CN114380795A - 氘代fap抑制剂及其应用 - Google Patents
氘代fap抑制剂及其应用 Download PDFInfo
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- CN114380795A CN114380795A CN202011140650.8A CN202011140650A CN114380795A CN 114380795 A CN114380795 A CN 114380795A CN 202011140650 A CN202011140650 A CN 202011140650A CN 114380795 A CN114380795 A CN 114380795A
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- Prior art keywords
- deuterated
- fap
- compound
- fap inhibitor
- inhibitor
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- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 title claims abstract description 60
- 239000003112 inhibitor Substances 0.000 title claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- -1 hydroxylNitro Chemical class 0.000 claims abstract description 9
- 230000002285 radioactive effect Effects 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 239000011593 sulfur Substances 0.000 claims abstract description 7
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
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- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 125000002560 nitrile group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
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Abstract
本发明涉及FAP抑制剂,具体涉及一种氘代FAP抑制剂及其应用,属于药物化学领域。氘代FAP抑制剂,所述氘代FAP抑制剂为如(I)所示的化合物或其药学上可接受的盐、水合物、溶剂合物、相应的放射性元素标记物:其中,R1和R2分别独立的选自氢、氘、卤素、羟基、硝基、腈基或氟代甲基;R3为氧、硫、氮、氮甲基、亚甲基、氟代甲基、直链或支链或环状C1~C6烷基氨基、直链或支链C1~C6烷氧基、取代芳香基氧基或取代芳香基硫基;R4为放射性组分、金属螯合基团、荧光染料、造影剂中的至少一种。本发明的氘代FAP抑制剂具有治疗或诊断FAP过表达相关疾病的效果。
Description
技术领域
本发明涉及FAP抑制剂,具体涉及一种氘代FAP抑制剂及其应用,属于药物化学领域。
背景技术
肿瘤的生长和扩散不仅取决于癌细胞,还取决于肿瘤组织中的非恶性成分,即肿瘤基质。在有纤维增生反应的肿瘤如乳腺癌、结肠癌和胰腺癌中,基质可能占肿瘤质量的90%以上。基质中,存在大量成纤维细胞,尤其是癌相关成纤维细胞(cancer-associatedfibroblasts,CAFS),已知其参与肿瘤的生长、迁移和进展。因此,CAFS是一个非常有价值的肿瘤诊断和治疗靶点。CAFS的一个显著特征是成纤维细胞激活蛋白α(FAP)的表达,FAP是一种属于二肽酶 4(DPP4)家族的II型膜结合糖蛋白。FAP具有二肽基肽酶和内肽酶的活性。内肽酶的活性使 FAP与DPP4家族的其它成员区分开来,迄今为止,鉴定出的FAP内肽酶活性底物是I型胶原蛋白,α1-抗胰蛋白酶和几种神经肽。FAP在胚胎发育和组织形成的过程中起着重要作用。 FAP在成人正常组织中的表达水平较低,但在伤口愈合,关节炎,动脉粥样硬化斑块,纤维化和90%以上的上皮癌中高表达。
