CN1053911C - 闭大环内酯和闭氮杂内酯类新化合物以及它们的制备方法 - Google Patents
闭大环内酯和闭氮杂内酯类新化合物以及它们的制备方法 Download PDFInfo
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- CN1053911C CN1053911C CN95121122A CN95121122A CN1053911C CN 1053911 C CN1053911 C CN 1053911C CN 95121122 A CN95121122 A CN 95121122A CN 95121122 A CN95121122 A CN 95121122A CN 1053911 C CN1053911 C CN 1053911C
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Abstract
本发明涉及闭大环内酯和闭氮杂内酯类新化合物,涉及它们的制备方法以及制备这类闭衍生物的新中间体。
Description
本发明涉及闭大环内酯和闭氮杂内酯(Secoazalide)类新化合物,这类化合物是制备新大环内酯和氮杂内酯(azalide)抗菌素的潜在中间体,本发明还涉及这类化合物的制备方法。
红霉素A是一种有价值的大环内酯抗菌素,它的结构特征是,14元内酯环,C9位有一酮基(见于MeGuire,Antibiot,Chemother.,1952,2,281)。40多年来,红霉素A一直被看作是治疗格兰氏阳性细菌感染的安全而又有活性的抗菌素。使用红霉素A作为人用药品的主要缺点是,它对格兰氏阴性菌株作用的范围有限,它在许多病人的胃部不能耐受,以及在酸性介质中失活,生成无活性的代谢产物脱水红霉素。通过C9位酮基或C6和/或C12位羟基的化学转化,可以成功地抑制红霉素A的糖苷配基环的螺环化作用。例如C9位酮基用盐酸羟胺进行肟化,接着使得到的9(E)-红霉素A肟进行Beckmann重排,并将生成的双环6,9-亚氨基醚还原,得到9-脱氧-9a-氮杂-9a-高红霉素A,这是第一个15元大环氮杂内酯环的大环内酯(见于Kobrehel G.et al.,US Pat.4,328,334,5/1982)。按照Eschweiler-Clark方法进行9a-氨基的还原性甲基化反应,合成了氮杂内酯类新抗菌素9-脱氧-9a-甲基-9a-氮杂-9a-高红霉素A(阿齐霉素)(见于Kobrehel G.et al.,BEPat.892357,7/1982)。除包括格兰氏阴性细菌和胞内微生物在内的广抗菌谱外,阿齐霉素还具有往用药部位的专属的转运机制,半衰期长,以及治疗周期短等特征。
目前报道了红霉素A和B的C1内酯通过水解和醇解生成对应的闭酸或酯(见于Martin S.F.,J.Am,Chem,Soe.,1991,113,5478-5480)。还报道了在碱催化下大环开环,生成C1羧酸酯(见于Waddel S.T.and Blizzard T.A.,WO 94/15617,7/1994)。还报道了将9-脱氧-8a-氮杂-8a高红霉素A以及具有不同片段的9-脱氧-9a-氮杂-9a-高红霉素A的东部8a-氮杂(C-1/C8)与9a-氮杂-(C1/C9)片段结合,这样构成西部分子部分,从而生成新的大环内酯和氮杂内酯环。应当强调,若考虑C9碳原子上的额外亚乙基,那么上面提到的制得的C1/C9线性片段就不同于对应的阿齐霉素片段。
R1和R2相同,为H或CH3,
R3和R4不同,为H或CH3,
Y为O或NH,
Z为CH3或CH(CH3)CH(OH)COH(CH3)CH(OH)C2H5基,也未见它们与无机酸或有机酸加成的可以药用的盐的报道。取代基R3和R4表征了所述通式(I)的化合物的两种端基异构体形态,它们的结构差别仅在于C9碳的手性中心的构型。尽管C9碳的立体化学尚未确立,但对于其中R3为CH3的化合物来说,根据这些化合物的化学位移与原料C8(R)构型的6,9-亚氨基硅的化学位移类似,认为是(R)-构型。
X为O或NoR7,其中R7为H,酰基或芳磺酰基,
R3和R4不同,为H或CH3,
R5和R6相同或不同,为H或酰基,
Y为O或NH,
Z为CH3,CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9或CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5基,
R8为H或酰基,
R9为H,酰基或芳磺酰基,
R10和R11相同,为氢或酰基。
本发明还涉及它们和无机酸或有机酸生成的可以药用的加成盐。
一般可以说,在通式(I)和(II)的新化合物上,分子的包括两种糖的“东”部分在结构上与红霉素A6,9-亚氨基醚或9-脱氧-9α-氮杂-9α-同(型)红霉素A的大环内酯环的对应的C1/C9片段相同,而“西”部分代表具有末端未取代或取代的初级基原料亚氨基醚的C1甲酯基或未取代或取代C10/C15片段,或代表相同的片段反过来连接到C1原子上,生成迄今尚未报道的新的C1酰胺,而不是C1内酯。
通式(I)的新的9α-氮杂内酯片段,以及它们与无机酸或有机酸生成的可以药用的加成盐,其中R1和R2相同,为H或CH3,R3和R4不同,为H或CH3,Y为O或NH,Z为CH3或CH(CH3)CH(OH)COH(CH3)CH(OH)C2H5基,可使用通式(III)的红霉素A6,9-亚氨基醚为原料,按下法制备,
A)在亚氨基水解条件下与酸反应,适当的话,然后与酸酐或酰氯进行N-和/或O-酰化反应,适当的话,然后溶剂解,或
B)在适宜的无机碱或有机碱的存在下分一步或二步与盐酸羟胺反应,适当的话,然后
B1)在羟胺基水解的条件下与适宜的无机酸或有机酸反应,适当的话,然后按A)项下描述的方法进行N-和/或O-酰化反应及溶剂解反应,或者适宜的话,
B2)与酸酐和酰氯进行N-和/或O-酰化反应,适宜的话,然后进行溶剂解反应,或者适宜的话,
B3)在内胺酰化的条件下与适宜的有机碱或无机碱反应,适宜的话,然后与酸酐或酰氯进行N-和/或O-酰化反应,适宜的话,然后进行溶剂解反应,生成通式(II)的化合物和它们与无机酸或有机酸反应生成的可以药用的加成盐,其中X为O或NoR7,其中R7为H,酰基或芳磺酰基,R3和R4不同,为H或CH3,R5和R6相同或不同,为H或酰基,Y为O或NH,
Z为CH3,CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9或CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5基,
R8为H或酰基,
R9为H,酰基或芳磺酰基,
R10和R11相同,为氢或酰基。
适宜的话,进行催化还原,适宜的话,然后用适宜的烷基化试剂在适宜的还原剂存在下进行还原性N-烷基化反应,生成通式(I)的化合物,其中R1、R2、R3、R4,Y和Z的定义同上。通式(I)和(II)的新化合物的制备可用反应路线1和2描述。
按照方法A)通过酸的作用,最好是冰乙酸的作用,使通式(III)的红霉素A6,9-亚氨基醚发生亚氨基水解,室温反应3天,使C9/9α-N键断裂制得通式(II)的化合物,其中X和Y相同,为0,R3为CH3,R4为H,R5和R6相同,为H,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,其中R8和R9相同,为H(反应路线1,2α),该化合物或者通过无机酸或有机酸在羟胺基水解的条件下作用于按方法B)制得的通式(II)的化合物,其中X为NoR7,其中R7为H,R3为CH3,R4为H,R5和R6相同,为H,Y为0,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,其中R8和R9相同,为H,而制得0羟胺基的水解最好在甲醇/HCl的混合物中室温放置10天,完成反应0得到的具有新的5元内酯环的产物通过普通的梯度萃取方法(PH5.5,6.5和8.3)分离,接着蒸发合并的PH8.3的有机萃取液,适宜的话,然后用酸酐或酰氯进行N-和/或O-酰化反应。
采用普通的方法,以酸酐对获得的内酯进行酰化反应(见于Jones et al.,J,Med,Chem.,1971,5:631和Banaszek et al.,Rocy,Chem.,1969,43:7637,生成对应的四脂肪酰衍生物。例如在对反应是惰性的溶剂中,最好在吡啶中,室温下,用乙酸酐进行酰化反应,反应时间为7天,得到通式(II)的2′,4″,11-0,10-N四乙酰化物,其中X和Y相同,为0,R3为CH3,R4为H,R5和R6相同,为COCH3,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,其中R8和R9相同,为COCH3(化合物2b)。将2′,4″,11-0,10-N四乙酰化物在甲醇中室温放置3天,使2′-位的酯基溶剂解,生成通式(II)的4″,11-0,10-N-三乙酰化物,其中R5为H,X、Y、Z,R3,R4,R6,R8和R9与上面提到的四乙酰化合物的定义相同(化合物2c)。用酰氯进行的酰化反应,最好用4-溴苯甲酰氯在惰性溶剂中完成反应,最好用乙醚作溶剂,反应温度为0℃至50℃,反应3天,得通式(II)的10-N-溴代苯甲酰衍生物,其中X和Y相同,为0,R3为CH3,R4为H,R5和R6相同,为H,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9其中,R8为H,R9为4-溴苯甲酰基(化合物2d)。
