CN106573953A - C‑4"位取代大环内酯化合物 - Google Patents
C‑4"位取代大环内酯化合物 Download PDFInfo
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- CN106573953A CN106573953A CN201580043943.5A CN201580043943A CN106573953A CN 106573953 A CN106573953 A CN 106573953A CN 201580043943 A CN201580043943 A CN 201580043943A CN 106573953 A CN106573953 A CN 106573953A
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- compound
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- cfu
- ethyl acetate
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Abstract
对以往的大环内酯类抗生素无法获得足够的抗菌活性的红霉素耐药菌,例如耐药性肺炎链球菌、链球菌和支原体等也显示良好的抗菌活性的下述[1]的化合物或其药学上允许的盐、或者它们的水合物或它们的溶剂合物。
Description
技术领域
本发明涉及具有红霉素类似骨架的新型抗生素。本发明更具体地涉及含有在克拉定糖(cladinose)的4"位具有被含氮原子的取代基取代的甲基的大环内酯化合物作为有效成分的用于传染病的预防和/或治疗的药物。
背景技术
红霉素A是被作为由革兰氏阳性菌、支原体等引起的传染病的治疗药物广泛使用的抗生素。但是,红霉素会被胃酸分解,因此存在体内动力学不稳定的缺点。于是,探讨了增加对酸的稳定性的衍生物,其结果开发出了克拉霉素、阿奇霉素(专利文献1和2)、罗红霉素等体内动力学稳定的大环内酯药物。以门诊患者的呼吸道传染病为治疗领域的这些大环内酯药物需要特别是对临床分离频率高的肺炎链球菌、链球菌以及流感嗜血杆菌具有较强的抗菌活性。进而,从社区获得性肺炎高频率地分离出大环内酯耐药性的肺炎链球菌,所以对耐药性肺炎链球菌有效也很重要。
近年来,经过广泛研究的结果,作为对红霉素耐药性肺炎链球菌、红霉素耐药性链球菌都有效的大环内酯,Agouridas等于1995发现了HMR3647(泰利霉素,专利文献3),接着Or等于1998年发现了ABT-773(喹红霉素,专利文献4)。然后,报道了进一步实现药效增强的2-氟酮内酯(2-fluoroketolide)(专利文献5)。
另一方面,关于在克拉定糖的4"位具有被含氮原子的取代基取代的甲基的大环内酯化合物,几乎都是具有在内酯环内有氮原子这一结构特征的氮杂内酯(azalide)型化合物(专利文献6)。
另外,作为对红霉素耐药性肺炎链球菌、红霉素耐药性链球菌都有效的大环内酯,对于在克拉定糖的4"位具有被含氮原子的取代基取代的甲基的大环内酯化合物,申请人也进行了报道(专利文献7、8和9)。其中,特别是专利文献7、8中所记载的实施例15为优选的化合物。
现有技术文献
专利文献
专利文献1:美国专利说明书第4474768号
专利文献2:美国专利说明书第4517359号
专利文献3:欧洲专利第680967号
专利文献4:国际公开WO98/09978号
专利文献5:国际公开WO02/32919号
专利文献6:国际公开WO98/56801号
专利文献7:国际公开WO2012/115256号
专利文献8:日本公表专利公报第2014-505723号
专利文献9:日本公开专利公报第2014-058509号。
发明内容
发明所要解决的技术问题
本发明的课题在于提供不仅对于以往的红霉素敏感菌有效,对于红霉素耐药菌(例如耐药性肺炎链球菌、耐药性链球菌和支原体)也有效的化合物。
于是,本发明人专心进行了新的大环内酯化合物的研究,结果发现以下所示的化合物具有良好的抗菌活性,从而完成了本发明。
即,作为实现该目的的发明,本发明提供
(1)以式[1]:
表示的化合物或其药学上允许的盐、或者它们的水合物或它们的溶剂合物。
此外,本发明还提供包含该化合物作为有效成分的传染病的预防剂和/或治疗剂。
发明的效果
本发明的化合物或其盐、或者其水合物或其溶剂合物具有如下特征:对微生物、优选革兰氏阳性菌或革兰氏阴性菌等需氧性或厌氧性细菌类、支原体或衣原体等具有广谱的抗菌活性,特别是对以往的大环内酯类抗生素无法获得足够抗菌活性的红霉素耐药菌(例如耐药性肺炎链球菌、耐药性链球菌和支原体)等也显示良好的抗菌活性。
附图说明
图1是表示试验例3的结果的图;
