CN1059678C - It－62－b物质 - Google Patents
It－62－b物质 Download PDFInfo
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- CN1059678C CN1059678C CN95107614A CN95107614A CN1059678C CN 1059678 C CN1059678 C CN 1059678C CN 95107614 A CN95107614 A CN 95107614A CN 95107614 A CN95107614 A CN 95107614A CN 1059678 C CN1059678 C CN 1059678C
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- compound
- bacterial strain
- medium
- culture
- streptomyces
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Abstract
化合物IT-82-B的结构式如下所示：
该化合物的制法，含有该化合物有效成分的医药组成物以及用该化合物对细菌引起的感染和肿瘤的治疗方法。
本化合物，对革兰氏阳性细菌和部分革兰氏阴性细菌有抗菌活性，并对人鼻咽癌等肿瘤有良好的抗肿瘤活性，是有用的药物。
Description
本发明是有关具有抗菌及抗肿瘤作用的有用的药物的新化合物IT-62-B、其制造方法和含有该化合物的药物，以及对细菌引起的感染和肿瘤的治疗方法。
过去已知微生物可产生具有广泛结构特征和具有抗菌、抗肿瘤等药理活性的种种物质。
而本发明目的旨在于利用微生物获得具有更优异药理活性的物质。
鉴于如此实际情况，本发明者从天然土壤中分离出多种微生物，并进行了有用药理活性物质的检索，结果发现链霉菌变株(Streptomyces.SP.)IT-62菌株能产生具有优异抗菌及抗肿瘤活性的新化合物IT-62-B。
与本发明化合物具有类似结构的微生物产物已报告的虽有TAN-1120(特开平2-288892号公报)，但本发明化合物则是具有四氢噁唑新的环缩合结构的新化合物。
则：本发明提供了具有下列(1)式所示的IT-62-B化合物。
即：本发明关系到式(1)所表示的IT-62-B物质及其制造方法。
本发明还关系到含有有效剂量的上述IT-62-B物质(1)和药学上允许的载体为特征而组成的药剂。
此外，本发明还涉及将有效剂量的上述IT-62-B化合物投与患者或哺乳动物为特征的对于细菌引起的感染及肿瘤的治疗方法。
本发明的IT-62-B化合物，可由具有产生本化合物能力的菌株(以下称IT-62物质产生菌)，在适当的条件下培养，进行制造。
IT-62物质产生菌，是属于链霉菌属的菌株。可以链霉菌IT-62为例，此菌株是本发明者从中华人民共和国新疆维吾尔自治区的土壤中新分离出的属于链霉菌属的一个菌株。该菌株以Strain IT-62为标记，于1994年5月l3日寄存在日本通商产业省工业技术院生命工学工业技术研究所，委托番号为(FEMR BP-4666)。
有关IT-82菌株，依据《国际系统细菌学杂志》(International Journal ofSystemati Bacteriology)，16(3)，313-340，1960所记述的方法，进行了研讨，其菌学性质如下：(a).形态
孢子形成菌丝的分枝法：单分枝
孢子形成的形态：直状或波曲状、有时呈环状、孢子的形态为圆柱状。
孢子的数目：10-50孢子或以上
孢子的表面构造：平滑
孢子的大小：0.5～0.8×0.7～1.1微米
鞭毛的孢子的有无；无
孢子囊的有无；无
孢子柄的着生位置：气生菌丝
菌核形成的有无：无(b).在各种培养基上生长状况
在各种培养基上的生长状况如表1所示。分类颜色用财团法人日本色彩研究所监修的《标准色彩图表A，1981年》表示，并将详细的颜色用美国容器公司(Container Corporation of America)的《色调手册》(The Color HarmongManual，第4版，1958年的色调编码附在括弧( )内。
表1
(c) 生理特性：
| 培养基 | 培养基上的生长状况 | 气生菌丝的颜色 | 基内菌丝的颜色 | 溶解性色素的产生 | 菌落的背面颜色 |
| 蔗糖、硝酸盐琼脂培养基 | 不良 | 不形成 | 无色 | 不产生 | 无色 |
| 葡萄糖-天门冬酰胺琼脂培养基 | 良好 | 不形成 | 鲜红橙色(6pa-6pc) | 微橙色 | 鲜红橙色(6pa-6lc) |