通式(III)的红霉素A,6,9-亚氨基醚和盐酸羟胺的反应按方法B)完成,在无机碱或有机碱的存在下,在对反应是惰性的溶剂中进行反应,反应分一步或二步进行,反应温度为25℃至70℃。一步完成反应时,发生C9/9α-N键断裂,并形成C9原子上的羟亚氨基和C10原子上的氨基,生成通式(II)的化合物,其中X为NOR7,其中R7为H,Y为0,R3为CH3,R4为H,R5和R6相同,为H,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9基,其中R8和R9相同,为H,这是唯一的产物(反应路线1,3a)。反应时,盐酸羟胺过量1.1至30摩尔,最好过量5.2摩尔。对反应显示惰性的典型溶剂为C1-C4醇,最好是甲醇。无机碱可作为酸的受体使用,例如碱金属碳酸盐或酸式碳酸盐,最好是碳酸钠或碳酸钾,有机碱亦可用作酸的受体,它们同时又是对反应呈惰性的溶剂。用普通的萃取方法以有机溶剂萃取,即可完成分离,最好用氯代烃,例如在PH10用二氯甲烷进行萃取。如果反应分两步进行,即在第一步,通式(III)的红霉素A6,9-亚氨基醚在对反应呈惰性的溶剂中,最好在C1-C4醇中,最好在甲醇中,与至少过量1.3摩尔的上述无机碱或有机碱反应,反应混合物回流,直至亚氨基醚消失(TLC),得到的产物混合物然后萃取分离,最好用氯代烃例如在PH8用二氯甲烷萃取,第二步将粗产品与盐酸羟胺在上述无机碱或有机碱的存在下进行反应,该反应不明确。得到的产物混合物用有机溶剂进行梯度萃取,最好是用二氯甲烷在PH8和10进行萃取,合并PH10的有机萃取物,浓缩,得到两种产物的混合物,其中之一与化合物(3a)相同,另一种是它的通式(II)的C-8(S)对映体,其中X为NOR7,其中R7为H,Y为O,R3为H,R4为CH3,R5和R6相同,为H,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9基,其中R8和R9相同,为H(路线2,3b)。合并PH8的有机萃取液,蒸发,除化合物(3a)和(3b)外,还得到两种通式(II)的异构C8肟,其中X为NOR7,其中R7为H,Y为O,R3和R4不同,为H或CH3,R5和R6相同,为H,Z为CH3(路线2,7a和7b),它们是由于形成C1甲氧基化而同时断裂C9/9α-N键和大环C1内酯的结果。用硅胶柱层析分离得到的化合物(7a)和(7b),用6∶1∶0.1氯仿∶甲醇∶浓氨水系统洗脱,适宜的话,然后进行催化还原。
适宜的话,具有末端氨基的肟(3a)和(3b)按照方法A),用酸酐或酰氯进行N-和/或O-酰基化反应,适宜的话,然后进行溶剂解反应。例如化合物(3a)用乙酸酐进行酰化反应,得到通式(II)的2′,4″11-0,10-N-四乙酰基9(E)-丙酮肟,其中X为NOR7,其中R7为COCH3基,R3为CH3,R4为H,R5和R6相同,为COCH3,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9基,其中R8和R9相同,为COCH3(化合物3c),适宜的话,使进行溶剂解反应,最好进行甲醇解反应,生成通式(II)的化合物,其中X为NOR7,其中R7为H,R3为CH3,R4和R5相同,为H,R6为COCH3,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9基,其中R8和R9相同,为COCH3(化合物3d)。化合物(3a)和(3b)在对反应呈惰性的溶剂中,在无机碱或有机碱的存在下,与酰氯反应,反应温度为0℃至25℃,得到单取代或二取代的酰基衍生物,适宜的话,用硅胶柱层析分离,用85∶15的二氯甲烷∶甲醇溶剂系统洗脱。最好是化合物(3a)与对甲苯磺酰氯在NaHCO3的存在下,在丙酮中反应3小时,得到通式(II)的化合物,其中X为NOR7,其中R7为对甲苯磺酰基,R3为CH3,R4,R5和R6相同,为H,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9基,其中R8为H,R9为对甲苯磺酰基(化合物3e),或其中X为NOR7,其中R7为H,R3为CH3,R4,R5和R6相同,为H,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9基,其中R8为H,R9为对甲苯磺酰基(化合物3f)。
适宜的话,化合物(3a)和(3b)在内胺酰化的条件下与碱反应,适宜的话,然后催化还原。上述一级胺的内酰化反应,在室温下和在无机碱或有机碱的存在下完成,最好在氢氧化铵,氢氧化钠,氢氧化钾,或三乙胺的存在下进行反应,其间,发生C1酰氧基由氧往内部氨基迁移,发生C10/C15西部分子片段的转化和生成通式(II)的C1酰胺,其中X为NOR7,其中R7为H,R3和R4不同,为H或CH3,R5和R6相同,为H,Y为NH,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9基,其中R10和R11相同,为H(路线2,4a和4b),适宜的话,将它们用酸酐或酰氯进行N-和/或O-酰化反应,适宜的话,进行催化还原。
化合物(4a)和(4b)与酸酐按照方法A)进行N-和/或O-酰化反应,生成2′,4″-O-二酰基-1N-(2,4-O-二酰基)-9(E)丙酮肟。例如化合物(4a)与乙酸酐在吡啶中室温反应10天,进行乙酰化反应,得到通式(II)的化合物,其中X为NOR7,其中R7为COCH3基,R3为CH3,R4为H,R5和R6相同,为COCH3,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5基,其中R10和R11相同,为COCH3(化合物4c)。适宜的话,化合物4c进行溶剂解反应,最好进行甲醇解反应,其间发生2′-位或2′-和9-肟酯基的脱乙酰化反应,生成通式(III)的化合物,其中X为NOR7,其中R7为COCH3基,R3为CH3,R4为H,R5为H,R6为COCH3,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5基,其中R10和R11相同,为COCH3(化合物4d),或X为NOR7,其中R7为H,R3为CH3,R4为H,R5为H,R6为COCH3,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5基,其中,R10和R11相同为COCH3(化合物4e)。类似地,用酰氯进行反应,对甲苯磺酰基衍生物(3e)和(3f)亦可作为单取代的酰基衍生物获得。最好是化合物(4a)与对甲苯磺酰氯在丙酮中,在NaHCO3存在下,室温反应12小时,得到通式(II)的对甲苯磺酰衍生物,其中X为NOR7,其中R7为对甲苯磺酰基,R3为CH3,R4,R5和R6为H,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5基,其中R10和R11相同,为H(化合物4f)。
上述肟(4a,4b,7a和7b)的催化还原在对反应呈惰性的溶剂中在贵金属或贵金属的氧化物的存在下进行反应,反应在室温下进行,氢气压为5×105至7×105磅/英寸2,反应时间为10小时至3天。还原反应最好在冰乙酸中进行,用pto2作催化剂,反应10小时,氢气压为7×106磅/英寸2,然后用普通的梯度萃取方法(PH5.5,9.0和10.5)用氯代烃,最好用氯仿分离产物,合并PH10.5的有机萃取液,蒸发,得产物。适宜的话,将得到的通式(I)的胺,其中R1和R2相同,为H,R3为CH3,R4为H,或R3为H,R4为CH3,Y为O或NH,Z为CH3或CH(CH3)CH(OR10)COH(CH3)CH(OH)C2H5基,(路线2,5a,5b,8a和8b),进行还原性烷基化。最好用1至4当量甲醛(37%),在相等当量或2倍当量甲酸(98-100%)存在下,在对反应呈惰性的溶剂中,例如在卤代烃中,最好在氯仿中,在反应混合物的回流温度下进行还原性的N-甲基化反应,反应时间为2至20小时,反应条件取决干使用的醛或酸。得到的产物用普通的梯度萃取方法(PH5.0和9.5)分离,接着蒸发合并的PH9.5的有机萃取液,适宜的话,用硅胶柱层析纯化,用6∶1∶0.1氯仿∶甲醇∶浓氨水系统洗脱,得到通式(I)的二甲胺衍生物,其中R1和R2相同,为CH3,R3为CH3,R4为H,或R3为H,R4为CH3,Y为O或NH,Z为CH3或CH(CH3)CH(OH)COH(CH3)CH(OH)C2H5基,(路线2,6a,6b,9a和9b)。
通过通式(I)或(II)的闭衍生物与至少等摩尔量的适宜的无机酸或有机酸反应,例如与氯氢酸,碘氢酸,硫酸,磷酸,乙酸,丙酸,三氟乙酸,顺丁烯二酸,柠檬酸,硬脂酸,丁二酸,丁二酸单乙脂,甲磺酸,苯甲磺酸,对甲苯磺酸,月桂磺酸等,在对反应呈惰性的溶剂中反应制备。如果这些盐在对反应呈惰性的溶剂中不溶,可以滤出加合盐,或通过加非溶剂使加合盐沉淀,或蒸发溶剂得到加合盐,绝大多数场合是采用冷冻干燥。
按照前面说的步骤完成反应时,红霉素A6,9-亚氨基醚的15元氮杂内酯环发生开环,生成不同的具有非常活泼的内部功能基的闭衍生物,这就使得有可能用修饰的大环糖苷化合物制备整系列的新大环内酯或azalides。在具有分子的“西”部分(4,5和6)转换的化合物上,2,3,4-三羟基-1,3-二甲基己基代表红霉素A,6,9亚氨基醚的C10/C15片段,为了简便起见,在片段转移之前就已经存在的碳原子的位置指定一直保留到描述光谱数据的这些指定,表示在反应路线1和2中。
下面的实施例仅用来阐明本发明的方法,并不限制本发明的范围。
实施例1
9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-10-氨基-9,10-闭红霉素A9(E)-肟(3a)
方法A
往红霉素A6。9-亚氨基醚(1)(3.60g,0.049mole)与无水甲醇(750ml)的溶液中加NH2OH.HCl(18g,0.259mole)和Na2CO3(6.8g,0.0642mole),然后反应混合物回流搅拌3小时。反应悬浮液减压浓缩,往得到的固体残留物中加240ml水和240mlCH2Cl2(PH6.8)。加20%(W/V)NaOH水溶液调PH至10,分离的水层部分用CH2Cl2萃取。合并的有层萃取液用K2CO3干燥,蒸发至干,得到的产物高真空干燥(6小时,40℃),得到34.3g(91%)TLC单一的化合物(3a)。IR(CHCl3)cm-1:3425,2970,1720,1690,1580,1455,1380,1300,1260,1165,1050.1H NMR(300MHz,CDCl3)δ:4.98(H-1”),4.78(H-13),4.45(H-1’),4.60(H-3),3.90(H-5),3.49(H-11),3.28(3”-OCH3),3.05(H-10),2.92(H-8),2.84(H-2),2.28/3’N(CH3)2/,2.08(H-7a),1.88(H-7b),1.87(H-14a),1.82(H-4),1.51(H-14b),0.87(H-15).13C NMR(75MHz,CDCl3)δ:175.5(C-1),161.1(C-9),103.1(C-1’),95.0(C-1”),88.5(C-6),81.9(C-5),78.1(C-13),76.7(C-3),73.5(C-12),72.5(C-11),48.7(3”-OCH3),46.7(C-10),43.4(C-2),39.8/3’N(CH3)2/,39.7(C-4),31.9(C-8),21.3(C-14),10.6(C-15).FAB(MH+)764.4.
