CN1505603A - 具有nf-kb抑制作用的取代苯甲酸衍生物 - Google Patents
具有nf-kb抑制作用的取代苯甲酸衍生物 Download PDFInfo
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- CN1505603A CN1505603A CNA028028732A CN02802873A CN1505603A CN 1505603 A CN1505603 A CN 1505603A CN A028028732 A CNA028028732 A CN A028028732A CN 02802873 A CN02802873 A CN 02802873A CN 1505603 A CN1505603 A CN 1505603A
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- Prior art keywords
- methyl
- pyridyl
- benzyl
- tetramethoxy
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
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- VOGQQRSOSNDWBW-UHFFFAOYSA-N piperidin-1-yl-[2-pyridin-4-yl-3-[(2,3,4,5-tetramethoxy-6-methylphenyl)methyl]phenyl]methanone Chemical class COC1=C(OC)C(OC)=C(C)C(CC=2C(=C(C(=O)N3CCCCC3)C=CC=2)C=2C=CN=CC=2)=C1OC VOGQQRSOSNDWBW-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D295/18—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 carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A—HUMAN NECESSITIES
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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Abstract
下列通式(I)所表示的具有NF-κB阻碍作用的取代的苯甲酸衍生物(式中,R3,R4和R5各自独立地表示氢原子,碳数1~6的烷基或碳数1~6的烷氧基,R9和R10各自独立地表示氢原子,碳数1~6的烷基或碳数2~11的酰基);R2表示可以被取代的芳烃基或可以被取代的杂环基;X表示可以被酯化或酰胺化的羧基)。
Description
技术领域
本发明涉及新的取代的苯甲酸衍生物,更详细地说,涉及以取代的苯甲酸衍生物或者其氢醌体或其药理学可允许的盐为有效成分的NF-κB抑制剂,由NF-κB活化导致的疾病的预防或治疗药。
背景技术
NF-κB是调节基因表达的蛋白质,是一个所谓复制调节因子。正常细胞在被称为白细胞介素-1(IL-1)或TNF-α的炎症性细胞因子,聚多糖或紫外线等刺激时,NF-κB被活化并从细胞质向核内转移,与基因组DNA上的特异性碱基序列结合并与各种基因的表达有关(Blackwell,T.S.and Christman,J.W.(1997)Am.J.Respir.Cell.Mol.Biol.,17,3-9)。
通过受NF-κB表达调节的基因,大多被认为与IL-1,IL-6,IL-8,TNF-α等炎症性细胞因子或ICAM-1,VCAM-1,ELAM-1等细胞粘接分子,和诱导型NO合成酶(iNOS)等的免疫炎症反应有关(Collins,T.,Read,M.A.Neish,A.S.,Whitley,M.Z.,Thanos,D.and Maniatis,T.(1995)Faseb.J.,9,899-909)。而且炎症性细胞因子,已知一旦与受体结合,通过各种路径传递活化NF-κB的信号,这被认为是使炎症进一步恶化的原因。因此,炎症中的NF-κB活化,被理解为是疾病的原因和恶化的因素(Baeuerle,P.A.and Baichwal,V.R.(1997)Adv.Immunol.65,111-137)。
另外,近年来有报告说HIV,HTLV-1,CMV,腺病毒等活化宿主细胞中的NF-κB(Dezube,B.J.,Pardee,A.B.,Beckett,L.A.,Ahlers,C.M.,Ecto,L.,Allen-Ryan,J.,Anisowicz,Z.A.,Sager,R.andCrumpacker,C.S.(1992)J.Acquir.Immune Defic.Syndr.,5,1099-1104;Nabel,G.and Baltimore,D.(1987)Nature 326,711-713;Fazely,F.,Dezube,B.J.,Allen-Ryan,J.,Pardee,A.B.and Ruprecht,R.M.(1991)Blood,77,1653-1656;Munoz,E.and Israel,A.(1995)Immunobiology,193,128-136),NF-κB的活化被认为与感染宿主细胞中的病毒的自我复制,增殖有关。
因此,通过抑制NF-κB的活化,可以彻底抑制这些炎症性细胞因子,细胞粘接分子基因和病毒的表达诱导,NF-κB活化抑制物质,有望被用作由NF-κB的活化直接或间接导致的疾病,特别是各种炎症性疾病,自身免疫性疾病的治疗药,免疫抑制剂,病毒性疾病的治疗药。
现在,多种抗炎剂以治疗变形性关节炎,腰痛,慢性风湿性关节炎为目的在临床上广泛使用,但作为抑制各种炎症性细胞因子的产生或细胞粘接分子的表达的物质,还未发现有效的药物。广泛使用的NSAID(非甾体抗炎剂),通过在花生油烯酸代谢路径中抑制环氧化酶,抑制前列腺素的产生,但通常不直接抑制细胞因子的产生。甾体类,虽然可以抑制多数细胞因子的产生,但会出现不希望的激素作用或感染的恶化,消化性溃疡的发生,中枢作用等严重的副作用是已知的,存在不能长期给药的问题。
但是,近年来出现了几个在这些抗炎剂中在高用量下抑制NF-κB的活化的药物的报告(Auphan,N.,DiDonato,J.A.,Rosette,C.,Helmberg,A.and Karin,M.(1995)Science 270,286-290.;Shacklford,R.E.,Alford,P.B.,Xue,Y.,Thai,S.F.,Adams,D.O.and Pizzo,S.(1997)Mol.Pharmacol.,52,421-429.;Bitko,V.,Velazquez,A.,Yang,L.,Yang,Y.C.and Barik,S.(1997)Virology,232,369-378)。例如,报告了水杨酸或阿司匹林等苯甲酸衍生物抑制NF-κB的活化(Science,265,956-959,1994),但指出了效力不充分,或通过多重药理作用引起的副作用的出现等问题。
因此,希望开发更加特异的抑制NF-κB活化的安全性高的药物,许多研究者进行了NF-κB活化抑制物质的探索或分子设计。
近年来,作为NF-κB的活化抑制物质,有异咔唑衍生物(特开平8-319238号公报,特开2000-169479号公报),异喹啉衍生物(特开平10-87491号公报,特开平11-180873号公报),苯醌衍生物(特开平7-291859号公报,特开平11-266872号公报),β-内酰胺衍生物(特开平11-71278号公报),木聚糖衍生物(特开平10-175861号公报),苯亚甲基衍生物(PCT/JP98/04774),嘧啶-5-羧酰胺衍生物(WO97/09315号公报,WO97/09325号公报),环戊苯并呋喃衍生物(WO00/08007号公报),苯衍生物(WO00/15603号公报),吡咯烷二硫代碳酸酯(PDTC)(Eur.J.Immunol.(1999)29,1890-1900),3-脱氮杂腺苷(DZA)(J.Biol.Chem.(1999)274,27,18981-18988),2,2’-双-1H-吡咯衍生物(J.Immunol.(1999)162,7102-7109)等报告。
这些物质,关于是抑制NF-κB活化的作用机制大多还不明确,但是作为关于被认为是通过抗氧化作用或蛋白质的磷酸化抑制作用的物质,其稳定性或作用的特异性被认为是成问题的。另外,现在作为复制因子NF-κB的活化抑制剂得不到具有充分效果的药物。
取代的苯甲酸衍生物作为作用于转录调节因子或转录因子型受体的例子,例如,报告了作为取代的苯甲酸衍生物的视黄苯甲酸衍生物作用于视黄酸受体(RAR)或视黄酸X受体(RXR)等的转录因子型受体上,显示激动剂作用或拮抗剂作用(Kagechika H.,Kawachi E.,Hashimoto Y.,HimiT.,Shudo K.,J.Med.Chem.,1989,31,2182.:Boehm M.F.,Zhang L.,Badea B.A.,White S.K.,Mais D.E.,Suto C.M.,Goldman M.E.,HeymanR.A.,J.Med.Chem.,1994,37,2930.:Boehm M.F.,Zhang L.,Zhi L.,McClurg M.R.,Berger E.,Wagoner M.,Mais D.E.,Suto C.M.,Davis P.J.A.,Heyman R.A.,Nadzan A.M.,J.Med.Chem.,1995,38,3146)。但是,没有关于这些视黄苯甲酸衍生物的NF-κB抑制活性的报告。
另一方面,特开平7-291859号公报中公开了下述苯醌衍生物(A),作为NF-κB的活化抑制物质。
另外,特开平11-266872号公报中,公开了抑制NF-κB活化物质的新的筛选方法,列举了根据该方法发现的作为抑制NF-κB活化物质的下述苯醌衍生物(B)
但是,不能说这些是作为NF-κB抑制物质具有充分效力的化合物,希望寻找NF-κB抑制活性更强的物质。
发明的公开
本发明,通过抑制NF-κB的活化,提供对于NF-κB活化引起的疾病,例如各种炎症介质产生过多或病毒的增殖引起的疾病的预防或治疗药。更具体地说,提供被认为是NO或TNF-α过剩产生为发病原因的疾病,例如败血症休克,变形性关节炎,慢性风湿性关节炎,恶病质,多器官不全,炎症性肠病,疟疾,后天性免疫不全综合症,人T细胞白血病,髓膜炎,肝炎,心肌炎,II型糖尿病,多发性硬化,贝切特氏病,系统性红斑狼疮,缺血性心脏病等的治疗和预防药。
本发明者们对于抑制NF-κB活化进行了反复深入的研究,结果发现通式(I)所示的新的取代的苯甲酸衍生物或其氢醌体或其药理学可允许的盐强力地抑制NF-κB的活化,由此完成了本发明。
即,本发明,涉及以下列通式(I)
(式中,
R1,是下述通式(II)
或下述通式(III)
(式中,R3,R4和R5各自独立地表示氢原子,碳数1~6的烷基或碳数1~6的烷氧基,R9和R10各自独立地表示氢原子,碳数1~6的烷基或碳数2~11的酰基);
R2,表示可以被取代的芳烃基或可以被取代的杂环基;
X,表示可以被酯化或酰胺化的羧基)
所表示的新的取代的苯甲酸衍生物,以该新的取代的苯甲酸衍生物或其氢醌体或其药理学上允许的盐为有效成分的NF-κB抑制剂,和其在炎症性疾病,自身免疫性疾病,病毒性疾病的预防或治疗药中的应用,其作为选自IL-1,TNF-α,IL-2,IL-6,IL-8,iNOS,粒细胞集落刺激因子,干扰素-γ,ICAM-1,VCAM-1,ELAM-1,主要组织相容性抗原I型,主要组织相容性抗原II型,β-2微球蛋白,免疫球蛋白轻链,血清淀粉A,血管紧张素原,补体B,补体C4,c-myc,HIV,HTLV-1,SV-40,CMV和腺病毒中的1种或1种以上物质的基因表达抑制剂使用。
另外,还提供以通式(I)所表示的新的取代的苯甲酸衍生物或其氢醌体或其药理学上可允许的盐为有效成分的,由NF-κB活化引起的疾病的预防或治疗药。
另外,作为本发明有效成分的取代的苯甲酸衍生物在分子内具有苯醌环的情况下,可以容易还原得到对应的氢醌体。因此,在本发明中,作为本发明有效成分的取代的苯甲酸衍生物的分子内的苯醌环被还原的氢醌体,也可作为本发明的有效成分使用。所谓氢醌体,是指本发明所涉及的苯醌衍生物通过催化剂等化学的或酶等生物化学的在苯醌环的1位和/或4位的氧被还原成羟基,或者,在生物体内被还原,并且,与苯醌衍生物具有相同的活性的物质。
另外,作为药理学上可容许的盐,可以列举例如与盐酸,硝酸,硫酸,磷酸,氢溴酸等无机酸或者马来酸,富马酸,酒石酸,乳酸,柠檬酸,乙酸,甲磺酸,对-苯甲磺酸,己二酸,棕榈酸,单宁酸等有机酸,锂,钠,钾等碱金属,钙,镁等碱土金属等无机金属,赖氨酸等碱性氨基酸成的盐。
式中,R1表示下列通式(II):
或下列通式(III):
另外,式中,R3,R4和R5各自独立地表示氢原子,碳数1~6的烷基或碳数1~6的烷氧基,作为烷基的优选实例可以列举甲基,乙基,丙基,异丙基,正丁基,仲丁基,叔丁基,戊基,异戊基,新戊基,叔戊基,正己基等碳数1~6的直链或支链饱和脂肪族烃基,环丙基,环丁基,环戊基,环己基等饱和脂环状烃基和环丙基甲基,环丙基乙基,环丁基甲基等饱和脂环状烃基-脂肪族烃基等。另外,所谓烷氧基,是上述烷基与氧原子结合的基团,作为烷氧基优选的实例可以列举甲氧基,乙氧基,丙氧基,异丙氧基,正丁氧基,异丁氧基,仲丁氧基,叔丁氧基等碳数1~6的直链或支链烷氧基。
