CN101481397B - 一种新的卡那霉素a衍生物及其制备方法和用途 - Google Patents
一种新的卡那霉素a衍生物及其制备方法和用途 Download PDFInfo
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- CN101481397B CN101481397B CN2009100778784A CN200910077878A CN101481397B CN 101481397 B CN101481397 B CN 101481397B CN 2009100778784 A CN2009100778784 A CN 2009100778784A CN 200910077878 A CN200910077878 A CN 200910077878A CN 101481397 B CN101481397 B CN 101481397B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种新的卡那霉素A衍生物,即式(I)化合物,其具有抗菌活性,各个基团的定义详见说明书。此外,本发明还公开了该衍生物的制备方法以及含有该衍生物的药物组合物。
Description
技术领域
本发明涉及氨基糖苷类抗生素,更具体地说,涉及一种新的卡那霉素A衍生物及其制备方法和用途。
背景技术
卡那霉素A(Kanamycin A)是一种氨基糖苷类抗生素,其化学结构为:
卡那霉素A的抗菌谱广,可有效抑制革兰氏阳性菌、革兰氏阴性菌以及分支杆菌。它杀菌能力强、速度快,常用于泌尿道感染、下呼吸道感染,特别是针对某些有药物过敏症的替代用药。但是其存在的耳肾毒性以及耐药菌的出现,限制了它的临床应用。对卡那霉素A环III的已有改造包括:对其6″-羟基单氟代及4″,6″-羟基的双氟代物[Albert,R.et al.,J.Carbohydr.Chem.,1984,3,267-78.][Takagi,Y.et al.,Nippon KagakuKaishi,1985,10,2001-9]。
相比母体化合物卡那霉素A,对大肠杆菌和奇异变形杆菌的抗菌活性MIC值,从2.5mg/mL和10mg/mL提高到1.6mg/mL。而4″,6″-羟基的氟代物相比母体化合物卡那霉素A,对奇异变形杆菌的抗菌活性MIC值,从10mg/mL提高到5mg/mL。
对卡那霉素A 6″-羟基修饰还包括脱氧以及氯代(Umezawa,S.et al.Bull.Chem.Soc.Jpn.,1967,40,1972-1974.)。
对卡那霉素A 6″-氯代物进行的体外抗菌活性实验发现,抗菌谱与卡那霉素A基本相同,在测试的16个菌株中,对其中7个菌株的抗菌活性有所提高。
对卡那霉素A 6″-糖醛酸以及其酯类和酰胺衍生物进行的抗菌活性测试发现(Kobayash.T.et al.J.Antibiot.,1970,23,225-230.),相比母体卡那霉素A其活性基本丧失。
类似的,还有对卡那霉素B的6″-羟基改造成甲胺基的报道[VanSchepdael,A.et al.J.Med.Chem.,1991,34,1468-75]。
相比母体化合物卡那霉素B,甲胺基修饰的化合物对所有选测的革兰氏阳性菌和革兰氏阴性菌的活性都没有提高。
尽管对卡那霉素A的修饰已有报道,但是现有技术中仍然存在新型卡那霉素A衍生物的需要。氨基糖苷类抗生素家族中,新霉胺是活性比较高的一种,但是由于它的毒性、不稳定性、不易口服性和病毒抗性等原因,直接把新霉胺作为药物来使用是不可行的,但是只是比新霉胺结构多一个环III结构的卡那霉素却是临床上可以应用的药物,说明卡那霉素的环III结构在降低药物毒性、提高药物稳定性等方面具有不可或缺的作用,因此对卡那霉素环III的结构改造具有重要的意义。
发明内容
本发明采用卡那霉素A的6″-羟基选择性转化为醛基和羧基从而制备一系列具有抗菌活性的卡那霉素A新的衍生物。
本发明的目的是提供新的卡那霉素衍生物。
本发明的另一个目的是提供上述衍生物的制备方法。
本发明的另一个目的是提供上述衍生物的用途。
本发明的再一个目的是提供含有上述衍生物的药物组合物。
本发明是通过如下技术方案而实施:
一方面,本发明提供了新的卡那霉素A衍生物,即式(I)化合物,或其药学上可接受的酸盐或溶剂化物:
这里,R1为氢或羟基保护基,所述的羟基保护基选自,但不限于,C1-C4烷基或烯基或者C1-C4烷氧基取代的C1-C4烷基或烯基,优选地甲基或者甲氧基或乙氧基取代的甲基保护基,乙基、甲基或乙氧基取代的乙基保护基,烯丙基;苄基或者苯环上任意位置被一个以上C1-C4烷基、C1-C4烷氧基、卤素(例如氟、氯、溴或碘)或硝基取代的苄基,优选地,对甲氧苄基,3,4-二甲氧基苄基;C1-C4烷酰基或者C1-C4烷基、烷氧基、烷酰基或卤素取代的C1-C4烷酰基,优选地,乙酰基、三氟乙酰基;苯甲酰基或苯环上任意位置被一个以上C1-C4烷基、C1-C4烷氧基、卤素(例如氟、氯、溴或碘)或硝基取代的苯甲酰基,优选地对甲氧苯甲酰基,对硝基苯甲酰基;
