17.由(CAS:859213-39-1,百灵威,北京)与2-氨基-4-硝基甲苯(CAS:99-55-8,安耐吉,上海)反应得到再与N-甲基哌嗪(CAS:109-01-3,安耐吉,上海)得到最后还原硝基而得;
18.由间三氟甲基苯胺(CAS:98-16-8,安耐吉,上海)与二(三氯甲基)碳酸酯(CAS:32315-10-9,安耐吉,上海)制得间三氟甲基苯基硫代异氰酸酯,再与4-甲基-3-硝基苯胺(CAS:99-55-8,安耐吉,上海)反应得到再还原硝基而得;
以下中间体经类似的方法获得:
所涉及的原料为:2-氯-5-氨基三氟甲苯(CAS:320-51-4,一飞,上海),5-溴-2-甲氧基苯胺(CAS:6358-77-6,毕得医药,上海),硫光气(CAS:463-71-8,安耐吉,上海);
19.吡啶-3-硼酸(CAS:1692-25-7,安耐吉,上海);
20.吡啶-4-硼酸(CAS:1692-15-5,安耐吉,上海);
21.苯硼酸(CAS:98-80-6,Adamas,瑞士);
22.对甲基苯硼酸(CAS:5720-05-8,安耐吉,上海);
23.对羟基苯硼酸(CAS:71597-85-8,毕得,上海);
24.间羟基苯硼酸(CAS:87199-18-6,安耐吉,上海);
25.对氯苯硼酸(CAS:1679-18-1,安耐吉,上海);
26.间氯苯硼酸(CAS:63503-60-6,安耐吉,上海);
27.3-呋喃硼酸(CAS:55552-70-0,安耐吉,上海);
28.3-噻吩硼酸(CAS:6165-69-1,安耐吉,上海);
29.4-氨基苯硼酸盐酸盐(CAS:80460-73-7,安耐吉,上海);
30.3-氨基苯硼酸盐酸盐(CAS:80460-73-7,百灵威,北京);
31.4-甲氧基苯硼酸(CAS:5720-07-0,安耐吉,上海);
32.2-呋喃硼酸(CAS:13331-23-2,安耐吉,上海);
33.2-噻吩硼酸(CAS:6165-68-0,安耐吉,上海);
34.苯并呋喃-2-硼酸(CAS:13331-23-2,安耐吉,上海);
35.苯并噻吩-2-硼酸(CAS:6165-68-0,安耐吉,上海);
36.4-氨甲基吡啶(CAS:3731-53-1,安耐吉,上海);
37.3-氨甲基吡啶(CAS:3731-52-0,安耐吉,上海);
38.4-乙氧羰基苯硼酸(CAS:4334-88-7,安耐吉,上海);
39.4-二甲氨基哌啶(CAS:50533-97-6,韶远,上海);
40.2,6-二甲基吗啉(CAS:141-91-3,安耐吉,上海);
41.环丙胺(CAS:765-30-0,安耐吉,上海);
42.4-氨基吡啶(CAS:504-24-5,西亚,上海);
43.3-氨基吡啶(CAS:462-08-8,安耐吉,上海);
44.2-氨基-5-甲基吡啶(CAS:1603-41-4,书亚,上海);
44.2-氨基-4-甲基吡啶(CAS:695-34-1,韶远,上海);
45.3.4-(亚甲基二氧基)苯硼酸(CAS:94839-07-3,安耐吉,上海);
46.对氟苯硼酸(CAS:1765-93-1,Adamas,瑞士);
47.对甲磺酰基苯硼酸(CAS:149104-88-1,安耐吉,上海)。
下面通过具体实施例详细描述本发明的实施方式,但是无论如何它们不能解释为对本发明的限制。
化合物I-a-1、I-b-1、I-c-1的合成路线:
化合物2a的合成:
方法A:将化合物1(6g,32mmol)溶于30mL干燥的N,N-二甲基甲酰胺中,并在冰水浴下搅拌10min,分批次加入氢化钠(1.9g,48mmol),搅拌15min之后再往反应体系中滴加2-(三甲基硅烷基)乙氧甲基氯(6.8mL,38.4mmol),然后在室温下搅拌至反应结束(LC-MS跟踪)。停止反应,在低温条件下往反应液中慢慢加入300mL水及250mL乙酸乙酯,分液,有机相以水洗涤两次,无水硫酸钠干燥,过滤,浓缩后硅胶柱层析(石油醚),得化合物2(无色液体,8.79g,产率87%)。
MS(ESI)m/z:318[M+H]+.