| 甘油-天门冬酰胺琼脂培养基(ISP-5培养基) | 良好 | 白色～微黄(2ca) | 橄榄黄(2le) | 不产生 | 橄榄黄(2le) |
| 淀粉-无机盐琼脂培养基(ISP-4培养基) | 良好 | 带微黄的粉红色(4ca) | 深红橙色(5le) | 微橙色 | 深红橙色(5le) |
| 酪氨酸琼脂培养基(ISP-7培养基) | 良好 | 带黄的白色(3cb)～带黄灰色(2ec) | 浅黄褐色(3ie) | 微褐色 | 黄褐色(3pg、3ne) |
| 燕麦琼脂培养基(ISP-3培养基) | 良好 | 浅黄灰色(2cb-1ec) | 浅红橙色(5le) | 微橙色 | 浅红橙色(4ne) |
| 酵母膏-麦芽膏琼脂培养基(ISP-2) | 良好 | 大多不形成、微白色 | 深红橙色(6ne) | 微橙色 | 深红橙色(6ne) |
| 营养琼脂培养基 | 中等程度 | 大多不形成、微白色 | 浅红橙色(5le) | 微橙色 | 浅红橙色(4ic) |
| (贝纳特)Benette琼脂培养基 | 良好 | 不形成 | 鲜红色(6 1/2pc) | 微橙色 | 深红色(6pc) |
生长温度范围：在20～37℃的温度范围内生长良好。
明胶的液化(葡萄糖、蛋白胨、明胶培养基、27℃)：阴性。
明胶的液化(单纯明胶培养基、20℃)：阳性。
牛奶凝固(37℃)：阳性。
牛奶胨化(37℃)：阳性。
类黑色素产生：在酪氨琼脂(ISP-7)培养基上、蛋白胨、酵母膏、铁琼脂(ISP-6)培养基上、胰胨、酵母膏(ISP-1)液体培养基中呈阴性。
硫化氢产生：把0.5％酵母膏添加至蛋白胨、酵母膏、铁琼脂(ISP-6)：阳性
淀粉水解(淀粉、无机盐琼脂、ISP-4培养基)：阳性
硝酸盐还原(含有1％硝酸钾的肉汤、ISP-8培养基)：阳性
纤维素分解：阴性(d) 碳源的利用(Pridham & Gottlieb琼脂、ISP-9培养基)
能利用D-葡萄糖、L-阿拉伯糖、D-木糖、D-果糖、D-甘露糖醇、D-半乳糖、可溶性淀粉、糊精、甘油以及麦芽糖。不能利用肌醇、蔗糖、L-鼠李糖、棉子糖以及水杨甙。(e) 菌体组成
依据日本放线菌学会编《放线菌的鉴定实验法-根据HPLC菌体成分的定性分析、定量分析-1～8页，1989年》书上所记载的高压液相层析法对全细胞酸水解物的分析结果，检出LL-型的二氨基庚二酸。
以上的该菌特性，特别是由基内菌丝而形成的由许多孢子组成链状的气生菌丝，细胞壁组成的氨基酸是LL-二氨基庚二酸，不形成鞭毛孢子和孢子囊等特性，判明本菌株应归属于链霉菌属，故将本菌株称为链霉菌IT-62(Streptomyces SP.IT-62)。
本发明的IT-62-B物质，例如，首先采用适宜的培养基培养上述归属于链霉菌属的IT-62菌株或它的变株的各种IT-62物质产生菌。其次，从培养液中分离含粗提取物的本发明物，再从粗提物中能分离精制出IT-62-B物质。
上述微生物的培养，原则上按一般微生物的培养进行，通常液体培养，采用振荡培养法、通气搅拌培养法等的好气条件下进行。
培养用的培养基，既可用IT-62物质产生菌能利用的营养源的培养基，亦可用各种合成培养基、半合成培养基、天然培养基等。培养基的碳源：可单独使用葡萄糖、蔗糖、果糖、甘油、糊精、淀粉、糖蜜、玉米浆、有机酸等，或两种以上组合的使用。氮源：可单独或两种以上组合使用花生饼粉、蛋白胨、肉膏、酵母膏、大豆粉、酪蛋白氨基酸、尿素等的有机氮源；与硝酸钠、硫酸铵等的无机氮源。此外，培养基中适当地添加钠盐、钾盐、镁盐、磷酸盐，及其他重金属盐。
又，培养中泡沫显著时，可以适当地向培养基中添加消沫剂，如大豆油、亚麻仁油等的植物油、十八烷醇、十四烷醇、十七烷醇等的高级醇类、各种硅化合物等。
培养基的PH以中性附近为佳；培养温度应保持在IT-62物质产生菌最佳生长的温度，20-37℃，尤以维持在25-30℃左右为好；培养时间，液体振荡培养及通气搅拌均以4-7天为好。
上述各种培养条件可根据使用微生物种类特性及外部条件进行适当的改变，并可根据各自的需要，从上述范围中选择和调节最适条件。
从发酵液分离含有IT-62-B的粗提物，可采用发酵产物的一般提取分离方法进行。例如：可单独地使用溶媒提取、液体交换、层析法与结晶化等手段，亦可将二种以上任意组合使用。更详细的说，因为按上述培养所产生的IT-62-B物质主要存在于菌丝体中，放按照常规方法，首先进行过滤或离心，分离出固形的菌丝与培养滤液，得到合有IT-62-B的菌丝体用甲醇、丙酮等溶媒提取IT-62-B，然后减压蒸除溶媒，即可得到含有IT-62-B粗提浓缩液，再向此浓缩液中加入乙酸乙酯、氯仿、正丁醇等与水不混溶的有机溶媒，将IT-62-B转移到有机溶媒层中，用无水硫酸钠脱水后，减压蒸除溶媒，即可得到含有IT-62-B的粗提物，必要时，可采用氢氧化钠或盐酸调节PH，或加入工业食盐以提高萃取率，还可应用防止乳化生成等方法。