M为-NH-,R2为氢或氨基保护基,所述的氨基保护基选自,但不限于,叔丁氧羰酰基(BOC)、苄氧羰酰基(Cbz)、芴氧羰酰基(Fmoc);苄基或者苯环上任意位置被一个以上C1-C4烷基、C1-C4烷氧基、卤素(例如氟、氯、溴或碘)或硝基取代的苄基,优选地,4-甲氧基苄基,3,4-二甲氧基苄基;或者MR2一起组成叠氮基;
Y为二卤代亚甲基,即-CX2-,这里,X选自氟、氯、溴或碘,特别优选地为氟,而Z为H;或Y为-CH2-NH-,而Z为C1-C4的烷基,或者羟基取代的C1-C4烷基,特别优选地为甲基、乙基、丙基、丁基或2-羟基乙基;或Y为羰基,而Z为-NH2、或-NHR,这里-NHR为天然氨基酸的α氨基,所述天然氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、组氨酸、色氨酸、半胱氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、酪氨酸、甲硫氨酸、精氨酸、胱氨酸,或者上述氨基酸的C1-C4烷基酯。
优选地,本发明提供了式(II)化合物:
其中,取代基R1、X、M和R2的定义如式(I)中的定义。
优选地,本发明提供了式(III)化合物:
其中,取代基R1、M和R2的定义如式(I)中的定义,Z为C1-C4的烷基、或羟基取代的C1-C4烷基,特别优选地为甲基、乙基、丙基、丁基或羟基取代的乙基、丙基。
优选地,本发明提供了式(IV)化合物:
其中,取代基R1、M和R2的定义如式(I)中的定义,这里-NHR为天然氨基酸的α氨基,所述天然氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、组氨酸、色氨酸、半胱氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、酪氨酸、甲硫氨酸、精氨酸、胱氨酸,或者上述氨基酸的C1-C4烷基酯。
更优选地,本发明提供了新的卡那霉素A衍生物,即式(I-I)化合物,或其药学上可接受的酸盐或溶剂化物:
其中,Y为二卤代亚甲基,即-CX2-,这里,X选自氟、氯、溴或碘,特别优选地为氟,而Z为H;
或Y为-CH2-NH-,而Z为C1-C4的烷基,或者羟基取代的C1-C4烷基,特别优选地为甲基、乙基、丙基、丁基或2-羟基乙基;
或Y为羰基,而Z为-NH2、或-NHR,这里-NHR为天然氨基酸的α氨基,所述天然氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、组氨酸、色氨酸、半胱氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、酪氨酸、甲硫氨酸、精氨酸、胱氨酸,或者上述氨基酸的C1-C4烷基酯。
特别优选地,本发明提供了下列化合物:
6″-脱氧-6″,6″-二氟-卡那霉素A(化合物7);
6″-脱氧-6″-甲胺基-卡那霉素A(化合物9a);
6″-脱氧-6″-羟乙胺基-卡那霉素A(化合物9b);
6″-脱氧-6″-乙胺基-卡那霉素A(化合物9c);
6″-脱氧-6″-丙胺基-卡那霉素A(化合物9d);
6″-脱氧-6″-羟丙胺基-卡那霉素A(化合物9e);
N-[1-(1-甲氧羰基-2-甲基)丙基-卡那霉素A6″-糖醛酸酰胺(化合物12a);
N-[1-(1-甲氧羰基-2-苯基)乙基-卡那霉素A6″-糖醛酸酰胺(化合物12b)。
此外,本发明还提供了上述化合物的制备方法,包括下列步骤:(i).以式(V)化合物(关于式(V)化合物可参照下列文献制备1.Umezawa,S.et al.Bull.Chem.Soc.Jpn.,1967,40,1972-1974;2.Albert,R.et al. J.Carbohyd r.Chem.,1984,3,267-78;3.Yan,R.et al.Tetrahedron Lett.,2005,46,8993-8995;4.Scriven,E.et al.Chem.Rev.,1988,88,297-368;5.Alper, P.et al Tetrahedron Lett.,1996,37,6029-6032.)为原料与Q-R3反应,从而选择性地保护6″-羟基,得到式(VI)化合物;在式(V)和(VI)中,M为-NH-,R2为氨基保护基,所述的氨基保护基选自,但不限于,叔丁氧羰酰基(BOC)、苄氧羰酰基(Cbz)、芴氧羰酰基(Fmoc);苄基或者苯环上任意位置被一个以上C1-C4烷基、C1-C4烷氧基、卤素(例如氟、氯、溴或碘)或硝基取代的苄基,优选地,4-甲氧基苄基,3,4-二甲氧基苄基;或者MR2一起组成叠氮基;R3为空间位阻大的羟基保护基,非限定性地选自三苯甲基、叔丁基二甲基硅、叔丁基二苯基硅、三异丙基硅;Q为卤素(如氯、溴或碘)或羟基;
