CN1376144A - 作为tace抑制剂的炔属芳基氨磺酰和次膦酰胺异羟肟酸 - Google Patents
作为tace抑制剂的炔属芳基氨磺酰和次膦酰胺异羟肟酸 Download PDFInfo
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- CN1376144A CN1376144A CN00810895A CN00810895A CN1376144A CN 1376144 A CN1376144 A CN 1376144A CN 00810895 A CN00810895 A CN 00810895A CN 00810895 A CN00810895 A CN 00810895A CN 1376144 A CN1376144 A CN 1376144A
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- Prior art keywords
- methyl
- carbon atom
- amino
- benzenesulfonyl
- phenyl
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Abstract
本文公开了一种式(B)的可用于治疗受TNF-α介导的疾病如类风湿性关节炎、骨关节炎、脓毒病、AIDS、溃疡性结肠炎、多发性硬化、局限性回肠炎和退化性软骨丧失的异羟肟酸,本文还定义了它的各种变化。
Description
发明领域
本发明涉及炔属芳基氨磺酰异羟肟酸作为TNF-α转化酶(TACE)的抑制剂。本发明的化合物可用于治疗TNF-α所介导的病症,如类风湿性关节炎、骨性关节炎、脓毒病、AIDS、溃疡性结肠炎、多发性硬化、局限性回肠炎和退化性软骨丧失。
发明背景
TNF-α转化酶(TACE)催化膜结合TNF-α前体蛋白形成TNF-α。TNF-α是一种促炎症细胞因子,据信在以下疾病中起作用:类风湿性关节炎(Shire,M.G.;Muller,G.W.Exp.Opin.Ther.Patents 1998,8(5),531;Grossman,J.M.;Brahn,E.J.Women′s Health 1997,6(6),627;Isomaki,P.;Punnonen,J.Ann.Med.1997,29,499;Camussi,G.;Lupia,E.Drugs,1998,55(5),613)、脓毒性休克(Mathison,等人,J.Clin.Invest.1988,81,1925;Miethke,等人,J.Exp.Med.1992,175,91)、移植排斥(Piguet,P.F.;Grau,G.E.;等人,J.Exp.Med.1987,166,1280.),恶质病(Beutler,B.;Cerami,A.Ann.Rev.Biochem.1988,57,505)、厌食、炎症(Ksontini,R,;MacKay,S.L.D.;Moldawer,L.L.Arch.Surg.1998,133,558.)、充血性心力衰竭(Packer,M.Circulation,1995,92(6),1973;Ferrari,R.;Bachetti,T.:等人.Circulation,1995,92(6),1479)、局部缺血后重复灌注(ischaemic)的损伤、中枢神经系统炎性疾病、肠炎、胰岛素抗性(Hotamisligil,G.S.Shargill,N.S.;Spiegelman,B.M.;等人.Science,1993,259,87.)和HIV感染(Peterson,P.K.;Gekker,G.;等人,J.Clin.Invest.1992,89,574;Pallares-Trujillo,J.;Lopez-Soriano,F.J.Argiles,J.M.Med.Res.Reviews,1995,15(6),553),及其熟知的抗肿瘤特性(Old,L.Science,1985,230,630)。例如,用抗TNF-α抗体和转基因动物作的研究表明阻断TNF-α的形成抑制了关节炎的发展(Rankin,E.C.;Choy,E.H.;Kassimos,D.;Kingsley,G.H.;Sopwith,A.M.;Isenberg,D.A.;Panayi,G.S.Br.J.Rheumatol.1995,34,334;Pharmaprojects,1996,Therapeutic Updates 17(10月)au197-M2Z)。最近这个观察已扩展到人,如“人类疾病中的TNF-α”,CurrentPharmaceutical Design,1996,2,662所述。
预计TACE的小分子抑制剂具有治疗各种疾病症状的潜力。虽然已知有许多TACE抑制剂,但这些分子中的许多是肽类或类肽,存在生物可利用性和药物动力学问题。另外,这些分子中许多是非选择性的基质金属蛋白酶(尤其是MMP-1)的强抑制剂。已假设对MMP-1(胶原酶1)的抑制会造成MMP抑制剂临床实验中的关节疼痛(Scrip,1998,2349,20)。因此长效、选择性、口服生物可利用性的非肽类TACE抑制剂对治疗上述疾病是非常理想的。
WIPO国际出版物WO9816503、WO9816506、WO9816514和WO9816520和美国专利No.5,776,961公开了呈下式的异羟肟酸氨磺酰MMP/TACE抑制剂的例子,其中2碳链将异羟肟酸和氨磺酰氮分开。
美国专利N0.5,455,258、5,506,242、5,552,419、5,770,624、5,804,593和5,817,822以及欧洲专利EP606,046A1和WIPO国际出版物WO9600214和WO9722587公开了基质金属蛋白酶和/或TACE的非肽类抑制剂,即以下所示的异羟肟酸芳基氨磺酰,其中1碳将异羟肟酸和氨磺酰氮分开。其他出版物公开的氨磺酰为基础的MMP抑制剂,是以下所示的氨磺酰-异羟肟酸的变体或氨磺酰-异羟肟酸的类似物,公开于欧洲专利EP-757037-A1和EP-757984-A1和WIPO国际出版物WO9535275、WO9535276、WO9627583、WO9719068、WO9727174、WO9745402、WO9807697和WO9831664、WO9833768、WO9839313、WO9839329、WO9842659和WO9843963。MacPherson,等人在J.Med.Chem,(1997),40,2525和Tamura等人在J.Med.Chem.(1998),41,640中进一步详细公开了这种类型的MMP抑制剂。
公开MMP和/或TACE的β-氨磺酰-异羟肟酸抑制剂(其中异羟肟酸的α碳与氨磺酰的氮呈环状连接,如下所示)的出版物包括美国专利No.5,753,653、WIPO国际出版物WO9633172、WO9720824、WO9827069、WO9808815、WO9808822、WO9808823、WO9808825、WO9834918、WO9808827、Levin等人,Bioorg.&Med.Chem.Letters 1998,8,2657和Pikul等人,J.Med.Chem.1998,41,3568。
氨磺酰的类似物是次膦酸酰胺异羟肟酸MMP/TACE抑制剂,如以下结构所示,公开于WIPO国际出版物WO9808853。
本发明的目的是公开芳基氨磺酰异羟肟酸MMP/TACE抑制剂,其中磺酰基芳基是被取代的丁炔基部分或炔丙醚、炔丙胺或炔丙硫醚对取代。这些化合物在体外和细胞试验中提供增强的抑制TACE活性的水平和/或优于MMP-1的选择性。所以这些化合物可用于治疗由TNF介导的疾病。
发明详述
可用下式表示本发明的抑制TACE和MMP的邻亚磺酰氨基芳基异羟肟酸或其药学上可接受的盐:其中C(=O)NHOH部分和-NR5-部分连接于基团A的相邻的碳原子;
其中A是苯基;萘基或与5-7元饱和的或不饱和环烷基环稠合的苯基;5-9元饱和的或不饱和的杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S;或5-10元杂芳环,所述的杂芳环的1-3个杂原子选自N、NR9、O或S;
X是SO2或-P(O)R10;
Y是苯基;萘基;或5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;条件是X和Z不连接于Y的相邻原子;
Z是O、NH、CH2或S;
R5是氢;或1-6个碳原子的烷基;或R5-N-A可形成苯并氮(benzazepine)、苯并氧氮杂(benzoxazepine)、苯并硫氮杂(benzothiazepine)、苯并二氮、苯并吖辛因(benzazocine)、苯并二吖辛因(benzodiazepine)、苯并噁吖辛因(benzoxazocine)或苯并噻吖辛因环,可任选地稠合于另一个苯环(如式B的化合物,其中R5-N-A形成呈下式的苯并氮环:
R6和R7各是氢、1-6个碳原子的烷基、-CN、-CCH;
和R8是氢;1-6个碳原子的烷基;2-6个碳原子的链烯基;2-6个碳原子的炔基;3-6个碳原子的环烷基;苯基;萘基;5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;或5-9元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S;
R9是氢、苯基、萘基、1-6个碳原子的烷基、或3-6个碳原子的环烷基;
和R10是苯基;萘基;1-6个碳原子的烷基;3-6个碳原子的环烷基;5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S,或5-9元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S。
本发明的优选化合物包括结构式B的化合物,其中与-NR5-基团相邻的A的两个碳原子含有非氢的取代基。
本发明更优选的化合物包括结构式B的化合物,其中A是苯基,且与-NR5-基团相邻的A的两个碳原子含有非氢的取代基,与-NR5-基团相对的A基团的碳原子含有非氢的取代基。
本发明更优选的化合物包括结构式B的化合物,其中A是苯基,且
与-NR5-基团的相邻的A的碳原子都含有非氢的取代基;
与-NR5-基团的相对的A的碳原子含有非氢的取代基;和
Y是在1-和4-位分别被X和Z取代的苯环。
本发明更优选的化合物包括结构式B的化合物,其中A是苯基,且
与-NR5-基团的相邻的A的碳原子都含有非氢的取代基;
与-NR5-基团的相对的A的碳原子含有非氢的取代基;
Y是在1-和4-位分别被X和Z取代的苯环;和
X是SO2。
本发明更优选的化合物包括结构式B的化合物,其中A是苯基,且
与-NR5-基团的相邻的A的碳原子都含有非氢的取代基;
与-NR5-基团的相对的A的碳原子含有非氢的取代基;
Y是在1-和4-位分别被X和Z取代的苯环;
X是SO2;
和Z是氧。
本发明更优选的化合物包括结构式B的化合物,其中A是苯基,且
与-NR5-基团的相邻的A的碳原子都含有非氢的取代基;
与-NR5-基团的相对的A的碳原子含有非氢的取代基;
Y是在1-和4-位分别被X和Z取代的苯环;
X是SO2;
Z是氧;
和R6及R7为氢。
本发明更优选的化合物包括结构式B的化合物,其中A是苯基,且
与-NR5-基团的相邻的A的碳原子都含有非氢的取代基;
与-NR5-基团的相对的A的碳原子含有非氢的取代基;
Y是在1-和4-位分别被X和Z取代的苯环;
X是SO2;
Z是氧;
R6和R7为氢;
和R8是-CH2OH或甲基。
本发明特别优选的化合物包括
5-溴-2-{[4-(4-环丁基氨基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-N-羟基-3-甲基-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-{甲基-[4-(4-甲基氨基-丁-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺;
5-溴-2-({4-[4-(3-二甲基氨基-丙基氨基)-丁-2-炔氧基]-苯磺酰基}甲基-氨基)-N-羟基-3-甲基-苯甲酰胺;
5-溴-2-({4-[4-(2-二甲基氨基-乙基氨基)-丁-2-炔氧基]-苯磺酰基}甲基-氨基)-N-羟基-3-甲基-苯甲酰胺;
4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-甲基-联苯-3-羧酸羟基酰胺;
5-溴-N-羟基-3-甲基-2-[甲基-(4-丙-2-炔氧基-苯磺酰基)-氨基]-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-[甲基-(4-戊-2-炔氧基-苯磺酰基)-氨基]-苯甲酰胺;
5-溴-2-[(4-庚-2-炔氧基-苯磺酰基)-甲基-氨基]-N-羟基-3-甲基-苯甲酰胺;
5-溴-2-[(4-己-2-炔氧基-苯磺酰基)-甲基-氨基]-N-羟基-3-甲基-苯甲酰胺;
5-溴-N-羟基-2-{[4-(4-甲氧基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-{甲基-[4-(3-苯基-丙-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺;
5-溴-N-羟基-2-({4-[3-(3-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺;
5-溴-N-羟基-2-({4-[3-(2-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺;
5-溴-N-羟基-2-({4-[3-(4-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺;
2-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-N-羟基-5-碘-3-甲基-苯甲酰胺;
2-[苄基-(4-丁-2-炔氧基-苯磺酰基)-氨基]-N-羟基-3,5-二甲基-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-{甲基-[4-(4-吡咯烷-1-基-丁-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺;
