CN113480596A - 一种调节nmda受体活性的化合物、其药物组合物及用途 - Google Patents
一种调节nmda受体活性的化合物、其药物组合物及用途 Download PDFInfo
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- CN113480596A CN113480596A CN202110762609.2A CN202110762609A CN113480596A CN 113480596 A CN113480596 A CN 113480596A CN 202110762609 A CN202110762609 A CN 202110762609A CN 113480596 A CN113480596 A CN 113480596A
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- threonyl
- prolyl
- carbonyl
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- thiazolidine
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Abstract
本发明属于医药化工领域,涉及调节NMDA受体活性的化合物、其药物组合物及用途。具体地,本发明涉及式I所示的化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物。本发明还涉及包含式I化合物的药物组合物和药盒产品,以及式I化合物在制备治疗和/或预防抑郁症、焦虑症、脑卒中、亨廷顿氏病、阿尔茨海默病、神经痛或精神分裂症的药物中的用途。NH2‑P1‑P2‑P3‑P4‑COR 式I。
Description
本发明是申请号为201910280399.6的母案的分案申请,该母案的申请日为2019年04月09日,发明名称为“调节NMDA受体活性的化合物、其药物组合物及用途”。
技术领域
本发明属于医药化工领域,涉及调节NMDA受体活性的化合物、其药物组合物及用途。具体地,本发明涉及在NMDA受体活性的调节中具有增强效能的化合物,以及此类化合物用于预防/治疗抑郁、焦虑、紧张、学习及认知缺陷、神经性疼痛等疾病的用途。
背景技术
目前抑郁症的发病率及危害性日益升高,但抑郁症的治疗药物却未能完全满足临床需求。已上市的抗抑郁药以选择性5-羟色胺(5-HT)重摄取抑制剂(SSRIs)及5-羟色胺-去甲肾上腺素重摄取抑制剂(SNRIs)类为主,这些以调节5-羟色胺为核心机制的抗抑郁药有不少缺陷,包括起效慢、不良反应较多、无应答患者(难治性抑郁患者)较多等。临床上对新机制新特点的抗抑郁药有着强烈需求。
N-甲基-D-天冬氨酸(NMDA)受体在诸多中枢活动当中发挥重要作用,例如学习、记忆、情感、认知、痛觉等。NMDA受体过度激活会导致脑卒中、亨廷顿氏病、阿尔茨海默病、神经痛、精神分裂症、抑郁症等等(NMDA receptors in nervous systemdiseases.Neuropharmacology,2013,74:69-75)。
以NMDA受体为靶点的抗抑郁药是目前药物研发界的热点(NMDA receptorpathways as drug targets.Nature Neuroscience,2002,5:1039-1042),包括Esketamine(结构式如下面的式A所示)和Rapastinel(GLYX-13,结构式如下面的式B所示)。Esketamine和Rapastinel在快速起效、对难治性抑郁患者应答较多等方面有较强优势。但是,Esketamine具有成瘾性、诱发解离症和躁狂症等风险;Rapastinel不能口服,临床应用中必须静脉给药。这严重限制了上述化合物的临床应用。
目前,尚需要开发新的针对NMDA受体的药物特别是可口服的药物。
发明内容
本发明人经过深入的研究和创造性的劳动,得到了式I所示的化合物。本发明人惊奇地发现,式I的化合物或其药学上可接受的盐、溶剂合物或者它们的混合物是NMDA受体的激动剂特别是部分激动剂,且与NMDA受体存在高度的亲和力;反映在动物模型上,能够快速有效并持久地预防和治疗模型动物的抑郁及焦虑状态。
由此提供了下述发明:
本发明的一个方面涉及式I所示的化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,
NH2-P1-P2-P3-P4-COR
式I
其中,
其中,对于P2和P3,
R选自OR2和NR3R4,其中,R2、R3和R4各自独立地选自氢、C1-C6烷基和以下取代基:
在本发明的一些实施方案中,所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其特征在于如下的(1)至(4)项中的任意一项:
在本发明的一些实施方案中,所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其特征在于如下的1)至9)项中的任意一项:
9)
上述的(1)至(4)项中的任意一项可以与上述的1)至9)项中的任意一项组合。在本发明的一些实施方式中,所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,当NH2-P1和P4-CO-选自上述的(1)至(4)项中的任意一项,并且P2和P3选自上述的1)至9)项中的任意一项时,本领域技术人员能够理解,有共计36种(4×9)具体的实施方式,这些均在本发明的保护范围之内。
在本发明的一些实施方案中,所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其中,
R1均独立地选自C1-C5烷基,例如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基或新戊基;
或者
在本发明的一些实施方案中,所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其中:
