CN1284071A - 作为天冬氨酰蛋白酶抑制剂前药的磺胺衍生物 - Google Patents
作为天冬氨酰蛋白酶抑制剂前药的磺胺衍生物 Download PDFInfo
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- CN1284071A CN1284071A CN98813233A CN98813233A CN1284071A CN 1284071 A CN1284071 A CN 1284071A CN 98813233 A CN98813233 A CN 98813233A CN 98813233 A CN98813233 A CN 98813233A CN 1284071 A CN1284071 A CN 1284071A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
本发明涉及一类天冬氨酰蛋白酶抑制剂的磺胺类前药。在一具体实施方案中,本发明涉及一类新的HIV天冬氨酰蛋白酶抑制剂的前药,其特征是活性成分具有良好的水溶性,高口服生物利用率和易于体内产生。本发明还涉及含有这些前药的药物组合物。本发明的前药和药物组合物特别适合于减少药丸负荷和增加患者的顺应性。本发明还涉及用这些前药和药物组合物治疗哺乳动物的方法。
Description
发明领域
本发明涉及一类天冬氨酰蛋白酶抑制剂的磺胺类前药。在一具体实例中,本发明涉及一类新的HIV天冬氨酰蛋白酶抑制剂的前药,其特征是活性成分具有良好的水溶性,高口服生物利用率和易于体内产生。本发明还涉及含有这些前药的药物组合物。本发明前药和药物组合物特别适合于减少药丸负担和增加患者的顺应性。本发明还涉及用这些前药和药物组合物治疗哺乳动物的方法。
发明背景
天冬氨酰蛋白酶抑制剂被认为是目前抗HIV感染的最有效的药物。但是,为了获得抵御此酶的良好效力,这些抑制剂需要某些理化性能。所说性能之一是高疏水性。然而不幸的是,该性能会使水溶性变差和口服生物利用率降低。
美国专利5,585,397描述了一类作为天冬氨酰蛋白酶抑制剂的磺胺化合物。这些化合物表明了与含有疏水性天冬氨酰蛋白酶抑制剂的药物组合物相伴的缺点。例如,VX-478[4-氨基-N-((2-顺,3S)-2-羟基-4-苯基-2((S)-四氢呋喃-3-基-氧羰基氨基)-丁基-N-异丁基-苯磺酰胺]是一种公开于美国专利5,585,397的天冬氨酰蛋白酶抑制剂。它只有比较低的水溶性。尽管这种抑制剂在“溶液”制剂中的口服生物利用率极好,但这种形式的VX-478的剂量因存在于特定液体剂量形式中,例如,封装在软明胶胶囊中的液体的量而受到严格限制。较高的水溶性将使每单位剂量VX-478的药物负荷增加。
最近,VX-478的溶液制剂被制成每个胶囊含有最多150mgVX-478的胶囊剂。如果VX-478的治疗剂量为2400mg/天,则该制剂要求患者每天消耗16粒胶囊。如此高的药丸负担可能会导致患者的顺应性变坏,从而使药物不能达到最佳的治疗效果。高药丸负担还会遏制增加给患者每日服用的药量。药丸负担和相伴的患者顺应性问题的另一个缺点出现在感染HIV的孩子的治疗方面。
而且,这些“溶液”制剂如甲磺酸盐制剂是处于VX-478的饱和溶解状态。这使得药物具有在各种储存和/或装运条件下从溶液中结晶出来的潜在可能性。这反过来又可能导致由VX-478获得的一些口服生物利用率的丧失。
克服这些问题的途径之一是开发标准的固体剂型,如片剂或胶囊剂或悬浮液形式。但不幸的是,这样的固体剂型会使药物的口服生物利用率降低很多。
因此,这就需要改进每单位剂型天冬氨酰蛋白酶抑制剂的药物负荷。如此改进的剂型将减少药丸负担和增加患者顺应性。这样还提供了增加给患者的每日服用药量的可能性。
发明概述
本发明提供了一类新型磺胺类化合物前药,其是天冬氨酰蛋白酶、尤其是HIV天冬氨酰蛋白酶抑制剂。这些前药的特征在于有极好的水溶性,提高了的口服生物利用率,并在体内迅速代谢成活性抑制剂。本发明还提供了含有这些前药的药物组合物,以及用这些前药及其药物组合物治疗哺乳动物HIV感染的方法。
这些前药可以单独使用,也可以与其它治疗剂或预防剂,例如,抗病毒药,抗菌素,免疫调节剂或疫苗结合使用,用于治疗或预防病毒感染。
本发明一个主要目的是提供一类天冬氨酰蛋白酶抑制剂,尤其是HIV天冬氨酰蛋白酶抑制剂的新型磺胺类化合物前药。这类新型磺胺类可用式Ⅰ表示,其中,A选自H;Ht;-R1-Ht;-R1-(C1-C6)烷基,它可以任选被一个或多个下列取代基取代:羟基,C1-C4烷氧基,Ht,-O-Ht,-NR2-CO-N(R2)2或-CO-N(R2)2;-R1-(C2-C6)链烯基,它可以任选被一个或多个下列取代基取代:羟基,C1-C4烷氧基,Ht,-O-Ht,-N(R2)-C(O)-N(R2)2或-CO-N(R2)2;或R7;
各R1分别选自-C(O)-,-S(O)2-,-C(O)-C(O)-,-O-C(O)-,-O-S(O)2-,-NR2-S(O)2-,-NR2-C(O)-或-NR2-C(O)-C(O)-;各Ht分别选自C3-C7环烷基,C5-C7环烯基,C6-C10芳基;或一个5-7员饱和或不饱和杂环,其中含有一个或多个选自N,N(R2),O,S和S(O)n的杂原子;其中所说芳基或所说杂环任选与Q稠合;而且其中任何一个所说Ht都可以任选被一个或多个下列取代基取代:氧代,-OR2,-SR2,-R2,-N(R2)(R2),-R2-OH,-CN,-CO2R2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)-R2,-S(O)n-R2,-OCF3,-S(O)n-Q,亚甲基二氧基,-N(R2)-S(O)2-R2,卤素,-CF3,-NO2,Q,-OQ,-OR7,-SR7,-R7,-N(R2)(R7)或-N(R7)2;
各R2分别选自H,或任选被Q取代的C1-C4烷基;
B,如果存在,是-N(R2)-C(R3)2-C(O)-;
各x分别是0或1;
各R3分别选自H,Ht,C1-C6烷基,C2-C6链烯基,C3-C6环烷基,C5-C6环烯基;其中任何一个所说R3(H除外)可以任选被一个或多个下列取代基取代:-OR2,-C(O)-NH-R2,-S(O)n-N(R2)2,Ht,-CN,-SR2,-CO2R2,-N(R2)-C(O)-R2;
各n分别是1或2;
G,如果存在,选自H,R7或C1-C4烷基,或者,当G是C1-C4烷基时,G与R7彼此直接相连或通过一个C1-C3链接物连接形成一个杂环;或如果G不存在(即(G)x中的x是O时),则与G相连的氮原子直接与-OR7上的R7基团相连;D和D'分别选自Q;C1-C6烷基,它可以任选被一个或多个下列取代基取代:C3-C6环烷基,-OR2,-R3,-O-Q或Q;C2-C4链烯基,它可以任选被一个或多个下列取代基取代:C3-C6环烷基,-OR2,-R3,-O-Q或Q;C3-C6环烷基,它可以任选被Q取代或与Q稠合;C5-C6环烯基,它可以任选被Q取代或与Q稠合;
各Q分别选自一个3-7员饱和、部分饱和或不饱和碳环体系;或一个5-7员饱和、部分饱和或不饱和的含有一个或多个下列杂原子的杂环:O,N,S,-S(O)n或-N(R2);所说Q可以任选被一个或多个下列基团取代:氧代,-OR2,-R2,-N(R2)2,-NR2-C(O)-R2,-R2-OH,-CN,-CO2R2,-C(O)-N(R2)2,卤素或-CF3;E选自Ht;O-Ht;Ht-Ht;-O-R3;-N(R2)(R3);C1-C6烷基,它可以任选被一个或多个R4或Ht取代;C2-C6链烯基,它可以任选被一个或多个选自R4或Ht的基团取代;C3-C6饱和碳环,它可以任选被一个或多个选自R4或Ht的基团取代;或C5-C6不饱和碳环,它可以任选被一个或多个选自R4或Ht的基团取代;
各R4分别选自-OR2,-SR2,-C(O)-NHR2,-S(O)2-NHR2,卤素,-NR2-C(O)-R2,-N(R2)2或-CN;
各R7分别选自下列基团:其中各M分别选自H,Li,Na,K,Mg,Ca,Ba,-N(R2)4,C1-C12烷基,C2-C12链烯基,或-R6;其中,烷基或链烯基中的1-4个-CH2基团(连到Z的-CH2除外)任选被下列杂原子取代:O,S,S(O),S(O2)或N(R2);其中,所说烷基,链烯基或R6中的任何氢原子任选被下列取代基取代:氧代,-OR2,-R2,-N(R2)2,-N(R2)3,-R2OH,-CN,-CO2R2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)R2,-S(O)n-R2,-OCF3,-S(O)n-R6,-N(R2)-S(O)2(R2),卤素,-CF3或-NO2;M'是H,C1-C12烷基,C2-C12链烯基,或-R6;其中,烷基或链烯基中的1-4个-CH2基团任选被下列杂原子取代:O,S,S(O),S(O2)或N(R2);其中,所说烷基,链烯基或R6中的任何氢原子任选被下列取代基取代:氧代,-OR2,-R2,-N(R2)2,-N(R2)3,-R2OH,-CN,-CO2R2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)R2,-S(O)n-R2,-OCF3,-S(O)n-R6,-N(R2)-S(O)2(R2),卤素,-CF3或-NO2;Z是CH2,O,S,N(R2)2,或者,当M不存在时,Z是H;Y是P或S;X是O或S;及R9是C(R2)2,O或N(R2);而且当Y是S时,Z不是S;及
R6是一个5-6员饱和、部分饱和或不饱和碳环或杂环体系,或是一个8-10员饱和、部分饱和或不饱和的双环体系,其中所说任何一个杂环体系都含有一个或多个下列杂原子:O,N,S,-S(O)n或-N(R2);任何一个所说环系任意含有独立地选自下列基团的1-4个取代基:OH,C1-C4烷基,O-C1-C4烷基或OC(O)C1-C4烷基。
本发明还一个目的是提供含有式Ⅰ磺胺前药的药物组合物和将它们用作HIV天冬氨酰蛋白酶抑制剂的前药的方法。发明详述
为了使读者更充分地理解本文所述的发明,我们给出了下面详细论述。在说明书中用到以下缩写:
缩写 试剂或片段
Ac 乙酰基
Me 甲基
Et 乙基
Bzl 苄基
Trityl 三苯甲基
Asn D-或L-天冬酰胺Ile D-或L-异亮氨酸Phe D-或L-苯丙氨酸Val D-或L-缬氨酸Boc 叔丁氧羰基Cbz 苄氧羰基Fmoc 9-芴基甲氧羰基DCC 二环己基碳化二亚胺DIC 二异丙基碳化二亚胺EDC 1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐HOBt 1-羟基苯并三唑HOSu 1-羟基琥珀酰亚胺TFA 三氟乙酸DIEA 二异丙基乙胺DBU 1,8-二氮杂双环[5.4.0]十一-7-烯EtOAc 乙酸乙酯
文中用到以下术语:
除非有相反意义的表述,本文所用术语“-SO2-”和“-S(O)2-”指砜或砜衍生物(即两个附加基团都连到S),而且不指亚磺酸酯。
对于式Ⅰ化合物及其中间体,如果OR7被画成是伸展的锯齿形状(如式Ⅺ,ⅩⅤ,ⅩⅫ,ⅩⅫⅠ和ⅩⅩⅪ化合物所画的那样),则该分子的立体化学结构被定义为与相邻的碳原子上的D有关。如果OR7和D位于化合物延伸的主链所定义的平面的相同一侧,则OR7的立体化学结构将被称作“顺(syn)”。相反,如果OR7和D位于该平面相对的两侧,则OR7的立体化学结构将被称作“反(anti)”。
无论是单独使用还是与其它术语结合使用,术语“芳基”均指含有指定数量碳原子的碳环芳香基。
术语“杂环”指稳定的5-7员单环或8-11员双环杂环,它们可以是饱和的或不饱和的;如果是单环,它可以任选被苯并稠合。每个杂环含有一定数量的碳原子和1-4个选自氮、氧和硫的杂原子。本文中用到的术语“氮和硫杂原子”还包括氮和硫的任何氧化形式,以及任何碱性氮的季铵化形式。所说杂环还可以与任何能够建立稳定结构的环上的杂原子相连。定义如上的优选杂环包括,例如,苯并咪唑基,咪唑基,咪唑啉酮基,咪唑烷基,喹啉基,异喹啉基,吲哚基,吡啶基,吡咯基,吡咯啉基,吡唑基,吡嗪基,喹喔啉基,哌啶基,吗啉基,硫吗啉基,呋喃基,噻吩基,三唑基,噻唑基,β-咔啉基,四唑基,噻唑烷基,苯并呋喃基,硫吗啉基砜,苯并噁唑基,氧代哌啶基,氧代吡咯烷基,氧代氮杂_基,氮杂_基,异噁唑基,四氢吡喃基,四氢呋喃基,噻二唑基,苯并二氧戊环基,苯硫基,四氢苯硫基和环丁砜基。
术语“HIV蛋白酶”和“HIV天冬氨酰蛋白酶”可以交换使用,均指由人体免疫缺陷病毒1型或2型编码的天冬氨酰蛋白酶。在本发明优选实例中,这些术语特指人体免疫缺陷病毒1型天冬氨酰蛋白酶。
术语“药物有效量”指治疗患者HIV感染有效的量。术语“预防有效量”指预防患者HIV感染有效的量。术语“患者”指哺乳动物,也包括人类。
术语“可药用载体或辅剂”指可与本发明化合物一起施用于患者的无毒的载体或辅剂,它不破坏化合物本身的药物活性。
本发明化合物的可药用盐包括从可药用无机或有机酸和碱衍生的那些盐。合适的酸包括盐酸,氢溴酸,硫酸,硝酸,高氯酸,富马酸,马来酸,磷酸,乙醇酸,乳酸,水扬酸,琥珀酸,甲苯-对-磺酸,酒石酸,乙酸,柠檬酸,甲磺酸,甲酸,苯甲酸,丙二酸,萘-2-磺酸和苯磺酸。其它酸,如草酸,虽然其本身不是可药用的,但其可以用作获得本发明化合物及其可药用酸加成盐的中间体用来制备盐。