5-溴-2-{[4-(4-二乙基氨基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-N-羟基-3-甲基-苯甲酰胺;
5-溴-2-[(4-丁-2-炔氧基-苯磺酰基)-(4-甲基-哌嗪-1-基甲基)-氨基]-N-羟基-3-甲基-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-(甲基-{4-[4-(四氢-吡喃-2-基氧)丁-2-炔氧基]-苯磺酰基}-氨基}-苯甲酰胺;
5-溴-N-羟基-2-{[4-(4-羟基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酰胺;
4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-(4-甲基-哌嗪-1-基甲基)-联苯-3-羧酸羟基酰胺二盐酸盐;
和它们的药用盐。
本文所用的杂芳基是5-10元单环或双环芳族环,其中1-3个杂原子选自N、NR9、S和O。杂芳基较佳的是其中K是NR9、O或S,R9是氢、苯基、萘基、1-6个碳原子的烷基、或3-6个碳原子的环烷基。优选的杂芳环包括吡咯、呋喃、噻吩、吡啶、嘧啶、哒嗪、吡嗪、三唑、吡唑、咪唑、异噻唑、噻唑、异噁唑、噁唑、吲哚、异吲哚、苯并呋喃、苯并噻吩、喹啉、异喹啉、喹噁啉、喹唑啉、苯并三唑、吲唑、苯并咪唑、苯并噻唑、苯并异噁唑和苯并噁唑。本发明的杂芳基可任选地为单取代或双取代。
本文所用的杂环烷基是5-10元饱和的或不饱和单环或双环,其中1或2个杂原子选自N、NR9、S和O。本发明的杂环烷基较佳地选自其中K是NR9、O或S,R9是氢、苯基、萘基、1-6个碳原子的烷基、或3-6个碳原子的环烷基。优选的杂环烷基环包括哌啶、哌嗪、吗啉、四氢吡喃、四氢呋喃或吡咯烷。本发明的杂环烷基可任选地为单取代或双取代。
本文所用的芳基指苯基或萘基,可任选地单、双或三取代。
烷基、链烯基、炔基和全氟烷基包括直链和支链部分。烷基、链烯基、炔基和环烷基可以是未取代的(碳原子连接于氢、或链或环中的其他碳原子)或单或多取代的。
卤素指溴、氯、氟和碘。
芳基、杂芳基、烷基、链烯基、炔基、环烷基适合的取代基包括(但不限于)卤素、1-6个碳原子的烷基、2-6个碳原子的链烯基、2-6个碳原子的炔基、3-6个碳原子的环烷基、-OR2、-CN、-COR2、1-4个碳原子的全氟烷基、1-4个碳原子的-O-全氟烷基、-CONR2R3、-S(O)nR2、-OPO(OR2)OR3、-PO(OR2)R3、-OC(O)NR2R3、-C(O)NR2OR3、-COOR2、-SO3H、-NR2R3、-N[(CH2)2]2NR2、-NR2COR3、-NR2COOR3、-SO2NR2R3、-NO2、-N(R2)SO2R3、-NR2CONR2R3、-NR2C(=NR3)NR2R3、-NR2C(=NR3)N(SO2)R2R3、NR2C(=NR3)N(C=O)R2R3、NR2C(=NR3)N(SO2R2)R3、NR2C(=NR3)N(COR2)R3、-SO2NHCOR4、-CONHSO2R4、-四唑-5-基、-SO2NHCN、-SO2NHCONR2R3、苯基、萘基、杂芳基或杂环烷基;
其中-NR2R3可形成吡咯烷、哌啶、吗啉、硫代吗啉、噁唑烷、噻唑烷、吡唑烷、哌嗪或氮杂环丁烷环;
R2和R3各是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基、苯基、萘基、杂芳基或杂环烷基;
R4是1-6个碳原子的烷基、2-6个碳原子的链烯基、2-6个碳原子的炔基、3-6个碳原子的环烷基、1-4个碳原子的全氟烷基、苯基、萘基、杂芳基或杂环烷基;n是0-2。
本发明杂环烷基的合适的取代基包括(但不限于):1-6个碳原子的烷基、3-6个碳原子的环烷基、苯基、萘基、杂芳基和杂环烷基。
当某部分含有相同名称的一个以上的取代基时,这些取代基各自可以是相同的和不同的。
当本发明的化合物含有碱性部分时,可从以下无机和有机酸形成药学上可接受的盐,如醋酸、丙酸、乳酸、柠檬酸、酒石酸、丁二酸、反式丁烯二酸、顺式丁烯二酸、丙二酸、扁桃酸、羟基丁二酸、苯二甲酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、甲磺酸、萘磺酸、苯磺酸、甲苯磺酸、樟脑磺酸和类似已知的可接受的酸。当本发明的化合物含有酸性部分时,也可从无机和有机碱形成盐,较佳地为碱金属盐如钠盐、锂盐或钾盐。
本发明的化合物可含有不对称碳原子,本发明的一些化合物可含有一个或多个不对称中心,且因此可能产生旋光异构体和非对映异构体。不考虑立体化学而言,本发明包括这种旋光异构体和非对映异构体;以及消旋和拆解的、对映体纯化的R和S立体异构体;以及R和S立体异构体的其他混合物和它们药学上可接受的盐。据信一种旋光异构体包括非对映异构体和对映体或立体异构体具有比其他有利的特性。所以当公开和说明本发明权利时,当公开一种消旋混合物时,显然考虑了公开和要求了这两种光学异构体的权利包括非对映异构体和对映异构体,或基本无其他物质的立体异构体。
本发明的化合物表现出能抑制酶MMP-1、MMP-9、MMP-13和TNF-α转化酶(TACE),并因此可用于治疗关节炎、肿瘤转移、组织溃烂、异常伤口的愈合、牙周病、移植排斥、胰岛素抗性、骨骼疾病和HIV感染。具体说,本发明的化合物在体外和细胞试验中提供增强的抑制TACE活性的水平和/或提高优于MMP-1的选择性,因此这些化合物可特别用于治疗TNF所介导的疾病。
本发明还提供制备如下定义的式B化合物的方法,所述的方法包括如下步骤:
c)拆解式B化合物的旋光活性异构体的混合物(如外消旋物),从而分离出基本无其他对映异构体或非对映异构体的一种对映异构体或非对映异构体;
或
d)用药学上可接受的酸来酸化式B的碱性化合物,得到药学上可接受的盐。
对步骤a)而言,反应可用本领域已知的方法进行,如用卤化剂进行反应形成活性衍生物(即酰基氯),然后再用羟胺进行反应。
如步骤b)所示的除去保护基团的反应也可用本领域已知的方法进行,得到异羟肟酸。
对步骤c)而言,可用标准分离技术分离特定的对映体或非对映异构体形式。例如,通过与‘拆解试剂’的单对映体(如非对映异构体盐形式或共价键形式)反应,可将消旋混合物转化成旋光性非对映异构体的混合物。可用标准方法(如结晶或层析)分离得到的旋光性非对映异构体的混合物,然后处理各旋光性非对映异构体以除去‘拆解试剂’,从而释放出本发明化合物的单对映异构体。可用手性层析(用手性载体、洗脱液或离子配对剂)直接分离对映异构体混合物。
可以药学上可接受的盐的形式分离式B的化合物,如用上述酸处理的有机或无机酸。
本发明还涉及制备结构B化合物的方法,包括如下的一个或多个反应:
1)将式I的化合物或其盐或溶剂合物烷基化,
形成式II的化合物
通过将该化合物与1,2,4-三唑、咪唑或苯并三唑反应,分别可进一步将得到的磺酰氯、磺酰氟或磺酰溴转化成酰三唑(triazolide)、酰咪唑(imidazolide)或酰苯并噻唑(benzothiazolide)衍生物,其中J为1,2,4-三唑基、苯并三唑基或咪唑基,R6、R7和R8的定义如上。
本发明还涉及制备结构B化合物的方法,包括如下一个或多个反应:
2)将上述式IV的化合物或其盐或溶剂合物与氯磺酸反应,制备上述式II的化合物。
特别优选的中间体是式II和III的化合物,条件是R6不是氢。
可用有机合成领域技术人员已知的常规方法制备本发明的化合物。用于制备本发明化合物的起始物是已知的,或用已知方法可制备的或可购得的。美国专利No.5,776,961公开了一些起始材料和中间体及用于制备所述的起始物和中间体的方法。
本领域技术人员将会认识到当分子上其他潜在的反应官能团受到屏蔽或保护,因而避免不利的副反应和/或增加反应的产量时,可最佳地进行某些反应。为此,本领域技术人员可以使用保护基团。这些保护基团的例子可见于T.W.Greene,P.G.M.Wuts“有机合成中的保护基团”,第二版,1991,Wiley & Sons,New York。较佳地,将氨基酸起始原料上反应性侧链的官能团保护起来。对特定反应保护基团的需要和选择是本领域技术人员已知的,这取决于被保护的官能团(羟基、氨基、羧基等)的性质、含该取代基的分子的结构和稳定性及反应条件。
当制备或加工本发明的含芳基、杂芳基或杂环化合物时,本领域技术人员知道可在构建该环的同时、之前或之后制备该环上的取代基。为清晰起见,以下从该流程中删去了这些环上的取代。
本领域技术人员会明白为了最佳制备本发明化合物,合成步骤的性质和顺序可作改变。
按流程1制备本发明的异羟肟酸化合物1,通过将羧酸2转化成相应的酰基氯或酸酐,或通过将它与适当的肽偶联试剂反应,然后与羟胺反应形成1,或与被保护的羟胺衍生物反应,得到3。然后可用已知的方法使化合物3去保护得到异羟肟酸1,其中R30是叔丁基、苄基、三烷基甲硅烷基或其他合适的屏蔽基团。
可按流程2所示制备羧酸2。通过与化合物5反应,将氨基酸衍生物4磺酰化或磷酰化,其中R40是氢或合适的羧酸保护基团,其中J是合适的离去基团包括(但不限于)氯。然后在极性质子惰性溶剂如丙酮、N,N-二甲基甲酰胺(DMF)或四氢呋喃(THF)中,用R3J和碱如碳酸钾或氢化钠将N-H化合物6烷基化得到氨磺酰7。化合物7也可直接通过5与N-取代的氨基酸衍生物8反应得到。用酸、碱水解或其他方法(包括选择保护基团R40和存在碳碳三键)将7转化成羧酸。
由流程3显示了制备磺酰剂5的方法。因此,用炔10(其中J是合适的离去基团如卤素、甲磺酸酯、甲苯磺酸酯或三氟甲烷磺酸酯(triflate))将磺酸盐9(其中ZR50是羟基、硫醇或取代的氨基部分)烷基化,得到11。炔10是可购得的或是已知的化合物,或它们可用本领域技术人员已知的方法合成。通过已知的方法如与草酰氯或其他与取代基R6、R7和R8和炔相容的试剂反应,将磺酸盐11转化成相应的磺酰氯或其他磺酰剂5。另外,通过与化合物10反应可将二硫化物12转化成二炔13,然后还原二硫键得到类似的硫醇,再可用已知的方法将其转化成5。用10将酚、硫酚、苯胺或被保护的苯胺14烷基化得15,然后与氯磺酸反应得到磺酸16,可用草酰氯或类似的试剂将其转化成5。通过保护硫醇、ZH的烷基化(Z是O、N或S)和硫的去保护及随后磺酸16的氧化,硫酚17也是5的前体。
流程3:如流程4所示,用类似的方法制备8的含磷的类似物。
如流程5所示,在氨基酸衍生物的磺酰基化或磷酸化后还可再加上炔侧链。所以,可用化合物20(其中ZR50是羟基或被保护的羟基、硫醇或胺)将氨基酸衍生物4和8磺酰基化或磷酸化,若需要可用R7J(如流程2所示)烷基化,得到21。除去R50屏蔽基团得到22,随后用10烷基化得到的苯酚、硫醇或胺,得到7。在此情况中ZR50为OH,无需去保护步骤可得到22。
流程5:如流程6所示,以氨基酸衍生物4和/或8为起始物可合成炔丙胺类似物7。在DMF中用对硝基芳基化合物23(如4-硝基苯磺酰氯)磺酰基化或磷酸化,然后在DMF中用碱如碳酸钾或氢化钠以R5J(对4)烷基化,得到24。用氢和钯碳、氯化锡或其他已知的方法还原硝基部分,得到苯胺25,随后用10烷基化得到7。可用合适的氮保护基团如叔丁氧基羰基,衍生化苯胺25,得到26然后用10烷基化,去保护。
如流程7所示,炔衍生物7还可通过氟化合物27制备,化合物27易通过氨基酸衍生物4和/或8与氟芳基26反应制得。在极性质子惰性溶剂如DMF中,存在碱如氢化钠时用屏蔽的羟基、硫醇或氨基(HZR70,其中R70是合适的保护基团)置换27的氟,随后去保护得到28,然后可用10将其烷基化得到7。可用Na2S、K2S、NaSH或KS(C=S)OEt,将27转化成28,其中Z是硫。还可在极性质子惰性溶剂中,存在碱如氢化钠时,用炔丙基衍生物29(其中Z是O、S或NH)置换27的氟,直接得到7。
流程7:
如流程8所示,可通过30得到化合物7(其中Z是亚甲基)。在氯代烃溶剂中用N-溴琥珀酰亚胺将30苄基溴化,得到溴化物31。随后溴化物用合适的铜酸丙炔置换可得到氨磺酰8。
流程8:
本发明的化合物还可通过以下方法制备:在磺酰化或磷酰化起始的氨基酸衍生物4或8后的任何一个阶段,修饰炔侧链上的取代基。可用标准方法操作官能团如卤素、羟基、氨基、醛、酯、酮等,形成由化合物1的R1-R8定义的部分。有机合成领域的技术人员可看出这些方法的成功使用取决于分子其他部分上取代基的相容性。本文的保护基团和/或反应步骤的顺序可有变化。
流程9显示了衍生结构为32的化合物(相当于化合物7,其中R12是氢)的一些方法。将末端炔烃32进行金属取代,然后以醛或烷基卤、磺酸酯或三氟甲烷磺酸酯加成,产生衍生物33和34。32与甲醛和胺反应产生Mannich加成产物35。溴化氰加成于35产生炔丙基溴化物36,它可用各种亲核试剂置换,生成如醚、硫醚和胺37。32的钯催化的偶联反应产生芳基或杂芳基炔38。有机合成领域技术人员懂得这些方法的成功使用取决于分子其他部分上取代基的相容性。本文所述的保护基团和/或反应步骤的顺序可能需要变化。
以下具体实施例说明了本发明代表性化合物的制备。起始原料、中间体和试剂可购得或可用有机合成领域技术人员已知的标准方法不难制备。
实施例1
3-甲基-5-溴-2-(4-氟-苯磺酰基氨基)-苯甲酸
在300ml吡啶配制的25.0g(0.102mol)2-氨基-3-甲基-5-溴苯甲酸甲酯溶液(美国专利No.5,776,961)中加入21.93g(0.113mol)4-氟苯磺酰氯。80℃搅拌反应混合物18小时,冷却至室温,倾倒入水中。用乙酸乙酯提取如此得到的混合物,用5%HCl溶液和水洗涤合并的有机层。然后用MgSO4干燥有机层,过滤并真空浓缩。用乙酸乙酯/己烷(1∶3)洗脱,在硅胶上层析残留物得到14.53g(39%)呈褐色固体的所需产物。电喷雾质谱为:388.0(M-H)+
实施例2
5-溴-2-[(4-氟-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸甲酯
