CN102227411B - 抗菌化合物 - Google Patents
抗菌化合物 Download PDFInfo
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- CN102227411B CN102227411B CN200980148065.8A CN200980148065A CN102227411B CN 102227411 B CN102227411 B CN 102227411B CN 200980148065 A CN200980148065 A CN 200980148065A CN 102227411 B CN102227411 B CN 102227411B
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
本发明披露了用于治疗细菌疾病和感染的式(I)化合物、包含这些化合物的组合物、以及利用化合物治疗细菌疾病和感染的方法。特别地,该化合物可用于治疗艰难梭菌(Clostridium difficile)感染和艰难梭菌引起的疾病。
Description
技术领域
本发明涉及用于治疗细菌疾病和感染的化合物,包含这些化合物的组合物以及利用该化合物治疗细菌疾病和感染的方法。特别地,本发明化合物用于治疗艰难梭菌(Clostridium difficile)感染及艰难梭菌引起的疾病。
背景技术
(a)抗菌药物和艰难梭菌
抗菌药物的发展代表20世纪最重要的医疗进展之一。先前无法医治的疾病现在很容易得到控制,人们认为许多疾病都可以用这些新的神奇药物根除。尽管治疗上已取得这些显著进展,但在美国传染病是死亡率的第三个主要原因(Clin.Infect.Dis.,2004,38,1279-1286),而且仍然是最重要的全球医疗保健问题之一。所有的主要病原菌耐药率有了急剧的升高,逐渐增加的医院感染数目和严重性受到特别关注(Infectious Disease Societyof America,2004,Bad Bugs,No Drug)。抗多种药物的病原体的出现,已使得许多当前一线药物对许多疾病的控制彻底无效。
受关注细菌病原体的特定亚型是归类为产芽孢细菌的那些。细菌芽孢(内生孢子)是由细菌响应于环境应力所形成的休眠、非繁殖结构。一旦环境条件变得有利,该芽孢就会发芽(出芽,germinate)并且该细菌就会增殖。在病原细菌的情况下,人宿主中的发芽可导致疾病。
细菌芽孢对许多药剂以及包括辐射、干燥、温度、饥饿在内的环境条件和化学药剂都具有极大的耐受性。这种对化学药剂的天然耐受性使得芽孢能够在重要环境(关键环境,key environment)中持续存在数月,例如医院、其它医疗保健中心和食品生产设施中,在这些环境中标准清洗剂、杀菌剂和灭菌工艺都无法根除该细菌。生产食品时,芽孢的存在可能会造成从简单的食物腐败到食源性病原体蔓延及食物中毒的严重后果。最近,与炭疽的致病物,炭疽芽孢杆菌(Bacillus anthracis)的芽孢关联的风险受到关注。这些芽孢容易制成可通过多种方法传播的干粉,并可以用作生物恐怖剂(bioterrorist agent)。炭疽被认为是最令人担忧的生物恐怖剂之一(CDC Emerg.Infect.Dis.,2004,5(4),552-555)。2001年美国发生的邮政炭疽病毒攻击事件就突显了这点。证实有22例感染,导致5例死亡,攻击之后的清理和净化费用估计为10亿美元。
重要的产芽孢细菌为芽孢杆菌属(Bacillus)和梭菌属(Clostridium)的革兰氏阳性产内生孢子细菌。关系到健康的芽孢杆菌属的实例包括,但不局限于炭疽芽胞杆菌(B.anthracis)和蜡样芽胞杆菌(B.cereus)。炭疽芽胞杆菌作为炭疽的致病物而受到特别关注。炭疽感染可以通过摄食、吸气或皮肤与炭疽芽胞杆菌芽孢接触而发生,导致三种不同的临床形式。皮肤感染约占所有感染的95%,一般利用合适的抗生素可以得到有效控制。未经治疗的皮肤炭疽病例中,约有20%导致死亡。肠感染的特点是急性肠道炎症,导致恶心、食欲不振、呕吐、发热、腹痛、呕血和严重腹泻。肠炭疽可导致25%~60%的病例死亡。最严重的疾病形式是肺炭疽,即使积极、及时地给予抗生素,其通常也是致命的。容易通过空气大范围内分散炭疽芽孢从而诱导肺炭疽的能力,使得炭疽成为主要的生物恐怖剂。
梭菌属成员为革兰氏阳性的产芽孢专性厌氧微生物。引起人类疾病的示例物种包括,但不局限于产气荚膜梭菌(C.perfringens)、破伤风梭菌(C.tetani)、肉毒梭菌(C.botulinium)、索氏梭菌(C.sordellii)和艰难梭菌(C.difficile)。梭菌与多种多样的人疾病关联,包括破伤风、气性坏疽(gasgangrene)、肉毒中毒(botulism)和伪膜性结肠炎(pseudomembraneouscolitis),并可能是食物中毒的致病物。
由艰难梭菌引起的疾病受到特别的关注。艰难梭菌引起艰难梭菌相关性疾病(CDAD),在过去的10年中病例数目已增长了10倍,其中超毒性(hyper-virulent)耐药菌株现正变得流行。最新HPA数字显示,2006年英国65岁以上的患者中有55,681例艰难梭菌感染病例(达到过去年份的8%)。也许最令人担忧的是潜在抗生素使用现在还未被报道的CDAD病例。
艰难梭菌是共生肠道细菌,该细菌水平由正常肠道菌群(normal gutflora)抑制。然而,该细菌是艰难梭菌相关性疾病(CDAD)的致病物,并已被确认为CDAD的最严重表现,伪膜性结肠炎的主要原因。CDAD与从轻度腹泻到伪膜性结肠炎、中毒性巨结肠和死亡的各种各样的症状相关联。形成CDAD的主要危险因素是抗生素的使用破坏了正常肠道菌群,导致艰难梭菌过度生长。虽然克林霉素(clindamycin)是与CDAD关联的主要抗生素,但该疾病现在与几乎所有的抗生素都关联,包括氟喹诺酮(fluoroquinolone)、头孢菌素(cephalosporin)、大环内酯物(macrolide)、β-内酰胺和许多其它类别的成员。
CDAD主要在医院环境中受到关注,并且在死亡率特别高的老年患者中受到特别的关注。报道近年来CDAD发生率急剧增大,2006年英国报道了超过55,000个病例(Health Protection Agency Surveillance ofHealthcare Associated Infections Report 2007)。
在美国,死亡率已从1999年的每100万人口中5.7人死亡上升到2004年的每100万人口中23.7人死亡。普通人群的艰难梭菌定殖率(colonisationrates)多达3%,然而住院使得该定殖率急剧增加到多达25%。新流行菌株的出现受到特别关注。特别相关的实例是超毒性的(hyper-virulent)BI/NAP1(也称为核糖核酸型027)菌株,其产生的毒素A和B增多并产生其它新型二元毒素(binary toxins)。
与梭菌关联的关键因素是医院环境中存在的高细菌芽孢率。最近已显示,正使用的许多标准的医院去垢剂都无法根除该环境中的梭菌芽孢,导致疾病控制无效(Infect Cont.Hosp.Epidemiol.,2007,28,920-5)。诸如BI/NAP1等菌株的过多孢子形成(hyper-sporulaion)特性是引起该问题的重要原因。
虽然与CDAD关联的主要风险因素是潜在的抗生素使用和年龄(CMAJ,2008,179(8),767-772;J.Antimicrob.Chem.,2003,51,1339-1350),但还有很多其它相关因素,包括例如质子泵抑制剂的使用、H2受体拮抗剂的使用、利尿剂的使用、住院时间长短(length of hospitalstay)、饲管的使用、机械通气和潜在的共病率(co-morbidity)。
胃酸度是抵御所摄取病原体的天然防御机制的一部分,并且胃酸度的任何减小都可以导致正常无菌的上消化道的定殖,这可以导致正常肠道微菌群的紊乱。因此,胃酸抑制剂如质子泵抑制剂(PPI)和组胺H2受体拮抗剂(H2RA)的使用与艰难梭菌定殖风险增大以及随后形成CDAD相关联。PPI和H2RA的使用先前已与其它肠感染相关联,如旅行者腹泻(traveller’s diarrhoea)、沙门氏菌病和霍乱。Dial等人已报道随着在社区(JAMA,2005,294(23),2989-2995)和医院环境(CMAJ,2004,171(1),33-38)中使用胃酸抑制剂增大的CDAD风险。
PPI包括但不局限于奥美拉唑(omeprazole)(Losec,Prilosec,Zegerid)、兰索拉唑(lansoprazole)(Prevacid,Zoton,Inhibitol)、艾美拉唑(esomeprazole)(Nexium)、泮托拉唑(pantoprazole)(Protonix,Somac,Pantoloc,Pantozol,Zurcal,Pan)和雷贝拉唑(rabeprazole)(Rabecid,Aciphex,Pariet,Rabeloc)。
H2RA包括但不局限于甲氰咪胺(cimetidine)(Tagamet)、甲胺呋硫(ranitidine)(Zinetac,Zantac)、法莫替丁(famotidine)(Pepcidine,Pepcid)、罗沙替丁(roxatidine)(Roxit)和尼扎替丁(nizatidine)(Tazac,Axid)。
利用PPI或H2RA与两种抗生素结合物(组合或联用,combination)一起治疗的三联疗法是用于根除幽门螺旋杆菌(Helicobacter pylori)感染的认可疗法(Aliment.Pharmacol.Ther.,2001,15(5),613-624;Helicobacter.,2005,10(3),157-171)。然而,关于这种三联疗法方案可能导致CDAD副作用的报道很少(Am.J.Gastroenterol.,1998,93(7),1175-1176;J.Int.Med.,1998,243(3),251-253;Aliment.Pharm.Ther.,2001,15(9),1445-1452;Med.Sci.Monit.,2001,7(4),751-754)。用于治疗幽门螺旋杆菌感染的典型抗菌剂是选自但不局限于以下药物的结合物(组合或联用),即,甲硝哒唑(metronidazole)、阿莫西林(amoxicillin)、左氧氟沙星(levofloxacin)和克拉霉素(clarithromycin)-它们中的许多都与CDAD的形成密切相关。目前的疗法非常有限;特别是考虑到几乎所有抗生素类别都与引起该疾病关联这一事实。FDA批准用于治疗CDAD的唯一药物是万古霉素(vancomycin),但是甲硝哒唑的使用也很广泛。由于万古霉素对梭菌的抑菌作用、相对高的费用以及抗性艰难梭菌菌株和其它细菌(特别是肠球菌属(Enterococcus spp.))的可能选择性,因此用于治疗CDAD的分布广泛的万古霉素受到关注。甲硝哒唑和万古霉素都存在的关键问题是高复发率,至少20%的患者经受至少一次复发。治疗期间无法根除梭菌芽孢致使复发的发生,导致随后形成致病状态。这种无力控制芽孢形成的状况使得医院环境继续受到污染。因此,能够根除营养细胞和控制内生孢子的药剂将具有显著优势。
治疗CDAD的主要疗法选择方案是中止任何当前的抗微生物治疗,随后适当地使用万古霉素或甲硝哒唑。这两种药剂通常都是口服给予,但是甲硝哒唑也可以通过静脉给予,并且在严重的情况下万古霉素也可以通过许多其它途径给予,包括结肠内给予,通过鼻胃管或作为万古霉素-保留灌肠剂给予(vancomycin-retention enema)。已报道用于治疗CDAD的其它抗生素药剂包括羧链孢酸(fusidic acid)、利福霉素(rifamycin)及其类似物、替考拉宁(teicoplanin)和崔西杆菌素(bacitracin),但它们都没有表现出优于万古霉素或甲硝哒唑的特别效力。除了中断任何损害性(offending)抗菌治疗,还应当避免使用逆蠕动药剂(抗蠕动剂,antiperistaltic agents)、麻醉剂或洛哌丁胺(loperamide),因为它们可以降低艰难梭菌毒素的清除率并使毒素介导的结肠损伤恶化。此种药剂还可以促成肠梗阻并导致结肠的毒性扩张(toxic dilation)(J.Med.Microbiol.,2005,54,101-111;JAMA,1993,269,71-5;Postgrad.Med.J.,1990,66(777),582)。
用作标准的单独药剂或与抗菌剂结合(联用)的供替换疗法旨在试图重建天然的肠道微生物种群、降低艰难梭菌毒素的水平或刺激免疫***(综述参见Antibiotic Treatment for Clostridium difficile-AssociatedDiarrhea in Adults,Cochrane Database of Systematic Reviews 2007,Issue 3.Art.No.:CD004610.;Clin.Inf.Dis.,2008,46(S1),S32-S42;Clin.Inf.Dis.,2007,45(S2),S122-S128;J.Med.Microbiol.,2005,54,101-111及其中的参考文献)。因而,供替换的CDAD疗法包括提供布拉氏酵母菌(Saccharomyces boulardii)或嗜酸乳酸杆菌(Lactobacillus acidophilus)连同抗生素、***物(faecal)移植,并且在所有疗法选择都失败的严重情况下提供手术。虽然结肠切除率低(达3%的病例),但它与高死亡率关联(多达60%)。
因此,迫切需要新的有效药剂来治疗与产芽孢细菌关联的疾病,特别是梭菌属和芽孢杆菌属成员引起的那些疾病,且特别是与艰难梭菌感染关联的疾病。考虑到艰难梭菌为许多广谱抗生素(包括β-内酰胺和喹诺酮抗生素)难治的性质以及耐药性出现的频率,这种需要就特别强烈(Antimicrob.Agents Chemother.,1985,28(6):842-844)。
(b)现有技术
WO2007056330、WO2003105846和WO2002060879公开了用作抗菌剂(抗细菌剂,antibacterial agents)的各种2-氨基苯并咪唑。