从适当碱衍生的盐包括碱金属盐(如钠盐),碱土金属盐(如镁盐),铵盐和N-(C1-4烷基)4+盐。
术语“硫代氨基甲酸酯”指含有官能团N-SO2-O的化合物。
本发明化合物可以具有一个或多个不对称碳原子,因此存在外消旋体和外消旋混合物,单一对映体,非对映体混合物和各单独的非对映体。这些化合物的所有这些异构体形式都属于本发明范围。每个立体中心(stereogenic)碳都可以是R或S构型。明确显示的羟基优选为顺式D型,在式Ⅰ化合物中以氮原子之间的延伸的锯齿形态表示。
本发明涉及的取代基与变量的结合只是形成稳定化合物的那些。本文所用术语“稳定的”指具有用现有技术中已知方法足以进行制造和给哺乳动物服用的稳定性的化合物。一般这种化合物在40℃或以下温度,在不潮湿或没有其它化学反应的条件下可以稳定至少一星期。
本发明化合物可以无机或有机酸衍生的盐的形式使用。这些酸加成盐包括,例如,乙酸盐,乙二酸盐,藻酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,柠檬酸盐,樟脑氨酸盐,樟脑磺酸盐,环戊烷丙酸盐,葡萄糖酸氢盐,十二烷基硫酸盐,乙磺酸盐,富马酸盐,葡萄庚糖酸盐,甘油磷酸盐,半硫酸盐,庚酸盐,己酸盐,盐酸盐,氢溴酸盐,氢碘酸盐,2-羟基乙磺酸盐,乳酸盐,苹果酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,草酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,新戊酸盐,丙酸盐,琥珀酸盐,酒石酸盐,硫氰酸盐,甲苯磺酸盐和十一烷酸盐。
本发明还涉及本文所述化合物的任何含碱性氮基团的季铵化。这些碱性氮可以用本领域普通技术人员已知的任何反应剂季铵化,所说反应剂包括,例如,低级烷基卤化物,如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二烷基硫酸酯,如二甲基、二乙基、二丁基和二戊基硫酸酯;长链卤化物,如癸基、月桂基、肉豆蔻基和硬脂酰基氯化物、溴化物和碘化物;及芳烷基卤化物,如苄基和苯乙基溴化物。可以通过这种季铵化反应得到水或油溶性或可分散性产物。
本发明新磺胺类化合物是式Ⅰ化合物,其中,A选自H;Ht;-R1-Ht;-R1-C1-C6烷基,它可以任选被一个或多个下列取代基取代:羟基,C1-C4烷氧基,Ht,-O-Ht,-NR2-CO-N(R2)2或-CO-N(R2)2;-R1-C2-C6链烯基,它可以任选被一个或多个下列取代基取代:羟基,C1-C4烷氧基,Ht,-O-Ht,-NR2-CO-N(R2)2或-CO-N(R2)2;或R7;
各R1分别选自-C(O)-,-S(O)2-,-C(O)-C(O)-,-O-C(O)-,-O-S(O)2-,-NR2-S(O)2-,-NR2-C(O)-或-NR2-C(O)-C(O)-;各Ht分别选自C3-C7环烷基,C5-C7环烯基,C6-C10芳基;或一个5-7员饱和或不饱和杂环,其中含有一个或多个选自N,N(R2),O,S和S(O)n的杂原子;其中所说芳基或所说杂环任选与Q稠合;而且其中任何一个所说Ht都可以任选被一个或多个下列取代基取代:氧代,-OR2,-SR2,-R2,-N(R2)(R2),-R2-OH,-CN,-CO2R2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)-R2,-S(O)n-R2,-OCF3,-S(O)n-Q,亚甲基二氧基,-N(R2)-S(O)2(R2),卤素,-CF3,-NO2,Q,-OQ,-OR7,-SR7,-R7,-N(R2)(R7)或-N(R7)2;各R2分别选自H,或任选被Q取代的C1-C4烷基;
B,如果存在,是-N(R2)-C(R3)2-C(O)-;
各x分别是0或1;
各R3分别选自H,Ht,C1-C6烷基,C2-C6链烯基,C3-C6环烷基,C5-C6环烯基;其中任何一个所说R3(H除外)可以任选被一个或多个下列取代基取代:-OR2,-C(O)-NH-R2,-S(O)n-N(R2)(R2),Ht,-CN,-SR2,-CO2R2,-NR2-C(O)-R2;
各n分别是1或2;
G,如果存在,选自H,R7或C1-C4烷基,或者,当G是C1-C4烷基时,G与R7彼此直接相连或通过一个C1-C3链接物连接形成一个杂环;或如果G不存在(即(G)x中的x是0时),则与G相连的氮原子直接与-OR7上的R7相连,并伴随着R7中的一个-ZM基团被置换;D和D'分别选自Q;C1-C6烷基,它可以任选被一个或多个下列取代基取代:C3-C6环烷基,-OR2,-R3,-O-Q或Q;C2-C4链烯基,它可以任选被一个或多个下列取代基取代:C3-C6环烷基,-OR2,-R3,-O-Q或Q;C3-C6环烷基,它可以任选被Q取代或与Q稠合;C5-C6环烯基,它可以任选被Q取代或与Q稠合;
各Q分别选自一个3-7员饱和、部分饱和或不饱和碳环体系;或一个5-7员饱和、部分饱和或不饱和的含有一个或多个下列杂原子的杂环:O,N,S,-S(O)n或-N(R2);其中,Q可以任选被一个或多个下列基团取代:氧代,-OR2,-R2,-N(R2)2,-NR2-C(O)-R2,-R2-OH,-CN,-CO2R2,-C(O)-N(R2)2,卤素或-CF3;E选自Ht;O-Ht;Ht-Ht;-O-R3;-N(R2)(R3);C1-C6烷基,它可以任选被一个或多个R4或Ht取代;C2-C6链烯基,它可以任选被一个或多个选自R4或Ht的基团取代;C3-C6饱和碳环,它可以任选被一个或多个选自R4或Ht的基团取代;或C5-C6不饱和碳环,它可以任选被一个或多个选自R4或Ht的基团取代;
各R4分别选自-OR2,-SR2,-C(O)-NHR2,-S(O)2-NHR2,卤素,-NR2-C(O)-R2,-N(R2)2或-CN;
各R7分别选自下列基团:其中各M分别选自H,Li,Na,K,Mg,Ca,Ba,-N(R2)4,C1-C12烷基,C2-C12链烯基,或-R6;其中,烷基或链烯基中的1-4个-CH2基团(连到Z的-CH2除外)任选被下列杂原子取代:O,S,S(O),S(O2)或N(R2);其中,所说烷基,链烯基或R6中的任何氢原子任选被下列取代基取代:氧代,-OR2,-R2,-N(R2)2,-N(R2)3,-R2OH,-CN,-CO2R2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)R2,-S(O)n-R2,-OCF3,-S(O)n-R6,-N(R2)-S(O)2(R2),卤素,-CF3或-NO2;M'是H,C1-C12烷基,C2-C12链烯基,或-R6;其中,烷基或链烯基中的1-4个-CH2基团任选被下列杂原子取代:O,S,S(O),S(O2)或N(R2);其中,所说烷基,链烯基或R6中的任何氢原子任选被下列取代基取代:氧代,-OR2,-R2,-N(R2)2,-N(R2)3,-R2OH,-CN,-CO2R2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)R2,-S(O)n-R2,-OCF3,-S(O)n-R6,-N(R2)-S(O)2(R2),卤素,-CF3或-NO2;Z是CH2,O,S,N(R2)2,或者,当M不存在时,Z是H;Y是P或S;X是O或S;及R9是C(R2)2,O或N(R2);而且当Y是S时,Z不是S;及
R6是一个5-6员饱和、部分饱和或不饱和碳环或杂环体系,或是一个8-10员饱和、部分饱和或不饱和的双环体系,其中所说任何一个杂环体系都含有一个或多个下列杂原子:O,N,S,-S(O)n或-N(R2);任何一个所说环系任意含有独立地选自下列基团的1-4个取代基:OH,C1-C4烷基,O-C1-C4烷基或OC(O)C1-C4烷基。
本领域技术人员应该理解,上述结构式中的M或M’部分可以与Z或R9是共价、共价/两性离子或离子性结合,这取决于实际所选的M或M’。当M或M’是氢,烷基,链烯基或R6时,M或M’与R9或Z共价结合。如果M是单价或二价金属或其它带电物质(即NH4 +),则在M和Z之间有离子相互作用,而且所得化合物是盐。
当(M)x中的x是O,Z可以是带电物质。如果发生这种情况,其它M则可以带有相反的电荷以使分子上的净电荷为O。或者,在分子的其它部位可以有反荷离子。
除非有相反的表述,这里所用的变量A,R1-R4,R6-R9,Ht,B,x,n,D,D',M,Q,X,Y,Z和E的定义同式Ⅰ化合物中的定义。
根据本发明优选实例,本发明优选化合物是式ⅩⅫ,ⅩⅫⅠ或ⅩⅩⅪ化合物,其中A,R3,R7,Ht,D,D',x和E同式Ⅰ化合物中的定义。为了便于区分,式ⅩⅩⅪ中的两个R3部分分别记为R3和R3’。
对于式ⅩⅫ化合物,更优选的是其中各变量如下的化合物:A选自3-四氢呋喃基-O-C(O)-,3-(1,5-二噁烷)-O-C(O)-或3-羟基-六氢呋喃并[2,3-b]-呋喃基-O-C(O)-;D’是可以任选被一个或多个下列取代基取代的C1-C4烷基:C3-C6环烷基,-OR2,-R3,-O-Q或Q;E是可以任选被一个或多个下列取代基取代的C6-C10芳基:氧代,-OR2,-SR2,-R2,-N(R2),-R2-OH,-CN,-CO2R2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)-R2,-S(O)n-R2,-OCF3,-S(O)n-Q,亚甲基二氧基,-N(R2)-S(O)2(R2),卤素,-CF3,-NO2,Q,-OQ,-OR7,-SR7,-R7,-N(R2)(R7)或-N(R7)2;或一个含有一个S并任意含有N作为附加杂原子的5员杂环,该杂环可以任选被一个或两个下列取代基取代:-CH3,R4或Ht;正如作为R3的一部分所定义的那样,Ht定义如上,只是不包括杂环;及所有其它变量的定义同式Ⅰ中的定义。
更加优选的式ⅩⅫ化合物是其中变量如下的化合物:A是3-四氢呋喃基-O-C(O)-;G是氢;D'是异丁基;E是被-N(R7)2取代的苯基;各M分别选自H,Li,Na,K,Mg,Ca,Ba,C1-C4烷基或-N(R2)4;及各M’是H或C1-C4烷基。
式ⅩⅫ化合物的其它优选实例是其中变量如下的化合物:E是含有一个S并任意含有N作为附加杂原子的5员杂环,该杂环可以任选被一个或两个下列取代基取代:-CH3,R4或Ht;及所有其它变量的定义同式Ⅰ中的定义。
更加优选的式ⅩⅫ化合物是上述任何一个,只是其中-OR7中的R7是-PO(OM)2或C(O)CH2OCH2CH2OCH2CH2OCH3,而-N(R7)2中的两个R7均为H,其中M是H,Li,Na,K或C1-C4烷基;或者,-OR7中的R7是C(O)CH2OCH2CH2OCH3,而-N(R7)2中的一个R7是C(O)CH2OCH2CH2OCH3,另一个是H。
最优选的式ⅩⅫ化合物的结构如下:
对于式ⅩⅫⅠ化合物,最优选的是其中变量如下的化合物:R3是C1-C6烷基,C2-C6链烯基,C5-C6环烷基,C5-C6环烯基或一个5-6员饱和或不饱和杂环;其中,任何一个所说R3可以任选被一个或多个下列取代基取代:-OR2,-C(O)-NH-R2,-S(O)n-N(R2)(R2),Ht,-CN,-SR2,-CO2R2和-NR2-C(O)-R2;D’是C1-C3烷基或C3链烯基,所说烷基或烯基可以任选被一个或多个下列取代基取代:C3-C6环烷基,-OR2,-O-Q或Q;及所有其它变量的定义同上面式Ⅰ中的定义。
更加优选的式ⅩⅫⅠ化合物是上述任何一个,只是其中R7是-PO(OM)2或-C(O)-M’。
对于式ⅩⅩⅪ化合物,最优选的是其中变量如下的化合物:A是R1-Ht;各R3分别是C1-C6烷基,它可以任选被一个下列取代基取代:-OR2,-C(O)-NH-R2,-S(O)n-N(R2)(R2),Ht,-CN,-SR2,-CO2R2和-NR2-C(O)-R2;D’是C1-C4烷基,它可以任选被一个下列取代基取代:C3-C6环烷基,-OR2,-O-Q;及E是Ht,Ht-Ht和-NR2R3。
更加优选的式ⅩⅩⅪ化合物是上述任何一个,只是其中R7是-PO(OM)2或-C(O)-M’。
本发明的前药可以用常规合成技术合成。美国专利5,585,397公开了式Ⅰ化合物的合成技术,其中A,B,n,D,D'和E定义如上。本发明式Ⅰ前药可以用常规技术由美国专利5,585,397所述化合物容易地合成。本领域技术人员非常熟悉用于将美国专利5,585,397所述化合物中的-OH基团转化成本发明所要的-OR7官能团(其中R7定义如上)的常规合成试剂。用这种方法合成本发明化合物相对容易,体现出在大规模生产这些化合物方面的巨大优势。
除了VX-478之外,其它可以用类似方法转化成本发明前药的具体化合物的实例(和生成本发明化合物的那些中间体的合成)公开于WO94/05639和WO 96/33184,这些专利公开在此全部引作参考。
本发明化合物的可药用盐也可以用已知技术很容易地制备。例如,上述一磷酸酯的二钠盐可用以下流程制备:
本发明化合物还可以通过附加适当官能团的方式进行修饰,以提高选择性生物性能。这样的修饰是现有技术中已知的,而且包括那些增加向所给生物系统(如血液,淋巴系统,中枢神经系统)的生物渗透性,增加口服利用度,增加溶解性进而可以注射给药,改变代谢机能和改变排泄速率的修饰。