图2是表示试验例4的结果的图;
图3是表示试验例5的结果的图。
具体实施方式
本发明中,“其药学上允许的盐”可以是酸加成盐或碱加成盐中的任一种,作为酸加成盐,可列举例如与乙酸、丙酸、丁酸、甲酸、三氟乙酸、马来酸、酒石酸、柠檬酸、硬脂酸、琥珀酸、乙基琥珀酸、乳糖酸、葡萄糖酸、葡庚糖酸(glucoheptonic acid)、苯甲酸、甲磺酸、乙磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、十二烷基硫酸、苹果酸、天门冬氨酸、谷氨酸、己二酸、半胱氨酸、N-乙酰基半胱氨酸、盐酸、氢溴酸、磷酸、硫酸、氢碘酸、烟酸、草酸、苦味酸、硫氰酸、十一烷酸、丙烯酸聚合物、羧乙烯基聚合物等酸的盐,作为碱加成盐,可列举例如钠盐、钾盐、钙盐等与无机碱的盐,与吗啉、哌啶等有机胺、氨基酸的盐,但并不仅限于这些盐。
本发明中,“抗菌剂”是指具有作用于革兰氏阳性菌、革兰氏阳性菌或支原体等细菌而抑制其生长或杀菌的能力的物质。可以是抑制菌的繁殖,或者杀死部分菌而减少其数量的抗菌剂。作为革兰氏阳性菌,可列举例如葡萄球菌属(金黄色葡萄球菌、表皮葡萄球菌等)、链球菌属(酿脓链球菌、B组链球菌、肺炎链球菌等)、肠球菌属(粪肠球菌、屎肠球菌等)。作为革兰氏阴性菌,可列举例如假单胞菌属(绿脓杆菌等)、埃希氏菌属(大肠杆菌等)、克雷伯氏菌属(肺炎克雷伯氏菌、产酸克雷伯氏菌等)、嗜血杆菌属(流感嗜血杆菌、副流感嗜血杆菌等)、博德特氏菌属(百日咳博德特氏菌、支气管炎博德特氏菌等)、沙雷氏菌属(粘质沙雷氏菌等)、变形杆菌属(奇异变形杆菌等)、肠杆菌属(阴沟肠杆菌等)、弯曲菌属(空肠弯曲菌等)、柠檬酸杆菌属、弧菌属(副溶血性弧菌、霍乱弧菌等)、摩根氏菌属(摩氏摩根氏菌(Morganella morganii)等)、沙门氏菌属(伤寒沙门氏菌、副伤寒沙门氏菌等)、志贺氏菌属(痢疾志贺氏菌等)、不动杆菌属(鲍曼不动杆菌、乙酸钙不动杆菌等)、军团菌属(嗜肺军团菌等)、拟杆菌属(脆弱拟杆菌等)、奈瑟菌属(淋病奈瑟菌、脑膜炎奈瑟菌等)、莫拉氏菌属(卡他莫拉氏菌等)、衣原体属(沙眼衣原体、鹦鹉热衣原体等)和螺杆菌属(幽门螺杆菌等)。作为支原体,可列举鸡毒支原体、生殖支原体、人型支原体、猪肺炎支原体、实验室合成支原体、丝状支原体、绵羊肺炎支原体、肺炎支原体。
本发明的化合物具有如下特征:特别是对于用以往的大环内酯类抗生素无法获得充分的抗菌活性的红霉素耐药菌(例如耐药性肺炎链球菌、耐药性链球菌和支原体)等也显示良好的抗菌活性。
上述以式[1]表示的化合物可存在光学异构体,以式[1]表示的化合物包括它们的光学异构体、及光学异构体的混合物。此外,以式[1]表示的化合物或其药学上允许的盐、或者它们的各种水合物或溶剂合物也包含在本发明的范围中。
只要没有特别示出,本发明中的“溶剂合物”的“溶剂”是指例如极性溶剂(例如甲醇、乙醇、1-丙醇、2-丙醇、丁醇等醇类溶剂,乙酸乙酯等)、惰性溶剂(例如氯仿或二氯甲烷等卤代烃类溶剂,二乙醚、四氢呋喃或二噁烷等醚类溶剂,二甲基甲酰胺、二甲基乙酰胺等酰胺类溶剂,二甲亚砜、乙腈等非质子性溶剂,甲苯等芳香烃类,或者环己烷等烃类等)、以及2-丁酮、己烷、异丙醚、丙酮、二氯甲烷等,或者这里示例的溶剂的混合溶剂,但不限于这些溶剂。
上述以式[1]表示的本发明的化合物或其盐、或者其水合物或其溶剂合物显示良好的安全性。安全性通过各种试验评价,例如可通过细胞毒性试验、hERG试验、细胞色素P450(CYP)活性抑制试验等进行评价。
上述以式[1]表示的本发明的化合物或其盐、或者其水合物或其溶剂合物显示良好的代谢稳定性。代谢稳定性通过各种试验评价,例如可通过人肝微粒体代谢稳定性试验等进行评价。
本发明的化合物可与一种或二种以上的药物中允许的载体、赋形剂或稀释剂组合而制成药物制剂。作为上述载体、赋形剂和稀释剂,可列举水、乳糖、右旋糖、果糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、聚乙二醇、丙二醇、淀粉、树胶、明胶、海藻酸盐、硅酸钙、磷酸钙、水糖浆、纤维素、甲基纤维素、羟丙基纤维素、聚乙烯吡咯烷酮、烷基对羟基苯并山梨酸酯(alkyl para-hydroxybenzosorbate)、滑石、硬脂酸镁、硬脂酸、肉豆蔻酸、甘油、芝麻油、橄榄油、大豆油等各种油等。此外,可在上述的载体、赋形剂或稀释剂中根据需要混合通常使用的增量剂、粘合剂、崩解剂、pH调节剂、溶解剂等添加剂,通过常用的制剂技术制备成片剂、丸剂、胶囊剂、颗粒剂、粉剂、液剂、乳剂、悬浮剂、软膏剂、注射剂、皮肤贴剂等口服或非口服(胃肠外)用药物。
本发明的化合物对于成人患者可按照1次1~10000mg、优选5~1000mg的给药量1天1次或分数次以非口服或口服的方式给药。给药量可根据作为治疗对象的疾病的种类、患者的年龄、体重、症状等适当增减。此外,本发明的化合物还可与其他的药剂组合使用。
