CN1217929C - 阿考霉素,其生产方法及其作为药物的用途 - Google Patents
阿考霉素,其生产方法及其作为药物的用途 Download PDFInfo
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- CN1217929C CN1217929C CN008135207A CN00813520A CN1217929C CN 1217929 C CN1217929 C CN 1217929C CN 008135207 A CN008135207 A CN 008135207A CN 00813520 A CN00813520 A CN 00813520A CN 1217929 C CN1217929 C CN 1217929C
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- amycomycin
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Abstract
本发明涉及名称为阿考霉素的式(I)化合物及其可药用盐和衍生物，包括其所有的立体异构体和互变异构体形式，该化合物可以通过培养拟无枝酸菌属(Amycolatopsissp.)微生物ST101170(DSM12216)制得，并可用作药物、特别是抗生素。
Description
本发明涉及名称为阿考霉素(Amycomycin)的化合物、其可药用盐和衍生物，该化合物可以通过培养拟无枝酸菌属(Amycolatopsissp.)微生物ST101170(DSM 12216)制得。本发明还涉及生产阿考霉素的方法、阿考霉素及其可药用盐和衍生物作为药物、特别是抗生素的用途，以及含有阿考霉素或其可药用盐或衍生物的药物组合物。
甲氧西林抗药性的金黄色葡萄球菌(MRSA)感染在许多感染性病症例如伤口和烧伤中是非常常见的。万古霉素和替考拉宁(属于糖肽类)是临床上用于治疗MRSA感染的仅有的两种抗生素。但是，由于最近出现的万古霉素和替考拉宁抗药性的菌株，这些感染已经变成危险和致命性的。因此，人们开始广泛寻找对这些万古霉素和替考拉宁抗药性菌株有活性的不同结构类型的化合物。例如，曾报道了对万古霉素和替考拉宁抗药性菌株具有抗生素活性的甲基硫霉素I(一种环状的硫肽)[EP-A-0818539，1996年7月11日申请]。
现已发现，名称为阿考霉素的新化合物具有抗生素活性。因此，本发明涉及下式的化合物及其可药用盐和衍生物，例如酯、醚和其它显而易见的化学等同物，包括所有的立体异构体形式和所有的互变异构体形式：
阿考霉素具有特征性的tetramic acid部分，有高度氧合的C45-侧链。其分子式为C65H115NO18，可以通过在需氧条件下、在含有碳和氮源的营养培养基中培养拟无枝酸菌属微生物ST101170(DSM 12216)，然后以常规方式分离和纯化制得。微生物ST101170属于放线菌目拟无枝酸菌属，于1998年6月4日在德国微生物和细胞培养物保藏中心(DSMZ-Deutsche Sammlung von Mikroorganismen und ZellkulturenGmbH)，Braunschweig，Deutschland保藏，保藏号为DSM No.12216。
本发明还提供了在需氧条件下、在含有一种或多种碳源和一种或多种氮源以及选择性的营养无机盐和/或微量元素的营养培养基中，从拟无枝酸菌属ST101170、其突变体和变异体生产名称为阿考霉素的化合物，然后分离所述化合物并以常规方式进行纯化的方法。
微生物ST101170的突变体和变异体也可以合成本发明的化合物。所述突变体可以以已知的方式、通过物理方法例如用紫外线或X射线辐射或用化学诱变剂例如甲基磺酸乙酯(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)进行生产。
对于可生产本发明化合物的适宜突变体和变异体的筛选可以通过测定培养肉汤中积聚的活性化合物的生物学活性来证实，例如，测试抗菌作用、特别是对万古霉素抗药性菌株的抗菌作用(参见下表2)。