WO2007148093公开了用作抗菌剂的各种2-氨基苯并噻唑。
WO2006076009、WO2004041209和Bowser等人(Bioorg.Med.Chem.Lett.,2007,17,5652-5655)公开了各种取代的苯并咪唑化合物,其用作降低微生物的耐药性、病毒性或生长的抗感染药物。据说该化合物在活体外没有表现出固有的抗微生物活性。
US 5,824,698公开了作为广谱抗生素的各种二苯并咪唑,公开了它们对抗包括葡萄球菌属(Staphylococcus spp.)和肠球菌属(Enterococcus spp.)在内的革兰氏阴性和***的活性。然而,这篇文献没有公开它们对抗厌氧产芽孢细菌的活性,特别没有公开它们对抗任何梭菌属(包括艰难梭菌)的活性。
US 2007/0112048A1公开了作为广谱抗生素的各种二芳基咪唑啉和三芳基咪唑啉以及二芳基脒和三芳基脒,公开了它们对抗包括葡萄球菌属、肠球菌属和梭菌属在内的革兰氏阴性和***的活性。然而,这篇文献没有公开本文描述的通式(I)化合物。
Chaudhuri等人(J.Org.Chem.,2007,72,1912-1923)描述了作为DNA结合剂的各种双-2-(吡啶基)-1H-苯并咪唑(包括本文描述的式I化合物)。这篇文献对于潜在的抗菌活性只字未提。
发明内容
因此,在本发明的第一方面,提供了通式(I)化合物:
其中:
L1是直连键(直接键,direct bond)或连接基团(linker group);
R1和R2各自独立地选自H和可选取代的C1-6烷基、芳基、杂芳基、碳环基和杂环基,该可选取代可以是被选自卤素、CN、NO2、R6、OR6、N(R6)2、COR6、CO2R6、SO2R6、NR7COR6、NR7CO2R6、NR7SO2R6、NR7CONR6R7、CONR6R7和SO2NR6R7的一个或多个取代基取代,条件是R1和R2中至少一个是环状的;
每个R5独立地选自H、卤素、C1-6烷基、OR7、N(R7)2、CN和NO2;
X1和X2各自独立地选自N和CR3;
X3选自NR4、O和S;
X4是NH;以及
R3选自H、卤素和C1-6烷基;R4选自H和C1-6烷基;R6选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C4-C7碳环基、C4-C7杂环基以及5-或6-元芳基或杂芳基,其中的任一个可以可选地被一个或多个卤原子取代;并且R7选自氢和C1-C4烷基,其中的任一个可选地被一个或多个卤原子取代;
或其药学上可接受的N-氧化物、盐、水合物、溶剂化物、复合物(络合物,complex)、生物电子等排体、代谢物或前药(药物前体,prodrug),其可选地用于治疗细菌的感染或细菌引起的疾病。
通式(I)的某些化合物是新颖的。因而,根据本发明,我们也提供了那些新颖的通式(I)化合物、以及它们的制备方法、包含它们的组合物、以及它们作为药物的用途。
因而,在另一方面,提供了通式(I)化合物
其中:
L1是直连键或连接原子或基团;
R1和R2各自独立地选自H和可选取代的C1-6烷基、芳基、杂芳基、碳环基和杂环基,该可选取代可以是被选自卤素、CN、NO2、R6、OR6、N(R6)2、COR6、CO2R6、SO2R6、NR7COR6、NR7CO2R6、NR7SO2R6、NR7CONR6R7、CONR6R7和SO2NR6R7的一个或多个取代基取代,条件是R1和R2中至少一个是环状的;
每个R5独立地选自H、卤素、C1-6烷基、OR7、N(R7)2、CN和NO2;
X1和X2各自独立地选自N和CR3;
X3选自NR4、O和S;
X4是NH;以及
R3选自H、卤素和C1-6烷基;R4选自H和C1-6烷基;R6选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C4-C7碳环基、C4-C7杂环基和5-或6-元芳基或杂芳基,其中的任一个可以可选地用一个或多个卤原子取代;以及R7选自氢和C1-C4烷基,其中的任一个可选被一个或多个卤原子取代;
或其药学上可接受的N-氧化物、盐、水合物、溶剂化物、复合物、生物电子等排体、代谢物或前药。
L1可以可选地选自O、S、SO2、NR7、C(R7)2和C=O。
以上限定的化合物可以用于例如在治疗细菌感染或疾病中治疗或预防。
在另一个方面,提供了治疗主体(受验者、或受治疗者,subject)的细菌感染或细菌疾病的方法,包括向所述主体给予有效量的以上限定的化合物。
在另一方面,提供了杀灭细菌或抑制、降低或阻止其生长的方法,包括使所述细菌与以上限定的化合物接触。
也考虑了包含以上限定的本发明化合物和以下限定的各种辅剂(adjunctive agents)的结合物(组合,combinations)。
本发明的其它方面限定在本申请陈述的权利要求中。
具体实施方式
本文所述的所有出版物、专利、专利申请和其它参考文献出于所有目的通过引用完整地并入本申请中,犹如每篇单独的出版物、专利或专利申请通过引用具体并单独地并入以及叙述它们的全部内容。
1、定义和一般优选
除非另外明确说明,否则本文使用的以下术语除了该术语在本领域中可能享有的任何广义(或狭义)的含义之外还具有下列含义:
除非上下文另有要求,否则本文使用的单数应解读为包括复数,反之亦然。相对于实体使用的术语“一”或“一个”应解读为涉及一个或多个该实体。因此,术语“一”(或“一个”)、“一个或多个”,和“至少一个”在本文可以互换使用。
如本文使用的术语“包含”或其各种变型如“包括”或“含有”应解读为包括列举的任何整体(整数,integer)(例如,特征、元素、特性、性能、方法/工艺步骤或极限)或整体的组(例如,多个特征、元素、特性、性能、方法/工艺步骤或极限),但不排除任何其他的整体或整体组。因而,如本文使用的术语“包含”是包括端点的(inclusive)或者是开放式的,并不排除另外未列举的整体或方法/工艺步骤。
短语“基本上由......组成”用在此处是指需要指定的整体(或多个整体)或步骤以及不显著影响所要求保护的本发明的特征或功能的那些。
如本文使用的术语“由......组成”是指单独存在所列举的整体(例如,特征、元素、特性、性能、方法/工艺步骤或极限)或整体组(例如,特征、元素、特性、性能、方法/工艺步骤或极限)。
如本文使用的术语“疾病”用于限定损害生理功能并与特定症状相关的任何异常病况。该术语广泛地用于包括生理功能受到损害而不论病因性质如何(或者实际上疾病的病因学基础是否确立)的任何紊乱、病情(illness)、异常、病状、不健康(sickness)、病况或症状。所以,它包括由创伤、损伤、手术、放射消融(radiological ablation)、中毒或营养缺乏引起的病况。
如本文使用的术语“细菌疾病”是指涉及在主体身体和/或细胞中寄居(reside)和/或复制的细菌(例如,由于该细菌的存在而引起、加重,或者与该细菌的存在相关联或以其为特征)的任何疾病。所以该术语包括细菌毒素引起或加重的疾病(其在本文也称为“细菌中毒”)。
如本文使用的术语艰难梭菌相关性疾病(CDAD)用于限定涉及在主体身体中寄居和/或复制的艰难梭菌(例如,由存在该细菌引起、加重,与其关联或以其为特征)的任何疾病。因而,该术语涵盖任何疾病、紊乱、病状、症状、临床病况或病症,其中艰难梭菌物种的细菌作为发病原因或其中牵涉、检测到或涉及一种或多种艰难梭菌菌株的感染。所以该术语包括各种形式的结肠炎、伪膜性结肠炎、腹泻和抗生素相关性疾病。
如本文使用的术语“细菌感染”用于限定主体受到细菌感染的病况。这种感染可以是有症状或无症状的。在后者情况下,可以根据各种测试方法确定该主体是否感染,该测试包括例如生物化学试验、血清学试验、微生物培养和/或显微术。
术语抑菌和杀菌分别是用于限定阻止细菌生长(或降低细菌生长率)和介导(直接或间接)细菌细胞的细胞损害的能力的技术术语。该术语并不是互相排斥的,许多药剂既表现抑菌作用,又表现杀菌作用(在一些情况下以剂量特异性或靶向特异性方式)。一般地,杀菌剂产生更好的治疗结果,并是优选的。
如本文使用的术语“广谱抗生素”限定了对包括***和革兰氏阴性细菌在内的一系列细菌具有杀菌和/或抑菌作用的药剂。
如本文使用的术语“耐多药性(multi-drug resistant,MDR)”限定了对两种或多种抗生素有抗性的细菌,该抗生素包括但不局限于选自青霉素(penicillin)、甲氧西林(methicillin)、喹诺酮、大环内酯和/或万古霉素的抗生素。
如本文使用的术语“治疗”指的是干预(例如,向主体给予药剂),该干预可治愈、改善或减轻疾病症状或消除(或减轻)其病因(或多个病因)(例如,致病细菌)(的影响)。在这种情况下,该术语与术语“疗法(therapy)”同义使用。因而,根据本发明的感染治疗的特征是本发明化合物的(直接或间接)抑菌和/或杀菌作用。
另外,术语“治疗”指的是干预(例如,向主体给予药剂),该干预可阻止或延缓疾病发作或进展或者降低(或消除)其在受治疗群体中的发病率。在这种情况下,该术语治疗与术语“预防”同义使用。
术语“主体”(该术语应解读为,在上下文许可的情况下包括“个体”、“动物”、“患者”或“哺乳动物”)限定了接受治疗的任何主体,特别是哺乳动物主体。哺乳动物主体包括,但不局限于人、家畜、农场动物、动物园动物、运动动物(sport animals)、宠物动物如狗、猫、豚鼠(guinea pig)、兔子、大鼠、小鼠、马、牛、母牛;灵长类动物如猿、猴、猩猩和黑猩猩;犬科动物如狗和狼;猫科动物如猫、狮子和老虎;马科动物(equids)如马,驴和斑马;食用动物如母牛、猪和绵羊;有蹄类动物如鹿和长颈鹿;啮齿动物如小鼠、大鼠、仓鼠和豚鼠;等等。在优选的实施方式中,该主体是人,例如幼儿。
术语***是限定根据某些细胞壁染色特性归为一类的特定类别的细菌的技术术语。
术语低G+C***是根据DNA中碱基的组成,限定在革兰氏阳性范围内特定亚类的进化上相关细菌的技术术语。该亚类包括链球菌属(Streptococcus spp.)、葡萄球菌属(Staphylococcus spp.)、李氏杆菌属(Listeria spp.)、芽孢杆菌属、梭菌属、肠球菌属(Enterococcus spp.)和乳酸菌属(Lactobacillus spp.)。
术语“最低抑制浓度”或“MIC”限定了需要用来抑制细菌分离物活体外生长的测试化合物最低浓度。测定抗生素的MIC的常用方法为:准备包含连续稀释的测试化合物的数个管子,然后将感兴趣的细菌分离物接种于该管中。接种后在适当的气氛和温度下,抗生素的MIC可以从显示无混浊的最低浓度的管子确定。
如本文使用的,用于两种或多种化合物和/或药剂(在本文也称为组分)的术语“结合(结合物、组合或联用(combination))”旨在限定其中两种或多种化合物/药剂相关联的材料。术语“被结合的(被组合或被联用(combined))”和“结合的(组合的或联用的(combining))”在上下文中也相应地解释。
结合(组合或联用)的两种或多种化合物/药剂可以是物理关联的或非物理关联的。物理关联的结合化合物/药剂的实例包括:
●包含混合的两种或多种化合物/药剂(例如同一单位剂量(dose)内的)的组合物(例如,单一制剂);
●包含其中两种或多种化合物/药剂通过化学/物理化学连接(例如,通过交联、分子团聚或结合到常用媒剂(vehicle)部分上)的材料的组合物;
●包含其中两种或多种化合物/药剂通过化学/物理化学共同封装(co-packaged)(例如,设置在脂囊泡、颗粒(例如,微颗粒或纳米颗粒)或乳化液液滴上或内)的材料的组合物;
●药物试剂盒、药物包(packs)或患者包(patient packs),其中两种或多种化合物/药剂共同封装或共同递呈(例如,作为系列单位剂量的一部分);
非物理关联的结合化合物/药剂的实例包括:
●包含该两种或多种化合物/药剂中的至少一种以及说明书的材料(例如,非单一制剂),该说明书用于指示临时联合该至少一种化合物/药剂从而形成物理关联的两种或多种化合物/药剂的方法;
●包含该两种或多种化合物/药剂中的至少一种以及说明书的材料(例如,非单一制剂),该说明书用于指示用两种或多种化合物/药剂联合治疗的方法;
●包含该两种或多种化合物/药剂中的至少一种以及说明书的材料,该说明书用于指示向已给予(或正给予)该两种或多种化合物/药剂中的另一种(或其余几种)的患者群体给予的方法;
●包含该两种或多种化合物/药剂中的至少一种的材料,该至少一种化合物/药剂的量或形式特别地适于与该两种或多种化合物/药剂中的另一种(或其余几种)结合使用。
如本文使用的术语“联合治疗”旨在限定包含使用两种或多种化合物/药剂(如上限定的)的结合物(组合)的治疗。因而,在本申请中所涉及的“联合治疗”、“结合物”以及“结合”使用的化合物/药剂是指作为同一总治疗方案的一部分给予的化合物/药剂。因此,该两种或多种化合物/药剂中的每种的剂量学可以不同:每种均可以在相同时间或不同时间给予。因此,应当理解结合的化合物/药剂在同一药物制剂(即,在一起)或在不同的药物制剂(即,分开的)中相继(例如,之前或之后)或同时给予。同时给予的同一制剂是单一制剂,而同时给予的不同药剂中是非单一制剂。在组合疗法中,该两种或多种化合物/药剂中的每种的剂量学在给予途径也可以不同。
如本文使用的术语“药物试剂盒”限定了可选地全部包含在常见外包装中的一系列一种或多种单位剂量的药物组合物以及计量装置(例如测量设备)和/或递送装置(例如吸入器或注射器)。在包含两种或多种化合物/药剂结合物的药物试剂盒中,该单独的化合物/药剂可以是单一制剂或非单一制剂。该单位剂量(或多种单位剂量)可以包含在泡罩包装(薄膜包装,blister pack)中。该药物试剂盒可以可选地进一步包含使用说明书。
如本文使用的术语“药物包”限定了可选地包含在常见外包装中的一系列一种或多种单位剂量的药物组合物。在包含两种或多种化合物/药剂结合物的药物包中,该单独的化合物/药剂可以是单一或非单一制剂。该单位剂量(或多种单位剂量)可以包含在泡罩包装中。该药物包可以可选地进一步包含使用说明书。