不拘泥于理论,我们相信,将本发明前药转变成活性药物涉及两种不同的机理,这是由前药的结构所决定的。第一种机理涉及前药物质向活性形式进行的酶促或化学转化过程。第二种机理涉及为了产生活性化合物前药上的官能团的酶促或化学裂解。
这些蛋白酶抑制剂和利用它们作为天冬氨酰蛋白酶的抑制剂已在美国专利5,585,397中描述,该公开在此全部引作参考。
本发明前药的特征是具有意想不到的高水溶性。此特性使前药可以进行较高剂量的给药,可使每单位剂量的药物负荷更大。本发明前药还有一个特征是容易水解,从而在体内释放活性天冬氨酰蛋白酶抑制剂。这种高水溶性和易于体内代谢的性质使药物有较大的生物利用率。结果,患者所承担的药丸负担显著减少。
本发明前药可以常规方式用于治疗病毒,如HIV和HTLV,这些病毒依赖于在它们的生活周期中的专性事件的天冬氨酰蛋白酶。这些治疗方法,它们的剂量水平和要求都可以由本领域普通技术人员从可用的方法和技术中进行选择。例如,本发明前药可以与可药用辅剂结合,以可药用的方式和减轻病毒感染严重程度的有效量给病毒感染的患者用药。
或者,可以将本发明前药用于疫苗和保护个体使之在一段延长的时间内抵抗病毒感染的方法。该前药可以单独或与本发明其它化合物一起以通常在疫苗中利用蛋白酶抑制剂的方式在疫苗中使用。例如,本发明前药可以与通常用于疫苗的可药用辅剂结合,以保护个体使之在一段延长的时间内抵抗HIV感染的预防有效量给药。因此,本发明新的蛋白酶抑制剂可以作为治疗或预防哺乳动物HIV感染的药剂给药。
本发明前药可以给健康的或HIV感染的患者以单剂形式或与其它抗病毒剂结合给药,这些抗病毒剂能干扰HIV的复制周期。通过本发明化合物与其它抗病毒剂(它们针对病毒的生活周期中的不同事件)结合给药,这些化合物的治疗效果得以加强。例如,共同给药的抗病毒剂可以针对病毒生活周期中的早期事件,例如,细胞进入,逆转录和病毒DNA整合到细胞DNA中的。针对早期生活周期事件的抗HIV剂包括2’,3’-双脱氧肌苷(ddI),2’,3’-双脱氧胞苷(ddC),双脱氧胸苷(d4T),叠氮胸苷(AZT),多硫酸化多糖类,sT4(可溶性CD4),9-(1,3-二羟-2-丙氧甲基)鸟嘌呤,双脱氧胞苷,膦酰基甲酸三钠,依氟鸟氨酸,三氮唑核苷,无环鸟苷,α干扰素和trimenotrexate。另外,逆转录酶的非核苷抑制剂如TIBO或奈韦拉平,以及病毒脱壳抑制剂,反式激活蛋白如tat或rev的抑制剂,或病毒整合酶的抑制剂也可以用来加强本发明化合物的效果。
根据本发明的结合治疗法在抑制HIV复制方面表现出协同效果,因为结合治疗中的各部分药剂对HIV复制的不同部位起作用。这些结合治疗法的使用还可以有利地减少所给常规抗逆转录病毒剂的剂量,该剂量是与单独使用这种常规药剂进行治疗时相比达到预期的治疗或预防效果所需要的。这些结合治疗法可以减少或消除用常规的单一抗逆转录病毒剂进行治疗时出现的副作用而不影响这些药剂的抗逆转录病毒活性。这些结合治疗法降低了耐单剂治疗的潜力,同时使相关毒性减小到最小程度。这些结合治疗法还可以在不增加相关毒性的同时增加常规药剂的药效。特别是,我们已经发现这些前药协同作用防止HIV在人体T细胞中复制。优选的结合治疗法包括将本发明的前药与AZT,ddI,ddC或d4T联合给药。
或者,本发明的前药也可以与其它HIV蛋白酶抑制剂如Ro 31-8959(Roche),L-735,524(MerCk),XM323(Du-Pont Merck)和A-80,987(Abbott)一同给药,以增加治疗或预防其它HIV类似种类的各种病毒突变体或成员的效果。
我们优选将本发明的前药作为单剂或与逆转录病毒逆转录酶抑制剂如AZT的衍生物或其它HIV天冬氨酰蛋白酶抑制剂结合给药。我们认为,本发明化合物与逆转录病毒逆转录酶抑制剂或HIV天冬氨酰蛋白酶抑制剂联合给药可以发挥实质性协同效果,因此可以防止,实质上是减少,或完全消除病毒感染及其相关症状。
本发明的前药还可以与免疫调节剂(如溴匹立明,抗人体α干扰素抗体,IL-2,GM-CSF,蛋氨酸脑啡肽,干扰素α,二乙基二硫代氨基甲酸酯,肿瘤坏死因子,环丙羟二氢吗啡酮和rEPO)及抗生素(如戊烷脒β-羟乙磺酸盐)联合给药,以预防或战胜与HIV感染相关的感染和疾病,如AIDS和ARC。
当本发明的前药与其它药剂结合给药进行治疗时,可以连续或并行地给患者用药。或者,本发明药物或预防组合物可以含有本发明前药和另一种治疗或预防药剂的结合体。
虽然本发明着重本文公开的前药在预防和治疗HIV感染方面的应用,但是本发明化合物也可用作其它病毒的抑制剂,所说病毒依赖于在它们的生活周期中的专性事件的类似的天冬氨酰蛋白酶。除了由逆转录病毒引起的其它AIDS类疾病之外,这些病毒还包括,例如,猿猴免疫缺陷病毒,但不限于,HTLV-Ⅰ和HTLV-Ⅱ。此外,本发明化合物还可以用于抑制其它天冬氨酰蛋白酶,尤其是其它人体天冬氨酰蛋白酶,包括肾素和加工内皮素前体的天冬氨酰蛋白酶。
本发明药物组合物含有任何一种本发明化合物及其可药用盐,并含有任何可药用载体、辅剂或赋形剂。可用于本发明药物组合物中的可药用载体、辅剂和赋形剂包括,但不限于,离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白,如人血清白蛋白,缓冲物质如磷酸盐,甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的偏甘油酯混合物,水,盐或电解质如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶体二氧化硅,三硅酸镁,聚乙烯吡咯烷酮,基于纤维素的物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜡,聚乙烯-聚氧丙烯-嵌段聚合物,聚乙二醇和羊毛脂。
本发明药物组合物可以通过口服,胃肠外,喷雾吸入,局部,直肠,鼻内,颊内,阴道内或通过一个植入库给药。我们优选口服或注射给药。本发明药物组合物可以含有任何常用无毒可药用载体、辅剂或赋形剂。这里所用术语“胃肠外”包括皮下,皮内,静脉内,肌肉内,动脉内,滑膜内,胸骨内,鞘内,病灶内和颅内注射或滴注技术。
这些药物组合物可以是无菌注射制剂形式,例如,无菌注射水性或油性悬浮液。这种悬浮液可以根据本领域已知技术用适当的分散剂或润湿剂(如Tween 80)和悬浮剂配制。无菌注射制剂可以是在无毒的胃肠外可用的稀释剂或溶剂中形成的无菌注射溶液或悬浮液,例如,在1,3-丁二醇中制成的溶液。可以使用的可接受赋形剂和溶剂包括甘露糖醇,水,林格氏溶液和等渗氯化钠溶液。另外,无菌固定油通常也被用作溶剂或悬浮介质。为此,任何温和的固定油都可以使用,包括合成的单酸甘油酯或甘油二酯。脂肪酸如油酸及其甘油酯衍生物,还包括天然可药用油如橄榄油或蓖麻油,尤其是它们的聚氧乙基化变体,都可以用于注射制剂。这些油溶液或悬浮液还可以含有长链醇稀释剂或分散剂如Ph.Helv或类似的醇。
本发明药物组合物可以任何可口服剂量形式口服给药,它包括,但不限于,胶囊剂,片剂及水性悬浮液和溶液。对于口服的片剂来说,通常用到的载体包括乳糖和玉米淀粉。一般还要加入润滑剂如硬脂酸镁。对于用胶囊剂口服给药情况,有用的稀释剂包括乳糖和干玉米淀粉。当用水悬浮液进行口服给药时,将活性成分与乳化剂和悬浮剂混合。如果需要,还可以加入一些甜味剂和/或矫味剂和/或着色剂。
本发明药物组合物还可以栓剂形式进行直肠给药。这些组合物可以通过将本发明化合物与适当无刺激赋形剂混合制成,所说赋形剂在室温下是固体,但在直肠温度下是液体,因此在直肠中将融化释放出活性成分。这种材料包括,但不限于,可可脂,蜂蜡和聚乙二醇。
当需要治疗的区域或器官容易采取局部给药方式时用本发明药物组合物进行局部给药是特别有用的。为了局部施用于皮肤,可将含有悬浮于或溶解于载体的活性成分的合适软膏配制成药物组合物。用于本发明化合物局部给药的载体包括,但不限于,矿物油,液体石油,白凡士林,丙二醇,聚氧乙烯聚氧丙烯化合物,乳化蜡和水。或者,用含有悬浮于或溶解于载体的活性成分的合适洗液或乳膏配制成药物组合物。合适的载体包括,但不限于,矿物油,脱水山梨糖醇一硬脂酸酯,聚山梨糖酯60,鲸蜡酯蜡,cetearyl醇,2-辛基十二醇,苄醇和水。本发明药物组合物还可以直肠栓剂形式或合适的灌肠剂形式局部施用于肠道下部。局部透皮贴剂也包括在本发明中。
本发明药物组合物还可以鼻内喷雾或吸入进行给药。这样的组合物可以根据药物制剂领域已知的技术进行制备,可以制成盐水溶液,用苄醇或其它合适的防腐剂,吸收促进剂以提高生物利用率,碳氟化合物和/或其它本领域已知的溶解剂或分散剂。
每日的剂量水平约为0.01-100mg/kg(体重),优选约0.5-50mg/kg/日,用来预防和治疗病毒感染,包括HIV感染。本发明药物组合物一般每天给药约1-5次,或者,进行连续灌注。这种给药方式可以用于慢性或急性治疗。可以与载体材料混合形成单剂的活性成分的用量将取决于所要治疗的宿主和给药的具体方式。局部给药的制剂通常含有约5-95%(w/w)活性化合物,优选含有约20-80%活性化合物。
一旦患者的病情有所改善,如果必要,可以服用维持剂量的本发明化合物、组合物或结合体。因此,给药剂量或次数或二者可以随着症状的变化减少到一定水平,在该水平下使改善的病情得以保持。一旦症状缓解到所期望的程度就应该停止治疗。但是,患者可以根据病症复发情况要求长期间歇式治疗。
本领域技术人员都会理解,比上述剂量低或高的剂量也可以使用。针对任何具体患者的具体剂量和治疗方案将取决于多种因素,包括所用具体化合物的活性,年龄,体重,总的健康状况,性别,食欲,给药时间,排泄速率,联合给药的药物,感染的严重程度和病程,患者对感染的处置和治疗医生的判断。
为了更进一步理解本发明,我们给出了下列实施例。这些实施例仅仅是为了说明本发明,而不以任何方式构成对本发明范围的限制。实施例1一般条件:
(A)HPLC分析0-100%B/30min,1.5mL/min,A=0.1%TFA于水,B=0.1%TFA于乙腈。在254和220nm处探测,C18反相Vydac,t0=2.4min。
(B)1/3 v/v EtOAc/己烷。
(C)1/2 v/v EtOAc/己烷。
(D)分析用HPLC 0-100%B/10min,1.5mL/min,A=0.1%TFA于水,B=0.1%TFA于乙腈。在254和220nm处检测,C18反相Vydac,t0=2.4min。
将2.0g(3.7mmol)化合物197和3.0g(16mmol)二对硝基苯基碳酸酯的l0ml二甲基甲酰胺混合物在25℃用4ml(4mmol)P4-膦嗪(phosphazene)碱(Fluha,lM于己烷)处理。在25℃局部混合物6小时直到耗尽所有的原料醇。将反应混合物在乙酸乙酯和1N盐酸之间分配。有机相用1N氢氧化钠和盐水洗涤,硫酸镁干燥,真空浓缩。与二氯甲烷一起研磨,得到所要的碳酸盐混合物(1.2g产物1和0.6g产物2)为精细粉末。综合产率:69%。Rf=0.13(1/3 EtOAc/己烷,条件C),tHPLC=23.83min(A),MS(ES+)701(M+1)。1H-NMR(CDCl3):0.82(6H,dd),1.9(2H,m),2.15(1H,m),2.8(1H,m),3.0(4H,m),3.5(2H,m),3.6(1H,m),3.8(4H,m),4.3(1H,bs),4.8(1H,m),5.17(2H,m),7.7(7H,m),7.95(2H,d),8.35(4H,m).13C(CDCl3):155.2 152.2,149.9,145.6,135.9,+12 9.0,+128.8,+128.5,+127.2,+125.4,+124.4,+121.8,+78.1,+75.8,-73.1,-66.9,-56.5,+52.7,-48.2,-35.9,-35.9,32.6,-+26.4,+19.9,+19.8.实施例2
在溶解于3ml THF的0.20g(0.286mM)化合物198中加入0.11g(1.14mM)1-甲基-哌啶,并将混合物在室温(“rt”)搅拌过夜。蒸除所有溶剂,固体剩余物在EtOAc和水之间分配。除去挥发物,如果合适,剩余物用1∶1TFA/DCM在室温处理30分钟以除去Boc保护基。将产物溶解于0.25ml TFA和1.5ml THF。在30mg 10%Pd/C存在下氢解10小时,得到所要的化合物。最后的纯化过程在制备性反相C18上进行,采用实施例1的条件,只是流速改为18ml/min。C,H,N:计算值:49.27,5.57,8.25,实测值49.15,5.76,8.29C31H45N5O7S1.1.9CF3COOHLC/MS(Es+)632(M+1)1个峰于4.71min分析用HPLC(A)t=N/A min1H:0.71(3H,d),0.74(3H,d),1.80(2H,m),2.03(1H,m),2.63(2H,m),2.74(1H,m),2.82(3H,s),2.92(2H,m),3.20(4H,m),3.42(3H,m),3.62(2H,m),3.75(1H,m),4.05(3H,m),4.97(2H,m),6.2(1H,bs),6.60(2H,m),7.22(5H,m),7.40(3H,m),13C(DMSO):156.4,154.0,153.8,138.8,129.6,129.5,128.3,126.5,123.7,112.7,74.8,72.9,66.7,58.2,54.0,53.1,49.3,42.3,40.8,36.0,33.3,25.8,20.4,20.3实施例3