适于需氧发酵的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-Mannit以及含有碳水化合物的天然产物例如麦芽汁。适宜的氮源是，例如氨基酸、肽和蛋白质，包括其降解产物例如胨或胰胨、肉膏、研碎的玉米、白豆、大豆或棉树等的种子、生产酒的蒸馏残渣、肉和酵母提取物，以及铵盐和硝酸盐。营养溶液中可以含有的适宜的无机盐是，例如碱金属或碱土金属、铁、锌、钴或锰的氯化物、碳酸盐、硫酸盐或磷酸盐。
阿考霉素的形成在例如含有约0.5至5％淀粉(可溶性的)、优选1至2％，约0.5至5％葡萄糖、优选1至3％，约0.5至5％甘油、优选1至2％，约0.1至0.5％玉米浆、优选0.2至0.3％，约0.2至1％胨、优选0.4至0.6％，约0.1至0.5％酵母提取物、优选0.2至0.4％，约0.05至0.2％氯化钠、优选0.1至0.2％和约0.1至0.5％CaCO3、优选0.2至0.3％的营养培养基中进行的特别好。这些含量是以整个营养培养基的重量计的。
ST101170的培养在需氧条件下进行，例如，在振荡或搅拌下、在振动烧瓶或实验室发酵罐中浸没培养，并可以选择性地通入空气或氧气。发酵培养可以在例如各种容积的无菌广口瓶或圆底烧瓶中、在玻璃发酵罐或V2A-钢罐中进行。
ST101170的培养可以在约20℃至约35℃、优选约25℃至约30℃的温度下和4至10、优选6至8的pH下进行。在这些条件下将微生物培养20至200小时、优选24至150小时。
培养优选分多个阶段进行。首先，可以在液体营养培养基中制备一种或多种预培养物。然后将主要培养物(实际的生产培养基)用预培养物以例如1∶10的体积比接种。通过将营养培养基用生成孢子的菌丝体接种并使其生长约20至约120小时、优选24至90小时得到预培养物。生成孢子的菌丝体可以通过例如使微生物在固体或液体营养培养基例如酵母-麦芽琼脂或土豆-葡萄糖琼脂上生长约1至约40天、优选5至12天制得。
发酵和形成阿考霉素的过程可以通过技术人员已知的方法进行监测，例如，通过在生物测定中测定培养肉汤的生物学活性或者通过色谱方法例如薄层色谱(DC)或高压液相色谱(HPLC)进行监测。
化合物阿考霉素存在于培养物的滤液以及菌丝体中。通常主要是存在于菌丝体中。可将化合物用已知的分离技术进行分离。因此，可将其通过例如过滤或离心从培养物的滤液中回收。可将滤液用与水不相混溶的溶剂例如1-丁醇、乙酸乙酯、氯仿、二氯甲烷等萃取，优选丁醇或乙酸乙酯。
还可将活性物质通过用可与水混溶的溶剂例如甲醇、丙酮、乙腈、正丙醇或异丙醇、优选甲醇或丙酮，或与水不相混溶的溶剂例如叔丁醇、乙酸乙酯、氯仿、二氯甲烷等、优选丁醇或乙酸乙酯萃取从菌丝体回收。
对培养物滤液的萃取可以在宽的pH值范围内进行。但优选在中性或弱酸性的介质中、优选在pH4到9的条件下进行萃取。可将有机萃取液真空浓缩然后干燥得到活性粗品物质。
化合物阿考霉素的分离或纯化可以根据天然化合物的化学、物理和生物学性质以已知的方式进行。
本发明的一种分离阿考霉素的方法是以已知的方式进行溶液分配。
另一种纯化阿考霉素的方法是在吸附树脂例如DiaionHP-20(Mitsubishi Casei Corp.，Tokyo)、AmberliteXAD 7(Rohm和Haas，USA)、AmberchromCG(Toso Haas，Philadelphia，USA)或类似的树脂上进行色谱分离。分离可以在宽的pH值范围内进行。优选的pH值范围是1到9，更优选2到8。还可以采用各种反相载体，例如在关于高压液相色谱(HPLC)的文章中所公开的RP8和RP18。另一种纯化本发明化合物的方法包括以已知的方式使用所谓的正相色谱载体例如硅胶或Al2O3(氧化铝)等，或其它已知的载体。有许多洗脱剂适用于该目的，例如二氯甲烷、氯仿、甲醇、乙酸乙酯、丙酮、石油醚或其组合。可以通过例如加入三乙胺改变pH值。
另一种分离化合物阿考霉素的方法是以已知的方式使用分子筛例如FractogelTSK HW-40、SephadexLH-20等。此外，还可以通过结晶从粗品物质中回收化合物阿考霉素。适宜的溶剂是例如无水或含水的有机溶剂及其混合物。
