CN101641095B - 用于治疗细菌感染的组合药物 - Google Patents
用于治疗细菌感染的组合药物 Download PDFInfo
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- CN101641095B CN101641095B CN2008800093460A CN200880009346A CN101641095B CN 101641095 B CN101641095 B CN 101641095B CN 2008800093460 A CN2008800093460 A CN 2008800093460A CN 200880009346 A CN200880009346 A CN 200880009346A CN 101641095 B CN101641095 B CN 101641095B
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- officinal salt
- carbapenem antibiotics
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- drug products
- salt
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- 208000022218 streptococcal pneumonia Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Abstract
其中氧基亚氨基、即>C=N-O-具有Z-定向的式(I)单环内酰胺抗生素或其可药用盐在制备用于与碳青霉烯抗生素或其可药用盐组合来治疗细菌感染的药物中的用途。
Description
本发明涉及如下文描述的式(I)单环内酰胺抗生素的用途以及包含组合的新的药物产品,所述组合包含所述的化合物和碳青霉烯抗生素。
β-内酰胺抗生素已经广泛用于治疗医院和一般公众场所的细菌感染。有数类已经发现其临床应用的β-内酰胺抗生素,包括青霉素类、头孢菌素类、头霉素类、碳头孢烯类(carbacephems)、氧头孢烯类、碳青霉烯类和单环内酰胺类。
对抗生素耐药的细菌的出现已经消弱了所有这些类别治愈细菌感染的效力。在革兰氏阴性细菌中该耐药性的普遍原因是细菌可表达称为β-内酰胺酶的酶,这些酶能够将β-内酰胺抗生素水解而使其失活。细菌能够产生多种β-内酰胺酶,包括青霉素酶、头孢菌素酶、头霉素酶、碳青霉烯酶、单环内酰胺酶、广谱β-内酰胺酶和超广谱β-内酰胺酶。
单环内酰胺抗生素(例如氨曲南)已经被认为对许多β-内酰胺酶而言是稳定的。尽管如此,仍然有很多革兰氏阴性细菌菌株现在显示出由β-内酰胺酶介导的针对氨曲南的耐药性。
已经将氨曲南、即(Z)-2-[[[(2-氨基-4-噻唑基)[[(2S,3S)-2-甲基-4-氧代-1-磺基-3-氮杂环丁基]-氨甲酰基]亚甲基]氨基]氧基]-2-甲基丙酸与碳青霉烯类(亚胺培南或美罗培南)之间的组合作为克服细菌耐药性的可能方法进行了研究。虽然观察到在氨曲南和碳青霉烯之间存在对抗肠杆菌科(Enterobacteriaceae)的细菌的一定协同作用[Sader HS,Huynh HK,JonesRN;Contemporary in vitro synergy rates for aztreonam combined withnewer fluoroquinolones and β-lactams tested against Gram-negative bacilli;Diagn.Microbiol.Infect.Dis.47(2003)547-550],但是这些组合对抗铜绿假单胞菌(Pseudomonas aeruginosa)的活性没有协同作用或者甚至显示出拮抗作用[Sader HS,Huynh HK,Jones RN;Contemporary in vitro synergyrates for aztreonam combined with newer fluoroquinolones and β-lactamstested against Gram-negative bacilli;Diagn.Microbiol.Infect.Dis.47(2003)547-550;Yamaki K,Tanaka T,Takagi K,Ohta M;Effects ofaztreonam in combination with antipseudomonal antibiotics againstPseudomonas aeruginosa isolated from patients with chronic or recurrentlower respiratory tract infection.J.Infect.Chemother.4(1998)50-55]。
WO 98/47895涉及如下通式的2-氧代-1-氮杂环丁烷磺酸衍生物:
其中氧基亚氨基片段具有如上式所示的‘反’定向。‘反’是用于命名肟化合物的反式异构体的早期术语(前缀‘顺’相应地用于命名肟的顺式异构体);参见:IUPAC黄金书(IUPAC Gold Book);《IUPAC化学术语概要》(IUPAC Compendium of Chemical Terminology),电子版本,http://goldbook.iupac.org/E0204.html和PAC,1996,68,2193,《立体化学的基本术语》(Basic terminology of stereochemistry)(IUPAC推荐,1996),第2207页。所公开的2-氧代-1-氮杂环丁烷磺酸衍生物可用于与碳青霉烯抗生素、包括亚胺培南、美罗培南或比阿培南组合来治疗细菌感染。R1Ref.优选是2-噻吩基并且在所述参考文献的所有示例的发明化合物中使用。除了其它基团以外,R2Ref.可以例如是下式基团:
据描述,氧基亚氨基片段的‘反’(反式)定向提供了与头孢他啶的优良协同作用。参考文献的实施例1例如涉及(3S)-反式-3-[(E)-2-(2-噻吩基)-2-{(1,5-二羟基-4-吡啶酮-2-基甲氧基)亚氨基}-乙酰氨基]-4-甲基-2-氧杂氮杂环丁烷-1-磺酸并且被证明与头孢他啶一起具有对抗多种致病菌株的抗菌活性。
但是,对常规单环内酰胺抗生素如氨曲南的耐药性的形成日益增长。特别是由于这种日益增长的耐药性,一直需要有新的供选物来代替已知的单环内酰胺抗生素以及发现新的抗生素组合。
本发明基于近来发现了新的单环内酰胺抗生素,更具体而言,基于如下新发现:这些单环内酰胺的特定实施方案、即如下文描述的式(I)单环内酰胺抗生素当与其它抗生素、特别是碳青霉烯抗生素组合使用时,显示出对抗宽范围的细菌、包括革兰氏阳性细菌和尤其是革兰氏阴性细菌、包括肠杆菌科和铜绿假单胞菌的效能增强。特别是,对于很多重要的致病细菌菌株而言,式(I)单环内酰胺抗生素与碳青霉烯抗生素的新组合的效力相对于氨曲南与各种碳青霉烯抗生素的组合、例如氨曲南与美罗培南或亚胺培南的组合而言被显著提高。
而且,本发明的组合当与单独的组合组分的最佳效力相比时通常显示出显著提高的对抗细菌的效力,并且通常显示出协同作用、即比从纯粹相加作用所预期的作用更有效的作用。
因此,本发明涉及式(I)单环内酰胺抗生素或其可药用盐在制备用于与一种或一种以上碳青霉烯抗生素或其可药用盐组合来治疗细菌感染的药物中的用途:
其中氧基亚氨基、即>C=N-O-是Z-定向(在上文对WO 98/47895所示的含义上,对应于=顺式定位或顺定位)。
在另一方面,本发明涉及药物产品,其包含如上文所述的式(I)单环内酰胺抗生素或其可药用盐以及一种或一种以上碳青霉烯抗生素或其可药用盐。
这些药物产品代表用于治疗由致病细菌、包括革兰氏阳性细菌和特别是革兰氏阴性细菌引起的感染的改进药物。
根据本发明,特别优选式(I)单环内酰胺抗生素或其盐在制备用于与单一碳青霉烯抗生素或其可药用盐组合来治疗细菌感染的药物中的用途。
式(I)单环内酰胺抗生素可以例如按照以下通用流程1来制备:
流程1
其中“HOBT”代表“羟基苯并三唑”,“DCC”代表“二环己基碳二亚胺”,“TFA”代表“三氟乙酸”。在Org.Process Res.&Dev.2002,863中描述了通式1a化合物和化合物2按照所述流程进行的反应。或者,通式1a化合物与化合物2的偶联反应可以例如用相应的酰氯(Chem.Pharm.Bull.1983,2200)或者用化合物1的活化酯如N-羟基琥珀酰亚氨基酯(参见Org.Process Res.&Dev.2002,863)或硫代酸苯并噻唑基酯(参见J.Antibiotics2000,1071)进行。或者,用于氨基酸偶联反应的其它偶联试剂如羟基氮杂苯并三唑(HOAT)、2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐甲胺鎓(HATU)、O-苯并三唑-N,N,N′,N′-四甲基-脲鎓-六氟磷酸盐(HBTU)可以代替羟基苯并三唑(HOBT)或苯并三唑基氧基三(二甲基氨基)磷鎓六氟磷酸盐(PyBOP)(关于适宜偶联试剂的更多详情,参见N.Sewald,H.-D.Ja-kubke,《肽:化学和生物学》(Peptides:Chemistry and Biology),Wiley-VCH,2002)。
通式1a化合物的制备可以按照常规方法、通过使适当的酮酸1-A3与适当醚化的羟胺1-A4反应来进行,如以下流程2中所示:
流程2
在以上流程2中,由曲酸制备化合物1-A4及化合物1-A4与化合物1-A3的反应例如在EP-A-0 251 299中有详细描述。化合物1-A3可以由化合物1-A0开始、按照以上流程2的上面部分中所示的方法而得到。化合物1-A0可以按照已知方法来制备并且部分可市售获得,例如来自CHEMOSGmbH(93128 Regenstauf,德国)的2-(2-氨基-1,3-噻唑-4-基)乙酸乙酯(式1-A0中的R=乙基)。可以按照GB-A-1 575 804的实施例1的第二步中描述的氧化反应将1-A0氧化为1-A2、例如用二氧化硒将1-A0氧化为1-A2。
流程1的化合物2可以例如按照流程3中的途径来制备:
流程3
其中“DMF.SO3”代表二甲基甲酰胺-三氧化硫复合物,“TFA”代表三氟乙酸。在以上流程3中,原料2-A3可以按照Tetrahedron Lett.(1986,第2789-2792页)的2790页中所述来制备(在J.Org.Chem.2003,68,第177-179页的最后一项实施例中可以找到用于具有旋光活性的(S)-N-Boc-3-羟基缬氨酸(在那里又作为原料被要求)的直接合成)。由2-A3转化为2-A4、转化为2-A5和转化为2例如在J.Antibiotics,1985,第1536-1549页的实施例中有更详细的描述(参见所述参考文献的流程1)。
在以上流程1中,RA代表胺保护基团,例如甲酰基、三氟乙酰基、O-硝基苯氧基乙酰基、氯乙酰基、三氯乙酰基、γ-氯丁酰基、苄氧基羰基、对氯苄氧基羰基、对硝基苄氧基羰基、对溴苄氧基羰基、对甲氧基苄氧基羰基、二苯基-甲氧基羰基、叔丁氧基羰基、异丙氧基羰基、二苯基甲基、三苯基甲基、苄基、对甲氧基苄基、3,4-二甲氧基苄基;且RB和RC相互独立地代表醇保护基团,例如苄氧基羰基、对氯苄氧基羰基、对硝基苄氧基羰基、对溴苄氧基羰基、对甲氧基苄氧基羰基、二苯基-甲氧基羰基、叔丁氧基羰基、异丙氧基羰基、二苯基甲基、三苯基甲基、苄基、对甲氧基苄基、3,4-二甲氧基苄基、三烷基甲硅烷如三甲基甲硅烷、三乙基甲硅烷或叔丁基二甲基甲硅烷。
所述的胺和醇保护基团可以容易地除去、例如通过酸水解或其它众所周知的技术除去。[更多详情参见例如:T.W.Greene等人,《有机化学中的保护基团》(Protective Groups in Organic Chemistry),Wiley intersience,1999]。通式1a化合物中的保护基团可以容易地通过众所周知的合成方法引入。[更多详情参见例如:T.W.Greene等人,《有机化学中的保护基团》,Wiley intersience,1999]。