化合物2b的合成:
由化合物1(187mg,1.0mmol)与碘甲烷(124μL,2.0mmol),经方法A获得2(200mg,产率100%)。
MS(ESI)m/z:202[M+H]+.
化合物4a、4c的合成:
方法B:将化合物2a(500mg,1.58mmol)、芳胺化合物3(465mg,1.58mmol)三(二亚苄基丙酮)二钯(72mg,0.08mmol)、2-二环己基磷-2’,4’,6’-三异丙基联苯(57mg,0.12mmol)以及碳酸钾(654mg,4.74mmol)分散于叔丁醇中,体系置换为氮气,并置于预热至100℃的油浴中加热搅拌至反应结束(TLC跟踪),停止反应,冷却后过滤除去固体,以MeOH冲洗滤饼收集滤液浓缩,经硅胶柱层析,得化合物4a(540mg,产率60%)与4c(77mg,产率8.5%)。
MS(ESI)m/z:575[M+H]+.
化合物4b的合成:
方法C:化合物2b(201mg,1mmol)与3(294mg,1mmol)于叔丁醇(5mL)中在三氟乙酸(89μL,1.2mmol)作用下85℃加热至反应结束(LC-MS跟踪),冷却后加乙酸乙酯(50mL),以饱和碳酸氢钠溶液洗涤2次,无水硫酸钠干燥,过滤,浓缩后硅胶柱层析(石油醚/乙酸乙酯)得化合物4b(280mg,产率61%)。
MS(ESI)m/z:459[M+H]+.
化合物5a的合成:
方法D:化合物4a(288mg,0.5mmol)、3-吡啶硼酸(73mg,0.6mmol)、PdCl2(dppf)·CH2Cl2(41mg,0.05mmol)及Na2CO3(265mg,2.5mmol)在反应瓶中分散于1,4-dioxane/H2O(4/1mL)中,置换空气为氮气,100℃加热至反应结束(LC-MS跟踪),过滤除去不溶物,滤液浓缩后硅胶柱纯化得目标产物5a(500mg,产率81%)。
MS(ESI)m/z:618[M+H]+.
化合物I-a-1的合成:
方法E:化合物5a(200mg,0.32mmol)在TFA(2mL)中室温下搅拌至反应结束(LC-MS跟踪),浓缩后加入MeOH/THF/LiOH(1M aq.)(2/2/2mL),室温下搅拌至反应结束(LC-MS跟踪),析出的固体经过滤、水洗,干燥,得142mg,产率91%。
化合物I-b-1由4b经方法D合成;化合物I-c-1由4c经方法D、方法E合成。
其他此类化合物可由类似的方法合成。
下表列出具体化合物及结构鉴定数据。
化合物II-a-1、II-b-1的合成路线:
化合物6b由6a经方法A合成。
MS(ESI)m/z:202[M+H]+。
化合物7的合成:
方法F:化合物6(2mmol)溶于MeOH中0℃搅拌,加入NaSMe(20%aq,1.8eq.),自然升至室温,反应过夜,TLC跟踪直至转化完全,加入DCM,水洗,有机相浓缩后得白色固体,直接用于下一步反应。
7a:MS(ESI)m/z:200[M+H]+;7b:MS(ESI)m/z:214[M+H]+。
化合物8由化合物7与3-吡啶硼酸经方法D合成。
8a:MS(ESI)m/z:243[M+H]+;8b:MS(ESI)m/z:257[M+H]+。
化合物9的合成:
方法G:化合物8(1mmol)溶于DCM(5mL),-30℃下缓慢滴入mCPBA(1.5eq.)的DCM溶液(5mL),保温2-4h,TLC跟踪直至转化完毕,加入DCM稀释,饱和NaHCO3水溶液洗,有机相浓缩后硅胶柱纯化,得微黄色固体。
9a:MS(ESI)m/z:259[M+H]+;9b:MS(ESI)m/z:273[M+H]+。
化合物II-a-1、II-b-1的合成分别由9a、9b与3经方法C合成。
其他该类化合物可由类似的方法合成。
下表列出具体化合物与结构表征数据。
化合物III-a-1、III-b-1的合成路线:
化合物11a的合成:
方法H:化合物10(211mg,1.0mmol)溶于乙醇(5mL)在-78℃下搅拌,缓慢加入水合肼(53μL,1.1mmol),TLC跟踪直至反应结束,加入乙酸乙酯(50mL),水洗一次,有机相以无水硫酸钠干燥,过滤,浓缩后硅胶柱层析得化合物11a(127mg,产率67%)。
MS(ESI)m/z:190[M+H]+.