方法B。
往红霉素A6,9-亚氨醚(1)(36.0g,0.049mole)与吡啶(100ml)的溶液中加NH2OH.HCl(18g,0.259mole),反应混合物室温搅拌3小时。往反应溶液中加水(400ml)和CH2Cl2(140ml),在PH7.0和10.0下梯度萃取分离产物。将PH10.0的有机萃取液合并,蒸发,得到25.0g(66.4%)产物(3a),理化常数与方法A的产物相同。
实施例2
2′,4″,11-0,10-N-四乙酰基-9-脱氧-6-脱氧-6.9-环氧-8(R)-甲基-10-氨基-9,10-闭红霉素A9(E)-丙酮肟(3c)。
往化合物(3a)(1.0g,0.0013mole)与吡啶(40ml)的溶液中,加乙酸酐(4ml),反应溶液然后于室温放置7天。TLC指示乙酰化完成后,反应混合物倾入水和冰的混合物(200ml)中,并于PH9下用CHCl3萃取。合并有机萃取液,减压浓缩,得1.3g粗产品,该粗产品经乙醚-石油醚混合溶剂再沉淀,得1.13g TLC单一的产物(3c)。1H NMR(300MHz,CDCl3)δ:6.15(CONH),4.97(H-13),4.81(H-2’),4.78(H-1”),4.69(H-4”),4.67(H-11),4.48(H-10),4.59(H-1’),4.11(H-3),3.79(H-5),3.30(H-3”-OCH3),3.14(H-8),2.75(H-2),2.27/3’N(CH3)2/,2.16,2.13,2.12,2.05 and 1.96(COCH3),1.90(H-4),1.52(H-14),0.90(H-15).
实施例3
4″,11-0,10-N-三乙酰基-9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-10-氨基-9,10-闭红霉素A9(E)-肟(3d)。
五乙酰化物(3c)(0.5g,0.0005mole)与甲醇(20ml)的溶液室温放置3天。反应混合物减压浓缩,得到的粗产品用硅胶柱色谱纯化,用90∶9∶1.5的氯仿∶甲醇∶浓氨水系统洗脱,得到0.250g4″,11-0,10-N-三乙酰化物(3d),理化常数如下:1H NMR(300MHz,CDCl3)δ:6.31(CONH),4.95(H-13),4.85(H-1”),4.67(H-4”),4.65(H-11),4.49(H-10),4.49(H-1’),4.21(H-3),3.79(H-5),3.29(H-3”-OCH3),3.28(H-2’),3.02(H-8),2.78(H-2),2.30/3’N(CH3)2/, 2.17,2.13,and 1.96(COCH3),2.07(H-7a),2.02(H-4),1.85(H-14a),1.49(H-14b),0.88(H-15).13C NMR(75MHz,CDCl3)δ:175.0(C-1),172.0,170.7 and 169.3(COCH3,1621(C-9),103.5(C-1’),95.5(C-1”),89.6(C-6),81.2(C-5),78.3(C-11),78.1(C-3),76.8(C-13),74.9(C-12),49.3(3”-OCH3),45.0(C-10),42.5(C-2),40.1/3’N(CH3)2/,39.5(C-7),38.4(C-4),32.7(C-8),23.1,20.6 and 20.6(COCH3),21.9(C-14),10.7(C-
实施例4
9-0,10-N-二对甲苯磺酰基-9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-10-氨基-9,10-闭红霉素A9(E)-肟(3e)
10-N-对甲苯磺酰基-9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-10-氨基-9.10-闭红霉素A9(E)二肟(3f)
将实施例1制得的化合物(3a)(2.0g,0.0026mole)悬浮到70ml丙酮中,冷至0-5℃。往反应混合物中同时滴对甲苯磺酰氯(1.34g,0.007mole)与丙酮(30ml)的溶液如NaHCO3(0.6g’0.007mole)与水(95ml)的溶液,滴加时间为30分钟,同时搅拌。反应悬浮液室温搅拌3小时,减压蒸去丙酮,水性残留物用氯仿于PH5.0萃取。K2CO3干燥后蒸去氯仿,得到2.58g(3e)和(3f)的混合产物。粗产品(1.8g)用硅胶柱色谱纯化,用85∶15氯仿∶甲醇洗脱,得到TLC纯(氯仿∶甲醇,7∶3展开)的化合物(3e),Rf值为0.63,得到1.1g化合物3f,Rf值为0.43。
化合物(3e):IR(CHCl3)cm-1:3460,2975,2940,1730,1660,1600,1455,1370,1190,1180,1160,1090,1050,1000,975,855,815,665.1H NMR(300MHz,CDCl3)δ:7.80(p-Ph),7.30(p-Ph),4.81(H-13),4.78(H-1”),4.48(H-1’),4.26(H-3),3.96(H-5”),3.76(H-5),3,68(H-5’),3.60(H-11),3.50(H-10),3.41(H-2’),3.23(3”-OCH3),3.09(H-8),3.03(H-4”),2.94(H-2),2.54/3’N(CH3)2/,2.43(p-Ph-CH3),2.41(p-Ph-CH3),2.24(H-7a),2.09(H-7b),1.91(H-4),1.83(H-4’a),1.68(H-14a),1.52(H-2”b),1.41(H-14b),1.49(6-CH3),0.89(H-15).化合物(3f):1H NMR(300MHz,CDCl3)δ7.43(p-Ph),7.14(SO2NH),4.91(H-13),4.78(H-1”)4.60(H-1’),4.36(H-3),4.00(H-5”),3.82(H-5),3.73(H-10),3.68(H-5’),3.64(H-11)3.41(H-2’),3.28(3”-OCH3),3.08(H-8),3.00(H-4”),2.79(H-2),2.39(p-Ph-CH3)2.24(H-2’a),1.73(H-14a),1.52(6-CH3),0.85(H-15).实施例5
6-脱氧-6,9-环氧-8(R)-甲基-10-氨基-9.10-闭红霉素A(2a)。
方法A
将红霉素A6,9-亚氨基醚(1)(10.0g,0.014mole)与冰乙酸(60ml)的溶液室温放置3天。反应溶液减压蒸发除去溶剂,然后往油状残留物中加水(100ml),反应混合物用氯仿于PH5.5,6.5和8.3下萃取。合并PH8.3的有机层,用K2CO3干燥,减压浓缩至干,得到的产物高真空干燥(6小时,40℃),得到8.2g(800%)TLC单一产物(2a)。IR(CHCl3)cm-1:1740(C-1,lactone)and 1710(C-9,lactone).1H NMR(300MHz,CDCl3)δ:4.77(H-1”),5.00(H-13),4.39(H-1’),4.18(H-3),3.74(H-5),3.35(H-11),3.29(H-3”-OCH3),3.16(H-10),2.76(H-8),2.72(H-2),2.29/3’N(CH3)2/,2.22(H-7a),2.10(H-7b),2.00(H-4),1.85(H-14a),1.55(H-14b),0.88(H-15).13C NMR(75MHz,CDCl3)δ:179.6(C-1),176.1(C-9),103.9(C-1’),95.7(C-1”),86.1(C-6),81.2(C-5),78.8(C-13),77.9(C-3),75.7(C-11),74.5(C-12),49.5(3”-OCH3),47.9(C-10),43.2(C-2),40.4/3’N(CH3)2/,39.7(C-4),38.0(C-7),34.1(C-8),22.2(C-14,11.6(C-15).EI-MS(M+)748.