R为OR2,其中,R2选自氢、C1-C6烷基(例如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基或3-己基)和以下取代基:
或者
R选自NR3R4,其中,R3和R4各自独立地选自氢、C1-C6烷基(例如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基或3-己基)和以下取代基:
在本发明的一些实施方案中,所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其中,所述式I化合物选自下面的表1所示的化合物。
表1:本发明的实施例化合物
在本发明的一些实施方案中,所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其中,所述溶剂合物为水合物。
本发明的另一方面涉及一种药物组合物,其包含有效量的本发明中任一项所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物;
可选地,所述药物组合物还包含一种或几种药学上可接受的辅料。
在本发明的一些实施方案中所述的药物组合物,其还包含选自5-羟色胺重摄取抑制剂、5-羟色胺-去甲肾上腺素重摄取抑制剂、米氮平、安非他酮、维拉佐酮、沃替西汀中的一种或多种;
优选地,所述5-羟色胺重摄取抑制剂为选自西酞普兰、舍曲林、帕罗西汀和氟西汀中的一种或多种;
优选地,所述5-羟色胺-去甲肾上腺素重摄取抑制剂为选自度洛西汀、文法拉辛、去甲文法拉辛和米那普仑中的一种或多种。
在本发明的一些实施方案中所述的药物组合物,其还包含选自苯二氮卓类、卡立普多和定泰乐中的一种或多种;
优选地,所述苯二氮卓类为选自氯氮卓、地西泮、劳拉西泮和艾司唑仑中的一种或多种。
本发明的再一方面涉及一种药盒产品,其包含独立包装的药物制剂1和独立包装的药物制剂2,其中:
所述药物制剂1包含有效量的本发明中任一项所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物;
所述药物制剂2包含选自5-羟色胺重摄取抑制剂、5-羟色胺-去甲肾上腺素重摄取抑制剂、米氮平、安非他酮、维拉佐酮、沃替西汀中的一种或多种,或者所述药物制剂2包含自苯二氮卓类、卡立普多和定泰乐中的一种或多种;
可选地,所述药物制剂1和/或药物制剂2还包含一种或者几种药学上可接受的辅料;
优选地,所述5-羟色胺重摄取抑制剂为选自西酞普兰、舍曲林、帕罗西汀和氟西汀中的一种或多种;
优选地,所述5-羟色胺-去甲肾上腺素重摄取抑制剂为选自度洛西汀、文法拉辛、去甲文法拉辛和米那普仑中的一种或多种;
优选地,所述苯二氮卓类为选自氯氮卓、地西泮、劳拉西泮和艾司唑仑中的一种或多种。
本发明的再一方面涉及本发明中任一项所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物在制备治疗和/或预防抑郁症、焦虑症、脑卒中、亨廷顿氏病、阿尔茨海默病、神经痛或精神分裂症的药物中的用途。
本发明的再一方面涉及本发明中任一项所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物在制备在体内或在体外调节(例如上调或下调)NMDA受体(例如人NMDA受体)活性的药物中的用途。
本发明的再一方面涉及一种治疗和/或预防郁症、焦虑症、脑卒中、亨廷顿氏病、阿尔茨海默病、神经痛或精神分裂症的方法,包括给予有需求在受试者以有效量的本发明中任一项所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物的步骤。
本发明的再一方面涉及一种在体内或在体外调节(例如上调或下调)NMDA受体(例如人NMDA受体)活性的方法,包括给予受试者、哺乳动物细胞或NMDA受体溶液以有效量的本发明中任一项所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物的步骤。
在本发明的一些实施方案中,所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其用于治疗和/或预防抑郁症、焦虑症、脑卒中、亨廷顿氏病、阿尔茨海默病、神经痛或精神分裂症。
在本发明的一些实施方案中所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其用于在体内或在体外调节(例如上调或下调)NMDA受体(例如人NMDA受体)活性。
下面对本发明涉及的部分术语进行解释。
在本发明中,术语“C1-C6烷基”是指具有1-6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基等;C1-C5烷基和C1-C3烷基也可做类似理解。
术语“代谢稳定性”在本申请中是指化合物以原型药物的形式进入及稳定地存在于体内、不被代谢为其他结构形式的能力。
通常本发明药物组合物含有0.1-90重量%的式Ⅰ化合物和/或其生理上可接受的盐。药物组合物可根据本领域已知的方法制备。用于此目的时,如果需要,可将式Ⅰ化合物和/或立体异构体与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人用的适当的施用形式或剂量形式。
术语“有效量”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。
术语“受试者”可以指患者或者其它接受本发明组合物以治疗、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。
术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。术语“药学上可接受的”在本申请中是指:化合物或组合物在化学上和/或在毒理学上与构成制剂的其它成分和/或与用其预防或治疗疾病或病症的人类或哺乳动物相容。
术语“受试者”或“患者”在本申请中包括人类和哺乳动物。
