CN103781787B - 含氮化合物及其用途 - Google Patents
含氮化合物及其用途 Download PDFInfo
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- CN103781787B CN103781787B CN201280039835.7A CN201280039835A CN103781787B CN 103781787 B CN103781787 B CN 103781787B CN 201280039835 A CN201280039835 A CN 201280039835A CN 103781787 B CN103781787 B CN 103781787B
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- Prior art keywords
- germicide
- compound
- antiseptic
- acceptable salt
- pharmacy acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 41
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- 102000006635 beta-lactamase Human genes 0.000 claims description 19
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- 108020004256 Beta-lactamase Proteins 0.000 claims description 12
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Abstract
公开了式(I)的化合物,其制备以及在预防或治疗细菌感染中的用途。
Description
发明领域
本发明涉及含氮化合物、其制备及其在预防或治疗细菌感染中的用途。
发明背景
对于已知抗菌剂的细菌耐受性的出现正成为治疗细菌感染的主要挑战。面对治疗细菌感染,尤其是由耐药性细菌造成的细菌感染的一种方法是开发更新的能够克服细菌耐药性的抗菌剂。Coates等(Br.J. Pharmacol.2007;152(8),1147-1154)已经综述了开发新抗生素的新方式。然而,新抗菌剂的开发是一个挑战性的任务。例如,Gwynn等(Annals of the New YorkAcademy of Sciences,2010,1213:5-19)已经综述了抗菌剂发现中的挑战。
另一种克服针对已知抗菌剂的细菌耐药性的方法是靶向细菌机制,该机制帮助细菌获得和维持耐药性。例如,已知几种细菌产生酶(β-内酰胺酶),其将一般的β-内酰胺抗菌剂中的β-内酰胺环水解。一旦β-内酰胺环被水解之后,所述抗菌剂变得对于这些细菌无效。已知细菌产生几种类型的β-内酰胺酶。根据它们的氨基酸序列同源性,β-内酰胺酶宽泛地分类为以下四类:A、B、C和D(Ambler R.P.,Phil.Trans.R.Soc.Lon.,B289,321-331,1980)。属于A、C和D类的β-内酰胺酶使用丝氨酸作为活性位点来促进催化,而那些属于B类的β-内酰胺酶在活性位点上含有一个或多个金属离子(例如,锌离子)来促进β-内酰胺切割。
一般已知作为β-内酰胺酶抑制剂的几种化合物能够抑制一种或多种β-内酰胺酶的活性,从而恢复常规的β-内酰胺抗菌剂的功效。β-内酰胺酶抑制剂的典型例子包括舒巴坦(sulbactam)、他唑巴坦(tazobactam)和克拉维酸(clavulanic acid)。Drawz等(Clinical Microbiology Reviews,2010年1月,卷23(1),第160-201页)已经综述了β-内酰胺酶抑制的对象。美国专利号7,112,592公开了几种杂环化合物及其作为抗菌剂的用途。
发明人已经惊讶地发现含氮化合物在预防或治疗细菌感染中是有用的。
发明内容
因此,提供了含氮化合物、制备这些化合物的方法、含有这些化合物的药物组合物以及在对象中使用这些化合物来预防或治疗细菌感染的方法。
在一个总的方面,提供了式(I)的化合物:
或其立体异构体或其药学上可接受的盐;其中M是阳离子。
在另一个总的方面,提供了包括式(I)的药物组合物,或其立体异构体或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述方法包括向所述对象给予药学上有效量的式(I)的化合物或其立体异构体或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述感染由产生一种或多种β-内酰胺酶的细菌引起,其中所述方法包括向所述对象给予药学上有效量的式(I)的化合物或其立体异构体或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述方法包括向所述对象给予药学上有效量的药物组合物,所述药物组合物包括式(I)的化合物或其立体异构体或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述感染由产生一种或多种β-内酰胺酶的细菌引起,其中所述方法包括向所述对象给予药学上有效量的药物组合物,所述药物组合物包括式(I)的化合物或其立体异构体或其药学上可接受的盐。
在另一个总的方面,提供了药物组合物,其包括:(a)式(I)的化合物,或其立体异构体或其药学上可接受的盐,以及(b)至少一种抗菌剂或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防和治疗细菌感染的方法,所述方法包括向所述对象提供药学上有效量的:(a)式(I)的化合物,或其立体异构体或其药学上可接受的盐,以及(b)至少一种抗菌剂或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述感染由产生一种或多种β-内酰胺酶的细菌引起,所述方法包括向所述对象给予药学上有效量的:(a)式(I)的化合物,或其立体异构体或其药学上可接受的盐,以及(b)至少一种抗菌剂或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中增加抗菌剂的抗菌效果的方法,所述方法包括所述抗菌剂或其药学上可接受的盐与药学上有效量的式(I)的化合物或其立体异构体或其药学上可接受的盐的共同给药。
下面的内容中详细描述了本发明的一种或多种实施方式。通过下面的说明书包括权利要求书,不难了解本发明的其它特征、目的和优点。