方法B:
化合物(3a)(2.0g,0.0026mole)与甲醇(30ml)的溶液用1NHCl酸化至PH3.0,并室温放置10天。反应混合物用10%NaOH水溶液调PH至7.0,减压浓缩除去甲醇,往水性残留物中加CHCl3,于PH5.5,6.5和8.3下萃取。合并PH8.3的有机萃取物,K2CO3干燥,蒸发至干,得到产物(2a),理化常数与方法A的产物相同。
实施例6
2′4″,11-0,10-N-四乙酰基-6-脱氧-6,9-环氧-8(R)-甲基-10-氨基-9,10-闭红霉素A(2b)
往化合物(2a)(3.4g,0.0045mole)与吡啶(45ml)的溶液中加乙酸酐(12ml),然后室温放置7天。TCL显示乙酸化反应完成后,反应混合物倾入冰(200ml)中,并于PH9.0用CHCl3萃取。合并有机萃取液,用饱和NaHCO3水溶液和水洗,K2CO3干燥,减压浓缩。得到的粗产品高真空干燥(6小时,40℃),得4.10g(98.0%)色谱单一的产物(2b)。IR(CHCl3)cm-1:1740(C-1,lactone),1720(C-6,lactone),1720 and 1240(C=O,ester),1655(C=O,amide).1H NMR(300MHz,CDCl3)δ:6.35(CONH),4.99(H-13),4.79(H-1”),4.79(H-2’),4.68(H-11),4.62(H-1’),4.44(H-10),4.14(H-3),3.76(H-5),3.32(H-3”-OCH3),2.74(H-8),2.65(H-2),2.28/3’N(CH3)2/,2.10,2.06,2.03 and 1.92(COCH3),2.08(H-7a),1.96(H-7b),1.90(H-4),1.81(H-14a),1.60(H-14b),0.86(H-15).13C NMR(75MHz,CDCl3)δ:179.3(C-1),174.7(C-9),171.9 170.5,169.9 and 169.2(COCH3).EI-MS(M+)916.
实施例7
4″,11-0,10-N-三乙酰基-6-脱氧-6,9-环氧-8(R)-甲基-10-氨基-9,10-闭红霉素A(2c)
化合物(2b)(1.5g,0.0016mole)与甲醇(40ml)的溶液室温放置3天。反应混合物减压浓缩,得到的油状残留物溶入CH2Cl2(50ml),然后加100ml水(PH6.6),用10%W/VNaOH调反应混合物的PH至9.0。分离到的水层部分再用CH2Cl2萃取2次。合并有机萃取液,K2CO3干燥,减压蒸去溶剂,得1.35g粗产品,该粗产品用硅胶柱层析纯化,用6∶1∶0.1氯仿∶甲醇∶浓氨水系统洗脱,得到TLC单一的三乙酰化物(2c),理化常数如下:1H NMR(300MHz,CDCl3)δ:6.39(CONH),4.99(H-13),4.79(H-1”),4.68(H-4”),4.66(H-11),4.48(H-1’),4.46(H-10),4.21(H-3),3.76(H-5),3.30(3”-OCH3),3.23(H-2’),2.75(H-8),2.70(H-2),2.29/3’N(CH3)2/, 2.26(H-7a),2.16,2.12 and 1.96(COCH3),2.02(H-7b),1.94(H-4),1.83(H-14a),1.56(H-14b),0.86(H-15).13C NMR(75MHz,CDCl3)δ:179.2(C-1),174.7(C-9),171.7,170.3 and 169.0(COCH3),102.9(C-1’),94.9(C-1”),85.6(C-6),80.5(C-5),78.3(C-3),78.2(C-11),76.7(C-13),74.7(C-12),49.2(3”-OCH3),45.1(C-10),42.4(C-2),40.0/3’N(CH3)2/,39.3(C-4),37.3(C-7),33.9(C-8),21.9(C-14),21.1,20.9 and 20.6(COCH3),10.7(C-15).
实施例8
10-N-(4-溴苯甲酸基)-6-脱氧-6,9-环氧-8(R)-甲基-10-氨基-9,10-闭红霉素A(2d)
往化合物(2a)(10.0g 0.013mole)乙醚(60ml)的溶液中,滴加NaHCO3(8.0g,0.095mole)和4-溴苯甲酰氯(4.0g,0.018mole)与乙醚(20ml)的溶液,滴加时间为1小时,滴加温度为0至5℃,同时搅拌。反应混合物在相同温度下再搅拌2小时,减压蒸去溶剂,往得到的固体残留物中加CHCl3(70ml)和水(50ml),然后在PH8.5萃取。反应混合物减压浓缩,得到的固体残留物(5.0g)用硅胶柱层析纯化,用90∶9∶1.5氯仿∶甲醇∶浓氨水系统洗脱,得到TLC单一的4-溴苯甲酸酯(2d),理化常数如下:IR(CHCl3)cm-1:1740(C-1,lactone),1710(C-9,lactone),1640 and 1500(C-10,-ainide),1580(Ph).1H NMR(300MHz,CDCl3)δ:7.60(Ph),7.05(CONH),4.91(H-13),4.70(H-1”),4.35(H-1’),4.37(H-10),4.21(H-3),3.70(H-5),3.67(H-11),3.27(3”-OCH3),3.15(H-2’),2.91(H-4”),2.73(H-8),2.71(H-2),2.26/3’N(CH3)2/,2.21,(H-7a),2.10(H-7b),1.94(H-4),1.86(H-14a),1.57(H-14b),0.89(H-15).13C NMR(75MHz,CDCl3)δ:179.6(C-1),176.7(C-9),165.4(CONH),133.8,131.6,128.9 and 125.8(Ph),104.0(C-1’),95.0C-1”),86.4(C-6),81.7(C-5),79.9(C-3),75.6(C-13),73.4(C-11),74.6(C-12), 49.4(3”-OCH3),47.3(C-10),43.2(C-2),40.0/3’N(CH3)2/,40.0(C-4),37.8(C-7),34.2(C-8),22.5(C-14),11.2(C-15).EI-MS(M+)931.实施例9
1-N-(2,3,4-三羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-9,10-闭红霉素A9(E)-肟(4a)
实施例1制得的化合物(3a)(31g,0.041mole)溶入CH2cl2-CH3OH(1∶1,80ml),加浓氨水(350ml),反应混合物室温搅拌6小时,溶液放置过夜,减压浓缩,得到的固体残留物悬浮到CH2cl2中,过滤,滤液蒸发至干,得29.5g(95%)TLC单一的产物(4a)(氯仿∶甲醇∶浓氨水,6∶1∶0.1展开)。IR(CHCl3)cm-1:3420,2980,1690,1650,1530,1455,1380,1260,1175,1050.1H NMR(300MHz,CDCl3)δ:7.53(CONH),4.93(H-1”),4.45(H-1’),4.20(H-3),4.11(H-10),3.79(H-11),3.66(H-5),3.39(3”-OCH3),3.22(H-13),3.04(H-8),2.53(H-2),2.29/3’N(CH3)2/,2.10(H-7a),1.97(H-4),1.79(H-7b),1.59(H-14a),1.33(H-14b),1.04(H-15).13C NMR(75MHz,CDCl3)δ:174.4(C-1),162.0(C-9),105.6(C-1’),96.2(C-1”),90.3(C-6),86.3(C-5),83.0(C-13),79.8(C-3),75.1(C-11),74.9(C-12)49.3(3”-OCH3),48.6(C-10),42.8(C-2),41.0(C-7),39.8/3’N(CH3)2/,38.6(C-4),32.9(C-8),24.8(C-14),11.5(C-15).FAB(MH+)764.4.
