CN86104774A - 偏端霉素衍生物的制备方法 - Google Patents
偏端霉素衍生物的制备方法 Download PDFInfo
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- CN86104774A CN86104774A CN86104774.5A CN86104774A CN86104774A CN 86104774 A CN86104774 A CN 86104774A CN 86104774 A CN86104774 A CN 86104774A CN 86104774 A CN86104774 A CN 86104774A
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
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Abstract
本发明涉及下列结构式为[I]的偏端霉素A衍生物的制备方法:
其中R是一个单取代或双取代氨基,并且每一个R1可以任意地是氢或烷基。按照本发明的方法,结构式为[I]的化合物可以通过诸如酰化的方法来改变N-脱甲酰基偏端霉素A的氨基来制备,由本发明的方法制得的这些化合物可以用作抗病毒和抗肿瘤剂。
Description
本发明涉及偏端霉素衍生物的制备方法。
偏端霉素A是一种熟知的化合物,它具有如下的结构式。
提到偏端霉素A的文献有,例如,
Nature(自然)203,1064(1964)。
本发明提供的偏端霉素A的衍生物,有下列通式(Ⅰ)
其中
R是a)-NHR3,其中R3是
a′)-CON(NO)R4,在该基团中R4是未取代的或被卤素取代的C1-C4烷基;或
b′)-CO(CH2)m-R5,在该基团中R5是卤素、环氧乙烷基、甲基环氧乙烷基、吖丙啶基、环丙基或一个脂环的α、β不饱和酮基或内酯基,m是零或1到4的整数;或
,在该基团中,R6和R7相同,都是环氧乙烷甲基、吖丙啶甲基或2位上被卤素或被-OSO2R8基团取代的C2-C4烷基,而基团-OSO2R8中,R8是C1-C4烷基或苯基,或R6和R7中的一个基团是氢而另一个是上面所规定的基团;以及
每一个R1基团可以是任意的氢或C1-C4烷基。
本发明也包括结构式为(Ⅰ)的这些药用上容许化合物的盐以及结构式(Ⅰ)所包含的所有可能的异构体,二者可以分别地存在也可以混合。
当R4是未取代的C1-C4烷基时,则甲基和乙基最好,特别是甲基。
当R4是由卤素取代的C1-C4烷基时,则卤素最好是氯或溴;在这种情况下,推荐的R4是氯乙基和氟乙基。
当R5是卤素时,它最好是氯或溴。
R6/R7为被卤素在2位取代的C2-C4烷基,最好是2-氯乙基。
R6/R7为被-OSO2R8基团在2位取代的C2-C4烷基,最好是-CH2-CH2-OSO2R8基团,其中R8是C1-C4烷基,最好是甲基。
每一个R1基团,可以是任意的C1-C4烷基,尤其是甲基,而且最好所有的R1基团都是甲基。
如上所述,本发明还包括药用上容许的结构式为(Ⅰ)化合物的盐。这些盐包括药用上容许的酸,既可以是无机酸,例如,盐酸、氢溴酸、硝酸和硫酸,也可以是有机酸,例如,柠檬酸、酒石酸、马来酸、富马酸、甲磺酸和乙磺酸的盐。
本发明推荐的一类化合物是用结构式为(Ⅰ)的化合物以及这些化合物与药用酸,尤其是盐酸所形成的盐。来表示的,其中
R是-NHR3,该基团中R3是
a′)-CON(NO)R4,该基团中的R4是被卤素取代的C1-C4烷基或
b′)-CO(CH2)m-R5,该基团中的R5是卤素、环氧乙烷基、1-吖丙啶基、环丙烷基、或一种脂环的α,β-不饱和内酯基,而m是零、1或2;
各个R1基团可任意地是C1-C4烷基。
在上述推荐的结构式为(Ⅰ)的这类化合物的范围内,尤其要推荐的是这些化合物的基团,其中:
