CN1784380A - 新的放线酰胺素生物电子等排体 - Google Patents

新的放线酰胺素生物电子等排体 Download PDF

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CN1784380A
CN1784380A CNA2004800124850A CN200480012485A CN1784380A CN 1784380 A CN1784380 A CN 1784380A CN A2004800124850 A CNA2004800124850 A CN A2004800124850A CN 200480012485 A CN200480012485 A CN 200480012485A CN 1784380 A CN1784380 A CN 1784380A
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alkyl
cycloalkyl
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hydrogen atom
thiazolinyl
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米夏尔多·托尔曼
米夏尔多·阿尔姆施泰特尔
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Novartis AG
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Abstract

本发明涉及通式(I)的抗生素放线酰胺素的新的生物电子等排体。所述的新化合物作为金属蛋白酶抑制剂的用途特别令人感兴趣。

Description

新的放线酰胺素生物电子等排体
本发明涉及抗生素放线酰胺素的新的生物电子等排体。所述的新化合物作为金属蛋白酶抑制剂的用途特别令人感兴趣。
放线酰胺素(A)是一种具有抗菌活性的抗生素，其通过一种放线菌株(US 3240787)的发酵获得。
放线酰胺素抑制很多种酶例如肽酶、金属蛋白酶、脑磷脂酶和ACE。据最近描述，放线酰胺素抑制肽脱甲酰基酶(PDF)(C.Giglione，T.Meinnel，Emerging Therapeutic Targets 2001，5(1)，41-57)。
本发明的目的是提供新的能够通过简单路线合成的放线酰胺素类似物。所述化合物用作金属蛋白酶(特别是PDF)抑制剂的用途特别令人感兴趣。
本发明涉及式(I)化合物或其药学可接受的盐、溶剂合物或水合物或药学可接受的制剂
Figure A20048001248500051
其中
R1是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R2是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R3是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R4是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R5是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R6是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
或R1、R2、R3、R4和R6中的两个基团一起是任选取代的环烷基环或杂环烷基环的一部分，并且
n为1、2或3。
术语烷基是指具有1至20个碳原子、优选具有1至12个碳原子、特别是具有1至6个碳原子的饱和直链或支链烃基，例如甲基、乙基、丙基、异丙基、异丁基、叔丁基、正己基、2，2-二甲基丁基或正辛基。
术语烯基和炔基是指具有2至20个碳原子、优选具有2至12个碳原子、特别是具有2至6个碳原子的至少部分不饱和的直链或支链烃基，例如乙烯基、烯丙基、乙炔基、炔丙基、异戊二烯基和己-2-烯基。优选烯基具有一个或两个(特别是一个)双键，炔基具有一个或两个(特别是一个)三键。
