CN100475206C - 可用于治疗炭疽和抑制致死因子的化合物 - Google Patents

可用于治疗炭疽和抑制致死因子的化合物 Download PDF

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CN100475206C
CN100475206C CNB038120437A CN03812043A CN100475206C CN 100475206 C CN100475206 C CN 100475206C CN B038120437 A CNB038120437 A CN B038120437A CN 03812043 A CN03812043 A CN 03812043A CN 100475206 C CN100475206 C CN 100475206C
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chemical compound
lethal factor
base
anthrax
amino
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CN1655773A (zh
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Y·熊
K·查普曼
S·辛
J·郭
A·A·帕彻特
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Merck Sharp and Dohme Corp
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Abstract

本发明涉及式(I)化合物以及通过施用含有式(I)化合物和可药用载体的组合物治疗炭疽或抑制致死因子的方法。本发明还涉及使用式(I)化合物治疗与炭疽感染有关的其它病症。

Description

可用于治疗炭疽和抑制致死因子的化合物
发明背景
本申请中引用的参考文献不被认为是要求保护的本发明的现有技术。
炭疽是由炭疽杆菌造成的细胞感染。炭疽杆菌内生孢子可以通过皮肤擦伤、吸入或摄食进入体内。炭疽杆菌产生通常是致命的炭疽毒素(Dixon等，(1999)N.Engl.J.Med.341，815-26)。
炭疽毒素由三种蛋白质组成，一种称为保持性抗原的受体结合组分，和称作水肿因子和致死因子(“LF”)的两种酶组分(Mock等，(2001)Annu.Rev.Microbiol.55，647-71)。致死因子是一种锌依赖性金属蛋白酶，它像是通过裂解促分裂原活化蛋白激酶激酶(MKKs)发挥毒性作用(Vitale等，(1998)Biochem.Biophys.Res.Commun.248，706-11，Vitale等，(2000)Biochem.J.352 Pt 3，739-45，Duesbery等，(1998)Sicence 280，734-7，Duesbery等，国际公布号WO99/50439，国际公布日期1999年10月7日)。
Vital及合作者曾利用微量测序法鉴定不同MKKs中被致死因子裂解的部位(见表1，Vitale等，(2000)Biochem.J.352Pt 3，739-45)。不同MKKs的致死因子裂解发生在激酶域之前的N端区。裂解部位侧翼的序列对比揭示了某些共有基序：在P2和P1′位的疏木残基和在P4与P7之间的至少一个碱性残基(Vital等，(2000)Biochem.J.352 Pt 3，739-45)。
已经指出致死因子在体外裂解合成肽(Hammand等，(1998)Infect.Immun.66，2374-8)。在体外试验中，裂解被1，10-菲咯啉或10mMEDTA抑制，二者均能螯合锌。
炭疽杆菌是一种孢子形成的革兰氏阴性菌，它是炭疽的病原体。炭疽是一种可以在全球温带区域(例如南美和中美洲，南欧和东欧，亚洲，非洲，中东和加勒比)发现的疾病，并可通过接触或消费受沾污的动物产品(例如食用受感染动物的未烹熟的肉)而传染给人。野生动物例如鹿、角马、象，以及家畜例如山羊、绵羊、牛、马和猪，对于感染此病是极其危险的。感染一般是由于在被沾污的土地上放牧、食用受污染的饲料或饮用受污染的水坑的水而发生。炭疽杆菌孢子可以在土壤中存活很多年。关于炭疽杆菌的进一步讨论，参见Helgason et al.，Applied andEnvironmental Microbiology 200066(6)pgs.2627-2630；Wber et al.，Antimicrob Agents and Chemotherapy 198832(5)：642-645；和Doganayet al.，Scand.J.Inf.Dis.199123：333-335。
人类可发生三种形式的炭疽感染：皮肤感染，胃肠感染和吸入感染。对于皮肤感染形式，当细菌或孢子进入皮肤上的切口或擦伤时发生感染。参见在www.ban.asm.la.cp.102401f，2001年10月24日，1-20页，Synder，J.W.，Shapiro，D.S.，Gilchrist，M.J.R.等，“Basic Diagnostic TestingProtocols for Level A Laboratories(For The Presumptive Indentificationof Bacillus anthracis)”，和Dixon等，NEJM 341：815-826，Sept 9，1999Number 11。皮肤感染的症状一般是类似于昆虫叮咬的发痒的凸起肿块。在1-2天内，肿块发展成充满流体的水泡，它破裂后形成不痛的溃疡，其特征是中心有一个黑色的坏死(趋死)区域。如果不进行治疗，可能导致死亡，但是若进行适当的抗生素治疗，死亡是罕见的。