另外,R9和R10各自独立地表示氢原子,碳数1~6的烷基或碳数2~11的酰基,作为烷基的优选实例,可以列举甲基,乙基,丙基,异丙基,正丁基,仲丁基,叔丁基,戊基,异戊基,新戊基,叔戊基,正己基等碳数1~6的直链或支链饱和脂肪族烃基,环丙基,环丁基,环戊基,环己基等饱和脂环状烃基和环丙基甲基,环丙基乙基,环丁基甲基等饱和脂环状烃基-脂肪族烃基等。另外,作为酰基的优选实例,可以列举乙酰基,丙酰基,丁酰基,环丙基羰基,环戊基羰基,环己基羰基,苯甲酰基,2-吡啶基羰基,3-吡啶基羰基,4-吡啶基羰基等基团。
另外,R2表示可以被取代的芳烃基或可以被取代的杂环基,优选可以被取代的碳数6~12的芳基或可以被取代的碳数4~11的杂芳基。
作为可以被取代的碳数6~12的芳基的优选实例,可以列举苯基,4-甲氧基苯基,3-甲氧基苯基,2-甲氧基苯基,3,4-二甲氧基苯基,4-氯苯基,3-氯苯基,2-氯苯基,4-硝基苯基,4-氰基苯基,4-三氟甲基苯基,2,4-二甲氧基苯基,3,4,5-三甲氧基苯基,3,4-二氯苯基,4-吗啉基苯基,1-萘基等基团。
另外,作为可以被取代的碳数4~11的杂芳基的优选实例,可以列举4-吡啶基,3-吡啶基,2-吡啶基,2-呋喃基,3-呋喃基,2-嘧啶基,4-嘧啶基,2-喹啉基,3-异喹啉基等基团。
作为本发明中“可以被取代的”表示的取代基的具体的实例,可列举例如烷基,烷氧基,芳基,杂芳基,羟基,酰基,羧基,烷氧基羰基,芳氧基羰基,可以被取代的氨基甲酰基,可以被取代的氨基和氰基等取代基和卤素原子等。
X,表示可以被酯化或酰胺化的羧基,作为可以被酯化或酰胺化的羧基的优选实例,可以列举基团-COOR6(式中,R6表示氢原子,可以被取代的碳数1~6的低级烷基,可以被取代的碳数7~14的芳烷基),基团-CONR7R8(式中,R7和R8各自独立地表示氢原子,可以被取代的碳数1~6的烷基,可以被取代的碳数6~12的芳基,可以被取代的碳数4~11的杂芳基,可以被取代的碳数7~14的芳烷基,可以被取代的碳数5~13的杂芳基烷基,或R7和R8和与其相连的氮原子一起表示可进一步含有氮原子,氧原子,硫原子,或可以再进一步稠合的杂环基),基团-CONR7R8(式中,R7和R8和与其相连的氮原子一起表示除可以被取代的碳原子和氮原子之外,还可以含有1~3个选自氮原子,氧原子,硫原子的杂原子的5~8员含氮杂环基,这些环上的碳原子或硫原子可以被氧化)等。
作为可以取代的碳数1~6的低级烷基的优选实例,可以列举例如甲基,乙基,叔丁基,羟基乙基,烷氧基乙基,氨基乙基,单或二取代的氨基乙基(例如,N-甲基氨基乙基,N,N-二甲基氨基乙基),氰基甲基,羧基甲基,甲氧基羰基甲基,乙氧基羰基甲基,氨基甲酰基甲基等基团。
作为可以被取代的碳数7~14的芳烷基的优选实例,可以列举苄基,4-硝基苄基,3-硝基苄基,4-甲氧基苄基,3-甲氧基苄基,4-氯苄基,2-苯乙基,3-苯基丙基等基团。
作为可以被取代的碳数6~12的芳基的优选实例,可以列举苯基,4-甲氧基苯基,3-甲氧基苯基,2-甲氧基苯基,3,4-二甲氧基苯基,3,4,5-三甲氧基苯基,4-三氟甲基苯基,4-吗啉代苯基,4-氰基苯基,4-氯苯基,4-硝基苯基,1-萘基等基团。
作为可以被取代的碳数4~11的杂芳基的优选实例,可以列举2-吡啶基,3-吡啶基,4-吡啶基,2-呋喃基,2-噻吩基,2-嘧啶基,2-喹啉基,3-异喹啉基等基团。
作为可以被取代的碳数5~13的杂芳基烷基的优选实例,可以列举4-吡啶基甲基,3-吡啶基甲基,2-吡啶基甲基,2-(吡啶-4-基)乙基,2-(吡啶-3-基)乙基,2-喹啉基甲基,3-异喹啉基甲基等基团。
所谓卤原子,是氟原子,氯原子,溴原子或碘原子。
另外,作为本发明的优选化合物,可以列举下列通式(I)所示的化合物
式中,R1是下述通式(II)
(式中,R3和R4表示甲基或甲氧基,R5表示甲基);R2是苯基,4-甲氧基苯基,3-甲氧基苯基,2-甲氧基苯基,3,4-二甲氧基苯基,4-吡啶基,3-吡啶基,2-吡啶基,2-呋喃基,3-呋喃基;X是可被酯化或酰胺化的羧基),作为特别优选的具体化合物,可以列举下列化合物。
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸甲酯,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸甲酯,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯甲酸甲酯,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-甲氧基苯基)苯甲酸甲酯,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-甲氧基苯基)苯甲酸甲酯,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(2-甲氧基苯基)苯甲酸甲酯,
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸甲酯,
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸甲酯,
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸甲酯,
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯甲酸甲酯,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯甲酸,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-甲氧基苯基)苯甲酸,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-甲氧基苯基)苯甲酸,
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(2-甲氧基苯基)苯甲酸,
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸,
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸,
N-[4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]哌啶,
N-[4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]吗啉,
N-[4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]-4-三氟甲基苯胺,
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸,
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯甲酸,
N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]哌啶,
N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]吗啉,
N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]-4-三氟甲基苯胺,
N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]哌啶,
(S)-N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]-1-苯乙胺,
N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]哌啶,
(S)-N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]-1-苯乙胺,
N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]-4-三氟甲基苯胺,
N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]哌啶,
N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]吗啉,
N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]-4-三氟甲基苯胺,
5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酸,
5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酸,
5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酸,
5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-甲氧基苯基)苯甲酸,
5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-甲氧基苯基)苯甲酸,
5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(2-甲氧基苯基)苯甲酸,
N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酰基]哌啶,
N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酰基]吗啉,
N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酰基]-4-三氟甲基苯胺,
N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]哌啶,
4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酸,
4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酸,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]哌啶(甲磺酸盐),
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]吗啉,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-4-甲氧基苯胺(盐酸盐),
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-4-三氟甲基苯胺,
N-[5(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-甲氧基苯基)苯甲酰基]哌啶,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-甲氧基苯基)苯甲酰基]吗啉,
(S)-N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-1-苯乙胺(甲磺酸盐),
(R)-N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-1-苯乙胺(甲磺酸盐),
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]环己胺(甲磺酸盐),
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]环戊胺(甲磺酸盐),
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]环丙胺(甲磺酸盐),
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-1-乙基丙胺(甲磺酸盐),
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]哌啶,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]吗啉,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]-4-甲氧基苯胺,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]-4-三氟甲基苯胺,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酰基]-4-甲氧基苯胺,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-甲氧基苯基)苯甲酰基]-4-甲氧基苯胺,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-甲氧基苯基)苯甲酰基]哌啶,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-甲氧基苯基)苯甲酰基]吗啉,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-甲氧基苯基)苯甲酰基]-4-甲氧基苯胺,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(2-甲氧基苯基)苯甲酰基]-4-甲氧基苯胺,