(ii).将式(VI)化合物的羟基进行保护,即与Q-R1反应,从而得到式(VII)化合物;在式(VI)和(VII)中,M、R2、R3和Q的定义如步骤(i),而R1为羟基保护基,所述的羟基保护基选自,但不限于,C1-C4烷基或烯基或者C1-C4烷氧基取代的C1-C4烷基或烯基,优选地甲基或者甲氧基或乙氧基取代的甲基保护基,乙基、甲基或乙氧基取代的乙基保护基,烯丙基;苄基或者苯环上任意位置被一个以上C1-C4烷基、C1-C4烷氧基、卤素(例如氟、氯、溴或碘)或硝基取代的苄基,优选地,对甲氧苄基,3,4-二甲氧基苄基;C1-C4烷酰基或者C1-C4烷基、烷氧基、烷酰基或卤素取代的C1-C4烷酰基,优选地,乙酰基、三氟乙酰基;苯甲酰基或苯环上任意位置被一个以上C1-C4烷基、C1-C4烷氧基、卤素(例如氟、氯、溴或碘)或硝基取代的苯甲酰基,优选地对甲氧苯甲酰基,对硝基苯甲酰基;
(iii).将式(VII)化合物的R3保护基脱除,(酸性条件下脱除醚类保护基,碱性条件下脱除酯类保护基,详见文献:Wahlstrom,J.L.et al,J.Org.Chem.,1998,63,6021-6022;Bessodes,M.et al,Tetrahedron Lett.,1986,27,579-580)从而得到式(VIII)化合物;在式(VII)和(VIII)中,M、R1、R2和R3的定义如步骤(ii);
(iv).在氧化剂(例如Swern试剂,即二甲基亚砜和草酸酰氯;Jones试剂,即三氧化二铬的稀硫酸溶液)作用下,将式(VIII)化合物的6″-羟基氧化为式(IX)化合物或式(X)化合物;在式(VII)和(VIII)中,M、R1和R2的定义如步骤(ii)。
本发明所提供的卡那霉素A衍生物的制备方法,进一步地包括:
(V)将步骤(iv)所得的式(IX)化合物在卤化试剂(如DAST,即三氟化二乙氨基硫)作用下,从而得到式(II)化合物:
在式(II)化合物中,取代基R1、M和R2的定义如上述步骤(ii)中的定义;X为卤素(氟、氯、溴或碘);或者,
(V′)将步骤(iv)所得的式(IX)化合物在还原试剂(如氰基硼氢化钠)存在的条件下,和Z-NH2反应,从而得到式(III)化合物:
在式(III)化合物中,取代基R1、M和R2的定义如上述步骤(ii),Z为C1-C4的烷基、或羟基取代的C1-C4烷基,特别优选地为甲基、乙基、丙基、丁基或羟基取代的乙基、丙基;或者
(V″)将步骤(iv)所得的式(X)化合物与R-NH2反应,从而得到式(IV)化合物:
其中,取代基R1、M和R2的定义如上述步骤(ii),这里-NHR为天然氨基酸的α氨基,所述天然氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、组氨酸、色氨酸、半胱氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、酪氨酸、甲硫氨酸、精氨酸、胱氨酸,或者上述氨基酸的C1-C4烷基酯。
本发明所提供的卡那霉素A衍生物的制备方法,任选地,进一步地包括:将式(II)、式(III)或式(IV)化合物选择性地脱除羟基保护基(例如当R1为苄基时,经催化氢化,H2、Pd/C,R1转变为氢;MR3为叠氮时,经催化氢化,H2、Pd/C,MR3转变为氨基),从而得到R1为氢,或者MR3为氨基的化合物。
具体地说,以卡那霉素A为起始原料,对环III的6″-羟基选择性裸露。
卡那霉素A为起始原料,首先选用三氟甲磺酸酐、叠氮化钠/吡啶,将其四个氨基转化为叠氮,得到化合物1;然后用吡啶溶解,三苯甲基氯与化合物1反应,得到化合物2;用四氢呋喃溶解化合物2,在苄溴、氢化钠存在的条件下得到全苄基保护的化合物3;用三氟化硼乙醚脱除化合物3的三苯甲基,得到6″-羟基选择性裸露的化合4。
化合物4在Swern氧化条件下得到6″-羟基变成醛基的化合物5。
化合物5与DAST反应,生成6″6″-二氟代的化合物6叠氮转化为氨基,脱除苄基保护得到化合物7。
化合物5,在氰基硼氢化钠存在下与变换Z基团的不同胺类化合物反应,得到化合物8的一系列衍生物,叠氮转化为氨基,脱除苄基保护得到化合物9。
化合物5,用琼斯试剂氧化得到环III6″-羧基,用DCC缩合,与不同的氨基酸甲酯反应,得到化合物11的一系列衍生物,叠氮转化为氨基,脱除苄基保护得到化合物12。
另一方面,本发明提供了上述新的卡那霉素A衍生物作为抗菌剂的用途。体外抗菌活性测定实验表明,本发明卡那霉素氨基糖苷新化合物具有抗菌活性,例如6″,6″-二氟-卡那霉素A(化合物7)对敏感的大肠埃希菌和金黄色葡萄球菌具有抗菌作用,对ATCC25922和ATCC29213的MIC值均为2mg/L。
另一方面,本发明提供一种药物组合物,包含式(I)化合物,或其药学上可接受的酸盐或溶剂化物:
其中,R1为羟基保护基,选自苄基、取代的苄基保护基、乙酰基、苯甲酰基、甲基、取代的甲基保护基、乙基、取代的乙基保护基。
M为-NH-,R2为氢或氨基保护基,选自叔丁氧羰酰基、苄氧羰酰基、芴氧羰酰基;或者MR2一起组成叠氮基;
