CN1333780A - 用作平滑肌细胞增殖抑制剂的苄基糖基酰胺 - Google Patents
用作平滑肌细胞增殖抑制剂的苄基糖基酰胺 Download PDFInfo
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- CN1333780A CN1333780A CN99815705A CN99815705A CN1333780A CN 1333780 A CN1333780 A CN 1333780A CN 99815705 A CN99815705 A CN 99815705A CN 99815705 A CN99815705 A CN 99815705A CN 1333780 A CN1333780 A CN 1333780A
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- carbon atom
- malt
- ethanoyl
- base
- benzamide
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明提供具有结构(a)的式(Ⅰ)的平滑肌细胞增殖抑制剂,其中Y是C或N;n是0-3;X是(b);或其药学上可接受的盐。
Description
本发明的背景
本发明涉及取代的苄基糖基酰胺作为平滑肌细胞增殖抑制剂的用途和作为治疗以过度平滑肌增生为特征的疾病和症状例如再狭窄的治疗组合物的用途。
所有血管重建方式例如血管成形术和静脉分流术的过程,都引起对损伤的反应,最终导致平滑肌细胞(SMC)增殖和随后的大量细胞外基质沉积(Clowes,A.W.;Reidy,M.A.J.Vasc.Surg 1991,13,885)。这些情况也是动脉粥样硬化(Raines E.W.;Ross R.Br.Heart J.1993,69(增刊),S.30)以及移植动脉硬化(Isik,F.F.;McDonald,T.O,;Ferguson,M.;Yamanaka,E.;Gordon Am.J.Pathol.1992,141,1139)发病机理的主要过程。关于血管成形术后的再狭窄,临床有关通过药物介入控制SMC增殖的解决方法至今仍存在难以理解的问题(Herrman,J.P.R.;Hermans,W.R.M.;Vos,J.;Serruys P.W.Drugs 1993,4,18和249)。任何成功的选择性SMC增殖抑制的方法必须不妨碍内皮细胞修复或正常的增殖和其它细胞的功能(Weissberg,P.L.;Grainger,D.J.;Shanahan C.M.;Metcalfe,J.C.Cardiovascular Res.1993,27,1191)。
糖胺聚糖肝素和硫酸乙酰肝素是SMC增殖的内源性抑制剂,此外还能够促进内皮细胞的生长(Castellot,J.J.Jr.;Wright,T.C.;Karnovsky,M.J.Seminars in Thrombosis and Hemostasis 1987,13,489)。然而,由于与许多制剂的异质性有关的其它药理的不利因素(特别是由于抗凝作用引起过量的出血),使肝素、肝素片段、化学改性的肝素、低分子量的肝素和其它拟肝素阴离子多糖完好的临床效果受到损害(Borman,S.Chemical and Engineering News,1993,6月28,27)。
WO96/14325公开了作为平滑肌细胞增殖抑制剂的酰化的苄基苷。本发明化合物的不同点在于:(a)糖具有端基酰胺,(b)糖主链上的取代基本质上不同,和(c)抑制平滑肌细胞增殖的活性更大。
Zehavi,U.在Carbohyd.Res.1986,151,371中公开了4-羧基-2-硝基苄基4-O-α-D-吡喃葡萄糖基-β-D-吡喃葡萄糖苷,该化合物连接在用于糖元合酶反应研究中作为受体的聚合物上。本发明的化合物与其不同点在于:(a)糖具有端基酰胺,(b)苄基上的取代基不同和(c)其作用(平滑肌抗增殖)不同。
专利号US5,498,775、WO96/14324和US5,464,827公开了聚阴离子苄基苷或环糊精作为平滑肌细胞增殖抑制剂,用于治疗以过度平滑肌增生为特征的疾病和症状。在(Reilly,C.F.;Fujita,T.;McFall,R.C.;Stabilito,I.I.;Wai-se E.;Johnson,R.G.Drug Development Research1993,29,137)中已公开了β-环糊精十四硫酸酯作为平滑肌细胞增殖抑制剂和作为再狭窄的有效抑制剂。US5019562公开了环糊精的阴离子衍生物,用于治疗与不需要的细胞或组织生长有关的病理症状。WO93/09790公开了每个糖残基带有至少2个阴离子残基的环糊精的抗增殖的聚阴离子衍生物。Meinetsberger(EP312087A2和EP312086A2)公开了硫酸化双-醛糖酸酰胺的抗血栓形成和抗凝血的特性。US4431637公开了聚硫酸化酚苷作为补体系统的调节剂。本发明的化合物与先有技术的不同点在于:该化合物(a)是与肝素、硫酸化环糊精或硫酸化乳糖酸二聚体结构上不相似的苄基糖基酰胺,(b)含有不超过两个连接的糖残余(二糖),(c)确定的结构和(d)没有被硫酸化。
本发明的说明
本发明提供式I的苄基糖基酰胺或其药学上可接受的盐其中Y是C或N;其中n是0-3;X是R1和R2各独立是氢、具有1-6个碳原子的烷基、卤代、乙酰基、苯基、CF3、CN、OH、NO2、NH2、具有1-6个碳原子的烷氧基或具有2-7个碳原子的氰基烷氧基;R3是氢、具有2-6个碳原子的酰胺或具有1-6个碳原子的烷氧基;R4、R5、R6、R7和R8各独立是氢、具有1-6个碳原子的酰基、由R1和R2取代的苄基;或由R1和R2取代的苯甲酰基;R9和R10各独立是具有1-6个碳原子的酰基、或在麦芽糖的4’和6’位上的R9和R10基团一起形成环状缩醛,该环状缩醛可以被下列基团取代:具有1-6个碳原子的烷基、每一个具有1-6个碳原子的两个烷基基团、由R1取代的吡啶基、由R1取代的苯基、由R1取代的苄基、由R1取代的2-苯基乙基或由R1取代的3-苯基丙基;以当R1或R2是具有2-7个碳原子的氰基烷氧基时,R3不是酰胺为条件和另外规定当R1、R2或R3是具有1-6个碳原子的烷氧基时,至少R1、R2、R3或R4之一不是氢。
烷基包括直链和支链部分。卤素是指溴、氯、氟和碘。当Y是氮时,优选的吡啶甲酰胺是吡啶3-甲酰胺。
药学上可接受的盐可由有机的和无机的酸形成,例如乙酸、丙酸、乳酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、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可接受的酸。盐也可由有机和无机碱形成,优选碱金属盐,例如钠、锂或钾盐。当Y是氮或式I的化合物含有碱性氮时,可制备酸加成盐,当式I的化合物含有羟基时,一般可制备碱加成盐。
本发明的化合物可含有不对称的碳原子和一些本发明的化合物可含有一个或多个不对称的中心,因此可产生光学异构体和非对映异构体。尽管式I中没有显示出立体化学,本发明包括这些光学异构体和非对映异构体;以及外消旋的和拆分的、对映异构体纯的R和S立体异构体;以及其它所述R和S立体异构体和其药学上可接受的盐的混合物。
本发明优选的式I化合物是具有以下特征的那些化合物,其中n是0-1;R1和R2各独立是氢、卤素、CF3、OH、NO2、NH2、甲氧基、丁氧基或丁氧基腈;R3是氢、乙酰胺或甲氧基;R4、R5、R6、R7和R8各独立是氢、具有1-6个碳原子的酰基或苯甲酰基;R9和R10各独立是具有1-6个碳原子的酰基、或在麦芽糖的4’和6’位上的R9和R10基团一起形成亚苄基环;或其药学上可接受的盐,所有的其它取代基如上所定义。
更优选的式I的化合物是具有以下特征的那些化合物,其中n是0;R1和R2各独立是氢或卤素;R3是氢;R4、R5、R6、R7和R8各独立是氢、具有1-6个碳原子的酰基或苯甲酰基;R9和R10各独立是具有1-6个碳原子的酰基、或在麦芽糖的4’和6’位上的R9和R10基团一起形成亚苄基环;或其药学上可接受的盐,所有的其它取代基如上所定义。
本发明特别优选的化合物是:N-(七-O-乙酰基-1-脱氧-β-D-麦芽糖-4-氯代-3-硝基-苯甲酰胺;3-氨基-4-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺;3-(乙酰氨基)-4-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺;(R)-3-(乙酰氨基)-4-氯代-N-[4-O-[4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-β-D-吡喃葡萄糖基]-苯甲酰胺;(R)-4-氯代-3-硝基-N-[4-O-[4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺;(R)-3-(乙酰氨基)-N-[6-O-苯甲酰基-4-O-[4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-4-氯代苯甲酰胺;(R)-N-[2-O-乙酰基-4-O-[2-O-乙酰基-4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-6-O-苯甲酰基-β-D-吡喃葡萄糖基]-3-(乙酰氨基)-4-氯代苯甲酰胺;(R)-4-氯代-N-[(6-O-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-3-硝基-苯甲酰胺;4-氯代-N-[(2,2’,3,3’-四-O-乙酰基-6-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-3-硝基-苯甲酰胺;N-(七-O-乙酰基-β-D-麦芽糖基)-4-氯代-苯甲酰胺;N-(4’,6’-亚苄基-β-D-麦芽糖基)-4-氯代-苯甲酰胺;N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-苯甲酰胺;N-[(2,2’,3,3’4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-3-氯代-4-次氮基丁氧基-苯甲酸酰胺;N-[(2,2’,3,3’4’,6,6’-七-O-乙酰基-α-D-麦芽糖基]-3-氯代-4-次氮基丁氧基-苯甲酸酰胺;N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-3-氯代-4-(次氮基-丁氧基)-苯甲酰胺;N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-3-氯代-4-(4-次氮基-丁氧基)-苯基酰胺;N-(2,2’,3,3’-四-O-乙酰基-6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-3-氯代-4-(4-次氮基-丁氧基)-苯甲酰胺;4-丁氧基-3-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]苯甲酰胺;4-丁氧基-3-氯代-N-[(6-O-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-苯甲酰胺;4-丁氧基-3-氯代-N-[(2,3,2’,3’-四-O-乙酰基-6-O-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-苯甲酰胺;4-氯代-3-甲氧基-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]苯甲酰胺;N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-3-甲氧基-苯甲酰胺;N-(2,2’,3,3’,4,6,6’-七-O-乙酰基-β-D-麦芽糖基)-4-丁氧基-5-氯代-3-甲氧基-苯甲酰胺;N-[(6-O-苯甲酸基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-4-丁氧基-3-氯代-5-甲氧基-苯甲酰胺;N-[(2,2’,3,3’4,’6,6’-七-O-乙酰基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺;N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺;N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺;N-(2,2’,3,3’-四-O-乙酰基-6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基]-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺;N-[(2,2’,3,3’4’,6,6’-七-O-乙酰基-β-D-麦芽糖基)-3-氨基-4-(4-次氮基-丁氧基)-苯甲酰胺;3-乙酰氨基-N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-苯甲酰胺;N-[(2,2’,3,3’4’,6,6’-七-O-乙酰基-β-D-麦芽糖基)-6-氯吡啶-3-甲酰胺;N-(七-O-乙酰基-β-D-麦芽糖基)-2,6-二甲氧基-吡啶-3-甲酰胺;N-(七-O-乙酰基-β-D-麦芽糖基)-5-溴吡啶-3-甲酰胺;N-(七-O-乙酰基-β-D-麦芽糖基)-3-(三氟代甲基)-苯甲酰胺;N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-3-(三氟代甲基)-苯甲酰胺;N-[{6-O-苯甲酰基-4’,6’-O-亚苄基}-β-D-麦芽糖基]-3-(三氟代甲基)-苯甲酰胺;N-(七-O-乙酰基-β-D-麦芽糖基)-6-甲基吡啶-3-甲酰胺;N-(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-麦芽糖基)-4-丁氧基-3,5-二氯代-苄基酰胺;N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-丁氧基-3,5-二氯代-苯甲酰胺;N-(七-O-乙酰基-D-麦芽糖基)-3-氯代-4-甲氧基-苯甲酰胺;N-(2,2’,3,3’4’,6,6’-七-O-乙酰基-β-D-麦芽糖基)-1-(3,4-二甲氧基)-苯基-乙酰胺;N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-2-(3,4-二甲氧基-苯基)-乙酰胺;N-(七-O-乙酰基-β-D-麦芽糖基)-2-(4-羟基-3-硝基-苯基)-乙酰胺;N-(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基)-2-(4-氯代-3-硝基-苯基)-乙酰胺;2-[3-乙酰基-氨基)-4-氯代-苯基]-N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-乙酰胺;或其药学上可接受的盐。
本发明的化合物由可购买得到的原料或用文献的方法可制备的原料开始,根据以下方案制备。该方案表示本发明的代表性化合物的制备方法。方案1在方案1中,Y、n、R1、R2、R3、R4、R5、R6、R7、R8、R9和R10如上所定义。
如此,在偶合剂例如EEDQ、DEC/HOBT或DCC/HOBT存在下,在合适的溶剂体系例如苯、乙醇、二氯甲烷、三乙胺中,在室温下,使麦芽糖基胺1与苯甲酸衍生物2偶合得到糖苷3。该糖苷也可通过下列方法制备:在三乙胺存在下,在合适的溶剂体系例如四氢呋喃、二氯甲烷、乙腈和乙酸乙酯中,通过将胺1偶合到取代的酰氯2上,得到糖苷3。当R3为硝基时,用还原剂例如氯化亚锡或铁金属,在极性非质子溶剂例如乙酸乙酯或极性质子溶剂例如乙醇或甲醇中,在室温至回流的温度下或通过在催化剂例如披钯碳存在下催化氢化作用,完成3的硝基的还原,得到苯胺基化合物4。在胺碱例如三乙胺或二异丙基乙胺存在下,在非质子溶剂例如二氯甲烷或四氢呋喃中,在从-20℃至室温的温度范围内,将4与酰氯或磺酰氯偶合,得到目标化合物5。
在室温至回流的温度下,通过用碱例如催化甲醇钠甲醇溶液或含水的氢氧化钠的甲醇溶液水解可除去3或5的乙酸基得到6。将乙酸基水解后,在酸性催化剂例如樟脑磺酸或甲苯磺酸存在下,在极性非质子溶剂例如乙腈或二甲基甲酰胺中,在室温至70℃的温度范围内,可使麦芽糖的4’和6’羟基基团与苯甲醛缩二甲醇反应,得到亚苄基衍生物。在可力丁/四氢呋喃混合物中,在-78℃至室温的温度范围内,可将6羟基基团选择性苯甲酰化得到7。在胺碱例如吡啶或三乙胺存在下,在从0℃到室温的温度范围内,用酸酐再酰化得到8。