R是-NHR3,该基团中的R3是
a′)一种-CON(NO)R4基团,该基团中的R4是-CH2-CH2-Cl或
b′)一种-CO(CH2)m-R5基团,该基团中,m可以是1或2而R5是氯,或m是零而R5是环氧乙烷基,1-吖丙啶基或环丙基,或m是2而R5是
;
每一个R1基团是甲基,
和它们的这些盐,都具有药用上容许的酸,特别是盐酸。
本发明推荐的另一类结构式为(Ⅰ)的化合物,其中
每一个R1基可以是任意的C1-C4烷基;
而它们的这些盐,都具有药用上容许的酸,尤其是盐酸。
在上面推荐的这类基团中,R6/R7中的C2-C4烷基,最好是乙基;卤素最好是氯;当R6和R7都是2位被卤素取代的C2-C4烷基时,它们最好的是2-氯乙基;当R6和R7是2-位被-OSO2R8基团取代的C2-C4烷基时,其中R8是C1-C4烷基,它们最好是甲磺酰乙氧基;对于R1的C1-C4烷基,则最好是甲基。
上述推荐的这类化合物中,特别要推荐的是结构式为(Ⅰ)的这些化合物的基团,其中
每一个R1基团是甲基,
和它们的盐都具有可药用的酸,尤其是盐酸。
本发明推荐的这些化合物的具体实例,特别是以盐酸盐的形式,如下:
N-脱甲酰-N-〔N′-(2-氯乙基)-N′-亚硝基-氨基甲酰基〕-偏端霉素A;
N-脱甲酰-N-〔N′-甲基-N′-亚硝基氨基甲酰基〕偏端霉素A;
N-脱甲酰-N-(环氧乙烷羰基)偏端霉素A;
N-脱甲酰-N-(环丙基羰基)偏端霉素A;
N-脱甲酰-N-(3-甲基环氧乙烷羰基)偏端霉素A;
N-脱甲酰-N-(2-氯乙基羰基)偏端霉素A;
N-脱甲酰-N-〔1-(氮丙啶)羰基〕偏端霉素A;
N-脱甲酰-N-〔N,N-双(2-氯乙基)〕偏端霉素A。
本发明的对象是可以通过一种方法加以制备的化合物,包括:
A)结构式为Ⅱ的化合物
其中
R1按上面所规定的与结构式为(Ⅲ)的化合物反应,
结构式(Ⅲ)中
R4按上面所规定的,Z是一个离去基团,这样就得到了结构式为(Ⅰ)的一个化合物,式(Ⅰ)中的R是-NHR3,而R3是-CON(NO)R4,该式中的R4按上面所规定的;或
B)结构式为(Ⅱ)的化合物,其中R1是上面所规定的,与结构式为(Ⅳ)的化合物反应
其中
R5和m都按上面规定的而Z′是一个离去基团,这样得到了结构式为(Ⅰ)的一个化合物,式(Ⅰ)中的R是-NHR3,而R3是-CO(CH2)m-R5,式中的m和R5上面的已规定过;或
C)结构式为(Ⅱ)的化合物,式(Ⅱ)中R1上面作过规定,与结构式为(Ⅴ)的化合物反应,
结构式(Ⅴ)中,X可以是氢、C1-C2烷基或卤代甲基,得到结构式为(Ⅵ)的一个化合物
R1为上面规定过的,每一个X具有的含义与化合物(Ⅴ)中所表示的X一致,将结构式(Ⅵ)的化合物转变成结构式(Ⅰ)的化合物,式(Ⅰ)中的R是
,该基团中R6和R7上面已规定过;并且,如果需要,可使结构式(Ⅰ)的一种化合物转变成结构式(Ⅰ)的另一种化合物,和/或,如果需要,可使结构式(Ⅰ)的一种化合物或盐或由盐得到一游离的化合物和/或,如果需要,可将结构式为(Ⅰ)的混合异构体分离成为单个异构体。
在结构式为(Ⅳ)的这些化合物中,其离去基团Z可以是一个叠氮基或一个三氯苯氧基或琥珀酸亚胺基-N-氧化基团。
结构式为(Ⅱ)的化合物与结构式为(Ⅲ)的化合物之间的反应,最好是在有溶剂存在下进行,并最好使用过量的结构式为(Ⅲ)的化合物,例如,每摩尔化合物(Ⅱ)大约要用1.1到2摩尔的化合物(Ⅲ)。溶剂最好是一种惰性有机溶剂,例如,选自二烷基亚砜,如二甲基亚砜,脂肪酸二烷基酰胺,如,二甲基甲酰胺或二甲基乙酰胺,磷酸三酰胺或六甲基磷酰胺,或例如二恶烷或二甲氧基乙烷。二甲基甲酰胺(DMF)是特别推荐的溶剂。
反应温度的范围可以大约-10℃到大约25℃,不过0℃是特别推荐的反应温度。
反应所需时间可以从大约0.5到6小时范围内变动。
