CN108026057B - 用作选择性组蛋白脱乙酰酶抑制剂的杂环烷基衍生化合物及含其的药物组合物 - Google Patents
用作选择性组蛋白脱乙酰酶抑制剂的杂环烷基衍生化合物及含其的药物组合物 Download PDFInfo
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- CN108026057B CN108026057B CN201680028224.0A CN201680028224A CN108026057B CN 108026057 B CN108026057 B CN 108026057B CN 201680028224 A CN201680028224 A CN 201680028224A CN 108026057 B CN108026057 B CN 108026057B
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- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- NGPONWYYFOFPIC-UHFFFAOYSA-N pyridin-2-ylmethyl methanesulfonate Chemical compound CS(=O)(=O)OCC1=CC=CC=N1 NGPONWYYFOFPIC-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 150000004666 short chain fatty acids Chemical class 0.000 description 1
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- 239000012279 sodium borohydride Substances 0.000 description 1
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- 230000000707 stereoselective effect Effects 0.000 description 1
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- BWMGVWMNTKIPNF-GOSISDBHSA-N tert-butyl (2R)-4-benzhydryl-2-methylpiperazine-1-carboxylate Chemical compound C(C1=CC=CC=C1)(C1=CC=CC=C1)N1C[C@H](N(CC1)C(=O)OC(C)(C)C)C BWMGVWMNTKIPNF-GOSISDBHSA-N 0.000 description 1
- BWMGVWMNTKIPNF-SFHVURJKSA-N tert-butyl (2S)-4-benzhydryl-2-methylpiperazine-1-carboxylate Chemical compound C(C1=CC=CC=C1)(C1=CC=CC=C1)N1C[C@@H](N(CC1)C(=O)OC(C)(C)C)C BWMGVWMNTKIPNF-SFHVURJKSA-N 0.000 description 1
- DATRVIMZZZVHMP-MRVPVSSYSA-N tert-butyl (2r)-2-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-MRVPVSSYSA-N 0.000 description 1
- DATRVIMZZZVHMP-QMMMGPOBSA-N tert-butyl (2s)-2-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-QMMMGPOBSA-N 0.000 description 1
- HWLNKJXLGQVMJH-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC21CCNCC2 HWLNKJXLGQVMJH-UHFFFAOYSA-N 0.000 description 1
- YLLQWQAWIYVBOZ-UHFFFAOYSA-N tert-butyl 4-(n-phenylanilino)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N(C=1C=CC=CC=1)C1=CC=CC=C1 YLLQWQAWIYVBOZ-UHFFFAOYSA-N 0.000 description 1
- MPPMJIIHNXAKJT-UHFFFAOYSA-N tert-butyl 4-[(7-methoxy-7-oxoheptyl)carbamoyl]piperazine-1-carboxylate Chemical compound COC(CCCCCCNC(=O)N1CCN(CC1)C(=O)OC(C)(C)C)=O MPPMJIIHNXAKJT-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- SLRXUJZEMSZGOF-UHFFFAOYSA-N tert-butyl 7-benzhydryl-2,7-diazaspiro[3.5]nonane-2-carboxylate Chemical compound C(C1=CC=CC=C1)(C1=CC=CC=C1)N1CCC2(CN(C2)C(=O)OC(C)(C)C)CC1 SLRXUJZEMSZGOF-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
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Images
Classifications
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/54—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及具有组蛋白脱乙酰酶(HDAC)抑制活性的新型杂环烷基衍生物,其光学异构体或其药学上可接受的盐,其用于制备药物及含相同成分的药物组合物的用途,使用该组合物治疗疾病的方法,以及制备新型杂环烷基衍生物的方法。本发明所述的新型杂环烷基衍生物是选择性组蛋白脱乙酰酶(HDAC)抑制剂,可有效地用于治疗组蛋白脱乙酰酶介导的疾病,如细胞增殖性疾病、炎性疾病、常染色体显性疾病、遗传代谢疾病、自身免疫性疾病、急性/慢性神经疾病、肥大、心力衰竭、眼部疾病或神经退行性疾病。
Description
技术领域
本发明涉及新型杂环烷基衍生物,更具体地涉及具有组蛋白脱乙酰酶(HDAC)抑制活性的新型杂环烷基衍生物,其光学异构体或其药学上可接受的盐,其用于制备治疗HDAC介导的疾病的药物的用途、含有相同成分的药物组合物,使用该药物组合物治疗疾病的方法,以及制备该新型杂环烷基衍生物的方法。
背景技术
细胞转录调控是一个复杂的生物过程。转录调控的一个基本原理是基于组蛋白的翻译后修饰,即组蛋白H2A/B、H3和H4形成八聚体组蛋白核心复合物。通过在赖氨酸残基处的乙酰化或甲基化及在丝氨酸残基处的磷酸化进行的复杂N-末端修饰构成所谓的“组蛋白代码”的一部分(参见Strahl&Ellis,Nature 403,41-45,2000)。
在一个简单的模型中,带正电荷的赖氨酸残基的乙酰化降低了对带负电荷DNA的亲和力,因此转录因子可能很容易进入。
组蛋白乙酰化和脱乙酰化分别由组蛋白乙酰转移酶(HATs)和组蛋白脱乙酰酶(HDACs)催化。HDAC与转录阻抑物复合物相关,将染色质转化为沉默结构,转录失活。(参见Marks et al.,Nature cancer Rev.1,189-202,2001)。反之,由与转录激活子复合物相关的HAT激活。迄今已知三种不同类别的HDAC,即I类(HDAC 1-3,8;Mr=42-55kDa),主要位于细胞核中,对曲古霉素A(TSA)的抑制敏感,II类(HDAC 4-7,9,10;Mr=120-130kDa),其具有TSA敏感性,III类(SIRT1~7),其具有NAD+依赖性和TSA不敏感性。
组蛋白脱乙酰酶(HDAC)抑制剂构成了具有细胞分化和凋亡诱导活性的新一类抗癌药物。通过靶向组蛋白脱乙酰酶(HDAC),HDAC抑制剂通过组蛋白乙酰化影响染色质结构,诱导复杂转录的重新编程,例如肿瘤抑制基因的再激活和致癌基因的抑制。除了乙酰化核心组蛋白中的N-末端赖氨酸残基外,HDAC抑制剂靶向非组蛋白,包括热休克蛋白90(HSP90)、微管蛋白或p53肿瘤抑制蛋白,这对癌症生物学很重要。因此,HDAC抑制剂不仅可用于抗癌治疗,还可用于治疗遗传代谢疾病、自身免疫性疾病等,由于其已经在动物模型中显示了用于炎性疾病、类风湿性关节炎和神经退行性疾病的功效。
与HDAC抑制相关的组蛋白脱乙酰酶介导的疾病的实例包括细胞增殖性疾病,例如恶性肿瘤疾病,例如癌症;炎性疾病如炎性肠病、克罗恩病(Crohn's disease)或溃疡性肠炎;常染色体显性疾病如亨廷顿病(Huntington's disease)、唐氏综合征(Downssyndrome)、爱德华综合征(Edwards syndrome)或帕塔斯综合征(Pataus syndrome);遗传代谢疾病如糖尿病、尼曼-皮克病(Niemann-Pick disease)、戈谢病(Gaucher disease)、苯丙酮尿症、威尔逊病(Wilson's disease)或纤维化疾病,例如囊性纤维化、肝纤维化、肾纤维化、肺纤维化或皮肤纤维化;自身免疫疾病如类风湿性关节炎、哮喘、狼疮、牛皮癣、牛皮癣关节炎、多发性硬化、白塞病(Behcet'sdisease)或器官移植排斥反应;急性/慢性神经***疾病如中风或多囊肾病;肥大如心脏肥大;心力衰竭如充血性心力衰竭或出血性心力衰竭;眼部疾病如青光眼、干眼综合征、干性黄斑变性、湿性黄斑变性、糖尿病性视网膜病变或葡萄膜炎;神经变性疾病如阿尔茨海默氏病(Alzheimer's disease)、肌萎缩性侧索硬化症、进行性腓骨肌萎缩症(Charcot Marie Tooth disease)或脊髓性肌萎缩,以及由HDAC酶异常功能引起的病症和疾病。
迄今已知的HDAC抑制剂可根据其结构分为四类:1)短链脂肪酸(丁酸和丙戊酸);2)异羟肟酸(曲古霉素A、SAHA和LBH-589);3)环肽(缩酚酸肽);和4)苯甲酰胺(MS-275和MGCD-0103)(Sonia et al.,,International Journal of onocology 33,637-646,2008)。这些许多组蛋白脱乙酰酶(HDAC)抑制剂(SAHA、LBH-589和MS-275等)抑制细胞生长,并且不仅在培养基中而且在动物模型中有效诱导各种转化细胞的细胞分化和凋亡(Paul A.Markset.al.,Curr Opin.Oncol.13,477-483,2001)。因此,为了治疗各种癌症,临床研究中已经评估了HDAC抑制剂如SAHA、LBH-589和MS-275(Johnstone R.W.Nat.Rev.Drugvideo 1,287-299,2002)。目前HDAC抑制剂的代表性化合物包括异羟肟酸化合物SAHA(美国再发行公报No.385069,Zolinza,Vorinostat)、PXD101(WO 02/30879,Belinostat)和LBH-589(WO 02/22577,Panobinostat),以及苯甲酰胺化合物MS-275(欧洲专利号0847992,Entinostat)和MGCD0103(WO 04/69823,Mocetinostat)。在这些化合物中,SAHA于2006年10月获得批准,已被用作治疗CTCL(皮肤T细胞淋巴瘤)的药剂,并且其适应症已经扩大,但是已知SAHA在功效和副作用方面不足(Paul A.Marks et al.,Cancer Res 66,5781-5789,2006)。
各种HDAC抑制剂处于临床前或临床开发,但迄今为止,只有非选择性HDAC抑制剂已被鉴定为抗癌剂。已知非选择性HDAC抑制剂通常以高剂量引起副作用,例如疲劳和恶心(Piekarz et al.,Pharmaceuticals 2010,3,2751-2767)。据报道这种副作用是由于I类HDAC的抑制。由于这种副作用,非选择性HDAC抑制剂在除抗癌药物以外的药物开发中的应用受到限制(Witt et al.,Cancer Letters,2009,277,8-21)。
同时,据报道,II类HDAC的选择性抑制不会显示出I类HDAC抑制中显示的毒性。此外,选择性HDAC抑制剂的开发,可以克服由非选择性HDAC抑制引起的副作用如毒性。因此,选择性HDAC抑制剂有可能被开发为有效治疗各种疾病的治疗试剂(Matthias et al.,Mol.Cell.Biol.2008,28,1688-1701)。
已知HDAC 6是IIb类HDAC的一种,主要存在于细胞质中,并且涉及许多非组蛋白底物(HSP90、cortactin等)的脱乙酰化,包括微管蛋白(Yao et al.,Mol.Cell 2005,18,601-607)。此外,HDAC 6具有两个催化结构域,其C-末端锌指结构域可以与泛素化蛋白结合。已知HDAC 6具有许多非组蛋白作为底物,因此在诸如癌症、炎性疾病、自身免疫性疾病、神经***疾病和神经退行性疾病等各种疾病中起重要作用(Santo et al.,Blood 2012 119:2579-258;Vishwakarma et al.,International Immunopharmacology 2013,16,72-78;Huet al.,J.Neurol.Sci.2011,304,1-8)。