为了从粗提物中进一步分离精制IT-62-B，可采用一般脂溶性低分子物质的分离、精制方法，例如，可使用硅胶、氧化铝、非离子性大孔吸附树脂等种种的吸附层析及ODS-键合型硅胶的反相层析。其中尤以使用氯仿、氯仿/甲醇、氯仿/甲醇/苯、甲苯/甲醇等混合溶媒为洗脱剂的硅胶层析法和以乙腈/水，甲醇水混合溶媒为洗脱剂的反相层析法更好。如果有必要进一步精制时，可重复采用上述层析方法或适当地结合使用以氯仿、甲醇等为洗脱溶煤的Sephadex LH-20(pharmacia公司制)凝胶过滤层析等方法可得到高纯度的IT-82-B。
精制过程中IT-62-B的确认，可使用本物质对其有抑制作用的微生物，如藤黄微球菌(Miorococcus luteus)ATCC 9341的生物检测法、检测对来源于人鼻咽癌的株化培养细胞(KB细胞)的杀伤作用的方法或高效液相层折检测方法并用更好。
以上方法精制得到的IT-62-B物质用作医药组成物时的给药形态，可为片剂、胶囊、散剂、颗粒剂、细粒剂、液剂、丸剂、乳剂、悬浊剂等为口服制剂，亦可为栓剂、软膏、硬膏、贴剂、喷雾剂、滴眼剂等非口服制剂。此等给药形态都是采用专业人员熟知常用的制造方法制造的。
在调制口服用固态制剂时，可向本发明的有效成分中加入赋形剂，根据需要也可加入粘合剂、崩解剂、润滑剂、着色剂、矫味剂、矫臭剂等，然后采用通常的方法制成片剂，胶
、散剂、颗粒剂、细粒剂等。赋形剂可用，乳糖、蔗糖、淀粉、滑石粉、硬脂酸镁、结晶纤维素，甲基纤维素、羧甲基纤维素、甘油、藻(朊)酸钠、阿拉伯胶等、结合剂可用：硬脂酸镁、滑石粉等，其它亦可使用通常熟知的着色剂，崩解剂等。片剂亦可用周知的方法进行包衣。
在调制注射剂时，可向本发明的有效成分中添加PH调节剂、缓冲剂、稳定剂、等渗剂与局部麻醉剂等，用常规方法制成静脉、肌肉、皮下、皮内以及腹腔内注射剂。PH调制剂及缓冲剂如：枸椽酸钠、醋酸钠、磷酸钠等。稳定剂可用：焦亚硫酸讷、乙二胺四乙酸、硫代乙二醇酸、硫代乳酸等。
在调制栓剂时，需向本发明的有效成分中加入基质，再根据需要加入界面活性剂等等之后，采用常规方法制成栓剂。基质可用聚乙二醇、羊毛脂、可可豆油、脂肪酸三甘油酯、Witepsol(系一种半合成脂肪酸酯)(Diamond-Nobers公司制)等的油性基质。
配给上述各给药形式，本发明有效成分应用的量，可根据用法，患者的年龄、性别、状态，给予化合物的种类，以及其它的条件等进行适宜的选择，通常每天为0.005-20毫克，可1次或分2-4次给药。[实例]
以下列举实施例与实验例更具体的说明本发明，但本发明并人仅限于以下具体的实施例。
实施例1 本发明IT-62-B物质的制造。(a).培养工程
由葡萄糖0.5％、可溶性淀粉2.4％、牛肉膏0.3％、酵母膏0.5％、蛋白胨0.5％、玉米浆0.4％、二氯化钴0.002％、碳酸钙0.4％组成的培养基(PH7.2)100ml分装到500ml的三角瓶中，灭菌后，接种一白金耳量的Streptomyces SP.IT-62菌株(委托番号FERM BP-4666)，在27℃旋转振荡培养2天(220次/分，振幅7cm)。然后用含有葡萄糖0.5％、糊精2.5％、芝麻饼粉2.0％、玉米浆0.5％、磷酸氢二钾0.05％、硫酸镁0.05％、氯化钾0.03％、碳酸钙0.3％的培养基(PH7.2)在500ml的三角瓶中分装100ml，灭菌后加入2％的上述培养的种子，在27℃旋转振荡培养5天(220次/分，振幅7cm)。(b).分离工程
取由上述培养得到的发酵液(40升，PH7.6)离心分离，过滤后菌丝体用丙酮(5升)提取两次，丙酮提取液减压浓缩，得到的浓缩液用稀氢氯化钠水溶液调PH8.0，用乙酸乙酯(2升)提取两次，乙酸乙酯提取部分减压浓缩得到油状物11克，溶于40毫升氯仿中，然后加入正已烷使之沉淀，得到的沉淀物用正已烷冲洗、干燥，得到粗提物2.7克。(c).分离、精制工程
上述粗提物溶于氯仿中，进行硅胶柱层析(Merck公司制，Silica gel 60内径4.1cm×长度25cm)，首先用氯仿然后氯仿/甲醇(体积/体积50∶1及25∶1)的混合溶媒进行梯度洗脱，洗脱各部用Micrococcus Luteus ATCC 9341进行生物检测，收集含有IT-62-B物质的活性部分，除去溶媒后得到油状物155毫克。