实施例
以下,通过参考例、实施例和试验例对本发明进行进一步的详细说明。本发明的化合物的合成方法并不限于以下的方法,还可使用交换各工序的顺序、经过官能团的保护-脱保护等本领域技术人员周知的方法进行合成。
以下的参考例、实施例记载的各设备数据通过以下的测定设备进行测定;
NMR谱:日本电子株式会社JNM-ECA600(600MHz)、日本电子株式会社JNM-ECA500(500MHz)
MS谱:株式会社岛津制作所LCMS-2010EV或Micromass公司Platform LC。
以下的参考例、实施例中,高效液相色谱-质谱分析(LCMS)通过以下的条件进行测定;
测定设备:Agilent 2900和Agilent 6150
柱:沃特斯公司(Waters)Acquity CSH C18,1.7μm,φ2.1×50mm
溶剂:A液,含0.1%甲酸的水;B液,含0.1%甲酸的乙腈
(条件1)
梯度:0分钟(A液/B液=80/20),1.2-1.4分钟(A液/B液=1/99)
流速:0.8mL/分钟;检测方法:UV、ELSD
(条件2)
梯度:0分钟(A液/B液=95/5),1.20分钟(A液/B液=50/50),1.0mL/分钟,1.38分钟(A液/B液=3/97)
流速:0.8mL/分钟;检测方法:UV、ELSD
离子化方法:ESI。
参考例、实施例中的缩写如下所示;
ESI:电喷雾离子化法
MS:质谱
CDCl3:氘代氯仿
NMR:核磁共振
s:单峰
brs:宽单峰(宽范围的单峰)
d:二重峰
m:多重峰
t:三重峰
q:四重峰。
参考例1 N,N-二异丙基-N-甲基乙烷-1,2-二胺的合成
<方案A>
在冰冷条件下向8.9mol/L甲胺的甲醇溶液135mL中滴加二异丙基氨基氯乙烷盐酸盐24.0g的甲醇溶液72mL,在室温下搅拌20分钟。反应液减压浓缩,将所得的残渣溶解于氯仿,在冰冷条件下加入2mol/L氢氧化钠水溶液。反应液用氯仿萃取2次,有机层在减压下浓缩后,将所得的残渣用氨基硅胶柱层析(己烷:氯仿=5:1至仅氯仿)纯化,获得标题化合物19.4g;
MS(ESI) m/z= 159 [M+H]+
1H-NMR (400 MHz, CDCl3) δ(ppm) : 0.99 (d, J=1.71 Hz, 6 H) 1.00 (d, J=1.71Hz, 6 H) 2.43 (s, 3 H) 2.54 -2.57 (m, 4 H) 2.96 -3.03 (m, 2 H)。
参考例2 2-氨基-N-乙基乙酰胺的合成
<方案B>
(1)向N-(苄氧羰基)甘氨酸209g的氯仿溶液1.0L中加入70%乙胺水溶液108mL,在冰冷条件下加入1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐249g后,在室温下搅拌一晚。向反应液中加入饱和碳酸氢钠水溶液,用氯仿萃取。有机层在减压下浓缩后,将所得的残渣悬浮于400mL乙酸乙酯,加入200mL己烷搅拌,滤取产生的固体而获得150g酰胺化合物。
<方案C>
(2)向上述的参考例2-(1)中得到的150g酰胺化合物的630mL甲醇溶液中加入10%钯碳15g,在氢气气氛下于室温搅拌6天。过滤反应液后,将滤液在减压下浓缩,获得标题化合物64.4g;
MS(ESI) m/z= 103 [M+H]+
1H-NMR (400 MHz, CDCl3) δ(ppm) : 1.17 (t, J=7.2 Hz, 3 H) 1.38 (brs, 2 H)3.29 - 3.37 (m, 4 H) 7.20 (brs, 1 H)。
参考例3 以式[2]表示的化合物的制造
式[2]:
<方案D>
(1)将200g克拉霉素溶解于1.5L丙酮,滴加30.3mL乙酸酐,在室温下搅拌一晚。反应液减压浓缩,向所得的残渣中加入乙酸乙酯、己烷、氢氧化钠水溶液后,加入饱和碳酸氢钠水溶液调整至pH=9。用玻璃滤器滤取析出的固体,用蒸馏水清洗后,在减压下干燥,获得202g乙酰基化合物;
MS(ESI) m/z= 790.6 [M+H]+。
<方案E>
(2)将上述的参考例3-(1)中得到的202g乙酰基化合物溶解于1.8L氯仿,加入210mL吡啶后进行冰冷,用40分钟滴加77.4g三光气的0.8L氯仿溶液。将反应液升温至室温后,搅拌3小时。向反应液中加入158mL吡啶,在冰冷条件下滴加57.9g三光气的氯仿溶液,在室温下搅拌15分钟。向反应液中加入蒸馏水、饱和碳酸氢钠水溶液,用氯仿萃取,用无水硫酸镁干燥有机层并过滤。滤液减压浓缩,向所得的残渣中加入乙酸乙酯和己烷的1:1混合溶剂并搅拌,再加入己烷在室温下搅拌一晚。滤取生成的固体,用乙酸乙酯和己烷的1:2混合溶剂清洗后,在减压下干燥而获得220g碳酸酯化合物;