在结构式为(Ⅳ)的这个化合物中,离去基团Z′可以是一卤原子,例如氯或溴,也可以是一个咪唑基或苯氧基。
结构式为(Ⅱ)的化合物与结构式为(Ⅳ)的化合物之间的反应,最好是在有溶剂存在下进行,并且最好使用过量的结构式为(Ⅳ)的化合物,例如,每摩尔的化合物(Ⅱ)大约需用1.1到大约2摩尔的化合物(Ⅳ)。溶剂最好是一种惰性的有机溶剂,选自二烷基亚砜如,二甲基亚砜,脂肪酸二烷基酰胺,如,二甲基甲酰胺,杂环胺如吡啶,脂肪酸以及水。特别推荐的溶剂是二甲基甲酰胺(DMF)。
反应温度的范围,可以从大约-50℃到大约50℃。反应所需时间大约可以在0.5到24小时范围内变动。
在结构式为(Ⅴ)的化合物中,当X是卤代甲基时,它最好是氯甲基或溴甲基。
结构式为(Ⅱ)的化合物和结构式为(Ⅴ)的化合物之间的反应,最好是有溶剂存在下进行,而且最好使用过量的结构式为(Ⅴ)的化合物,例如,每摩尔的化合物(Ⅱ)大约需25摩尔到大约50摩尔的化合物(Ⅴ)。
溶剂可以是水、脂肪醇,例如甲醇或乙醇、脂肪羧酸、例如醋酸、脂肪酸二烷基酰胺,例如二甲基甲酰胺、或二烷基亚砜,例如二甲基亚砜、二恶烷或二甲氧基乙烷。甲醇是特别推荐的溶剂。
反应温度范围可以从大约-20℃到大约25℃。
反应所需时间,可以从大约2到大约48小时范围内变动。
例如,结构式为(Ⅵ)的化合物,其中每一个X基团是氢或C1-C2烷基可以与卤化剂反应,如与卤素诸如氯或溴化物,或亚硫酰卤化物,如亚硫酰氯反应,生成结构式为(Ⅰ)的化合物,式(Ⅰ)中R是一个
基团,在该基团中,每一个R6和R7是2-位被卤素,例如氯或溴取代的C2-C4烷基。类似地,结构式为(Ⅵ)的化合物,X是氢或C1-C2烷基可以与分子式R8SO3H的磺酸起反应,而分子式R8SO3H中的R8按上面所规定的,或最好与它们的活泼衍生物反应,例如,相应的磺酰卤化物,如氯化物或酸酐,以得到结构式为(Ⅰ)的化合物,式(Ⅰ)中R是
基团,该基团中,每一个R6和R7是2位上被-O-SO2R8基团取代的C2-C4烷基,而-O-SO2R8基团中的R8如上面所规定的。
这种碱既可以是一种无机碱,例如,碱金属,如氢氧化钠或钾,或一碱土金属,如氢氧化钙或镁,或是一种有机碱,例如,脂肪胺,如三甲胺,或杂环胺,如吡啶、哌啶、吗啉或甲基吗啉。
同样地,结构式为(Ⅰ)的一种化合物,可以任意转化成结构式为(Ⅰ)的另一种化合物,结构式为(Ⅰ)的化合物成盐和由盐制备游离化合物都可按已知的方法来进行。
通用的方法,例如部分结晶和色层法,也可以用来将结构式为(Ⅰ)的异构体混合物,任意地分离为单个异构体。
结构式为(Ⅱ)的化合物可以用下列已知方法制备,例如,这些步骤类似与那些在Gazz.Chim.Ital.(意大利化学杂志)97 1110(1967)中制备偏端霉素衍生物所述的方法。
结构式为(Ⅲ)的这些化合物,都是已知的化合物,它们可以,例如,按照J.Med.Chem.(药物化学杂志)(1982),25,178-182来制备。
结构式为(Ⅳ)和(Ⅴ)的这些化合物也是已知的化合物,也是可以用已知化合物通过已知方法来制备的。例如,尤其是结构式为(Ⅳ)的化合物既是商品(工业用)的化合物又可以用通常的方法,使羧基母体化合物的活化来制得。
结构式为(Ⅴ)的化合物,市场上都能买得到。
结构式(ⅠA)的本发明的化合物,能有用于作抗病毒和抗肿瘤剂。
它们在病原病毒的再生活性的干扰上显示出显著的有效性,并能保护组织细胞免于病毒感染。
例如,它们对抵抗DNA病毒显示了活性,DNA病毒,例如,如疱疹,单纯性疱疹和带状疱疹、病毒和腺病毒,并对抵抗逆转病毒例如肉瘤病毒如鼠性(Marine)肉瘤病毒和白血病病毒,例如弗兰德(Friend)白血病病毒也显示活性。因此,如疱疹、柯萨基和呼吸合胞体病毒都在液体介质中作如下试验。连续的将这些化合物由200到1.5毫厘克/毫升稀释两倍、以一式两份的0.1毫升/孔穴配置在微片的96个孔穴中,供细胞组织培养。