在300ml DMF配制的14.53g(0.040mol)实施例1的产物溶液中加入66.1g(0.479mol)碳酸钾,然后再加入9.94ml(0.160mol)碘代甲烷。室温搅拌如此得到的混合物48小时,然后加入水和乙醚稀释。分离有机层,用水洗涤,以MgSO4干燥,过滤并真空浓缩。用乙酸乙酯/己烷(1∶10)洗脱,在硅胶上层析残留物得到12.83g(82%)呈浅黄色固体的所需产物。电喷雾质谱为:415.8(M+H)+
实施例3
5-溴-2-[(4-羟基-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸
于室温下,在375ml DMF配制的17.0ml(0.227mol)2-丁炔-1-醇溶液中加入9.08g(0.227mol)60%氢化钠。搅拌得到的混合物0.5小时,然后将50ml DMF配制的17.8g(0.045mol)实施例2产物的溶液加到该反应中。加热此反应混合物回流24小时,冷却至室温,然后用10%HCl溶液酸化至pH2。搅拌1小时后,用水稀释得到的混合物,用乙酸乙酯提取。然后以MgSO4干燥合并的有机层,过滤并真空浓缩。用乙酸乙酯/己烷(1∶3)洗脱,在硅胶上层析残留物得到12.5g(69%)呈白色固体的所需的酚-羧酸产物。电喷雾质谱为:401.8(M-H)+
实施例4
5-溴-2-[(4-羟基-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸甲酯
在125ml DMF配制的15.2g(0.038mol)实施例3产物的溶液中加入9.58g(0.114mol)重碳酸钠,然后再加入4.7ml(0.076mol)碘代甲烷。室温搅拌如此得到的混合物5小时,然后加入水和乙醚稀释。分离有机层,用水洗涤,用MgSO4干燥,过滤并真空浓缩。用乙酸乙酯/己烷(1∶3)洗脱,在硅胶上层析残留物得到12.27g(78%)呈浅黄色固体的所需的酚-酯产物。电喷雾质谱为:413.7(M+H)+
实施例5
5-溴-3-甲基-2-[甲基-(4-丙-2-炔氧基-苯磺酰基)-氨基]-苯甲酸甲酯
溶解于5ml苯和2ml THF的0.317g(1.208mmol)三苯基膦溶液中加入0.070ml(1.208mmol)炔丙醇。5分钟后,将溶解于2ml THF的0.500g(1.208mmol)实施例4的产物加到反应物中,然后加入0.190ml(1.208mmol)偶氮二羧酸二乙酯。室温搅拌得到的反应混合物18小时,然后真空浓缩。用乙酸乙酯/己烷(1∶10)洗脱,在硅胶上层析残留物,得到0.389g(71%)呈白色固体的所需的炔丙醚产物。电喷雾质谱为:451.8(M+H)+
实施例6
5-溴-2-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸
按实施例5的流程,将0.150g(0.363mmol)实施例4的产物与0.027ml(0.362mmol)2-丁炔-1-醇反应,产生0.106g(63%)炔氧基醚。
将炔氧基醚溶解在2.2ml THF/甲醇(1∶1)中,加入1.1ml 1.0N氢氧化钠溶液。加热此反应物以回流过夜,冷却至室温,用10%HCl溶液酸化。用乙酸乙酯提取混合物,以MgSO4干燥合并的有机层,过滤并真空浓缩。得到0.099g(97%)呈白色固体的所需的羧酸产物。电喷雾质谱为:451.8(M+H)+
实施例7
5-溴-3-甲基-2-[甲基-(4-戊-2-炔氧基苯磺酰基)-氨基]-苯甲酸
按实施例6的流程,将0.250g(0.604mmol)实施例4的产物与0.056ml(0.604mmol)2-戊炔-1-醇反应,产生0.233g醚酯,然后碱水解,得到0.22g(97%)呈白色固体的羧酸。电喷雾质谱为:465.9(M+H)+
实施例8
5-溴-2-[(4-庚-2-炔氧基-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸
按实施例6的流程,将0.250g(0.604mmol)实施例4的产物与0.077ml(0.604mmol)2-庚炔-1-醇反应,产生0.246g醚酯,然后碱水解,得到0.214g(90%)呈白色固体的羧酸。电喷雾质谱为:494.0(M+H)+
实施例9
5-溴-2-[(4-己-2-炔氧基-苯磺酰基)-甲基-氨基]-3-甲基苯甲酸甲酯
按实施例5的流程,将0.250g(0.604mmol)实施例4的产物与0.059ml(0.604mmol)2-己炔-1-醇反应,产生0.206g(69%)炔氧基醚。电喷雾质谱为:494.0(M+H)+
实施例10
5-溴-2-[(4-己-2-炔氧基-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸
在溶解于4.0ml THF/甲醇(1∶1)的0.206g(0.417mmol)实施例9产物的溶液中加入0.5ml 5.0N氢氧化钠溶液。室温搅拌反应物过夜,然后用10%HCl溶液酸化。用二氯甲烷提取混合物,以MgSO4干燥合并的有机层,过滤并真空浓缩,得到的白色固体以乙醚/己烷(1∶1)洗涤,真空干燥得到0.163g(82%)呈白色固体的所需的羧酸产物。电喷雾质谱为:477.9(M-H)+
实施例11
5-溴-3-甲基-2-{甲基-[4-(3-苯基-丙-2-炔氧基)-苯磺酰基]-氨基}-苯甲酸甲酯
按实施例5的流程,将0.250g(0.604mmol)实施例4的产物与0.080g(0.604mmol)3-苯基炔丙醇反应,产生0.272g(85%)褐色油状的炔氧基醚。电喷雾质谱为:527.8(M+H)+
实施例12
5-溴-2-({4-[3-(3-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酸甲酯
按实施例5的流程,将0.250g(0.604mmol)实施例4的产物与0.098g(0.604mmol)3-(3-甲氧基)-苯基炔丙醇反应,产生0.285g(85%)浅黄色油状的炔氧基醚。电喷雾质谱为:557.8(M+H)+
实施例13
5-溴-2-({4-[3-(2-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酸甲酯
按实施例5的流程,将0.250g(0.604mmol)实施例4的产物与0.098g(0.604mmol)3-(2-甲氧基)-苯基炔丙醇反应,产生0.296g(88%)呈无色油状的炔氧基醚。电喷雾质谱为:557.8(M+H)+
实施例14
5-溴-2-({4-[3-(4-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基苯甲酸甲酯
按实施例5的流程,将0.250g(0.604mmol)实施例4的产物与0.098g(0.604mmol)3-(4-甲氧基)-苯基炔丙醇反应,产生0.240g(71%)呈褐色油状的炔氧基醚。电喷雾质谱为:557.8(M+H)+
实施例15
5-溴-3-甲基-2-(甲基-{4-[4-(四氢-吡喃-2-基氧)-丁-2-炔氧基]-苯磺酰基}-氨基)-苯甲酸甲酯
按实施例5的流程,将0.500g(1.208mmol)实施例4的产物与0.226g(1.328mmol)4-四氢吡喃-2-丁炔-1,4-二醇反应,产生0.60g(88%)无色油状的炔氧基醚。电喷雾质谱为:567.9(M+H)+
实施例16
5-溴-2-{[4-(叔-丁基-二甲基-甲硅烷氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酸甲酯
在5.0ml DMF配制的1.25g(3.019mmol)实施例4产物的溶液中,加入0.514g(7.548mmol)咪唑,然后再加入0.546g(3.623mmol)氯叔-丁基二甲基甲硅烷。室温搅拌如此得到的混合物15小时,然后用乙醚和水稀释。用水洗涤有机层,以Na2SO4干燥,过滤并真空浓缩。用乙酸乙酯/己烷(1∶10)洗脱,在硅胶上层析残留物,得到1.34g(84%)呈白色固体的甲硅烷基醚。电喷雾质谱为:527.8(M+H)+
实施例17
2-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-碘-3-甲基-苯甲酸甲酯
在30ml二噁烷配制的0.340g(0.644mmol)实施例16产物的溶液中加入1.30ml(2.576mmol)双(三丁基锡),然后加入0.059g(0.051mmol)四(三苯基膦)钯(0)。加热此混合物回流过夜,然后真空浓缩。以乙酸乙酯/己烷(1∶20)洗脱,在硅胶上层析残留物,得到0.34g(72%)所需的芳基锡烷。
然后将此锡烷溶解在50ml氯仿中,逐滴加入10ml以氯仿配制的0.1M碘溶液。室温15分钟后,用30ml甲醇配制的1.5g氟化钾溶液随后再用30ml 5%亚硫酸氢钠溶液淬灭反应。分离有机层,用二氯甲烷提取水层。Na2SO4干燥合并的有机层,过滤并真空浓缩。残留物在已烷和乙腈中分配,然后真空浓缩乙腈层得到0.265g(100%)粗芳基碘化物。
将芳基碘化物溶解在5ml THF中,加入1.0ml用THF配制的1.0M氟化四丁铵溶液。室温搅拌反应物1小时,用5%HCl溶液酸化,用二氯甲烷提取。MgSO4干燥合并的有机层,过滤并真空浓缩得到0.185g(87%)酚。
按实施例5的流程,将0.185g(0.401mmol)酚和0.030ml 2-丁炔-1-醇反应产生0.143g(69%)无色油状的所需醚。电喷雾质谱为:513.8(M+H)+
实施例18
2-[苄基-(4-羟基-苯磺酰基)-氨基]-3,5-二甲基苯甲酸
按实施例3的流程,由1.360g(3.185mmol)2-[苄基-(4-氟-苯磺酰基)-氨基]-3,5-二甲基-苯甲酸甲酯(美国专利No.5,776,961)反应,与醚一起研磨后,产生0.956g(73%)呈白色固体的酚-羧酸。电喷雾质谱为:411.9(M+H)+
实施例19
2-[苄基-(4-羟基-苯磺酰基)-氨基]-3,5-二甲基-苯甲酸甲酯
在10ml DMF配制的0.820g(1.995mml)实施例18产物的溶液中加入0.826g(5.985mmol)碳酸钾,然后加入0.124ml(1.995mmol)碘代甲烷。室温搅拌反应物2小时,用乙醚和水稀释,并用5%HCl溶液酸化。用乙酸乙酯提取水层,以MgSO4干燥合并的有机层,过滤并真空浓缩。用乙酸乙酯/甲烷(1∶3)洗脱,在硅胶上层析残留物,得到0.090g(87%)酚-酯。电喷雾质谱为:425.9(M+H)+
实施例20
2-[苄基-(4-丁-2-炔氧基-苯磺酰基)-氨基]-3,5-二甲基-苯甲酸甲酯
按实施例5的流程,将0.250g(0.588mmol)实施例19的产物与0.44ml(0.588mmol)2-丁炔-1-醇反应产生0.203g(72%)呈白色固体的炔氧基醚。电喷雾质谱为:477.9(M+H)+
实施例21
5-溴-2-[(4-羟基-苯磺酰基)-(4-甲基-哌嗪-1-基甲基)-氨基]-3-甲基-苯甲酸甲酯
在60ml四氯化碳配制的1.0g(1.894mmol)实施例16产物的溶液中加入0.405gN-溴丁二酰亚胺。太阳灯照射下,加热此混合物回流2小时。然后将反应物冷却至室温,用水洗涤,Na2SO4干燥,过滤并真空浓缩。
然后将残留物溶解在5.0ml DMF中,加入0.784g(5.682mmol)碳酸钾,然后加入0.21ml(1.894mmol)1-甲基哌嗪。室温搅拌如此得到的混合物48小时,用水和乙酸乙酯稀释。用水洗涤有机层,然后用10%HCl溶液提取。酸层用1.0N NaOH溶液中和,用二氯甲烷提取。以Na2SO4干燥合并的二氯甲烷提取液,过滤并真空浓缩,得到0.501g(52%)呈白色固体的哌嗪-酚。电喷雾质谱为:511.9(M+H)+
实施例22
5-溴-2-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-3-(4-甲基-哌嗪-1-基-甲基)-苯甲酸甲酯
在5.0mlTHF配制的0.963g(3.672mmol)三苯基膦溶液中加入0.275ml(3.672mmol)2-丁炔-1-醇,然后加入溶解于2ml二氯甲烷溶液中的0.376g(0.734mmol)实施例21的产物。置室温5分钟后,逐滴加入0.578ml(3.672mmol)偶氮二羧酸二乙酯,室温搅拌所得反应混合物过夜,然后真空浓缩。用乙酸乙酯稀释残留物,用10%HCl溶液提取有机层。用1.0N NaOH溶液碱化合并的酸提取液,然后用二氯甲烷提取。以Na2SO4干燥合并的二氯甲烷提取液,过滤并真空浓缩。以二氯甲烷/甲醇/三乙胺(100∶2∶0.5)洗脱,在硅胶上层析残留物,得到0.149g(36%)浅黄色油状的丁炔醚。电喷雾质谱为:563.9(M+H)+
实施例23
5-溴-3-甲基-2-{甲基-[4-(4-吡咯烷-1-基-丁-2-炔氧基)-苯磺酰基]-氨基}-苯甲酸甲酯
在2.0ml二噁烷配制的0.300g(0.664mmol)实施例5产物的溶液中加入0.054g(1.659mmol)聚甲醛、0.111ml(1.327mmol)吡咯烷、0.245ml乙酸和2.5mg氯化亚铜。室温搅拌如此得到的混合物15分钟,然后加热回流2小时。冷却至室温后,用10%HCl溶液提取反应混合物,用1.0N NaOH溶液碱化水性提取液,用乙醚提取,合并的醚提取液以Na2SO4干燥,过滤并真空浓缩得到0.216g(61%)褐色油状的吡咯烷-炔。电喷雾质谱为:520.9(M+H)+
实施例24
5-溴-2-{[4-(4-二乙胺基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酸甲酯
按实施例23的流程,用1.00g(2.212mmol)实施例5的产物,以乙酸乙酯洗脱在硅胶上层析后产生0.749g(63%)黄色油状的二乙胺基-炔。电喷雾质谱为:536.9(M+H)+
实施例25
5-溴-2-{[4-(4-溴-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酸甲酯
在0°溶解于10ml乙醚的0.707g(1.317mmol)实施例24产物的溶液中加入0.53ml由二氯甲烷配制的3.0M溴化氰溶液。将反应物升温至室温,并搅拌过夜。然后过滤反应混合物,用乙醚稀释滤液,用5%HCl溶液和盐水洗涤。以Na2SO4干燥有机层,过滤并真空浓缩,得到0.628g(88%)浅棕色油状的炔丙基溴。
实施例26