另一种分离和纯化本发明化合物的方法是使用阴离子交换剂(优选在7到10的pH范围内)和阳离子交换剂(优选在3到7的pH范围内)。特别优选使用加有一定量有机溶剂的缓冲溶液。
此外，也可以通过使用由两种或多种溶剂(例如水、甲醇、乙醇、丁醇、异丙醇、丙酮、二氯甲烷、乙酸乙酯或石油醚)组成的两相洗脱剂系统的反流色谱法进行纯化。
化合物阿考霉素或其化学衍生物可以通过本领域技术人员已知的方法转化成相应的可药用盐。
本发明化合物的可药用盐是无机盐或有机盐，例如雷明顿药物科学(Remington’s Pharmaceutical Sciences)(第17版，1418页(1985))中所描述的那些。可以使用的盐是碱金属盐、铵盐、碱土金属盐、与生理可接受的胺形成的盐以及与无机或有机酸例如HCl、HBr、H2SO4、马来酸和富马酸形成的盐。
本发明化合物的显而易见的化学等同物是那些有微小的化学差异但具有相同或相似活性的化合物，或者是可以在温和条件下转化成本发明化合物的化合物。显而易见的化学等同物的例子是酯、醚、氨基衍生物、本发明化合物的复合物或加合物。
酯可以通过例如将阿考霉素与羧酸在试剂例如二环己基碳二亚胺(DCC)的存在下反应，或通过将化合物与酰化试剂例如酰氯反应来制备。
醚可以通过例如将阿考霉素与烷基化试剂在碱性条件下反应来制备。
在文献例如有机合成进展(Advanced Organic Synthesis)，第4版，J.March，John Wiley&Sons.，1992中给出了制备酯和醚的其它方法。
化学等同物可以是与金属离子例如过渡金属如La3+、Sm3+、Eu3+、Gd3+的稳定的复合物，这是tetramic acid衍生物的特点，并且可以通过文献(K.Tanaka等，化学药物通报(Chem.Pharm.)Bull.1979，27，1901；K.Matsuo，Chem.Pharm.Bull.1980，28，2494)中给出的方法进行制备。
烷基侧链的双键可以通过文献例如P.N.Rylander，“氢化方法”，Academic Press，New York(1985)，第2章中给出的方法进行还原，或者通过H.O.House在“现代合成反应(Modern SyntheticReactions)”，W.A.Benjymin，Inc.，New York(1972)，pp 446-452中描述的方法氢卤化。羟基化的衍生物可以通过将双键与试剂例如OsO4按照文献例如Chem.Rev.1980，80，187中的描述反应进行制备。
还可以通过用例如MCPBA按照有机合成进展(Advanced OrganicSynthesis)，第4版，J.March，John Wiley&Sons.，1992中的描述进行氧化将双键转化成环氧化物来形成衍生物。
本发明的化合物阿考霉素的物理化学以及光谱学性质如下：外观：无色固体，可溶于甲醇、DMSO、吡啶分子式：C65H115NO18
HPLC(高压液相色谱)：
柱：Purospher Star RP.18e(Merck)，55×4mm，3μm
洗脱剂：CH3CN/0.01％H3PO4(85％)
梯度： 时间(分钟) ％CH3CN
0.00 5.0
3.00 95.0
5.00 95.0
6.00 5.0
10.00 5.0
流速：2ml/分钟
温度：40℃
检测：210nm，254，280，320，380
tR：2.67分钟
分子量：1198.64Da
HR-FAB-MS：1220.801187[M+Na]+
1H-和13C-NMR：参见表1
UV/VIS：MeOH，max(log)＝229nm(3.29)，281(3.16)
表1：
阿考霉素在MeOD中在300K下的化学位移。
| 1H | 13C | |
| 1 | 0.86 | 14.76 |
| 2 | 0.97 | 20.83 |
| 3 | 1.89 | 31.20 |
| 4 | 3.41 | 82.20 |
| 5 | 1.70 | 39.55 |
| 6 | 0.77 | 13.63 |