N-[3-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]哌啶,
(S)-N-[3-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]-1-苯乙胺,
N-[3-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]哌啶,
(S)-N-[3-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-1-苯乙胺,
N-[3-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-4-三氟甲基苯胺,
N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]吗啉,
N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]-4-三氟甲基苯胺,
N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]-4-甲氧基苯胺,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酰基]哌啶,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酰基]吗啉,
N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酰基]-4-三氟甲基苯胺,
下面,说明为实施本发明的化合物的制备方法的实例。
但是,作为本发明有效成分的化合物的制备方法不限于这些。
[一般制法]
作为本发明有效成分使用的通式(I)所示的取代的苯甲酸衍生物,可以通过其本身已知的方法,即论文(Suzuki,K.,Tatsuoka,T.,Ishihara,T.,Ogino,R.,Miyazaki,T.,Satoh,F.,Miyano,S.,Sumoto,K.,Chem.,Pharm.Bull.,(1997)45,668-674)中记载的方法和根据其的相似方法使用可制备的合成中间体制备。
具体地说,通过使通式(IV)所表示的醛化合物:
(式中,R3~R5,R9和R10定义同前),与从卤代苯酚衍生物制备的格利雅试剂或有机锂试剂反应,得到通式(V):
(式中,R3~R5,R9和R10定义同前,Bn表示可以被取代的苄基),通过将该化合物在路易斯酸或三甲基甲硅烷基三氟甲磺酸酯(TMSOTf)等催化剂存在下,用三乙基硅烷等还原剂还原后,在钯炭等催化剂存在下,在氢气气氛中搅拌进行催化还原,得到通式(VI):
(式中,R3~R5,R9和R10定义同前)所表示的苯酚衍生物。
将该化合物在例如三氟乙酸等溶剂中,与六亚甲基四胺,在室温~100℃的温度下搅拌后,再通过水解,得到通式(VIIa):
(式中,R3~R5,R9和R10定义同前)。
然后,将该化合物通过在丙酮等与反应无关的溶剂中,在碳酸钾,氢氧化钠等碱存在下,与苄基溴等烷基化试剂,在0℃~回流温度、优选在室温~50℃的温度下搅拌,得到通式(VIIb)所表示的化合物:
(式中,R3~R5,R9,R10和Bn定义同前)。
将该化合物例如通过溶解在乙腈等与反应无关的溶剂中,在与磷酸缓冲液的混合液中,在次氯酸钠和过氧化氢等氧化剂存在下,在0~50℃的温度下搅拌,得到通式(VIII)所表示的取代的苯甲酸衍生物:
(式中,R3~R5,R9和R10及Bn定义同前)。
然后,将该羧酸化合物通过在甲醇等与反应无关的溶剂中用重氮甲烷,三甲基甲硅烷基重氮甲烷等处理,或在二氯甲烷等与反应无关的溶剂中,在4-二甲基氨基吡啶等催化剂存在下或没有该催化剂存在下,例如用1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(WSC-HCl)等脱水缩合剂,或者,用草酰氯等形成下酰氯化物体,通过与通式(IX)所表示的醇类:
R6-OH (IX)
(式中,R6表示碳数1~6的低级烷基,碳数7~14的芳烷基)缩合后,在乙醇、1,4-二噁烷等与反应无关的溶剂中,在钯炭等催化剂存在下,通过在氢气气氛中搅拌进行催化还原,得到通式(Xa)所表示的化合物:
(式中,R3~R5,R9和R10定义同前;X’表示被酯化或酰胺化的羧基)。
该化合物(Xa),在二氯甲烷等与反应无关的溶剂中,在三乙胺等碱存在下,通过与氯化三氟甲基磺酰或无水三氟甲基磺酸反应,可得到通式(Xb)所表示的化合物:
(式中,R3~R5,R9,R10和X’同前定义)。
该化合物(Xb),在甲苯,乙腈,1,4-二噁烷,二甲基甲酰胺,水等与反应无关的溶剂,或在它们的混合溶剂中,在氯化锂,碳酸钠,磷酸二氢钠等试剂共同存在下,在四(三苯基膦)钯等催化剂存在下,与下列通式(XI)所表示的硼酸衍生物:
(式中,R2表示可以被取代的芳烃基,或者可以被取代的杂环基)缩合,或者与下列通式(XII)所表示的有机锡试剂:
R2-Sn(n-Bu)3 (XII)
(式中,R2表示可以被取代的芳烃基,或可以被取代的杂环基)缩合,可得到通式(Ia)所表示的化合物:
(式中R2表示可以被取代的芳烃基,或可以被取代的杂环基,R3~R5,R9,R10和X’,定义同前)。
在氢氧化钠等的碱存在下,例如在二噁烷和水的混合溶剂中,通过搅拌、加水分解该化合物,可以得到通式(Ib)所表示的取代的苯甲酸衍生物:
(式中,R2,R3~R5,R9和R10定义同前)。
通过在甲醇等与反应无关的溶剂中用重氮甲烷,三甲基甲硅烷基重氮甲烷等处理该化合物,或在二氯甲烷等与反应无关的溶剂中,在4-二甲基氨基吡啶等催化剂存在下或没有该催化剂存在下,用例如1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐等脱水缩合剂,通过该化合物与通式(XIII)所表示的醇类:
R6-OH (XIII)
(式中,R6表示碳数1~6的低级烷基,碳数7~14的芳烷基),或者通式(XIV)所表示的胺类:
(式中,R7和R8分别独立地表示氢,可以被取代的碳数1~6的烷基,可以被取代的碳数6~12的芳基,可以被取代的碳数4~11的杂芳基,可以被取代的碳数7~14的芳烷基或可以被取代的碳数5~13的杂芳烷基,或者R7和R8和它们结合的氮一起表示,进一步也可以含有氮,氧,硫,或者也可以缩合的不同环基)缩合,得到通式(Ic)所表示的化合物:
(式中,R2,R3~R5,R9和R10定义同前;X’表示被酯化或酰胺化的羧基)。
将上述化合物(Ia),(Ib)和(Ic)在乙腈和水的混合溶剂等与反应无关的溶剂中,通过用硝酸亚铈铵(CAN)等氧化剂进行氧化可以得到通式(I):
(式中,R2,R3~R5和X定义同前)所表示的苯醌衍生物。
通式(I)所表示的本发明涉及的物质,由于可以抑制NF-κB活化,可以期待其具有作为对NF-κB活化引起的疾病,例如各种炎症性介质过剩产生或病毒增殖引起的疾病的预防药,治疗药的实用性。具体地说,作为例如对被认为是NO或TNF-α过剩产生为发病原因的疾病,败血症休克,变形性关节炎,慢性风湿性关节炎,恶病质,多器官不全,炎症性肠病,疟疾,后天性免疫不全综合症,人T细胞白血病,髓膜炎,肝炎,心肌炎,II型糖尿病,多发性硬化,贝切特氏病,系统性红斑狼疮,缺血性心脏病等的治疗和预防药是有用的。
将本发明所涉及的化合物作为上述药物组合物使用的情况下,可以例如以片剂,胶囊剂,酏剂,微胶囊剂等剂型口服使用,或者以与水或其以外的药学上可允许的液体形成的溶液,或悬浮液剂等注射剂的形式非口服使用。例如,可以通过将该化合物,与生理学上认可的载体,香味剂,赋形剂,稳定剂等,以一般认可的形态混合而制备。作为可以在片剂等中混合的添加剂,可以使用例如,明胶等粘合剂,玉米淀粉等膨化剂,结晶纤维素等赋形剂,硬脂酸镁等润滑剂。在胶囊剂型的情况下,上述组合物可以进一步含有液态载体。注射用无菌组合物也可以使用通常的配方。
作为注射用的水溶液,可以列举含有葡萄糖等的等渗液等,也可以联合使用聚乙二醇等适宜的助溶剂。另外,也可以结合使用缓冲剂,稳定剂,保鲜剂,抗氧化剂,无痛化剂等。如此得到的制剂,例如,可以对以人为首的哺乳动物给药。给药量,根据症状等的不同,在口服给药的情况下,通常对于成人1日约0.01~100mg,优选约0.1~50mg,更优选约1.0~25mg。在非口服给药的情况下,例如,在注射剂的情况下,一般对于成人1日以约0.001~50mg左右,优选约0.01~25mg,更优选约0.1~10mg左右,优选通过静脉给药。
NF-κB抑制效果,可以通过直接,或间接测定由于NF-κB活化被抑制的基因的表达来进行研究。
另外,抑制炎症性蛋白质的过度表达的效果,可通过用IL-1或TNF-α等的细胞因子或脂多糖等刺激细胞或动物固体,直接或间接测定在培养液或体液中上升的炎症性蛋白质的量来进行研究。另外,作为确认广义的抗炎症作用的方法,可以通过抑制角叉菜胶或葡聚糖等引起的浮肿的效果来确定。
在这些模型中可以确认抑制NO或TNF-α的产生是有效的(Filion,M.C.and Phillips,N.C.(1997)Br.J.Pharmacol,.122,551-557.;Tsao,P.W.Suzuki,T.,Totsuka,R.,Murata,T.,Takagi,T.,Ohmachi,Y.,Fujiwara,H.,and Takata,I.(1997)Clin.Immunol.Immunopathol.(1997)83,173-178.;Cuzzocrea,S.,Zingarelli,B.,Hake,P.,Salzman,A. and Szabo,C.Free Radic.Biol.Med.(1998)24,450-459)。
而且,对于具体的疾病,作为败血症治疗药的效果,可通过对小鼠等动物给药脂多糖,测定改善生存率的效果,或在血中的炎症性细胞因子的量来判断。作为慢性风湿性关节炎治疗药的效果,可以通过在由佐剂或骨胶原引起的关节炎的模型动物中评价药效(Y.Iigo等,J.Immunol.,(1991)147,4167)。
另外,作为对于难治的炎症,例如节段性回肠炎,肝炎,肾炎的治疗药的效果,可以通过根据本身已知或相似方法制备的动物模型推测(K.Nishikawa等,J.Exp.Med.,(1994)180,95;K.Kawasaki等,J.Immunol.,(1992)150,1074)。而且,作为对器官移植排斥反应抑制剂的效果,可以通过例如GVH(移植物对抗宿主)病或各种器官移植模型动物评价药效(A.,B.Cosimi等J.Immunol.,(1990)142,2617;M.Isobe等,Science,(1992)255,1125)。
这样,作为NF-κB抑制剂的疾病治疗药的效果,可以通过已知方法或类似方法可以制备的各种模型动物来确认。
下面,列举实施例和实验例进一步说明本发明,但本发明并不限于这些实施例和实验例。
参考例1.
3-(苄基氧)溴苯
将3-溴苯酚(50g,0.289mol)溶解在丙酮(500ml)中,依次加入无水碳酸钾(80g,0.580mmol)和苄基溴(59g,0.345mol),加热回流3小时。将反应混合物过滤,减压浓缩滤液。将所得粗产物重结晶(用己烷作溶剂,进行2次重结晶操作),得到标题化合物(45.0g,0.171mol,59%)。
参考例2.
4-(苄基氧)溴苯
将4-溴苯酚(100g,0.587mol)溶解在丙酮(1100ml)中,依次加入无水碳酸钾(159.53g,1.156mmol)和苄基溴(103.78g,0.607mol),加热回流3小时。将反应混合物过滤,减压浓缩滤液。将所得粗产物用己烷重结晶,得到标题化合物(120.76g,0.459mol,79%)。
参考例3.
2-(苄基氧)溴苯
将2-溴苯酚(50g,0.289mol)溶解在丙酮(400ml)中,依次加入无水碳酸钾(79.89g,0.578mmol)和苄基溴(59.32g,0.347mol),加热回流3小时。将反应混合物过滤,减压浓缩滤液。将所得粗产物用硅胶柱色谱纯化(己烷∶AcOEt=95∶5),得到标题化合物(30.0g,0.114mol,40%)。
参考例4.
1-(3,4,5,6-四甲氧基-2-甲基苯基)-1-(3- 苄基氧苯基)甲醇
在冰冷却下,向由3-(苄基氧)溴苯(18.4g,0.070mol)和镁(1.87g,0.077mol)制备的格利雅试剂(150ml,四氢呋喃溶液)中,滴加3,4,5,6-四甲氧基-2-甲基苯甲醛(14g,0.058mol)的无水四氢呋喃(50ml)溶液后,进一步搅拌2小时。将反应液倒入饱和氯化铵水溶液中,用醚萃取。将萃取液用饱和盐水洗净后,干燥。将反应液过滤,通过浓缩滤液得到的粗产物用硅胶柱色谱纯化(己烷∶乙酸乙酯=4∶1),得到标题化合物(23.5g,0.055mol,95%)。
参考例5.