化合物11b由10与甲基肼经方法H合成。
MS(ESI)m/z:204[M+H]+.
化合物13的合成:
化合物11(0.5mmol)与12(0.5mmol)在叔丁醇(2mL)中微波反应器中150℃反应4小时,浓缩后硅胶柱层析得化合物。
13a:MS(ESI)m/z:490[M+H]+;13b:MS(ESI)m/z:504[M+H]+。
化合物III-a-1、III-a-2分别由13a、13b与3-吡啶硼酸经方法D合成。
其他该类化合物可由类似的方法合成。
下表列出具体化合物与结构表征数据。
化合物IV-a-1、IV-b-1的合成路线:
化合物IV-a-1、IV-b-1可分别由14a、14b先后经方法C、方法D合成。
其他该类化合物可由类似的方法合成。
下表列出具体化合物及结构表征数据。
化合物V-a-1、V-b-1的合成路线:
化合物V-a-1、V-b-1分别由16a、16b先后经方法C、方法D合成。
化合物V-c-1合成路线:
化合物V-c-1由16c先后经方法D、方法B、方法E合成。
其他该类化合物可由类似的方法合成。
下表列出具体化合物及结构表征数据。
化合物VI-a-1、VI-b-1的合成路线:
化合物21a由19先后经方法F、方法D合成,MS(ESI)m/z:243[M+H]+.
化合物21b的合成:
方法J:化合物21a(484mg,2mmol)与NBS(427mg,2.4mmol)在乙醇(10mL)中室温下搅拌3小时,浓缩后以乙酸乙酯溶解,水洗后无水硫酸钠干燥、过滤、浓缩,硅胶柱纯化得目标产物591mg,为白色固体,产率92%。
MS(ESI)m/z:321[M+H]+.
化合物VI-a-1、VI-a-1分别由21a、21b先后经方法G、方法C合成。
其他该类化合物可由类似的方法合成。
下表列出具体化合物与结构表征数据。
化合物VII-a-1的合成路线:
化合物25a的制备:
方法K:化合物23a(410mg,2mmol)、环丙基胺(166μL,2.4mmol)与二异丙基乙基胺(0.5mL,3mmol)于2-丁醇中75℃反应,TLC跟踪直至反应完全,浓缩后柱纯化得目标产物347mg,产率77%。
MS(ESI)m/z:226[M+H]+.