| 7 | 3.54 | 80.19 |
| 8 | 1.65 | 36.32 |
| 9 | 0.86 | 12.71 |
| 10 | 1.43 | 31.20 |
| 11 | 1.44 | 36.46 |
| 12 | 3.75 | 71.98 |
| 13 | 1.62/1.54 | 44.79 |
| 14 | 3.74 | 72.22 |
| 15 | 1.58/1.37 | 36.46 |
| 16 | 1.63/1.14 | 29.27 |
| 17 | 1.51 | 40.69 |
| 18 | 0.90 | 15.70 |
| 19 | 3.70 | 72.90 |
| 27 | 1.51/1.46 | 42.12 |
| 28 | 4.07 | 66.31 |
| 29 | 1.52 | 42.12 |
| 30 | 3.80 | 72.54 |
| 31 | 4.33 | 73.26 |
| 32 | 6.62 | 142.18 |
| 33 | - | 138.47 |
| 34 | 1.83 | 12.75 |
| 35 | - | 206.04 |
| 36 | 4.21 | 41.00 |
| 37 | 1.14 | 17.77 |
| 38 | 5.36 | 128.37 |
| 39 | - | 138.72 |
| 40 | 1.69 | 12.75 |
| 41 | 3.98 | 80.54 |
| 42 | 1.64 | 41.25 |
| 43 | 0.88 | 8.02 |
| 44 | 3.59 | 73.88 |
| 45 | 1.49 | 36.46 |
| 46 | 1.62/1.32 | 23.50 |
| 47 | 1.55/1.32 | 33.34 |
| 48 | 3.80 | 75.09 |
| 49 | 1.74 | 42.71 |
| 50 | 0.77 | 11.92 |
| 51 | 3.41 | 77.87 |
| 52 | 1.61 | 36.46 |
| 53 | 0.86 | 12.75 |
| 54 | 1.55/1.32 | 31.37 |
| 55 | 1.61/1.44 | 36.46 |
| 56 | 3.77 | 71.83 |
| 57 | 1.67 | 44.53 |
| 58 | 3.92 | 71.12 |
| 59 | 2.30 | 37.54 |
| 60 | 5.84(b) | ～131.7(c) |
| 61 | - | (c) |
| 62 | 1.82 | 13.81 |
| 63 | - | (c) |
| 64 | - | (c) |
| 65 | 3.24(b) | 27.91 |
| 66 | - | (c) |
| 67 | - | (c) |
| 68 | - | (c) |
| 69 | 5.50(b) | ～119.3(c) |
| 70 | 3.09 | 26.52 |
| 71 | 1.10 | 24.31 |
| 72 | 1.10 | 24.31 |
b)宽信号
c)这些信号看不到。C60和C69只能用HMQC-波谱指定。
阿考霉素具有突出的抗细菌活性，特别是对革兰氏阳性菌例如葡萄球菌和肠球菌。下表2中给出了阿考霉素对各种细菌的最低抑制浓度。这些菌株最近已逐渐成为问题菌株，即，这些微生物已经开始对现有的抗生素具有抗药性了。在对万古霉素-和替考拉宁抗药性菌株如粪肠球菌、屎肠球菌或鹑鸡肠球菌的抑制作用中证实了本发明化合物与其它抗生素相比的优越性。
表2：最低抑制浓度(mg/L)(微量稀释试验)
革兰氏阳性菌株 代码 阿考霉素 万古霉素
金黄色葡萄球菌 011HT3 oxa S ery S 0.08 0.3
金黄色葡萄球菌 011HT18 ATCC 13709 Smith 0.08 0.3
表皮葡萄球菌 012G020 oxa S ery S tet R 0.3 0.6
金黄色葡萄球菌 011HT1 nov R ＜＝0.04 0.08
金黄色葡萄球菌 011DU5 nov R tet R 0.08 0.15