对于细胞毒性控制用的细胞悬浮体(2×105个细胞/毫升)未被感染的,或感染上大约5×103TCID50的病毒/细胞都立即加入0.1毫升/孔穴的上述化合物。在37℃、5%的CO2中保温3-5天以后,细胞培养就可用显微镜的观察结果来估量而且可测定出最大耐药力的剂量(MXTD)和最小抑制浓度(MIC)。MXTD是该化合物的最大浓度,它使之单层的生长,类似于以密度和形态方面的控制。MIC是最小浓度,它决定了致细胞病变的作用要比感染控制低。当用MXTD/MIC之比计算出它们的活性指数≥2时,就可以认为这些化合物是有活性的。
本发明的结构式(lA)化合物对肿瘤细胞也显示有细胞抑制性能,因此它们能够有用于抑制各种各样肿瘤的生长,例如癌,如乳房癌、肺癌、膀胱癌、结肠癌、卵巢癌、子宫内膜癌。其他的瘤子,而其中发现能使用本发明的这些化合物有,例如肉瘤如软组织和骨肉瘤和血液中的恶性毒素,例如白血病。
本发明的这些化合物,可以通过一般的常规方式用药,例如,非肠道的,例如,也可以通过静脉注射或输注,肌注、皮下用药、局部用药或口服用药。
用药剂量决定于病人的年龄、体重和身体状况,也决定于用药的方式。例如,对成年人最合适的用药剂量,可以按一日四次,每次约0.1到约100毫克。
本发明的药用组成,含有结构式为(Ⅰ)的化合物作为活性物质,和与之有关的一种或几种药用容许的赋形剂。
本发明的药用组成通常按惯用的方法来制取,并以适宜的药用形式用药,例如,输注用的静脉注射液,其中可以含载液,例如,无菌水,或最好是无菌生理盐水溶液。
悬浮液或肌注用的溶液可以同时含有活性化合物和药用容许的载液,例如无菌水、橄榄油、油酸乙酯、邻二醇,如丙二醇。如果需要,还可含有适量的盐酸利多卡因。
局部用的形式,例如乳剂、洗剂或糊剂,是用于皮肤的治疗,主要的活性组成部分可以与常用的含油的或乳化的赋形剂混合。
固体口服的形式,例如片剂和胶囊可以同时含有活性化合物、稀释剂,例如乳糖、葡萄糖、蔗糖、纤维素、玉米淀粉和马铃薯淀粉;润滑剂例如硅石、滑石粉、硬酯酸、硬酯酸镁或硬酯酸钙和/或聚乙二醇;粘合剂如淀粉、阿拉伯树胶、明胶、甲基纤维素、羧甲基纤维素、聚乙烯吡咯烷酮;解聚剂如淀粉、藻酸、藻酸盐、羟基乙酸淀粉钠;泡腾合剂;着色剂、增香剂、润湿剂例如卵磷脂、多乙氧基醚、硫酸十二酯,以及一般的非毒性的和药理上无活性的物质都可用于药用配方中。以上所述的药物制备可以用熟知的方法来生产,例如用混合、造粒、压片,涂渍糖衣或包膜的方法。
此外,在病人需要用此药时,按照本发明提供治疗病毒感染和肿瘤的方法,包括给上述病人一种本发明组成的用药方法。
缩写DMSO,THF和DMF分别代表二甲基亚砜、四氢呋喃和二甲基甲酰胺。
下列的实施例作举例说明,但并不限制本发明的内容。
实施例1
将N-脱甲酰偏端霉素A二盐酸盐(2克)的(100毫升)甲醇溶液,搅拌,冷却至-10℃,再加入冷的环氧乙烷(20毫升)。
密封反应烧瓶,使其在室温下过夜。
在减压下除去甲醇和过量的环氧乙烷。
残留物在硅胶上进行色层分离,并用盐酸冲洗,用氯仿70/甲醇30作洗提液,得到1.32克的N-脱甲酰-N-〔N,N-双-(2-羟乙基)〕偏端霉素A盐酸盐
紫外光谱 λmax(乙醇95%)(ε):244(24,140);306(27,142)纳米
质谱 m/e(f.d):542M++1,524M+-NH3;
核磁共振谱(DMSO-d6)δ:2.63(2H,t);
3.00-3.30(4H,m);3.3-3.7
(6H,m);4.6(2H,t);6.25-
7.25(6H,m);7.20(1H,t);
7.62(2H,S);7.95(2H,S);
9.62(1H,S);9.86(1H,S)。
实施例2
将N-脱甲酰-N-1N,N-双(2-羟乙基)偏端霉素A盐酸盐(680毫克)的吡啶(7毫升)溶液,冷却至0-5℃,并用甲磺酰氯(0.21毫升)的吡啶(2毫升)溶液处理1小时。