化合物VII-a-1由25a与26经方法制备。
其他该类化合物可由类似的方法合成。
下表列出具体化合物与结构表征数据。
化合物VIII-a-1的合成路线:
化合物VIII-a-1由27a先后经方法C、方法D制备。
其他该类化合物可由类似的方法合成。
下表列出具体化合物与结构表征数据。
生物活性测试。
一、化合物抑制PIKfyve导致MDA-MB-231细胞产生空泡化的检测。
当PIKfyve激酶活性受到抑制时,细胞质中会产生空泡,通过显微镜观察空泡的数量可以得知化合物抑制PIKfyve激酶活性的强弱。
实验方法:
1、细胞铺板:取生长对数期的细胞制成单细胞悬液,用细胞计数仪计数并稀释至细胞浓度约为2×105个/mL,之后将细胞接种于12孔板中,在37℃,5%CO2培养箱中培养。
2、细胞给药:待细胞贴壁后加入用培养液稀释好的药物样品(每个药物样品设1μmol/L、10μmol/L两个浓度梯度),以DMSO为阴性对照。
3、空泡化检测:培养24、48h后分别在电子显微镜下拍照观察细胞空泡化程度强弱。
下表列出部分化合物空泡化检测结果。(表中的“+”代表空泡化的程度,“+”越多,则表明空泡化越明显;“-”表示没有空泡化)
二、化合物与PIKfyve蛋白的解离常数(Kd值)的测定。
Kd值通过DiscoverX公司的KINOMEscanTM技术完成,具体方法:
1、磁珠的准备:生物素标记的小分子配体与亲和素覆盖的磁珠在室温下作用30分后加过过量生物素,再以封闭液(1%BSA,0.05%Tween 20,1mM DTT)洗去未结合的配体。
2、结合反应:384平板,0.02mL体系中,将DNA标记的蛋白、连接小分子配体的磁珠及不同浓度待测化合物混合于反应液(0.17x PBS,0.05%Tween 20,6mM DTT)中室温下振摇1小时,加入洗脱液(1x PBS,0.05%Tween 20)洗脱。磁珠再以淋洗液(1x PBS,0.05%Tween 20,0.5μM无生物素标记的小分子配体)重悬,室温下振摇30分后分离出淋洗液。
3、Kd值测定:以上淋洗液中蛋白的含量通过qPCR。待测化合物测定11个3倍稀释浓度,每个浓度设3个DMSO对照,通过曲线拟合获得Kd值。
下表列出部分化合物的Kd值。
三、MTS法测定化合物抑制肿瘤细胞生长的IC50值。
实验方法:
1、细胞铺板:取生长对数期的细胞计数并接种于96孔板内(20000细胞每孔)。
2、细胞给药:10mM化合物DMSO母液3倍梯度稀释,设8个浓度,加入各孔,设三个重复孔,每个板上设三个空白孔(仅加培养液)和三个阴性对照(含0.1%DMSO)。
3、IC50值测定:培养5天后再加入20μL的MTS反应液,混匀后置于细胞培养箱中(37℃;5%CO2)孵育1-4小时,采用酶标仪OD490测量490nm波长下的OD值。细胞生长抑制率由如下公式计算:
细胞抑制率%=1-(OD实验组-OD空白组)/(OD阴性组-OD空白组)*100%
根据测量的细胞抑制率利用GradPad Prism 5软件计算化合物作用于细胞的半抑制浓度IC50。
下表列出部分化合物对JeKo-1细胞的IC50值或10μM时的抑制率。
a代表在化合物10μM浓度下细胞的生长抑制率。
下表列出化合物I-a-1在3.3μM时对多种肿瘤细胞的抑制率。
四、Cell Titer Glo法测定化合物对PIKfyve介导的肿瘤细胞的生长抑制率。
实验方法:
1、细胞铺板:取生长对数期的细胞计数并接种于384孔板内。
2、细胞给药:加入化合物(3.3μM DMSO溶液)或空白对照(DMSO),各孔设两个重复。
3、生长抑制率测定:培养(37℃;5%CO2)5天后再加入CellTiter-振摇2分钟,离心(90xg)30秒后室温静置10分钟,在PHERAstar Plus上测定RLU。细胞生长抑制率由如下公式计算:
细胞抑制率%=1-RLU实验组/RLUDMSO*100%
下表列出部分化合物对Toledo及ST486细胞的抑制率(3.3 10μM)。
五、化合物V-c-17抑制PIKfyve引起溶酶体功能紊乱(图3)。
JeKo-1细胞以V-c-17处理24小时后裂解以Wstern Blot检测,可见未成熟的组织蛋白酶A与组织蛋白酶D增多,具有良好的浓度依耐性。这与已知PIKfyve抑制剂apilimod的处理结果类似。
六、化合物I-a-1在三阴性乳腺癌异种移植瘤模型中有效抑制肿瘤生长,具有良好的剂量依耐性(图4)。
1、4-6周龄的雌性裸鼠皮下注射5X106左右的MDA-MB-231细胞;