官能团的脱保护可以通过氢化或通过水解用适当酸在溶剂中进行,所述的酸例如有盐酸、甲酸、乙酸、三氟乙酸、磷酸、NaH2PO4、Na2HPO4、对甲苯磺酸或甲磺酸,所述的溶剂例如有甲醇、乙醇、丙醇、乙酸乙酯、乙腈、二氯甲烷或氯化乙烯。氢化通常在金属催化剂如Pd、Pt或Rh的存在下、在常压至高压下进行。不同官能团的脱保护可以同时或依次进行。
选择用于反应的溶剂是根据所用的反应物进行选择的,选自诸如苯、甲苯、乙腈、四氢呋喃、乙醇、甲醇、氯仿、乙酸乙酯、二氯甲烷、二甲基甲酰胺、二甲基亚砜、六甲基磷酰三胺等的溶剂。还可以使用溶剂混合物。
反应温度将通常是-70℃至150℃。优选的反应物摩尔比为1∶1至1∶5。反应时间为0.5至72小时,这取决于反应物。
式(I)化合物的可药用盐的实例包括例如:无机碱的盐,例如铵盐,碱金属盐、特别是钠或钾盐,碱土金属盐、特别是镁或钙盐;有机碱的盐,特别是由环己胺、苄胺、辛胺、乙醇胺、二乙醇胺、二乙胺、三乙胺、乙二胺、普鲁卡因、吗啉、吡咯啉、哌啶、N-乙基哌啶、N-甲基吗啉、哌嗪作为有机碱衍生的盐;或者与碱性氨基酸如赖氨酸、精氨酸、鸟氨酸、组氨酸等形成的盐。
这类盐可以按照本身已知的方法、例如通过使式(I)化合物与适当的碱反应、优选于室温或在室温以下、例如于约2℃至约25℃使式(I)化合物与适当的碱反应以及分离所形成的盐、例如通过冷冻干燥分离所形成的盐来制备。
式(I)化合物任选以基本上结晶的形式使用。以前尚未描述过基本上结晶的式(I)化合物。它可以通过结晶方法、例如如本申请的实施例中所述获得。对于本申请的目的,术语“基本上结晶”表示相应物质的X-射线粉末衍射(XRPD)图显示出一个或多个分离的峰(distinct peaks),这些峰所具有的最大高度相当于它们在最大高度一半位置的宽度的至少五倍。通常,物质的结晶度随着某个峰的高度与其在最大高度一半位置的宽度的比例的平均值增加而增加。而且,XRPD图应当在整个扫描的2-θ范围内显示出基本上恒定的基线(基线=连接XRPD图曲线最低点的线),这表明在所记录的样品中基本上不存在非晶形物质。对于本申请的目的,“基本上恒定的基线”表示基线优选未上升超过所述图的最低峰的高度。
因此,本发明的另外的主题是基本上结晶形式的式(I)化合物。
在X-射线粉末衍射图(XRPD)中,所述的基本上结晶的式(I)化合物在约6.8±0.1、15.1±0.1、15.6±0.1和25.4±0.1处显示出相对强度大于50%的峰(用Cu K-α放射记录并以[°2-θ]给出),呈现出用Cu K-α放射记录的、基本如下所述的X-射线粉末衍射图:
2Θ[°±0.1°] | 相对强度 |
6.86 | m |
13.32 | w |
13.72 | w |
15.11 | st |
15.57 | vst |
22.84 | w |
25.37 | m |
26.32 | w |
27.08 | w |
28.38 | w |
28.74 | w |
其中:
vst代表相对强度为100%至90%;
st代表相对强度小于90%至65%;
m代表相对强度小于65%至50%;并且
w代表相对强度小于50%至30%,
更具体而言,呈现出用Cu K-α放射记录的和表明相对强度为20%和更高的衍射峰的以下X-射线粉末衍射图:
2Θ[°±0.1°] | 相对强度** |
6.86 | 64±13 |
13.32 | 27±6 |
13.72 | 28±6 |
15.11 | 69±14 |
15.57 | 100±20 |
17.41 | 29±6 |
17.88 | 20±4 |
22.84 | 31±6 |
2Θ[°±0.1°] | 相对强度** |
24.49 | 22±4 |
25.37 | 52±10 |
26.32 | 36±7 |
27.08 | 34±7 |
28.38 | 33±7 |
28.74 | 32±6 |
31.00 | 23±5 |
**相对强度具有所示值的通常变异(typical variation)
已知峰的相对强度的值比线的位置更强地依赖于所测样品的某些性质、例如样品中结晶的大小和/或其定向。因此,所示峰强度可能出现约±20%的变异。
图1显示了用Cu K-α放射记录的式(I)化合物的典型结晶物质的XRPD图。
按照本发明将式(I)化合物及其药学上相容的盐与其它抗生素如特别是碳青霉烯抗生素或其可药用盐组合用作在抗生方面有效的药物来控制或预防哺乳动物(人和非人)的感染性疾病、特别是细菌感染、更特别是其中涉及革兰氏阳性细菌和更优选是其中涉及革兰氏阴性细菌的感染,例如医院性肺炎、社区获得性肺炎、泌尿道感染、复杂性腹腔内感染(complicatedintra-abdominal infection)、复杂性皮肤/皮肤结构感染、囊性纤维化的感染性转剧、脓毒病、类鼻疽。
在该意义上,按照本发明将式(I)化合物及其可药用盐与碳青霉烯抗生素或其可药用盐组合用于这类治疗。虽然不是优选的,但是可以有这样一些情况:其中化合物(I)或其盐与两种或甚至更多种不同的碳青霉烯抗生素的使用可以是有利的并且被指示。
对于本申请的目的,术语“碳青霉烯抗生素”指包含如下结构元素的在抗生方面有效的化合物:
许多碳青霉烯抗生素是本领域已知的,它们通常可以用于本发明的目的。适宜的实例例如在A.BRYSKIER,《“碳青霉烯类”,抗微生物剂:抗细菌剂和抗真菌剂》(″Carbapenems″,ANTIMICROBIAl AGENTS:ANTIBACTERIALS AND ANTIFUNGALS,第270-321页,出版社:美国微生物学协会,华盛顿特区,2005)和其中引用的参考文献中有描述。术语“碳青霉烯抗生素”包括内盐,例如ME 1036或比阿培南。
除了提到的内盐外,碳青霉烯抗生素的其它可药用盐也可以用于本发明的目的,例如由可药用的有机酸和/或无机酸衍生的酸加成盐。
优选根据本发明使用的碳青霉烯抗生素是式(II)化合物或其可药用盐:
其中:
R1代表氢或C1-C6烷基;
R2代表氢或C1-C6烷基;
R3代表氢、C1-C6烷基、C1-C6烷氧基;-(C1nH2n)-R5或-O-(C1nH2n)-R5;
其中:
R5代表卤素、氰基、C1-C6烷氧基、氨基、(C1-C6烷基)氨基、二(C1-C6烷基)氨基或者式-CO-R6、-NH-CO-R6 -CO-NH2、-NH-CO-NH2、-NH-SO2-NH2或-NH-(C=NH)-NH2的基团,在这些基团中,一个或多个氢原子还可以被R6替换或者基团的-NH2残基可以被通过环中存在的氮原子与基团结合的5-6元杂环替换,所述的杂环可以是未取代的或者被一个或多个取代基S2所取代,其中每个S2独立于其它取代基S2而具有以下定义的含义之一;且R6代表C1-C6烷基、苯基或5-6元杂环并且可以是未取代的或者被一个或多个取代基S1所取代,其中每个S1独立于其它取代基S1而具有以下定义的含义之一;且
n是1至6的整数;
R4代表式-(S)m-R7的基团,其中:
m是0或1,且
R7代表氢;未取代的或者被一个或多个取代基S1所取代的C1-C6烷基;未取代的或者被一个或多个取代基S1所取代的苯基;或者含有一个或一个以上选自氮、硫和氧的杂原子的3-6元杂环基,所述的杂环基还可以任选与苯基环或5-6元杂环稠合,并且所述的整个基团是未取代的或者被一个或多个取代基S1所取代;其中每个S1独立于其它取代基S1而选自未取代的或者被一个或多个取代基S2所取代的C1-C6烷基;未取代的或者被一个或多个取代基S2所取代的苯基;或者含有一个或一个以上选自氮、硫和氧的杂原子的3-6元杂环基,所述的杂环基还可以任选与苯基环或5-6元杂环稠合,并且所述的整个基团是未取代的或者被一个或多个取代基S2所取代;C1-C6烷氧基、羟基、羧基、氨基、C1-C6烷基氨基、二(C1-C6)烷基氨基、氰基、卤素或者式-CO-R8、-NH-CO-NH2、-CO-NH2、-NH-CH=NH、-(C=NH)-C1-C6烷基、-NH-CO-NH2、-NH-SO2-NH2或-NH-(C=NH)-NH2的基团,在这些基团中,一个或多个氢原子还可以被R8替换或者基团的-NH2残基可以被通过环中存在的氮原子与基团结合的5-6元杂环替换,所述的杂环可以是未取代的或者被一个或多个取代基S2所取代,其中每个S2独立于其它取代基S2而具有以下定义的含义之一;且
R8代表未取代的或者被一个或多个取代基S2所取代的C1-C6烷基;未取代的或者被一个或多个取代基S2所取代的苯基;或者含有一个或一个以上选自氮、硫和氧的杂原子的3-6元杂环基,所述的杂环基还可以任选与苯基环或5-6元杂环稠合,并且所述的整个基团是未取代的或者被一个或多个取代基S2所取代,其中每个S2独立于其它取代基S2而选自未取代的或者被一个或多个取代基S3所取代的C1-C6烷基;未取代的或者被一个或多个取代基S3所取代的苯基;或者含有一个或一个以上选自氮、硫和氧的杂原子的3-6元杂环基,所述的杂环基还可以任选与苯基环或5-6元杂环稠合,并且所述的整个基团是未取代的或者被一个或多个取代基S3所取代;C1-C6烷氧基、羟基、羧基、氨基、C1-C6烷基氨基、二(C1-C6)烷基氨基、氰基、卤素或者式-CO-R9、-NH-CO-R9、-CO-NH2、-NH-CH=NH、-NH-CO-NH2、-NH-SO2-NH2或-NH-(C=NH)-NH2的基团,在这些基团中,一个或多个氢原子还可以被R9替换或者基团的-NH2残基可以被通过环中存在的氮原子与基团结合的5-6元杂环替换,所述的杂环可以是未取代的或者被一个或多个取代基S3所取代,其中每个S3独立于其它取代基S3而具有以下定义的含义之一;且R9代表未取代的或者被一个或多个取代基S3所取代的C1-C6烷基;未取代的或者被一个或多个取代基S3所取代的苯基;或者含有一个或一个以上选自氮、硫和氧的杂原子的3-6元杂环基,所述的杂环基还可以任选与苯基环或5-6元杂环稠合,并且所述的整个基团是未取代的或者被一个或多个取代基S3所取代,其中每个S3独立于其它取代基S3而代表未取代的C1-C6烷基、未取代的苯基或未取代的5-6元杂环;C1-C6烷氧基、羟基、羧基、氨基、C1-C6烷基氨基、二(C1-C6)烷基氨基、氰基、卤素或者式-NH-CO-NH2、-CO-NH2、-NH-CH=NH、-NH-CO-NH2、-NH-SO2-NH2或-NH-(C=NH)-NH2的基团;或者R3和R4一起形成C3-C7聚亚甲基,该基团是未取代的或者被一个或多个取代基S3所取代,其中每个S3独立于其它取代基S3而具有以上定义的含义之一。
如在本申请中所用的术语“C1-C6烷基”和“-(C1nH2n)-”指支链或者优选直链C1-C6烷基或-(C1nH2n)-,其中n是1至6、优选1至4的整数,例如特别是甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、叔丁基或新戊基。优选C1-C4烷基。术语“C1-C6烷氧基”表示基于根据以上定义的C1-C6烷基的烷氧基。
术语“C3-C7聚亚甲基”指式-(CH2)3-7-的基团,该基团可以包含一条或两条双键并且可以是未取代的或者如所示的那样被取代。
术语“杂环基”和“杂环”指饱和或不饱和的相应基团。
术语“含有一个或一个以上选自氮、硫和氧的杂原子的3-6元杂环基,所述的杂环基还可以任选与苯基环或5-6元杂环稠合”例如指氮杂环丁烷、噻吩、苯并噻吩、呋喃、吡喃、苯并呋喃、异苯并呋喃、吡咯、咪唑、吡唑、吡啶、吡嗪、嘧啶、哒嗪、indazolin(吲唑啉)、吲哚、异吲哚、吲唑、嘌呤、噁唑、异噁唑、呋咱、吡咯烷、吡咯啉、咪唑烷、哌啶、哌嗪、噻唑、异噻唑、硫杂氮杂或氢硫杂氮杂(hydrothiazepin)。适于本发明目的的许多其它杂环基团是技术人员已知的和/或可以容易地在文献中找到。优选含有一个或一个以上选自氮、硫和氧、特别是氮和硫的杂原子的5-6元杂环基团,所述的杂环基还可以任选与苯基环或含有一个或一个以上选自氮、硫和氧、特别是氮和硫的杂原子的5-6元杂环稠合。
“被一个或一个以上......取代”优选表示“被一个或两个......取代”,例如“被一个......取代”。
更优选R5代表卤素、氰基、C1-C6烷氧基、氨基、(C1-C6烷基)氨基、二(C1-C6烷基)氨基或者式-CO-R6、-NH-CO-R6 -CO-NH2、-NH-CO-NH2、-NH-SO2-NH2或-NH-(C=NH)-NH2的基团,其中R6代表C1-C6烷基、苯基或5-6元杂环并且可以是未取代的或者被一个或多个选自如上定义的取代基S3之一的取代基所取代。