金黄色葡萄球菌 011CB20 oxa R ery Rc tet R 0.08 0.15
金黄色葡萄球菌 011G071 of1 S oxa R ery S tet R 0.15 0.6
金黄色葡萄球菌 011G064 ofl R oxa R ery Rc tet R 0.3 1.2
表皮葡萄球菌 012G042 oxa R 0.3 1.2
Staph.coag.negative 012HT5 ofl R oxa R tet R 0.15 0.6
金黄色葡萄球菌 011GR91 pri R oxa R ery R nov R 1.2 1.2
化脓性葡萄球菌 02A1SJ1 van S ery Rc 0.3 0.15
化脓性葡萄球菌 02A1UC1 van S ery S 0.6 0.15
化脓性葡萄球菌 O2A1F16 ery R 0.6 0.08
Strepto gr.G 02G0CB2 tet R rif R nov R 0.6 0.15
肺炎链球菌 030BI2 ery R 0.15 0.15
米氏链球菌 O2milGR12 ery S van S 1.2 0.3
缓症链球菌 O2mitGR16 ery Ri van S 1.2 0.3
屎肠球菌 02D3AP9 nov S van R ery S tei R 0.6 ＞40
屎肠球菌 02D3HT12 tei R van R ery R tet R 0.6 ＞40
屎肠球菌 O2D3IP2 tei R van R ery R tet R ND ＞40
屎肠球菌 02D3HM3 nov S van A ery R tei R 1.2 ＞40
鹑鸡肠球菌 02D0HM8 van C tet R ery S 1.2 ＞40
粪肠球菌 02D2HM9 nov R van B ery R tei S 2.5 ＞40
粪肠球菌 02D2UC5 ATCC 29212 nov R 2.5 2.5
粪肠球菌 02D2DU18 tet R nov R 1.2 0.3
粪肠球菌 02D2HT10 nov R van S tet R 1.2 0.6
革兰氏阴性菌 代码
大肠杆菌 DB10250IP5 ery S fuc S nov S ND ＞40
铜绿假单胞菌 1771 391HT2 ＞40 ＞40
铜绿假单胞菌 1771m 391HT3 突变体渗透性的 ＞40 ＞40
阿考霉素及其可药用盐和衍生物可以作为药物单独、以相互之间的混合物以及可以通过胃肠外或其它给药方式给药的药物组合物的形式向动物、优选哺乳动物、特别是人给药。因此，本发明还涉及阿考霉素及其可药用盐和衍生物用作药物以及阿考霉素及其可药用盐和衍生物在生产具有抗菌活性的药物中的用途。本发明还涉及含有有效量的阿考霉素和/或它的一种或多种可药用盐和/或衍生物以及可药用载体的药物组合物。
阿考霉素可以肠内(口服途径)、胃肠外(静脉内或肌肉内)、直肠或局部给药。含有阿考霉素或其可药用盐或衍生物以及其它药物活性物质的药物组合物可以通过如下方法制备：将活性化合物与一种或多种药理学可耐受的辅剂和/或赋形剂混合，将该混合物转化成适于给药的适当药物形式例如溶液剂、散剂(片剂、胶囊，包括微胶囊)、软膏(霜剂或凝胶)、脂质体制剂、脂类复合物、胶态分散液或栓剂。
可用于该类型制剂的辅剂和/或赋形剂是制药中常用的液体或固体填充剂和填料、溶剂、乳化剂、润滑剂、矫味剂、着色剂和/或缓冲物质。
通常，适于具体情况的盖伦制剂和给药方法以及剂量范围取决于所治疗的物种以及各病症或疾病的状态，并且可以用本领域已知的方法使其最佳化。例如，对于体重约为75kg的患者，适宜的剂量是0.001-10mg，优选0.1-5mg，更优选1.0mg。该剂量应至少能够产生所需的效果。
以下是本发明的说明性实施例，该实施例并不限定本发明的范围。
实施例1：
接种物的制备
将无菌的300ml Erlenmeyer烧瓶中的100ml营养溶液(4g/l酵母提取物，15g/l可溶性淀粉，1g/l K2HPO4，0.5g/1硫酸镁x7 H2O，加水至1000ml，灭菌前pH7.0)用拟无枝酸菌属的菌株(DSM 12216)接种然后在28℃和180rpm下在旋转摇动器上培养5天。然后将1.5ml该培养物用1.5ml 99％的甘油稀释并于20℃下存放。