胃肠感染的炭疽一般因消费沾染该菌的肉类时发生，它造成肠道急性发炎。恶心，丧失食欲、呕吐、发烧以及腹痛、吐血和严重腹泻是胃肠炭疽的症状。这种形式的人类炭疽的死亡率估计为25-60％。
吸入感染的炭疽很可能是有意释放炭疽杆菌气溶胶，例如生物恐怖活动的结果。这种形式的人类炭疽感染通常有1-6天的潜伏期，有时有发热、不适、疲劳、干咳和/或轻微的胸部不适等初始症状。这些初始症状之后常常是短时间的改善，随后则突然发展成严重的呼吸窘迫和勉力呼吸、出汗及皮肤颜色发蓝。尽管积极治疗，但通常在呼吸窘迫发作后24-36小时内死亡。
大多数炭疽杆菌菌株对于很多种抗生素敏感。目前常见的处方治疗是环丙沙星、青霉素或多西环素。然而，这些药剂的效力和副作用并不理想。
虽然抗生素能杀死引起炭疽的细菌，但是三分的炭疽毒素即使在细菌本身已死亡时仍继续危害身体。因此，仍然需要新的和有效的疗法，它们的效力提高，很小或没有副作用，并能抑制致死因子剪断重要的宿主分子的剪刀样能力。
发明概要
本发明涉及式I的新颖化合物：
Figure C0381204300061
式I
或其可药用盐、对映体、非对映体或体内可水解的酯，或它们的混合物，其中，
R1代表C6-10芳基，C5-10杂芳基或C5-10杂环基，该芳基、杂芳基和杂环基可任选地被1-3个Ra基团取代；
Ra代表C1-6烷基，卤素，OH，芳基(C1-6)烷基，(C1-6)烷氧基、(C1-6)烷氧基(C1-6)烷基，卤代(C1-6)烷基，硝基，氨基，一或二-N-(C1-6)烷基氨基，酰氨基，酰氧基，羧基，羧酸盐，羧酸酯，氨甲酰基，一和二-N-(C1-6)烷基氨甲酰基，(C1-6)烷氧羰基，芳氧羰基，脲基，胍基，磺酰氨基，氨磺酰基，(C1-6)烷硫基，(C1-6)烷基亚磺酰基，(C1-6)烷基磺酰基，杂环基，杂环基(C1-6)烷基；和
R代表C1-8烷基，C3-10环烷基，C3-10杂环烷基，C5-10杂芳基或C5-11杂环基，所述杂芳基和杂环基可任选地被1-3个Ra基团取代，所述烷基可任选地被选自以下基团的1-3个基团取代：芳基、杂环基、(C1-6)烷硫基、氰基、杂芳基、胍基、((1-氨乙基)羰基)氨基、((氨甲基)羰基)氨基、((2-氨基)丙-2-基)羰基)氨基、乙酰氨基、4-(氨甲基)苯基、硫基、叔丁基磺酰基、(C2-6)烯硫基、(C2-6)炔硫基、氨基、一或二(C1-6)烷氨基、芳硫基、杂环硫基、(C1-6)烷氧基、芳基(C1-6)烷氧基、芳基(C1-6)烷硫基、环烷基、环烯基、羧基及其酯、羟基和卤素。
本发明还涉及式I化合物在治疗炭疽和与炭疽感染有关的其它病症中的应用。
在全面审查本发明时将会认识到本发明的这一方面和其它方面。
发明详述
本发明涉及式I化合物和通过施用(优选静脉内或肌内施用)含有式I化合物及可药用的载体的组合物治疗炭疽或抑制致死因子的方法。
除非另外说明，本文将采用以下定义的术语详细描述本发明。
当任何变量(例如，芳基、杂环、R1、R等)在任何成分中出现一次以上时，它在每次出现时的定义均与其它出现时无关。另外，取代基和/或变量的组合仅在这种组合形成稳定化合物时才是可允许的。
术语“烷基”，除非另外定义，是指一价的链烷(烃)衍生的含1-10个碳原子的基团。它可以是直链、支链或环状的。优选的烷基包括甲基、乙基、丙基、异丙基、丁基、叔丁基、环戊基和环己基。当认为该烷基是被烷基取代时，则可互换地使用“支链烷基”一词。
链烯基优选是C2-C6链烯基。
炔基优选是C2-C6炔基。
环烷基是一种含3-15个碳原子的烷基，除非另外指明，在碳原子之间没有更迭双键或共振双键。它可以含有1-4个稠合的环。环烷基的实例有环丙基、环丁基、环戊基、环己基和环庚基。
杂环烷基是由碳原子和选自N、O和S的1-4个杂原子构成的环烷基环状基团，包括任何双环。该杂环烷基可以任选地被本文所述的1-3个Ra基团取代。杂环烷基的实例有环氧乙烷、甲基环氧乙烷、二氧杂环己烷、吡喃、硫杂环戊烷、哌啶、吡咯烷、氮杂环丙烷、氮杂环丁烷等。
烷氧基指C1-C6烷基-O-，其中该烷基可任选地如本文中所述地被取代。烷氧基的实例有甲氧基、乙氧基、丙氧基、丁氧基及其异构基团。
卤是卤素的简称，指氯、氟、溴和碘。
这里所用的“芳基”一词是指任何稳定的单环或双环碳环，每个环中有最多达7个环原子，其中至少一个环是芳香环。这种芳基单元的实例包括苯基、萘基、四氢萘基、二氢化茚基、联苯基、菲基、蒽基或苊基。