2、待肿瘤体积(长×宽×宽×0.5)到100mm3左右时随机分成四组:对照组、5mg/kg一天给药一次组、20mg/kg一天给药一次组,记录初始瘤体积;
3、每天定点通过静脉注射给药或者对照溶剂,并且测量记录每天的瘤体积,持续给药12天;
4、最后一天给药后6小时,处死老鼠,完整剥下皮下生长的肿瘤,记录肿瘤的重量。
七、化合物V-c-17在非霍奇金淋巴瘤JeKo-1异种移植模型中有效抑制肿瘤生长,具有良好的剂量依耐性(图5)。
1、4-6周龄的雌性裸鼠皮下注射1X107左右的JeKo-1细胞;
2、待肿瘤体积(长X宽X高Xπ/4)到100mm3左右时随机分成三组:对照组、25mg/kg一天给药一次V-c-17组、25mg/kg一天给药两次V-c-17组、25mg/kg一天给药一次apilimod组,记录初始瘤体积;
3、每天定点通过静脉注射给药或者对照溶剂,并且测量记录每天的瘤体积,持续给药7天;
4、最后一天给药后6小时,处死老鼠,完整剥下皮下生长的肿瘤,记录肿瘤的重量。
Claims (8)
1.式V所示的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,
其中,
R1选自:
2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基、HOOC-、C1-C6烷氧基甲酰基;
优选为其中Z1,Z2,Z3,Z4,Z5中的1个选自以下,其余为氢:氢、C1-C6烷基、C1-C3烷氧基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、HOOC-、C1-C6烷氧基甲酰基;
氢、氟,氯,氨基,羟基、C1-C3烷基、HOOC-、乙氧基甲酰基(EtOOC-);
L1选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L1为NHCO、CONH、NHCONH、NHCSNH;
R4选自氢、取代或未被取代的的C6-C10芳基、优选取代或未被取代的苯基,或取代或未被取代的的杂芳基、优选取代或未被取代的吡啶基;
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;
优选L2选自NHCO、CONH、NHSO2、NHCONH、NHCSNH;
R5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;
R5优选为其中Z1,Z2,Z3,Z4,Z5中的1个或2个独立地选自以下,其余为氢:氢、卤素,氨基,羟基、C1-C3含氟烷基、C1-C3烷氧基、C1-C6酰胺基、C1-C6烷基磺酰胺基、C1-C3含氟烷氧基、硝基、氰基、经任选被取代的杂环基所取代的C1-C6烷基、任选被取代的杂芳基;
最优选R5为其中,Z2或Z4为氢或-OCF3,或Z3为氢、-NO2、-CN或-OMe,或Z2或Z4、Z3中的一个为氢、-CF3或-NHAc,或Z1或Z5、Z2或Z4、Z3中的一个为氢、-NH2或-NHMs;或Z2与Z4独立地选自-CF3、或Z2与Z3独立地选自-CF3、或Z1与Z4独立地选自-CF3、-OMe、-F、-Cl;其余为氢;
R7选自
1)H、卤素、任选被取代的杂环基;
2)取代或未取代的C1-C6烷基,取代基为任选被取代的杂环基、双C1-C3烷基取代的氨基;
3)双取代的氨基,取代基选自C1-C3烷基、双C1-C3烷氨基取代的C1-C3烷基;
5)经任选被取代的苯基取代的氨基,
优选为未取代的苯基或被以下取代的苯基取代的氨基:被甲磺酰氨基单取代的苯基,被杂环基双取代的苯基;
R2选自:
1)任选被取代的杂芳基,
2)任选被取代的C6-C10芳基,在取代的情况下,其取代基为C1-C6烷基、C1-C3烷氧基、C1-C3含氧烷基、C1-C3含氟烷基、C1-C3含氟烷氧基、卤素、氨基、羟基、硝基,氰基、C1-C6烷基磺酰基;
L2选自NHCO、CONH、SO2NH、NHSO2、NHCONH、NHCSNH;优选L2为NHCO、CONH、NHSO2、NHCONH、NHCSNH;
R5选自取代或未被取代的C6-C10芳基、优选取代或未被取代的苯基;
R5优选为其中Z1,Z2,Z3,Z4,Z5中的1个或2个独立地选自以下,其余为氢:氢、卤素,氨基,双C1-C3烷基取代的氨基、羟基、C1-C3烷基、C1-C3烷氧基、C1-C3含氟烷基、C1-C3含氟烷氧基、任选被取代的杂芳基、经任选被取代的杂环基所取代的C1-C6烷基;