术语卤素指氟、氯、溴和碘,优选氟和氯。
另一组特别优选的式(II)化合物是如下定义的化合物:其中R4代表式-(S)m-R7的基团,m是0或1且R7代表含有一个或一个以上选自氮、硫和氧的杂原子的3-6元杂环基团,所述的杂环基还可以任选与苯基环或5-6元杂环稠合,并且所述的整个基团是未取代的或者如以上详细定义的那样被取代。甚至更优选当m是1时的式(II)化合物。
还优选如下定义的式(II)化合物:其中
R1代表氢或C1-C6烷基;
R2代表氢或C1-C6烷基;且
R3代表C1-C6烷基;
特别是当R1和R2之一代表氢且另一个代表-CH3且R3是-CH3时的化合物。
式(III)化合物或其可药用盐形成碳青霉烯的另一组实施方案,其对于本发明的目的而言是特别优选的:
其中:
Y代表氮或>CH-;
S4代表氢或具有如上定义的S1的含义;且
R代表氢;C1-C4烷基、特别是甲基;或-(N=H)-C1-C4烷基、特别是-(N=H)-CH3,或者
S4和R与它们所结合的氮原子或基团Y一起形成5-6元杂环;
R最优选是氢或甲基。
以下碳青霉烯抗生素或其可药用盐是可用于本发明的特别优选的实例:
在医药实践中,帕尼培南通常与倍他米隆一起使用,倍他米隆是一种抑制肾脏对帕尼培南摄取的肾脏抑制剂,这是本领域已知的。
用于本发明的特别优选的碳青霉烯抗生素选自以下化合物或其可药用盐:
本发明的另外优选的主题是如上描述的式(I)单环内酰胺抗生素或其可药用盐在制备用于与亚胺培南或其可药用盐组合来治疗细菌感染的药物中的用途。在医药实践中,亚胺培南通常与西拉司丁(Cilastin)一起使用,西拉司丁是肾脏近端小管中肾脏二肽酶的抑制剂,使用西拉司丁是为了使亚胺培南稳定以对抗失活,这类似于如上提到的倍他米隆与帕尼培南的组合。
本发明的另一项优选的主题是如上描述的式(I)单环内酰胺抗生素或其可药用盐在制备用于与美罗培南或其可药用盐组合来治疗细菌感染的药物中的用途。与亚胺培南类似,美罗培南有时还与西拉司丁一起使用(Antimicrob.Agents Chemother.2000,44,885-890)。
本发明的另一项优选的主题是如上描述的式(I)单环内酰胺抗生素或其可药用盐在制备用于与厄他培南或其可药用盐组合来治疗细菌感染的药物中的用途。
本发明的另一项优选的主题是如上描述的式(I)单环内酰胺抗生素或其可药用盐在制备用于与多利培南或其可药用盐组合来治疗细菌感染的药物中的用途。
根据本发明,式(I)化合物或其可药用盐可以在施用碳青霉烯抗生素或其可药用盐之前、与其同时或在其之后施用。通常优选基本上同时或精确地同时施用组合组分。
式(I)化合物或其可药用盐和碳青霉烯抗生素或其可药用盐可以通过任意施用途径、优选以适于这类途径的药物组合物的形式施用。施用的剂量和途径应该通过病原生物体的敏感性、感染的严重性和部位以及患者的具体状况来确定并由此进行选择。优选的药物组合物类型例如是经口服、通过吸入或者更优选经胃肠道外如经静脉内或经肌内施用的。
用于胃肠道外施用的制剂包括但不限于如下形式:水性等张的无菌注射剂、溶液、用于进一步稀释的浓缩物或溶液(例如对于输注)或者混悬液、包括纳米混悬液和纳米晶体。这些溶液或混悬液可以由无菌粉末、颗粒或冷冻干燥物来制备。可以将化合物溶解在无菌水或各种无菌缓冲液中,所述的无菌缓冲液可以含有但不限于含有氯化钠、聚乙二醇、丙二醇、乙醇、蔗糖、葡萄糖、精氨酸、赖氨酸、枸橼酸、乳酸、磷酸和相应的盐。制剂可以含有0.1%至99%重量、优选10%-90%重量的各活性成分。如果组合物含有剂量单位,则每个单位优选含有50mg至4g的各活性物质。
因此,本发明的另外的主题是包含式(I)化合物或其可药用盐和碳青霉烯抗生素或其可药用盐的药物产品。
本发明的药物产品可以例如包含式(I)化合物或其可药用盐的一个或一个以上剂量单位以及一个或一个以上含有碳青霉烯抗生素或其可药用盐且不含式(I)化合物的其它剂量单位。例如,本发明的药物产品可以包含两个各自包含药物制剂的单独包装,所述药物制剂以适当的剂量形式包含组合组分中的仅一种。
本发明的药物产品的另一项实施方案包含一个或一个以上剂量单位,每个剂量单位既包含式(I)化合物或其可药用盐也包含碳青霉烯抗生素或其可药用盐。这种固定的剂量组合通常包含式(I)化合物或其可药用盐和碳青霉烯抗生素或其可药用盐以及可药用载体和任选的适当的另外赋形剂,所述赋形剂对于各剂量形式而言是常用的。
本发明的药物产品包含适当重量比、例如10∶1至1∶10、优选5∶1至1∶5、更优选3∶1至1∶3如2∶1至1∶2或约1∶1的重量比的式(I)化合物或其可药用盐和碳青霉烯抗生素或其可药用盐。
本发明的药物产品可活性对抗多种细菌生物体,特别是对抗革兰氏阳性细菌,例如包括金黄色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococccus epidermidis)、粪肠球菌(Enterococcus faecalis)、链球菌性肺炎(Streptococcus pneumonia),以及革兰氏阴性细菌,包括肠杆菌科(Enterobacteriaceae),例如大肠埃希氏菌(Escherichia coli)、阴沟肠杆菌(Enterobacter cloacae)、产气肠杆菌(Enterobacter aerogenes)、弗氏柠檬酸杆菌(Citrobacter freundii)、肺炎克雷伯氏菌(Klebsiella pneumoniae)、奥克西托克雷白杆菌(Klebsiella oxytoca)、普通变形杆菌(Proteus vulgaris)、雷氏普罗威登斯菌(Providencia rettgeri);假单胞菌属(Pseudomonas),例如铜绿假单胞菌(P.aeruginosa);不动杆菌属(Acinetobacter),例如鲍氏不动杆菌(A.baumannii);伯克霍尔德菌属(Burkholderia),例如B.cepacea;鼻疽伯克霍尔德菌(B.mallei);假鼻疽伯克霍尔德菌(B.pseudomallei);寡养单胞菌属(Stenotrophomonas),例如嗜麦芽寡养单胞菌(S.maltophilia);流感嗜血杆菌(Haemophilus influenzae)。