发明详述
现在将参考示例性实施方式,在本文中使用特定的语言对其加以描述。然而,应理解这些实施方式不是旨在限制本发明的范围。任何本领域和相关领域技术人员基于本说明书能够想到的,对本文所描述的本发明特征的替代和进一步改进,以及本文所描述的本发明原理的任何其它应用,都认为在本发明的范围内。必须注意,除非上下文另外明确说明,否则在本说明书和所附权利要求中使用的单数形式的“一个”、“一种”和“所述”包括复数指代物。本说明书引用的所有专利、专利申请和参考文献均通过引用全文纳入本文。
本发明人已惊讶地发现了具有抗菌性质的新型含氮化合物。
本文所用术语“立体异构体”是指含有相同的化学组成,但是在空间上的原子和基团的排列不同的化合物。式(I)的化合物可以含有不对称或手性中心并且,因此以不同的立体异构的形式存在。除非另有说明,式(I)的化合物的所有立体异构形式及其混合物,包括外消旋混合物应被视为形成本发明的部分。另外,本发明包括的所有的几何和位置异构体(包括顺式和反式形式)及其混合物,它们都包括在本发明的范围之内。通常,描述一种化合物时被视为覆盖其立体异构体或多种立体异构体的混合物。
本文所用术语“药学上可接受的盐”是指给定化合物的一种或多种盐,其有游离化合物的所需的药物活性并且不是生物学的或其它方面不合乎希望的。通常,“药学上可接受的盐”是指适于与人和动物的组织接触且没有过度毒性、刺激和过敏反应等,并且与合理的效益/风险比相称。药学上可接受的盐是本领域众所周知的。例如,S.M.Berge等(J. Pharmaceutical Sciences,66:1-19,1977)详细描述了多种药学上可接受的盐,其通过引用纳入本文。
通常,按照本发明的化合物含有碱性部分(如氮原子)和酸性部分(如式(I)的化合物,其中M是氢)。因此,本领域技术人员应该理解这样的化合物,能够形成酸性盐(与无机酸和/或有机酸形成)和碱性盐(与无机碱和/或有机碱形成)。能够使用本领域中描述的步骤制备这样的盐。例如,通过用合适的量的酸处理化合物,碱性部分能够被转化为盐。这样的合适的酸的典型非限制性示例包括盐酸、三氟乙酸或者甲磺酸等。或者,通过用合适的碱处理,酸性部分可以被转化为盐。这样的碱的典型非限制性示例包括碳酸盐、碳酸氢钠、碳酸钾或者碳酸氢钾等。在化合物含有超过一个能够被转化为盐的功能性基团的情况下,每个这样的功能性基团可以独立地被转化为盐。例如,在化合物含有两个碱性氮原子的情况下,一个碱性氮能够与一种酸形成盐而另一个碱性氮能够与另一种酸形成盐。一些按照本发明的化合物同时含有酸性部分和碱性部分,并且因此能够形成内盐或相应的两性分子。通常,按照本发明的式(I)的化合物的所有药学上可接受的盐的形式包括酸加成盐、碱加成盐或者两性分子等,它们被考虑在本发明的范围之内并且通常是指药学上可接受的盐。
本文所用术语“感染”或“细菌感染”包括在对象内或对象上存在细菌,如果其生长受到抑制会对对象产生益处。这样,术语“感染”除了指细菌的存在外也指不希望的正常菌群的存在。术语“感染”包括由细菌引起的感染。
本文所用术语“治疗”、“处理”或“疗法”是指为了预防性和/或治疗性目的给予药物,包括药物组合物或一种或多种药学上有活性的成分。术语“预防性治疗”是指对还没有感染的,但是易于被感染或有感染的风险(预防细菌感染)的对象进行处理。术语“治疗性治疗”指的是对一个已经遭受感染的对象进行给药治疗。本文所用术语“治疗”、“处理”或“疗法”也指在有或没有药学上有活性或惰性成分时,给药本文所述的组合物或一种或多种药学上有活性的成分,从而:(i)减少或消除细菌感染或者一种或多种细菌感染的症状,或者(ii)阻滞细菌感染或一种或多种细菌感染症状的发展,或者(iii)降低细菌感染或一种或多种细菌感染症状的严重程度,或者(iv)抑制细菌感染的临床表现,或者(v)抑制细菌感染的不良症状的表现。
本文所用术语“药学上有效量”或“治疗上有效量”或“有效量”是指具有治疗效果的量或在对象中产生治疗效果所需要的量。例如,抗菌剂或药物组合物的治疗上有效量或药学上有效量是产生需要的治疗效果所需要的抗菌剂或药物组合物的量,所述治疗效果可以通过临床试验结果、模型动物感染研究和/或体外研究(如在琼脂或肉汤培养基中)进行判断。药学上有效量取决于几个因素,包括但不限于涉及的微生物(如细菌)、对象的特征(如身高、体重、性别、年龄和用药史)、感染的严重程度和使用的特定类型的抗菌剂。对于预防性治疗,治疗上有效量或药学上有效量是在预防微生物(如细菌)感染中起到效果的量。
术语“给药”或“给予”包括向对象递送组合物或一种或多种药学上有活性的成分,包括例如通过任意合适的方法,其起到向感染的部位递送组合物或其活性成分或其他药学上有活性的成分的作用。给药的方法可以取决于多个因素变化,例如,药物组合物的组分或药学上活性或惰性成分的类型/性质、潜在或实际感染的部位、涉及的微生物、感染的严重程度以及对象的年龄和身体情况等。按照本发明向对象给予组合物或药学上活性成分的方法的一些非限制性示例包括口服、静脉内、局部、呼吸道内、腹膜内、肌肉内、肠胃外、舌下、透皮、鼻内、气雾、眼内、气管内、直肠内、阴道、基因枪、皮肤贴片、滴眼液、滴耳液或漱口剂。在药物组合物包括超过一种(活性或惰性)成分的情况下,对此类组合物进行给药的方式之一是通过混合各成分(例如以合适的单位剂量的形式如片剂、胶囊、溶液以及粉末等),然后以剂型给药。或者,也可以独立地给药这些成分,只要这些成分达到有益的治疗水平,使得组合物作为整体提供协同和/或希望的效果。
本文所用术语“生长”是指一种或多种微生物的生长并且包括微生物(如细菌)的繁殖或扩增。该术语也包括微生物的持续代谢过程的维持,包括保持微生物存活的过程。
本文所用术语“功效”是指在对象中,治疗或组合物或一种或多种药学上活性的成分产生希望的生物效果的能力。例如,术语组合物或抗菌剂的“抗菌功效”是指所述组合物或抗菌剂在对象中预防或治疗微生物(如细菌)感染的能力。
本文所用术语“协同性”或“协同”是指两种或更多种药剂的相互作用使其组合效果强于它们的单独效果。
本文所用术语“抗菌剂”是指任意物质、化合物或物质组合或化合物组合,其能够:(i)抑制、降低或防止细菌的生长;(ii)抑制或降低细菌在对象中产生感染的能力;或(iii)抑制或降低细菌在环境中繁殖或保持感染性的能力。术语“抗菌剂”也指能够降低细菌感染性或毒性的化合物。
本文所用术语“β-内酰胺抗菌剂”是指具有抗菌性质并且在其分子结构中含有β-内酰胺核的化合物。
本文所用术语“β-内酰胺酶”是指分解β-内酰胺环的任意酶或蛋白或任意其他物质。术语“β-内酰胺酶”包括由细菌产生的,并且具有部分或完全水解β-内酰胺化合物中的β-内酰胺环的能力的酶。
本文所用术语“β-内酰胺酶抑制剂”是指能够部分或完全抑制一种或多种β-内酰胺酶活性的化合物。
