CN115504964A - 氘代杂环酮类化合物及其用途 - Google Patents
氘代杂环酮类化合物及其用途 Download PDFInfo
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- CN115504964A CN115504964A CN202211064664.5A CN202211064664A CN115504964A CN 115504964 A CN115504964 A CN 115504964A CN 202211064664 A CN202211064664 A CN 202211064664A CN 115504964 A CN115504964 A CN 115504964A
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- Prior art keywords
- compound
- pharmaceutically acceptable
- solvate
- hydrate
- acceptable salt
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- -1 Deuterated heterocyclic ketone compound Chemical class 0.000 title description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 239000003814 drug Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000012453 solvate Substances 0.000 claims abstract description 20
- 230000003287 optical effect Effects 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 12
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 8
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- 239000000463 material Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
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- 229910019142 PO4 Inorganic materials 0.000 claims description 3
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- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 claims description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
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- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
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- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 2
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- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 claims description 2
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 5
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- 241000699666 Mus <mouse, genus> Species 0.000 description 4
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
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- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
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- AXHRGVJWDJDYPO-UHFFFAOYSA-N 2-bromo-1h-imidazole Chemical compound BrC1=NC=CN1 AXHRGVJWDJDYPO-UHFFFAOYSA-N 0.000 description 1
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- 229960004538 alprazolam Drugs 0.000 description 1
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- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