在加入甲醇(7毫升)酸,将反应混合物加热至室温。
用真空除去溶剂,残留物在硅胶上进行色层分离,用氯仿-甲醇(75∶25)作洗提液,得到N-脱甲酰-N-1N,N-双-(2-氯乙基)-偏端霉素A盐酸盐(310毫克)。
紫外光谱 λmax(乙醇95%)(ε):245(21,139),309(21,273)纳米,
质谱m/e(f.d):578M++1,559M+-NH+ 4
505M+-CHCl,
452M++1-2(CH2CH2Cl)
M.W.游离基峰=577
核磁共振谱(DMSO-d6):δ2.64(2H,t);
3.2-3.8(10H,m);
6.40-7.25(6H,m);
8.20(H,t);8.62(2H,S);
8.90(2H,S);9.78(2H,S);
9.88(H,S)。
实施例3
在一冰水冷却的N-脱甲酰偏端霉素A,盐酸盐(0.132克)的DMF(2毫升)溶液和78毫克的2,4,5-三氯苯基-N-甲基-N-亚硝基氨基甲酸酯中〔根据J.Med.Chem 25,178(1982)加以制备的〕,滴加二异丙基乙胺(0.041毫升)的DMF(2毫升)溶液。
将所得到的溶液,在0℃,搅拌40分钟。反应混合物在真空下浓缩,而残留物是用色谱柱提纯的,得到62毫克的N-脱甲酰-N-〔N′-甲基-N′-亚硝基氨基甲酰〕偏端霉素A.的盐酸盐。
紫外(乙醇95%)波长,λmaxε(消光系数)
239 21,611
306-8 28,207
红外KBr:γcm-13500-2800;
2500-2200;1460;
970;660。
核磁共振DMSO-d6:δ2.63(2H,m);
3.17(3H,S);3.48(2H,m);
3.81(3H,S);3.84(3H,S);
3.87(3H,S);6.90-7.27(6H,
m);8.17(1H,bt);8.62(2H,
bt);8.98(2H,br);9.86(1H,
bs);9.93(1H,bs);
10.66(1H,bs)。
用类似的方法,得到下列化合物:
N-脱甲酰-N-〔N′-(2-氯乙基)-N′-亚硝基氨基甲酰-〕-偏端霉素A.盐酸盐
核磁共振(DMSO-d6):δ2.61(2H,t);
3.50(2H,dt);
3.65(2H,t);3.81(3H,s);
3.86(3H,S);3.89(3H,s);
4.19(2H,t);6.90-7.25(6H,
m);8.18(1H,t);8.56(2H,s);
8.94(2H,S);9.88(1H,S);
9.93(1H,S);10.93(1H,S);
紫外(乙醇95%):波长λmax240 ε=30,286
λmax310 ε=42,783。
实施例4
将(2R,3R)-3-甲基环氧乙烷羧酸(153毫克)溶于干燥的四氢呋喃(4毫升)中的溶液,冷却至-20℃,加入N-甲基吗啉(0.165毫升),再加入三甲基乙酰氯(0.184毫升)。得到的悬浮液,在-20℃下搅拌20分钟,然后将全部悬浮液加入到N-脱甲酰偏端霉素A(500毫克)的DMF(10毫升)和NaHCO3(80毫克)的冷却溶液中。混合物在温度为0℃下搅拌30分钟,然后在室温下搅拌4小时。溶剂在真空下蒸发至干燥,残留物在二氧化硅上(溶剂:CHCl380/ CH3OH 20)进行色压分离,得到280毫克的N-脱甲酰-N-〔3-甲基-(2R,3R)环氧乙烷-1-羰基〕偏端霉素A盐酸盐。核磁共振(DMSO)-d6):δ 1.26(3H,d);3.3(1H,m);3.36(1H,d)〔J 4.7Hz(顺式)〕
用类似的方法得到下列各化合物:
N-脱甲酰-N-(2-氯乙基羰基)偏端霉素A。盐酸盐,熔点为160℃(分解)。
核磁共振(DMSO-d6):δ2.67(2H,bt);
2.75(2H,t);3.52(2H,m);