因此,亟须开发用于治疗癌症、炎性疾病、自身免疫性疾病、神经***疾病和神经退行性疾病,且与非选择性抑制剂不同不引起副作用的选择性HDAC 6抑制剂。
发明内容
技术问题
本发明的目的是提供具有选择性HDAC抑制活性的新型化合物、其光学异构体或其药学上可接受的盐。
本发明的另一目的是提供含有具有高选择性HDAC抑制活性的新型化合物、其光学异构体或其药学上可接受的盐的药物组合物。
本发明的再一目的是提供制备所述新型化合物的方法。
本发明的再一目的是提供用于治疗HDAC活性相关疾病(包括癌症、炎性疾病、自身免疫性疾病、神经***疾病或神经退行性疾病)的含有上述化合物的药物组合物。
本发明的再一目的是提供所述化合物用于制备用于治疗HDAC介导的疾病(包括癌症、炎性疾病、自身免疫性疾病、神经***疾病或神经退行性疾病)的药物的用途。
本发明的又一目的是提供用于治疗HDAC介导的疾病(包括癌症、炎性疾病、自身免疫性疾病、神经***疾病或神经退行性疾病)的方法,其包括施用治疗有效量的含有所述化合物的药物组合物。
技术方案
本发明人已经发现了具有HDAC抑制活性的新化合物,并且已经使用这些化合物来抑制或治疗组蛋白脱乙酰酶介导的疾病,从而完成了本发明。
新型HDAC抑制剂
为了实现上述目的,本发明提供了式I化合物、其光学异构体或其药学上可接受的盐。
其中,X选自杂环烷基
(其中,Z和W各自独立地为C或N,且Z和W中至少一个为N,
a、b、c和d各自独立地为1、2或3,且
R3、R4、R5和R6各自独立地为-H或-C1-C4烷基);
Y为C或N;
A和B各自独立地为-C1-C4烷基、-C6-C10芳基、-C3-C12杂芳基、-C3-C10环烷基、-C2-C10杂环烷基或-C3-C10环烯基(其中-C1-C4烷基的一个或多个氢原子可经-OH或卤素取代,-C6-C10芳基、-C3-C12杂芳基、-C3-C10环烷基、-C2-C10杂环烷基和-C3-C10环烯基可各自独立地为未取代或在其一个或多个氢原子处经-OH、-C1-C4烷基、-OC1-C4烷基、-CF3或卤素取代);
Q为C=O或SO2;
R1为-H或-C1-C4烷基;
R2为-H、-OH、-C1-C4烷基、-C1-C4烷基羟基、卤素或不存在(若Y为C,则R2为-H、-OH、-C1-C4烷基或-C1-C4烷基羟基,若Y为N,则R2不存在);且
n为1、2、3或4。
根据本发明一实施例,
(其中,Z和W各自独立地为C或N,且Z和W中至少一个为N,
a、b、c和d各自独立地为1、2或3,且
R3、R4、R5和R6各自独立地为-H或-C1-C4烷基);
Y为C或N;
A和B各自独立地为-C1-C4烷基、-C6-C10芳基、-C3-C12杂环芳基(其中-C1-C4烷基的一个或多个氢原子可经-OH或卤素取代,-C6-C10芳基或-C3-C12杂芳基可各自独立地为未取代或在其一个或多个氢原子处经-OH、-C1-C4烷基、-OC1-C4烷基、-CF3或卤素取代);
Q为C=O或SO2;
R1为-H或-C1-C4烷基;
R2为-H、-OH、卤素或不存在(若Y为C,则R2为-H、-OH或卤素,若Y为N,则R2不存在);且
n为1、2、3或4。
根据本发明另一实施例,
(其中,Z和W各自独立地为C或N,Z和W中至少一个为N,且R3和R4各自独立地为-H或-C1-C4烷基);
Y为C或N;
A和B各自独立地为-C1-C4烷基、-C6-C10芳基或-C3-C12杂芳基(其中-C1-C4烷基的一个或多个氢原子可经-OH或卤素取代,-C6-C10芳基和-C3-C12杂芳基可各自独立地为未取代或在其一个或多个氢原子处经-OH、-C1-C4烷基、-OC1-C4烷基、-CF3或卤素取代);
Q为C=O;
R1为-H或-C1-C4烷基;
R2为-H、-OH、卤素或不存在(若Y为C,则R2为-H、-OH或卤素,若Y为N,则R2不存在);且
n为3。
式I化合物如下表1至3所示:
表1
表2
表3
在本发明中,上述表1~3所示的化合物或其药学上可接受的盐较佳地选自化合物1102、1124、1188、1189、1190、1209、1221、1224、1241和1243,且更佳地选自化合物1102、1124、1188和1209。
如本发明所用,术语“药学上可接受的盐”是指药物领域中通常使用的任一盐。药学上可接受的盐的实例包括但不限于含无机离子(如钙离子、钾离子、钠离子或镁离子)的盐,含无机酸(如盐酸、硝酸、磷酸、溴酸、碘酸、高氯酸或硫酸)的盐,含有机酸(如乙酸、三氟乙酸、柠檬酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡萄糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸或氢碘酸)的盐,含磺酸(如甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸或萘磺酸)的盐,含氨基酸(如甘氨酸、精氨酸或赖氨酸)的盐,以及含胺(如三甲胺、三乙胺、氨、吡啶或甲基吡啶)的盐。
式I化合物可以含有一个或多个不对称碳,因此可以以外消旋体、外消旋混合物、单一对映异构体、非对映体混合物和单独的非对映异构体的形式存在。式I化合物可以通过本领域已知的方法(例如柱色谱法或HPLC)分离出这些异构体。或者,式I化合物的各个立体异构体可以通过使用已知构型的光学纯原料和/或试剂的立体特异性合成来合成。
包含新型HDAC抑制化合物的组合物、其用途和用其治疗疾病的方法
本发明提供了用于预防或治疗组蛋白脱乙酰酶介导的疾病的药物组合物,其含式I化合物、其光学异构体或其药学上可接受的盐作为活性成分。
其中,R1、R2、A、B、X、Y、Q和n如上述定义。
组蛋白脱乙酰酶介导的疾病的实例包括细胞增殖性疾病,例如恶性肿瘤疾病,例如癌症;炎性疾病如炎性肠病、克罗恩病或溃疡性肠炎;常染色体显性疾病如亨廷顿病、唐氏综合症、爱德华综合症或帕塔斯综合症;遗传代谢疾病如糖尿病、尼曼-皮克病、戈谢病、苯丙酮尿症、威尔逊病或纤维化疾病,例如囊性纤维化、肝纤维化、肾纤维化、肺纤维化或皮肤纤维化;自身免疫疾病如类风湿性关节炎、哮喘、狼疮、牛皮癣、牛皮癣关节炎、多发性硬化、白塞病或器官移植排斥反应;急性/慢性神经***疾病如中风或多囊肾病;肥大如心脏肥大;心力衰竭如充血性心力衰竭或出血性心力衰竭;眼部疾病如青光眼、干眼综合征、干性黄斑变性、湿性黄斑变性、糖尿病性视网膜病变或葡萄膜炎;神经变性疾病如阿尔茨海默氏病、肌萎缩性侧索硬化症、进行性腓骨肌萎缩症或脊髓性肌萎缩,以及由HDAC酶异常功能引起的病症和疾病。
上述药学上可接受的盐为根据本发明式I化合物药学上可接受的盐。
对于给药,除了式I化合物、其异构体或其药学上可接受的盐之外,本发明的药物组合物还可以含有至少一种药学上可接受的载体。用于本发明的药学上可接受的载体可以是生理盐水、无菌水、林格溶液、缓冲盐水、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇及其两种或多种的混合物中的至少一种。若需要,组合物可以含有其它常规添加剂,例如抗氧化剂、缓冲剂或抑菌剂。此外,可以使用稀释剂、分散剂、表面活性剂、粘合剂和润滑剂将组合物配制成注射制剂(例如溶液、悬浮液、混浊液等)、丸剂、胶囊、颗粒剂或片剂。因此,本发明的组合物可以是贴剂、液体、丸剂、胶囊、颗粒剂、片剂、栓剂等形式。这些制剂可以通过本领域制剂的常规方法或通过Remington's Pharmaceutical Science(最新版),MackPublishing Company,Easton PA公开的方法来制备。
本发明的药物组合物可以根据预期用途口服或胃肠外(例如静脉内、皮下、腹膜内或局部)给药。药物组合物的剂量视以下因素而有所变化:患者的体重、年龄、性别、健康状况和饮食、给药时间、给药方式、***率、疾病的严重程度等。本发明所述式I化合物的日剂量可以为约1至500㎎/kg,优选5至100㎎/kg,且可以每天给药一次至若干次。
除式I化合物、其光学异构体或其药学上可接受的盐以外,本发明的药物组合物还可以进一步含有一种或多种表现出与之相同或相似药效的活性成分。
本发明还提供了一种预防或治疗组蛋白脱乙酰酶介导的疾病的方法,其包括施用治疗有效量的式I化合物、其光学异构体或其药学上可接受的盐。
如本发明所用,术语“治疗有效量”是指有效预防或治疗组蛋白脱乙酰酶介导的疾病的式I化合物的量。
本发明还提供一种抑制组蛋白脱乙酰酶(HDAC)的方法,其通过向哺乳动物(包括人类)施用式I化合物、其旋光异构体或其药学上可接受的盐来进行。
本发明用于预防或治疗组蛋白脱乙酰酶介导的疾病的方法包括通过在症状出现之前施用式I化合物来抑制或防止疾病以及解决疾病本身。在管控疾病时,特定活性成分的预防或治疗剂量将随着疾病或病症的性质和严重程度而变化,并且还可根据施用活性成分的途径而变化。剂量和给药频率也将根据个别患者的年龄、体重和反应而变化。适当的给药方案可易于本领域技术人员通过适当考虑这些因素来予以选择。此外,根据本发明的用于预防或治疗组蛋白脱乙酰酶介导的疾病的方法可进一步包括施用治疗有效量的有助于与式I化合物一起治疗疾病的另一活性剂,其中另一活性剂可以表现出与式I化合物的协同作用或辅助作用。
本发明还旨在提供式I化合物、其光学异构体或其药学上可接受的盐在制备用于治疗组蛋白脱乙酰酶介导的疾病的药物中的用途。为了制备药物,可以将式I化合物与药学上可接受的佐剂、稀释剂、载体等混合,并与其它活性剂混合,并与其它活性剂联用使活性成分具有协同作用。
本发明用途、组合物和治疗方法中提及的特定情况可以适当地组合,除非彼此矛盾。
制备新型HDAC抑制剂化合物的方法
本发明还提供了制备式I化合物、其光学异构体或其药学上可接受的盐的方法。参照以下反应方案1至10阐述这些制备方法。
反应方案1
如上述反应方案1所示,将式1-1化合物与6-氨基己酸甲酯盐酸盐、7-氨基庚酸甲酯盐酸盐或8-氨基辛酸甲酯盐酸盐(式1-2)进行脲形成反应,合成式1-3化合物。将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式1-3化合物中,并在室温下反应,从而合成最终化合物1102、1240和1257。
此外,其中引入了7-氨基庚酸甲酯的式1-3化合物与碘甲烷反应以合成式1-4化合物。将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式1-4化合物中,并在室温下反应,从而合成最终化合物1213。
反应方案2
如上述反应方案2所示,使式2-1化合物与7-氨基庚酸甲酯盐酸盐(式1-2)进行脲形成反应,合成式2-2化合物,然后将其与4M盐酸溶液反应除去氨基保护基(Boc),从而合成式2-5化合物。将式2-3化合物与亚硫酰氯反应以合成式2-4化合物,然后将其与式2-5化合物进行取代反应以合成式2-6化合物。将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式2-6化合物中,并在室温下反应,合成最终化合物1223、1224、1647和1648。
反应方案3
如上述反应方案3所示,用硼氢化钠还原式3-1化合物以合成式3-2化合物,然后与甲磺酰氯反应以合成式3-3化合物。将式3-3化合物与式2-5化合物进行取代反应以合成式3-4化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式3-4化合物中,并在室温下反应,合成最终化合物1222。
反应方案4
如上述反应方案4所示,式4-1化合物与(2S,6R)-2,6-二甲基哌嗪(式4-2)进行取代反应,合成式4-3化合物,然后与7-氨基庚酸甲酯盐酸盐进行脲形成反应,合成式4-4化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式4-4化合物中,并在室温下反应,合成最终化合物1188。
此外,式4-1化合物与A-Boc化合物反应,然后用4M盐酸溶液处理以除去保护基(Boc),由此合成式4-6化合物。将式4-6化合物与式1-2化合物进行脲形成反应以合成式4-7化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式4-7化合物中,并在室温下反应,合成最终化合物1189、1190、1763和1764。
反应方案5
如反应方案5所示,式5-1化合物与(氯亚甲基)二苯(式4-1)进行取代反应,合成式5-2化合物,然后用氢氧化锂(LiOH)水解合成式5-3化合物。将式5-3化合物与6-氨基己酸甲酯盐酸盐、7-氨基庚酸甲酯盐酸盐或8-氨基辛酸甲酯盐酸盐进行酰胺偶联以合成式5-4化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式5-4化合物中,并在室温下反应,合成最终化合物1209、1316和1317。
此外,其中引入了7-氨基庚酸甲酯的式5-4化合物与碘甲烷反应以合成式5-5化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式5-5化合物中,并在室温下反应,合成最终化合物1256。
反应方案6
如上述反应方案6所示,将式6-1化合物用苯胺进行还原胺化以合成式6-2化合物,然后将其进行巴克瓦尔德反应以合成式6-3化合物。使式6-3化合物与4M盐酸溶液反应以除去氨基保护基(Boc),然后与饱和碳酸氢钠溶液反应以合成式6-5化合物。使式6-5化合物与7-氨基庚酸甲酯盐酸盐(式1-2)进行脲形成反应,合成式6-6化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式6-6化合物中,并在室温下反应,合成最终化合物1221、1719、1726和1734。