FAP在许多上皮肿瘤中的CAFS中的高表达与癌症患者预后较差相关,即FAP活性与癌症的发展以及癌细胞的迁移和扩散有关。因此,将FAP用于成像和放射治疗可以被认为是检测和治疗恶性肿瘤的有效策略。
发明内容
本发明的第一个目的是为临床提供一种新型的FAP抑制剂。
为达到本发明的第一个目的,本发明所述的氘代FAP抑制剂为如(I)所示的化合物或其药学上可接受的盐、水合物、溶剂合物、相应的放射性元素标记物:
其中,R1和R2分别独立的选自氢、氘、卤素、羟基、硝基、腈基或氟代甲基;
R3为氧、硫、氮、氮甲基、亚甲基、氟代甲基、直链或支链或环状C1~C6烷基氨基、直链或支链C1~C6烷氧基、取代芳香基氧基或取代芳香基硫基;
在一种具体实施方式中,所述R1和R2分别独立的选自氢、氘或卤素。
在一种具体实施方式中,R3为氧、硫、氮、氮甲基或亚甲基。
在一种具体实施方式中,所述R1和R2分别独立的选自氢或氟。
在一种具体实施方式中,所述R3为氧或氮甲基。
在一种具体实施方式中,所述氘代FAP抑制剂为下列化合物中的至少一种:
本发明的第二个目的是提供一种氘代FAP抑制剂药物组合物。
为达到本发明的第二个目的,所述的氘代FAP抑制剂药物组合物包含上述的氘代FAP抑制剂为活性成分。
在一种具体实施方式中,所述氘代FAP抑制剂为所述化合物的药学上可接受的盐,所述盐优选为盐酸盐、硫酸盐、富马酸盐、琥珀酸盐、甲磺酸盐或磺酸盐。
本发明的第三个目的是提供上述的氘代FAP抑制剂或上述的氘代FAP抑制剂药物组合物在制备治疗或诊断FAP过表达相关疾病的药物中的应用。
有益效果:
本发明的氘代FAP抑制剂具有治疗或诊断FAP过表达相关疾病的效果,为FAP过表达相关疾病药物的开发提供新的选择。
本发明的基于氘代FAP抑制剂的小分子还可以结合相应放射性元素用于FAP相关疾病的治疗和诊断。
本发明提供氘代FAP抑制剂药峰浓度大、生物利用度高、消除半衰期长,可以提高临床使用的药效,降低给药量,从而降低毒副作用。
此外,本发明的基于氘代FAP抑制剂还可用于治疗和诊断非恶性疾病,例如慢性炎症,动脉粥样硬化,组织重塑和瘢痕疾病。
具体实施方式
为达到本发明的第一个目的,本发明所述的氘代FAP抑制剂为如(I)所示的化合物或其药学上可接受的盐、水合物、溶剂合物、相应的放射性元素标记物:
其中,R1和R2分别独立的选自氢、氘、卤素、羟基、硝基、腈基或氟代甲基;
R3为氧、硫、氮、氮甲基、亚甲基、氟代甲基、直链或支链或环状C1~C6烷基氨基、直链或支链C1~C6烷氧基、取代芳香基氧基或取代芳香基硫基;
在一种具体实施方式中,所述R1和R2分别独立的选自氢、氘或卤素。
在一种具体实施方式中,R3为氧、硫、氮、氮甲基或亚甲基。
在一种具体实施方式中,所述R1和R2分别独立的选自氢或氟。
在一种具体实施方式中,所述R3为氧或氮甲基。
在一种具体实施方式中,所述氘代FAP抑制剂为下列化合物中的至少一种:
本发明的第二个目的是提供一种氘代FAP抑制剂药物组合物。
为达到本发明的第二个目的,所述的氘代FAP抑制剂药物组合物包含上述的氘代FAP抑制剂为活性成分。
在一种具体实施方式中,所述氘代FAP抑制剂为所述化合物的药学上可接受的盐,所述盐优选为盐酸盐、硫酸盐、富马酸盐、琥珀酸盐、甲磺酸盐或磺酸盐。
本发明的第三个目的是提供上述的氘代FAP抑制剂或上述的氘代FAP抑制剂药物组合物在制备治疗或诊断FAP过表达相关疾病的药物中的应用。
下面结合实施例对本发明的具体实施方式做进一步的描述,并不因此将本发明限制在所述的实施例范围之中。
实施例1
化合物1的制备
化合物12的合成:
取(S)-4,4-二氟吡咯烷-2-氰基盐酸盐168mg(1mmol)溶于10mL N,N-二甲基甲酰胺,加入 Boc-氘代甘氨酸177mg(1mmol)、N,N-二异丙基乙胺260mg(2mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯456mg(1.2mmol),室温反应5小时,TLC检测至反应完全。加入乙酸乙酯,依次用水、饱和水盐水洗涤,取有机层,浓缩。残留物溶于10mL二氯甲烷:三氟乙酸=4:1混合液中,室温反应2小时,TLC检测至反应完全,浓缩反应液,残留物溶于乙酸乙酯中,依次用饱和碳酸氢钠水溶液、饱和水盐水洗涤,取有机层,浓缩后经硅胶柱层析分离纯化得到固体136mg,收率:71.3%。MS(ESI):192.21[M+1]+.