1-(3,4,5,6-四甲氧基-2-甲基苯基)-1-(4- 苄基氧苯基)甲醇
在冰冷却下,向由4-(苄基氧)溴苯(8.00g,0.030mol)和镁(0.81g,0.033mol)制备的格利雅试剂(30ml,四氢呋喃溶液)中,滴加3,4,5,6-四甲氧基-2-甲基苯甲醛(3.65g,0.015mol)的无水四氢呋喃(20ml)溶液后,进一步搅拌2小时。将反应液倒入饱和氯化铵水溶液中,用醚萃取。将萃取液用饱和盐水洗涤后,干燥。将反应液过滤,通过浓缩滤液得到的粗产物用硅胶柱色谱纯化(己烷∶乙酸乙酯=4∶1),得到标题化合物(5.93g,0.014mol,92%)。
参考例6.
1-(3,4,5,6-四甲氧基-2-甲基苯基)-1-(2- 苄基氧苯基)甲醇
在冰冷却下,向由2-(苄基氧)溴苯(11.50g,0.044mol)和镁(1.16g,0.048mol)制备的格利雅试剂(35ml,四氢呋喃溶液)中,滴加3,4,5,6-四甲氧基-2-甲基苯甲醛(5.00g,0.021mol)的无水四氢呋喃(30ml)溶液后,进一步搅拌2小时。将反应液倒入饱和氯化铵水溶液中,用醚萃取。将萃取液用饱和盐水洗涤后,干燥。将反应液过滤,将通过浓缩滤液得到的粗产物用硅胶柱色谱纯化(己烷∶乙酸乙酯=4∶1),得到标题化合物(8.80g,0.021mol,99%)。
参考例7.
3-(3,4,5,6-四甲氧基-2-甲基苄基)苯酚
向三乙基硅烷(8.33g,71.64mmol)和TMSOTf(2.65g,11.92mmol)的二氯甲烷溶液(1000ml)中,滴加参考例4中得到的化合物(25.3g,59.67mmol)的二氯甲烷溶液,在室温搅拌1小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。将残余物溶解在乙醇(100ml)和二噁烷(150ml)中,加入5%Pd-C(3g)的乙醇悬浮液(50ml)后,在氢气气氛中在室温搅拌16小时。将反应液过滤,将浓缩滤液得到的残余物用硅胶柱色谱纯化(己烷∶乙酸乙酯=3∶1),得到标题化合物(18.4g,57.9mmol,97%)。
参考例8.
4-(3,4,5,6-四甲氧基-2-甲基苄基)苯酚
向三乙基硅烷(0.99g,8.52mmol)和TMSOTf(0.31g,1.39mmol)的二氯甲烷溶液(80ml)中,滴加参考例5得到的化合物(3.00g,7.08mmol)的二氯甲烷溶液(70ml),在室温搅拌1小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。将残余物溶解在乙醇(50ml)中,加入5%Pd-C(500mg)的乙醇悬浮液(250ml)后,在氢气气氛中在室温搅拌16小时(此时,也可以在乙醇和二噁烷的混合溶剂下反应)。将反应液过滤,将浓缩滤液得到的残余物用硅胶柱色谱(己烷∶乙酸乙酯=4∶1)纯化,得到标题化合物(1.96g,6.15mmol,87%)。
参考例9.
2-(3,4,5,6-四甲氧基-2-甲基苄基)苯酚
向三乙基硅烷(2.95g,25.43mmol)和TMSOTf(0.94g,4.23mmol)的二氯甲烷溶液(150ml)中,滴加参考例6中得到的化合物(9.00g,21.23mmol)的二氯甲烷溶液(130ml),在室温搅拌1小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。将残余物溶解在乙醇(50ml)中,加入5%Pd-C(1.5g)的乙醇悬浮液(350ml)后,在氢气气氛中在室温搅拌16小时(此时,也可以在乙醇和二噁烷的混合溶剂下反应)。将反应液过滤,将浓缩滤液得到的残余物用硅胶柱色谱(己烷∶乙酸乙酯=4∶1)纯化,得到标题化合物(5.67g,17.83mmol,84%)。
参考例10.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基 苯甲醛(10a)和6-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基 苯甲醛(10b)
将3-(3,4,5,6-四甲氧基-2-甲基苄基)苯酚(11.17g,35.13mmol)和六亚甲基四胺(6.39g,0.046mol)溶解在三氟乙酸中,在80℃加热搅拌4小时。反应结束后,在蒸馏除去溶剂得到的残余物中加入水并搅拌30分钟,用二氯甲烷萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂,将得到的残余物用硅胶柱色谱(己烷∶乙酸乙酯=9∶1)纯化,得到标题化合物10a(3.35g,9.68mmol,28%)和10b(2.03g,18%)。
参考例11.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯 甲醛
将4-(3,4,5,6-四甲氧基-2-甲基苄基)苯酚(14.5g,45.60mmol)和六亚甲基四胺(8.30g,59.29mol)溶解在三氟乙酸(100ml)中,在80℃加热搅拌4小时。反应结束后,向蒸馏除去溶剂得到的残余物中加入水(100ml)并搅拌30分钟,用二氯甲烷萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂,将得到的残余物用硅胶柱色谱(己烷∶乙酸乙酯=4∶1)纯化,得到标题化合物(12.20g,35.26mmol,78%)。
参考例12.
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基 苯甲醛
将2-(3,4,5,6-四甲氧基-2-甲基苄基)苯酚(8.64g,27.17mmol)和六亚甲基四胺(5.00g,35.67mmol)溶解在三氟乙酸(100ml)中,在80℃加热搅拌4小时。反应结束后,向蒸馏除去溶剂得到的残余物中加入水(100ml)并搅拌30分钟,用二氯甲烷萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂,将得到的残余物用硅胶柱色谱(己烷∶乙酸乙酯=4∶1)纯化,得到标题化合物(2.50g,7.23mmol,27%)。
参考例13.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基 氧苯甲醛
将4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯甲醛(743mg,2.14mmol)溶解在丙酮(50ml)中,加入无水碳酸钠(593mg,4.30mmol)和苄基溴(477mg,2.79mmol)后,在室温搅拌16小时。将反应液过滤,将浓缩滤液得到的残余物用硅胶柱色谱(己烷∶乙酸乙酯=3∶1)纯化,得到标题化合物(864mg,1.98mmol,93%)。
参考例14.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基 氧苯甲醛
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯甲醛(0.100g,0.290mol)溶解在丙酮(10ml)中,加入无水碳酸钠(0.080g,0.579mmol)和苄基溴(0.059g,0.347mmol)后,加热回流3小时。将反应液过滤,将浓缩滤液得到的残余物用硅胶柱色谱(己烷∶乙酸乙酯=4∶1)纯化,得到标题化合物(0.114g,0.261mmol,90%)。
参考例15.
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基 氧苯甲醛
将3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯甲醛(1.16g,3.35mol)溶解在丙酮(5.0ml)中,加入无水碳酸钠(1.02g,7.38mmol)和苄基溴(0.69g,4.02mmol)后,加热回流3小时。将反应液过滤,将浓缩滤液得到的残余物用硅胶柱色谱(己烷∶乙酸乙酯=2∶1)纯化,得到标题化合物(1.45g,3.32mmol,99%)。
参考例16.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧 苯甲酸
向4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧苯甲醛(735mg,1.69mmol)的乙腈溶液(5ml)中,加入磷酸二氢钠(157mg,1.31mmol)水溶液(2ml),亚氯酸钠(795mg,80%,7.07mmol)水溶液(7ml)和过氧化氢水(0.5ml,30%)后,在室温搅拌16小时。将反应液用水稀释后,用乙酸乙酯萃取。萃取液用10%的硫代硫酸钠(Na2S2O4)水溶液和饱和盐水洗涤,干燥后,通过浓缩得到标题化合物(603mg,1.33mmol,79%)。
参考例17.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧 苯甲酸
向5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧苯甲醛(5.60g,0.0128mol)的乙腈溶液(30.0ml)中,加入磷酸二氢钠(12.0g,0.100mol)水溶液(10.0ml),亚氯酸钠(5.19g,0.0577mol)水溶液(30.0ml)和过氧化氢水(1.701ml,30%)后,在室温搅拌5小时。将反应液用水稀释后,用乙酸乙酯萃取。萃取液用饱和的硫代硫酸钠(Na2S2O4)水溶液和饱和盐水洗涤,干燥后,通过浓缩得到标题化合物(5.20g,0.0115mol,90%)。
参考例18.
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧 苯甲酸
向3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧苯甲醛(1.87g,4.28mmol)的乙腈溶液(12ml)中,加入磷酸二氢钠(4.01g,33.42mmol)水溶液(7ml),亚氯酸钠(1.74g,19.33mmol)水溶液(7ml)和过氧化氢水(1.89ml,30%)后,在室温搅拌5小时。将反应液用水稀释后,用乙酸乙酯萃取。萃取液用饱和硫代硫酸钠(Na2S2O4)水溶液和饱和盐水洗涤,干燥后,通过浓缩得到标题化合物(1.90g,4.20mmol,98%)。
参考例19.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧 苯甲酸甲酯
向3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧苯甲醛(525mg,1.1615mmol)溶解在甲醇(20ml)中,在冰冷却下加入三甲基甲硅烷基重氮甲烷(15.9g,10%己烷溶液,13.9473mmol)后,在室温搅拌2小时。在反应液中加入醋酸(2ml)后,在室温下放置16小时分解残余成分的试剂。通过浓缩反应液,得到标题化合物(530mg,1.1373mmol,98%)。
参考例20.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧 苯甲酸甲酯
向5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧苯甲醛(1.22g,2.6548mmol)溶解在甲醇(100ml)中,在冰冷却下加入三甲基甲硅烷基重氮甲烷(36.3g,10%己烷溶液,31.8421mmol)后,在室温搅拌2小时。在反应液中加入醋酸(0.5ml)后,在室温下放置16小时分解残余成分的试剂。通过浓缩反应液得到的残余物用硅胶柱色谱(己烷∶乙酸乙酯=4∶1)纯化,得到标题化合物(1.18g,2.5321mmol,95%)。
参考例21.
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧 苯甲酸甲酯
向3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧苯甲醛(652mg,1.4424mmol)溶解在二氯甲烷(20ml)中,加入无水甲醇(231mg,7.2187mmol),4-二甲基氨基吡啶(264mg,2.1639mmol)和WSC-HCl(830mg,4.3296mmol)后,在室温搅拌16小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=4∶1)纯化,得到标题化合物(490mg,1.0515mmol,73%)。
参考例22.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯 甲酸甲酯
将4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧苯甲酸甲酯(530mg,1.1373mmol)溶解在甲醇(20ml)中,加入10%Pd-C(100mg)的甲醇悬浮液(20ml)中后,在氢气气氛中在室温搅拌16小时。将反应液过滤,减压浓缩滤液,得到标题化合物(414mg,1.101mmol,97%)。
参考例23.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯 甲酸甲酯
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧苯甲酸甲酯(15.0g,32.1459mmol)溶解在甲醇(200ml)中,加入10%Pd-C(1.0g)的甲醇悬浮液(200ml)中后,在氢气气氛中在室温搅拌16小时。将反应液过滤,减压浓缩滤液,得到标题化合物(11.2g,29.7340mmol,92%)。
参考例24.