反应方案7
如反应方案7所示,将式7-1化合物与4-硝基苯基氯甲酸酯(式7-2)反应,合成式7-3化合物,然后将其与7-氨基庚酸甲酯盐酸盐(式1-2)进行取代反应,合成式7-4化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式7-4化合物中,并在室温下反应,合成最终化合物1124。
此外,将式7-1化合物与7-氨基庚酸甲酯盐酸盐(式1-2)进行脲形成反应,合成式7-4化合物,然后将其与二乙基氨基三氟化硫(DAST)反应合成式7-5化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入式7-5化合物中,并在室温下反应,合成最终化合物1649。
反应方案8
如上述反应方案8所示,式8-1化合物与三氟甲磺酸甲酯(式8-2)反应,合成式8-3化合物。使式8-3化合物与二苯基(哌啶-4-基)甲醇(式7-1)反应以合成式8-4化合物,然后与三氟甲磺酸甲酯(式8-2)反应,合成式8-5化合物。式8-5化合物与7-氨基庚酸甲酯盐酸盐(式1-2)反应,合成式8-6化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式8-6化合物中,并在室温下反应,合成最终化合物1210。
反应方案9
如上述反应方案9所示,将式2-5化合物与苯乙酮进行还原胺化以合成式9-2化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入到式9-2化合物中,并在室温下反应,合成最终化合物1241。
反应方案10
如上述反应方案10所示,将式10-1化合物与苯乙酮进行还原胺化以合成式10-2化合物,然后用氢氧化锂(LiOH)水解,合成式10-3。将式10-3化合物与7-氨基庚酸甲酯盐酸盐进行酰胺偶联以合成式10-4化合物。然后,将氢氧化钾(KOH)、甲醇和羟胺水溶液加入式10-4化合物中,并在室温下反应,合成最终化合物1243。
本发明的积极进步效果
本发明式I化合物、其光学异构体或其药学上可接受的盐可以选择性地抑制HDAC,因此对组蛋白脱乙酰酶介导的疾病的预防或治疗表现出优异的效果。
附图说明
图1为化合物1102对佐剂诱导的关节炎模型中关节炎缓解作用的分析结果。
具体实施方式
下面通过实施例的方式进一步帮助理解本发明,但并不因此将本发明限制在所述的实施例范围之中,提供这些实施例只是为了更好地理解本发明。
除非另有指定,否则以下提及的试剂和溶剂均购自Sigma-Aldrich和TCI,并使用Waters e2695进行HPLC。柱色谱的硅胶,使用来自Merck的硅胶(230-400目)。使用Bruker400MHz测量1H-NMR数据,并使用Agilent 1100系列获得质谱。
实施例1:化合物1102的合成
步骤1:7-(4-二苯甲基哌嗪-1-甲酰氨基)庚酸甲酯(式1-3)的合成
在室温下,将1-二苯甲基哌嗪(0.200g,0.793mmol)、7-氨基庚酸甲酯(0.151g,0.951mmol)、三光气(0.118g,0.396mmol)和DIPEA(0.415mL,2.378mmol)溶于二氯甲烷(5mL),将溶液在相同温度下搅拌1小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(Waters,C18;1%甲酸水溶液/乙腈=100%~20%)纯化,并通过SPE柱(PL-HCO3树脂)浓缩,获得所需式1-3化合物(0.075g,21.6%),为淡黄色油状物。
步骤2:4-二苯甲基-N-(7-(羟基氨基)-7-氧代庚基)哌嗪-1-甲酰胺(化合物1102)的合成
在室温下,将步骤1制备的式1-3化合物(0.075g,0.171mmol)、羟胺(50.00%水溶液,0.210mL,3.428mmol)和氢氧化钾(0.096g,1.714mmol)溶于甲醇(3mL),在相同温度下搅拌30分钟。将反应混合物减压浓缩以除去溶剂,加入饱和碳酸氢钠水溶液(20mL)至浓缩物,然后搅拌。将沉淀的固体过滤,水洗,干燥,得到黄色固体状的所需化合物1102(0.047g,62.5%)。
1H NMR(400MHz,DMSO-d6):δ9.39(brs,1H),7.42(d,4H,J=7.2Hz),7.29(t,4H,J=7.5Hz),7.18(t,2H,J=7.3Hz),6.40(t,1H,J=5.3Hz),4.28(s,1H),3.27(s,4H),2.98-2.93(m,2H),2.08(s,4H),1.89(t,2H,J=7.3Hz),1.44-1.43(m,2H),1.34-1.33(m,2H),1.20(s,4H);MS(ESI)m/z 439.6(M++H).
实施例2:化合物1124的合成
步骤1:4-(羟基二苯基甲基)哌啶-1-羧酸4-硝基苯酯的合成(式7-3)
在0℃,将二苯基(哌啶-4-基)甲醇(0.100g,0.374mmol)和三乙胺(0.104mL,0.748mmol)溶于二氯甲烷(5mL)中,加入氯甲酸4-硝基苯酯(0.083g,0.411mmol)加入到溶液中,然后在相同温度下搅拌1小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱(SiO2,4g柱;乙酸乙酯/己烷=0%~20%)纯化并浓缩,得到所需化合物7-3(0.152g,94.0%),为无色油状物。
步骤2:7-(4-(羟基二苯基甲基)哌啶-1-甲酰胺基)庚酸甲酯的合成(式7-4)
将步骤1制备的式7-3化合物(0.152g,0.351mmol)、7-氨基庚酸甲酯盐酸盐(0.280g,1.757mmol)和碳酸钾(0.097g,0.703mmol)溶于N,N-二甲基甲酰胺(5mL)中,在100℃下搅拌17小时。然后,将温度降至室温以终止反应。将反应混合物减压浓缩以除去溶剂,浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=10%~40%)纯化并浓缩,得到式7-4化合物(0.075g,39.4%),为橙色油状物。
步骤3:N-(7-(羟基氨基)-7-氧代庚基)-4-(羟基二苯基甲基)哌啶-1-甲酰胺(化合物1124)
室温下,将步骤2制备的式7-4化合物(0.075g,0.166mmol)、羟胺(50.00%水溶液,0.203mL,3.314mmol)和氢氧化钾(0.093g,1.657mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入水,用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。将沉淀的固体过滤,用己烷洗涤,干燥,得到白色固体所需化合物1124(0.007g,9.3%)。
1H NMR(400MHz,DMSO-d6)δ9.36(brs,1H),7.52(d,4H,J=7.6Hz),7.27(t,4H,J=7.7Hz),7.13(t,2H,J=7.3Hz),6.30(t,1H,J=5.3Hz),5.32(brs,1H),3.94(d,2H,J=13.4Hz),2.99-2.94(m,2H),2.67-2.58(m,3H),1.91(t,2H,J=7.4Hz),1.48-1.46(m,2H),1.35-1.34(m,2H),1.30-1.25(m,6H).
实施例3:化合物1188的合成
步骤1:(3S,5R)-1-二苯甲基-3,5-二甲基哌嗪(化合物4-3)的合成
在室温下,将(2R,6S)-2,6-二甲基哌嗪(1.000g,8.757mmol)、(氯亚甲基)二苯(3.550g,17.515mmol)和碳酸钾(6.052g,43.787mmol)溶于N,N-二甲基甲酰胺(10mL),并将该溶液在相同温度下搅拌17小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入水,用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;甲醇/二氯甲烷=0%~10%)纯化并浓缩,得到所需化合物4-3(0.798g,32.5%),为白色固体。
步骤2:7-((2S,6R)-4-二苯甲基-2,6-二甲基哌嗪-1-甲酰氨基)庚酸甲酯的合成(式4-4)
在0℃,将三光气(0.159g,0.535mmol)和二异丙基胺(0.561mL,3.210mmol)溶于二氯甲烷(5mL)中,向溶液中加入7-氨基庚酸甲酯盐酸盐(0.251g,1.284mmol),随后在相同温度下搅拌。将步骤1制备的式4-3化合物(0.300g,1.070mmol)加入到反应混合物中,然后在相同温度下搅拌30分钟。向反应混合物中加入水,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%~30%)纯化并浓缩,得到所需化合物4-4(0.212g,42.6%),为白色固体。
步骤3:(2S,6R)-4-二苯甲基-N-(7-(羟基氨基)-7-氧代庚基)-2,6-二甲基哌嗪-1-甲酰胺(化合物1188)的合成
室温下,将步骤2制备的式4-4化合物(0.100g,0.215mmol)、羟胺(50.00%水溶液,0.263mL,4.295mmol)和氢氧化钾(0.121g,2.148mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液(30mL),然后搅拌。将沉淀的固体过滤,用水洗涤并干燥,得到所需化合物1188(0.099g,98.8%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ7.51(d,4H,J=7.5Hz),7.30(t,4H,J=7.6Hz),7.19(t,2H,J=7.3Hz),6.23(t,1H,J=5.3Hz),4.23(s,1H),3.94(brs,2H),3.03-2.98(m,2H),2.60(d,2H,J=10.9Hz),1.96-1.90(m,4H),1.46-1.45(m,2H),1.38-1.36(m,2H),1.26-1.22(m,10H).
实施例4:化合物1189的合成
步骤1:(R)-4-二苯甲基-2-甲基哌嗪-1-甲酸叔丁酯(式4-5)的合成
室温下,将(R)-2-甲基哌嗪-1-甲酸叔丁酯(1.000g,4.993mmol)、(氯亚甲基)二苯(2.024g,9.986mmol)和碳酸钾(3.450g,24.965mmol)溶于N,N-二甲基甲酰胺(10mL)中,在80℃下搅拌17小时,然后冷却至室温终止反应。减压浓缩反应混合物以除去溶剂,向浓缩物中加入水,用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%~10%)纯化并浓缩,得到所需化合物4-5(0.813g,44.4%),为白色固体。
步骤2:(R)-1-二苯甲基-3-甲基哌嗪(式4-6)的合成
将在步骤1制备的式4-5化合物(0.813g,2.218mmol)在室温下溶于二氯甲烷(10mL)中,向该溶液中加入盐酸(4.00M二氧六环溶液,5.546mL,22.183mmol),然后在相同温度下搅拌17小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。得到所需式4-6化合物(0.590g,99.8%),为白色固体,无需额外纯化。
步骤3:(R)-7-(4-二苯甲基-2-甲基哌嗪-1-甲酰氨基)庚酸甲酯(式4-7)的合成
将三光气(0.167g,0.563mmol)和DIPEA(1.180mL,6.757mmol)在0℃下溶于二氯甲烷(5mL)中,向溶液中加入7-氨基庚酸甲酯盐酸盐(0.264g,1.351mmol),随后在相同温度下搅拌。向反应混合物中加入式4-6化合物(0.300g,1.126mmol),然后在相同温度下搅拌30分钟。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%~30%)纯化并浓缩。然后,通过色谱法(Waters,C18;1%甲酸水溶液/乙腈=75%~5%)再次纯化浓缩物,并通过SPE柱(PL-HCO3树脂)浓缩,得到所需式4-7化合物(0.106g,20.8%)。
步骤4:(R)-4-二苯甲基-N-(7-(羟基氨基)-7-氧代庚基)-2-甲基哌嗪-1-甲酰胺(化合物1189)的合成
室温下,将步骤3制备的式4-7化合物(0.100g,0.221mmol)、羟胺(50.00%水溶液,0.271mL,4.429mmol)和氢氧化钾(0.124g,2.214mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入碳酸氢钠水溶液(30mL),然后搅拌。将沉淀的固体过滤,用水洗涤并干燥,得到所需化合物1189(0.099g,98.8%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ9.42(brs,2H),7.45(t,4H,J=6.3Hz),7.30(t,4H,J=7.6Hz),7.19(t,2H,J=6.8Hz),6.36-6.34(m,1H),4.23(s,1H),4.04(brs,1H),3.62(d,1H,J=12.4Hz),3.01-2.93(m,3H),2.67(d,1H,J=9.6Hz),2.60(d,1H,J=10.8Hz),1.95(dd,1H,J=11.0,3.0Hz),1.88(t,2H,J=7.3Hz),1.78(t,1H,J=10.1Hz),1.44-1.43(m,2H),1.36-1.35(m,2H),1.20-1.18(m,7H).