化合物1的合成:
取化合物12(190mg,1mmol)溶于10mL N,N-二甲基甲酰胺,加入喹啉-4-羧酸(173mg, 1mmol)、N,N-二异丙基乙胺260mg(2mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯456mg(1.2mmol),室温反应5小时,TLC检测至反应完全。加入乙酸乙酯,依次用水、饱和水盐水洗涤,取有机层,浓缩经硅胶柱层析分离纯化得到固体183mg,收率:53.2%。 MS(ESI):347.21[M+1]+.
实施例2
化合物2的制备
化合物15的合成:
取1-氯-3-溴丙烷(468mg,3mmol)、6-羟基喹啉-4-羧酸(189mg,1mmol)和碳酸铯(653mg,2mmol)加入10mL N,N-二甲基甲酰胺中,加热至60℃过夜,TLC检测至反应完全。将反应混合物冷却至室温,加入乙酸乙酯,依次用水、饱和水盐水洗涤,取有机层,浓缩经硅胶柱层析分离纯化得到固体157mg,收率:59.2%。MS(ESI):266.05[M+1]+.
化合物17的合成:
取N-Boc哌嗪(373mg,2mmol)、化合物15(663mg,2.5mmol)和碘化钾(34mg,0.2mmol)加入10mL N,N-二甲基甲酰胺中,加热至60℃过夜,TLC检测至反应完全。将反应混合物冷却至室温,加入乙酸乙酯,依次用水、饱和水盐水洗涤,取有机层,浓缩经硅胶柱层析分离纯化得到固体590mg,收率:70.8%。MS(ESI):416.19[M+1]+.
化合物18的合成:
取化合物17(415mg,1mmol)、化合物12(191mg,1mmol)、N,N-二异丙基乙胺260 mg(2mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯456mg(1.2mmol)溶于10mL N,N-二甲基甲酰胺中,室温反应5小时,TLC检测至反应完全。加入乙酸乙酯,依次用水、饱和水盐水洗涤,取有机层,浓缩。残留物溶于10mL二氯甲烷:三氟乙酸=4:1混合液中,室温反应2小时,TLC检测至反应完全,浓缩反应液,残留物溶于乙酸乙酯中,依次用饱和碳酸氢钠水溶液、饱和水盐水洗涤,取有机层,浓缩后经硅胶柱层析分离纯化得到固体275mg,收率:56.3%。MS(ESI):489.28[M+1]+.
化合物2的合成:
取化合物18(489mg,1mmol)、化合物19(790mg,1.5mmol)和N,N-二异丙基乙胺260mg(2mmol)加入10mL N,N-二甲基甲酰胺中,室温反应2小时,TLC检测至反应完全。浓缩,使用制备型HPLC纯化得到固体601mg,收率:68.6%。MS(ESI):875.53[M+1]+.
实施例3
化合物3的制备
化合物3的合成:
化合物3的合成类似于与化合物2的合成。取化合物18(489mg,1mmol)、化合物20(637mg,1.5mmol)和N,N-二异丙基乙胺260mg(2mmol)加入10mL N,N-二甲基甲酰胺中,室温反应2小时,TLC检测至反应完全。浓缩,使用制备型HPLC纯化得到固体601mg,收率:68.6%。MS(ESI):774.42[M+1]+.
