CN115124586A - 甲氨蝶呤药物化合物、药物组合物及其用途 - Google Patents
甲氨蝶呤药物化合物、药物组合物及其用途 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及甲氨蝶呤衍生物及其用途。
背景技术
用以实现母体药物的一种或多种期望的特性的药物改性已被研究并应用于当今临床使用的许多化合物。改性的形式通常旨在以期望的方式改变母体化合物的吸收、代谢、排泄、组织分布、毒性和活性。此外,已经对一些化合物进行了药物改性,目的是创造一种在靶组织中选择性激活或失活的药物,以增加预期的药物作用的特异性,同时减少与母体化合物相关的意外副作用。改性的药物方法已应用于一些最成功的抗生素和化疗化合物,它们被设计为对某些活细胞有毒,但是同时对其他活细胞群无毒或毒性低得多。
甲氨蝶呤(MTX),((2S)-2-[(4-{[(2,4-二氨基蝶啶-6-基)甲基](甲基)氨基}苯基)甲酰胺基]戊二酸),(CAS 59-05-2),是一种抗代谢药物,被广泛用作有效的抗癌剂和免疫抑制剂(1,2)。迄今为止,已经构建了若干种MTX衍生物,其中当与MTX相比时,这些衍生物表现出额外的不同特性(3,4)。尽管已发现若干种衍生物比临床使用的MTX表现出更大的细胞毒性,但通常也观察到全身毒性的伴随增加。众所周知,抑制嘌呤代谢的关键酶二氢叶酸还原酶(DHFR),并从而抑制DNA合成是MTX的主要作用(1)。给药后,MTX主要分布在非脂肪组织中并且不穿过血脑屏障。若干个理化报告表明MTX在油中的溶解性很差(5)。众所周知,脂溶性药物在脂肪组织中的分布比水溶性药物更好。基于目前脂质递送药物系统的进展,MTX的脂溶性衍生物可能扩大治疗范围(6)。
生物缀合是一种用于通过共价键将生物活性分子附连到另一个分子的过程,这导致形成新的化学结构,与原始分子相比,该结构可能具有增强的特性(7)。虽然该过程或方法是已知的,但还没有尝试合成能够根据上述需要发挥作用的衍生物。
参考文献
(1)Bedoui Y,Guillot X,Sélambarom J,Guiraud P,Giry C,Jaffar-BandjeeMC,Ralandison S,Gasque P.Methotrexate an old drug with new trick.Int J MolSci.20:5023.
(2)Visentin M,Zhao R,Goldman ID.The antifolates.Hematol Oncol ClinNorth Am.26:629-648.
(3)Sirotnak FM,DeGraw JI,Moccio DM,Samuels LL,Goutas LJ.New folateanalogs of the 10-deaza-aminopterin series.Basis for structural design andbiochemical and pharmacologic properties.Cancer Chemother Pharmacol.1984;12:18-25.
(4)Tamura T,Higuchi Y,Kitamura H,Murao N,Saitoh R,Morikawa T,SatoH.Novel hyaluronic acid-methotrexate conjugate suppresses joint inflammationin the rat knee:efficacy and safety evaluation in two rat arthritis models
(5)Kim DS,Cho JH,Park JH,Kim JS,Song ES,Kwon J,Giri BR,Jin SG,Kim KS,Choi HG,Kim DW.Self-microemulsifying drug delivery system(SMEDDS)for improvedoral delivery and photostability of methotrexate.Int J Nanomedicine.2019 5;14:4949-4960.doi:10.2147/IJN.S211014.eCollection2019
(6)Moura JA,Valduga CJ,Tavares ER,Kretzer IF,Maria DA,RC.Novel formulation of a methotrexate derivative with a lipidnanoemulsion.Int J Nanomedicine.2011;6:2285–2295.