术语“辅料”在本申请中是指用以将化合物给药的赋形剂或者媒介物,其包括但不限于稀释剂、崩解剂、沉淀抑制剂、表面活性剂、助流剂、粘合剂、润滑剂、包衣材料等。辅料在E.W.Martin的“Remington's Pharmaceutical Sciences”中被一般性描述。辅料的实例包括但不限于单硬脂酸铝、硬脂酸铝、羧甲基纤维素、羧甲基纤维素钠、交聚维酮、异硬脂酸甘油酯、单硬脂酸甘油酯、羟基乙基纤维素、羟基甲基纤维素、羟基硬脂酸羟基二十八酯、羟基丙基纤维素、羟基丙基甲基纤维素、乳糖、乳糖一水合物、硬脂酸镁、甘露醇、微晶纤维素等。
术语“溶剂合物”在本申请中指的是通过组合式I化合物或其药学上可接受的盐和溶剂而形成的复合物。应理解的是,在治疗本申请所述的疾病或病症中使用的式I化合物的任何溶剂合物尽管可能提供不同的性质(包括药代动力学性质),但是一旦吸收至受试者中,会得到式I化合物,使得式I化合物的使用分别涵盖式I化合物的任何溶剂合物的使用。
术语“水合物”指的是上述术语“溶剂合物”中溶剂为水的情形。
应进一步理解,式I化合物或其药学上可接受的盐可以溶剂合物形式分离,并且因此任何所述溶剂合物皆包括于本发明的范围内。例如,式I化合物或其药学上可接受的盐可以未溶剂化形式以及与药学上可接受的溶剂(诸如,水、乙醇等)形成的溶剂化形式存在。
术语“药学上可接受的盐”是指本发明化合物的相对无毒、无机酸或有机酸加成盐。例如,参见S.M.Berge等人“Pharmaceutical Salts”,J.Pharm.Sci.1977,66,1-19。其中,无机酸例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸或硝酸等;有机酸例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡萄糖酸、3-羟基-2-萘甲酸、烟酸、巴莫酸、果胶酯酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、胺基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对-甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、海藻酸、马来酸、富马酸、D-葡萄糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬胺酸、磺基水杨酸等。例如,可使用HCl(或盐酸)、HBr(或氢溴酸溶液)、甲磺酸、硫酸、酒石酸或富马酸与式I所示的化合物形成药学上可接受的盐。
本发明化合物可配制成药物制剂,包括适用于口服给药的剂型,适用于胃肠外注射(例如静脉注射、皮下注射)的剂型(例如作为溶液剂),适用于表面给药的剂型(例如作为软膏剂、贴剂或者乳膏剂),以及适用于直肠给药的剂型(例如作为栓剂)等。
取决于待治疗的疾病和患者以及给药途径,本发明的药物制剂可以以不同剂量每日一次或者多次给药。例如本发明化合物的每日剂量可以为口服给药约0.1-10mg/kg体重。
本发明的化合物、其药学可接受的盐、其溶剂化物、或其N-氧化物或者本发明的药物组合物的给药剂量取决于许多因素,例如所要治疗或辅助治疗的肿瘤的性质和严重程度,患者或动物的性别、年龄、体重及个体反应,所用的具体化合物,给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个,例如二、三、四个剂量形式给药。
可改变本发明药物组合物中各活性成分的实际剂量水平,以便所得的活性化合物量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据具体化合物的活性、给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。但是,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,直到得到所需的效果。
根据本发明的化合物可以有效地预防和/或治疗本发明所述的各种疾病或病症。
发明的有益效果
本发明的式I的化合物或其药学上可接受的盐、溶剂合物,或者它们的混合物可以用于预防/治疗抑郁症和/或焦虑症。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
P2/P3片段的具体合成方法如下面的制备例1-制备例8所示。
其中,制备例1-3的合成路线示意如下:
制备例1:L-噻唑烷酸的合成
将12.1g(0.1mol)的L-半胱氨酸溶于60ml热水当中,缓慢倾入10mL 36%的甲醛水溶液,摇匀后静置过夜,次日过滤所析出晶体,再用乙醇和水重结晶得针状白色晶体12.8g,收率为96.2%。
制备例2:L-噻唑烷酸甲酯盐酸盐的合成
将L-噻唑烷酸13.3g(0.1mol)溶于100ml无水甲醇中,通氯化氢气体至原料全部溶解,继续通气2h以上,通气结束搅拌过夜。次日减压蒸干溶剂,残余物用甲醇溶解再蒸干,重复2次以带走氯化氢气体。蒸干溶剂得到粗品,用甲醇-乙醚重结晶,收率91%。
制备例3:N-叔丁氧羰基-L-噻唑烷酸的合成
冰浴下,将0.10mol的L-噻唑烷酸溶于50mL的2N的氢氧化钠水溶液(0.10mol)中,搅拌下将24.4g(0.11mol)的叔丁氧羰基酸酐和50mL的丙酮混合溶液缓慢滴入,加毕,继续搅拌2h。加入200mL的水稀释反应液,用乙酸乙酯萃取3次,每次用乙酸乙酯80mL;弃去有机相。水相冰浴下用1mol/L的盐酸调节pH值为2,再用乙酸乙酯萃取3次,每次用乙酸乙酯80mL;合并有机相,无水硫酸钠干燥后减压除去溶剂,用石油醚和乙酸乙酯重结晶得白色晶体,收率88%。
制备例4-5的合成路线示意如下:
制备例4:2,2-二甲基-L-噻唑烷酸甲酯的合成
将3.5g L-半胱氨酸甲酯盐酸盐(20mmol)与40ml丙酮混合回流10分钟后,加入10ml甲醇使体系中固体全部溶解,继续回流0.5h后,冷却析晶,母液浓缩继续析晶,得到无色晶体2,2-二甲基-L-噻唑烷酸甲酯盐酸盐,收率94%。
制备例5:N-叔丁氧羰基-2,2-二甲基-L-噻唑烷酸的合成