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- 239000010413 mother solution Substances 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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Abstract
本发明公开了式(I)所示的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物,其中,R1‑R17分别独立选自氢、氘,R18、R19为氢且R1‑R19不同时为氢。本发明提供的氘代化合物及其盐类、水合物或溶剂合物,具备优异的代谢稳定性和药代动力学,在制备微管蛋白抑制剂,抗癌药物,抗病毒药物,治疗新冠肺炎药物方面应用前景优良。
Description
技术领域
本发明涉及一种氘代杂环酮类化合物及其用途。
背景技术
Sabizabulin(VERU-111,ABI-231)是一种口服有效的α和β微管蛋白抑制剂抑制剂,结构式为其对前列腺癌等肿瘤细胞系具有显著抗增殖活性,临床用于治疗晚期乳腺癌和前列腺癌。近期研究发现,Sabizabulin具有抗炎作用,可以防止新冠病毒感染引起的细胞因子风暴,在三期临床试验中将患者的死亡风险相对降低了55%。
氘代药物是指将药物分子中的部分氢原子替换为氘。由于氘在药物分子中形状和体积与氢接近,氘代药物一般会保留原来药物的生物活性和选择性。由于C-D键比C-H键更稳定,使得氘代药物在化学反应过程中,C-D键更不容易断裂,其半衰期会延长。
由于生物系统的代谢过程复杂,药物在生物体内的药代动力学性质受到多方面因素影响,也表现出相应的复杂性。与相应的非氘代药物相比,氘代药物药代动力学性质的变化表现出极大的偶然性和不可预测性。某些位点的氘代非但不能延长半衰期,反而可能会使其缩短(Scott L.Harbeson,Roger D.Tung.Deuterium in Drug Discovery andDevelopment,P405-406。),劣化其药代动力学性质;另一方面,药物分子上某些位置的氢因为空间位阻等原因也不易被氘代,因此,药物的氘代并非随心所欲,可氘代的位点是不可预期的。
若能通过对Sabizabulin进行氘代,进一步提升其药代动力学性质,降低毒副作用,有利于进一步开发应用于恶性肿瘤治疗和新型冠状病毒感染治疗的药物,具有重要的意义。
发明内容
本发明的目的在于提供一种氘代Sabizabulinb化合物。
本发明提供了式(I)所示的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物:
其中,R1-R17分别独立选自氢、氘R18、R19为氢且R1-R19不同时为氢。
进一步地,上述化合物具有式(II)所示结构:
进一步地,上述化合物具有式(III)所示结构:
更进一步地,上述化合物具有式(IV)所示结构:
更进一步地,上述化合物具有式(V)所示结构:
进一步地,上述化合物具有式(VI)所示结构:
进一步地,上述化合物具有式(VII)所示结构:
进一步地,上述化合物具有式(VIII)所示结构:
更进一步地,上述化合物中R1、R2、R3同时为氢或同时为氘;R4、R5、R6同时为氢或同时为氘;R7、R8、R9同时为氢或同时为氘。
进一步地,上述化合物为如下化合物之一:
进一步地,上述药学上可接受的盐为所述化合物的磷酸盐、右旋樟脑磺酸盐,盐酸盐、氢溴酸盐、氢氟酸盐、硫酸盐、硝酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、苯甲磺酸盐、苯磺酸盐、天冬氨酸盐或谷氨酸盐。
本发明还提供了上述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物在制备治疗癌症和/或新冠病毒感染、流感病毒感染、多核体病毒感染和/或急性呼吸型窘迫性综合症的药物中的用途。
进一步地,上述癌症包括但不局限于黑色素瘤和前列腺癌,乳腺癌。
本发明还提供了上述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物在制备微管蛋白抑制剂中的用途。
本发明还提供了一种药物,它是以上述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物为活性成分,再加上药学上可接受的辅料制备而成的制剂。
本发明的有益效果:本发明通过对Sabizabulin进行氘代,制得的氘代化合物具备抗癌活性和比Sabizabulin更好的代谢稳定性,药代动力学,应用前景优良。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
实施例1:合成(2-(1H-吲哚-3-基)-1H-咪唑-4-基)(3,4,5-三(甲氧基-d3)苯基)甲酮
第一步:合成3-(1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚
在100mL茄型瓶中称取化合物1-(苯磺酰基)-3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-1H-吲哚(2g,5.22mmol),化合物2-溴-1H-咪唑(1eq.,0.77g,5.22mmol),加入无水Dioxane/H2O(30/10mL),加入碳酸钠(2eq.,1.45g,10.44mmol),四(三苯基膦)钯(0.1eq.,0.6g,0.52mmol),氩气置换三次后,100℃下反应过夜。加入饱和氯化铵溶液淬灭反应,EA萃取5*50mL,旋干柱层析纯化(EA/PE=1/1)。得到化合物3-(1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚
(1.8g,5.52mmol,>100%)。LC/MS(ESI+)calcd for C17H13N3O2S([M+H]+)m/e324.07,found 324.2。