(7)Chaikomon K,Chattong S,Chaiya T,et al.Doxorubicin-conjugateddexamethasone induced MCF-7apoptosis without entering the nucleus and able toovercome MDR-1-induced resistance.Drug Des Devel Ther.2018;12:2361-2369。
发明内容
本发明涉及利用新的MTX衍生物治疗疾病和疾患的分子和方法,该新的衍生物是通过以下衍生得到的:使用亚精胺(((4-氨基丁基)(3-氨基丙基)胺),(CAS 124-20-9))作为接头,将MTX的α羧基基团与胆固醇(CAS57-88-5)(((3β-羟基-5-胆甾烯,5-胆甾烯-3β-醇),(CAS 57-88-5))的3β-羟基基团缀合,具有的化合物式为(4S)-4-{[3-({4-[({[(1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-二甲基-1-[(2R)-6-甲基庚烷-2-基]-1H,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,11H,11aH-环戊二烯并[a]菲-7-基]氧基}羰基)氨基]丁基}氨基)丙基]氨甲酰基}-4-[(4-{[(2,4-二氨基蝶啶-6-基)甲基](甲基)氨基}苯基)甲酰胺基]丁酸。在一方面,包括所公开的化合物的药物组合物涵盖所述化合物的对映异构体及其药学上可接受的多晶型物、前药、水合物、溶剂化物、盐、水合物、笼形包合物和溶剂化物。
缀合的产物快速抑制DHFR酶,并因此可以满足上述需求。因此,使用的主要目的是用于癌症和自身免疫疾病治疗。这种情况下的癌症包括,但不限于,头癌、甲状腺癌、颈癌、眼癌、皮肤癌、口癌、喉癌、食道癌、胸癌、心脏癌、骨癌、血液癌、骨髓癌、肺癌、结肠癌、乙状结肠癌、直肠癌、胃癌、前列腺癌、乳腺癌、卵巢癌、肾癌、肝癌、胰腺癌、脑癌、肠癌、心脏癌、肾上腺癌、皮下组织癌、淋巴结癌、心脏癌及其组合。更特定地说,可以使用该化合物治疗的特定类型的癌症包括多发性骨髓瘤、恶性黑素瘤、恶性胶质瘤、淋巴瘤、白血病和实体瘤。这种情况下的自身免疫疾病包括,但不限于,成人斯蒂尔病(Adult Still's disease)、斑秃、淀粉样变性、强直性脊柱炎、抗GBM/抗TBM肾炎、抗磷脂综合征、自身免疫性血管性水肿、自身免疫性自主神经功能障碍、自身免疫性脑脊髓炎、自身免疫性肝炎、自身免疫性内耳病(AIED)、自身免疫性心肌炎、自身免疫性胰腺炎、自身免疫性视网膜病、自身免疫性荨麻疹、轴突和神经元神经病(AMAN)、白塞病(Behcet’s disease)、良性黏膜类天疱疮、大疱性类天疱疮、卡斯尔曼病(CD)、乳糜泻、美洲锥虫病(Chagas disease)、慢性炎性脱髓鞘性多发性神经病(CIDP)、许尔许斯特劳斯综合征(CSS)或嗜酸性肉芽肿(EGPA)、瘢痕性类天疱疮、克罗恩病、疱疹样皮炎、皮肌炎、德维克病(视神经脊髓炎)、盘状狼疮、结节性红斑、原发性混合型冷球蛋白血症、纤维肌痛、纤维化肺泡炎、巨细胞性动脉炎(颞动脉炎)、巨细胞性心肌炎、肾小球肾炎、古德帕斯丘综合征、肉芽肿性多血管炎、自身免疫性溶血性贫血、过敏性紫癜(HSP)、妊娠类天疱疮(PG)、化脓性汗腺炎(HS)(反常性痤疮)、IgA肾病、IgG4相关硬化性疾病、免疫性血小板减少性紫癜(ITP)、包涵体肌炎(IBM)、间质性膀胱炎(IC)、幼年型关节炎、幼年肌炎(JM)、川崎病、白细胞碎裂性血管炎、扁平苔藓、硬化性苔藓、木样结膜炎、线性IgA病(LAD)、系统性红斑狼疮(SLE)、慢性莱姆病、显微镜下多血管炎(MPA)、混合性结缔组织病(MCTD)、多灶性运动神经病(MMN)或MMNCB、多发性硬化症(MS)、重症肌无力、新生儿狼疮、视神经脊髓炎、中性粒细胞减少、眼瘢痕性类天疱疮、视神经炎、复发性风湿病(PR)、天疱疮、类天疱疮、周围神经病、静脉周围脑脊髓炎、结节性多动脉炎、风湿性多肌痛、多发性肌炎、原发性胆汁性肝硬变、原发性硬化性胆管炎、孕酮皮炎、银屑病、银屑病关节炎、坏疽性脓皮病、雷诺氏现象、反应性关节炎、复发性多软骨炎、不宁腿综合征(RLS)、腹膜后纤维化、风湿热、类风湿性关节炎、结节病、施密特综合征、巩膜炎、硬皮病、舍格伦综合征、精子和睾丸自身免疫、僵人综合征(SPS)、多发性大动脉炎、颞动脉炎/巨细胞性动脉炎、血小板减少性紫癜(TTP)、横贯性脊髓炎、溃疡性结肠炎(UC)、未分化结缔组织疾病(UCTD)、葡萄膜炎、血管炎、白癜风、Vogt-小柳原田病。该化合物可用于治疗(包括改善(包括预防性改善)和预防)本申请中列举的以及甲氨蝶呤在体内或适当的筛选试验或动物模型中对其有效的任何适应症。
