CN116870176A - PSMA靶向的PSMA-PARPi偶联物及制备方法和应用 - Google Patents
PSMA靶向的PSMA-PARPi偶联物及制备方法和应用 Download PDFInfo
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- CN116870176A CN116870176A CN202310969614.XA CN202310969614A CN116870176A CN 116870176 A CN116870176 A CN 116870176A CN 202310969614 A CN202310969614 A CN 202310969614A CN 116870176 A CN116870176 A CN 116870176A
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Abstract
本发明公开了一种PSMA靶向的PSMA‑PARPi偶联物及制备方法和应用。本发明物通过PSMA介导的主动靶向作用将化合物定向转运至肿瘤部位,降低其对健康细胞和正常组织的杀伤力,提高前列腺肿瘤选择性的同时,提升抗肿瘤效应。本发明解决了PARP临床使用中外周不良反应的发生,提高安全窗,为临床前列腺癌等实体瘤的治疗提供一种新型的双功能分子靶向药物。所述PSMA‑PARPi偶联物通式如下所示:
Description
技术领域
本发明属于药物化学领域,涉及一种化合物及其制备方法和应用,具体涉及一种PSMA靶向的PSMA-PARPi偶联物及制备方法和应用,是一种具有靶向前列腺癌抗肿瘤活性的化合物及其制备方法和应用。
背景技术
前列腺癌(PCa)是一种实体恶性肿瘤,全球男性发病率最高,西方国家死亡率第二高。早期局限性前列腺癌的治疗方案包括根治性前列腺切除术和体外放射治疗。对于晚期或转移性PCa,雄激素剥夺疗法更合适。然而,大多数肿瘤最终会发展为去势抵抗前列腺癌(CRPC)或转移性去势抵抗前列腺癌(mCRPC)。mCRPC是PCa进展的最后阶段,也是死亡的主要原因。一旦进展至mCRPC,患者只能选择细胞毒药物化疗如紫杉醇、醋酸阿比特龙、恩扎鲁胺、或二氯化镭-223来延长生存期。但常规的化疗药大多存在选择性差、毒副作用大和耐药性等缺陷,从而导致临床疗效不佳且患者生存质量差。因此寻找新型靶向抗肿瘤药物用于前列腺癌具有非常大的临床价值和意义。
奥拉帕利是首个上市获批于前列腺癌的PARP抑制剂,其在体内外对PARP1、PARP2和PARP3具有抑制活性,PARP1、2、3参与DNA损伤修复过程,其中PARP1是PARP家族中最丰富的亚型,PARP1在DNA损伤的信号传导和修复中起着关键作用。在细胞自身活动、化学物质或电离辐射引起的DNA损伤后,PARP1被快速激活,识别并结合DNA单链断裂(SSBs),催化烟酰胺腺嘌呤二核苷酸(NAD)分解成ADP核糖和烟酰胺,然后转移ADP核糖单元合成聚(ADP核糖)(PAR)链,通过降低PARP1和DNA之间的亲和力使PARP1脱离DNA,然后引导DNA单链修,这是DNA碱基切除修复途径的关键过程。奥拉帕利通过抑制剂PARP酶活性和增加PARP-DNA复合物的形成,导致肿瘤细胞DNA无法修复,从而破坏细胞分裂导致凋亡。目前奥拉帕利已被FDA批准用于卵巢癌、乳腺癌、胰腺癌和前列腺癌的治疗,是首个获批的PARP抑制剂。但该类药物组织选择性差,常出现骨髓抑制毒性包括中性粒细胞减少、血小板减少和严重贫血等,其中贫血最为常见。临床上接受奥拉帕利的治疗者中,约有45%患者因各种不良反应导致中断治疗,22%患者由于不良反应而降低剂量。导致中断治疗的最常见不良反应为贫血(25%)和血小板减少(6%),导致剂量减少治疗的最常见不良反应为贫血(16%)。临床约18%患者因各种严重不良反应停止治疗,最常见导致终止治疗的不良反应是贫血(7%)。虽然PARP抑制剂在多种恶性肿瘤中均有较好的疗效,但这些缺陷限制了其进一步的开发和临床应用。
前列腺特异性膜抗原(Prostate specific membrane antigen,PSMA)是位于前列腺上皮细胞膜表面的II型跨膜蛋白。在绝大多数前列腺癌细胞表面过表达,而正常细胞不表达或极低表达。PSMA表达水平随着前列腺肿瘤分级的增加而上调。国内外学者针对PSMA设计出抗体、多肽和小分子靶向模块,其中抗体偶联药物已进入临床阶段,目前FDA已批准基于靶向PSMA的放射性元素68Ga、177Lu、18F作为前列腺癌PET/CT成像试剂,显示出良好的前列腺肿瘤的选择性和靶向性,对PSMA具有出色的特异性亲和力。
发明内容
本发明的目的之一是提供一种PSMA靶向的PSMA-PARPi偶联物,是具有结构通式I和通式II的化合物,所述的PSMA-PARPi偶联物包含如下所示的双功能偶联物:
Linker包含不同长度的二酸、烷基链、二硫醚、酰胺、氨基甲酸酯、杂环基烷基、烷氧羰基、烷氨基、天然或非天然氨基酸等,具体为通式I,通式II。
X=CH2、NH、O;
Y=羰基、CH2;
n=0-10的整数(优选1-5);
R1=H、1-10个碳原子数的烷基、杂烷基、芳香基,其中烷基优选甲基、异丙基、环丙基或异丁基,杂烷基优选羟甲基,芳香基优选苯基;
R2=H、1-5个碳原子数的烷基,其中烷基优选甲基;
*是R构型或S构型。
进一步,本发明选自如下化合物:
(((S)-1-羧基-5-(5-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-5-氧代戊酰胺基)戊基)氨基甲酰基)-L-谷氨酸(CQ-01),
(11S,15S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,5,13-三氧代-2-氧杂-6,12,14-三氮杂十七烷-11,5,17-三羧酸(CQ-02),
(14S,18S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,8,16-三氧代-4,5-二硫-9,15,17-三氮杂二十烷-14,18,20-三羧酸(CQ-03),
(((S)-1-羧基-5-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-4-氧代丁酰胺基)戊基)氨基甲酰基)-L-谷氨酸(CQ-04),
(((S)-1-羧基-5-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰胺基)戊基)氨基甲酰基)-L-谷氨酸(CQ-05),
(((S)-1-羧基-5-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-甲酰胺基)戊基)氨基甲酰基)-L-谷氨酸(CQ-06),
(11S,15S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,5,13-三氧基-2,6,12,14-四氮杂十七烷-11,5,17-三羧酸(CQ-07),
(12S,16S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,6,14-三氧代-2,7,13,15-四氮杂十八烷-12,16,18-三羧酸(CQ-08),
(((S)-1-羧基-5-(8-(4-(2-氟-5-(4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-8-氧代辛酰胺基)戊基)氨基甲酰基)-L-谷氨酸(CQ-09),
(((S)-1-羧基-5-(3-(4-(2-氟-5-(4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)丙酰胺基)戊基)氨基甲酰基)-L-谷氨酸(CQ-10),
(3S,7S)-25-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-5,13,18,25-四氧代-4,6,12,17-四氮杂二十五烷-1,3,7-三羧酸(CQ-11),
(3S,7S,18S)-18-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-19-甲基-5,13,16-三氧代-4,6,12,17-四氮杂二十烷-1,3,7-三羧酸(CQ-12),
(3S,7S,18R)-18-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-19-甲基-5,13,16-三氧代-4,6,12,17-四氮杂二十烷-1,3,7-三羧酸(CQ-13),
(2S,13S,17S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-甲基-1,4,7,15-四氧代-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸(CQ-14),
(13S,17S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-3-甲基-1,4,7,15-四氧代-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸(CQ-15),
(((S)-1-羧基-5-(4-(1-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)环丙基)氨基)-4-氧代丁酰胺基)戊基)氨基甲酰基)-L-谷氨酸(CQ-16),
(((S)-1-羧基-5-(4-(2-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-氧乙基)氨基)-4-氧代丁酰胺基)戊基)氨基甲酰基)-L-谷氨酸(CQ-17),
(2S,13S,17S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-(羟甲基)-1,4,7,15-四氧代-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸(CQ-18),
(5S,16S,20S)-5-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲嗪-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-7,10,18-三氧代-2-硫-6,11,17,19-四氮杂二十二烷-16,22-三羧酸(CQ-19),
(3S,7S,18S)-18-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-20-甲基-5,13,16-三氧代-4,6,12,17-四氮杂苯二甲酸-1,3,7-三羧酸(CQ-20),
(3S,7S,18S,19R)-18-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-19-甲基-5,13,16-三氧代-4,6,12,17-四氮杂环己烷-1,3,7-三羧酸(CQ-21),
(2S,13S,17S)-2-苄基-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,4,7,15-四氧代-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸(CQ-22),
(2R,13S,17S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,4,7,15-四氧代-2-苯基-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸(CQ-23),
(3S,7S)-21-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-5,13,6,21-四氧代-4,6,12,17-四氮杂二十烷-1,3,7-三羧酸(CQ-24),
(6S,17S,21S)-1-氨基-6-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-1,8,11,19-四氧代-2,7,12,18,20-五氮杂三嗪-17,23-三羧酸(CQ-25),
(((S)-1-羧基-5-(4-(S)-2-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-羰基)吡咯烷-1-基)-4-氧代丁酰胺基)戊基)氨基甲酰基)-L-谷氨酸(CQ-26)。
本发明化合物在药学上可接受的盐,所述的药学上可接受的盐为所述的化合物与无机酸、有机酸反应成盐。所述的药学上可接受的盐为盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、丙酸盐、丁酸盐、草酸盐、酒石酸盐、甲磺酸盐、对甲苯磺酸盐、富马酸盐、牛磺酸盐、柠檬酸盐或琥珀酸盐。
本发明的目的之二是提供通式I和通式II化合物的制备方法,通过以下步骤实现:
其中,上述反应溶解于有机溶剂在-20℃至200℃下进行,所述有机溶剂是含有1-20个碳原子的醚、醇、烷烃、芳香烃、酮、卤代烷、酰胺、腈、酯或者它们各种比例的混合物,所述催化剂为4-二甲氨基吡啶(DMAP),所述缩合剂为O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU),所用的脱保护剂为三氟乙酸(TFA)、钯碳(Pd/C)、浓盐酸或哌啶;此外,所用碱为DIPEA、TEA、氢氧化锂或氢氧化钠。
其中取代基的定义与上面通式I、通式II相同。
本发明的目的之三是提供通式I和通式II化合物在制备抗前列腺肿瘤细胞模型中的应用。
本发明的目的之四是提供通式I和通式II化合物在制备前列腺肿瘤荷瘤裸鼠模型中的应用。
本发明首次设计并合成一系列前列腺癌特异性靶向的PARP抑制剂,解决PARP临床使用中外周不良反应的发生,提高安全窗,为临床前列腺癌等实体瘤的治疗提供一种新型的双功能分子靶向药物。
与现有技术相比,本发明的有益之处在于:
提供了一种PSMA靶向抗肿瘤化合物PSMA-PARPi,体内外实验结果证实所发明所提供的化合物对PSMA阳性的前列腺肿瘤细胞LNCaP、C4-2B和22RV1细胞具有较好的抑制增殖作用和PSMA选择性,对PSMA阳性肿瘤细胞选择性和对正常前列腺上皮细胞安全性均优于奥拉帕利,在前列腺癌22RV1裸鼠模型中,该化合物等摩尔剂量口服灌胃后的抗肿瘤效果优于奥拉帕利。本发明提供的化合物给药后,小鼠的淋巴细胞未见明显降低,而奥拉帕利组淋巴细胞降低,结果说明本发明提供的化合物相比于奥拉帕利具有更好的安全性。解决了PARP抑制剂在临床使用中的无选择性导致外周不良反应的发生,提高了安全窗,为前列腺癌等实体瘤的治疗提供一种新型的双功能分子靶向药物。
附图说明
图1:PSMA竞争性抑制CQ-04、CQ-16的抗肿瘤活性实验。
图2:22RV1裸鼠模型治疗终点取血白细胞(WBC)、中性粒细胞(Neu#)、红细胞(RBC)、血小板(PLT)计数。
图3:22RV1裸鼠模型治疗终点取血平均红细胞体积(MCV)、淋巴细胞计数(Lym#)、血红蛋白(HGB)、血肌酐浓度(CRE-J)。
图4:22RV1裸鼠体重随时间变化。
图5:22RV1裸鼠瘤体积随时间变化。
图6:治疗终点各组肿瘤重量和抑瘤率。
图7:各组肿瘤组织拍照图。
具体实施方式
下面结合附图和实施例对本发明作进一步地详细说明,但本发明的实施方式不限于此,在不脱离本发明上述技术思想的情况下,根据本领域普通技术知识和惯用手段,做出各种替换和变更,均应包括在本发明的范围内。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均可通过正规渠道商购买得到的常规产品。
化合物的结构通过核磁共振和高分辨质谱来确定。1H-NMR和13C-NMR采用Bruker500MHz核磁共振仪,TMS为内标。LC-HRMS:Agilent 1290–HPLC–6224液质联用仪。熔点采用Buchi M565熔点仪测定。柱层析采用200–300目硅胶。
实施例1
PSMA-B的合成:
将三光气(2.9g,10mmol)加入500mL三口瓶中,加入50mL干燥二氯甲烷溶解,冰浴搅拌。将混合有PSMA-SM2(9.1g,27mmol),DIPEA(10.4mL,60mmol)的50mL二氯甲烷溶液缓慢滴加至500mL三口瓶中,冰浴搅拌反应2.5小时。加入混合有PSMA-SM1(8.0g,27mmol),DIPEA(10.4mL,60mmol)的50mL二氯甲烷溶液滴加至500mL三口瓶中。室温搅拌12小时,LC-MS监测原料消失。冰浴中加入1M盐酸200mL洗涤3次,饱和碳酸氢钠200mL洗涤,饱和食盐水200mL洗涤,收集有机相,无水硫酸钠干燥,浓缩,乙酸乙酯石油醚柱层析纯化得到10.1无色透明油状物PSMA-B,收率61%。MS(ESI+):m/z实测值:622.3685,计算值:622.3704[M+H]+。1H NMR(500MHz,Chloroform-d)δ7.39–7.28(m,5H),5.41–5.33(m,2H),5.10(q,J=12.3Hz,2H),4.35(dtd,J=19.7,8.0,4.7Hz,2H),3.17(dp,J=17.1,6.7Hz,2H),2.35–2.20(m,2H),1.85–1.68(m,2H),1.44(s,18H),1.43(s,9H),1.26(t,J=7.2Hz,2H),0.89–0.85(m,2H).
PSMA-C的合成
将3.1g PSMA-B加入250mL三口瓶中,加入30mL无水甲醇溶解,加入0.62g 5% Pd/C,氢气置换3次后室温搅拌过夜反应。LC-MS监测原料消失,硅藻土抽滤,100mL甲醇洗涤滤饼,浓缩至恒重,无需进一步纯化,2.4g无色透明油状物PSMA-C,收率98%。MS(ESI+):m/z实测值:488.3330,计算值:488.3319[M+H]+。1H NMR(500MHz,Chloroform-d)δ5.15(dd,J=8.1,3.7Hz,2H),4.34(td,J=7.9,4.8Hz,2H),2.73–2.64(m,2H),2.39–2.23(m,2H),2.07(dddd,J=14.2,9.4,6.4,5.2Hz,2H),1.91–1.72(m,2H),1.68–1.53(m,2H),1.52(s,2H),1.48–1.45(s,18H),1.44(s,9H),1.36–1.24(m,2H).
tBuDUPA的合成
将1.774g PSMA-SM1加入250mL三口瓶中,加入50mL二氯甲烷溶解,加入1548mgDIPEA。冰浴下加入297mg三光气。升至室温搅拌过夜。LC-MS显示原料消失,加入50mL饱和氯化铵洗涤三次,50mL饱和碳酸氢钠洗涤三次,50mL饱和食盐水洗涤一次。保留有机相,加入无水硫酸钠干燥,浓缩后柱层析,PE:EA=8:1—5:1梯度洗脱浓缩至干得到1.14g白色固体,收率75%。MS(ESI+):567.3298,m/z实测值:567.3282,计算值:567.3258[M+Na]+。1H NMR(500MHz,Chloroform-d)δ5.18(d,J=8.0Hz,2H),4.35(td,J=8.0,4.9Hz,2H),2.40–2.25(m,4H),2.11–2.05(m,2H),1.86(dddd,J=14.1,9.5,8.1,6.0Hz,2H),1.45(d,J=15.8Hz,27H).