第二、三步:合成3-(4,5-二溴-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚
在100mL茄型瓶中加入化合物3-(1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚
(1.8g,5.52mmol),加入30mL无水THF,室温下缓慢加入NBS(2.5eq.,2.3g,13.8mmol),搅拌2h后,加入饱和硫代硫酸钠溶液淬灭反应,EA萃取三次后,旋干,加入30mLDCM,DIPEA(1.7mL,11.04mmol),冰水浴下缓慢加入SEMCl(1.2eq.,1.2mL,6.8mmol),搅拌2h后,加入饱和碳酸氢钠溶液淬灭反应,DCM萃取4*30mL,柱层析纯化(EA/PE=1/5),得到化合物3-(4,5-二溴-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚(0.975g,1.60mmol,30%)。LC/MS(ESI+)calcd for C23H25Br2N3O3SSi([M+H]+)m/e611.97,609.98,found 612.1,614.1。
第四步:合成3,4,5-三(甲氧基-d3)苯甲醛
在50mL封管中,称取3,4,5-三羟基苯甲醛(2.0g,12.98mmol),加入15mL无水DMF,加入碳酸钾(4.0eq.,7.2g,51.94mmol),小心加入CD3I(4.0eq.,3.5mL,51.94mmol)。在80℃下搅拌过夜。冷却至室温后,加入饱和氯化铵溶液淬灭反应。EA萃取5*50mL,旋干柱层析纯化(EA/PE=1/3),得到化合物3,4,5-三(甲氧基-d3)苯甲醛(2.15g,10.48mmol,81%)
第五步:合成(5-溴-2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基)(3,4,5-三(甲氧基-d3)苯基)甲醇
在100mL茄型瓶中加入化合物3-(4,5-二溴-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚(0.66g,1.08mmol),加入30mL无水THF,氩气置换三次后,室温下滴加异丙基氯化镁氯化锂(2eq.,1.3M,2mL,2.16mmol),室温下搅拌30min,将化合物3,4,5-三(甲氧基-d3)苯甲醛(2eq,0.5g,2.16mmol)溶于10mL无水THF中,滴加入上诉反应液中,搅拌3h。加入饱和氯化钠溶液淬灭反应,EA萃取,旋干柱层析(EA/PE=1/3),得到化合物(5-溴-2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基)(3,4,5-三(甲氧基-d3)苯基)甲醇(0.571g,,0.77mmol,72%)。LC/MS(ESI+)calcd for C33H29D9Br2N3O7SSi([M+H]+)m/e 737.19,739.19,found 737.2,739.2。
第六步:合成(5-溴-2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基)(3,4,5-三(甲氧基-d3)苯基)甲酮
在100mL茄型瓶中加入化合物(5-溴-2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基)(3,4,5-三(甲氧基-d3)苯基)甲醇(0.571g,0.77mmol),加入30mLDCM,冰水浴下加入碳酸氢钠(4eq.,0.31g,3.08mmol),缓慢加入DMP(2eq.,0.66g,1.56mmol),反应1.5h后,缓慢加入饱和碳酸氢钠溶液淬灭反应。DCM萃取,旋干柱层析(EA/PE=1/4),得到化合物(5-溴-2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基)(3,4,5-三(甲氧基-d3)苯基)甲酮(0.498g,0.68mmol,87%)。LC/MS(ESI+)calcd for C33H27D9Br2N3O7SSi([M+H]+)m/e 735.18,737.18,found 735.2,737.2。
第七、八步:合成(2-(1H-吲哚-3-基)-1H-咪唑-4-基)(3,4,5-三(甲氧基-d3)苯基)甲酮
在100mL茄型瓶中加入化合物(5-溴-2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基)(3,4,5-三(甲氧基-d3)苯基)甲酮(0.498g,0.68mmol)加入5mL正丁醇,碳酸钾(4eq.,0.376g,2.72mmol),三苯基膦(0.4eq.,0.071g,0.27mmol),醋酸钯(0.1eq.,0.015g,0.07mmol),120℃下反应5h,加入饱和氯化钠溶液淬灭反应,EA萃取。高温旋干正丁醇后,直接加入DCM/TFA(10mL/5mL),搅拌1.5h,缓慢加入饱和碳酸氢钠溶液淬灭,DCM萃取,旋干柱层析,得到化合物HC-8174-01,(2-(1H-吲哚-3-基)-1H-咪唑-4-基)(3,4,5-三(甲氧基-d3)苯基)甲酮(0.25g,0.64mmol,两步95%)。LC/MS(ESI+)calcd for C21H10D9N3O4([M+H]+)m/e 387.19,found 387.20。目标化合物为互变异构体混合物(3:2)。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),11.61(s,1H),8.45(dd,J=18.4,7.8Hz,1H),8.38–7.75(m,3H),7.55–7.35(m,1H),7.33–6.97(m,3H).