缀合的产物在其脂肪溶剂中显示出更高的溶解度,因此用途的应用可能适用于但不限于乳液制剂、脂质递送系统、局部制剂和化学栓塞。
本发明对许多不同的治疗药物以及多种疾病和病症具有广泛的适用性。在另一方面,立体异构纯的公开的化合物也可用于治疗或预防微生物感染或微生物感染的症状,包括但不限于细菌感染、真菌感染、寄生虫感染、疟疾、分枝杆菌感染和HIV引起的机会性感染。
本文公开的一些实施方式涉及一种药物化合物,该药物化合物包括第一组分如甲氨蝶呤和第二组分如胆固醇,其中第一组分与第二组分共价缀合,其具有由以下化学式(I)表示的结构:
其中使用亚精胺作为接头将甲氨蝶呤的α羧基基团与胆固醇缀合。
本文公开的一些实施方式涉及一种药物组合物,该药物组合物包括如上限定的化合物和药学上可接受的载体、赋形剂和/或佐剂。
本文公开的一些实施方式涉及如上限定的化合物在医学中的用途,诸如具体化合物在药物中的用途。在本文公开的一些实施方式中,包括如本文限定的化合物的药物适用于治疗哺乳动物,诸如人。
本文公开的一些实施方式涉及如上限定的化合物在制备用于治疗包括癌细胞的癌症的药物中的用途。癌症的实例包括乳腺癌、肺癌、多发性骨髓瘤、恶性黑素瘤、恶性胶质瘤、淋巴瘤、白血病或其他恶性血液病。
本文公开的一些实施方式涉及如上限定的化合物在制备用于治疗自身免疫疾病的药物中的用途。自身免疫疾病的实例包括类风湿性关节炎、系统性红斑狼疮(SLE)、银屑病、天疱疮、类天疱疮、结节病、白癜风。
附图说明
图1示出了根据本公开的一种实施方式的以下公开的化合物的化学结构和1HNMR:(4S)-4-{[3-({4-[({[(1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-二甲基-1-[(2R)-6-甲基庚烷-2-基]-1H,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,11H,11aH-环戊二烯并[a]菲-7-基]氧基}羰基)氨基]丁基}氨基)丙基]氨甲酰基}-4-[(4-{[(2,4-二氨基蝶啶-6-基)甲基](甲基)氨基}苯基)甲酰胺基]丁酸。
图2示出了根据本公开的一种实施方式的化合物(化合物A)对二氢叶酸还原酶的抑制作用。
图3示出了MTX(3A.)和根据本公开的一种实施方式的化合物(3B.)的细胞毒性。
图4示出了在光学显微镜下可视化的具体化合物在O/W液滴中的图像。
具体实施方式
下面详细描述本发明的各个方面,每个方面都作为单独的实例附上。提供这些实例是为了说明的目的,而不是为了限制本发明的范围。
本发明涉及利用以下化合物和其药学上可接受的盐、水合物,溶剂化物、笼形包合物、前药和多晶型物治疗疾病和疾患的分子和方法:(4S)-4-{[3-({4-[({[(1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-二甲基-1-[(2R)-6-甲基庚烷-2-基]-1H,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,11H,11aH-环戊二烯并[a]菲-7-基]氧基}羰基)氨基]丁基}氨基)丙基]氨甲酰基}-4-[(4-{[(2,4-二氨基蝶啶-6-基)甲基](甲基)氨基}苯基)甲酰胺基]丁酸。
本发明涵盖所述化合物的体外和体内用途以及将所述化合物掺入用于治疗和预防多种疾病和疾患的药物组合物中。这样的治疗特别包括抑制肿瘤细胞增殖、治疗或预防癌症,包括但不限于实体瘤、血源性肿瘤、白血病,以及尤其是急性淋巴细胞白血病(ALL)。
本发明涵盖所述化合物的体外和体内用途以及将所述化合物掺入用于治疗和预防多种疾病和疾患的药物组合物中。这样的治疗特别包括抑制自身免疫疾病中的炎症,包括但不限于类风湿性关节炎、系统性红斑狼疮(SLE)、银屑病、天疱疮、类天疱疮、结节病、白癜风。
包括公开的化合物的药物组合物与至少一种额外的治疗剂一起辅助地给药。额外的治疗剂的实例包括但不限于抗癌药、抗炎药、抗组胺药和解充血药。