本文所用的术语杂环基代表稳定的5-7元单环或稳定的8-11元双环杂环，它或是饱和的或是不饱和的，由碳原子和1-4个选自N、O和S的杂原子组成，包括上面定义的任何杂环与苯环稠合形成的任何双环基团。该杂环可以在能导致产生稳定结构的任何杂原子或碳原子处连结。稠合的杂环环系可以包括碳环并只需包含一个杂环。术语杂环包括杂芳基部分。这些杂环单元的实例包括但不限于：氮杂环庚烯基，苯并咪唑基，苯并异噁唑基，苯并呋咱基，苯并吡喃基，苯并噻喃基，苯并呋喃基，苯并噻唑基，苯并噻吩基，苯并噁唑基，苯并二氢吡喃基，噌啉基，二氢苯并呋喃基，二氢苯并噻吩基，二氢苯并噻喃基，二氢苯并噻喃基砜，1，3-二氧杂环戊烷基，呋喃基，咪唑烷基，咪唑啉基，咪唑基，二氢吲哚基，吲哚基，异苯并二氢吡喃基，异二氢吲哚基，异喹啉基，异噻唑烷基，异噻唑基，吗啉基，1，5-二氮杂萘基，噁二唑基，2-氧代氮杂环庚烯基，噁唑基，2-氧代哌嗪基，2-氧代哌啶基，2-氧代吡咯烷基，哌啶基，哌嗪基，吡啶基，吡嗪基，吡唑烷基，吡唑基，哒嗪基，嘧啶基，吡咯烷基，吡咯基，喹唑啉基，喹啉基，喹喔啉基，四氢呋喃基，四氢异喹啉基，四氢喹啉基，硫杂吗啉基，硫杂吗啉基亚砜，噻唑基，噻唑啉基，噻吩并呋喃基，噻吩并噻吩基和噻吩基。这些杂环单元实例的一种实施方案包括但不限于：氮杂环庚烯基，苯并咪唑基，苯并异噁唑基，苯并呋咱基，苯并吡喃基，苯并噻喃基，苯并呋喃基，苯并噻唑基，苯并噻吩基，苯并噁唑基，苯并二氢吡喃基，噌啉基，二氢苯并呋喃基，二氢苯并噻吩基，二氢苯并噻喃基，二氢苯并噻喃基砜，呋喃基，咪唑烷基，咪唑啉基，咪唑基，二氢吲哚基，吲哚基，异苯并二氢吡喃基，异二氢吲哚基，异喹啉基，异噻唑烷基，异噻唑基，异噻唑烷基，吗啉基，1，5-二氮杂萘基，噁二唑基，2-氧代氮杂环庚烯基，噁唑基，2-氧代哌嗪基，2-氧代哌啶基，2-氧代吡咯烷基，哌啶基，哌嗪基，吡啶基，2-吡啶酮基，吡嗪基，吡唑烷基，吡唑基，哒嗪基，嘧啶基，吡咯烷基，吡咯基，喹唑啉基，喹啉基，喹喔啉基，四氢呋喃基，四氢异喹啉基，四氢喹啉基，硫杂吗啉基，硫杂吗啉基亚砜，噻唑基，噻唑啉基，噻吩并呋喃基，噻吩并噻吩基，噻吩基和三唑基。
优选杂环是选自2-氮杂环庚烯酮基，苯并咪唑基，2-二氮杂环庚烯酮基，咪唑基，2-咪唑烷酮基，吲哚基，异喹啉基，吗啉基，哌啶基，哌嗪基，吡啶基，吡咯烷基，2-哌啶酮基，2-嘧啶酮基，2-吡咯烷酮基，喹啉基，四氢呋喃基，四氢异喹啉基和噻吩基。
这里使用的“杂芳基”一词是指任何稳定的单环或双环碳环，每个环中有最多7个环原子，其中至少一个环是芳族环，而且其中有1-4个碳原子被选自N、O和S的杂原子置换。这类杂环单元的实例包括但不限于：苯并咪唑基，苯并异噁唑基，苯并呋咱基，苯并吡喃基，苯并噻喃基，苯并呋喃基，苯并噻唑基，苯并噻吩基，苯并噁唑基，苯并二氢吡喃基，噌啉基，二氢苯并呋喃基，二氢苯并噻吩基，二氢苯并噻喃基，二氢苯并噻喃基砜，呋喃基，咪唑基，二氢吲哚基，吲哚基，异苯并二氢吡喃基，异二氢吲哚基，异喹啉基，异噻唑基，1，5-二氮杂萘基，噁二唑基，吡啶基，吡嗪基，吡唑基，哒嗪基，嘧啶基，吡咯基，喹唑啉基，喹啉基，喹喔啉基，四氢异喹啉基，四氢喹啉基，噻唑基，噻吩并呋喃基，噻吩并噻吩基，噻吩基和三唑基。
在涉及式I化合物的本发明一项实施方案中，R是一个杂环烷基，所有其它变量均如同原来所述。
在涉及式I化合物的本发明另一实施方案中，R是一个杂芳基，所有其它变量均如同原来所述。
在涉及式I化合物的本发明又一实施方案中，R1是一个可任选被1-3个Ra基团取代的苯基，R是一个杂环烷基或杂芳基。
在涉及式I化合物的本发明另一实施方案中，R1是被1-3个甲氧基、卤素、甲基、乙基、丙基、丁基、萘基、5-(2-吡啶基)噻吩-2-基或其混合物取代的苯基，R是一个杂环烷基或杂芳基。
在涉及式Ia化合物的本发明另一实施方案中，R是杂环烷基，所有其它变量均如同原来所述。
在涉及式Ia化合物的本发明又一实施方案中，R是杂芳基，所有其它变量均如同原来所述。
大涉及式Ia化合物的本发明另一实施方案中，R是一个C1-4烷基，所有其它变量均如同原来所述。
在涉及式Ia化合物的本发明又一实施方案中，R1是一个可任选地被1-3个Ra基团取代的苯基，R是一个烷基、杂环烷基或杂芳基。
在涉及式Ia化合物的本发明另一实施方案中，R1是一个被1-3个甲氧基、卤素、甲基、乙基、丙基、丁基、萘基、5-(2-吡啶基)噻吩-2-基或其混合物取代的苯基，R是烷基、杂环烷基或杂芳基。
本发明的另一实施方案涉及一种药物组合物，其中含有一种式I化合物和一种可药用的载体。
本发明的另一实施方案涉及式I化合物在制造用于治疗或预防炭疽及其有关病症的药物方面的应用。又一实施方案则涉及式I化合物用于制造抑制致死因子的药物。
式I化合物可以与以下的一种或多种已知药物组合：临床适用的抗菌药(例如其它β-内酰胺或氨基葡糖苷)，β-内酰胺酶抑制剂，肾小管阻塞剂(例如丙磺舒)和代谢酶抑制剂(例如脱氢肽酶，如Z-2-酰氨基-3-取代的丙烯酸酯，如西司他丁)和减小对肾的不利作用的N-酰基化氨基酸(例如见EP-A-178911)。可以与式I化合物组合使用的药物实例有亚胺培南、美罗培南、万古霉素、西司他丁、头孢西丁、青霉素、克拉维酸、丙磺舒、四环素、环丙沙星、诺氟沙星或其混合物。当使用亚胺培南作为药物时，最好与西司他丁结合使用(该组合商品称为普麦克司
Figure C0381204300101
)。
本发明所用化合物的合适的可药用盐包括酸加成盐，例如，盐酸盐、氢溴酸盐、柠檬酸盐、马来酸盐和与磷酸及硫酸形成的盐。在另一方面，合适的盐是碱式盐，例如碱金属盐(如钠或钾盐)，碱土金属盐(如钙或镁盐)，有机胺盐，例如三乙胺、吗啉、N-甲基哌啶、N-乙基哌啶、普鲁卡因、二苄胺、N-N-二苄基乙胺或氨基酸(如赖氨酸)的盐。优选的可药用盐是钠盐和钾盐。