MS(ESI)m/z= 816.5 [M+H]+。
<方案F>
(3)将N-氯琥珀酰亚胺99.7g溶解于1L氯仿,冷却至-25℃。用20分钟向反应液中滴加210mL二甲基硫醚的0.2L氯仿溶液,搅拌15分钟后,用30分钟滴加上述(2)中得到的碳酸酯化合物的1L氯仿溶液,搅拌15分钟。向反应液中加入136mL三乙胺的0.2L氯仿溶液,搅拌30分钟。向反应液中加入饱和碳酸氢钠水溶液,升温至室温,用氯仿分液。有机层用无水硫酸镁干燥并过滤后,滤液减压浓缩,向所得的残渣中加入乙酸乙酯和己烷的1:5混合溶剂,在室温下搅拌一晚。滤取生成的固体,用乙酸乙酯和己烷的1:2混合溶剂清洗,获得109g酮化合物。滤液减压浓缩,将所得的残渣用硅胶柱层析(乙酸乙酯:己烷=1:1至丙酮:己烷:三乙胺 = 10:10:0.2)纯化后,通过与上述同样的方法进行结晶而获得59.5g酮化合物;
MS(ESI)m/z= 814.5 [M+H]+。
<方案G>
(4)将210g三甲基碘化亚砜溶解于二甲亚砜和四氢呋喃的5:1混合溶剂1.2L,少量逐次加入70%氢化钠32.6g,在室温下搅拌1.5小时。在冰冷条件下,滴加上述(3)中得到的酮化合物155g的0.8L四氢呋喃溶液,室温下搅拌30分钟。将反应液冰冷,加入蒸馏水,加入乙酸乙酯并分液,用蒸馏水清洗所得的有机层。水层用乙酸乙酯萃取,用蒸馏水清洗有机层。收集的有机层用无水硫酸镁干燥并过滤。滤液减压浓缩,获得146g环氧化合物;
MS(ESI)m/z= 784.5 [M+H]+
1H-NMR (600 MHz, CDCl3) δ(ppm) : 0.90 (t, J=7.57 Hz, 3 H) 0.97 (d, J=7.34Hz, 3 H) 1.04 (d, J=6.88 Hz, 3 H) 1.07 (s, 3 H) 1.14 (d, J=6.88 Hz, 3 H) 1.18(d, J=5.96 Hz, 3 H) 1.21 - 1.36 (m, 7 H) 1.42 (s, 3 H) 1.47 - 1.55 (m, 1 H)1.67 - 1.73 (m, 1 H) 1.83 - 1.98 (m, 5 H) 2.02 (d, J=1.83 Hz, 6 H) 2.18 -2.29 (m, 1 H) 2.25 (s, 6 H) 2.58 - 2.69 (m, 1 H) 2.63 (d, J=4.13 Hz, 1 H)2.80 - 2.89 (m, 1 H) 2.94 (d, J=4.13 Hz, 1 H) 3.12 - 3.26 (m, 1 H) 3.17 (s, 3H) 3.34 (s, 3 H) 3.43 - 3.51 (m, 1 H) 3.66 (d, J=6.42 Hz, 1 H) 3.94 (brs, 1H) 4.57 (d, J=7.34 Hz, 1 H) 4.73 (dd, J=10.55, 7.34 Hz, 1 H) 4.80 (q, J=6.42Hz, 1 H) 4.98 - 5.06 (m, 2 H) 6.50 (s, 1 H)。
<方案H>
(5)将138g上述参考例3-(4)中得到的环氧化合物溶解于四氢呋喃和二甲基甲酰胺的1:1混合溶剂1.4L,加入1,1'-羰基二咪唑85.6g。在冰冷条件下,用40分钟加入70%氢化钠18.1g,在室温下搅拌0.5小时。将反应液冰冷,加入蒸馏水,用乙酸乙酯萃取,用蒸馏水清洗有机层2次。水层用乙酸乙酯萃取,用蒸馏水清洗有机层2次。收集的有机层用无水硫酸镁干燥并过滤。滤液减压浓缩,将所得的残渣用硅胶柱层析(己烷至己烷:乙酸乙酯=1:1至丙酮:己烷:三乙胺 = 10:10:0.2)纯化。向所得的纯化产物中加入乙酸乙酯、己烷(1:1),在室温下搅拌一晚。滤取生成的固体,用乙酸乙酯和己烷的1:4混合溶剂清洗,获得以式[2]表示的化合物87.1g;
MS(ESI)m/z= 878.6 [M+H]+
1H-NMR (600 MHz, CDCl3) δ(ppm) : 0.85 - 1.41 (m, 25 H) 1.64 - 1.78 (m, 3H) 1.79 (s, 3 H) 1.90 (dd, J=14.67, 5.04 Hz, 4 H) 1.86 (s, 3 H) 2.04 (s, 3 H)2.19 - 2.28 (m, 1 H) 2.25 (s, 6 H) 2.60 - 2.68 (m, 1 H) 2.65 (d, J=4.13 Hz, 1H) 2.86 - 2.97 (m, 1 H) 2.95 (d, J=4.13 Hz, 1 H) 3.15 (s, 3 H) 3.22 - 3.29(m, 1 H) 3.35 (s, 3 H) 3.38 - 3.47 (m, 1 H) 3.66 (d, J=6.42 Hz, 1 H) 3.79 -3.88 (m, 1 H) 4.56 (d, J=6.88 Hz, 1 H) 4.72 (dd, J=10.32, 7.57 Hz, 1 H) 4.79(q, J=6.27 Hz, 1 H) 5.01 - 5.09 (m, 1 H) 5.83 (dd, J=10.55, 2.75 Hz, 1 H)6.66 (s, 1 H) 7.07 (s, 1 H) 7.34 - 7.38 (m, 1 H) 8.08 (s, 1 H)。