DUPA的合成
将544mg tBuDUPA加入100mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL三氟乙酸,室温搅拌反应,LC-MS监测原料消失。加入50mL乙醚,有大量白色固体析出。抽滤,50mL乙醚洗涤滤饼两次。干燥得210mg白色固体。收率66%。MS(ESI+):m/z实测值:321.0945,计算值:321.0934[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.41(s,4H),6.34(d,J=8.4Hz,2H),4.09(td,J=8.2,4.7Hz,2H),2.23(qd,J=16.9,16.5,7.6Hz,4H),1.92(dq,J=13.8,6.5Hz,2H),1.71(dq,J=14.9,7.8Hz,2H).
ALPL-A的合成
将3.4g ALPL-SM1加入100mL三口瓶中,加入30mL DMA溶解,加入5.6g HBTU,4.4mLDIPEA室温搅拌30分钟,加入2.6g N-Boc-哌嗪,室温反应2h,TLC监测原料消失,停止反应。将反应液缓慢滴加至300mL水中,剧烈搅拌,大量白色固体析出,抽滤。100mL水洗涤三次,50mL甲叔醚洗涤3次,滤饼真空干燥。30mL无水乙醇溶解滤饼,回流1h,自然降温至室温析晶,抽滤,15mL无水乙醇洗涤滤饼,真空干燥得白色固体4.5g,收率80.5%。MS(ESI+):489.1925,m/z实测值:489.1912,计算值:489.1914[M+Na]+。1H NMR(500MHz,DMSO-d6)δ12.62(s,1H),8.27(dd,J=7.8,1.4Hz,1H),7.97(d,J=8.0Hz,1H),7.90(td,J=8.1,7.7,1.5Hz,1H),7.84(td,J=7.5,1.2Hz,1H),7.45(ddd,J=8.2,5.2,2.3Hz,1H),7.36(dd,J=6.6,2.3Hz,1H),7.24(t,J=9.0Hz,1H),4.34(s,2H),3.59(s,2H),3.39(s,2H),3.24(s,2H),1.41(s,9H).
ALPL-B的合成
将4g ALPL-A加入100mL三口瓶中,加入10mL乙醇溶解,加入10mL浓盐酸,室温搅拌,1h反应完毕。加入20mL水,50mL二氯甲烷洗涤三次。冰浴下用浓氨水调pH至9-10,50mL二氯甲烷萃取三次,合并有机相,无水硫酸钠干燥,浓缩至干得2.98g泡沫状固体,收率95.1%。MS(ESI+):m/z实测值:367.1554,计算值:367.1565[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.27(dd,J=8.0,1.6Hz,1H),7.97(dt,J=7.9,1.6Hz,1H),7.89(td,J=7.6,1.6Hz,1H),7.86–7.81(m,1H),7.44(ddt,J=9.1,6.5,3.2Hz,1H),7.34(ddd,J=29.5,6.5,2.3Hz,1H),7.23(td,J=9.0,4.0Hz,1H),4.34(s,2H),3.64(d,J=29.4Hz,2H),3.19(dt,J=40.5,5.0Hz,2H),2.89(s,2H),2.75(t,J=5.0Hz,2H).
ALPL的合成
将915mg ALPL-B加入25mL三口瓶中,加入10mL DCM溶解,冰浴,加入387mg环丙甲酰氯,缓慢升至室温。约1h反应完毕,10mL饱和碳酸氢钠洗涤3次,10mL饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩柱层析得到白色固体976mg,收率75%。MS(ESI+):m/z实测值:435.1809,计算值:435.1827[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.27(dd,J=7.9,1.5Hz,1H),8.00–7.95(m,1H),7.93–7.87(m,1H),7.84(td,J=7.5,1.2Hz,1H),7.45(ddd,J=8.3,5.2,2.2Hz,1H),7.39(s,1H),7.25(t,J=9.0Hz,1H),4.34(s,2H),3.82–3.57(m,4H),3.51–3.37(m,2H),3.20(d,J=33.9Hz,2H),1.95(d,J=48.4Hz,1H),0.79–0.70(m,4H).
1-1的合成
将732mg ALPL-B加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入228mg戊二酸酐,加入200mg三乙胺,室温搅拌反应。约2h反应原料消失,停止反应。10mL 0.1mM盐酸洗涤有机相3次,保留有机相,无水硫酸钠干燥,浓缩至干得白色固体825mg,收率85%。MS(ESI+):m/z实测值:950.5021,计算值:950.5034[M+H]+。1H NMR(500MHz,Chloroform-d)δ12.24(s,1H),11.69(s,1H),8.46(t,J=7.8Hz,1H),7.92(d,J=4.1Hz,1H),7.88–7.73(m,2H),7.38–7.27(m,2H),7.08(dt,J=14.8,8.7Hz,1H),4.31(d,J=8.7Hz,2H),3.76(d,J=33.3Hz,2H),3.58(dt,J=10.5,5.8Hz,2H),3.56–3.43(m,2H),3.28(s,2H),2.45(q,J=7.2,5.3Hz,4H),1.99–1.95(m,2H).
1-2的合成
将480mg化合物1-1加入100mL三口瓶中,加入20mL二氯甲烷溶解,加入494mgHBTU,加入322mg DIPEA,室温搅拌约10min,加入487mg PSMA-C。室温搅拌约1h反应完毕。30mL饱和氯化铵洗涤。DCM:MeOH=50:1—30:1梯度柱层析洗脱浓缩干,得到白色泡沫状固体578mg,收率59%。MS(ESI+):m/z实测值:950.5021,计算值:950.5034[M+H]+。1H NMR(500MHz,Chloroform-d)δ11.20(d,J=55.5Hz,1H),8.48(dt,J=7.4,1.9Hz,1H),7.78(ddd,J=9.6,7.6,4.7Hz,2H),7.76–7.67(m,1H),7.37–7.31(m,2H),7.04(td,J=9.1,1.9Hz,1H),6.61(dt,J=11.5,5.7Hz,1H),6.00(dd,J=19.5,8.3Hz,1H),5.80(dd,J=21.5,8.1Hz,1H),4.34(dt,J=8.6,3.9Hz,2H),4.30(s,2H),3.62(s,1H),3.52–3.48(m,1H),3.38–3.33(m,1H),3.31–3.26(m,1H),3.12–3.02(m,1H),2.47(t,J=7.2Hz,1H),2.43–2.20(m,6H),2.06(qd,J=7.8,7.3,5.1Hz,1H),1.96(dq,J=21.2,7.0Hz,2H),1.47–1.40(m,27H),1.32–1.24(m,2H).
化合物CQ-01的合成
将468mg 1-2加入100mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL三氟乙酸,室温搅拌过夜。LC-MS监测反应完毕。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得325mg白色固体,收率85%。熔点:194.5-194.9℃。MS(ESI+):m/z实测值:782.3149,计算值:782.3161[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.27(d,J=7.8Hz,1H),7.97(d,J=7.9Hz,1H),7.90(d,J=7.0Hz,1H),7.83(q,J=6.9,6.0Hz,2H),7.45(dq,J=8.6,2.7Hz,1H),7.41–7.36(m,1H),7.24(td,J=9.0,3.3Hz,1H),6.33(dd,J=16.9,8.2Hz,2H),4.34(s,2H),4.12–4.04(m,2H),3.68–3.50(m,8H),3.19(m,2H),3.01(q,J=6.7Hz,2H),2.58(t,J=7.0Hz,1H),2.34–2.29(m,2H),2.29–2.19(m,2H),1.98–1.70(m,2H),1.68–1.49(m,2H),1.42–1.37(m,2H),1.28(m,J=7.9Hz,2H)。13CNMR(126MHz,DMSO-d6)δ175.02,174.65,174.20,171.64,170.70,164.54,159.89,157.78,155.87,145.35,135.29,134.00,132.05(d,J=25Hz),129.55,129.41,128.35,126.55,125.92,123.99,116.48,116.31,65.38,52.73,52.12,47.01,46.73,45.27,44.85,42.03,41.73,41.17,38.84,36.90,32.22,30.80,30.35,29.25,28.31,27.97,23.06,15.62.
实施例2
参考实施例1将PSMA-SM1替换为3-羟基丙酸甲酯盐酸盐,PSMA-SM2替换为ALPL-B。
2-1的合成
将200mg三光气加入25mL三口瓶中,加入10mL无水DCM溶解,冰浴搅拌。将3-羟基丙酸甲酯208mg加入三口瓶中,加入506mg DIPEA,搅拌反应1h。加入734mg ALPL-B,升至室温搅拌过夜。TLC显示原料消失,10mL 1mM盐酸洗涤3次,饱和食盐水洗涤3次,保留有机相,浓缩柱层析得到745mg白色固体,收率76%。MS(ESI+):m/z实测值:497.1819,计算值:497.1831[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.60(s,1H),8.29–8.24(m,1H),7.96(d,J=8.0Hz,1H),7.86(dddd,J=28.7,8.3,7.3,1.3Hz,2H),7.44(ddd,J=8.5,5.1,2.3Hz,1H),7.36(dd,J=6.5,2.3Hz,1H),7.23(dd,J=9.4,8.6Hz,1H),4.33(s,2H),4.22(t,J=6.2Hz,2H),3.62(s,3H),3.41(t,J=5.3Hz,2H),3.34(s,7H),3.16(s,2H),2.67(t,J=6.1Hz,2H).
2-2的合成
将497mg化合物2-2加入100mL三口瓶中,加入1.5mL四氢呋喃溶解,加入0.5mL水,加入80mg水合氢氧化锂,1h反应完毕后调pH至3-4,大量固体析出。过滤干燥后,加入10mL二氯甲烷溶解,加入494mg HBTU,加入322mg DIPEA,室温搅拌约10min,加入487mg PSMA-C。室温搅拌约1h反应完毕。30mL饱和氯化铵洗涤。DCM:MeOH=50:1—30:1梯度柱层析洗脱浓缩干,得到白色泡沫状固体484mg,收率51%。MS(ESI+):m/z实测值:952.4826,计算值:952.4832[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.54(s,1H),8.43–8.37(m,1H),7.75–7.67(m,2H),7.67–7.61(m,1H),7.30–7.23(m,2H),6.97(q,J=8.2Hz,1H),5.85(dd,J=16.5,8.3Hz,1H),4.27(ddd,J=18.2,8.7,4.8Hz,2H),4.22(s,2H),3.68(ddt,J=7.7,6.1,2.2Hz,2H),3.59(dq,J=13.3,6.5Hz,2H),3.38(dt,J=19.4,6.2Hz,2H),3.24(d,J=30.6Hz,2H),2.93(d,J=12.3Hz,2H),2.34(d,J=16.0Hz,2H),2.28–2.19(m,2H),2.06–1.78(m,2H),1.77–1.62(m,2H),1.48–1.42(m,6H),1.40–1.34(m,27H).
CQ-02的合成
将468mg化合物2-2加入100mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL三氟乙酸,室温搅拌过夜。LC-MS监测反应完毕。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得325mg白色固体,收率85%。熔点:192.4–192.8℃。MS(ESI+):m/z实测值:784.2956,计算值:784.2948[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),12.46(s,3H),8.26(d,J=7.9Hz,1H),7.95(t,J=8.8Hz,2H),7.89(t,J=7.6Hz,1H),7.84(t,J=7.4Hz,1H),7.44(ddd,J=8.2,5.1,2.4Hz,1H),7.35(dd,J=6.4,2.3Hz,1H),7.23(t,J=8.9Hz,1H),6.32(s,2H),4.33(s,2H),4.18(t,J=6.4Hz,2H),4.07(d,J=30.1Hz,2H),3.67–3.54(m,2H),3.40(s,2H),3.27–3.22(m,2H),3.16(s,2H),3.08–2.95(m,2H),2.39(d,J=6.4Hz,2H),2.24(s,2H),2.04–1.86(m,2H),1.67(d,J=46.4Hz,2H),1.48(d,J=16.2Hz,2H),1.38(s,2H).13C NMR(126MHz,DMSO-d6)δ169.63,164.52,159.89,157.78,156.65,153.97,153.30,145.37,135.10,134.00,132.08,129.54(d,J=20Hz),128.33,126.55,125.95,123.91,116.49,62.28,41.54,38.82,36.89,35.59,31.88,29.28,23.06.
实施例3
3-1的合成
将3,3'-二硫代二丙酸420mg加入100mL三口瓶中,加入20mL二氯甲烷溶解,加入988mg HBTU,加入644mg DIPEA,室温搅拌约10min,加入732mg ALPL-B。室温搅拌约1h反应完毕。30mL饱和氯化铵洗涤。浓缩至干,无需纯化直接向下投料。MS(ESI+):m/z实测值:559.1495,计算值:559.1480[M+H]+。
化合物3-2的合成
将化合物3-1 294mg加入100mL三口瓶中,加入20mL二氯甲烷溶解,加入247mgHBTU,加入166mg DIPEA,室温搅拌约10min,加入244mg PSMA-C。室温搅拌约1h反应完毕。30mL饱和氯化铵洗涤。DCM:MeOH=50:1—30:1梯度柱层析洗脱浓缩干,得到白色泡沫状固体298mg,收率59%。MS(ESI+):m/z实测值:1028.4645,计算值:1028.4632[M+H]+。1HNMR(500MHz,Chloroform-d)δ10.44(d,J=86.8Hz,1H),8.44–8.38(m,1H),7.74–7.71(m,1H),7.71–7.69(m,1H),7.69–7.61(m,1H),7.26(dq,J=8.3,3.0,2.3Hz,2H),7.06(dd,J=8.6,1.8Hz,1H),6.98(td,J=8.9,4.4Hz,1H),6.81–6.60(m,1H),6.41–6.26(m,1H),5.76–5.58(m,2H),4.32–4.24(m,2H),4.22(d,J=1.9Hz,2H),3.50(m,4H),3.35(d,J=6.4Hz,2H),3.24(s,2H),3.07–2.94(m,2H),2.93–2.87(m,2H),2.79–2.64(m,2H),2.60–2.47(m,2H),2.25(ddd,J=17.1,9.8,6.9Hz,2H),2.08–1.88(m,2H),1.76(dt,J=14.3,8.5Hz,2H),1.53–1.40(m,4H),1.40–1.34(m,27H).
化合物CQ-03的合成
将257mg 1-2加入100mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL三氟乙酸,室温搅拌过夜。LC-MS监测反应完毕。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得325mg白色固体,收率85%。熔点:188.9–189.4℃。MS(ESI+):m/z实测值:890.2741,计算值:890.2754[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.27(d,J=7.9Hz,1H),7.97(dd,J=8.2,3.3Hz,1H),7.93–7.89(m,1H),7.84(td,J=7.6,3.6Hz,1H),7.48–7.33(m,2H),7.24(t,J=9.0Hz,1H),7.08(d,J=8.7Hz,2H),6.83(d,J=8.8Hz,2H),6.29(dd,J=16.7,8.4Hz,1H),4.34(s,2H),4.16–3.98(m,2H),3.99–3.85(m,2H),3.65–3.55(m,2H),3.53(s,2H),3.21(s,2H),3.16(s,2H),3.02(s,2H),2.92–2.86(m,2H),2.69(t,J=7.2Hz,2H),2.45(q,J=6.8Hz,2H),2.34–2.05(m,2H),1.54(m,4H).13CNMR(126MHz,DMSO-d6)δ175.02,174.66,174.20,170.27,169.50,159.87,158.95,158.64,157.76,145.32,135.30,133.97,132.03(d,J=26.3Hz),129.55,129.44,128.36,126.55,125.92,116.48,116.31,65.39,52.71,52.10,47.03,46.69,45.28,42.02,41.75,38.89,36.90,35.45,34.30,32.77,32.23,30.35,29.23,27.98,23.09,15.63.