实施例4
化合物4的制备
化合物4的合成:
化合物4的合成类似于与化合物2的合成。取化合物18(489mg,1mmol)、化合物21(547mg,1.5mmol)和N,N-二异丙基乙胺260mg(2mmol)加入10mL N,N-二甲基甲酰胺中,室温反应2小时,TLC检测至反应完全。浓缩,使用制备型HPLC纯化得到固体331mg,收率:51.4%。MS(ESI):652.30[M+1]+.
实施例5
化合物5的制备
化合物5的合成:
化合物5的合成类似于与化合物2的合成。取化合物18(489mg,1mmol)、化合物22(1230mg,1.5mmol)和N,N-二异丙基乙胺260mg(2mmol)加入10mL N,N-二甲基甲酰胺中,室温反应2小时,TLC检测至反应完全。浓缩,使用制备型HPLC纯化得到固体445mg,收率:38.5%。MS(ESI):1168.29[M+1]+.
实施例6
化合物6的制备
化合物25的合成:
取化合物23(307mg,1mmol)、化合物24(107mg,1.2mmol)、碳酸铯(650mg,2mmol)、三(二亚苄基丙酮)二钯(50mg,0.05mmol)、1,1'-联萘-2,2'-双二苯膦(34mg,0.05mmol)加入20mL甲苯中,氮气保护下90℃反应过夜,TLC检测至反应完全,浓缩除去溶剂,加入乙酸乙酯,依次用水、饱和水盐水洗涤,取有机层,浓缩后经硅胶柱层析分离纯化得到固体 225mg,收率:70.9%。MS(ESI):317.21[M+1]+.
化合物26的合成:
取化合物25(316mg,1mmol)、三乙胺(304mg,3mmol)溶于10mL二氯甲烷中,0℃滴加甲磺酰氯(150mg,1.3mmol)的二氯甲烷溶液,滴加完毕后室温反应5小时,TLC检测至反应完全,浓缩除去溶剂,加入乙酸乙酯,依次用水、饱和水盐水洗涤,取有机层,浓缩。残留物复溶于20mL二氯甲烷中,加入Boc酸酐(933mg,5mmol)、碘化钾(166mg,1 mmol),60℃反应2小时,TLC检测至反应完全,加入乙酸乙酯,依次用水、饱和水盐水洗涤,取有机层,浓缩后经硅胶柱层析分离纯化得到固体291mg,收率:60.2%。MS(ESI):485.21 [M+1]+.
化合物27的合成:
取化合物26(485mg,1mmol)溶于10mL二氯甲烷:三氟乙酸=4:1的混合溶液中,室温反应2小时,TLC检测至反应完全,浓缩除去溶剂,加入乙酸乙酯,依次用饱和碳酸氢钠溶液、水、饱和水盐水洗涤,取有机层,浓缩。残留物复溶于10mL N,N-二甲基甲酰胺中,加入Boc酸酐(330mg,1.5mmol)、三乙胺(304mg,3mmol),室温反应2小时,TLC检测至反应完全,依次用水、饱和水盐水洗涤,取有机层,浓缩。后经硅胶柱层析分离纯化得到固体271mg,收率:63.2%。MS(ESI):429.36[M+1]+.
化合物28的合成:
取化合物27(428mg,1mmol)、化合物12(191mg,1mmol)、N,N-二异丙基乙胺260 mg(2mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯456mg(1.2mmol)溶于10mL N,N-二甲基甲酰胺中,室温反应5小时,TLC检测至反应完全。加入乙酸乙酯,依次用水、饱和水盐水洗涤,取有机层,浓缩。残留物溶于10mL二氯甲烷:三氟乙酸=4:1混合液中,室温反应2小时,TLC检测至反应完全,浓缩反应液,残留物溶于乙酸乙酯中,依次用饱和碳酸氢钠水溶液、饱和水盐水洗涤,取有机层,浓缩后经硅胶柱层析分离纯化得到固体289mg,收率:57.6%。MS(ESI):502.29[M+1]+.