从所得的油状物中取75毫克，溶解在氯仿/甲醇(体积/体积1∶1)中，进行凝胶滤过层析(Pharmacia公司制，Sephadex LH-20，内径2.0cm×长度92cm)用氯仿/甲醇(体积/体积1∶1)洗脱，收集含有IT-62-B物质的活性部分，除去溶媒后得到油状物26mg。得到的油状物用乙腈/水(体积/体积2∶3)溶解，进行ODS-键合型硅胶柱(山善公司，Ultraback ODS 30-50um，内径1.0cm×长度50cm)的反相液体层析，用乙腈/水(体积/体积2∶3)洗脱，流速1.5ml/分，洗脱部分用生物检测法及高效液相层析法检测，合并含有IT-62-B物质的组分，减压除去有机溶媒后，水溶液进行冷冻干燥，得到IT-62-B红色粉末12毫克。
所得到的IT-62-B化合物的理化性质如表2所示。[表2](1).性状：红色粉末(2).实验式：C39H47NO15(高分辨FAB-MS法，由C39H47NO15Na得到实验值
792.294，计算值792.284)。(3).分子量：769(FAB-MS法)(4).比旋光度：[α]D 28+360°，甲醇中)(5).紫外吸收光谱：λmax(nm)(ε)：233(33100)，251(23400)，289(6600)，480
(11300)，495(11400)，530(6200，肩峰)甲醇中。(图1)(6).红外吸收光谱：νmax(cm-1)：3435，2970，2935，1710，1620，1580，1415，1285，
1210，1120，1035，995(KBr片)。(图2)(7).核磁共振谱：CDCl3溶液中测定400MHz1H-NMR谱(图3)及100MHz13C-NMR
谱的化学位移值如表3及表4所示。[表3]
[表4]
| 位置 | 1H(δ) |
| 123781014OCH3-4OH-6OH-9OH-111′2′3′4′5′6′1″2″3″4″5″6″7″9″10″11″12″ | 8.01，d.8Hz7.77，t，8Hz7.38，d，8Hz5.27，dd，4.1Hz2.12，dd，15.4Hz、2.36，dt，15.1Hz2.91，d，19Hz、3.22，dd，19，1.5Hz2.44，s4.07，s13.94，s4.49，br，s13.23，s5.60，d，4Hz1.61，dd，13.5，4Hz、2.64，td，13.5，4Hz4.61，dd，13.5，4Hz3.61，s4.29，q，6.5Hz1.26，d，6.5Hz4.74，dd，7.4Hz1.78，ddd，14，9.5，4Hz、1.85，ddd，14，7.3Hz4.03，m1.23，d，6Hz3.48，dq，8，6.5Hz4.70，d，8Hz1.31，d，6.5Hz4.15，d，4.5Hz2.12，m3.58，dd，11，7.5Hz、3.65，dd，11，4.5Hz0.98，d，7Hz |
| 位置 | 13C(δ) | 位置 | 13C(δ) |
| 12344a55a66a7891010a1111a1212a1314OCH3-4 | 119.80，d135.65，d118.36，d161.03，s120.95，s187.03，s111.38，s156.41，s134.14，s69.68，d35.13，t78.61，s3 36，t13 64，s155 92，s111.21，s186.59，s135.55，s212.19，s24.87，q56.64，q | 1′2′3′4′5′6′1″2″3″4″5″6″7″8″9″10″11″12″ | 100.67，d28.70，t50.41，d79.18，d69.51，d17.17，q106.53，d45.64，t64.38，d23.97，q80.37，d91.03，d17.77，q173.18，s80.20，d38.02，d64.21，t12.44，q |
上述质子位置在结构式中标出。
(8).溶解性：易溶于甲醇、乙醇、丙酮、氯仿以及二甲基亚砜，难溶于正己烷、
乙醚及水。(9).熔点：153-155℃(10).高效液相层析：依下述条件保留时间约6.9分的峰值
柱：(Inertsil)ODS-25微米(内径4.6mm×150mm)
移动相：乙腈/0.05％三氟醋酸水溶液(V/V 50∶50)
流速：1ml/分
检测：210nm 0.04a.u.f.s.试验例1(1).IT-62-B物质的抗菌活性的测定
根据日本化疗法学会MIC测定法(日本化学疗法学会志，第29卷，第1号，76-79页，1981年参照)，测定了本发明化合物对各种细菌的最低抑制浓度(MIC)。即：向含有各种浓度的本发明化合物的Mueller-Hinton琼脂培养基(Difco公司制)中，接种相同的培养基稀释106细胞/毫升的各种试验菌，于37℃、18小时培养后，观察供试菌的生长状况，以完全抑制生长的最低浓度作为MIC值(ug/ml)。(菌落在5个以下，即视为生长抑制)。其结果如表5所示。[表5]