实施例2:合成(2-(1H-吲哚-3-基)-1H-咪唑-4-基-5-d)(3,4,5-三甲氧基苯基)甲酮
第一、二步:合成3-(4,5-二碘-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚
在100mL茄型瓶中加入化合物3-(1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚
(2.65g,8.21mmol),加入50mLNaOH溶液(2M,20mL),加入10mLTHF助溶,室温下缓慢加入碘(2.5eq.,5.2gg,20.53mmol),搅拌2h后,加入饱和硫代硫酸钠溶液淬灭反应,EA萃取三次后,旋干,柱层析。后加入30mLDCM,DIPEA(1.1mL),冰水浴下缓慢加入SEMCl(0.7mL),搅拌2h后,加入饱和碳酸氢钠溶液淬灭反应,DCM萃取4*30mL,柱层析纯化(EA/PE=1/5),得到化合物3-(4,5-二碘-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚(2.19g,3.12mmol,51%)。LC/MS(ESI+)calcd for C23H25I2N3O3SSi([M+H]+)m/e705.95,found 706.1。
第三步:合成(5-碘-2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基)(3,4,5-三甲氧基苯基)甲醇在100mL茄型瓶中加入化合物(4,5-二碘-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-2-基)-1-(苯磺酰基)-1H-吲哚(2.19g,3.12mmol),加入30mL无水THF,氩气置换三次后,室温下滴加异丙基氯化镁氯化锂(2eq.,1.3M,2.0mL,2.16mmol),室温下搅拌30min,将化合物3,4,5-三甲氧基苯甲醛(2eq,1.2g,6.2mmol)溶于10mL无水THF中,滴加入上诉反应液中,搅拌3h。加入饱和氯化钠溶液淬灭反应,EA萃取,旋干柱层析(EA/PE=1/3),得到化合物(5-碘-2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基)(3,4,5-三甲氧基苯基)甲醇(1.55g,1.98mmol,64%)。LC/MS(ESI+)calcd for C33H38IN3O7SSi([M+H]+)m/e 776.12,found 776.2。
第四步:合成(2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基-5-d)(3,4,5-三甲氧基苯基)甲醇
在100mL茄型瓶中加入化合物(5-碘-2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基)(3,4,5-三甲氧基苯基)甲醇(0.2g,0.2 6mmol),溶于5mL氘代甲醇中,计入1mL无水THF助溶。加入0.2g氢氧化钯,D2置换三次,D2氛围下反应5h,直接抽滤旋干,柱层析,得到化合物(2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基-5-d)(3,4,5-三甲氧基苯基)甲醇(0.128g,0.194mmol,75%)。LC/MS(ESI+)calcd for C33H38DN3O7SSi([M+H]+)m/e 651.23,found 651.20。
第五、六、七步:合成(2-(1H-吲哚-3-基)-1H-咪唑-4-基-5-d)(3,4,5-三甲氧基苯基)甲酮
在100mL茄型瓶中加入化合物(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基-5-d)(3,4,5-三甲氧基苯基)甲醇(0.128g,0.197mmol),加入30mLDCM,冰水浴下加入碳酸氢钠(4eq.,0.068g,0.7 8mmol),缓慢加入DMP(2eq.,0.25g,0.3 9mmol),反应1.5h后,缓慢加入饱和碳酸氢钠溶液淬灭反应。DCM萃取,直接下一步。得到(2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基-5-d)(3,4,5-三甲氧基苯基)甲酮粗产品。
在100mL茄型瓶中加入(2-(1-(苯磺酰基)-1H-吲哚-3-基)-1-(2-(三甲基硅基)乙氧基)甲基)-1H-咪唑-4-基-5-d)(3,4,5-三甲氧基苯基)甲酮粗产品,室温下加入DCM/TFA(10mL/5mL),搅拌1.5h,缓慢加入饱和碳酸氢钠溶液淬灭,DCM萃取,旋干。加入氢氧化钠(20eq,0.16g,3.88mmol),甲醇/水=5mL/20mL,100℃下搅拌过夜。EA萃取,旋干,柱层析,得到化合物HC-8550-01,(2-(1H-吲哚-3-基)-1H-咪唑-4-基-5-d)(3,4,5-三甲氧基苯基)甲酮
(0.054g,0.140mmol,三步72%)。LC/MS(ESI+)calcd for C21H18DN3O4([M+H]+)m/e379.14,found 379.20。目标化合物为互变异构体混合物(3:2)。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),11.61(s,1H),8.58–7.83(m,3H),7.56–7.37(m,1H),7.26–7.06(m,3H).,3.91(s,6H),3.78(s,3H).