本发明的化合物用作抗增殖剂。以下方法显示出以标准药理学试验方法对本发明代表性化合物的评定,所述试验测定所评定的化合物对抑制平滑肌细胞增殖的能力。用3H胸腺嘧啶脱氧核苷结合试验测定化合物对细胞增殖的效应
在分会合(sub-confluent)培养的条件下,在早期传代(一般传3-7代)下测试人和猪平滑肌细胞。使培养物在含补加10%胎牛血清和2%抗生素/抗真菌剂的培养基199的16mm(24孔)多孔培养皿中生长。在分会合时,将细胞放置在确定的无血清培养基(AIM-V;Gibco)中持续24-48小时,然后起动实验流程。
尽管发现延长预温育期可使化合物更有效,一般通过将化合物、3H胸腺嘧啶脱氧核苷和血清/生长因子加入到不含血清的同步细胞中起动所述过程并由此报告结果。
向每一孔中加入50倍稀释度的化合物(20μL/孔),并在37℃下在5%CO2中,将平板温育24-36小时。先将化合物溶解于50%乙醇中并系列稀释到培养基中。常规评定1-100μM浓度的化合物。作为对照,常规评定0.1-100μg/mL浓度的所有细胞制品中II级猪肠粘膜肝素(钠盐)。
在实验过程结束时,将平板放置在冰上,用冰冷的磷酸缓冲盐水(PBS)洗涤三次并在冰冷的10%三氯乙酸(TCA)中温育30分钟以除去酸可溶蛋白。将溶液转移到含有0.4N HCl(500μL/小瓶以中和NaOH)的闪烁瓶中且用水(500μL)、以总量2mL/小瓶将每孔漂洗两次。
得到一式三份数据,对照和实验样品均如此。从最大刺激的细胞中得到对照(100%)数据,作为生长因子或血清刺激的结果。从用生长因子或血清最大刺激的和用化合物处理的细胞中得到实验数据。下表I表示以IC50表达的数据。
表1
实施例化合物 | 猪平滑肌细胞抗增殖IC50 |
1 | 21.2μM |
2 | 11.13μM |
3 | 54.3μM |
4 | 3.2μM |
5 | 37%在50μM |
6 | 0.45μM |
7 | 0.55μM |
8 | 0.26μM |
9 | 1.253μM |
10 | 36.6μM |
11 | 15%在50μM |
12 | 49.2μM |
13 | 32.8 μM |
14 | 51.3μM |
15 | 30%在50μM |
16 | 0.27μM |
17 | 33%在50μM |
18 | 3.5μM |
19 | 35%在50μM |
20 | 3.14μM |
21 | 9.8μM |
22 | 18.5μM |
23 | 2%在50μM |
24 | 2.0μM |
25 | 2.7μM |
26 | 32%在50μM |
27 | 45%在50μM |
28 | 3%在50μM |
29 | 4%在50μM |
30 | 1.4μM |
31 | 15%在50μM |
32 | 10%在50μM |
33 | 0%在50μM |
34 | 0.98μM |
35 | 66.6μM |
36 | 13.6μM |
37 | 16.4μM |
38 | 5.8μM |
39 | 15%在50μM |
40 | 7.15μM |
表1(续)
41 | 65.77μM |
42 | 28.9μM |
43 | 44.5μM |
44 | 5.4μM |
45 | 16.6μM |
46 | 0%在50μM |
47 | 8.0μM |
48 | 37%在50μM |
49 | 12.6μM |
50 | 4.23μM |
51 | 0.916μM |
本发明的化合物用于治疗或抑制以过度平滑肌细胞增殖(平滑肌细胞增殖过多)为特征的疾病。该化合物尤其用于治疗以平滑肌细胞增殖过多为特征的增生过多的血管疾病,例如再狭窄,所述疾病多由血管重造术和移植术,例如气囊血管成形术、血管移植术、冠状动脉分流术和心脏移植术引起。其它疾病指有不希望的“细胞”血管增生的疾病,包括高血压、哮喘和充血性心力衰竭。本发明的化合物也用作血管生成抑制剂。血管生成(新血管形成),即通过其形成新的毛细血管的过程,对于一些包括慢性炎症和恶性肿瘤的病理过程是尤为重要的。因此本发明的化合物用作抗肿瘤药。
本发明的化合物可配制成纯的或与药用载体一起配制给药,其比例取决于化合物的溶解性和化学性质、所选择的给药途径和标准的药学实践。所述药用载体可以是固体或液体。
固体载体可包括一种或多种物质,它们可以用作调味剂、润滑剂、增溶剂、悬浮剂、填充剂、glidants、压缩助剂、粘合剂或片剂崩解剂;也可是包封材料。在散剂中,载体是细碎的固体,该固体与细碎的活性成分混合。在片剂中,活性成分与具有必需的可压缩性的载体以合适的比例混合,并压制成所需的形状和大小。散剂和片剂最好含高至99%的活性成分。合适的固体载体包括例如磷酸钙、硬脂酸镁、滑石、糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、低熔点的蜡和离子交换树脂。
液体的载体用于配制溶液、悬浮液、乳液、糖浆、酏剂和加压组合物。活性成分可溶解或悬浮于药学上可接受的液体载体例如水、有机溶剂、两者的混合物或药学上可接受的油或脂肪中。该液体载体可含有其它合适的药用添加剂例如增溶剂、乳化剂、缓冲剂、防腐剂、甜味剂、调味剂、悬浮剂、增稠剂、着色剂、粘度调节剂、稳定剂或渗透调节剂。用于口服和肠胃外给药的合适的液体载体实例包括水(部分含有如上所述的添加剂,例如纤维素衍生物,优选羧甲基纤维素钠溶液)、醇类(包括一元醇和多元醇,例如二元醇)和它们的衍生物、lethicins和油(例如分级椰子油和花生油)。对于肠胃外给药,载体也可以是油性酯例如油酸乙酯和十四酸异丙酯。无菌液体载体用于制备肠胃外给药的无菌液体形式组合物。对于加压组合物的液体载体可以是卤代烃或其它药学上可接受的抛射剂。
无菌溶液或悬浮液的液体药用组合物可用于例如肌内、腹膜内或皮下注射。无菌溶液也可以静脉给药。本发明的化合物也可以液体或固体组合物的形式口服给药。
本发明的化合物可以常规栓剂形式直肠或阴道内给药。对于鼻内或支气管吸入或吹入给药,本发明的化合物可配制成含水的或部分含水的溶液,该溶液可以喷雾剂的形式使用。本发明的化合物也可通过使用含有活性化合物和对活性化合物为惰性的载体的经皮贴片经皮给药,该载体对皮肤是无毒的并允许用于系统吸收的药物经皮肤传递进入血流。该载体可制备成若干剂型例如乳膏和软膏、糊剂、凝胶和包藏装置。乳膏和软膏可以是水包油或油包水型的粘性液体或半固体乳剂。由分散在含有活性成分的石油醚或亲水石油醚中的吸收性粉末组成的糊剂也是合适的。可使用各种包藏装置以释放活性成分进入血流中,例如覆盖含有活性成分、有或没有载体的贮器,或含有活性成分基体的半透膜。其它包藏装置在文献中为已知的。
给药的剂量需根据所使用的具体组合物、给药途径、症状的严重程度和所治疗的具体对象而变化。根据从标准药理试验方法中得到的结果,经肠胃外(优选静脉内)给药的预计活性化合物的日剂量应是0.1-10mg/kg,预计日口服剂量比该剂量高约十倍。在急性血管性损伤(即气囊血管成形术或移植术)后,预期的静脉内给药将持续约5-30天且对于治疗慢性疾病还要延长时间。一般以比化合物的最佳剂量低的小的剂量开始治疗。以后增加剂量直到在这种情况下达到最佳效果;用于口服、肠胃外、经鼻或支气管内给药的实际剂量,将由主治医生根据经验和所治疗的个体患者的情况决定。药用组合物优选为单位剂量形式,例如片剂或胶囊。在这些剂型中,该组合物可再分为含有适量活性成分的单位剂量,该单位剂量形式可以是包装的组合物,例如包装的散剂、管形瓶、安瓿、预先充满的注射器或含有液体的香囊。该单位剂量形式可以是例如胶囊或片剂本身或者是合适数量的任何这类组合物的包装形式。
以下提供本发明的代表性化合物的制备方法。
实施例1N-(七-O-乙酰基-1-脱氧-β-D-麦芽糖基)-4-氯代-3-硝基-苯甲酰胺步骤1七-O-乙酰基-1-β-麦芽糖基胺
通过用氧化铂还原经A.Bertho,Justus Liebigs Ann.Chem.,562,229(1949)的方法制备的叠氮化物,得到七-O-乙酰基-1-β-麦芽糖基胺。步骤2N-(七-O-乙酰基-1-脱氧-β-D-麦芽糖基)-4-氯代-3-硝基-苯甲酰胺
向搅拌的4-氯代-3-硝基苯甲酸(3.806g,0.0189mol)的苯-乙醇(1∶1,v/v,140ml)的溶液中加入一份2-乙氧基-N-羰基-1,2-二氢喹啉(5.057g,0.0205mol)。0.5小时后,加入七-O-乙酰基-1-β-麦芽糖基胺(10.0g,0.0157mol)并将该混合物在室温下搅拌过夜。蒸发溶剂并将残余物溶于二氯甲烷中。用1N盐酸、水、1%碳酸氢钠和水连续洗涤有机层,干燥(MgSO4)并浓缩。经快速层析(40%-60%EtOAc/石油醚梯度)纯化,得到10.785g(84%)的标题化合物,为白色固体,mp185℃;1HNMR(CDCl3)δ2.011(s,3H),2.029(s,3H),2.032(s,3H),2.062(s,3H),2.081(s,3H),2.101(s,3H),2.133(s,3H),3.86-3.96(m,2H),4.02-4.07(m,2H),4.21-4.28(m,2H),4.47(dd,J=12.3,2.2Hz,1H),4.83-4.89(m,2H),5.07(表观t,J=10.1Hz,1H),5.34-5.49(m,4H),7.04(d,J=9 Hz,1H),7.65(d,J=8.3Hz,1H),7.85(dd,J=8.6,2.2Hz,1H),8.27(d,J=2.2 Hz,1H)。IR(KBr)2950,1750,1250和1050cm-1,质谱(FAB),m/e 819(M+H),841(M+Na)。对于C33H39ClN2O20的计算值:C,48.39;H,4.80;N,3.42。实测值:C,48.33,H,4.83,N,3.30。
实施例23-氨基-4-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺
将溶于EtOAc(40ml)中的N-(七-O-乙酰基-1-脱氧-β-D麦芽糖基)-4-氯代-3-硝基-苯甲酰胺(1.355g,1.65mmol)的氯化锡(II)二水合物(1.87g,8.27mmol)的溶液回流2小时。将反应物冷却至室温,用饱和的NaHCO3水溶液小心地猝灭(直至碱性),用EtOAc(250ml)稀释,搅拌过夜并过滤。分离双相滤液并用EtOAc萃取含水层。干燥(MgSO4)合并的有机萃取液并浓缩。经快速层析(30%EtOAc/二氯甲烷)纯化,得到0.953g(76%)的3-氨基-4-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-3-硝基-苯甲酰胺,为白色固体,mp115-119℃;1H NMR(CDCl3)δ2.00(s,3H),2.01(s,3H),2.03(s,3H),2.05(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.85-3.89(m,1H),3.92-3.96(m,1H),3.99-4.07(m,2H),4.25(dt,J=12.5,4.2Hz,2H),4.45(dd,J=12.3,2.6Hz,1H),4.84-4.89(m,2H),5.07(t,J=10.1Hz,1H),5.39-5.47(m,4H),6.83(d,J=9.2Hz,1H),6.95(dd,J=8.35,2Hz,1H),7.22(d,J=2Hz,1H),7.29(d,J=8.13Hz,1H)。IR(KBr)3500,2950,1750,1240和1050cm-1,质谱(FAB),m/e 789/791(M+H),811/813(M+Na)。对于C33H41ClN2O18.0.5H2O的计算值:C,49.66;H,5.30;N,3.51。实测值:C,49.62,H,5.33,N,3.30。
实施例33-(乙酰氨基)-4-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺
在0℃下,向搅拌的3-氨基-4-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺(0.883g,1.17mmol)和三乙胺(0.326ml,2.34mmol)的THF(8ml)的溶液中滴加入乙酰氯(0.1ml,1.4mmol)并加热至室温。4小时后,用二氯甲烷(20ml)稀释该反应物,用饱和的NaHCO3水溶液(10ml)猝灭,用盐水(100ml)稀释并用二氯甲烷萃取。干燥(MgSO4)合并的有机萃取液并浓缩。经快速层析(30-50%EtOAc/二氯甲烷梯度)纯化,得到0.836g(86%)的标题化合物,为白色固体,mp122-124℃;1H NMR(CDCl3)δ2.00(s,3H),2.01(s,3H),2.03(s,3H),2.05(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.85-3.89(m,1H),3.92-3.96(m,1H),3.99-4.06(m,2H),4.25(dt,J=12.0,3.7Hz,2H),4.45(dd,J=12.5,2.2Hz,1H),4.86-4.93(m,2H),5.07(表观t,J=10.1Hz,1H),5.35-5.46(m,4H),7.06(d,J=8.8Hz,1H),7.45(d,J=8.3Hz,1H),7.52(dd,J=8.3,2.2Hz,1H),7.64(s,1H),8.71(s,1H)。IR(KBr)3400,2950,1750,1245和1050cm-1,质谱(FAB),m/e 831/833(M+H),853/855(M+Na)。对于C35H43ClN2O19.0.5H2O的计算值:C,50.04;H,5.28;N,3.33。实测值:C,49.87,H,5.25,N,3.13。
实施例4(R)-3-(乙酰氨基)-4-氯代-N-[4-O-[4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-β-D-吡喃葡萄糖基]-苯甲酰胺步骤13-(乙酰氨基)-4-氯代-N-[(4-O-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺
向3-(乙酰氨基)-4-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺(738mg,0.90mmol)的甲醇(5ml)溶液中加入0.075ml 0.34M的甲醇钠溶液。将该反应物搅拌过夜并用Dowex H+树脂猝灭。0.5小时后,将溶液过滤并在真空中浓缩,得到461mg(97%)的标题化合物,为白色固体,mp在165℃分解;1H NMR(DMSO-d6)δ2.10(s,3H),3.06(表观t,J=9.0Hz,1H),3.22-3.70(m,12H),4.96(表观t,J=8.8Hz,1H),5.04(d,J=4.0Hz,1H),7.60(d,J=8.3Hz,1H),7.72(dd,J=8.3Hz,2.2Hz,1H),8.17(d,J=2.0Hz,1H),8.98(d,J=8.8Hz,1H),9.67(s,1H)。IR(KBr)3375,2900,1660,1550和1050cm-1,质谱(FAB),m/e 537/539(M+H),559/561(M+Na)。对于C21H29ClN2O12.H2O的计算值:C,45.05;H,5.63;N,5.05。实测值:C,45.35,H,5.75,N,5.21。步骤2(R)-3-(乙酰氨基)-4-氯代-N-[4-O-[4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-β-D-吡喃葡萄糖基]-苯甲酰胺
