CN1177597A - 新的多烯抗菌素3874 h1－h6, 其制备方法及用途 - Google Patents
新的多烯抗菌素3874 h1－h6, 其制备方法及用途 Download PDFInfo
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- CN1177597A CN1177597A CN97118573A CN97118573A CN1177597A CN 1177597 A CN1177597 A CN 1177597A CN 97118573 A CN97118573 A CN 97118573A CN 97118573 A CN97118573 A CN 97118573A CN 1177597 A CN1177597 A CN 1177597A
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
- C12P17/162—Heterorings having oxygen atoms as the only ring heteroatoms, e.g. Lasalocid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
下式化合物3874H1,分子式:C58H86N2O18,MW1099.33874H2,分子式:C59H88N2O18,MW1113.33874H3,分子式:C57H87NO14,MW1074.33874H4,分子式:C58H84N2O18,MW1097.33874H5,分子式:C59H86N2O18,MW1111.33874H6,分子式:C57H85NO18,MW1072.3适用于治疗真菌性疾病和与类固醇浓度增加有关的疾病。
Description
本发明涉及新的七烯抗菌素、其制备方法及用途。
许多七烯抗菌素是已知的。七烯抗菌素属大环内酯类，它含有特征性的7个共轭双键。它们是来源于微生物的天然物质，可以用作抗真菌剂、抗毛滴虫剂或作为与类固醇(胆固醇)结合的药物。然而，它们当中有一些是毒性非常大的化合物，由于该原因，不能将它们用于全身给药(注射)，但商品两性霉素B(Merck索引，第11版，1989，93页)除外，该物质是多烯抗菌素的原型。由于真菌性疾病的增加，目前仍非常需要新的抗真菌的抗菌素，这些抗菌素比已知的多烯抗菌素更有效或更易耐受。
我们惊奇地发现，链霉菌(Streptomyces spec.)HAG 3874，DSM11007可以产生新的、高活性的七烯抗菌素，这些抗菌素不仅非常有效，而且在有些情况下耐受性良好。
因此，本发明涉及化合物3874 H1-H6、其生理可接受的盐及其显而易见的化学等同物。3874H1，分子式：C58H86N2O18，MW1099.33874H2，分子式：C59H88N2O18，MW1113.3
3874H3，分子式：C57H87NO18，MW1074.33874H4，分子式：C58H84N2O18，MW1097.33874H5，分子式：C59H86N2O18，MW1111.33874H6，分子式：C57H85NO18，MW1072.3
抗菌素3874H1-H6与文献中公开的物质不同，它们具有所示的结构式和分子式以及Δ28/29和Δ30/31位置的两个顺式双键，这在本发明的所有化合物中均是相同的。本发明的化合物具有特征性的紫外光谱。
本发明还涉及制备所述化合物的方法。制备所述化合物的方法之一包括将微生物链霉菌HAG 3874(DSM 11007)在含水营养培养基中培养，随后分离并纯化目标化合物。所述微生物根据布达佩斯条约于1996年6月21日保藏在Deutsche Sammlung von Mikroorganismen und Zellkulturen，Mascheroder Weg 1b，D-38124 Braunschweig，保藏号为DSM 11007。
链霉菌DSM 11007有白色的气生菌丝体和灰色的孢子链。它形成了链霉菌的特征性孢子链。在含碳源和氮源、以及常用无机盐的营养液中，链霉菌DSM 11007产生化合物3874 H1-H6。
还可用链霉菌DSM 11007株的突变体或变异体代替链霉菌DSM11007，只要它们能够合成本发明的化合物。所述突变体可以用已知的方式通过物理方法产生，例如用诸如紫外线或X射线等辐射、或用化学诱变剂，如甲磺酸乙酯(EMS)；2-羟基-4-甲氧基二苯酮(MOB)或N-甲基-N’-硝基-N-亚硝基胍(MNNG)。
可以通过测定在培养液中积累的活性物质的生物活性来筛选可产生本发明抗菌素的突变体和变异体，例如，通过下述的方法测试抗真菌的作用。