术语“药学上惰性成分”或“载体”或“赋形剂”是指用于促进化合物给药例如增加化合物的溶解性,的化合物或物质。固体载体包括,例如淀粉、乳糖、磷酸二钙、蔗糖和高岭土。液体载体包括,例如无菌水、盐水、缓冲液、非离子型表面活性剂和可食用油类如油、花生油和芝麻油。另外,可包含各种本领域中常用的佐剂。这些和其他此类化合物在文献中有描述,例如,在新泽西州罗韦默克公司的默克索引(Merck Index,Merck&Company,Rahway,NJ)。在Gilman等(编)(1990);Goodman和Gilman的《治疗剂的药理学基础》(ThePharmacological Basis of Therapeutics),第8版,培格曼出版公司(PergamonPress)中,描述了在药物组合物中加入各种成分的考虑,它们通过引用全文纳入本文。
本文所用术语“对象”指的是脊椎动物或无脊椎动物,包括哺乳动物。术语“对象”包括人、动物、鸟类、鱼类或两栖类。典型、非限制性的“对象”的例子包括人、猫、狗、马、绵羊、牛、猪、羔羊、大鼠、小鼠和豚鼠。
本文所用术语“头孢特咯瓒(ceftolozane)”是指被称为CXA-101的化合物(CAS注册号:689293-68-3;化学名称:(6R,7R)-3-[(5-氨基-4-{[(2-氨基乙基)氨甲酰基]氨基}-1-甲基-1H-吡唑-2-鎓-2-基)甲基]-7-({(2Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-[(1-羧基-1-甲基乙氧基)亚氨基]乙酰基}氨基)-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸酯)。因此,提及头孢特咯瓒被视为包括其药学上可接受的盐、前药、代谢物、酯、醚、水合物、多形体、溶剂合物、络合物、对映异构体、加合物及其任意其他药学上可接受的衍生物。
在一个总的方面,提供了式(I)的化合物:
或其立体异构体或其药学上可接受的盐;其中M是阳离子。
通常,能够按照方案1-3的一般步骤制备本发明的化合物。本领域技术人员会理解能够改变或进一步优化所述的方法以提供希望的和相关的化合物。在下面的步骤中,所有的变量如上定义。
在另一个总的方面,提供了包括式(I)的药物组合物,或其立体异构体或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述方法包括向所述对象给予药学上有效量的式(I)的化合物或其立体异构体或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述感染由产生一种或多种β-内酰胺酶的细菌引起,其中所述方法包括向所述对象给予药学上有效量的式(I)的化合物或其立体异构体或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述方法包括向所述对象给予药学上有效量的药物组合物,所述药物组合物包括式(I)的化合物或其立体异构体或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述感染由产生一种或多种β-内酰胺酶的细菌引起,其中所述方法包括向所述对象给予药学上有效量的药物组合物,所述药物组合物包括式(I)的化合物或其立体异构体或其药学上可接受的盐。
a:碱,水,室温;b:Boc-酐,TEA,DMAP,DCM,室温;c:LiOH,丙酮;
d:新戊酰氯,TEA;e:氨(g);f:三氟乙酸酐,TEA,DCM
g:TFA,DCM;h:三光气,TEA,DMAP,DCM;i:H2,Pd/C;j:SO3-DMF;
k:四丁基乙酸铵,DCM;l:Dowex50WX8200Na+树脂
a:水,回流,24小时;b:1-羟基苯并三唑铵盐,DCC,DMF;
c:Boc-酐,TEA,DMAP,DCM,室温;d:三氟乙酸酐,TEA,DCM;
e:TMSOI,NaH,DMSO,THF,-10℃1小时;f:O-苄基羟基胺.HCl,EtOAc60℃,2.5小时;
g:甲磺酸,乙酸乙酯,40℃;h:KHCO3,水,55℃;
i:三乙酰氧基硼氢化钠,STABH,H2SO4;j:三光气,TEA,DMAP,DCM;
方案-1:如方案-1所示的其它步骤
a:水,回流,24h;b:1-羟基苯并三唑铵盐,DCC,DMF;
c:Boc-酐,TEA,DMAP,DCM,室温;d:TMSOI,NaH,DMSO,THF,-10℃1小时;
e:O-苄基羟基胺.HCl,EtOAc60℃,2.5小时;f:甲磺酸,乙酸乙酯,40℃;g:KHCO3,水,55℃;g:三乙酰氧基硼氢化钠,STABH,H2SO4;h:三光气,TEA,DMAP,DCM;i:三氟乙酸酐,TEA,DCM;方案-1:如方案-1所示的其它步骤
在一些实施方式中,使用方案1中所述的一般步骤制备式(I)的化合物,其中M是钠。通常,(S)-5-(苄氧基氨基)-哌啶-2-羧酸苄酯草酸盐(II)通过在室温下用合适的碱处理转化为游离的碱,以得到化合物(IIa)。在-5到40℃的温度范围下,在碱和如DMAP的合适催化剂存在的情况下,这个反应是用Boc酐进行的,得到化合物(IIb)。在-5到25℃的温度下,该化合物在用像氢氧化锂的碱水解时得到反式-5-苄氧基氨基-哌啶-1,2-二羧酸-1-叔丁基酯化合物(III)。
在-5到35℃下,在合适的碱如N-甲基吗啉、三乙胺或二异丙基乙胺存在下,在溶剂如二氯甲烷、四氢呋喃、1,4-二噁烷或氯仿中,用酰基氯如新戊酰氯与化合物(III)反应约1-2个小时得到酐(IV)。
随后在-50到5℃的温度范围内,用氨气处理酐(IV)约0.5-2个小时,以得到酰胺中间体化合物(V)。
通过在-5到35℃的温度范围内,通过在合适的溶剂(如甲苯、氯仿、四氢呋喃或二氯甲烷)中,用三氟乙酸酐处理中间体(V)约1-24个小时,实现中间体化合物(V)的脱水效果,以得到腈中间体化合物(VI)。
在-25到50℃的温度范围内,在溶剂(如二氯甲烷、氯仿、乙腈或水)中使用去保护试剂(如三氟乙酸或盐酸),持续约1-24小时,使中间体化合物(VI)去保护,以得到中间体化合物(VII)。在-5到50℃的温度范围内,在碱(如三乙胺或二异丙基乙胺)存在的情况下,通过在溶剂(如甲苯、氯仿、乙腈)中,使用试剂(如光气溶液或双光气或三光气)处理中间体(VII),持续约1-24小时,以实现中间体化合物(VII)的环化,以得到环化的中间体化合物(VIII)。
在25到60℃的温度范围内,在氢源(如氢气、甲酸铵、甲酸或环己烯)存在的情况下,在合适的溶剂(如甲醇、乙醇、甲醇-二氯甲烷混合物或N,N二甲基甲酰胺-二氯甲烷混合物)中,通过使用催化剂(如5%或10%碳载钯或20%碳载氢氧化钯),使中间体化合物(VIII)经过氢解,持续约1-24小时,以得到N-羟基中间体化合物(IX)。