实施例5:化合物1190的合成
步骤1:(S)-4-二苯甲基-2-甲基哌嗪-1-甲酸叔丁酯(式4-5)的合成
室温下,将(S)-2-甲基哌嗪-1-甲酸叔丁酯(1.000g,4.993mmol)、(氯亚甲基)二苯(2.024g,9.986mmol)和碳酸钾(3.450g,24.965mmol)溶于N,N-二甲基甲酰胺(10mL)中,在80℃下搅拌17小时,然后冷却至室温终止反应。减压浓缩反应混合物以除去溶剂,向浓缩物中加入水,用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%~10%)纯化并浓缩,得到所需化合物4-5(0.742g,40.5%),为白色固体。
步骤2:合成(S)-1-二苯甲基-3-甲基哌嗪(式4-6)
将步骤1制备的式4-5化合物(0.742g,2.025mmol)在室温下溶解于二氯甲烷(10mL)中,向其中加入盐酸(4.00M二氧六环溶液,5.061mL,20.246mmol)溶液,然后在相同温度下搅拌17小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩,得到产物(0.530g,98.3%,白色固体),无需额外纯化即可使用。
步骤3:(S)-7-(4-二苯甲基-2-甲基哌嗪-1-甲酰氨基)庚酸甲酯(式4-7)的合成
在0℃,将三光气(0.111g,0.375mmol)和DIPEA(0.582g,4.505mmol)溶于二氯甲烷(5mL)中,向溶液中加入7-氨基庚酸甲酯盐酸盐(0.176g,0.901mmol),随后在相同温度下搅拌。将步骤2制备的式4-6化合物(0.200g,0.751mmol)加入到反应混合物中,然后在相同温度下搅拌30分钟。向反应混合物中加入水,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=0%~30%)纯化并浓缩,得到所需化合物4-7(0.213g,62.8%),为淡黄色油状物。
步骤4:(S)-4-二苯甲基-N-(7-(羟氨基)-7-氧代庚基)-2-甲基哌嗪-1-甲酰胺(化合物1190)的合成
室温下,将步骤3制备的式4-7化合物(0.100g,0.221mmol)、羟胺(50.00%水溶液,0.271mL,4.429mmol)和氢氧化钾(0.124g,2.214mmol)溶于甲醇(3mL),相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入碳酸氢钠水溶液(30mL),然后搅拌。将沉淀的固体过滤,用水洗涤并干燥,得到所需化合物1190(0.093g,92.8%),为浅橙色固体。
1H NMR(400MHz,DMSO-d6)δ9.43(brs,2H),7.45(t,4H,J=6.3Hz),7.30(t,4H,J=7.6Hz),6.35(t,1H,J=5.5Hz),4.23(s,1H),4.04(brs,1H),3.62(d,1H,J=12.6Hz),3.03-2.92(m,3H),2.67(d,1H,J=10.6Hz),2.60(d,1H,J=11.2Hz),1.95(dd,1H,J=11.1,3.1Hz),1.88(t,2H,J=7.4Hz),1.80-1.75(m,1H),1.45-1.43(m,2H),1.36-1.34(m,2H),1.20-1.18(m,7H).
实施例6:化合物1209的合成
步骤1:1-二苯甲基哌啶-4-羧酸乙酯(式5-2)的合成
将哌啶-4-羧酸乙酯(3.000g,19.083mmol)、(氯亚甲基)二苯(5.802g,28.624mmol)和碳酸钾(13.187g,95.414mmol)溶解在N,N-二甲基甲酰胺(50mL)中,溶液在室温下搅拌17小时,然后在80℃下搅拌3小时。然后,将溶液冷却至室温以终止反应。减压浓缩反应混合物以除去溶剂,向浓缩物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,40g柱;乙酸乙酯/己烷=0%至15%)纯化并浓缩,得到所需的无色油状式5-2化合物(1.410g,22.8%)。
步骤2:1-二苯甲基哌啶-4-羧酸(式5-3)的合成
在室温下,将步骤1制备的式5-2化合物(1.410g,4.360mmol)和LiOH(0.209g,8.719mmol)溶解在甲醇(10mL)/水(5mL)中,并将溶液在60℃下搅拌17小时,然后冷却至室温终止反应。减压浓缩反应混合物以除去溶剂,然后用1N盐酸水溶液中和,减压浓缩除去溶剂,得到产物(1.300g,101.0%,白色固体),无需额外纯化即可使用。
步骤3:7-(1-二苯甲基哌啶-4-甲酰氨基)庚酸甲酯的合成(式5-4)
在室温下,将步骤2制备的式5-3化合物(1.500g,5.078mmol)、7-氨基庚酸甲酯盐酸盐(1.988g,10.156mmol)、EDC(1.947g,10.156mmol)、HBOt(1.372g,10.156mmol)和二异丙胺(4.435mL,25.391mmol)溶于二氯甲烷(30mL)中,将溶液在相同温度下搅拌17小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,40g柱;乙酸乙酯/己烷=0%~40%)纯化并浓缩,得到所需的无色油状式5-4化合物(1.810g,81.6%)。
步骤4:合成1-二苯甲基-N-(7-(羟基氨基)-7-氧代庚基)哌啶-4-甲酰胺(化合物1209)
在0℃下,将步骤3制备的式5-4(1.000g,2.290mmol)、羟基胺(50.00%水溶液,2.802mL,45.809mmol)和氢氧化钾(1.285g,22.904mmol)溶于甲醇(15mL)中,将溶液在相同温度下搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。
得到所需化合物1209(1.000g,99.8%),为浅橙色固体,无需额外纯化。
1H NMR(400MHz,DMSO-d6)δ7.71(t,1H,J=5.4Hz),7.40(d,4H,J=7.3Hz),7.27(t,4H,J=7.5Hz),7.16(t,2H,J=7.3Hz),4.25(s,1H),2.98(q,2H,J=6.4Hz),2.79(d,2H,J=11.0Hz),2.09~2.02(m,1H),1.89(t,2H,J=7.3Hz),1.77(t,2H,J=9.8Hz),1.66~1.59(m,4H),1.45~1.39(m,2H),1.34~1.32(m,2H),1.29~1.27(m,4H);MS(ESI)m/z438.2(M++H).
实施例7:化合物1210的合成
步骤1:1-((1H-咪唑-1-基)磺酰基)-3-甲基-1H-咪唑-3-基三氟甲磺酸酯(式8-3)的合成
在室温下,将1,1'-磺酰基双(1H-咪唑)(5.000g,25.227mmol)和三氟甲磺酸甲酯(2.855mL,25.227mmol)溶解在二氯甲烷(100mL)中,在相同温度下搅拌该溶液3小时。将沉淀的固体过滤并干燥,得到所需式8-3化合物(5.160g,45.3%),为淡黄色油状物。
步骤2:(1-((1H-咪唑-1-基)磺酰基)哌啶-4-基)二苯基甲醇(式8-4)的合成
将二苯基(哌啶-4-基)甲醇(1.000g,3.740mmol)和在步骤1制备的式8-3化合物(2.033g,5.610mmol)在室温下溶于乙腈(20mL)中,在相同温度下搅拌17小时。将反应混合物减压浓缩,浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=0%~40%)纯化并浓缩,得到所需式8-4化合物(0.487g,32.8%),为白色固体。
步骤3:(1-((3-甲基-1H-3-鎓-咪唑-1-基)磺酰基)哌啶-4-基)二苯基甲醇三氟甲磺酸酯(式8-5)的合成
在0℃,将步骤2制备的式8-4化合物(0.487g,1.225mmol)和三氟甲磺酸甲酯(0.146mL,1.286mmol)溶于二氯甲烷(10mL)中,将溶液在室温下搅拌2小时。将沉淀的固体过滤,用二氯甲烷洗涤并干燥,得到所需式8-5化合物(0.670g,97.4%),为白色固体。
步骤4:7-((4-(羟基二苯基甲基)哌啶)-1-亚磺酰氨基)庚酸甲酯(式8-6)的合成
在80℃,将步骤3制备的式8-5化合物(0.504g,0.897mmol)和7-氨基庚酸甲酯盐酸盐(0.228g,1.167mmol)溶于乙腈(3mL)中,将溶液在相同温度下保持12小时,然后冷却至室温以终止反应。向反应混合物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=10%~60%)纯化并浓缩,得到所需式8-6化合物(0.147g,33.5%),为白色固体。
步骤5:N-羟基-7-((4-(羟基二苯基甲基)哌啶)-1-亚磺酰氨基)庚酰胺(化合物1210)的合成
室温下,将步骤4制备的式8-6化合物(0.150g,0.307mmol)、氢氧化钾(0.172g,3.070mmol)和羟胺(50.00%溶液,0.188mL,3.070mmol)溶解在甲醇(1mL)中,将溶液在相同温度下搅拌1小时。向反应混合物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。得到所需化合物1210(0.067g,44.6%),为白色固体,无需额外纯化即可使用。
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.68(s,1H),7.52(d,4H,J=7.4Hz),7.26(t,4H,J=7.6Hz),7.12(m,3H),3.46(m,2H),2.82(m,2H),2.63(m,3H),1.93(t,2H,J=7.3Hz),1.48-1.22(m,13H);MS(ESI)m/z 490.6(M++H).
实施例8:化合物1213的合成
步骤1:7-(4-二苯甲基-N-甲基哌嗪-1-甲酰氨基)庚酸甲酯(式1-4)的合成
在0℃下,将7-(4-二苯甲基哌嗪-1-甲酰氨基)庚酸甲酯(0.100g,0.229mmol)和氢化钠(60.00%,0.046g,1.143mmol)溶于N,N-二甲基甲酰胺(3mL)中,向该溶液中加入碘甲烷(0.071mL,1.143mmol),然后在相同温度下搅拌10分钟。向反应混合物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,4g柱;乙酸乙酯/己烷=10%~40%)纯化,并浓缩,得到所需无色油状式1-4化合物(0.097g,94.0%)。
步骤2:4-二苯甲基-N-(7-(羟基氨基)-7-氧代庚基)-N-甲基哌嗪-1-甲酰胺(化合物1213)的合成
室温下,将步骤1制备的式1-4化合物(0.097g,0.215mmol)、羟胺(50.00%水溶液,0.263mL,4.296mmol)和氢氧化钾(0.121g,2.148mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。得到所需化合物1213(0.010g,10.3%),为白色固体,无需额外纯化。
1H NMR(400MHz,CD3OD)δ7.44(d,4H,J=7.4Hz),7.27(t,4H,J=7.5Hz),7.17(t,2H,J=7.3Hz),4.26(s,1H),3.24-3.22(m,4H),3.17(t,2H,J=7.2Hz),2.81(s,3H),2.41-2.38(m,4H),2.07(t,2H,J=7.4Hz),1.62-1.52(m,4H),1.33-1.24(m,4H);MS(ESI)m/z453.4(M++H).
实施例9:化合物1221的合成
步骤1:N,N-二苯基哌啶-4-胺盐酸盐(式6-4)的合成
在室温下,将4-(二苯基氨基)哌啶-1-甲酸叔丁酯(1.000g,2.837mmol)溶于二氯甲烷(10mL)中,将盐酸(4.00M,1,4-二氧六环溶液,3.546mL,14.185mmol)加入到溶液中,然后在相同温度下搅拌17小时。将沉淀的固体过滤,用二氯甲烷洗涤并干燥,得到所需式6-4化合物(0.800g,97.6%),为白色固体。
步骤2:N,N-二苯基哌啶-4-胺(式6-5)的合成
将步骤1制备的式6-4化合物(0.600g,2.077mmol)在室温下溶于水(5mL)中,向溶液中加入饱和碳酸氢钠水溶液(50mL),在相同温度下搅拌1小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。产物(0.496g,94.6%,无色油)无需额外纯化。
步骤3:7-(4-(二苯基氨基)哌啶-1-甲酰胺基)庚酸甲酯(式6-6)的合成
0℃下,步骤2制备的式6-5化合物(0.100g,0.396mmol)、7-氨基庚酸甲酯盐酸盐(0.078g,0.396mmol)、三光气(0.059g,0.198mmol)和DIPEA(0.415mL,2.378mmol)溶于二氯甲烷(3mL)中,溶液在相同温度下搅拌1小时。然后,在0℃下向反应混合物中加入饱和碳酸氢钠水溶液(50mL),搅拌10分钟。反应完成后,向反应混合物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,4g柱;乙酸乙酯/己烷=10%~60%)纯化并浓缩,得到所需化合物6-6(0.096g,55.4%),为浅黄色油状物。
步骤4:4-(二苯基氨基)-N-(7-(羟基氨基)-7-氧代庚基)哌啶-1-甲酰胺(化合物1221)的合成
室温下,将步骤3制备的式6-6化合物(0.096g,0.219mmol)、羟胺(50.00%水溶液,0.268mL,4.388mmol)和氢氧化钾(0.123g,2.194mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液(20mL)和二氯甲烷(5mL),然后搅拌。将沉淀的固体过滤,用水洗涤并干燥,得到所需化合物1221(0.076g,79.0%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ7.27(t,4H,J=7.8Hz),6.97(t,2H,J=7.2Hz),6.79(d,4H,J=7.8Hz),6.35(t,1H,J=5.4Hz),4.10-4.04(m,1H),3.97(d,2H,J=13.1Hz),2.90(q,2H,J=6.4Hz),2.78(t,2H,J=12.5Hz),1.90(t,2H,J=7.3Hz),1.84(d,2H,J=12.5Hz),1.46-1.39(m,2H),1.31-1.27(m,2H),1.17-1.10(m,4H),1.08-1.01(m,2H).