用于有氧发酵的合适和优选的碳源是可同化的碳水化合物和糖醇，例如葡萄糖、乳糖或D-甘露糖醇；以及含有碳水化合物的天然产物，例如麦芽提取物。合适的含氮营养物质是：氨基酸、肽、蛋白质和其降解产物，如胨或胰胨；肉提取物，研碎的种子，例如玉米、小麦、豆、大豆或棉花植物；生产醇的蒸馏残渣，肉粉或酵母提取物，以及铵盐和硝酸盐。可加入培养液中的无机盐是，例如，碱金属或碱土金属、铁、锌、钴和锰的氯化物、碳酸盐、硫酸盐或磷酸盐。
七烯3874 H1-H6的生产特别适于在例如含有大约0.5至5％、优选1至2％葡萄糖，0.5至5％、优选1至2％大豆粉，优选0.2至1％玉米浆，0.05至1.0％优选0.1至0.5％CaCO3和0.1至2％优选0.2至1％NaCl的培养液中进行，每种物质均以培养液的总重量计。
培养在通气下进行，也就是说，例如，在振荡或搅拌下于振荡烧瓶或发酵灌中浸泡，向其中适当地通入空气或氧气。发酵可以在例如各种容积的广口瓶或圆底烧瓶中、在玻璃发酵罐或不锈钢罐中进行。可以在大约20至35℃的温度范围内进行，优选大约25至30℃。pH应在4到10之间，最好在5.5到8.5之间。通常将微生物在这些条件下培养20至300小时，优选24至140小时。培养最好分多个阶段进行，即在液体营养培养基中进行初始的一次或多次预培养，然后以例如1∶10的体积比转移至实际的生产培养基中进行主培养。预培养物可以通过例如将形成孢子的菌丝体转移至营养液中并让其生长大约20至120小时、优选24至72小时而得到。形成孢子的菌丝体可以通过例如让菌株在固体或液体营养培养基(例如酵母-麦芽琼脂或土豆-右旋糖琼脂)中生长大约1至40天、优选3至10天而得到。
可以通过技术人员已知的方法对发酵及抗菌素3874 H1-H6产生的进展进行监测，所述方法是例如通过测试在生物鉴定中的生物活性，或通过色谱的方法，例如薄层色谱(TLC)或高效液相色谱(HPLC)。
菌株HAG 3874(DSM 11007)的特征是，除可以产生这些七烯外，还可以产生文献中已知的抗菌素咔唑霉素B和pimprinin。
在菌丝体和培养液的滤液中均可以发现抗菌素3874 H1-H6，但大部分通常都是在生命体(菌丝体)中发现的。因此优选通过过滤或离心使菌丝体和滤液分离。将滤液用不与水互溶的溶剂如1-丁醇、乙酸乙酯、氨仿等提取。菌丝体优选用甲醇或丙酮提取，但也可使用上述不与水互溶的溶剂。
提取可以在宽的pH范围内进行，但最好是在中性介质中进行，优选pH5到pH9之间。有机提取物可以在真空下浓缩和干燥。
分离七烯3874 H1-H6的方法之一是以已知的方式进行萃取。
另一种纯化方法是在吸附树酯上进行色谱分离，所述树酯是例如DiaionHP-20(Mitsubishi Casei Corp.，Tokyo)、AmberliteXAD7(Rohm和Haas，USA)、AmberchromCG，(Toso Haas，Philadelphia，USA)等。分离可以在宽的pH范围内进行。优选pH1-pH13的范围；并特别优选pH2-pH12的范围。还适用多种反相载体，例如高压液相色谱(HPLC)领域所公知的RP18。
另一种纯化本发明抗菌素的可能方法是用所谓的正相色谱载体，例如硅胶或Al2O3等以已知的方式进行。多种溶液及其混合物均适用于该目的，例如加有碱性溶剂如吡啶的氯仿/甲醇混合物。
另一种分离方法是使用分子筛如FractogelTSK HW-40、SephadexLH-20等以已知的方式进行。还可以通过结晶的方法从富含七烯的原料中将其分离。适用于该目的的是例如无水或加水的有机溶剂及其混合物。分离和纯化本发明的抗菌素的其它方法包括使用阴离子交换物质(优选在7到10的pH范围内)和阳离子交换物质(优选在3到7的pH范围内)。特别适用于该目的的是加有一定比例有机溶剂的缓冲液。
抗菌素3874H1-H6或其化学衍生物可以通过技术人员已知的方法转变成相应的可药用盐。
本发明化合物的显而易见的等同物是仅有微小化学差异(也就是说具有相同活性)的化合物，或可以在温和条件下转变成本发明化合物的化合物。所述等同物包括，例如本发明化合物的酯、氨基衍生物、配合物或加合物。
本发明化合物的可药用盐指Remington’s Pharmaceutical Sciences(17版，1418页(1985))中所记载的无机和有机盐。特别合适的盐是碱金属、铵和碱土金属盐、与生理可耐受的胺形成的盐；以及与无机或有机酸如HCl、HBr、H2SO4、马来酸和富马酸形成的盐。