3.81(3H,s);3.84(6H,s);
3.87(2H,t);6.85-7.30
(6H,m);8.22(1H,bt);
8.74(2H,br);9.04(2H,br);
9.90(2H,ds);10.08(1H,
bs);紫外(乙酯95%):波长λmax=241 ε=26.283;λmax=307 ε=33,420
N-脱甲酰-N-(3-甲基环氧乙烷羰基)偏端霉素A。盐酸盐
核磁共振(DMSO-d6):δ1.26(3H,d);
3.3(1H,m);3.60
(1H,d)〔J 4.7
Hz(顺式)〕;
N-脱甲酰-N-(环丙基羰基)偏端霉素A.盐酸盐
核磁共振(DMSO-d1):δ0.75(4H,m);
1.76(1H,m);2.65(2H,t);
3.52(2H,m);3.83(9H,s);
6.8-7.3(6H,m);8.21(1H,
bt);8.69(2H,bt);9.00
(2H,br);9.88(2H,bs);
10.09(1H,s);
紫外(乙醇 95%):λmax241 ε=28,471
λmax309 ε=33,125
N-脱甲酰-N-〔1-(氮丙啶)羰基〕偏端霉素A.盐酸盐,
核磁共振(DMSO-d6):δ2.08(4H,s);
2.65(2H,t);3.52(2H,m);
3.70-3.90(9H,m);
6.80-7.25(6H,m);
8.24(1H,t);8.95(4H,bs);
9.70(1H,s);9.90(2H,s);
紫外(乙醇95%):λmax242 ε=27,757;
λmax308 ε=33,287;
N-脱甲酰-N-(溴甲基羰基)偏端霉素A.盐酸盐,
核磁共振(DMSO-d6):δ2.63(2H,bt);
3.51(2H,dt);3.81(3H,s);
3.84(6H,s);4.20(2H,s);
6.9-7.35(6H,m);
8.12(1H,t);8.53(2H,br);
8.94(2H,br);9.87(1H,s);
9.90(1H,s);10.28(1H,s);
N-脱甲酰-N-(氯甲基羰基)偏端霉素A.盐酸盐,
核磁共振(DMSO-d6)δ:2.66(2H,bt);
3.6(2H,m);3.81(9H,s);
4.01(1H,s);4.22(1H,s);
6.9-7.3(6H,m);8.26(1H,
bt);9.05(4H,bt);
9.90(1H,bs);9.97(1H,bs);
10.54(1H,bs);
N-脱甲酰-N-(环氧乙烷羰基)偏端霉素A.盐酸盐,
核磁共振(DMSO-d6)δ:2.64(2H,m);
2.89(2H,m);3.50(2H,m);
3.55(1H,dd);3.81(3H,s);
3.84(6H,s);6.9-7.3(6H,
m);8.22(1H,bt);8.4-9.4
(4H,br);9.9(3H,br)。
实施例5
每片重0.250克,并含有50毫克活性物质的片剂,可以按下列配方加工:
组成(10,000片)
N-脱甲酰-N,N-双(2-氯乙基)
-偏端霉素A.盐酸盐 500克
乳糖 1400克
玉米淀粉 500克
滑石粉 80克
硬脂酸镁 20克
将N-脱甲酰-N,N-双(2-氯乙基)偏端霉素A.盐酸盐、乳糖和一半的玉米淀粉混合,混合物用0.5毫米筛目过筛。将玉米淀粉(10克)悬浮在温水(90毫升)中,并将所得糊剂用于使粉成粒,干燥该颗粒,并在1.4毫米筛目的筛子上面细分,然后加入剩余的淀粉,滑石粉和硬脂酸镁,经充分混合,制成片剂。
实施例6
每剂为0.200克,并含20毫克活性物质的胶囊,可以按下列方法制备:
500粒胶丸的组成:
N-脱甲酰-N-(N′-甲基-N′-亚硝基氨基甲酰基)-偏端霉素A.盐酸盐 10克
乳糖 80克
玉米淀粉 5克
硬脂酸镁 5克
这种配制方法可以用二个硬明胶胶囊套包住,每粒胶丸的剂量为0.200克