供试菌 MIC(ug/ml)
Staphylococcus aureus Smith
(金黄色葡萄球菌 史密斯 6.25
Staphylococcus aureus(MRSA) 70
(金黄色葡萄球菌MRSA 70) 12.5
Staphylococcus aureus(MRSA)92-1192
(金黄色葡萄球菌MRSA 92-1192) 12.5
Staphylococcus epicermidis ATCC 12228
(表皮葡萄球菌ATCC 12228) 25
Enterococcus faecalis IFO 12968
(粪便肠球菌IFO 12968) 50
Micrococcus luters ATCC 9341
(滕黄色微球菌ATCC 9341) 3.13
Micrococcus luters ATCC 10240
(藤黄色微球菌ATCC 10240) 1.56
Bacillus subtilis ATCC 6633
(枯草芽孢杆菌ATCC 6633) 3.13
Bacillus subtilis(rec+)
(枯草芽孢杆菌rec+) 6.25
Bacillus subtilis(rec-)
(枯氧芽孢杆菌rec-) 0.39
Bacillus cereus IFO 3001
(蜡状芽孢杆菌IFO 3001) 12.5
Escherichia coli NIHJ
(大肠埃希氏菌NIHJ) 100
Escherichia coli IAM 1268
(大肠埃希氏菌IAM 1268) 50
Proteus Vulgaris IID OX-19
(普通变形杆菌IID OX-19) ＞100
Klebsiella preumoniae ATCC 29665
(肺炎克雷氏菌ATCC 29665) ＞100
Serratia marcescescens IFO 12648
(粘质沙雷氏菌IFO 12648) ＞100
Salmonella typhymurium G-46
(鼠伤寒沙门氏菌G-46) ＞100
Alcaligenes faecalis IAM 1015
(粪产碱杆菌IAM 1015) 12.5
Pseudomonas aeruginosa NCTC 10490
(绿脓杆菌NCTC 10490) ＞100(2).IT-62-B物质的抗肿瘤活性的测定
A.对来自人鼻咽癌的株化培养细胞(KB细胞)的50％增殖抑制浓度的测定。
测定了本发明化合物对于来自人鼻咽癌的株化培养细胞(KB细胞)的50％增殖抑制浓度(IC50)。即将来源于人鼻咽癌的KB细胞(2×103细胞/毫升培养液，移植于添加10％小牛血清的Eagle氏低限营养培养基中，取3ml加于60mm塑料培养板上，在二氧化碳孵箱(5％CO2)中，37℃培养。培养过夜后，将本发明物从1微克/毫升按10倍稀释法稀释至1×106微克/毫升的浓度，3天培养后，将细胞培养板表面的细胞用胰蛋白酶洗下，再用台盼兰色素排除法，在光学显微镜下计量细胞数，并与对照相比较，算出实际50％抑制浓度，结果IC50为0.006微克/毫升。
B.对腹腔内移植小鼠白血病P388细胞的延长寿命的效果
根据对小鼠白血病有延长寿命的效果，判定了本发明化合物的抗肿瘤活性。试验动物用雄性CDF1小白鼠(6周龄)给药组为3只，未处置的对照组为10只，向腹腔内移植小鼠白血病P388细胞(1×106个)。移植的第二天(作为第一天)，向腹腔内给予用3.5％二甲基亚砜生理盐水溶解的IT-62-B物质0.25毫克/公斤，观察小鼠的存活天数，由得到的生存天数用下式算出生命延长率为119％。
生命延长率＝(给药组的平均生存天数/无处理对照组的平均生存天数-1)＜100(％)结果
由试验例1证明本发明的IT-62-B物质对革兰氏阳性细菌和部分革兰氏阴性细菌具有抗菌活性。而且由试验例2显示出本化合物对来源于人鼻咽癌的株化培养细胞(KB细胞)的50％增殖抑制浓度(IC50)为0.006微克/毫升，对腹腔内移植小鼠白血病P388细胞的小鼠的生命延长率为119％。在体内体外试验均显示出强力的抗肿瘤活性。
本发明的IT-62-B物质，对革兰氏阳性细菌及部分革兰氏阴性细菌有抗菌活性，并对入鼻咽癌等的肿瘤有良好的活性，是有用的药物。图面的简单说明
图1 用实施例1，得到本发明物质的紫外吸收光谱图。
图2 用实施例1，得到本发明物质的红外吸收光谱图。
图3 用实施例1，得到本发明物质的1H-NMR光谱图。
Claims (7)
1.由下列结构式(1)表示的IT-62-B化合物