Y为二卤代亚甲基,即-CX2-,这里,X选自氟、溴、氯或碘,特别优选地为氟,而Z为H;或Y为-CH2-NH-,而Z为C1-C4的烷基,或者羟基取代的C1-C4烷基,;或Y为羰基,而Z为-NH2、或-NHR,这里-NHR为天然氨基酸的α氨基,所述天然氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、组氨酸、色氨酸、半胱氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、酪氨酸、甲硫氨酸、精氨酸、胱氨酸,或者上述氨基酸的C1-C4烷基酯。
对于本领域的普通技术人员而言,根据药剂学的教导,本发明所提供的药物组合物可制备成不同的剂型,例如口服固体制剂(片剂、胶囊剂、颗粒剂)、外用制剂(软膏剂、乳膏剂或凝胶剂)、或者非胃肠给药的剂型(注射剂)。
具体实施方式
实施例1
化合物1(1,3,6′,3″-四叠氮基-卡那霉素A):
往乙腈200mL中加入叠氮化钠(10.8g,166.2mmol),冰浴,滴加三氟甲磺酸酐(23.2mL,138.2mmol),滴加完毕,继续冰浴搅拌2小时后停止搅拌,滤除固体,上清液慢慢滴加到卡那霉素A单硫酸盐(10.8g,18.4mmol),无水硫酸铜(146mg,1mmol),三乙胺(20.4mL,147.2mmol),水50mL混合液中,反应48小时以上。蒸除溶剂,硅胶柱层析(氯仿、甲醇梯度洗脱),得到黄色泡沫状固体6.8g,收率62.8%。1H NMR(300MHz,DMSO-d6)δ5.32(brs,4H),5.08(d,J=3.6Hz,1H),5.06(d,J=3.6Hz,1H),3.93-3.82(m,2H),3.69(m,1H),3.56-3.06(m,14H),2.28-2.24(m,1H,H-2eq),1.59-1.47(m,1H,H-2ax);13C NMR(75MHz,DMSO-d6)δ100.9,97.7,83.3,79.2,73.9,72.7,72.0,72.0,71.8,70.5,70.3,67.5,67.1,60.3,59.7,58.9,51.4,31.9.ESI-TOF-MS:Calcd for C18H28N12O11[M]+588.2,C18H28N12O11Na[M+Na]+:611.2,found:611.2.
实施例2
化合物2(6″-O-三苯甲基-1,3,6′,3″-四叠氮基-卡那霉素A)
化合物1(1.13g,1.92mmol),三苯甲基氯(0.64g,2.30mmol),DMAP24.0mg,加入吡啶20mL,50℃反应48小时以上。蒸除吡啶,硅胶柱层析(氯仿/甲醇=15/1),得1.1g白色泡沫,收率69%。1HNMR(300MHz,CDCl3)δ7.43-7.20(m,15H,HAr),5.32(s,1H),5.20(s,1H),4.43-2.81(m,23H),2.35-2.32(m,1H,H-2eq),1.52-1.26(m,1H,H-2ax);13C NMR(75MHz,CDCl3)δ148.2,143.4,128.6,128.0,127.3,124.4,100.9,95.2,87.1,83.8,78.4,73.8,72.9,72.3,71.7,70.9,70.5,70.1,65.9,63.7,59.2,58.6,51.1,32.2.ESI-TOF-MS:Calcd for C37H42N12O11[M]+ 830.3,C37H42N12NaO11[M+Na]+:853.3,found:853.3.
实施例3
化合物3(六-O-2′,3′,4′,5,2″,4″-苄基-6″-O-三苯甲基-1,3,6′,3″-四叠氮基-卡那霉素A)
化合物2(1.8g,2.16mmol),四丁基碘化铵0.1g,加入四氢呋喃20mL溶解,冰浴10分钟,少量多次加入氢化钠(3.1g,64.9mmol),2小时后滴加溴苄(6.16mL,51.84mmol),慢慢从0℃升到室温,反应2天后,加入甲醇中止反应,硅胶柱层析(石油醚/乙酸乙酯=10/1),得油状物2.9g,收率定量。1H NMR(300MHz,CDCl3)δ7.48-6.66(m,45H,HAr),5.75-3.41(m,23H),2.58-2.38(m,1H,H-2eq),1.78-1.62(m,1H,H-2ax);13C NMR(75MHz,CDCl3)δ143.8,138.3,138.0,137.6,137.5,137.1,128.7,128.5,128.4,128.2,128.0,127.7,127.3,127.2,127.0,126.8,126.5,124.9,97.0,95.2,86.0,82.4,81.6,79.0,78.1,78.0,76.2,75.4,74.9,74.2,73.8,73.7,73.0,70.5,70.0,65.2,61.8,60.3,59.2,51.2,32.0.ESI-TOF-MS:Calcd for C79H78N12O11[M]+ 1370.6,C79H78N12NaO11[M+Na]+:1393.6,found:1393.5.