体内可水解的酯是那些在人体内水解成母体化合物的或药用的酯。这类酯可以通过向试验动物施用(例如静脉内)所试验的化合物并随后检验试验动物的体液来鉴别。对于羧基的合适的体内可水解酯包括C1-6烷氧甲基酯，如甲氧甲基酯；C1-6烷酰氧基甲基酯，如新戊酰氧基甲基酯、2-苯并[c]呋喃酮基酯；以及在美国专利5,478,820中公开的其它的酯，该文在本发明中全文引用作为参考。
在本发明中使用的化合物是：
N-叔丁氧基-2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-3-甲基丁酰胺；
N-羟基-2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-3-甲基丁酰胺；
N-叔丁氧基-2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-2-(4′-四氢吡喃基)乙酰胺；
N-羟基-2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-2-(4′-四氢吡喃基)乙酰胺；
N-羟基-2(R)-[(4-氟-3-甲基苯磺酰)]氨基-3-(S)-环丙基丁酰胺；以及它们的可药用盐、对映体、非对映体或体内可水解的酯或它们的混合物。
本发明的其它化合物公开在表1中：
表1
Figure C0381204300111
Figure C0381204300112
Figure C0381204300121
Figure C0381204300131
Figure C0381204300141
Figure C0381204300151
Figure C0381204300161
Figure C0381204300171
Figure C0381204300181
Figure C0381204300191
Figure C0381204300201
Figure C0381204300211
Figure C0381204300221
Figure C0381204300241
以及它们的可药用盐、对映体、非对映体或体内可水解的酯或其混合物。
另一些本发明化合物公开于表2中：
表2
Figure C0381204300251
Figure C0381204300252
以及它们的可药用盐、对映体、非对映体或体内可水解的酯或其混合物。
优选用于本发明的化合物是：
N-叔丁氧基-2(R)-[4-氟-3-甲基苯磺酰基]]氨基-3-甲基丁酰胺；
N-羟基-2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-3-甲基丁酰胺；
N-叔丁氧基-2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-2-(4′-四氢吡喃基)乙酰胺；
N-羟基-2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-2-(4′-四氢吡喃基)乙酰胺；
N-羟基-2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-3-(S)-环丙基丁酰胺；以及它们的可药用盐、对映体、非对映体或体内可水解的酯或其混合物。
为了用式I化合物或其可药用盐、对映体、非对映体或体内或水解的酯或它们的混合物治疗哺乳动物，包括人，特别是治疗炭疽或抑制致死因子，通常按照标准的药学操作规程将其配制成药物组合物。
本发明中使用的化合的可以按治疗有效量以静脉内、皮下、肌内或本领域技术人员已知的其它任何方法(例如，直肠、口肠、非肠道)给药。一种适合用于本发明的药物组合物是用于无菌注射的含有1-50％w/w本发明中所用化合物的组合物。
本发明制剂的合适给药对象包括灵长目、人及其它动物，特别是人和驯养动物，例如猫、兔和狗。
以下以示例说明方式给出的非限制性实施例阐明了本发明，即，本发明使用的化合物可用于治疗炭疽和抑制致死因子。
术语的定义：
HOBT-羟基苯并三唑
DMF-二甲基甲酰胺
DIEA-二异丙基乙胺
TMSONH2-O-三甲基甲硅烷基羟胺
PyBOP-六氟磷酸苯并三唑-1-基-氧-三吡咯烷基鏻盐
TFA-三氟乙酸
HPLC-高效液相色谱
DCM-二氯甲烷
EDC-1-(3-二甲基氨丙基)-3-乙基碳化二亚胺
THF-四氢呋喃
DIC-N，N′-二异丙基碳化二亚胺
MDF-二甲基甲酰胺
DMAP-4-二甲基氨基吡啶
NMP-1-甲基-2-吡咯烷酮
EDTA-乙二胺四乙酸
实施例1
Figure C0381204300271
在0℃下将N-叔丁氧基-2(R)[(4-氟-3-甲基苯磺酰基)]氨基-3-甲基丁酰胺(1.8g，4.99mmol)溶于75ml含有乙醇(0.30ml，5mmol)的无水二氯乙烷中。鼓入氯化氢气30分钟。用隔膜封住烧瓶，将反应混合物搅拌2天。在旋转蒸发仪上除去溶剂后，残余物溶于甲醇(1～2ml)，用DCM(20ml)稀释。收集形成的晶体，用DCM洗，真空干燥后得到N-羟基-2(R)[(4-氟-3-甲基苯磺酰)]氨基-3-甲基丁酰胺。
NMR(500MHz，CD3OD)δ：0.86(d，3H)，0.91(d，3H)，1.86(m，1H)，2.30(d，3H)，3.30(d，1H)，7.16(t，1H)，7.67(m，1H)，7.72(m，1H).