在-5到50℃的温度范围内,通过在溶剂(如吡啶、N,N-二甲基甲酰胺、二氯甲烷或其混合物)中,使中间体化合物(IX)与磺酸化试剂(如吡啶三氧化硫络合物或N,N-二甲基甲酰胺三氧化硫络合物)进行反应,持续约0.5-24小时,从而使所述中间体化合物(IX)磺酸化,得到磺酸的吡啶盐(pyridine salt ofsulfonic acid)(X),随后其用四丁基乙酸铵处理得到磺酸的四丁基铵盐(terabutylammonium salt of sulfonic acid)的中间体化合物(XI)。
通过如下步骤将本发明的化合物分离为钠盐:使得中间体化合物(XI)经过水性四氢呋喃中的钠形式的Dowex50WX8200树脂,然后在减压下蒸发溶剂组分,得到化合物I。
或者,在室温至80℃的温度下,能够通过在溶剂(如丙酮、乙酸乙酯、四氢呋喃、乙醇、异丙醇)中,用乙基己酸钠(当M=Na时)处理化合物XI制备该化合物。
已经制备了这些化合物的各种多形体(当M=Na时)。
在另一个总的方面,提供了药物组合物,包括:(a)式(I)的化合物,或其立体异构体或其药学上可接受的盐,以及(b)至少一种抗菌剂或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防和治疗细菌感染的方法,所述方法包括向所述对象提供药学上有效量的:(a)式(I)的化合物,或其立体异构体或其药学上可接受的盐,以及(b)至少一种抗菌剂或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中预防或治疗细菌感染的方法,所述感染由产生一种或多种β-内酰胺酶的细菌引起,所述方法包括向所述对象给予药学上有效量的:(a)式(I)的化合物,或其立体异构体或其药学上可接受的盐,以及(b)至少一种抗菌剂或其药学上可接受的盐。
在另一个总的方面,提供了用于在对象中增加抗菌剂的抗菌效果的方法,所述方法包括所述抗菌剂或其药学上可接受的盐与药学上有效量的式(I)的化合物或其立体异构体或其药学上可接受的盐的共同给药。
在一些实施方式中,按照本发明的组合物和方法,与至少一种抗菌剂结合使用式(I)的化合物或其立体异构体或药学上可接受的盐。能够使用广泛的抗菌剂。抗菌剂的典型非限制性示例包括一种或多种通常被分类为氨基糖苷类、安莎霉素类、碳头孢烯类、先锋霉素类、头孢霉素类、林可酰胺类(Lincosamides)、脂肽类、大环内酯类、单环β-内酰胺类、硝基呋喃类、青霉素类、多肽类、喹诺酮类、磺酰胺类、四环素类、噁唑烷酮类等的抗菌化合物。
氨基糖苷类抗菌剂的典型非限制性示例包括丁胺卡那霉素、庆大霉素、卡那霉素、新霉素、乙基西梭霉素、妥布霉素、巴龙霉素、阿贝卡星(Arbekacin)、链霉素、阿普拉霉素等。
安莎霉素类抗菌剂的典型非限制性示例包括格尔德霉素、除莠霉素等。
碳头孢烯类抗菌剂的典型非限制性示例包括氯碳头孢等。
碳青霉烯类抗菌剂的典型非限制性示例包括尔他培南(Ertapenem)、多尼培南(Doripenem)、亚胺培南、美洛培南等。
先锋霉素类和头孢霉素类抗菌剂的典型非限制性示例包括头孢唑林、头孢乙腈、头孢羟氨苄、头孢氨苄、头孢来星、头孢洛宁、头孢噻啶、头孢噻吩、头孢吡啉、羟胺唑头孢菌素、头孢西酮、头孢氮氟、头孢拉啶、头孢甲氧环烯胺、头孢替唑、头孢克洛、头孢孟多、头孢米诺、头孢尼西、头孢雷特、头孢替安、头孢丙烯、头孢拉宗、头孢呋辛、头孢唑南、头孢霉素、头孢西丁、头孢替坦、头孢美唑、碳头孢烯、头孢克肟、头孢他啶、头孢曲松、头孢卡品、头孢达肟、头孢地尼、头孢妥仑、头孢他美、头孢甲肟、头孢地嗪、头孢哌酮、头孢噻肟、头孢米唑、头孢匹胺、头孢泊肟、头孢磺啶、头孢特仑、头孢布烯、头孢噻林、头孢唑肟、氧头孢烯、头孢吡肟、头孢唑兰、头孢匹罗、头孢喹诺、头孢吡普、头孢噻呋、头孢喹诺、头孢维星、CXA-101、头孢洛林、头孢吡普等。
林可酰胺类抗菌剂的典型非限制性示例包括克林霉素、林可霉素等。
大环内酯类抗菌剂的典型非限制性示例包括阿奇霉素、克拉霉素、地红霉素、红霉素、罗红霉素、醋竹桃霉素、泰利霉素、壮观霉素等。
单环β-内酰胺类抗菌剂的典型非限制性示例包括氨曲南等。
硝基呋喃类抗菌剂的典型非限制性示例包括呋喃唑酮、呋喃妥因等。
青霉素类抗菌剂的典型非限制性示例包括阿莫西林、氨苄青霉素、阿洛西林、羧苄青霉素、邻氯青霉素、双氯青霉素、氟氯青霉素、美洛西林、甲氧西林、乙氧萘青霉素、苯唑西林、青霉素G、青霉素V、氧哌嗪青霉素、替莫西林、替卡西林等。
多肽类抗菌剂的典型非限制性示例包括杆菌肽、粘菌素、多粘霉素B等。
喹诺酮类抗菌剂的典型非限制性示例包括环丙沙星、依诺沙星、加替沙星、左氧氟沙星、洛美沙星、莫西沙星、萘啶酸、诺氟沙星、氧氟沙星、曲伐沙星、格帕沙星、司氟沙星、替马沙星等。
磺酰胺类抗菌剂的典型非限制性示例包括磺胺米隆、偶氮磺胺(Sulfonamidochrysoidine)、磺胺醋酰胺、磺胺嘧啶、磺胺甲二唑、磺胺甲恶唑、柳氮磺胺吡啶、磺胺异恶唑、甲氧苄啶等。
四环素类抗菌剂的典型非限制性示例包括地美环素、强力霉素、二甲胺四环素、土霉素、四环素、替加环素等。
噁唑烷酮类抗菌剂的典型非限制性示例包括利奈唑胺、兰贝唑来(Ranbezolid)、托勒唑来(Torezolid)、雷得唑来(Radezolid)等。
按照本发明的药物组合物可包括一种或多种药学上可接受的载体或赋形剂等,这样的载体或赋形剂的典型非限制性示例包括甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、交联羧甲基纤维素钠、葡萄糖、明胶、蔗糖、碳酸镁、湿润剂、乳化剂、增溶剂、pH缓冲剂、润滑剂、稳定剂、结合剂等。
按照本发明的药物组合物能够以多种形式存在。在一些实施方式中,所述药物组合物为粉末或溶液的形式。在一些其他的实施方式中,按照本发明的药物组合物是粉末的形式,其能够在胃肠外给药之前通过加入相容的重建稀释剂重建。这样的相容的重建稀释剂的非限制性示例包括水。
在一些其他的实施方式中,按照本发明的药物组合物是冷冻组合物的形式,其能够在胃肠外给药之前通过用相容的稀释剂稀释。
在一些其他的实施方式中,按照本发明的药物组合物以胃肠外即用的形式存在。
在按照本发明的方法中,本文所揭示的药物组合物和/或其他药物活性成分可以通过任意合适的方法给药,其起了向需要的部位递送所述组合物或其组分或所述活性成分的作用。给药的方法能够取决于多个因素变化,例如,药物组合物的组分和活性成分的性质、潜在或实际感染的部位、涉及的微生物(如细菌)、感染的严重程度、对象的年龄和身体情况等。按照本发明向对象给予所述组合物的方法的一些非限制性示例包括口服、静脉内、局部、呼吸道内、腹膜内、肌肉内、肠胃外、舌下、透皮、鼻内、气雾、眼内、气管内、直肠内、阴道、基因枪、皮肤贴片、滴眼液、滴耳液或漱口剂。