实施例10:化合物1222的合成
步骤1:二(吡啶-2-基)甲醇(式3-2)的合成
在0℃,将二(吡啶-2-基)甲酮(2.000g,10.858mmol)溶于甲醇(20mL)中,向该溶液中加入NaBH4(0.452g,11.944mmol),在相同温度下搅拌1小时。然后,在0℃下向反应混合物中加入饱和碳酸氢钠水溶液(10mL),搅拌10分钟。反应完成后,向反应混合物中加入水,用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。得到所需式3-2化合物(2.000g,98.9%),为红色油状物,无需额外纯化即可使用。
步骤2:二(吡啶-2-基)甲基甲磺酸酯(式3-3)的合成
在0℃,将步骤1制备的式3-2化合物(1.000g,5.370mmol)、甲磺酰氯(0.623mL,8.055mmol)和三乙胺(2.246mL,16.111mmol)溶于二氯甲烷(10mL),并将该溶液在相同温度下搅拌1小时。向反应混合物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%~30%)纯化,并浓缩,得到所需化合物3-3(0.670g,47.2%),为粉红色固体。
步骤3:7-(4-(二(吡啶-2-基)甲基)哌嗪-1-甲酰氨基)庚酸甲酯(式3-4)的合成
室温下,将步骤2制备的式3-3化合物(0.258g,0.975mmol)、式2-5化合物(0.200g,0.650mmol)和碳酸钾(0.449g,3.249mmol)溶于N,N-二甲基甲酰胺(4mL),并将溶液在80℃下搅拌17小时,然后冷却至室温终止反应。减压浓缩反应混合物以除去溶剂,向浓缩物中加入水,用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,4g柱;甲醇/二氯甲烷=0%~10%)纯化并浓缩,得到所需式3-4化合物(0.255g,89.3%),为橙色油状物。
步骤4:4-(二(吡啶-2-基)甲基)-N-(7-(羟基氨基)-7-氧代庚基)哌嗪-1-甲酰胺(化合物1222)的合成
室温下,将步骤3制备的式3-4化合物(0.255g,0.580mmol)、羟胺(50.00%水溶液,0.710mL,11.603mmol)和氢氧化钾(0.326g,5.801mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,浓缩物通过柱色谱法(Waters,C18;1%甲酸水溶液/乙腈水溶液=70%~5%)纯化,通过SPE柱(PL-HCO3树脂)浓缩,得到所需化合物1222(0.051g,20.0%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ8.46(dt,2H,J=4.8,0.8Hz),7.77(td,2H,J=7.7,1.7Hz),7.62(d,2H,J=7.8Hz),7.25-7.22(m,2H),6.40(t,1H,J=5.2Hz),4.64(s,1H),3.28-3.27(m,4H),2.96(q,2H,J=6.6Hz),2.25(t,4H,J=4.7Hz),1.92(t,2H,J=7.3Hz),1.48-1.43(m,2H),1.35-1.33(m,2H),1.21-1.20(m,4H).
实施例11:化合物1223的合成
步骤1:4-((7-甲氧基-7-氧代庚基)氨基甲酰基)哌嗪-1-甲酸叔丁酯(式2-2)的合成
在0℃,将三光气(4.780g,16.107mmol)和二异丙基胺(16.879mL,96.644mmol)溶于二氯甲烷(100mL)中,向溶液中加入7-氨基庚酸甲酯盐酸盐(6.304g,32.215mmol),随后在相同温度下搅拌。向反应混合物中加入哌嗪-1-羧酸叔丁酯(6.000g,32.215mmol),同时搅拌1小时。然后,在0℃下向反应混合物中加入饱和碳酸氢钠水溶液(100mL),搅拌10分钟。反应完成后,向反应混合物中加入水,用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,80g柱;甲醇/二氯甲烷=0%~5%)纯化并浓缩,得到所需式2-2化合物(3.430g,28.7%),为淡黄色油状物。
步骤2:7-(哌嗪-1-甲酰氨基)庚酸甲酯盐酸盐(式2-5)的合成
将步骤1制备的式2-2化合物(3.430g,9.233mmol)在室温下溶解于二氯甲烷(50mL)中,并将盐酸(4.00M二氧六环溶液,11.542mL,46.167mmol)加入到该溶液中,然后在相同温度下搅拌17小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入乙酸乙酯(50mL),然后搅拌。将沉淀的固体过滤,用乙酸乙酯洗涤并干燥,得到所需式2-5化合物(2.300g,80.9%),为白色固体。
步骤3:4,4'-(氯亚甲基)双(氟苯)(式2-4)的合成
将双(4-氟苯基)甲醇(5.000g,22.706mmol)溶解在二氯甲烷(50mL)中,在室温下搅拌4小时,加入亚硫酰氯(1.812mL,24.976mmol)。然后,将溶液在40℃下搅拌2小时,然后冷却至室温终止反应。将反应混合物减压浓缩以除去溶剂。作为产物,得到所需式2-4化合物(5.350g,98.7%),为橙色油,无需额外纯化即可使用。
步骤4:7-(4-(双(4-氟苯基)甲基)哌嗪-1-甲酰胺基)庚酸甲酯(式2-6)的合成
室温下,将步骤3制备的式2-4化合物(0.233g,0.975mmol)、7-(哌嗪-1-甲酰胺基)庚酸甲酯盐酸盐(0.200g,0.650mmol)和碳酸钾(0.449g,3.249mmol)溶解在N,N-二甲基甲酰胺(4mL)溶液中,将溶液在80℃下搅拌17小时,然后冷却至室温终止反应。减压浓缩反应混合物以除去溶剂,向浓缩物中加入水,用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,4g柱;甲醇/二氯甲烷=0%~10%)纯化并浓缩,得到所需式2-6化合物(0.101g,32.8%),为浅棕色油状物。
步骤5:4-(双(4-氟苯基)甲基)-N-(7-(羟基氨基)-7-氧代庚基)哌嗪-1-甲酰胺(化合物1223)的合成
室温下,将步骤4制备的式2-6化合物(0.101g,0.213mmol)、羟胺(50.00%水溶液,0.261mL,4.266mmol)和氢氧化钾(0.120g,2.133mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。将反应混合物减压浓缩以除去溶剂,浓缩物通过柱色谱法(Waters,C18;1%甲酸水溶液/乙腈=70%~5%)纯化,并通过SPE柱(PL-HCO3树脂)浓缩,得到所需化合物1223(0.002g,2.0%),为白色固体。
1H NMR(400MHz,CD3OD)δ7.48-7.44(m,4H),7.04(t,4H,J=8.8Hz),6.44(t,1H,J=5.3Hz),4.31(s,1H),3.39(t,4H,J=5.0Hz),3.16-3.12(m,2H),2.36(t,4H,J=5.0Hz),2.09(t,2H,J=7.4Hz),1.64-1.61(m,2H),1.51-1.48(m,2H),1.35-1.33(m,4H);MS(ESI)m/z 475.3(M++H).
实施例12:化合物1224的合成
步骤1:4,4'-(氯亚甲基)双(氯苯)(式2-4)的合成
在0℃,将双(4-氯苯基)甲醇(10.000g,39.507mmol)溶于二氯甲烷(100mL)中,向该溶液中加入亚硫酰氯(3.153mL,43.458mmol),然后在室温下搅拌5个小时。将反应混合物减压浓缩以除去溶剂。得到所需式2-4化合物(10.700g,99.7%),为白色固体,无需额外纯化。
步骤2:7-(4-(双(4-氯苯基)甲基)哌嗪-1-甲酰胺基)庚酸甲酯(式2-6)的合成
室温下,将步骤1制备的式2-4化合物(0.265g,0.975mmol)、式2-5化合物(0.200g,0.650mmol)和碳酸钾(0.449g,3.249mmol)溶于N,N-二甲基甲酰胺(4mL),并将该溶液在80℃下搅拌17小时,然后冷却至温度以终止反应。减压浓缩反应混合物以除去溶剂,向浓缩物中加入水,用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,4g柱;甲醇/二氯甲烷=0%~10%)纯化并浓缩,得到所需化合物2-6(0.271g,82.4%),为浅黄色油状物。
步骤3:4-(双(4-氯苯基)甲基)-N-(7-(羟基氨基)-7-氧代庚基)哌嗪-1-甲酰胺(化合物1224)的合成
室温下,将步骤2制备的式2-6化合物(0.271g,0.535mmol)、羟胺(50.00%水溶液,0.655mL,10.702mmol)和氢氧化钾(0.300g,5.351mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。将反应混合物减压浓缩以除去溶剂,浓缩物通过柱色谱法(Waters,C18;1%甲酸水溶液/乙腈=70%~5%)纯化,并通过SPE柱(PL-HCO3树脂)浓缩,得到所需化合物1224(0.035g,12.9%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ10.34(brs,1H),8.69(brs,1H),7.43(d,4H,J=8.6Hz),7.37(d,4H,J=8.4Hz),6.41(t,1H,J=5.3Hz),4.40(s,1H),3.28-3.27(m,4H),2.96(q,2H,J=6.4Hz),2.22-2.21(m,4H),1.92(t,2H,J=7.4Hz),1.48-1.44(m,2H),1.37-1.35(m,2H),1.24-1.21(m,4H);MS(ESI)m/z 507.4(M++H).
实施例13:化合物1240的合成
步骤1:8-(4-二苯甲基哌嗪-1-羧酰氨基)辛酸甲酯(式1-3)的合成
在0℃,将三光气(0.118g,0.396mmol)和二异丙基胺(0.830mL,4.755mmol)溶于二氯甲烷(5mL)中,向溶液中加入8-氨基辛酸甲酯盐酸盐(0.166g,0.793mmol),随后搅拌1小时。将原料(0.200g,0.793mmol)加入到反应混合物中,然后在相同温度下搅拌1小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,4g柱;乙酸乙酯/己烷=10%~70%)纯化并浓缩,得到所需式1-3化合物(0.158g,44.1%),为浅黄色固体。
步骤2:4-二苯甲基-N-(8-(羟基氨基)-8-氧代乙基)哌嗪-1-甲酰胺(化合物1240)的合成
室温下,将步骤1制备的式1-3化合物(0.158g,0.350mmol)、羟胺(50.00%水溶液,0.428mL,6.997mmol)和氢氧化钾(0.196g,3.499mmol)溶于甲醇(3mL),在相同温度下搅拌30分钟。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液(20mL),然后搅拌。将沉淀的固体过滤,用水洗涤并干燥,得到所需化合物1240(0.074g,46.7%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ9.49(brs,2H),7.43(d,4H,J=7.5Hz),7.30(t,4H,J=7.6Hz),7.19(t,2H,J=7.3Hz),6.42(t,1H,J=5.2Hz),4.29(s,1H),3.28-3.27(m,4H),2.97(q,2H,J=6.4Hz),2.23-2.22(m,4H),1.90(t,2H,J=7.3Hz),1.47-1.44(m,2H),1.37-1.34(m,2H),1.22(brs,4H);MS(ESI)m/z 453.6(M++H).