因此,产品可以用于治疗感染性疾病,例如包括医院性肺炎、社区获得性肺炎、泌尿道感染、复杂性腹腔内感染、复杂性皮肤/皮肤结构感染、囊性纤维化、脓毒病。
用于所述治疗的式I化合物及其药学上相容的盐和碳青霉烯抗生素或其盐的剂量可以在宽限度内变化,并且在各具体情况下适合于所治疗患者的个体需要和所控制的病原体。通常,在24小时期间施用1至4次的约0.1至约4g、例如约0.5至约2g剂量的总抗生素应该是适当的。
本发明通过以下非限制性实施例进行了进一步说明。
实施例1
羟基磺酸(3S)-3-{(2Z)-2-(2-氨基(1,3-噻唑-4-基))-3-[(1,5-二羟基-4-氧代(2-氢
吡啶基))甲氧基]-3-氮杂丙-2-烯酰基氨基}-4,4-二甲基-2-氧代氮杂环丁基酯
(式(I)化合物)的制备
按照流程4中概述的合成以及按照下述方法制得单环内酰胺抗生素I。
羟基磺酸(3S)-3-{(2Z)-3-{[1,5-双(二苯基甲氧基)-4-氧代(2-氢吡啶基)]甲氧
基}-2-{2-[(三苯基甲基)氨基](1,3-噻唑-4-基)}-3-氮杂丙-2-烯酰基氨基}-4,4-
二甲基-2-氧代氮杂环丁基酯(3)的制备
使用HOBt作为偶联试剂
于室温将(2Z)-3-{[1,5-双(二苯基甲氧基)-4-氧代(2-氢吡啶基)]-甲氧基}-2-{2-[(三苯基甲基)氨基](1,3-噻唑-4-基)}-3-氮杂丙-2-烯酸1(0.89g,0.95mmol,J.Antibiotics 1990,1450和WO-A-02/22613)、羟基苯并三唑(HOBT)(0.14g,1.03mmol)和二环己基碳二亚胺(0.26g,1.41mmol)溶解在DMF(25mL)中。首先将羟基磺酸(3S)-3-氨基-4,4-二甲基-2-氧代氮杂环丁基酯2(0.20g,0.95mmol,J.Org.Chem.2003,177和Tetrahedron Lett.1986,2786)加入到先前的溶液中,然后30min后加入NaHCO3(0.09g,1.05mmol)。将产生的混合物搅拌18h。将形成的沉淀物过滤,将乙酸乙酯加入到滤液中。使用用NaCl饱和的水溶液将有机相洗涤2次,通过Na2SO4干燥,真空蒸发溶剂。将残余物用乙酸乙酯(30mL)研制,过滤后得到0.5g白色固态的预期化合物3。
HPLC纯度:98%。
使用HATU作为偶联试剂
于室温将含有HATU(1.38g,3.64mmol)的DMSO(10mL)溶液加入到(2Z)-3-{[1,5-双(二苯基甲氧基)-4-氧代(2-氢吡啶基)]甲氧基}-2-{2-[(三苯基甲基)氨基](1,3-噻唑-4-基)}-3-氮杂丙-2-烯酸1(3.0g,3.16mmol,J.Antibiotics 1990,1450和WO-A-02/22613)和羟基磺酸(3S)-3-氨基-4,4-二甲基-2-氧代氮杂环丁基酯2(1.18g,5.06mmol,J.Org.Chem.2003,177和Tetrahedron Lett.1986,2786)在DMSO(20mL)中的混悬液中。然后加入固体NaHCO3(0.81g,9.65mmol)。所得混合物1小时后变为液体,将所得混合物于室温搅拌24小时。然后加入乙酸乙酯(50mL),将产生的溶液用盐水(6×30mL)洗涤6次。将有机相通过Na2SO4干燥,通过真空蒸发溶剂将混合物浓缩至瓶中剩余约25mL溶液。于室温将环己烷(40mL)逐滴加入到该黄色溶液中。通过过滤收集产生的沉淀物,然后将滤饼用环己烷(2×5mL)洗涤,得到3.3g预期的化合物3。
HPLC纯度:95%。
两种方法产生了具有相同NMR和MS光谱的产物。
1H-NMR(DMSO-d6)δ:1.05(s,3H),1.34(s,3H),4.49(d,1H,J=7.8Hz),4.62(m,2H),6.12(s,1H),6.33(s,1H),6.39(s,1H),6.72(s,1H),7.20-7.43(m,35H),7.72(s,1H),8.83(1,1H),9.52(d,1H,J=7.8Hz).
羟基磺酸(3S)-3-{(2Z)-2-(2-氨基(1,3-噻唑-4-基))-3-[(1,5-二羟基-4-氧代(2-氢
吡啶基))甲氧基]-3-氮杂丙-2-烯酰基氨基}-4,4-二甲基-2-氧代氮杂环丁基酯
(I)的制备
(a)使用三氟乙酸
将羟基磺酸(3S)-3-{(2Z)-3-{[1,5-双(二苯基甲氧基)-4-氧代(2-氢吡啶基)]甲氧基}-2-{2-[(三苯基甲基)氨基](1,3-噻唑-4-基)}-3-氮杂丙-2-烯酰基氨基}-4,4-二甲基-2-氧代氮杂环丁基酯3(0.25g,0.23mmol)和三乙基甲硅烷(0.08g,0.69mmol)溶解在二氯甲烷(15mL)中,于-10℃冷却。然后将三氟乙酸(1.04g,9.2mmol)缓慢加入到冷却的混合物中。将温度缓慢升至25℃,将反应物另外搅拌4h。真空除去溶剂,将残余物用含有己烷和乙酸乙酯(1∶4)的溶剂混合物研制,得到0.11g预期的固体化合物I。
HPLC纯度:94%。
(b)使用甲酸
于5℃将羟基磺酸(3S)-3-{(2Z)-3-{[1,5-双(二苯基甲氧基)-4-氧代(2-氢吡啶基)]甲氧基}-2-{2-[(三苯基甲基)氨基](1,3-噻唑-4-基)}-3-氮杂丙-2-烯酰基氨基}-4,4-二甲基-2-氧代氮杂环丁基酯3(0.40g,0.31mmol)加入到甲酸(3mL)中,于5-10℃将澄清溶液搅拌5h。然后加入乙酸乙酯(40mL),将产生的沉淀物滤出。将白色沉淀物另外用乙酸乙酯(2×5mL)洗涤,在真空下干燥后得到0.09g预期的化合物I。
HPLC纯度:92%。
两种方法产生了具有相同NMR和MS光谱的产物。
1H-NMR(DMSO-d6)δ:1.22(s,3H),1.42(s,3H),4.63(d,1H,J=7.7Hz),5.28(s,2H),6.81(s,1H),7.13(s,1H),7.27(br s,2H),8.19(s,1H),9.59(d,1H,J=7.7Hz).