实施例10
1-N-(2,3,4-三羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-9,10-闭红霉素A9(E)-肟(4a)
1-N-(2,3,4-三羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-6-脱氧-6,9-环氧-8(S)-甲基-9,10-闭红霉素A9(E)-肟(4b)
红霉素A6,9-亚氨基醚(1)(30g,0.041mol)溶解到甲醇(600ml)中,往里加Na2CO3(5.6g,0.053mole),反应混合物回流搅拌使生成原料亚氨基醚(8小时)。反应悬浮液减压浓缩,往里加CH2Cl2(130ml)和水(130ml)(PH11.1),然后在PH8萃取。合并有机萃取液,K2CO3干燥,浓缩,得28g固体残留物。沉淀溶解到甲醇(600ml)中,往里加NH2OH·HCl(14g)和Na2CO3(5.1g),然后回流搅拌3小时。反应混合物蒸发至干,加CH2Cl2(150ml)和水(300ml)(PH6.6),然后在PH8和10梯度萃取。合并PH10的有机萃取液,K2CO3干燥,浓缩,得15.6g沉淀。沉淀溶入CH3OH-CH2Cl2(1∶1,40ml)和浓氨水(170ml)中,室温搅拌12小时。反应混合物浓缩至干,得到的混合产物用硅胶柱层析纯化,用6;1∶0.1氯仿∶甲醇∶浓氨水系统洗脱,从2.2g粗产品得1.08g色谱单一的产物(4a)(Rf0.38),理化常数与实施例9的产物相同,得0.80g化合物(4b)(Rf0.26),理化常数如下:
化合物(4b)IR(CHCl3)cm-1:3340,2975,1685,1650,1530,1450,1380,1280,1240,1160,1040.1H NMR(300MHz,CDCl3)δ:7.30(CONH),4.88(H-1”),4.35(H-1’),4.23(H-3),4.15(H-10),3.82(H-11),3.60(H-5),3.29(3”-OCH3),3.26(H-13),3.14(H-8),2.78(H-7a),2.52(H-2),2.29/3’N(CH3)2/,2.06(H-4),1.61(H-14a),1.51(H-7b),1.37(H-14b),1.04(H-15).13C NMR(75MHz,CDCl3)δ:173.9(C-1),162.7(C-9),104.6(C-1’),95.4(C-1”).90.7(C-6),84.3(C-5),81.6(C-13),78.5(C-3),74.5(C-11),74.4(C-12)48.8(3”-OCH3).47.4(C-10),42.7(C-2),42.0(C-7),39.4/3’N(CH3)2/,38.7(C-4),33.8(C-8),24.1(C-14),11.0(C-15).FAB(MH+)764.5.
实施例11
2′4″-O-二乙酰基-1-N-(2,4-O-二乙酰基-3-羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-9,10-闭红霉素A9(E)-丙酮肟(4c)
往实施例9制得的化合物(4a)(1.0g,0.0013mole)与吡啶(40ml)的溶液中,加入乙酸酐(4ml),然后室温放置10天。反应溶液倾到冰水混合物(200ml,PH4.8)中,用20%NaOH水溶液碱化后,于PH9.0用氯仿萃取。合并有机层,用K2CO3干燥,减压浓缩,得1.25g(98%)五乙酰化物(4c),理化常数如下:1H NMR(300MHz,CDCl3)δ:6.61(CONH),4.94(H-13),4.82(H-1”),4.80(H-2’),4.69(H-4”),4.58(H-1’),4.58(H-10),4.55(H-11),4.04(H-3),3.79(H-5),3.32(3”-OCH3),3.13(H-8),2.59(H-2),2.27/3’N(CH3)2/,2.15,2.12,2.12,2.06,and 2.01(COCH3),2.07(H-7a),2.03(H-4),2.03(H-7b),1.82(H-14a),1.55(H-14b),0.90(H-15).13C NMR(75MHz,CDCl3)δ:173.4(C-1),171.8,170.6,170.2,169.8,and 168.8(COCH3),167.2(C-9),100.6(C-1’),95.5(C-11”),91.7(C-6),79.8(C-3),79.6(C-5),78.6(C-11),75.7(C-13),74.7(C-12)49.3(3”-OCH3),45.1(C-10),42.6(C-2),40.2/3’N(CH3)2/,38.8(C-7),36.7(C-4),33.5(C-8),21.6(C-14),20.9,20.5,20.5,20.4 and19.4(COCH3),10.5(C-15).
实施例12
4″-O-乙酰基-1-N-(2,4-O-二乙酰基-3-羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-9,10-闭红霉素A9(E)丙酮肟(4d)
4″-O-乙酰基-1-N-(2,4-O-二乙酰基-3-羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-9,10-闭红霉素A9(E)-肟(4e)
实施例11
制备的化合物(4c)(0.5g,0.0005mole)与甲醇(20ml)的溶液室温搅拌3天。减压蒸发除去溶剂,得到的混合物用硅胶柱层析纯化,用6∶1∶0.1氯仿∶甲醇∶浓氨水系统洗脱。收集到的色谱单一馏份浓缩,分别得到0.213g四乙酰化物(4d,Rf0.47)和0.151g三乙酰化物(4e,Rf0.34),理化常数如下:
化合物(4d):1H NMR(300MHz,CDCl3)δ:7.38(CONH),4.94(H-13),4.83(H-1”),4.66(H-4”),4.62(H-11),4.55(H-10),4.44(H-1’),4.10(H-3),3.80(H-5),3.32(3”-OCH3),3.35(H-2’),3.18(H-8),2.76H-2),2.30/3’N(CH3)2/,2.07(H-7a),2.13,2.10,2.09 and 2.03(COCH3),1.90(H-7b),1.96(H-4),1.84(H-14a),1.53(H-14b),0.90(H-15).13C NMR(75MHz,CDCl3)δ:174.4(C-1),171.1,170.7,170.4 and 168.4(COCH3),167.2(C-9),105.2(C-1’),96.9(C-1”),92.9(C-6),84.5(C-5),81.3(C-3),78.5(C-11),75.9(C-13)75.0(C-12),49.4(3”-OCH3),44.6(C-10),41.1(C-2),40.1/3’N(CH3)2/,40.8(C-7),38.0(C-4),33.8(C-8),21.7(C-14),20.7,20.5,20.4 and 19.2(COCH3),10.5(C-15).化合物(4e):1H NMR(300MHz,CDCl3)δ:7.24(CONH),4.88(H-13),4.81(H-1”),4.68(H-4”),4.62(H-11),4.50(H-10),4.45(H-1’),4.07(H-3),3.75(H-5),3.34(3”-OCH3),3.26(H-2’),2.98(H-8),2.56(H-2),2.30/3’N(CH3)2/,2.09(H-7a),2.14,2.09 and 2.03(COCH3),1.92(H-7b),1.89(H-4),1.83(H-14a),1.51(H-14b),0.89(H-15).13C NMR(75MHz,CDCl3)δ:174.6(C-1),171.1,170.8,170.8(COCH3),162.5(C-9),104.2(C-1’),96.4(C-1”),90.4(C-6),83.9(C-5),79.6(C-3),78.7(C-11),76.1(C-13)75.1(C-12),49.5(3”-OCH3),44.7(C-10),43.7(C-2),40.1/3’N(CH3)2/40.4(C-7),39.3(C-4),32.5(C-8),21.8(C-14),20.7,20.7 and 20.6(COCH3),10.7(C-15).
实施例13
1-N-(2,3,4-三羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-9,10-闭红霉素A9(E)对甲苯磺酰肟(4f)
实施例9制得的化合物(4a)(0.5g,0.0007mole)悬浮到丙酮(10ml)中,冷至0-5℃。搅拌下往里同时滴加对甲苯磺酰氯(0.486g,0.0026mole)与丙酮(10ml)的溶液及NaHCO3(0.425g,0.0051mole)与水(25ml)的溶液,滴加时间为30分钟。反应溶液再于室温搅拌12小时,然后减压萎去丙酮,往水性残留物中加CHCl3(30ml),然后在PH5.0和8.0梯度萃取。合并PH5.0的有机萃取液,蒸发得到0.320g粗产品(4f)。硅胶柱层析纯化,6∶1∶0.1氯仿∶甲醇∶浓氨水系统洗脱,得0.26CgTLC单一产物(4f)。1H NMR(300MHz,CDCl3)δ:7.80(CONH),7.62(Ph),3.21(H-13),4.96(H-1”),4.41(H-1’),4.17(H-3),4.11(H-10),3.79(H-11),3.58(H-5),3.39(H-2’),3.25(3”OCH3),3.10(H-8),2.94(H-4”),2.55(H-2),2.29/3’N(CH3)2/,2.08(H-7a),1.86(H-4),1.64(H-7b),1.56(H-14a),1.43(H-14b),1.05(H-15).