将含有3-(乙酰氨基)-4-氯代-N-[4-O-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺(0.40g,0.7468mmol)、苯甲醛缩二甲醇(0.17ml,1.12mmol)和樟脑磺酸(10mg,0.043mmol)的溶液在70℃下加热。4小时后,将反应物冷却至室温并用0.5ml的1N的NaOH溶液猝灭。将该溶液浓缩并经快速层析(2,5-10%MeOH/二氯甲烷梯度)纯化,得到0.327g(70%)的标题化合物,为白色固体,mp175℃;1H NMR(DMSO-d6)δ2.1(s,3H),3.35-3.40(m,5H),3.49-3.62(m,3H),3.64-3.77(m,3H),4.12(dd,J=9.2,4.2Hz,1H),4.66(bs,1H),4.99(表观t,J=8.8Hz,1H),5.07(d,J=5.9Hz,1H),5.16(d,J=4.0Hz,1H),5.32(d,J=4.6Hz,1H),5.57(s,1H),5.59(d,J=2.2Hz,1H),5.70(d,J=6.2Hz,1H),7.35-7.40(m,3H),7.43-7.46(m,2H),7.60(d,J=8.3Hz,1H),7.73(dd,J=8.3,2.0Hz,1H),8.17(d,J=1.5Hz,1H),8.99(d,J=8.8Hz,1H),9.68(s,1H)。IR(KBr)3400,2900,1650和1075cm-1,质谱(+FAB),m/e 625/627(M+H),647/649(M+Na)。对于C28H33ClN2O12.0.5H2O的计算值:C,53.04;H,5.41;N,4.42。实测值:C,52.86,H,5.45,N,4.5。
实施例5(R)-4-氯代-3-硝基-N-[4-O-(4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-β-D-吡喃葡萄糖基]-苯甲酰胺步骤14-氯代-N-(4-O-α-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基)-3-硝基-苯甲酰胺水合物
根据实施例4的方法制备标题化合物,为白色固体,mp在150℃分解;1H NMR(CD3OD-d4)δ3.44-3.57(m,3H),3.59-3.74(m,6H),3.83-3.85(m,3H),5.13(d,J=9.2Hz,1H),5.18(d,J=3.7Hz,1H),7.79(d,J=8.3Hz,1H),8.12(dd,J=8.3Hz,2.2Hz,1H),8.47(d,J=2.2Hz,1H)。IR(KBr)3400,2900,1670,1550和1050cm-1,质谱(ESI),m/e 523(M-H)。对于C19H25ClN2O13.H2O的计算值:C,42.04;H,4.97;N,5.16。实测值:C,42.30,H,5.12,N,4.96。步骤2(R)-4-氯代-3-硝基-N-[4-O-(4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺
根据实施例4的方法制备标题化合物,为白色固体,mp235℃;1HNMR(DMSO-d6)δ3.35-3.42(m,5H),3.50-3.63(m,3H),3.65-3.75(m,3H),4.12(dd,J=9.2,4.4Hz,1H),4.64(表观t,J=5.5Hz,1H),4.99(表观t,J=9.0Hz,1H),5.16-5.19(m,J=5.9Hz,2H),5.32(d,J=5.3Hz,1H),5.57(s,1H),5.62(d,J=3.3Hz,1H),5.69(d,J=6.6Hz,1H),7.35-7.38(m,3H),7.43-7.46(m,2H),7.93(d,J=8.6Hz,1H),8.2(dd,J=8.6,2.0Hz,1H),8.58(d,J=2.0Hz,1H),9.29(d,J=8.8Hz,1H)。IR(KBr)3400,2900,1650,1550和1075cm-1,质谱(ESI),m/z 613.1/615.2(M+H),630.2/632.2(M+NH4)。对于C26H29ClN2O13.0.5H2O的计算值:C,50.21;H,4.86;N,4.50。实测值:C,50.48,H,4.67,N,4.38。
实施例6(R)-3-(乙酰氨基)-N-[6-O-苯甲酰基-4-O-[4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-β-D-吡喃葡萄糖基]-4-氯苯甲酰胺
将溶于干燥的四氢呋喃(1.5ml)和无水2,4,6-可力丁(1.5ml)中的(R)-3-(乙酰氨基)-4-氯代-N-[4-O-[4,6-O-(苯基-亚甲基)-α-D-吡喃葡萄糖基]-β-D-吡喃葡萄糖基]-苯甲酰胺(0.20g,0.32mmol)的溶液冷却至-40℃0.5小时。缓慢加入苯甲酰氯(0.047ml,0.384mmol)并将反应物加热至室温过夜。用乙酸乙酯(30ml)稀释反应物,用1N的HCl(15ml)、饱和的碳酸氢钠水溶液(15ml)和盐水(15ml)连续洗涤。干燥(MgSO4)有机层并过滤。蒸发并经快速层析(2,5-10%MeOH/二氯甲烷梯度),得到0.327g(70%)的标题化合物,为白色固体,mp225℃;1H NMR(DMSO-d6)δ2.09(s,3H),3.29-3.36(m,1H),3.39-3.41(m,1H),3.49-3.66(m,5H),3.71-3.76(m,1H),3.84(bs,1H),4.00(dd,J=9.7,4.8Hz,1H),4.34(dd,J=12.5,4.0Hz,1H),4.51(d,J=11.2Hz,1H),5.08(表观t,J=8.8Hz,1H),5.15(d,J=3.7Hz,1H),5.21(bs,1H),5.36(bs,1H),5.51(s,1H),5.67(s,1H),5.86(bs,1H),7.35-7.37(m,3H),7.40-7.43(m,2H),7.52(t,J=7.9Hz,1H),7.59(d,J=8.3Hz,1H),7.63-7.67(m,1H),7.73(dd,J=8.6,2.0Hz,1H),7.96(dd,J=8.6,1.1Hz,1H),8.17(d,J=1.8Hz,1H),9.05(d,J=8.8Hz,1H),9.66(s,1H)。IR(KBr)3400,2900,1660,1275和1075cm-1,质谱(+FAB),m/z 729/731(M+H),751/753(M+Na)。对于C33H37ClN2O13.1.0H2O的计算值:C,56.27;H,5.26;N,3.75。实测值:C,56.34,H,5.18,N,3.68。
实施例7(R)-4-氯代-N-[(6-O-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-3-硝基-苯甲酰胺
根据实施例6的方法制备标题化合物,为白色固体,mp174℃;1HNMR(DMSO-d6)δ3.34-3.66(m,7H),3.69-3.73(m,1H),3.87(bd,J=4.0Hz,1H),4.01(dd,J=10.1,4.6Hz,1H),4.34(dd,J=12.0,4.0Hz,1H),4.52(d,J=11.4Hz,1H),5.09(表观t,J=9.0Hz,1H),5.18(d,J=3.7Hz,1H),5.30(d,J=5.3Hz,1H),5.35(d,J=5.1Hz,1H),5.51(s,1H),5.69(s,1H),5.83(d,J=6.2Hz,1H),7.34-7.37(m,3H),7.40-7.43(m,2H),7.52(表观t,J=7.9Hz,1H),7.63-7.67(m,1H),7.90-7.96(m,3H),8.20(dd,J=8.6,2.0Hz,1H),8.58(d,J=2.0Hz,1H),9.34(d,J=8.8Hz,1H)。IR(KBr)3400,2900,1725,1550和1075cm-1,质谱(+FAB),m/z 717/719(M+H),739/741(M+Na)。对于C33H33ClN2O14.1.0H2O的计算值:C,53.92;H,4.80;N,3.81。实测值:C,54.09,H,4.77,N,3.64。
实施例84-氯代-N-[(2,2’,3,3’-四-O-乙酰基-6-苯甲酰基-4’6’-O-亚苄基)-β-D-麦芽糖基]-3-硝基苯甲酰胺
在0℃下,向搅拌的含有(R)-4-氯代-N-[(6-O-苯甲酰基-4’6’-O-亚苄基)-β-D-麦芽糖基]-3-硝基-苯甲酰胺(2.33g,3.2493mmol)、三乙胺(3.62ml,25.98mmol)和催化的4-二甲基氨基吡啶的无水二氯甲烷(60ml)的溶液中加入乙酐(2.15ml,22.75mmol)。6小时后,将反应物用二氯甲烷(100ml)稀释,用饱和的NaHCO3水溶液(2x)和盐水(2x)连续洗涤,干燥(MgSO4)并浓缩。经快速层析(40%-50%EtOAc/石油醚梯度)纯化,得到2.865g(99%)的标题化合物,为白色固体,mp230℃;1HNMR(CDCl3)δ2.04(s,3H),2.05(s,3H),2.09(s,3H),2.11(s,3H),3.54-3.63(m,2H),3.82-3.85(m,1H),3.97-4.04(m,2H),4.23(表观t,J=1H),4.51(dd,J=12.3,3.5Hz,1H),4.85-4.93(m,3H),5.41-5.56(m,5H),6.94(d,J=9.0Hz,1H),7.32-7.34(m,3H),7.36-7.40(m,2H),7.45(t,J=8.0Hz,1H),7.55-7.60(m,2H),7.62(d,J=8.6Hz,1H),7.83(dd,J=8.4,2.2Hz,1H),8.05(dd,J=7.7,0.7Hz,1H),8.23(d,J=2.0Hz,1H)。IR(KBr)3400,2930,1750,1550,1245和1075cm-1,质谱(+FAB),m/z885/887(M+H),907/909(M+Na)。对于C41H41ClN2O18的计算值:C,55.63;H,4.67;N,3.16。实测值:C,55.61,H,4.77,N,2.92。
实施例9(R)-N-[2-O-乙酰基-4-O-[2-O-乙酰基-4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-6-O-苯甲酰基-β-D-吡喃葡萄糖基]-3-(乙酰氨基)-4-氯苯甲酰胺
根据实施例8的方法制备标题化合物,为白色固体;1H NMR(DMSO-d6)δ1.94(s,3H),2.07(s,3H),2.08(s,3H),3.48(表观t,J=9.4Hz,1H),3.54(表观t,J=10.1Hz,1H),3.64-3.67(m,1H),3.77-3.87(m,4H),3.95-3.99(m,1H),4.36(dd,J=12.3,3.3Hz,1H),4.52-4.59(m,2H),4.85(表观t,J=9.2Hz,1H),5.33-5.39(m,2H),5.5-5.56(m,3H),7.33-7.40(m,5H),7.52-7.59(m,4H),7.65-7.69(m,1H),7.98-8.00(m,2H),8.09(s,1H),9.14(d,J=9.2Hz,1H),9.64(s,1H)。IR(KBr)3400,2900,1750,1660,1250和1075cm-1,质谱(+FAB),m/z 813/815(M+H),835/837(M+Na)。对于C39H41ClN2O15.2.5H2O的计算值:C,54.58;H,5.40;N,3.26。实测值:C,54.81,H,5.23,N,3.28。
实施10N-(七-O-乙酰基-β-D-麦芽糖基)-4-氯代-苯甲酰胺
向搅拌的溶于二氯甲烷(8ml)和四氢呋喃(4ml)中的七-O-乙酰基-1-β-麦芽糖基胺(0.90g,1.42mmol)和三乙胺(0.538g,3.54mmol)的混合物中加入一份4-氯代苯甲酰氯(0.322g,1.84mmol)。12小时后,用二氯甲烷(50ml)稀释该反应物并用水(20ml)、10%氢氧化钠(20ml)和0.1N盐酸(20ml)连续洗涤,干燥(MgSO4)并浓缩。经快速层析(20%-30%EtOAc/二氯甲烷梯度)纯化,得到0.70g(74%)标题化合物,为白色固体,mp113-115℃;1H NMR(CDCl3)δ2.01(s,6H),2.03(s,3H),2.06(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.86-4.13(m,4H),4.21-4.29(m,2H),4.45(dd,J=12.1,2.42Hz,2H),4.84-4.89(m,2H),5.07(表观t,J=9.9Hz,1H),5.35-5.49(m,4H),6.86(d,J=9.2,1H),7.42(d,J=8.6Hz,2H),7.68(d,J=8.4,2H)。IR(KBr)3400,2930,1750,1550,1245和1075cm-1,质谱(+ESI),m/z 774(M+H),791(M+NH4)。对于C33H40ClNO18的计算值:C,51.20;H,5.21;N,1.81。实测值:C,51.04,H,5.24,N,1.81。
实施例11N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-苯甲酰胺
根据实施例4的方法制备标题化合物,为白色固体,mp225-230℃分解;1H NMR(DMSO-d6)δ3.34-3.75(m,11H),4.12(dd,J=9.4,4.4Hz,1H),4.63(表观t,J=5.5Hz,1H),4.98(表观t,J=9.0Hz,1H),5.09(d,J=5.7Hz,1H),5.16(d,J=4.0Hz,1H),5.31(d,J=5.1Hz,1H),5.57(s,1H),5.59(d,J=3.1Hz,1H),5.69(d,J=6.6Hz,1H),7.36-7.38(m,3H),7.43-7.46(m,2H),7.55(d,J=8.6Hz,1H),7.93(d,J=8.6Hz,1H),8.98(d,J=8.8Hz,1H)。IR(KBr)3400,2900,2200,1650,1550和1050cm-1,质谱(+ESI),m/z 568(M+H)。对于C26H30ClNO11.0.5H2O的计算值:C,54.12;H,5.42;N,2.43。实测值:C,54.16,H,5.24,N,2.47。
实施例12N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-苯甲酰胺
根据实施例6的方法制备标题化合物,为白色固体,mp250℃;1HNMR(DMSO-d6)δ3.34-3.76(m,8H),3.82-3.85(m,1H),3.99-4.03(m,1H),4.34(dd,J=12.3,4.0Hz,1H),4.51(d,J=12.3Hz,1H),5.08(表观t,J=9.0Hz,1H),5.17(d,J=3.7Hz,1H),5.22(d,J=5.7Hz,1H),5.36(d,J=5.3Hz,1H),5.51(s,1H),5.67(d,J=2.4Hz,1H),5.85(d,J=6.2Hz,1H),7.34-7.43(m,5H),7.50-7.56(m,4H),7.63-7.67(m,1H),7.91-7.96(m,4H),9.05(d,J=8.8Hz,1H)。IR(KBr)3400,2900,1725,1600,1550和1075cm-1,质谱(+FAB),m/z 672(M+H),694(M+Na)。对于C33H34ClNO12的计算值:C,58.98;H,5.10;N,2.08。实测值:C,58.54,H,4.92,N,2.00。
实施例13和14N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-3-氯代-4-次氮基丁氧基-苯甲酸酰胺(13)N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-α-D-麦芽糖基]-3-氯代-4-次氮基丁氧基-苯甲酸酰胺(14)步骤13-氯代-4-(4-次氮基-丁氧基)-苯甲酸甲酯
将3-氯代-4-羟基苯甲酸甲酯(5.0g,26.8mmol)、4-溴代丁腈(4.0ml,40.19mmol)、碳酸钾(7.4g,53.6mmol)和甲基亚砜(40ml)的2-丁酮(100ml)中的混合物回流24小时。将反应混合物冷却并过滤。将该混合物在真空中浓缩,用乙醚稀释,用水洗涤两次并用饱和的氯化钠溶液再洗涤一次。干燥(MgSO4)有机层,过滤并浓缩,得到6.75g(99%)的浅棕色固体。经硅胶层析(10%-20%EtOAc/石油醚梯度)得到分析的样品,mp90℃;1H NMR(CDCl3)δ2.20-2.26(m,2H),2.68(t,J=7.0Hz,2H),3.90(s,3H),4.21(t,J=5.5Hz,2H),6.93(d,J=8.6Hz,1H),7.93(dd,J=8.6,2.0Hz,1H),8.06(d,J=2.0Hz,1H)。IR(KBr)3400,2280,1700,1600,1500,1245和1050cm-1,质谱(EI),m/z 253/255。对于C12H12ClNO3的计算值:C,56.82;H,4.77;N,5.52。实测值:C,56.69,H,4.69,N,5.47。步骤23-氯代-4-(4-次氮基-丁氧基)-苯甲酸