本发明抗菌素的物理化学及波谱学性质如下所述：3874H1外观：绿黄色物质，可溶于甲醇、乙腈和氯仿。在中性及弱碱性的介质中稳定，但在酸性和强碱性溶液中以及光照、受热、与氧接触时不稳定。分子式：C58H86N2O18分子量：1099.31H-NMR：参见表1UV最大吸收峰(logε)：232nm(4.49)，286nm(4.32)，338nm(4.64)，357nm(4.86)，377nm(5.00)，398nm(4.98)3874H2外观：绿黄色物质，可溶于甲醇、乙腈和氯仿。在中性及弱碱性的介质中稳定，但在酸性和强碱性溶液中以及光照、受热、与氧接触时不稳定。分子式：C59H88N2O18分子量：1113.3UV最大吸收峰(logε)：232nm(4.49)，286nm(4.32)，338nm(4.64)，357nm(4.86)，377nm(5.00)，398nm(4.98)3874H3外观：绿黄色物质，可溶于甲醇和其它低级醇、乙腈和氯仿。在中性及弱碱性的介质中稳定，但在酸性和强碱性溶液中以及光照、受热、与氧接触时不稳定。分子式：C57H87NO18分子量：1074.31H-NMR：参见表1UV最大吸收峰(logε)：233nm(4.39)，241nm(4.39)，249nm(4.28)，275nm(4.41)，341nm(4.54)，358nm(4.82)，378nm(5.00)，399nm(4.94)3874H4外观：绿黄色物质，可溶于甲醇、乙腈和氯仿。在中性及弱碱性的介质中稳定，但在酸性和强碱性溶液中以及光照、受热、与氧接触时不稳定。分子式：C58H84N2O18分子量：1097.3UV最大吸收峰(logε)：232nm(4.49)，286nm(4.32)，338nm(4.64)，357nm(4.86)，377nm(5.00)，398nm(4.98)3874H5外观：绿黄色物质，可溶于甲醇、乙腈和氯仿。在中性及弱碱性的介质中稳定，但在酸性和强碱性溶液中以及光照、受热、与氧接触时不稳定。分子式：C59H86N2O18分子量：1113.3UV最大吸收峰(logε)：232nm(4.49)，286nm(4.32)，338nm(4.64)，357nm(4.86)，377nm(5.00)，398nm(4.98)3874H6外观：绿黄色物质，可溶于甲醇或其它低级醇、乙腈和氯仿。在中性及弱碱性的介质中稳定，但在酸性和强碱性溶液中以及光照、受热、与氧接触时不稳定。分子式：C57H85NO18分子量：1072.31H-NMR：参见表1UV最大吸收峰(logε)：233nm(4.39)，241nm(4.39)，249nm(4.28)，275nm(4.41)，341nm(4.54)，358nm(4.82)，378nm(5.00)，399nm(4.94)。
良好的溶解度意味着本发明的抗菌素要比两性霉素B优越，后者在所述溶剂及其它溶剂中的溶解度非常小，从而给使用造成了很大的问题。表1：3874H3和3874H1的1H-NMR波谱中的化学位移值，在17℃下于氘代甲醇中测得。在C原子3874H3 3874H1在C原子3874H3 3874H1上的位置 上的位置1 - - 29 6.61 6.612 2.49/2.14 2.45/2.15 30 6.51 6.513 4.28 4.28 31 6.06 6.064 1.66/1.41 1.66/1.41 32 6.82 6.825 3.36 3.37 33 6.22 6.206 1.30 1.30 34 6.19 6.207 1.84/1.12 1.85/1.11 35 5.38 5.388 1.31 1.30 36 2.48 2.489 3.69 3.70 36-Me 1.02 1.0210 1.44 1.43 37 4.76 4.7711 4.04 4.05 38 1.85 1.8612 1.52/1.25 1.51/1.38 38-Me 0.98 0.9813 4.43 4.42 39 1.36 1.4014 1.72/1.56 1.72/1.55 40 1.58/1.46 1.62/1.5115 - - 41 3.97 4.0616 2.00/1.24 1.99/1.24 42 2.68 2.98/2.9217 4.25 4.25 43 - -
18 1.99 1.99 44 6.10 -18-CO - - 45 7.23 7.75
19 4.38 4.39 46 6.26 6.62
20 2.24/1.68 2.24/1.67 47 6.28 -
21 4.37 4.38 48 1.87 -
22 6.10 6.10 1’ 4.53 4.54
23 6.17 6.17 2’ 3.85 3.88
24 6.50 6.49 3’ 2.71 2.80
25 6.35 6.35 4’ 3.12 3.17
26 6.50 6.49 5’ 3.21 3.23
27 6.79 6.79 5’-Me 1.24 1.25
28 6.28 6.28