实施例14
1-N-(2,3,4-三羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-9-二氢-9α-氨基-8(R)-甲基-9α-闭红霉素A(5a)
实施例9制得的粗产品(4a)(6.0g 0.008mole)溶解到冰乙酸(60ml)中,加入PtO2(2.0g,83%Pt),然后在7×106磅1/英寸2的氢气压下氢化并搅拌10小时。反应悬浮液过滤,滤液减压浓缩,往里加水(100ml)和氯仿(60ml),然后在PH5.5,9.0和10.5梯度萃取。合并PH10.5的有机萃取液,减压蒸发,得4.3g(73%)TLC单一的产物(5a),理化常数如下:IR(CHCl3)cm-1:3400,2975,1650,1535,1450,1375,1165,1040.1H NMR(300MHz,CDCl3)δ:7.52(CONH),4.94(H-1”),4.37(H-1’),4.26(H-3),4.17(H-10),3.76(H-11),3.41(H-5),3.28(3”-OCH3),3.17(H-13),2.62(H-9a),2.52(H-2),2.27/3’N(CH3)2/,2.20(H-7a),2.01(H-4),1.85(H-8),1.55(H-14a),1.34(H-7b),1.34(H-14b),1.05(H-15).13C NMR(75MHz,CDCl3)δ:174.1(C-1),106.7(C-1’),96.0(C-1”),92.3(C-5),83.8(C-13),79.7(C-3),75.1(C-12),74.8(C-11)74.6(C-6),49.3(3”-OCH3),49.2(C-10),49.1(C-9),42.8(C-7),41.6(C-2),/3’N(CH3)2/,37.5(C-4),31.0(C-8),25.0(C-14),11.5(C-15).FAB(NH+)752.3.
实施例15
1-N-(2,3,4-三羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-9-二氢-9-a-氨基-8(S)-甲基-9a-高红霉素A(5b)
化合物(4b)(0.71g,0.009mole)溶入冰乙酸(30ml)中,往里加PtO2(3.50g,83%Pt),然后在7×106磅/英寸2的氢气压下搅拌并氢化10小时。反应混合物过滤,滤液减压浓缩成稠油状物,该油状物然后象实施例14那样在pH5.5,9.6和10.5梯度萃取,合并pH10.5的有机萃取液,减压浓缩,得0.260g(38.0%)TLC单一的产物(5b)。1H NMR(300MHz,CDCl3)δ:7.63(CONH),4.93(H-1”),4.40(H-1’),4.23(H-3),4.19(H-10),3.75(H-11),3.53(H-5),3.29(3”-OCH3),3.18(H-13),2.72(H-9a),2.57(H-9b),2.52(H-2),2.27/3’N(CH3)2/,1.93(H-4),1.78(H-8).1.57(H-14a),1.47(H-7a),1.36(H-14b),1.23(H-7b),1.04(H-15).13C NMR(75MHz,CDCl3)δ:174.3(C-1),107.2(C-1’),97.0(C-1”),92.3(C-5),83.8(C-13),80.7(C-3),75.7(C-12),75.2(C-11),75.2(C-6),49.6(3”-OCH3),49.2(C-9),49.2(C-10),43.7(C-7),42.1(C-2),39.8/3’N(CH3)2/,37.8(C-4),31.3(C-8),25.0(C-14),11.7(C-15).实施例161-N-(2,3,4-三羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-9-二氢-9a-二甲氨基-8(R)-甲基-9a-高红霉素A(6a)
往实施例14制备的化合物(5a)(1g,0.0013mole)和氯仿(80ml)的溶液中,加甲酸(0.2ml,0.005mole)和36%甲醛(0.232ml,0.003mole)。用2%W/V NaOH水溶液将反应混合物的PH调至5.0,然后回流搅拌9小时,接着加水(100ml),并在pH5.0和9.5用氯仿梯度萃取,进行分离,合并pH9.5的有机萃取液,减压浓缩。得到的产物用硅胶柱层析纯化,用6∶1∶0.1氯仿∶甲醇∶浓氨水系统洗脱,得0.63gTLC单一的产物(6a)。IR(CHCl3)cm-1:3400,2970,1650,1530,1450,1375,1165,1040.1H NMR(300MHz,CDCl3)δ:7.26(CONH),4.91(H-1”),4.37(H-1’),4.27(H-3),4.18(H-10),3.77(H-11),3.41(H-5),3.29(3”-OCH3),3.18(H-13),2.57(H-2),2.52(H-9a),2.30/3’N(CH3)2/,2.27/9-N(CH3)2/,2.20(H-9b),2.16(H-4),2.01(H-8),1.56(H-14a),1.50(H-7a),1.37(H-14b),1.15(H-7b),1.04(H-15).13C NMR(75MHz,CDCl3)δ:174.7(C-1),106.1(C-1’),95.4(C-1”),90.5(C-5),83.3(C-13),79.8(C-3),74.8(C-12),74.6(C-11),73.7(C-6),68.2(C-9),49.2(3”-OCH3),48.6(C-10),45.3/9-N(CH3)2/,44.2(C-7),41.7(C-2),39.6/3’N(CH3)2/,37.3(C-4),26.4(C-8),24.9(C-14),11.5(C-15).FAB(MH+)780.6.
实施例17
1-N-(2,3,4-三羟基-1,3-二甲基己基)-酰胺基-10,11,12,13,14,15-六去甲基-9-脱氧-9-二氢-9a-二甲氨基-8(S)-甲基-9a-高红霉素A(6b)
往实施例15制得的化合物(5b)(0.3g,0.0004mole)与氯仿(50ml)的溶液中加甲酸(0.12ml,0.0032mole,98-100%)和36%甲醛(0.13ml,0.0016mole)。同2%W/V NaOH水溶液将反应混合物的PH调至5.0,然后回流搅拌4小时。粗产物按实施例16的方法处理以便分离产物,硅胶柱层析纯化,6∶1∶0.1氯仿∶甲醇∶浓氨水系统洗脱后,得0.150gTLC单一的产物(6b)。1H NMR(300MHz,CDCl3)δ:7.58(CONH),4.95(H-1”),4.41(H-1’),4.25(H-3),4.18(H-10),3.76(H-11),3.43(H-5),3.28(3”-OCH3),3.17(H-13),2.51(H-2),2.27/3’N(CH3)2/,2.23/9a-N(CH3)2/,2.06(H-9b),2.19(H-4),1.97(H-8),1.57(H-14a),1.47(H-7a),1.37(H-14b),1.16(H-7b),1.05(H-15).13C NMR(75MHz,CDCl3)δ:173.5(C-1),106.0(C-1’),95.3(C-1”),91.9(C-5),83.2(C-13),79.0(C-3),74.4(C-12),74,1(C-11),74.2(C-6),67.5(C-9),48.6(3”-OCH3),48.4(C-10),44.9/9-N(CH3)2/,43.1(C-7),40.8(C-2),38.9/3’N(CH3)2/,36.7(C-4),25.8(C-8),23.9(C-14),10.4(C-15).
实施例18
9-脱氧-6-脱氧-6,9-环氧-8(R)-甲基-10,11,12,13,14,15-六去甲基-红霉素A9(E)肟(7a)
9-脱氧-6-脱氧-6,9-环氧-8(S)-甲基-10,11,12,13,14,15-六去甲基-红霉素A9(E)肟(7b)
实施例10得到的PH8.0的氯仿萃取液合并后用K2CO3干燥,减压浓缩,得到8.0g(7a)和(7b)的混合物。同硅胶柱层析分离,用6∶1∶0.1氯仿∶甲醇∶浓氨水系统洗脱,从2g粗产品得到0.530g化合物(7a)(Rf0.44)和0.880g化合物(7b)(Rf0.30),它们用光谱方法确定为C-8的主体异构体。
化合物(7a):IR(CHCl3)cm-1:3360,2980,2940,1730,1690,1650,1455,1380,1245,1165,1040.1H NMR(300MHz,CDCl3)δ:4.72(H-1”),4.44(H-1’),4.11(H-3),3.84(H-5),3.67(1-OCH3),3.29(3”-OCH3),3.26(H-2’),3.03(H-8),3.01(H-4”),2.84(H-2),2.09((H-7a),2.33/3’N(CH3)2/,1.97(H-4),2.01(H-7b).13C NMR(75MHz,CDCl3)δ:176.1(C-1),161.8(C-9),103.8(C-1’),95.8(C-1”),89.7(C-6),81.0(C-5),79.8(C-3),51.8(1-OCH3),49.4(3”-OCH3),39.9(C-7),41.7(C-2),40.4/3’N(CH3)2/,37.8(C-4),33.0(C-8).FAB(MH+)619.4.化合物(7b):IR(CHCl3)cm-1:3360,2980,2940,1730,1690,1650,1455,1380,1245,1165,1040.1H NMR(300MHz,CDCl3)δ:4.61(H-1”),4.43(H-1’),4.09(H-3),3.71(H-5),3.68(1-OCH3),3.28(3”-OCH3),3.17(H-8),2.89(H-7a),2.74(H-2),2.33/3’N(CH3)2/,2.16(H-4),1.47(H-7b).13C NMR(75MHz,CDCl3)δ:176.0(C-1),162.9(C-9),102.7(C-1’),95.1(C-1”),90.4(C-6),80.1(C-5),79.0(C-3),51.6(1-OCH3),49.2(3”-OCH3),42.5(C-7),41.0(C-2),40.3/3’N(CH3)2/,38.1(C-4),34.5(C-8).