将3-氯代-4-(4-次氮基-丁氧基)-苯甲酸甲酯(6.24g,24.6mmol的THF(100ml)和甲醇(100ml)的溶液搅拌下用5N氢氧化钠溶液(35ml)在室温下处理1小时。将反应混合物在真空中浓缩,用水稀释并用5N盐酸酸化至pH为1。将得到的悬浮液用乙酸乙酯萃取。干燥(MgSO4)有机层,过滤并在真空中浓缩。用热的石油醚研磨得到灰白色固体,冷却并过滤,得到5.58g(95%)标题化合物,为白色固体mp150℃;1HNMR(CDCl3)δ2.22-2.28(m,2H),2.69(t,J=7.0Hz,2H),3.90(s,3H),4.23(t,J=5.5Hz,2H),6.97(d,J=8.6Hz,1H),8.01(dd,J=8.6,2.2Hz,1H),8.14(d,J=2.0Hz,1H)。IR(KBr)3400,2200,1700,1600,1450,1275和1050cm-1,质谱(EI),m/z 239/241。对于C11H10ClNO3的计算值:C,55.13;H,4.21;N,5.85。实测值:C,54.84,H,4.01,N,5.69。步骤3N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-3-氯代-4-次氮基丁氧基-苯甲酸酰胺
根据以下方法制备标题化合物。向七-O-乙酰基-1-β-麦芽糖基胺(1.255g,1.97mmol)和3-氯代-4-(4-次氮基-丁氧基)-苯甲酸(0.591g,2.47mmol)的混合物中加入三乙胺(0.40g,3.95mmol)、HOBT(0.480g,3.55mmol)和DEC(0.567g,2.96mmol)。在室温下搅拌过夜后,将反应物浓缩并分配在乙酸乙酯(80ml)和1N氢氧化钠(50ml)之间。分离含水层并用乙酸乙酯(3×30ml)萃取。用1N盐酸(50ml)、然后用水(50ml)洗涤有机层,干燥(MgSO4)并浓缩。经快速层析(20%-50%EtOAc/石油醚梯度)纯化,得到47%β端基异构体和7%α端基异构体,为白色固体,β端基异构体mp 02-103℃;1H NMR(CDCl3)δ2.011(s,3H),2.01(s,3H),2.03(s,3H),2.05(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),2.19-2.26(m,2H),2.67(t,J=7.0Hz,2H),3.85-4.06(m,4H),4.17-4.25(m,3H),4.45(dd,J=12.7,2.6Hz,1H),4.84-4.89(m,2H),5.07(表观t,J=10.1Hz,1H),5.35-5.48(m,4H),6.79(d,J=9.2Hz,1H),6.94(d,J=8.6Hz,1H),7.59(dd,J=8.6,2.4Hz,1H),7.82(d,J=2.2Hz,1H)。IR(KBr)3400,2950,2280,1750,1250和1050cm-1,质谱(+ESI),m/z 857.4/859.4(M+H),874.4/876.3(M+NH4),879.4/881.31(M+Na)。对于C37H45ClN2O19.1.0H2O的计算值:C,50.78;H,5.41;N,3.20。实测值:C,50.93,H,5.17,N,3.35。N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-α-D-麦芽糖基]-3-氯代-4-次氮基丁氧基-苯甲酸酰胺
α端基异构体mp105-106℃;1H NMR(CDCl3)δ1.98(s,3H),2.00(s,3H),2.03(s,3H),2.10(s,6H),2.14(s,3H),2.20-2.27(m,2H),2.67(t,J=7.0Hz,2H),3.94-3.98(m,2H),4.03-4.08(m,2H),4.21-4.40(m,4H),4.42(d,J=2.0Hz,1H),4.87(dd,J=10.5,4.0Hz,1H),5.07(表观t,J=10.1Hz,1H),5.18(dd,J=9.7,5.3Hz,1H),5.33-5.44(m,3H),5.95(表观bt,J=6.2Hz,1H),6.34(d,J=8.0Hz,1H),6.97(d,J=8.8Hz,1H),7.84(dd,J=8.8,1.8Hz,1H),7.97(d,J=1.1Hz,1H)。IR(KBr)3400,2950,2280,1750,1250和1050cm-1,质谱(+ESI),m/z 857.4/859.4(M+H),874.4/876.4(M+NH4),879.4/881.4(M+Na)。
实施例15N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-3-氯代-4-(4-次氮基-丁氧基)-苯甲酰胺步骤13-氯代-4-(3-氰基丙氧基)-N-(4-O-α-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基)-苯甲酰胺水合物
根据实施例4步骤1的方法制备标题化合物,为白色固体,mp203℃;1H NMR(CD3OD-d4)2.15-2.22(m,2H),2.70(t,J=7.2Hz,2H),3.26(t,J=9.4Hz,2H),3.43-3.53(m,3H),3.57-3.73(m,4H),3.78-3.84(m,3H),4.23(表观t,J=5.7Hz,1H),5.08-5.13(m,1H),5.18(d,J=3.7Hz,1H),7.17(d,J=8.8Hz,1H),7.86(dd,J=8.6,2.0 Hz,1H),7.98(d,J=2.2Hz,1H),8.91(d,J=9.0Hz,1H)。IR(KBr)3375,2900,2200,1600,1550和1050cm-1,质谱(+FAB),m/z 563/565(M+H),585/587(M+Na)。对于C23H31ClN2O12.1.0H2O的计算值:C,47.55;H,5.73;N,4.82。实测值:C,47.26,H,5.84,N,4.75。步骤2N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-3-氯代-4-(4-次氮基-丁氧基)-苯甲酰胺
根据实施例4步骤2的方法制备标题化合物,为白色固体,mp在190℃分解;1H NMR(DMSO-d6)2.05-2.12(m,2H),2.67(t,J=7.5Hz,2H),3.34-3.42(m,4H),3.48-3.62(m,4H),3.64-3.78(m,3H),4.14(dd,J=9.4,4.6Hz,1H),4.19(表观t,J=5.9Hz,1H),4.62(表观t,J=5.5Hz,1H),4.97(表观t,J=9.0Hz,1H),5.09(d,J=5.7Hz,1H),5.16(d,J=3.7Hz,1H),5.32(d,J=5.1Hz,1H),5.57(s,1H),5.59(d,J=2.9Hz,1H),5.70(d,J=6.6Hz,1H),7.26(d,J=8.8Hz,1H),7.34-7.40(m,3H),7.42-7.46(m,2H),7.90(dd,J=8.6,2.2Hz,1H),8.04(d,J=2.2Hz,1H),8.89(d,J=8.8Hz,1H)。IR(KBr)3400,2900,2200,1650,1550和1050cm-1,质谱(+ESI),m/z 651(M+H)。对于C30H35ClN2O12的计算值:C,55.34;H,5.42;N,4.30。实测值:C,55.00,H,5.30,N,4.10。N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-3-氯代-4-(4-次氮基-丁氧基)-苯基酰胺
根据实施例6的方法制备标题化合物,为白色固体,mp;1H NMR(DMSO-d6)2.04-2.11(m,2H),2.66(t,J=7.2Hz,2H),3.33-3.75(m,8H),4.14(bd,J=4.6Hz,1H),4.00(dd,J=9.9,4.4Hz,1H),4.18(表观t,J=6.0Hz,1H),4.34(dd,J=12.3,4.0Hz,1H),4.50(bd,J=11.2Hz,1H),5.06(表观t,J=9.0Hz,1H),5.17(d,J=3.7Hz,1H),5.22(d,J=5.7Hz,1H),5.36(d,J=5.3Hz,1H),5.51(s,1H),5.67(d,J=2.0Hz,1H),5.85(d,J=6.2Hz,1H),7.25(d,J=8.8Hz,1H),7.34-7.40(m,3H),7.41-7.43(m,2H),7.52(t,J=7.7Hz,1H),7.89(dd,J=8.6,2.2Hz,1H),7.94-7.96(m,2H),8.04(d,J=2.2Hz,1H),8.95(d,J=8.8Hz,1H)。IR(KBr)3400,2900,2200,1650,1550,1225和1050cm-1,质谱(+FAB),m/z 755(M+H),777(M+Na)。对于C37H39ClN2O13.0.5H2O的计算值:C,58.16;H,5.28;N,3.66。实测值:C,58.12,H,5.32,N,3.73。
实施例17N-(2,2’,3,3’-四-O-乙酰基-6-O-苯甲酰基-4’,6’-O-苄亚基-β-D-麦芽糖基)-3-氯代-4-(4-次氮基丁氧基)-苯甲酰胺
根据实施例8的方法制备标题化合物,为白色固体,mp230-232℃;1H NMR(CDCl3)2.02(s,3H),2.04(s,3H),2.07(s,3H),2.11(s,3H),2.20-2.24(m,2H),2.66(t,J=7.0Hz,2H),3.52-3.62(m,2H),3.81-3.87(m,1H),3.95-4.04(m,2H),4.17(表观t,J=5.5Hz,2H),4.22(表观t,J=9.5Hz,1H),4.51(dd,J=12.5,J=3.0Hz,1H),4.84-4.93(m,3H),5.40(s,1H),5.43-5.54(m,4H),7.73(d,J=9.2Hz,1H),6.91(d,J=8.8Hz,1H),7.31-7.39(m,5H),7.43-7.47(m,2H),7.55-7.60(m,2H),7.78(d,J=2.2 Hz,1H),8.04-8.07(m,2H)。IR(KBr)3400,2900,2200,1750,1650,1550,1250和1050cm-1,质谱(+FAB),m/z 923(M+H),945(M+Na)。
实施例184-丁氧基-3-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺步骤13-氯代-4-(4-次氮基-丁氧基)-苯甲酸甲酯
根据实施例13步骤1的方法制备标题化合物,得到95%清澄的油状物;1H NMR(CDCl3)δ1.0(t,J=7.2Hz,3),1.49-1.58(m,2H),1.81-1.88(m,2H),3.89(s,3H),4.09(t,J=6.6Hz,2H),6.92(d,J=8.8Hz,1H),7.91(dd,J=8.6,2.2Hz,1H),8.05(d,J=2.2Hz,1H)。IR(KBr)2950,1675,1600,1500,1225和1050cm-1,质谱(-ESI),m/z 227.3。对于C11H13ClO3的计算值:C,57.78;H,5.73。实测值:H,57.89,H,5.62。步骤23-氯代-4-(4-次氮基-丁氧基)-苯甲酸甲酯
根据实施例13步骤2的方法制备标题化合物,得到95%为白色的固体,mp144℃;1HNMR(CDCl3)δ1.0(t,J=7.5Hz,3),1.50-1.60(m,2H),1.83-1.90(m,2H),4.12(t,J=6.4Hz,2H),6.96(d,J=8.8Hz,1H),7.98(dd,J=8.6,2.2Hz,1H),8.12(d,J=2.2Hz,1H)。IR(KBr)2950,1700,1600,1500,1225和1050cm-1,质谱(+EI),m/z 242/244。对于C12H15ClO3的计算值:C,59.39;H,6.23。实测值:C,59.22,H,6.25。步骤34-丁氧基-3-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺
根据实施例10步骤3的方法制备标题化合物,得到92%白色的固体,mp℃;1H NMR(CDCl3)δ0.99(t,7.5Hz,3H),1.50-1.58(m,2H),1.80-1.87(m,2H),2.01(s,6H),2.03(s,3H),2.05(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.86-3.89(m,1H),3.92-3.96(m,1H),3.99-4.09(m,4H),4.45(dd,J=12.3,2.4Hz,1H),4.84-4.90(m,2H),5.07(表观t,J=9.7Hz,1H),5.35-5.48(m,4H),6.76(d,J=9.2Hz,1H),6.92(d,J=4.3Hz,1H),7.57(dd,J=8.6,2.2Hz,1H),7.80(d,J=2.4Hz,1H)。IR(KBr)3400,2950,1750,1250和1050cm-1,质谱(+ESI),m/z 846.1/848.1(M+H),863.1(M+NH4)。对于C37H48ClN2O19的计算值:C,52.52;H,5.72;N,1.65。实测值:C,52.31,H,5.64,N,1.61。
实施例194-丁氧基-3-氯代N-[(4’,6’-O-亚苄基)-β-D-麦芽糖基]-苯甲酰胺水合物步骤14-丁氧基-3-氯代-N-(β-D-麦芽糖基)-苯甲酰胺水合物
根据实施例4步骤1的方法制备标题化合物,为白色固体,mp在180℃分解;1H NMR(CD3OD-d4)δ0.94(t,7.2Hz,3H),1.41-1.50(m,2H),1.70-1.77(m,2H),3.03-3.09(m,1H),3.17(d,4.8Hz,1H),3.22-3.70(m,11H),4.12(表观t,J=6.4Hz,1H),4.46-4.51(m,2H),4.90(bd,J=4.2Hz,2H),4.95(t,J=9.0Hz,1H),5.05(bd,3.7Hz,1Hz),5.06(bs,1Hz),5.5(bs,1Hz),5.6(bs,1Hz),7.23(d,J=8.8Hz,1H),7.88(dd,J=8.6,2.2Hz,1H),8.02(d,J=2.2Hz,1H),8.86(d,4.4Hz,1Hz)。IR(KBr)3375,2900,1600,1550和1050cm-1,质谱(-ESI),m/z 550.1(M-H)。对于C23H34ClNO12.0.5H2O的计算值:C,49.25;H,6.29;N,2.50。实测值:C,49.28;H,6.27;N,2.49。步骤24-丁氧基-3-氯代-N-[(4’,6’-O-亚苄基)-β-D-麦芽糖基]-苯甲酰胺水合物
根据实施例4步骤2的方法制备标题化合物,为白色的固体,mp在215-220℃分解;1H NMR(DMSO-d6)0.94(t,7.2Hz,3H),1.41-1.51(m,2H),1.70-1.77(m,2H),3.28-3.42(m,4H),3.48-3.65(m,4H),3.67-3.78(m,4H),4.12(表观t,J=6.2Hz,3H),4.63(表观t,J=5.5Hz,1H),4.97(表观t,J=8.8Hz,1H),5.15(表观t,J=7.7Hz,1H),5.34(d,J=5.1Hz,1H),5.57(s,1H),5.62(d,J=2.9Hz,1H),5.73(d,J=6.6Hz,1H),7.23(d,J=9.0Hz,1H),7.34-7.40(m,3H),7.43-7.46(m,2H),7.88(dd,J=8.8,2.2Hz,1H),8.03(d,J=2.2Hz,1H),8.90(d,J=8.8Hz,1H)。IR(KBr)3400,2900,1650,1550和1050cm-1,质谱(+FAB),m/z 640/642(M+H),662/664(M+Na)。对于C30H38ClNO12.0.5H2O的计算值:C,55.52;H,6.06;N,2.16。实测值:C,55.72,H,6.01;N,2.07。
实施例204-丁氧基-3-氯代-N-[(6-O-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-苯甲酰胺