另外，术语烷基、烯基和炔基也指其中一个或多个氢原子被卤素原子(优选F或Cl)替代的基团，例如2，2，2-三氯乙基和三氟甲基。
术语杂烷基是指其中一个或多个(优选1、2或3个)碳原子被氧、氮、磷、硼、硒、硅或硫原子(优选氧、硫或氮)替代的烷基、烯基或炔基。术语杂烷基也指羧酸或衍生于羧酸的基团，例如酰基、酰基烷基、烷氧羰基、酰氧基、酰氧烷基、羧烷基酰胺或烷氧基羰氧基。
杂烷基的实例的化学式为Ra-O-Ya-、Ra-S-Ya-、Ra-N(Rb)-Ya-、Ra-CO-Ya-、Ra-O-CO-Ya-、Ra-CO-O-Ya-、Ra-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-Ya-、Ra-O-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-O-Ya-、Ra-N(Rb)-CO-N(Rc)-Ya-、Ra-O-CO-O-Ya-、Ra-N(Rb)-C(＝NRd)-N(Rc)-Ya、Ra-CS-Ya-、Ra-O-CS-Ya-、Ra-CS-O-Ya-、Ra-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-Ya-、Ra-O-CS-N(Rb)-Ya-、RaN(Rb)-CS-O-Ya-、Ra-N(Rb)-CS-N(Rc)-Ya-、Ra-O-CS-O-Ya-、Ra-S-CO-Ya-、Ra-CO-S-Ya-、Ra-S-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-S-Ya-、Ra-S-CO-O-Ya-、Ra-O-CO-S-Ya-、Ra-S-CO-S-Ya-、Ra-S-CS-Ya-、Ra-CS-S-Ya-、Ra-S-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-S-Ya-、Ra-S-CS-O-Ya-、Ra-O-CS-S-Ya-，其中Ra是氢原子或C1-C6烷基、C2-C6烯基或C2-C6炔基，Rb是氢原子或C1-C6烷基、C2-C6烯基或C2-C6炔基，Rc是氢原子或C1-C6烷基、C2-C6烯基或C2-C6炔基，Rd是氢原子或C1-C6烷基、C2-C6烯基或C2-C6炔基，Ya是直接键或C1-C6亚烷基、C2-C6亚烯基或C2-C6亚炔基，其中每个杂烷基含有至少一个碳原子且一个或多个氢原子可以被氟或氯原子替代。杂烷基的具体实例是甲氧基、三氟甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、异丙基乙氨基、甲基氨甲基、乙基氨甲基、二异丙基氨乙基、烯醇醚、二甲基氨甲基、二甲基氨乙基、乙酰基、丙酰基、丁酰氧基、乙酰氧基、甲氧羰基、乙氧羰基、N-乙基-N-甲基氨基甲酰基和N-甲基氨基甲酰基。杂烷基的其它实例是腈、异腈、氰酸盐酯、硫氰酸酯、异氰酸酯、异硫氰酸酯和烷基腈基团。
术语环烷基是指含有一个或多个(优选1或2个)形成具有3至14个碳原子、优选3至10个(特别是3、4、5、6或7个)碳原子的结构的环的饱和或部分不饱和(例如环烯基)环状基团。术语环烷基也指其中一个或多个氢原子被氟、氯、溴或碘原子或OH、＝O、SH、＝S、NH2、＝NH或NO2基团替代的基团，即例如环酮如环己酮、2-环己酮或环戊酮。环烷基的其它具体实例是环丙基、环丁基、环戊基、螺[4，5]癸基、降冰片烷基、环己基、环戊烯基、环己二烯基、萘烷基、立方烷基、二环[4.3.0]壬烷基、四氢萘基(Tetralin)、环戊基环己基、氟环己基和环己-2-烯基基团。
术语杂环烷基是指其中一个或多个(优选1、2或3个)环碳原子被氧、氮、硅、硒、磷或硫原子(优选氧、硫或氮原子)替代的以上定义的环烷基。杂环烷基优选含有一个或两个具有3至10个(特别是3、4、5、6或7个)环原子的环。术语杂环烷基也指其中一个或多个氢原子被氟、氯、溴或碘原子或OH、＝O、SH、＝S、NH2、＝NH或NO2基团替代的基团。实例是哌啶基、吗啉基、乌洛托品基、吡咯烷基、四氢噻吩基、四氢吡喃基、四氢呋喃基、氧杂环丙基、氮杂环丙基和2-吡唑啉基基团以及内酰胺、内酯、环二酰亚胺和环酐。