实施例1的起始物制备如下：
将D-缬氨酸(1.39g，11.9mmol)溶于含K2CO3(3.3g，24mmol)的二氧杂环己烷/水(1∶1)中。在充分搅拌下滴加4-氟-3-甲基苯基磺酰氯(10mmol)在二氧杂环己烷(4ml)中的溶液。将反应混合物在室温下搅拌30分钟，加入乙酸乙酯(80ml)和1N盐酸(50ml)。有机层用1N盐酸洗2次，用5％K2CO3(3×25ml)萃取。将合并的碱萃取液酸化并用乙酸乙酯(80ml)萃取。有机层用盐水洗2次，用Na2SO4脱水。在旋转蒸发仪上除去溶剂，残余物用己烷研制。将形成的固体干燥，得到2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-3-甲基丁酸。
将2(R)-[(4-氟-3-甲基苯磺酰)]氨基-3-甲基丁酸(2.64g，9.12mmol)溶于DCM(30ml)中，随后加入DIEA(3.18ml，2eq.)和O-叔丁基羟胺盐酸盐(2.3g，2eq.)。接着分批加入固体形式的EDC·HCl(2.1g，1.2eq.)。40分钟后再另入EDC(0.6，0.5eq.)，将反应混合物再搅拌30分钟。在室温下用旋转蒸发代除去溶剂，残余物分配在乙酸乙酯(80ml)和1N盐酸(50ml)中。有机层用1N盐酸、盐水洗，用Na2SO4脱水。粗产物用快速色谱柱纯化，用5％-12％的乙酸乙酯/DCM梯度溶剂洗脱，得到白色泡沫状产物N-叔丁氧基-2(R)-[(4-氟-3-甲基苯磺酰基)]氨基-3-丁酰胺。TLC(1∶10乙酸乙酯∶DCM)Rf 0.16。
NMR(500MHz，CD3OD)δ：0.89(d，3H)，0.90(d，3H)，1.08(s，9H)，1.86(m，1H)，2.30(d，3H)，3.44(d，1H)，7.18(t，1H)，7.70(m，1H)，7.77(m，1H).
实施例2
实施例2，N-羟基-2(R)-[(4-氟-3-甲基苯磺酰)]氨基-2-(4′-四氢吡喃基)乙酰胺，按照与实施例1相同的方式由D-4′-四氢吡喃甘氨酸制备。
NMR(500MHz，CD3OD)δ：1.19(m，1H)，1.34(m，1H)，1.40(m，1H)，1.74(m，1H)，1.80(m，1H)，2.32(d，3H)，3.31(m，2H)，3.37(d，1H)，3.90(m，2H)，7.18(t，1H)，7.65(m，1H)，7.72(m，1H).
实施例3-144
表1中的实施例3-144是在固相上制备并示例说明如下：
步骤1.树脂官能化
将N-羟基邻苯二甲酰亚胺(2.8g，17mmol)、DIEA(3.0ml，17mmol)在二氯甲烷(30ml)和DMF(15ml)中的溶液迅速加到装在一只烧结玻璃固定柱中的4.39g 2-Chlorotrityl树脂上(载量1.1mmol/g)。不时地摇动该树脂悬浮液并放置过夜。将树脂用DMF洗5次，然后用40ml肼溶液(0.5M THF溶液)处理2小时。在树脂周围形成大量的白色固体。用DMF-H2O(1∶1)洗2次，用DMF洗4次。再次重复肼处理3小时。树脂用DMF-H2O(1∶1)洗2次，DMF洗4次，DCM洗5次，真空干燥过夜，得到4.53g树脂1。根据重量变化，载量为约1.0mmol/g。
步骤2.装载氨基酸
Figure C0381204300292
在一只烧结玻璃固定柱内用DCM将O-结合的羟胺树脂1(500g，～1.0mmol/g载量)溶胀并排液。加入Fmoc-D-allo-异亮氨酸(530mg，1.5mmol，3eq.)和DIC(0.120ml，0.75mmol，1.5eq.)在3mlDMF中的溶液。将柱子短暂摇动，于台上放置1小时。加入另一剂量的DIC(0.04ml，0.25mmol，0.5eq.)。再过1小时后，用DMF洗树脂4次，用DCM洗4次，真空干燥过夜，得到树脂2。根据重量的增加得知载量约为0.70mmol/g。
步骤3
Figure C0381204300301
树脂2(150mg，～0.7mmol/g载量)用2ml哌啶/DMF(25％)处理2小时。该树脂用MDF洗3次，用DCM洗3次。向树脂中加入DIEA(73μl，0.42mmol，4eq.)在含DMAP(～2mg)的THF-DCM(1∶1，0.5ml)中的溶液，随后加入3-氯苯基磺酰氯(66mg，3eq.)在THF-DCM(0.5ml)中的溶液。3小时后，该树脂用DMF洗3次，DCM洗3次，并用5％TFA/DCM(0.5ml)两次裂解30分钟。将合并的裂解液蒸发，残余物溶于CH3CN∶H2O中，在反相HPLC上纯化，得到实施例25N-羟基-2(R)-(3-氯苯磺酰)氨基-3(S)-甲基戊酰胺。
NMR(500MHz，CD3OD)δ：0.82(d，d，6H)，1.04(m，1H)，1.35(m，1H)，1.64(m，1H)，3.52(d，1H)，7.50(t，1H)，7.60(d，1H)，7.76(d，1H)，7.84(m，1H).