按照本发明的组合物能够被配制成各种剂型,其中活性成分和/或赋形剂可以一起存在(如作为混合物)或作为分离的组分存在。当组合物中的各种成分作为混合物配制时,这样的组合物能够通过给予这样的混合物进行递送。在成分不以混合物出现而以分离的组分出现的组合物或剂型情况下,这样的组合物/剂型可以以多种方式给药。在一个可能的方式中,可以以希望的比例混合成分并且然后按照要求给予混合物。或者,组分或成分(活性或惰性)可以被分开(同时或一个接着一个)以合适的比例给予,从而实现相等的混合物的给药所能达到的相同或相等的治疗水平或效果。
相似地,在按照本发明的方法中,取决于要求,本文所揭示的活性成分可以多种方式向对象给药。在一些实施方式中,活性成分以合适的量混合并且然后向对象给予该混合物。在一些其他的实施方式中,活性成分被分开给药。由于本发明考虑到活性成分药物可以被分开给药,本发明还提供以药盒的形式结合分离的药物组合物。所述药盒可包括一种或多种分离的药物组合物,每种药物组合物包括一种或多种活性成分。每个这样的分离的组合物可以存在于分离的容器中,如罐、小瓶、注射器、盒、包等。通常,所述药盒包括分离的组分的给药说明书。当分离的组分优选以不同的剂型(如口服和胃肠外)给药或以不同的剂量间隔给药时,药盒的形式是特别有优势的。当分开给药活性成分时,其可以同时或依次给药。
按照本发明的药物组合物或活性成分可以被配制成各种剂型。剂型的典型非限制性示例包括固体、半固体、液体和气溶胶剂型;例如片剂、胶囊、粉末、溶液、混悬剂、栓剂、气溶胶、颗粒、乳液、糖浆、酏剂等。
通常,本文所述的药物组合物和方法用于预防或治疗细菌感染。较佳地,本文所述的组合物和方法在预防和治疗由细菌引起的感染中也是有效的,所述细菌被认为对于一种或多种已知的抗菌剂或其已知组合物是较不易或不易受影响的。这样的已知对于多种抗菌剂形成耐药性的细菌的一些非限制性示例包括不动杆菌(Acinetobacter)、大肠杆菌(E.coli)、脓假单胞菌(Pseudomonasaeruginosa)、金黄色葡萄球菌(Staphylococcus aureus)、肠杆菌(Enterobacter)、克雷伯菌(Klebsiella)、柠檬酸杆菌(Citrobacter)等。使用本发明的组合物和/或方法可以预防或治疗的感染的其他非限制性示例包括:皮肤和软组织感染、发热性嗜中性白细胞减少症、泌尿道感染、腹内感染、呼吸道感染、肺炎(医院)、菌血症、脑膜炎、手术感染等。
令人惊讶的是,按照本发明的化合物、组合物和方法在预防或治疗由产生一种或多种β-内酰胺酶的细菌引起的细菌感染中也是有效的。按照本发明的组合物和方法治疗这样的β-内酰胺抗生素耐药性细菌的能力在本领域中展现出显著的改进。
通常,按照本发明的式(I)的化合物或其立体异构体或药学上可接受的盐也可用于增加抗菌剂在对象中的抗菌功效。例如通过将一种或多种抗菌剂或其药学上可接受的盐与按照本发明的药学上有效量的式(I)的化合物或其立体异构体或药学上可接受的盐共同给药,可增强所述的抗菌剂的抗菌功效。
对本领域的普通技术人员而言,显而易见的是,可以对本发明进行各种取代和修改而不会偏离本发明的范围和精神。例如,本领域技术人员会理解本发明能用通用说明内描述的多种不同的化合物实践。
实施例
以下的实施例说明现在已知的本发明的实施方式。然而,应该理解,以下内容仅仅是对应用本发明原理的举例或说明。只要不脱离本发明的精神和范围,本领域的技术人员可以对组合物、方法和系统作出许多修改和替代。所附权利要求意在包括这些修改和安排。因此,尽管以上已经对本发明进行了具体描述,以下的实施例进一步提供了有关目前认为是最可行和优选的本发明的实施方式的细节。
反式-7-氧代-6-(磺基氧基(sulphoxy))-1,6-二氮杂双环[3.2.1]-辛烷-2-腈I的
钠盐的制备
步骤1:游离碱的制备和-Boc保护
在水(300ml)和乙酸乙酯(300ml)之间分配草酸盐II(30g,0.0697摩尔),然后搅拌加入碳酸氢钠(11.7g,0.139摩尔)。1小时后分离有机层并且用乙酸乙酯(150ml)对水层进行萃取。用水(150ml)然后用盐水(150ml)洗涤合并的有机层,干燥(用Na2SO4)并且减压蒸发溶剂得到24g的游离碱IIa。
向冷却的5-10℃的DCM(240ml)中的游离碱(24g,0.0705摩尔)的溶液中搅拌加入三乙胺(19.68ml,0.141摩尔)、Boc酐(17.8ml,0.0775摩尔)。在30分钟后,加入DMAP(0.86g,0.00705摩尔)并且所得的溶液升温至室温并进一步搅拌16小时。用饱和氯化铵水溶液(10ml)稀释反应混合物,充分搅拌并且分离DCM层,用水(10ml)洗涤并且最后用盐水(10ml)洗涤。减压蒸发溶剂并且在硅胶柱(60-120目)上进行残留物层析。用乙酸乙酯∶己烷25-50%的混合物洗脱并且合并的部分的浓缩得到25g的无色油状产物(产率:80%)。
MS:439[M+];MF:C26H33NO5;MW:439.
步骤2:苄酯的水解
在0℃下,在剧烈搅拌下,向丙酮(500ml)中的化合物IIb(25g,0.0567摩尔)溶液逐滴加入氢氧化锂溶液(在228.6ml水和76.2ml丙酮的混合物中3.81g,0.0908摩尔)。反应混合物升温至室温,并进一步持续搅拌5小时。所得的混合物冷却至0℃并且用2N HCl(约10ml)将pH调节至8-8.5。在搅拌下用盐水(75ml)和甲苯(250ml)稀释反应混合物,并且在10分钟后分离有机层。用甲苯(2X120ml)再萃取水性层。用2N HCl将水性层酸化至pH3-4并且用乙酸乙酯(3X200ml)萃取溶液。用水(200ml)和盐水(200ml)洗涤合并的有机层,干燥(用Na2SO4),并且减压蒸发溶剂得到21g的浓稠油状产物(定量产率)。
MS:349(M+);MF:C19H27NO5;MW:349
步骤3:酸转化为酰胺
在0℃下向DCM(210ml)中的化合物IV(21g,0.06摩尔)的搅拌溶液加入TEA(25.12ml,0.18摩尔),然后缓慢加入新戊酰氯(11.07ml,0.09摩尔)。进一步搅拌所得混合物1.5小时。反应混合物冷却至-40℃并且用干燥的氨气对反应混合物鼓泡30分钟。反应混合物升温至室温并且滤去悬浮的白色固体。减压蒸发溶剂并且在硅胶柱(60-120目)上进行残留物层析。用丙酮∶己烷体系(1∶4)的混合物洗脱并且浓缩合并的溶剂得到10.2g的浓稠油状产物(产率:49%)。
MS:348[M+];MF:C19H28N2O4;MW:348.