术语烷基环烷基是指含有环烷基和烷基、烯基或炔基的与以上定义一致的基团，例如烷基环烷基、烷基环烯基、烯基环烷基和炔基环烷基基团。烷基环烷基优选含有具有形成含有3至10个(特别是3、4、5、6或7个)碳原子的结构的一个或两个环系统的环烷基以及一个或两个具有1或2个至6个碳原子的烷基、烯基或炔基基团。
术语杂烷基环烷基是指其中一个或多个(优选1、2或3个)碳原子被氧、氮、硅、硒、磷或硫原子(优选氧、硫或氮原子)替代的以上定义的烷基环烷基。杂烷基环烷基优选具有由3至10个(特别是3、4、5、6或7个)环原子形成的一个或两个环系统以及一个或两个具有1或2个至6个碳原子的烷基、烯基、炔基或杂烷基基团。这种基团的实例是烷基杂环烷基、烷基杂环烯基、烯基杂环烷基、炔基杂环烷基、杂烷基环烷基、杂烷基杂环烷基和杂烷基杂环烯基，其中环状基团是饱和的或单-、二-或三-不饱和的。
术语芳基或Ar是指具有一个或多个环的、由含有6至14个优选6至10个(特别是6个)碳原子的结构形成的芳香性基团。术语芳基或Ar也指其中一个或多个氢原子被氟、氯、溴或碘原子或OH、SH、NH2或NO2基团替代的基团。实例是苯基、萘基、联苯基、2-氟苯基、苯胺基、3-硝基苯基和4-羟基苯基基团。
术语杂芳基是指具有一个或多个环的、由含有5至14个优选5至10个(特别是5或6个)环原子和一个或多个(优选1、2、3或4个)氧、氮、磷或硫环原子(优选氧、硫或氮原子)的结构形成的芳香性基团。术语杂芳基也指其中一个或多个氢原子被氟、氯、溴或碘原子或OH、SH、NH2或NO2基团替代的基团。实例是4-吡啶基、2-咪唑基、3-苯基-吡咯基、噻唑基、噁唑基、三唑基、四唑基、异噁唑基、吲唑基、吲哚基、苯并咪唑基、哒嗪基、喹啉基、嘌呤基、咔唑基、吖啶基、嘧啶基、2，3′-联呋喃基、3-吡唑基和异喹啉基基团。
术语芳烷基是指含有芳基和烷基、烯基、炔基和/或环烷基的与上述定义一致的基团，例如芳基烷基、芳基烯基、芳基炔基、芳基环烷基、芳基环烯基、烷基芳基环烷基和烷基芳基环烯基基团。芳烷基的具体实例是甲苯、二甲苯、均三甲苯、苯乙烯、苄基氯、邻氟甲苯、1H-茚、四氢萘、二氢萘、茚满酮、苯基环戊基、异丙基苯、环己基苯基、芴和茚满。芳烷基优选含有一个或两个具有6至10个碳原子的芳香环系统(1或2环)与一个或两个具有1或2个至6个碳原子的烷基、烯基和/或炔基和/或具有5或6个环碳原子的环烷基。
术语杂芳烷基是指其中一个或多个(优选1、2、3或4个)碳原子被氧、氮、硅、硒、磷、硼或硫原子(优选氧、硫或氮原子)替代的以上定义的芳烷基，即含有芳基或杂芳基与烷基、烯基、炔基和/或杂烷基和/或环烷基和/或杂环烷基基团的与以上定义一致的基团。杂芳烷基优选含有一个或两个具有5或6个至10个碳原子的芳香性环系统(1或2个环)与一个或两个具有1或2个至6个碳原子的烷基、烯基和/或炔基和/或具有5或6个环碳原子的环烷基基团，其中1、2、3或4个碳原子被氧、硫或氮原子替代。
实例是芳基杂烷基、芳基杂环烷基、芳基杂环烯基、芳基烷基杂环烷基、芳基烯基杂环烷基、芳基炔基杂环烷基、芳基烷基杂环烯基、杂芳基烷基、杂芳基烯基、杂芳基炔基、杂芳基杂烷基、杂芳基环烷基、杂芳基环烯基、杂芳基杂环烷基、杂芳基杂环烯基、杂芳基烷基环烷基、杂芳基烷基杂环烯基、杂芳基杂烷基环烷基、杂芳基杂烷基环烯基和杂芳基杂烷基杂环烷基基团，其中环状基团是饱和的或单-、二-或三-不饱和的。具体实例是四氢异喹啉基、苯甲酰基、2-或3-乙基吲哚基、4-甲基吡啶基、2-、3-或4-甲氧基苯基、4-乙氧基苯基和2-、3-或4-羧基苯基烷基基团。
术语环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基和杂芳烷基也指其中这些基团的一个或多个氢原子被氟、氯、溴或碘原子或OH、＝O、SH、＝S、NH2、＝NH或NO2基团替代的基团。