根据本公开的一方面,公开了一种药物化合物,该药物化合物包括第一组分如甲氨蝶呤和第二组分如胆固醇,其中第一组分与第二组分共价缀合,其具有由以下化学式(I)表示的结构:
其中使用亚精胺作为接头将甲氨蝶呤的α羧基基团与胆固醇缀合。
在一些实施方式中,提供了一种药物化合物,该药物化合物包括如上限定的化合物和药学上可接受的载体、赋形剂和/或佐剂。
在一种示例中,公开的化合物(其为甲氨蝶呤-亚精胺-胆固醇缀合物),(4S)-4-{[3-({4-[({[(1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-二甲基-1-[(2R)-6-甲基庚烷-2-基]-1H,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,11H,11aH-环戊二烯并[a]菲-7-基]氧基}羰基)氨基]丁基}氨基)丙基]氨甲酰基}-4-[(4-{[(2,4-二氨基蝶啶-6-基)甲基](甲基)氨基}苯基)甲酰胺基]丁酸,的合成利用羟基基团的活化并遵循方案A。将悬浮在二甲基亚砜(DMSO)(10ml)中的胆固醇(1.93g,5mmol)和1,1'-羰基二咪唑(CDI)(如GregT.Hermanson.,Bioconjugate.2013,p 229公开的)混合。将所获得的混合物在室温下孵育1小时以形成活性物质。孵育1小时之后,将亚精胺(0.73g,5mmol)添加到混合物中。随后,将所有混合物在室温下孵育过夜。反应方案B,将甲氨蝶呤(2.27g,5mmol)和1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(0.96g,5mmol)悬浮在DMSO中。然后,将来自方案A的混合物添加到溶液中并在室温下孵育24小时。将新产物通过硅胶柱上快速色谱纯化。将纯化的产物进一步真空干燥,得到淡黄色材料,最终产量为3.25g(65.92%)ES(-)-MS:M-994.4。
根据本公开的另一方面,本文提供了如上限定的化合物在医学中的用途,诸如具体化合物在药物中的用途。在一些实施方式中,包括如本文限定的化合物的药物适用于治疗哺乳动物,诸如人。此外,本公开的另一方面包括如上限定的化合物在制备用于治疗包括癌细胞的癌症的药物中的用途,其中癌症的实例包括白血病、淋巴瘤、乳腺癌、肺癌、宫颈癌、脑癌和其他血液癌。此外,本公开的另一方面包括如上限定的化合物在制备用于治疗结缔组织和自身免疫疾病的药物中的用途,其中结缔组织和自身免疫疾病的实例包括系统性红斑狼疮(SLE)、银屑病、天疱疮、类天疱疮、结节病、白癜风。
现在将描述包括公开的化合物的组合物的测试的进一步实例。
实施例1:具体化合物和MTX的二氢叶酸还原酶抑制剂测定
用二氢叶酸还原酶(DHFR)测定试剂盒(Sigma-Aldrich,密苏里州,美国)测试终浓度为5、50、50nM的具体化合物(化合物A)和MTX的DHFR抑制活性。根据供应商方案,用Biochrom Anthos 2010酶标仪(Biochrom Ltd.,坎伯恩(Cambourne),剑桥,英国),在340nM处测量DHFR还原酶的活性,每15秒一次,持续2.5分钟。酶活性由下式计算:
ΔOD/min空白=Δ对于空白OD/分钟
ΔOD/min样品=Δ对于反应OD/分钟
12.3=消光系数(Δ,mM-1cm-1),用于340nm处的DHFR反应
V=测定中使用的以ml的酶体积,
d=酶样品的稀释因子
mgP/ml=稀释前原始样品的酶浓度
单位/mgP=以微摩尔/min/mg蛋白质的比活性
OD 340的变化示出在图2中以及酶活性示出在表1中。
表1.二氢叶酸还原酶活性
实施例2:用于具体化合物对肿瘤细胞的细胞毒性作用的3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物(MTT)测定
