CN86100997A - 7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的管瓶沉积法 - Google Patents
7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的管瓶沉积法 Download PDFInfo
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Abstract
本文叙述了以无菌的单位剂量形式在管瓶中沉积7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的方法。将该化合物的叔丁醇溶液灌进无菌管瓶中,然后用蒸发法或冷冻干燥法除去叔丁醇,再用适当方法封住管瓶口。这样沉积的物料含有高达0.5摩尔当量以半溶剂化物形式存在的叔丁醇,并且物料对热很稳定。
Description
本发明涉及7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的管瓶沉积新方法。
丝裂霉素C是用发酵法制造的抗生素,目前经美国食品药物管理局批准上市,与其它核准的化学治疗剂并用,治疗胃或胰的扩散腺癌。当其它治疗方式失败后,它可以作为姑息疗法〔自力霉素(Mutamycin商品名)即丝裂霉素C,Bristol Lab.,Syracuse,New York 13201,Physicians′Desk Reference 38th Edition,1984,p750〕。丝裂霉素C及其发酵生产法是1972年5月2日取得专利权的美国专利3,660,578的主题,从较早的申请,包括1957年4月6日本归档的申请在内的优先案。
丝裂霉素A.B.C和紫菜霉素的结构,首先由美国氰氨公司Lederle研究处的J.S.Webb等报道〔J.Amer.Chem.Soc.84,3185-3187(1962)〕。说明丝裂霉素A与丝裂霉素C关系的结构研究所用的化学变化之一是使7、9a-二甲氧基米托沙奈与氨反应转化成7-氨基-9a-甲氧基米托沙奈。取代丝裂霉素A的7-甲氧基已被证实是制备具有抗肿瘤作用的丝裂霉素C衍生物相当重要的反应。下列论文和专利说明书都是关于丝裂霉素A转化成具有抗肿瘤活性的7-取代氨基丝裂霉素C衍生物的。
松井等“The Journal of Antibiotics”,ⅩⅪ,189-198(1968)
木下等“J.Med.Chem.”14,103-109(1971)(1981)Iyengar等“J、Med Chem”24,915-981(1981)
Iyengar,Sami,Remers,and Bradner Abstracts of Papars-Annual Meeting of the American Chemical Society,Las Vegas,Nevada,March 1982,Abstract No.MEDI 72。
Sasaki等:Internat,J.Pharm,1983,15,49。
下列专利说明书论及丝裂霉素A、丝裂霉素B,或者NLa-取代衍生物与伯胺或肿胺反应制备7-取代氨基米托沙奈衍生物。
Cosulich等,美国专利3,332,944(1967.7.25)
松井等,美国专利3,420,846(1969.1.7)
松井等,美国专利3,514,452(1970.5.26)
松井等,美国专利
中野等,美国专利4,231,936(1980.11.4)
Remers,美国专利4,268,676(1981.5.19)
7-位上有取代氨基取代的丝裂霉素C衍生物也已经用直接生物合成法制出。方法是用一系列伯胺补充发酵肉汤(培养基),进行常规的丝裂霉素发酵(C.A.Claridge等Abst.of the Annual Meeting of American Soc.for Microbiology 1982.Abs 028)
比利时专利896,963,编在这里参考用的发明,公开了一组新型的丝裂霉素C的单胍基或单脒基和双脒基类似物,其中丝裂霉素C的7-氨基氮原子或/和N10氨基甲酰基氮原子是脒基取代基的一部分,或者7-氨基氮原子是胍基的一部分。按照该比利时专利实施例8和15描述的方法制出的这种化合物之一是具有下列结构的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈。
得到的这一非晶形固体化合物抗P-388小白鼠白血病病毒具有很高活性,其最大效力和毫克效力(同等效力剂量大小的比较)都优于丝裂霉素C。但是,在25-56℃之间它通常是不稳定的。至今还没有找到在无菌管瓶中加入某一注射赋形剂,能使该化合物重新构成单位剂量形成的简便方法。由于7-(二甲氨基亚甲基)-9a-甲氧基米托沙奈以单位剂量形成的用量极其少,并且由于它具有极其强的毒性,所以人们不愿大量地(如以干粉的形式)处理它。而且,由于该化合物在水中不稳定,所以不能用它的水溶液使它以单位剂量的形式灌进无菌管瓶中。