表1列出了实施例3至144的结构。正如普通专业人员能够理解的那样，实施例4至144是根据实施例3提供的说明，经过某些修改后制备的。一些化合物在从树脂上裂解后需要去保护的步骤(用50％TFA/DCM处理)。
实施例145
Figure C0381204300302
将2(R)-[(4-氟-3-甲基苯基)磺酰]氨基-3-(S)-环丙基丁酸(10mg，31μmol)与HOBt(4.5mg，0.031mmol)、DIEA(11μl，0.062mmol)、O-三甲基甲硅烷基羟胺(20μl，0.16mmol)一起溶于DMF(0.3ml)中。加入PyBOP(20mg，0.038mmol)在DMF(0.3ml)中的溶液。30分钟后用CH3CN∶H2O(1∶1，5％TFA)猝灭反应，流过反相HPLC，经冷冻干燥后，得到N-羟基-2-(R)-[(4-氟-3-甲基苯基)磺酰]氨基-3-(S)-环丙基丁酰胺。
NMR(500MHz，CD3OD)δ：-0.04(m，1H)，0.20(m，1H)，0.35(m，1H)，0.41(m，1H)，0.54(m，1H)，0.90(d，3H)，1.08(m，1H)，2.32(d，3H)，3.60(d，1H)，7.17(t，1H)，7.68(m，1H)，7.75(m，1H).MS：331.1(M+H+).
实施例145的起始物制备如下：
羟基乙酸甲酯(10.4g，114mmol)和巴豆醇(100ml，过量)在K2CO3(0.8g)存在下回流1小时，在此期间通过Dean-Stock分水器除去约10ml冷凝物。用己烷(100ml)稀释后，固体经短硅胶柱(50g)过滤，用1∶5的乙酸乙酯∶己烷(250ml)洗。合并的滤液和洗液浓缩至100ml，再次用己烷(100ml)稀释，流过硅胶柱并洗涤。将溶液浓缩至约12.5g油，将该油真空蒸馏，得到羟基乙酸巴豆酯9.3g(97℃/20mmHg)，为顺∶反(1∶10)混合物。NMR(500MHz，CDCl3)δ：1.3(m，3H)，4.15(s，2H)，4.62(d，2H)，5.6(m，1H)，5.84(m，1H)。顺式异构体：1.71(m，3H)，其余的峰与反式异构体重叠。
将在THF(10ml)中的以上制得的羟基乙酸巴豆酯(9.3g，71mmol)慢慢加到LiN(TMS)2(200ml，1.0M)在THF(200ml)中的-78℃溶液中。在该温度下40分钟后，加入三甲基甲硅烷基氯(25.5ml，200mmol)。撤除冷浴，将反应混合物搅拌过夜，浓缩至～150ml，用乙酸乙酯(500ml)稀释。用2N盐酸洗两次。该洗液用乙酸乙酯反萃取。合并的有机层用5％K2CO3洗3次。合并的碱溶液用冷的浓盐酸酸化，用乙酸乙酯萃取。乙酸乙酯溶液用饱和NaCl洗，用Na2SO4脱水。蒸发溶剂后真空干燥，得到2-羟基-3-甲基丙烯-4-酸，为非对映体的混合物。对于非对映体1[(2R，3S)和(2S，3R)]，NMR(500MHz，CD3OD)δ：1.02(d，3H)，2.60(m，1H)，4.05(d，1H)，5.02(m，1H)，5.09(m，1H)；5.87(m，1H)；非对映体2[(2R，3R)和(2S，3S)]δ：1.11(d，3H)，2.6(m，1H)，4.03(d，1H)，5.0(m，1H)，5.09(m，1H)，5.80(m，1H)。根据NMR，非对映异构比为约7∶1，以非对映体1为主。
将以上制备的酸(8.5g，65mmol)溶于无水DMF(100ml)和DIEA(16ml，91mmol)中。加入甲基碘(11.7ml，85mmol)。搅拌15小时，用乙酸乙酯(500ml)稀释，用0.1N盐酸洗3次，盐水洗2次，用Na2SO4脱水。溶剂蒸发后留下2-羟基-3-甲基戊-4-烯酸甲酯。对于非对映体1[(2R，3S)和(2S，3R)]，NMR(500MHz，CD3OD)δ：1.02(d，3H)，2.55(m，1H)，3.70(s，3H)，4.04(d，1H)，5.02(m，1H)，5.06(m，1H)，5.81(m，1H)；非对映体2[(2R，3R)和(2S，3S)]δ：1.08(d，3H)，2.58(m，1H)，3.70(δ，3H)，4.07(d，1H)，5.00(m，1H)，5.06(m，1H)，5.80(m，1H)。
将以上制备的甲酯(2.9g，20mmol)与二碘甲烷(8.1ml，100mmol)溶于无水DCM(100ml)中，冷却到0℃。加入二乙基锌的己烷溶液(100ml，1.0M)。撤除冷却浴，将混合物在氮气下搅拌3天。加入NH4Cl溶液使反应猝灭。有机层用盐酸洗2次，盐水洗2次，用Na2SO4脱水，蒸发溶剂，得到含70％产物2-羟基-3-环丙基丁酸甲酯和30％起始物的油状物。它在使用前不作进一步纯化。
以上制备的酯(3g，20mmol)和吡啶(2.0ml，24mmol)在无水DCM(10ml)中的溶液于0℃和搅拌下慢慢加到Tf2O(4.0ml，24mmol)在DCM(100ml)中的溶液里。在0℃下1小时后，加水以猝灭反应。然后用稀盐酸(0.1N)和盐水洗，用Na2SO4脱水。蒸发溶剂得到5.3g三氟甲磺酸酯，为油状物。将其与NaN3(2.4g，36mmol)在DMF(80ml)中搅拌15小时。反应混合物用乙酸乙酯(400ml)稀释，用稀盐酸洗3次，盐水洗2次，用Na2SO4脱水。蒸发溶剂得到2.96g油状物。经硅胶快速柱色谱分离，用5％的乙醚/己烷洗脱，得到无色油状的2-叠氮基-3-环丙基丁酸甲酯。通过用CH3CN∶H2O梯度溶剂洗脱的制备型反相HPLC可以分离出所要的非对映异构体1[(2R，3S)和(2S，3R)]。对于非对映体1[(2R，3S)和(2S，3R)]，NMR(500MHz，CDCl3)δ：0.04(m，1H)0.18(m，1H)，0.48(m，2H)，0.74(m，1H)，1.09(d，3H)，1.35(m，1H)，3.80(s，3H)，3.92(d，1H).