如本文使用的术语“患者包”限定了为患者开处方的包装,其包含整个疗程用的药物组合物。患者包通常包含一个或多个泡罩包装。患者包具有优于其中药剂师从整体供应划分患者药物供给量的传统处方的优点,因为患者总是可以取出包含在该患者包中的包装插页(包装说明书,packageinsert),这在患者处方中通常是没有的。已显示包含的包装插页改进了患者在医师指导下的顺从性。
本发明结合物(组合)相对于单独化合物/药剂分开给予时的治疗效果可以产生治疗上有效的效果。
如本文使用的,有效量或治疗有效量的化合物限定了可给予主体的量,该量不产生过度毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称,但足以提供期望的效果例如由主体病况的永久或临时改善表明的治疗或预防效果。对于不同的主体,该量是不同的,其取决于个体年龄和总体状况、给予模式和其它因素。因而,虽然不可能指定确切的有效量,但本领域技术人员可以运用例行试验和背景常识为任何个案确定适当的“有效”量。在上下文中的治疗结果包括症状消除或减少、疼痛或不适感减少、存活期延长、活动性改善以及临床改善的其它标志。治疗结果不必是完全治愈。
如本文使用的,“预防有效量”指的是在剂量下并在所需时间段内有效而获得期望的预防结果的量。典型地,因为预防剂量在疾病之前或前期给予给主体,所以该预防有效量少于治疗有效量。
术语“有效”包括有利的效果如相加作用(加和作用)、协同作用、副作用减少、毒性降低或者性能或活性得到改善。有利地,有效作用使得可以向患者给予较低剂量的每种或任一种组分,从而降低毒性,同时产生和/或维持相同的治疗效果。在上下文中协同作用指的是通过结合产生的治疗效果,其大于该结合物中的组分单独呈递时的治疗效果之和。在上下文中相加作用指的是通过结合产生的治疗效果,其大于该结合物中任何一种组分单独呈递时的治疗效果。
如本文使用的术语“辅助(ancillary)化合物”(或“辅助药剂”)旨在限定当与本发明化合物结合时产生有效结合(如本文限定的)的任何化合物。该辅助化合物因此可以用作本发明化合物的辅剂(adjunct),或者可以其他方式促成该结合效果(例如,通过产生协同作用或相加作用或通过加强本发明化合物的活性)。
针对本发明化合物和结合物在治疗或预防中的用途运用的术语“辅助”限定了这样的用途,其中该材料与一种或多种其它药物、干预、方案或治疗(如外科手术和/或辐射)一起给予。此种辅助治疗可以包含本发明材料和其它治疗(或多种治疗)的同时、分开或相继给予/应用。因而,在一些实施方式中,本发明材料的辅助使用可反映在本发明药物组合物的制剂上。例如,辅助使用可反映在特定的单位剂量或制剂上,其中本发明化合物存在于与其它药物(或多种药物)的混合物中,并用来辅助该其它药物(要不然与单一剂量中其它药物(或多种药物)物理关联)。在其它实施方式中,本发明化合物或组合物的辅助使用可反映在本发明药物试剂盒的组成上,在该试剂盒中共同封装本发明化合物以及使用发明化合物辅助的其它药物(或多种药物)(作为系列单位剂量的一部分)。在另外的其它实施例中,本发明化合物的辅助使用可反映在涉及制剂和/或剂量学、与该化合物共同封装的资料(信息)和/或说明书的内容上。
应用于本发明化合物上的术语“药学上可接受的衍生物”限定了通过本发明母体化合物的化学衍生获得(或可获得)的化合物。该药学上可接受的衍生物因此适合于给予到哺乳动物组织上或通过与哺乳动物组织接触使用,而不产生不适当的毒性、刺激性或过敏性反应(即,与合理的利益/风险比相称)。优选的衍生物是通过本发明化合物的烷基化、酯化或酰化获得(或可获得)的那些。该衍生物可能本身就是有活性的,或可能一直无活性直到在活体内进行处理为止。在后者情况下,本发明衍生物用作前药。特别优选的前药是酯衍生物,其一个或多个游离羟基酯化并且通过活体内的水解而活化。其它优选的前药是共价结合的化合物,其在除去活体内共价键(或多个共价键)之后根据通式(I)释放活性母体药物。
药学上可接受的本发明衍生物保留了母体化合物的一些或全部活性。在一些情况下,该活性通过衍生而增大。衍生还可以提高化合物的其它生物活性,例如生物利用度。
应用于本发明化合物上的术语“药学上可接受的盐”限定了游离碱化合物的任何无毒的有机或无机酸加成盐,其适合通过与哺乳动物组织接触使用,而不产生不适当的毒性、刺激性、过敏性反应并且与合理的利益/风险比相称。合适的药学上可接受的盐在本领域中是众所周知的。实例为与无机酸(例如盐酸、氢溴酸、硫酸和磷酸)的盐、与有机羧酸(例如,乙酸、丙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、二羟基马来酸、苯甲酸、苯乙酸、4-氨基苯甲酸、4-羟基苯甲酸、氨茴酸(anthranilic)、肉桂酸、水杨酸、2-苯氧基苯甲酸、2-乙酰氧基苯甲酸和扁桃酸)和有机磺酸(例如甲磺酸和对苯基甲磺酸)的盐。本发明化合物也可以通过与碱金属卤化物,例如氯化钠、碘化钠或碘化锂反应转化成盐。优选地,本发明化合物通过与化学计量的氯化钠在溶剂如丙酮的存在下反应而转化成它们的盐。
这些盐和游离碱化合物可以水合形式或基本无水的形式存在。也考虑了本发明化合物的结晶形式,并且一般地本发明化合物酸加成盐是结晶材料,其在水和各种亲水有机溶剂中是可溶的并且与它们的游离碱形式相比而表现为熔点升高及溶解度增大。
应用于本发明化合物上的术语“药学上可接受的溶剂化物”限定了所指定化合物的任何药学上可接受的溶剂化物形式,其保留了此种化合物的生物有效性。溶剂化物的实例包括与水(水合物)、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、乙醇胺或丙酮结合的本发明化合物。也包括可混合的溶剂化物混合物制剂如与丙酮和乙醇混合物结合的本发明化合物。在优选的实施方式中,该溶剂化物包括与约20%乙醇和约80%丙酮结合的本发明化合物。因而,该结构式包括具有所指示结构的化合物,包括水合形式和未水合形式。
应用于本发明化合物上的术语“药学上可接受的前药”限定了任何药学上可接受的化合物,其可在生理条件下或通过溶剂分解成所指定化合物而被转化成此种化合物的药学上可接受盐或共有所指定化合物的至少一些抗菌活性(例如,表现出对抗艰难梭菌的活性)的化合物。
应用于本发明化合物上的术语“药学上可接受的代谢物”限定了通过所指定化合物或其盐在身体内代谢产生的药理活性产物。
本发明化合物的前药和活性代谢物可利用本领域中已知的常规技术鉴定(参见例如,Bertolini等人,J.Med.Chem.,1997,40,2011-2016)。
应用于本发明化合物上的术语“药学上可接受的复合物”限定了其中本发明化合物形成组成部分的化合物或组合物。因而,本发明复合物包括其中本发明化合物物理关联到(例如,通过共价或非共价结合)到另一个部分或多个部分上的衍生物。因此,该术语包括本发明化合物的多聚体形式。此种多聚体可以通过使多份本发明化合物紧邻彼此而连接或放置(例如,经由支架或载体部分)而产生。
术语“生物电子等排体”(或简单的电子等排体)是用于限定药物类似物的技术术语,在该药物类似物中一个或多个原子(或原子组)已被替代原子(或原子组)取代,该替代原子与其所取代的这些原子具有类似的空间排列和/或电子特征。用氟原子取代氢原子或羟基是通常采用的生物电子等排体取代。Sila-取代(C/Si-交换)是产生电子等排体的相对最新的技术。这个途径涉及用硅替代一个或多个具体碳原子(综述参见Tacke andZilch in Endeavour,New Series,1986,10,191-197)。Sila-取代的电子等排体(硅电子等排体)表现出改进的药物特性,并且例如可以更好地被耐受,具有较长的半衰期或表现出增大的效力(参见例如文章:Englebienne inMed.Chem.,2005,1(3),215-226)。在最广的方面,本发明考虑了本发明化合物的所有生物电子等排体(具体地,所有硅生物电子等排体)。
在最广的方面,本发明考虑了本文所述化合物的所有光学异构体、外消旋形式和非对映异构体。本领域技术人员应理解,由于本发明化合物中存在不对称取代的碳原子,所以该化合物可以制成光学活性和外消旋形式。如果本发明化合物中存在手性中心或另外形式的异构体中心,则此种异构体或多种异构体的所有形式,包括对映异构体和非对映异构体,都涵盖在本文中。包含手性中心(或多个手性中心)的本发明化合物可以用作外消旋混合物,对映体富集的混合物或外消旋混合物可采用熟知的技术分离并且单一对映异构体可单独使用。因而,提到的本发明化合物包括作为非对映异构体的混合物、单独的非对映异构体、对映异构体混合物以及单独对映异构体形式的产物。
因此,本发明考虑了本发明化合物的所有光学异构体及其外消旋形式,并且除非另外指出(例如,通过利用虚线-楔线结构式指出的),否则本文示出的化合物都旨在包括所描述化合物所有可能的光学异构体。当该化合物的立体化学形式对于药物实用性重要时,本发明考虑了使用分离的优性异构体(优对映体,eutomer)。
在本说明书中,术语“烷基”限定了直链或支链饱和烃链。术语“C1-C6烷基”指的是具有1~6个碳原子的直链或支链饱和烃链。实例包括甲基、乙基、n-丙基、异丙基、叔丁基、正己基。术语“C1-C9烷基”指的是具有1~9个碳原子的直链或支链饱和烃链。术语“C1-C15烷基”指的是具有1~15个碳原子的直链或支链饱和烃链。本发明烷基可以可选地被一个或多个卤原子取代。
“C1-C4烷基”具有相似的含义,除了它包含1~4个碳原子。
“C2-C6烯基”指的是具有2~6个碳原子并包含至少一个碳-碳双键的直链或支链烃链。实例包括乙烯基、2-丙烯基和3-己烯基。
术语“C1-C6卤代烷基”指的是被一个或多个卤原子取代的如上限定的C1-C6烷基。
在本说明书中,术语“烯基”限定了具有至少一个碳-碳双键的直链或支链烃链。术语“C1-C6烯基”指的是具有1~6个碳原子的直链或支链不饱和烃链。术语“C1-C9烯基”指的是具有1~9个碳原子的直链或支链不饱和烃链。术语“C1-C15烯基”指的是具有1~15个碳原子的直链或支链不饱和烃链。优选为C1-C6烯基。实例包括乙烯基、2-丙烯基和3-己烯基。本发明烯基可以可选地被一个或多个卤原子取代。
在本说明书中,术语“炔基”限定了具有至少1个碳-碳三键的直链或支链烃链。术语“C1-C6炔基”指的是具有1~6个碳原子的直链或支链不饱和烃链。术语“C1-C9炔基”指的是具有1~9个碳原子的直链或支链不饱和烃链。术语“C1-C15炔基”指的是具有1~15个碳原子的直链或支链不饱和烃链。优选为C1-C6炔基。实例包括乙炔基、2-丙炔基和3-己炔基。本发明炔基可以可选地被一个或多个卤原子取代。
术语“杂环基”限定了饱和或部分饱和的3元~14元环体系(除了指定了供替换环原子数的情况),该环体系类似于环烷基,但其中至少一个碳原子被N、O、S、SO或SO2代替。实例包括哌啶、哌嗪、吗啉、四氢呋喃和吡咯烷。
如本文使用的术语“碳环基”表示包含3个或更多(例如,3-14个、3-10个或3-8个)碳原子的单环或多环残基。本发明碳环残基可以可选地被一个或多个氯原子取代。优选单环或双环的碳环基残基。该碳环基残基可以是饱和或部分不饱和的并包括稠合双环或三环体系。此种基团的实例包括环丙基、环丁基、环戊基、环己基、环己烯基,以及桥接体系如降冰片基(norbornyl)和金刚烷基。
饱和的碳环基残基是优选的并且在此称为“环烷基”,该术语“环烷基”在本文用于限定饱和的3元~14元碳环,包括稠合双环或三环体系。此种基团的实例包括环丙基、环丁基、环戊基、环己基,以及桥接体系如降冰片基和金刚烷基。本发明环烷基残基可以可选地被一个或多个卤原子取代。
在本说明书中,术语“芳基”限定了5-14(例如5-10)元芳香单环、双环或三环基团,其中至少一个环是芳香族环。因而,双环芳基可以包含仅一个芳香环。芳香部分的实例是苯、萘、咪唑和吡啶。该术语也包括双环或三环体系,其中一个或多个环具有芳香性。二氢化茚(indane,茚满)是这种类型体系的实例。
如本文使用的术语“杂芳基”是以上限定的芳基部分,其包含杂原子(例如,氮、硫和/或氧)。该术语也包括这样的体系,其中具有芳香性的环稠合到饱和或部分饱和的环上。实例包括吡啶、嘧啶、呋喃、噻吩、吲哚、异吲哚、二氢吲哚、苯并呋喃、苯并咪唑、苯并咪唑啉喹啉、异喹啉、四氢异喹啉、喹唑啉、噻唑、苯并噻唑、苯并噁唑、吲唑和咪唑环体系。除非另有指示,否则术语“芳基”应解读为包括如上限定的杂芳基。
本发明芳基和杂芳基可以可选地被一个或多个卤原子取代。
在本说明书中,“卤素”指的是氟、氯、溴或碘。
在本发明通式(特别是如下描述的通式(I))中,当各种可能的杂原子(或多种杂原子)有特别需要(specific requirements)时,指定环的键级(bond orders)可以改变,以便满足芳香性、阻止反芳香性和稳定局部化所引起的互变异构形式。在此种情况下,本文考虑了本发明结构式中的环结构的适当键级。
应用于式(I)化合物上的术语“对称的”可以限定其中取代基R1和R2相同的化合物。
应用于式(I)化合物上的术语“不对称的”可以限定其中取代基R1和R2不同的化合物。
II.根据本发明的化合物
(a)结构考虑因素
本发明化合物具有通式(I):
其中该取代基如同上文所限定的,或者可以是其药学上可接受的N-氧化物、盐、水合物、溶剂化物、复合物、生物电子等排体、代谢物或前药。
特别优选的通式(I)化合物在(以下)表1所列:
表1
化合物序号 | 化合物名称 |
1 | 4,4′-(1H,3′H-5,5′-二苯并[d]咪唑-2,2’-二基)二苯胺 |
2 | 3,3′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2’-二基)二苯胺 |
3 | 4,4′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2’-二基)二苯酚 |
4 | 4,4′-(3′-甲基-1H,3′H-5,5′-二苯并[d]咪唑-2,2’-二基)二苯胺 |
5 | 4,4′-(1-甲基-1H,1′H-5,5′-二苯并[d]咪唑-2,2’-二基)二苯胺 |
6 | 4,4′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2’-二基)双(N-甲苯胺) |
7 | 2,2′-双(4-甲氧苯基)-1H,1′H-5,5′-二苯并[d]咪唑 |
8 | 4-(1H,1′H-5,5′-二苯并[d]咪唑-2-基)苯胺 |