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯 甲酸甲酯
将3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苄基氧苯甲酸甲酯(343mg,0.7360mmol)溶解在甲醇(10ml)中,加入10%Pd-C(100mg)的甲醇悬浮液(40ml)中后,在氢气气氛中在室温搅拌16小时。将反应液过滤,通过减压浓缩滤液,得到标题化合物(223mg,0.5930mmol,81%)。
参考例25.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟 甲基磺酰基)氧苯甲酸甲酯
向4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯甲酸甲酯(175mg,0.4654mmol)的无水二氯甲烷溶液(10ml)中,加入4-二甲基氨基吡啶(77mg,0.6311mmol),三乙胺(85mg,0.8415mmol)和无水三氟甲磺酸(177mg,0.6276mmol)后,在冰冷却下搅拌16小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=6∶1)纯化,得到标题化合物(160mg,0.3149mmol,68%)。
参考例26.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟 甲基磺酰基)氧苯甲酸甲酯
向5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯甲酸甲酯(3.10g,8.2446mmol)的无水二氯甲烷溶液(200ml)中,加入4-二甲基氨基吡啶(1.51g,12.377mmol),三乙胺(1.67g,16.5346mmol)和无水三氟甲磺酸(3.49g,12.3758mmol)后,在冰冷却下搅拌3小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=6∶1)纯化,得到标题化合物(4.06g,7.9921mmol,97%)。
参考例27.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟 甲基磺酰基)氧苯甲酸甲酯
向3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-羟基苯甲酸甲酯(540mg,1.4361mmol)的无水二氯甲烷溶液(30ml)中,加入4-二甲基氨基吡啶(263mg,2.1557mmol),三乙胺(290mg,2.8712mmol)和无水三氟甲磺酸(607mg,2.1524mmol)后,在冰冷却下搅拌3小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=6∶1)纯化,得到标题化合物(701mg,1.3799mmol,96%)。
实施例1.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯 甲酸甲酯
向4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟甲基磺酰基)氧苯甲酸甲酯(102mg,0.2007mmol)的甲苯溶液(2.3ml)中,加入四(三苯基膦)钯(4.6mg,0.0039mmol),碳酸钠水溶液(2M水溶液,0.35ml),氯化锂(17mg,0.4010mmol)和苯硼酸(27mg,0.2214mmol)的乙醇溶液(1.0ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(100ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=6∶1)纯化,得到标题化合物(84mg,0.1926mmol,96%)。
实施例2.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3- 吡啶基)苯甲酸甲酯
向4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟甲基磺酰基)氧苯甲酸甲酯(333mg,0.6555mmol)的甲苯溶液(6ml)中,加入四(三苯基膦)钯(23mg,0.0199mmol),碳酸钠水溶液(2M水溶液,1.00ml),氯化锂(56mg,1.3241mmol)和吡啶-3-硼酸1,3-丙二醇环状酯(159mg,0.9814mmol)的乙醇溶液(1.3ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(100ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(284mg,0.6498mmol,99%)。
实施例3.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯 甲酸甲酯
向5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟甲基磺酰基)氧苯甲酸甲酯(444mg,0.8740mmol)的甲苯溶液(12ml)中,加入四(三苯基膦)钯(60mg,0.0519mmol),碳酸钠水溶液(2M水溶液,1.35ml),氯化锂(89mg,2.0995mmol)和苯硼酸(320mg,2.6244mmol)的乙醇溶液(2.1ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(100ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=5∶1)纯化,得到标题化合物(349mg,0.8004mmol,68%)。
实施例4.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3- 吡啶基)苯甲酸甲酯
向5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟甲基磺酰基)氧苯甲酸甲酯(1.43g,2.8149mmol)的甲苯溶液(32ml)中,加入四(三苯基膦)钯(98mg,0.0848mmol),碳酸钠水溶液(2M水溶液,3.66ml),氯化锂(239mg,5.6381mmol)和吡啶-3-硼酸1,3-丙二醇环状酯(684mg,4.2222mmol)的乙醇溶液(5.9ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(200ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(1.20g,2.7459mmol,98%)。
实施例5.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4- 吡啶基)苯甲酸甲酯
向5-(3,4,5,6-四甲氧基-2-甲基苄基)-3-(三氟甲基磺酰基)氧苯甲酸甲酯(1.43g,2.8149mmol)的甲苯溶液(32ml)中,加入四(三苯基膦)钯(98mg,0.0848mmol),碳酸钠水溶液(2M水溶液,3.66ml),氯化锂(239mg,5.6381mmol)和吡啶-4-硼酸频哪醇环状酯(866mg,4.2243mmol)的乙醇溶液(5.9ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(200ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(910mg,2.0823mmol,74%)。
实施例6.
-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4- 甲氧基苯基)苯甲酸甲酯
向5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟甲基磺酰基)氧苯甲酸甲酯(411mg,0.8090mmol)的甲苯溶液(12ml)中,加入四(三苯基膦)钯(60mg,0.0519mmol),碳酸钠水溶液(2M水溶液,1.35ml),氯化锂(89mg,2.0995mmol)和4-甲氧基苯硼酸(369mg,2.4282mmol)的乙醇溶液(2.0ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(100ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=5∶1)纯化,得到标题化合物(351mg,0.7532mmol,93%)。
实施例7.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3- 甲氧基苯基)苯甲酸甲酯
向5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟甲基磺酰基)氧苯甲酸甲酯(1.50g,2.9527mmol)的甲苯溶液(40ml)中,加入四(三苯基膦)钯(205mg,0.1774mmol),碳酸钠水溶液(2M水溶液,4.58ml),氯化锂(300mg,7.0771mmol)和3-甲氧基苯硼酸(1.34g,8.8186mmol)的乙醇溶液(7.2ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(100ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=5∶1)纯化,得到标题化合物(1.23g,2.6394mmol,89%)。
实施例8.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(2- 甲氧基苯基)苯甲酸甲酯
向5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟甲基磺酰基)氧苯甲酸甲酯(1.50g,2.9527mmol)的甲苯溶液(40ml)中,加入四(三苯基膦)钯(205mg,0.1774mmol),碳酸钠水溶液(2M水溶液,4.58ml),氯化锂(300mg,7.0771mmol)和2-甲氧基苯硼酸(1.34g,8.8186mmol)的乙醇溶液(7.2ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(100ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=5∶1)纯化,得到标题化合物(1.34g,2.8755mmol,97%)。
实施例9.
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3- 吡啶基)苯甲酸甲酯
向3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟甲基磺酰基)氧苯甲酸甲酯(316mg,0.6220mmol)的甲苯溶液(7.1ml)中,加入四(三苯基膦)钯(22mg,0.0190mmol),碳酸钠水溶液(2M水溶液,0.81ml),氯化锂(53mg,1.2502mmol)和吡啶-3-硼酸1,3-丙二醇环状酯(151mg,0.9320mmol)的乙醇溶液(1.3ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(100ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(231mg,0.5286mmol,85%)。
实施例10.
3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4- 吡啶基)苯甲酸甲酯
向3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(三氟甲基磺酰基)氧苯甲酸甲酯(385mg,0.7578mmol)的甲苯溶液(8.6ml)中,加入四(三苯基膦)钯(26mg,0.0224mmol),碳酸钠水溶液(2M水溶液,0.99ml),氯化锂(64mg,1.5097mmol)和吡啶-4-硼酸频哪醇环状酯(233mg,1.1365mmol)的乙醇溶液(1.59ml)后,在95℃下搅拌16小时。将反应液用乙酸乙酯(100ml)稀释,水洗,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(301mg,0.6887mmol,91%)。
实施例11.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基 苯甲酸
将4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯甲酸甲酯(84mg,0.1926mmol)溶解在1N氢氧化钠水溶液(5ml)和1,4-二噁烷(5ml)的混合溶液中,在室温下搅拌16小时。将反应液用水(20ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(45mg,0.1800mmol,93%)。
实施例12.
4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3- 吡啶基)苯甲酸
将4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸甲酯(70mg,0.1601mmol)溶解在1N氢氧化钠水溶液(5ml)和1,4-二噁烷(5ml)的混合溶液中,在室温下搅拌l6小时。将反应液用水(20ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(45mg,0.1063mmol,66%)。
实施例13.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基 苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯甲酸甲酯(349mg,0.8004mmol)溶解在1N氢氧化钠水溶液(10ml)和1,4-二噁烷(20ml)的混合溶液中,在室温下搅拌16小时。将反应液用水(100ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(340mg,0.7819mmol,98%)。
实施例14.