实施例4
参考实施例1将戊二酸酐替换为丁二酸酐。
中间体4-1的合成
将732mg ALPL-B加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入200mg丁二酸酐,加入200mg三乙胺,室温搅拌反应。约2h反应原料消失,停止反应。10mL 0.1mM盐酸洗涤有机相3次,保留有机相,无水硫酸钠干燥,浓缩至干得白色固体830mg,收率89%。MS(ESI+)467.1742:m/z实测值:467.1751,计算值:467.1731[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),12.07(s,1H),8.30–8.24(m,1H),7.97(d,J=8.0Hz,1H),7.90(q,J=6.4Hz,1H),7.84(t,J=7.5Hz,1H),7.45(ddt,J=8.3,5.3,2.5Hz,1H),7.38(ddd,J=8.6,6.4,2.3Hz,1H),7.24(td,J=9.0,3.7Hz,1H),5.76(s,1H),4.34(s,2H),3.68–3.50(m,4H),3.38(s,2H),3.15(s,2H),2.58(t,J=6.6Hz,2H),2.46–2.42(m,2H)。
中间体4-2的合成
将466mg 4-1加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入494mg HBTU,加入322mg DIPEA,室温搅拌约10min,加入487mg PSMA-C。室温搅拌约1h反应完毕。30mL饱和氯化铵洗涤。DCM:MeOH=50:1—30:1梯度柱层析洗脱浓缩干,得到白色泡沫状固体560mg,收率60%。MS(ESI+):m/z实测值:936.4860,计算值:936.4883[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.74(s,1H),8.40(dt,J=7.9,2.9Hz,1H),7.76–7.62(m,3H),7.30–7.23(m,2H),6.97(q,J=8.2Hz,1H),5.87(dd,J=42.6,10.1Hz,2H),4.30–4.23(m,2H),4.22(s,2H),3.78–3.47(m,4H),3.29(d,J=73.1Hz,4H),2.59(d,J=15.4Hz,2H),2.29–2.19(m,2H),1.53–1.44(m,2H),1.39–1.32(m,27H),1.18(s,2H).
化合物CQ-04的合成
将468mg 4-2加入100mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL三氟乙酸,室温搅拌过夜。LC-MS监测反应完毕。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得325mg白色固体,收率85%。熔点:213.6–214.4℃。MS(ESI+):m/z实测值:768.3021,计算值:768.3005[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.27(d,J=7.8Hz,1H),7.97(d,J=7.9Hz,1H),7.90(d,J=7.0Hz,1H),7.83(q,J=6.9,6.0Hz,2H),7.45(dq,J=8.6,2.7Hz,1H),7.41–7.36(m,1H),7.24(td,J=9.0,3.3Hz,1H),6.33(dd,J=16.9,8.2Hz,2H),4.34(s,2H),4.12–4.04(m,2H),3.68–3.50(m,8H),3.19(m,2H),3.01(q,J=6.7Hz,2H),2.58(t,J=7.0Hz,1H),2.34–2.29(m,2H),2.29–2.19(m,2H),1.98–1.70(m,2H),1.68–1.49(m,2H),1.42–1.37(m,2H),1.28(m,J=7.9Hz,2H).13CNMR(126MHz,DMSO-d6)δ175.02,174.65,174.20,171.64,170.70,164.54,159.89,157.78,155.87,145.35,135.29,134.00,132.05(d,J=25Hz),129.55,129.41,128.35,126.55,125.92,123.99,116.48,116.31,65.38,52.73,52.12,47.01,46.73,45.27,44.85,42.03,41.73,41.17,38.84,36.90,32.22,30.80,30.35,29.25,28.31,27.97,23.06,15.62.
实施例5 5-1的合成
将ALPL-SM1 298mg加入50mL三口瓶中,加入5mL二氯甲烷溶解,加入494mg HBTU,加入322mg DIPEA,室温搅拌约10min,加入487mg PSMA-C。室温搅拌约1h反应完毕。30mL饱和氯化铵洗涤。DCM:MeOH=50:1—30:1梯度柱层析洗脱浓缩干,得到白色泡沫状固体578mg,收率59%。MS(ESI+):m/z实测值:782.3152,计算值:782.3161[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.34(s,1H),8.48–8.43(m,1H),8.06(dd,J=7.3,2.5Hz,1H),7.80–7.70(m,3H),7.33(ddd,J=7.7,4.8,2.5Hz,1H),7.03(dd,J=11.5,8.5Hz,1H),6.80(dt,J=11.8,5.6Hz,1H),5.33(t,J=8.4Hz,2H),4.34(ddt,J=8.4,7.1,3.4Hz,2H),4.31(s,2H),3.44(q,J=6.7Hz,2H),2.32(qdd,J=16.3,9.4,6.1Hz,2H),2.13–1.84(m,2H),1.84–1.66(m,2H),1.64–1.55(m,2H),1.46–1.41(m,27H),1.37–1.21(m,2H).
CQ-05的合成
将化合物5-1 384mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得240mg白色固体,收率80%。熔点:205.5–206.3℃。MS(ESI+):m/z实测值:600.2091,计算值:600.2100[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),12.42(s,3H),8.36–8.24(m,2H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.6Hz,1H),7.83(t,J=7.5Hz,1H),7.56(dd,J=6.8,2.4Hz,1H),7.43(ddd,J=7.8,4.8,2.4Hz,1H),7.19(dd,J=10.2,8.4Hz,1H),6.33(dd,J=12.2,8.2Hz,2H),4.33(s,2H),4.08(dtd,J=22.2,8.1,5.1Hz,2H),3.20(q,J=6.8Hz,2H),2.32–2.17(m,2H),1.97–1.69(m,2H),1.69–1.53(m,2H),1.52–1.43(m,2H),1.33(q,J=7.7Hz,2H).13C NMR(126MHz,DMSO-d6)δ175.03,174.66,174.21,163.89,159.87,159.24,157.77,157.28,145.45,134.77,134.02,132.75,132.05(d,J=25Hz),130.49,130.47,129.53,128.34,126.53,126.02,124.70,124.58,116.68,116.50,52.74,52.09,36.91,32.22,30.34,29.12,27.98,23.08.
实施例6化合物6-1的合成
将ALPL-B 732mg加入50mL三口瓶中,加入10mL四氢呋喃溶解,加入402mg氯甲酸对硝基苯酯,加入260mg DIPEA。LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到796mg白色泡沫状固体,收率75%。MS(ESI+):m/z实测值:532.1621,计算值:532.1627[M+H]+。1H NMR(500MHz,Chloroform-d)δ11.30(s,1H),8.52–8.46(m,1H),8.25(t,J=9.7Hz,2H),7.82–7.75(m,2H),7.74(s,1H),7.40–7.35(m,2H),7.35–7.28(m,2H),7.27(s,1H),7.07(t,J=8.9Hz,1H),5.30(s,1H),4.32(s,2H),3.94–3.67(m,4H),3.49(d,J=72.6Hz,4H).
化合物6-2的合成
将531mg 6-1加入50mL三口瓶中,加入10mL二氯甲烷溶解,加入130mg DIPEA,加入487mg PSMA-C。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到650mg白色泡沫状固体,收率74%。MS(ESI+):m/z实测值:880.4604,计算值:880.4615[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.92(s,1H),8.50–8.45(m,1H),7.83–7.70(m,3H),7.32(ddd,J=11.3,6.9,2.3Hz,2H),7.04(t,J=8.7Hz,1H),5.70(dd,J=35.4,8.0Hz,2H),4.30(d,J=1.8Hz,2H),4.26(dt,J=8.1,4.1Hz,2H),3.76(t,J=5.3Hz,2H),3.47(s,2H),3.33(s,2H),3.27(s,2H),3.19(d,J=6.1Hz,2H),2.34–2.21(m,2H),1.82–1.69(m,2H),1.65–1.50(m,2H),1.49(d,J=6.3Hz,2H),1.46–1.40(m,27H),1.34(td,J=7.1,1.0Hz,2H).
化合物CQ-06的合成
将化合物6-2 220mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得134mg白色固体,收率75%。熔点:248.8–249.8℃。MS(ESI+):m/z实测值:712.2729,计算值:712.2737[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.60(s,1H),12.44(s,3H),8.27(dd,J=7.8,1.4Hz,1H),8.00–7.95(m,1H),7.90(ddd,J=8.1,7.2,1.5Hz,1H),7.84(td,J=7.5,1.2Hz,1H),7.43(ddd,J=8.5,5.1,2.3Hz,1H),7.37(dd,J=6.5,2.3Hz,1H),7.23(t,J=9.0Hz,1H),6.57(t,J=5.5Hz,1H),6.31(dd,J=12.7,8.2Hz,2H),4.33(s,2H),4.08(dtd,J=25.8,8.1,5.1Hz,2H),3.58(t,J=5.3Hz,2H),3.35(t,J=5.4Hz,2H),3.22(dd,J=6.8,3.6Hz,2H),3.14(t,J=5.0Hz,2H),3.00(q,J=6.4Hz,2H),2.37–2.15(m,2H),1.98–1.69(m,2H),1.69–1.45(m,2H),1.40(ddd,J=13.6,7.9,4.8Hz,2H),1.27(p,J=8.8,8.2Hz,2H).13C NMR(126MHz,DMSO-d6)δ175.04,174.65,174.19,164.44,159.86,157.79,157.75,157.70,155.84,145.35,135.26,133.96,132.05(d,J=23.8Hz),129.55,129.40,129.37,128.36,126.55,125.93,124.24,124.09,116.47,116.30,65.38,52.76,52.10,46.85,43.98,43.65,41.78,36.89,32.33,30.35,29.93,27.99,23.07,15.63.
实施例7
化合物7-1的合成
将600mg三光气加入100mL三口瓶中,加入10mL二氯甲烷溶解。280mg 3-氨基丙酸甲酯盐酸盐、260mg DIPEA加入20mL二氯甲烷溶解后滴加至100mL三口瓶中,冰浴搅拌反应2.5小时。加入734mg ALPL-B,室温搅拌过夜。50mL 0.1M盐酸洗涤三次,50mL饱和食盐水洗涤三次,收集有机相,无水硫酸钠干燥,浓缩柱层析得到643mg白色固体,收率65%。MS(ESI+):m/z实测值:496.1986,计算值:496.1991[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.27(dd,J=7.9,1.4Hz,1H),7.98(d,J=8.0Hz,1H),7.90(td,J=7.6,1.5Hz,1H),7.84(td,J=7.6,1.2Hz,1H),7.44(ddd,J=8.1,5.0,2.3Hz,1H),7.37(dd,J=6.6,2.4Hz,1H),7.23(t,J=9.0Hz,1H),6.71(t,J=5.4Hz,1H),4.33(s,2H),3.59(s,3H),3.57(s,2H),3.30–3.18(m,4H),3.14(t,J=5.2Hz,2H),2.46(t,J=7.0Hz,2H).
化合物7-2的合成
将594mg 7-1加入50mL三口瓶中,加入3mL THF,加入1mL水,加入80mg LiOH·H2O,室温搅拌过夜。浓缩至小体积,0.1M盐酸调pH至3,大量固体析出,过滤烘干后得到白色固体482mg,收率83%。MS(ESI+):m/z实测值:482.1825,计算值:482.1834[M+H]+。1HNMR(500MHz,DMSO-d6)δ12.61(s,1H),12.18(s,1H),8.27(dd,J=7.8,1.4Hz,1H),7.97(d,J=7.9Hz,1H),7.90(td,J=8.0,7.6,1.5Hz,1H),7.86–7.81(m,1H),7.43(ddd,J=8.1,5.1,2.4Hz,1H),7.37(dd,J=6.5,2.3Hz,1H),7.23(t,J=9.0Hz,1H),6.67(t,J=5.4Hz,1H),4.33(s,2H),3.57(s,2H),3.35–3.03(m,8H),2.38(t,J=7.1Hz,2H).
化合物7-3的合成
将385mg 7-2加入50mL三口瓶中,加入10mL二氯甲烷溶解,加入103mg DIPEA,加入390mg PSMA-C。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到456mg白色泡沫状固体,收率60%。熔点:200.4–201.4℃。MS(ESI+):m/z实测值:951.4575,计算值:951.4586[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.38(s,1H),8.49–8.44(m,1H),7.78(ddd,J=6.9,4.3,1.9Hz,2H),7.72(dd,J=6.6,2.5Hz,1H),7.35–7.31(m,1H),7.30–7.28(m,1H),7.04(t,J=8.8Hz,1H),6.45(s,1H),5.78(s,1H),5.74(s,1H),5.68(d,J=8.0Hz,1H),4.32–4.29(m,1H),4.28(s,2H),3.76(s,2H),3.71(s,1H),3.47(s,2H),3.41(dd,J=13.5,6.5Hz,2H),3.29(s,2H),3.26(s,2H),3.06(dd,J=13.2,6.2Hz,2H),2.55–2.42(m,2H),2.38–2.29(m,2H),2.12–2.00(m,2H),1.85(dd,J=14.5,6.5Hz,2H),1.56–1.34(m,27H),1.34–1.28(m,4H).
化合物CQ-07的合成
将化合物7 200mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得125mg白色固体,收率76%。MS(ESI+):m/z实测值:783.3115,计算值:783.3108[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.60(s,1H),11.93(s,3H),8.27(dd,J=7.8,1.4Hz,1H),7.97(d,J=8.0Hz,1H),7.90(td,J=7.7,1.5Hz,1H),7.83(dd,J=9.7,5.3Hz,2H),7.43(ddd,J=8.1,5.1,2.3Hz,1H),7.36(dd,J=6.5,2.3Hz,1H),7.23(t,J=9.0Hz,1H),6.64(t,J=5.5Hz,1H),6.32(dd,J=17.6,8.2Hz,2H),4.33(s,2H),4.07(dtd,J=27.8,8.2,5.1Hz,2H),3.57(d,J=6.9Hz,2H),3.34(t,J=5.3Hz,2H),3.24–3.18(m,4H),3.13(dd,J=6.9,3.6Hz,2H),3.00(q,J=6.6Hz,2H),2.32–2.17(m,4H),1.98–1.67(m,2H),1.68–1.44(m,2H),1.38(dq,J=8.9,6.2Hz,2H),1.26(p,J=7.4Hz,2H).13CNMR(126MHz,DMSO-d6)δ175.02,174.67,174.20,170.90,164.45,159.86,157.77,157.66,145.36,135.30,133.98,132.06(d,J=23.5Hz),129.57,129.40,128.36,126.56,125.95,124.22,52.71,52.10,46.79,43.98,43.60,41.73,38.75,37.51,36.89,36.61,32.24,30.35,29.30,27.97,23.09.
实施例8
参考实施例7将3-氨基丙酸甲酯盐酸盐替换为3-氨基丁酸甲酯盐酸盐。
化合物8-1的合成
将600mg三光气加入100mL三口瓶中,加入10mL二氯甲烷溶解。308mg 3-氨基丁酸甲酯盐酸盐、260mg DIPEA加入20mL二氯甲烷溶解后滴加至100mL三口瓶中,冰浴搅拌反应2.5小时。加入734mg ALPL-B,室温搅拌过夜。50mL 0.1M盐酸洗涤三次,50mL饱和食盐水洗涤三次,收集有机相,无水硫酸钠干燥,浓缩柱层析得到661mg白色固体,收率65%。MS(ESI+):m/z实测值:510.2155,计算值:510.2147[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.25(s,1H),8.50–8.43(m,1H),7.82–7.74(m,2H),7.74–7.69(m,1H),7.32(dd,J=7.7,5.3Hz,2H),7.04(ddd,J=9.1,7.8,1.2Hz,1H),4.28(s,2H),3.78(s,2H),3.68(s,3H),3.44(t,J=5.4Hz,2H),3.36(d,J=5.1Hz,2H),3.29(td,J=6.6,5.2Hz,4H),2.41(t,J=6.8Hz,2H),1.86(p,J=6.7Hz,2H).
化合物8-2的合成
将594mg 7-1加入50mL三口瓶中,加入3mL THF,加入1mL水,加入80mg LiOH·H2O,室温搅拌过夜。浓缩至小体积,0.1M盐酸调pH至3,大量固体析出,过滤烘干后得到白色固体505mg,收率83%。MS(ESI+):m/z实测值:496.1985,计算值:496.1991[M+H]+。1HNMR(500MHz,DMSO-d6)δ12.61(s,1H),12.06(s,1H),8.26(dd,J=7.9,1.4Hz,1H),7.98(d,J=8.0Hz,1H),7.90(td,J=8.2,7.7,1.5Hz,1H),7.84(td,J=7.6,1.2Hz,1H),7.43(ddd,J=8.1,5.2,2.4Hz,1H),7.37(dd,J=6.5,2.3Hz,1H),7.23(t,J=9.0Hz,1H),6.61(t,J=5.5Hz,1H),4.33(s,2H),3.63–3.51(m,2H),3.32–3.09(m,4H),3.03(q,J=6.5Hz,2H),2.21(t,J=7.4Hz,2H),1.63(p,J=7.2Hz,2H).