2.一种用于制备如权利要求1所述的IT-62-B化合物的方法，该方法包括在培养基中培养Streptomyces sp.IT-62 FERM BP-4666菌株或其具有产生所述IT-62-B化合物能力的所述菌株的变株，使之在培养物中生成和积累，然后从培养物中分离所述化合物。
3.权利要求2所述的制备IT-62-B化合物的方法，其特征是：在培养所述菌株的过程中，向灭菌后的种子培养基中接种一定量的Streptomyces SP.IT-62 FERM BP-4666菌株，在27℃旋转振荡培养2天，然后向灭菌后的发酵培养基中加入2％的上述培养的种子，在27℃旋转振荡培养5天。
4.权利要求2所述的制备IT-62-B化合物的方法，其特征是：在分离过程中首先进行过滤或离心，分离出的菌丝体用甲醇、丙酮溶媒提取，将提取液蒸除溶媒后的浓缩液中的IT-62-B化合物转入乙酸乙酯中，经干燥脱水及减压蒸除溶媒得到含有IT-62-B的粗提物，然后采用硅胶吸附层析、键合型反相层析及凝胶过滤层析得到所述的IT-62-B化合物。
5.一种药物组合物，该药物组合物含有有效剂量的权利要求1所述的IT-62-B化合物和药学上允许的载体。
6.权利要求1所述的IT-62-B化合物用于制备治疗细菌引起的感染以及肿瘤的药物。
7.Streptomyces SP.IT-62FERM BP-4666或其具有产生如权利要求1所述的IT-62-B化合物能力的所述菌株的变株。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16203794 | 1994-07-14 | ||
| JP162037 | 1994-07-14 |
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| Publication Number | Publication Date |
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| CN1127300A CN1127300A (zh) | 1996-07-24 |
| CN1059678C true CN1059678C (zh) | 2000-12-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN95107614A Expired - Fee Related CN1059678C (zh) | 1994-07-14 | 1995-07-10 | It－62－b物质 |
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| Country | Link |
|---|---|
| US (1) | US5698528A (zh) |
| EP (1) | EP0721985B1 (zh) |
| JP (1) | JP2748048B2 (zh) |
| KR (1) | KR0173195B1 (zh) |
| CN (1) | CN1059678C (zh) |
| AT (1) | ATE196929T1 (zh) |
| AU (1) | AU674115B2 (zh) |
| CA (1) | CA2171116C (zh) |
| DE (1) | DE69519084T2 (zh) |
| WO (1) | WO1996002659A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE69636652T2 (de) * | 1995-02-14 | 2007-10-04 | Kao Corp. | Die verwendung von biologisch abbaubaren schmier-grundöl |
| AU2343900A (en) | 1998-11-02 | 2000-05-22 | Board Of Regents, The University Of Texas System | Methods and compositions for the manufacture of highly potent anthracycline-based antitumor agents |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0376177A2 (en) * | 1988-12-27 | 1990-07-04 | Takeda Chemical Industries, Ltd. | TAN-1120, its derivatives, production and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6133194A (ja) * | 1984-07-25 | 1986-02-17 | Sanraku Inc | 新規アントラサイクリン抗生物質 |