参考例4 以式[3]表示的化合物的制造
式[3]:
<方案I>
(1)将360mg参考例3中得到的以式[2]表示的化合物溶解于1.5mL乙腈,加入280μl的1,8-二氮杂双环[5,4,0]-7-十一烯、273mg的3-甲磺酰基丙胺盐酸盐,在室温下搅拌一天。向反应液中加入乙酸乙酯、饱和氯化铵水溶液并分液。有机层用无水硫酸镁干燥并过滤,滤液减压浓缩,将所得的残渣用硅胶柱层析(氯仿至氯仿:甲醇:28%氨水=25:1:0.1至15:1:0.1)纯化而获得117mg氨基甲酸酯化合物。
<方案J>
(2)将115mg上述的参考例4-(1)得到的氨基甲酸酯化合物溶解于1mL乙醇,加入N,N-二乙基-N'-甲基乙烷-1,2-二胺195μl,封管中在100℃搅拌1天。向反应液中加入乙酸乙酯、饱和氯化铵水溶液并分液。有机层用无水硫酸镁干燥并过滤,滤液减压浓缩,将所得的残渣用硅胶柱层析(氯仿至氯仿:甲醇:28%氨水=12:1:0.1)、制备薄层层析(氯仿:甲醇:28%氨水=20:1:0.1)纯化,获得62.7mg以式[3]表示的化合物。
应予说明,以式[3]表示的化合物是专利文献7、8中作为优选化合物所记载的实施例15。
实施例1 以式[1]表示的化合物的制造
式[1]:
<方案K>
(1)将277g参考例3中得到的以式[2]表示的化合物溶解于315mL乙腈,加入64.4g参考例2中得到的化合物和191mL的1,8-二氮杂双环[5,4,0]-7-十一烯,在室温下搅拌1.5小时。向反应液中加入500mL水,用400mL乙酸乙酯萃取。将有机层用饱和盐水清洗,用硫酸镁干燥、过滤后,在减压下浓缩。将残渣通过300mL乙酸乙酯和300mL己烷重结晶,获得83.5g氨基甲酸酯化合物。将残渣在减压下浓缩后,进行重结晶(200mL乙酸乙酯、200mL己烷),从而获得34.4g氨基甲酸酯化合物。再将滤液在减压下浓缩,残渣用硅胶柱层析(氯仿:甲醇:28%氨水=99:1:0.1至85:15:1.5)纯化后,通过100mL乙酸乙酯和100mL己烷重结晶,获得16.3g氨基甲酸酯化合物。将滤液与由所述柱得到的部分组分合并,用氨基硅胶柱层析(乙酸乙酯:己烷=20:80至仅乙酸乙酯)纯化后,通过200mL乙酸乙酯和200mL己烷重结晶,从而获得55.3g氨基甲酸酯化合物。这些氨基甲酸酯化合物合并共获得189.5g;
MS(ESI)m/z= 912.6 [M+H]+
1H-NMR (499 MHz, CDCl3) δ(ppm) : 0.85 - 0.90 (m, 6 H) 0.95 (d, J=7.55 Hz,3 H) 0.99 - 1.29 (m, 19 H) 1.33 (s, 3 H) 1.44 (s, 3 H) 1.50 - 1.65 (m, 3 H)1.68 - 1.73 (m, 1 H) 1.84 - 2.00 (m, 3 H) 2.05 (s, 3 H) 2.21 (dd, J=14.75,3.09 Hz, 1 H) 2.26 (s, 6 H) 2.53 - 2.60 (m, 1 H) 2.62 (d, J=4.12 Hz, 1 H)2.63 - 2.70 (m, 1 H) 2.86 - 2.91 (m, 1 H) 2.93 (s, 3 H) 2.94 (d, J=4.12 Hz, 1H) 3.06 (q, J=6.86 Hz, 1 H) 3.27 - 3.36 (m, 2 H) 3.34 (s, 3 H) 3.41 - 3.50(m, 1 H) 3.68 (d, J=6.17 Hz, 1 H) 3.73 (d, J=10.29 Hz, 1 H) 3.76 (s, 1 H)4.20 (d, J=16.81 Hz, 1 H) 4.49 (d, J=16.81 Hz, 1 H) 4.63 (d, J=7.55 Hz, 1 H)4.68 - 4.77 (m, 2 H) 5.04 (dd, J=4.63, 3.26 Hz, 1 H) 5.25 (dd, J=10.63, 2.40Hz, 1 H) 6.17 (t, J=5.66 Hz, 1 H)。
<方案L>