化合物8-3的合成
将385mg 7-2加入50mL三口瓶中,加入10mL二氯甲烷溶解,加入103mg DIPEA,加入390mg PSMA-C。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到472mg白色泡沫状固体,收率60%。MS(ESI+):m/z实测值:965.5137,计算值:965.5143[M+H]+。1HNMR(500MHz,Chloroform-d)δ10.82(s,1H),8.49–8.45(m,1H),7.80–7.73(m,3H),7.35–7.30(m,2H),7.04(t,J=8.7Hz,1H),6.65(t,J=5.4Hz,1H),5.97(d,J=8.3Hz,1H),5.88(t,J=4.8Hz,1H),5.82(d,J=8.2Hz,1H),4.32(dt,J=8.5,6.8Hz,2H),4.29(s,2H),3.79–3.74(m,2H),3.48(t,J=5.5Hz,2H),3.42–3.15(m,8H),2.31(dt,J=14.9,6.3Hz,4H),1.95–1.84(m,2H),1.60–1.46(m,4H),1.47–1.41(m,27H),1.35(dd,J=16.0,8.2Hz,2H).
化合物CQ-08的合成
将化合物7 180mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得131mg白色固体,收率76%。熔点:202.2–202.7℃。MS(ESI+):m/z实测值:797.3259,计算值:797.3265[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.59(s,1H),8.26(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.89(t,J=7.5Hz,1H),7.83(t,J=7.5Hz,1H),7.77(t,J=5.7Hz,1H),7.43(ddd,J=8.0,5.0,2.2Hz,1H),7.36(dd,J=6.4,2.3Hz,1H),7.23(t,J=9.0Hz,1H),6.58(t,J=5.5Hz,1H),6.30(dd,J=18.7,8.2Hz,2H),4.33(s,2H),4.07(dtd,J=27.2,8.2,5.1Hz,2H),3.61–3.55(m,2H),3.23–3.20(m,2H),3.13(t,J=5.1Hz,2H),3.00(q,J=6.5Hz,4H),2.51(s,13H),2.30–2.18(m,2H),2.03(q,J=6.9,6.4Hz,2H),2.02–1.83(m,2H),1.80–1.43(m,6H),1.41–1.33(m,2H),1.26(dd,J=15.6,6.5Hz,4H).13CNMR(126MHz,DMSO-d6)δ175.00,174.64,174.19,172.24,164.46,159.86,157.79,157.76,155.85,145.35,135.30,135.27,133.96,132.04(d,J=25Hz),129.55,129.40,128.37,126.55,125.93,124.24,124.09,116.47,116.30,65.38,52.72,52.12,46.83,43.99,43.63,41.77,38.78,36.90,33.46,32.27,30.36,29.32,27.99,26.45,23.08,15.63.
实施例9
参考实施例3将3,3'-二硫代二丙酸替换为辛二酸。
化合物9-1的合成
将辛二酸348mg加入100mL三口瓶中,加入20mL二氯甲烷溶解,加入988mg HBTU,加入644mg DIPEA,室温搅拌约10min,加入732mg ALPL-B。室温搅拌约1h反应完毕。30mL饱和氯化铵洗涤。DCM:MeOH=50:1—30:1梯度柱层析洗脱浓缩干,得到白色泡沫状固体626mg。收率:60%。MS(ESI+):m/z实测值:523.2345,计算值:523.2351[M+H]+。
1H NMR(500MHz,Chloroform-d)δ12.23(s,1H),8.47(d,J=8.0Hz,1H),7.95–7.92(m,2H),7.85(ddd,J=8.2,5.2,3.0Hz,1H),7.78(d,J=6.3Hz,1H),7.08(dt,J=18.0,8.7Hz,2H),4.32(s,2H),3.75(d,J=28.5Hz,4H),3.58–3.50(m,4H),3.43(d,J=5.5Hz,2H),2.37–2.35(m,4H),1.66(d,J=8.0Hz,2H),1.41–1.37(m,4H).
化合物9-2的合成
将417mg 9-1加入50mL三口瓶中,加入10mL二氯甲烷溶解,加入103mg DIPEA,加入390mg PSMA-C。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到395mg白色泡沫状固体,收率50%。MS(ESI+):m/z实测值:992.5521,计算值:992.5503[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.26(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.8Hz,1H),7.86–7.81(m,1H),7.80–7.74(m,2H),7.44(s,1H),7.41–7.33(m,1H),7.24(t,J=8.9Hz,1H),6.33–6.24(m,2H),4.33(s,2H),4.03(td,J=8.6,5.2Hz,1H),3.97–3.93(m,1H),3.57(s,2H),3.51(s,2H),3.16(d,J=21.2Hz,2H),2.99(s,4H),2.32–2.17(m,6H),2.02(s,4H),1.86(td,J=12.3,10.8,5.4Hz,2H),1.59(d,J=8.6Hz,2H),1.48(dd,J=15.5,7.8Hz,8H),1.40–1.37(m,27H),1.30(s,2H),1.12(d,J=6.5Hz,2H).
化合物CQ-09的合成
将化合物9-2 175mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得127mg白色固体,收率76%。熔点:200.5–201.1℃。MS(ESI+):m/z实测值:824.3612,计算值:824.3625[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),12.28(s,3H),8.27(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.7Hz,1H),7.84(t,J=7.5Hz,1H),7.75(t,J=4.6Hz,1H),7.45(dd,J=7.9,4.4Hz,1H),7.40–7.34(m,1H),7.28–7.20(m,1H),6.32(dd,J=17.1,8.2Hz,2H),4.34(s,2H),4.14–3.98(m,2H),3.60(d,J=30.1Hz,2H),3.51(t,J=5.2Hz,2H),3.37(ddd,J=11.0,7.6,4.5Hz,2H),3.16(dt,J=20.7,5.2Hz,2H),2.99(q,J=6.2Hz,2H),2.30(dt,J=24.2,7.1Hz,2H),2.26–2.19(m,2H),2.03(td,J=7.3,3.6Hz,2H),1.97–1.67(m,2H),1.66–1.49(m,2H),1.46(t,J=7.4Hz,4H),1.38(dd,J=11.8,5.1Hz,2H),1.25(t,J=9.6Hz,6H).13C NMR(126MHz,DMSO-d6)δ175.02,174.66,174.20,172.38,171.37,159.86,157.75,145.32,135.30,133.97,132.26,132.04(d,J=26.3Hz),129.55,129.43,128.36,126.55,125.93,52.71,52.10,45.41,44.98,42.13,41.74,41.01,38.72,36.89,35.85,32.69,32.25,30.34,29.33,29.02,28.99,27.98,25.69,25.05,23.09.
实施例10
化合物10-1的合成
将ALPL-B 732mg加入100mL三口瓶中,加入20mL乙腈溶解,加入306mg 3-溴丙酸,加入276mg碳酸钾,室温搅拌约10min。室温搅拌约1h反应完毕。加入20mL 0.1M氢氧化钠溶液,30mL乙酸乙酯洗涤三次,保留水相。0.1M盐酸调pH=3-4,大量固体析出,过滤,干燥得到白色泡沫状固体613mg。收率:75%。MS(ESI+):m/z实测值:439.1789,计算值:439.1776[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),8.26(dd,J=7.9,1.4Hz,1H),7.98(d,J=8.0Hz,1H),7.90(td,J=7.7,1.5Hz,1H),7.83(t,J=7.5Hz,1H),7.42(ddd,J=8.0,5.0,2.3Hz,1H),7.32(dd,J=6.4,2.3Hz,1H),7.21(t,J=9.0Hz,1H),4.33(s,2H),3.57(s,2H),3.11(t,J=5.1Hz,2H),2.49–2.43(m,2H),2.35(t,J=5.3Hz,2H),2.22(s,2H),1.97(dd,J=8.6,6.8Hz,2H).
化合物10-2的合成
参考实施例1将1-1替换为10-1。
将439mg 10-1加入50mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入488mg PSMA-C。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到362mg白色泡沫状固体,收率45%。MS(ESI+):m/z实测值:908.4941,计算值:908.4928[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.74(s,1H),7.79–7.76(m,2H),7.72(s,1H),7.58(s,1H),7.35(s,1H),7.21(d,J=5.9Hz,1H),7.06(t,J=8.8Hz,1H),5.68(s,2H),4.30(s,3H),3.82(s,4H),2.71(d,J=6.8Hz,2H),2.60(s,4H),2.42–2.27(m,6H),1.66–1.55(m,2H),1.51(q,J=7.2Hz,2H),1.46(d,J=1.9Hz,18H),1.42(s,9H).
化合物CQ-10的合成
将化合物10-2 250mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得132mg白色固体,收率65%。熔点:>250℃。MS(ESI+):m/z实测值:740.3039,计算值:740.3050[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.63(s,3H),9.85(s,1H),8.27(d,J=7.7Hz,1H),8.16(t,J=5.6Hz,1H),7.96(d,J=8.0Hz,1H),7.90(t,J=7.5Hz,1H),7.84(t,J=7.5Hz,1H),7.50(ddd,J=8.1,5.1,2.3Hz,1H),7.39(dd,J=6.5,2.3Hz,1H),7.27(t,J=9.1Hz,1H),6.34(dd,J=16.0,8.3Hz,2H),4.34(s,2H),4.07(dtd,J=25.5,8.2,5.1Hz,2H),3.44–3.27(m,8H),3.06(q,J=6.7Hz,4H),2.57(t,J=7.1Hz,2H),2.35–2.17(m,2H),1.82(m,2H),1.58(m,2H),1.46–1.36(m,2H),1.29(p,J=7.8Hz,2H).13CNMR(126MHz,DMSO-d6)δ175.03,174.67,174.21,168.98,164.39,159.91,157.76,155.96,145.27,134.03,132.10(d,J=23.8Hz),129.55,128.36,126.57,125.94,123.14,122.95,116.46,65.39,52.67,52.10,38.72,36.93,32.26,30.34,29.05,27.96,23.12,15.64.
实施例11
化合物11-1的合成
将522mg 9-1加入50mL三口瓶中,加入10mL二氯甲烷溶解,加入300mg DIPEA,加入154mg 4-氨基丁酸甲酯盐酸盐。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到434mg白色泡沫状固体,加入3mL THF,加入1mL水,加入80mg LiOH·H2O,室温搅拌过夜。浓缩至小体积,0.1M盐酸调pH至3,大量固体析出,过滤烘干后得到白色固体316mg,收率56%,无需进一步纯化直接投下一步。MS(ESI+):m/z实测值:608.2886,计算值:608.2879[M+H]+。
化合物11-2的合成
将303mg 11-1加入50mL三口瓶中,加入10mL二氯甲烷溶解,加入160mg DIPEA,加入244mg PSMA-C。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到350mg白色泡沫状固体,收率65%。MS(ESI+):m/z实测值:1077.6021,计算值:1077.6031[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.26(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.8Hz,1H),7.86–7.81(m,1H),7.80–7.74(m,2H),7.44(s,1H),7.41–7.33(m,1H),7.24(t,J=8.9Hz,1H),6.33–6.24(m,2H),4.33(s,2H),4.03(td,J=8.6,5.2Hz,1H),3.97–3.93(m,1H),3.57(s,2H),3.51(s,2H),3.16(d,J=21.2Hz,2H),2.99(s,4H),2.32–2.17(m,6H),2.02(s,4H),1.86(td,J=12.3,10.8,5.4Hz,2H),1.59(d,J=8.6Hz,2H),1.48(dd,J=15.5,7.8Hz,8H),1.40–1.37(m,27H),1.30(s,2H),1.12(d,J=6.5Hz,2H).
化合物CQ-11的合成
将化合物11-3 300mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得180mg白色固体,收率71%。熔点:>250℃。MS(ESI+):m/z实测值:909.4145,计算值:909.4153[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.26(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.8Hz,1H),7.86–7.81(m,1H),7.80–7.74(m,2H),7.44(s,1H),7.41–7.33(m,1H),7.24(t,J=8.9Hz,1H),6.33–6.24(m,2H),4.33(s,2H),4.03(td,J=8.6,5.2Hz,1H),3.97–3.93(m,1H),3.57(s,2H),3.51(s,2H),3.16(d,J=21.2Hz,2H),2.99(s,4H),2.32–2.17(m,6H),2.02(s,4H),1.86(td,J=12.3,10.8,5.4Hz,2H),1.59(d,J=8.6Hz,2H),1.48(dd,J=15.5,7.8Hz,8H),1.40–1.37(m,27H),1.30(s,2H),1.12(d,J=6.5Hz,2H).13C NMR(126MHz,DMSO-d6)δ175.01,174.66,174.20,172.50,172.01,159.87,157.75,145.33,133.98,132.05(d,J=25Hz),129.55,129.43,128.42,126.55,125.94,52.71,52.10,45.40,38.78,38.62,36.89,35.87,33.38,32.68,32.25,30.35,29.32,29.00,25.96,25.68,25.05,23.09.
PSMA-D的合成
将2.440g PSMA-C加入20mL二氧六环中,加入600mg丁二酸酐,80℃搅拌反应过夜。浓缩至小体积,加入50mL DCM溶解,50mL饱和氯化铵溶液洗涤三次,浓缩至干得到无色油状物2.377g,无须进一步纯化,收率81%。MS(ESI+):m/z实测值:588.3520,计算值:588.3491[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.76(s,-1H),6.60(s,1H),5.89(d,J=8.5Hz,1H),5.64(s,1H),4.37(tt,J=8.6,4.1Hz,1H),4.28–4.13(m,1H),3.45–3.11(m,2H),2.79–2.65(m,2H),2.62–2.41(m,2H),2.33(pt,J=10.2,4.7Hz,2H),1.94–1.67(m,2H),1.67–1.50(m,2H),1.46(d,J=6.5Hz,27H),1.42–1.35(m,2H),1.35–1.26(m,2H).
实施例12
12-1的合成
将434mg N-Boc-L-缬氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体604mg,收率65%。MS(ESI+):m/z实测值:466.2261,计算值:466.2249[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.49(s,1H),8.50–8.43(m,1H),7.77(dd,J=6.5,2.7Hz,2H),7.72(s,1H),7.38–7.29(m,2H),7.09–6.98(m,1H),4.29(s,2H),3.73(d,J=63.3Hz,4H),3.57(s,1H),3.54–3.42(m,2H),3.31(s,2H),1.87–1.78(m,1H),1.01–0.81(m,6H).
12-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入465mg 12-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到403mg白色泡沫状固体,收率39%。MS(ESI+):m/z实测值:1035.5557,计算值:1035.5561[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.96(s,1H),8.41(dt,J=9.2,2.4Hz,1H),7.77–7.61(m,3H),7.43(d,J=8.3Hz,1H),7.30–7.22(m,2H),6.96(q,J=8.9Hz,1H),6.81–6.71(m,1H),6.27(d,J=9.1Hz,1H),6.17–5.90(m,1H),4.81–4.53(m,1H),4.42–4.30(m,2H),4.22(s,2H),3.93(d,J=43.0Hz,2H),3.79(t,J=14.5Hz,2H),3.62–3.42(m,2H),3.42–3.25(m,2H),3.14(d,J=40.8Hz,2H),3.05(d,J=6.4Hz,1H),2.66–2.43(m,2H),2.43–2.33(m,2H),2.30–2.18(m,2H),2.03–1.91(m,2H),1.76–1.63(m,2H),1.46(t,J=10.6Hz,2H),1.40–1.30(m,27H),1.23(dd,J=21.8,13.4Hz,2H),0.88(ddd,J=15.2,7.6,5.2Hz,6H).