5-溴-2-{[4-(4-甲氧基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酸
在1.0ml THF和3.0ml甲醇配制的0.117g(0.215mmol)实施例25产物的溶液中加入0.5ml 5.0N氢氧化钠溶液,然后再加入3.6mg硫酸氢四丁铵。室温搅拌如此得到的反应混合物15小时,用10%HCl溶液酸化,用二氯甲烷提取。以MgSO4干燥合并的有机层,过滤并真空浓缩得到0.083g(81%)呈白色固体的双炔丙基醚羧酸。电喷雾质谱为:481.8(M+H)+
实施例27
5-溴-2-{[4-(4-环丁基氨基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酸甲酯
在3.0ml THF配制的0.300g(0.550mmol)实施例25产物的溶液中加入0.103ml(1.211mmol)环丁胺,室温搅拌反应物15小时。用乙醚稀释得到的混合物,用水和盐水洗涤有机层,以Na2SO4干燥、过滤并真空浓缩。用乙酸乙酯/己烷(1∶1)至氯仿/己烷(9∶1)梯度洗脱液,在硅胶上层析残留物,得到0.199g(69%)无色油状的炔丙基环丁胺。电喷雾质谱为:535.0(M+H)+
实施例28
(4-{4-[(4-溴-2-羟基氨基甲酰基-6-甲基-苯基)-甲基-氨磺酰]-苯氧基}-丁-2-炔基)-环丁基-氨基甲酸叔丁酯
在用2.0ml DMF配制的0.167g(0.312mmol)实施例27产物的溶液中加入0.075g(0.343mmol)焦碳酸二-叔-丁酯和7.6mg 4-二甲氨基吡啶。室温搅拌反应物15小时,用乙醚稀释,用水、5%HCl溶液和盐水洗涤。以Na2SO4干燥有机层,过滤并真空浓缩得到0.173g(87%)氨基甲酸酯。
在溶解于6.0ml THF/甲醇(1∶1)的0.173g(0.272mmol)氨基甲酸叔丁酯溶液中加入1.4ml 1.0N NaOH溶液,然后加热反应混合物回流15小时。冷却至室温后,用5%HCl溶液酸化反应混合物,用二氯甲烷提取。以MgSO4干燥合并的有机层、过滤并真空浓缩。以乙酸乙酯/己烷(1∶1)洗脱,在硅胶上层析残留物得到0.149g(88%)呈白色固体的羧酸。
在0°,于溶解于3.4ml二氯甲烷的0.040ml(0.792mmol)2.0M草酰氯的二氯甲烷溶液中加入0.061ml(0.792mmol)DMF,0℃搅拌混合物15分钟。然后加入以1mlDMF配制的0.164g该羧酸溶液,将反应物升温至室温。室温搅拌反应混合物1小时,然后倾倒入0°的0.8ml水、4.0ml THF和0.25ml 50%羟胺水溶液的混合物中。让反应物升温至室温过夜,然后真空浓缩有机层。用乙酸乙酯稀释残留物,用水和饱和重碳酸钠洗涤,Na2SO4干燥,过滤并真空浓缩得到0.153g(91%)呈白色泡沫状的氨基甲酸酯-异羟肟酸。电喷雾质谱为:639.9(M+H)+
实施例29
5-溴-3-甲基-2-{甲基-[4-(4-甲基氨基-丁-2-炔氧基)-苯磺酰基]-氨基}-苯甲酸甲酯
按实施例27的流程,将0.325g(0.596mmol)实施例25的产物与甲胺反应,生成0.132g(45%)呈褐色油状的炔丙基甲胺。电喷雾质谱为:495.0(M+H)+
实施例30
(4-{4-[(4-溴-2-羟基氨基甲酰基-6-甲基-苯基)-甲基-氨磺酰]-苯氧基}-丁-2-炔基)-甲基-氨基甲酸叔丁酯
按实施例28的流程,将0.110g(0.222mmol)实施例29的产物转化成0.090g氨基甲酸酯-异羟肟酸。电喷雾质谱为:598.0(M+H)+
实施例31
5-溴-2-{[4-(4-环丁基氨基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-N-羟基-3-甲基-苯甲酰胺
在2.0ml二氯甲烷配制的0.100g(0.157mmol)实施例28产物的溶液中加入1.0ml三氟乙酸。室温搅拌如此得到的溶液1小时,然后真空浓缩。用二氯甲烷稀释残留物,用饱和重碳酸钠溶液洗涤,Na2SO4干燥、过滤并真空浓缩,得到0.083g(99%)氨基-异羟肟酸。
在溶解于2.0ml二氯甲烷的0.078g(0.146mmol)氨基-异羟肟酸溶液中加入0.29ml(0.29mmol)1.0M以乙醚配制的HCl溶液。室温搅拌如此得到的混合物1小时,然后用乙醚稀释。过滤沉淀物,用乙醚洗涤,真空干燥得到0.068g(82%)呈褐色固体的氨基-异羟肟酸的盐酸盐。电喷雾质谱为:535.8(M+H)+
实施例32
5-溴-N-羟基-3-甲基-2-{甲基-[4-(4-甲基氨基-丁-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺
按实施例31的流程,用0.066g(0.111mmol)实施例30的产物产生0.042g所需的氨基-异羟肟酸的盐酸盐。电喷雾质谱为:495.8(M+H)+
实施例33
5-溴-2-({4-[4-(3-二甲基氨基-丙基氨基)-丁-2-炔氧基]-苯磺酰基}-甲基-氨基)-N-羟基-3-甲基-苯甲酰胺
按实施例27的流程,0.300g(0.550mmol)实施例25的产物与0.362ml(2.75mmol)二甲基氨基丙胺反应生成0.076g(24%)炔丙基二胺酯。
按实施例28的流程,0.135g(0.239mmol)二胺酯转化成氨基甲酸叔丁酯,然后水解该酯,将此羧酸转化成0.059g氨基甲酸酯-异羟肟酸。
按实施例31的流程,将0.058g氨基甲酸酯-异羟肟酸转化成0.037g所需二氨基-异羟肟酸的二盐酸盐,为褐色固体。电喷雾质谱为:569.0(M+H)+
实施例34
5-溴-2-({4-[4-(2-二甲基氨基-乙基氨基)-丁-2-炔氧基]-苯磺酰基}-甲基-氨基)-N-羟基-3-甲基-苯甲酰胺
按实施例27的流程,0.300g(0.550mmol)实施例25的产物与0.302ml(2.75mmol)N,N-二甲基乙二胺反应生成0.114g(38%)炔丙基二胺-酯。
按实施例28的流程,0.192g(0.348mmol)二胺-酯转化成氨基甲酸叔丁酯,然后水解该酯,将此羧酸转化成0.073g氨基甲酸酯-异羟肟酸。
按实施例31的流程,将0.057g氨基甲酸酯-异羟肟酸转化成0.040g所需二氨基-异羟肟酸的二盐酸盐,为褐色固体。电喷雾质谱为:553.0(M+H)+
实施例35
5-溴-2-[(4-甲氧基-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸甲酯
在40ml DMF配制的5.00g(0.012mol)5-溴-2-(4-甲氧基-苯磺酰基氨基)-3-甲基-苯甲酸甲酯溶液(美国专利No.5,776,961)中加入0.604g(0.015mol)60%氢化钠。室温搅拌如此得到的混合物0.5小时,然后加入1.2ml(0.018mol)碘代甲烷。搅拌此反应物15小时,然后用乙醚稀释。用水洗涤有机层,MgSO4干燥,过滤并真空浓缩。残留物用乙醚研磨,过滤收集白色固体,真空干燥得到4.45g(86%)N-甲基氨磺酰。电喷雾质谱为:429.8(M+H)+
实施例36
5-溴-N-羟基-2-[(4-甲氧基-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酰胺
在用6.0ml THF/甲醇(1∶1)配制的0.200g(0.467mmol)实施例35产物的溶液中加入2.3ml 1.0N氢氧化钠溶液。加热此反应物回流过夜,冷却至至室温,用5%HCl溶液酸化。混合物用乙酸乙酯提取,用盐水洗涤,MgSO4干燥合并的有机层、过滤并真空浓缩。以乙醚/己烷(1∶1)研磨残留物,收集固体真空干燥,得到0.136g(70%)呈白色固体的所需的羧酸产物。
在0°于溶解于3.1ml二氯甲烷的0.036ml(0.710mmol)2.0M草酰氯的二氯甲烷溶液中加入0.055ml(0.710mmol)DMF,于0℃搅拌混合物15分钟。然后加入以1mlDMF配制的0.098g(0.237mmol)羧酸溶液,室温搅拌如此得到的混合物1小时,然后倾倒入0°的0.7ml水、3.6ml THF和0.23ml 50%羟胺水溶液的混合物中。让反应物升温至室温过夜,然后真空浓缩有机层。用乙酸乙酯稀释残留物,用5%HCl溶液、水和饱和重碳酸钠洗涤,Na2SO4干燥,过滤并真空浓缩得到0.081g(79%)白色泡沫状的异羟肟酸。电喷雾质谱为:428.8(M+H)+
实施例37
5-溴-2-[(4-丁氧基-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸甲酯
按实施例5的流程,将0.250g(0.604mmol)实施例4的产物与0.055ml(0.604mmol)正丁醇反应生成0.241g(85%)正丁醚。电喷雾质谱为:469.8(M+H)+
实施例38
5-溴-2-[(4-丁氧基-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸
在6.0ml THF/甲醇(1∶1)配制的0.204g(0.434mmol)实施例37产物的溶液中加入2.2ml 1.0N氢氧化钠溶液。加热反应物以回流过夜,冷却至室温,用5%HCl溶液酸化。用乙酸乙酯提取混合物,用盐水洗涤,然后以MgSO4干燥合并的有机层,过滤并真空浓缩。用乙醚/己烷(1∶1)研磨残留物,收集固体,真空干燥得到0.206g(104%)呈白色固体的所需的羧酸产物。电喷雾质谱为:455.8(M+H)+
实施例39
5-溴-2-[(4-丁氧基-苯磺酰基)-甲基-氨基]-N-羟基-3-甲基-苯甲酰胺
在0°于溶解于4.7ml二氯甲烷的0.54ml(1.072mmol)2.0M草酰氯的二氯甲烷溶液中加入0.083ml(1.072mmol)DMF,于0℃搅拌反应物15分钟。然后加入以1mlDMF配制的0.163g(0.357mmol)实施例38的羧酸产物溶液,室温搅拌如此得到的混合物1小时,然后倾倒入0°的1.0ml水、5.4ml THF和0.34ml 50%羟胺水溶液的混合物中。让反应物升温至室温过夜,然后真空浓缩有机层。用乙酸乙酯稀释残留物,用5%HCl溶液、水和饱和重碳酸钠洗涤,Na2SO4干燥,过滤并真空浓缩得到0.157g(93%)白色泡沫状的异羟肟酸。电喷雾质谱为:506.8(M+H)+
实施例40
4-氨基-5-甲基-联苯-3-羧酸甲酯
在150ml二甲氧基乙烷配制的5.0g(0.021mol)2-氨基-5-溴-3-甲基-苯甲酸甲酯和2.8g(0.023mol)苯基硼酸溶液中加入20.5ml 2.0M Na2CO3水溶液和1.18g(1.02mmol)Pd(PPh3)4。将反应混合物抽真空,用N2填充三次,然后加热以回流过夜。然后将反应物冷却至室温,倾倒入乙酸乙酯和水中。用乙酸乙酯提取水层3次。用盐水洗涤合并的有机层,MgSO4干燥,真空浓缩。用(100%己烷至4/1己烷/乙酸乙酯)梯度洗脱在硅胶上层析残留物,得到2.5g(50%)4-氨基-5-甲基-联苯-3-羧酸甲酯。电喷雾质谱为:241.8(M+H)+
实施例41
5-甲基-4-[4-(吡啶-4-基氧)-苯磺酰基氨基]-联苯-3-羧酸甲酯
在20ml吡啶配制的1.43g(5.93mmol)实施例40产物的溶液中加入1.98g(6.52mmol)4-(吡啶-4-基氧)-苯磺酰氯,搅拌反应物过夜。此后第二天再加入2次4-(吡啶-4-基氧)-苯磺酰氯(0.5g,1.6mmol)。然后用水稀释反应物,用二氯甲烷提取3次。合并有机层,用盐水洗涤,Na2SO4干燥,真空浓缩,以梯度洗脱(100%己烷至100%乙酸乙酯)在硅胶上层析,得到呈白色固体的5-甲基-4-[4-(吡啶-4-基氧)-苯磺酰基氨基]-联苯-3-羧酸甲酯2.54g(90%)。电喷雾质谱为:475.2(M+H)+
实施例42
4-[(4-羟基-苯磺酰基)-甲基-氨基]-5-甲基-联苯-3-羧酸甲酯
在7ml DMF配制的1.25g(2.63mmol)实施例41产物的0℃溶液中加入0.132g(3.29mmol)60%氢化钠。将反应物维持在0℃15分钟,加热至室温。加入碘代甲烷(0.49ml,7.89mmol),搅拌反应物过夜。添加水以淬灭反应混合物,用二氯甲烷提取水层3次。合并有机层,用水和盐水洗涤,MgSO4干燥,真空浓缩,得到0.9g(68%)呈黄色固体的5-甲基-4-[4-(1-甲基吡啶鎓-4-氧基-苯磺酰基)-甲基-氨基]-联苯-3-羧酸甲酯碘化物。电喷雾质谱为:503.1(M+H)+
在THF∶MeOH∶H2O(2∶1∶1,总共3ml)配制的0.4g(0.79mmol)吡啶鎓盐溶液中加入0.037g(0.88mmol)氢氧化锂,加热反应物以回流过夜。用6M HCl溶液中和反应物,用乙酸乙酯提取3次。合并有机层,用盐水洗涤,MgSO4干燥,真空浓缩得到282mg(86%)4-[(4-羟基-苯磺酰基)-甲基-氨基]-5-甲基-联苯-3-羧酸甲酯。电喷雾质谱为:412.0(M+H)+
实施例43
4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-甲基-联苯-3-羧酸羟基酰胺
按实施例5的流程,242mg(0.58mmol)实施例42的产物与0.049ml(0.65mmol)2-丁炔-1-醇反应生成0.239g(98%)4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-甲基-联苯-3-羧酸甲酯。电喷雾质谱为:464.2(M+H)+
按实施例38的流程,水解0.239g(0.58mmol)酯,生成0.2g(76%)4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-甲基-联苯-3-羧酸。电喷雾质谱为:448.0(M-H)-
按实施例39的流程,将0.20g(0.44mmol)羧酸转化成异羟肟酸4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-甲基-联苯-3-羧酸羟基酰胺,得0.150g(73%)纯产物。电喷雾质谱为:465.0(M+H)+
实施例44
5-溴-3-甲基-2-{甲基-[4-(3-苯基-丙-2-炔氧基)-苯磺酰基]-氨基}苯甲酸