用实施例1所述方法,只是用N,N-二甲基-氨基乙醇代替二对硝基苯基碳酸酯,从化合物198开始合成化合物200。1HNMR(丙酮-d6):0.82(6H,dd),1.83(2H,m),2.07(1H,m),2.64(2H,m),2.82(6H,s),2.90(2H,m),3.19(1H,m),3.38(4H,m),3.63(2H,m),3.76(1H,m),4.17(2YH,m),4.40(1H,m),4.56(1H,m),4.96(1H,m),5.06(1H,m),6.06(1H,d),6.68(2H,d),7.23(5H,m),7.47(2H,d).13CNMR(丙酮d6):20.2,20.3,27.5,33.4,35.6,43.8,50.1,54.2,56.4,58.5,63.1,67.4,73.6,76.2,79.9,114.2,118.3,127.4,129,2,130.1,130.3,13 9.3,153.4,157.0.LC/MS:1个峰 621(MH+)。实施例4
用实施例1所述方法,只是用N-乙酰基-亚乙基二胺代替二对硝基苯基碳酸酯,从化合物198开始合成化合物201。C,H,N:计算值49.66,5.64,8.83,实测值4 9.76,5.98,8.93C30H43N5O8S1.1.4CF3COOH.LC/Ms(ES+)634(M+1)1个峰于 5.08min.分析用 HPLC(A)t=15.92min.1H:d-3乙腈:0.88(6H,dd),1.92(3H,s),1.94(2H,m),2.17(1H,m),2.72(2H,m),2.96(2H,m),3.07(3H,m),3.29(1H,m),3.42(3H,m),3.69(1H,m),3.77(1H,m),3.82(1H,m),4.133(1H,m),4.40(1H,bs),5.05(2H,m),5.80(1H,m),6.10(1H,d),6.78(2H,d),6.83(1H,bs),7.28(5H,m),7.58(2H,d).13C(d3-乙腈):157.1,157.0,153.2,13 9.6,+130.3,+130.2,+129.2,+127.2,126.2,+114.2,+76.0,+75.4,-73.6,-67.4,-58.2,+54.9,-50.2,-41.6,-39.8,-35.9,-33.4,+27.3,+23.1,+20.4,+20.2.实施例5
用实施例1所述方法,只是用一-N-Boc-哌嗪代替二对硝基苯基碳酸酯,从化合物198开始合成化合物202。C,H,N:计算值48.28,5.68,8.41,实测值48.28,5.36,8.28C30H43N5O7S1×2CF3COOHLC/MS(ES+)618(M+1)1个峰于4.36min.分析用 HPLC(A)t=14.84min.1H:d6-DMSO:0.72(3H,d),0.77(3H,d),1.78(2H,m),2.09(1H,m),2.64(2H,m),2.73(1H,m),2.80(1H,m),3.08(4H,m),3.32(2H,m),3.41(1H,m),3.50(4H,m),3.54(1H,m),3.63(1H,m),3.70(1H,m),3.98 1H,m),4.89(1H,m),4.97(1H,m),6.61(2H,d),7.23(5H,m),7.42(3H,m),8.88(2H,bs).13C:(DMSO):155.7,153.6,153.0,138.4,+129.1,+129.0,+128.1,+126.1,123.2,+112.7,+75.2,+74.4,-72.5,-66.2,-56.9,+53.1,-48.8,-42.5,-40.8,-35.0,-32.2,+26.2,+20.0,+19.8.实施例6
用实施例1所述方法,只是用一-N-Boc-亚乙基二胺代替二对硝基苯基碳酸酯,从化合物198开始合成化合物203。C,H,N:计算值46.89,5.29,8.54,实测值46.50,5.51,8.54C28H41N5O7S1×2CF3COOH.LC/MS(ES+)592(M+1)1个峰于4.32min.分析用 HPLC(A)t=14.69min.1H:d-6 DMSO:0.77(6H,d),1.82(2H,m),2.06(1H,m),2.57(2H,m),2.82(4H,m),2.97(1H,m),3.30(5H,m),3.55(1H,m),3.65(1H,m),3.70(1H,m),3.95(1H,m),4.88(1H,m),4.95(1H,m),6.62(2H,d),7.20(6H,m),7.39(3H,m),7.78(3H,bs).13C(dmso):155.9,152.9,138.5,129.2,128.9,128.1,126.1,122.9,112.7,74.7,74.5,72.6,66.2,57.2,53.2,49.4,3 8.8,37.94,3 5.1,32.1,26.3,20.0,19.8.实施例7
用实施例1所述方法,只是用1,3-二氨基-3-N-Boc-丙烷代替二对硝基苯基碳酸酯,从化合物198开始合成化合物204。C,H,N:计算值49.07,5.64,8.89,实测值48.95,6.00,8.92C29H43N5O7S1×1.6CF3COOHLC/Ms(Es+)605(M+1)1个峰于4.27min.分析用 HPLC(A)t=14.72min.1H:d-6 DMSO:0.78(6H,dd),1.64(2H,m),1.83(2H,m),2.03(1H,m),2.57(1H,m),2.78(4H,m),2.94(1H,m),3.03.(2H,m),3.32(2H,m),3.58(1H,m),3.63(1H,m),3.73(1H,m),3.87(1H,m),4.84(1H,m),4.92(1H,m),6.61(2H,d),7.22(6H.m),7.36(1H,d),7.28(2H,d),7.76(3H,ns).13C(dmso):155.8,155.7,138.5,+129.1,+129.0,+128.0,+126.1,122.9,+112.7,+74.6,+74.3,-72.7,-66.2,-57.2,+53.6,-49.5,-37.4,-36.7,-35.5,-32.1,-27.6,+26.2,+20.0.+19.8.实施例8
用实施例1所述方法,只是用1,4-二氨基-4-N-Boc-丁烷代替二对硝基苯基碳酸酯,从化合物198开始合成化合物205。C,H,N:计算值48.17,5.59,8.26,实测值48.02,5.96,8.24C30H45N5O7S1.2CF3COOHLC/MS(ES+)620(M+1)1个峰于4.36min.分析用 1HPLC(A)t=14.93min.1H:d-6 DMSO:0.77(6H,dd),1.43(4H,m),1.82(2H,m),2.03(1H,m),2.77(4H,m),2.95(3H,m),3.31(2H,m),3.56(1H,m),3.63(1H,m),3.70(1H,bq),3.82(1H,m),4.85(1H,m),4.92(1H,m),6.62(2H,d),7.2(7H,m),7.38(2H,d),7.72(3H,bs).13C:155.7,152.9,+138.6,+129.1,+129.0,+128.0,+126.1,+123.0,+112.7,+74.4,+74.3,-72.7,-66.2,-57.2,+53.7,-49.7,-38.6,-38.5,-35.4,-32.1,-26.3,+26.2,-24.4,+20.1,+19.9.实施例9
用实施例1所述方法,只是用(3R)-(+)-3-Boc-氨基吡咯烷代替二对硝基苯基碳酸酯,从化合物198开始合成化合物206。C,H,N:计算值48.28,5.36,8.28,实测值47.89,5.53,8.57C30H43N5O7S1×2TFALC/MS(ES+)618(M+1)1peak at.4.32min.分析用 HPLC(A)t=14.31min.1H和13CNMR:外消旋体(rotomers)的复合物和重叠混合物。实施例10
用实施例1所述方法,只是用(3S)-(-)-3-Boc-氨基吡咯烷代替二对硝基苯基碳酸酯,从化合物198开始合成化合物207。LC/MS(ES+)618(M+1)1个峰于4.19min处。分析用HPLC(A)t=14.75min。1H和13C NMR:外消旋体(rotomer)的复合物和重叠混合物。实施例11
用实施例1所述方法,只是用N-三苯基甲基-N,N'-二甲基乙二胺代替二对硝基苯基碳酸酯,从化合物198开始合成化合物308。1H-NMR:0.76(6H,dd),1.65(2H,m),1.95(1H,m),2.07(1H,m),2.7(2H,m),2.75(3H,s),2.95(3H,m),3.45(2H,m),3.7(4H,m),4.2(2H,bm),5.05(2H,bd),6.62(2H,d),7.2(5H,m),7.5(2H,d).LC/MS:1个峰,620(MH+).实施例12一般方法酰基化反应
在溶解于5m1CH2Cl2的200mg(0.37mM)化合物197中依次加入183mg(0.41mM)N-CBz-L-苄基酪氨酸,231mg(1.12mM)DCC和29mg(.23mM)DMAP。将反应在室温搅拌24小时。滤除产生的沉淀,然后真空浓缩滤液。最后,将化合物在制备性反相C18上用HPLCC18WaterDelta Prep 3000 Column纯化:YMC-Pack ODS AA 12S05-2520WT 250×20mm I.D.S-5mm,120埃,0-100%B进行1/2小时,流速=18ml/min,监测220nm,B=0.1%三氟乙酸于乙腈,A=0.1%三氟乙酸于水。分析用柱:YMC-Pack ODS AA1 2SO5-2520WT 250×4.6mm I.D.S-5mm,120埃,0-100%B 流速=1.5ml/min,进行1/2小时,监测220nm,B=0.1%三氟乙酸于乙腈,A=0.1%三氟乙酸于水。
冻干水相,得到59mg(16.3%)GW431896X,(U11484-72-10)tHPLC=11.71 min.,MW=966.04,LC/MS=MH+967。硝基官能团的还原将化合物209(170mg)和10mg Pd/C的95% EtOH浆液在装有隔膜和搅拌棒的闪烁小瓶中用氢冲洗。在氢气环境中氢解过夜,使反应物完全转化。从粗产物中滤除催化剂,在RPC18HPLC(Prep Nova-PackC186um,60埃,梯度0-100%B进行30min)上纯化。收集所需产物,冻干后得到白色蓬松固体(50mg,30.8%)。实施例13
用实施例12方法进行酰基化和还原反应,得到化合物211。ES+669.2(M+1),tHPLC=8.06min(D),13CNMR(DMSO)168.9,156.9,155.7,153.1,138.1,130.5,129.2,129.1,128.1,126.2,124.7,122.5,112.8,76.2,74.5,72.5,66.1,58.0,53.6,52.6,49.2,33.6,32.1,26.6,25.3,20.0.tHPLC=11.71min(D),ES+967(M+1).实施例14
用实施例12方法得到化合物212。tHPLC=9.45min/(D),ES+592.2(M+1).13CNMR(DMSO)171.5,155.8,148.9,137.8,129.5,129.3,128.5,126.7,115.2,75.2,73.8,73.1,68.3,67.0,58.7,57.1,53.3,49.2,35.4,32.4,26.7,20.1,19.8.1H(CDCl3,399.42KHz):8.33(2H,d,J=8.8),7.95(2H,d,J=8.8),7.23(5H,m)5.22(m,2H),5.08(m,1H),4.08(m,1H),3.80-3.45(7H,m),3.41(3H,s),2.98(m,3H),2.66(m,1H),2.57(m,2H),2.10(s,1H),1.93(2H,m),0.82(3H,d),0.78(3H,d).Es+622(M+1),644(M+Na)tHPLC=10.29min(D).13C NMR(CDCl3):171.3,155.5,149.9,145.6,136.9,129.2,128.6,128.5,126.8,124.4,76.7,75.3,73.2,72.9,68.2,66.9,58.7,55.9,53.1,48.3,35.3,32.7,26.3,19.9,19.8.实施例15
用实施例12方法得到化合物213。tHPLC=9.21min(D);ES+622(M+1).13C NMR(CDC13):170.54,156.2,148.6,136.8,129.4,129.2,128.6,126.6,115.7,76.7,74.6,73.2,71.8,70.6,68.2,66.9,58.9,57.3,53.8,49.4,36.2,33.1,26.8,19.8,19.5.中间体:t HPLC=10.05min(D);Es+=652(M+H)674(M+Na).实施例16