5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3- 吡啶基)苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸甲酯(1.20g,2.7459mmol)溶解在1N氢氧化钠水溶液(13.7ml)和1,4-二噁烷(30ml)的混合溶液中,在室温下搅拌16小时。将反应液用水(200ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(1.02g,2.4113mmol,88%)。
实施例15. 5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-
吡啶基)苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸甲酯(910mg,2.0823mmol)溶解在1N氢氧化钠水溶液(10.4ml)和1,4-二噁烷(25ml)的混合溶液中,在室温下搅拌16小时。将反应液用水(200ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(655mg,1.5484mmol,74%)。
实施例16. 5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-
甲氧基苯基)苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-甲氧基苯基)苯甲酸甲酯(472mg,1.0128mmol)溶解在1N氢氧化钠水溶液(10ml)和1,4-二噁烷(20ml)的混合溶液中,在室温下搅拌16小时。将反应液用水(100ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(440mg,0.9734mmol,96%)。
实施例17. 5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-
甲氧基苯基)苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-甲氧基苯基)苯甲酸甲酯(1.23g,2.6394mmol)溶解在1N氢氧化钠水溶液(20ml)和1,4-二噁烷(40ml)的混合溶液中,在室温下搅拌16小时。将反应液用水(200ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(1.03g,2.2787mmol,86%)。
实施例18. 5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(2-
甲氧基苯基)苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(2-甲氧基苯基)苯甲酸甲酯(1.34g,2.8755mmol)溶解在1N氢氧化钠水溶液(20ml)和1,4-二噁烷(40ml)的混合溶液中,在室温下搅拌16小时。将反应液用水(200ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(1.21g,2.6769mmol,93%)。
实施例19. 3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-
吡啶基)苯甲酸
将3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸甲酯(231mg,0.5286mmol)溶解在1N氢氧化钠水溶液(10ml)和1,4-二噁烷(10ml)的混合溶液中,在室温下搅拌16小时。将反应液用水(200ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(170mg,0.4018mmol,76%)。
实施例20.3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-
吡啶基)苯甲酸
将3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸甲酯(301mg,0.5508mmol)溶解在1N氢氧化钠水溶液(10ml)和1,4-二噁烷(10ml)的混合溶液中,在室温下搅拌16小时。将反应液用水(100ml)稀释,用醚洗涤后,加入浓盐酸使其成为酸性后,用醚萃取。萃取液用水洗涤,干燥后,蒸馏除去溶剂,得到标题化合物(233mg,0.5508mmol,80%)。
实施例21. N-[4-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(3-吡啶基)苯甲酰基]哌啶
将4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(60mg,0.1415mmol),4-二甲基氨基吡啶(8.6mg,0.0704mmol)和哌啶(24mg,0.2823mmol)溶解在二氯甲烷(5ml)中,加入WSC-HCl(81mg,0.4225mmol)后,在室温搅拌16小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(62mg,0.1265mmol,89%)。
实施例22.N-[4-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(3-吡啶基)苯甲酰基]吗啉
将4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(7mg,0.0165mmol),4-二甲基氨基吡啶(1.0mg,0.0081mmol)和吗啉(2.9mg,0.0333mmol)溶解在二氯甲烷(2ml)中,加入WSC-HCl(9.5mg,0.0495mmol)后,在室温搅拌6小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(8.0mg,0.0162mmol,98%)。
实施例23.N-[4-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(3-吡啶基)苯甲酰基]-4-三氟甲基苯胺
在4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(82mg,0.1933mmol)的二氯甲烷溶液(10ml)中,加入4-三氟甲基苯胺(47mg,0.2919mmol),三乙胺(39mg,0.3861mmol)和氯化2-氯-1,3-二甲基咪唑鎓(98mg,0.5798mmol)后,在室温搅拌16小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(58mg,0.1024mmol,53%)。
实施例24.N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(3-吡啶基)苯甲酰基]哌啶
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(80mg,0.1886mmol),4-二甲基氨基吡啶(12mg,0.0983mmol)和哌啶(32mg,0.3764mmol)溶解在二氯甲烷(10ml)中,加入WSC-HCl(109mg,0.5685mmol)后,在室温搅拌16小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(45mg,0.0918mmol,49%)。
实施例25.N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(3-吡啶基)苯甲酰基]吗啉
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(80mg,0.1886mmol),4-二甲基氨基吡啶(12mg,0.0983mmol)和吗啉(33mg,0.3793mmol)溶解在二氯甲烷(10ml)中,加入WSC-HCl(109mg,0.5685mmol)后,在室温搅拌16小时。用水洗涤反就应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(51mg,0.1036mmol,55%)。
实施例26.N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(3-吡啶基)苯甲酰基]-4-三氟甲基苯胺
在5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(85mg,0.2004mmol)的二氯甲烷溶液(5ml)中,加入4-三氟甲基苯胺(48mg,0.2981mmol),三乙胺(41mg,0.4059mmol)和氯化2-氯-1,3-二甲基咪唑鎓(102mg,0.6035mmol)后,在室温搅拌3小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(60mg,0.1060mmol,53%)。
实施例27.N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(4-吡啶基)苯甲酰基]哌啶
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(430mg,1.0165mmol)和哌啶(173mg,2.0352mmol)溶解在二氯甲烷(30ml)中,加入4-二甲基氨基吡啶(62mg,0.5081mmol)和WSC-HCl(487mg,2.5404mmol)后,在室温搅拌6小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(5%甲醇-二氯甲烷)纯化,得到标题化合物(334mg,0.6816mmol,67%)。
实施例28.N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(4-吡啶基)苯甲酰基]吗啉
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(100mg,0.2364mmol)和吗啉(44mg,0.5057mmol)溶解在二氯甲烷(20ml)中,加入WSC-HCl(122mg,0.6364mmol)后,在室温搅拌6小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。残余物用硅胶柱色谱(5%甲醇-二氯甲烷)纯化,得到标题化合物(102mg,0.2073mmol,88%)。
实施例29.N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(4-吡啶基)苯甲酰基]-4-三氟甲基苯胺
在5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(200mg,0.4716mmol)的二氯甲烷溶液(10ml)中,加入4-三氟甲基苯胺(114mg,0.7080mmol),三乙胺(95mg,0.9405mmol)和氯化2-氯-1,3-二甲基咪唑鎓(239mg,1.4142mmol)后,在室温搅拌16小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(166mg,0.2932mmol,62%)。
实施例30.N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(3-吡啶基)苯甲酰基]哌啶
将3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(21mg,0.0496mmol)和哌啶(8.4mg,0.0988mmol)溶解在二氯甲烷(3ml)中,加入WSC-HCl(29mg,0.1512mmol)后,在室温搅拌16小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(11mg,0.0224mmol,45%)。
实施例31.(S)-N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)
-2-(3-吡啶基)苯甲酰基]-1-苯乙胺
将3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(17mg,0.0401mmol)和(S)-苯乙胺(9.7mg,0.0801mmol)溶解在二氯甲烷(5ml)中,加入WSC-HCl(23mg,0.1199mmol)后,在室温搅拌6小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(10mg,0.0190mmol,47%)。
实施例32.N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(4-吡啶基)苯甲酰基]哌啶
将3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(21mg,0.0496mmol)和哌啶(8.4mg,0.0988mmol)溶解在二氯甲烷(3ml)中,加入WSC-HCl(29mg,0.1512mmol)后,在室温搅拌16小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇= 95∶5)纯化,得到标题化合物(8.2mg,0.0167mmol,34%)。
实施例33.(S)-N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)
-2-(4-吡啶基)苯甲酰基]-1-苯乙胺
将3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(24mg,0.0567mmol)和(S)-苯乙胺(14mg,0.1157mmol)溶解在二氯甲烷(5ml)中,加入WSC-HCl(33mg,0.1721mmol)后,在室温搅拌16小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(15.9mg,0.0302mmol,53%)。
实施例34.N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2
-(4-吡啶基)苯甲酰基]-4-三氟甲基苯胺
在3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(18mg,0.0424mmol)的二氯甲烷溶液(3ml)中,加入4-三氟甲基苯胺(10.2mg,0.0633mmol),三乙胺(8.6mg,0.0851mmol)和氯化2-氯-1,3-二甲基咪唑鎓(21.5mg,0.1272mmol)后,在室温搅拌16小时。用水洗涤反应液,干燥后,蒸馏除去溶剂。将得到的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(17mg,0.0300mmol,71%)。
实施例35.4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)
甲基-2-苯基苯甲酸
将4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯甲酸(76mg,1.1800mmol)溶解在乙腈(3ml)和水(1ml)的混合溶液中,在室温下加入CAN(247mg,0.4507mmol)后,搅拌1小时。将反应液用水稀释,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(5%甲醇-二氯甲烷)纯化,得到标题化合物(54mg,0.1377mmol,77%)。
实施例36.4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)
甲基-2-(3-吡啶基)苯甲酸
将4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(30mg,1.1820mmol)溶解在乙腈(6ml)和水(2ml)的混合溶液中,在室温下加入CAN(97mg,0.1770mmol)后,搅拌3小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(10%甲醇-二氯甲烷)纯化后,得到标题化合物(10mg,0.0254mmol,36%)。
实施例37.5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)
甲基-2-苯基苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-苯基苯甲酸(340mg,0.7819mmol)溶解在乙腈(30ml)和水(10ml)的混合溶液中,在室温下加入CAN(1.10g,2.0072mmol)后,搅拌3小时。将反应液倒入水中,用醚萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(5%甲醇-二氯甲烷)纯化,得到标题化合物(234mg,0.5969mmol,76%)。
实施例38.5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)
甲基-2-(3-吡啶基)苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酸(500mg,1.1820mmol)溶解在乙腈(30ml)和水(10ml)的混合溶液中,在室温下加入CAN(1.62g,2.9562mmol)后,搅拌3小时。将反应液倒入水中,用1N氢氧化钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(10%甲醇-二氯甲烷)纯化后,得到标题化合物(270mg,0.6870mmol,58%)。
实施例39.5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)
甲基-2-(4-吡啶基)苯甲酸
在5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(500mg,1.1820mmol)的四氢呋喃(THF)溶液(20ml)中,加入2-叔丁基-1,3-二异丙基异脲(2.36g,11.8mmol)后,在室温下搅拌16小时。浓缩反应液,将残余物用硅胶柱色谱(己烷∶乙酸乙酯=2∶1)纯化后,得到5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸叔丁酯(400mg,0.8350mmol,70%)。将该化合物溶解在乙腈(30ml)和水(10ml)的混合溶液中,在室温下加入CAN(1.12g,2.0437mmol)后,搅拌3小时。
将反应液倒入水中,用1N氢氧化钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(二氯甲烷∶甲醇=95∶5)纯化后,得到5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)-2-(4-吡啶基)苯甲酸叔丁酯(251mg,0.5590mmol,67%)。将该化合物(251mg,0.5590mmol)溶解在甲酸(10ml)中,在室温下搅拌6小时。将蒸馏除去溶剂得到的残余物用乙醚洗涤,得到标题化合物(202mg,0.5139mmol,92%)。(总收率:43%)
实施例40.5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)