在6.0ml THF/甲醇(1∶1)配制的0.240g(0.455mmol)实施例11产物的溶液中加入2.3ml 1.0N氢氧化钠溶液。加热反应物以回流过夜,冷却至室温,用5%HCl溶液酸化。用乙酸乙酯提取混合物,用盐水洗涤,MgSO4干燥合并的有机层,过滤并真空浓缩。用乙醚/己烷(1∶1)研磨残留物,收集固体,真空干燥得到0.181g(77%)呈白色固体的所需的羧酸产物。电喷雾质谱为:513.7(M+H)+
实施例45
5-溴-2-({4-[3-(3-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酸
在6.0ml THF/甲醇(1∶1)配制的0.251g(0.450mmol)实施例12产物的溶液中加入2.3ml 1.0N氢氧化钠溶液。加热反应物以回流过夜,冷却至室温,用5%HCl溶液酸化。用乙酸乙酯提取混合物,用盐水洗涤,以MgSO4干燥合并的有机层,过滤并真空浓缩。用乙醚/己烷(1∶1)研磨残留物,收集固体,真空干燥得到0.184g(75%)呈浅黄色固体的所需的羧酸产物。电喷雾质谱为:543.8(M+H)+
实施例46
5-溴-2-({4-[3-(2-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酸
在6.0ml THF/甲醇(1∶1)配制的0.264g(0.473mmol)实施例13产物的溶液中加入2.4ml 1.0N氢氧化钠溶液。加热反应物以回流过夜,冷却至室温,用5%HCl溶液酸化。用乙酸乙酯提取混合物,用盐水洗涤,以MgSO4干燥合并的有机层,过滤并真空浓缩。用乙醚/己烷(1∶1)研磨残留物,收集固体,真空干燥得到0.159g(62%)呈白色固体的所需的羧酸产物。电喷雾质谱为:543.8(M+H)+
实施例47
5-溴-2-({4-[3-(4-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酸
在6.0ml THF/甲醇(1∶1)配制的0.217g(0.389mmol)实施例14产物的溶液中加入1.9ml 1.0N氢氧化钠溶液。加热反应物以回流过夜,冷却至室温,用5%HCl溶液酸化。用乙酸乙酯提取混合物,用盐水洗涤,以MgSO4干燥合并的有机层,过滤并真空浓缩。用乙醚/己烷(1∶1)研磨残留物,收集固体,真空干燥得到0.191g(90%)呈白色固体的所需的羧酸产物。电喷雾质谱为:543.8(M+H)+
实施例48
2-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-碘-3-甲基-苯甲酸
在6.0ml THF/甲醇(1∶1)配制的0.102g(0.199mmol)实施例17产物的溶液中加入1.0ml 1.0N氢氧化钠溶液。加热反应物以回流过夜,冷却至室温,用5%HCl溶液酸化。用乙酸乙酯提取混合物,用盐水洗涤,以MgSO4干燥合并的有机层,过滤并真空浓缩,得到0.089g(90%)呈白色固体的所需的羧酸产物。电喷雾质谱为:499.8(M+H)+
实施例49
2-[苄基-(4-丁-2-炔氧基-苯磺酰基)-氨基]-3,5-二甲基-苯甲酸
在4.0ml THF/甲醇(1∶1)配制的0.161g(0.338mmol)实施例20产物的溶液中加入1.7ml 1.0N氢氧化钠溶液。加热反应物以回流过夜,冷却至室温,用5%HCl溶液酸化。用二氯甲烷提取混合物,然后以MgSO4干燥合并的有机层,过滤并真空浓缩,得到0.151g(97%)呈白色固体的所需的羧酸产物。电喷雾质谱为:464.0(M+H)+
实施例50
5-溴-3-甲基-2-{甲基-[4-(4-吡咯烷-1-基-丁-2-炔氧基)-苯磺酰基]-氨基}-苯甲酸
在4.0ml THF/甲醇(1∶1)配制的0.157g(0.293mmol)实施例23产物的溶液中加入1.5ml 1.0N氢氧化钠溶液。加热反应物以回流过夜,冷却至室温,用5%HCl溶液酸化至pH 6-7。用二氯甲烷提取混合物,然后以Na2SO4干燥合并的有机层,过滤并真空浓缩,得到0.139g(91%)呈白色固体的所需的羧酸产物。电喷雾质谱为:520.9(M+H)+
实施例51
5-溴-2-{[4-(4-二乙基氨基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酸
按实施例50的流程,用0.180g(0.335mmol)实施例24的产物生成0.175g(100%)呈褐色泡沫状的所需的羧酸。电喷雾质谱为:522.9(M+H)+
实施例52
5-溴-3-甲基-2-[甲基-(4-丙-2-炔氧基-苯磺酰基)-氨基]-苯甲酸
按实施例38的流程,用0.250g(0.553mmol)实施例5的产物生成0.237g(98%)呈白色固体的所需的羧酸。电喷雾质谱为:435.8(M-H)+
实施例53
5-溴-N-羟基-3-甲基-2-[甲基-(4-丙-2-炔氧基-苯磺酰基)-氨基]-苯甲酰胺
按实施例39的流程,用0.173g实施例52的产物生成0.176g(98%)呈白色固体的所需的异羟肟酸。电喷雾质谱为:452.8(M+H)+
实施例54
5-苯并呋喃-2-基-2-[(4-甲氧基-苯磺酰基)-吡啶-3-基甲基-氨基]-3-甲基-苯甲酸甲酯
按实施例39的流程,用0.084g实施例6的产物生成0.087g(100%)呈白色泡沫状的所需的异羟肟酸。电喷雾质谱为:466.8(M+H)+
实施例55
5-溴-N-羟基-3-甲基-2-[甲基-(4-戊-2-炔氧基-苯磺酰基)-氨基]-苯甲酰胺
按实施例39的流程,用0.162g实施例7的产物生成0.135g(81%)呈褐色泡沫状的异羟肟酸。电喷雾质谱为:480.8(M+H)+
实施例56
5-溴-2-[(4-庚-2-炔氧基-苯磺酰基)-甲基-氨基]-N-羟基-3-甲基-苯甲酰胺
按实施例39的流程,用0.180g实施例8的产物生成0.127g(69%)呈褐色泡沫状的异羟肟酸。电喷雾质谱为:508.8(M+H)+
实施例57
5-溴-2-[(4-己-2-炔氧基-苯磺酰基)-甲基-氨基]-N-羟基-3-甲基-苯甲酰胺
按实施例39的流程,用0.128g实施例10的产物生成0.087g(100%)呈透明玻璃状物的异羟肟酸。电喷雾质谱为:497.0(M+H)+
实施例58
5-溴-N-羟基-2-{[4-(4-甲氧基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酰胺
按实施例39的流程,用0.064g实施例26的产物生成0.062g(100%)呈褐色泡沫状的异羟肟酸。电喷雾质谱为:496.8(M+H)+
实施例59
5-溴-N-羟基-3-甲基-2-{甲基-[4-(3-苯基-丙-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺
按实施例39的流程,用0.146g实施例44的产物生成0.141g(94%)呈浅黄色泡沫状的异羟肟酸。电喷雾质谱为:528.8(M+H)+
实施例60
5-溴-N-羟基-2-({4-[3-(3-甲氧基-苯基)丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺
按实施例39的流程,用0.154g实施例45的产物生成0.151g(96%)呈浅橙色固体的异羟肟酸。电喷雾质谱为:558.8(M+H)+
实施例61
5-溴-N-羟基-2-({4-[3-(2-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺
按实施例39的流程,用0.135g实施例46的产物生成0.132g(95%)呈白色泡沫状的异羟肟酸。电喷雾质谱为:558.9(M+H)+
实施例62
5-溴-N-羟基-2-({4-[3-(4-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺
按实施例39的流程,用0.158g实施例47的产物生成0.116g(72%)呈浅黄色泡沫状的异羟肟酸。电喷雾质谱为:588.9(M+H)+
实施例63
2-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-N-羟基-5-碘-3-甲基-苯甲酰胺
按实施例39的流程,用0.109g实施例48的产物生成0.112g(100%)呈白色泡沫状的异羟肟酸。电喷雾质谱为:514.8(M+H)+
实施例64
2-[苄基-(4-丁-2-炔氧基-苯磺酰基)-氨基]-N-羟基-3,5-二甲基-苯甲酰胺
按实施例39的流程,用0.135g实施例49的产物生成0.134g(96%)呈白色固体的异羟肟酸。电喷雾质谱为:479.0(M+H)+
实施例65
5-溴-N-羟基-3-甲基-2-{甲基-[4-(4-吡咯烷-1-基-丁-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺
于0°在用2.7ml二氯甲烷稀释的0.33ml(0.650mmol)2.0M草酰氯的二氯甲烷溶液中加入0.050ml(0.650mmol)DMF,0℃搅拌反应物15分钟。将溶解于1ml DMF的0.113g(0.217mmol)实施例50羧酸产物的溶液加到反应物中,室温搅拌如此得到的混合物1小时,然后倾倒入0°的0.7ml水、3.4ml THF和0.2ml 50%羟胺水溶液的混合物中。让反应物升温至室温过夜,真空浓缩有机层。用乙酸乙酯稀释残留物,用水和饱和重碳酸钠洗涤,Na2SO4干燥,过滤和真空浓缩得到0.087g(75%)呈褐色泡沫状的异羟肟酸。
在溶解于2.0ml二氯甲烷的0.065g(0.121mmol)氨基-异羟肟酸溶液中加入0.24ml(0.24mmol)用乙醚配制的1.0M HCl溶液。室温搅拌如此得到的混合物1小时,然后用乙醚稀释。过滤沉淀物,用乙醚洗涤,真空干燥得到0.064g(93%)呈褐色固体的氨基-异羟肟酸的盐酸盐。电喷雾质谱为:535.9(M+H)+
实施例66
5-溴-2-{[4-(4-二乙基氨基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-N-羟基-3-甲基-苯甲酰胺
于0°在以3.1ml二氯甲烷稀释的0.38ml(0.757mmol)2.0M草酰氯的二氯甲烷溶液中加入0.059ml(0.757mmol)DMF,0℃搅拌反应物15分钟。将溶解于1ml DMF的0.132g(0.252mmol)实施例51羧酸产物的溶液加到反应物中,室温搅拌如此得到的混合物1小时,然后倾倒入0°的0.8ml水、3.9ml THF和0.24ml 50%羟胺水溶液的混合物中。让反应物升温至室温过夜,真空浓缩有机层。用乙酸乙酯稀释残留物,用水和饱和重碳酸钠洗涤,Na2SO4干燥,过滤和真空浓缩得到0.126g(93%)呈褐色泡沫状的异羟肟酸。
在溶解于3.0ml二氯甲烷的0.093g(0.173mmol)氨基-异羟肟酸溶液中加入0.35ml(0.35mmol)用乙醚配制的1.0M HCl溶液。室温搅拌如此得到的混合物1小时,然后用乙醚稀释。过滤沉淀物,用乙醚洗涤,真空干燥得到0.091g(92%)呈褐色固体的氨基-异羟肟酸的盐酸盐。电喷雾质谱为:540.0(M+H)+
实施例67
5-溴-2-[(4-丁-2-炔氧基-苯磺酰基)-(4-甲基-哌嗪-1-基甲基)-氨基]-N-羟基-3-甲基-苯甲酰胺
按实施例50的流程,用0.128g(0.228mmol)实施例22的产物生成0.117g(94%)羧酸。电喷雾质谱为:550.0(M+H)+
于0°在用2.4ml二氯甲烷稀释的0.27ml(0.547mmol)2.0M草酰氯的二氯甲烷溶液中加入0.042ml(0.547mmol)DMF,于0℃搅拌反应物15分钟。将溶解于1mlDMF的0.100g(0.182mmol)羧酸的溶液加到反应物中,室温搅拌如此得到的混合物1小时,然后倾倒入0°的0.5ml水、2.7ml THF和0.5ml 50%羟胺水溶液的混合物中。让反应物升温至室温过夜,真空浓缩有机层。用乙酸乙酯稀释残留物,用水和饱和重碳酸钠洗涤,Na2SO4干燥,过滤和真空浓缩得到0.080g(78%)呈褐色泡沫状的异羟肟酸。电喷雾质谱为:565.1(M+H)+
在溶解于4.0ml二氯甲烷的0.060g(0.107mmol)氨基-异羟肟酸溶液中加入0.43ml(0.43mmol)用乙醚配制的1.0M HCl溶液。室温搅拌如此得到的混合物1小时,然后用乙醚稀释。过滤沉淀物,用乙醚洗涤,真空干燥得到0.068g(100%)呈褐色固体的哌嗪-异羟肟酸的二盐酸盐。电喷雾质谱为:565.0(M+H)+
实施例68
5-溴-3-甲基-2-(甲基-{4-[4-(四氢-吡喃-2-基氧)-丁-2-炔氧基]-苯磺酰基}-氨基)-苯甲酸
按实施例50的流程,用0.550g(0.972mmol)实施例15的产物生成0.448g(84%)呈白色固体的羧酸。电喷雾质谱为:549.9(M-H)-
实施例69
5-溴-N-羟基-3-甲基-2-(甲基-{4-[4-(四氢-吡喃-2-基氧)-丁-2-炔氧基]-苯磺酰基}-氨基)-苯甲酰胺
在4.0ml DMF配制的0.411g(0.745mmol)实施例68产物的溶液中加入0.121g(0.893mmol)1-羟基苯并三唑(HOBT),然后再加入0.190g(0.990mmol)盐酸1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺(EDC)。室温搅拌如此得到的混合物1小时,然后加入0.23ml 50%羟胺水溶液,搅拌此反应物过夜。用乙酸乙酯稀释反应物,用水、5%HCl溶液和饱和重碳酸钠溶液洗涤。以Na2SO4干燥有机层,过滤、真空浓缩得到0.337g(80%)呈白色泡沫状的异羟肟酸。电喷雾质谱为:568.8(M+H)+
实施例70
5-溴-N-羟基-2-{[4-(4-羟基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酰胺
在4.0ml甲醇配制的0.274g(0.483mmol)实施例69产物的溶液中加入0.012g(0.048mmol)对甲苯磺酸吡啶鎓,加热得到的混合物以回流18小时反应物,随后真空浓缩,用乙酸乙酯稀释,并用5%HCl溶液、水和饱和重碳酸钠溶液洗涤。以Na2SO4干燥有机层,过滤真空浓缩得到0.159g(68%)呈白色粉末的异羟肟酸。电喷雾质谱为:482.8(M+H)+