实施例14:化合物1241的合成
步骤1:7-(4-(1-苯基乙基)哌嗪-1-甲酰氨基)庚酸甲酯(式9-2)的合成
将式2-5化合物(0.150g,0.553mmol)和苯乙酮(0.100g,0.829mmol)溶于二氯甲烷(3mL)中,将溶液在室温下搅拌10分钟。然后,向溶液中加入NaBH(OAc)3(0.234g,1.106mmol),在相同温度下搅拌17小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,4g柱;甲醇/二氯甲烷=0%~5%)纯化并浓缩,得到所需式9-2化合物(0.038g,18.3%),为无色油状。
步骤2:N-(7-(羟基氨基)-7-氧代庚基)-4-(1-苯乙基)哌嗪-1-甲酰胺(化合物1241)的合成
室温下,将步骤1制备的式9-2化合物(0.038g,0.101mmol)、羟胺(50.00%水溶液,0.124mL,2.024mmol)和氢氧化钾(0.057g,1.012mmol)溶于甲醇(3mL),在相同温度下搅拌30分钟。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。得到所需化合物1241(0.013g,34.1%),为浅橙色固体,无需额外纯化。
1H NMR(400MHz,DMSO-d6)δ7.32-7.30(m,4H),7.26-7.23(m,1H),3.71-3.34(m,5H),3.11(t,2H,J=7.1Hz),2.50-2.45(m,2H),2.37-2.32(m,2H),2.05(t,2H,J=7.4Hz),1.61-1.56(m,2H),1.49-1.44(m,2H),1.37(d,3H,J=7.6Hz),1.33-1.29(m,4H);MS(ESI)m/z 477.2(M++H).
实施例15:化合物1243的合成
步骤1:1-(1-苯基乙基)哌啶-4-羧酸乙酯(式10-2)的合成
将苯乙酮(1.050g,8.739mmol)和哌啶-4-甲酸乙酯(1.751mL,11.361mmol)在室温下溶于二氯甲烷(10mL)中,向该溶液中加入STAB(2.408g,11.361mmol),然后在相同温度下搅拌12小时。向反应混合物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=0%~50%)纯化并浓缩,得到所需式10-2化合物(0.700g,30.6%),为无色油状物。
步骤2:1-(1-苯基乙基)哌啶-4-甲酸(式10-3)的合成
在40℃,将步骤1制备的式10-2化合物(0.700g,2.678mmol)和LiOH(0.096g,4.017mmol)溶于甲醇(3mL)/水(1mL)中,并将溶液在相同温度下搅拌5小时,然后冷却至室温。然后在0℃向反应混合物中加入1M HCl,搅拌10分钟。反应完成后,向反应混合物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩,得到产物(0.500g,69.2%,白色泡沫固体),无需额外纯化即可使用。
步骤3:7-(1-(1-苯基乙基)哌啶-4-甲酰氨基)庚酸甲酯(式10-4)的合成
步骤2制备的式10-3化合物(0.300g,1.286mmol)、7-氨基庚酸甲酯盐酸盐(0.503g,2.572mmol)、EDC(0.493g,2.572mmol)、HOBt(0.347g,2.572mmol)和二异丙基胺(1.123mL,6.429mmol)在室温下溶于二氯甲烷(4mL)/N,N-二甲基甲酰胺(1mL)中,将溶液在相同温度下搅拌17小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,4g柱;甲醇/二氯甲烷=0%~10%)纯化并浓缩,得到所需化合物10-4(0.122g,25.3%),为棕色油状物。
步骤4:N-(7-(羟基氨基)-7-氧代庚基)-1-(1-苯基乙基)哌啶-4-甲酰胺(化合物1243)的合成
室温下,将步骤3制备的式10-4化合物(0.122g,0.326mmol)、羟胺(50.00%水溶液,0.398mL,6.515mmol)和氢氧化钾(0.183g,3.257mmol)溶于甲醇(3mL),在相同温度下搅拌30分钟。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。得到所需化合物1243(0.074g,60.5%),为橙色固体,无需额外纯化。
1H NMR(400MHz,DMSO-d6)δ10.19(brs,1H),8.71(brs,1H),7.64(t,1H,J=5.6Hz),7.32-7.27(m,4H),7.23-7.20(m,1H),3.40-3.37(m,1H),3.00-2.95(m,3H);MS(ESI)m/z376.3(M++H)
实施例16:化合物1256的合成
步骤1:7-(1-二苯甲基-N-甲基哌啶-4-甲酰氨基)庚酸甲酯(式5-5)的合成
将7-(1-二苯甲基哌啶-4-甲酰氨基)庚酸甲酯(0.200g,0.458mmol)和氢化钠(60.00%,0.092g,2.290mmol)溶于N,N-二甲基甲酰胺(5mL)中,溶液在室温下搅拌10分钟。然后,向搅拌的溶液中加入碘甲烷(0.143mL,2.290mmol),在相同温度下搅拌17小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,4g柱;乙酸乙酯/己烷=10%~70%)纯化并浓缩,得到所需化合物5-5(0.089g,43.1%),为浅黄色油状物。
步骤2:1-二苯甲基-N-(7-(羟基氨基)-7-氧代庚基)-N-甲基哌啶-4-甲酰胺(化合物1256)
室温下,将步骤1制备的式5-5化合物(0.089g,0.198mmol)、羟胺(50.00%水溶液,0.242mL,3.950mmol)和氢氧化钾(0.111g,1.975mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。得到所需化合物1256(0.089g,99.8%),为白色固体,无需额外纯化。
1H NMR(400MHz,DMSO-d6)δ9.50(brs,2H),7.40(d,4H,J=7.2Hz),7.29(t,4H,J=7.6Hz),7.18(t,2H,J=7.3Hz),4.30(s,1H),3.23(q,2H,J=7.5Hz),2.94(s,2H),2.81(d,2H,J=11.4Hz),2.76(s,1H),1.91-1.83(m,4H),1.69-1.53(m,4H),1.46-1.37(m,4H),1.24-1.19(m,4H);MS(ESI)m/z 452.6(M++H).
实施例17:化合物1257的合成
步骤1:6-(4-二苯甲基哌嗪-1-甲酰氨基)己酸甲酯(式1-3)的合成
在0℃,将三光气(0.294g,0.991mmol)和二异丙基胺(2.076mL,11.888mmol)溶于二氯甲烷(10mL)中,向溶液中加入6-氨基己酸甲酯盐酸盐(0.360g,1.981mmol),随后在相同温度下搅拌。将1-二苯甲基哌嗪(0.500g,1.981mmol)加入到反应混合物中,然后在相同温度下搅拌1小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=0%至40%)纯化并浓缩,得到所需式1-3化合物(0.320g,38.1%),为黄色油状物。
步骤2:4-二苯甲基-N-(6-(羟基氨基)-6-氧代己基)哌嗪-1-甲酰胺(化合物1257)的合成
室温下,将步骤1制备的式1-3化合物(0.200g,0.472mmol)、羟胺(50.00%水溶液,0.578mL,9.444mmol)和氢氧化钾(0.265g,4.722mmol)溶于甲醇(5mL),在相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。得到所需化合物1257(0.049g,24.4%),为浅黄色固体,无需额外纯化。
1H NMR(400MHz,DMSO-d6)δ7.43(d,4H,J=7.2Hz),7.30(t,4H,J=7.6Hz),7.19(t,2H,J=7.3Hz),6.42(t,1H,J=5.4Hz),4.29(s,1H),3.27(t,4H,J=4.5Hz),2.96(q,2H,J=6.4Hz),2.23(t,4H,J=4.6Hz),1.90(t,2H,J=7.4Hz),1.47-1.44(m,2H),1.38-1.34(m,2H),1.20-1.16(m,2H);MS(ESI)m/z 425.5(M++H).
实施例18:化合物1316的合成
步骤1:6-(1-二苯甲基哌啶-4-甲酰氨基)己酸甲酯(式5-4)的合成
室温下,将式5-3化合物(0.300g,1.016mmol)、6-氨基己酸甲酯盐酸盐(0.369g,2.031mmol)、EDC(0.389g,2.031mmol)、HOBt(0.274g,2.031mmol)和二异丙基胺(0.887mL,5.078mmol)溶解在二氯甲烷(3mL)/N,N-二甲基甲酰胺(0.5mL)中,将溶液在相同温度下搅拌17小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%~30%)纯化并浓缩,得到所需式5-4化合物(0.161g,37.5%),为浅黄色油状物。
步骤2:1-二苯甲基-N-(6-(羟基氨基)-6-氧代己基)哌啶-4-甲酰胺(化合物1316)的合成
室温下,将步骤1制备的式5-4化合物(0.161g,0.381mmol)、羟胺(50.00%水溶液,0.466mL,7.620mmol)和氢氧化钾(0.214g,3.810mmol)溶于甲醇(3mL),在相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。得到所需化合物1316(0.056g,34.7%),为白色固体,无需额外纯化。
1H NMR(400MHz,DMSO-d6)δ10.33(brs,1H),8.66(brs,1H),7.70(t,1H,J=5.6Hz),7.41(d,4H,J=7.4Hz),7.17(t,2H,J=7.4Hz),4.26(s,2H),2.99-2.28(m,2H),2.80(d,2H,J=11.5Hz),2.09-2.02(m,1H),1.91(t,2H,J=7.5Hz),1.80-1.75(m,2H),1.68-1.59(m,4H).
实施例19:化合物1317的合成
步骤1:8-(1-二苯甲基哌啶-4-甲酰氨基)辛酸甲酯(式5-4)的合成
室温下,将式5-3化合物(0.300g,1.016mmol)、8-氨基辛酸甲酯盐酸盐(0.426g,2.031mmol)、EDC(0.389g,2.031mmol)、HOBt(0.274g,2.031mmol)和二异丙基胺(0.887mL,5.078mmol)溶解在二氯甲烷(3mL)/N,N-二甲基甲酰胺(0.5mL)中,将溶液在相同温度下搅拌17小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=0%~30%)纯化并浓缩,得到所需式5-4化合物(0.220g,49.6%),为无色油状物。
步骤2:1-二苯甲基-N-(8-(羟基氨基)-8-氧代乙基)哌啶-4-甲酰胺(化合物1317)的合成
室温下,将步骤1制备的式5-4化合物(0.220g,0.488mmol),羟胺(50.00%水溶液,0.597mL,9.764mmol)和氢氧化钾(0.274g,4.882mmol)溶于甲醇(5mL),在相同温度下将溶液搅拌1小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入饱和碳酸氢钠水溶液(20mL),然后搅拌。将沉淀的固体过滤,用水洗涤并干燥,得到所需化合物1317(0.189g,85.7%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ9.46(brs,2H),7.73(t,1H,J=5.3Hz),7.41(d,4H,J=8.0Hz),7.28(t,4H,J=7.5Hz),7.17(t,2H,J=7.3Hz),4.26(s,1H),2.99(q,2H,J=6.4Hz),2.80(d,2H,J=11.1Hz),2.10-2.04(m,1H),1.87(t,2H,J=7.3Hz),1.78(t,2H,J=10.0Hz),1.67-1.56(m,4H),1.46-1.42(m,2H),1.36-1.33(m,2H),1.21(brs,6H).
实施例20:化合物1647的合成
步骤1:2,2'-(氯亚甲基)双(氟苯)(式2-4)的合成
将双(2-氟苯基)甲醇(0.500g,2.270mmol)和三乙胺(0.348mL,2.498mmol)在室温下溶于二氯甲烷(5mL)中,加入甲磺酰氯(0.193mL,2.498mmol),然后在相同温度下搅拌18小时。向反应混合物中加入水,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%~5%)纯化并浓缩,得到所需式2-4化合物(0.290g,53.5%),为无色油状物。
步骤2:7-(4-(双(2-氟苯基)甲基)哌嗪-1-甲酰氨基)庚酸甲酯(式2-6)的合成
80℃下,将步骤1制备的式2-4化合物(0.448g,1.877mmol)、7-(哌嗪-1-基)庚酸甲酯盐酸盐(0.746g,2.816mmol)和碳酸钾(1.297g,9.386mmol)溶解在N,N-二甲基甲酰胺(8mL)中,在相同温度下搅拌16小时,然后冷却至室温终止反应。向反应混合物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%~60%)纯化并浓缩,得到所需式2-6化合物(0.170g,19.1%),为亮黄色固体。
步骤3:4-(双(2-氟苯基)甲基)-N-(7-(羟基氨基)-7-氧代庚基)哌嗪-1-甲酰胺(化合物1647)的合成
在0℃,将步骤2制备的式2-6化合物(0.200g,0.422mmol)和羟胺(50.00%水溶液,0.258mL,4.223mmol)溶于甲醇(5mL)中,将溶液在室温3小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入甲醇(10mL)和饱和碳酸氢钠水溶液(90mL),然后搅拌。将沉淀的固体过滤,用水洗涤并干燥,得到所需化合物1647(0.200g,99.8%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ7.59-7.55(m,2H),7.31-7.26(m,2H),7.23-7.19(m,2H),7.16-7.11(m,2H),6.42(t,1H,J=5.5Hz),4.96(s,1H),3.29-3.28(m,4H),2.99-2.94(m,2H),2.28-2.26(m,4H),1.93-1.89(m,2H),1.47-1.43(m,2H),1.37-1.33(m,2H),1.19-1.20(m,4H);MS(ESI)m/z 475.4(M++H).