甲基-2-(4-甲氧基苯基)苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-甲氧基苯基)苯甲酸(440mg,0.9734mmol)溶解在乙腈(30ml)和水(10ml)的混合溶液中,在室温下加入CAN(1.10g,2.0072mmol)后,搅拌3小时。将反应液倒入水中,用醚萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(5%甲醇-二氯甲烷)纯化,得到标题化合物(259mg,0.6137mmol,63%)。
实施例41.5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)
甲基-2-(3-甲氧基苯基)苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-甲氧基苯基)苯甲酸(1.03g,2.2787mmol)溶解在乙腈(30ml)和水(10ml)的混合溶液中,在室温下加入CAN(3.12g,5.6934mmol)后,搅拌3小时。将反应液倒入水中,用醚萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(5%甲醇-二氯甲烷)纯化,得到标题化合物(817mg,1.9360mmol,85%)。
实施例42.5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)
甲基-2-(2-甲氧基苯基)苯甲酸
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(2-甲氧基苯基)苯甲酸(1.21g,2.6769mmol)溶解在乙腈(30ml)和水(10ml)的混合溶液中,在室温下加入CAN(3.60g,6.6914mmol)后,搅拌3小时。将反应液倒入水中,用醚萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(5%甲醇-二氯甲烷)纯化,得到标题化合物(859mg,2.0355mmol,76%)。
实施例43.N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-苯基苯甲酰基]哌啶
将4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酸(18mg,0.0459mmol)和哌啶(5.9mg,0.0692mmol)溶解在二氯甲烷(3ml)中,加入WSC-HCl(22mg,0.1147mmol)后,在室温搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(12mg,0.0261mmol,57%)。
实施例44.N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-苯基苯甲酰基]吗啉
将4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酸(18mg,0.0459mmol)和吗啉(6mg,0.0689mmol)溶解在二氯甲烷(3ml)中,加入WSC-HCl(22mg,0.1147mmol)后,在室温搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(10mg,0.0216mmol,47%)。
实施例45.N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-苯基苯甲酰基]-4-三氟甲基苯胺
将4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酸(16mg,0.0408mmol)溶解在二氯甲烷(3ml)中,在室温下加入4-三氟甲基苯胺(13mg,0.0807mmol),三乙胺(8.2mg,0.0811mmol)和氯化2-氯-1,3-二甲基咪唑鎓(21mg,0.1242mmol)后,搅拌16小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(8mg,0.0149mmol,37%)。
实施例46.N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-吡啶基)苯甲酰基]哌啶
将N-[4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]哌啶(70mg,0.1428mmol)溶解在乙腈(6ml)和水(2ml)的混合溶液中,在室温下加入CAN(231mg,0.4293mmol)后,搅拌3小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(26mg,0.0565mmol,40%)。
实施例47.N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-吡啶基)苯甲酰基]吗啉
将N-[4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]吗啉(8mg,0.0162mmol)溶解在乙腈(3ml)和水(1ml)的混合溶液中,在室温下加入CAN(26mg,0.0483mmol)后,搅拌3小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(4.5mg,0.0097mmol,60%)。
实施例48.N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-吡啶基)苯甲酰基]-4-三氟甲基苯胺
将N-[4-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]-4-三氟甲基苯胺(55mg,0.0971mmol)溶解在乙腈(3ml)和水(1ml)的混合溶液中,在室温下加入CAN(157mg,0.2918mmol)后,搅拌2小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇= 95∶5)纯化,得到标题化合物(10mg,0.0186mmol,19%)。
实施例49.N-[4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-吡啶基)苯甲酰基]-4-甲氧基苯胺
将4-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酸(44mg,0.1119mmol)溶解在二氯甲烷(10ml)中,在室温下加入对甲氧基苯胺(28mg,0.2276mmol),三乙胺(23mg,0.2277mmol)和氯化2-氯-1,3-二甲基咪唑鎓(38mg,0.1982mmol)后,搅拌16小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(33mg,0.0662mmol,59%)。
实施例50.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-苯基苯甲酰基]哌啶
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酸(40mg,0.1020mmol),4-二甲基氨基吡啶(6.2mg,0.0508mmol)和哌啶(17mg,0.2000mmol)溶解在二氯甲烷(5ml)中,加入WSC-HCl(59mg,0.3077mmol)后,在室温搅拌16小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(16mg,0.0348mmol,34%)。
实施例51.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-苯基苯甲酰基]吗啉
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酸(40mg,0.1020mmol),4-二甲基氨基吡啶(6.2mg,0.0508mmol)和吗啉(18mg,0.2068mmol)溶解在二氯甲烷(5ml)中,加入WSC-HCl(59mg,0.3077mmol)后,在室温搅拌16小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(13mg,0.0281mmol,28%)。
实施例52.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-苯基苯甲酰基]-4-甲氧基苯胺
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酸(33mg,0.0841mmol)溶解在二氯甲烷(3ml)中,在室温下加入对甲氧基苯胺(21mg,0.1707mmol),三乙胺(34mg,0.3366mmol)和氯化2-氯-1,3-二甲基咪唑鎓(57mg,0.3372mmol)后,搅拌16小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(28mg,0.0563mmol,67%)。
实施例53.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-苯基苯甲酰基]-4-三氟甲基苯胺
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-苯基苯甲酸(40mg,0.1020mmol)溶解在二氯甲烷(5ml)中,在室温下加入4-三氟甲基苯胺(25mg,0.1552mmol),三乙胺(21mg,0.2079mmol)和氯化2-氯-1,3-二甲基咪唑鎓(52mg,0.3076mmol)后,搅拌16小时。将反应液倒入水中,用乙酸乙酯萃取,萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=3∶1)纯化,得到标题化合物(5mg,0.0093mmol,9%)。
实施例54.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-吡啶基)苯甲酰基]哌啶
将N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-(3-吡啶基)苯甲酰基]哌啶(33mg,0.0673mmol)溶解在乙腈(6ml)和水(2ml)的混合溶液中,在室温下加入CAN(92mg,0.1678mmol)后,搅拌1小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(20mg,0.0434mmol,64%)。
实施例55.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-吡啶基)苯甲酰基]吗啉
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酸(40mg,0.1017mmol)和吗啉(18mg,0.2608mmol)溶解在二氯甲烷(3ml)中,加入WSC-HCl(49mg,0.2556mmol)后,在室温下搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(32mg,0.0692mmol,68%)。
实施例56.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-吡啶基)苯甲酰基]-4-甲氧基苯胺
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-吡啶基)苯甲酸(73mg,0.1857mmol)溶解在二氯甲烷(5ml)中,在室温下加入对甲氧基苯胺(46mg,03739mmol),三乙胺(75mg,0.7425mmol)和氯化2-氯-1,3-二甲基咪唑鎓(126mg,0.7455mmol)后,搅拌16小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶4)纯化,得到标题化合物(33mg,0.0662mmol,36%)。
实施例57.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-吡啶基)苯甲酰基]-4-三氟甲基苯胺
将N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]-4三氟甲基苯胺(60mg,0.1060mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(228mg,0.4237mmol)后,搅拌3小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(18mg,0.0335mmol,32%)。
实施例58.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-吡啶基)苯甲酰基]哌啶(甲磺酸盐)
将N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]哌啶(630mg,1.2857mmol)溶解在乙腈(30ml)和水(10ml)的混合溶液中,在室温下加入CAN(1.73g,3.1569mmol)后,搅拌1小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(470mg,0.1217mmol,79%)。将该化合物(470mg,0.1217mmol)溶解在无水二氯甲烷中,和1N的甲磺酸处理后,进行浓缩。通过将得到的残余物用乙酸乙酯·甲苯·乙醚的混合溶剂进行重结晶,得到标题化合物的甲磺酸盐(450ng)。
实施例59.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-吡啶基)苯甲酰基]吗啉
将N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]吗啉(102mg,0.2073mmol)溶解在乙腈(15ml)和水(5ml)的混合溶剂中,在室温下加入CAN(279mg,0.5091mmol)后,搅拌3小时。将反应液倒入水中,用1N氢氧化钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(60mg,0.1298mmol,63%)。
实施例60.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-吡啶基)苯甲酰基]-4-甲氧基苯胺
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-吡啶基)苯甲酸(100mg,0.2544mmol)溶解在二氯甲烷(30ml)中,在室温下加入对甲氧基苯胺(56mg,0.4552mmol),三乙胺(75mg,0.7425mmol)和氯化2-氯-1,3-二甲基咪唑鎓(126mg,1.3663mmol)后,搅拌16小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶4)纯化,得到标题化合物(33mg,0.0963mmol,38%)。
实施例61.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-吡啶基)基甲酰基]-4-三氟甲基苯胺
将N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]-4三氟甲基苯胺(140mg,0.2473mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(399mg,0.7416mmol)后,搅拌3小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(60mg,0.1119mmol,45%)。
实施例62.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-甲氧基苯基)苯甲酰基]哌啶
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-甲氧基苯基)苯甲酸(50mg,0.1184mmol)和哌啶(20mg,0.2352mmol)溶解在二氯甲烷(30ml)中,加入WSC-HCl(68mg,0.3547mmol)后,在室温下搅拌16小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(23mg,0.0468mmol,40%)。
实施例63.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-甲氧基苯基)苯甲酰基]吗啉
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-甲氧基苯基)苯甲酸(50mg,0.1184mmol)和吗啉(21mg,0.2413mmol)溶解在二氯甲烷(30ml)中,加入WSC-HCl(68mg,0.3547mmol)后,在室温下搅拌16小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(30mg,0.0613mmol,52%)。
实施例64.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-甲氧基苯基)苯甲酰基]-4-甲氧基苯胺
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(4-甲氧基苯基)苯甲酸(100mg,0.2369mmol)溶解在二氯甲烷(20ml)中,在室温下加入对甲氧基苯胺(58mg,0.4715mmol),三乙胺(48mg,0.4752mmol)和氯化2-氯-1,3-二甲基咪唑鎓(80mg,0.4733mmol)后,搅拌16小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶4)纯化,得到标题化合物(78mg,0.1480mmol,62%)。
实施例65.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-甲氧基苯基)苯甲酰基]哌啶
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-甲氧基苯基)苯甲酸(100mg,0.2369mmol)和哌啶(40mg,0.4705mmol)溶解在二氯甲烷(20ml)中,加入4-二甲基氨基吡啶(6mg,0.0491mmol)和WSC-HCl(136mg,0.7094mmol)后,在室温下搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(58mg,0.1186mmol,50%)。
实施例66.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-甲氧基苯基)苯甲酰基]吗啉
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-甲氧基苯基)苯甲酸(100mg,0.2369mmol)和吗啉(41mg,0.4712mmol)溶解在二氯甲烷(20ml)中,加入4-二甲基氨基吡啶(6mg,0.0491mmol)和WSC-HCl(136mg,0.7094mmol)后,在室温下搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶3)纯化,得到标题化合物(80mg,0.1629mmol,69%)。
实施例67.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-甲氧基苯基)苯甲酰基]-4-甲氧基苯胺