实施例71
4-[(4-羟基-苯磺酰基)-甲基-氨基]-5-甲基-联苯-3-羧酸甲酯
在28ml脱气的乙二醇二甲醚中加入2.15g(5.19mmol)实施例4的产物、0.696g(5.71mmol)苯基硼酸、0.300g(0.26mmol)四(三苯基膦)钯(0)和10.4ml(20.8mmol)2M Na2CO3,氮气下回流此混合物18小时。然后冷却此反应物,用乙酸乙酯稀释,用水和盐酸洗涤,Na2SO4干燥,过滤并真空浓缩。用1∶3二氯甲烷/己烷研磨残留物得到1.89g(89%)呈浅橙色固体的所需的联苯产物。电喷雾质谱为:412.4(M+H)+
实施例72
4-{[4-(叔-丁基-二甲基-甲硅烷氧基)-苯磺酰基]-甲基-氨基}-5-甲基-联苯-3-羧酸甲酯
室温下搅拌1.89g(4.6mmol)实施例71的产物、0.833g(5.52mmol)氯叔丁基二甲基甲硅烷和0.783g(11.51mmol)咪唑在8ml DMF中的混合物18小时。用水淬灭反应,并用二氯甲烷提取。分离有机层,用盐水洗涤,Na2SO4干燥,真空浓缩。以乙酸乙酯/己烷(1∶20)洗脱,在硅胶上层析残留物得到1.89g(78%)呈白色固体的所需的甲硅烷基醚。电喷雾质谱为:526.0(M+H)+
实施例73
4-[(4-羟基-苯磺酰基)-甲基-氨基]-5-(4-甲基-哌嗪-1-基甲基)-联苯-3-羧酸甲酯
在氮气下以太阳灯照射,1.84g(3.5mmol)实施例72的产物和0.748g(4.2mmol)N-溴琥珀酰亚胺在35ml四氯化碳中的混合物回流2.5小时。冷却反应物,用水和盐水洗涤,Na2SO4干燥并真空浓缩得到2.33g苄基溴(benzylic bromide)。在20mlDMF中将此溴化物与0.350g(3.5mmol)N-甲基哌嗪和1.45g(10.5mmol)K2CO3混合,室温搅拌此混合物18小时。用二氯甲烷稀释此反应混合物,用水和盐水洗涤,Na2SO4干燥并真空浓缩。以2%甲醇/二氯甲烷洗脱,在硅胶上层析此残留物,得到1.33g(74%)呈浅黄色固体的所需的产物。电喷雾质谱为:510.0(M+H)+
实施例74
4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-(4-甲基-哌嗪-1-基甲基)-联苯-3-羧酸甲酯
在8ml THF配制的0.810g(1.59mmol)实施例73的产物和0.594ml(7.95mmol)2-丁炔-1-醇溶液中加入2.08g(7.95mmol)三苯基膦,然后再加入1.25ml(7.95mmol)偶氮二羧酸二乙酯。室温搅拌此混合物18小时,用乙酸乙酯稀释,用水和盐水洗涤,Na2SO4干燥,并真空浓缩。以2%甲醇/二氯甲烷洗脱,在硅胶使层析残留物,得到0.830g(93%)呈米黄色固体的所需产物。电喷雾质谱为:562.1(M+H)+
实施例75
4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-(4-甲基-哌嗪-1-基甲基)-联苯-3-羧酸
加热以8.6ml THF和8.6ml甲醇配制的0.965g(1.72mmol)实施例74的产物和8.6ml(8.59mmol)1N NaOH的混合物以回流18小时。冷却反应混合物,用3N HCl中和。除去有机溶剂,用二氯甲烷提取残留的水溶液。分离有机层,用水和盐水洗涤,Na2CO3干燥并真空浓缩。用乙醚研磨残留物得到0.829g(89%)呈奶油色固体的所需的产物。电喷雾质谱为:548.1(M+H)+
实施例76
4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-(4-甲基-哌嗪-1-基甲基)-联苯-3-羧酸羟基酰胺二盐酸盐
于0℃在0.244ml(0.487mmol)二氯甲烷配制的2M草酰氯的溶液中加入0.038ml(0.487mmol)DMF,室温搅拌此混合物1小时。然后在该反应混合物中加入由0.5ml二氯甲烷配制的0.089g(0.163mmol)实施例75的产物,室温搅拌此混合物1小时。
在另一烧瓶中将由2.5ml THF和0.5ml水配制的0.149ml(2.44mmol)50%羟胺水溶液的混合物在0℃冷却15分钟,将酰基氯溶液一次加到其中。搅拌让生成的溶液升温至室温过夜。用二氯甲烷稀释反应混合物,用水和盐水洗涤,Na2SO4干燥,过滤并真空浓缩。用乙醚研磨残留物,得到0.066g(72%)呈米黄色固体的所需的异羟肟酸。
在5ml二氯甲烷配制的0.240g(0.418mmol)异羟肟酸的溶液中加入1.67ml(1.67mmol)1M HCl/乙醚溶液。搅拌此反应物1小时,然后用乙醚稀释。过滤得到的沉淀,真空干燥得到0.245g(92%)呈米黄色固体的所需的盐酸盐。电喷雾质谱为:563.1(M+H)+
实施例77
5-溴-3-甲基-2-{甲基-[4-(1-甲基-丙-2-炔氧基)-苯磺酰基]-氨基}-苯甲酸甲酯
按实施例5的流程,用0.400g(0.966mmol)实施例4的产物和0.083ml(1.063mmol)3-丁炔-2-醇生成0.266g(59%)呈无色油状的炔丙醚。电喷雾质谱为:465.8(M+H)+
实施例78
5-溴-3-甲基-2-{甲基-[4-(1-甲基-丙-2-炔氧基)-苯磺酰基]-氨基}-苯甲酸
按实施例10的流程,用2.6ml 1.0N氢氧化钠溶液水解0.241g实施例77的产物,得到0.073g(31%)呈白色固体的所需的羧酸和0.034g(14%)起始物醚。电喷雾质谱为:451.8(M+H)+
实施例79
5-溴-N-羟基-3-甲基-2-{甲基-[4-(1-甲基-丙-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺
按实施例39的流程,用0.068g(0.150mmol)实施例34的产物得到0.070g(100%)呈白色泡沫状的异羟肟酸。电喷雾质谱为:466.9(M+H)+
实施例80
3-[3-(叔-丁基-二甲基-甲硅烷氧基)-苯基]-丙-2-炔-1-醇
在10ml DMF配制的2.0g(9.091mmol)3-碘苯酚溶液中加入1.55g(0.023mol)咪唑和1.64g(0.011mol)氯叔-丁基二甲基甲硅烷,室温搅拌如此得到的混合物48小时。用乙醚稀释反应物,用水洗涤,Na2SO4干燥,过滤并真空浓缩。无需纯化将此残留物用于下一步骤。
在55ml二乙胺配制的3.04g(9.091mmol)甲硅烷基化的碘代芳基溶液中加入0.53ml炔丙醇,然后再加入0.173g(0.909mmol)碘化铜(I)和0.32g(0.456mmol)二氯化双(三苯基-膦)-钯(II)。室温搅拌此反应混合物4小时,然后真空浓缩。以乙酸乙酯/己烷(1∶10)洗脱,在硅胶上层析残留物,得到0.73g(31%)呈褐色油状的芳基乙炔。电喷雾质谱为:262(M+)
实施例81
5-溴-2-({4-[3-(3-羟基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酸
按实施例5的流程,用0.158g(0.604mmol)实施例80的产物和0.250g(0.604mmol)实施例4的产物,生成0.315g炔丙基醚。
按实施例10的流程,用0.315g炔丙基醚得到0.169g(67%)呈褐色固体的酚-羧酸。电喷雾质谱为:527.9(M-H)-
实施例82
5-溴-2-[(4-{3-[3-(叔-丁基-二甲基-甲硅烷基氧)-苯基]-丙-2-炔氧基}-苯磺酰基)-甲基-氨基]-3-甲基-苯甲酸
在1.0ml DMF配制的0.14.4g(0.271mmol)实施例81产物的溶液中加入0.092g(1.356mmol)咪唑和0.098g(0.651mmol)氯叔-丁基二甲基甲硅烷,室温搅拌此混合物15小时。然后将反应混合物倾倒入20ml水中,搅拌5小时,然后用乙醚提取。用水洗涤有机层,Na2SO4干燥,过滤并真空浓缩。以乙酸乙酯/己烷(1∶3)洗脱,在硅胶上层析残留物,得到0.136g呈白色固体的羧酸-甲硅烷基化的苯酚。电喷雾质谱为:643.8(M+H)+
实施例83
5-溴-2-[(4-{3-[3-(叔-丁基-二甲基-甲硅烷氧基)-苯基]-丙-2-炔氧基}-苯磺酰基)-甲基-氨基]-N-羟基-3-甲基-苯甲酰胺
按实施例39的流程,用0.097g(0.150mmol)实施例82的产物得到0.099g呈白色固体的异羟肟酸。电喷雾质谱为:658.9(M+H)+
实施例84
5-溴-N-羟基-2-({4-[3-(3-羟基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺
在1ml乙腈配制的0.099g(0.150mmol)实施例83产物的溶液中加入3ml用乙腈配制的5%的48%HF溶液,室温搅拌如此得到混合物15小时。用水和乙酸乙酯稀释反应混合物。用水洗涤有机层,Na2SO4干燥并真空浓缩,得到0.031g(38%)呈浅黄色固体的酚异羟肟酸。电喷雾质谱为:544.9(M+H)+
实施例85
4-丁-2-炔氧基-苯磺酸钠盐
在1L异丙醇和225ml 1.0N氢氧化钠溶液配制的52.35g(0.225mol)4-羟基苯磺酸钠溶液中加入59.96g(0.45mol)1-溴-2-丁炔。将如此得到的混合物加热至70℃15小时,然后真空蒸发除去异丙醇。过滤收集残留下的白色沉淀,用异丙醇和乙醚洗涤,真空干燥得到56.0g(100%)呈白色固体的丁炔醚。
实施例86
4-丁-2-炔氧基-苯磺酰氯
在29ml二氯甲烷配制的43.8ml(0.087mol)2M草酰氯/二氯甲烷的0°溶液中逐滴加入6.77ml(0.087mol)DMF,随后加入7.24g(0.029mol)实施例85的产物。0°搅拌此反应混合物10分钟,然后让其升温至室温,搅拌2天。然后将反应物倾倒入冰中,用150ml己烷提取。用水和盐水洗涤有机层,Na2SO4干燥,过滤并真空浓缩,得到6.23g(88%)呈黄色固体的磺酰氯;m.p.63-65℃。电喷雾质谱为:243.9MH+
实施例87
丁-2-炔氧基-苯
按实施例5的流程,用2.00g(0.021mol)苯酚和1.64g(0.023mol)2-丁炔-1-醇生成2.18g(70%)呈清澈液体的丁炔醚。电喷雾质谱为:146.0MH+
实施例88
4-丁-2-炔氧基-苯磺酰氯
在丙酮/冰浴中于N2下,逐滴将0.3ml二氯甲烷配制的0.073ml(1.1mmol)氯磺酸加到由0.3ml二氯甲烷配制的0.146g(1.0mmol)实施例87产物的溶液中。添加完毕后,移去冰浴,室温搅拌反应物2小时。然后在反应物中逐滴加入0.113ml(1.3mmol)草酰氯,随后加入0.015ml DMF。加热反应物以回流2小时,然后用己烷稀释,倾倒入冰水中。用盐水洗涤有机层,硫酸钠干燥,真空浓缩得到0.130mg(53%)呈浅褐色固体的所需的产物。
药理学
将本发明的典型化合物作为酶MMP-1、MMP-9、MMP-13和TNF-α转化酶(TACE)的抑制剂进行评估。以下列出了用于证实此生物学特性所用的标准药理测试流程及得到的结果。
测定MMP-1、MMP-9和MMP-13抑制的测试程序
这些标准药理测试程序是基于基质金属蛋白酶MMP-1、MMP-13(胶原酶)或MMP-9(明胶酶)切割硫肽(thiopeptide)底物如Ac-Pro-Leu-Gly(2-巯基-4-甲基-戊醇基)-Leu-Gly-OEt,导致释放出能与DTNB(5,5′-二硫二(2-硝基-苯甲酸)产生颜色反应的底物产物。用颜色增加的速率衡量酶的活性。用溶于100%DMSO的20mM硫肽底物的新配制原液,将DTNB溶解在100%DMSO中作为100mM原液,室温储存在暗处。使用前用底物缓冲液(50mM HEPES pH 7.5,5mMCaCl2)将底物和DTNB一起稀释至1mM。用缓冲液(50mM HEPES,pH 7.5,5mMCaCl2,0.02%Bij)将酶原液稀释至所需的最终浓度。按缓冲液、酶、运载体或抑制剂、和DTNB/底物的顺序将这些物质加到96孔板中(终反应体积为200μl),在405nm用分光光度议平板读数仪上监测颜色的增加5分钟,绘制随时间颜色增加的线性图。
另外,使用荧光肽底物。在该测试程序中,肽底物含有荧光基团和淬灭基团。一旦MMP切割底物,在荧光平板读数仪上定量测定产生的荧光。在HCBC试验缓冲液(50mM HEPES,pH 7.0,5mM Ca+2,0.02%Brij,0.5%半胱氨酸)中用人重组MMP-1、MMP-9或MMP-13进行该试验。将底物溶解在甲醇中,以1mM等份冰冻储存。该试验中,用HCBC缓冲液将底物和酶稀释至所需的浓度。将化合物加到含酶的96孔板中,加入底物开始反应。读取(340nm激发,444nm发射)应10分钟,绘制随时间荧光增加的线性图。
对硫肽或荧光肽测试程序而言,计算直线的斜率,其代表反应速率。证实反应速率的线性(r2>0.85)。计算对照速率的平均值(x±sem),并用Dunnett多重比较检验与药物处理速率比较有统计学显著性(p<0.05)。用多种剂量的药物可得到剂量-反应关系,用线性回归估计95%CI的IC50值。
测定TACE抑制的试验程序
用96孔黑色微量滴定板,各孔加入由10μl TACE(终浓度为1μg/ml)、70μl Tris缓冲液、pH 7.4含有10%甘油(终浓度为10mM)、和10μl以DMSO配制的测试化合物(终浓度为1μM,DMSO浓度<1%)组成的溶液,室温培育10分钟。各孔中加入荧光肽底物(终浓度为100μM)以引发反应,然后在摇床上振荡5秒。
读取反应10分钟(340nm激发,420nm发射),绘制随时间荧光增加的线性图。计算该线的斜率,其代表反应速率。
证实反应速率的线性(r2>0.85)。计算对照速率的平均值(x±sem),并用Dunnett多重比较检验与药物处理速率比较有统计学显著性(p<0.05)。用多种剂量的药物可得到剂量-反应关系,用线性回归估计95%CI的IC50值。
可溶性蛋白质的人单核THP-1细胞分化试验(THP可溶性蛋白质试验)
有丝分裂刺激THP-1细胞致使分裂成巨噬细胞样细胞,伴有除其他蛋白质外同时分泌肿瘤坏死因子(TNF-α)和TNF受体(TNF-R,p75/80和TNF-R p55/60)以及白细胞介素-8(IL-8)。另外,在该时间以后未受刺激的THP-1细胞分泌出p75/80和p55/60受体。称为TNF-a转化酶或TACE的酶介导了膜结合TNF-α的释放和可能的TNF-R p75/80和TNF-R p55/60的释放但无IL-8释放。可用该试验来证明抑制性或刺激性化合物对此TACE酶的作用和该化合物的细胞毒性结果。