| JPS62238298A (ja) * | 1986-04-08 | 1987-10-19 | Sanraku Inc | 新規アントラサイクリン抗生物質ｄｃｐ−１及び２ |
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1995
- 1995-07-10 CN CN95107614A patent/CN1059678C/zh not_active Expired - Fee Related
- 1995-07-12 US US08/601,023 patent/US5698528A/en not_active Expired - Fee Related
- 1995-07-12 WO PCT/JP1995/001384 patent/WO1996002659A1/ja active IP Right Grant
- 1995-07-12 AT AT95925105T patent/ATE196929T1/de not_active IP Right Cessation
- 1995-07-12 AU AU29359/95A patent/AU674115B2/en not_active Ceased
- 1995-07-12 CA CA002171116A patent/CA2171116C/en not_active Expired - Fee Related
- 1995-07-12 JP JP8500677A patent/JP2748048B2/ja not_active Expired - Lifetime
- 1995-07-12 KR KR1019960700855A patent/KR0173195B1/ko not_active IP Right Cessation
- 1995-07-12 DE DE69519084T patent/DE69519084T2/de not_active Expired - Fee Related
- 1995-07-12 EP EP95925105A patent/EP0721985B1/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0376177A2 (en) * | 1988-12-27 | 1990-07-04 | Takeda Chemical Industries, Ltd. | TAN-1120, its derivatives, production and use thereof |
| JPH02288892A (ja) * | 1988-12-27 | 1990-11-28 | Takeda Chem Ind Ltd | 生理活性物質ｔａｎ―１１２０，その還元体，それらの製造法および用途ならびに微生物 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2748048B2 (ja) | 1998-05-06 |
| DE69519084D1 (de) | 2000-11-16 |
| KR960703927A (ko) | 1996-08-31 |
| AU674115B2 (en) | 1996-12-05 |
| EP0721985A4 (en) | 1998-08-26 |
| AU2935995A (en) | 1996-02-16 |
| CN1127300A (zh) | 1996-07-24 |
| US5698528A (en) | 1997-12-16 |
| EP0721985B1 (en) | 2000-10-11 |
| WO1996002659A1 (fr) | 1996-02-01 |
| EP0721985A1 (en) | 1996-07-17 |
| CA2171116C (en) | 1999-02-23 |
| KR0173195B1 (ko) | 1999-02-01 |
| DE69519084T2 (de) | 2001-05-10 |
| CA2171116A1 (en) | 1996-02-01 |
| ATE196929T1 (de) | 2000-10-15 |
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