现在已经发现,通过用该化合物的叔丁醇溶液灌进无菌管瓶的方法,可以使7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈以无菌的单位剂量形式沉积在管瓶中。然后用蒸发法或冷冻干燥法除去叔丁醇。可用适当的方法,如塞子,来封闭管瓶。象这样沉积的物料,可含多达0.5摩尔当量半溶剂化物形式的叔丁醇,并且对热很稳定,只要和合适的注射赋形剂混合,就随时能够应用。
在本发明中实际应用的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈可以是非晶形的、也可以是结晶状的。
非晶形的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈是按比利时专利896,963实施例8和15的方法制备的。其制备方法描述如下:
比利时专利896,963实施例8的方法
化合物1,7-〔(二甲氨基)亚甲基〕氨基N10-(二甲氨基)亚甲基-9a-甲氧基米托沙奈的制法如下:
向500毫克(1.5毫摩尔)的丝裂霉素C和25毫升三氯甲烷的悬浮液中加入总体积为9.6毫升(在第0、18、21和23小时各加入2.4毫升)的N.N-二甲基甲酰胺二甲基乙缩醛,悬浮液在约50℃下搅拌41小时。减压蒸发溶剂和过量试剂,得到暗绿色的残余物;薄层色谱(TLC)(二氯甲烷/甲醇20∶1)显示不存在丝裂霉素C,而有二个新的绿色成分存在(比移值Rf=0.16和0.22)。用闪蒸色谱(flash Chromatografhy)离析其主成分(Rf=1.6);以二氯甲烷/甲醇20∶1作洗脱剂,得绿色固体(340毫克,51.5%),将其溶在乙醚中,接着加入己烷,得到化合物Ⅰ,为暗绿色非晶形的粉末。
NMR(吡啶d5,δ);2.18(S,3H),2.70(bs,1H),2.76(S,3H),2.82(S,3H),2.86(S,6H),3.22(S,3H),3.30(bs,1H),3.60(d,J=12HZ),4.12(dd,1H,J=10.4Hz),4.43(d,1H,J=12Hz),4.90(bs,1H),5.10(t,1H,J=10Hz),5.20(dd,1H,J=10.4Hz),7.85(S,1H),8.64(S,1H)。
IR(KBr)maxcm-1:3300,2930,1675,1620,1545,1230,1060
UV(H2O)λmax nm:390 and 244
分析:C21H28N6O5,计算值C,56.71;H,6.08;N,18.90
实验值:C,56.20;H,6.28;N,17.88
7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈(化合物Ⅱ)的制法如下:
向溶有化合物Ⅰ(600毫克,1.35毫摩尔)的甲醇(10毫升)中加入氨基二苯基甲烷(2.2毫升,10.8毫摩尔),所得溶液在54℃下搅拌4小时。用薄层色谱(二氯甲烷/甲醇90∶10)监控反应的进行。原料(Rf=0.35)在第4小时末消失,代之以较长的新的绿色色斑(Rf=0.29)。溶液减压浓缩,所得的糖浆状物用闪蒸色谱(25克硅胶)进行分离,用二氯甲烷/甲醇20∶1作洗脱剂,汇集含绿色成分的部分(Rf=0.29),干燥(Na2SO4)并加以浓缩。得化合物Ⅱ,为非晶形的固体(215毫克,41%)。
NMR(吡啶d5,δ):2.18(S,3H),2.70(bs,1H),2.80(S,3H),2.88(S,3H),3.08(bs,1H),3.24(S,3H),3.56(bd,1H,J=12Hz),4.00(dd,1H),4.44(d,1H,J=12Hz),5.06(t,1H,j=10Hz),5.56(dd,1H,J=10.4Hz),7.58(bs,2H),7.88(S,1H)。
IR(KBr)νmax Cm-1:3300-3450,29602910,1715,1620,1535,1050
UV(H2O)λmax nm:390和226
分析:C18H23N5O5计算值:C,55.48;
H,5.91;N,17.98; 实验值:C,54.83;
H,5.67;N,16.90
比利时专利896,963实施例15的方法
在0℃下,向含二甲基甲酰胺(915毫克,12.5毫摩尔)的三氯甲烷(25毫升)溶液中滴加草酰氯(1.57克,12.5毫摩尔),接着在室温下搅拌30分钟,制得氯化N,N-二甲基氯亚甲亚胺盐酸盐(N,N-dimethylchloromethyl-eniminium)溶液。另外,向含NaH(36毫克,1.5毫摩尔)的二甲基甲酰胺(3毫升)的悬浮液中加入丝裂霉素C(334毫克,1毫摩尔)的二甲基甲酰胺(5毫升)溶液。所得的溶液在室温下搅拌20分钟并冷却到-40℃~-50℃,加入上述N,N-二甲基氯亚甲亚胺盐酸盐溶液(3毫升,1.5毫摩尔)。在-40℃下搅拌10分钟后,加入补充的NaH(18毫克,0.75毫摩尔)。溶液在-40℃下保持1小时,然后用CH2Cl2稀释并过滤。滤液蒸发后所得的残余物在硅胶(10%CH3OH-CH2Cl2作洗脱剂(上用薄层色谱进行离析。萃取主要绿色区,得78毫克(43%,根据回收的丝裂霉素C计算)非晶形固体,其NMR谱和TLC与上述化合物Ⅱ相同。