我们还发现，本发明的化合物具有极强的抗真菌作用，并且该活性对广谱的真菌属和酵母有效。表2以举例的方式概述了3874H1和3874H3的最低抑制浓度。表2：对皮肤真菌、酵母和霉菌的体外活性(在RPMI 1640培养基中的微量稀释试验)最低抑制浓度，MIC(ug/ml)菌株 3874H1 3874H3皮肤真菌须发癣菌100/25 4 8深红色发癣菌101/58 16 16絮状表皮癣菌190/143 16 16酵母白色念珠菌ATCC 90028 2 4白色念珠菌ATCC 90029 2 4无毛念珠菌ATCC 90030 4 4无毛念珠菌Berlin 12 2 4克鲁斯念珠菌203/230 4 4克鲁斯念珠菌Berlin1 2 2热带念珠菌201/201 2 4热带念珠菌201/202 2 4假热带念珠菌202/218 2 4近平滑念珠菌ATCC 90018 4 4新型细珠念珠菌ATCC 90112 2 2霉菌黑色曲霉ATCC 16404 2 8烟曲霉ATCC 9197 4 4黄色曲霉ATCC 9643 8 16保温：在35℃下48小时(酵母)或30℃下6天(皮肤真菌和霉菌)
本发明化合物的优越性可以通过所谓的扩散试验得到证实，在该试验中，化合物在含有试验微生物的琼脂层上扩散。抑制区的直径则是抗菌素活性的量度(表3)。表3：与两性霉素B相比，抗菌素3874H1和H3产生的浓度依赖性抑制区(mm)浓度(mg/mL) 3874H1 3874H3 两性霉素B
0.2 26 22 14
0.1 25 20 12
0.05 24 18 10
0.025 21 14 8
0.0125 19 13
0.0063 17 12
在某些情况下，本发明化合物的效果显著优于商品两性霉素B，从而是非常有价值的药物。据推测，该效果是由于新的七烯化合物与麦角甾醇以七烯/麦角甾醇配合物的形式结合的能力。麦角甾醇是真菌原生质膜的重要成分。配合物的形成改变了膜的麦角甾醇，从而破坏了原生质膜的结构并导致真菌细胞的死亡。
在温血动物的细胞中，对应于麦角甾醇的膜成分是胆固醇。文献中公开的许多七烯对麦角甾醇和胆固醇均有很强的结合能能力，从而是有毒的化合物。抗菌素3874H3和H6和麦角甾醇的结合比胆固醇强的多，从而这些化合物特别适用于控制人和动物的真菌感染。
除抗真菌效果外，本发明的抗菌素还对原生动物如毛滴虫具有很强的抑制作用。
此外，由于和胆固醇或类固醇结合的能力，3874H1-H6还可用于控制当类固醇浓度过高而有害时的药物。其例子是在对良性前列腺增生进行一般性治疗或专门治疗时降低胆固醇的水平。
因此，本发明还涉及本发明的化合物用作药物的用途，以及相关化合物在生产用于治疗和/或预防真菌感染及治疗与类固醇浓度增加有关之疾病的药物中的用途。
本发明还涉及含有至少一种本发明化合物的药物。
本发明的药物可用于肠道给药(口服)、非胃肠道给药(静脉内)、直肠或局部给药(局部)。可以以溶液剂、粉末、片剂、胶囊(包括微胶囊)、软膏(霜剂或凝胶)、脂质体产品、类脂配合物、胶体态分散体或栓剂的形式给药。适用于这些类型制剂的助剂是常用的液体或固体药物填充剂和增量剂、溶剂、乳化剂、润滑剂、掩蔽剂、染料和/或缓冲物质。合适的给药剂量是0.1-10、优选0.2-8mg/kg体重。适于以剂量单位进行给药，所述剂量单位至少含有每日有效量的本发明化合物，例如30-3000、优选50-1000mg。
通过以下实施例以及权利要求的内容对本发明进行详细的解释。实施例1：生产菌株孢子悬浮液的制备
将所述菌株接种于500ml无菌锥形烧瓶中的100ml营养液(20g麦芽提取物、2g酵母提取物、10g葡萄糖、0.5g(NH4)2HPO4的1升自来水溶液，灭菌前的pH：6.0)并将其在25℃及140rpm的旋转振荡器上保温72小时。随后，将120ml培养液均匀地分散于含营养培养基燕麦浸汁(2.0g/l)的500ml无菌锥形烧瓶中，然后倒掉上清液，往所述培养基中加入琼脂(15g/l)以便固化，然后滗析。将培养液在25℃保温10到14天。然后，将在烧瓶中得到的孢子用含一滴市售非离子表面活性剂(例如，由Serva提供的Triton X 100)的500ml去离子水漂洗，随后立即使用或于-22℃贮存于50％甘油中或于-140℃贮存于10％二甲基亚砜中。实施例2：在锥形烧瓶中制备生产菌株的培养物或预培养物
用在斜面试管中生长的培养物或0.2ml孢子悬浮液接种实施例1中所述的含100ml营养液的无菌500ml锥形烧瓶，然后在振荡器上，以140rpm在25℃下暗处培养。在约72小时后，达到本发明化合物的最大产量。来自相同营养液的、培养了72小时的浸没培养物足以接种10到100升的发酵罐(接种约5％)。实施例3：抗菌素3874H1-H6的生产
将10升发酵罐在下述条件下操作：营养培养基： 葡萄糖 15g/l