实施例19
9-脱氧-9-二氢-9a-氨基-8(R)-甲基-10,11,12,13,14,15-六去甲基-9a-高红霉素A(8a)
将化合物(7a)(0.90g,0.0015mole)溶入冰乙酸(30ml),往里加PtO2(0.30,83%Pt),然后在6×106磅/英寸2的氢气压下搅拌并氢化15小时。反应混合物过滤,滤液浓缩成稠油状物,该油状物按实施例14的方法在pH5.5,9.0和10.5梯度萃取,进行分离,合并pH10.5的有机萃取液,浓缩,得0.530g(60%)TLC单一的标题产物(8a)。1H NMR(300MHz,CDCl3)δ:4.64(H-1”),4.40(H-1’),4.14(H-3),3.67(1-OCH3),3.54(H-5),3.29(H-3”OCH3),2.85(H-2),2.74(H-9a),2.50(H-9b),2.30/3’N(CH3)2/,2.10(H-4),1.84(H-8),1.44(H-7a),1.22(H-7b).13C NMR(75MHz,CDCl3)δ:176.4(C-1),104.4(C-1’),96.0(C-1”),85.9(C-5),80.3(C-3),73.8(C-6),51.5(1-OCH3),49.2(3”-OCH3),49.1(C-9),42.9(C-7),41.2(C-2)40.2/3’N(CH3)2,37.3(C-4),31.1(C-8).
实施例20
9-脱氧-9-二氢-9a-氨基-8(S)-甲基-10,11,12,13,14,15-六去甲基-9a-高红霉素A(8b)
将化合物(7b)(0.70g,0.0011mole)溶入冰乙酸,往里加PtO2(0.23g,83%Pt),然后在6×106磅/英寸2的氢气压下搅拌并氢化15小时。反应混合物过滤,滤液浓缩成稠油状物,该油状物按实施例14的方法在PH5.5,9.0和10.5梯度萃取,进行分离,合并pH10.5的有机萃取液,浓缩,得0.350g(52.4%)TLC单一的标题产物(8b)。IR(CHCl3)cm-1:3400,2975,2940,1735,1580,1455,1375,1260,1170,1050,1000.1H NMR(300MHz,CDCl3)δ:4.64(H-1”),4.37(H-1’),4.15(H-3),4.04(H-5”),3.67(1-OCH3,3.60(H-5’),3.51(H-5),3.37(H-2’),3.28(H-3”OCH3),2.98(H-4”),2.75(H-2),2.68(H-9a),2.56(H-9b),2.54(H-3’),2.31/3’N(CH3)2/,1.93(H-4),1.79(H-8),1.70(H-4’a),1.47(H-2”b).实施例219-脱氧-9-二氢-9a-二甲氨基-8(R)-甲基-10,11,12,13,14,15-六去甲基-9a-高红霉素A(9a)
往实施例19制备的化合物(8a)(0.3g,0.0005mole)与氯仿(50ml)的溶液中加甲酸(0.05ml,0.0013mole,98-100%)和36%甲醛(0.052ml,0.0007mole)。用2%W/VNaOH水溶液将反应混合物的pH调至5.2,然后回流搅拌2.5小时。产物按实施例16的方法分离,得0.280g(89.0%)TLC单一的产物(9a)。IR(CHCl3)cm-1:3450,2975,2940,1735,1465,1375,1260,1200,1165,1000.1H NMR(300MHz,CDCl3)δ:4.641(H-1”),4.43(H-1’),4.13(H-3),4.06(H-5”),3.65(1-OCH3),3.64(H-5),3.53(H-5’),3.30(H-3”-OCH3),3.27(H-2’),2.97(H-2),2.53((H-3’),2.29/3’N(CH3)2/,2.28(H-2’a),2.24/9a-N(CH3)2/,2.10(H-4),1.96(H-8),1.67(H-47a).
实施例22
9-脱氧-9-二氢-9a-二甲氨基-8(S)-甲基-10,11,12,13,14,15-六去甲基-9a-高红霉素A(9b)
往实施例19制得的化合物(8b)(0.6g,0.001mole)与氯仿(50ml)的溶液中,加甲酸(0.1ml,0.0026mole,98-100%)和36%甲醛(0.104ml,0.0014mole)。用2%W/VNaOH水溶液将反应混合物的pH调至5.2,然后回流搅拌2.5小时。按实施例16的方法分离产物,得0.55g(87.7%)TLC单一的产物(9b)。
Claims (45)
2.权利要求1的化合物,其中R1,R2和R4相同,为H,R3为CH3,Y为NH,Z为CH3或CH(CH3)CH(OH)COH(CH3)CH(OH)C2H5基。
3.权利要求1的化合物,其中R1、R2和R3相同,为H,R4为CH3,Y为NH,Z为CH3或CH(CH3)CH(OH)COH(CH3)CH(OH)C2H5。
4.权利要求1的化合物,其中R1,R2和R3相同,为CH3,R4为H,Y为NH,Z为CH(CH3)CH(OH)COH(CH3)CH(OH)C2H5基。
5.权利要求1的化合物,其中R1,R2和R4相同,为CH3,R3为H,Y为NH,Z为CH(CH3)CH(OH)COH(CH3)CH(OH)C2H5。
6.权利要求1的化合物,其中R1,R2和R4相同,为H,R3为CH3,Y为O,Z为CH3。
7.权利要求1的化合物,其中R1,R2,R3相同,为H,R4为CH3,Y为O,Z为CH3。
8.权利要求1的化合物,其中R1,R2和R3相同,为CH3,R4为H,Y为O,Z为CH3。
9.权利要求1的化合物,其中R1,R2和R4相同,为CH3,R3为H,Y为O,Z为CH3。
11.权利要求10的化合物,其中X和Y相同,为O,R3为CH3,R4,R5和R6相同,为H,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,R8和R9相同,为H。
12.权利要求10的化合物,其中X和Y相同,为O,R3为CH3,R4为H,R5和R6相同,为乙酰基,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,R8和R9相同,为乙酰基。
13.权利要求10的化合物,其中X和Y相同,为O,R3为CH3,R4和R5相同,为H,R6为乙酰基,Z为CH(C2H5)COH(CH3) CH(OR8)CH(CH3)NHR9,其中R8和R9相同,为乙酰基。
14.权利要求10的化合物,其中X和Y相同,为O,R3为CH3,R4,R5和R6相同,为H,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH) 3 NHR 9 ,其中R8为H,R9为对溴苯甲酰基。
15.权利要求10的化合物,其中X为NOR7,其中R7为H,R3为CH3,R4,R5和R6相同,为H,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,其中R8和R9相同,为H。
16.权利要求10的化合物,其中X为NOR7,其中R7为乙酰基,R3为CH3,R4为H,R5和R6相同,为乙酰基,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,其中R8和R9相同,为乙酰基。
17.权利要求10的化合物,其中X为NOR7,其中R7为H,R3为CH3,R4和R5为H,R6为乙酰基,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,其中R8和R9相同,为乙酰基。
18.权利要求10的化合物,其中X为NOR7,其中R7为对甲苯磺酰基,R3为CH3,R4,R5和R6相同,为H,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,其中R8为H,R9为对甲苯磺酰基。
19.权利要求10的化合物,其中X为NOR7,其中R7为H,R3为CH3,R4,R5和R6相同,为H,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,其中R8为H,R9为对甲苯磺酰基。
20.权利要求10的化合物,其中X为NOR7,其中R7为H,R3为H,R4为CH3,Y为O,Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9,其中R8和R9相同,为H。
21.权利要求10的化合物,其中X为NOR7,R7为H,R3为CH3,R4,R5和R6相同,为H,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5,其中R10和R11相同,为H。
22.权利要求10的化合物,其中X为NOR7,其中R7为乙酰基,R3为CH3,R4为H,R5和R6相同,为乙酰基,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5,其中R10和R11相同,为乙酰基。
23.权利要求10的化合物,其中X为NOR7,其中R7为乙酰基,R3为CH3,R4和R5相同,为H,R6为乙酰基,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11C2H5,其中R10和R11相同,为乙酰基。
24.权利要求10的化合物,其中X为NOR7,其中R7为H,R3为CH3,R4和R5相同为H,R6为乙酰基,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5,其中R10和R11相同,为乙酰基。
25.权利要求10的化合物,其中X为NOR7,其中R7为对甲苯磺酰基,R3为CH3,R4,R5和R6相同,为H,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5,其中R10和R11相同,为H。
26.权利要求10的化合物,其中X为NOR7,其中R7为H,R3,R5和R6相同,为H,R4为CH3,Y为NH,Z为CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5,其中R10和R11相同,为H。
27.权利要求10的化合物,其中X为NOR7,其中R7为H,R3为CH3,R4,R5和R6相同,为H,Y为O,Z为CH3。
28.权利要求10的化合物,其中X为NOR7,其中R7为H,R3,R5和R6相同,为H,R4为CH3,Y为O,Z为CH3。
R1和R2相同,为H或CH3,
R3和R4不同,为H或CH3,
Y为O或NH,
A)在亚氨基水解条件下与乙酸反应,如必要,然后用酸酐或酰氯进行N-和/或O-酰化反应,如必要然后进行甲醇解反应,
B)在无机碱或有机碱的存在下,在对反应呈惰性的溶剂中分1步或2步与盐酸羟胺反应,如必要,然后
B1)在羟亚氨基水解的条件下与无机酸或有机酸反应,如必要,然后用酸酐或酰氯进行N-和/或O-酰化反应,如必要,然后象A)项下描述的那样进行甲醇解反应,如必要
B2)在对反应呈惰性的溶剂中,用酸酐或酰氯进行N-和/或O-酰化反应,如必要,然后进行甲醇解反应,如必要
X为O或NOR7,其中R7为H,酰基或芳磺酰基,
R3和R4不同,为H或CH3,
R5和R6相同或不同,为H或酰基,
Y为O或NH,
Z为CH3,CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9或CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5,
R8为H或酰基,
R9为H,酰基或芳磺酰基,
R10和R11相同,为H或酰基,
如必要,它们在对反应呈惰性的溶剂中进行催化还原,如必要,然后在还原剂存在下,用烷基化试剂进行还原性的N-烷基化反应,得到其中R1,R2,R3,R4,Y和Z具有前面提到的含义的通式(I)的化合物。
30.权利要求29的方法,其特征在于通式(III)的红霉素A亚氨基醚在亚氨基水解的条件下,与乙酸室温反应3天。
31.权利要求29的方法,其特征在于,通式(III)的红霉素A亚氨基醚与盐酸羟胺在25℃至70℃完成反应。
32.权力要31的方法,其特征在于,所述的无机碱或有机碱为碳酸钠,碳酸钾或吡啶。
33.权利要求31的方法,其特征在于,对反应呈惰性的溶剂为甲醇或吡啶。