实施例4
化合物4(2′,3′,4′,5,2″,4″-六-O-苄基-1,3,6′,3″-四叠氮基-卡那霉素A)
化合物3(1.64g,1.2mmol),用二氯甲烷10mL,甲醇2mL溶解,慢慢滴加47%三氟化硼/乙醚溶液(0.32mL,1.2mmol),室温反应5小时后,加入饱和碳酸氢钠水溶液中止反应,加入二氯甲烷稀释,萃取,分液,无水硫酸钠干燥有机相,浓缩,柱层析(石油醚/乙酸乙酯=6/1),得1.2g白色泡沫,收率95%,1H NMR(300MHz,CDCl3)δ7.40-6.95(m,30H,HAr),5.57-3.12(m,32H),2.48-2.32(m,1H,H-2eq),1.78-1.52(m,1H,H-2ax);13CNMR(75MHz,CDCl3)δ138.2,137.9,137.7,137.5,137.4,137.2,128.5,128.4,128.3,128.1,128.0,127.8,127.6,127.5,127.1,126.9,125.5,97.1,95.7,82.5,81.6,79.1,78.2,77.8,75.4,75.3,74.9,74.4,73.9,73.0,70.7,70.4,65.0,60.7,60.2,59.2,51.2,32.0.ESI-TOF-MS:Calcd for C60H64N12O11[M]+ 1128.5,C60H64N12NaO11 +[M+N]+:1151.5,found:1151.3.
实施例5
化合物5(6″-甲酰基-2′,3′,4′,5,2″,4″-六-O-苄基-1,3,6′,3″-四叠氮基-卡那霉素A)
草酰氯(1.62mL,1.86mmol),用二氯甲烷10mL溶解,保持零下60℃,滴加二甲亚砜(2.61mL,3.68mmol),滴加完毕10分钟后,滴加化合物4(1.8g,1.6mmol)溶于二氯甲烷10mL的溶液,零下60℃升温到零下50℃,反应2小时后,滴加三乙胺6.39mL中止反应,浓缩得化合物5粗品。ESI-TOF-MS:Calcd for C60H62N12O11,[M]+ 1126.5,found:C60H62N12NaO11[M+H]+:1149.5。一般不经纯化直接用于后续反应。
实施例6
化合物6(6″-脱氧-6″,6″二氟-2′,3′,4′,5,2″,4″-六-O-苄基-1,3,6′,3″-四叠氮基-卡那霉素A)
从化合物4(1.8g,1.6mmol)Swern氧化制得的化合物5粗品溶于二氯甲烷20mL中,零下30℃搅拌0.5小时后,滴加DAST(0.63mL,4.8mmol),升到室温反应5小时后,降温到零下30℃后,滴加甲醇中止反应,硅胶柱层析(石油醚/乙酸乙酯=6/1),得1.43g油状物,收率78.14%.1HNMR(300MHz,CDCl3)δ7.39-6.96(m,30H,HAr),5.66-4.82(m,3H),4.78-3.38(m,27H),2.52-2.48(m,1H,H-2eq),1.78-1.52(m,1H,H-2ax);13C NMR(75MHz,CDCl3)δ138.3,137.9,137.6,137.1,137.0,136.9,128.5,128.4,128.2,128.1,128.0,127.8,127.6,127.5,127.4,127.1,127.0,125.5,97.3,95.0,82.4,81.6,79.2,78.2,77.7,77.4,76.6,75.4,75.3,75.2,74.9,74.5,74.4,73.9,73.0,70.7,68.3,64.7,60.1,59.2,51.2,31.9.ESI-TOF-MS:Calcd for C60H62F2N12O10,[M]+ 1148.5,C60H62F2N12NaO10[M+H]+:1171.5,found:1171.5.
实施例7
化合物7(6″,6″-脱氧-二氟-卡那霉素A)
化合物6(1g,0.87mmol),溶于吡啶/三乙胺/水=3/2/1混合溶剂10mL中,通入硫化氢气体,TLC检测原料点消失后,浓缩,硅胶柱层析,梯度洗脱,确保除掉副产物硫,得到的中间产物溶于甲醇,盐酸调节PH到3-4,加入氢氧化钯,催化氢化,TLC检测,反应2天,滤除固体,反应液冻干,得到化合物7的盐酸盐,收率定量。1H NMR(300MHz,D2O)δ6.08(t,J=50Hz,1H,H6″),5.39(s,1H),5.09(s,1H),4.12-3.01(m,18H),2.48-2.45(m,1H,H-2eq),1.86-1.82(m,1H,H-2ax);13C NMR(75MHz,D2O)δ117.7,101.2,95.2,84.9,79.0,73.0,72.1,70.8,69.2,68.3,65.5,62.2,58.5,55.1,50.6,47.8,44.5,40.9,28.0.HR-ESI-TOF-MS Calcd for C18H34F2N4O10,[M]+504.2,C18H35F2N4O10[M+H]+:505.2,found:505.2.
实施例8
化合物8(6″-烷胺基-2′,3′,4′,5,2″,4″-六-O-苄基-1,3,6′,3″-四叠氮基-卡那霉素A)
从化合物4进行Swern氧化制得的化合物5粗品(1.4g,1.22mmol)溶于甲醇20mL中,加入氰基硼氢化钠(0.15g,2.45mmol),滴加醋酸(0.35mL,6.1mmol),滴加ZNH2(4.9mmol),反应过夜,TLC检测,硅胶柱层析,得到化合物8,根据取代基ZNH2的不同,收率有变化。
化合物8a(当ZNH2为甲胺时),油状物1.1g,产品收率78.9%.1H NMR(300MHz,CDCl3)δ7.63-6.92(m,30H,HAr),5.61-5.56(m,2H),4.90-1.97(m,36H);13C NMR(75MHz,CDCl3)δ138.3,137.9,137.6,137.1,128.5,128.4,128.2,127.8,127.6,127.3,126.4,97.1,95.1,82.7,81.7,79.4,78.3,75.4,75.2,75.0,74.6,74.0,73.0,70.8,67.8,65.2,60.2,59.5,51.2,50.0,34.7,32.0.ESI-TOF-MS:Ca1cd for C61H67N13O10,[M]+ 1141.5,C61H68N13O10 +[M+H+]:1142.5,found:1142.5.