9 | 4-(2′-苯基-1H,1′H-5,5′-二苯并[d]咪唑-2-基)苯胺 |
10 | 2′-(4-甲氧苯基)-2-苯基-1H,3′H-5,5′-二苯并[d]咪唑 |
11 | 5,5′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2’-二基)二吡啶-2-胺 |
12 | 2,2′-二(吡啶-4-基)-1H,1′H-5,5′-二苯并[d]咪唑 |
在每种情况下,本发明均考虑了所列每个化合物的药学上可接受的盐、水合物、溶剂化物、复合物、生物电子等排体、代谢物或前药。
本文所提到的特定化合物序号在本文中是指表1中的数字。
某些通式(I)化合物是新颖的。因而,根据本发明,本发明考虑了化合物本身就新颖的那些通式(I)化合物、以及其制备方法、包含它们的组合物、以及它们作为药物的用途。
因而,本发明考虑了选自以下的化合物:
4,4′-(3′-甲基-1H,3′H-5,5′-二苯并[d]咪唑-2,2’-二基)二苯胺
4,4′-(1-甲基-1H,1′H-5,5′-二苯并[d]咪唑-2,2’-二基)二苯胺
4,4′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2’-二基)双(N-甲苯胺)
4-(1H,1′H-5,5′-二苯并[d]咪唑-2-基)苯胺
4-(2′-苯基-1H,1′H-5,5′-二苯并[d]咪唑-2-基)苯胺
2′-(4-甲氧苯基)-2-苯基-1H,3′H-5,5′-二苯并[d]咪唑
5,5′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2’-二基)二吡啶-2-胺
或其药学上可接受的N-氧化物、盐、水合物、溶剂化物、复合物、生物电子等排体、代谢物或前药,以及包含所述化合物的组合物(例如药物组合物)。
通式(I)化合物可以通过对US 5,824,698(其内容通过引用合并在此)中描述的方法进行常规修改来制备并如实施例1(以下)所描述。
(b)功能考虑因素
(i)对抗艰难梭菌菌株的效果和选择性
优选的本发明化合物是选择性艰难梭菌药剂。
术语“选择性艰难梭菌药剂”在本文用于限定这样的化合物,其表现出对抗一种或多种艰难梭菌菌株的抑菌和/或杀菌活性,但没有表现出对抗选自以下的正常肠道菌群的一个或多个代表物的抑菌和/或杀菌活性:(a)埃希氏菌属(Escherichia spp.)(例如,大肠杆菌(Escherichia coli))、(b)拟杆菌属(Bacteroides spp.)(例如,脆弱拟杆菌(B.fragilis))、(c)梭杆菌属(Fusobacterium spp.)、(d)真杆菌属(Eubacterium spp.)(e)瘤胃球菌属(Ruminococcus spp.)、(f)消化球菌属(Peptococcus spp.)、(g)消化链球菌属(Peptostreptococcus spp.)、(h)双歧杆菌属(Bifidobacteriumspp.)和(i)乳酸杆菌属。
特别优选的选择性艰难梭菌药剂表现出对抗一种或多种艰难梭菌菌株的抑菌和/或杀菌活性,但没有表现出对抗脆弱拟杆菌ATCC25285的抑菌和/或杀菌活性(MIC>64μg/mL)。
还更特别优选的选择性艰难梭菌药剂表现出对抗一种或多种艰难梭菌菌株的抑菌和/或杀菌活性,但没有表现出对抗脆弱拟杆菌ATCC25285和大肠杆菌ATCC25922的抑菌和/或杀菌活性(MIC>64μg/mL)。
优选的本发明化合物是选择性艰难梭菌药剂,其因此可用来治疗CDAD,而不致使现有肠道菌群紊乱到临床上显著的程度。因此,此种化合物可以用作抗微生物药剂,而不引起抗生素相关性疾病(如本文限定的)。
用作选择性艰难梭菌药剂的本发明化合物可以通过测定该化合物对艰难梭菌和代表正常肠道菌群的一种或多种指示生物(或多种指示生物)的相对抗菌活性来鉴定。对于此用途合适的指示生物包括大肠杆菌和/或各种拟杆菌属(例如,脆弱拟杆菌)。
可替换地,或另外地,用作选择性艰难梭菌药剂的本发明化合物可以通过对从服用测试化合物的主体获得的系列粪便样品进行定量的粪便培养(stool culture)来鉴定。这种途径的活体外变体是以确定当与稀释并过滤的***物样品一起在活体外培养时测试化合物是否产生主要的菌群变化(floral shifts)为基础的。在这种情况下,菌群变化可以通过确定测试化合物对二种或多种以下菌属的相对数目的细菌代表物的效果来检查:拟杆菌属、(c)梭杆菌属、(d)真杆菌属、(e)瘤胃球菌属、(f)消化球菌属、(g)消化链球菌属、(h)双歧杆菌属和(i)乳酸杆菌属。
(ii)对芽孢发芽的效果
本发明化合物可以抑制或阻止芽孢发芽。
抑制芽孢发芽的化合物可以通过活体外检测内生孢子折射率、耐热性和染色性的变化来鉴定:发芽的内生孢子变得相暗(phase dark)、易受热影响并可用某些染料染色。
(iii)对芽孢长出(outgrowth)的效果
本发明化合物可以抑制或阻止芽孢长出。
抑制芽孢长出的化合物可以通过在活体外用显微镜检查暴露于芽的芽孢来鉴定。
(iv)杀菌和/或抑菌效果
本发明化合物可以杀菌和/或抑菌。
优选上文限定的杀菌化合物。此种杀菌化合物也可以抑菌(例如,取决于靶细菌和浓度)。
III医学应用
本发明化合物在治疗各种各样的疾病方面有应用。因而,本发明考虑了用于医学(例如,用于治疗和预防)的如本文描述的式(I)化合物、涉及给予如本文描述的式(I)化合物的医学治疗或预防的方法,以及包含如本文描述的式(I)化合物的药物组合物。
以下更详细地描述本发明化合物在医学应用中的具体应用。
(a)细菌疾病和感染的治疗
本发明在治疗任何***感染或疾病方面有广泛的应用。
特别优选用于治疗厌氧***引起或与其关联的疾病或感染。在此种实施方式中,该厌氧细菌可以是兼性厌氧菌或专性厌氧菌。
特别优选用于治疗产内生孢子的***引起或与其关联的疾病或感染。在此种实施方式中,这种产内生孢子的***可以是厌氧菌(例如,兼性厌氧菌或专性厌氧菌)。
特别优选用于治疗由选自以下的细菌引起或与其关联的疾病或感染:(a)梭菌属、(b)葡萄球菌属、(c)肠球菌属,以及(d)即(a)~(c)的结合物(组合)。在此种实施方式中,特别优选用于治疗由选自以下的细菌引起或与其关联的疾病或感染:(a)艰难梭菌(例如,菌株BI/NAP1)、(b)产气荚膜梭菌(Clostridium perfringens)、(c)金黄色葡萄球菌(Staphylococcus aureus)及(d)它们的结合物(组合)。
该细菌疾病可以是CDAD、结肠炎、伪膜性结肠炎、腹泻或抗生素相关性疾病(包括抗生素相关性腹泻和抗生素相关性结肠炎)。
(b)细菌中毒的治疗
细菌疾病或感染可能涉及包括例如内毒素、外毒素和/或有毒酶在内的一种或多种细菌毒素引起的中毒。
因而,本发明化合物可应用在治疗细菌中毒上。在此种实施方式中,优选用于治疗细菌内毒素、外毒素和/或有毒酶,例如由前述段落中描述的细菌产生的内毒素、外毒素和/或有毒酶引起的中毒,其中该细菌特别包括选自以下的细菌:(a)梭菌属、(b)葡萄球菌属、(c)肠球菌属以及(d)(a)~(c)的结合物(组合)。
特别优选用于治疗由梭菌外毒素,包括艰难梭菌毒素A(TcdA)、毒素B(TcdB)和/或二元毒素CDT引起的中毒。因而,本发明化合物可应用于艰难梭菌毒素A(TcdA)、毒素B(TcdB)和/或二元毒素CDT的存在所引起(或加重)的疾病的治疗上。
(c)艰难梭菌相关性疾病(CDAD)的治疗
艰难梭菌相关性疾病(CDAD)限定了与艰难梭菌感染和/或中毒关联的一组症状和疾病。CDAD包括腹泻、肿胀(bloating)、类似流感的症状(flu-like symptoms)、发热、食欲不振、腹痛、恶心、脱水和肠道炎症(结肠炎)。CDAD最严重的表现是伪膜性结肠炎(PMC),其在组织学上表现为带有粘膜斑的结肠炎,并在临床上表现为严重腹泻、腹部绞痛(abdominal cramps)和全身毒性(systemic toxicity)。
本发明化合物应用于所有形式的CDAD的治疗上,包括腹泻、肿胀、类似流感的症状、发热、食欲不振、腹痛、恶心、脱水、结肠炎和伪膜性结肠炎。
(d)抗生素相关性疾病的治疗
抗生素相关性疾病限定了由构成正常肠道菌群的微生物相对量发生变化所引起的病况,该变化是由于抗生素的给予致使菌群被(部分)消除而产生的。当所给予的抗生素(特别是广谱抗生素)允许致病生物生长(通常由正常肠道菌群制止的内生群体过度生长,或抗生素致使正常肠道菌群被清除的部位上的机会定殖所引起)时,将会出现此种疾病。
抗生素相关性疾病典型地表现为腹泻(及相关性脱水)、腹部绞痛、里急后重(tenesmus)和发热。它也可以导致各种形式的结肠炎,包括伪膜性结肠炎(PMC)。因而,抗生素相关性疾病包括抗生素相关性腹泻(AAD)和抗生素相关性结肠炎(AAC)。
抗生素相关性疾病通常由艰难梭菌、金黄色葡萄球菌(包括耐甲氧西林的金黄色葡萄球菌)和产气荚膜梭菌引起。艰难梭菌是医院AAD的最常见根源并导致大部分AAC病例。该细菌在已给予广谱抗生素或接受癌症化疗的患者结肠中增殖。
本发明化合物因此可应用于包括AAD和AAC在内的抗生素相关性疾病治疗上。特别优选用于治疗由选自以下的细菌引起的AAD和AAC:艰难梭菌、金黄色葡萄球菌和产气荚膜梭菌,最优选艰难梭菌引起的AAD或AAC。
特别优选用于这类应用中的化合物是为选择性(如上文限定的)的本发明化合物,因为此种化合物基本上不损害(spare)正常肠道菌群。
本发明化合物在预防包括AAD和AAC在内的抗生素相关性疾病方面有着特别的应用。在此种应用中,本发明化合物可以与可诱导构成正常肠道菌群的微生物相对量发生变化的其它抗生素或治疗一起共同给予。
因而,本发明化合物可以用于治疗已用广谱抗生素(或正在接受广谱抗生素)治疗的主体。
(e)结肠炎、伪膜性结肠炎和腹泻的治疗
如上所解释的,选自艰难梭菌、金黄色葡萄球菌和产气荚膜梭菌的细菌都牵涉到结肠炎、伪膜性结肠炎(PMC)和腹泻。
因此,本发明化合物可应用于结肠炎、伪膜性结肠炎(PMC)或腹泻的治疗上。
特别优选用于治疗伪膜性结肠炎。
IV.与本发明结合使用的辅剂
(a)概要
除本发明化合物之外,本发明还考虑了一种或多种下列辅剂作为本发明进一步组分的用途。
因而,本发明提供了包含与选自下述那些药剂的一种或多种辅剂结合的本发明化合物的组合物。
(b)抗病毒辅剂
该结合物优选进一步包含一种或多种辅助的抗病毒剂。此种辅助的抗病毒剂可以选自以下药剂中的一种或多种:(a)病毒酶抑制剂(例如选自(i)蛋白酶抑制剂、(ii)螺旋酶抑制剂和(iii)聚合酶抑制剂)、(b)核苷/核苷酸逆转录酶抑制剂、(c)非核苷类逆转录酶抑制剂、(d)整合酶抑制剂、(e)成熟抑制剂、(f)细胞因子或细胞因子刺激因子、(g)病毒进入抑制剂,例如选自(i)粘附抑制剂(attachment inhibitor)、(ii)共受体结合抑制剂和(iii)膜融合抑制剂。
(c)抗细菌的辅剂
本发明化合物可结合各种抗菌剂使用,该抗菌剂包括但不局限于选自以下药剂的一种或多种抗生素。
●氨基糖苷(如丁胺卡那霉素(amikacin)、庆大霉素(gentamicin),卡那霉素(kanamycin)、新霉素(neomycin)、奈替米星(netilmicin)、链霉素(streptomycin)、妥布霉素(tobramycin)和巴龙霉素(paromomycin))。
●安沙霉素(Ansamycins)(如格尔德霉素(geldanamycin)和除莠霉素(herbimycin))。
●碳头孢烯(Carbacephems)(如氯拉卡比(loracarbef))。
●碳青霉烯(Carbapenems)(如厄他培南(ertapenem)、多尼培南(doripenem)、亚胺培南(imipenem)/西司他丁(cilastatin)和美罗培南(meropenem))。
●头孢菌素(第一代),包括如头孢羟氨苄(cefadroxil)、头孢唑啉(cefazolin)、头孢噻吩(cefalotin)/头孢金素(cefalothin)和头孢氨苄(cephalexin))。
●头孢菌素(第二代),包括如头孢克洛(cefaclor)、头孢孟多(cefamandole)、头孢西丁(cefoxitin)、头孢丙烯(cefprozil)和头孢呋辛(cefuroxime)。
●头孢菌素(第三代),包括如头孢克肟(cefixime)、头孢地尼(cefdinir)、头孢托仑(cefditoren)、头孢哌酮(cefoperazone)、头孢噻肟(cefotaxime)、头孢泊肟(cefpodoxime)、头孢他啶(ceftazidime)、头孢布烯(ceftibuten)、头孢唑肟(ceftizoxime)、头孢曲松(ceftriaxone)和头孢地尼(cefdinir)。
●头孢菌素(***),包括如头孢吡肟(cefepime)。
●糖肽(如万古霉素和替考拉宁(teicoplanin))。
●大环内酯(如阿奇霉素(azithromycin)、克拉霉素、地红霉素(dirithromycin)、红霉素(erythromycin)、罗红霉素(roxithromycin)、醋竹桃霉素(troleandomycin)、泰利霉素(telithromycin)和壮观霉素(spectinomycin))。
●单内酰环(monobactams)(如氨曲南(aztreonam))。
●青霉素(如阿莫西林(amoxicillin)、氨苄西林(ampicillin)、阿洛西林(azlocllin)、羧苄青霉素(carbenicillin)、邻氯青霉素(cloxacillin)、双氯青霉素(dicloxacillin)、氟氯西林(flucloxacillin)、美洛西林(mezlocillin)、奈夫西林(nafcillin)、青霉素、哌拉西林(piperacillin)和替卡西林(ticarcillin))。
●多肽(如杆菌肽(bacitracin)、多粘菌素B(polymixin B)和粘菌素(colistin))。
●喹诺酮(如环丙沙星(ciprofloxacin)、依诺沙星(enoxacin)、加替沙星(gatifloxacin)、左氧氟沙星(levofloxacin)、洛美沙星(lomefloxacin)、莫西沙星(moxifloxacin)、诺氟沙星(norfloxacin)、氧氟沙星(ofloxacin)和曲伐沙星(trovafloxacin)。