用实施例12方法得到化合物214。ES+634.4(M+1);tHPLC=7.17min(D).13C(DMSO):169.3,155.8,153.1,138.0,129.1,129.0,128.1,126.3,122.6,112.8,94.3,75.6,74.6,72.4,66.1,57.8,52.7,52.0,49.3,38.4,34.7,32.2,29.1,26.6,21.4,20.1,20.0.实施例17
用实施例12方法得到化合物215。t HPLC=9.12 min(D)1H(DMSO)所有信号为宽峰:7.38(3H,brm),7.20(5H,br m),6.62(2H,br m),5.15(1H,br m),4.92(1H,br m),4.00(3H,m),3.7-3.0(16H,m),2.78(2H,m),2.57(3H,m),2.04(m,1H),1.78(m,2H),0.77(6H,m)13C(DMSO)170.6,156.3,153.7,139.1,129.8,128.4,126.7,123.7,113.3,79.8,79.2,77.3,76.1,75.4,75.2,73.0,71.9,52.3,51.8,48.2,46.7,39.9,38.7,25.8,22.6.中间体:t HPLC=10.18 min(D);ES+696.3(M+1).实施例18
用实施例12方法得到化合物216。1H-NMR:0.97(6H,t),1.95(2H,m),2.20(1H,m),2.9(2H,m),2.96(6H,s),3.00(3H,s),3.38(1H,m),3.42(3H,m),3.36(1H,m),3.6(2H,m),3.7(6H,m),3.98(2H,m),4.2(2H,dd),5.1(1H,bs),5.4(1H,m),6.8(2H,d),7.4(5H,m),7.6(2H,d).LC-Ms:1个峰,692(MH+).实施例19
用实施例12方法得到化合物217。1H-NMR(CDCl3):0.78(6H,dd),1.9(2H,m),2.1(1H,m),2.3(3H,s),2.9(8H,m),2.9(2H,m),3.15(1H,m),3.35(1H,m),3.5(1H,m),3.75(4H,m),4.06(2H,s),4.15(2H,m),4.9(1H,dd),5.05(1H,bs),5.2(1H,bs),6.63(2H,d),7.2(5H,m),7.55(2H,d),8.0(2H,m).ESMSP:676(MH+).实施例20制备N-酰基化化合物的一般方法
将0.5g(1mmol)(3S)-四氢-3-喃甲基-N-[(1S,2R)-1-苄基-2-羟基-3-(N-异丁基-4-氨基苯磺酰氨基)丙基]氨基甲酸酯,0.4g(1.5mmol)Boc-(S)-3-吡啶基丙氨酸,0.29g(1.5mmol)EDCI和0.1g 4-二甲氨基吡啶的10ml N,N-二甲基甲酰胺混合物在25℃搅拌12小时。抽真空除去挥发物,剩余物在乙酸乙酯和1N盐酸之间分配。有机相用1N氢氧化钠和盐水洗涤,硫酸镁干燥,真空浓缩。剩余物在2英寸厚的硅胶塞上进行色谱分离(1∶1乙酸乙酯∶己烷),得到所要的N-酰基化物质。通过用50ml三氟乙酸处理实现脱保护,然后将剩余的酸与甲醇一起蒸发,得到所要的前药,为白色粉末(0.2g,26%)。H1-NMR(乙腈-D3):0.95(6H,dd),2.0(2H,m),2.25(1h,m),2.8-3.1(5H,m),3.6-4.0(7H,m),4.25(1H,m),4.75(1H,m),5.18(1H,m),5.45(1H,m),7.0(2H,d),7.4(5H,m),7.75(2H,d),8.2(1H,m),8.8(1H,d),8.85(1H,d),9.15(1H,s).LC/MS:1个峰,654(MH+).实施例21
用实施例20的一般方法得到化合物220。1H-NMR(丙酮-d6/甲醇-d4):0.95(6H,t),2.0(2H,m),2.2(1H,m),2.90(1H,dd),2.95(2H,d),3.12(1H,dd),3.4(2H, m),6(1H,d),3.8(5H,m),4.4(2H,bm),6.82(2H,d),7.20(1H,s),7.4(5H,m),7.65(2H,d),8.0(1H,s).LC/MS:1个峰,643(MH+).实施例22
用实施例20的一般方法得到化合物221。1H-NMR(DMSO d-6):0.76(6H,t),1.80(2H,m),2.10(1H,m),3.7(4H,m),3.75(3H,s),3.2(5H,m),3.58(2H,s),3.7(4H,m),4.97(1H,bm),5.18(1H,bs),6.7(2H,d),7.22(5H,m),7,45(2H,d).LC/MS:1个峰,646(MH+).实施例23
用实施例20的一般方法得到化合物222。1HNMR(乙腈d-3):1.0(6H,t),2.0(2H,m),2.2(1H,m),3.00(6H,s),3.02(3H,s),3.1(4H,m),3.5(3H,m),3.8(8H,m),4.4(2H,s),5.15(1H,bs),7.4(5H,m),7.97(2H,d),8.04(2H,d).LC/MS:1个峰692(MH+).实施例24
用实施例20的一般方法得到化合物223。t HPLC=9.22min(D);ES+622(M+1).1H NMR d6-DMSO:0.76(6H,dd),1.0-1.8(15H,m),2.03(1H,m),2.58(2H,m),2.79(2H,m),3.11(1H,m),3.28(3H,s),3.3-3.5(12H,m),3.94(1H,m),4.08(1H,m),4.94(1H,m),5.14(1H,m),6.61(2H,d),7.22(5H,m),7.40(3H,m).13C(DMSO)169.7,165.9,152.9,138.4,129.2,129.1,128.1,126.2,123.1,112.8,74.4,74.1,72.5,71.2,69.8,66.1,58.1,57.1,52.9,47.5,33.4,33.2,26.3,24.5,18.9,18.8.实施例25
用实施例20的一般方法得到化合物224。实施例26O,N-二酰基化前药
制备N,O-二酰基化化合物的一般方法遵从上述实施例20概括的法则,只是要用相对于起始原料5倍的过量试剂。t HPLC 9.26min(D);ES+738(M+1)760(M+Na).13C(DMSO):170.2,169.8,156.4,143.4,138.8,129.5,128.8,128.5,126.8,119.7,74.9,74.2,73.7,71.6,70.7,70.3,68.0,67.2,59.3,57.6,53.8,49.6,35.7,33.8,27.1,20.4.1H(DMSO):10.1(1H,s),7.84(d,2H,J=8.5),7.76(d,J=8.7,2H),7.40(1H,d,J=9.2),7.22(m,5H),5.14(1H,m),4.95(1H,m),4.1(m,8H),3.7-3.3(m,13H),3.28(s,3H),3.26(s,3H),2.86(m,2H),2.73(m,1H),2.59(m,1H),2.04(m,1H),1.83(m,2H),0.78(m,6H).实施例27
在化合物197(2.93g,5.47mmol)和磷酸(Aldrich,2.2当量,12.03mmol,987mg)的20ml吡啶混合物中加入1,3-二环己基碳化二亚胺(Aldrich,2.1当量,11.49mmol,2.37g),并在氮气中于60℃加热3小时。真空除去溶剂,剩余物用200ml 0.1N碳酸氢钠水溶液处理,并在室温搅拌1小时。过滤混合物,滤液用浓HCl酸化至pH1.5,然后用乙酸乙酯采取(3×100ml)。合并的有机相用硫酸镁干燥,过滤后真空浓缩,得到3.15g(96%)所要产物226,它可以直接用于下步反应。HPLC:Rt=8.91 min(96%),MS(AP+)600.5(M+1)。实施例28
将化合物226(约5.47mmol)的18ml六甲基二甲硅氮烷悬浮液在120℃搅拌直到混合均匀,然后加入双(三甲基甲硅烷基)过氧化物(Gelest,Inc.,2.3当量,12.58mmol,2.24g,2.71ml)。1小时后将混合物冷却到室温。真空除去溶剂,剩余物与100ml甲醇一起搅拌。真空除去溶剂,剩余物与100ml 0.1N碳酸氢钠水溶液一起搅拌。加入浓HCl将混合物酸化至pH 1.5,用盐水饱和,然后用乙酸乙酯采取(3×100ml)。合并的有机相用硫酸镁干燥,过滤后真空浓缩,得到2.98g(88%)所要产物227,它可以直接用于下步反应。HPLC∶Rt=9.28 min(90%),MS(AP+)616.5(M+1)。
或者直接从化合物197合成化合物227。首先,将化合物197溶解于吡啶(300ml)。将所得溶液在50-55℃真空浓缩至约150ml。然后将溶液在N2下冷却到5℃,用POCl3(6.5ml,1.24当量)处理2分钟。除去冷却浴,将反应物在室温搅拌2.5小时。再将溶液冷却到5℃,并用30分钟加入300ml水。
所得溶液用4-甲基戊-2-酮(MIBK,2×150ml)萃取。合并的萃取液用2NHCl洗涤(2×250ml)。再用MIBK(60ml)萃取酸性洗涤液,然后,用2N Hcl(150ml)处理合并的MIBK溶液。将所得两相混合物迅速搅拌,并在50℃加热2小时。将反应混合物冷却到20℃,分离各相,用盐水(150ml)洗涤MIBK溶液。溶液经硫酸镁干燥,滤除干燥剂,在40℃真空浓缩,分离得到产物227,为浅黄色泡沫(31g,90%产率)。实施例29
将化合物227(2.98g,4.84mmol)的50ml乙酸乙酯溶液用10%钯炭(Aldrich,300mg)处理,然后放在充有35psi氢气的Parr摇动器中15小时。滤除催化剂,真空除去溶剂,得到2.66g(94%)所要产物228。HPLC∶Rt=7.23min(92%),MS(ES+)586.3(M+1)。实施例30
将化合物228固体(2.66g,4.54mmol)用10ml碳酸氢钠水溶液(Baker,3.0当量,13.63mmol,1.14g)处理,然后装入树脂柱(Mitsubishi Kasei Corp.,MCI-gel,CHP-20)。让蒸馏水流过洗脱柱直到洗脱剂呈中性,然后用1%乙腈水溶液洗脱。收集纯的馏分并冻干,得到918mg纯二钠盐229。
或者,将7g化合物228溶解于加温的100ml EtOAc,并用100ml250mM三乙基碳酸氢铵(TEABC)(2×)萃取所得溶液。合并水性萃取液,用1500ml水稀释。将所得溶液加到用50mM TEABC平衡的300mlDEAE-52柱(Whatman)中。用8L 50mM TEABC洗涤该柱,然后用2L 250mMTEABC稀释TEA盐。将溶液真空蒸发至100ml,然后冻干,得到TEA盐(1.5TEA当量)。将TEA盐(5.8g)溶解于200ml水,加入300ml 1NHCl,然后用EtOAc萃取混合物(3×200ml)。用MgSO4干燥乙酸乙酯溶液,真空蒸发,得到4g游离酸。将2g游离酸溶解于50ml乙腈,并加入537mgNaHCO3的200ml水溶液。冻干混合物,得到2.1g二钠盐(化合物229)。实施例31
将0.53g(3.0mmol)2-[2-(2-甲氧基乙氧基)乙氧基]乙酸加到搅拌的1.2g(3.15mmol)HATU,0.2g(1.47mmol)HOAt和0.4g(4.0mmol)HMM的10ml无水N,N-二甲基甲酰胺溶液中。将混合物在室温搅拌30分钟,然后在溶液中一次性加入0.5g(1mmol)(3S)-四氢-3-喃甲基-N-[(1S,2R)-1-苄基-2-羟基-3-(N-异丁基-4-氨基苯磺酰氨基)丙基]氨基甲酸酯。将混合物在20℃搅拌1小时,然后在50℃搅拌12小时。然后再冷却到20℃,加入50ml乙醚,并用水洗涤溶液三次。水相用乙醚洗涤。合并的有机相用无水硫酸镁干燥,然后过滤。减压浓缩滤液,剩余物经硅胶色谱纯化,得到所要的一-(N)酰基化(102mg,15%)和二-(O,N)酰基化(262mg,32%)化合物。一-(N)-酰基化:1H-NMR(CDCl3):0.85(dd,6H),1.85(m,2H),2.08(m,1H),2.8-3.1(m,7H),3.33(s,3H),3.55(m,3H),3.70-3.90(m,8H),4.1(s,2H),5.0(d,1H),5.08(s(br),1H),7.2(m,5H),7.70(d,2H),7.80(d,2H),9.09(s,1H).MS(FAB+):666(M+1).二-(N)-酰基化:1H-NMR(CDCl3):0.77(m,6H),1.81(m,1H),1.95(m,1H),2.05(m,1H),2.6-3.0(m,6H),3.2(m,1H),3.332(s,3H),3.33 8(s,3H),3.5-3.8(m,18H),4.1(s,2H),4.14(s,2H),4.17(m,1H),5.05(m,2H),5.25(s(br),1H),7.2(m,5H),7.69(d,2H),7.78(d,2H),9.06(s,1H).Ms(FAB+):826(M+1),848(M+Na).