R5更优选为其中Z1,Z2,Z3,Z4,Z5中的1个或2个独立地选自以下,其余为氢:氢、氟、氯、溴、氨基、双C1-C3烷基取代的氨基、羟基、三氟甲基、三氟甲氧基、C1-C6烷基取代的经任选被C1-C6烷基取代的杂环基所取代的C1-C6烷基、C1-C3烷基、C1-C3烷氧基;
R7选自H、C1-C6烷基;优选R7为H、甲基;
4)任选经C3-C7环烷基、任选被取代的杂芳基或任选被杂芳基取代的C1-C6烷基所取代的氨基;
优选选自被以下取代的氨基:C3-C6环烷基,任选经C1-C6烷基取代的杂芳基或任选经杂芳基取代的C1-C6烷基;
最优选选自以下取代的氨基:
5)任选被取代的杂环基,
优选选自经二(C1-C6烷基)氨基、C1-C6烷基取代的杂芳基取代的杂环基,
R3选自:-H,C1-C6烷基;优选选自:-H,-CH3。
2.根据权利要求1所述的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中,所述药学上可接受的盐为:无机酸盐,选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐;或有机酸盐,选自甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐;优选地,所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐;所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐等。
4.药物组合物,其包含权利要求1-3中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物以及任选的药学上可以接受的赋形剂。
5.权利要求1-3中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物或者权利要求4所述的药物组合物在制备用于预防或治疗与生物体内PIKfyve介导的疾病的药物中的用途,尤其是在制备用于预防或治疗具有K-RAS突变、营养物质获取障碍特点的肿瘤以及非霍奇金淋巴瘤的生长与转移的药物中的用途。
6.根据权利要求5的用途,所述药物导致细胞产生空泡化,任选地,所述药物通过抑制PIKfyve导致细胞产生空泡化。
7.根据权利要求5的用途,所述PIKfyve介导的疾病是癌症,优选是乳腺癌,最优选是三阴性乳腺癌。
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CN111825674A (zh) * | 2019-04-22 | 2020-10-27 | 上海仕谱生物科技有限公司 | 嘧啶并五元杂环类化合物及其作为突变型idh2抑制剂的用途 |
WO2021050900A1 (en) | 2019-09-13 | 2021-03-18 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Receptor tyrosine kinase inhibitors for treatment of protein kinase modulation-responsive disease or disorder |
US11814388B1 (en) | 2020-08-28 | 2023-11-14 | Ferris State University | Substituted pyrrolo[2,3-d]pyrimidines and pyrazolo[3,4-d]pyrimidines as inhibitors for multi-resistant cancers |
KR20230047047A (ko) * | 2021-09-30 | 2023-04-06 | 한미약품 주식회사 | PIKfyve 키나아제 억제제 |
CN114149409B (zh) * | 2021-11-16 | 2024-03-22 | 中国药科大学 | 一种具有蛋白激酶抑制活性的(杂)芳基酰胺类化合物 |
US11814384B2 (en) | 2022-02-03 | 2023-11-14 | Kinnate Biopharma Inc. | Inhibtors of Raf kinases |
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