●磺酰胺(如磺胺米隆(mafenide)、百浪多息(prontosil)、磺醋酰胺(sulfacetamide)、磺胺甲噻二唑(sulfamethizole)、磺胺(sulfanilimide)、硫氮磺胺吡啶(sulfasalazine)、硫代异唑(sulfisoxazole)、甲氧苄氨嘧啶(trimethoprim)、甲氧苄氨嘧啶-磺胺甲恶唑(复方新诺明(co-trimoxazole)、TMP-SMX))。
●四环素(如地美环素(demeclocycline)、强力霉素(doxycycline)、米诺环素(minocycline)、氧四环素(oxytetracycline)和四环素)。
●氨基香豆素(如新生霉素(novobiocin)、阿巴霉素(albamycin)、香豆霉素(coumermycin)和氯新生霉素(clorobiocin))。
●噁唑烷酮(Oxazolidinones)(如利奈唑胺(linezolid)和AZD2563)。
●脂肽(如达托霉素(daptomycin))。
●链霉杀阳菌素(streptogramins)(如奎奴普丁(quinupristin)/达福普汀(dalfopristin))。
●甘氨酰环素(Glycylcyclines)(如替加环素(tigecycline))。
●羊毛硫抗生素(Lantibiotics)(如A型羊毛硫抗生素(如乳酸链球菌素(nisin)、枯草杆菌素(subtilin)、表皮素(epidermin)、变异菌肽II(mutacin II)、变异菌肽I&III)和B型羊毛硫抗生素(如美杀菌素(mersacidin)、阿卡加定(actagardine)和肉桂霉素(cinnamycin))。
用作辅剂的其它合适的抗生素包括选自以下药剂的一种或多种抗生素:胂凡纳明(arsphenamine)、氯霉素(chloramphenicol)、克林霉素(clindamycin)、林可霉素(lincoamycin)、乙胺丁醇(ethambutol)、磷霉素(fosfomycin)、夫西地酸(fusidic acid)、呋喃唑酮(furazolidone)、异烟肼(isoniazid)、利奈唑胺(linezolid)、甲硝哒唑(metronidazole)、莫匹罗星(mupirocin)、硝基呋喃妥英(nitrofurantoin)、平板霉素(platensimycin)、吡嗪酰胺(pyrazinamide)、奎奴普丁(quinupristin)/达福普汀(dalfopristin)、利福平(rifampin)/利福平(rifampicin)和替硝唑(tinidazole)。
因而,本发明化合物可以与选自以下药剂的一种或多种抗生素结合使用:青霉素、邻氯青霉素、双氯青霉素、甲氧西林、奈夫西林、苯唑西林(oxacillin)、氨比西林(ampicillin)、阿莫西林、巴卡西林(bacampicillin)、卷曲霉素(capreomycin)、环丝氨酸(cycloserine)、阿洛西林、羧苄青霉素(carbenicillin)、美洛西林、哌拉西林(piperacillin)、替卡西林(ticarcillin)、阿奇霉素(azithromycin)、克拉霉素、克林霉素、红霉素、林可霉素(lincomycin)、地美环素、强力霉素、乙胺丁醇、乙硫异烟胺(ethionamide)、二甲胺四环素(minocycline)、氧四环素、四环素、喹诺酮、西诺沙星(cinoxacin)、萘啶酸(nalidixic acid)、氟喹诺酮类(如左氧氟沙星、莫西沙星(moxafloxacin)和加替沙星、环丙沙星、依诺沙星、格雷沙星(grepafloxacin))、卡那霉素、左氧氟沙星、洛美沙星、诺氟沙星、氧氟沙星、对氨基水杨酸、司帕沙星(sparfloxacin)、特伐沙星(trovafloxacin)、杆菌肽素(bacitracin)、粘菌素、多粘菌素B、磺酰胺、甲氧苄氨嘧啶-磺胺甲恶唑、复合阿莫西克拉维(co-amoxyclav)、头孢霉素(cephalothin)、头孢呋辛(cefuroxime)、头孢曲松、万古霉素、庆大霉素、丁胺卡那霉素、甲硝哒唑、氯霉素、链霉素、硝基呋喃妥因、复方新诺明、利福霉素及其衍生物(如利福平、利福布丁(rifabutin)和利福喷丁(rifapentine))、异烟肼、吡嗪酰胺、黄色霉素(kirromycin)、硫链丝菌素(thiostrepton)、微球菌素(micrococcin)、夫西地酸、硫乳霉素(thiolactomycin)和膦胺霉素(fosmidomycin)。
其它合适的抗菌辅剂可以选自下表所列的那些:
化合物 | 类别 |
DU-6859 | 氟喹诺酮 |
司丙红霉素(Erythromycin stinoprate) | 大环内酯 |
奥利万星(Oritavancin) | 糖肽 |
特拉万星(Telavancin) | 糖肽 |
达巴万星(Dalbavancin) | 糖肽 |
头孢比普酯(Ceftobiprole medocaril) | 头孢霉素 |
替比培南酯(Tebipenem pivoxil) | 碳青霉烯 |
埃拉普林(Iclaprim) | DHFR |
OPT-80 | Difimicin |
头孢洛林酯(Ceftaroline fosamil) | 头孢霉素 |
RX-3341 | 氟喹诺酮(Fluoroquinolone) |
喹红霉素(Cethromycin) | 酮内酯(Ketolide) |
TD-1792 | 糖肽-β-内酰胺二聚体 |
EDP-420 | 大环内酯 |
RX-1741 | 噁唑烷酮 |
MK-2764 | 甘氨酰环素(Glycycline) |
奈诺沙星(Nemonoxacin) | 氟喹诺酮 |
Flopristin+Linopristin | 链霉杀阳菌素 |
头茂培南(Tomopenem) | 碳青霉烯 |
雷莫拉宁(Ramoplanin) | Glycolipodepsipeptide |
利奈唑胺 | 噁唑烷酮 |
孢妥仑匹酯(Cefditoren pivoxil) | 头孢霉素 |
厄他培南 | 碳青霉烯 |
吉米沙星(Gemifloxacin) | 氟喹诺酮 |
达托霉素(Daptomycin) | 脂肽 |
泰利霉素(Telithromycin) | 脂肽 |
替加环素(Tigecyline) | 甘氨酰环素(Glycylcycline) |
(d)抗真菌辅剂
本发明化合物可以与各种抗真菌剂(杀真菌药)结合使用。
(e)抗原虫(抗原生动物)辅剂
本发明化合物可以与各种抗原虫剂(抗原生动物剂)结合使用,这种抗原虫剂包括但不局限于,氯喹、强力霉素、甲氟喹、甲硝哒唑、依氟鸟氨酸(eplornithine)、呋喃唑酮、羟氯喹、碘醌醇(iodoquinol)、喷他脒(pentamidine)、甲苯咪唑(mebendazole)、哌嗪、卤泛曲林(halofantrine)、伯氨喹、乙胺嘧啶磺胺多辛(pyrimethamine sulfadoxine)、强力霉素、克林霉素、二硫酸奎宁、葡糖酸奎尼丁、盐酸奎宁、硫酸羟氯喹、氯胍(proguanil)、奎宁、克林霉素、阿托伐醌(atovaquone)、阿奇霉素、苏拉明(suramin)、硫胂密胺(melarsoprol)、依氟鸟胺酸(eflornithine)、硝呋莫司(nifurtimox)、两性霉素B、葡萄糖酸锑钠(sodium stibogluconate)、羟乙基磺酸戊双脒、甲氧苄氨嘧啶-磺胺甲恶唑、乙胺嘧啶和磺胺嘧啶(sulfadiazine)。
(f)其他辅剂
本发明化合物可以与治疗或阻止抗感染治疗引起的和/或作为感染后遗症而存在的副作用的其它联合治疗剂一起共同给予。这类辅剂可以具有或可以不具有抗感染活性,并包括例如PPI和H2RA(如上文描述的)。
因而,本发明化合物可用来辅助PPI,该PPI包括但不局限于奥美拉唑(Losec,Prilosec,Zegerid)、兰索拉唑(lansoprazole)(Prevacid,Zoton,Inhibitol)、艾美拉唑(esomeprazole)(Nexium)、泮托拉唑(pantoprazole)(Protonix,Somac,Pantoloc,Pantozol,Zurcal,Pan)和雷贝拉唑(rabeprazole)(Rabecid,Aciphex,Pariet,Rabeloc)。
本发明化合物也可以用来辅助H2RA,该H2RA包括但不局限于甲氰咪胺(cimetidine)(Tagamet)、甲胺呋硫(ranitidine)(Zinetac,Zantac)、法莫替丁(famotidine)(Pepcidine,Pepcid)、罗沙替丁(roxatidine)(Roxit)和尼扎替丁(nizatidine)(Tazac、Axid)。
本发明化合物也可以用来辅助涉及PPI或H2RA以及两种抗体的结合的三联疗法(包括但不局限于选自甲硝哒唑、阿莫西林、左旋氧氟沙星和克拉霉素的抗生素)。
多种益生菌可以用作辅剂,包括例如布拉氏酵母菌(Saccharomycesboulardii)或嗜酸乳酸杆菌(Lactobacillus acidophilus)细胞。益生菌是单或混合的活微生物培养物,其计划用来帮助重新建立已被诱导CDAD的攻击性(offending)抗微生物药或甚至用于治疗CDAD的药剂而扰乱的患者天然肠道微菌群。另外,此种微生物可以发挥作用从而刺激患者的免疫***并诱导使与艰难梭菌关联的毒素降解的酶的产生。感兴趣的特定微生物是,但不局限于酵母属(例如布拉氏酵母菌和啤酒酵母菌(Saccharomycescerevisiae))和乳酸杆菌属(如鼠李糖乳酸杆菌(Lactobacillus rhamnosus)、干酪乳酸杆菌(Lactobacillus casei)、嗜酸性乳酸杆菌、保加利亚乳酸杆菌(Lactobacillus bulgaris)和植物乳酸杆菌(Lactobacillus plantarum))。还可以考虑任何其它常用的益生菌组合物或作为人肠道正常成员的微生物。
旨在刺激肠道菌群生长的益生元(pre-biotics),药剂也可以用作辅剂。例如,已显示,低聚果糖的使用可增大双歧杆菌属(Bifidobacterium spp.)的水平并降低患者的随后复发率。因此,当与旨在重新建立正常肠道微生物种群的治疗结合给药时,靶向梭菌物种、具有窄谱活性的任何抗菌剂都具有显著的益处。
旨在重新建立正常肠道菌群的其它途径包括***物生物治疗和由健康个体的粪便制成的***物灌肠剂(faecal enemas),该粪便包含肠道的正常微生物。***物细菌治疗因此也可以用来辅助本发明化合物。
为了隔绝(扣押、或螯合,sequester)艰难梭菌产生的毒素,结合并隔绝各种不同类型的细菌毒素的吸收剂可以用作辅剂。离子交换树脂如胆汁酸螯合剂消胆胺(cholsetyramine)或考来替泊(colestipol)结合到艰难梭菌细胞毒素并因而旨在降低对肠道的有毒攻击程度。然而,已知离子交换树脂可结合到药剂如万古霉素上,因而可能会导致感染部位处的抗菌剂水平未达到最佳水平。可以用来辅助本发明化合物的其它吸收剂包括聚合物如Synsorb 90和Tolevamer。
虽然益生菌疗法被揭示可以改进CDAD患者,静脉内免疫球蛋白的免疫***反应(J.Antimicrob.Chem.,2004,53,882-884),例如,还可以用于治疗CDAD患者,特别是其中任何其他抗微生物治疗都将进一步使肠道菌群紊乱恶化的复发病例。因而,本发明化合物可以用来辅助各种免疫球蛋白。
虽然旨在减轻腹泻的药剂一般避免用于CDAD患者,但在某些情况下可以设想,当试图增大感染部位处抗微生物剂水平和/或当试图增加抗菌剂与肠道病原接触的时间长度时,此种药剂与抗菌药的结合使用可能是有利的。此种药剂可以包括,但不局限于洛哌丁胺(loperamide)(Lopex,Imodium,Dimor,Pepto)、地芬诺酯(diphenoxylate)(Lomotil,Co-phenotrope)、地芬诺新(difenoxin)(Motofen),和消旋卡多曲(racecadotril)。因而,本发明化合物可以用来辅助各种抗腹泻剂,包括以上列出的那些中之任何一个。
治疗或阻止下列副作用之任何一个的联合治疗剂可以用作与本发明化合物相同的治疗方案的一部分:(a)脂肪代谢障碍和消瘦(wasting)、(b)面部脂肪萎缩、(c)高血脂、(d)疲劳、(e)贫血、(f)周围神经病变、(g)恶心、(h)腹泻、(i)肝中毒、(j)骨质减少(osteopenia)、(k)脱水和(l)骨质疏松(osteoporosis)。
该治疗或预防可包含给予本文限定的化合物,以辅助下列治疗或干预中的一种或多种。
(a)癌症治疗;
(b)AIDS治疗;
(c)免疫抑制干预;
(d)移植后移植物/植入物管理;
(e)灰指甲(Onychomycotic nail)手术或清创术;
(f)局部抗真菌治疗(例如用选自唑、烯丙胺(例如特比萘芬(terbinafine))或吗啉(例如阿莫罗芬(amorolfine)的抗真菌剂)
(g)全身抗真菌治疗;
(h)抗细菌治疗;
(i)抗病毒治疗;
(j)抗炎症治疗(例如用类固醇);
(k)止痛剂给予;
(l)止痒剂给予;
(m)益生菌给予;
(n)***物细菌治疗;或
(o)皮肤移植。
因此,本发明可以包含正(已经)执行(a)~(o)治疗或干预中的一种或多种的患者群体的治疗或预防。
(g)辅助治疗
该治疗或预防可包含给予本文限定的化合物作为下列治疗或干预中一种或多种的辅剂(辅助,adjunctive):
1.癌症治疗;
2.免疫抑制干预;
3.免疫刺激干预;
4.移植后移植物/植入物管理;
5.灰指甲手术或清创术;
6.抗炎症治疗(例如用类固醇);
7.止痛剂给予;
8.止痒剂给予;
9.手术;
10.细胞或组织消融;
11.放射治疗;
12.冷冻治疗(Cryotherapy);
13.***物移植治疗(***物细菌治疗);
14.益生菌治疗;或
15.皮肤移植。
因而,本发明可以包含正(已经)执行(1)~(15)治疗或干预中的一种或多种的患者群体的治疗或预防。