步骤4:酰胺转化为氰基
向冷却(0℃)并且搅拌的DCM(306ml)中的化合物VI(10.2g,0.0286摩尔)的溶液中加入三乙胺(17.99ml,1.289摩尔)然后缓慢加入三氟乙酸酐(12.08g,0.0573摩尔)。所得的溶液升温至室温并且进一步搅拌6小时。用水(100ml,3次)、饱和氯化铵溶液(100ml)和盐水(100ml)洗涤反应混合物。对有机层进行干燥(Na2SO4),并减压蒸发溶剂。使用丙酮∶己烷(1∶19)的混合物将残留物在硅胶柱(60-120目)上层析。浓缩合并的部分得到9.7g的白色固体产物(产率-定量)。
MS:331(M+);MF:C18H25N3O3;MW:331
步骤5:氰基的去保护
向冷冻的(-15℃)和搅拌的在DCM(150ml)中的化合物VII(6g)的溶液中加入三氟乙酸(12ml)并且混合物升温至室温。进一步搅拌反应混合物4小时。在40±5℃下减压蒸发溶剂并且用饱和碳酸氢钠水溶液(60ml)稀释残留物并且用DCM(2X60ml)萃取混合物。用水(60ml)洗涤合并的萃取物,干燥,并且在35±5℃下减压蒸发得到4.2g的化合物VIII。
步骤6:双环化合物的形成
向冷却的(0-5℃)和搅拌的在乙腈(63ml)中的化合物VIII(4.2g)的溶液中加入三乙胺(5.28ml)然后缓慢加入乙腈(16.8ml)中的三光气(1.9g)溶液。进一步搅拌30分钟然后加入二甲基氨基吡啶(0.178g)。反应混合物升温至室温,并进一步搅拌16小时。向反应混合物中加入饱和碳酸氢钠水溶液(33.6ml)并且搅拌所得混合物30分钟。接着减压浓缩该混合物至1/3体积。用水(42ml)稀释残留物并且用DCM(2X42ml)萃取所得混合物。减压蒸发溶剂并且残留物在硅胶柱(60-120目)上进行纯化。用丙酮∶己烷1∶4的混合物洗脱并且浓缩合并的部分得到2.3g白色固体产物(产率:48%)。
MS:314(M+);MF;C16H18N4O3;MW;314
步骤7:TBA硫酸盐的合成
向DCM(30ml)和DMF(30ml)的1∶1混合物中的苄基化合物VIII(6g,0.0233摩尔)的溶液中加入1.5g干燥的10%披钯木炭并且在25-30℃下在3kg氢气压力下氢化3小时。反应混合物通过微米过滤器过滤以去除催化剂并且减压浓缩滤液得到脱苄基的化合物IX。
在氩气氛围下,将脱苄基的化合物(IX)溶解在N,N’-二甲基甲酰胺(30ml)中并且溶液冷却至0℃。向冷却的溶液中加入DMF:SO3(4.26g,0.0278mol)并且在0℃下进一步持续搅拌30分钟。然后使该混合物升温至室温并搅拌1小时。TLC显示N-羟基化合物完全转化为产物X。
含有硫酸盐(X)的溶液被再冷却至0℃并且向其加入四丁基乙酸铵(9g,0.0301mol溶于30ml水中)溶液。反应混合物升温至25℃并且搅拌1小时。减压去除挥发性物质并且用2x50ml二甲苯共蒸发残留物以去除痕量的N,N’-二甲基甲酰胺。残留物在水和二氯甲烷的1∶1混合物(120ml)之间分配。用二氯甲烷(30ml)再萃取水性层。用水(2X30ml)和盐水(30ml)洗涤合并的有机提取物。并且用Na2SO4干燥并减压蒸发溶剂得到粗TBA硫酸盐(5.2g)。用己烷(2X30ml)研磨粗化合物并且在4mmHg压力下在旋转蒸发仪中干燥得到5.0g的TBA盐(XI),产率44%。
质量:硫酸盐246(M-H)M.W:488,M.F:C23H44N4O5S.
步骤8:反式-7-氧代-6-(磺基氧基)-1,6-二氮杂双环[3.2.1]-辛烷-2-腈I的钠盐的合成
TBA硫酸盐(4.4g,0.009mol)溶解于水(2ml)中的5%THF中,并且使溶液通过用Dowex50WX8200Na+树脂填充的柱(45cm长,2.0cm直径)。用5%THF-水混合物(100ml)洗脱柱。减压(4mmHg)蒸发合并的部分以得到1.5g的白色半固体产物,产率:62%。
MS:硫酸盐246(M-H);M.W.:269;M.F.:C7H8N3O5SNa,
1H NMR(DMSO):64.54(d,1H),4.06(s,1H),3.22(m,2H),1.96(m,2H),1.84(m,2H).
当从不同的溶剂中结晶时该化合物的各种多形体的X-射线粉末衍射图谱示于图1-6(以下给出详述)
图1是当从丙酮中结晶时,反式-7-氧代-6-(磺基氧基)-1,6-二氮杂双环[3.2.1]-辛烷-2-腈的钠盐的多形体I的X-射线粉末衍射图谱。
图2是当从乙醇中结晶时,反式-7-氧代-6-(磺基氧基)-1,6-二氮杂双环[3.2.1]-辛烷-2-腈的钠盐的多形体II的X-射线粉末衍射图谱。
图3是当从水中结晶时,反式-7-氧代-6-(磺基氧基)-1,6-二氮杂双环[3.2.1]-辛烷-2-腈的钠盐的多形体III的X-射线粉末衍射图谱。
图4是当从乙腈中结晶时,反式-7-氧代-6-(磺基氧基)-1,6-二氮杂双环[3.2.1]-辛烷-2-腈的钠盐的多形体IV的X-射线粉末衍射图谱。
图5是当从甲苯中结晶时,反式-7-氧代-6-(磺基氧基)-1,6-二氮杂双环[3.2.1]-辛烷-2-腈的钠盐的多形体V的X-射线粉末衍射图谱。
图6是当从四氢呋喃中结晶时,反式-7-氧代-6-(磺基氧基)-1,6-二氮杂双环[3.2.1]-辛烷-2-腈的钠盐的多形体VI的X-射线粉末衍射图谱。
生物活性数据
研究了本发明的代表性化合物对抗各种细菌菌株(与另一种抗菌剂结合)的生物活性。在典型的研究中,适当地稀释过夜生长的细菌培养基并且在含有双倍稀释的抗生素的琼脂培养基上接种。在35±2℃下在环境空气中孵育16-20小时后进行生长或无生长的观察。按照临床实验室标准化研究所(CLSI)的建议(临床实验室标准化研究所(CLSI),《抗微生物敏感性试验的实施标准》(Performance Standards for Antimicrobial Susceptibility Testing),第20版说明增刊,M100-S20,卷30,No.1,2010)实施全过程。这些研究的结果列于表1和表2。表1详述了头孢他啶与按照本发明的代表性化合物(式(I)的化合物,其中M是钠)结合对抗各种产生A、C和D类β-内酰胺酶的MDR(多种药物耐药性)革兰氏阴性菌株的效力。以MIC(mcg/ml)表示活性。为了比较,也提供了各种其它已知的β-内酰胺酶抑制剂如克拉维酸、他唑巴坦、MK-7655和NXL-104的活性。可以看出,按照本发明的化合物的使用显著地降低了抗菌剂的MIC值(例如,在头孢他啶的情况中)。结果也表明当抗菌剂与药学上有效量的式(I)的化合物或其立体异构体或药学上可接受的盐共同给药时,按照本发明的化合物增强了所述抗菌剂的抗菌功效。
表1.式(I)的化合物(其中M是钠)与头孢他啶结合对抗A类、C类和D类ESBL产生菌株的比较活性
所有的抑制剂在4mcg/ml下测试,在该浓度下它们未显示出它们自身的、单独的抗菌活性
表2详述了美洛培南与式(I)的化合物(其中M是钠)结合对抗产生D类ESBL菌株的相应数据。赋予其对碳青霉烯高度的耐药性的产生D类ESBL的病原体是临床环境中的治疗性问题,因为极其有限的治疗选项可用来治疗它们。可以看出,按照本发明的化合物的使用显著地降低了抗菌剂的MIC值(例如,在美洛培南的情况中)。结果也表明当抗菌剂与药学上有效量的式(I)的化合物或其立体异构体或药学上可接受的盐共同给药时,按照本发明的化合物增强了所述抗菌剂的抗菌功效。
表2.WCK4234与美洛培南结合对抗产生D类ESBL的菌株的比较活性
所有的抑制剂在4mcg/ml下测试,在该浓度下它们未显示出它们自身的、单独的抗菌活性
Claims (19)
1.一种式(I)的化合物:
或其立体异构体或其药学上可接受的盐;其中M是阳离子。
2.如权利要求1所述的化合物,其特征在于,M是氢、钠或钾。
3.一种包括权利要求1或2所述的化合物的药物组合物。
4.如权利要求1或2所述的化合物在制备用于在对象中预防或治疗细菌感染的药物中的用途。
5.如权利要求1或2所述的化合物在制备用于在对象中预防或治疗细菌感染的药物中的用途,所述感染由产生一种或多种β-内酰胺酶的细菌引起。
6.如权利要求3所述的药物组合物在制备用于在对象中预防或治疗细菌感染的药物中的用途。
7.如权利要求3所述的药物组合物在制备用于在对象中预防或治疗细菌感染的药物中的用途,所述感染由产生一种或多种β-内酰胺酶的细菌引起。
8.如权利要求3所述的药物组合物,其特征在于,所述药物组合物还包括至少一种抗菌剂或其药学上可接受的盐。
9.权利要求1所述的式(I)的化合物或其立体异构体或药学上可接受的盐以及至少一种抗菌剂或其药学上可接受的盐在制备用于在对象中预防和治疗细菌感染的药物中的用途。
10.权利要求1所述的式(I)的化合物或其立体异构体或药学上可接受的盐以及至少一种抗菌剂或其药学上可接受的盐在制备用于在对象中预防或治疗细菌感染的药物中的用途,所述感染由产生一种或多种β-内酰胺酶的细菌引起。