化合物8b(当ZNH2为乙醇胺时),油状物1.2g,产品收率83.9%。1HNMR(300MHz,CDCl3)δ7.43-6.95(m,30H,HAr),5.61-5.52(m,2H),4.90-3.11(m,27H),2.58(s,6H),2.41(m,3H),2.39-2.18(m,1H,H-2eq),1.78-1.56(m,1H,H-2ax);13C NMR(75MHz,CDCl3)δ138.2,137.8,137.7,137.5,137.3,137.2,128.4,128.3,128.2,128.0,127.8,127.7,127.6,127.1,126.9,125.7,97.0,95.2,82.7,81.6,79.1,78.2,77.6,77.4,75.4,74.8,74.4,73.8,72.9,70.6,69.6,65.1,60.8,60.1,59.2,51.2,50.8,48.5,40.8,32.0.ESI-TOF-MS:Calcdfor C62H69N13O11[M]+:1171.5;C62H70N13O11 +[M+H+]:1172.5,found:1172.5.
实施例9
化合物9(6″-烷胺基-卡那霉素A)
化合物8(1mmol),溶于吡啶/三乙胺/水=3/2/1混合溶剂10mL中,通入硫化氢气体,TLC检测原料点消失后,浓缩,硅胶柱层析,梯度洗脱,确保除掉副产物硫,得到的中间产物溶于甲醇,盐酸调节pH到3-4,加入氢氧化钯,催化氢化,TLC检测,反应2天,滤除固体,反应液冻干,得到化合物9的盐酸盐,收率定量。
化合物9a(当R为甲基时),白色泡沫。1H NMR(300MHz,D2O)δ5.57-4.99(m,3H),4.12-2.70(m,21H),2.48-2.44(m,1H,H-2eq),1.93-1.81(m,1H,H-2ax);13C NMR(75MHz,D2O)δ100.8,98.5,96.5,92.7,83.9,79.4,75.9,74.6,74.4,73.3,73.1,73.0,72.5,72.1,71.9,71.6,69.4,68.7,67.9,55.4,54.8,51.0,50.6,50.1,49.0,41.2,34.5,34.4,28.4,23.1.ESI-TOF-MS:Calcdfor C19H39N5O10[M]+:497.3,C19H40N5O10 +[M+H+]:498.3,found:498.3.
化合物9b(当R为羟乙基时),白色泡沫。1H NMR(300MHz,D2O)δ5.53-5.52(m,1H),5.04-5.03(m,1H),4.09-2.64(m,25H),2.44-2.39(m,1H,H-2eq),1.85-1.77(m,1H,H-2ax);13C NMR(75MHz,D2O)δ101.0,98.9,84.0,74.5,72.4,71.5,71.2,69.3,68.8,68.6,67.8,57.1,55.2,50.3,48.9,48.4,40.8,28.2.ESI-TOF-MS:Calcd for C20H41N5O11[M]+527.3,C20H42N5O11 +[M+H+]:528.3,found:528.3.
化合物9c(当R为乙基时),白色泡沫。1H NMR(300MHz,D2O)δ5.57-4.99(m,3H),4.12-2.70(m,23H),2.48-2.44(m,1H,H-2eq),1.93-1.81(m,1H,H-2ax)。
化合物9d(当R为丙基时),白色泡沫。1H NMR(300MHz,D2O)δ5.57-4.99(m,3H),4.12-2.70(m,25H),2.48-2.44(m,1H,H-2eq),1.93-1.81(m,1H,H-2ax);
化合物9e(当R为羟丙基时),白色泡沫。1H NMR(300MHz,D2O)δ5.53-5.52(m,1H),5.04-5.03(m,1H),4.09-2.64(m,27H),2.44-2.39(m,1H,H-2eq),1.85-1.77(m,1H,H-2ax)。
实施例10
化合物10(2′,3′,4′,5,2″,4″-六-O-苄基-1,3,6′,3″-四叠氮基-卡那霉素A 6″-糖醛酸)
取7g三氧化铬,6mL浓硫酸,50mL水配制琼斯试剂,然后,取5.5mL上述琼斯试剂于圆底瓶中,磁力搅拌,滴加化合物4(2.4g,2.1mmol)溶于40mL丙酮的溶液,滴加完毕继续搅拌6小时,TLC检测反应,浓缩,水溶,乙酸乙酯萃提,无水硫酸钠干燥,硅胶柱层析,得到油状物1.72g,收率71.7%。1H NMR(300MHz,CDCl3)δ7.38-6.98(m,30H,HAr),5.63-5.54(m,2H),5.04-3.27(m,28H),2.58-2.00(m,1H,H-2eq),1.62-1.58(m,1H,H-2ax);13C NMR(75MHz,CDCl3)δ171.7,138.2,137.8,137.5,136.9,128.4,128.3,128.0,127.7,127.5,127.3,127.1,127.0,125.6,96.9,95.1,82.3,81.4,79.0,78.1,77.4,76.6,75.3,74.8,74.5,74.3,73.6,72.9,70.6,69.9,69.2,64.1,60.4,59.9,59.2,53.4,51.1,31.8,31.5,28.9.ESI-TOF-MS:Calcd forC60H62N12O12[M]+:1142.5,C60H66N13O12 +[M+NH4]+:1160.5,found:1160.5.