(V)剂量学
本发明化合物可以通过口服或肠胃外途径给予,包括静脉内、肌肉内、腹膜内、皮下、经皮、呼吸道(气道,airway)(气雾剂(aerosol))、直肠、***和局部(包括颊(buccal)和舌下)给予。
根据所采用的特定剂量单位、治疗周期、受治疗患者的年龄和性别、受治疗紊乱的性质和程度以及所选的特定化合物,所给予化合物的量可能差别很大。
一般地,所给予化合物的有效量一般为约每日0.01mg/kg~10000mg/kg。单位剂量可以包含0.05~500mg该化合物,并可以每天给予1次或多次。利用传统剂量单位形式,该化合物可以与药物载体一起给予,通过口服、肠胃外或局部给予进行,如下所述。
优选的给予途径是口服给予。一般地,合适的剂量为每日每千克接受者体重0.01~500mg,优选每日每千克体重0.01~1000mg,最优选每日每千克体重1~5mg。
期望剂量优选以每日给予的单剂量呈递。然而,也可以采用一天中以适当间隔给予的2、3、4、5或6或更多个亚剂量(子剂量、分剂量,sub-doses)。这些亚剂量可以单位剂型给予,每单位剂型包含例如0.001~100mg,优选0.01~10mg,最优选0.5~1.0mg活性成分。
在确定有效量或剂量时,主治医师需要考虑许多因素,包括但不局限于所使用化合物的效力和作用持续时间、受治疗疾病的性质和严重性以及受治疗患者性别、年龄、体重、总体健康状况和个体反应性及其它相关情况。本领域技术人员应理解,也可以在Goodman & Goldman′s ThePharmacological Basis of Therapeutics,Ninth Edition(1996),Appendix II,pp.1707-1711的指导下确定剂量。
可与载体材料结合从而产生单一剂型的化合物的量将随受治疗的主体和特定给予模式而变化。例如,旨在用于人类口服给予的制剂可以包含约0.5mg~7g活性剂,该活性剂可以可选地与适当且方便的量的载体材料混合,该量在约5%~约95%总组合物之间变化。本发明化合物的剂量单位形式一般包含约1mg~约500mg活性成分,例如5mg、10mg、20mg、25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
本发明化合物特定剂量的有效性可以通过监测给定剂量对疾病或其干预的进展的效果来确定。
(VI)制剂
本发明化合物可以采取任何形式。它可以是合成的、利用本领域描述的技术从天然来源纯化或分离出的。
示例性药学上可接受的盐是由下列酸制备的:甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡萄糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、氨茴酸、甲磺酸、硬脂酸、水杨酸、对羟基苯甲酸、苯乙酸、扁桃酸、帕莫酸(embonic)(扑酸(pamoic))、甲磺酸、乙磺酸、苯磺酸、泛酸、甲苯磺酸、2-羟基乙磺酸、磺胺酸(sulfanilic)、环己基氨基磺酸、海藻酸(algenic)、b-羟基丁酸、半乳糖二酸和半乳糖醛酸。
合适的药学上可接受碱加成盐包括金属离子盐和有机离子盐。金属离子盐包括,但不局限于适当的碱金属(Ia族)盐、碱土金属(IIa族)盐和其它生理上可接受的金属离子。此种盐可由铝、钙、锂、镁、钾、钠和锌离子制成。有机盐可以由叔胺和季铵盐制成,部分地包括三甲胺、二乙胺、N,N′-二苄基乙二胺、氯普鲁卡因(chloroprocaine)、胆碱、二乙醇胺、乙二胺、甲葡胺(N-甲基葡糖胺)和普鲁卡因(procaine)。以上所有的盐都可以由本领域技术人员通过相应化合物的常规方式制备。
药物组合物可以包括稳定剂、抗氧化剂、着色剂和稀释剂。对药学上可接受的载体和添加剂加以选择,以便将药物化合物的副作用减到最小并且不使该化合物性能降低到治疗无效的程度。
该药物组合物可以肠内和/或肠胃外给予。口服(胃内)是典型的给予途径。药学上可接受的载体可以为固体剂型,包括片剂、胶囊、丸剂和粒剂,该固体剂型可以由包衣和外壳(shell)制成,例如肠溶衣和本领域熟知的其它物质。用于口服给予的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆和酏剂。
肠胃外给予包括皮下、肌肉内、经皮、静脉内和本领域中已知的其它途径。肠道给予包括溶液、片剂、持久释放型胶囊、肠溶衣胶囊和糖浆。
给予时,该药物组合物可能在体温下或接近体温。
旨在用于口服使用的组合物可以根据本领域已知的制造药物组合物的任何方法制备,此种组合物可以包含选自由甜味剂、调味剂、着色剂和防腐剂组成的组的一种或多种药剂,以便提供药学上良好(elegant)而可口的药剂。片剂包含与适于制造片剂的无毒的药学上可接受赋形剂混合的活性成分。这些赋形剂为,例如,惰性稀释剂如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠、造粒和崩解剂如玉米淀粉或海藻酸、粘合剂如浆糊、明胶或***胶(acacia)、以及润滑剂如硬脂酸镁、硬脂酸或滑石粉。片剂可以未包衣(涂层)或者它们可以根据已知技术进行包衣(涂层),以便例如延缓在胃肠道中的崩解和吸收,从而在较长的时间段内提供持续作用。例如,可以采用延时材料如单硬脂酸甘油酯或双硬脂酸甘油酯。
用于口服使用的制剂也可以硬明胶胶囊形式存在,其中活性成分与惰性固体稀释剂如碳酸钙、磷酸钙或高岭土混合,或者可以软明胶胶囊形式存在,其中活性成分以同样的方式存在,或者与水或油介质如花生油、液体石蜡或橄榄油混合。
可以制造水性悬浮液,其包含与适于制造水性悬浮液的赋形剂混合的活性成分。此种赋形剂包括悬浮剂,如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯基吡咯烷酮、黄蓍胶(gum tragacanth)和***胶;分散或润湿剂可以为天然产生的磷脂,如卵磷脂或环氧烯烃与脂肪酸的缩合产物(如硬脂酸聚氧乙烯酯)、或环氧乙烯与长链脂肪醇的缩合产物(如十七乙烯氧基十六醇(heptadecaethyleneoxycetanol))、或者环氧乙烯与由脂肪酸和己糖醇产生的偏酯(部分酯,partial ester)的缩合产物(如聚氧乙烯山梨糖醇单油酸酯)、或环氧乙烯与由脂肪酸和己糖醇酐产生的偏酯的缩合产物(如聚氧乙烯山梨糖醇酐单油酸酯)。
水性悬浮液还可以包含一种或多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种调味剂,或者一种或多种甜味剂如蔗糖或糖精。
油性悬浮液可以通过将活性成分悬浮在ω-3脂肪酸、植物油如花生油、橄榄油、芝麻油或椰子油、或矿物油如液体石蜡中来调配。该油性悬浮液可以包含增稠剂,如蜂蜡、硬石蜡或十六醇。
可以加入甜味剂如上述那些和调味剂,从而提供可口的口服制剂。这些组合物可以通过加入抗氧化剂如抗坏血酸来保存。
适于通过加入水制备水性悬浮液的可分散粉末和颗粒提供了与分散剂或润湿剂、悬浮剂以及一种或多种防腐剂混合的活性成分。合适的分散剂或润湿剂和悬浮剂例如为以上已经提到的那些。还可以存在另外的赋形剂,如甜味剂、调味剂和着色剂。
包含本发明化合物的糖浆和酏剂可以与甜味剂如甘油、山梨糖醇或蔗糖一起调配。此种制剂还可以包含缓和剂(demulcent)、防腐剂以及调味剂(矫味剂)和着色剂。
本发明化合物可以无菌可注射水或油脂性悬浮液形式在肠胃外给予,例如皮下、静脉内、肌肉内或通过输注技术给予。此种悬浮液可以根据已知技术使用合适的分散剂或润湿剂和悬浮剂如上述那些或其它可接受药剂进行调配。无菌可注射制剂可以是无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如1,3-丁二醇中的溶液。在可接受媒剂和溶剂当中,可采用水、林格氏溶液和等渗氯化钠溶液。另外,无菌固定油按照惯例用作溶剂或悬浮介质。出于这个目的,可以采用任何温和的固定油,包括合成的单-或双-甘油酯。另外,ω-3多不饱和脂肪酸可以用于制备注射剂。
也可以以用于喷雾器的气雾剂或溶液形式通过吸入给予,或以栓剂形式通过直肠给予,该栓剂是通过将药物与合适的无刺激性赋形剂混合制备,它在常温下为固体但在直肠温度下为液体并因此熔化在直肠中从而释放该药物。此种材料为可可油和聚乙二醇。
本发明还包含了颊和舌下给予,包括含有本文所述化合物的含片、锭剂或咀嚼口香糖形式的给予。该化合物可以沉积在调味基质(flavouredbase),通常为蔗糖和***胶或黄芪胶中。
给予本发明化合物的其它方法包括真皮贴片,其将药物直接释放到主体皮肤中和/或释放通过主体皮肤。
局部递送***也包括在本发明中,并包括软膏、粉末、喷雾剂、霜剂、凝胶剂、洗眼剂、溶液或悬浮液。
本发明组合物可以可选地补充另外的药剂,如粘度增强剂、防腐剂、表面活性剂和渗透促进剂。粘度增加剂(Viscosity-building agent)包括例如聚乙烯醇、聚乙烯吡咯烷酮、甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧甲基纤维素、羟丙基纤维素或本领域技术人员已知的其它药剂。按照药物组合物重量计,典型地采用约0.01%~约2%水平的此种药剂。
可选地采用防腐剂从而阻止在使用之前或使用期间微生物生长。合适的防腐剂包括聚季胺-1、氯化苯甲烷胺、硫柳汞(水杨乙汞,thimerosal)、氯丁醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯乙醇、依地酸二钠(乙二胺四乙酸二钠,edetate disodium)、山梨酸或本领域技术人员已知的其它药剂。典型地,按照药物组合物重量计,采用约0.001%~约1.0%水平的此种防腐剂。
本发明组合物的组分的溶解性可通过表面活性剂或组合物中其它合适的共溶剂增强。此种共溶剂包括聚山梨醇酯20、60和80,聚氧乙烯/聚氧丙烯表面活性剂(例如,Pluronic F-68、F-84和P-103)、环糊精或本领域技术人员已知的其它药剂。典型地,按照药物组合物重量计,采用约0.01%~约2%水平的此种共溶剂。
药学上可接受的赋形剂和载体包括所有前述药剂等。涉及有效配方和给予程序的上述考虑因素是本领域熟知的,并描述在标准教科书中。参见例如Remington:The Science and Practice of Pharmacy,20th Edition(Lippincott,Williams and Wilkins),2000;Lieberman等人,ed.,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.(1980)andKibbe等人,ed.,Handbook of Pharmaceutical Excipients(第3版),AmericanPharmaceutical Association,Washington(1999)。
因此,在本发明化合物与药学上可接受赋形剂一起调配的实施方式中,可以使用任何合适的赋形剂,包括例如惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、调味剂、着色剂和防腐剂。合适的惰性稀释剂包括碳酸钠和碳酸钙、磷酸钠和磷酸钙、以及乳糖,而玉米淀粉和海藻酸是合适的崩解剂。粘合剂可以包括淀粉和明胶,而润滑剂如果存在的话,它一般是硬脂酸镁、硬脂酸或滑石。该药物组合物可以采取任何合适的形式,并包括例如片剂、酏剂、胶囊、溶液、悬浮液、粉剂、粒剂、指甲漆(nail lacquers)、清漆(varnishes)和贴面(veneers)、皮肤贴片和气雾剂。
该药物组合物可以采取试剂盒(a kit of parts)形式,该试剂盒可以包含本发明组合物以及使用说明书和/或单剂量形式的多种不同组分。
对于口服给予,本发明化合物可以调配成固体或液体制剂如胶囊、丸剂、片剂、锭剂、含片、融化剂(melts)、粉剂、粒剂、溶液、悬浮液、分散液或乳液(该溶液、悬浮液、分散液或乳液可以是水性或非水性的)。该固体单位剂型可以是胶囊,该胶囊可以是普通的硬壳或软壳明胶型,其包含例如表面活性剂、润滑剂和惰性填充剂如乳糖、蔗糖、磷酸钙和玉米淀粉。用于口服使用的片剂可以包括单独的或与药学上可接受的赋形剂在一起的本发明化合物,该赋形剂为,例如惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、调味剂、着色剂和防腐剂。合适的惰性稀释剂包括碳酸钠和碳酸钙、磷酸钠和磷酸钙以及乳糖,而玉米淀粉和海藻酸是合适的崩解剂。粘合剂可以包括淀粉和明胶,而润滑剂如果存在的话,它一般是硬脂酸镁、硬脂酸或滑石。期望时,该片剂可以用诸如单硬脂酸甘油酯或双硬脂酸甘油酯的材料进行包衣,从而延缓胃肠道中的吸收。用于口服使用的胶囊包括本发明化合物与固体稀释剂混合在其中的硬明胶胶囊,以及该活性成分与水或油如花生油、液体石蜡或橄榄油混合在其中的软明胶胶囊。
用于直肠给予的制剂可以利用合适的基质以栓剂形式存在,该基质包含例如可可油或水杨酸盐/酯。适于***给予的制剂可以***栓剂(pessaries)、止血栓(tampons)、霜剂、凝胶、糊状物、泡沫或喷雾制剂形式存在,该制剂除了包含活性成分之外,还包含本领域已知适宜的载体。
对于肌肉内、腹膜内、皮下和静脉内使用,本发明化合物一般可以提供在缓冲至适宜pH和等渗性的无菌水性溶液或悬浮液中。
合适的水性媒剂包括林格氏溶液和等渗氯化钠。根据本发明的水性悬浮液可以包括悬浮剂如纤维素衍生物、海藻酸钠、聚乙烯吡咯烷酮和黄蓍胶,以及润湿剂如卵磷脂。水性悬浮液用的合适防腐剂包括对羟基苯甲酸乙酯和对羟基苯甲酸正丙酯。
本发明化合物也可以脂质体制剂形式存在。
在另一个实施方式中,本发明化合物可以利用与以下药剂结合的常规片剂基质如乳糖、蔗糖和玉米淀粉制备成片剂,所述药剂为:粘合剂,如***胶、玉米淀粉或明胶;旨在帮助片剂在给予之后崩裂和溶解的崩解剂,如马铃薯淀粉、海藻酸、玉米淀粉和瓜尔胶(guar gum);旨在提高片剂颗粒的流动和旨在阻止片剂材料粘附到片剂模具和冲头表面上的润滑剂,如滑石、硬脂酸、或硬脂酸镁、硬脂酸钙或硬脂酸锌;染料;着色剂;以及旨在增强片剂的感官质量并使它们更容易被患者接受的调味剂。