-ESI-MS光谱:m/z:517[M-H]+。
按照上述方法,通常得到非晶形的式(I)化合物。虽然它可以以所述的形式使用,但是它可以任选被转化为结晶物质,例如如下文所述。
式I化合物的结晶方法
于室温将先前制备的式I化合物的粗物质(1.31g)混悬在乙腈(15mL)中。然后将水(3.30mL)加入到前混悬液中。于室温将澄清溶液(如果溶液不澄清,则可以将混悬液微热)搅拌数分钟直到开始结晶。于室温将混悬液搅拌1h,于0℃另外搅拌1小时。过滤后,得到1.05g式I化合物,为白色结晶物质,它具有与前面对非晶形物质所报道相同的NMR和MS光谱。
通过如下表所列的红外光谱表征了该结晶物质(在2cm-1的分辨率下用粉末记录了FTIR,从4000至500cm-1收集了16次扫描,带有ATR Goldengate的Bruker Vector 22分光计)。
式(I)化合物的结晶物质的FTIR光谱:
波数(cm-1) | 波数(cm-1) |
3102.51 | 1010.65 |
2739.68 | 941.13 |
1766.15 | 907.87 |
1634.10 | 861.18 |
1587.99 | 823.99 |
1527.49 | 802.53 |
1449.58 | 712.18 |
1357.88 | 678.48 |
1335.03 | 628.91 |
1286.46 | 583.63 |
1239.18 | 569.68 |
1204.65 | 550.26 |
1165.49 | 536.37 |
1129.59 | 525.52 |
1044.69 | 515.44 |
1021.99 |
该结晶物质显示出如下表和图1中所示的使用CuKα放射得到的X-射线粉末衍射(“XRPD”)图。
XRPD图
2θ角(°) | 相对强度% |
6.86 | 64 |
7.19 | 3 |
10.73 | 7 |
10.97 | 5 |
13.32 | 27 |
13.72 | 28 |
15.11 | 69 |
15.57 | 100 |
17.41 | 29 |
17.68 | 13 |
17.88 | 20 |
18.78 | 15 |
18.95 | 14 |
19.34 | 16 |
19.76 | 4 |
20.38 | 8 |
20.66 | 16 |
20.86 | 15 |
21.55 | 3 |
22.27 | 10 |
22.84 | 31 |
23.45 | 18 |
23.62 | 19 |
23.97 | 16 |
2θ角(°) | 相对强度% |
24.49 | 22 |
24.87 | 16 |
25.37 | 52 |
26.32 | 36 |
27.08 | 34 |
27.74 | 12 |
28.38 | 33 |
28.74 | 32 |
29.17 | 11 |
29.97 | 10 |
30.53 | 12 |
31.00 | 23 |
32.47 | 2 |
33.27 | 17 |
34.47 | 5 |
36.12 | 3 |
37.04 | 9 |
37.44 | 6 |
37.98 | 12 |
38.19 | 12 |
38.68 | 9 |
39.30 | 5 |
39.75 | 7 |
2θ角具有的误差为约±0.1°。已知峰的相对强度的值比线的位置更强地依赖于所测样品的某些性质、例如样品中结晶的大小和其定向。因此,所示峰强度可能出现约±20%的变异。
而且,还通过如下表中所示和采用10度/min的扫描速率(珀金埃尔默(Perkin-Elmer)TGS2)得到的热重量分析(“TGA”)数据表征了该结晶物质。当该物质的温度从室温升至100℃时,该物质的失重约为7%。于192-193℃观察到了另外的失重,该温度对应于样品的熔化/分解温度。
温度[℃] | 失重[%] |
25 | 1.12 |
50 | 4.46 |
75 | 5.70 |
100 | 8.05 |
125 | 8.09 |
150 | 8.14 |
175 | 8.29 |
200 | 55.60 |
225 | 56.10 |
250 | 56.31 |
275 | 56.52 |
300 | 56.75 |
325 | 57.06 |
350 | 57.55 |
375 | 58.35 |
400 | 29.54 |
425 | 60.99 |
450 | 62.51 |
475 | 63.95 |
500 | 65.30 |
实施例2
(a)式I化合物的钠盐的制备
将碳酸氢钠(0.0077g,0.095mmol)分批加入到含有式I化合物(0.05g,0.1mmol)的于5℃冷却的水溶液(20mL)中(pH2-3)。于5℃将澄清溶液搅拌15分钟(pH5-6)。将溶液冷冻并冷冻干燥过夜,得到0.052g白色固体。1H-NMR(DMSO-d6)δ:1.24(s,3H),1.45(s,3H),4.65(d,1H,J=7.7Hz),5.20(s,2H),6.82(s,1H),6.90(s,1H),7.26(br s,2H),7.95(s,1H),9.60(d,1H,J=7.7Hz).
(b)式I化合物的L-精氨酸盐的制备
于室温将式I化合物(0.20g,0.39mmol)和L-精氨酸(0.0672g,0.39mmol)以固体形式一起剧烈混合。将产生的粉末溶解在水(40mL)中,于室温搅拌2-3min。将溶液冷冻并冷冻干燥过夜,得到0.260g白色固体。
1H-NMR(DMSO-d6)δ:1.24(s,3H),1.44(s,3H),1.50-1.80(m,4H),3.11(br m,2H),3.53(br m,1H),4.65(d,1H,J=7.7Hz),5.10(s,2H),6.72(s,1H),6.80(s,1H),7.22(brs,2H),7.72(s,1H),8.13(br s,1H),9.60(d,1H,J=7.7Hz).