将2,2-二甲基-L-噻唑烷酸甲酯盐酸盐4.03g(19mmol)与1.92g三乙胺混合溶解在20ml二氯甲烷当中,搅拌下滴入4.15g(19mmol)叔丁氧羰基酸酐溶解在20ml二氯甲烷当中的溶液,室温反应3h之后用20ml 10%柠檬酸、20ml水依次洗涤,旋干后溶于25ml甲醇当中,加入25ml 2N氢氧化钠水溶液,室温反应4h,减压尽量除去甲醇,用水稀释至50ml,用20ml×3的乙醚洗去多余叔丁氧羰基酸酐,相冰浴下用1mol/L的盐酸调节pH值为2,有大量白色固体析出,过滤水洗得到N-叔丁氧羰基-2,2-二甲基-L-噻唑烷酸,收率86%。
制备例6:2-烷基取代-L-噻唑烷酸甲酯的合成
其中,R为甲基、乙基、异丙基等。
合成路线示意如下:
具体步骤如下:
将3.5g L-半胱氨酸甲酯盐酸盐(20mmol)、1.96g乙酸钾(20mmol)搅拌溶解于60ml冰浴的甲醇中,20mmol脂肪醛溶解于20ml甲醇中,滴入体系中,继续搅拌5小时后处理。旋干溶剂,用饱和食盐水和二氯甲烷分配,有机相干燥后旋干,得无色油状物,及为2-烷基取代-L-噻唑烷酸甲酯,收率92%-96%。
制备例7:2-苯基-L-噻唑烷酸甲酯的合成
合成路线示意如下:
具体步骤如下:
将2.4g L-半胱氨酸溶于50ml乙醇中,室温搅拌下加入2ml苯甲醛,继续搅拌6小时,有大量白色固体生成。反应液过滤,固体用20ml×3的乙醇洗涤,放入培养皿中干燥。滤液旋蒸出部分溶剂至有固体析出,静置后过滤,洗涤,干燥。得到2-苯基-L-噻唑烷酸4.0g,收率97%。
将得到的4.0g 2-苯基-L-噻唑烷酸溶于40ml甲醇中,冰浴下滴加8ml氯化亚砜,反应过夜后,旋干反应液,加入二氯甲烷旋干两次,得到淡黄色固体5.0g,收率96%。
制备例8:2-苄基-L-噻唑烷酸甲酯的合成
合成路线示意如下:
具体步骤如下:
将2.4g L-半胱氨酸溶于50ml乙醇中,室温搅拌下加入2ml苯乙醛,继续搅拌6小时,有大量白色固体生成。反应液过滤,固体用20ml×3的乙醇洗涤,放入培养皿中干燥。滤液旋蒸出部分溶剂至有固体析出,静置后过滤,洗涤,干燥。得到2-苄基-L-噻唑烷酸4.4g,收率94%。
将得到的4.4g 2-苄基-L-噻唑烷酸溶于40ml甲醇中,冰浴下滴加8ml氯化亚砜,反应过夜后,旋干反应液,加入二氯甲烷旋干两次,得到白色固体5.5g,收率95%。
实施例A-1:化合物A-1的制备
合成路线示意如下:
具体步骤如下:
(1)中间体1(N-叔丁氧羰基-L-噻唑烷酸-L-脯氨酸甲酯)的合成:
将L-脯氨酸甲酯盐酸盐3.3g(20mmol)溶于100ml二氯甲烷中,冰浴条件下,滴加三乙胺2.0g(20mmol),5分钟后,加入4.66g N-叔丁氧羰基-L-噻唑烷酸(20mmol),1-羟基苯并三唑2.7g(20mmol),1-乙基-3(3-二甲基丙胺)碳二亚胺3.8g(20mmol),搅拌下自然升至室温,点板监测反应。反应完全后,反应液旋转蒸发,浓缩物加入乙酸乙酯和水溶解,分液,乙酸乙酯层依次用柠檬酸水溶液、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩成无色油状物。石油醚:乙酸乙酯=1:1柱纯化,得无色透明油状物4.74g,产率68.9%。1H-NMR(400MHz,DMSO-d6),δppm:4.77(m,1H,-CH),4.43(m,1H,-CH),3.71(m,2H,-CH2),3.64(s,3H,-CH3),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,-CH2),1.37(m,6H,-CH3,-CH3),1.15(m,3H,-CH3).M+1:344.1。
(2)中间体2(L-噻唑烷酸-L-脯氨酸甲酯盐酸盐)的合成:
将4.74g中间体1(13.7mmol)溶于30ml乙酸乙酯,冰浴下加入10ml 4N HCl/乙酸乙酯溶液,反应完全后,旋干反应液,得白色固体3.73g,产率96.1%。1H-NMR(400MHz,DMSO-d6),δppm:4.77(m,1H,-CH),4.43(m,1H,-CH),3.71(m,2H,-CH2),3.64(s,3H,-CH3),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,-CH2).M+1:281.1。
(3)中间体3(N-叔丁氧羰基-O-叔丁基-L-苏氨酸-L-噻唑烷酸-L-脯氨酸甲酯)的 合成:
将2.2g中间体2(7.8mmol)溶于40ml二氯甲烷,冰浴条件下加入三乙胺0.78g(7.8mmol),原料溶解后,加入N-叔丁氧羰基-O-叔丁基-L-苏氨酸2.15g(7.8mmol),1-羟基苯并三唑1.05g(7.8mmol),1-乙基-3-(3-二甲基丙胺)碳二亚胺1.5g(7.8mmol),搅拌过夜,反应完全后旋干反应液,浓缩物用乙酸乙酯和水溶解,分液,乙酸乙酯层依次用柠檬酸水溶液、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩。石油醚:乙酸乙酯=1:1柱纯化,得到白色固体2.09g,产率53.6%。1H-NMR(400MHz,DMSO-d6),δppm:7.91(m,1H,-NH),4.94(m,1H,-CH),4.52-4.23(m,3H,-CH),3.71(m,2H,-CH2),3.64(s,3H,-CH3),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,-CH2),1.37(m,9H,-CH3),1.12-1.01(m,13H,-CH3).M+1:484.3。
(4)中间体4(N-叔丁氧羰基-O-叔丁基-L-苏氨酸-L-噻唑烷酸-L-脯氨酸)的合成:
将2.09g中间体3溶于20ml甲醇,室温下加入20ml 2N氢氧化钠溶液,搅拌3小时后,旋蒸出大部分溶剂,剩余反应液中加入20ml水,冰浴下用饱和柠檬酸溶液调节pH至2-3,加入乙酸乙酯25ml*3萃取,合并有机相,无水硫酸钠干燥,浓缩至白色固体2.03g,产率100%。1H-NMR(400MHz,DMSO-d6),δppm:7.91(m,1H,-NH),4.94(m,1H,-CH),4.52-4.23(m,3H,-CH),3.71(m,2H,-CH2),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,-CH2),1.37(m,9H,-CH3),1.12-1.01(m,13H,-CH3).M+1:470.3。