用在口服液体剂型中的合适的赋形剂包括稀释剂如水和醇,例如乙醇、苯甲醇和聚乙烯醇,其中加入或不加入药学上可接受的表面活性剂、悬浮剂或乳化剂。
本发明化合物也可以肠胃外给予,即,皮下、静脉内、肌肉内或腹膜内给予。在此种实施方式中,该化合物以生理上可接受的稀释剂中的可注射剂量形式连同药物载体(其可以是无菌液体或液体混合物)提供。合适的液体包括水、盐水、水性葡萄糖和相关的化合物溶液、醇(如乙醇、异丙醇或十六醇)、二醇(如丙二醇或聚乙二醇)、甘油缩酮(如2,2-二甲基-1,3-二氧戊环-4-甲醇)、醚(如聚(乙二醇)400)、油、脂肪酸、脂肪酸酯或甘油酯、或乙酰化脂肪酸甘油酯,其中加入或不加入药学上可接受的表面活性剂(如脂肪酸盐(皂,soap)或去垢剂)、悬浮剂(如果胶、卡波姆(carbomer)、甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素)、或乳化剂以及其它药学上的辅剂。可用在本发明肠胃外制剂中的合适的油是石油、动物油、植物油,或合成来源,例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄榄油、矿脂和矿物油。
合适的脂肪酸包括油酸、硬脂酸和异硬脂酸。合适的脂肪酸酯为,例如油酸乙酯和肉豆蔻酸异丙酯。合适的脂肪酸盐包括脂肪酸碱金属、铵和三乙醇胺盐,并且合适的去垢剂包括阳离子去垢剂,例如二甲基二烷基卤化铵、烷基吡啶卤化物和烷基胺乙酸盐;阴离子去垢剂,例如烷基、芳基和烯烃磺酸盐,烷基、烯烃、醚和单甘油酯硫酸盐,和磺基琥珀酸盐;非离子去垢剂,例如脂肪胺氧化物、脂肪酸烷醇酰胺和聚氧乙烯-聚丙烯共聚物;以及两性去垢剂,例如,烷基-β-氨基丙酸盐,和2-烷基咪唑啉季铵盐及混合物。
本发明肠胃外组合物典型地在溶液中包含约0.5~约25重量%的本发明化合物。也可以使用防腐剂和缓冲剂。为了使对注射部位的刺激减到最低或将其消除,此种组合物可以包含非离子表面活性剂,其具有约12~约17的亲水-亲脂平衡(HLB)。此种制剂中表面活性剂的量为约5~15重量%。该表面活性剂可以是具有以上HLB的单一组分,或者可以是具有期望HLB的两种或多种组分的混合物。用在肠胃外制剂中的示例表面活性剂是聚乙烯山梨糖醇酐脂肪酸酯类别,例如山梨糖醇酐单油酸酯以及氧化乙烯与疏水基质的高分子量加成物,该疏水基质是通过氧化丙烯与丙二醇缩合形成的。
本发明化合物也可以局部给予,当局部给予时,该载体可适当地包括溶液、软膏或凝胶基质。该基质,例如可以包含以下的一种或多种:矿脂、羊毛脂、聚乙二醇、蜂蜡、矿物油、稀释剂如水和醇、以及乳化剂和稳定剂。局部制剂可以包含浓度为约0.1~约10%w/v(重量每单位体积)的化合物。
当辅助使用时,本发明化合物可以调配用于一种或多种其他药物。特别地,本发明化合物可以结合止痛剂、抗炎剂(例如,类固醇)、免疫调节剂和抗痉挛药使用。
因而,辅助使用可反映在设计用于与其它药物(或多种药物)相容(或协同)的特定单位剂量上,或其中该化合物与一种或多种抗炎剂、细胞因子或免疫抑制剂混合(要不然与单一单位剂量中的其它药物(或多种药物)物理关联的)的制剂上。辅助使用也可以反映在本发明药物试剂盒的组成上,在该试剂盒中共同封装本发明化合物与抗微生物剂和/抗炎剂(例如,作为系列单位剂量的一部分)。辅助使用还可以反映在涉及该化合物与抗微生物剂和/或抗炎剂共同给予的信息和/或说明书上。
(VII)例示
本发明将参考具体实施例进行描述。这施些实例为示例性的,仅用于说明:它们并不是要以任何方式限制要求保护的专利权和所描述的本发明范围。这些实施例构成当前考虑的实施本发明的最佳方式。
(a)实施例1:制备通式(I)化合物
(1)总体实验
在Gilson 321HPLC上进行HPLC-UV-MS,并通过以电喷雾电离方式运行的Gilson 170DAD和Finnigan AQA质谱仪进行检测。所使用的HPLC柱是Phenomenex Gemini C 18150x4.6mm或Phenomenex Gemini C1850x4.6mm 3μ。制备型HPLC在Gilson 321上进行,并通过Gilson 170DAD进行检测。利用Gilson 215馏分收集器收集馏分(流分,fractions)。使用的制备型HPLC柱是Phenomenex Gemini C18150x10mm,流动相是乙腈/水。
1H NMR谱记录在以300MHz运行的Bruker仪器上,利用氯仿作为参考标准(7.26ppm)或DMSO-d6(2.50ppm),获得作为CDCl3或DMSO-d6溶液(以ppm报告)的NMR谱。当报告有多重峰(峰多样性,peakmultiplicities)时,使用以下缩写词:s(单峰)、d(双峰)、t(三重峰)、m(多重峰)、br(宽峰)、dd(双重双峰)、dt(双重三峰)、td(三重双峰)、obsc.(模糊的)、app.(明显的)。当给出耦合常数时,它以赫兹(Hz)形式报告。
通过快速色谱(40-65μm硅胶)或利用自动纯化***(来自ISCO的或CombiFlash Companion的SP1TM纯化***),进行柱色谱。在启动器8TM(Biotage)或在Explorer 48(CEM)中进行微波反应。
所使用的缩写词为:DMSO(二甲亚砜)、DMF(二甲基甲酰胺)、IMS(工业甲基化酒精)、TLC(薄层色谱)、Boc(叔丁基氧羰基)、RT(保留时间)、DCM(二氯甲烷)、TFA(三氟乙酸)、LCMS(液相色谱-质谱)、NMR(核磁共振)、DME(1,2-二甲氧基乙烷)。
根据Methods for Antimicrobial Susceptibility Testing of AnaerobicBacteria;Approved Standard-Seventh Edition[M11-A7,Vol.27,No2,Jan2007]和Methods for Dilution Antimicrobial Susceptibility Tests for BacteriaThat Grow Aerobically;Approved Standard-Seventh Edition[M7-A7,Vol.26,No2,Jan 2006]描述的CLS1方案,通过肉汤微稀释法确定MIC数据。
(ii)商购化合物
以下所有的化合物都是从ChemDiv购买的:
3,3′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2′-二基)二苯胺(化合物2)。
(iii)苯并咪唑
方法1
4,4′-(1H,3′H-5,5′-二苯并[d]咪唑-2,2′-二基)二苯胺(化合物1)
在200℃下,将联苯基-3,3′,4,4′-四胺(500mg,2.34mmol)和4-氨基苯甲酸(640mg,4.67mmol)的均质混合物分批(portionwise)加入到搅拌的PPA(20mL)中。将该混合物在200℃下搅拌2.5h。冷却该混合物(至<100℃)并将其倒入水中。搅拌所得混合物,直至形成均匀的绿色沉淀。滤出固体并用含水K2CO3和水洗涤,然后通过抽吸干燥。粗产物用柱色谱(99∶1EtOAc-NEt3~89∶10∶1EtOAc-MeOH-NEt3)纯化从而产生黄色固体。将该黄色固体溶解在MeOH和1M HCl中,然后在真空下浓缩。然后将该材料研磨成细粉末并在含水NaHCO3中搅拌。滤出固体,用水洗涤并进行干燥(真空炉)从而得到产物,为黄色固体(475mg,49%)。
LCMS RT=3.28min,MH+417.3;1H NMR(DMSO+D2O):7.90-7.84(6H,m),7.74-7.65(4H,m)和6.79-6.73(4H,m)。
以类似的方式制备下列化合物,必要时通过结晶或柱色谱纯化。
4,4′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2′-二基)双(N-甲基苯胺)(化合物6)
LCMS RT=1.46min,MH+445.2;1H NMR(DMSO):12.52(2H,br s),7.98-7.90(4H,m),7.72(2H,br s),7.60-7.52(2H,m),7.48-7.43(2H,m),6.66(4H,d,J 8.8),6.24-6.17(2H,m)和2.76(6H,d,J4.8)。
5,5′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2′-二基)二吡啶-2-胺(化合物11)
LCMS RT=1.36min,MH+419.2;1H NMR(DMSO):12.82(2H,br s),8.75(2H,d,J2.4),8.13(2H,dd,J8.9和2.4),7.76(2H,br s),7.64-7.57(2H,m),7.53-7.47(2H,m)和6.61-6.52(6H,m)。
方法2
4,4′-(1H,1′H-5,5′-二苯并[d]咪唑-2,2′-二基)二苯酚(化合物3)
在微波辐射下,在160℃下加热联苯基-3,3′,4,4′-四胺(214mg,2.00mmol)、4-羟基苯甲醛(489mg,4.00mmol)和Na2S2O5(380mg,2.00mmol)在IMS-H2O(3∶1,20mL)中的混合物10分钟,然后在180℃加热10分钟。过滤该混合物,并用IMS洗涤。将H2O加入到滤液中,过滤形成的白色沉淀,用水和Et2O洗涤。对粗固体进行柱色谱纯化(EtOAc~95∶5EtOAc-MeOH),得到产物,为黄色固体(50mg,6%)。
LCMS RT=10.36min[Dionex],MH+419.1;1HNMR(DMSO):12.75-12.66(2H,m),10.00-9.96(2H,m),8.06-7.99(4H,m),7.86(1H,br s),7.72-7.63(2H,m),7.58-7.45(3H,m)和6.96-6.89(4H,m)。
方法3
叔丁基-4,4′-(1-甲基-1H,1′H-5,5′-二苯并[d]咪唑-2,2′-二基)双(4,1-亚苯基)二氨基甲酸酯(中间体8)
将N4-甲基联苯基-3,3′,4,4′-四胺(150mg,0.66mmol)溶解在DMF(10mL)中。加入(810mg,1.32mmol),接着加入N-Boc-4-氨基苯甲醛(根据J.Med.Chem.,1992,35,4150和J.Med.Chem.,2004,47,2411制备)(320mg,1.45mmol)在DMF(5mL)中的溶液。将该混合物在室温下搅拌5h。加入含水K2CO3,滤出所产生的沉淀,并用水(3x100mL)洗涤。通过抽吸干燥该粗物质,并通过柱色谱(75∶25EtOAc-汽油~100%EtOAc)纯化。通过从MeOH重结晶进一步纯化该物质,从而得到产物,为白色固体(83mg,20%)。
1H NMR(DMSO):12.81(1H,br s),9.67(2H,d,J 6.1),8.15-8.05(2H,m),7.96-7.89(1.5H,m),7.86-7.77(2.5H,m),7.73-7.49(8H,m),3.91(3H,s)和1.51(18H,s)。
下列化合物以类似的方式制备,必要时可通过结晶或柱色谱纯化。
2,2′-双(4-甲氧基苯基)-1H,1′H-5,5′-二苯并[d]咪唑(化合物7)
LCMS RT=1.52min,MH+447.5;1H NMR(DMSO):12.84-12.77(2H,m),8.19-8.10(4H,m),7.90(1H,br s),7.75-7.66(2H,m),7.61-7.48(3H,m),7.17-7.09(4H,m)和3.85(6H,s)。
2,2′-二(吡啶-4-基)-1H,1′H-5,5′-二苯并[d]咪唑(化合物12)
LCMS RT=1.46min,MH+389.1;1H NMR(DMSO+D2O):8.79-8.74(4H,m),8.12-8.08(4H,m),8.00-7.89(2H,br m),7.81-7.73(2H,m)和7.70-7.63(2H,br m)。
(iv)N-烷基化的化合物
3′-氟-3,4′-二硝基联苯基-4-胺(中间体1)
将4-溴-2-氟-1-硝基苯(500mg,2.27mmol)、2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(660mg,2.50mmol)和K2CO2(940mg,6.81mmol)悬浮在DME-H2O(4∶1,15mL)中,并用氮气吹扫(purge)。通过声波降解法(sonication)对该溶液进行脱气,之后加入Pd(dppf)Cl2(185mg,10mol%)。在微波辐射下将该混合物加热到130℃10min。冷却的混合物在EtOAc和H2O之间分配(分液,partitioned)。水层用EtOAc(2x50mL)萃取。合并的有机萃取物用盐水洗涤并进行干燥(MgSO4)、过滤和浓缩。所获得的黑色固体吸收到硅石(二氧化硅)上并通过柱色谱(4∶1~1∶1汽油-EtOAc)纯化,从而得到产物,为橙色固体(285mg,45%)。
1H NMR(DMSO):8.43(1H,d,J2.3),8.19(1H,t,J 8.5),7.96(1H,dd,J4.8和2.1),7.92(1H,d,J2.0),7.79-7.73(3H,m)和7.15(1H,d,J8.8)。
N3-甲基-3′,4-二硝基联苯基-3,4′-二胺(中间体2)
将3′-氟-3,4′-二硝基联苯基-4-胺(285mg,1.03mmol)悬浮在DCM(10mL)中。加入K2CO3(284mg,2.06mmol),接着加入MeNH2(H2O中40%,10mL)。室温下搅拌该混合物72h。然后用水和盐水洗涤该溶液。干燥(MgSO4)有机层,过滤并真空浓缩从而得到产物,为红色固体(296mg,100%)。
1H NMR(DMSO):8.34(1H,d,J2.2),8.33-8.26(1H,m),8.11(1H,d,J 9.0),7.91(1H,dd,J 8.8和2.1),7.71(2H,br s),7.15(1H,d,J 9.0),7.11-7.08(1H,m),6.97(1H,dd,J 9.0和1.8)和3.05(3H,d,J 5.0).