CQ12的合成
将化合物12-2 310mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得166mg白色固体,收率64%。熔点:227.7–228.0℃。MS(ESI+):m/z实测值:867.3698,计算值:867.3683[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.60(s,1H),8.27(d,J=7.9Hz,1H),8.07(d,J=8.5Hz,1H),7.97(dd,J=7.8,3.0Hz,1H),7.90(t,J=6.8Hz,1H),7.84(t,J=7.5Hz,1H),7.80–7.75(m,1H),7.44(td,J=5.9,2.9Hz,1H),7.38(dd,J=6.5,2.3Hz,1H),7.24(d,J=8.8Hz,1H),6.32(d,J=8.0Hz,2H),4.55(t,J=8.3Hz,1H),4.33(d,J=2.3Hz,2H),4.08–4.02(m,2H),3.65–3.60(m,4H),3.52–3.49(m,4H),3.17(dd,J=6.1,3.2Hz,2H),2.34(dd,J=12.0,4.9Hz,2H),2.29–2.23(m,4H),1.97–1.88(m,2H),1.75–1.63(m,2H),1.38–1.34(m,2H),1.26(d,J=7.9Hz,2H),0.84(d,J=5.2Hz,6H),0.81(m,1H).13C NMR(126MHz,DMSO-d6)δ175.07,174.69,174.35,171.89,171.54,164.51,159.88,158.93,157.75,156.81,145.34,133.99,132.05(d,J=25Hz),129.55,128.35,126.55,125.92,116.50,91.14,70.38,66.19,66.02,65.64,63.26,63.19,53.71,52.81,52.31,47.27,42.59,41.15,38.83,36.91,32.26,31.27,30.98,30.75,30.41,29.26,28.31,23.08,19.86,18.52.
实施例13
参考实施例12将N-Boc-L-缬氨酸替换为N-Boc-D-缬氨酸。
13-1的合成
将434mg N-Boc-D-缬氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体596mg,收率64%。MS(ESI+):m/z实测值:466.2261,计算值:466.2249[M+H]+。1H NMR(500MHz,Chloroform-d)δ11.26(s,1H),8.51–8.43(m,1H),7.82–7.70(m,3H),7.34(t,J=6.4Hz,2H),7.04(q,J=8.2,7.5Hz,1H),4.62(s,1H),4.30(s,2H),3.87–3.34(m,8H),3.31(s,1H),1.87–1.85(m,2H),1.28(p,J=5.7Hz,1H),1.00–0.90(m,6H).
13-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入465mg 13-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到415mg白色泡沫状固体,收率40%。MS(ESI+):m/z实测值:1035.5557,计算值:1035.5561[M+H]+。1H NMR(500MHz,Chloroform-d)δ12.25(s,1H),8.42(d,J=7.8Hz,1H),7.98(d,J=2.5Hz,2H),7.88(dd,J=8.1,2.9Hz,1H),7.47–7.40(m,2H),7.10(dt,J=9.3,4.8Hz,2H),6.76(d,J=23.8Hz,1H),5.97–5.77(m,2H),4.91–4.57(m,1H),4.36(s,2H),4.31(dt,J=8.6,4.3Hz,2H),3.69(dd,J=103.6,67.7Hz,8H),3.30(d,J=29.5Hz,2H),2.65–2.39(m,4H),2.33–2.25(m,2H),2.11(s,2H),2.05–2.00(m,2H),1.75(d,J=40.5Hz,2H),1.55(s,1H),1.42(dd,J=12.3,8.5Hz,27H),1.30–1.24(m,2H),0.92(dd,J=19.3,6.6Hz,6H).
CQ13的合成
将化合物13-2 300mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得140mg白色固体,收率56%。熔点:217.5–218.1℃。MS(ESI+):m/z实测值:867.3698,计算值:867.3683[M+H]+。1H NMR(500MHz,DMSO-d6)δ14.43(s,1H),12.60(s,1H),11.06(s,2H),8.27(dd,J=7.8,1.4Hz,1H),8.07(d,J=8.6Hz,1H),7.97(dd,J=8.2,2.6Hz,1H),7.90(q,J=6.8Hz,1H),7.84(t,J=7.5Hz,1H),7.78(dd,J=14.3,8.6Hz,1H),7.44(ddt,J=7.9,5.1,2.4Hz,1H),7.38(dd,J=6.4,2.3Hz,1H),7.23(t,J=8.9Hz,1H),6.32(dd,J=16.8,8.3Hz,2H),4.46(d,J=9.6Hz,1H),4.33(s,2H),4.07–4.00(m,2H),3.68(d,J=8.3Hz,4H),3.58(s,2H),3.48(s,4H),3.19–3.15(m,2H),3.02–3.00(m,2H),2.96(dd,J=14.5,7.3Hz,2H),2.34(ddd,J=33.2,17.3,7.7Hz,4H),2.25(dt,J=15.3,7.5Hz,4H),2.04–1.84(m,2H),1.84–1.71(m,2H),1.65–1.48(m,2H),1.35(s,2H),1.27(t,J=7.6Hz,2H),0.89–0.85(m,1H),0.85–0.80(m,6H).13C NMR(126MHz,DMSO-d6)δ175.10,174.68,174.41,171.87,171.51,159.86,157.71,145.32,136.29,133.99,132.43(d,J=21.3Hz),132.04,129.56,128.37,126.55,125.93,65.38,53.70,52.82,52.41,42.60,41.15,38.83,36.92,32.28,30.41,29.28,28.56,23.10,19.87,18.53,15.63.
实施例14
参考实施例12将N-Boc-L-缬氨酸替换为N-Boc-L-Ala。
14-1的合成
将378mg N-Boc-L-Ala加入100mL三口瓶中,加入20mL DCM溶解,加入988mg HBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mLDCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体460mg,收率53%。MS(ESI+):m/z实测值:438.1921,计算值:438.1936[M+H]+。1H NMR(500MHz,Chloroform-d)δ11.34(s,1H),8.50–8.45(m,1H),7.77(dt,J=5.9,2.3Hz,2H),7.72(t,J=6.3Hz,1H),7.34(t,J=6.5Hz,2H),7.04(t,J=8.6Hz,1H),4.30(s,2H),3.94–3.66(m,4H),3.63(s,1H),3.58–3.27(m,4H),1.85(s,2H),1.31–1.22(m,3H).
14-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入437mg 14-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到400mg白色泡沫状固体,收率40%。MS(ESI+):m/z实测值:1007.5233,计算值:1007.5248[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.64(s,1H),8.39(d,J=7.6Hz,1H),7.74(dd,J=17.9,8.9Hz,1H),7.70–7.61(m,2H),7.28(h,J=7.6,6.0Hz,3H),6.96(t,J=8.8Hz,1H),6.87(s,1H),6.17(t,J=10.3Hz,1H),6.10–5.99(m,1H),4.92(dt,J=29.2,7.2Hz,1H),4.32–4.29(m,2H),4.21(s,2H),3.86(s,2H),3.71–3.54(m,2H),3.50–3.31(m,2H),3.27(d,J=37.0Hz,2H),3.11(d,J=68.2Hz,2H),2.58(t,J=12.2Hz,2H),2.47–2.38(m,4H),2.24(dt,J=9.5,6.8Hz,4H),1.99–1.73(m,2H),1.38(d,J=1.9Hz,9H),1.35–1.30(m,18H),1.25(d,J=6.9Hz,3H),1.20(d,J=11.7Hz,2H).
CQ14的合成
将化合物14-2 300mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得133mg白色固体,收率56%。熔点:224.6–224.8℃。MS(ESI+):m/z实测值:839.3385,计算值:839.3370[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.60(s,1H),8.27(dd,J=7.8,1.4Hz,1H),8.16(d,J=7.7Hz,1H),7.97(d,J=8.2Hz,1H),7.90(t,J=7.6Hz,1H),7.87–7.81(m,1H),7.77(dt,J=19.5,5.6Hz,1H),7.44(ddd,J=8.1,5.0,2.3Hz,1H),7.38(dd,J=6.4,2.3Hz,1H),7.24(t,J=9.0Hz,1H),6.31(dd,J=21.4,8.2Hz,2H),4.71(d,J=23.1Hz,1H),4.34(s,2H),4.10(td,J=8.0,5.0Hz,1H),4.06–4.02(m,1H),3.82–3.49(m,4H),3.45(s,2H),3.18(d,J=16.9Hz,2H),2.97(dq,J=31.2,6.5Hz,2H),2.30(dt,J=18.9,6.4Hz,4H),2.26–2.17(m,2H),1.96–1.66(m,2H),1.57(dq,J=57.6,7.2Hz,2H),1.36(p,J=7.6Hz,2H),1.26(q,J=8.4,7.7Hz,2H),1.14(d,J=6.1Hz,3H).13C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.49,171.26,171.10,164.52,159.87,157.77,145.32,135.30,133.98,132.05(d,J=25Hz),129.46,128.36,126.55,125.92,116.48,52.74,52.12,44.64,38.78,36.91,32.24,31.00,30.36,29.27,27.98,23.06,18.16.
实施例15
参考实施例12将Boc-L-缬氨酸替换为N,N-Me-Boc-L-甘氨酸。
15-1的合成
将378mg N,N-Me-Boc-L-甘氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mg HBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mLDCM萃取三次。浓缩至干得到白色泡沫状固体448mg,收率51%。MS(ESI+):m/z实测值:438.1921,计算值:438.1936[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.95(s,1H),8.49–8.43(m,1H),7.81–7.69(m,3H),7.33(d,J=6.8Hz,2H),7.05(t,J=9.0Hz,1H),4.29(s,2H),3.66(d,J=71.0Hz,4H),3.59(s,1H),3.53(s,2H),3.52–3.18(m,4H),2.62(d,J=16.8Hz,2H),2.50(s,3H).
15-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入437mg 15-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到390mg白色泡沫状固体,收率39%。MS(ESI+):m/z实测值:1007.5233,计算值:1007.5248[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.41(s,1H),8.46(d,J=7.6Hz,1H),7.79–7.71(m,3H),7.36(d,J=6.1Hz,1H),7.29(s,1H),7.01(d,J=13.1Hz,1H),6.79(s,1H),6.00–5.78(m,2H),4.36(d,J=37.4Hz,2H),4.27(s,2H),3.73(s,2H),3.59–3.37(m,4H),3.38–3.18(m,4H),3.14(d,J=4.3Hz,3H),3.01(d,J=31.4Hz,2H),2.89(s,2H),2.67–2.56(m,2H),2.39–2.29(m,2H),2.27(s,2H),2.11–1.87(m,2H),1.75(s,2H),1.59(s,9H),1.45(d,J=15.9Hz,18H),1.26–1.24(m,2H).
CQ15的合成
将化合物15-2 300mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得133mg白色固体,收率56%。熔点:249.9–250.9℃。MS(ESI+):m/z实测值:839.3385,计算值:839.3370[M+H]+。1H NMR(500MHz,DMSO-d6)δ14.03(s,1H),12.60(d,J=3.0Hz,1H),12.41(s,2H),8.27(d,J=7.8Hz,1H),7.97(d,J=8.1Hz,1H),7.90(q,J=7.7,6.6Hz,1H),7.84(t,J=7.6Hz,1H),7.79(t,J=5.6Hz,1H),7.52–7.41(m,1H),7.41–7.35(m,1H),7.25(dt,J=11.9,7.1Hz,1H),6.31(dd,J=18.0,8.2Hz,2H),4.34(s,2H),4.24–4.10(m,2H),4.06(ddd,J=21.4,8.5,4.9Hz,2H),3.76–3.57(m,4H),3.51(s,3H),3.38–3.31(m,2H),3.24–3.14(m,2H),3.06–2.98(m,2H),2.96(s,2H),2.66–2.52(m,2H),2.29–2.24(m,2H),1.97–1.68(m,2H),1.68–1.44(m,2H),1.44–1.32(m,2H),1.28(q,J=7.6Hz,2H).13C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,172.89,172.32,171.73,171.62,159.87,157.77,145.32,133.99,132.06(d,J=26.3Hz),120.56,129.43,128.37,126.56,125.93,65.38,52.73,52.12,38.84,36.91,36.45,35.13,32.24,30.36,29.28,27.98,23.08,15.63
实施例16
参考实施例12将N-Boc-L-缬氨酸替换为Boc-1-氨基环丙基甲酸。
16-1的合成
将402mg Boc-1-氨基环丙基甲酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mg HBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mLDCM萃取三次。浓缩至干得到白色泡沫状固体475mg,收率53%。MS(ESI+):m/z实测值:450.1921,计算值:450.1931[M+H]+。1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),8.51–8.44(m,1H),7.82–7.74(m,2H),7.74–7.70(m,1H),7.34(tt,J=8.4,2.4Hz,2H),7.05(t,J=8.7Hz,1H),4.30(s,2H),4.05–3.70(m,4H),3.69–3.28(m,4H),1.08–1.02(m,2H),0.84–0.78(m,2H).
16-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入450mg 16-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到230mg白色泡沫状固体,收率23%。MS(ESI+):m/z实测值:1019.5232,计算值:1019.5248[M+H]+。1H NMR(500MHz,Chloroform-d)δ11.29(s,1H),8.47(dd,J=8.1,1.6Hz,1H),7.98(s,1H),7.85–7.70(m,3H),7.34(dd,J=7.6,5.2Hz,2H),7.04(t,J=8.9Hz,1H),6.78(s,1H),6.06(d,J=39.7Hz,2H),4.40–4.30(m,2H),4.29(d,J=4.6Hz,2H),3.73(d,J=24.1Hz,4H),3.27(d,J=24.5Hz,2H),3.24–2.97(m,2H),2.57(d,J=15.6Hz,2H),2.46(d,J=12.4Hz,2H),2.33(ddd,J=8.9,6.7,1.9Hz,2H),2.16–1.88(m,2H),1.86–1.72(m,2H),1.61–1.48(m,2H),1.45(s,9H),1.43(d,J=2.7Hz,18H),1.39–1.32(m,2H),1.28(d,J=21.0Hz,4H),1.04(d,J=19.5Hz,2H)
CQ16的合成
将化合物16-2 200mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得95mg白色固体,收率57%。熔点:247.7–248.6℃。MS(ESI+):m/z实测值:851.3389,计算值:851.3370[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.59(s,1H),12.42(s,3H),8.44(s,1H),8.27(dt,J=7.8,2.0Hz,1H),7.96(t,J=8.5Hz,1H),7.90(td,J=7.6,1.6Hz,1H),7.84(t,J=7.5Hz,1H),7.79(q,J=5.4Hz,1H),7.43(dt,J=5.1,2.6Hz,1H),7.38(td,J=6.3,2.3Hz,1H),7.25(dt,J=15.3,9.0Hz,1H),6.33(d,J=8.2Hz,1H),6.28(dd,J=8.2,4.1Hz,1H),4.34(d,J=3.8Hz,2H),4.12–4.01(m,2H),3.58(t,J=10.0Hz,4H),3.42(t,J=10.0Hz,4H),3.14(d,J=5.4Hz,2H),2.97(q,J=6.4Hz,2H),2.31–2.19(m,6H),1.92–1.66(m,2H),1.66–1.57(m,2H),1.41–1.33(m,2H),1.26(q,J=7.3Hz,2H),1.14(q,J=4.6Hz,2H).13C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,172.51,171.40,169.53,164.51,159.87,157.76,145.33,133.97,132.06(d,J=26.5Hz),129.56,129.42,128.36,126.56,125.92,124.12,52.73,52.12,41.82,38.83,36.91,34.95,32.24,30.90,30.36,29.29,27.98,23.10,13.54.
实施例17
参考实施例12将N-Boc-L-缬氨酸替换为Boc-甘氨酸。
17-1的合成
将350mg Boc-甘氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mg HBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mLDCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体458mg,收率54%。MS(ESI+):m/z实测值:424.1766,计算值:424.1779[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.69(s,1H),8.50–8.43(m,1H),7.77(dd,J=6.5,2.8Hz,2H),7.72(s,1H),7.34(s,2H),7.06(d,J=8.9Hz,1H),4.29(s,2H),3.77(s,2H),3.67–3.46(m,4H),3.46–3.25(m,4H),2.81(s,2H)
17-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入423mg 17-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到215mg白色泡沫状固体,收率22%。MS(ESI+):m/z实测值:993.5083,计算值:993.5092[M+H]+。1H NMR(500MHz,Chloroform-d)δ8.49–8.45(m,1H),7.82–7.76(m,2H),7.72(dt,J=8.6,3.7Hz,1H),7.36–7.31(m,2H),7.14–6.98(m,2H),6.71(d,J=49.9Hz,1H),6.15(d,J=8.8Hz,2H),4.35(dt,J=18.7,9.9Hz,2H),4.29(d,J=4.0Hz,2H),4.17–4.07(m,1H),3.82(s,2H),3.70–3.18(m,8H),3.08–2.77(m,2H),2.77–2.56(m,2H),2.54–2.38(m,2H),2.31(dtt,J=10.0,7.7,4.3Hz,2H),1.80–1.62(m,2H),1.61–1.53(m,2H),1.51–1.36(m,27H),1.26(s,2H).