(2)将189g上述的实施例1-(1)得到的氨基甲酸酯化合物溶解于410mL甲醇,加热回流4小时后,在室温下搅拌1昼夜。将反应液在减压下浓缩。向残渣中加入50mL乙酸乙酯和300mL己烷,搅拌30分钟,滤取生成的固体,获得41.2g脱乙酰基化合物。将滤液用氨基硅胶柱层析(乙酸乙酯:己烷=20:80至100:0)和硅胶柱层析(氯仿:甲醇:28%氨水=99:1:0.1至85:15:1.5)纯化3次。向所得的粗纯化物中加入50mL乙酸乙酯和600mL己烷,搅拌30分钟,滤取生成的固体,获得62.8g脱乙酰基化合物。再将滤液用硅胶柱层析(氯仿:甲醇:28%氨水=99:1:0.1至85:15:1.5)纯化,同样地通过20mL乙酸乙酯和50mL己烷重结晶,获得2.99g脱乙酰基化合物;
MS(ESI)m/z= 870.6 [M+H]+
1H-NMR (499 MHz, CDCl3) δ(ppm) : 0.88 (t, J=7.38 Hz, 3 H) 1.00 - 1.08 (m,9 H) 1.09 - 1.27 (m, 1 H) 1.10 - 1.15 (m, 9 H) 1.18 (d, J=6.17 Hz, 3 H) 1.24(d, J=7.20 Hz, 3 H) 1.36 (s, 3 H) 1.43 (s, 3 H) 1.58 (ddd, J=14.24, 10.46,7.20 Hz, 1 H) 1.62 - 1.78 (m, 3 H) 1.88 (dd, J=14.92, 4.97 Hz, 1 H) 1.91 -2.00 (m, 2 H) 2.23 (dd, J=14.75, 2.74 Hz, 1 H) 2.28 (s, 6 H) 2.42 - 2.50 (m,1 H) 2.59 (dd, J=7.03, 4.29 Hz, 1 H) 2.62 (d, J=4.12 Hz, 1 H) 2.89 - 2.96 (m,1 H) 2.93 (d, J=4.12 Hz, 1 H) 2.95 (s, 3 H) 3.08 (q, J=6.86 Hz, 1 H) 3.18(dd, J=10.29, 7.20 Hz, 1 H) 3.27 - 3.39 (m, 2 H) 3.32 (s, 3 H) 3.42 - 3.50(m, 1 H) 3.71 (d, J=6.52 Hz, 1 H) 3.76 (d, J=9.95 Hz, 1 H) 3.77 (s, 1 H) 4.21(d, J=16.81 Hz, 1 H) 4.50 (d, J=10.63 Hz, 1 H) 4.52 (s, 1 H) 4.76 (q, J=6.52Hz, 1 H) 5.04 (dd, J=4.80, 2.74 Hz, 1 H) 5.21 (dd, J=10.63, 2.40 Hz, 1 H)6.25 (t, J=5.66 Hz, 1 H)。
<方案M>
(3)将104g上述的实施例1-(2)得到的脱乙酰基化合物溶解于120mL乙醇,加入56.5g参考例1得到的化合物,加热回流2小时。将反应液在减压下浓缩。将残渣溶解于乙酸乙酯,用饱和碳酸氢钠水溶液清洗3次后,加水进行分液。水层用乙酸乙酯再次萃取,用水清洗。合并的有机层用饱和盐水清洗,用硫酸镁干燥、过滤后,在减压下浓缩。将残渣通过100mL乙酸乙酯和600mL己烷重结晶,获得41.4g以式[1]表示的化合物。再将滤液在减压下浓缩,残渣用硅胶柱层析(氯仿:甲醇:28%氨水=99:1:0.1至85:15:1.5)纯化后,通过100mL乙酸乙酯和500mL己烷重结晶,获得62.1g以式[1]表示的化合物。合并这样得到的以式[1]表示的化合物,共获得103.5g;
MS(ESI)m/z= 1028.8 [M+H]+
1H-NMR (499 MHz, CDCl3) δ(ppm) : 0.87 (t, J=7.20 Hz, 3 H) 1.00 (m, J=10.60, 6.50 Hz, 15 H) 1.06 - 1.26 (m, 22 H) 1.38 (s, 3 H) 1.42 (s, 3 H) 1.52- 1.79 (m, 4 H) 1.84 - 2.07 (m, 5 H) 2.29 (s, 6 H) 2.35 (s, 3 H) 2.39 - 2.55(m, 5 H) 2.57 - 2.64 (m, 1 H) 2.83 (d, J=14.75 Hz, 1 H) 2.89 (dd, J=9.26,7.20 Hz, 1 H) 2.94 (s, 3 H) 2.95-3.03 (m, 2 H) 3.08 (q, J=7.09 Hz, 1 H) 3.17(dd, J=10.12, 7.38 Hz, 1 H) 3.22 - 3.32 (m, 1 H) 3.28 (s, 3 H) 3.34 - 3.48(m, 3 H) 3.64 (d, J=7.55 Hz, 1 H) 3.73 (d, J=9.61 Hz, 1 H) 3.78 (s, 1 H) 4.08(q, J=6.40 Hz, 1 H) 4.21 (d, J=17.15 Hz, 1 H) 4.40 (d, J=7.20 Hz, 1 H) 4.57(d, J=16.81 Hz, 1 H) 4.95 (brs, 1 H) 4.99 (d, J=4.80 Hz, 1 H) 5.11 (dd, J=10.63, 2.06 Hz, 1 H) 6.39 (t, J=5.66 Hz, 1 H)。