实施例11
化合物11(N-烷基-2′,3′,4′,5,2″,4″-六-O-苄基-1,3,6′,3″-四叠氮基-卡那霉素A6″-糖醛酸酰胺)
取化合物10(0.61g,0.53mmol),溶于二氯甲烷10mL中,冰浴,加入DCC(0.44g,2.13mmol),半小时后,加入HOBt(0.29g,2.15mmol),另取氨基酸甲酯(2.15mmol),用二氯甲烷溶解,DIPEA调节PH=8-9,冰浴10分后,滴加到化合物10的溶液中,升到室温,反应2天,TLC检测反应,加入二氯甲烷稀释,萃取,有机相用无水硫酸钠干燥,浓缩,硅胶柱层析,得到化合物11,不同的氨基酸甲酯有不同的收率。
化合物11a:N-[1-(1-甲氧羰基-2-甲基)丙基]-2′,3′,4′,5,2″,4″-六-O-苄基-1,3,6′,3″-四叠氮基-卡那霉素A6″-糖醛酸酰胺(当RNH2为H-Val·OMe·HCl时),油状物0.61g,收率91.7%。1H NMR(300MHz,CDCl3)δ7.39-6.96(m,30H,HAr),5.66-5.63(m,2H),4.87-3.31(m,30H),2.56-1.18(m,5H),0.84(t,J1=6Hz,J2=9Hz,6H);13C NMR(75MHz,CDCl3)δ171.5,138.3,137.9,137.7,137.4,137.0,136.8,128.6,128.5,128.3,128.1,127.8,127.6,127.4,126.6,97.0,95.2,82.3,81.7,79.2,78.3,77.7,77.4,77.0,76.8,76.6,75.5,74.9,74.5,74.1,73.0,70.8,70.4,64.7,60.0,59.3,57.2,51.9,51.2,32.0,30.9,18.8,18.2.ESI-TOF-MS:Calcd for C66H81N5O13[M]+:1151.6,C66H73N13NaO13 +[M+Na+]:1278.5,found:1278.5.
化合物11b:N-[1-(1-甲氧羰基-2-苯基)乙基]-2′,3′,4′,5,2″,4″-六-O-苄基-1,3,6′,3″-四叠氮基--卡那霉素A6″-糖醛酸酰胺(当RNH2为H-Phe·OMe·HCl时),油状物0.64g,收率92.6%。1H NMR(300MHz,CDCl3)δ7.38-6.92(m,35H,HAr),5.79-5.60(m,2H),4.99-2.85(m,38H),2.48-2.28(m,1H,H-2eq),1.66-1.26(m,1H,H-2ax);13C NMR(75MHz,CDCl3)δ170.9,167.7,138.1,137.8,137.6,137.4,136.9,136.8,135.8,129.2,128.4,128.2,128.0,127.9,127.6,127.5,127.1,126.9,126.2,97.0,94.9,82.2,81.6,79.1,78.2,77.8,75.3,74.8,74.3,74.0,72.8,70.8,70.1,64.4,59.9,59.1,52.8,51.9,51.1,37.1,31.9.ESI-TOF-MS:Calcd for C70H81N5O13[M]+:1199.6,C70H73N13NaO13 +[M+Na]+:1326.5,found:1326.5.
实施例12
化合物12(N-烷基-卡那霉素A6″-糖醛酸酰胺)
化合物11(1mmol),溶于吡啶/三乙胺/水=3/2/1混合溶剂10mL中,通入硫化氢气体,TLC检测原料点消失后,浓缩,硅胶柱层析,梯度洗脱,确保除掉副产物硫,得到的中间产物溶于甲醇,盐酸调节PH到3-4,加入氢氧化钯,催化氢化,TLC检测,反应2天,滤除固体,反应液冻干,得到化合物12的盐酸盐,收率定量。
化合物12a:N-[1-(1-甲氧羰基-2-甲基)丙基]-卡那霉素A6″-糖醛酸酰胺(当R为1-(1-甲氧羰基-2-甲基)丙基时),白色泡沫。1H NMR(300MHz,D2O)δ5.46-5.03(m,2H),4.65-4.24(m,2H),3.89-2.89(m,18H),2.43-2.39(m,1H),2.09-2.07(m,1H),1.87-1.75(m,1H),1.13-1.09(m,3H),0.79-0.77(m,6H);13C NMR(75MHz,D2O)δ174.2,101.2,97.1,84.3,78.9,73.2,72.6,72.4,71.3,69.2,68.3,58.7,55.3,53.4,50.6,48.4,47.2,40.9,30.7,28.1,18.8,17.9,8.8.HR-ESI-TOF-MS:Calcd for C24H45N5O13[M]+:611.30139,C24H45N5NaO13 +[M+Na+]:634.29061,found:634.29029.