实施例21:化合物1648的合成
步骤1:3,3'-(氯亚甲基)双(氟苯)(式2-4)的合成
将二(3-氟苯基)甲醇(1.000g,4.541mmol)和三乙胺(0.696mL,4.995mmol)溶解在二氯甲烷(10mL)中,向溶液中加入甲磺酰氯(0.387mL,4.995mmol),随后在相同温度下搅拌18小时。向反应混合物中加入水,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%~5%)纯化,并浓缩,得到所需式2-4化合物(0.670g,61.8%),为无色油状物。
步骤2:7-(4-(双(3-氟苯基)甲基)哌嗪-1-甲酰氨基)庚酸酯(式2-6)的合成
80℃下,步骤1制备的式2-4化合物(0.670g,2.807mmol)、7-(哌嗪-1-基)庚酸甲酯盐酸盐(1.115g,4.211mmol)和碳酸钾(1.940g,14.037mmol)溶解在N,N-二甲基甲酰胺(10mL)中,在相同温度下搅拌16小时,然后冷却至室温终止反应。向反应混合物中加入水,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,24g柱;乙酸乙酯/己烷=0%~50%)纯化并浓缩,得到所需式2-6(0.294g,22.1%),为白色固体。
步骤3:4-(双(3-氟苯基)甲基)-N-(7-(羟基氨基)-7-氧代庚基)哌嗪-1-甲酰胺(化合物1648)的合成
在0℃,将步骤2制备的式2-6化合物(0.100g,0.211mmol)和羟胺(50.00%水溶液,0.129mL,2.112mmol)溶于甲醇(3mL)中,将溶液在室温下搅拌3小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入甲醇(10mL)和饱和碳酸氢钠水溶液(90mL),然后搅拌。将沉淀的固体过滤,用水洗涤并干燥,得到所需化合物1648(0.097g,97.1%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.72(s,1H),7.38-7.33(m,2H),7.28-7.25(m,4H),7.06-7.01(m,2H),6.40(t,1H,J=5.5Hz),4.41(s,1H),3.29-3.27(m,4H),2.99-2.94(m,2H),2.24-2.22(m,4H),1.93-1.90(m,2H),1.47-1.44(m,2H),1.37-1.33(m,2H),1.21-1.20(m,4H);MS(ESI)m/z 475.4(M++H).
实施例22:化合物1649的合成
步骤1:7-(4-(羟基二苯基甲基)哌啶-1-甲酰氨基)庚酸甲酯(式7-4)的合成
在0℃,将7-氨基庚酸甲酯盐酸盐(0.366g,1.870mmol)和三光气(0.277g,0.935mmol)溶于二氯甲烷(10mL)中,加入N,N-二异丙基乙胺(0.977mL,5.610mmol)溶液,然后搅拌1小时。将二苯基(哌啶-4-基)甲醇(0.500g,1.870mmol)加入到反应混合物中,然后在相同温度下搅拌1小时。向反应混合物中加入水,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%至50%)纯化并浓缩,得到所需无色油状式7-4化合物(0.609g,71.9%)。
步骤2:7-(4-(氟代二苯基甲基)哌啶-1-甲酰氨基)庚酸甲酯(式7-5)
在0℃,将步骤1制备的式7-4化合物(0.300g,0.663mmol)溶于二氯甲烷(5mL)中,并向溶液中加入二乙基氨基三氟化硫(DAST,0.114mL,0.862mmol),随后通过在室温下搅拌16小时。向反应混合物中加入水,然后用二氯甲烷萃取。将萃取液通过塑料过滤器过滤以除去固体残余物和水层,然后减压浓缩。浓缩物通过柱色谱法(SiO2,12g柱;乙酸乙酯/己烷=0%至50%)纯化并浓缩,得到所需式7-5化合物(0.143g,47.5%),为白色固体。
步骤3:4-(氟二苯基甲基)-N-(7-(羟基氨基)-7-氧代庚基)哌啶-1-甲酰胺(化合物1649)的合成
在0℃,将步骤2制备的式7-5化合物(0.140g,0.308mmol)和羟胺(50.00%水溶液,0.188mL,3.080mmol)溶于甲醇(3mL)中,将溶液在室温3小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入甲醇(10mL)和饱和碳酸氢钠水溶液(90mL),然后搅拌。将沉淀的固体过滤,用水洗涤并干燥,得到所需化合物1649(0.122g,87.0%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ7.49-7.47(m,4H),7.37-7.33(m,4H),7.26-7.22(m,2H),6.36(t,1H,J=5.5Hz),3.95-3.92(m,2H),2.98-2.79(m,3H),2.65-2.59(m,2H),1.93-1.89(m,2H),1.47-1.44(m,2H),1.36-1.33(m,2H),1.29-1.20(m,8H);MS(ESI)m/z 456.6(M++H).
实施例23:化合物1719的合成
步骤1:4-(苯基氨基)哌啶-1-甲酸叔丁酯(式6-2)的合成
在室温下,将4-氧代哌啶-1-甲酸叔丁酯(5.000g,25.094mmol)、苯胺(2.749mL,30.113mmol)和乙酸(2.155mL,37.641mmol)溶于二氯甲烷(50mL)中,将三乙酰氧基硼氢化钠(5.850g,27.604mmol)加入到该溶液中,然后在相同温度下搅拌16小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。将乙酸乙酯(100mL)加入浓缩物中,然后搅拌。将沉淀的固体过滤,用己烷洗涤并干燥,得到所需式6-2化合物(4.640g,66.9%),为白色固体。
步骤2:4-((3-氟苯基)(苯基)氨基)哌啶-1-甲酸叔丁酯(式6-3)的合成
在110℃,将步骤1制备的式6-2化合物(0.500g,1.809mmol)、1-氟-3-碘苯(0.422g,1.900mmol)、乙酸钯(II,0.016g,0.072mmol)、2,2'-双(二苯基膦基)-1,1'-联萘(0.051g,0.081mmol)和叔丁醇钾(0.254g,2.261mmol)溶于甲苯(5mL)中,将溶液在相同温度下搅拌16小时,然后冷却至室温终止反应。将反应混合物通过硅藻土垫过滤以除去固体,向滤液中加入饱和氯化钠水溶液,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=0%~10%)纯化并浓缩,得到所需式6-3化合物(0.292g,43.6%),为黄色固体。
步骤3:N-(3-氟苯基)-N-苯基哌啶-4-胺盐酸盐(式6-4)的合成
将在步骤2制备的式6-3化合物(0.285g,0.769mmol)在相同温度下溶于二氯甲烷(10mL)中,向溶液中加入氯化氢(4.00M二氧六环溶液,0.962mL,3.846mmol),然后在相同温度下搅拌16小时。将反应混合物减压浓缩以除去溶剂,得到产物(0.212g,89.8%,黄色固体),无需额外纯化即可使用。
步骤4:7-(4-((3-氟苯基)(苯基)氨基)哌啶-1-甲酰氨基)庚酸甲酯(式6-6)的合成
在0℃,将7-氨基庚酸甲酯盐酸盐(0.135g,0.691mmol)和三光气(0.103g,0.345mmol)溶于二氯甲烷(10mL)中,向溶液中加入N,N-二异丙基乙胺(0.361mL,2.073mmol),然后在相同温度下搅拌。向反应混合物中加入步骤3制备的式6-4化合物(0.212g,0.691mmol),在室温下搅拌3小时。然后,向反应混合物中加入饱和碳酸氢钠水溶液,用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,4g柱;乙酸乙酯/己烷=0%~50%)纯化并浓缩,得到所需式6-6化合物(0.219g,69.6%),为无色油状物。
步骤5:4-((3-氟苯基)(苯基)氨基)-N-(7-(羟基氨基)-7-氧代庚基)哌啶-1-甲酰胺(化合物1719)的合成
在0℃下,将步骤4制备的式6-6化合物(0.219g,0.481mmol)、羟胺(50.00%水溶液,0.294mL,4.807mmol)和氢氧化钾(0.270g,4.807mmol)溶于甲醇(5mL),将溶液在室温下搅拌3小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入甲醇(1mL)和饱和碳酸氢钠水溶液(30mL),然后搅拌。将沉淀的固体过滤,用己烷洗涤并干燥,得到所需化合物1719(0.196g,89.3%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ7.44-7.42(m,2H),7.32-7.28(m,1H),7.16-7.10(m,1H),7.05-7.03(m,2H),6.51-6.46(m,1H),6.37-6.32(m,3H),4.10-4.08(m,1H),3.97-3.94(m,2H),2.92-2.87(m,2H),2.83-2.77(m,2H),1.92-1.88(m,2H),1.85-1.52(m,2H),1.45-1.41(m,2H),1.30-1.27(m,2H),1.16-1.08(m,4H),1.06-1.00(m,2H);MS(ESI)m/z 457.5(M++H).
实施例24:化合物1726的合成
步骤1:4-(苯基(4-(三氟甲基)苯基)氨基)哌啶-1-甲酸叔丁酯(式6-3)的合成
在110℃下,将4-(苯基氨基)哌啶-1-羧酸叔丁酯(1.000g,3.618mmol)、1-碘-4-(三氟甲基)苯(1.033g,3.799mmol)、乙酸钯(II,0.032g,0.145mmol)、2,2'-双(二苯基膦基)-1,1'-联萘(0.101g,0.163mmol)和叔丁醇钾(0.507g,4.523mmol)溶于甲苯(5mL)中,溶液在相同温度下搅拌16小时,然后冷却至室温以终止反应。将反应混合物通过硅藻土垫过滤以除去固体,并将水加入到滤液中,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=0%~10%)纯化并浓缩,得到所需化合物6-3(0.040g,2.9%),为棕色油状物。
步骤2:N-苯基-N-(4-(三氟甲基)苯基)哌啶-4-胺盐酸盐(式6-4)的合成
将步骤1制备的式6-3化合物(0.890g,2.494mmol)在室温下溶于二氯甲烷(20mL)中,向溶液中加入盐酸(4.00M溶液,3.118mL,12.471mmol),然后在相同温度下搅拌16小时。将反应混合物减压浓缩以除去溶剂,得到产物(0.890g,100.0%,黄色固体),无需额外纯化即可使用。
步骤3:7-(4-(苯基(4-(三氟甲基)苯基)氨基)哌啶-1-甲酰氨基)庚酸甲酯(式6-6)的合成
在0℃,将7-氨基庚酸甲酯盐酸盐(0.219g,1.121mmol)和三光气(0.166g,0.561mmol)溶于二氯甲烷(10mL)中,向溶液中加入N,N-二异丙基乙胺(0.586mL,3.363mmol),然后在相同温度下搅拌。向反应混合物中加入式6-4化合物(0.400g,1.121mmol),然后在室温下搅拌3小时。向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=0%~50%)纯化并浓缩,得到所需式6-6化合物(0.277g,48.9%),为无色油状物。
步骤4:N-(7-(羟基氨基)-7-氧代庚基)-4-(苯基(4-(三氟甲基)苯基)氨基)哌啶-1-甲酰胺(化合物1726)的合成
在室温下,将在步骤3制备的式6-6(0.170g,0.336mmol)和羟胺(50.00%水溶液,0.205mL,3.356mmol)的化合物溶于甲醇(5mL)中,向该溶液中加入氢氧化钾(0.188g,3.356mmol),然后在相同温度下搅拌18小时。减压浓缩反应混合物以除去溶剂,过滤沉淀的固体,用己烷洗涤并干燥,得到所需化合物1726(0.139g,81.8%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.66(s,1H),7.21-7.16(m,4H),6.97-6.93(m,2H),6.84-6.80(m,1H),6.67-6.65(m,2H),6.36-6.34(m,1H),4.07-4.02(m,1H),3.98-3.95(m,2H),2.93-2.88(m,2H),2.81-2.75(m,2H),1.93-1.89(m,2H),1.85-1.82(m,2H),1.45-1.43(m,2H),1.31-1.27(m,2H),1.18-1.15(m,4H),1.05-1.01(m,2H);MS(ESI)m/z 457.5(M++H).