本发明化合物的作用通过以下的药理试验确认。
试验例1 体外抗菌活性
本发明制品、实施例1的以式[1]表示的化合物对各种试验菌的体外抗菌力按照微量液体稀释法(CLSI法)进行测定。此外,参考例4的以式[3]表示的化合物也同样进行测定。使用的试验菌示于表1。对于菌体编号A、B、C、D、E、F、G、H、I、J、K和L的试验菌的MIC值(最小抑菌浓度 μg/ml)示于表2。
[表1]
。
[表2]
。
试验例2 流感嗜血杆菌敏感性试验
使用39种流感嗜血杆菌(Haemophilus influenzae)的临床分离株,使用与试验例1同样的方法,对药剂敏感性实施了评价。结果示于表3。
[表3]
。
试验例3 流感嗜血杆菌感染动物的治疗效果试验
药理效果的评价使用以下所示的方法。
作为细菌,使用流感嗜血杆菌(Haemophilus influenzae)ATCC43095株(菌体编号A)。刮取用巧克力琼脂培养基培养了1晚的菌体,悬浮于嗜血杆菌敏感性试验培养基或添加法尔兹增菌液(Fildes Enrichment)的脑心浸液肉汤培养基后,培养1晚。将其用嗜血杆菌敏感性试验培养基或添加法尔兹增菌液的脑心浸液肉汤培养基稀释,作为接种菌液。对小鼠(ICR系,雄性,4周龄)气管内接种0.05mL接种菌液使其感染。接种菌量为2.25×106CFU/小鼠或9.00×105CFU/小鼠。从接种第2天起,口服给药实施例1的以式[1]表示的化合物(100mg/kg和200mg/kg)或者介质(0.1mol/L乳糖酸溶液和0.5w/v%碳酸氢钠溶液的等量混合液),每天1次,共2天。接种3天后的肺内活菌数(1组6例,平均值±标准差)示于图1。
应予说明,关于图1的备注如下。与介质的显著差异:Steel检验 *:p<0.05,**:p<0.01实施例1、式[1]的化合物MIC值为4μg/mL,参考例4、式[3]的化合物MIC值为4μg/mL。
以下,作为试验结果的肺内活菌数以肺内活菌数(CFU/肺)的常用对数(常用对数以下记作log)表示。
介质给药组的肺内活菌数为5.88±0.14[log(CFU/肺)]。实施例1的以式[1]表示的化合物100mg/kg给药组和200mg/kg给药组的肺内活菌数分别为3.54±0.49[log(CFU/肺)]和2.83±0.53[log(CFU/肺)],与介质给药组相比显著减少。同样地,口服给药参考例4的以式[3]表示的化合物(100mg/kg和200mg/kg)或者介质(0.1mol/L乳糖酸溶液和0.5w/v%碳酸氢钠溶液的等量混合液)。结果若以肺内活菌数(CFU/肺)的常用对数(常用对数以下记作log)表示,对于接种3天后的肺内活菌数,介质给药组为5.67±0.32[log(CFU/肺)]。参考例4的以式[3]表示的化合物100mg/kg给药组和200mg/kg给药组的肺内活菌数分别为4.37±0.27[log(CFU/肺)]和2.53±0.23[log(CFU/肺)],与介质给药组相比显著减少。由上可知,实施例1的以式[1]表示的化合物对该菌株显示出与参考例4的以式[3]表示的化合物同等程度的治疗效果。
试验例4 红霉素耐药性(有erm(B)基因)肺炎链球菌感染动物的治疗效果试验
药理效果的评价使用以下所示的方法。
作为细菌,使用肺炎链球菌(Streptococcus pneumoniae)1101 株(临床分离株)。将使用菌株的冷冻保存液添加至“添加30vol%灭活马血清的托德休伊特(Todd Hewitt)液体培养基”,培养至浊度(OD600)达到约0.3。将其用添加30vol%灭活马血清的托德休伊特(Todd Hewitt)液体培养基稀释,作为接种菌液。对小鼠(CBA/JN系,雄性,5周龄)经鼻接种0.05mL接种菌液使其感染。接种菌量为7.50×104CFU/小鼠或1.65×105CFU/小鼠。从接种第2天起,口服给药实施例1的以式[1]表示的化合物(30mg/kg和100mg/kg)或者介质(0.1mol/L乳糖酸溶液和0.5w/v%碳酸氢钠溶液的等量混合液),每天1次,共2天。接种3天后的肺内活菌数(1组5~6例,平均值±标准差)示于图2。
应予说明,关于图2的备注如下。与介质的显著差异:Steel检验 *:p<0.05,**:p<0.01实施例1、式[1]的化合物MIC值为0.25μg/mL,参考例4、式[3]的化合物MIC值为0.12μg/mL。