THP-1细胞(由ATCC获得)是一种人单核细胞系,获自一个一岁的患急性单核细胞白血病男童的外周血液。它们可以在培养基中生长,且受促细胞分裂剂刺激后能分裂成巨噬细胞样细胞。
在该试验中,由上述生长的和以5×106ml/瓶冷冻保藏的ATCC原液中采集THP-1细胞。将一管接种到T25瓶中,其中含有16ml补充有Glutamax(Gibco)的RPMI-1640培养基(含10%胎牛血清、100单位/ml青霉素、100μg/ml链霉素和5×10-5M 2-巯基-乙醇(THP-1培养基))。在用于试验前,将各管细胞培养约2星期,然后再使用4-6周来筛选化合物。在星期一和星期四传代细胞至浓度1×105/ml。
为了进行试验,37℃在5%CO2中,将THP-1细胞以1.091×106个细胞/ml(1.1ml/孔)在24孔平板中,与每孔含有50ml 24mg/ml的脂多糖(LPS)(CalbiochemLot#B13189)原液共培养24小时。同时将50ml/孔的药物、运载体或THP-1培养液置于适当的孔中,终体积为1.2ml/孔。将标准化合物和测试化合物溶解在浓度为36mM的DMSO中,并从此浓度用THP-1培养基稀释至适当的浓度,在培养开始时加到诸孔中,使终浓度为100mM、30mM、10mM、3mM、1mM、300nM和100nM。将与DMSO接触的细胞限制在0.1%终浓度。试验中包括阳性对照孔,其中有促细胞分裂剂但无药物。还包括运载体对照孔,除加入终浓度为0.083%的DMSO外都与阳性对照相同。试验中还包括阴性对照孔,细胞中加入了运载体但不加促细胞分裂剂或药物。可通过用50ml/孔的THP-1培养基代替LPS评估化合物对受体基础性(无刺激)分泌的作用。将平板置于设置为5%CO2和37℃的培养箱中。培养4小时后,取出300ml/孔组织培养物上清液(TCS)用于TNF-a ELISA。培养24小时后,取出700ml/孔TCS,用于TNF-R p75/80、TNF-R p55/60和IL-8 ELISA分析。
另外在24小时时,将细胞重悬浮于500μl/孔的THP-1培养液中收集各处理组的细胞,并转移到FACS管中。加入2ml/管0.5mg/ml二碘化丙锭原液(PI)(Boerhinger Mannheim cat.#1348639)。将这些样品在Becton Dickinson FaxCaliberFLOW细胞记数仪上跑样,以红外线波长(FL3)测定各细胞摄取的染料量。只有膜受损的细胞(死或濒死)才吸收PI。通过计数未被PI染色的细胞除以样品中细胞的总量来计算活细胞百分比。将药物处理组的活力计算值与运载体处理的促细胞分裂剂刺激组(“载体阳性对照”)的活力计算值相比较,确定“相当于对照的变化百分比”。这个“相当于对照的变化百分比”是表明药物细胞毒性的一种指标。
采用从R&D Systems购得的ELISAs测得THP-1细胞培养物的TCS中可溶性TNF-a、TNF-R p75/80和TNF-R p55/60和IL-8的量,通过用试剂盒标准品所产生的标准曲线外推。用FLOW细胞记数仪测定了摄取或排斥PI的细胞数量,并用可购得的Cytologic软件绘制直方图直观化各处理组(包括所有对照)的数据。
对于刺激条件下可溶性蛋白质(TNF-a、p75/80、p55/60、IL-8)的研究,测定了重复孔的平均值pg/ml,结果以相当于“载体阳性对照”的变化百分比表示。对于非刺激条件下可溶性蛋白质(p75/80和p55/60受体)的研究,测定了重复孔的平均值pg/ml,结果用以下公式表示成相当于“载体阳性对照”的变化百分比:
用定制的软件(使用JUMP统计软件包),由非线性的回归分析计算出各化合物的IC50值。
对于细胞活力研究,测定了合并的重复孔的活力(PI排斥),以相当于“载体阳性对照”的变化百分比表示结果。将计算出的化合物处理组的活力值与计算出的“载体阳性对照”的活力值相比较,以确定以下的“相对于对照的变化百分比”。该“相对于对照的变化百分比”的值是药物细胞毒性的一种指标。
参考文献:
Bjornberg,F.,Lantz,M.,Olsson,I.,和Gullberg,U.“将p55和p75肿瘤坏死因子(TNF)受体加工成可溶性受体形式有关的机制”,Lymphokine Cytokine Res.13:203-211,1994。
Gatanaga,T.,Hwang.C.,Gatanaga,M.,Cappuccini,F.,Yamamoto,R.,和Granger,G.“体外PMA-和LPS刺激的人单核THP-1细胞对TNF mRNA合成、膜表达和释放的调节”,CellularImmun.138:1-10,1991。
Tsuchiya,S.,Yamabe,M.,Yamagughi,Y.,Kobayashi,Y.,Konno,T.,和Tada,K.“人急性单核细胞白血病细胞系(THP-1)的建立和特性分析”,Int.J.Cancer.26:1711-176,1980。
下表I列出了上述体外基质金属蛋白酶抑制、TACE抑制和THP标准药理测试流程的结果。
表I.MMP、TACE和THP分析中的抑制作用:
表1
IC50(nM)或%抑制(μM) | %抑制@3μM | ||||
实施例# | MMP-1 | MMP-9 | MMP-13 | TACE | THP |
31 | 19%(10) | 301 | 724 | 44 | 6 |
32 | 26%(10) | 643 | 255 | 58 | 15 |
33 | 32%(10) | 1205 | 908 | 29 | 14 |
34 | 39%(10) | 790 | 383 | 127 | 22 |
36 | 114 | 11 | 21 | 32 | 14 |
39 | 2488 | 21 | 68 | 67 | 0 |
43 | 4243 | 578 | 518 | 135 | 76 |
53 | 113 | 15 | 52 | 11 | 55 |
54 | 1616 | 304 | 154 | 16 | 84 |
55 | 1228 | 800 | 289 | 12 | 48 |
56 | 53%(10) | 389 | 701 | 34 | 16 |
57 | 2364 | 232 | 358 | 47 | 11 |
58 | 7803 | 387 | 233 | 11 | 46 |
59 | 3815 | 857 | 321 | 66 | 20 |
60 | 1029 | 671 | 935 | 91 | 1 |
61 | 52%(10) | 1507 | 1199 | 193 | 0 |
62 | 3602 | 901 | 588 | 104 | 15 |
63 | 901 | 840 | 275 | 16 | 87 |
64 | 1187 | 830 | 312 | 105 | 48 |
65 | 3352 | 602 | 537 | 148 | 12 |
66 | 21%(10) | 2827 | 2377 | 346 | 5 |
67 | 1658 | 166 | 252 | 25 | 94 |
69 | 25%(10) | 396 | 177 | 30 | 19 |
70 | 3203 | 477 | 83 | 6.8 | 88 |
76 | 1923 | 28 | 47 | 42 | 95 |
79 | 1534 | 455 | 433 | 122 | 9 |
84 | 113 | 694 | 189 | 34 | 0 |
基于由上述标准药理测试流程得到的结果,本发明的化合物表明是酶MMP-1、MMP-9、MMP-13和TNF-a转化酶(TACE)的抑制剂,并因此可用于治疗病症如关节炎、肿瘤转移、组织溃疡、异常伤口愈合、牙周病、移植排斥、胰岛素抗性、骨骼病和HIV感染等疾病。
本发明的化合物还可用于治疗或抑制基质金属蛋白酶介导的病理变化如动脉粥样硬化、动脉粥样硬化斑形成、动脉粥样硬化斑破溃所致的冠脉血栓形成的复原、再狭窄、MMP一介导的骨质疏松、中枢神经系统的炎性疾病、肌肤老化、新血管生成、肿瘤转移、肿瘤生长、骨关节炎、类风湿性关节炎、脓毒性关节炎、角膜溃疡、蛋白尿、动脉瘤病、创伤性关节损伤后的退化性软骨丢失、神经系统的脱髓鞘病、肝硬化、肾小球疾病、胎膜早破、肠炎病、年龄相关的黄斑变性、糖尿病视网膜病、增生性玻璃体视网膜变态、视网膜未熟病、眼部炎症、圆锥形角膜、斯耶格伦综合症、近视、眼部肿瘤、眼部血管生成/血管再生和角膜移植排斥。
本发明的化合物可单独给予或与药用载体一起给予需要其的患者。药用载体可以是固体或液体。
可采用的固体载体包括一种或多种物质,这些载体也可作为增香剂、润滑剂、稳定剂、悬浮剂、填充剂、助流剂、助压剂、粘合剂或药片崩解剂或封装材料。在粉状制剂中,载体是分散得很细的固体,可与分散得很细的活性组分相混合。在片剂中,活性组分与适当比例的具有必需的助压特性的载体相混合,被压制成所需的性状和尺寸。粉末制剂和片剂较佳地含有多至99%活性组分。合适的固体载体包括如磷酸钙、硬脂酸镁、滑石粉、糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠盐、聚乙烯吡咯烷酮、低熔点蜡和离子交换树脂。
液态载体可用于制备溶液、悬浮液、乳剂、糖浆和酏剂。可将本发明的活性组分溶解于或悬浮于药学上可接受的液态载体如水、有机溶剂、这两者的混合物或药学上可接受的油或脂肪中。液态载体可含有其他合适的药用添加剂如稳定剂、乳化剂、缓冲剂、防腐剂、甜味剂、增香剂、悬浮剂、增稠剂、色素、粘度调节剂、稳定剂或渗透调节剂。合适的用于口服和肠胃外给药的液态载体的例子包括水(尤其含有上述添加剂如纤维素衍生物,较佳地是羧甲基纤维素钠盐的溶液)、醇(包括一元醇和多元醇如甘油)和它们的衍生物,和油(如分级椰子油和花生油)。用于肠胃外给药的载体也可以是油酯,如油酸乙酯和肉豆蔻酸异丙酯。无菌液态载体可用于肠胃外给药的无菌液体形式的组合物中。
可将无菌溶液或悬浮液的液体药物组合物用于例如肌内、腹腔内或皮下注射。也可静脉内注射给予无菌溶液。口服给药可以是液体或固体组合物形式。
可以常规栓剂的形式直肠给予本发明的化合物。对于鼻内或支气管内吸入或吹入给药,可将本发明的化合物配制成水溶液或部分水溶液,然后以气雾剂形式使用。本发明的化合物还可以透皮给予,采用含有活性化合物和对该活性化合物为惰性、对皮肤无毒的载体的透皮贴片,通过皮肤让该药剂全身吸收送递入血流。运载体可以采取多种形式如乳剂、软膏、糊剂、凝胶和包藏装置。乳剂和软膏可以是粘性液体或水包油或油包水类型的半固体乳剂。由分散在含该活性组分的石油或亲水性石油中的吸收性粉末构成的糊膏。可用各种包藏装置将该活性组分释放到血流中,如覆盖含有该活性组分的有或无载体的储器、或含有该活性组分的基质的半透膜。其他包藏装置是本领域已知的。
必须由主治医生主观确定用于治疗患MMP或TACE依赖性病症的具体患者的剂量。所涉及的各种变化包括功能紊乱的严重程度、和患者的体形、年龄和反应模式。通常从低于该化合物最佳剂量的小剂量开始治疗。随后逐渐增加剂量直到在此情况下达到最佳效果。可由给药的医生依据治疗个体的经验和标准的用药原则,确定口服、肠胃外、鼻内或支气管内给药的精确剂量。
较佳地,此药用组合物以单位剂量形式如片剂或胶囊。在该形式中,将此组合物再分成含有适当量该活性组分的单位剂量;单位剂量形式可以是包装的组合物如包装的粉末、小瓶、安瓿、预先充满的针筒或含有液体的小袋。单位剂量形式可以是例如胶囊或片剂本身,或者也可是适当数量的包装形式的这些组合物。
Claims (16)
其中A是苯基;萘基或与5-7元饱和的或不饱和环烷基环稠合的苯基;5-9元饱和的或不饱和的杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S;或5-10元杂芳环,所述的杂芳环的1-3个杂原子选自N、NR9、O或S;
X是SO2或-P(O)R10;
Y是苯基、萘基或杂芳基,条件是X和Z不连接于Y的相邻原子;
Z是O、NH、CH2或S;
R5是氢或1-6个碳原子的烷基;
或R5-N-A可形成苯并氮、苯并氧氮杂、苯并硫氮杂、苯并二氮、苯并吖辛因、苯并二吖辛因、苯并噁吖辛因或苯并噻吖辛因环,可任选地稠合于另一个苯环;
R6和R7各是氢、1-6个碳原子的烷基、-CN、-CCH;
和R8是氢;1-6个碳原子的烷基;2-6个碳原子的链烯基;2-6个碳原子的炔基;3-6个碳原子的环烷基;苯基;萘基;5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;或5-9元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S;
R9是氢、苯基、萘基、1-6个碳原子的烷基、或3-6个碳原子的环烷基;
和R10是苯基;萘基;1-6个碳原子的烷基;3-6个碳原子的环烷基;5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;或5-9元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S。
2.如权利要求1所述的化合物,其特征在于,与-NR5-基团相邻的A的两个碳原子含有非氢的取代基。
3.如权利要求1所述的化合物,其特征在于,与-NR5-基团相邻的A的两个碳原子含有非氢的取代基,与-NR5-基团相对的A基团的碳原子含有非氢的取代基。
4.如权利要求1所述的化合物,其特征在于,A是苯基,与-NR5-基团相邻的A的两个碳原子含有非氢的取代基,与-NR5-基团相对的A基团的碳原子含有非氢的取代基。
5.如权利要求1-4任一所述的化合物,其特征在于,所述的Y是在1-和4-位分别被X和Z取代的苯环。
6.如权利要求1-5任一所述的化合物,其特征在于,所述的X是SO2。
7.如权利要求1-6任一所述的化合物,其特征在于,所述的Z是氧。
8.如权利要求1-7任一所述的化合物,其特征在于,所述的R6和R7是氢。
9.如权利要求1-8任一所述的方法,其特征在于,所述的R8是CH2OH或甲基。