(5)中间体5(N-叔丁氧羰基-O-叔丁基-L-苏氨酸-L-噻唑烷酸-L-脯氨酸-L-苏氨 酸甲酯)的合成:
将L-苏氨酸甲酯盐酸盐0.35g(2mmol)溶于30ml二氯甲烷中,冰浴条件下加入三乙胺0.21g(2mmol),5分钟后加入1.0g中间体4(2mmol),1-羟基苯并三唑0.28g(2mmol),1-乙基-3(3-二甲基丙胺)碳二亚胺0.39g(2mmol),反应自然升至室温。反应完全后,旋干反应液,浓缩物用乙酸乙酯和水溶解,分液,乙酸乙酯层依次用柠檬酸水溶液、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,得白色固体。二氯甲烷:甲醇=40:1柱纯化,得白色固体890mg,产率74.3%。1H-NMR(400MHz,DMSO-d6),δppm:7.94(m,1H,-NH),6.4(m,1H,-NH),5.05(m,1H,-CH),4.91(m,1H,-CH),4.56-4.54(m,2H,-CH2),4.32(m,1H,-CH2),4.24(m,1H,-CH2),4.12(m,1H,-CH2),3.72(m,2H,-CH2),3.60(s,3H,-CH3),3.50(m,1H,-CH2),2.91(m,1H,-CH2),2.17-1.86(m,5H,-CH2),1.37(s,9H,-CH3),1.21(m,1H,-CH3),1.11-1.01(m,13H,-CH3).M+1:603.3。
(6)中间体6(N-叔丁氧羰基-O-叔丁基-L-苏氨酸-L-噻唑烷酸-L-脯氨酸-L-苏氨 酸酰胺)的合成:
将890mg中间体5溶于3ml甲醇,冰浴下,加入10N氨气/甲醇溶液10ml,反应12小时,旋干反应液,得白色固体860mg。1H-NMR(400MHz,DMSO-d6),δppm:7.94(m,1H,-NH),7.18(s,2H,CO-NH2),6.4(m,1H,-NH),5.04(m,1H,-OH),4.91(t,1H,-CH,J=6.54Hz),4.58-4.54(m,3H,-CH),4.32-4.25(m,2H,-CH),3.72(m,2H,-CH2),3.50(m,2H,-CH2),2.91(m,2H,-CH2),2.15-1.86(m,4H,-CH2),1.37(s,9H,-CH3),1.21(m,3H,-CH3),1.11-1.01(m,12H,-CH3).M+1:588.3
(7)化合物A-1的合成:
将中间体6溶于10ml乙酸乙酯,冰浴下,加入4N HCl/乙酸乙酯溶液,反应6小时,旋干反应液,得白色固体为最终产物630mg。1H-NMR(400MHz,DMSO-d6),δppm:7.61(d,1H,CO-NH,J=8.16Hz),7.05(s,2H,CO-NH2)5.20(d,1H,OH,J=9.84Hz),4.93(t,1H,OH,J=7.84Hz),4.59-4.24(m,4H,CH),4.4(m,2H,CH2),3.8(m,2H,-CH2),3.6(m,2H,2-CH),3.0(m,2H,-CH2),1.9-2.0(m,4H,-CH2),1.2(m,3H,-CH3),1.0(m,3H,-CH3),M+1:432.2。
实施例A-2至A-20:化合物A-2至A-20的制备
方法同A-1,只需要将相应的P2/P3片段进行替换即可。
A-2:将中间体3合成步骤中的原料N-叔丁氧羰基-O-叔丁基-L-苏氨酸替换为N-叔丁氧羰基-O-叔丁基-L-丝氨酸,其余操作与A-1合成相同;
A-3:将中间体5合成步骤中的原料L-苏氨酸甲酯盐酸盐替换为L-丝氨酸甲酯盐酸盐,其余操作与A-1合成相同;
A-4:将中间体3合成步骤中的原料N-叔丁氧羰基-O-叔丁基-L-苏氨酸替换为N-叔丁氧羰基-O-叔丁基-L-丝氨酸,中间体5合成步骤中的原料L-苏氨酸甲酯盐酸盐替换为L-丝氨酸甲酯盐酸盐,其余操作与A-1合成相同;
A-5:将中间体1合成步骤中的原料L-脯氨酸甲酯盐酸盐替换为L-噻唑烷酸甲酯盐酸盐,N-叔丁氧羰基-L-噻唑烷酸替换为N-叔丁氧羰基-L-脯氨酸,其余操作与A-1合成相同;
A-6:将中间体3合成步骤中的原料N-叔丁氧羰基-O-叔丁基-L-苏氨酸替换为N-叔丁氧羰基-O-叔丁基-L-丝氨酸,其余操作与A-5合成相同;
A-7:将中间体5合成步骤中的原料L-苏氨酸甲酯盐酸盐替换为L-丝氨酸甲酯盐酸盐,其余操作与A-5合成相同;
A-8:将中间体3合成步骤中的原料N-叔丁氧羰基-O-叔丁基-L-苏氨酸替换为N-叔丁氧羰基-O-叔丁基-L-丝氨酸,中间体5合成步骤中的原料L-苏氨酸甲酯盐酸盐替换为L-丝氨酸甲酯盐酸盐,其余操作与A-5合成相同;
A-9:将中间体1合成步骤中的原料L-脯氨酸甲酯盐酸盐替换为L-噻唑烷酸甲酯盐酸盐,其余操作与A-1合成相同;
A-10:将中间体3合成步骤中的原料N-叔丁氧羰基-O-叔丁基-L-苏氨酸替换为N-叔丁氧羰基-O-叔丁基-L-丝氨酸,其余操作与A-9合成相同;
A-11:将中间体5合成步骤中的原料L-苏氨酸甲酯盐酸盐替换为L-丝氨酸甲酯盐酸盐,其余操作与A-9合成相同;
A-12:将中间体1合成步骤中的原料N-叔丁氧羰基-L-噻唑烷酸替换为N-叔丁氧羰基-2,2-二甲基-L-噻唑烷酸,其余操作与A-1合成相同;
A-13:将中间体1合成步骤中的原料L-噻唑烷酸甲酯盐酸盐替换为2,2-二甲基-L-噻唑烷酸甲酯盐酸盐,其余操作与A-5合成相同;
A-14:将中间体3合成步骤中的原料N-叔丁氧羰基-O-叔丁基-L-苏氨酸替换为N-叔丁氧羰基-O-叔丁基-L-丝氨酸,其余操作与A-13合成相同;
A-15:将中间体5合成步骤中的原料L-苏氨酸甲酯盐酸盐替换为L-丝氨酸甲酯盐酸盐,其余操作与A-13合成相同;
A-16:将中间体1合成步骤中的原料L-噻唑烷酸甲酯盐酸盐替换为2-甲基-L-噻唑烷酸甲酯盐酸盐,其余操作与A-5合成相同;
A-17:将中间体1合成步骤中的原料L-噻唑烷酸甲酯盐酸盐替换为2-乙基-L-噻唑烷酸甲酯盐酸盐,其余操作与A-5合成相同;