N3-甲基联苯基-3,3′,4,4′-四胺(中间体3)
将N3-甲基-3′,4-二硝基联苯基-3,4′-二胺(290mg,1.01mmol)悬浮在IMS(25mL)中,并用氮气吹扫。加入Pd(在碳上为10%,30mg,10mol%),并将该混合物放置在H2(5x真空/气球循环)气氛下。室温下搅拌该混合物18h,此时TLC(EtOAc)显示无原始材料残余。通过硅藻土过滤该混合物,用MeOH洗涤。在真空下浓缩滤液从而产生棕色油。通过柱色谱(EtOAc~97∶3EtOAc-MeOH)纯化粗产物从而得到产物,为粉红色泡沫(158mg,69%)。
1H NMR(DMSO):6.74(1H,d,J 2.0),6.61-6.47(5H,m),4.62-4.53(1H,m),4.46-4.31(6H,m)和2.75(3H,d,J2.8)。
叔丁基-4,4′-(3′-甲基-1H,3′H-5,5′-二苯并[d]咪唑-2,2′-二基)双(4,1-亚苯基)二氨基甲酸酯(中间体4)
通过上述方法3制备。
1H NMR(DMSO):12.81(1H,d,J 8.3),9.69-9.75(2H,m),8.12-8.06(2H,m),8.01-7.99(0.5H,m),7.93-7.89(1H,m),7.83-7.76(2.5H,m),7.74-7.55(8H,m),3.95(3H,s)和1.51(18H,s)。
4,4′-(3′-甲基-1H,3′H-5,5′-二苯并[d]咪唑-2,2′-二基)二苯胺(化合物4)
将叔丁基-4,4′-(3′-甲基-1H,3′H-5,5′-二苯并[d]咪唑-2,2′-二基)双(4,1-亚苯基)二氨基甲酸酯(63mg,0.10mmol)在TFA(3mL)中搅拌30min。真空除去溶剂,并将含水K2CO3加入到残留物中。滤出所得沉淀并用水洗涤,然后通过抽吸干燥从而得到产物,为浅黄色固体(36mg,86%)。
LCMS RT=10.28min[Dionex],MH+431.2;1H NMR(DMSO):12.48(1H,br s),7.91-7.79(4H,m),7.67-7.49(6H,m),6.75-6.63(4H,m),5.64-5.59(4H,br m)和3.92(3H,s)。
4-溴-N-甲基-2-硝基苯胺(中间体5)
将4-溴-1-氟-2-硝基苯(1.50g,6.82mmol)和K2CO3(1.88g,13.6mmol)悬浮在DCM(7mL)中。缓慢地加入MeNH2(在H2O中40%,7mL),并在室温下搅拌该混合物4h。用H2O稀释该混合物,并用DCM(3x40mL)萃取。合并的DCM层用盐水洗涤,干燥(MgSO4)、过滤并浓缩从而得到产物,为鲜橙色固体(1.47g,93%)。
1H NMR(CDCl3):8.32(1H,d,J 2.4),8.03(1H,br s),7.52(1H,dd,J9.2和2.5),6.76(1H,d,J9.2)和3.02(3H,d,J4.2)。
N4-甲基-3,3′-二硝基联苯基-4,4′-二胺(中间体6)
将4-溴-N-甲基-2-硝基苯胺(100mg,0.43mmol)、2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(115mg,0.43mmol)、联苯基-2-基二环己基膦(30mg,20mol%)和K3PO4(275mg,1.3mmol)悬浮在DME-H2O(4∶1,5mL)中。用氮气吹扫该混合物,然后通过声波降解脱气。加入Pd(OAc)2(5mg,5mol%),并在微波辐射下将该混合物加热到130℃10min。冷却的混合物用EtOAc和H2O稀释。分离出有机物,并用EtOAc(3x50mL)萃取水层。合并的有机萃取物用盐水洗涤,并进行干燥(MgSO4)、过滤和真空下浓缩从而得到粗产物,为黑棕色固体(210mg)。可以获取该粗产物,无需进一步纯化。
1H NMR(DMSO):8.29-8.14(3H,m),7.90(1H,dd,J 9.1和2.3),7.77(1H,td,J 8.5和2.3),7.54(2H,br s),7.15-7.05(2H,m)和3.00(3H,d,J5.0)。
N4-甲基联苯基-3,3′,4,4′-四胺(中间体7)
将N4-甲基-3,3′-二硝基联苯基-4,4′-二胺(粗,150mg)悬浮在IMS(10mL)中。用氮气吹扫该***,之后加入Pd(在碳上10%,15mg,10mol%)。将该混合物放置在H2气氛(3x真空/气球循环)下,并在室温下搅拌2.5h。通过硅藻土过滤该混合物,并用MeOH洗涤。真空下浓缩滤液。粗产物通过柱色谱(EtOAc~95∶5EtOAc-MeOH)纯化从而得到产物,为浅棕色油(65mg,66%,2步骤)。
1H NMR(DMSO):6.73-6.63(3H,m),6.56-6.45(2H,m),6.37(1H,d,J 8.1),4.42(7H,br s)和2.71(3H,s)。
叔丁基-4,4′-(1-甲基-1H,1′H-5,5′-二苯并[d]咪唑-2,2′-二基)双(4,1-亚苯基)二氨基甲酸酯(中间体8)
通过上述方法3制备。
1H NMR(DMSO):12.81(1H,br s),9.67(2H,d,J 6.1),8.15-8.05(2H,m),7.96-7.89(1.5H,m),7.86-7.77(2.5H,m),7.73-7.49(8H,m),3.91(3H,s)和1.51(18H,s)。
4,4′-(1-甲基-1H,1′H-5,5′-二苯并[d]咪唑-2,2′-二基)二苯胺(化合物5)
将叔丁基-4,4′-(1-甲基-1H,1′H-5,5′-二苯并[d]咪唑-2,2′-二基)双(4,1-亚苯基)二氨基甲酸酯(83mg,0.13mmol)在TFA(4mL)中搅拌30分钟。真空下除去溶剂,并将含水K2CO3加入到残留物中。滤出所得沉淀,并用水洗涤,然后干燥(真空炉)从而得到产物,为白色固体(46mg,81%)。
LCMS RT=1.44min,MH+431.2;1H NMR(DMSO):12.49(1H,br s),7.89-7.83(3H,m),7.72(1H,br s),7.63-7.42(6H,m),6.74-6.64(6H,m),5.62(4H,m)和3.88(3H,s)。
(v)不对称双化合物
4-(2-(4-氨基苯基)-1H-苯并[d]咪唑-6-基)苯-1,2-二胺(中间体9)
通过方法1,利用1∶1比例的联苯基-3,3′,4,4′-四胺和4-氨基苯甲酸反应2h制备。
1H NMR(DMSO):12.33(1H,br s),7.86-7.80(2H,m),7.45(2H,brm),7.25(1H,dd,J 8.4和1.7),6.86(1H,d,J 2.1),6.72(1H,dd,J 7.9和2.1),6.69-6.63(2H,m),6.57(1H,d,J7.9)和5.80-4.40(6H,br s)。
4-(1H,1′H-5,5′-二苯并[d]咪唑-2-基)苯胺(化合物8)
将4-(2-(4-氨基苯基)-1H-苯并[d]咪唑-6-基)苯-1,2-二胺(200mg,0.64mmol)和甲酸(0.24mL,6.35mmol)溶解在H2O(2mL)中,在微波辐射下将该混合物加热到160℃20分钟。冷却的过程中,有沉淀形成,滤出该沉淀并用水洗涤。用K2CO3碱化滤液并搅拌30min,此时有沉淀形成。过滤该混合物,用水洗涤沉淀并通过抽吸干燥。通过柱色谱(EtOAc~85∶15EtOAc-MeOH)纯化粗产物,从而得到产物,为白色固体(12mg,6%)。
LCMS RT=1.35min,MH+326.3;1H NMR(DMSO):12.48(2H,br s),8.23(1H,br s),7.91-7.68(4H,m),7.65-7.41(4H,m),6.70-6.64(2H,m)和5.62(2H,br s)。
4-(2′-苯基-1H,1′H-5,5′-二苯并[d]咪唑-2-基)苯胺(化合物9)
通过方法1制备,利用仅1当量的苯甲酸,反应2小时。
LCMS RT=1.48min,MH+402.0;1H NMR(DMSO):12.97(1H,br s),12.50(1H,br s),8.24-8.18(2H,m),7.96-7.80(3.5H,m),7.76-7.70(1.5H,m),7.68-7.43(8H,m),6.67(2H,d,J8.7)和5.63(2H,br s)。
4-(2-(4-甲氧基苯基)-1H-苯并[d]咪唑-6-基)苯-1,2-二胺(中间体10)
通过方法2制备,利用1∶1比例的联苯基-3,3′,4,4′-四胺和4-甲氧基苯甲醛,并加热到180℃10分钟。
1H NMR(DMSO):12.68-12.62(1H,br m),8.14-8.07(2H,m),7.66-7.54(1H,m),7.51-7.43(1H,m),7.35-7.27(1H,m),7.16-7.08(2H,m),6.88(1H,d,J 2.1),6.76-6.71(1H,m),6.61-6.56(1H,m),4.55(4H,br s)和3.84(3H,s)。
2′-(4-甲氧基苯基)-2-苯基-1H,3′H-5,5′-二苯并[d]咪唑(化合物10)
通过方法2制备,利用仅1当量的苯甲醛,并加热到180℃10分钟。
LCMS RT=1.52min,MH+417.0;1H NMR(DMSO):12.99(1H,br s),12.82(1H,br s),8.24-8.19(2H,m),8.18-8.12(2H,m),7.97-7.96(1H,br m),7.80-7.66(2H,br m),7.63-7.47(4H,m),7.17-7.10(2H,m)和3.85(3H,s)。
(b)实施例2:本发明化合物对抗艰难梭菌的活性
一系列优选的通式(I)化合物,及其对抗艰难梭菌ATCC700057和艰难梭菌临床分离物(CI)的最低抑制浓度(MIC)总结在表2(以下)中。
表2
化合物序号 | MIC(ATCC700057) | MIC(CI) |
1 | +++ | +++ |
2 | ++ | +++ |
3 | +++ | +++ |
4 | + | + |
5 | ++ | +++ |
6 | ++ | +++ |
7 | +++ | +++ |
8 | ++ | ++ |
9 | ++ | +++ |
10 | +++ | +++ |
11 | +++ | +++ |
12 | +++ | +++ |
在上表中,用于指示MIC值的符号为:
+++=<1μg/mL
++=1-16μg/mL
+=17-64μg/mL
-=>64μg/mL
(c)实例3:本发明化合物对抗产气荚膜梭菌的活性
一系列化合物,及其对抗产气荚膜梭菌ATCC13124和产气荚膜梭菌临床分离物(CI)的最低抑制浓度(MIC)总结在表3(以下)中。用于指示MIC值的符号与表2(以上)相同。
表3
化合物序号 | MIC(ATCC13124) | MIC(CI) |
1 | +++ | +++ |
2 | - | - |
3 | ++ | ++ |
4 | - | - |
5 | ++ | ++ |
6 | ++ | ++ |
7 | +++ | +++ |
8 | + | ++ |
9 | + | ++ |
10 | ++ | +++ |
11 | + | - |
12 | - | - |
(d)实施例4:本发明化合物对抗肺炎链球菌的活性
一系列化合物,及其对抗肺炎链球菌ATCC49619和MDR肺炎链球菌菌株(MDR)的最低抑制浓度(MIC)总结在表4(以下)中。用于指示MIC值的符号与表2(以上)相同。
表4
化合物序号 | MIC(ATCC49619) | MIC(MDR) |
1 | +++ | +++ |
2 | ++ | ++ |
3 | +++ | +++ |
4 | +++ | ++ |
5 | +++ | +++ |
6 | +++ | +++ |
7 | +++ | +++ |
8 | ++ | ++ |
9 | +++ | +++ |
10 | +++ | +++ |
11 | +++ | +++ |
12 | +++ | +++ |
(e)实施例5:本发明化合物对抗金黄色葡萄球菌的活性
一系列化合物,及其对抗金黄色葡萄球菌ATCC29213和MDR金黄色葡萄球菌菌株(MDR)的最低抑制浓度(MIC)总结在表5(以下)中。用于指示MIC值的符号与表2(以上)相同。
表5
化合物序号 | MIC(ATCC29213) | MIC(MDR) |
1 | +++ | +++ |
2 | ++ | - |
3 | +++ | +++ |
4 | - | - |
5 | ++ | ++ |
6 | +++ | +++ |
7 | +++ | +++ |
8 | ++ | + |
9 | ++ | ++ |
10 | +++ | +++ |
11 | - | - |
12 | - | - |
(f)实施例6:本发明化合物对抗屎肠球菌(E.faecium)的活性
一系列化合物,及其对抗屎肠球菌(Enterococcus faecium)和MDR屎肠球菌菌株(MDR)的最低抑制浓度(MIC)总结在表6(以下)中。用于指示MIC值的符号与表2(以上)相同。
表6
化合物序号 | MIC | MIC(MDR) |
1 | +++ | +++ |
2 | ++ | ++ |
3 | +++ | +++ |
4 | ++ | +++ |
5 | +++ | +++ |
6 | +++ | +++ |
7 | +++ | +++ |
8 | ++ | ++ |
9 | +++ | +++ |
10 | +++ | +++ |
11 | ++ | ++ |
12 | - | - |
(g)实施例7:本发明化合物对抗粪肠球菌(E.faecalia)的活性
一系列化合物,及其对抗粪肠球菌(Enterococcus faecali)ATCC51299(VR)的耐万古霉素菌株的最低抑制浓度(MIC)总结在表7(以下)中。用于指示MIC值的符号与表2(以上)相同。
表7
化合物序号 | MIC |
1 | +++ |
2 | ++ |
3 | +++ |
4 | +++ |
5 | +++ |
6 | +++ |
7 | +++ |
8 | ++ |
9 | +++ |
10 | +++ |
11 | + |
12 | - |
(h)实施例8:本发明化合物的特异性
以上列出的化合物中没有一个表现出对抗革兰氏阴性的兼性厌氧细菌大肠杆菌(ATCC25922)的显著活性(MIC>64μg/mL)。仅化合物7和10表现出对抗革兰氏阴性的专性厌氧脆弱拟杆菌(测试了ATCC25285和临床分离物)的一些活性。
大肠杆菌和脆弱拟杆菌代表正常肠道菌群,因而用作微生物肠道菌群的替代物。
实施例2~7中给出的数据表明,相对于产气荚膜梭菌、金黄色葡萄球菌、屎肠球菌和粪肠球菌,化合物12对艰难梭菌的选择性高。该化合物也没有表现出对抗枯草杆菌(bacillus subtilis)或脆弱拟杆菌的显著抗菌活性。
因而,该数据表明本发明化合物可以应用于治疗CDAD,而不引起正常肠道菌群的病理性紊乱。
(VIII)等同物
以上描述详述了当前优选的本发明的实施方式。在考虑这些描述之后,本领域技术人员可以想到实施它的许多修改和变型。这些修改和变型旨在包括在所述权利要求中。
Claims (1)
1.2,2'-二(吡啶-4-基)-1H,1'H-5,5'-二苯并[d]咪唑或其药学上可接受的盐在制备用于治疗由艰难梭菌感染引起的腹泻的药物中的用途。
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GB2480813A (en) * | 2010-06-01 | 2011-12-07 | Summit Corp Plc | Compounds for the treatment of clostridium difficile-associated disease |
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