实施例2：
在Erlenmeyer烧瓶中制备拟无枝酸菌属ST101170(DSM 12216)的培养物或预培养物。
将含有100ml营养培养基(10g/l淀粉溶液，10g/l葡萄糖，10g/l甘油99％，2.5g/l玉米浆，5g/l胨，2g/l酵母提取物，1g/l NaCl和3g/l CaCO3)的无菌的Erlenmeyer烧瓶用菌环量的生长培养物(相同的营养溶液，但含有2％的琼脂)或1ml甘油培养物(参见实施例1)接种然后在28℃和180rpm下在摇动器上培养。在72小时后，化合物阿考霉素的产量达到最大。
培养了72小时的浸没培养物(按照实施例1描述的摇动培养的方法生产，但采用如下培养基：15g/l葡萄糖，15g/l大豆粉，3g/l CaCO3和5g/l NaCl，pH7.5)足以以10％的接种量接种10和200L的发酵罐中。
实施例3
化合物阿考霉素的生产
采用如下参数运行200L的发酵罐：
营养培养基 10g/l淀粉
10g/l葡萄糖
10g/l甘油99％
2.5g/l玉米浆
5g/l胨
2g/l酵母提取物
7g/l NaCl
3g/l CaCO3
pH7.2(灭菌前)
接种物： 10％发酵罐体积
培养时间： 60至80小时
培养温度： 28℃
搅拌： 50rpm
换气 150升/分钟
通过加入1至2ml多元醇的乙醇溶液，可以抑制泡沫的形成。在69小时后达到产量最大值。
实施例4：化合物阿考霉素的分离
将200升实施例3制得的培养物溶液离心并用甲醇将菌丝体提取完全。将甲醇提取液浓缩至约十分之一得到无色沉淀，滤出沉淀。重复该过程直至在滤液中不再能够检测到阿考霉素(HPLC)。将残余物冷冻干燥然后通过HPLC纯化：
1.柱：Fractogel TSK-HW 40(4L，500×100mm)
洗脱剂：MeOH
流速：20ml/分钟
检测：204和236nm。
富含阿考霉素的级份在125分钟后洗脱。根据HPLC(条件如上所述)收集级份。将合并的含有所需化合物的活性级份真空浓缩然后冷冻干燥。
2.柱：硅胶60(Merek)；Erimatech(300×20mm，100ml)洗脱剂：A)CH2Cl2 B)CH2Cl2∶MeOH 9∶1 C)MeOH。
梯度 分钟 ％A ％B ％C
0 100 0 0
15 100 0 0
35 0 100 0
45 0 100 0
65 0 0 100
流速：25ml/分钟
检测：236和288nm
活性化合物阿考霉素在42分钟后洗脱。根据HPLC(条件如上所述)收集级份。将合并的含有所需化合物的活性级份真空浓缩然后冷冻干燥。
3.柱：Fractogel TSK-HW 40(1L，500×50mm)
洗脱剂：MeOH
流速：5ml/分钟
检测：204和236nm
活性成分阿考霉素在112分钟后洗脱。
按照上述方法，可以从200L发酵肉汤中回收110mg阿考霉素。
Claims (6)
1.下式化合物
或其可药用盐。
2.生产权利要求1所述化合物的方法，该方法包括，在需氧条件下、在含有碳和氮源的营养培养基中培养拟无枝酸菌属微生物ST101170，即DSM 12216，然后以常规方式分离和纯化化合物。
3.权利要求2所述的方法，进一步包括将得到的化合物转化成药理学上可耐受的盐。
4.权利要求1所述的化合物或其可药用盐用于制备抗生素药物的用途。
5.根据权利要求4的用途，其中所述药物用于治疗细菌性感染。
6.药物组合物，含有有效量的权利要求1所述的化合物和/或其可药用盐。
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| JPH05163289A (ja) * | 1991-08-27 | 1993-06-29 | Microbial Chem Res Found | 新規な免疫抑制物質、ｍｉ７１０−５１ｆ６物質およびその製造法 |
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