A-18:将中间体1合成步骤中的原料L-噻唑烷酸甲酯盐酸盐替换为2-异丙基-L-噻唑烷酸甲酯盐酸盐,其余操作与A-5合成相同;
A-19:将中间体1合成步骤中的原料L-噻唑烷酸甲酯盐酸盐替换为2-苄基-L-噻唑烷酸甲酯盐酸盐,其余操作与A-5合成相同;
A-20:将中间体1合成步骤中的原料L-噻唑烷酸甲酯盐酸盐替换为2-苯基-L-噻唑烷酸甲酯盐酸盐,其余操作与A-5合成相同。
实施例A-21至A-24:化合物A-21至A-24的制备
化合物A-21至A-24的合成与化合物A-1基本相同,只需要在以下步骤进行相应调整即可:
A-21:将中间体5以4N HCl/乙酸乙酯溶液脱保护,得化合物A-21。
A-22:将中间体5以甲胺/甲醇溶液进行氨解,再以4N HCl/乙酸乙酯溶液脱保护,得化合物A-22。
A-23:将L-苏氨酸甲酯盐酸盐替换为L-苏氨酸乙酯盐酸盐,然后通过与化合物A-1同样合成路径,在中间体5步骤中以4N HCl/乙酸乙酯溶液脱保护,得到化合物A-23。
A-24:将L-苏氨酸甲酯盐酸盐替换为L-苏氨酸异丙酯盐酸盐,然后通过与化合物A-1同样合成路径,在中间体5步骤中以4N HCl/乙酸乙酯溶液脱保护,得到化合物A-24。
化合物B-1至B-9的合成路线如下:
其中,
R分别依次选自下述9个基团:
其中,中间体b5的合成路线与中间体5类似,除了将起始原料N-叔丁氧羰基-噻唑烷酸替换为N-叔丁氧羰基脯氨酸。
实施例B-1:实施例化合物B-1的制备
(1)将2.3g中间体b5(3.9mmol)溶于20ml甲醇,搅拌下加入20ml 2N氢氧化钠溶液,搅拌4小时,反应完全后,旋蒸出大部分溶剂,残余溶液中加入30ml水,用饱和柠檬酸溶液调节pH=2-3,加入乙酸乙酯萃取3次,每次用乙酸乙酯20mL,合并有机相,无水硫酸钠干燥,旋干,得2.2g白色固体中间体b。
1H-NMR(400MHz,DMSO-d6),δppm:12.58(br,1H,CO-OH),7.6(m,1H,CO-NH),6.4(m,1H,CO-NH),5.05(s,1H,-OH),4.63(m,1H,-CH),4.56-4.54(m,2H,-CH),4.32(m,1H,-CH),4.24(m,1H,-CH),4.12(m,1H,-CH),3.42(m,4H,-CH2),2.91(m,4H,-CH2),2.17-1.86(m,4H,-CH2),1.37(s,9H,-CH3),1.21(m,3H,-CH3),1.11-1.01(m,12H,-CH3).M+1:571.3。
(2)将2.2g中间体b6(4mmol)溶于60ml二氯甲烷,冰浴下加入天然薄荷醇1.25g(8mmol),4-二甲氨基吡啶0.54g(4.4mmol),二环己基碳二亚胺1.1g(5.2mmol),搅拌过夜,反应完全后过滤,滤液依次用柠檬酸溶液、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,旋干,玻璃层析柱纯化,二氯甲烷:甲醇=50:1,得白色固体1.5g,产率53.5%。将该白色固体溶于20ml乙酸乙酯,冰浴下,加入6ml HCl/乙酸乙酯溶液,反应4小时后旋干反应液,得1.2g化合物B-1。
1H-NMR(400MHz,DMSO-d6),δppm:8.11(s,2H,-NH2),7.47(s,1H,CO-NH),5.17-5.14(m,2H,-OH),4.61-4.30(m,5H,-CH),4.11-3.65(m,6H,CH),2.34-1.35(m,18H,-CH2),1.22-0.83(m,16H,CH2,-CH3).M+1:553.4。
实施例B-2至B-5:化合物B-2至B-5的制备
步骤同实施例B-1,不同之处是将步骤(2)中的天然薄荷醇分别替换为(+)-2-莰醇、L-奥拉西坦、羟乙基茶碱、羟丙基茶碱,分别制得化合物B-2至B-5。
实施例B-6:化合物B-6的制备
将570mg中间体b6(1mmol)溶于60ml二氯甲烷,冰浴下加入金刚烷胺165mg(1mmol),1-羟基苯并三唑135mg(1mmol),1-乙基-(3-二甲基丙胺)碳二亚胺200mg(1mmol),搅拌过夜,反应完全后过滤,滤液依次用柠檬酸溶液、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,旋干,二氯甲烷:甲醇=50:1柱纯化,得白色固体260mg,产率36.2%。产物溶于20ml乙酸乙酯,冰浴下,加入6ml HCl/乙酸乙酯溶液,反应4小时后旋干反应液,得200mg化合物B-6。
1H-NMR(400MHz,DMSO-d6),δppm:8.38(s,1H,CO-NH),8.11(s,2H,-NH2),7.47(s,1H,CO-NH)5.14(s,1H,-OH),4.61(s,1H,-OH),4.33-3.60(m,10H,-CH,-CH2),2.33-1.81(m,8H,-CH2),1.80-1.71(m,6H,-CH2),1.59-1.55(m,4H,-CH2),1.32-1.22(m,7H,-CH2),1.10-0.80(m,8H,-CH2,-CH3).M+1:576.4。
实施例B-7至B-9:化合物B-7、B-8、B-9的制备
步骤同实施例B-6,只是将金刚烷胺分别替换为美金刚、多巴胺和2-(7-甲氧基萘基-1-)乙胺,分别制得化合物B-7、B-8和B-9。
另外,通过质谱验证制备的化合物的结构,如下面的表2所示;制备的化合物结构正确。
表2:化合物结构确证(质谱)
编号 | MS:(M+1) | 编号 | MS:(M+1) |
A-1 | 432.2 | A-2 | 418.2 |
A-3 | 418.2 | A-4 | 404.2 |
A-5 | 432.2 | A-6 | 418.2 |
A-7 | 418.2 | A-8 | 404.2 |
A-9 | 450.1 | A-10 | 436.1 |
A-11 | 436.1 | A-12 | 460.2 |
A-13 | 460.2 | A-14 | 446.2 |
A-15 | 446.2 | A-16 | 446.2 |
A-17 | 460.2 | A-18 | 474.2 |
A-19 | 522.2 | A-20 | 508.2 |