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(3-甲氧基苯基)苯甲酸(100mg,0.2369mmol)溶解在二氯甲烷(20ml)中,在室温下加入对甲氧基苯胺(58mg,0.4715mmol),三乙胺(48mg,0.4752mmol)和氯化2-氯-1,3-二甲基咪唑鎓(80mg,0.4733mmol)后,搅拌16小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(68mg,0.1290mmol,54%)。
实施例68.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(2-甲氧基苯基)苯甲酰基]-4-甲氧基苯胺
将5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)甲基-2-(2-甲氧基苯基)苯甲酸(66mg,0.1563mmol)溶解在二氯甲烷(5ml)中,在室温下加入对甲氧基苯胺(38mg,0.3089mmol),三乙胺(47mg,0.4653mmol)和氯化2-氯-1,3-二甲基咪唑鎓(53mg,0.3136mmol)后,搅拌16小时。将反应液倒入水中,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶1)纯化,得到标题化合物(38mg,0.0721mmol,46%)。
实施例69.N-[3-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(3-吡啶基)苯甲酰基]哌啶
将N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]哌啶(80mg,0.1632mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(128mg,0.2335mmol)后,搅拌1小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶3)纯化,得到标题化合物(51mg,0.1108mmol,68%)。该化合物按照实施例58的方法转化为甲磺酸盐。
实施例70.(S)-N-[3-(5,6-二甲氧基-3-甲基-1,4-苯
醌-2-基)甲基-2-(3-吡啶基)苯甲酰基]-1-苯乙胺
将(S)-N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(3-吡啶基)苯甲酰基]-1-苯乙胺(69mg,0.1311mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(180mg,0.3284mmol)后,搅拌3小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶3)纯化,得到标题化合物(48mg,0.0967mmol,74%)。
实施例71.N-[3-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-吡啶基)苯甲酰基]哌啶
将N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]哌啶(74mg,0.1510mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(206mg,0.3759mmol)后,搅拌1小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶5)纯化,得到标题化合物(32mg,0.0695mmol,46%)。
实施例72.(S)-N-[3-(5,6-二甲氧基-3-甲基-1,4-苯
醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-1-苯乙胺
将(S)-N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]-1-苯乙胺(64mg,0.1216mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(166mg,0.3029mmol)后,搅拌3小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶3)纯化,得到标题化合物(30mg,0.0604mmol,50%)。
实施例73.N-[3-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-吡啶基)苯甲酰基]-4-三氧甲基苯胺
将N-[3-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]-4-三氟甲基苯胺(17mg,0.0300mmol)溶解在乙腈(6ml)和水(2ml)的混合溶液中,在室温下加入CAN(48mg,0.0892mmol)后,搅拌3小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(6mg,0.0111mmol,37%)。
实施例74.(S)-N-[5-(5,6-二甲氧基-3-甲基-1,4-苯
醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-1-苯乙胺(甲磺酸盐)
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(100mg,0.2364mmol)和(S)-1-苯乙胺(93mg,0.7674mmol)溶解在二氯甲烷(10ml)中,加入4-二甲基氨基吡啶(6mg,0.0491mmol)和WSC-HCl(146mg,0.7616mmol)后,在室温下搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。
将残余物用硅胶柱色谱(二氯甲烷∶甲醇=95∶5)纯化,得到(S)-N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]-1-苯乙胺(90mg,0.1711mmol,72%)。将该化合物(102mg,0.2073mmol)溶解在乙腈(15ml)和水(5ml)的混合溶液中,在室温下加入CAN(279mg,0.5091mmol)后,搅拌3小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶5)纯化,得到标题化合物(55mg,0.1298mmol,63%)。该化合物按照实施例58的方法转化为甲磺酸盐。
实施例75.(R)-N-[5-(5,6-二甲氧基-3-甲基-1,4-苯
醌-2-基)甲基-2-(4-吡啶基)苯甲酰基]-1-苯乙胺(甲磺酸盐)
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(100mg,0.2364mmol)和(R)-1-苯乙胺(93mg,0.7674mmol)溶解在二氯甲烷(10ml)中,加入4-二甲基氨基吡啶(6mg,0.0491mmol)和WSC-HCl(146mg,0.7616mmol)后,在室温下搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。
将残余物用硅胶柱色谱(二氯甲烷∶甲醇=95∶5)纯化,得到(R)-N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]-1-苯乙胺(98mg,0.1863mmol,79%)。将该化合物(98mg,0.1863mmol)溶解在乙腈(15ml)和水(5ml)的混合溶液中,在室温下加入CAN(251mg,0.4580mmol)后,搅拌3小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(己烷∶乙酸乙酯=1∶5)纯化,得到标题化合物(60mg,0.1209mmol,65%)。该化合物按照实施例58的方法转化为甲磺酸盐。
实施例76.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-
基)甲基-2-(4-吡啶基)苯甲酰基]环己胺(甲磺酸盐)
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(100mg,0.2364mmol)和环己胺(76mg,0.7663mmol)溶解在二氯甲烷(10ml)中,加入4-二甲基氨基吡啶(6mg,0.0491mmol)和WSC-HCl(146mg,0.7616mmol)后,在室温下搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。
将残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶5)纯化,得到N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]环己胺(58mg,0.1149mmol,49%)。将该化合物(58mg,0.1150mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(155mg,0.2828mmol)后,搅拌1小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=1∶5)纯化,得到标题化合物(35mg,0.0738mmol,64%)。该化合物按照实施例58的方法转化为甲磺酸盐。
实施例77.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-吡啶基)苯甲酰基]环戊胺(甲磺酸盐)
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(100mg,0.2364mmol)和环戊胺(65mg,0.7633mmol)溶解在二氯甲烷(10ml)中,加入4-二甲基氨基吡啶(6mg,0.0491mmol)和WSC-HCl(146mg,0.7616mmol)后,在室温下搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。
将残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶5)纯化,得到N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]环戊胺(58mg,0.1183mmol,50%)。将该化合物(58mg,0.1183mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(155mg,0.2901mmol)后,搅拌1小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(5%甲醇-二氯甲烷)纯化,得到标题化合物(28mg,0.0608mmol,51%)。该化合物按照实施例58的方法转化为甲磺酸盐。
实施例78.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-吡啶基)苯甲酰基]环丙胺(甲磺酸盐)
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(100mg,0.2364mmol)和环丙胺(44mg,0.7719mmol)溶解在二氯甲烷(5ml)中,加入4-二甲基氨基吡啶(6mg,0.0491mmol)和WSC-HCl(146mg,0.7616mmol)后,在室温下搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶5)纯化,得到N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]环丙胺(71mg,0.1536mmol,65%)。
将该化合物(71mg,0.1536mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(207mg,0.3777mmol)后,搅拌1小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(51mg,0.1180mmol,77%)。该化合物按照实施例58的方法转化为甲磺酸盐。
实施例79.N-[5-(5,6-二甲氧基-3-甲基-1,4-苯醌-2
-基)甲基-2-(4-吡啶基)苯甲酰基]-1-乙基丙胺(甲磺酸盐)
将5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酸(100mg,0.2364mmo1)和1-乙基丙胺(66mg,0.7586mmol)溶解在二氯甲烷(5ml)中,加入4-二甲基氨基吡啶(6mg,0.0491mmol)和WSC-HCl(146mg,0.7616mmol)后,在室温下搅拌6小时。将反应液用水洗涤,干燥后,蒸馏除去溶剂。将残余物用硅胶柱色谱(己烷∶乙酸乙酯=1∶5)纯化,得到N-[5-(3,4,5,6-四甲氧基-2-甲基苄基)-2-(4-吡啶基)苯甲酰基]-1-乙基丙胺(63mg,0.1280mmol,54%)。
将该化合物(63mg,0.1280mmol)溶解在乙腈(9ml)和水(3ml)的混合溶液中,在室温下加入CAN(172mg,0.3777mmol)后,搅拌1小时。将反应液倒入水中,用饱和碳酸氢钠水溶液使其成为中性后,用乙酸乙酯萃取。将萃取液用水洗涤,干燥后,蒸馏除去溶剂。所得的残余物用制备性薄层色谱(二氯甲烷∶甲醇=95∶5)纯化,得到标题化合物(46mg,0.0995mmol,78%)。该化合物按照实施例58的方法转化为甲磺酸盐。
表1
表2
表3
表4
表5
表6
表7
表8
表9
表10
表11
表12
表13
表14
表15
表16
表17
表18
表19
表20
表21
表22
表23
表24
表25
表26
表27
表28
表29
实验例1.对于来自于稳定导入了通过NF-κB结合排列被抑制的荧
光素酶质粒(pNFκB-Luc,ストラタジ-ン社,美国)的人肺癌的细胞
株A549(A549/NF-κBluc)的反应
在A549细胞(ATCC CCL185)上使用脂质转染胺(ラィフテツクォリェンタル社,东京),按照常规方法,同时转染pNFκB-Luc和pSV2neo(クロ-ンテツク社,美国),通过在培养基上添加G418硫酸盐(1mg/ml,ラィフテツクォリェンタル社),选择pNFκB-Luc被稳定导入的细胞A549/NF-κBluc。
向A549/NF-κBluc中添加在实施例得到的化合物,1小时后,添加能够活化NF-κB的IL-1β,并继续保温3小时。实施例得到的化合物,抑制由IL-1β的刺激引起的NF-κB活化,通过以荧光素酶活性为指标而确定。其IC50值示于表中。
表30
化合物 | IC50值 |
实施例12 | 有毒的 |
实施例14 | >15μg/ml |
实施例15 | >15μg/ml |
实施例17 | >15μg/ml |
实施例18 | >15μg/ml |
实施例35 | >15μg/ml |
实施例36 | >15μg/ml |
实施例37 | >45μg/ml |
实施例38 | >45μg/ml |
实施例39 | >30μg/ml |
实施例40 | >45μg/ml |
实施例45 | >30μg/ml |
实施例47 | 24μg/ml |
实施例48 | >30μg/ml |
实施例49 | 24μg/ml |
实施例51 | >30μg/ml |
实施例52 | >45μg/ml |
实施例53 | >30μg/ml |
实施例54 | 15μg/ml(33μM) |
实施例55 | >45μg/ml |
实施例56 | >45μg/ml |
实施例57 | >30μg/ml |
实施例58a | 15μg/ml(30μM) |
实施例58b | 45μg/ml(81μM) |
实施例59 | >45μg/ml |
实施例60a | >30μg/ml |
实施例60b | >30μg/ml |
实施例61 | >30μg/ml |
实施例64 | 12μg/ml(23μM) |
实施例65 | 40μg/ml(82μM) |
表31
化合物 | IC50值 |
实施例66 | 42μg/ml(85μM) |
实施例67 | >45μg/ml |
实施例68 | >45μg/ml |
实施例73 | >30μg/ml |
实施例74a | >45μg/ml |
实施例74b | >45μg/ml |
实施例75a | >45μg/ml |
实施例75b | >45μg/ml |
实施例76a | >45μg/ml |
实施例76b | >45μg/ml |
实施例77a | >45μg/ml |
实施例77b | >45μg/ml |
实施例78a | >45μg/ml |
实施例78b | >45μg/ml |
实施例79a | >45μg/ml |
实施例79b | >45μg/ml |
Claims (15)
2.如权利要求1中记载的新的取代的苯甲酸衍生物,其中R1为下列通式(II):
(式中,R3和R4各自独立地表示氢原子,甲基或甲氧基)。
4.如权利要求1~3中任意一项中记载的新的取代的苯甲酸衍生物,其中R2为可以被取代的碳数6~12的芳基或可以被取代的碳数4~11的杂芳基。
5.如权利要求1~4中任意一项中记载的新的取代的苯甲酸衍生物,其中R2为苯基,4-甲氧基苯基,3-甲氧基苯基,2-甲氧基苯基,3,4-二甲氧基苯基,4-吡啶基,3-吡啶基,2-吡啶基,2-呋喃基,3-呋喃基。
6.如权利要求1~5中任意一项中记载的新的取代的苯甲酸衍生物,其中X为基团-COOR6(式中R6表示氢原子,可以被取代的碳数1~6的烷基,可以被取代的碳数7~14的芳烷基)。
7.如权利要求1~5中任意一项中记载的新的取代的苯甲酸衍生物,其中X为基团-CONR7R8(式中,R7和R8各自独立表示氢原子,可以被取代的碳数1~6的烷基,可以被取代的碳数6~12的芳基,可以被取代的碳数4~11的杂芳基,可以被取代的碳数7~14的芳烷基,可以被取代的碳数5~13的杂芳基烷基,或者R7和R8与和它们相连的氮原子一起表示还可以含有氮原子,氧原子,硫原子,或者可以稠合的杂环基)。
8.权利要求1~5中任意一项中记载的新的取代的苯甲酸衍生物,其中X为基团-CONR7R8(式中,R7和R8和与其相连的氮原子一起表示除可以被取代的碳原子和氮原子之外,还可以含有1~3个选自氮原子,氧原子,硫原子的杂原子的5~8员含氮杂环基,这些环上的碳原子或硫原子可以被氧化)。
10.以权利要求1~9中任意一项中记载的新的取代的苯甲酸衍生物或其氢醌体或其药理学上容许的盐为有效成分的NF-κB抑制剂。
11.如权利要求10中记载的NF-κB抑制剂,是选自IL-1,TNF-α,IL-2,IL-6,IL-8,iNOS,粒细胞颗粒球集落刺激因子,干扰素-γ,ICAM-1,VCAM-1,ELAM-1,主要组织相容性抗原I型,适合主要组织抗原系种II,β-2微球蛋白,免疫球蛋白轻链,血清淀粉A,血管紧张素原,补体B,补体C4,c-myc,HIV,HTLV-1,SV-40,CMV和腺病毒中的1种或2种以上物质的基因表达抑制剂。
12.如权利要求10或11中记载的NF-κB抑制剂,是炎症性疾病的预防或治疗药。
13.如权利要求10或11中记载的NF-κB抑制剂,是自身免疫性疾病的预防或治疗药。
14.如权利要求10或11中记载的NF-κB抑制剂,是病毒性疾病的预防或治疗药。
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JP2007290972A (ja) * | 2006-04-21 | 2007-11-08 | Daicel Chem Ind Ltd | 芳香族カルボン酸の製造法 |
US20080081035A1 (en) * | 2006-10-03 | 2008-04-03 | National Enzyme Company | Therapeutic protease compositions |
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