实施例7
肌注注射液 25毫克/毫升
将25克N-脱甲酰-N-(3-甲基环氧乙烷羰基)偏端霉素A.盐酸盐溶解于注射用水(1000毫升)中并封装于1-5毫升的密封安瓿中,可以制得可注射的药用组成。
Claims (3)
1、结构式为[I]化合物的制备方法
其中
R是a/-NHR3,其中的R3是
a′/一CON[NO]R4,在该基团中R4是未取代的或被卤素取代的C1-C4烷基;或
b′/-CO[CH2]m-R5,在该基团中R5是卤素、环氧乙烷基、甲基环氧乙烷基、氮丙啶基、环丙基或一个脂环的α,β一不饱和酮基或内酯基,和m是零或1到4的整数;或
b/
,在该基团中R6和R7相同,都是环氧乙烷甲基、氮丙啶甲基或2-位被卤素或被-OSO2R8基团取代的C2-C4烷基,而基团-OSO2R8中,R8是C1-C4烷基或苯基,或R6和R7中的一个基团是氢而另一个基团按上面所规定的;和
每一个R1基团是任意的氢或C1-C4烷基以及它们的药用容许的盐。所述的方法包括:
A)结构式为[Ⅱ]的一种化合物
其中
R1按上面所规定的,和结构式为[Ⅲ]的一种化合物反应
在结构式Ⅲ中
R4按上面所规定的,Z是一个离去基团,这样就得到了结构式为[I]的化合物,式[I]中的R是-NHR3,而R3是-CON[NO]R4,该式中的R4按上面所规定的;或
B)结构式为[Ⅱ]的一种化合物,其中R1按上面所规定的,与结构式为[Ⅳ]的一种化合物反应
式[Ⅳ]中
R5和m如上面规定的,而Z′是一个离去基团,这样得到了结构式为[I]的化合物,式[I]中R是-NHR3和R3是
-CO[CH2]m-R5,式中的m和R5
如上面所规定的;或
C)结构式为[Ⅱ]的一种化合物,式[Ⅱ]中R1按上面所规定的,与结构式为[Ⅴ]的一种化合物反应,
式中的X可以是氢、C1-C2烷基或卤代甲基,得到结构式为[Ⅵ]的一
2、根据权利要求1所述的方法,在权利要求1中报导的结构式为(Ⅰ)化合物的制备
其中
R是-NHR3,其中R3是
a′/-CON(NO)R4,该基团中的R4是被卤素取代的C1-C4烷基或
b′/-CO(CH2)m-R5,该基团中的R5是卤素、环氧乙烷基、1-氮丙啶基、环丙基、或一种脂环的α,β-不饱和内酯,和m是零、1或2;
每一个R1基团是任意的C1-C4烷基,和它们的药用容许的盐。
3、根据权利要求1所述的方法,在权利要求1中报导的结构式(Ⅰ)化合物的制备,
其中
R是
,该基团中的R6和R7是相同的,每一个都可以是环氧乙烷甲基、1-氮丙啶甲基,或2位被卤素或被-OSO2R8基团取代的C2-C4烷基,而基团-OSO2R8中,R8是C1-C4烷基;
每一个R1基团,是任选的C1-C4烷基,以及它们的药用容许的盐。
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ITTO20010633A1 (it) * | 2001-07-02 | 2003-01-02 | Univ Ferrara | Nuovo impiego di poliammidi eterocicliche e benzoeterocicliche strutturalmente correlate all'antibiotico naturale distamicina a. |
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AU2003285958A1 (en) * | 2002-10-25 | 2004-05-25 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