将0.521g(1mM)1273W94溶解于5ml THF,然后在氮气中冷却到-78℃,并加入1.56ml(2.5mM)1.6M nBuLi的己烷溶液。在-78℃20分钟后加入105μL(1.1mM)氯氨基甲酸乙酯,并将反应物升温至室温。再加入105μL氯氨基甲酸乙酯。
重新搅拌4小时后用水淬灭反应,然后蒸发有机溶剂。在硅胶上纯化部分粗产物[Rf=0.69(1∶2乙酸乙酯∶己烷)],得到0.131g产物。C,H,N:计算值46.06,4.97,5.88,实测值45.90,4.97,5.88C23H33N5O5S1.2.2TFALC/Ms(ES+)594(M+1)1个峰于6.96min.分析用 HPLC(A)t=24.57min.13C(CDCl3):155.8,154.4,149.9,145.7,136.8,+129.2,+128.7,+126.8,+124.2,80.1,+76.9,-64.3,-56.2,-52.5,-48.7,-36.2,+28.1,+26.4,+20.0,+19.8,+14.3.实施例33
将0.131g上述碳酸乙酯溶解于4ml DCM,然后加入4ml TFA。在室温45分钟后除去溶剂,得到标题化合物。1H(DMSO):8.37(2H,d,J=7.2),8.15(2H,m),8.00(2H,d,J=7.0),7.37(5H,m),5.04(1H,d,J=6.9),4.06(2H,q,J=7.0),3.82((1H,m),3.35(2H,m),2.95(4H,m),1.82(1H,m),1.20(3H,t,J=7.0),0.72(重叠双峰,6H,J=6.2).LC/Ms 1个峰于4.76min.ES+497,3(M+1)。实施例34O,N-酰氧基化重排C,H,N:计算值53.26,6.14,7.57,实测值53.22,6.14,7.57C23H33N5O5S1×0.8TFALC/MS(ES+)594(M+1)1个峰于6.96min.分析用 HPLC(A)t=24.57min.1H(DMSO):8.34(2H,d,J=8.7),8.02(2H,d,J=8.0),7.19(5H,m),6.98(1H,d,J=7.2),5.00(1H,m),3.83(2H,q),3.50(2H,m),3.06(m,2H),2.96(2H,m),2.43(1H,m),1.97(1H,m),1.02(3H,t),0.84(3H,d),0.82(3H,d).13C(DMSO):156.2,150.1,145.7,140.0,+129.7,+129.2,+128.5,+126.3,+125.0,+71.8,-60.0,+56.2,-56.0,-51.8,-36.0,+26,3,+20.3,+20.1,+14.6.实施例35
用类似实施例1所述方法完成化合物235的合成。
产率15.2%;tHPLC=25.2min(A).
Rf=0.S4(B);ES+687.3(M+1).
1H(CDCl3):8.34(重叠d+d,4H),7.97(d,2H,J=8.9),7.35(7H,m),5.09(1H,m),4.56(1H,d,J=8.4),4.20(1H,m),3.54(1H,m),3.00(3H,m),2.82(1H,m),1,84(1H,m),1.37(9H,s),0.84(3H,d),0.82(3H,d).实施例36
将150mg化合物235溶解于3ml无水二噁烷,再加入0.35ml S(+)-3-OH-THF和0.14ml三乙胺。将混合物在氮气中温和地回流2天,得到一定量的化合物236。除去溶剂并在氧化硅(B)上纯化,得到标题化合物。tHPLC=22.98min(A);ES+636.2(M+1).1H NMR(CDCl3):8.29(2H,d),7.91(2H,d),7.22(5H,m),5.13(1H,m),4.96(1H,m).4.52(1H,d),4.02(1H,m),3.84(2H,m),3.44(1H,m),3.36(1H,m),3.10(3H,m,重叠),2.88(2H,m),2.64(1H,m),2.14(1H,m),2.05(1H,m),1.84(1H,m),1.27(9H,s),0.78(6H,两个重叠峰d).实施例37基于碳水化合物的前药
将0.54g(1mmol)(3S)-四氢-3-喃甲基-N-[(1S,2R)-1-苄基-2-羟基-3-(N-异丁基-4-氨基苯磺酰氨基)丙基]氨基甲酸酯,0.46g(2mmol)5-二甲基-叔丁基甲硅烷氧基戊酸,0.346g(1.8mmol)EDCI和0.556ml(4mmol)三乙胺的10ml二甲基甲酰胺的混合物在室温搅拌24小时。再加入3mmol上述酸、EDCI和三乙胺,并继续搅拌96小时。加入第三批酸和EDCI(各3mmol)。搅拌混合物72小时得以完成反应。
用乙酸乙酯稀释反应混合物,然后用1N盐酸萃取,饱和碳酸氢钠和水洗涤。蒸除溶剂,在硅胶上纯化(30%乙酸乙酯的己烷),得到所要的产物(500mg),为蜡状固体。LCMS:1个峰,772.5(M+Na)1H NMR(CDCL3):0.01(6H,s),0.78(6H,dd),0.95(9H,s),1.4-1.8(6H,m),1.9(2H,m),2.05(1H,m),2.3(2H,m),2.65(1H,m),2.95(2H,m),3.22(1H,m),3.4(1H,m),3.6(2H,m),3.75(3H,m),4.8(1H,d),5.1(1H,bs),5.2(1H,bs),7.2(5H,m),7.95(2H,d),8.36(2H,d).
将450mg化合物238溶解于30ml四氢呋喃,并用20ml水和50ml乙酸处理。将混合物在室温搅拌2小时并蒸发。与己烷一起研磨,得到所要的醇(290mg),为白色固体。
将0.15g(0.24mmol)上步反应所得的醇,0.205g(0.5mmol)四乙酰基葡糖基溴化物和0.191g(0.7mmol)碳酸银的3ml二氯甲烷混合物在室温搅拌6小时。再加入150mg葡糖基溴化物和150mg碳酸银,并将混合物在室温搅拌过夜。将混合物倒在硅胶饼上,用30%乙酸乙酯的己烷洗脱,得到所要的碳水化合物前药(200mg),为白色泡沫。LCMS:1个峰,966(M+H).1H-NMR(CDCl3):0.78(6H,dd),1.9(2H,m),2.00(3H,s),2.02(3H,s),2.05(3H,s),2.06(3H,s),2.1(2H,m),2.3(2H,m),2.7(1H,m),2.94(3H,bd),3.35(2H,m),3.45(2H.m),3.8(5H,m),4.1(3H,m),4.5(1H,d),4.9(1H,bs),4.95(1H,t,),5.08(4H,m),2H,d),8.35(2H,d).实施例38
将1.5g(9.4mmol)S03.py复合物加到搅拌着的1g(1.87mmol)化合物197的25ml无水四氢呋喃中。将混合物在20℃搅拌12小时,然后过滤。减压浓缩滤液,然后移到硅胶柱中并用EtOAc(纯)洗脱,然后用EtOAc∶EtOH(4∶1),得到471mg(47%)化合物239,为无色泡沫。1H-NMR(CDCl3):0.80(m,6H),1.8-2.1(m,3H),4.15(s(br),1H),4.8(t,1H),5.04(s(br),1H).MS(ES-):614(M-1).
将100mg(0.162mmol)化合物239溶解于15ml无水四氢呋喃中,并在溶液中加入200mgPd/BaSO4(5%)。将混合物在一个大气压的氢气下搅拌8小时,然后滤除催化剂。减压浓缩滤液,真空干燥(约1Hgmm,48小时),得到80mg(81%)化合物240,为无色泡沫。1H-NMR(DMSO-d6):0.85(dd,6H),0.90(m,1H),2.05(m,2H),2.58(m,3H),2.84(dd,1H),3.05(m,2H),3.55-3.80(m,6H),4.20(t,1H),4.42(m,1H),4.93(s(br),1H),6.09(s,2H),6.70(d,2H),6.80(d,1H),7.15-7.40(m,4H),7.51(d,2H).MS(ES-):584(M-1).实施例39
将780mg(3mmol)2-氯-1,3,2-dioxaphospholane加到0℃的搅拌着的1.07g(2mmol)化合物197和0.7ml(4mmol)N,N-二异丙基乙胺的25ml二氯甲烷溶液中。允许混合物升至室温,然后搅拌2小时。将混合物冷却到0℃,然后加入1.5g(9.3mmol)的5ml二氯甲烷。将混合物在20℃搅拌1小时,然后减压蒸发。将15ml 50%三甲胺水溶液加到剩余物中,然后将混合物在20℃搅拌12小时。
减压除去溶剂,在剩余物中加入50ml EtOAc∶EtOH(9∶1),然后减压浓缩滤液。将剩余物在3英寸硅胶塞上进行色谱分离,用乙酸乙酯(纯),然后用甲醇(纯)作洗脱剂洗脱,得到1.15g(82%)化合物241,为乳白色固体。1H-NMR(CDCl3):0.60(dd,6H),1.70(m,1H),1.95(m,1H),2.10(m,1H),2.8-3.2(m,6H),3.4(s(bt),9H),5.09(s(br),1H),7.25(m,5H),7.83(d,2H),8.28(d,2H).MS(ES+):701(M+1),184(磷脂酰胆碱+)。实施例40
将250mg 10%Pd/C加到搅拌着的250mg(0.35mmol)化合物241的10ml甲醇溶液中,并将混合物在20℃一个大气压氢气下搅拌4小时。过滤混合物,减压浓缩滤液。将剩余物溶解于10ml水,冻干后得到174mg(74%)化合物242,为白色固体。1H-NMR(DMSO-d6):0.82(dd,6H),1.80-2.00(m,2H),2.10(m,1H),2.80(m,3H),3.00(m,2H),3.2(s(br),9H),4.0-4.3(m,4H),4.91(s(br),1H),6.08(s(br),2H),6.67(d,2H),7.30(m,5H),7.48(d,2H),8.12(d,1H).Ms(ES+):671(M+1),184(磷脂酰胆碱:+)。实施例41
将0.175ml(2mmol)三氯化磷加到在20℃搅拌着的1.07g(2mmol)化合物197和0.35ml(2mmol)N,N-二异丙基乙胺的25ml二氯甲烷溶液中。将混合物在20℃2搅拌4小时,然后加入1ml水,并在20℃继续搅拌12小时。加入3g无水硫酸镁,搅拌30分钟,然后过滤。减压浓缩滤液,剩余物经硅胶色谱纯化,用EtOAc∶己烷(4∶1),然后用EtOAc∶EtOH(1∶1)洗脱,得到402mg(48%)化合物226和427mg(36%)化合物243。226:1H-NMR(DMSO-d6):0.82(dd,6H),1.84(m,1H),1.98(m,1H),2.10(m,1H),2.68(dd,1H),2.9-3.2(m,4H),3.6-3.8(m,3H),3.94(t,1H),4.30,(s(br),1H),4.97(s(br),1H),7.30(m,5H),8.14(d,2H),8.43(d,2H).MS(ES-):598(M-1).243:(1∶1非对映体混合物):1H-NMR(CDCl3):0.80(m,6H),1.8-2.1(m,4H),2.8-3.2(m,6H),3.7-3.9(m,4H),4.15(m,1H),4.8-5.15(m,2H),5.57,5.72((d,d),1H),7.25(m,5H),7.95(dd,2H),8.35(m,2H).MS(ES-):580(M-1),598((M+H2O)-1).实施例42
依照实施例40所述进行还原反应(产率79%)。1H-NMR(DMSO-d6):0.81(dd,6H),1.82(m,1H),1.95(m,1H),2.08(m,1H),2.6-3.15(m,6H),3.6-3.75(m,3H),4.03(t,1H),4.28,(m,1H),4.96(s(br),1H),6.07(s,2H),6.65(d,2H),7.25(m,5H),7.42(d,2H).MS(ES-):568(M-1).实施例43
依照实施例40所述进行还原反应(产率98%)。(1∶1的非对映体混合物):1H-NMR(DMSO-d6):0.82(m,6H),1.75-2.0(m,2H),2.05(m,1H),2.6-3.2(m,6H),3.55-3.8(m,4H),4.02,4.22(m,t,1H),4.75(m,1H),4.90,5.01((d,d),1H),6.12(s,1H),6.68(d,2H),7.30(m,5H),7.49(d,2H).MS(ES-):550(M-1),568((M+H2O)-1).实施例44口服单一剂量之后Sprague-Dewley大鼠中的药物动力学研究
为了研究本发明前药的药物动力学,我们给雄性和雌性Sprague-Dewley大鼠进行了一系列本发明前药和VX-478的单一口服剂量的给药。以各种药物载体中的一系列本发明前药的摩尔当量给药进行了试验。