化合物6的合成:
化合物6的合成类似于与化合物2的合成。取化合物28(502mg,1mmol)、化合物19(790mg,1.5mmol)和N,N-二异丙基乙胺260mg(2mmol)加入10mL N,N-二甲基甲酰胺中,室温反应2小时,TLC检测至反应完全。浓缩,使用制备型HPLC纯化得到固体566mg,收率:63.8%。MS(ESI):888.62[M+1]+.
实施例7
化合物7的制备
化合物7的合成:
化合物7的合成类似于与化合物2的合成。取化合物28(502mg,1mmol)、化合物20(637 mg,1.5mmol)和N,N-二异丙基乙胺260mg(2mmol)加入10mL N,N-二甲基甲酰胺中,室温反应2小时,TLC检测至反应完全。浓缩,使用制备型HPLC纯化得到固体522mg,收率:66.3%。MS(ESI):787.49[M+1]+.
实施例8
化合物8的制备
化合物8的合成:
化合物6的合成类似于与化合物2的合成。取化合物28(502mg,1mmol)、化合物21(547mg,1.5mmol)和N,N-二异丙基乙胺260mg(2mmol)加入10mL N,N-二甲基甲酰胺中,室温反应2小时,TLC检测至反应完全。浓缩,使用制备型HPLC纯化得到固体331mg,收率:51.4%。MS(ESI):665.51[M+1]+.
实施例9
化合物9的制备
化合物9的合成:
化合物9的合成类似于与化合物2的合成。取化合物28(502mg,1mmol)、化合物22(1230mg,1.5mmol)和N,N-二异丙基乙胺260mg(2mmol)加入10mL N,N-二甲基甲酰胺中,室温反应2小时,TLC检测至反应完全。浓缩,使用制备型HPLC纯化得到固体445mg,收率:38.5%。MS(ESI):888.62[M+1]+。
Claims (10)
2.根据权利要求1所述的氘代FAP抑制剂,其特征在于,所述R1和R2分别独立的选自氢、氘或卤素。
3.根据权利要求1或2所述的氘代FAP抑制剂,其特征在于,R3为氧、硫、氮、氮甲基或亚甲基。
5.根据权利要求1~4任一项所述的氘代FAP抑制剂,其特征在于,所述R1和R2分别独立的选自氢或氟。
6.根据权利要求1~5任一项所述的氘代FAP抑制剂,其特征在于,所述R3为氧或氮甲基。
8.氘代FAP抑制剂药物组合物,其特征在于,所述组合物中包含权利要求1~7任一项所述的氘代FAP抑制剂为活性成分。
9.权利要求8所述的氘代FAP抑制剂药物组合物,其特征在于,所述氘代FAP抑制剂为所述化合物的药学上可接受的盐,所述盐优选为盐酸盐、硫酸盐、富马酸盐、琥珀酸盐、甲磺酸盐或磺酸盐。
10.如权利要求1~7任一项所述的氘代FAP抑制剂或权利要求8或9所述的氘代FAP抑制剂药物组合物在制备治疗或诊断FAP过表达相关疾病的药物中的应用。
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US20140357650A1 (en) * | 2012-01-17 | 2014-12-04 | Fox Chase Cancer Center | Novel fap inhibitors |
AU2016205988A1 (en) * | 2015-01-09 | 2017-07-13 | Mabimmune Diagnostics Ag | Novel anti-Fibroblast Activation Protein (FAP) antibodies and uses derived thereof |
US20200206216A1 (en) * | 2018-12-21 | 2020-07-02 | Praxis Biotech LLC | Inhibitors of fibroblast activation protein |
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US20140357650A1 (en) * | 2012-01-17 | 2014-12-04 | Fox Chase Cancer Center | Novel fap inhibitors |
AU2016205988A1 (en) * | 2015-01-09 | 2017-07-13 | Mabimmune Diagnostics Ag | Novel anti-Fibroblast Activation Protein (FAP) antibodies and uses derived thereof |
CN111699181A (zh) * | 2018-02-06 | 2020-09-22 | 海德堡大学 | Fap抑制剂 |
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