10.如权利要求1所述的化合物,其特征在于,所述的化合物选自:
5-溴-2-{[4-(4-环丁基氨基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-N-羟基-3-甲基-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-{甲基-[4-(4-甲基氨基-丁-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺;
5-溴-2-({4-[4-(3-二甲基氨基-丙基氨基)-丁-2-炔氧基]-苯磺酰基}甲基-氨基)-N-羟基-3-甲基-苯甲酰胺;
5-溴-2-({4-[4-(2-二甲基氨基-乙基氨基)-丁-2-炔氧基]-苯磺酰基}甲基-氨基)-N-羟基-3-甲基-苯甲酰胺;
4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-甲基-联苯-3-羧酸羟基酰胺;
5-溴-N-羟基-3-甲基-2-[甲基-(4-丙-2-炔氧基-苯磺酰基)-氨基]-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-[甲基-(4-戊-2-炔氧基-苯磺酰基)-氨基]-苯甲酰胺;
5-溴-2-[(4-庚-2-炔氧基-苯磺酰基)-甲基-氨基]-N-羟基-3-甲基-苯甲酰胺;
5-溴-2-[(4-己-2-炔氧基-苯磺酰基)-甲基-氨基]-N-羟基-3-甲基-苯甲酰胺;
5-溴-N-羟基-2-{[4-(4-甲氧基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-{甲基-[4-(3-苯基-丙-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺;
5-溴-N-羟基-2-({4-[3-(3-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺;
5-溴-N-羟基-2-({4-[3-(2-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺;
5-溴-N-羟基-2-({4-[3-(4-甲氧基-苯基)-丙-2-炔氧基]-苯磺酰基}-甲基-氨基)-3-甲基-苯甲酰胺;
2-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-N-羟基-5-碘-3-甲基-苯甲酰胺;
2-[苄基-(4-丁-2-炔氧基-苯磺酰基)-氨基]-N-羟基-3,5-二甲基-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-{甲基-[4-(4-吡咯烷-1-基-丁-2-炔氧基)-苯磺酰基]-氨基}-苯甲酰胺;
5-溴-2-{[4-(4-二乙基氨基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-N-羟基-3-甲基-苯甲酰胺;
5-溴-2-[(4-丁-2-炔氧基-苯磺酰基)-(4-甲基-哌嗪-1-基甲基)-氨基]-N-羟基-3-甲基-苯甲酰胺;
5-溴-N-羟基-3-甲基-2-(甲基-{4-[4-(四氢-吡喃-2-基氧)丁-2-炔氧基]-苯磺酰基}-氨基}-苯甲酰胺;
5-溴-N-羟基-2-{[4-(4-羟基-丁-2-炔氧基)-苯磺酰基]-甲基-氨基}-3-甲基-苯甲酰胺;或
4-[(4-丁-2-炔氧基-苯磺酰基)-甲基-氨基]-5-(4-甲基-哌嗪-1-基甲基)-联苯-3-羧酸羟基酰胺二盐酸盐;或它们的药用盐。
11.一种呈下式的化合物:其中R6和R7各是氢、1-6个碳原子的烷基、-CN、-CCH;
和R8是1-6个碳原子的烷基;2-6个碳原子的链烯基;2-6个碳原子的炔基;3-6个碳原子的环烷基;苯基;萘基;5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S,或5-9元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S。
14.一种在需要抑制的哺乳动物中抑制TNF-α转化酶(TACE)介导的病理变化的方法,其特征在于,所述的方法包括给予所述的哺乳动物治疗有效剂量的下式的化合物或其药学上可接受的盐其中C(=O)NHOH部分和-NR5-部分连接于基团A的相邻的碳原子;
其中A是苯基;萘基或与5-7元饱和的或不饱和环烷基环稠合的苯基;5-9元饱和的或不饱和的杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S;或5-10元杂芳环,所述的杂芳环的1-3个杂原子选自N、NR9、O或S;
X是SO2或-P(O)R10;
Y是苯基;萘基;或5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;条件是X和Z不连接于Y的相邻原子;
Z是O、NH、CH2或S;
R5是氢或1-6个碳原子的烷基;
或R5-N-A可形成苯并氮、苯并氧氮杂、苯并硫氮杂、苯并二氮、苯并吖辛因、苯并二吖辛因、苯并噁吖辛因或苯并噻吖辛因环,可任选地稠合于另一个苯环;
R6和R7各是氢、1-6个碳原子的烷基、-CN、-CCH;
R8是氢;1-6个碳原子的烷基;2-6个碳原子的链烯基;2-6个碳原子的炔基;3-6个碳原子的环烷基;苯基;萘基;5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;或5-9元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S;
R9是氢、苯基、萘基、1-6个碳原子的烷基、或3-6个碳原子的环烷基;和
R10是苯基;萘基;1-6个碳原子的烷基;3-6个碳原子的环烷基;5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;或5-9元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S。
15.如权利要求14所述的方法,其特征在于,所述的治疗的病症是类风湿性关节炎、移植排斥、恶病质、炎症、发烧、胰岛素抗性、脓毒性休克、充血性心力衰竭、中枢神经系统炎性疾病、肠炎病或HIV感染。
其中A是苯基;萘基或与5-7元饱和的或不饱和环烷基环稠合的苯基;5-9元饱和的或不饱和的杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S;或5-10元杂芳环,所述的杂芳环的1-3个杂原子选自N、NR9、O或S;
X是SO2或-P(O)R10;
Y是苯基;萘基;或5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;条件是X和Z不连接于Y的相邻原子;
Z是O、NH、CH2或S;
R5是氢或1-6个碳原子的烷基;
或R5-N-A可形成苯并氮、苯并氧氮杂、苯并硫氮杂、苯并二氮、苯并吖辛因、苯并二吖辛因、苯并噁吖辛因或苯并噻吖辛因环,可任选地稠合于另一个苯环;
R6和R7各是氢、1-6个碳原子的烷基、-CN、-CCH;
R8是氢;1-6个碳原子的烷基;2-6个碳原子的链烯基;2-6个碳原子的炔基;3-6个碳原子的环烷基;苯基;萘基;5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;或5-9元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S;
R9是氢、苯基、萘基、1-6个碳原子的烷基、或3-6个碳原子的环烷基;和
R10是苯基;萘基;1-6个碳原子的烷基;3-6个碳原子的环烷基;5-10元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、O或S;或5-9元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、O或S;
和药学上可接受的载体。
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US09/239,070 | 1999-01-27 |
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JP (1) | JP2003524617A (zh) |
KR (1) | KR20010101733A (zh) |
CN (1) | CN1376144A (zh) |
AT (1) | ATE271540T1 (zh) |
AU (1) | AU769180B2 (zh) |
BR (1) | BR0007750A (zh) |
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AR022422A1 (es) * | 1999-01-27 | 2002-09-04 | American Cyanamid Co | Inhibidores de tace acetilenicos de acido hidroxamico de heteroarilfulfonamida y amida del acido fosfinico |
US6465508B1 (en) | 2000-02-25 | 2002-10-15 | Wyeth | Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors |
AR027943A1 (es) * | 2000-02-25 | 2003-04-16 | Wyeth Corp | Acidos orto-sulfonamido aril hidroxamicos como inhibidores de metaloproteinasa de matriz y preparacion de los mismos |
CA2357110A1 (en) * | 2001-04-11 | 2002-10-11 | American Cyanamid Company | Method for the treatment of polycystic kidney disease |
US7488754B2 (en) | 2002-04-05 | 2009-02-10 | Wyeth | Method for the treatment of polycystic kidney disease |
AU2003304456A1 (en) | 2002-12-23 | 2005-03-16 | Wyeth Holdings Corporation | Acetylenic aryl sulfonate hydroxamic acid tace and matrix metalloproteinase inhibitors |
FR2899895B1 (fr) * | 2006-04-12 | 2010-09-17 | Servier Lab | Nouveaux sels de strontium d'acides sulfoniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
CA3115038A1 (en) | 2018-10-04 | 2020-04-09 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Egfr inhibitors for treating keratodermas |
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BR9712525A (pt) * | 1996-10-16 | 1999-10-19 | American Cyanamid Co | O preparo e uso de ácidos orto-sulfonamido aril hidroxmicos como inibidores da metaloproteinase matricial e da tace |
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KR20010101733A (ko) | 2001-11-14 |
HUP0200729A2 (hu) | 2002-07-29 |
BR0007750A (pt) | 2001-10-30 |
PL357647A1 (en) | 2004-07-26 |
DK1144369T3 (da) | 2004-11-01 |
EA200100810A1 (ru) | 2002-02-28 |
AU3474400A (en) | 2000-08-18 |
HUP0200729A3 (en) | 2005-04-28 |
IL144322A0 (en) | 2002-05-23 |
DE60012302T2 (de) | 2005-08-04 |
EP1144369A2 (en) | 2001-10-17 |
ES2225108T3 (es) | 2005-03-16 |
WO2000044710A3 (en) | 2000-12-21 |
AU769180B2 (en) | 2004-01-15 |
JP2003524617A (ja) | 2003-08-19 |
PT1144369E (pt) | 2004-11-30 |
DE60012302D1 (en) | 2004-08-26 |
EP1144369B1 (en) | 2004-07-21 |
NO20013676D0 (no) | 2001-07-26 |
WO2000044710A2 (en) | 2000-08-03 |
CZ20012710A3 (cs) | 2002-04-17 |
ZA200104507B (en) | 2002-08-31 |
ATE271540T1 (de) | 2004-08-15 |
CA2356855A1 (en) | 2000-08-03 |
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