表达法“任选取代的”是指其中一个或多个氢原子被氟、氯、溴或碘原子或OH、＝O、SH、＝S、NH2、＝NH或NO2基团替代的基团。该表达法也指被未取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C3-C10环烷基、C2-C9杂环烷基、C6-C10芳基、C1-C9杂芳基、C7-C12芳烷基或C2-C11杂芳烷基基团取代的基团。
式(I)化合物由于其取代基的存在可能含有一个或多个手性中心。因此本发明包括所有的纯对映体和全部纯非对映体以及它们的任何比例的混合物。本发明还包括通式(I)化合物的全部顺式/反式异构体及其混合物。本发明也包括式(I)化合物的全部互变异构形式。
优选式(I)化合物中R1是氢原子的化合物。
优选式(I)化合物中R2是氢原子的化合物。
优选式(I)化合物中n是1的化合物。
还优选式(I)化合物中R3是氢原子的化合物。
再优选式(I)化合物中R6是氢原子的化合物。
式(I)化合物的药学可接受的盐的实例是生理可接受的无机酸如盐酸、硫酸和磷酸的盐，或者有机酸如甲磺酸、对甲苯磺酸、乳酸、甲酸、乙酸、三氟乙酸、柠檬酸、琥珀酸、富马酸、马来酸和水杨酸的盐。式(I)化合物可以是溶剂合物特别是水合物的形式。例如在制备过程中或者由于起始无水式(I)化合物的吸湿性可导致水合物的形成。
本发明的药物组合物含有至少一种作为活性成分的式(I)化合物和任选的载体和/或辅剂。
本发明还涉及前药(例如R.B.Silverman，Medizinische Chemie，VCH Weinheim，1995，Chapter 8，page 361 ff)，所述前药由式(I)或(II)的化合物与至少一种药学可接受的、在生理条件下被除去的保护基团如羟基、烷氧基、芳烷氧基、酰基或酰氧基，例如甲氧基、乙氧基、苄氧基、乙酰基或乙酰氧基基团组成。
本发明还涉及式(I)化合物、它们的药物可接受的盐、溶剂合物和水合物以及药物组合物及制剂的治疗用途。
本发明还涉及所述活性成分在制备预防和/或治疗疾病特别是PDF介导的疾病的药物中的用途。式(I)化合物通常使用已知的可接受的方法单独给药或与任何期望的其它治疗活性剂联合给药。例如可通过以下方法之一给药：例如以锭剂、包衣片剂、丸剂、半固体制剂、软或硬胶囊剂、溶液剂、乳剂或混悬剂的形式口服给药，例如以注射溶液的形式经非胃肠途径给药，以栓剂的形式直肠给药，例如以粉末制剂或喷剂的形式吸入给药，以透皮或鼻内方式给药。可通过将治疗可接受的产品与药学惰性的无机或有机药物载体物质混合，例如与乳糖、蔗糖、葡萄糖、明胶、麦芽、硅胶、淀粉或其衍生物、滑石粉、硬脂酸或其盐、脱脂奶粉等混合来制备这种片剂、丸剂、半固体制剂、包衣片剂、锭剂和硬胶囊剂。制备软胶囊剂可使用药物载体如植物油、石油、动物油或合成油、蜂蜡、脂肪和多元醇。制备液体溶液剂和糖浆剂可使用药物载体如水、醇、盐水溶液、右旋糖水溶液、多元醇、甘油、植物油、石油和动物油或合成油。对于栓剂可使用药物载体如植物油、石油、动物油或合成油、蜂蜡、脂肪和多元醇。对于气溶胶制剂，可使用适用于该目的的压缩气体如氧气、氮气和二氧化碳。所述药学可接受的制剂还可以含有添加剂作为防腐剂、稳定剂、乳化剂、甜味剂、调味剂、调节渗透压的盐、缓冲剂、包衣添加剂和抗氧化剂。
式(I)化合物可通过Ugi三组分反应(例如A.D mling，I.Ugi，Angew.Chem.2000，112，3300-3344)然后将所使用的酯转化为异羟肟酸来制备：
Figure A20048001248500131
                        实施例
一般方法：
将1mmol异腈(II)、1mmol羰基化合物(III)和1mmol氨基酸衍生物(IV)溶于5ml甲醇中，在室温下搅拌24小时。若期望，反应可在催化剂如对甲苯磺酸或BF3*Et2O的存在下进行。然后加入10当量的羟胺(50％水溶液)，继续搅拌12小时。除去溶剂后，除去任何存在的保护基团，期望的产物用HPLC方法纯化。
以下化合物根据一般方法制备，用HPLC-MS和LCMS-CLND方法表征。
Figure A20048001248500141
Figure A20048001248500161
Figure A20048001248500171