化合物12b:N-[1-(1-甲氧羰基-2-苯基)乙基]-卡那霉素A6″-糖醛酸酰胺(当R为1-(1-甲氧羰基-2-苯基)乙基时),白色泡沫。1H NMR(300MHz,D2O)δ7.23-7.14(m,5H,HAr),5.43(s,1H),5.04(s,1H),4.65-2.99(m,22H),2.44-2.41(m,1H,H-2eq),1.88-1.80(m,1H,H-2ax),1.52(br s,1H),1.13(br s,1H),1.03(br s,1H);13C NMR(75MHz,D2O)δ173.8,170.7,136.9,129.9,129.4,127.8,101.1,96.4,84.4,78.8,72.7,71.3,69.2,68.3,55.2,54.2,53.7,50.6,48.2,41.0,37.0,28.1.HR-ESI-TOF-MS:Calcd for C28H45N5O13[M]+:659.30139,C28H46N5O13 +[M+H+]:660.30866,found:660.30902.
体外抗菌活性测定实验
实验材料与方法
用M-H(OxiodCM-01)肉汤试管二倍稀释法进行药品的体外抗菌活性筛选实验,对照药选用效价65.5%的标准品阿米卡星,实验菌株选用终浓度为105cfu/ml的ATCC25922大肠杆菌、ATCC29213金黄色葡萄球菌、阿米卡星耐药金黄色葡萄球菌Q284。
将稀释药液与菌应用液(105cfu/ml)各加0.5ml,混匀后置37℃孵育18小时,次日观察细菌生长结果。以最低药浓度不生长菌管浓度为MIC值。
实验结果
本试验对照药阿米卡星对大肠杆菌ATCC25922、金葡球菌ATCC29213,阿米卡星耐药菌Q284MIC值分别为:4mg/L、2mg/L、64mg/L(NCCLS判断标准大肠杆菌为0.5-4mg/L;金葡球菌为1-4mg/L)。
测试化合物及对照药阿米卡星的MIC结果(mg/L)
Claims (5)
2.权利要求1的化合物,选自下列化合物之一:
6″-脱氧-6″,6″-二氟-卡那霉素A;
6″-脱氧-6″-甲胺基-卡那霉素A;
6″-脱氧-6″-羟乙胺基-卡那霉素A;
6″-脱氧-6″-乙胺基-卡那霉素A;
6″-脱氧-6″-丙胺基-卡那霉素A;
6″-脱氧-6″-羟丙胺基-卡那霉素A;
N-[1-(1-甲氧羰基-2-甲基)丙基]-卡那霉素A6″-糖醛酸酰胺;
N-[1-(1-甲氧羰基-2-苯基)乙基]-卡那霉素A6″-糖醛酸酰胺。
3.权利要求1所述化合物的制备方法,包括下列步骤:
(i)以式(V)化合物为原料与Q-R3反应,从而选择性地保护6″羟基,得到式(VI)化合物;在式(V)和(VI)中,MR2一起组成叠氮基;R3为空间位阻大的羟基保护基,选自三苯甲基、叔丁基二甲基硅、叔丁基二苯基硅、三异丙基硅;Q为卤素或羟基;
(ii)将式(VI)化合物的羟基进行保护,即与Q-R1反应,从而得到式(VII)化合物;在式(VI)和(VII)中,M、R2、R3和Q的定义如步骤(i),而R1为羟基保护基,所述的羟基保护基选自:C1-C4烷基或烯基或者C1-C4烷氧基取代的C1-C4烷基或烯基;苄基或者苯环上任意位置被一个以上C1-C4烷基、C1-C4烷氧基、卤素或硝基取代的苄基;C1-C4烷酰基或者C1-C4烷基、烷氧基、烷酰基或卤素取代的C1-C4烷酰基;苯甲酰基或苯环上任意位置被一个以上C1-C4烷基、C1-C4烷氧基、卤素或硝基取代的苯甲酰基;
(iii)将式(VII)化合物的R3保护基脱除,从而得到式(VIII)化合物;在式(VII)和(VIII)中,M、R1、R2和R3的定义如步骤(ii);
(iv)在氧化剂作用下,将式(VIII)化合物的6″羟基氧化,从而得到式(IX)化合物或式(X)化合物;在式(IX)和(X)中,M、R1和R2的定义如步骤(ii),
(v)将步骤(iv)所得的式(IX)化合物在卤化试剂作用下,从而得到式(II)化合物:
在式(II)化合物中,取代基R1、M和R2的定义如上述步骤(ii)中的定义;X为卤素;或者,
(v′)将步骤(iv)所得的式(IX)化合物在还原试剂存在的条件下,和Z-NH2反应,从而得到式(III)化合物:
在式(III)化合物中,取代基R1、M和R2的定义如上述步骤(ii),Z为C1-C4的烷基、或羟基取代的C1-C4烷基;或者
(v″)将步骤(iv)所得的式(X)化合物与R-NH2反应,从而得到式(IV)化合物:
在式(IV)中,取代基R1、M和R2的定义如上述步骤(ii),这里-NHR为天然氨基酸的α氨基,所述天然氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、组氨酸、色氨酸、半胱氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、赖氨酸、酪氨酸、甲硫氨酸、精氨酸、胱氨酸,或者上述氨基酸的C1-C4烷基酯;
将式(II)、式(III)或式(IV)化合物选择性地脱除羟基保护基,R1转变为氢;MR3经催化氢化,MR3转化为氨基,从而得到权利要求1所述的式(I-I)化合物。
4.一种包含权利要求1或2所述化合物的药物组合物。
5.权利要求1或2所述化合物在制备抗菌药品中应用。
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