(c)式I化合物的L-赖氨酸盐的制备
于室温将式I化合物(0.20g,0.39mmol)和L-赖氨酸(0.0564g,0.39mmol)以固体形式一起剧烈混合。将产生的粉末溶解在水(45mL)中,于室温搅拌2-3min。将溶液冷冻并冷冻干燥过夜,得到0.250g白色固体。1H-NMR(DMSO-d6)δ:1.24(s,3H),1.30-1.80(m,9H),2.77(br m,2H),3.50(br m,1H),4.66(d,1H,J=7.7Hz),5.11(s,2H),6.73(s,1H),6.79(s,1H),7.22(br s,2H),7.73(s,1H),9.61(d,1H,J=7.7Hz).
实施例3
按照由全国临床实验标准委员会(NCCLS文件M7-A6)描述的标准方法测定了化合物及其组合对抗供选生物体的抗微生物活性。根据化合物的水溶性将其溶解在100%DMSO或无菌肉汤中,在微生物生长培养基(IsoSensiTest肉汤+16μg/mL 2,2′-联吡啶)中稀释至最终反应浓度(0.06-32μg/mL)。在所有情况下,与细菌一起孵育的DMSO的终浓度小于或等于1%。为了估计最小抑制浓度(MIC),将化合物的2倍稀释物加入到含有106个细菌/mL的微量滴定板的孔中。在适当的温度(30℃或37℃)下将板孵育过夜,用肉眼评估光密度。MIC值被定义为完全抑制受试生物体的可见生长的最低化合物浓度。在与上文相同的条件下进行协同试验,但是有两种抗微生物剂被分配在方格板模式中[Isenberg HD(1992)协同试验:肉汤微稀释方格板和肉汤大量稀释法,在《临床微生物学方法手册》(ClinicalMicrobiology Procedures Manual),第1卷,华盛顿特区:美国微生物学协会,第5.18.1至5.18.28节]。所用菌株为:铜绿假单胞菌6067(在DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH,Inhoffenstr.7B,D-38124 Braunschweig的登记号:DSM 18987)、铜绿假单胞菌(67/2B)2R.A.(DSM 18988)、木糖氧化无色杆菌(Achromobacter(以前称为产碱杆菌属(Alcaligenes))xylosoxidans)QK3/96(DSM 18991)、产气肠杆菌Zayakosky 5(DSM 18992)。
氨曲南以及化合物A和化合物B(后两种化合物在WO 98/47895中公开)用作对比物,它们在结构上与式I化合物类似。
表1显示,将相等重量的本发明的式(I)单环内酰胺抗生素和式II碳青霉烯进行组合使得碳青霉烯对抗碳青霉烯耐药菌株的MIC降低,降低的量多于由两种活性化合物的组合所预期的量。本发明的组合的MIC也小于氨曲南和相应的碳青霉烯的类似的等重量组合的MIC。最后,其证明
本发明的组合显示出的MIC值低于WO 98/47895、例如WO 98/47895的实施例1(对应于表1中提到的化合物A)的组合的MIC值。
表1:单环内酰胺抗生素和碳青霉烯之间的代表性组合的最小抑制浓度(mg/L)
*本申请的化合物
按照下式测定部分抑制浓度(FIC,fractional inhibitory concentrations):
[Isenberg HD(1992);Eliopoulos,G.M.&Moellering,R.C.(1996).《实验室医学中的抗生素》(Antibiotics in Laboratory Medicine),第4版,(Lorian,V.,编者),第330-96页.Williams和Wilkins,Baltimore,MD.]。
表2显示了采用方格板滴定法测定的式I化合物或参比化合物氨曲南、化合物A和化合物B与碳青霉烯之间的相互作用。仅在式I化合物与碳青霉烯抗生素之间观察到了相加或协同的相互作用。在相同条件下,含有氨曲南、化合物A或化合物B的组合显示不相关或者甚至显示出拮抗作用。
FIC值的解释是根据Sader HS,Huynh HK,Jones RN;Contemporaryin vitro synergy rates for aztreonam combined with newerfluoroquinolones and β-lactams tested against Gram-negative bacilli;Diagn.Microbiol.Infect.Dis.47(2003)547-550给出的,即如下解释:
S=FIC≤0.5:协同作用
s=0.5<FIC<1:部分协同作用
D=FIC=1:相加作用
I=1<FIC<4:不相关
N=4≤FIC:拮抗作用
表2:对单环内酰胺抗生素和碳青霉烯之间的代表性组合所观察到的部分抑制浓度(FIC)
Claims (17)
2.根据权利要求1的用途,用于与一种所述碳青霉烯抗生素或其可药用盐组合来治疗细菌感染。
6.根据权利要求2的用途,其中碳青霉烯抗生素是:
或其可药用盐。
8.根据权利要求7的药物产品,包含一个或一个以上含有所述式(I)化合物或其可药用盐的剂量单位以及一个或一个以上含有所述碳青霉烯抗生素或其可药用盐的剂量单位。
9.根据权利要求7的药物产品,包含一个或一个以上剂量单位,每个所述的剂量单位既包含所述式(I)单环内酰胺抗生素或其可药用盐也包含所述碳青霉烯抗生素或其可药用盐:
其中氧基亚氨基、即>C=N-O-具有Z-定向。
10.根据权利要求8或9的药物产品,其中碳青霉烯抗生素是亚胺培南或其可药用盐。
11.根据权利要求8或9的药物产品,其中碳青霉烯抗生素是美罗培南或其可药用盐。
12.根据权利要求8或9的药物产品,其中碳青霉烯抗生素是厄他培南或其可药用盐。
13.根据权利要求8或9的药物产品,其中碳青霉烯抗生素是多利培南或其可药用盐。
14.根据权利要求8或9的药物产品,其中式(I)单环内酰胺抗生素或其可药用盐和碳青霉烯抗生素或其可药用盐的重量比为3∶1至1∶3。
15.根据权利要求7或9的药物产品,其是包含所述式(I)单环内酰胺抗生素或其可药用盐和所述碳青霉烯抗生素或其可药用盐以及可药用载体的组合物。
16.根据权利要求8或9的药物产品,与产品中包含的所述式(I)化合物或其可药用盐和所述碳青霉烯抗生素或其可药用盐在单独使用时的效能相比,其显示出对抗革兰氏阴性细菌的协同效能。
17.根据权利要求8或9的药物产品,用于治疗医院性肺炎、社区获得性肺炎、泌尿道感染、复杂性腹腔内感染、复杂性皮肤/皮肤结构感染、囊性纤维化、脓毒病。
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