Claims (11)

1.式(I)化合物或其药学可接受的盐、溶剂合物或水合物或药学可接受的制剂
其中
R1是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R2是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R3是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R4是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R5是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
R6是氢原子或烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基；
或R1、R2、R3、R4和R6中的两个基团一起是任选取代的环烷基环或杂环烷基环的一部分，并且
n为1、2或3。
2.权利要求1的化合物，其中R1是氢原子。
3.权利要求2的化合物，其中R2是氢原子。
4.权利要求1-3任一项的化合物，其中n是1。
5.权利要求1-4任一项的化合物，其中R3是氢原子。
6.权利要求1-5任一项的化合物，其中R6是氢原子。
7.含有权利要求1-6任一项的化合物与任选的载体和/或辅剂的药物组合物。
8.权利要求1-8任一项的化合物或药物组合物用于抑制金属蛋白酶的用途。
9.权利要求1-8任一项的化合物或药物组合物用于抑制肽脱甲酰基酶(PDF)的用途。
10.权利要求1-8任一项的化合物或药物组合物用于治疗和/或预防由金属蛋白酶活性介导的疾病的用途。
11.权利要求1-8任一项的化合物或药物组合物用于治疗和/或预防由肽脱甲酰基酶(PDF)活性介导的疾病的用途。
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CN101652346B (zh) * 2007-02-01 2013-10-30 约瑟夫·傅立叶大学 吲哚衍生物、其制备方法以及其用途，尤其是作为抗菌剂的用途
CN107365302A (zh) * 2016-05-11 2017-11-21 如东瑞恩医药科技有限公司 螺三元环、螺五元环类肽脱甲酰基酶抑制剂

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EP1912662B1 (en) * 2005-07-29 2013-08-21 GlaxoSmithKline LLC Peptide deformylase inhibitors
US20100286280A1 (en) * 2007-09-26 2010-11-11 The University Of North Carolina At Chapel Hill Inhibitors of eppin/semenogelin binding as male contraceptives
CN103201263A (zh) * 2010-09-08 2013-07-10 匹兹堡高等教育联邦体系大学 p53-Mdm2拮抗剂
WO2016048643A1 (en) 2014-09-26 2016-03-31 The Chemours Company Fc, Llc Isocyanate derived organosilanes
ES2958531T3 (es) 2015-10-14 2024-02-09 X Therma Inc Composiciones y métodos para reducir la formación de cristales de hielo
WO2017210489A1 (en) 2016-06-01 2017-12-07 M3 Biotechnology, Inc. Compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101652346B (zh) * 2007-02-01 2013-10-30 约瑟夫·傅立叶大学 吲哚衍生物、其制备方法以及其用途，尤其是作为抗菌剂的用途
CN107365302A (zh) * 2016-05-11 2017-11-21 如东瑞恩医药科技有限公司 螺三元环、螺五元环类肽脱甲酰基酶抑制剂
CN107365302B (zh) * 2016-05-11 2019-12-13 如东瑞恩医药科技有限公司 螺三元环、螺五元环类肽脱甲酰基酶抑制剂

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ECSP056205A (es) 2006-04-19
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WO2004099124A3 (de) 2005-01-20
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AU2004235958A1 (en) 2004-11-18
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IS8145A (is) 2005-11-24
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US7504436B2 (en) 2009-03-17
US20070060624A1 (en) 2007-03-15
WO2004099124A2 (de) 2004-11-18
CA2531484C (en) 2011-07-05
NO20055657D0 (no) 2005-11-30
BRPI0410157A (pt) 2006-05-16
ZA200509935B (en) 2007-04-25
DE10320453A1 (de) 2004-11-25

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