将非晶形7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈溶于丙酮和/或乙醇中,然后将所得溶液加入乙醚,即可使物料转变为结晶状。更可取的是在持续的时间间隔(如20分钟)内,将溶液加入乙醚。结晶状7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的另一制法是使一定量的非晶形物料在乙醚中形成泥浆状,然后加入少量结晶状物料。这导致非晶形7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈转化成结晶状。
很容易制成7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的叔丁醇溶液,或其含乙醇高达20%(重量)的叔丁醇溶液。该溶液在24℃下至少稳定48小时。溶液能进行无菌过滤,并沉积在无菌管瓶中。用升华法除去溶剂,得到海绵状橄榄绿色的非晶状块,或在25~30℃下用控制蒸发法得到主要呈结晶状暗绿色玻璃样残余物。上述二种固体形式的物料作为产品剂型都是足够稳定的。根据本发明的实际应用,叔丁醇有下列几个优点。首先,叔丁醇溶液在使用时非常稳定,它与不稳定的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的水溶液形成鲜明的对比。其次,叔丁醇容易升华,因而易于除去。还有,比起前述的非晶形7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈其叔丁醇溶液在管瓶中沉积出的固体形式要稳定得多。
下列实施例叙述了7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈在管中沉积的详细方法。
实施例1
1克7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙游离碱与叔丁醇形成泥浆状,再加适量的叔丁醇至总容积达200毫升,置于26-32℃,漫射柔光下2小时,生成溶液。这就提供了含有5毫克1毫升的7-(二甲基亚甲基)氨基-9a-甲氧基米托沙奈的叔丁醇溶液。在无菌条件下,用氮气压力使溶液穿过供醇溶剂用的0.22微米无菌微孔滤器,滤液汇集在无菌容器中。溶液温度不得低于26℃,因为叔丁醇在低于25℃时会结晶。若干个无菌玻璃管瓶中灌进总量2毫升的上述溶液。用冷冻干燥的裂解丁基橡胶塞子部分地塞住管瓶。把管瓶放进专为凝结叔丁醇而设计的无菌冷冻干燥器中,使管瓶内容物在-40℃冷冻。然后用冷冻干燥法或在高真空下,于高温度为24-27℃升华24小时,以除去叔丁醇。然后使温度升到40-50℃,并维持3-5小时;再使温度降到24-27℃,用无菌氮气中止真空。用无菌铝密封管瓶。在每个管瓶中得到暗绿色松散海绵状的管瓶块状物,其中主要是非晶形的,也有部分为结晶状的。块状物料中含有高达0.5摩尔当量的叔丁醇。管瓶应贮藏在20-26℃的暗处。
实施例2
1克7-(二甲基亚甲基)氨基-9a-甲氧基米托沙奈游离碱与叔丁醇形成泥浆状,再加适量的叔丁醇至总容量达100毫升,置于26-32℃,漫射柔光下4小时,生成溶液。这提供了含有10毫克1毫升的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的叔丁醇溶液。在无菌条件下,用氮气压力使溶液穿过供醇溶剂用的0.22微米无菌微孔滤器,滤器汇集在无菌容器中。1毫升的滤液分灌进若干个无菌玻璃管瓶中。用冷冻干燥的塞子部分地塞住管瓶。把管瓶放进专为除去或凝结叔丁醇而设计的无菌真空烘箱中。真空烘箱的搁架温度为26-30℃,并使管瓶内容物加热到这一温度。用一可调真空源,使管瓶真空度在2-3小时时限内逐渐达到24-27英寸-汞柱。叔丁醇的蒸发率为5小时1毫升。由于叔丁醇的缓慢蒸发,导致溶液浓度增加,而使7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈从溶液中结晶而出。在26-30℃的搁架温度下,使继续保持25-27英寸-汞柱的真空度16~24小时。然后应用较高的真空度(例如10-60毫乇)并使搁架温度升到40~45℃,保持该温度4-6小时;搁架温度再降到24℃,使管瓶内容物冷却到24~27℃。用无菌氮气中止真空。用无菌铝密封管瓶口。在每个管瓶中得到较稠密的结晶状为主的暗绿色管瓶块状物。块状物料中含有高达0.5摩尔当量的叔丁醇。这样沉积而得的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的稳定性可用下法测定:
把含有所需沉积的7-(二甲氨基亚甲基)氨基的管瓶放在不同温度的测点上,在每一时间一温度间隔,把含有沉积的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的管瓶交给高效液体色谱(PLC)进行测定。被测物料的活性以微克/毫升的形式记录。测定结果见表Ⅰ。表中称作“非晶”的物料是按比利时专利896,963中描述的方法制得的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈。这种物料仅折合成管瓶中物料的含量来进行测定,而不是按本发明的实际应用那样把物料沉积在管瓶中进行测定的。称作实施例1和2的物料指的就是本发明实施例1和2所描述的沉积的7-(二甲氨基亚甲基氨基-9a-甲氧基米托沙奈。如果表中出现两个以上数值时,是指多次测定的结果。
表1
表2
7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的百分比
余额
时间(小时) 0%烟酰胺 10%烟酰胺 30%烟酰胺
0 100.0 100.0 100.0
1 88.7 94.1 96.5
2 83.6 91.5 92.8
3 81.2 90.5 94.2
4 79.0 89.0 93.3
5 77.0 88.4 92.5
6 74.8 86.9 91.6
为了重新组成叔丁醇管瓶沉积的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈游离碱,应优先选用加入下述几种水性注射赋形剂的方法。第一种方法是加入PH为6.6的含有0.01摩尔柠檬酸盐的缓冲溶液和1毫克/毫升的Pluronic F68;第二种方法是加入含有0.01摩尔的L-结页氨酸,使其PH调到6.5的缓冲液。上述重新组成的赋形剂具有可接受的有效时间,例如,小于10%的损耗至少要3小时,达到可接受的返回原浓度有效时间的另一更好实例是使水性赋形剂中含有高达30%(重量),最好是10~30%(重量)的烟酰胺。表2表明烟酰胺在水性赋形剂中所起的作用。
Claims (16)
1、7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈,以无菌的单位剂量形式在管瓶中沉积的方法,其特征在于此法包括将7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈的叔丁醇溶液灌进无菌管瓶中,然后除去叔丁醇。
2、根据权利要求1的方法所述,其中该叔丁醇用冷冻干燥法除去。
3、根据权利要求2的方法所述,其中将该叔丁醇溶液冷冻到-40℃,并在高真空下使叔丁醇升华。
4、根据权利要求1的方法所述,其中该叔丁醇用蒸发法除去。
5、根据权利要求4的方法所述,其中该叔丁醇借助真空在从25到30℃的温度下蒸发。
6、根据权利要求1的方法所述,其中5到10毫克的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈沉积在该管瓶中。
7、根据权利要求2的方法所述,其中5到10毫克的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈沉积在该管瓶中。
8、根据权利要求3的方法所述,其中5到10毫克的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈沉积在该管瓶中。
9、根据权利要求4的方法所述,其中5到10毫克的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈沉积在该管瓶中。
10、根据权利要求5的方法所述,其中5到10毫克的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈沉积在该管瓶中。
11、根据权利要求1的方法所述,其中该沉积的7-(二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈接着加入水性注射赋形剂。
12、根据权利要求11的方法所述,其中该水性注射赋形剂的PH值为6.6,含有0.1摩尔的柠檬酸盐缓冲剂。
13、根据权利要求11的方法所述,其中该水性注射赋形剂含有0.1摩尔的L-结页氨酸PH值为6.5。
14、根据权利要求11的方法所述,其中该水性注射赋形剂含有高达30%(重量)的烟酰胺。
15、根据权利要求11的方法所述,其中该水性注射赋形剂含有从10到30%(重量)的烟酰胺。
16、7-二甲氨基亚甲基)氨基-9a-甲氧基米托沙奈中含有高达0.5摩尔当量的叔丁醇。
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CN105744957B (zh) * | 2013-10-22 | 2019-07-02 | 默德克学会特殊临床公司 | 制备冷冻干燥的含有丝裂霉素c的药物组合物的方法 |
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