实施例3:合成(2-(1H-吲哚-3-基)-1H-咪唑-4-基-5-d)(3,4,5-三(甲氧基-d3)苯基)甲酮
用类似于化合物实施例1和2的方法制备得到目标化合物。LC/MS(ESI+)calcd forC21H9D10N3O4([M+H]+)m/e 379.14,found 379.20。目标化合物为互变异构体混合物(3:2)。1HNMR(400MHz,DMSO)δ13.1(s,1H),11.6(s,1H),8.43(d,J=7.7Hz,1H),7.53–7.03(m,5H).
实施例4:合成(2-(1H-吲哚-3-基)-1H-咪唑-4-基-5-d)(3,5-二甲氧基-4-(甲氧基-d3)苯基)甲酮
用类似于实施例1和2的方法制备得到目标化合物。LC/MS(ESI+)calcd forC21H15D4N3O4([M+H]+)m/e 379.14,found 379.20。目标化合物为互变异构体混合物(3:2)。1HNMR(400MHz,DMSO)δ13.0(d,J=53.5Hz,1H),11.6(d,J=53.6Hz,1H),8.44(dd,J=18.6,7.7Hz,1H),8.37–7.91(m,2H),7.53–7.39(m,1H),7.24–7.07(m,3H),3.91(s,6H).
实施例5:合成(2-(1H-吲哚-3-基)-1H-咪唑-4-基-5-d)(3,4-二甲氧基-5-(甲氧基-d3)苯基)甲酮
用类似于实施例1和2的方法制备得到目标化合物。LC/MS(ESI+)calcd forC21H15D4N3O4([M+H]+)m/e 379.14,found 379.20。目标化合物为互变异构体混合物(3:2)。1HNMR(400MHz,DMSO)δ13.0(s,1H),11.54(s,1H),8.45(dd,J=18.0,7.9Hz,1H),8.39–7.89(m,2H),7.56–7.37(m,1H),7.26–7.07(m,3H),3.91(s,3H),3.78(s,3H).
实施例6:合成(2-(1H-吲哚-3-基)-1H-咪唑-4-基-5-d)(3-甲氧基-4,5-双(甲氧基-d3)苯基)甲酮
用类似于实施例1和2的方法制备得到目标化合物。LC/MS(ESI+)calcd forC21H12D7N3O4([M+H]+)m/e 385.18,found 385.20。1H NMR(400MHz,DMSO)δ13.1(s,1H),11.6(s,1H),8.43(d,J=7.7Hz,1H),8.46–7.61(m,2H),7.47(d,J=8.0Hz,1H),7.23–7.10(m,3H),3.90(s,3H).
实施例7:合成(2-(1H-吲哚-3-基)-1H-咪唑-4-基-5-d)(4-甲氧基-3,5-双(甲氧基-d3)苯基)甲酮
用类似于实施例1和2的方法制备得到目标化合物。LC/MS(ESI+)calcd forC21H12D7N3O4([M+H]+)m/e 385.18,found 385.20。目标化合物为互变异构体混合物(3:2)。1HNMR(400MHz,DMSO-d6)δ13.07(s,1H),11.61(s,1H),8.43(dt,J=26.9,13.6Hz,1H),8.38–7.94(m,1H),7.93(s,1H),7.53–7.38(m,1H),7.30–7.03(m,3H),3.78(s,3H).