35.权利要求34的方法,其特征在于:通式(II)的化合物,其中
X为O或NOR7,其中R7为乙酰基,
R3为CH3,R4为H,或
R3为H,R4为CH3,
R5和R6相同,为乙酰基,
Y为O或NH,
Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9或CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5,
其中R8,R9,R10和R11相同,为乙酰基,
进行甲醇解反应,生成通式(II)的化合物,其中
X为O或NOR7,其中R7为H或乙酰基,
R3为CH3,R4为H,或
R3为H,R4为CH3,
R5为H,
R6为乙酰基,
Y为O或NH,
Z为CH(C2H5)COH(CH3)CH(OR8)CH(CH3)NHR9或CH(CH3)CH(OR10)COH(CH3)CH(OR11)C2H5,
其中R8,R9,R10和R11相同,为乙酰基。
36.权利要求29的方法,其特征在于羟亚氨基水解条件下的无机酸或有机酸是盐酸或乙酸。
37.权利要求29的方法,其特征在于:内胺酰化条件的无机碱或有机碱是氢氧化按,氢氧化钠,氢氧化钾或三乙胺。
38.权利要求29的方法,其特征在于:催化还原在对反应呈惰性的溶剂中完成,用贵金属或它们的氧化物作催化剂,室温反应,氢气压力为5×105磅/英寸2至7×106磅/英寸2。
39.权利要求38的方法,其特征在于:所述的催化剂为PtO2。
40.权利要求38的方法,其特征在于:对反应呈惰性的溶剂为冰乙酸。
41.权利要求29的方法,其特征在于:通式(I)的化合物或它们与无机或有机酸生成的加成盐,其中
R1和R2相同,为H,
R3为CH3,R4为H,或
R3为H,R4为CH3,
Y为NH,
Z为CH3或CH(CH3)CH(OH)COH(CH3)CH(OH)C2H5,
在还原剂存在下,在对反应呈惰性的溶剂中,在回流温度下,与烷基化试剂反应,完成还原性的N-烷基化反应,生成通式(I)的化合物或它们与无机酸或有机酸生成的可以药用的加成盐,其中
R1和R2相同,为CH3,
R3为CH3,R4为H或
R3为H,R4为CH3,
Y为NH,
Z为CH3或CH(CH3)CH(OH)COH(CH3)CH(OH)C2H5。
42.权利要求41的方法,其特征在于:用于还原性烷基化反应
的烷基化试剂为醛。
43.权利要求42的方法,其特征在于:醛为甲醛。
44.权利要求41的方法,其特征在于:还原剂为甲酸。
45.权利要求41的方法,其特征在于:对反应呈惰性的溶剂为氯仿。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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HR950145A HRP950145A2 (en) | 1995-03-27 | 1995-03-27 | New compounds of the secomacrolide and secoazalide class and a process for the preparation thereof |
HRP950145A | 1995-03-27 |
Publications (2)
Publication Number | Publication Date |
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CN1133294A CN1133294A (zh) | 1996-10-16 |
CN1053911C true CN1053911C (zh) | 2000-06-28 |
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CN95121122A Expired - Fee Related CN1053911C (zh) | 1995-03-27 | 1995-12-21 | 闭大环内酯和闭氮杂内酯类新化合物以及它们的制备方法 |
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US (1) | US5721346A (zh) |
EP (1) | EP0735041A1 (zh) |
JP (1) | JPH08269078A (zh) |
CN (1) | CN1053911C (zh) |
BG (1) | BG62333B1 (zh) |
CA (1) | CA2164152C (zh) |
CZ (1) | CZ313495A3 (zh) |
HR (1) | HRP950145A2 (zh) |
PL (1) | PL312209A1 (zh) |
RO (1) | RO116017B1 (zh) |
RU (1) | RU2130936C1 (zh) |
SI (1) | SI9500358A (zh) |
SK (1) | SK152195A3 (zh) |
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CN109311929A (zh) * | 2016-05-11 | 2019-02-05 | 菲德尔塔公司 | Seco大环内酯化合物 |
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HRP970141A2 (en) * | 1997-03-12 | 1999-02-28 | Banić-Tomaueić Zrinka | New secomacrolydes of erythromicin a, and a process for the preparation thereof |
CZ211798A3 (cs) * | 1997-07-16 | 1999-02-17 | Pliva, Farmaceutska, Kemijska, Prehrambena I Kozmetička Industrije, Dioničko Društvo | Lineární 8a-sekoazalidy a způsob jejich výroby |
AU5995299A (en) | 1998-11-03 | 2000-05-22 | Pfizer Products Inc. | Novel macrolide antibiotics |
US7365174B2 (en) | 2003-08-22 | 2008-04-29 | Meiji Seika Kaisha, Ltd. | Azalide and azalactam derivatives and method for producing the same |
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WO1994015617A1 (en) * | 1993-01-11 | 1994-07-21 | Merck & Co., Inc. | 8a-aza and 9a-aza macrolide antibiotics, and a process for producing same and methods of use |
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US5210235A (en) * | 1992-08-26 | 1993-05-11 | Merck & Co., Inc. | Methods of elaborating erythromycin fragments into amine-containing fragments of azalide antibiotics |
-
1995
- 1995-03-27 HR HR950145A patent/HRP950145A2/hr not_active Application Discontinuation
- 1995-11-21 SI SI9500358A patent/SI9500358A/sl unknown
- 1995-11-24 BG BG100164A patent/BG62333B1/bg unknown
- 1995-11-27 CZ CZ953134A patent/CZ313495A3/cs unknown
- 1995-11-30 EP EP95118869A patent/EP0735041A1/en not_active Withdrawn
- 1995-11-30 CA CA002164152A patent/CA2164152C/en not_active Expired - Fee Related
- 1995-12-01 SK SK1521-95A patent/SK152195A3/sk unknown
- 1995-12-08 JP JP7320088A patent/JPH08269078A/ja active Pending
- 1995-12-18 RO RO95-02215A patent/RO116017B1/ro unknown
- 1995-12-21 RU RU95122457A patent/RU2130936C1/ru active
- 1995-12-21 CN CN95121122A patent/CN1053911C/zh not_active Expired - Fee Related
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1996
- 1996-01-09 PL PL96312209A patent/PL312209A1/xx unknown
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Patent Citations (1)
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WO1994015617A1 (en) * | 1993-01-11 | 1994-07-21 | Merck & Co., Inc. | 8a-aza and 9a-aza macrolide antibiotics, and a process for producing same and methods of use |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109311929A (zh) * | 2016-05-11 | 2019-02-05 | 菲德尔塔公司 | Seco大环内酯化合物 |
CN109311929B (zh) * | 2016-05-11 | 2022-10-04 | 塞尔维塔公司 | Seco大环内酯化合物 |
Also Published As
Publication number | Publication date |
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CN1133294A (zh) | 1996-10-16 |
BG100164A (bg) | 1996-11-29 |
RU2130936C1 (ru) | 1999-05-27 |
SI9500358A (en) | 1996-10-31 |
CZ313495A3 (en) | 1997-08-13 |
CA2164152C (en) | 2000-03-28 |
PL312209A1 (en) | 1996-09-30 |
RO116017B1 (ro) | 2000-09-29 |
CA2164152A1 (en) | 1996-09-28 |
BG62333B1 (bg) | 1999-08-31 |
SK152195A3 (en) | 1997-07-09 |
EP0735041A1 (en) | 1996-10-02 |
HRP950145A2 (en) | 1997-08-31 |
US5721346A (en) | 1998-02-24 |
JPH08269078A (ja) | 1996-10-15 |
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