根据实施例6的方法制备标题化合物,为白色的固体,mp224℃;1H NMR(DMSO-d6)0.92(t,7.5Hz,3H),1.42-1.47(m,2H),1.69-1.74(m,2H),3.33-3.65(m,7H),3.69-3.73(m,1H),3.81-3.83(m,1H),4.0(dd,J=9.9,4.8Hz,1H),4.12(表观t,J=6.4Hz,2H),4.33(dd,J=12.3,3.7Hz,1H),4.50(d,J=11Hz,1H),5.06(表观t,J=9.0Hz,1H),5.17(d,J=4.0Hz,1H),5.21(d,J=5.7Hz,1H),5.36(d,J=5.1Hz,1H),5.51(s,1H),5.67(d,J=2.0Hz,1H),5.85(d,J=6.2Hz,1H),7.22(d,J=8.8Hz,1H),7.35-7.37(m,3H),7.40-7.43(m,2H),7.52(t,J=8.0Hz,1H),7.63-7.67(m,1H),7.88(dd,J=8.6,2.2Hz,1H),7.95(d,J=8.3Hz,1H),8.02(d,J=2.2Hz,1H),8.02(d,J=2.2Hz,1H),8.93(d,J=8.8Hz,1H)。IR(KBr)3400,2900,1650,1500,1225和1050cm-1,质谱(+FAB),m/z 744/746(M+H),766/768(M+Na)。对于C37H42ClNO13的计算值:C,59.72;H,5.69;N,1.88。实测值:C,59.61,H,5.84;N,1.87。
实施例214-丁氧基-3-氯代-N-[(2,3,2’,3’-四-O-乙酰基-6-O-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-苯甲酰胺
根据实施例8的方法制备标题化合物,为白色的固体,mp260-261℃;1H NMR(CDCl3)0.98(t,7.5Hz,3H),1.49-1.55(m,2H),1.79-1.84(m,2H),2.02(s,3H),2.04(s,3H),2.07(s,3H),2.11(s,3H),3.52-3.61(m,2H),3.82-3.85(m,1H),3.95-4.03(m,3H),4.06(表观t,J=6.4Hz,1H),4.22(表观t,J=6.4Hz,1H),4.51(dd,J=12.5,3.1Hz,1H),4.83-4.93(m,3H),5.40(s,1H),5.43-5.54(m,4H),6.70(d,J=9.2Hz,1H),6.90(d,J=8.8Hz,1H),7.31-7.43(m,3H),7.36-7.40(m,2H),7.43-7.47(m,2H),7.55-7.59(m,2H),7.76(d,J=2.2Hz,1H),8.05(d,J=1.3Hz,1H),8.07(d,J=1.3Hz,1H)。IR(KBr)3400,2900,1750,1500,1250和1050cm-1,质谱(+FAB),m/z 912/914(M+H),934/936(M+Na)。对于C43H50ClNO17的计算值:C,59.24;H,5.52;N,1.54。实测值:C,59.24,H,5.59;N,1.61。
实施例224-氯代-3-甲氧基-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]苯甲酰胺
根据实施例10的方法制备标题化合物,得到83%为白色的固体,mp106-110℃;1H NMR(DMSO-d6)δ1.86(s,6H),1.95(s,3H),1.98(s,3H),2.00(s,3H),2.01(s,3H),2.04(s,3H),3.87-4.02(m,3H),3.90(s,3H),4.11-4.17(m,3H),4.35(bd,J=9.9Hz,1H),4.87(dd,J=10.5,3.7Hz,1H),4.98(q,J=10.1Hz,2H),5.23(表观t,J=9.7Hz,1H),5.34(d,J=3.7Hz,1H),5.44(表观t,J=9.2Hz,1H),5.59(表观t,J=9.2Hz,1H),7.40(dd,J=8.4,1.8Hz,1H),7.50(d,J=1.8Hz,1H),7.54(d,J=8.4Hz,1H),9.21(d,J=4.6Hz,1H)。IR(KBr)3400,2950,1750,1250和1050cm-1,质谱(+ESI),m/z(M+H),(M+NH4)。对于C34H42ClNO19的计算值:C,50.78;H,5.26;N,1.74。实测值:C,50.2,H,5.06;N,1.59。
实施例23N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-3-甲氧基-苯甲酰胺步骤1N-(β-D-麦芽糖基)-4-氯代-3-甲氧基-苯甲酰胺
根据实施例4步骤1的方法制备标题化合物,得到白色的固体,mp165-168℃;1H NMR(CD3OD-d4)δ3.24-3.34(m,2H),3.44-3.89(m,10H),3.95(s,3H),5.12-5.29(m,2H),7.45(d,J=1.3Hz,2H),7.58(s,1H),8.98(d,J=9.0Hz,1H)。IR(KBr)3400,2950,1650,1250和1045cm-1,质谱(+FAB),m/z 510/512(M+H),532/534(M+NH4)。对于C20H28ClNO12.0.5H2O的计算值:C,46.29;H,5.63;N,2.70。实测值:C,46.43,H,5.81;N,2.67。步骤2N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-3-甲氧基-苯甲酰胺
根据实施例4步骤2的方法制备标题化合物,得到白色的固体;1HNMR(DMSO-d6)δ3.34-3.43(m,4H),3.49-3.75(m,6H),3.93(s,3H),4.08-4.14(m,2H),4.65(表观t,J=5.3Hz,1H),5.01(表观t,J=8.8Hz,1H),5.12(d,J=5.7Hz,1H),5.16(d,J=3.7Hz,1H),5.28(d,J=5.1Hz,1H),5.57(s,1H),5.61(d,J=3.1Hz,1H),5.71(d,J=6.6Hz,1H),7.35-7.40(m,3H),7.43-7.46(m,2H),7.49-7.55(m,2H),7.61(d,J=1.3Hz,1H),8.98(d,J=8.8Hz,1H)。IR(KBr)3400,2900,1650,1300和1075cm-1,质谱(+FAB),m/z 599(M+H),620/622(M+Na)。对于C27H32ClNO12的计算值C,54.23;H,5.39;N,2.34。实测值:C,54.27,H,5.50;N,2.25。
实施例24N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-3-甲氧基-苯甲酰胺
根据实施例6的方法制备标题化合物,得到白色的固体;mp245℃;1H NMR(DMSO-d6)δ3.34-3.74(m,8H),3.84-3.87(m,1H),3.91(s,3H),4.00(dd,J=9.9,4.8Hz,1H),4.35(dd,J=12.3,4.2Hz,1H),4.51(d,J=11.0Hz,1H),5.10(表观t,J=9.0Hz,1H),5.17(d,J=3.7Hz,1H),5.26(d,J=5.7Hz,1H),5.37(d,J=5.1Hz,1H),5.51(s,1H),5.69(d,J=2.4Hz,1H),5.86(d,J=6.4Hz,1H),7.35-7.37(m,3H),7.38-7.43(m,2H),7.49-7.54(m,4H),7.61-7.67(m,2H),7.95(dd,J=8.6,1.0Hz,1H),9.04(d,J=9.0Hz,1H)。IR(KBr)3400,2900,1650,1250和1055cm-1,质谱(+FAB),m/z 702(M+H),724(M+Na)。对于C34H36ClNO13.0.5H2O的计算值:C,57.43;H,5.24;N,1.97。实测值:C,57.34,H,5.27;N,1.96。
实施例25N-(2,2’,3,3’,4,6,6’-七-O-乙酰基-β-D-麦芽糖基)-4-丁氧基-5-氯代-3-甲氧基-苯甲酰胺
根据实施例10的方法制备标题化合物,得到88%为白色的固体,mp104-106℃;1H NMR(CDCl3)δ0.97(t,7.2Hz,3H),1.49-1.56(m,2H),1.73-1.80(m,2H),2.01(s,3H),2.02(s,3H),2.03(s,3H),2.05(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.85-3.96(m,2H),3.89(s,3H),3.99-4.08(m,4H),4.21-4.28(m,2H),4.46(dd,J=12.3,2.4Hz,1H),4.84-4.89(m,2H),5.07(表观t,J=10.7Hz,1H),5.35-5.48(m,4H),6.79(d,J=9.0Hz,1H),7.26(m,2H)。IR(KBr)3400,2950,1750,1250和1050cm-1,质谱(+FAB),m/z 876/878(M+H),898/900(M+Na)。对于C38H50ClNO20的计算值:C,52.09;H,5.75;N,1.60。实测值:C,52.26,H,5.76;N,1.51。
实施例264-丁氧基-3-氯代-N-[(4’,6’-O-亚苄基)-β-D-麦芽糖基]-5-甲氧基-苯甲酰胺水合物步骤14-丁氧基-3-氯代-N-(β-D-麦芽糖基)-5-甲氧基-苯甲酰胺水合物
根据实施例4步骤1的方法制备标题化合物,得到100%为白色的固体,mp在210分解;1H NMR (DMSO-d6)0.91(t,7.5Hz,3H),1.41-1.50(m,2H),1.70-1.77(m,2H),3.06(bt,1H),3.22-3.70(m,12H),3.87(s,3H),4.00(表观t,J=6.4Hz,3H),4.48-4.51(m,2H),6.40(bd,J=3.5Hz),4.96(表观t,J=8.8Hz,1H),5.04(d,J=3.7Hz,1H),5.11(bs,1H),5.5(bs,1Hz),5.56(bs,1Hz),7.51(d,J=2.0Hz,1H),7.62(d,J=2.0Hz,1H),8.93(d,J=9.0Hz,1H)。IR(KBr)3300,2900,1600,1550和1050cm-1,质谱(+FAB),m/z 582/584(M+H),604/606(M+Na)。对于C24H36ClNO13.0.5H2O的计算值:C,48.78;H,6.26;N,2.37。实测值:C,48.99,H,6.13;N,2.43。步骤24-丁氧基-3-氯代N-[(4’,6’-O-亚苄基)-β-D-麦芽糖基)-5-甲氧基-苯甲酰胺水合物
根据实施例4步骤2的方法制备标题化合物,得到白色的固体;mp226℃;1H NMR(DMSO-d6)0.92(t,7.2Hz,3H),1.43-1.49(m,2H),1.63-1.70(m,2H),3.34-3.75(m,5H),3.34-3.75(m,11H),3.88(s,3H),4.00(表观t,J=6.4Hz,3H),4.12(dd,J=9.5,4.4Hz,1H),4.63(bs,1H),4.98(表观t,J=9.0Hz,1H),5.11(d,J=5.3Hz,1H),5.16(d,J=4.0Hz,1H),5.32(d,J=4.6Hz,1H),5.57(s,1H),5.60(d,J=2.6Hz,1H),5.70(d,J=6.4Hz,1H),7.35-7.38(m,3H),7.43-7.46(m,2H),7.52(d,J=1.8Hz,1H),7.63(d,J=2.0Hz,1H),8.94(d,J=9.0Hz,1H)。IR(KBr)3400,2900,1650,1550和1050cm-1,质谱(+ESI),m/z 670/672(M+H)。对于C31H40ClNO13.1.0H2O的计算值:C,54.11;H,6.15;N,2.03。实测值:C,54.30,H,6.10;N,2.06。
实施例27N-[(6-O-苯甲酸基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-4-丁氧基-3-氯代-5-甲氧基-苯甲酰胺
根据实施例6的方法制备标题化合物,得到64%为白色的固体,mp217;1H NMR(DMSO-d6)0.91(t,7.5Hz,3H),1.42-1.47(m,2H),1.63-1.67(m,2H),3.34-3.73(m,8H),3.83-3.86(m,4H),3.97-4.02(m,3H),4.34(dd,J=12.0,3.3Hz,1H),4.51(d,J=11.9Hz,1H),5.07(表观t,J=8.8Hz,2H),5.17(d,J=3.5Hz,1H),5.25(d,J=5.7Hz,1H),5.36(d,J=5.3Hz,1H),5.51(s,1H),5.68(s,1H),5.85(d,J=6.4Hz,1H),7.35-7.36(m,3H),7.40-7.42(m,2H),7.50-7.54(m,3H),7.63-7.67(m,2H),7.95(d,J=8.1Hz,2H),8.99(d,J=8.8Hz,1H)。IR(KBr)3400,2900,1725,1650,1500,1225和1050cm-1,质谱(-FAB),m/z 772/774(M-H)。对于C38H44ClNO14.0.5H2O的计算值:C,58.27;H,5.79;N,1.79。实测值:C,58.24,H,5.92;N,1.78。
实施例28N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺步骤14-(4-次氮基-丁氧基)-3-硝基-苯甲酸4-次氮基-丁酯
根据实施例13步骤1的方法制备标题化合物,得到黄色固体(74%),mp60℃;1H NMR(CDCl3)δ2.13-2.26(m,4H),2.55(t,J=7.2Hz,2H),2.70(t,J=6.8Hz,2H),4.32(t,J=5.7Hz,2H),4.47(t,J=6.0Hz,2H),7.14(d,J=8.8Hz,1H),8.25(dd,J=8.8,2.2Hz,1H),8.53(d,J=2.2Hz,1H)。IR(KBr)3400,2280,1700,1625,1550,1275和1050cm-1,质谱(EI),m/z 317。对于C15H15N3O5的计算值:C,56.78;H,4.77;N,13.24。实测值:C,56.53,H,4.62;N,13.06。步骤24-(4-次氮基-丁氧基)-3-硝基-苯甲酸
根据实施例13步骤2的方法制备标题化合物,得到浅褐色的固体,mp162-163℃;1H NMR(CDCl3)δ2.04-2.11(m,2H),2.64(t,J=7.3Hz,2H),4.30(t,J=5.9Hz,2H),7.48(d,J=9.0Hz,1H),8.16(dd,J=8.8,2.2Hz,1H),8.35(d,J=2.2Hz,1H),13.31(bs,1H)。IR(KBr)3400,3000,2200,1700,1600,1550,1275和1050cm-1,质谱(EI),m/z 250。对于C11H10N2O5的计算值:C,52.80;H,4.03;N,11.20。实测值:C,52.45,H,3.88;N,11.03。步骤3N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺
根据实施例1步骤2的方法制备标题化合物,得到66%为白色的固体,mp110℃;1H NMR(CDCl3)δ2.01(s,3H),2.02(s,3H),2.03(s,3H),2.06(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),2.15-2.24(m,2H),2.69(t,J=7.0Hz,2H),3.89-4.13(m,4H),4.22-4.32(m,3H),4.47(dd,J=12.3,2.4Hz,1H),4.85-4.89(m,2H),5.07(表观t,J=10.1 Hz,1H),5.35-5.49(m,5H),6.96(d,J=9.2Hz,1H),7.14(d,J=8.8Hz,1H),7.94(dd,J=8.8,2.2Hz,1H),8.29(d,J=2.4Hz,1H)。IR(KBr)3400,2950,2200,1750,1250和1050cm-1,质谱(+FAB),m/z 868(M+H),890(M+Na)。对于C37H45N3O21的计算值:C,51.21;H,5.23;N,4.84。实测值:C,50.62,H,5.15;N,4.66。