人乳腺癌细胞系,MCF-7获自American Type Cell Collection(ATCC)(罗克维尔(Rockville)市,密苏里州(MO),美国)。在37℃和5%CO2下,在含有10%胎牛血清(FBS)(Gibco)的杜尔贝科改良伊格尔培养基(DMEM)(Gibco,格兰德艾兰(Grand Island),纽约,美国)中,将细胞培养至70-80%汇合。将MCF-7细胞接种到96孔板中过夜(每孔4,000个细胞)。用终浓度为0、0.01、0.1、1和10mM的具体化合物或MTX处理细胞24小时。接下来,添加来自Quick Cell Proliferation Colorimetric Assay Kit(BioVision,Inc.,米尔皮塔斯(Milptas),加利福尼亚州,美国)的10μl/孔WST-1/ECS溶液,并将溶液在37℃和5%CO2下孵育2小时。用Biochrom Anthos 2010酶标仪(Biochrom Ltd.,坎伯恩,剑桥,英国)在480nm处测量吸光度。从吸光度光密度(OD)的对数线性回归计算半抑制浓度(IC50)。MTX的IC50为3.27mM,而具体化合物的IC50为0.06mM。图3A中示出了MTX的以及图3B中示出了具体化合物的24h细胞生存力。
实施例3:脂溶性和水包油(O/W)乳液分析
在40℃下,将在DMSO中的具体化合物或甲氨蝶呤(3μg/μl)溶解在橄榄油、卡诺拉油(Canola Oil)和向日葵油(Sigma-Aldrich(圣路易斯(St.Louis),密苏里州,美国))中。将悬浮液涡旋并以3000RPM定期离心10min。油溶剂体积逐步增加,直到观察到完全溶解并确定可溶浓度(表2)。将溶液在24℃下放置过夜,以及然后以5000RPM离心20min。将十微升的在油中的具体化合物添加到100μl去离子(DI)水中。将悬浮液剧烈涡旋并放置在室温下。在光学显微镜下观察具体化合物在O/W液滴中的分布(如图4中所示)。图4示出了在光学显微镜下可视化的具体化合物在O/W液滴中的图像。
表2油中溶解度(40℃)
公开的化合物(mg/100ml) | 甲氨蝶呤(mg/100ml) | |
橄榄油 | 48.1 | 小于0.1 |
卡诺拉油 | 81.3 | 小于0.1 |
葵花籽油 | 103.6 | 小于0.1 |
本发明的上述描述是为了说明和描述的目的而提出的。此外,该描述并不旨在将本发明限制为在本文中公开的形式。因此,与上述教导以及相关领域的技能或知识相称的变化和修改都在本发明的范围内。上文描述的实施方式进一步旨在解释用于实践本发明的已知最佳模式,并使本领域的其他技术人员能够在这样的或其他实施方式中利用本发明,并且具有本发明的特定应用或用途所需的各种修改。所附权利要求意在在现有技术允许的程度内被解释为包括替代实施方式。
Claims (20)
2.一种药物组合物,包括根据权利要求1所述的化合物和药学上可接受的载体、赋形剂和/或佐剂。
3.通过给药根据权利要求1所述的化合物来治疗可用甲氨蝶呤治疗的适应症的方法。
4.通过给药根据权利要求2所述的组合物来治疗可用甲氨蝶呤治疗的适应症的方法。
5.通过给药根据权利要求1所述的化合物来治疗包括癌细胞的癌症或自身免疫疾病的方法。
6.根据权利要求5所述的治疗方法,其中,所述癌症是乳腺癌、肺癌、多发性骨髓瘤、恶性黑素瘤、恶性胶质瘤、淋巴瘤、白血病或其他恶性血液病。
7.根据权利要求5所述的治疗方法,其中,所述自身免疫疾病是类风湿性关节炎、系统性红斑狼疮(SLE)、银屑病、天疱疮、类天疱疮、结节病或白癜风。
8.通过给药根据权利要求2所述的化合物来治疗包括癌细胞的癌症或自身免疫疾病的方法。
9.根据权利要求8所述的治疗方法,其中,所述癌症是乳腺癌、肺癌、多发性骨髓瘤、恶性黑素瘤、恶性胶质瘤、淋巴瘤、白血病或其他恶性血液病。
10.根据权利要求9所述的治疗方法,其中,所述自身免疫疾病是类风湿性关节炎、系统性红斑狼疮(SLE)、银屑病、天疱疮、类天疱疮、结节病或白癜风。
11.根据权利要求3所述的治疗方法,其中,向哺乳动物给药。
12.根据权利要求4所述的治疗方法,其中,向哺乳动物给药。
13.根据权利要求5的所述治疗方法,其中,向哺乳动物给药。
14.根据权利要求6所述的治疗方法,其中,向哺乳动物给药。
15.根据权利要求7所述的治疗方法,其中,向哺乳动物给药。
16.根据权利要求8所述的治疗方法,其中,向哺乳动物给药。
17.根据权利要求9所述的治疗方法,其中,向哺乳动物给药。
18.根据权利要求10所述的治疗方法,其中,向哺乳动物给药。
19.根据权利要求11所述的治疗方法,其中,所述哺乳动物是人。
20.根据权利要求13所述的治疗方法,其中,所述哺乳动物是人。
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