以下通过试验例的方式来说明本发明的有益效果。
试验例1、本发明化合物的人肝细胞微粒体代谢稳定性实验
第一步、用磷酸盐缓冲溶液(200mM),高纯水,MgCl2溶液(50mM)配制母溶液,其中磷酸盐浓度为100mM,MgCl2浓度为5mM。
第二步:两个实验分别进行如下:
A)加还原型辅酶Ⅱ(NADPH):10μL浓度为20mg/mL的人肝微粒体和40μL浓度为10mM的NADPH加入孵化试验中。肝微粒体和NADPH的最终浓度为0.5mg/mL和1mM。
B)不加NADPH:10μL浓度为20mg/mL的人肝微粒体和40μL的高纯水加入孵化试验中。肝微粒体的最终浓度为0.5mg/mL。
第三步:加入阳性对照物或者测试化合物后反应开始。测试化合物的最终浓度为2μM。
第四步:在0,15,30,45和60分钟的时间点由反应溶液中各取出50μL。往反应液中加入4倍体积的乙腈和IS(100nM浓度的alprazolam,200nM浓度的labetalol,200nM浓度的caffeine and 2μM浓度的ketoprofen)。样品在离心40分钟。取上层清夜100μL中加入100μL高纯水用LC-MS/MS分析。从提取的离子色谱图确定峰面积。斜率值k通过母体药物的剩余百分比与孵育时间曲线的自然对数的线性回归来确定。体外半衰期(体外t1/2)由斜率值确定。
本发明化合物在人肝微粒体代谢稳定性实验结果见表1:
表1:本发明化合物在人肝微粒体中的半衰期
如表1所示,本发明化合物在人肝微粒体实验中显示了比Sabizabulin更长的半衰期,表示本发明化合物比Sabizabulin具有更好的人体代谢稳定性,预计会有更好的人体药代动力学。
试验例2、本发明化合物的小鼠药代动力学
1)实验材料及仪器:
LC-20AD高效液相色谱系统(日本SHIMADZU(岛津)公司)
API4000三重四极杆质谱仪(美国Applied Biosystem公司)
PhenixWinnolin药动学软件(Version 6.3,美国Certara公司)
高速冷冻离心机(Thermo Fisher Scientific)
分析天平(赛多利斯,SECURA225D-1CN)
ICR小鼠(成都达硕实验动物有限公司)
2)实验方法及结果
分别精密称取适量药物,按配制终体积5%DMSO,15%HS-15,80%D5W依次按比例加入,超声、涡漩混匀,超声、涡漩混匀。分别配制成0.3mg/ml(i.g.)的药物浓度。
健康成年ICR小鼠18只,分成2组(i.v.组9只,i.g.组9只),禁食过夜(自由饮水)后,分别尾静脉或灌胃给药。灌胃给药剂量3mg/kg.采用卫星采血法,每个时间点3只动物,于不同时间点采集血液0.1ml经抗凝剂EDTA-K2抗凝后,4℃离心5min分离血浆,于-80℃保存待测。i.v.给药后采样时间点为5min、15min、0.5、1、2、4、8、12、24h;i.g.采样时间点为给药前(0h)、给药后0.5、1、2、4、6、8、12、24h。血浆中药物浓度采用LC/MS/MS法测定。小鼠药代动力学参数如表2所示。
表2、本发明化合物的小鼠药代动力学参数(口服3mg/kg)
由表2所示,本发明化合物在小鼠中显示了更高的暴露量。
试验例3、本发明化合物的大鼠药代动力学
1)实验材料及仪器:
LC-20AD高效液相色谱系统(SHIMADZU岛津公司)
API4000三重四极杆质谱仪(Applied Biosystem公司)
PhenixWinnolin药动学软件(Version 6.3,Certara公司)
高速冷冻离心机(Thermo Fisher Scientific公司)
SD大鼠(成都达硕实验动物有限公司)
2)实验方法及结果
精密称取适量药物(相当于原形药物3mg),按配制终体积5%DMSO,15%HS-15,80%D5W依次按比例加入,超声、涡漩混匀,超声、涡漩混匀。健康成年雄性SD大鼠3只(180-250g),禁食过夜(自由饮水)后,灌胃给药,给药体积5ml/kg;于给药前及给药后0.5,1,2,4,6,8,12,24h由眼眶后静脉丛采血0.1ml,4℃离心5min分离血浆,于-20℃保存待测。然后采用LC/MS/MS法测定血浆中的待测化合物浓度。
表3、本发明化合物的大鼠药代动力学参数(口服3mg/kg)
如表3所示,本发明化合物在大鼠中显示了更高的暴露量。
综上,本发明提供的Sabizabulin氘代化合物具备比Sabizabulin更好的人体代谢稳定性和动物药代动力学,预期具有更好的人体药代动力学,也相应地具有优良的应用前景。
Claims (15)
9.如权利要求8所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物,其特征在于:R1、R2、R3同时为氢或同时为氘;R4、R5、R6同时为氢或同时为氘;R7、R8、R9同时为氢或同时为氘。