实施例29N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺步骤1N-(β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺
根据实施例4步骤1的方法制备标题化合物,为白色的固体,mp144-145℃;1H NMR(DMSO-d6)2.03-2.09(m,2H),2.62(t,J=7.0Hz,2H),3.05(t,J=9.2Hz,2H),3.22-3.68(m,10H),4.28(t,J=5.7Hz,2H),4.95(表观t,J=8.8Hz,1H),5.04(d,J=3.7Hz,1H),7.46(d,J=9.0Hz,1H),8.17(dd,J=9.0,2.0Hz,1H),8.46(d,J=2.2Hz,1H),9.10(d,J=8.8Hz,1H)。IR(KBr)3400,2900,2200,1650,1545和1050cm-1,质谱(+FAB),m/z 574(M+H),596(M+Na)。对于C23H31N3O14.0.5H2O的计算值:C,47.42;H,5.54;N,7.21。实测值:C,47.41,H,5.61;N,7.05。步骤2N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺
根据实施例4步骤2的方法制备标题化合物,得到白色的固体(62%),mp165-170℃;1H NMR(CD3OD-d4)2.15-2.21(m,2H),2.69(t,7.0Hz,2H),3.44-3.62(m,5H),3.71-3.79(m,3H),3.82-3.92(m,3H),4.23(dd,J=10.1,4.8Hz,1H),4.33(表观t,J=5.7Hz,2H),5.13-5.18(m,1H),5.24(d,J=4.0Hz,1H),5.57(s,1H),7.32-7.35(m,3H),7.40(d,J=9.0Hz,1H),7.47-7.51(m,2H),8.17(dd,J=8.8,2.2Hz,1H),8.45(d,J=2.4Hz,1H),9.09(d,J=8.8Hz,1H)。IR(KBr)3400,2900,2250,1650,1525和1050cm-1,质谱(-FAB),m/z 660(M-H)。对于C30H35N3O14.0.5H2O的计算值:C,53.73;H,5.41;N,6.26。实测值:C,53.51,H,5.46;N,6.18。
实施例30N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺
根据实施例6的方法制备标题化合物,为白色的固体,mp174-176℃;1H NMR(DMSO-d6)2.03-2.10(m,2H),2.64(t,J=7.2Hz,2H),3.28-3.76(m,8H),3.85(bm,1H),4.00(dd,J=9.9,4.8Hz,1H),4.29(表观t,J=5.7Hz,1H),4.34(dd,J=12.3,3.7Hz,1H),4.51(d,J=11.4 Hz,1H),5.09(表观t,J=9.0Hz,1H),5.17(d,J=4.0Hz,1H),5.27(d,J=5.7Hz,1H),5.37(d,J=5.1Hz,1H),5.51(s,1H),5.69(d,J=2.0Hz,1H),5.85(d,J=6.2Hz,1H),7.34-7.37(m,3H),7.39-7.43(m,2H),7.47-7.54(m,3H),7.63-7.67(m,1H),7.95(d,J=7.0Hz,1H),8.20(dd,J=8.8,2.2 Hz,1H),8.49(d,J=2.2Hz,1H),9.15(d,J=8.8Hz,1H)。IR(KBr)3400,2900,2280,1650,1545,1225和1070cm-1,质谱(+FAB),m/z 788(M+Na)。对于C37H39ClN2O13.1.0H2O的计算值:C,56.70;H,5.27;N,5.36。实测值:C,56.71,H,5.06;N,5.34。
实施例31N-(2,2’,3,3’-四-O-乙酰基-6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺
根据实施例8的方法制备标题化合物,为白色的固体(90%),mp222-224℃;1H NMR(CDCl3)2.03(s,3H),2.03(s,3H),2.08(s,3H),2.10(s,3H),2.18-2.24(m,2H),2.68(t,J=6.8Hz,2H),3.53-3.62(m,2H),3.81-3.89(m,1H),3.96-4.04(m,2H),4.23(表观t,J=9.7Hz,1H),4.28(表观t,J=5.5Hz,1H),4.52(dd,J=12.5,3.1Hz,1H),4.85-4.93(m,3H),5.40(s,1H),5.44-5.55(m,4H),6.87(d,J=9.0Hz,1H),7.11(d,J=8.8 Hz,1H),7.31-7.34(m,3H),7.37-7.40(m,2H),7.43-7.47(m,2H),7.55-7.59(m,1H),7.93(dd,J=8.8,2.2Hz,1H),8.04-8.07(m,1H),8.24(d,J=2.4Hz,1H)。IR(KBr)3400,2900,2230,1750,1650,1545,1250和1070cm-1,质谱(+FAB),m/z 956(M+Na)。
实施例32N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-3-氨基-4-(4-次氮基-丁氧基)-苯甲酰胺
根据实施例2的方法制备标题化合物,为白色的固体(86%),mp185-187℃;1H NMR(CDCl3)δ2.00(s,3H),2.01(s,3H),2.03(s,3H),2.05(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),2.19-2.24(m,2H),2.59(t,J=7.0Hz,2H),3.84-4.07(m,4H),4.15-4.29(m,4H),4.44(dd,J=12.3,2.4Hz,1H),4.85-4.90(m,2H),5.07(t,J=10.1Hz,1H),5.35-5.47(m,4H),6.73-6.77(m,2H),7.05(dd,J=8.35,2.2Hz,1H),7.15(d,J=2.2Hz,1H)。IR(KBr)3300,2950,2250,1750,1500,1240和1050cm-1,质谱(+FAB),m/z 838(M+H),860(M+Na)。
实施例33N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-3-乙酰氨基-4-(4-次氮基-丁氧基)-苯甲酰胺
根据实施例3的方法制备标题化合物,为白色的固体(98%),mp213℃;1H NMR(CDCl3)δ2.01(s,6H),2.03(s,3H),2.04(s,3H),2.08(s,3H),2.11(s,3H),2.15(s,3H),2.21(s,3H),2.25-2.28(m,2H),2.58-2.62(m,2H),3.87-4.04(m,4H),4.21-4.27(m,4H),4.45(dd,J=12.1,2.2Hz,1H),4.86-4.94(m,2H),5.07(表观t,J=10.1Hz,1H),5.35-5.49(m,4H),6.88(d,J=8.8Hz,1H),7.00(d,J=8.8Hz,1H),7.60(dd,J=8.6,2.2Hz,1H),8.08(s,1H),8.76(d,J=2.0Hz,1H)。IR(KBr)3400,2950,2250,1750,1245和1050cm-1,质谱(+FAB),m/z 880(M+H),902(M+Na)。对于C39H49N3O20的计算值:C,53.24;H,5.61;N,4.78。实测值:C,52.83,H,5.49;N,4.67。
实施例343-乙酰氨基-N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-苯甲酰胺
根据实施例6的方法制备标题化合物,为白色的固体(92%),mp238℃;1H NMR(DMSO-d6)2.05-2.09(m,5H),2.75(t,J=7.0Hz,2H),3.33-3.40(m,1H),3.50-3.66(m,7H),3.70-3.85(bm,1H),4.0(dd,J=9.9,4.8Hz,1H),4.13(表观t,J=5.1Hz,1H),4.34(dd,J=12.3,3.7Hz,1H),4.50(d,J=11.0Hz,1H),5.08(表观t,J=8.8Hz,1H),5.13-5.16(m,2H),5.36(d,J=5.3Hz,1H),5.51(s,1H),5.65(d,J=1.8Hz,1H),5.85(d,J=6.2Hz,1H),7.08(d,J=8.6Hz,1H),7.35-7.37(m,3H),7.40-7.43(m,2H),7.50-7.54(m,2H),7.63-7.70(m,2H),7.94-7.96(m,2H),8.41(s,Hz,1H),8.80(d,J=9.0Hz,1H),8.99(s,1H)。IR(KBr)3400,2900,2280,1650,1545,1225和1070cm-1,质谱(+ESI),m/z 778(M+H),(-ESI),m/z776(M-H)。对于C39H43N3O14.1.5H2O的计算值:C,58.21;H,5.76;N,5.22。实测值:C,58.21,H,5.64;N,5.24。
实施例35N-(七-O-乙酰基-β-D-麦芽糖基)-6-氯吡啶-3-甲酰胺
根据实施例1步骤2的方法制备标题化合物,得到白色的固体,mp190℃;1H NMR(CDCl3)δ2.01(s,3H),2.02(s,3H),2.03(s,3H),2.05(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.86-3.96(m,2H),4.00-4.07(m,2H),4.21-4.29(m,2H),4.47(dd,J=12.3,2.4Hz,1H),4.84-4.89(m,2H),5.07(表观t,J=10.1Hz,1H),5.34-5.49(m,4H),6.99(d,J=8.8Hz,1H),7.42(dd,J=8.3,0.7Hz,1H),8.02(dd,J=8.3,2.6Hz,1H),8.73(dd,J=2.6,0.7Hz,1H)。IR(KBr)3400,2950,1750,1250和1050cm-1,质谱(+FAB),m/z 775(M+H),797(M+Na)。对于C32H39N2O18Cl.1.0H2O的计算值:C,48.46;H,5.21;N,3.53。实测值:C,48.60,H,4.95;N,3.45。
实施例36N-(七-O-乙酰基-β-D-麦芽糖基)-2,6-二甲氧基-吡啶-3-甲酰胺
根据实施例1步骤2的方法制备标题化合物,得到白色的固体,mp 125-130℃;1H NMR(CDCl3)δ1.98(s,3H),2.00(s,3H),2.03(s,6H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.86-3.99(m,2H),3.96(s,3H),4.01-4.06(m,2H),4.07(s,3H),4.22-4.30(m,2H),4.42(dd,J=12.3,2.6Hz,1H),4.87(dd,J=10.5,4.0Hz,1H),4.99(表观t,J=9.4Hz,1H),5.06(表观t,J=9.7Hz,1H),5.35-5.49(m,4H),6.45(d,J=8.3Hz,1H),8.35(d,J=8.4Hz,1H),8.37(d,J=8.8Hz,1H)。IR(KBr)3400,2950,1750,1400,1250和1050cm-1,质谱(+FAB),m/z 801(M+H),823(M+Na)。对于C34H44N2O20.0.5H2O的计算值:C,50.43;H,5.60;N,3.46。实测值:C,50.64,H,5.52;N,3.32。
实施例37N-(七-O-乙酰基-β-D-麦芽糖基)-5-溴吡啶-3-甲酰胺
根据实施例1步骤2的方法制备标题化合物,得到白色的固体,mp 167-170℃;1H NMR(CDCl3)δ2.01(s,3H),2.03(s,6H),2.06(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.86-4.00(m,2H),4.02-4.07(m,2H),4.22-4.28(m,2H),4.47(dd,J=12.3,2.4Hz,1H),4.85-4.90(m,2H),5.07(表观t,J=9.7Hz,1H),5.35-5.49(m,4H),7.03(d,J=9.0Hz,1H),8.25(t,J=2.2Hz,1H),8.83(s,1H)。IR(KBr)3300,2950,1750,1250和1050cm-1,质谱(+FAB),m/z 819/821(M+H),841/843(M+Na)。对于C32H39N2O18Br的计算值:C,46.90;H,4.80;N,3.42。实测值:C,46.77,H,4.82;N,3.14。
实施例38N-(七-O-乙酰基-β-D-麦芽糖基)-3-(三氟代甲基)-苯甲酰胺
根据实施例10的方法制备标题化合物,得到白色的固体,mp109-111℃;1H NMR(CDCl3)δ2.01(s,3H),2.02(s,3H),2.03(s,3H),2.06(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.88-3.96(m,2H),4.02-4.07(m,2H),4.21-4.29(m,2H),4.46(dd,J=12.3,2.4Hz,1H),4.86-4.91(m,2H),5.07(t,J=10.1Hz,1H),5.35-5.50(m,4H),6.96(d,J=9.0Hz,1H),7.59(t,J=7.7Hz,1H),7.80(d,J=7.7Hz,1H),7.88(d,J=7.9Hz,1H),8.05(s,1H)。IR(KBr)3400,2930,1750,1550,1245和1050cm-1,质谱(+FAB),m/z 808(M+H),830(M+Na)。对于C34H40F3NO18的计算值:C,50.56;H,4.99;N,1.73。实测值:C,49.97,H,4.87;N,1.68。
实施例39N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-3-(三氟代甲基)-苯甲酰胺步骤1N-(β-D-麦芽糖基)-3-(三氟代-甲基)-苯甲酰胺
根据实施例4步骤1的方法制备标题化合物,得到白色的固体,mp158-159℃;1H NMR(DMSO-d6)δ3.06(表观t,J=9.0Hz,2H),3.21-3.71(m,17H),4.97(d,J=3.7Hz,1H),5.01(d,J=8.8Hz,1H),7.63(t,J=7.7Hz,1H),7.79(d,J=7.7Hz,1H),8.19(d,J=7.9Hz,1H),8.26(s,1H)。IR(KBr)3400,2930,1675,1550,1350和1075cm-1,质谱(+FAB),m/z 514(M+H),536(M+Na)。对于C20H26F3NO11.2H2O的计算值:C,43.72;H,5.50;N,2.55。实测值:C,43.38,H,5.06;N,2.4。步骤2N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-3-(三氟代甲基)-苯甲酰胺
根据实施例4步骤2的方法制备标题化合物,得到白色的固体,mp在230℃分解;1H NMR(DMSO-d6)3.32-3.48(m,4H),3.50-3.60(m,4H),3.61-3.78(m,3H),4.67(bs,1H),5.02(t,J=9.0Hz,1H),5.15-5.17(m,2H),5.32(d,J=0.6Hz,1H),5.58(s,1H),5.61(d,J=2.2Hz,1H),5.71(d,J=6.4Hz,1H),7.32-7.40(m,3H),7.41-7.47(m,2H),7.74(t,J=7.9Hz,1H),7.92(d,J=7.7Hz,1H),8.21(d,J=7.7Hz,1H),8.28(s,1H),9.2(d,J=8.8Hz,1H)。IR(KBr)3400,2930,1700,1550,1255和1075cm-1,质谱(+FAB),m/z 602(M+H),624(M+Na)。对于C27H30F3NO11.0.5H2O的计算值:C,53.12;H,5.08;N,2.29。实测值:C,52.82,H,5.05;N,2.41。