大豆粉 15g/l
玉米浆 5g/l
CaCO3 2g/l
NaCl 2g/l
pH7.0 (灭菌前)保温时间： 24或48小时保温温度： 25℃搅拌速度： 200rpm，避光通气： 5升空气/分钟
通过反复加入数滴多羟基化合物的乙醇溶液可以抑制泡沫的形成。在48小时后达到最大产量。实施例4：抗菌素3874H1-H6的分离
将按照实施例3得到的9升培养液离心，将生物量(～1.1升)通过与甲醇一起搅拌提取两次，每次2.2升甲醇。将合并的提取液真空浓缩并干燥，将干燥的物质用乙醚浸提。将用该方法洗涤并脱脂的残余物(41g)溶于25％异丙醇/75％水，然后上样到容量为3升并填充有MCI GelCHP20P吸附树脂的柱子上。柱尺寸：宽×高：11.3cm×30cm。使用梯度从25％异丙醇水溶液到100％异丙醇的溶剂作为洗脱剂，并以2升/份收集从柱子流出的溶液。
收集含有七烯的馏分(通过HPLC分析鉴定)并真空浓缩，冷冻干燥(3.2g)。实施例5：七烯3874H1-H6的高压液相色谱(HPLC)。柱： Nucleosil100-5C18AB，250/4流动相： 37.5％的乙腈在10mM磷酸钾缓冲液中的溶液，
pH7.0流速： 1ml/分钟通过320nm下的UV吸收进行检测
测得各成分的保留时间如下。还给出了通过HPLC/质谱测定的相应的分子量(M+H)+。在HPLC-MS中，用10mM醋酸铵代替磷酸盐缓冲液。保留时间 化合物 (M+H)+7.05 min 3874H1 1099.68.64 min 3874H4 1097.713.93 min 3874H2 1113.717.90 min 3874H5 1111.819.23 min 3874H3 1074.524.28 min 3874H6 1072.5实施例6：3874H成分的浓缩。
将2g实施例4中制得的产物上到柱容量为3升的柱子上，柱子内填有FractogelTsk MW-40s(宽×高＝10cm×50cm)。将流动相甲醇以50ml/分钟的流速泵入柱子，以65ml每份收集从柱子流出的溶液。馏分28-35主要含有抗菌素3874H3(干燥后：210mg)，馏分39-43：H6(9mg)，馏分50-60：3874H1和H2(280mg)，馏分71-78：化合物3874H4和H5(17mg)。实施例7：3874H1、H2和H3的最终纯化。
将实施例6得到的浓缩的抗菌素3874H1和H2(280mg)以及H3(210mg)分别在Nucleosil12C18AB HPLC柱(宽×高＝3.2cm×25cm)上通过梯度洗脱的方法用25％-50％的乙腈水溶液进行分离。通过HPLC检测馏分(参见实施例5)并恰当地进行合并，真空浓缩并冷冻干燥。得到
29mg 3874 H1，纯度95％，
11mg 3874 H2，纯度94％，
65mg 3874 H3，纯度97％。实施例8：通过制备HPLC以磷酸盐缓冲液/异丙醇系统最终纯化。
按照实施例7的方法，但用pH7的10mM磷酸钾缓冲液和异丙醇作为流动相。按照实施例7除去分离成分中的盐。
38mg 3874H1，纯度97％，
21mg 3874H2，纯度96％，
83mg 3874H3，纯度98％。
Claims (10)
1.下式的化合物3874H1、H2、H3、H4、H5或H6，3874H1，分子式：C58H86N2O18，MW1099.3
3874H2，分子式：C59H88N2O18，MW1113.3
3874H4，分子式：C58H84N2O18，MW1097.33874H5，分子式：C59H86N2O18，MW1111.33874H6，分子式：C57H85NO18，MW1072.3其生理可接受的盐和显而易见的化学等同物。
2.权利要求1所述的化合物，所述化合物的制备通过微生物DSM11007或其突变体或变异体在合适的条件下发酵，然后分离化合物H1-H6中的一种或多种，并随需要将其转变为盐或化学等同物。
3.权利要求1所述化合物的制备方法，包括将微生物DSM 11007或其突变体或变异体中在合适的条件下发酵，然后分离化合物H1-H6中的一种或多种，并随需要将其转变为盐或化学等同物。
4.权利要求3所述的方法，其中，发酵在通气、20至35℃及pH 4-10的条件下进行。
5.权利要求1或2的化合物，可用作药物。
6.权利要求1或2的化合物在生产用于治疗真菌性疾病或由毛滴虫所引起疾病的药物中的用途。
7.权利要求1或2的化合物在生产用于治疗与类固醇浓度增加有关疾病的药物中的用途。
8.含有至少一种权利要求1或2所述化合物的药物。
9.生产权利要求8所述药物的方法，包括将至少一种权利要求1或2所述的化合物用合适的辅料和/或赋形剂制备成合适的剂型。