实施例25:化合物1734的合成
步骤1:4-((4-氟苯基)(苯基)氨基)哌啶-1-羧酸叔丁酯(式6-3)的合成
在110℃下,将4-(苯基氨基)哌啶-1-甲酸叔丁酯(0.820g,2.967mmol)、1-氟-4-碘苯(0.358mL,3.115mmol)、乙酸钯(II,0.027g,0.119mmol)、2,2'-双(二苯基膦基)-1,1'-联萘(0.083g,0.134mmol)和叔丁醇钾(0.416g,3.709mmol)溶于甲苯(5mL)中,并将溶液搅拌在相同温度下搅拌16小时,然后冷却至室温以终止反应。将反应混合物通过硅藻土垫过滤以除去固体,并将水加入到滤液中,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,12g柱;乙酸乙酯/己烷=0%~10%)纯化并浓缩,得到所需式6-3化合物(0.352g,32.0%),为亮黄色固体。
步骤2:N-(4-氟苯基)-N-苯基哌啶-4-胺盐酸盐(式6-4)的合成
将在步骤1制备的式6-3的化合物(0.340g,0.918mmol)和盐酸(4.00M溶液,1.147mL,4.589mmol)在室温下溶于二氯甲烷(5mL)中,并将溶液在相同温度下搅拌18小时。将反应混合物减压浓缩以除去溶剂,得到产物(0.281g,99.8%,黄色固体),无需额外纯化即可使用。
步骤3:7-(4-((4-氟苯基)(苯基)氨基)哌啶-1-甲酰氨基)庚酸甲酯(式6-6)的合成
在0℃,将7-氨基庚酸甲酯盐酸盐(0.179g,0.913mmol)和三光气(0.135g,0.456mmol)溶于二氯甲烷(10mL)中,向溶液中加入N,N-二异丙基乙胺(0.477mL,2.738mmol),然后在相同温度下搅拌。向反应混合物中加入步骤2制备的式6-4化合物(0.280g,0.913mmol),然后在室温下搅拌3小时。然后,向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱(SiO2,4g柱;乙酸乙酯/己烷=0%~50%)纯化并浓缩,得到所需式6-6化合物(0.185g,44.5%),为无色油状物。
步骤4:4-((4-氟苯基)(苯基)氨基)-N-(7-(羟基氨基)-7-氧代庚基)哌啶-1-甲酰胺(化合物1734)的合成
在0℃,将步骤3制备的式6-6化合物(0.260g,0.569mmol)和羟胺(50.00%水溶液,0.348mL,5.695mmol)溶于甲醇(5mL)中,将溶液在室温下搅拌3小时。减压浓缩反应混合物以除去溶剂,过滤沉淀的固体,用己烷洗涤并干燥,得到所需化合物1734(0.185g,71.2%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.66(s,1H),7.21-7.16(m,4H),6.97-6.93(m,2H),6.84-6.80(m,1H),6.67-6.65(m,2H),6.36-6.34(m,1H),4.07-4.02(m,1H),3.98-3.95(m,2H),2.93-2.88(m,2H),2.81-2.75(m,2H),1.93-1.89(m,2H),1.85-1.82(m,2H),1.45-1.43(m,2H),1.31-1.27(m,2H),1.18-1.15(m,4H),1.05-1.01(m,2H);MS(ESI)m/z 457.5(M++H).
实施例26:化合物1763的合成
步骤1:7-二苯甲基-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(式4-5)的合成
80℃下,(氯甲基)二苯(0.439mL,2.467mmol)、2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.614g,2.714mmol)和碳酸钾(1.705g,12.335mmol)溶于N,N-二甲基甲酰胺(10mL)中,在相同温度下搅拌16小时,然后冷却至室温终止反应。向反应混合物中加入饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,减压浓缩。然后,将乙酸乙酯(100mL)加入浓缩物中,搅拌,将沉淀的固体过滤,用乙酸乙酯洗涤并干燥,得到所需式4-5化合物(0.411g,42.4%),为白色固体。
步骤2:7-二苯甲基-2,7-二氮杂螺[3.5]壬烷盐酸盐(式4-6)的合成
将步骤1制备的式4-5化合物(0.411g,1.047mmol)在室温下溶于二氯甲烷(8mL)中,并将盐酸(4.00M二氧六环溶液,1.309mL,5.235mmol)加入到溶液中,然后在相同温度下搅拌16小时。减压浓缩反应混合物以除去溶剂,得到产物(0.344g,99.9%,白色固体),无需额外纯化即可使用。
步骤3:6-(7-二苯甲基-2,7-二氮杂螺[3.5]壬烷-2-甲酰氨基)己酸甲酯(式4-7)的合成
在0℃,将6-氨基己酸甲酯盐酸盐(0.100g,0.549mmol)和三光气(0.078g,0.261mmol)溶于二氯甲烷(5mL)中,向溶液中加入N,N-二异丙基乙胺(0.273mL,1.569mmol),然后在相同温度下搅拌。向反应混合物中加入步骤2制备的式4-6化合物(0.172g,0.523mmol),在室温下搅拌3小时。然后,向反应混合物中加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,然后减压浓缩。浓缩物通过柱色谱法(SiO2,4g柱;甲醇/二氯甲烷=0%~3%)纯化并浓缩,得到所需式4-7化合物(0.148g,61.0%),为亮红色固体。
步骤4:7-二苯甲基-N-(6-(羟基氨基)-6-氧代己基)-2,7-二氮杂螺[3.5]壬烷-2-甲酰胺(化合物1763)的合成
将在步骤3制备的式4-7化合物(0.148g,0.319mmol)和羟胺(50.00%水溶液,0.195mL,3.192mmol)在室温下溶于甲醇(5mL)中,将溶液在相同温度下搅拌3小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入甲醇(1mL)和饱和碳酸氢钠水溶液(30mL),然后搅拌。将沉淀的固体过滤,用己烷洗涤并干燥,所得物质在25℃下从乙酸乙酯(10mL)中重结晶并过滤。所得固体用己烷洗涤并干燥,得到所需化合物1763(0.044g,29.7%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ7.40-7.38(m,4H),7.29-7.25(m,4H),7.18-7.14(m,2H),6.18-6.17(m,1H),4.26(s,1H),3.42-3.33(m,4H),2.91-2.90(m,2H),2.20-2.19(m,4H),1.85-1.82(m,2H),1.65-1.64(m,4H),1.43-1.40(m,2H),1.33-1.30(m,2H),1.19-1.15(m,2H);MS(ESI)m/z 465.3(M++H).
实施例27:化合物1764的合成
步骤1:7-(7-二苯甲基-2,7-二氮杂螺[3.5]壬烷-2-甲酰氨基)庚酸甲酯(式4-7)的合成
在0℃,将7-氨基庚酸甲酯盐酸盐(0.107g,0.549mmol)和三光气(0.078g,0.261mmol)溶于二氯甲烷(5mL)中,向溶液中加入N,N-二异丙基乙胺(0.273mL,1.569mmol),在相同温度下搅拌。向反应混合物中加入实施例26步骤2制备的式4-6化合物(0.172g,0.523mmol),然后在室温下搅拌3小时。然后,向反应混合物中加入饱和碳酸氢钠水溶液,用二氯甲烷萃取。有机层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,过滤,减压浓缩。浓缩物通过柱色谱(SiO2,4g柱;甲醇/二氯甲烷=0%~3%)纯化并浓缩,得到所需式4-7化合物(0.136g,54.4%),为亮红色固体。
步骤2:7-二苯甲基-N-(7-(羟基氨基)-7-氧代庚基)-2,7-二氮杂螺[3.5]壬烷-2-甲酰胺(化合物1764)的合成
将在步骤1制备的式4-7化合物(0.136g,0.285mmol)和羟胺(50.00%,0.188g,2.847mmol)在室温下溶于甲醇(5mL)中,并将溶液在相同温度下搅拌3小时。减压浓缩反应混合物以除去溶剂,向浓缩物中加入甲醇(1mL)和饱和碳酸氢钠水溶液(30mL),然后搅拌。将沉淀的固体过滤,用己烷洗涤并干燥,所得物质在25℃下从乙酸乙酯(10mL)中重结晶并过滤。所得固体用己烷洗涤并干燥,得到所需化合物1764(0.021g,15.4%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ7.40-7.38(m,4H),7.29-7.25(m,4H),7.18-7.14(m,2H),6.16(t,1H,J=5.5Hz),4.26(s,1H),3.42-3.41(m,4H),2.92-2.88(m,2H),2.19-2.18(m,4H),1.88-1.84(m,2H),1.65-1.64(m,4H),1.43-1.42(m,2H),1.32-1.31(m,2H),1.19-1.18(m,4H);MS(ESI)m/z 479.6(M++H).
本发明所述化合物的活性测量和分析方案
实验实施例1:HDAC酶活性抑制的证实(体外)
因为选择性HDAC6抑制剂对于导致副作用的HDAC1的抑制选择性较为重要,因此分析了HDAC1/6酶选择性和细胞选择性(HDAC1:组蛋白乙酰化;HDAC6:微管蛋白乙酰化)。
1.实验方法
使用HDAC1荧光药物筛选分析试剂盒(Enzolifesciences:BML-AK511)和HDAC6人重组体(Calbiochem:382180),测定了受试化合物的HDAC酶抑制能力。对于HDAC1分析,使用100、1000和10000nM浓度处理,对于HDAC6分析,则使用0.1、1、10、100和1000nM浓度。在37℃下反应60分钟,然后用显影剂处理,并在37℃下反应30分钟,然后使用FlexStatin3(Molecular Device)测定荧光强度(Ex 390nm;Em 460nm)。
2.实验结果
实验结果如下表4所示。
表4.HDAC酶(HDAC1和HDAC6)活性抑制能力
如上表4所示,对照化合物ACY-1215显示48倍选择性(HDAC6为0.01μM,HDAC1为0.48μM),化合物1102显示960倍选择性(HDAC6为0.004μM,HDAC1为3.84μM),化合物1124显示170倍选择性(HDAC6为0.024μM,HDAC1为4.09μM),化合物1209显示193倍选择性(HDAC6为0.006μM,HDAC1为1.16μM),从而表明本发明的新型衍生物对HDAC1/6酶显示出优异的选择性。
实验实施例2:化合物1102在佐剂诱导的关节炎模型中的效用
1.实验方法
将100μL的完全弗氏佐剂(Chondrex)皮内注射到每只Lewis大鼠的尾部以诱导动物模型。诱导前一天,根据体重将大鼠分组,且将受试化合物以不同剂量每天一次向大鼠经口给药,随后进行评估。
自受试化合物首次给药之日起每周两次测量临床评分和体重。临床评分记录为0-4分,观察每只大鼠的脚后评估总临床评分(0:正常;16:最严重水肿)。
2.实验结果
实验结果如图1所示。根据关节水肿程度评价受试化合物在关节炎模型中的药效,且较高的临床评分表明水肿程度更严重。
如图1所示,未用化合物处理的组(空白对照)显示9-11分(严重水肿),而给予1mg/kg化合物1102的组显示6-8分,给予10mg/kg化合物1102的组显示4-6分,给予50mg/kg化合物1102的组显示1-3分,表明本发明的化合物1102可减轻关节炎症状。
工业实用性
本发明式I化合物、其旋光异构体或其药学上可接受的盐可以选择性地抑制HDAC,且由此可以有效地用于预防或治疗组蛋白脱乙酰酶介导的疾病。
Claims (8)
5.一种用于预防或治疗组蛋白脱乙酰酶介导的疾病的药物组合物,其包含作为活性成分的权利要求1至4任一项所述的化合物、其光学异构体或其药学上可接受的盐。
6.如权利要求1至4任一项所述的化合物、其光学异构体或其药学上可接受的盐在制备用于治疗组蛋白脱乙酰酶介导疾病的药物中的用途。
7.如权利要求6所述的用途,其中所述组蛋白脱乙酰酶介导的疾病是细胞增殖性疾病、炎性疾病、常染色体显性疾病、遗传代谢疾病、自身免疫疾病、急性/慢性神经疾病、肥大、心力衰竭或眼病。
8.如权利要求6所述的用途,其中所述组蛋白脱乙酰酶介导的疾病是神经退行性疾病。
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