将以上分离出的叠氮化物[(2R，3S)和(2S，3R)]非对映体(400mg，2.2mmol)溶于在20℃水浴中冷却的甲醇(10ml)。加入氯化亚锡(860mg，4.4mmol)，搅拌15小时。向该反应混合物中加入二氧杂环己烷(10ml)、K2CO3(1.5g，10.1mmol)/H2O(10ml)。过滤出固体，用二氧杂环己烷(5ml)洗。合并的滤液和洗液加到4-氟-3-甲基苯磺酰氯(560mg，2.4mmol)在二氧杂环己烷(5ml)中的溶液里。30分钟后，用盐酸将反应混合物酸化至pH 3，用CH3CN∶H2O稀释。经由制备型反相HPLC(反复注入)分离产物2-(4-氟-3-甲基苯磺酰氨基)-3-环丙基丁酸甲酯。进一步用Chiralpk柱AD分离，用7％EtOH/庚烷洗脱，得到两种对映体，所要的异构体1(2R，3S)首先洗出。
MR(500MHz，CD3OD)δ：0.01(m，2H)，0.39(m，2H)，0.62(m，1H)，1.01(d，3H)，1.19(m，1H)，2.312(d，3H)，3.23(s，3H)，3.90(d，1H)，7.18(t，1H)，7.68(m，1H)，7.73(m，1H).
将2(R)-[(4-氟-3-甲基苯基)磺酰]氨基-3-(S)-环丙基丁酸甲酯(20mg，0.061mmol)溶于甲醇(0.2ml)中，随后加入LiOH(8mg，过量)/H2O(0.15ml)。2小时后用1.5ml的CH3CN∶H2O(1∶1，5％TFA)将反应混合物酸化，用反相HPLC色谱分离，得到2-(R)-(4-氟-3-甲基苯基磺酰氨基)-3-(S)-环丙基丁酸。
NMR(500MHz，CD3OD)δ：-0.01(m，1H)，0.15(m，1H)，0.40(m，2H)，0.65(m，1H)，1.02(d，3H)，1.22(m，1H)，2.31(d，3H)，4.83(d，1H)，7.16(t，1H)，7.69(m，1H)，7.75(m，1H).
实施例146
Figure C0381204300341
将2(R)-[(4-氟-3-甲基苯基)磺酰]氨基-3(R)-环戊氧基丁酸(11mg，0.03mmol)与DIEA(12μl，0.12mmol)、HOBt(8mg，0.06mmol)和TMSONH2(10μl，0.08mmol)一起溶于DMF(200μl)中。加入PyBOP(31mg，0.06mmol)在DMF(100μl)中的溶液。20分钟后用TFA/H2O猝灭反应，用反相HPLC分离出产物，经冷冻干燥后得到N-羟基-2(R)-[(4-氟-3-甲基苯基)磺酰]氨基-3(R)-环戊氧基丁酰胺。
NMR(500MHz，CD3OD)δ：0.97(d，3H)，1.44～1.68(m，8H)，2.32(d，JH-F，3H)，3.61(d，1H)，3.72(m，1H)，3.67(m，1H)，7.18(m，1H)，7.70(m，1H)，7.76(m，1H).
实施例146的起始物制备如下：
将N-三苯甲基-D-苏氨酸苄酯(2.5g，5.5mmol)和TEA(2.8ml，20mmol)溶于-50℃的100ml无水甲苯中。在15分钟内加入磺酰氯(800μl，8mmol)在甲苯(20ml)中的溶液。将反应混合物温热至室温。加入乙酸乙酯(100ml)，用饱和NaCl溶液洗，用Na2SO4脱水。将产物在甲醇(10ml)中重结晶，得到N-三苯甲基-3(S)-甲基吖丙啶-2(R)-羧酸苄酯。
NMR(500MHz，CDCl3)δ：1.37(d，3H)，1.64(m，1H)，1.95(d，1H)，5.15(d，J＝12Hz，1H)，5.28(d，J＝12Hz，1H)，7.19～7.28(m，12H)，7.33～7.36(m，1H)，7.36～7.39(m，3H)，7.51～7.54(m，4H).
将N-三苯甲基-3(S)-甲基吖丙啶-2(R)-羧酸苄酯(2.13g，4.92mmol)在0℃下溶于20ml甲醇∶DCM(1∶1)中，随后加入TFA(20ml)。室温下搅拌1小时后，在旋转蒸发仪上除去多余的试剂和溶剂(T＜25℃)。残余物分配在DCM(50ml)和水(100ml)中。水相用DCM洗一次，用NaHCO3调节pH至碱性，用乙酸乙酯萃取，在Na2SO4上脱水。除去溶剂，留下650mg 3(S)-甲基吖丙啶-2(R)-羧酸苄酯。将其溶于0℃的DMF(15ml)中，加入TEA(2.1ml，15mmol)，随后加Boc2O(1.64g，7.5mmol)。室温下搅拌该反应混合物过夜。加入乙酸乙酯(100ml)和水(100ml)，有机层用10％柠檬酸洗2次，用盐水洗。用Na2SO4脱水。粗产物用快速柱色谱法分离，用含0.1％TEA的5～10％的EA/己烷梯度溶剂洗脱，得到N-Boc-3(S)-甲基吖丙啶-2(R)-羧酸苄酯。
MR(500MHz，CD3OD)δ：1.21(d，3H)，1.44(s，9H)，2.82(m，1H)，3.21(d，1H)，5.2(q，2H)，7.30～7.38(m，5H).