介质给药组的肺内活菌数为5.83±0.08[log(CFU/肺)]。实施例1的以式[1]表示的化合物30mg/kg给药组和100mg/kg给药组的肺内活菌数分别为4.14±0.19[log(CFU/肺)]和2.28±0.24[log(CFU/肺)],与介质给药组相比显著减少。同样地,口服给药参考例4的以式[3]表示的化合物(10mg/kg、30mg/kg和100mg/kg)或者介质(0.1mol/L乳糖酸溶液和0.5w/v%碳酸氢钠溶液的等量混合液),结果是,对于接种3天后的肺内活菌数,介质给药组为5.91±0.18[log(CFU/肺)]。参考例4的以式[3]表示的化合物10mg/kg给药组、30mg/kg给药组和100mg/kg给药组的肺内活菌数分别为5.86±0.12[log(CFU/肺)]、5.22±0.16[log(CFU/肺)]和3.65±0.36[log(CFU/肺)],参考例4的以式[3]表示的化合物100mg/kg给药组与介质给药组相比显著减少。由上可知,实施例1的以式[1]表示的化合物显示出比参考例4的以式[3]表示的化合物更好的治疗效果。
试验例5 红霉素耐药性(有mef(A)基因)肺炎链球菌感染动物的治疗效果试验
药理效果的评价使用以下所示的方法。
作为细菌,使用肺炎链球菌(Streptococcus pneumoniae)1028 株(临床分离株)。将使用菌株的冷冻保存液添加至“添加30vol%灭活马血清的托德休伊特(Todd Hewitt)液体培养基”,培养至浊度(OD600)达到约0.3。将其用添加30vol%灭活马血清的托德休伊特(Todd Hewitt)液体培养基稀释,作为接种菌液。对小鼠(CBA/JN系,雄性,5周龄)经鼻接种0.05mL接种菌液使其感染。接种菌量为3.45×104CFU/小鼠或3.90×104CFU/小鼠。从接种第2天起,口服给药实施例1的以式[1]表示的化合物(3mg/kg、10mg/kg、30mg/kg和100mg/kg)或者介质(0.1mol/L乳糖酸溶液和0.5w/v%碳酸氢钠溶液的等量混合液),每天1次,共2天。接种3天后的肺内活菌数(1组5~6例,平均值±标准差)示于图3。
应予说明,关于图3的备注如下。与介质的显著差异:Steel检验 *:p<0.05,**:p<0.01实施例1、式[1]的化合物MIC值为0.12μg/mL,参考例4、式[3]的化合物MIC值为0.03μg/mL。
介质给药组的肺内活菌数为6.94±0.07[log(CFU/肺)]。实施例1的以式[1]表示的化合物3mg/kg给药组、10mg/kg给药组、30mg/kg给药组和100mg/kg给药组的肺内活菌数分别为6.45±0.18[log(CFU/肺)]、1.30±0.00[log(CFU/肺)]、1.30±0.00[log(CFU/肺)]和1.30±0.00[log(CFU/肺)],实施例1的以式[1]表示的化合物10mg/kg给药组、30mg/kg给药组和100mg/kg给药组的肺内活菌数全部显示检测限值以下,与介质给药组相比显著减少。同样地,口服给药参考例4的以式[3]表示的化合物(10mg/kg、30mg/kg和100mg/kg)或者介质(0.1mol/L乳糖酸溶液和0.5w/v%碳酸氢钠溶液的等量混合液),结果是,对于接种3天后的肺内活菌数,介质给药组为7.03±0.22[log(CFU/肺)]。参考例4的以式[3]表示的化合物10mg/kg给药组、30mg/kg给药组和100mg/kg给药组的肺内活菌数分别为5.67±0.38[log(CFU/肺)]、1.30±0.00[log(CFU/肺)]和1.30±0.00[log(CFU/肺)],参考例4的以式[3]表示的化合物10mg/kg给药组、30mg/kg给药组和100mg/kg给药组与介质给药组相比显著减少。但是,全部显示在检测限值以下的仅参考例4的以式[3]表示的化合物30mg/kg给药组和100mg/kg给药组。由上可知,实施例1的以式[1]表示的化合物显示出比参考例4的以式[3]表示的化合物更好的治疗效果。
工业上的可利用性
本发明的化合物或其药学上允许的盐对革兰氏阳性菌、革兰氏阴性菌和支原体具有较强的抗菌活性,特别是对以往的大环内酯类抗生素无法获得足够的抗菌活性的红霉素耐药菌(例如耐药性肺炎链球菌、链球菌和支原体)等也具有良好的抗菌活性,可用作药物。
Claims (3)
1.式[1]:
表示的化合物或其药学上允许的盐、或者它们的水合物或它们的溶剂合物。
2.药物组合物,其含有选自权利要求1所述的化合物或其药学上允许的盐、或者它们的水合物或它们的溶剂合物中的化合物。
3.抗菌剂,其含有选自权利要求1所述的化合物或其药学上允许的盐、或者它们的水合物或它们的溶剂合物中的化合物。
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