CA2508769A1 (en) * | 2002-12-10 | 2004-06-24 | Oscient Pharmaceuticals Corporation | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
US20070269420A1 (en) * | 2003-11-24 | 2007-11-22 | Chunduru Srinivas K | Compounds, Compositions and Methods for Treatment and Prophylaxis of Hepatitis C Viral Infections and Associated Diseases |
EP3279206B1 (en) * | 2015-03-30 | 2020-04-22 | Meiji Seika Pharma Co., Ltd. | Method for producing epirubicin and novel production intermediate therefor |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA557568A (en) * | 1958-05-20 | J. Weiss Martin | Substituted aminopyrrolecarboxylic acids and esters | |
CA547128A (en) * | 1957-10-08 | W. Waller Coy | Substituted pyrrolecarboxamidopyrroles | |
FR86210E (zh) * | 1963-04-04 | 1966-03-23 | ||
DE1470284B1 (de) * | 1963-07-26 | 1971-12-16 | Farmaceutici Italia | Beta-{1-Methyl-4-[1-methyl-4-(1-methyl-4-formylamino-pyrrol-2-carboxamido)-pyrrol-2-carboxamido]-pyrrol-2-carboxamido}-propionamidin sowie dessen Saeureadditionssalze |
FR141F (zh) * | 1963-07-26 | |||
DE1795539A1 (de) * | 1963-07-26 | 1972-01-13 | Farmaceutici Italia | Verfahren zur Herstellung von neuen Pyrrolderivaten und ihren Salzen |
BE666612A (zh) * | 1963-07-26 | 1965-11-03 | ||
NL130086C (zh) * | 1964-07-14 | 1970-06-15 | ||
AT387013B (de) * | 1985-07-16 | 1988-11-25 | Erba Farmitalia | Verfahren zur herstellung von poly-4-aminopyrrol -2-carboxamidoderivaten |
GB8612218D0 (en) * | 1986-05-20 | 1986-06-25 | Erba Farmitalia | Site specific alkylating agents |
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1985
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1986
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