实施例40N-[{6-O-苯甲酰基-4’,6’-O-亚苄基}-β-D-麦芽糖基]-3-(三氟代甲基)-苯甲酰胺
根据步骤6的方法制备标题化合物,得到白色的固体,mp在190℃分解;1H NMR(DMSO-d6)δ3.28-3.76(m,8H),3.86(bs,1H),4.01(dd,J=9.9,4.6Hz,1H),4.30(dd,J=12.3,4.0Hz,1H),4.51(d,J=11.4 Hz,1H),5.17(表现t,J=3.7Hz,1H),5.29(d,J=5.5Hz,1H),5.37(d,J=5.1Hz,1H),5.51(s,1H),5.69(d,J=2.0Hz,1H),5.87(d,J=5.9Hz,1H),7.33-7.40(m,3H),7.41-7.43(m,2H),7.52(t,J=7.7Hz,2H),7.65(t,J=7.5Hz,1H),7.72(t,J=7.9Hz,1H),7.92(d,J=7.1Hz,1H),7.95(d,J=7.3Hz,1H),8.24(d,J=2.2Hz,1H),8.27(s,1H),9.26(d,J=8.8Hz,1H)。IR(KBr)3400,2930,1735,1550,1300和1070cm-1,质谱(+FAB),m/z 706(M+H),728(M+Na)。对于C34H34F3NO12.0.5H2O的计算值:C,57.14;H,4.94;N,1.96。实测值:C,57.29,H,4.88;N,1.99。
实施例41N-(七-O-乙酰基-β-D-麦芽糖基)-6-甲基吡啶-3-甲酰胺
根据实施例1步骤2的方法制备标题化合物,得到白色的固体,mp115℃;1H NMR(CDCl3)δ2.01(s,6H),2.03(s,3H),2.05(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),2.63(s,3H),3.86-4.00(m,2H),4.02-4.11(m,2H),4.21-4.29(m,2H),4.46(dd,J=12.1,2.6Hz,1H),4.85-4.91(m,2H),5.07(表观t,J=10.1Hz,1H),5.34-5.48(m,4H),7.03(d,J=8.6Hz,1H),7.30(d,J=7.9Hz,1H),7.97(dd,J=8.1,2.4Hz,1H),8.86(d,J=2.0Hz,1H)。IR(KBr)3400,2950,1750,1250和1050cm-1,质谱(+FAB),m/z 755(M+H),777(M+Na)。对于C33H42N2O18.0.5的计算值:C,51.90;H,5.68;N,3.67。实测值:C,51.99,H,5.63;N,3.55。
实施例424-丁氧基-3,5-二氯代-N-β-D-麦芽糖基-苯甲酰胺
根据实施例4、步骤1的方法制备标题化合物,得到白色的固体,mp在210℃分解;1H NMR(DMSO-d6)δ0.94(t,J=7.3Hz,4H),1.47-1.52(m,2H),1.72-1.79(m,2H),3.02-3.07(m,1H),3.22-3.70(m,11H),4.04(t,J=6.4,2H),4.46-4.52(m,2H),4.88-4.95(m,3H),5.04(d,J=3.7Hz,1H),5.13(d,J=5.5Hz,1H),5.48(d,J=5.9Hz,1H),5.59(d,J=3.8Hz,1H),8.01(s,2H),9.06(d,J=8.8Hz,1H)。IR(KBr)3400,2930,1600,1 550和1075cm-1,质谱(+FAB),m/z 586/588/590(M+H),608/610/612(M+Na)。对于C23H33Cl2NO12的计算值:C,47.11;H,5.67;N,2.39。实测值:C,46.78,H,5.74;N,2.39。
实施例43N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-丁氧基-3,5-二氯代-苯甲酰胺
根据实施例4、步骤2的方法制备标题化合物,得到白色的固体,mp105-107℃;1H NMR(DMSO)δ0.94(t,J=7.5Hz,3H),1.47-1.53(m,2H),1.72-1.77(m,2H),3.34-3.41(m,4H),3.48-3.61(m,9H),3.64-3.74(m,3H),4.04(t,J=6.4Hz,2H),4.12(dd,J=9.2,4.2Hz,1H),4.95(t,J=8.8Hz,1H),5.16(d,J=3.7Hz,1H),5.57(s,1H),7.36-7.38(m,3H),7.43-7.46(m,2H),8.02(s,2H),9.09(d,J=8.8Hz,1H)。IR(KBr)3400,2930,1550,1450,1350,1255和1075cm-1,质谱(+FAB),m/z 696/698(M+Na)。对于C30H37Cl2NO12.1.5H2O的计算值:C,51.36;H,5.75;N,2.00。实测值:C,51.25,H,5.46;N,2.12。
实施例44N-(七-O-乙酰基-β-D-麦芽糖基)-3-氯代-4-甲氧基-苯甲酰胺
根据实施例10的方法制备标题化合物,得到白色的固体,mp106-110℃;1H NMR(CDCl3)δ2.01(s,6H),2.03(s,3H),2.05(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.86-4.07(m,4H),3.95(s,3H),4.21-4.29(m,2H),4.45(dd,J=12.3,2.4Hz,1H),4.85-4.90(m,2H),5.07(表观t,J=10.1Hz,1H),5.35-5.48(m,4H),6.78(d,J=9.2Hz,1H),6.86(d,J=8.6 Hz,1H),7.61(dd,J=8.6,2.2Hz,1H),7.81(d,J=2.2Hz,1H)。IR(KBr)3400,2950,1750,1250和1050cm-1,质谱(+ESI),m/z 804(M+H),821.1(M+NH4)。
实施例45N-(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基)-1-(3,4-二甲氧基)-苯基-乙酰胺
根据实施例10的方法制备标题化合物,得到白色的固体,mp95-97℃;1H NMR(CDCl3)δ1.83(s,3H),1.98(s,3H),1.99(s,6H),2.02(s,3H),2.04(s,3H),2.09(s,3H),2.12(s,3H),3.47(ABq,J=15.6,δ=0.03,2H),3.75-3.79(m,1H),3.87-3.94(m,7H),4.02(dd,J=12.3,2.4Hz,1H),4.20(t,J=3.5Hz,1H),4.23(t,J=3.7Hz,1H),4.41(dd,J=10.5,3.9Hz,1H),5.04(t,J=9.7Hz,1H),5.21(表观t,J=9.7Hz,1H),5.29-5.36(m,3H),6.06(d,J=9.2Hz,1H),6.71-6.75(m,2H),6.83(d,J=8.12Hz,1H)。IR(KBr)3400,2930,1750,1530,1245和1050cm-1,质谱(+FAB),m/z 814(M+H),836(M+Na)。
实施例46N-(4’,6’-亚苄基-β-D-麦芽糖基)-2-(3,4-二甲氧基-苯基)-乙酰胺步骤1N-(β-D-麦芽糖基)-2-(3,4-二甲氧基-苯基)乙酰胺
根据实施例4、步骤1的方法制备标题化合物,得到白色的固体,mp210-213℃;1H NMR(DMSO-d6)δ3.02-3.64(m,20H),4.72(t,J=9.0Hz,1基),5.01(d,J=3.7Hz,1基),6.75(dd,J=8.3,1.7Hz,1基),6.83-6.88(m,2基),8.57(d,J=9.2Hz,1H)。IR(KBr)3400,2930,1675,1530,1265和1050cm-1,质谱(-FAB),m/z 518(M-H)。对于C22H33NO13的计算值:C,50.87;H,6.40;N,2.70。实测值:C,50.59,H,6.44;N,2.60。步骤2N-(4’,6’-亚苄基-β-D-麦芽糖基)-2-(3,4-二甲氧基-苯基)-乙酰胺
根据实施例4、步骤2的方法制备标题化合物,得到白色的固体,mp在200-205℃分解;1H NMR(DMSO-d6)3.13-3.70(m,19H),4.10(dd,J=9.0,4.0Hz,1H),4.60(表观t,J=5.5Hz,1H),4.74(表观t,J=9.0 Hz,1H),5.01(d,J=6.2Hz,1H),5.14(d,J=3.7Hz,1H),5.31(d,J=5.3 Hz,1H),5.55(d,J=4.6Hz,2H),5.70(d,J=6.6Hz,1H),6.76(d,J=8.1,1.8Hz,1H),6.83-6.89(m,2H),7.34-7.36(m,3H),7.42-7.45(m,2H),8.58(d,J=9.2Hz,1H)。IR(KBr)3400,2930,1750,1550,1245和1075cm-1,质谱(-FAB),m/z 606(M-H)。
实施例47N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-2-(3,4-二甲氧基-苯基)-乙酰胺
根据实施例6的方法制备标题化合物,得到白色的固体,mp205-207℃;1H NMR(DMSO-d6)δ3.28-3.50(m,5H),3.52-3.68(m,5H),3.71-3.97(m,1H),3.67(s,3H),3.69(s,3H),3.99(dd,J=9.9,4.8Hz,1H),4.30(dd,J=12.3,4.20Hz,1H),4.46(d,J=11Hz,1H),4.85(表观t,J=9.0Hz,1H),5.14(d,J=4.6Hz,2H),5.34(d,J=5.1Hz,1H),5.50(s,1H),5.62(d,J=2.6Hz,1H),5.84(d,J=6.2Hz,1H),6.74(dd,J=8.3,2.0Hz,1H),6.80(d,J=8.1Hz,1H),6.86(d,J=2.0Hz,1H),7.33-7.50(m,5H),7.52(t,J=7.9Hz,1H),7.63-7.67(m,2H),7.95(dd,J=7.0,1.3Hz,2H),8.66(d,J=9.0Hz,1H)。IR(KBr)3400,2930,1750,1550,1245和1050cm-1,质谱(+ESI),m/z 712(M+H),734(M+Na)。对于C36H41NO14·1.5H2O的计算值:C,58.53;H,5.87;N,1.90。实测值:C,58.93,H,5.77;N,1.78。
实施例48N-(七-O-乙酰基-β-D-麦芽糖基)-2-(4-羟基-3-硝基-苯基)-乙酰胺
根据实施例13、步骤3的方法制备标题化合物,得到白色的固体,mp106℃;1H NMR(CDCl3)δ1.93(s,3H),2.00(s,3H),2.01(s,3H),2.02(s,3H),2.05(s,3H),2.09(s,3H),2.13(s,3H),3.51(ABq,J=15.8Hz,Δδ=0.30,2H),3.76-3.80(m,1H),3.89-3.96(m,2H),4.03(dd,J=12.5,2.2Hz,1H),4.22(dd,J=12.5,4.0Hz,1H),4.43(dd,J=12.3,2.2Hz,1H),4.67(表观t,J=9.7Hz,1H),5.05(表观t,J=10.1Hz,1H),5.20(表观t,J=9.2Hz,1H),5.32-5.38(m,3H),6.15(d,J=9.0Hz,1H),7.15(d,J=8.6Hz,1H),7.46(dd,J=8.6,2.0Hz,1H),7.95(d,J=2.0Hz,1H),10.5(d,J=0.4Hz,1H).IR(KBr)3400,2950,1750,1250和1050cm-1,质谱(+FAB),m/z815(M+H),837(M+Na)。
实施例49N-(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-麦芽糖基)-4-丁氧基-3,5-二氯代-苄基酰胺
根据实施例10的方法制备标题化合物,得到白色的固体,mp104-105℃;1H NMR(CDCl3)δ0.99(t,J=7.5Hz,3H),1.52-1.60(m,2H),1.81-1.87(m,2H),2.01(s,3H),2.03(s,6H),2.06(s,3H),2.08(s,3H),2.10(s,3H),2.13(s,3H),3.84-3.94(m,2H),3.95-4.08(m,5H),4.22-4.27(m,2H),4.46(dd,J=12.1,2.4Hz,1H),4.83-4.89(m,2H),5.07(表观t,J=9.4Hz,1H),5.34-5.47(m,3H),6.77(d,J=9.23Hz,1H),7.78(s,2H)。IR(KBr)3400,2930,1750,1550,1325,1245和1075cm-1,质谱(+FAB),m/z 880/882/884(M+H),902/904/906(M+Na)。对于C37H47Cl2NO19的计算值:C,50.46;H,5.38;N,1.59。实测值:C,50.01,H,5.39;N,1.58。
实施例50N-(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基)-2-(4-氯代-3-硝基-苯基)-乙酰胺
根据实施例13、步骤3的方法制备标题化合物,得到白色的固体,mp103℃;1H NMR(CDCl3)δ1.93(s,3H),2.00(s,3H),2.01(s,3H),2.02(s,3H),2.06(s,3H),2.09(s,3H),2.13(s,3H),3.51(q,J=15.2Hz,2H),3.76-3.80(m,1H),3.90-3.97(m,2H),4.04(dd,J=12.5,2.2Hz,1H),4.20-4.24(m,2H),4.44(dd,J=12.1,2.4Hz,1H),4.69(表观t,J=9.4Hz,1H),4.85(dd,J=10.5,4.2Hz,1H),5.05(表观t,J=10.1Hz,1H),5.20(表观t,J=9.2Hz,1H),5.32-5.38(m,3H),6.23(d,J=9.0Hz,1H),7.41(dd,J=8.3,2.2Hz,1H),7.53(d,J=8.1Hz,1H),7.75(d,J=2.0Hz,1H)。IR(KBr)3400,2950,1750,1245和1050cm-1,质谱(+FAB),m/z 833(M+H),855(M+Na)。对于C34H41ClN2O20的计算值:C,49.02;H,4.96;N,3.36。实测值:C,48.67,H,5.06;N,3.19。
实施例512-[(3-乙酰基-氨基)-4-氯代-苯基]-N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-乙酰胺
根据实施例6的方法制备标题化合物,得到白色的固体,1HNMR(DMSO-d6)δ2.05(s,3H),3.21-3.75(m,11H),3.99(dd,J=9.9,4.8Hz,1H),4.31(dd,J=12.3,4.0Hz,1H),4.45(d,J=10.8Hz,1H),4.84(表观t,J=9.0Hz,1H),5.13-5.15(m,2H),5.34(d,J=5.3Hz,1H),5.50(s,1H),5.63(d,J=2.6Hz,1H),5.83(d,J=6.2Hz,1H),7.06(dd,J=8.3,2.0Hz,1H),7.33-7.42(m,6H),7.49-7.56(m,3H),7.63-7.68(m,1H),7.95(dd,J=8.6,1.1Hz,2H),8.74(d,J=9.0Hz,1H),9.45(s,1H)。IR(KBr)3400,2930,1750,1550,1245和1075cm-1,质谱(+FAB),m/z765/767(M+Na)。