A-21 | 447.1 | A-22 | 446.2 |
A-23 | 461.2 | A-24 | 475.2 |
B-1 | 553.4 | B-2 | 551.3 |
B-3 | 555.3 | B-4 | 621.3 |
B-5 | 635.3 | B-6 | 576.4 |
B-7 | 548.3 | B-8 | 549.3 |
B-9 | 598.3 | GLYX-13 | 414.2 |
实验例1:体外受体结合实验
1.实验目的
以GLYX-13(Rapastinel)为对照,通过受体配体结合实验,研究受试化合物对NMDA受体的亲和力。
2.实验方法实验方法
(1)前额皮层和海马粗制突触体的制备
SD大鼠断头处死后,冰上迅速分离出前额皮质和海马,称重后加入10倍体积的50mM Tris-HCl缓冲液(50mM Tris-HCl、5mM MgCl2·6H2O、1mM EDTA、0.5%(W/V)BSA、1mMPMSF、0.32M蔗糖,pH 7.4),1500转/min匀浆5次,每次30s。匀浆液经1000×g离心10min,取上清液再用40000×g离心10min,收集沉淀,10倍体积Tris-HCl缓冲液重悬,37℃孵育10min,再用40000×g离心10min最后将得到的沉淀用以上缓冲液重悬,分装后-80℃保存备用。
(2)受试药物对大鼠粗制突触体与[3H]-MK-801结合抑制功能的检测
所有管中依次加入大鼠粗制突触体蛋白的量50μg。非特异结合管中加入MK-801(dizocilpine)体积50μl,终浓度为100μM,预先反应15min。测试管中加入20μL相应浓度对照药物反应15min。全部试管依次加入标记配体[3H]-MK-801体积30μl,终末浓度为10nM。用50mM Tris-HCl缓冲液(50mM Tris-HCl、5mM MgCl2·6H2O、1mM EDTA、0.5%(W/V)BSA、0.1%NaN3,pH 7.4)补足所有反应管体积为200μl。在37℃反应条件下反应10min。准备49型玻璃纤维滤膜,同时点样。将滤膜放入多头细胞收集器,反应体系经负压抽滤,再用冰冷的50mMTris-HCl缓冲液洗涤,每次10ml,共计5次。抽烤干后,滤膜加入1ml闪烁夜放在摇床摇动1.5h,次日放在液闪计数仪中测定放射性强度。
(3)受试药物对大鼠粗制突触体蛋白中NMDA受体激动活性能的检测
所有管中依次加入大鼠粗制突触体蛋白的量100μg。非特异结合管中加入5,7二氯犬尿喹啉酸50μl,终浓度为10μM。所有试管中预先加入50μM的谷氨酸,预先反应15min。测试管中加入20μL相应浓度对照药物,反应15min。最大反应管中加入1mM的甘氨酸。全部试管依次加入标记配体[3H]-MK-801体积30μl,终末浓度为10nM,反应15min。用50mM Tris-HCl缓冲液(50mM Tris-HCl、5mM MgCl2·6H2O、1mM EDTA、0.5%(W/V)BSA、0.1%NaN3,pH 7.4)补足所有反应管体积为500μl。在37℃反应条件下反应15min。准备49型玻璃纤维滤膜,同时点样。将滤膜放入多头细胞收集器,反应体系经负压抽滤,再用冰冷的50mM Tris-HCl缓冲液洗涤,每次10ml,共计5次。抽烤干后,滤膜加入1ml闪烁夜放在摇床摇动1.5h,次日放在液闪计数仪中测定放射性强度。
(4)数据统计处理
采用GraphPad5.0软件分析处理数据,非线性拟合计算其竞争抑制百分率。其中:
抑制百分率%=[(总结合cpm数-加药管cpm数)/(总结合cpm数-非特异管cpm数)]×100%;
以抑制百分率对受试化合物的对数浓度进行非线性拟合,得到竞争抑制曲线并计算IC50值。
最大激动效能=[(测试化合物cpm数-5,7二氯犬尿喹啉酸cpm数)/(1mM甘氨酸cpm数-5,7二氯犬尿喹啉酸cpm数)]×100%。
表3:实施例化合物对NMDA受体的亲和力及最大激动效能
实验结果显示,实施例化合物均具有NMDA受体激动活性,最大激动效能处于13%-90%之间,属于NMDA受体部分激动剂。
实验例2:动物药效学实验
采用大鼠强迫游泳实验进行药效学评价。实验动物为SD大鼠,雄性,体重150g-180g,SPF级,购入后适应性饲养一周,进行强迫游泳实验,实验前需禁食12h。实施例化合物均用生理盐水溶解,设立空白对照组(生理盐水)、阳性对照组(GLYX-13尾静脉注射组及氟西汀灌胃给药组)、实施例化合物给药组以及GLYX-13灌胃给药组;每组8-10只大鼠。
实验前一天将大鼠置于高40cm、内径18cm、水深23cm的玻璃缸中预游15min,水温28℃。预游结束后取出大鼠,干布擦干后电暖气烤干,放回饲养笼。分别于正式实验前1h给药,给药1小时后进行5min游泳实验,记录5min内累计不动时间。判定不动的标准是动物在水中停止挣扎,呈漂浮状态,仅有轻微的肢体运动以保持头部浮在水面。结果见表4,实验数据采用GraphPad Prism 5.0软件进行统计分析,数据以漂浮时间与空白对照组相比降低的比例表示,N/A代表该组实验漂浮时间与空白对照组相比无显著性差异,“--”代表该组实验未进行。
表4:实施例化合物的大鼠强迫游泳实验结果
实验结果显示,对照化合物GLYX-13尾静脉给药有效,且3天后药效依然保持;GLYX-13灌胃给药无效;对照药氟西汀灌胃给药当天有效,但药效无法保持至次日;多个实施例化合物灌胃有效,且药效可保持到次日至3天后。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (12)
1.式I所示的化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,
NH2-P1-P2-P3-P4-COR
式I
其中,
其中,对于P2和P3,
R选自OR2和NR3R4,其中,R2、R3和R4各自独立地选自氢、C1-C6烷基和以下取代基:
5.根据权利要求1至4中任一权利要求所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其中:
R为OR2,其中,R2选自氢、C1-C6烷基(例如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基或3-己基)和以下取代基:
R选自NR3R4,其中,R3和R4各自独立地选自氢、C1-C6烷基(例如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基或3-己基)和以下取代基:
6.根据权利要求1至5中任一权利要求所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其中,所述式I化合物选自:
3-(L-苏氨酰基)-噻唑烷-(4R)-羰基-L-脯氨酰基-L-苏氨酰胺;
3-(L-丝氨酰基)-噻唑烷-(4R)-羰基-L-脯氨酰基-L-苏氨酰胺;
3-(L-苏氨酰基)-噻唑烷-(4R)-羰基-L-脯氨酰基-L-丝氨酰胺;
3-(L-丝氨酰基)-噻唑烷-(4R)-羰基-L-脯氨酰基-L-丝氨酰胺;
3-(L-苏氨酰基-L-脯氨酰基)-噻唑烷-(4R)-羰基-L-苏氨酰胺;
3-(L-丝氨酰基-L-脯氨酰基)-噻唑烷-(4R)-羰基-L-苏氨酰胺;
3-(L-苏氨酰基-L-脯氨酰基)-噻唑烷-(4R)-羰基-L-丝氨酰胺;
3-(L-丝氨酰基-L-脯氨酰基)-噻唑烷-(4R)-羰基-L-丝氨酰胺;
3-(3-L-苏氨酰基-噻唑烷-(4R)-羰基-)-噻唑烷-(4R)-羰基-L-苏氨酰胺;
3-(3-L-丝氨酰基-噻唑烷-(4R)-羰基-)-噻唑烷-(4R)-羰基-L-苏氨酰胺;
3-(3-L-苏氨酰基-噻唑烷-(4R)-羰基-)-噻唑烷-(4R)-羰基-L-丝氨酰胺;
3-(L-苏氨酰基)-2,2-二甲基噻唑烷-(4R)-羰基-L-脯氨酰基-L-苏氨酰胺;
3-(L-苏氨酰基-L-脯氨酰基)-2,2-二甲基噻唑烷-(4R)-羰基-L-苏氨酰胺;
3-(L-丝氨酰基-L-脯氨酰基)-2,2-二甲基噻唑烷-(4R)-羰基-L-苏氨酰胺;
3-(L-苏氨酰基-L-脯氨酰基)-2,2-二甲基噻唑烷-(4R)-羰基-L-丝氨酰胺;
3-(L-苏氨酰基-L-脯氨酰基)-2-甲基噻唑烷-4(R)-羰基-L-苏氨酰胺;
3-(L-苏氨酰基-L-脯氨酰基)-2-乙基噻唑烷-4(R)-羰基-L-苏氨酰胺;
3-(L-苏氨酰基-L-脯氨酰基)-2-异丙基噻唑烷-4(R)-羰基-L-苏氨酰胺;
3-(L-苏氨酰基-L-脯氨酰基)-2-苄基噻唑烷-4(R)-羰基-L-苏氨酰胺;
3-(L-苏氨酰基-L-脯氨酰基)-2-苯基噻唑烷-4(R)-羰基-L-苏氨酰胺;
3-(L-苏氨酰基)-噻唑烷-(4R)-羰基-L-脯氨酰基-L-苏氨酸甲酯;
3-(L-苏氨酰基)-噻唑烷-(4R)-羰基-L-脯氨酰基-L-苏氨酰甲胺;
3-(L-苏氨酰基)-噻唑烷-(4R)-羰基-L-脯氨酰基-L-苏氨酸乙酯;
3-(L-苏氨酰基)-噻唑烷-(4R)-羰基-L-脯氨酰基-L-苏氨酸异丙酯;
L-苏氨酰基-L-脯氨酰基-L-脯氨酰基-L-苏氨酰基-L-薄荷醇酯;
L-苏氨酰基-L-脯氨酰基-L-脯氨酰基-L-苏氨酰基-(+)-2-莰醇酯;
2-乙酰胺基-吡咯烷酮-(4S)-羟基-L-苏氨酰基-L-脯氨酰基-L-脯氨酰基-L-苏氨酸酯;
7-乙基-茶碱- -羟基-L-苏氨酰基-L-脯氨酰基-L-脯氨酰基-L-
苏氨酸酯;
7-丙基-茶碱- -羟基-L-苏氨酰基-L-脯氨酰基-L-脯氨酰基-L-
苏氨酸酯;
L-苏氨酰基-L-脯氨酰基-L-脯氨酰基-L-苏氨酰基-美金刚胺;
L-苏氨酰基-L-脯氨酰基-L-脯氨酰基-L-苏氨酰基-金刚烷胺;
L-苏氨酰基-L-脯氨酰基-L-脯氨酰基-L-苏氨酰基-多巴胺;和
1-((2-(7-甲氧基-萘-1-基)乙基)氨基-L-苏氨酰基-L-脯氨酰基-L-脯氨酰基-L-苏氨酰胺。
7.根据权利要求1至6中任一权利要求所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物,其中,所述溶剂合物为水合物。
8.一种药物组合物,其包含有效量的权利要求1至7中任一权利要求所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物;
可选地,所述药物组合物还包含一种或几种药学上可接受的辅料。
9.根据权利要求8所述的药物组合物,其还包含选自5-羟色胺重摄取抑制剂、5-羟色胺-去甲肾上腺素重摄取抑制剂、米氮平、安非他酮、维拉佐酮、沃替西汀中的一种或多种;
优选地,所述5-羟色胺重摄取抑制剂为选自西酞普兰、舍曲林、帕罗西汀和氟西汀中的一种或多种;
优选地,所述5-羟色胺-去甲肾上腺素重摄取抑制剂为选自度洛西汀、文法拉辛、去甲文法拉辛和米那普仑中的一种或多种。
10.根据权利要求8所述的药物组合物,其还包含选自苯二氮卓类、卡立普多和定泰乐中的一种或多种;
优选地,所述苯二氮卓类为选自氯氮卓、地西泮、劳拉西泮和艾司唑仑中的一种或多种。
11.一种药盒产品,其包含独立包装的药物制剂1和独立包装的药物制剂2,其中:
所述药物制剂1包含有效量的权利要求1至7中任一权利要求所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物;
所述药物制剂2包含选自5-羟色胺重摄取抑制剂、5-羟色胺-去甲肾上腺素重摄取抑制剂、米氮平、安非他酮、维拉佐酮、沃替西汀中的一种或多种,或者所述药物制剂2包含自苯二氮卓类、卡立普多和定泰乐中的一种或多种;
可选地,所述药物制剂1和/或药物制剂2还包含一种或者几种药学上可接受的辅料;
优选地,所述5-羟色胺重摄取抑制剂为选自西酞普兰、舍曲林、帕罗西汀和氟西汀中的一种或多种;
优选地,所述5-羟色胺-去甲肾上腺素重摄取抑制剂为选自度洛西汀、文法拉辛、去甲文法拉辛和米那普仑中的一种或多种;
优选地,所述苯二氮卓类为选自氯氮卓、地西泮、劳拉西泮和艾司唑仑中的一种或多种。
12.权利要求1至7中任一权利要求所述的式I化合物、其药学上可接受的盐或酯、其立体异构体或其溶剂合物在制备治疗和/或预防抑郁症、焦虑症、脑卒中、亨廷顿氏病、阿尔茨海默病、神经痛或精神分裂症的药物中的用途。
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