CN1159757A - 抑制白细胞介素5产生的抑制剂 - Google Patents
抑制白细胞介素5产生的抑制剂 Download PDFInfo
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- CN1159757A CN1159757A CN95195374A CN95195374A CN1159757A CN 1159757 A CN1159757 A CN 1159757A CN 95195374 A CN95195374 A CN 95195374A CN 95195374 A CN95195374 A CN 95195374A CN 1159757 A CN1159757 A CN 1159757A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
Abstract
本发明提供一种对白细胞介素5的产生有强有力的抑制活性的红霉素衍生物,它是一种对白细胞介素5的产生的抑制剂,含有作为活性成分的3-O-(4-联苯基)乙酰基-5-O-德糖胺基-6-O-甲基赤糖交脂A11,12-环碳酸酯、3-O-(2-硝基-3,4,5,6-四氟)苯基-5-O-德糖胺基-6-O-甲基赤糖交脂A,或其药学上可接受的酸加成盐。
Description
本发明涉及一种对白细胞介素5的产生的抑制剂,该抑制剂含有作为活性成分的红霉素衍生物。
已知白细胞介素5(下文中缩写为IL-5)为刺激嗜伊红性粒细胞分化和生长的重要因子,且后者会加剧过敏性炎症。因此,对IL-5产生的抑制剂对治疗如支气管哮喘、过敏性鼻炎、特应性皮炎、药物过敏和嗜伊红性粒细胞肺炎等各种过敏性疾病是有利的。
红霉素是一种抗生素,临床上广泛将它用作由革兰氏阳性菌、一些革兰氏阴性菌和支原体等引起的感染的治疗剂。最近报导了红霉素和罗希红霉素对IL-5的产生有抑制活性[“日本变态反应学杂志”(Japanese Jaumal ofAllergology),44(3-2),第424页(1993)],但是它们对产生IL-5的抑制作用是不足的。
本发明的目的就是提供一种对IL-5的产生具强有力的抑制活性的红霉素衍生物。
本发明的发明者已广泛研究了红霉素衍生物对IL-5的抑制活性,结果发现了以下的红霉素衍生物显示出有强有力的对IL-5的抑制活性,从而完成了本发明。
本发明提供了一种作用于IL-5产生的抑制剂:该抑制剂含有作为活性成分的3-O-(4-联苯基)乙酰基-5-O-德糖胺基-6-O-甲基赤糖交脂(erythronolide)A11,12-环碳酸酯,3-O-(2-硝基-3,4,5,6-四氟)苯基-5-O-德糖胺基-6-O-甲基赤糖交酯A,或者其药学上可接受的酸加成盐。
用于本发明的药学上可接受的酸加成盐包括乙酸盐、丙酸盐、丁酸盐、甲酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、柠檬酸盐、硬脂酸盐、琥珀酸盐、乙基琥珀酸盐、乳糖酸盐、葡糖酸盐、葡庚糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、P-甲苯磺酸盐、十二烷基硫酸盐、苹果酸盐、天冬氨酸盐、谷氨酸盐、己二酸盐、半胱氨酸盐、盐酸化物、氢溴化物、磷酸盐、硫酸盐、氢碘酸盐、烟酸盐、草酸盐、苦味酸盐、硫代氰酸盐、十一烷酸盐、丙烯酸聚合物的盐和羧基乙烯聚合物的盐。
本发明中所应用的3-O-(4-联苯基)乙酰基-5-O-德糖胺基-6-O-甲基赤糖交脂A11,12-环碳酸酯可以根据如WO93/13116中所描述的方法来制备。
本发明中所应用的3-O-(2-硝基-3,4,5,6-四氟)苯基-5-O-德糖胺基-6-O-甲基赤糖交脂A可以用例如以下方法制备。步骤(1):在一种碱的存在下,将溶于适宜溶剂的5-O-德糖胺基-6-O-甲基赤糖交脂A和五氟硝基苯反应。适宜的溶剂包括丙酮、四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、二氧杂环己烷和其混合物。适宜的碱包括氢化钠、氢氧化钠和氢氧化钾。反应温度在-20℃到50℃范围内变化,优选在0℃到25℃范围内变化。