Claims (19)
1.一种具有以下结构的式I的化合物其中Y是C或N;其中n是0-3;X是R1和R2各独立是氢、具有1-6个碳原子的烷基、卤代、乙酰基、苯基、CF3、CN、OH、NO2、NH2、具有1-6个碳原子的烷氧基或具有2-7个碳原子的氰基烷氧基;R3是氢、具有2-6个碳原子的酰胺或具有1-6个碳原子的烷氧基;R4、R5、R6、R7和R8各独立是氢、具有1-6个碳原子的酰基、由R1和R2取代的苄基;或由R1和R2取代的苯甲酰基;R9和R10各独立是具有1-6个碳原子的酰基、或在麦芽糖4’和6’位上的R9和R10基团可一起形成环状缩醛,该环状缩醛可以被下列基团取代:具有1-6个碳原子的烷基、每一个具有1-6个碳原子的两个烷基基团、由R1取代的吡啶基、由R1取代的苯基、由R1取代的苄基、由R1取代的2-苯基乙基或由R1取代的3-苯基丙基;以当R1或R2是具有2-7个碳原子的氰基烷氧基时,R3不是酰胺为条件和另外规定当R1、R2或R3是具有1-6个碳原子的烷氧基时,至少R1、R2、R3或R4之一不是氢;或其药学上可接受的盐。
2.根据权利要求1的化合物,其中n是0-1;R1和R2各独立是氢、卤素、CF3、OH、NO2、NH2、甲氧基、丁氧基或丁氧基腈;R3是氢、乙酰胺或甲氧基;R4、R5、R6、R7和R8各独立是氢、具有1-6个碳原子的酰基或苯甲酰基;R9和R10各独立是具有1-6个碳原子的酰基、或在麦芽糖4’和6’位上的R9和R10基团一起形成亚苄基环;或其药学上可接受的盐。
3.权利要求2的化合物,其中n是0;R1和R2各独立是氢或卤素;R3是氢;或其药学上可接受的盐。
4.权利要求1的化合物,它是(R)-3-(乙酰氨基)-N-[6-O-苯甲酰基-4-O-[4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-β-D-吡喃葡萄糖基]-4-氯代苯甲酰胺或其药学上可接受的盐。
5.权利要求1的化合物,它是4-氯代-N-[(2,2’,3,3’-四-O-乙酰基-6-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-3-硝基-苯甲酰胺。
6.权利要求1的化合物,它是(R)-N-[2-O-乙酰基-4-O-[2-O-乙酰基-4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-6-O-苯甲酰基-β-D-吡喃葡萄糖基]-3-(乙酰氨基)-4-氯苯甲酰胺氯代苯甲酰胺或其药学上可接受的盐。
7.权利要求1的化合物,它是N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-3-氯代-4-(4-次氮基-丁氧基)-苯基酰胺氯代苯甲酰胺或其药学上可接受的盐。
8.权利要求1的化合物,它是N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-3-甲氧基-苯甲酰胺氯代苯甲酰胺或其药学上可接受的盐。
9.权利要求1的化合物,它是N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺氯代苯甲酰胺或其药学上可接受的盐。
10.权利要求1的化合物,它是3-乙酰氨基-N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-苯甲酰胺氯代苯甲酰胺或其药学上可接受的盐。
11.权利要求1的化合物,它是N-(七-O-乙酰基-β-D-麦芽糖基)-3-氯代-4-甲氧基-苯甲酰胺。
12.权利要求1的化合物,它是N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-2-(3,4-二甲氧基-苯基)-乙酰胺氯代苯甲酰胺或其药学上可接受的盐。
13.权利要求1的化合物,它是2-[3-乙酰基-氨基]-4-氯代-苯基]-N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-乙酰胺氯代苯甲酰胺或其药学上可接受的盐。
14.权利要求1的化合物,它是:a)N-(七-O-乙酰基-1-脱氧-β-D-麦芽糖基)-4-氯代-3-硝基-苯甲酰胺;b)3-氨基-4-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺;c)3-(乙酰氨基)-4-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]-苯甲酰胺;d)(R)-3-(乙酰氨基)4-氯代-N-[4-O-[4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-β-D-吡喃葡萄糖基]-苯甲酰胺或其药学上可接受的盐;e)(R)-4-氯代-3-硝基-N-[4-O-(4,6-O-(苯基亚甲基)-α-D-吡喃葡萄糖基]-β-D-吡喃葡萄糖基]-苯甲酰胺或其药学上可接受的盐;f)(R)-4-氯代-N-[(6-O-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-3-硝基-苯甲酰胺或其药学上可接受的盐;g)N-(七-O-乙酰基-β-D-麦芽糖基)-4-氯代-苯甲酰胺;h)N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-苯甲酰胺或其药学上可接受的盐;i)N-(6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-氯代-苯甲酰胺或其药学上可接受的盐;j)N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-3-氯代-4-次氮基丁氧基-苯甲酸酰胺;k)N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-α-D-麦芽糖基]-3-氯代-4-次氮基丁氧基-苯甲酸酰胺;l)N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-3-氯代-4-(4-次氮基-丁氧基)-苯甲酰胺或其药学上可接受的盐;m)N-(2,2’,3,3’-四-O-乙酰基-6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-3-氯代-4-(4-次氮基-丁氧基)-苯甲酰胺;n)4-丁氧基-3-氯代-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]苯甲酰胺;o)4-丁氧基-3-氯代-N-[(6-O-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-苯甲酰胺或其药学上可接受的盐;p)4-丁氧基-3-氯代-N-[(2,3,2’,3’-四-O-乙酰基-6-O-苯甲酰基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-苯甲酰胺;q)4-氯代-3-甲氧基-N-[2,3,6-三-O-乙酰基-4-O-(2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖基]苯甲酰胺;r)N-(2,2’,3,3’,4,6,6’-七-O-乙酰基-β-D-麦芽糖基)-4-丁氧基-5-氯代-3-甲氧基-苯甲酰胺;s)N-[(6-O-苯甲酸基-4’,6’-O-亚苄基)-β-D-麦芽糖基]-4-丁氧基-3-氯代-5-甲氧基-苯甲酰胺或其药学上可接受的盐;t)N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺;u)N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺或其药学上可接受的盐;v)N-(2,2’,3,3’-四-O-乙酰基-6-O-苯甲酰基-4’,6’-O-亚苄基-β-D-麦芽糖基)-4-(4-次氮基-丁氧基)-3-硝基-苯甲酰胺;w)N-[(2,2’,3,3’,4’,6,6’-七-β-乙酰基-β-D-麦芽糖基]-3-氨基-4-(4-次氮基-丁氧基)-苯甲酰胺;x)N-[(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基]-6-氯吡啶-3-甲酰胺或其药学上可接受的盐;y)N-(七-O-乙酰基-β-D-麦芽糖基)-2,6-二甲氧基-吡啶-3-甲酰胺或其药学上可接受的盐;z)N-(七-O-乙酰基-β-D-麦芽糖基)-5-溴吡啶-3-甲酰胺或其药学上可接受的盐;aa)N-(七-O-乙酰基-β-D-麦芽糖基)-3-(三氟代甲基)-苯甲酰胺;bb)N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-3-(三氟代甲基)-苯甲酰胺或其药学上可接受的盐;cc)N-[{6-O-苯甲酰基-4’,6’-O-亚苄基}-β-D-麦芽糖基]-3-(三氟代甲基)-苯甲酰胺或其药学上可接受的盐;dd)N-(七-O-乙酰基-β-D-麦芽糖基)-6-甲基吡啶-3-甲酰胺或其药学上可接受的盐;ee)N-(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-麦芽糖基)-4-丁氧基-3,5-二氯代-苄基酰胺;ff)N-(4’,6’-O-亚苄基-β-D-麦芽糖基)-4-丁氧基-3,5-二氯代-苯甲酰胺或其药学上可接受的盐;gg)N-(2,2’,3,3’,4’,6,6’-七-β乙酰基-3-D-麦芽糖基)-1-(3,4-二甲氧基)-苯基-乙酰胺;hh)N-(七-O-乙酰基-β-D-麦芽糖基)-2-(4-羟基-3-硝基-苯基)-乙酰胺或其药学上可接受的盐;或ii)N-(2,2’,3,3’,4’,6,6’-七-O-乙酰基-β-D-麦芽糖基)-2-(4-氯代-3-硝基-苯基)-乙酰胺。
15.一种治疗或抑制需要此治疗的哺乳动物的增生过多的血管疾病的方法,包括给予所述哺乳动物有效量的具有以下结构的式I的化合物或其药学上可接受的盐其中Y是C或N;其中n是0-3;X是R1和R2各独立是氢、具有1-6个碳原子的烷基、卤代、乙酰基、苯基、CF3、CN、OH、NO2、NH2、具有1-6个碳原子的烷氧基或具有2-7个碳原子的氰基烷氧基;R3是氢、具有2-6个碳原子的酰胺或具有1-6个碳原子的烷氧基;R4、R5、R6、R7和R8各独立是氢、具有1-6个碳原子的酰基、由R1和R2取代的苄基;或由R1和R2取代的苯甲酰基;R9和R10各独立是具有1-6个碳原子的酰基、或在麦芽糖4’和6’位上的R9和R10基团可一起形成环状缩醛,该环状缩醛可以被下列基团取代:具有1-6个碳原子的烷基、每一个具有1-6个碳原子的两个烷基基团、由R1取代的吡啶基、由R1取代的苯基、由R1取代的苄基、由R1取代的2-苯基乙基或由R1取代的3-苯基丙基;以当R1或R2是具有2-7个碳原子的氰基烷氧基时,R3不是酰胺为条件和另外规定当R1、R2或R3是具有1-6个碳原子的烷氧基时,至少R1、R2、R3或R4之一不是氢。
16.一种治疗或抑制需要此治疗的哺乳动物的再狭窄的方法,包括给予所述哺乳动物有效量的具有以下结构的式I的化合物或其药学上可接受的盐其中Y是C或N;其中n是0-3;X是R1和R2各独立是氢、具有1-6个碳原子的烷基、卤代、乙酰基、苯基、CF3、CN、OH、NO2、NH2、具有1-6个碳原子的烷氧基或具有2-7个碳原子的氰基烷氧基;R3是氢、具有2-6个碳原子的酰胺或具有1-6个碳原子的烷氧基;R4、R5、R6、R7和R8各独立是氢、具有1-6个碳原子的酰基、由R1和R2取代的苄基;或由R1和R2取代的苯甲酰基;R9和R10各独立是具有1-6个碳原子的酰基、或在麦芽糖4’和6’位上的R9和R10基团可一起形成环状缩醛,该环状缩醛可以被下列基团取代:具有1-6个碳原子的烷基、每一个具有1-6个碳原子的两个烷基基团、由R1取代的吡啶基、由R1取代的苯基、由R1取代的苄基、由R1取代的2-苯基乙基或由R1取代的3-苯基丙基;以当R1或R2是具有2-7个碳原子的氰基烷氧基时,R3不是酰胺为条件和另外规定当R1、R2或R3是具有1-6个碳原子的烷氧基时,至少R1、R2、R3或R4之一不是氢。
17.根据权利要求16的方法,其中所述再狭窄由血管成形术、血管再造术或者器官或组织移植引起。
18.一种抑制需要此治疗的哺乳动物的恶性肿瘤、肉瘤或肿瘤组织中血管生成的方法,包括给予所述哺乳动物有效量的具有以下结构的式I的化合物或其药学上可接受的盐其中Y是C或N;其中n是0-3;X是R1和R2各独立是氢、具有1-6个碳原子的烷基、卤代、乙酰基、苯基、CF3、CN、OH、NO2、NH2、具有1-6个碳原子的烷氧基或具有2-7个碳原子的氰基烷氧基;R3是氢、具有2-6个碳原子的酰胺或具有1-6个碳原子的烷氧基;R4、R5、R6、R7和R8各独立是氢、具有1-6个碳原子的酰基、由R1和R2取代的苄基;或由R1和R2取代的苯甲酰基;R9和R10各独立是具有1-6个碳原子的酰基、或在麦芽糖4’和6’位上的R9和R10基团可一起形成环状缩醛,该环状缩醛可以被下列基团取代:具有1-6个碳原子的烷基、每一个具有1-6个碳原子的两个烷基基团、由R1取代的吡啶基、由R1取代的苯基、由R1取代的苄基、由R1取代的2-苯基乙基或由R1取代的3-苯基丙基;以当R1或R2是具有2-7个碳原子的氰基烷氧基时,R3不是酰胺为条件和另外规定当R1、R2或R3是具有1-6个碳原子的烷氧基时,至少R1、R2、R3或R4之一不是氢。
19.一种药用组合物,包含具有以下结构的式I的化合物其中Y是C或N;其中n是0-3;X是R1和R2各独立是氢、具有1-6个碳原子的烷基、卤代、乙酰基、苯基、CF3、CN、OH、NO2、NH2、具有1-6个碳原子的烷氧基或具有2-7个碳原子的氰基烷氧基;R3是氢、具有2-6个碳原子的酰胺或具有1-6个碳原子的烷氧基;R4、R5、R6、R7和R8各独立是氢、具有1-6个碳原子的酰基、由R1和R2取代的苄基;或由R1和R2取代的苯甲酰基;R9和R10各独立是具有1-6个碳原子的酰基、或在麦芽糖的4’和6’位上的R9和R10基团一起形成环状缩醛,该环状缩醛可以被下列基团取代:具有1-6个碳原子的烷基、每一个具有1-6个碳原子的两个烷基基团、由R1取代的吡啶基、由R1取代的苯基、由R1取代的苄基、由R1取代的2-苯基乙基或由R1取代的3-苯基丙基;以当R1或R2是具有2-7个碳原子的氰基烷氧基时,R3不是酰胺为条件和另外规定当R1、R2或R3是具有1-6个碳原子的烷氧基时,至少R1、R2、R3或R4之一不是氢;或其药学上可接受的盐和药用载体。
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1999
- 1999-11-23 CA CA002350755A patent/CA2350755A1/en not_active Abandoned
- 1999-11-23 CN CN99815705A patent/CN1333780A/zh active Pending
- 1999-11-23 EP EP99961783A patent/EP1144426A2/en not_active Withdrawn
- 1999-11-23 AU AU18293/00A patent/AU1829300A/en not_active Abandoned
- 1999-11-23 JP JP2000583922A patent/JP2002530419A/ja active Pending
- 1999-11-23 BR BR9915606-7A patent/BR9915606A/pt not_active Application Discontinuation
- 1999-11-23 WO PCT/US1999/027823 patent/WO2000031094A2/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
BR9915606A (pt) | 2001-08-14 |
WO2000031094A3 (en) | 2000-12-21 |
WO2000031094A2 (en) | 2000-06-02 |
AU1829300A (en) | 2000-06-13 |
JP2002530419A (ja) | 2002-09-17 |
EP1144426A2 (en) | 2001-10-17 |
CA2350755A1 (en) | 2000-06-02 |
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