11.权利要求1所述的式(I)的化合物或其立体异构体或药学上可接受的盐以及至少一种抗菌剂或其药学上可接受的盐在制备用于在对象中增加抗菌剂的抗菌效果的药物中的用途。
12.如权利要求8所述的药物组合物,其特征在于,所述抗菌剂是β-内酰胺抗菌剂。
13.如权利要求9-11中任一项所述的用途,其特征在于,所述抗菌剂是β-内酰胺抗菌剂。
14.如权利要求8所述的药物组合物,其特征在于,所述抗菌剂选自青霉素类、青霉烯类、碳青霉烯类、先锋霉素类和单环β-内酰胺类。
15.如权利要求9-11中任一项所述的用途,其特征在于,所述抗菌剂选自青霉素类、青霉烯类、碳青霉烯类、先锋霉素类和单环β-内酰胺类。
16.如权利要求8所述的药物组合物,其特征在于,所述抗菌剂是选自下组的头孢菌素抗生素:头孢噻吩、头孢噻定、头孢克洛、头孢羟氨苄、头孢孟多、头孢唑林、头孢氨苄、头孢霉定、头孢唑肟、头孢西丁、头孢乙腈、头孢替安、头孢噻肟、头孢磺啶、头孢哌酮、头孢唑肟、头孢甲肟、头孢美唑、头孢来星、头孢尼西、头孢地嗪、头孢匹罗、头孢他啶、头孢曲松、头孢匹胺、头孢拉宗、头孢唑兰、头孢吡肟、头孢瑟利、头孢瑞南、头孢唑南、头孢米唑、头孢克定、头孢克肟、头孢布烯、头孢地尼、头孢泊肟辛酯、头孢泊肟酯、头孢特伦新戊酯、头孢他美酯、头孢卡品酯或头孢妥仑匹酯、头孢呋辛、头孢呋辛酯、氯碳头孢、头孢洛林、头孢特咯瓒和头孢羟羧氧。
17.如权利要求9-11中任一项所述的用途,其特征在于,所述抗菌剂是选自下组的头孢菌素抗生素:头孢噻吩、头孢噻定、头孢克洛、头孢羟氨苄、头孢孟多、头孢唑林、头孢氨苄、头孢霉定、头孢唑肟、头孢西丁、头孢乙腈、头孢替安、头孢噻肟、头孢磺啶、头孢哌酮、头孢唑肟、头孢甲肟、头孢美唑、头孢来星、头孢尼西、头孢地嗪、头孢匹罗、头孢他啶、头孢曲松、头孢匹胺、头孢拉宗、头孢唑兰、头孢吡肟、头孢瑟利、头孢瑞南、头孢唑南、头孢米唑、头孢克定、头孢克肟、头孢布烯、头孢地尼、头孢泊肟辛酯、头孢泊肟酯、头孢特伦新戊酯、头孢他美酯、头孢卡品酯或头孢妥仑匹酯、头孢呋辛、头孢呋辛酯、氯碳头孢、头孢洛林、头孢特咯瓒和头孢羟羧氧。
18.如权利要求8所述的药物组合物,其特征在于,所述抗菌剂选自头孢他啶、头孢吡肟、头孢匹罗、氧哌嗪青霉素、尔他培南、多尼培南、美洛培南、亚胺培南、头孢洛林和头孢特咯瓒。
19.如权利要求9-11中任一项所述的用途,其特征在于,所述抗菌剂选自头孢他啶、头孢吡肟、头孢匹罗、氧哌嗪青霉素、尔他培南、多尼培南、美洛培南、亚胺培南、头孢洛林和头孢特咯瓒。
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Families Citing this family (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8969567B2 (en) * | 2011-09-13 | 2015-03-03 | Wockhardt Ltd. | Nitrogen containing compounds and their use |
MX349827B (es) * | 2011-09-13 | 2017-08-14 | Wockhardt Ltd | Compuestos que contienen nitrogeno y su uso. |
US8916709B2 (en) | 2012-03-30 | 2014-12-23 | Cubist Pharmaceuticals, Inc. | 1,2,4-oxadiazole and 1,2,4-thiadiazole β-lactamase inhibitors |
US8940897B2 (en) | 2012-03-30 | 2015-01-27 | Cubist Pharmaceuticals, Inc. | 1,3,4-oxadiazole and 1,3,4-thiadiazole β-lactamase inhibitors |
CA2869051A1 (en) | 2012-03-30 | 2013-10-03 | Cubist Pharmaceuticals, Inc. | Isoxazole .beta.-lactamase inhibitors |
US8969570B2 (en) | 2012-03-30 | 2015-03-03 | Cubist Pharmaceuticals, Inc. | Beta-lactamase inhibitors |
AR090539A1 (es) | 2012-04-02 | 2014-11-19 | Astrazeneca Ab | COMPUESTOS INHIBIDORES DE b LACTAMASA |
BR112014029368B1 (pt) | 2012-05-30 | 2020-10-27 | Meiji Seika Pharma Co., Ltd | inibidor de beta-lactamase e processo para preparar o mesmo |
JPWO2014069351A1 (ja) * | 2012-11-01 | 2016-09-08 | 株式会社カネカ | 光学活性二環式ウレア化合物の製造方法 |
KR101763056B1 (ko) * | 2013-03-08 | 2017-07-28 | 욱크하르트 리미티드 | (2s,5r)-2-카복스아미도-7-옥소-6-설포옥시-1,6-디아자-비사이클로[3.2.1]옥탄의 나트륨염을 위한 방법 |
NZ711329A (en) * | 2013-03-08 | 2016-06-24 | Wockhardt Ltd | A process for preparation of (2s, 5r)- sulfuric acid mono-{ [(4-aminopiperidin-4-yl) carbonyl]-7-oxo-1,6-diaza-bicyclo[3.2.1]-oct-6-yl} ester |
US9120795B2 (en) | 2013-03-14 | 2015-09-01 | Cubist Pharmaceuticals, Inc. | Crystalline form of a β-lactamase inhibitor |
EP3050883B1 (en) | 2013-09-24 | 2020-04-22 | Meiji Seika Pharma Co., Ltd. | Production method for diazabicyclooctane derivatives and intermediates |
WO2015051101A1 (en) | 2013-10-02 | 2015-04-09 | Cubist Pharmaceuticals, Inc. | B-lactamase inhibitor picoline salt |
BR122022016622B1 (pt) | 2013-10-08 | 2023-11-07 | Meiji Seika Pharma Co., Ltd. | Formas cristalinas de derivado de diazabiciclo-octano, seus processos de produção e uso das mesmas |
WO2015052682A1 (en) * | 2013-10-11 | 2015-04-16 | Wockhardt Limited | Nitrogen containing compounds and their use |
MX2016005160A (es) * | 2013-10-22 | 2016-10-05 | Wockhardt Ltd | Composiciones farmaceuticas que comprenden agentes antibacterianos. |
EP3102578A1 (en) | 2014-02-03 | 2016-12-14 | Wockhardt Limited | A process for preparation of (2s, 5r)-1,6-diaza-bicyclo [3.2.1]octane-2-carbonitrile-7-oxo-6-(sulfooxy)-mono sodium salt |
EP3107539A1 (en) * | 2014-02-20 | 2016-12-28 | Wockhardt Limited | Pharmaceutical combinations comprising antibacterial agents |
EP3116545A1 (en) * | 2014-03-14 | 2017-01-18 | Wockhardt Limited | Pharmaceutical compositions comprising antibacterial agents |