CQ17的合成
将化合物17-2 195mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得99mg白色固体,收率55%。熔点:>250℃。MS(ESI+):m/z实测值:825.3201,计算值:825.3214[M+H]+。1H NMR(500MHz,DMSO-d6)δ13.04(s,1H),12.59(s,1H),12.43(s,2H),8.27(d,J=7.7Hz,1H),7.99–7.94(m,2H),7.90(q,J=7.2,6.8Hz,1H),7.84(t,J=7.5Hz,1H),7.79(q,J=5.2Hz,1H),7.44(ddd,J=8.1,5.1,2.3Hz,1H),7.38(t,J=6.3Hz,1H),7.24(t,J=9.0Hz,1H),6.31(dd,J=18.6,8.3Hz,2H),4.33(s,2H),4.07(dtd,J=26.8,8.2,5.1Hz,2H),3.94(dd,J=29.3,5.4Hz,2H),3.62(d,J=24.0Hz,4H),3.50(t,J=5.0Hz,4H),3.19(d,J=24.4Hz,2H),3.04–2.94(m,2H),2.38(t,J=7.4Hz,2H),2.29(t,J=8.0Hz,2H),1.97–1.69(m,2H),1.69–1.45(m,2H),1.37(q,J=15.2,11.7Hz,2H),1.27(p,J=7.6Hz,2H).13C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,172.11,171.51,167.79,159.87,157.76,154.52,145.32,135.90,135.26,133.98,132.05(d,J=25Hz),129.68,129.56,128.37,126.55,125.93,65.38,52.73,52.12,40.93,38.82,36.90,32.24,31.26,31.16,30.36,29.28,27.97,23.06,15.63.
实施例18
参考实施例12将N-Boc-L-缬氨酸替换为Boc-L-丝氨酸。
18-1的合成
将410mg Boc-L-丝氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体493mg,收率54%。MS(ESI+):m/z实测值:454.1898,计算值:454.1885[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.94(s,1H),8.47(dd,J=7.1,2.2Hz,1H),7.84–7.75(m,2H),7.73(d,J=8.1Hz,1H),7.34(dd,J=8.1,5.0Hz,2H),7.06(t,J=8.7Hz,1H),4.30(s,2H),4.00–3.84(m,1H),3.87–3.67(m,4H),3.65(d,J=4.9Hz,1H),3.64–3.44(m,4H),3.33(s,2H),2.15–1.93(m,2H).
18-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入453mg 18-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到229mg白色泡沫状固体,收率22%。MS(ESI+):m/z实测值:1023.5182,计算值:1023.5197[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.86(d,J=74.8Hz,1H),8.47(dd,J=7.5,1.8Hz,1H),7.76(dq,J=19.9,8.4Hz,3H),7.34(s,3H),7.03(d,J=8.6Hz,1H),6.76(d,J=6.4Hz,1H),6.22(t,J=7.3Hz,1H),6.11(d,J=8.3Hz,1H),5.25–5.05(m,1H),4.33(d,J=7.7Hz,2H),4.29(s,2H),4.12(s,1H),3.74(s,8H),3.38(s,2H),3.31(s,1H),3.00(s,1H),2.80–2.64(m,2H),2.52–2.38(m,2H),2.31(h,J=8.3,7.8Hz,2H),2.05(t,J=7.0Hz,2H),1.92–1.74(m,2H),1.47–1.37(m,27H),1.29–1.22(m,2H).
CQ18的合成
将化合物18-2 200mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得105mg白色固体,收率62%。熔点:239.9–240.5℃。MS(ESI+):m/z实测值:855.3331,计算值:855.3319[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.60(s,1H),12.10(s,1H),8.27(dd,J=8.0,1.4Hz,1H),8.06(d,J=8.1Hz,1H),7.97(d,J=8.1Hz,1H),7.90(t,J=7.6Hz,1H),7.87–7.81(m,1H),7.80(s,1H),7.44(ddd,J=8.2,5.1,2.3Hz,1H),7.39(dd,J=6.7,2.4Hz,1H),7.24(t,J=9.0Hz,1H),6.32(dd,J=20.6,8.1Hz,2H),4.78(dd,J=37.5,7.3Hz,2H),4.34(s,2H),4.08(dd,J=28.7,6.5Hz,3H),3.65–3.54(m,4H),3.54–3.39(m,4H),3.19(d,J=18.5Hz,2H),3.05–2.88(m,2H),2.35(q,J=8.0Hz,2H),2.29–2.25(m,2H),1.99–1.68(m,2H),1.58(d,J=60.8Hz,2H),1.36(s,2H),1.31–1.20(m,2H).13C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.70,171.52,169.56,164.53,159.87,157.77,145.33,135.30,133.97,132.05(d,J=25Hz),129.55,129.45,128.36,126.55,125.92,116.48,116.31,65.38,62.13,52.73,52.12,50.80,47.21,42.17,38.81,36.92,32.24,30.97,30.36,29.27,27.97,23.08,15.62.
实施例19
参考实施例12将N-Boc-L-缬氨酸替换为Boc-L-甲硫氨酸。
19-1的合成
将500mg Boc-L-甲硫氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体515mg,收率52%。MS(ESI+):m/z实测值:498.1956,计算值:498.1970[M+H]+。1H NMR(500MHz,Chloroform-d)δ11.34(s,1H),8.50–8.45(m,1H),7.77(dt,J=5.9,2.3Hz,2H),7.72(t,J=6.3Hz,1H),7.34(t,J=6.5Hz,2H),7.04(t,J=8.6Hz,1H),4.30(s,2H),3.94–3.66(m,4H),3.63(s,1H),3.58–3.27(m,4H),1.85(s,2H),1.31–1.22(m,3H).
19-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入498mg 19-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到210mg白色泡沫状固体,收率20%。MS(ESI+):m/z实测值:1067.5298,计算值:1067.5282[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.70(s,1H),8.50–8.44(m,1H),7.85–7.76(m,2H),7.76–7.66(m,1H),7.57–7.39(m,1H),7.34(ddt,J=10.7,4.8,2.8Hz,2H),7.04(q,J=8.8Hz,1H),6.81(d,J=23.7Hz,1H),6.21(d,J=8.5Hz,1H),6.12–5.96(m,1H),5.12(dq,J=36.6,8.0,7.5Hz,1H),4.38(d,J=31.0Hz,2H),4.29(s,2H),4.07–3.68(m,4H),3.67–3.44(m,2H),3.40–3.24(m,4H),2.61(dd,J=19.5,7.2Hz,2H),2.54–2.43(m,4H),2.31(qd,J=10.6,9.3,5.5Hz,2H),2.08(d,J=16.3Hz,4H),1.95(dd,J=14.6,7.8Hz,2H),1.90(s,3H),1.85–1.71(m,2H),1.47(s,9H),1.41(dd,J=11.1,4.2Hz,18H),1.31–1.24(m,2H).
CQ19的合成
将化合物19-2 190mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得100mg白色固体,收率62%。熔点:246.0–246.8℃。MS(ESI+):m/z实测值:899.3421,计算值:899.3404[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.59(s,1H),12.57–11.93(m,3H),8.27(d,J=7.8Hz,1H),8.21(d,J=8.3Hz,1H),7.96(dd,J=8.2,4.4Hz,1H),7.90(t,J=7.6Hz,1H),7.84(t,J=7.5Hz,1H),7.77(dt,J=20.4,5.5Hz,1H),7.44(ddd,J=8.1,5.1,2.3Hz,1H),7.38(t,J=5.0Hz,1H),7.24(t,J=9.0Hz,1H),6.31(dd,J=19.9,8.2Hz,2H),4.88–4.72(m,1H),4.34(s,2H),4.07(dtd,J=28.4,8.1,5.1Hz,2H),3.78–3.48(m,4H),3.44(dd,J=28.2,8.2Hz,4H),3.20(s,2H),2.97(dq,J=31.0,7.0,6.4Hz,2H),2.46–2.39(m,2H),2.34(p,J=6.3,5.3Hz,2H),2.31–2.21(m,4H),2.03(d,J=13.9Hz,3H),1.97–1.82(m,2H),1.72(ddd,J=14.2,8.9,5.9Hz,2H),1.66–1.46(m,2H),1.36(dt,J=16.6,7.0Hz,2H),1.26(q,J=8.5,7.5Hz,2H).13C NMR(126MHz,DMSO-d6)δ175.02,174.65,174.20,171.74,171.44,165.00,159.86,157.76,145.32,135.31,133.97,132.05(d,J=26.3Hz),130.34,130.21,129.55,128.37,126.56,125.92,116.50,116.33,52.74,52.13,47.86,41.66,38.79,36.94,32.26,31.95,30.38,30.00,29.29,28.01,23.09,15.11
实施例20
参考实施例12将N-Boc-L-缬氨酸替换为Boc-L-亮氨酸。
20-1的合成
将460mg Boc-L-亮氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体515mg,收率52%。MS(ESI+):m/z实测值:480.2421,计算值:480.2405[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.65(s,1H),8.43–8.38(m,1H),7.70(dd,J=6.4,2.9Hz,2H),7.64(s,1H),7.32–7.23(m,2H),7.20(s,1H),6.98(t,J=8.8Hz,1H),4.22(s,2H),3.53(d,J=54.1Hz,4H),3.26(d,J=23.8Hz,4H),1.52(s,2H),1.31(d,J=11.2Hz,1H),1.23(d,J=11.6Hz,1H),0.87(dt,J=25.3,7.9Hz,6H).
20-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入479mg 20-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到210mg白色泡沫状固体,收率20%。MS(ESI+):m/z实测值:1049.5728,计算值:1049.5718[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.32(s,1H),8.49(d,J=7.2Hz,1H),7.85–7.78(m,2H),7.77–7.68(m,1H),7.44(s,1H),7.36(d,J=19.1Hz,2H),7.06(t,J=8.6Hz,1H),6.86(s,1H),6.38–6.09(m,2H),4.95(d,J=38.6Hz,1H),4.45(d,J=51.0Hz,2H),4.30(s,2H),4.08(t,J=6.7Hz,2H),3.92(dd,J=32.8,13.7Hz,2H),3.47(d,J=36.5Hz,4H),3.32(d,J=40.4Hz,4H),2.72–2.42(m,4H),2.38–2.29(m,2H),1.87–1.76(m,2H),1.62(d,J=7.7Hz,2H),1.49–1.38(m,27H),1.30(d,J=3.6Hz,2H),1.25–1.16(m,2H),1.16–1.11(m,1H),0.98–0.91(m,6H).
CQ20的合成
将化合物20-2 190mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得95mg白色固体,收率59%。熔点:235.5–235.9℃。MS(ESI+):m/z实测值:881.3852,计算值:881.3840[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.59(s,1H),12.42(s,3H),8.27(d,J=7.8Hz,1H),8.13(t,J=7.4Hz,1H),7.97(d,J=8.1Hz,1H),7.90(t,J=7.6Hz,1H),7.83(t,J=7.5Hz,1H),7.77(dt,J=19.3,5.7Hz,1H),7.44(ddd,J=8.1,5.1,2.2Hz,1H),7.38(d,J=6.3Hz,1H),7.24(t,J=9.0Hz,1H),6.31(dd,J=19.7,8.2Hz,2H),4.71(d,J=33.9Hz,1H),4.33(s,2H),4.07(dtd,J=28.4,8.1,5.0Hz,2H),3.87–3.53(m,4H),3.52–3.26(m,4H),3.23–3.11(m,2H),3.03–2.89(m,2H),2.33(dt,J=14.0,8.2Hz,2H),2.27(t,J=9.4Hz,2H),2.24–2.19(m,1H),1.97–1.68(m,2H),1.68–1.52(m,2H),1.51–1.39(m,2H),1.35(dd,J=13.1,7.2Hz,2H),1.26(q,J=7.9Hz,2H),0.85(dt,J=16.7,6.3Hz,6H).13C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.56,171.45,170.94,159.86,157.75,145.31,135.30,133.96,132.68,132.45,132.04(d,J=28.8Hz),129.56,128.37,126.55,125.94,116.49,116.32,52.73,52.11,46.93,41.08,38.83,36.93,32.26,31.01,30.36,29.28,27.99,24.61,23.52,23.08,22.25,22.14.
实施例21
参考实施例12将N-Boc-L-缬氨酸替换为Boc-L-异亮氨酸。
21-1的合成
将460mg Boc-L-异亮氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体501mg,收率51%。MS(ESI+):m/z实测值:480.2417,计算值:480.2405[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.34(s,1H),8.49–8.44(m,1H),7.77(dd,J=6.7,2.6Hz,2H),7.72(s,1H),7.33(d,J=6.4Hz,2H),7.05(d,J=6.8Hz,1H),4.28(s,2H),3.80(s,2H),3.62(d,J=34.8Hz,4H),3.53(s,2H),3.31(s,2H),1.53(s,2H),1.14(s,1H),1.03–0.92(m,3H),0.92(d,J=1.6Hz,1H),0.90(dd,J=7.8,3.3Hz,3H).
21-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入479mg 21-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到206mg白色泡沫状固体,收率20%。MS(ESI+):m/z实测值:1049.5732,计算值:1049.5718[M+H]+。1H NMR(500MHz,Chloroform-d)δ8.43–8.36(m,1H),7.84–7.55(m,3H),7.28(dd,J=6.3,2.3Hz,2H),7.03–6.89(m,1H),6.75(s,1H),6.37–6.01(m,2H),4.44–4.30(m,2H),4.22(s,2H),3.98(s,2H),3.64(s,1H),3.55(d,J=45.2Hz,2H),3.34(d,J=11.5Hz,2H),3.24(s,2H),2.96(s,2H),2.62–2.31(m,4H),2.29–2.19(m,2H),2.02–1.95(m,1H),1.74–1.68(m,2H),1.41–1.29(m,27H),1.19(s,6H),0.86–0.75(m,6H).
CQ21的合成
将化合物21-2 190mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得97mg白色固体,收率59%。熔点:238.8–239.6℃。MS(ESI+):m/z实测值:881.3829,计算值:881.3840[M+H]+。1H NMR(500MHz,DMSO-d6)δ14.82(s,1H),12.60(s,1H),12.42(s,2H),8.27(d,J=7.8Hz,1H),8.09(d,J=8.7Hz,1H),7.97(dd,J=8.3,4.5Hz,1H),7.84(tt,J=32.2,11.3Hz,3H),7.44(t,J=6.6Hz,1H),7.39(d,J=6.4Hz,1H),7.24(t,J=9.0Hz,1H),6.32(dd,J=19.3,8.2Hz,2H),4.54(dt,J=39.8,8.6Hz,1H),4.34(s,2H),4.17–3.99(m,2H),3.77–3.54(m,4H),3.52–3.46(m,2H),3.17(dt,J=11.7,6.4Hz,2H),2.98(dq,J=14.1,6.8Hz,2H),2.44–2.31(m,2H),2.25(dtd,J=22.5,16.3,14.0,5.9Hz,4H),1.98–1.73(m,2H),1.73–1.58(m,2H),1.56–1.41(m,2H),1.36(qd,J=12.6,7.6,6.8Hz,2H),1.27(p,J=7.7Hz,2H),1.11–1.00(m,1H),0.87–0.75(m,6H).13CNMR(126MHz,DMSO-d6)δ175.02,174.66,174.20,171.81,171.50,170.55,159.87,157.77,145.32,135.28,133.97,132.19,132.04(d,J=25Hz),129.56,128.36,126.55,125.92,116.46,116.31,52.74,52.58,52.13,47.30,42.08,38.82,36.92,36.54,32.25,31.28,30.97,30.38,29.27,28.01,24.46,23.08,16.00,11.46,11.42.
实施例22
参考实施例12将N-Boc-L-缬氨酸替换为Boc-L-苯丙氨酸。
22-1的合成
将530mg Boc-L-苯丙氨酸加入100mL三口瓶中,加入5mL DMA溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。倒入饱和氯化铵中,加入30mL DCM萃取,保留DCM,无水硫酸钠干燥,柱层析得到白色固体1042mg,收率85%。MS(ESI+):m/z实测值:614.2791,计算值:614.2773[M+H]+。1H NMR(500MHz,Chloroform-d)δ9.89(d,J=13.5Hz,1H),8.46(s,1H),7.77(s,2H),7.70(d,J=7.2Hz,1H),7.28(s,5H),7.19(dd,J=14.5,7.2Hz,3H),7.02(d,J=8.4Hz,1H),5.36(d,J=8.8Hz,1H),4.26(s,2H),3.51–3.24(m,4H),3.18–3.02(m,4H),2.99–2.90(m,2H),1.44–1.41(m,9H).