给不同组的雄性和雌性Sprague-Dewley大鼠(3/性别/组)用管饲法服用口服剂量的化合物229,对同样的剂量当量采用不同的载体(40mg/kg摩尔当量的VX-478)。化合物229所用的不同载体为:1)水;2)5/4/1;3)PEG400;4)TPGS/PEG400;及5)PEG。VX-478的载体为:1)33%TPGS/PEG400/PEG;及2)12.5%TPGS/PEG400/PEG。在以不同的时间间隔给药之后收集血样,用HPLC和MS方法对其中所含的化合物229及其代谢物,VX-478进行分析。研究结果列于表Ⅳ。
表Ⅳ
注释:-50mg/kg剂量的化合物229等于40mg/kg的VX-478。-15分钟后(第一个数据点)在血浆中没有检测到化合物229。*代表谐和平均数。+与原型临床制剂相比VX-478的相对利用率。++与原型毒理学制剂相比VX-478的相对利用率。
化合物 | 229 | 229 | 229 | 229 | VX-478 | VX-478 |
载体 | H2O | H2O∶PG∶EtOH5∶4∶1 | PEG 400 | TPGS/PEG400/PG | 33%TPGS/PEG400/PG | 12.5%TPGS/PEG400/PG |
大鼠的数量 | 3 | 3 | 3 | 3 | 6 | 13 |
摩尔当量剂量/478剂量(mg/Kg) | 40PO | 40PO | 40PO | 40PO | 41PO | 50PO |
AUC(ug*hr/ml) | 11.7±4.8 | 10.6±7.4 | 7.4±1.8 | 8.2+1.6 | 29.6±5.8 | 16.2+1.8 |
Cmax(μM) | 7.1±1.7 | 3.3+0.6 | 3.1±0.3 | 3.0±0.7 | 14.0±2.2 | 6.0±1.0 |
半衰期(hr) | 1.7* | 3.4* | 2.8* | 2.8* | 2.5±0.9 | 2.2±1.0 |
VX-478的相对利用率 | 39.5+90.2++ | 35.8+81.8++ | 25.0+57.1++ | 27.7+63.3++ | 参考 | 参考 |
对比VX-478的含TPGS溶液制剂,我们用化合物229的固体胶囊制剂和乙醇/甲基纤维素溶液制剂对狗进行了类似的研究。研究结果示于下面表Ⅴ。
表Ⅴ
化合物 | 229 | 229 | XV-478 |
载体 | 固体胶囊 | 甲基纤维素于5%EtOH/水 | 22%TPGS/PEG400/PG |
狗的数量 | 2 | 2 | >2 |
摩尔当量剂量/478剂量(mg/Kg) | 17 PO | 17 PO | 17 PO |
AUC(ug*hr/ml) | 16.7±2.7 | 14.2±3.2 | 23.5±7.4 |
Cmax(μg/ml) | 6.1±1.7 | 6.3±0.3 | 6.8±1.1 |
Tmax(hr) | 2.3±0.6 | 0.5±0.5 | 1.0±0.8 |
VX-478(%)的相对利用率 | 71.1 | 60.4 | 参考 |
结果表明,相比其它所研究的载体,化合物229以水溶液形式口服给药能改善生物利用率。而且,在口服化合物229之后,在第一时间点血样中(或以后的血样中)检测不到一点儿化合物,表明了首过代谢为VX-478。化合物229的于水溶液中的剂量与用于VX-478的两种非水性制剂的相比结果表明了如生物利用率范围所示的等价传递。实施例45
将0.28ml(3.0mmol)POCl3加到在5℃搅拌着的1.07g(2.0mmol)化合物197的10ml无水吡啶溶液中。允许让混合物升至室温,并在20℃搅拌3小时。将混合物冷却到0℃,然后用10ml水淬灭。减压蒸除溶剂,将剩余物溶解于100ml乙酸乙酯,再用20ml 1M碳酸氢钠溶液洗涤。有机相用无水硫酸镁干燥,过滤并浓缩。剩余物经色谱纯化(SiO2,EtOAc),得到280mg(23%)化合物400。1H-NMR(DMSO-d6):0.86(dd,6H),2.05(m,2H),2.84(d,2H),2.95(dd,1H),3.06(m,1H),3.25(dd,1H),3.50-3.70(m,4H),4.20(m,1H),4.35(m,1H),7.2-7.4(m,5H),7.9-8.1(m,2H),8.40(m,2H).MS(ES-):596(M-1).
采用上述标准氢化方法将化合物400转化成化合物401,反应条件是:H2/PdC(10%);大气压;在室温4小时;溶剂:MeOH-H2O(5∶1)。化合物401的产率为68%。1H-NMR(DMSO-d6):0.85(dd,6H),2.0(m,2H),2.6-3.1(m,4H),4.15(m,1H),4.40(m,1H),6.1(s(br),1H),6.61 m(2H),7.2-7.5(m,7H).MS(ES-):566(M-1).实施例46
将1.0g(2.8mmol)Na-t-Boc-nd-Cbz-L-鸟氨酸加到搅拌着的1.2g(3.15mmol)HATU,0.2g(1.47mmol)HOAt,0.4g(4.0mmol)NMM的10ml DMF溶液中。将混合物在室温搅拌2小时,然后加入0.5g(1.0mmol)化合物218,并将溶液在50℃搅拌12小时。将混合物冷却到室温,加入100ml乙醚,然后用水萃取(5×50ml)。有机相用无水硫酸镁干燥,过滤并减压浓缩。剩余物经硅胶色谱纯化(己烷/EtOAc(1∶1),然后是EtOAc(纯)),得到410mg(48%)化合物350。化合物350A1H-NMR(CDCl3):0.85(dd,6H),1.41(s,3H),1.45(s,6H),1.60(m,4H),1.90(m,2H),2.1(m,1H),2.75-3.25(m,6H),3.60-3.90(m,6H),5.15(dd,2H),7.2-7.4(m,10H),7.68(dd,4H).MS(ES-):852(M-1).MS(ES+):854(M+1).化合物350B1H-NMR(CDCl3):0.81(dd,6H),1.39(s,9H),1.40-2.10(m,9H),2.70-3.20(m,8H),3.60-3.90(m,6H),4.10(m,1H),4.80(d,1H),5.04(s(br),2H),7.1-7.3(m,10H),7.61(s,4H).MS(ES-):866(M-1).MS(ES+):868(M+1).化合物350C1H-NMR(CDCl3):0.86(dd,6H),1.40(s,3H),1.46(s,6H),1.60-2.10(m,7H),2.70-3.15(m,6H),3.60(d,1H),3.70-4.10(m,6H),4.81(d,1H),5.05-5.30(m,7H),7.18-7.4(m,17H),7.55(d,2H).MS(FAB+):1030(M+1),1052(M+Na).
采用上述标准氢化方法将化合物350A,350B和350C分别转化成化合物402,403和404,反应条件是:H2/PdC(10%);大气压;在室温4小时;溶剂:EtOH;产率:81%。化合物4021H-NMR(CDCl3):0.80(dd,6H),1.38(s,9H),1.8(m,6H),2.10(m,2H),2.75-3.30(m,8H),3.50-4.00(m,7H),4.55(s(br),1H),7.2(m,5H),7.60(d,2H),7.81(d,2H).MS(ES+):720(M+1).化合物4031H-NMR(CDCl3):0.87(dd,6H),1.45(s,9H),1.50-2.00(m,8H),2.08(m,1H),2.75-3.15(m,8H),3.60(d,1H),3.75-3.90(m,5H),4.28(s(br),1H),4.92(d,1H),5.11(m,1H),5.27(s(br),1H),7.28-7.35(m,5H),7.70(s,4H).MS(ES+):734(M+1).化合物4041H-NMR(CDCl3):0.80(dd,6H),1.32(s,9H),1.50-2.10(m,7H),2.60-3.20(m,8H),3.40-3.80(m,5H),5.0(s(br),1H),7.05-7.2(m,5H),7.50-7.80(m,4H).MS(ES+):762(M+1).实施例47
将5mlTFA加到搅拌着的260mg(0.3mmol)化合物350A,350B或350C的20ml氯仿溶液中。将混合物在室温搅拌5小时,然后减压除去溶剂。将剩余物溶解于20ml二氯甲烷,然后在反应混合物中加入2ml(11mmol)N,N-二异丙基乙胺和1ml(10mmol)乙酸酐。将溶液搅拌1小时,然后除去溶剂。剩余物经硅胶色谱纯化(洗脱剂:EtOAc/EtOH(9∶1)),分别得到170mg(71%)化合物351A,351B或351C。化合物351A1H-NMR(CDCl3):0.85(dd,6H),1.60(m,3H),1.80-2.00(m,3H),2.06(2,3H),2.75(dd,1H),2.80-3.20(m,5H),3.60-3.90(m,7H),4.85(d,2H),5.10(m,3H),6.46(d,1H),7.25(m,10H),7.67(s,4H),9.30(s,1H).MS(ES+):796(M+1),818(M+Na).化合物351B1H-NMR(CDCl3):0.80(dd,6H),1.38(m,2H),1.50(m,2H),1.70(m,2H),1.85(m,2H),2.00(s,3H),2.70(dd,1H),2.75-3.20(m,7H),3.55(d,1H),3.75(m,6H),4.45(q,1H),4.83(d,1H),4.95(t,1H),5.03(s(br),3H),6.46(d,1H),7.20(m,10H),7.61(s,4H),9.29(s,1H).MS(ES+):810(M+1),832(M+Na).化合物351C1H-NMR(CDCl3):0.85(dd,6H),1.70-2.00(m,6H),2.07(s,3H),2.70(dd,1H),2.80-3.00(m,3H),3.10(dd,1H),3.60(d,1H),3.65-4.00(m,6H),4.1(m,1H),4.62(q,1H),4.82(d,1H),5.00-5.30(m,5H),7.10-7.40(m,15H),7.55(d,2H),7.65(m,3H)9.18(s(br),1H),9.45(s(br),1H),9.56(s(br),1H).MS(FAB+):972(M+1),994(M+Na).
采用标准氢化方法将化合物351A,351B和351C分别转化成化合物405,406和407,反应条件是:H2/PdC(10%);大气压;在室温4小时;溶剂:EtOH;产率:46%。化合物4051H-NMR(DMSO-d6):0.85(dd,6H),1.62(m,3H),1.81(m,2H),1.94(s,3H),2.00-2.2(m,2H),2.75-3.00(m,5H),3.10(m,2H),3.50-3.80(m,5H),4.54(m,1H),5.00(m,1H),5.11(d,1H),7.2-7.4(m,5H),7.80-8.00(m,5H),10,72(s,1H).MS(ES+):662(M+1).化合物4061H-NMR(DMSO-d6):0.80(dd,6H),1.30-1.80(m,7H),1.85(s,3H),1.95-2.10(m,2H),2.70(m,4H),2.99(m,2H),3.30(m,5H),3.40-3.80(m,4H),4.35(m,1H),4.90(s,1H),5.00(d,1H),7.08-7.25(m,5H),7.50(s(br),1H),7.71(d,2H),7.79(d,2H),10.54(s,1H).MS(ES+):676(M+1).化合物4071H-NMR(DMSO-d6):0.80(dd,6H),1.40-1.60(m,4H),1.75(m,2H),1.86(s,3H),2.00(m,2H),2.75(dt,2H),3.00(m,2H),3.10(q,2H),3.40-3.70(m,5H),4.39(q,1H),4.92(s(br),1H),5.01(d,1H),7.20(m,5H),7.70(d+m,3H),7.81(d,2H),8.30(d,1H),10.60(s,1H).MS(ES+):704(M+1).实施例48
将1.0g(7.5mmol)甲膦酰二氯加到搅拌着的2.14g(4.00mmol)化合物197的20ml含有10%吡啶的甲苯溶液中。将混合物在100℃搅拌5小时,然后冷却到40℃,并加入2g(18.5mmol)苄醇,然后将混合物在20℃2搅拌12小时。滤出固体,用甲苯洗涤(2×10ml),然后减压浓缩滤液。剩余物用硅胶色谱纯化(洗脱剂:己烷/EtOAc(1∶1),然后是EtOAc(纯))得到550mg(20%)化合物352。1H-NMR(CDCl3):0.67(dd,6H),1.53(d,3H),1.70(m,1H),1.90-2.10(m,2H),2.65-3.20(m,6H),3.55(d,1H),3.80(m,3H),4.10(m,1H),4.70(q,1H),4.90-5.20(m,4H),6.37(d,1H),7.2-7.4(m,10H),7.90(d,2H),8,30(d,2H).MS(ES+):704(M+1),726(M+Na).