10.链霉菌DSM11007。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19633310.5 | 1996-08-19 | ||
| DE19633310 | 1996-08-19 | ||
| DE19649349 | 1996-11-28 | ||
| DE19649349.8 | 1996-11-28 |
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| Publication Number | Publication Date |
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| CN1177597A true CN1177597A (zh) | 1998-04-01 |
| CN1127508C CN1127508C (zh) | 2003-11-12 |
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| CN97118573A Expired - Fee Related CN1127508C (zh) | 1996-08-19 | 1997-08-19 | 多烯抗菌素3874 h1－h6, 其制备方法及用途 |
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| Country | Link |
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| US (1) | US5939399A (zh) |
| EP (2) | EP0829486A2 (zh) |
| JP (1) | JPH10120686A (zh) |
| KR (1) | KR19980018741A (zh) |
| CN (1) | CN1127508C (zh) |
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| CA (1) | CA2213285A1 (zh) |
| DE (1) | DE59709428D1 (zh) |
| DK (1) | DK0829487T3 (zh) |
| ES (1) | ES2194152T3 (zh) |
| MX (1) | MX9706283A (zh) |
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| CN104745651A (zh) * | 2015-03-30 | 2015-07-01 | 嘉应学院 | 用于多产色链霉菌发酵生产多烯大环内酯类抗真菌抗生素的发酵培养基及其制备方法 |
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| CA2394833A1 (en) | 2000-01-14 | 2001-07-19 | Binh T. Dang | Derivatives of polyene macrolides and preparation and use thereof |
| US20030104977A1 (en) * | 2000-03-31 | 2003-06-05 | Ugo Ripamonti | Methods for inducing angiogenesis using morphogenic proteins and stimulatory factors |
| US6575926B2 (en) | 2000-12-15 | 2003-06-10 | Bonutti 2003 Trust-A | Myofascial strap |
| US7654551B2 (en) * | 2007-02-02 | 2010-02-02 | Page James H | Skid steer attachment system |
| US8608926B2 (en) * | 2008-11-20 | 2013-12-17 | Neroxis Sa | Amperometric in-pipe electrochemical sensing probe |
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| US4027015A (en) * | 1974-03-11 | 1977-05-31 | Schering Corporation | Antibiotic 67-121, a polyene antifungal antibiotic produced by actinoplanes caeruleus |