22-2的合成
将990mg 22-1加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次,无水硫酸钠干燥,浓缩至干,加入10mL DCM,加入160mg丁二酸酐,加入419mg DIPEA,室温搅拌过夜反应。浓缩柱层析得到白色固体640mg,收率64%。MS(ESI+):m/z实测值:614.2421,计算值:614.2409[M+H]+。1H NMR(500MHz,Chloroform-d)δ12.34(s,1H),11.36(s,1H),8.46(d,J=8.0Hz,1H),8.23(d,J=8.4Hz,1H),7.90(s,1H),7.85(s,2H),7.34–7.28(m,2H),7.26–7.16(m,5H),7.09–7.01(m,1H),5.21(d,J=68.0Hz,1H),4.27(d,J=23.0Hz,2H),3.57(d,J=43.6Hz,4H),3.44–3.13(m,4H),3.13–3.07(m,2H),2.73–2.52(m,4H).
22-3的合成
将614mg 22-2加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入488mg PSMA-B。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到310mg白色泡沫状固体,收率29%。MS(ESI+):m/z实测值:1083.5545,计算值:1083.5561[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.16(s,1H),8.50–8.44(m,1H),7.78(dt,J=10.6,4.4Hz,2H),7.71(dd,J=16.1,8.4Hz,1H),7.49(d,J=19.5Hz,1H),7.34–7.27(m,4H),7.24(d,J=8.5Hz,2H),7.22–7.19(m,1H),7.01(t,J=8.7Hz,1H),6.83(s,1H),6.35(d,J=9.1Hz,1H),6.13–6.00(m,1H),5.17–5.05(m,1H),4.43(d,J=38.1Hz,2H),4.27(s,2H),3.61(t,J=58.0Hz,4H),3.28(d,J=42.2Hz,2H),3.20–3.04(m,4H),2.70–2.46(m,4H),2.34(ddd,J=14.7,10.1,5.5Hz,2H),1.84(dt,J=10.6,5.6Hz,2H),1.63(s,6H),1.48(s,9H),1.43–1.38(m,18H),1.27(d,J=14.4Hz,2H).
CQ22的合成
将化合物22-2 250mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得130mg白色固体,收率62%。熔点:231.7–232.7℃。MS(ESI+):m/z实测值:915.3699,计算值:915.3683[M+H]+。1H NMR(500MHz,DMSO-d6)δ13.91(s,1H),12.60(s,1H),11.08(s,2H),8.33(d,J=8.1Hz,1H),8.27(dd,J=7.8,1.4Hz,1H),8.01–7.93(m,1H),7.89(td,J=7.7,1.5Hz,1H),7.83(td,J=7.3,2.7Hz,1H),7.76(dt,J=18.6,5.6Hz,1H),7.43(ddd,J=8.1,5.1,2.3Hz,1H),7.34(dt,J=7.1,3.5Hz,1H),7.29–7.20(m,5H),7.20–7.16(m,1H),6.31(dd,J=20.9,8.1Hz,2H),4.88(dq,J=42.2,7.7Hz,1H),4.33(s,2H),4.07(dd,J=29.6,6.7Hz,2H),3.50(s,4H),3.30–3.06(m,2H),3.08–2.85(m,4H),2.91–2.67(m,2H),2.36–2.15(m,6H),2.00–1.67(m,2H),1.57(ddt,J=64.2,13.8,6.5Hz,2H),1.41–1.31(m,2H),1.27(p,J=7.8Hz,2H).13C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.45,170.14,159.86,158.92,158.62,157.76,145.31,138.94,135.29,133.97,132.04(d,J=27.5Hz),129.88,129.56,128.59,128.37,126.89,126.55,125.92,65.38,52.73,52.12,50.08,38.83,36.91,32.25,30.96,30.36,29.27,27.99,23.08,15.63.
实施例23
参考实施例12将N-Boc-L-缬氨酸替换为Boc-D-苯甘氨酸。
23-1的合成
将502mg Boc-D-苯甘氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体558mg,收率56%。MS(ESI+):m/z实测值:500.2081;,计算值:500.2092[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.10(s,1H),8.47–8.42(m,1H),7.77(dd,J=6.1,3.2Hz,2H),7.72–7.67(m,1H),7.38–7.36(m,2H),7.35–7.28(m,5H),7.06–6.98(m,1H),4.80(d,J=23.4Hz,1H),4.25(d,J=11.1Hz,2H),3.71(d,J=1.3Hz,2H),3.35(d,J=50.7Hz,8H).
23-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入499mg 23-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到290mg白色泡沫状固体,收率29%。MS(ESI+):m/z实测值:1069.5419,计算值:1069.5405[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.36(s,1H),8.48–8.43(m,1H),7.76(hept,J=4.8Hz,2H),7.71–7.63(m,1H),7.59–7.43(m,2H),7.37(d,J=7.4Hz,1H),7.34(d,J=6.5Hz,3H),7.30(s,2H),6.98(s,1H),6.76(d,J=47.2Hz,1H),6.36–6.10(m,1H),6.07–5.79(m,2H),4.39(s,2H),4.26(s,2H),3.84–3.17(m,8H),2.60–2.18(m,4H),2.09(s,2H),1.55(d,J=26.9Hz,2H),1.50–1.35(m,27H),1.33(s,2H),1.28(d,J=5.4Hz,2H),1.26(s,2H).
CQ23的合成
将化合物23-2 220mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得130mg白色固体,收率62%。熔点:216.9–217.5℃。MS(ESI+):m/z实测值:901.3541,计算值:901.3527[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.59(s,1H),12.42(s,3H),8.51(d,J=7.6Hz,1H),8.30–8.24(m,1H),7.95(t,J=6.3Hz,1H),7.92–7.81(m,2H),7.77(dt,J=10.6,5.6Hz,1H),7.40(d,J=19.6Hz,2H),7.38–7.27(m,5H),7.21(td,J=9.0,4.9Hz,1H),6.31(dd,J=19.3,8.2Hz,2H),5.86(dd,J=40.5,7.7Hz,1H),4.31(d,J=3.1Hz,2H),4.08(dtd,J=27.3,8.2,5.1Hz,2H),3.58(d,J=44.7Hz,4H),3.42(s,4H),3.22–3.09(m,2H),2.98(dd,J=11.6,6.0Hz,2H),2.40(q,J=6.9Hz,2H),2.31–2.20(m,4H),1.64(td,J=14.4,13.7,7.6Hz,2H),1.36(h,J=6.4,4.3Hz,2H),1.31–1.21(m,2H).13C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.50,159.86,157.76,145.30,138.04,135.25,133.95,132.04(d,J=18.8Hz),129.55,129.07,128.36,126.54,125.90,123.96,123.81,53.51,52.73,52.12,38.83,36.89,32.25,31.16,30.94,30.37,29.27,27.98,23.08
实施例24
参考实施例12将N-Boc-L-缬氨酸替换为Boc-4-氨基氨酸。
24-1的合成
将406mg Boc-4-氨基丁酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体507mg,收率56%。MS(ESI+):m/z实测值:452.2079;,计算值:452.2092[M+H]+。1H NMR(500MHz,Chloroform-d)δ13.26(s,1H),8.48(d,J=6.8Hz,1H),7.79(d,J=7.9Hz,2H),7.73(s,1H),7.35(t,J=7.1Hz,2H),7.10–7.05(m,1H),4.30(s,2H),3.65–3.17(m,8H),2.81(t,J=6.8Hz,2H),2.51–2.40(m,2H),2.20–1.95(m,2H),1.83(d,J=9.9Hz,2H).
24-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入451mg 24-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到290mg白色泡沫状固体,收率28%。MS(ESI+):m/z实测值:1021.5418,计算值:1021.5405[M+H]+。1H NMR(500MHz,Chloroform-d)δ11.25(s,1H),10.46(s,1H),8.46(t,J=6.3Hz,1H),7.84–7.67(m,3H),7.31(d,J=25.2Hz,2H),7.08–7.01(m,1H),6.80(d,J=20.8Hz,1H),6.10(dd,J=13.8,8.2Hz,1H),5.93(t,J=9.2Hz,1H),4.31(s,1H),4.28(s,2H),3.76(d,J=24.1Hz,2H),3.70(s,1H),3.56(d,J=6.1Hz,2H),2.99(d,J=34.5Hz,8H),2.66(d,J=11.3Hz,1H),2.63–2.54(m,1H),2.43(d,J=8.1Hz,2H),2.32(d,J=7.9Hz,2H),1.84(dq,J=14.2,6.8Hz,4H),1.44(d,J=12.9Hz,27H),1.27(d,J=15.6Hz,6H).
CQ24的合成
将化合物24-2 250mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得130mg白色固体,收率62%。熔点:200.4–200.8℃。MS(ESI+):m/z实测值:853.3508,计算值:853.3527[M+H]+。1H NMR(500MHz,DMSO-d6)δ14.41(s,1H),12.60(s,1H),10.94(s,2H),8.27(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.6Hz,1H),7.85(d,J=7.6Hz,1H),7.82–7.74(m,2H),7.48–7.42(m,1H),7.37(d,J=6.3Hz,1H),7.24(t,J=9.0Hz,1H),6.31(dd,J=22.9,8.1Hz,2H),4.33(s,2H),4.07(d,J=16.7Hz,2H),3.65–3.50(m,4H),3.39–3.34(m,2H),3.21–3.12(m,2H),3.06–2.94(m,4H),2.38–2.29(m,2H),2.28(d,J=6.4Hz,4H),2.26–2.21(m,2H),1.93–1.67(m,2H),1.62(d,J=7.2Hz,2H),1.61–1.44(m,2H),1.40–1.32(m,2H),1.26(dt,J=12.6,6.7Hz,2H).13CNMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.81,171.63,171.05,159.87,157.77,145.33,133.98,132.05(d,J=23.5Hz),129.55,129.41,128.37,126.56,125.92,52.73,52.12,38.56,36.90,32.23,31.33,30.36,30.06,29.26,27.98,25.25,23.06
实施例25
参考实施例12将N-Boc-L-缬氨酸替换为Boc-L-瓜氨酸。
25-1的合成
将550mg Boc-L-瓜氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体548mg,收率52%。MS(ESI+)m/z实测值:524.2416,计算值:524.2431[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.63(s,1H),8.52(s,1H),8.27(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.5Hz,1H),7.84(t,J=7.5Hz,1H),7.44(ddd,J=8.4,5.2,2.4Hz,1H),7.37(d,J=6.2Hz,1H),7.24(t,J=9.0Hz,1H),6.39–5.78(m,2H),5.39(s,2H),4.33(s,2H),3.60(d,J=37.4Hz,8H),3.16(s,1H),2.99–2.90(m,2H),1.49–1.38(m,2H),1.27(m,2H).
25-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入523mg 25-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到299mg白色泡沫状固体,收率27%。MS(ESI+):m/z实测值:1093.5713,计算值:1093.5728[M+H]+。1H NMR(500MHz,Chloroform-d)δ11.69(s,1H),8.47(d,J=7.7Hz,1H),7.86(d,J=4.1Hz,1H),7.83–7.62(m,2H),7.42–7.28(m,3H),7.07(dd,J=13.6,8.7Hz,1H),6.98–6.77(m,1H),6.48–6.18(m,2H),6.12(s,1H),5.94–5.65(m,2H),5.19(s,2H),5.05–4.84(m,2H),4.43–4.34(m,1H),4.28(s,2H),3.72(q,J=7.0Hz,8H),3.49(s,2H),3.32(d,J=28.4Hz,2H),3.02(s,2H),2.83–2.65(m,2H),2.53–2.38(m,2H),2.33(d,J=7.7Hz,2H),1.99(s,2H),1.51–1.39(m,27H),1.28(d,J=9.9Hz,6H).
CQ25的合成
将化合物25-2 250mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得130mg白色固体,收率62%。熔点:>250℃。MS(ESI+):m/z实测值:925.3838,计算值:925.3850[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.60(d,J=3.1Hz,1H),12.42(s,3H),8.27(d,J=7.8Hz,1H),8.14(d,J=8.2Hz,1H),7.97(d,J=8.3Hz,1H),7.90(q,J=7.0Hz,1H),7.84(t,J=7.6Hz,1H),7.78(dt,J=19.1,5.4Hz,1H),7.44(ddd,J=8.1,5.2,2.3Hz,1H),7.38(dd,J=6.5,2.3Hz,1H),7.24(t,J=9.0Hz,1H),6.36–6.27(m,2H),5.92(q,J=5.4Hz,1H),5.39(d,J=8.9Hz,2H),4.75–4.56(m,1H),4.34(s,2H),4.12–4.01(m,2H),3.60(s,2H),3.48(s,2H),3.42(d,J=18.4Hz,2H),3.18(d,J=19.8Hz,2H),2.99(p,J=7.3Hz,2H),2.96–2.89(m,2H),2.37–2.30(m,2H),2.30–2.22(m,4H),1.93–1.69(m,2H),1.63(s,2H),1.53–1.42(m,2H),1.35(q,J=11.6,10.7Hz,4H),1.28–1.21(m,2H).13CNMR(126MHz,DMSO-d6)δ175.02,174.67,174.20,171.63,171.49,164.52,159.88,159.25,157.77,145.33,134.01,132.06(d,J=25Hz),129.56,128.36,126.55,125.92,65.38,52.74,52.12,48.36,36.91,32.25,30.36,29.27,27.98,26.66,23.07,15.63
实施例26
参考实施例12将N-Boc-L-缬氨酸替换为Boc-L-脯氨酸。
26-1的合成
将406mg Boc-L-脯氨酸加入100mL三口瓶中,加入20mL DCM溶解,加入988mgHBTU,加入1mL DIEPA,室温搅拌5min。加入732mg ALPL-B,室温搅拌,2h反应完毕。20mL饱和氯化铵洗涤3次,20mL饱和食盐水洗涤三次,分液,保留DCM相,加入无水硫酸钠干燥,浓缩至干。加入2mL无水乙醇溶解,加入1mL浓盐酸,室温搅拌,约1h反应完毕,体系中加入10mL水。10mL DCM洗涤3次,弃去DCM,保留水相。冰浴,饱和碳酸钠溶液调pH至10-11,20mL DCM萃取三次。浓缩至干得到白色泡沫状固体488mg,收率53%。MS(ESI+):m/z实测值:464.2078;,计算值:464.2092[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.30(s,1H),8.47(d,J=7.3Hz,1H),7.77(dd,J=9.3,5.9Hz,3H),7.33(s,2H),7.05(t,J=8.7Hz,1H),4.28(s,2H),4.00(s,1H),3.75(t,J=7.3Hz,2H),3.68–3.06(m,8H),2.92(m,1H),2.06(s,4H).
26-2的合成
将587mg PSMA-D加入100mL三口瓶中,加入10mL二氯甲烷溶解,加入322mg DIPEA,加入463mg 26-1。室温搅拌反应,LC-MS监测原料消失,停止反应。浓缩至小体积,加入20mL水,20mL二氯甲烷萃取三次。合并二氯甲烷,无水硫酸钠干燥,浓缩柱层析得到265mg白色泡沫状固体,收率27%。MS(ESI+):m/z实测值:1033.5423,计算值:1033.5405[M+H]+。1H NMR(500MHz,Chloroform-d)δ10.55(s,1H),8.49–8.43(m,1H),7.76(ddt,J=13.7,11.7,7.5Hz,3H),7.40–7.35(m,1H),7.29(dd,J=5.8,3.3Hz,1H),7.08–6.95(m,2H),6.50–6.30(m,1H),6.12(d,J=9.3Hz,1H),5.10(s,1H),4.51–4.38(m,1H),4.30(q,J=4.9Hz,1H),4.27(s,2H),3.90(d,J=14.8Hz,2H),3.66(q,J=7.3,6.1Hz,2H),3.57(s,2H),3.46–3.33(m,2H),3.24(d,J=9.9Hz,2H),3.04–2.86(m,2H),2.76–2.49(m,2H),2.40–2.17(m,4H),2.02(s,4H),1.85(s,4H),1.77(s,4H),1.52–1.28(m,27H).