采用标准氢化方法将化合物352转化成化合物408,反应条件是:H2/PdC(10%);大气压;在室温2小时;溶剂:MeOH;产率:78%。1H-NMR(DMSO-d6):0.84(dd,6H),1.44(d,3H),1.82(m,1H),1.90-2.10(m,2H),2.62(m,2H),2.95(m,2H),3.10(d,1H),3.39(d,1H),3.45-3.80(m,4H),4.14(t,1H),4.53(m,1H),5.00(s(br),1H),6.68(d,2H),7.2-7.4(m,5H),7.50(d,2H).MS(ES-):582(M-1).
虽然我们已经描述了本发明许多实施方案,但很显然可以改变我们的基本构思以提供利用本发明的产物和方法的其它实施方案。因此,应该认识到,本发明范围是由所附权利要求书限定的,而不是由通过实施例给出的具体实施方案限定的。
Claims (27)
1.式Ⅰ化合物,其中,A选自H;Ht;-R1-Ht;-R1-(C1-C6)烷基,它任选被一个或多个下列取代基取代:羟基,C1-C4烷氧基,Ht,-O-Ht,-NR2-CO-N(R2)2或-CO-N(R2)2;-R1-(C2-C6)链烯基,它任选被一个或多个下列取代基取代:羟基,C1-C4烷氧基,Ht,-O-Ht,-N(R2)-C(O)-N(R2)2或-CO-N(R2)2;或R7;
各R1分别选自-C(O)-,-S(O)2-,-C(O)-C(O)-,-O-C(O)-,-O-S(O)2-,-N(R2)-S(O)2-,-N(R2)-C(O)-或-N(R2)-C(O)-C(O)-;各Ht分别选自C3-C7环烷基,C5-C7环烯基,C6-C10芳基;或一个5-7员饱和或不饱和杂环,其中含有一个或多个选自N,N(R2),O,S和S(O)n的杂原子;其中所说芳基或所说杂环任选与Q稠合;而且其中任何一个所说Ht都任选被一个或多个下列取代基取代:氧代,-OR2,-SR2,-R2,-N(R2)2,-R2-OH,-CN,-C(O)OR2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)-R2,-S(O)n-R2,-OCF3,-S(O)n-Q,亚甲基二氧基,-N(R2)-S(O)2-R2,卤素,-CF3,-NO2,Q,-OQ,-OR7,-SR7,-R7,-N(R2)(R7)或-N(R7)2;
各R2分别选自H,或任选被Q取代的C1-C4烷基;B,如果存在,是-N(R2)-C(R3)2-C(O)-;各x分别是0或1;
各R3分别选自H,Ht,C1-C6烷基,C2-C6链烯基,C3-C6环烷基或C5-C6环烯基;其中任何一个所说R3(H除外)任选被一个或多个下列取代基取代:-OR2,-C(O)-NH-R2,-S(O)n-N(R2)2,Ht,-CN,-SR2,-CO2R2,-N(R2)-C(O)-R2;
各n分别是1或2;
G,如果存在,选自H,R7或C1-C4烷基,或者,当G是C1-C4烷基时,G与R7彼此直接相连或通过一个C1-C3链接物连接形成一个杂环;或如果G不存在,则与G相连的氮原子直接与-OR7上的R7基团相连,并伴随着R7中的一个-ZM基团被置换;D和D'分别选自Q;C1-C6烷基,它任选被一个或多个下列取代基取代:C3-C6环烷基,-OR2,-R3,-O-Q或Q;C2-C4链烯基,它任选被一个或多个下列取代基取代:C3-C6环烷基,-OR2,-R3,-O-Q或Q;C3-C6环烷基,它任选被Q取代或与Q稠合;C5-C6环烯基,它任选被Q取代或与Q稠合;
各Q分别选自一个3-7员饱和、部分饱和或不饱和碳环体系;
或一个5-7员饱和、部分饱和或不饱和的含有一个或多个下列
杂原子的杂环:O,N,S,-S(O)n或-N(R2);其中,所说Q中的任
何一个环任选被一个或多个下列基团取代:氧代,-OR2,-R2,
-N(R2)2,-NR2-C(O)-R2,-R2-OH,-CN,-C(O)OR2,-C(O)-N(R2)2,
卤素或-CF3;E选自Ht;O-Ht;Ht-Ht;-O-R3;-N(R2)(R3);C1-C6烷基,它任选被一个或多个R4或Ht取代;C2-C6链烯基,它任选被一个或多个选自R4或Ht的基团取代;C3-C6饱和碳环,它任选被一个或多个选自R4或Ht的基团取代;或C5-C6不饱和碳环,它任选被一个或多个选自R4或Ht的基团取代;
各R4分别选自-OR2,-SR2,-C(O)-NHR2,-S(O)2-NHR2,卤素,
-N(R2)-C(O)-R2,-N(R2)2或-CN;各R7分别选自下列基团:其中各M分别选自H,Li,Na,K,Mg,Ca,Ba,-N(R2)4,C1-C12烷基,C2-C12链烯基,或-R6;其中,烷基或链烯基中的1-4个-CH2基团,而不是连到Z的-CH2,任选被下列杂原子取代:O,S,S(O),S(O2)或N(R2);其中,所说烷基,链烯基或R6中的任何氢原子任选被下列取代基取代:氧代,-OR2,-R2,-N(R2)2,-N(R2)3,-R2OH,-CN,-C(O)OR2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)R2,-S(O)n-R2,-OCF3,-S(O)n-R6,-N(R2)-S(O)2-R2,卤素,-CF3或-NO2;M’是H,C1-C12烷基,C2-C12链烯基,或-R6;其中,烷基或链烯基中的1-4个-CH2基团任选被下列杂原子取代:O,S,S(O),S(O2)或N(R2);其中,所说烷基,链烯基或R6中的任何氢原子任选被下列取代基取代:氧代,-OR2,-R2,-N(R2)2,-N(R2)3,-R2OH,-CN,-CO2R2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)R2,-S(O)n-R2,-OCF3,-S(O)n-R6,-N(R2)-S(O)2-R2,卤素,-CF3或-NO2;Z是CH3,O,S,N(R2)2,或者,当M不存在时,Z是H;Y是P或S;X是O或S;及R9是C(R2)2,O或N(R2);而且当Y是S时,Z不是S;及
R6是一个5-6员饱和、部分饱和或不饱和碳环或杂环体系,
或是一个8-10员饱和、部分饱和或不饱和的双环体系,其
中所说任何一个杂环体系都含有一个或多个下列杂原子:O,
N,S,-S(O)n或-N(R2);任何一个所说环系任意含有独立地
选自下列基团的1-4个取代基:OH,C1-C4烷基,O-C1-C4烷
基或OC(O)-C1-C4烷基。
2.根据权利要求1的化合物,其中至少有一个R7选自下列基团:
4.根据权利要求3的化合物,其中A选自3-四氢呋喃基-O-C(O)-,3-(1,5-二噁烷)-O-C(O)-或3-羟基-六氢呋喃并[2,3-b]-呋喃基-O-C(O)-;D'是任选被一个或多个下列取代基取代的C1-C4烷基:C3-C6环烷基,-OR2,-R3,-O-Q或Q;E是任选被一个或多个下列取代基取代的C6-C10芳基:氧代,-OR2,-SR2,-R2,-N(R2)2,-R2-OH,-CN,-C(O)OR2,-C(O)-N(R2)2,-S(O)2-N(R2)2,-N(R2)-C(O)-R2,-C(O)-R2,-S(O)n-R2,-OCF3,-S(O)n-Q,亚甲基二氧基,-N(R2)-S(O)2-R2,卤素,-CF3,-NO2,Q,-OQ,-OR7,-SR7,-R7,-N(R2)(R7)或-N(R7)2;或一个含有一个S并任意含有N作为附加杂原子的5员杂环,该杂环任选被一个或两个下列取代基取代:-CH3,R4或Ht;及正如作为R3的一部分所定义的那样,Ht定义同权利要求1,只是不包括杂环。
5.根据权利要求4的化合物,其中A是3-四氢呋喃基-O-C(O)-;G是氢;D'是异丁基;E是被-N(R7)2取代的苯基;各M分别选自H,Li,Na,K,Mg,Ca,Ba,C1-C4烷基或-N(R2)4;及各M'是H或C1-C4烷基。
6.根据权利要求3的化合物,其中E是含有一个S并任意含有N作为附加杂原子的5员杂环,其中所说杂环任选被一个或两个下列取代基取代:-CH3,R4或Ht。
7.根据权利要求3的化合物,其中E是被-N(R7)2取代的Ht;示于式ⅩⅫ的-OR7基团中的R7是-PO(OM)2或C(O)CH2OCH2CH2OCH2CH2OCH3,而Ht的取代基-N(R7)2中的两个R7均为H;或示于式ⅩⅫ的-OR7基团中的R7是C(O)CH2OCH2CH2OCH3,而Ht的取代基-N(R7)2中的一个R7是C(O)CH2OCH2CH2OCH3,Ht的取代基-N(R7)2中的另一个R7是H;及M是H,Li,Na,K或C1-C4烷基。
9.根据权利要求8的化合物,其中各M是Na。
11.根据权利要求10的化合物,其中R3是C1-C6烷基,C2-C6链烯基,C5-C6环烷基,C5-C6环烯基或一个5-6员饱和或不饱和杂环;其中,任何一个所说R3任选被一个或多个下列取代基取代:-OR2,-C(O)-NH-R2,-S(O)n-N(R2)2,Ht,-CN,-SR2,-C(O)OR2和-N(R2)-C(O)-R2;及D'是C1-C3烷基或C3链烯基;其中D’任选被一个或多个下列取代基取代:C3-C6环烷基,-OR2,-O-Q或Q。
12.根据权利要求11的化合物,其中示于式ⅩⅫⅠ的-OR7基团中的R7是-PO(OM)2或-C(O)-M’。
13.根据权利要求2的化合物,其中所说化合物具有结构式ⅩⅩⅪ,
14.根据权利要求13的化合物,其中A是R1-Ht;各R3分别是C1-C6烷基,它任选被一个下列取代基取代:-OR2,-C(O)-NH-R2,-S(O)n-N(R2)2,-Ht,-CN,-SR2,-CO2R2和-N(R2)-C(O)-R2;D’是C1-C4烷基,它任选被一个下列取代基取代:C3-C6环烷基,-OR2,-O-Q;及E是Ht,Ht-Ht和-N(R2)(R3)。
15.根据权利要求14的化合物,其中示于式ⅩⅩⅪ的-OR7基团中的R7是-PO(OM)2或-C(O)-M’。
16.根据权利要求1的化合物,其中所说化合物选自表Ⅰ所示化合物198-231,237-242,245-267或308中任何一个;表Ⅱ所示化合物232-236中任何一个;或表Ⅲ所示化合物243-244中任何一个。
17.下列化合物: 其中,R10选自异丙基或环戊基;R11选自NHR7或OR7;在化合物1005中,如果R7是PO3M,则(G)x不是H;及x,R7和G同权利要求1定义。
18.一种药物组合物,它含有治疗以天冬氨酰蛋白酶为特征的病毒感染的有效量的权利要求1-17之一化合物,及可药用载体、辅剂或赋形剂。
19.根据权利要求18的药物组合物,其中所说病毒是HIV。
20.根据权利要求18的药物组合物,其中所说药物组合物被制成口服给药制剂。
21.根据权利要求18的药物组合物,它还含有一种或多种下列药剂:抗病毒剂,除权利要求1所述化合物外的HIV蛋白酶抑制剂和免疫刺激剂。
22.根据权利要求21的药物组合物,它还含有一种或多种下列药剂:叠氮胸苷(AZT),2’,3’-双脱氧胞苷(ddC),2’,3’-双脱氧肌苷(ddI),双脱氧胸苷(d4T),3TC,935U83,1592U89,524W91,噻喹努佛(Ro 31-8959),L-735,524,SC-52151,ABT 538(A80538),AG 1341,XM 412,XM 450,CPG 53,437或tuscarasol。
23.抑制天冬氨酰蛋白酶在哺乳动物体内的活性的方法,包括给所说哺乳动物施用根据权利要求18的药物组合物的步骤。
24.治疗哺乳动物HIV感染的方法,包括将权利要求18的药物组合物施用于所说哺乳动物的步骤。
25.根据权利要求24的方法,其中给所说哺乳动物另外施用了一种或多种下列附加药剂:抗病毒剂,除权利要求1化合物外的HIV蛋白酶抑制剂,以及作为所说药物组合物单剂形式的一部分或作为单独的剂型的免疫刺激剂。
26.根据权利要求25的方法,其中所说的附加药剂选自叠氮胸苷(AZT),2’,3’-双脱氧胞苷(ddC),2’,3’-双脱氧肌苷(ddI),双脱氧胸苷(d4T),3TC,935U83,1592U89,524W91,噻喹努佛(Ro31-8959),L-735,524,SC-52151,ABT 538(A80538),AG 1341,XM 412,XM 450,CPG 53,437或tuscarasol。
27.根据权利要求24的方法,其中所说给药步骤包括口服给药。
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Cited By (2)
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CN1313472C (zh) * | 2002-04-26 | 2007-05-02 | 吉里德科学公司 | Hiv蛋白酶抑制剂化合物的膦酸酯类似物的细胞蓄积及这类化合物 |
CN1942436B (zh) * | 2004-08-02 | 2011-03-23 | 阿姆布里利亚生物制药公司 | 基于赖氨酸的化合物 |
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