将N-Boc-3(S)-甲基吖丙啶-2(R)-羧酸苄酯(50mg，0.17mmol)和环戊醇(0.5ml，5.5mmol)溶于DCM(0.5ml)中，随后加几滴BF3·Et2O。在室温下搅拌10小时。除去溶剂，残余物用反相HPLC纯化。收集产物，用50％TFA/DCM处理，得到2(R)-氨基-3(R)-环戊氧基丁酸苄酯三氟乙酸盐。
NMR(500MHz，CD3OD)δ：1.28(d，3H)，1.4～1.7(m，8H)，3.92(m，1H)，4.06(d，1H)，4.14(dq，1H)，5.26(d，J＝12Hz，1H)，5.31(d，J＝12Hz，1H)，7.38(m，3H)，7.43(m，2H).
将2(R)-氨基-3(R)-环戊氧基丁酸苄酯三氟乙酸盐(63mg，0.16mmol)、DIEA(174μl，1.0mol)、DMAP(1mg)溶于二氧杂环己烷(2ml)中，随后慢慢加入4-氟-3-甲基苯基磺酰氯(～0.33mmol)在二氧杂环己烷(1ml)中的溶液。15分钟后，用5％TFA/H2O猝灭反应，用反相HPLC纯化，得到2(R)-[(4-氟-3-甲基苯基)磺酰]氨基-3(R)-环戊氧基丁酸苄酯。该苄酯保护基团通过在MeOH:EA(1ml)中用10％Pd/C(2mg)加氢过夜除掉，得到2(R)-[(4-氟-3-甲基苯基)磺酰]氨基-3(R)-环戊氧基]丁酸。
按照实施例146并进行本领域技术人员已知的一些修改，制备了实施例147至153。
测定致死因子抑制作用的试验
下面的试验公开于Cummings等，PNAS，2002年5月14日，99卷10期，P.6603-6606和2003年2月21日提交的PCT申请US03/05552(美国专利申请No.60/359,707，2002年2月25日提交)，该文献在本申请中全文引用作为参考。该实验用来测定与被认为是致死因子的抑制剂的化合物反应后对致死因子的抑制作用。
致死因子抑制剂化合物可以用来进一步研究致死因子活性，那些具有适当的药理性质的抑制化合物可以用来帮助治疗或预防炭疽。合适的药理性质包括效力、代谢作用和不存在不良的副作用。
可以利用对致死因子抑制剂的高通量筛选试验来筛选大量的化合物，以便鉴定那些影响致死因子活性的化合物。利用一种容易自动化和使用低含量纯化酶的试验方法简化了高通量筛选试验。
测定活性
致死因子底物可以用于测定炭疽杆菌致死因子活性及化合物对该活性的作用的各种方法。这些方法包括将本文所述的致死因子底物与炭疽杆菌一起用培养基培养，其中炭疽杆菌致死因子是活性的，培养时可以有要试验的化合物存在。底物的裂解可以作为炭疽杆菌致死因子活性或化合物对致死因子活性的影响的量度。测量可以是定性的或定量的。对于本发明化合物，致死因子酶结合试验IC50结果为15μM或更低。具体地说，对于N-羟基-2(R)-[(4-氟-3-甲基苯磺酰)]氨基-3-甲基丁酰胺和N-羟基-2(R)-[(4-氟-3-甲基苯磺酰)]氨基-2-(4′-四氢吡喃基)乙酰胺，IC50分别是0.13μM和0.06μM。

Claims (10)

1.式I化合物或其可药用盐：
Figure C038120430002C1
其中
R1是任选被1-3个Ra基团取代的苯基；
Ra选自C1-6烷基和卤素；和
R选自C3-10杂环烷基。
2.权利要求1的化合物，其中R是
Figure C038120430002C2
3.权利要求1的化合物，其中R是
4.权利要求3的化合物，该化合物是N-羟基-2(R)-[(4-氟-3-甲基苯磺酰)]氨基-2-(4′-四氢吡喃基)乙酰胺，或其可药用的盐。
5.一种用于抑制哺乳动物中由细菌释放出的致死因子的活性的药物组合物，其含有权利要求1的化合物和可药用的载体。
6.一种用于抑制哺乳动物中由细菌释放出的致死因子的活性的药物组合物，其含有权利要求4的化合物和可药用的载体。
7.权利要求1的化合物在制备用于抑制哺乳动物中由细菌释放出的致死因子的活性的药物中的用途。
8.权利要求4的化合物在制备用于抑制哺乳动物中由细菌释放出的致死因子的活性的药物中的用途。
9.权利要求7或8的用途，其中所述化合物与选自β-内酰胺、氨基葡糖苷、β-内酰胺酶抑制剂、肾小管阻塞剂和代谢酶抑制剂、N-酰基化氨基酸的一种或多种已知药物相组合。
10.权利要求9的用途，其中的已知药物是选自亚胺培南、美罗培南、万古霉素、西司他丁、头孢西丁、青霉素、克拉维酸、丙磺舒、四环素、环丙沙星、诺氟沙星或它们的混合物，其中当使用亚胺培南作为药物时，它与西司他丁组合成普麦克司(
Figure C038120430003C1
)使用。
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