CQ26的合成
将化合物26-2 230mg加入50mL三口瓶中,加入1mL二氯甲烷溶解,加入1mL TFA,室温搅拌2h,LC-MS监测反应结束,停止反应。将反应液滴加至30mL乙醚中,大量白色固体析出。抽滤,30mL乙醚洗涤滤饼三次。干燥得80mg白色固体,收率42%。熔点:238.0–238.3℃。MS(ESI+):m/z实测值:865.3509,计算值:865.3527[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.60(s,1H),8.27(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(q,J=7.0Hz,1H),7.81(dt,J=21.0,6.6Hz,2H),7.48–7.36(m,2H),7.24(t,J=9.0Hz,1H),6.32(dd,J=16.2,8.3Hz,2H),4.34(s,2H),4.12–4.04(m,2H),3.70–3.59(m,2H),3.53(dd,J=17.5,8.8Hz,4H),3.37(dt,J=6.8,3.4Hz,2H),3.26–3.15(m,2H),3.00(p,J=8.7,7.7Hz,2H),2.57(dd,J=16.5,8.2Hz,1H),2.40(ddt,J=30.1,14.4,7.7Hz,2H),2.32–2.25(m,2H),2.25–2.16(m,2H),2.18–1.93(m,2H),1.90(q,J=7.7Hz,2H),1.77–1.69(m,2H),1.57(ddt,J=64.1,15.3,6.7Hz,2H),1.37(dq,J=13.9,6.3Hz,2H),1.27(t,J=7.7Hz,2H).13C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.63,169.95,159.87,158.94,158.64,157.77,145.34,135.30,133.99,132.05(d,J=25Hz),129.56,129.45,128.36,126.55,125.91,116.49,56.37,52.74,52.12,47.09,46.82,38.83,36.91,32.22,30.56,30.35,29.79,29.26,27.98,24.68,23.04.
为了深入全面研究该系列偶联物的靶向治疗效果及安全性,明确其能否作为有效的PSMA阳性前列腺癌靶向治疗策略,本发明将从一下几个方面进行研究
实施例27
首先通过体外细胞实验初步验证偶联物能特异性杀伤PSMA阳性前列腺肿瘤细胞,而对阴性细胞无明显影响,尤其是对正常细胞有足够的安全性。
取对数生长期的LNCaP、C4-2B、22RV1、PC3和RWPE-1细胞系,胰酶消化后,含血清培养基终止消化,吹打至悬转移至离心管,离心去上清,用1640培养基(LNCaP、C4-2B、22RV1、PC3)或Gibco K-SFM培养基含2管生长因子(RWPE-1)重悬细胞,配置细胞悬液浓度为3万个细胞/mL。种植96孔板,每孔100μL。培养24h后,以DMSO为对照,用不同浓度梯度的上述化合物处理细胞,以奥拉帕利为阳性对照,孵育72h后,每孔加入20μL的5mg/mL MTT溶液,培养箱孵育4h,弃去上清,每孔加入150μL DMSO,震荡10min溶解完全,设置调零孔,用酶标仪在570nm处读取吸光度。计算IC50、CC50,独立重复三次实验,结果表示为三次实验平均值±标准差。
表1偶联物对LNCaP、C4-2B、22RV1、PC3和RWPE-1的增值抑制率
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结果如表1所示,PARP抑制剂奥拉帕利单药毒性作用较强,对以上5种细胞的杀伤作用都很明显,对PSMA阳性与阴性细胞的杀伤作用无明显差异。而本发明提供的化合物对细胞的杀伤作用依赖于PSMA的表达,其对PSMA阳性的LNCaP、C4-2B、22RV1细胞系的杀伤作用显著性强于PSMA阴性的PC3和RWPE-1细胞系,对正常前列腺上皮细胞无明显毒性,提高了药物的安全窗。
DUPA作为一种已知的PSMA的高效抑制剂,文献报道其与PSMA结合抑制活性IC50=47nM。我们在实验中设计DUPA与偶联物CQ-04、CQ-16对PSMA阳性细胞共孵育,发现DUPA能够竞争性抑制偶联物对PSMA阳性细胞的抗肿瘤效果,进一步说明了偶联物依赖于PSMA的表达,对PSMA阳性细胞有较好的选择性,如图1。
实施例28
本发明偶联物CQ-04在人前列腺癌细胞22RV1裸鼠移植瘤体内抗肿瘤活性评价。
1.实验动物、试剂和仪器
SPF级BALB/c nude裸小鼠(4周龄),雄性,体重为21±1g,由浙江省实验动物中心供应,动物合格证号(SYXK(浙)2019-0011)。动物饲养于SPF级动物中心动物房,动物饲养笼具、饮水、饲料、垫料均经高压蒸汽灭菌处理,自由饮食饮水,保证动物营养。实验温度恒温约20℃,相对湿度约50%。光照周期昼夜各12小时。实验中所有操作均在无菌环境下进行。适应性饲养一周后开始实验。
2.实验方法
2.1荷22RV1前列腺癌移植瘤模型的建立
选取对数生长期的人前列腺癌22RV1细胞(密度约在80%–90%),胰酶消化后用含血清培养基终止消化吹打至悬,1000rpm离心5min收集细胞,收集后的细胞用PBS溶液离心清洗两次,随后用PBS重悬细胞调整细胞浓度为108个/mL,加入等体积的浓缩型基质胶(Corning 354248)混悬,然后迅速将细胞悬液置于冰盒中带至动物房,无菌条件下,用一次性吸管反复吹打至悬,用1mL注射器将22RV1细胞接种于裸小鼠右前肢皮下,接种量为0.1mL/只(约500万个细胞)。接种三天后发现在接种部位出现小突起、质硬,逐渐增大,每两天测量体重和肿瘤体积,待肿瘤体积达到100~200mm3,且状态较稳定时,模型制作成功。
2.2动物分组给药
将接种成功的模型裸鼠随机分成5组,每组6只,分别为(I)生理盐水组,(II)奥拉帕利组(80mg/kg/day,po),(III)CQ-04组(140mg/kg/day,po),(IV)CQ-04组(140mg/kg/day,iv),(V)CQ-04组(280mg/kg/day,po),共计给药14天。
2.3偶联物CQ-04药效学评价
裸鼠一般情况观察:每天观察药物对裸鼠皮毛、精神状况和饮食饮水等情况的影响,同时每两天用电子天平测量并记录裸鼠体重的变化。
肿瘤变化情况观察:当肿瘤结节形成后,每周2-3次采用游标卡尺测定肿瘤的最长直径(a)及垂直方向最大横径(b),计算肿瘤的体积并绘制肿瘤生长曲线。
肿瘤体积V(mm3)=a×b2/2
抑瘤率计算:治疗结束后脱颈椎处死裸鼠,完整剖出肿瘤并用分析天平称量肿瘤重量。
抑瘤率(IR):IR(%)=(1-给药组平均瘤重/对照组平均瘤重)×100%
治疗结束后实验动物处理
在末次给药结束后(第14天)将裸鼠禁食8h,随后将裸鼠转移至解剖间,在脱颈处死前摘眼球取血,分两部分,一部分加入抗凝剂,一部分不加抗凝剂。取血完成后将裸鼠脱颈椎处死并解剖取下裸鼠肿瘤并采用分析天平对各组肿瘤组织进行称重、记录和拍照。
2.4小鼠血液生化和血常规检查
将所取得未经抗凝处理的血样室温放置1h后,离心,收集血清进行血液生化分析,测定肌酐(CRE)指标,血常规测定淋巴细胞计数、白细胞计数、中性粒细胞计数、血小板计数、血红蛋白计数、平均红细胞体积(MCV)。
3.实验结果
40只BALB/c nude裸鼠在皮下接种22RV1细胞后,在接种部位可见小的皮丘,接种一天后随着PBS吸收,皮丘消失。接种三天后,在接种部位可见绿豆大小质地硬突起,在接种一周后80%裸鼠肿瘤体积达到100~200mm3,且状态较稳定,造模成功,将30只造膜成功的裸鼠随机分组至5组,每组6只,给予不同的药物处理。从造膜开始至实验结束,无一例裸鼠死亡。如图4所示,每组小鼠体重均无明显差异。从图5可以看出,模型组肿瘤体积随着时间进展显著增大,虽然治疗组和阳性对照组肿瘤体积也随着时间变大,但肿瘤生长被显著抑制,在给药14天后的治疗终点CQ-04的3个给药组和阳性对照组肿瘤体积和瘤重要显著性小于模型组,差异具有显著性差异(p<0.05)。阳性组Olaparib(80mg/kg,po),等摩尔剂量口服组CQ-04(140mg/kg,po),等摩尔剂量静注组CQ-04(140mg/kg,iv),高剂量口服组CQ-04(280mg/kg,po)肿瘤重量分别为0.618±0.081g、0.508±0.105g、0.402±0.110g、0.446±0.109g,均显著性低于模型组1.043±0.108g,且具有显著性差异(p<0.05)。CQ-04等摩尔剂量相同给药方式的抗肿瘤效果已优于奥拉帕利,且淋巴细胞未见明显降低,而奥拉帕利组淋巴细胞降低,具有较好的疗效和安全性(表2)。
表2
组别 | 平均瘤体积(mm3) | 平均瘤重(g) | 抑瘤率(%) |
Control(Saline) | 1305.7±364.4 | 1.043±0.108 | 0 |
Olaparib(80mg/kg,po) | 781.4±187.7 | 0.618±0.081 | 40.73 |
CQ-04(140mg/kg,po) | 585.8±194.4 | 0.508±0.105 | 51.29 |
CQ-04(140mg/kg,iv) | 543.8±153.9 | 0.402±0.110 | 61.52 |
CQ-04(280mg/kg,po) | 564.4±146.3 | 0.446±0.109 | 57.28 |
综上所述,对于奥拉帕利和PSMA靶向PARP抑制剂偶联物可看出,本发明的靶向治疗策略确实能够提高肿瘤组织内药物输送杀伤效率,可特异性高效杀伤PSMA阳性前列腺肿瘤细胞,同时能够对PSMA阴性的正常细胞有足够的小的毒性,降低毒副作用,做到了在控制减少药物毒副反应的同时实现对前列腺肿瘤的精准高效打击。
对于本领域技术人员而言,本发明的设备及方法不限于上述示范性实施例的细节,且在不背离本发明的目的或基本特征的情况下,能够以其他的具体形式实现本发明的技术方案。因此,无论从哪一点来看,均应将实施例看作是示范性的,而且是非限制性的,本发明的范围有所附权利要求而不是上述说明限定。
Claims (6)
1.一种PSMA靶向的PSMA-PARPi偶联物,其特征在于,所述偶联物通式如下所示,
其中:
Linker包含不同长度的二酸、烷基链、二硫醚、酰胺、氨基甲酸酯、杂环基烷基、烷氧羰基、烷氨基、天然或非天然氨基酸,具体为通式I和通式II,
X=CH2、NH、O,
Y=羰基、CH2,
n=0-10的整数;
R1=H、1-10个碳原子数的烷基、杂烷基、芳香基,其中烷基优选甲基、异丙基、环丙基或异丁基,杂烷基优选羟甲基,芳香基优选苯基,
R2=H、1-5个碳原子数的烷基,其中烷基优选甲基,
*是R构型或S构型。
2.根据权利要求1所述的PSMA靶向的PSMA-PARPi偶联物,其特征在于,选自如下任一化合物:
CQ-01:(((S)-1-羧基-5-(5-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-5-氧代戊酰胺基)戊基)氨基甲酰基)-L-谷氨酸,
CQ-02:(11S,15S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,5,13-三氧代-2-氧杂-6,12,14-三氮杂十七烷-11,5,17-三羧酸,
CQ-03:(14S,18S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,8,16-三氧代-4,5-二硫-9,15,17-三氮杂二十烷-14,18,20-三羧酸,
CQ-04:(((S)-1-羧基-5-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-4-氧代丁酰胺基)戊基)氨基甲酰基)-L-谷氨酸,
CQ-05:(((S)-1-羧基-5-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰胺基)戊基)氨基甲酰基)-L-谷氨酸,
CQ-06:(((S)-1-羧基-5-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-甲酰胺基)戊基)氨基甲酰基)-L-谷氨酸,
CQ-07:(11S,15S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,5,13-三氧基-2,6,12,14-四氮杂十七烷-11,5,17-三羧酸,
CQ-08:(12S,16S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,6,14-三氧代-2,7,13,15-四氮杂十八烷-12,16,18-三羧酸,
CQ-09:(((S)-1-羧基-5-(8-(4-(2-氟-5-(4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-8-氧代辛酰胺基)戊基)氨基甲酰基)-L-谷氨酸,
CQ-10:(((S)-1-羧基-5-(3-(4-(2-氟-5-(4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)丙酰胺基)戊基)氨基甲酰基)-L-谷氨酸,
CQ-11:(3S,7S)-25-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-5,13,18,25-四氧代-4,6,12,17-四氮杂二十五烷-1,3,7-三羧酸,
CQ-12:(3S,7S,18S)-18-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-19-甲基-5,13,16-三氧代-4,6,12,17-四氮杂二十烷-1,3,7-三羧酸,
CQ-13:(3S,7S,18R)-18-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-19-甲基-5,13,16-三氧代-4,6,12,17-四氮杂二十烷-1,3,7-三羧酸,
CQ-14:(2S,13S,17S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-甲基-1,4,7,15-四氧代-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸,
CQ-15:(13S,17S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-3-甲基-1,4,7,15-四氧代-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸,
CQ-16:(((S)-1-羧基-5-(4-(1-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)环丙基)氨基)-4-氧代丁酰胺基)戊基)氨基甲酰基)-L-谷氨酸,
CQ-17:(((S)-1-羧基-5-(4-(2-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-氧乙基)氨基)-4-氧代丁酰胺基)戊基)氨基甲酰基)-L-谷氨酸,
CQ-18:(2S,13S,17S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-(羟甲基)-1,4,7,15-四氧代-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸,
CQ-19:(5S,16S,20S)-5-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲嗪-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-7,10,18-三氧代-2-硫-6,11,17,19-四氮杂二十二烷-16,22-三羧酸,
CQ-20:(3S,7S,18S)-18-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-20-甲基-5,13,16-三氧代-4,6,12,17-四氮杂苯二甲酸-1,3,7-三羧酸,
CQ-21:(3S,7S,18S,19R)-18-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-19-甲基-5,13,16-三氧代-4,6,12,17-四氮杂环己烷-1,3,7-三羧酸,
CQ-22:(2S,13S,17S)-2-苄基-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,4,7,15-四氧代-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸,
CQ-23:(2R,13S,17S)-1-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-1,4,7,15-四氧代-2-苯基-3,8,14,16-四氮杂十一烷-13,17,19-三羧酸,
CQ-24:(3S,7S)-21-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-基)-5,13,6,21-四氧代-4,6,12,17-四氮杂二十烷-1,3,7-三羧酸,
CQ-25:(6S,17S,21S)-1-氨基-6-(4-(2-氟-5-((4-氧代-3,4-二氢邻苯二甲酸-1-基)甲基)苯甲酰基)哌嗪-1-羰基)-1,8,11,19-四氧代-2,7,12,18,20-五氮杂三嗪-17,23-三羧酸,
CQ-26:(((S)-1-羧基-5-(4-(S)-2-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-羰基)吡咯烷-1-基)-4-氧代丁酰胺基)戊基)氨基甲酰基)-L-谷氨酸。
3.根据利要求1所述的PSMA靶向的PSMA-PARPi偶联物,其特征在于,n选为1-5的整数。
4.权利要求1~2任意所述的PSMA靶向的PSMA-PARPi偶联物的制备方法,其特征在于,通过以下步骤实现:
步骤1:以化合物a和化合物b为原料,经缩合反应获得化合物c,
步骤2:c脱保护后得到化合物I,
步骤3:以化合物d和e为原料,经缩合反应后,脱Boc获得化合物f,
步骤4:化合物b与丁二酸酐反应得到化合物g,
步骤5:以化合物f和化合物g为原料,经缩合反应得到化合物h,
步骤6:h脱保护后得到化合物II,
X=CH2、NH、O;
Y=羰基、CH2;
n=0-10的整数;
R1=H、1-10个碳原子数的烷基、杂烷基或芳香基,其中烷基优选甲基、异丙基、环丙基或异丁基,杂烷基优选羟甲基,芳香基优选苯基;
R2=H、1-5个碳原子数的烷基,其中烷基优选甲基;
*是R构型或S构型。
5.根据利要求4所述的制备方法,其特征在于,n选为1-5的整数。
6.权利要求1~2任意所述的化合物在制备抗前列腺肿瘤疾病药物中的应用。
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