根据本发明,这些化合物可以以片剂、胶囊、颗粒剂、粉剂、药粉、锭剂、药膏、油膏、乳剂、悬浮剂、栓剂和可注射溶液的形式口服或非口服方式给药。这些剂型可以通过常规方法,如“日本药典”(第12次修订本)所规定的方法制备。根据患者的健康状况和年龄以及治疗目的来选择适宜的剂型。在制备各种剂型中,可以应用普遍使用的载体(如,晶状体蛋白纤维素、淀粉、乳糖和甘露醇)、结合剂(如,羟丙基纤维素和聚乙烯吡咯烷酮)、润滑剂(如,硬脂酸镁和滑石)、崩解剂(如,羧甲基纤维素钙)及其类似物等等。
本发明的化合物的剂量为,例如,成人口服给药每天2-3分剂时在50-2000mg的范围内,同时根据患者的年龄、体重和健康状况可以作适度变化。
根据本发明,这些化合物显示出对IL-5的产生有强有力的抑制活性,并且可用作为人和动物(包括家畜)体内的IL-5产生的抑制剂。因此,本发明的这些化合物对于由IL-5产生所导致的各种疾病是有效的,即对例如支气管哮喘、过敏性鼻炎、特应性皮炎、药物过敏和嗜伊红性粒细胞肺炎等各种过敏性疾病是有效的。
现在参考实施例对本发明进行更为详细的说明。
实施例1
制备3-O-(4-联苯基)乙酰基-5-O-德糖胺基-6-O-甲基赤糖交脂A11,12-环碳酸酯
(1)将11.78g(0.02mol)5-O-德糖胺基-6-O-甲基赤糖交脂A溶于100ml丙酮,在用冰冷却的条件下向溶液中加入2.27ml(0.024mol)乙酸酐,再于室温下搅拌6小时。在减压下通过蒸发除去丙酮,并用二氯甲烷抽提残余物。依次用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤二氯甲烷层,在无水硫酸镁上干燥,并于减压下蒸发以除去溶剂。从乙醚/正己烷中再结晶残余物,得到12.17g 2′-O-乙酰基-5-O-德糖胺基-6-O-甲基赤糖交酯A,为白色粉末。熔点:158-160℃荷质比(Mass)(FAB)m/z:632[MH]+
1H-核磁共振(NMR)[200兆赫(MHz),CDCl3]化学位移&ppm:
2.07(3H,S),2.26(6H,S),2.95(3H,S),3.26(1H,S),3.96(1H,S)
红外光谱(KBr),cm-1:3469,1750,1733,1693
(2)将50g(84.8mmol)上述(1)中所得的化合物溶于500ml二氯甲烷,在以冰冷却的条件下向溶液中加入102.6ml(1.27mol)吡啶。在同样温度下向溶液中滴加将25.4ml(212mmol)三氯甲基氯甲酸酯溶于40ml二氯甲烷得到的溶液,然后搅拌5.5小时。向反应混合物中小批量加入冷水和饱和碳酸氢钠水溶液,并用二氯甲烷抽提混合物。依次用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤二氯甲烷层,并将二氯甲烷层于无水硫酸镁上干燥。在减压下蒸发除去溶剂。用硅胶柱色谱法(洗脱液:丙酮/正己烷/三乙胺=6-10∶10∶0.2)纯化残余物,得到41.93g 2'-O-乙酰基-5-O-德糖胺基-6-O-甲基赤糖交脂A11,12-环碳酸酯,为白色泡沫状物。1H-NMR(200MHz,CDCl3)δppm:
2.05(3H,S),2.25(6H,S),2.92(3H,S),4.57(1H,d,J=9 Hz),4.74(1H,S),4.75(1H,dd,J=10Hz,9Hz),5.13(1H,dd,J=12Hz,2Hz)
(3)将1.274g(6mmol)4-联苯乙酸溶于30ml二氯甲烷,向溶液中加入0.84ml(6mmol)三乙胺。在用冰冷却的条件下,向溶液中加入0.75ml(6mmol)三甲基乙酰氯,然后搅拌30分钟。再向溶液中加入将1.65ml(20.4mmol)吡啶和1.31g(2mmol)上述(2)中得到的化合物溶于10ml二氯甲烷得到的溶液。搅拌18小时后,用如以上(1)中的同样方法对反应混合物进行后处理。在减压下蒸发掉溶剂,用硅胶柱色谱法(洗脱液:丙酮/正己烷/三乙胺=4∶10∶0.05)纯化所得的粗产物,得到580mg浅黄色泡沫状物。将所产生的化合物(580mg,0.72mmol)于10ml甲醇中回流加热3小时,在减压下蒸发除去溶剂,得到490mg标题化合物,为浅黄色粉末。1H-NMR(200MHz,CDCl3)δppm:
2.21(6H,S),3.01(3H,S),3.90(1H,d,J=7Hz),4.76(1H,S),5.10(1H,d,J=11Hz),7.30-7.49(5H,m),7.55-7.61(4H,m)。
实施例2
制备3-O-(2-硝基-3,4,5,6-四氟)-苯基-5-O-德糖胺基-6-O-甲基赤糖交脂A
向1.178g(2mmol)5-O-德糖胺基-6-O-甲基赤糖交脂A和4.02ml(10mmol)五氟硝基苯溶于10ml四氢呋喃得到的溶液中加入240mg(6mmol)的60%氢化钠,然后于室温下搅拌2小时。用乙酸乙酯抽提反应混合物,提取物用饱和氯化钠水溶液洗涤,并在无水硫酸镁上干燥。在减压下蒸发掉溶剂,用硅胶柱色谱法(洗脱液:氯仿/甲醇/氨水=19∶1∶0.1)纯化/残余物,得到210mg的标题化合物。荷质比(FAB)m/z:783[MH]+ 1H-NMR(200MHz,CDCl3)δppm:
2.25(6H,S),3.05(3H,S)。
实施例3
把10g实施例1中制备的化合物、550g乳糖、300g玉米淀粉、100g羧甲基纤维素钙和30g聚乙烯吡咯烷酮充分混合,以常规方法周乙醇粒化,干燥和分粒。将颗粒和10g硬脂酸镁混合,用常规方法将混合物压片,得到每片重100mg的药片。
实施例4
根据以下的M.Hikida等人,“免疫学通讯”(Immunology Letters),第34卷,297-302页(1992)中披露的方法检测对鼠体内IL-5产生的作用。
由ATCC购得鼠Th2克隆(D10.G4.1细胞)。通过将1×10-7个8周龄雌C3H/HeN鼠的脾脏细胞悬浮于5ml RPMI-1640培养基制备产生抗原的细胞,并将它和50μg/ml丝裂霉素C(MMC)一起37摄氏度培养30分钟,然后周3份各50ml的RPMI-1640洗涤。向含有10%牛血清的RPMI-1640中加入0.5单位白细胞介素2(IL-2)(由Genzyme生产)和5×10-5M的2-巯基乙醇来制备用于组织培养的培养基。将试验化合物溶于二甲基亚砜(DMSO),并用组织培养基稀释至DMSO终浓度为0.1%和具有不同的试验化合物浓度。
在一个96-孔微量滴定板(由Coming Glass Works制造)的每一孔中加入每孔50μl的浓度为4×10-5个细胞/每毫升D10.G4.1细胞,2×106个细胞/每毫升MMC处理过的产生抗原的细胞、400μg/每毫升作为抗原的伴清蛋白,以及溶于组织培养基的试验化合物。再于5%CO2和37℃的条件下培温48小时。培温结束后,收集培养物的上层液体,离心分离细胞。用ENDOGEN生产的的IL-5酶联免疫吸附实验(ELISA)试剂盒测定上层液体中的IL-5。用50%抑制的浓度(IC50)来表示试验化合物产生IL-5的抑制作用,见于以下表1。
表1
试验化合物 IC50(M)实施例1的化合物 <4×10-7实施例2的化合物 <1×10-7罗希红霉素 9.3×10-7红霉素 4.5×10-6
实施例5
向分成5组的ICR雄鼠经口给药实施例1和实施例2的化合物。在100mg/kg的剂量水平时未观察到死亡,证明这些化合物有高度的安全性。
Claims (3)
1、一种对白细胞介素5的产生的抑制剂,该抑制剂含有作为活性成分的3-O-(4-联苯基)乙酰基-5-O-德糖胺基-6-O-甲基赤糖交脂A11,12-环碳酸酯、3-O-(2-硝基-3,4,5,6-四氟)苯基-5-O-德糖胺基-6-O-甲基赤糖交脂A或其药学上可接受的酸加成盐。
2、3-O-(4-联苯基)乙酰基-5-O-德糖胺基-6-O-甲基赤糖交脂A11,12-环碳酸酯、3-O-(2-硝基-3,4,5,6-四氟)苯基-5-O-德糖胺基-6-O-甲基赤糖交脂A或其药学上可接受的酸加成盐在制备对白细胞介素5的产生的抑制剂中的应用。
3、一种治疗过敏性疾病的方法,该方法包括给药3-O-(4-联苯基)乙酰基-5-O-德糖胺基-6-O-甲基赤糖交脂A11,12-环碳酸酯、3-O-(2-硝基-3,4,5,6-四氟)苯基-5-O-德糖胺基-6-O-甲基赤糖交脂A或其药学上可接受的酸加成盐。
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