BR112016020333B1 (pt) | 2014-03-24 | 2022-08-09 | Novartis Ag | Compostos orgânicos de monobactam, seus usos, composições e combinações farmacêuticas |
MX2016012648A (es) | 2014-03-29 | 2017-01-11 | Wockhardt Ltd | Proceso para la preparacion de (2s,5r)-6-(benciloxi)-7-oxo-1,6-dia zabiciclo[3.2.1]octano-2-carboxilato de sodio. |
US20170027917A1 (en) * | 2014-04-18 | 2017-02-02 | Wockhardt Limited | Pharmaceutical compositions comprising antibacterial agents |
BR112016024235A2 (pt) | 2014-04-18 | 2017-08-15 | Wockhardt Ltd | composições farmacêuticas compreendendo agentes antibacterianos |
PT3221313T (pt) | 2014-11-17 | 2019-04-15 | Entasis Therapeutics Ltd | Terapia combinada para tratamento de infecções bacterianas resistentes |
ES2821826T3 (es) | 2014-12-05 | 2021-04-27 | Meiji Seika Pharma Co Ltd | Método para producir cristales de derivado de diazabiciclooctano y preparación liofilizada estable |
TW201725205A (zh) | 2015-10-02 | 2017-07-16 | 樂高化學生物科學股份有限公司 | 用於抑制β-內醯胺酶之組合物及方法 |
CN106749242B (zh) * | 2015-11-23 | 2021-04-02 | 上海医药工业研究院 | 阿维巴坦中间体的制备方法 |
MX2021010077A (es) | 2016-09-16 | 2022-05-23 | Entasis Therapeutics Ltd | Compuestos inhibidores de beta-lactamasa. |
JOP20190061A1 (ar) | 2016-09-28 | 2019-03-26 | Novartis Ag | مثبطات بيتا-لاكتاماز |
TW201831482A (zh) * | 2017-02-06 | 2018-09-01 | 法商木塔比利斯公司 | 新穎雜環化合物及其預防或治療細菌感染之用途 |
WO2018193368A1 (en) * | 2017-04-18 | 2018-10-25 | Wockhardt Limited | Antibacterial compositions |
SI3630111T1 (sl) | 2017-05-08 | 2022-05-31 | Entasis Therapeutics, Inc. | Spojine in postopki za zdravljenje bakterijskih okužb |
CA3070036A1 (en) | 2017-07-21 | 2019-01-24 | Antabio Sas | Chemical compounds |
CN109400521B (zh) * | 2017-08-18 | 2020-05-08 | 新发药业有限公司 | 一种改进的5r-苄氧氨基哌啶-2s-甲酸酯、其草酸盐的制备方法 |
EP3572411A1 (en) | 2018-05-21 | 2019-11-27 | Antabio SAS | Thiazole derivatives as metallo-beta-lactamase inhibitors |
US11905286B2 (en) | 2018-08-09 | 2024-02-20 | Antabio Sas | Diazabicyclooctanones as inhibitors of serine beta-lactamases |
CN109870583B (zh) * | 2019-04-15 | 2020-03-06 | 德阳市人民医院 | 急性胰腺炎相关的代谢物及其应用 |
WO2021165927A1 (en) | 2020-02-21 | 2021-08-26 | Wockhardt Bio Ag | 2-cyanopyrroldines, -piperidines or -dazepines as hyperglycemic agents |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1468242A (zh) * | 2000-08-01 | 2004-01-14 | ���ĵ�˹ҩƷ��˾ | 氮杂双环化合物,它们的制备方法以及它们作为药物的应用,特别地作为抗菌剂的应用 |
WO2011042560A1 (en) * | 2009-10-09 | 2011-04-14 | Novexel Sa | Polymorphic and pseudopolymorphic forms of a pharmaceutical compound |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995018129A1 (en) * | 1993-12-29 | 1995-07-06 | Pfizer Inc. | Diazabicyclic neurokinin antagonists |
FR2835186B1 (fr) * | 2002-01-28 | 2006-10-20 | Aventis Pharma Sa | Nouveaux composes heterocycliques, actifs comme inhibiteurs de beta-lactamases |
EP2921559A1 (en) * | 2008-06-19 | 2015-09-23 | Astra Zeneca Holding France | Use of (1r,2s,5r) 1,6-diazabicyclo [3.2.1]octane-2-carboxamide, 7-oxo-6-(sulfooxy)-, monosodium salt as a diagnostic reagent for detecting serine beta-lactamases |
FR2936798B1 (fr) * | 2008-10-03 | 2012-09-28 | Novexel | Nouveaux composes heterocycliques azotes, leur preparation et leur utilisation comme medicaments antibacteriens. |
MX349827B (es) * | 2011-09-13 | 2017-08-14 | Wockhardt Ltd | Compuestos que contienen nitrogeno y su uso. |
-
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1468242A (zh) * | 2000-08-01 | 2004-01-14 | ���ĵ�˹ҩƷ��˾ | 氮杂双环化合物,它们的制备方法以及它们作为药物的应用,特别地作为抗菌剂的应用 |
WO2011042560A1 (en) * | 2009-10-09 | 2011-04-14 | Novexel Sa | Polymorphic and pseudopolymorphic forms of a pharmaceutical compound |
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US9090616B2 (en) | 2015-07-28 |
ZA201308930B (en) | 2015-02-25 |
EP3052497A1 (en) | 2016-08-10 |
CA2846107A1 (en) | 2013-03-21 |
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