11.根据权利要求1~10任一项所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物,其特征在于:所述药学上可接受的盐为所述化合物的磷酸盐、右旋樟脑磺酸盐,盐酸盐、氢溴酸盐、氢氟酸盐、硫酸盐、硝酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、苯甲磺酸盐、苯磺酸盐、天冬氨酸盐或谷氨酸盐。
12.权利要求1~11任一项所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物在制备治疗癌症、新冠病毒感染、流感病毒感染、多核体病毒感染和/或急性呼吸型窘迫性综合症的药物中的用途。
13.根据权利要求12所述的用途,其特征在于:所述癌症包括黑色素瘤、前列腺癌或乳腺癌。
14.权利要求1~11任一项所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物在制备微管蛋白抑制剂中的用途。
15.一种药物,其特征在于:它是以权利要求1~11任一项所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物为活性成分,再加上药学上可接受的辅料制备而成的制剂。
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US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104592205A (zh) * | 2010-03-01 | 2015-05-06 | Gtx公司 | 用于治疗癌的化合物 |
CN105163584A (zh) * | 2013-03-05 | 2015-12-16 | 田纳西大学研究基金会 | 用于治疗癌症的化合物 |
CN112512522A (zh) * | 2018-05-15 | 2021-03-16 | 田纳西大学研究基金会 | 用于三阴性乳腺癌和卵巢癌的治疗的化合物 |
WO2021203100A1 (en) * | 2020-04-03 | 2021-10-07 | Veru Inc. | Methods of treating coronavirus |
CN114751891A (zh) * | 2022-04-27 | 2022-07-15 | 佛山市晨康生物科技有限公司 | 一种(2-(1h-吲哚-3-基)-1h-咪唑-4-基)苯基甲酮类化合物及其应用 |
CN114805307A (zh) * | 2022-04-29 | 2022-07-29 | 南京雷正医药科技有限公司 | 一种用于制备冠状病毒治疗药物的吲哚类化合物 |
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104592205A (zh) * | 2010-03-01 | 2015-05-06 | Gtx公司 | 用于治疗癌的化合物 |
CN105163584A (zh) * | 2013-03-05 | 2015-12-16 | 田纳西大学研究基金会 | 用于治疗癌症的化合物 |
CN112512522A (zh) * | 2018-05-15 | 2021-03-16 | 田纳西大学研究基金会 | 用于三阴性乳腺癌和卵巢癌的治疗的化合物 |
WO2021203100A1 (en) * | 2020-04-03 | 2021-10-07 | Veru Inc. | Methods of treating coronavirus |
CN114751891A (zh) * | 2022-04-27 | 2022-07-15 | 佛山市晨康生物科技有限公司 | 一种(2-(1h-吲哚-3-基)-1h-咪唑-4-基)苯基甲酮类化合物及其应用 |
CN114805307A (zh) * | 2022-04-29 | 2022-07-29 | 南京雷正医药科技有限公司 | 一种用于制备冠状病毒治疗药物的吲哚类化合物 |
Non-Patent Citations (1)
Title |
---|
江文峰;李文保;: "氘代作用在药物研究中的应用" * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
WO2023198066A1 (zh) * | 2022-04-12 | 2023-10-19 | 海创药业股份有限公司 | 氘代杂环酮类化合物及其用途 |
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