| GB1485207A (en) * | 1975-05-28 | 1977-09-08 | Ucb Sa | Anti-fungal agent lucknomycine |
| ZA795508B (en) * | 1978-10-23 | 1981-05-27 | Schering Corp | Derivatives of polyene macrolide antibiotics containing an amino sugar moiety, process for the preparation thereof, and pharmaceutical compositions containing them |
| US4272525A (en) * | 1978-10-23 | 1981-06-09 | Schering Corporation | Derivatives of polyene macrolide antibiotics containing an amino sugar moiety, process for the preparation thereof, and pharmaceutical compositions containing them |
| IT1243404B (it) * | 1990-12-03 | 1994-06-10 | Prodotti Antibiotici Spa | Derivati della partricina |
| JP3188325B2 (ja) * | 1992-10-28 | 2001-07-16 | 理化学研究所 | ポリエンマクロライド物質、その製造法、及びこれを用いた抗菌剤と抗腫瘍剤 |
| JPH06239848A (ja) * | 1993-02-19 | 1994-08-30 | Taisho Pharmaceut Co Ltd | ポリエン系化合物 |
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- 1997-08-19 EP EP97202571A patent/EP0829487B1/de not_active Expired - Lifetime
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104745651A (zh) * | 2015-03-30 | 2015-07-01 | 嘉应学院 | 用于多产色链霉菌发酵生产多烯大环内酯类抗真菌抗生素的发酵培养基及其制备方法 |
| CN104745651B (zh) * | 2015-03-30 | 2018-03-27 | 嘉应学院 | 用于多产色链霉菌发酵生产多烯大环内酯类抗真菌抗生素的发酵培养基及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9704385A (pt) | 1999-05-11 |
| ATE233781T1 (de) | 2003-03-15 |
| US5939399A (en) | 1999-08-17 |
| ES2194152T3 (es) | 2003-11-16 |
| AU721483B2 (en) | 2000-07-06 |
| PT829487E (pt) | 2003-07-31 |
| EP0829487B1 (de) | 2003-03-05 |
| CN1127508C (zh) | 2003-11-12 |
| MX9706283A (es) | 1998-02-28 |
| TW514664B (en) | 2002-12-21 |
| EP0829486A2 (de) | 1998-03-18 |
| AU3423097A (en) | 1998-02-26 |
| KR19980018741A (ko) | 1998-06-05 |
| EP0829487A3 (de) | 1998-09-09 |
| EP0829487A2 (de) | 1998-03-18 |
| DK0829487T3 (da) | 2003-06-23 |
| DE59709428D1 (de) | 2003-04-10 |
| JPH10120686A (ja) | 1998-05-12 |
| CA2213285A1 (en) | 1998-02-19 |
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